Side Effects of Drugs Annual 24, Volume 24: A world-wide survey of new data and trends in adverse drug reactions

Contributors M.C. ALLWOOD, B.PHARM., PH.D. University of Derby, School of Health and Community Studies, Pharmacy Academ...

Author: Jeffrey K. Aronson MA DPhil MBChB FRCP FBPharmacolS FFPM(Hon)

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Contributors

M.C. ALLWOOD, B.PHARM., PH.D. University of Derby, School of Health and Community Studies, Pharmacy Academic Practice Unit, Kingsway House, Derby, DE22 3HL, U.K. E-mail: [email protected] J.K. ARONSON, MA., D.PHIL., M.B.CH.B., F.R.C.P. University Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, U.K. E-mail: [email protected] I. AURSNES, M.D. University of Oslo, Department of Pharmacotherapeutics, EO. Box 1065 Blindern, N-0316 Oslo, Norway. E-mail: [email protected] A.M. BALDACCHINO, M.D., M.R.C.PSYCH., M.PHIL., DIP.ADD.BEH. St. George's Hospital Medical School, Centre for Addiction Studies, 6th Floor, Hunter Wing, Cranmer Terrace, London, SW17 ORE, U.K. A.G.C. BAUER, M.D. Havenziekenhuis, Haringvliet 2, 3011 TD Rotterdam, The Netherlands. E-mail: [email protected] EW.G. BROWN, F.R.C.S., F.R.C.R. Northem General Hospital NHS Trust, Department of Diagnostic Imaging, Sheffield, $5 7AU, U.K. A. CARVAJAL, M.D., PH.D. Instituto de Farmacoepidemiologia, Facultad de Medicine, 47005 Valladolid, Spain. E-mail: [email protected] C. CHIOU, M.D. Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 13N240, 10, Center Drive MSC, Bethesda, MA 20891, U.S.A. E-mail: [email protected] N.H. CHOULIS, M.D., PH.D. LAVIPHARM Research Laboratories, Agias Marinas Street, 19002 Peania (Attika), Greece. E-mail: [email protected] E COATES, M.B.B.S., F.R.A.C.P. Royal Adelaide Hospital, Department of Endocrinology, North Terrace, South Australia 5000, Australia. E-mail: [email protected] J. COSTA, M.D. Universitat Autbnoma de Barcelona, Hospital Universitari Germans Trias I Pujol, Clinical Pharmacology DepaIlment, Ctra de Canyet, 08916 Badalona, Spain. E-mail: [email protected]

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Contributors

P.J. COWEN, M.D. University Department of Psychiatry, Warenford Hospital, Oxford, OX3 7JX, U.K. E-mail: phil.cowen @psychiatry.oxford.ac.uk S. CURRAN, B.SC., M.B.CH.B., M.MED.SC., M.R.C.PSYCH., PH.D. Wakefield and Pontefract Community Health NHS Trust, Fieldhead Hospital, Calder Unit, Wakefield, WF2 3SP, U.K. E-mail: [email protected] H.J. DE SILVA, M.B.B.S., M.D., D.PHIL, F.R.C.P., F.R.C.P.E., F.C.C.P. University of Kelaniya, Department of Medicine, Faculty of Medicine, P.O. Box 6, Ragama, Sri Lanka. E-mail: [email protected] EA. DE WOLFF, M.A., PH.D., EUR.CLIN.CHEM.ERT.,F.A.T.S. Leiden University Medical Centre, Toxicology Laboratory, Department of Clinical Chemistry, Pharmacy and Toxicology, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mall: F.A.de_Wolff@ lumc.nl A. DEL FAVERO, M.D. Istituto di Medicina Intema e Science Oncologiche, Policlinico Monteluce, 06122 Perugia, Italy. E-mail: [email protected] J. DESCOTES, M.D., PH.D., PHARM.D. H6pital Edouard Herriot, Centre Antipoison----Centre de Pharmacovigilance, d'Arsonval, 69347 Lyon cedex 03, France. E-mail: [email protected]

5 Place

S. DITTMANN, M.D., D.SC.MED. International Immunization Consulting, 19 Hatzenporter Weg, 12681 Berlin, Germany. E-mail: sd.internat.immun.consult @t-online.de M.N.G. DUKES, M.D., M.A., LL.M. Trosterudveien 19, 0778 Oslo, Norway. E-mail: [email protected] I.R. EDWARDS, M.B., F.R.C.P., F.R.A.C.P. Uppsala Monitoring Centre, The WHO Collaborating Centre for International Drug Monitoring, Stora Torget 3, S-753 20 Uppsala, Sweden. E-mail: [email protected] H.W. EIJKHOUT, M.D. Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: H [email protected] C.J. ELLIS, M.D., F.R.C.P. East Birmingham Hospital, Department of Communicable and Tropical Diseases, Bordsley Green East, Birmingham, B9 5ST, U.K. E. ERNST, M.D., PH.D., F.R.C.P. (EDIN) University of Exeter, School of Postgraduate Medicine and Health Sciences, Division of Community Health Science, Department of Complementary Medicine, 25 Victoria Park Road, Exeter, EX2 4NT, U.K. E-mail: [email protected] M. FARRI~, M.D. Universitat Autbnoma de Barcelona, Institut Municipal d'Investigaci6 M~dica, Unitat de Farmacologia, Doctor Aiguader 80, 08003 Barcelona, Spain. E-mail: [email protected] J.A. FRANKLYN, M.D., PH.D., F.R.C.P., F.MED.SCI. University of Birmingham, Queen Elizabeth Hospital, Department of Medicine, Edgbaston, Birmingham, B15 2TH, U.K. E-mail: [email protected]

Contributors

vii

M.G. FRANZOSI, PH.D. Istituto di Ricerche Farmacologiche "Mario Negri", Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] A.H. GHODSE, M.D., PH.D., F.R.C.P., F.R.C.PSYCH. St. George's Hospital Medical School, Centre for Addiction Studies, 6th Floor, Hunter Wing, Cranmer Terrace, London, SW17 ORE, U.K. E-mail: [email protected] A.I. GREEN, M.D. Harvard Medical School, Commonwealth Research Center and Massachusetts Mental Health Center, Department of Psychiatry, 74 Fenwood Road, Boston, MA 02115, U.S.A. E-mail: alan_green @HMS.harvard.edu A.H. GROLL, M.D. Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 13N240, 10, Center Drive MSC, Bethesda, MA 20891, U.S.A. E-mail: [email protected] E. HEDAYATI, M.B.CH.B. The University of Auckland, Faculty of Medicine and Health Science, Department of Pharmacology and Clinical Pharmacology, Private Bag 92019, Auckland, New Zealand. A. HAVRYK, M.B., B.S. Royal Prince Alfred Hospital, Department of Respiratory Medicine, Camperdown, NSW 2050, Sydney, Australia. E-mail: [email protected] J.W. JEFFERSON, M.D. University of Wisconsin Medical School, Madison Institute of Medicine, 7617 Mineral Point Road, Madison, WI 53717, U.S.A. E-mail: jeffj @healthtechsys.com H.M.J. KRANS, M.D. Leiden University Medical Center, Department of Endocrinology and Metabolic Diseases, Building 1 C4-R, Postbus 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected] S. KRISHNA, B.A., D.PHIL., F.R.C.P. St. George's Hospital Medical School, Department of Infectious Diseases, Department of Cell and Molecular Sciences, Cranmer Terrace, London, SW17 ORE, U.K. E-mail: s.krishna@ sghms.ac.uk R. LATINI, M.D. Istituto di Ricerche Farmacologiche "Mario Negri", Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] M. LEUWER, M.D. The University of Liverpool, University Department of Anaesthesia, The Duncan Building, Daulby Street, Liverpool, L69 3GA, U.K. E-mail: [email protected] E MAGEE, B.SC., M.SC., M.R.PHARM.S. Director of Pharmaceutical Sciences, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry, CV2 2DX, U.K. E-mail: [email protected] A.E MAGGIONI, M.D. Istituto di Ricerche Farmacologiche "Mario Negri", Department of Cardiovascular Research, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected]

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Contributors

L.H. MARTIN ARIAS, M.D., PH.D. Instituto de Farmacoepidemiologia, Facultad de Medicina, 47005 Valladolid, Spain. E-mail: [email protected] G.T. MclNNES, B.SC., M.D., F.R.C.P., F.F.P.M. University of Glasgow, Department of Medicine & Therapeutics, Western Infirmary, Glasgow G11 6NT, Scotland. E-mail: [email protected] M.M.H.M. MEINARDI, M.D., PH.D Academic Medical Centre, Department of Dermatology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mall: [email protected] R.H.B. MEYBOOM, M.D.

Netherlands Pharmacovigilance Foundation LAREB, Goudsbloemvallei 7, 5237 MH 'sHertogenbosch, The Netherlands. E-mail: [email protected] T. MIDTVEDT, M.D., PH.D. Karolinska Institutet, Laboratory of Medical Microbial Ecology, Box 60 400, S-171 77 Stockholm, Sweden. E-mail: [email protected] S.K. MORCOS, F.R.C.S., F.F.R.R.C.S.I., F.R.C.R. Northern General Hospital NHS Trust, Department of Diagnostic Imaging, Sheffield, $5 7AU, U.K. E-mall: [email protected] W.M.C. MULDER, M.D., PH.D Academic Medical Center, Department of Dermatology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. S. MUSA, M.B.CH.B., M.R.C.PSYCH. Wakefield and Pontefract Community Health NHS Trust, Fieldhead Hospital, Chantry Unit, Ouchthorpe Lane, Wakefield, WF1 3SP, U.K. E-mail: [email protected] A.N. NICHOLSON, O.B.E., D.SC., M.D.(H.C.), F.R.C.P. (LOND. & EDIN.), F.R.C.PATH., F.F.O.M., F.R.AE.S.

"Applewood", Island, Steep, Petersfield, GU32 1AE, U.K. S. OLSSON, M.SCI.PHARM. Uppsala Monitoring Centre, The WHO Collaborating Centre for International Drug Monitoring, Stora Torget 3, S-753 20 Uppsala, Sweden. E-mail: [email protected] I. PALMLUND, B.A., PH.D. Wellcome Trust Institute for the History of Medicine at UCL, University College London, 24 Eversholt Street, London, NW1 lAD, U.K. E-mail: [email protected] J.K. PATEL, M.D. Harvard Medical School, Commonwealth Research Center and Massachusetts Mental Health Center, Department of Psychiatry, Boston, MA 02115, U.S.A. E-mail: [email protected] K. PEERLINCK, M.D. University of Leuven, Center for Molecular and Vascular Biology and Division of Bleeding and Vascular Disorders, Herestraat 49, B-3000 Leuven, Belgium. E-mall: Kathelij ne.peerlinck@ med.kuleuven.ac.be

Contributors

ix

E. PERUCCA, M.D., PH.D. University of Pavia, Clinical Pharmacology Unit, Piazza Botta 10, 27100 Pavia, Italy. E-mail: [email protected] B.C.P. POLAK, M.D. Vrije Universiteit Medical Center, Department of Ophthalmology, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: [email protected] H.D. REUTER, PH.D. Siebengebirgsallee 24, D-50939 Ktiln, Germany. E-mail: [email protected] T.D. ROBINSON, M.B., B.S.

Royal Prince Alfred Hospital, Department of Respiratory Medicine, Camperdown, NSW 2050, Sydney, Australia. E-mail: [email protected] M. SCHACHTER, M.D. Department of Clinical Pharmacology, Imperial College School of Medicine, National Heart and Lung Institute, St. Mary's Hospital, London, W2 1NY, U.K. E-mail: [email protected] S.A. SCHUG, M.D., F.A.N.Z.C.A., F.F.P.M.A.N.Z.C.A. University of Auckland, Division of Anaesthesiology, Faculty of Medicine and Health Sciences, Private Bag 92019, Auckland, New Zealand. E-mail: [email protected] J.P. SEALE, M.B., B.S., PH.D., F.R.A.C.P. Royal Prince Alfred Hospital, Department of Respiratory Medicine, Camperdown, NSW 2050, Sydney, Australia. E-mail: [email protected] R.P. SEQUEIRA, PH.D. Arabian Gulf University, College of Medicine and Medical Sciences, Department of Pharmacology and Therapeutics, P.O. Box 22979, Manama, Bahrain. E-mail: [email protected] T.G. SHORT, MB.CH.B., M.D.

The University of Auckland, Faculty of Medicine and Health Science, Department of Pharmacology and Clinical Pharmacology, Private Bag 92019, Auckland, New Zealand. E-mail: TimS @ahsl.co.nz A. STANLEY, PH.D., M.R.PHARM.S. Birmingham Oncology Centre, St. Chad's Unit, City Hospital, Dudley Road, Birmingham, B 18 7QH, U.K. E-mail: [email protected] W.G. VAN AKEN, M.D. Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. G.B. VAN DER VOET, M.D. Leiden University Medical Centre, Toxicology Laboratory, Department of Clinical Chemistry, Pharmacy and Toxicology, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: G.B.van der [email protected] R. VERHAEGHE, M.D. University of Leuven, Center for Vascular and Molecular Biology, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected]

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Contributors

J. VERMYLEN, M.D. University of Leuven, Center for Molecular and Vascular Biology and Division of Bleeding and Vascular Disorders, Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected] T. VIAL, M.D. Hrpital Edouard Herriot, Centre Antipoison--Centre de Phannacovigilance, 5 Place d'Arsonval, 69347 Lyon cedex 03, France. E-mail: [email protected] T.J. WALSH, M.D. Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 13N240, 10, Center Drive MSC, Bethesda, MD 20891, U.S.A. E-mail: walshtj @mail.nih.gov R. WALTER, M.D. University Hospital of Zurich, Department of Medicine, Medical Clinic B, R~mistrasse 100, CH-8091 Zurich, Switzerland. E-mall: [email protected] D. WATSON, MB.CH.B. University of Auckland, Faculty of Medicine and Health Sciences, Division of Anaesthesiology, Private Bag 92019, Auckland, New Zealand. E-mail: [email protected] C.J.M. WHITTY, M.A., M.SC., M.R.C.P. St. George's Hospital Medical School, Department of Infectious Diseases, Department of Cell and Molecular Sciences, Cranmer Terrace, London, SW17 ORE, U.K. E.J. WONG, M.D. Harvard Medical School, Massachusetts Mental Health Center, Department of Psychiatry, Boston, MA 02115, U.S.A. E-mail: [email protected] E ZANNAD, M.D., PH.D., F.E.S.C. Clinical Pharmacology and Cardiology Department, Hrpital Central, Universit6 Henri Poincar6 de Nancy, 54000 Nancy, France. E-mail: [email protected] O. ZUZAN, M.D. Hannover Medical School, Department of Anesthesiology, D-30625 Hannover, Germany. E-mail: Oliver.Zuzan@ t-online.de

Special reviews Cardiac valvulopathy associated with fenfluramines and phentermine Deaths related to ecstasy Heroin and progressive spongiform leukoencephalopathy QT interval prolongation, torsade de pointes, and sudden death Lamotrigine-induced serious skin rashes Vigabatrin-induced visual field defects The prevention of opioid-induced adverse effects Obstetric use of opioid analgesics Do new cyclo-oxygenase (COX-2) inhibitors provide benefits similar to those of traditional NSAIDs with less toxicity? Adverse effects of NSAIDs on the urinary tract Leukotriene receptor antagonists and Churg-Strauss syndrome Systemic availability of inhaled corticosteroids Tolerance to the effects of formoterol and salmeterol The use of digitalis and antidysrhythmic drugs to treat or prevent atrial fibrillation The use of activated charcoal in the treatment of digitalis overdose Indications for ACE inhibitors Aldosterone antagonists in heart failure Antibiotic resistance Postmarketing surveillance for reporting adverse effects--friend or foe? Antibiotics, the pill, and pregnancy Therapeutic effects of tetracyclines on microbes or enzymes Drug interactions with antifungal azole derivatives Adjunctive treatments in malaria Toxicity of prophylactic isoniazid in healthcare workers Adverse events after immunization--the need for improved research, surveillance, and communication Lyme disease vaccine and autoimmune disease Is there a causal link between hepatitis B vaccine and multiple sclerosis? Alcohol, vitamin A, and #-carotene: adverse interactions, including hepatotoxicity and carcinogenicity Formulations of oral contraceptives Can fertility drugs cause ovarian cancer? The use of androgens in women Drug interactions with thyroxine New synthetic insulin analogs Human growth hormone and insulin resistance Systemic adverse effects of enteral contrast media

4 32 40 54 88 95 100 102 115 120 183 185 187 197 201 233 246 273 274 274 278 318 330 352 364 366 374 442 472 474 477 484 489 504 525

Cumulative index of special reviews, Annuals 16-23

Index ofdrugs

Note: the format 23.171 refers to SEDA-23, p. 171. ACE inhibitors angio-edema, 22.225 cough, 19.211 Aluminium, in albumin solutions, 23.359 Aminoglycoside antibiotics, 17.304 deafness, 18.268 dosage regimens, 20.234, 21.265, 23.264 nephrotoxicity, 17.305 Amphotericin, liposomal, 17.319 Analgesics headache, 21.95 headaches in children, 23.114 nephropathy, 21.98 Anesthesia, dental, safety of, 16.122 Anesthetics halogenated, renal damage, 20.106 local, combinations, 20.121 local, neurotoxicity, 21.129 ocular, 17.542 Anorectic drugs, primary pulmonary hypertension, 21.2, 23.2 Antibiotics allergic reactions, 23.251 bacterial resistance, 22.265, 23.250 coagulation disorders, 18.258 colitis, 17.303 male fertility, 16.262 new, with adjuvants, 17.296 policies and politics, 16.273 preterm infants, 21.258 resistance, 19.237, 20.228, 21.257 seizures, 18.261 side chains, 16.264 Anitcholinergic drugs, 22.507 Anticonvulsants, see Antiepileptic drugs Antidepressants, during and after pregnancy, 21.17 Antidysrhythmic drugs, prodysrhythmic effects, 17.218, 23.196 Antiepileptic drugs death, 23.83

overdosage, 22.84 psychiatric effects, 22.82 Antifungal drugs, Pneumocystis carinii pneumonia, 18.289 Antihistamines cardiovascular adverse effects, 17.196, 22.176 drowsiness, 23.171 sedation, 21.170 Antihypertensive drugs, 19.209 fixed-dose combinations, 22.224 individualizing therapy, 17.246 Antimalarial drugs, 17.325, 20.257 prophylaxis, 23.304 Antioxidant vitamins, 20.363 Antiprotozoal drugs African trypanosomiasis, 18.293 toxoplasmosis, 20.262 Antitubercular drugs, 16.341 Mycobacterium avium-complex infection, 20.278 Appetite suppressants, primary pulmonary hypertension, 18.7, 23.2 Aspirin, 21.100 gastrointestinal effects, 17.95, 18.90 rhinosinusitis/asthma, 17.94 Asthma medications, exacerbation of asthma, 20.165 Atovaquone, 19.266 Bambuterol, cardiac failure, 23.181 Benzodiazepines, depression, 17.43 Beta2-adrenoceptor agonists, 18.159 asthma, 19.178, 21.179 asthma deaths, 17.164 Calcium antagonists, long-term safety, 20.185, 21.208, 22.214 Ciclosporin, urinary system, 19.348 Clozapine, agranulocytosis, 22.1359 Co-trimoxazole, hypersensitivity reactions, 20.264 Cocaine cardiovascular effects, 18.5 second-generation effects, 20.24 Cocamidopropylbetaine, allergy, 19.151

xviii Contrast agents anaphylactoid and allergic reactions, 20.422 in magnetic resonance imaging, 20.419 Corticosteroids bone, 16.447, 22.182 contact allergy, 21.158 effective dose and therapeutic ratio, 23.175 musculoskeletal adverse effects, 21.417 osteoporosis and osteonecrosis, 19.377, 20.374 preterm infants, 17.445 Cosmetics contact allergy, 16.150, 19.151 ingredient labeling 22.159 Deferoxamine, 16.247 bone dysplasia, 23.241 Diclofenac, liver damage, 20.91 Digoxin, heart failure in sinus rhythm, 18.196 Diuretics, renal cell carcinoma, 23.225 EDTA, pseudothrombocytopenia, 21.250 Erythromycin, versus the new macrolides, 21.269 Erythropoietin, status and safety, 16.400 Euxyl K 400, contact allergy, 16.150 Felbamate aplastic anemia, 19.68, 22.86 risk/benefit ratio, 23.86 Fenfluramine, cardiac valvulopathies, 22.3, 23.2 Fenoterol, safety in severe asthma, 23.182 Fentanyl, buccal and transdermal administration, 20.77 Flecainide, in supraventricular dysrhythmias, 21.200 Fluoroquinolones, 18.271 Fluorouracil, adverse effects, 23.476 Folic acid, dietary supplementation, 19.369 Fragrances, contact allergy, 20.149 Germanium, 16.545 Grapefruit juice, drug interactions 23.519 Growth hormone adults, 16.501 malignancy, 23.468 Hepatitis B vaccine, demyelinating diseases, 21.331, 22.346 HIV-protease inhibitors insulin resistance, 22.317 lipodystrophy, 22.317 Hormones, sex, tumors, 22.465 Hypnotics, 20.30 avoiding adverse effects, 21.37 Immunization, surveillance after, 22.333, 23.335 Indomethacin, fetal and neonatal complications, 18.102 Ketorolac, risk of adverse effects, 17.110 Lamotrigine, skin rashes, 20.62 Lithium

Cumulative index of special reviews, Annuals 16-23 adverse effects, prevention and treatment, 17.28 interactions, 16.13, 18.30 intoxication, prevention and treatment, 17.29 monitoring therapy, 18.25 mortality, 19.14 urinary system, 19.16 Macrolides, intestinal motility, 18.269 Malaria vaccines, 22.306 MAO inhibitors, 17.361 Measles immunization autism, 23.350 Crohn's disease, 23.350 neurological adverse effects, 23.348 Metformin, lactic acidosis, 23.459 Methyldibromoglutaronitrile, contact allergy, 16.150, 19.151 Mibefradil, drug interactions, 23.210 Milrinone, intravenous, acute heart failure, 21.196 MMR immunization autism, 23.350 Crohn's disease, 23.350 Muscle relaxants emergency medicine, 20.133 eyes, 21.145 intensive care, 19.140 Niacin, extended-release, 16.440 NSAIDs blood pressure, 19.92 children, 19.96 current controversies, 17.102 gastrointestinal adverse effects, 17.95, 18.90~ 18.99, 20.86, 21.96, 22.108, 23.114 gastrointestinal toxicity, prevention, 19.93 nephrotoxicity, 18.100, 20.89 topical, 18.163 Ocular drugs allergic reactions, 21.486 geriatric palients, 16.542 risk factors for adverse effects, 22.507 Omeprazole, tumors, 16.423 Opioids, tolerance in neonates, 23.97 Oral contraceptives, venous thromboembolism, 23.442 Paclitaxel, adverse effects, 21.463 Pancreatic enzyme supplements, fibrosing colonopathy, 20.322 Paracetamol liver damage, 17.98, 18.94 overdose, 23.117 Penicillins, acute desensitization, 23.252 Peritoneal dialysis fluids, effects on peritoneum, 22.381 Polio vaccine, AIDS, 23.352 Polyaspartic acid, protective against nephrotoxicity, 17.305 Polyvinylpyrrolidone, storage disease, 22.522 Propolis, allergy, 17.181

Cumulative index of special reviews, Annuals 16-23 Proton pump inhibitors, tumors, 23.383 PUVA, malignant melanoma, 22.166 Rotashield, intussusception, 23.354 Sex hormones, tumors, 22.465 Specific serotonin reuptake inhibitors, drug interactions, 22.13 Steroids, see corticosteroids Sumatriptan, 17.171 Suramin, patients with prostate cancer, 20.283 Tetracyclines in rheumatology, 23.255 comparative toxicity, 22.268 Theophylline, asthma, 17.2, 18.1, 18.2 Tiaprofenic acid, cystitis, 18.106

xix Total parenteral nutrition bone effects, 22.378 cholestasis, 22.376 infections 22.379 Tretinoin, topical, teratogenicity, 18.164 Triazolam, 16.33 Vaccines, poliomyelitis, 22.352 Vigabatrin psychosis and abnormal behavior, 18.71 visual field defects, 21.78 Vitamin A, 17.436 in pregnancy, 21.405 Vitamin B6, debate, 23.420 Vitamin K, cancer, 23.424 Vitamins, in old age, 22.431

Index of adverse effects Cardiovascular cardiac failure, bambuterol, 23.181 cardiotoxicity, antihistamines, 17.196 cardiotoxicity, calcium antagonists, 20.185 cardiotoxicity, cocaine, 18.5 dysrhythrnias, antihistamines, 22.176 hypertension, NSAIDs, 19.92 prodysrhythmic effects, antidysrhythmic drugs, 17.218, 23.196 valvulopathies, fenfluramine, 22.3, 23.2 venous thromboembolism, oral contraceptives, 23.442 Respiratory asthma, aspirin, 17.94 asthma, fenoterol, 23.182 asthma deaths, beta2-adrenoceptor agonists, 17.164 asthma exacerbation, asthma medications, 20.165 cough, ACE inhibitors, 19.211 primary pulmonary hypertension, appetite suppressants, 18.7, 21.2, 23.2 rhinosinusitis, aspirin, 17.94 Nervous system demyelinating diseases, hepatitis B vaccine, 21.331, 22.346 drowsiness, antihistamines, 23.171 headache, analgesics, 21.95, 23.114 neuroleptic malignant syndrome, 20.41 neurotoxicity, anesthetics, local, 21.129 neurotoxicity, measles immunization, 23.348 overdosage, antiepileptic drugs, 22.84 poliomyelitis, vaccines, 22.352 sedation, antihistamines, 21.170 seizures, antibiotics, 18.261 tardive dyskinesia, 20.38 tardive syndromes, 17.54 Sensory systems deafness, aminoglycosides, 18.268 eye effects, muscle relaxants, 21.145

visual field defects, vigabatrin, 21.78 Psychiatric antiepileptic drugs, 22.82 autism, MMR/measles immunization, 23.350 depression, benzodiazepines, 17.43 psychosis and abnormal behavior, vigabatrin, 18.71 Endocrine insulin resistance, H1V-protease inhibitors, 22.317 Metabolism lactic acidosis, metformin, 23.459 lipodystrophy, HIV-protease inhibitors, 22.317 polyvinylpyrrolidone storage disease, 22.522 Hematologic agranulocytosis, clozapine, 22.59 aplastic anemia, felbamate, 19.68, 22.86 coagulation disorders, beta-lactam antibiotics, 18.258 pseudothrombocytopenia, EDTA, 21.250 Gastrointestinal bleeding, aspirin, 17.95, 18.90 bleeding and perforation, NSAIDs, 16.103, 17.95, 18.90, 18.99, 19.93, 20.86, 21.96, 22.108, 23.114 cholestasis, total parenteral nutrition, 22.376 colitis, antibiotics, 17.303 Crohn's disease, MMR/measles immunization, 23.350 fibrosing colonopathy, pancreatic enzyme supplements, 20.322 intestinal motility, macrolides, 18.269 intussusception, Rotashield, 23.354 Liver bepatotoxicity, diclofenac, 20.91 hepatotoxicity, paracetamol, 17.98, 18.94 Urinary tract cystitis, tiaprofenic acid, 18.106 nephrotoxicity, aminoglycosides, 17.305 nephrotoxicity, analgesics, 21.98

xx nephrotoxicity, anesthetics, halogenated, 20.106 nephrotoxicity, ciclosporin, 19.348 nephrotoxicity, lithium, 19.16 nephrotoxicity, NSAIDs, 18.100, 20.89 renal cell carcinoma, diuretics, 23.225 Skin contact allergy, 23.160 rashes, lamotrigine, 20.62 Serosae peritoneum, peritoneal dialysis, 22.381 Musculoskeletal bone, total parenteral nutrition, 22.378 bone dysplasia, deferoxamine, 23.241 osteoporosis and osteonecrosis, corticosteroids, 16.447, 19.377, 20.374, 21.417, 22,182 Sexual function fertility, male, antibiotics, 16.262 Immunologic allergic reactions, antibiotics, 23.251 angio-edema, ACE inhibitors, 22.225 cocamidopropylbetaine, 19.151 contrast agents, 20.422 corticosteroids, 21.158 cosmetics, 16.150, 19.151 co-trimoxazole, 20.264 desensitization, penicillin, 23.252 Euxyl K 400, 16.150 fragrances, 20.149 methyldibromoglutaronitrile, 16.150, 19.151 ocular drugs, 21.486 propolis, 17.181 red man syndrome, 17.312 Infection risk AIDS, polio vaccine, 23.352 total parcnteral nutrition, 22.379 Body temperature malignant hyperthermia, 18.112 Death antiepileptic drugs, 23.83 calcium antagonists, 22.214

Cumulative index of special reviews, Annuals 16-23

lithium, 19.14 Drug tolerance antibiotic resistance, 19.237, 20.228, 21.257, 22.265, 23.250 opioids in neonates, 23.97 Carcinogenicity growth hormone, 23.468 omeprazole, 16.423 proton pump inhibitors, 23.383 PUVA, malignant melanoma, 22.166 sex hormones, 22.465 vitamin K, 23.424 Use in pregnancy affective disorders in, 21.17 vitamin A, 21.405 Teratogenicity tretinoin, topical, 18.164 Fetotoxicity cocaine, 20.24 indomethacin, 18.102 Risk factors children, NSAIDs, 19.96 intensive care, muscle relaxants, 19.140 neonatal complications, indomethacin, 18.102 ocular drugs, 22.507 old age, vitamins, 22.431 preterm infants, bcta-lactam antibiotics, 21.258 Drug administration dosage regimens, aminoglycosides, 23.264 labeling problems, cosmetics, 22.159 Drug overdose paracetamol, 23.117 Drug interactions grapefruit juice, 23.519 lithium, 16.13 lithium/specific serotonin reuptake inhibitors, 18.30 mibefradil, 23.210 specific serotonin reuptake inhibitors, 22.13

H o w to use this b o o k

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 1999. During the production of this Annual, some more recent papers have also been included. SELECTION OF MATERIAL In compiling the Side Effects of Drugs Annual particular attention is devoted to publications that provide essentially new information or throw a new light on problems already recognized. In addition, some authoritative new reviews are listed. Publications that do not meet these criteria are omitted. Readers anxious to trace all references on a particular topic, including those that duplicate earlier work, or to cross-check an electronic search, are advised to consult Adverse Reactions Titles, a monthly bibliography of rifles 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. 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. DRUG NAMES Drugs are usually dealt with under their recommended or proposed International Non-proprietary Names (fiNN or plNN); when these are not available, chemical names have been used. If a fixed combination has a generic combination name (e.g. co-trimoxazole for trimethoprim + sulfamethoxazole) that has been used; in some cases brand names have been used instead.

How to use this book

xxii SYSTEM OF REFERENCES

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

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

The various editions of Meyler's Side Effects of Drugs are cited in the text as SED-13, SED-14, etc; the Side Effects of Drugs Annuals 1-23 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 D R U G S E S S A Y

Secrecy hiding harm: case histories from the past that inform the future Ingar Palmlund *

Pharmaceutical products have contributed to spectacular improvements in public health across the world during the last century. Yet, among the two-thirds of the people in the world who can now get some medical care, an unknown number suffer at some time from illness because of drugs they have taken. Adverse effects of drugs can be sinister and can push some patients across the thin membrane that separates life from death. To others, they bring temporary ailments or chronic diseases that rob them of health and enjoyment of life. The victims may not always realize that the cause of their illness is a drug. How can patients be protected against the harmful effects of drugs? To approach this question it may be useful to consider three elements of the social context in which drugs are made available: 9

the freedom of the market forces that shape the role of prescribing physicians; 9 the methods of controlling drug usage, which have been developed mainly in response to disasters; 9 secrecy about the harmful effects of drugs, which often impedes the protection of patients from their harmful effects.

* This year's guest author is Ingar Palmlund, BA, MPA, PhD, who is Associate Professor, Department of Technology and Social Change, Linktiping University, Sweden and Honorary Research Fellow at The Wellcome Trust Centre for the History of Medicine at University College London.

The free market An English patient, who cannot get a prescription for ergotamine for migraine in her own country, buys it in Spain, because she has found that it helps her to function professionally. She disregards what doctors have told her about its dangers and the availability of other equally effective and safer remedies. Men in many countries who cannot obtain the potency-enhancing drug sildenafil (Viagra) on a doctor's prescription buy it on the Internet, because they want the benefits and disregard the risks. Aging glitterati in New York and Los Angeles testify in a television prime-time program about how they achieved success with the support of a slim blonde physiologist; she helped them to preserve health, youthfulness, memory, and happiness by giving them growth hormone injections well into old age and she subtly invites viewers to try the promising treatment. Women who have health insurance that covers medications, or who are otherwise wealthy enough to pay for drugs, are attractive targets all over the world for the promotion of drug use. The 20th century drive to medicalize the menopause (1) is just one example of such marketing campaigns. Advertisements and hidden persuasion in women's magazines, as well as the gynecologists that women in midlife consult, tell them that aging naturally past the menopause is bad for them. They are told that in order to survive with their youthfulness, vvlll

xxiv bones, hearts, and brains intact, they need to take estrogens (2), in spite of the increased risks of endometrial and breast cancer that accompany the cell proliferation that estrogen drugs produce. The freedom of the market is highly visible in adverts and on the Internet. Just type "prescription drug" and you will find a web site announcing "How to buy Prescription Drags at up to 50% off US prices with or without an Rx". It also features testimonials from satisfied customers, stating "The pain was unbearable. My doctor would not help me. But after a few quick phone calls relief was on the way. Thank you, again and again" (3). Another web site promises: "We can help you if you are experiencing symptoms of sexual dysfunction, hair loss, arthritis, obesity, or allergies. Our online virtual doctor consulting and ordering services are fast, simple and confidential" (4). Drug promotion and sales of drugs over the Internet is appreciated by patients who live in rural areas or are immobilized because of disease and old age. However, when consumers buy drugs over the Intemet and take them without medical supervision, they do expose themselves to risks. In July 1999, the US Federal Trade Commissioner identified about 800 "rogue sites" on the Internet, where products and treatments were touted as good against various illnesses (5). Moreover, prescription drugs, such as flu vaccine, are sold and resold in a booming gray market beyond the quality controls of the regulated market (6). This new promotion of drugs directly to patients, who are more or less subtly advised to ask their doctors for prescriptions of specific brand-name drugs, poses a new challenge in the protection of public health (7-9). Patients who buy drugs without the control of responsible physicians and pharmacists have no assurance of quality, efficacy, or safety. Nor do they get proper directions about the dosages and uses of the products. Moreover, they may be compromising their health by not seeking proper medical treatment. Organizations that represent medication-dependent groups, such as the American Association of Retired Persons (AARP), are alarmed and warn their members to be cautious (10, 11). So are government agencies that oversee the drug market. The US Food and Drug Administration (FDA) started a program in 2000 to identify, investigate, and prosecute websites that sell unapproved drugs

Ingar Palmlund and prescription drugs without a valid prescription (12). The World Health Organization (WHO) has also expressed its concerns (13). Advertising prescription drugs directly to patients was for a long time prohibited, although the restriction was more or less openly defied, not least in developing countries. However, in recent years it has been allowed in the USA and New Zealand, and the pharmaceutical industry is currently seeking to extend directto-consumer advertising to Europe and other parts of the world (14). Trends in the US medical marketplace show why. In the USA, retail spending on prescription drugs rose by nearly 20%, from $93.4 billion in 1998 to $111.1 billion, in 1999; in the same period the pharmaceutical industry's spending on consumer advertising rose by nearly 40%, from $1.3 billion to $1.8 billion. And 25 of the most heavily advertised drugs accounted for more than 40% of the increase in retail drug spending (15). The expenditure for sales promotion is of course recovered from sales of drugs, which are priced accordingly. Aggressive mass marketing of drugs to prescribing physicians and directly to consumers (via television, the internet, books, popular magazines, and newspapers) is eroding many of the safeguards for patients, that have been developed in the public control of drugs during the past 50 years.

Past is prologue: prevention in the wake of drug disasters When societies cope with risks to human health and environment, an initiating event of catastrophic nature, serious enough to engage the mass media and enrage the general public, has often been the trigger for improved safety measures. Rules and institutions for environmental protection, nuclear safety, safety on trains and ships, prevention of fires, and drug safety have all been created in response to public outcry over hazards and disasters after they occurred. At different paces in different countries, but gradually coalescing into internationally supported minimum standards for safety, they have become part of the infrastructure for protecting the public. The tragedies caused by drugs that struck many and were played out publicly via the mass media appear in retrospect as milestones in the

Secrecy hiding harm: case histories from the past that inform the future

development of the modem public control of pharmaceuticals.

Sulfanilamide The first major drug catastrophe in the 20th century history of the public control of drugs occurred in 1937 in the USA. A pharmacist introduced a drug--Elixir Sulfanilamide--that consisted of sulfanilamide dissolved in diethylene glycol. It had been tested for flavor, appearance, and fragrance, but not for safety. After taking the drug over 100 patients died in severe pain; many were children, who were given Elixir Sulfanilamide for sore throats and coughs. Public outrage created support for proposed legislation to reinforce the public control of drugs that was pending in the US Congress (16). And so, the US 1938 Food, Drug, and Cosmetic Act came into being, and is still the country's legal foundation for the public control of drugs and devices intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or animals. It has been a model for similar legislation in many other countries. The 1938 Food, Drug, and Cosmetic Act prohibited traffic in new drugs, unless they were safe for use under the conditions of use prescribed on their labels. The Act also explicitly required the labelling of drug products with adequate directions for use. The burden of proof of harm of new drugs was laid on the Federal Food and Drug Agency (FDA). Companies that Wanted to manufacture and sell new drugs in interstate commerce had to investigate their safety and report to the FDA. Unless the FDA, within a specified period of time, found that the safety of a drug had not been established, the company could proceed with its marketing. The FDA was also authorized to remove from the market any drug it could prove to be unsafe (17). The US Supreme Court also established in 1941, in a legal case over drug adulteration, that responsible individuals in a company can be held personally accountable for the quality of the products manufactured by the company, and that distributors of pharmaceuticals are responsible for the quality of their products, even if they are manufactured elsewhere (18). After the Second World War, the pharmaceuticals market changed radically, as many companies started industrial production of

XXV

drugs that had previously been manufactured in pharmacies. Announcements of new industrially produced drugs were hailed as part of technological advancement, as significant a sign of progress as the launching of satellites and putting a man on the moon. However, public safeguards against the risks of drugs remained unchanged in most countries. Thus, control of the effects of drugs largely lay in the hands of the manufacturers, even though the responsibility for taking precautions rested with pharmacists and doctors.

Thalidomide The next milestone in the development of the public control of drugs in most industrialized countries was the thalidomide disaster in around 1960. Thalidomide was used as a sedative in pregnant women in several countries in Europe and also distributed for trials in the USA, but was then identified as a cause of severe congenital limb malformations in many of the babies whose mothers had taken it while pregnant. The thalidomide disaster produced deep distrust in the way the public control of the effects of drugs was carried out. Suddenly, the edifices for the public control of drugs were in many countries perceived as gravely deficient and barely adapted to their purposes. People realized that drugs that were not safe could be produced by respected pharmaceutical companies, prescribed by trusted doctors, and sold by authorized pharmacies. It also became widely known that many marketed drugs were not providing their purported benefits and that claims of efficacy were barely checked by the drug regulatory authorities. The outrage over thalidomide stimulated considerable reinforcement of the public control of drugs. In the USA, an amendment of the Food, Drug, and Cosmetics Act was approved by Congress in 1962 (19). Not only the safety but also the efficacy of drugs would henceforth be part of the criteria that the FDA used as benchmarks in decisions over whether drugs should be allowed on the market. Since then pharmaceutical companies have had to show premarketing proof of both the safety and the efficacy of any new drug they want to introduce. Moreover, manufacturers of drugs in the US have since 1962 had a duty to report to the FDA any information on adverse effects of their products.

xxvi Existing drugs on the US market also came under scrutiny, and a review of their efficacy conducted by the US National Academy of Science (20) led to the voluntary withdrawal by pharmaceutical manufacturers of about twothirds of the approximately 7100 products that the FDA had previously approved (21). Similar legislative changes were called for in other countries, with a strong emphasis on applying the principle of premarketing testing of drugs, rather than relying on random, more or less voluntary, postmarketing surveillance and monitoring. In Britain the thalidomide tragedy led to calls for a revision of the existing drug safety regulations. However, the Government's position was ambiguous. It expressed a belief in the value of premarketing testing of all new drugs, but did not want to move against the interests of the pharmaceutical industry. The "goose which has laid so many golden therapeutic eggs" (22) was important for the economy. Instead of creating new legislation with far-reaching requirements on the testing of new drugs, a Committee on Safety of Drugs (CSD) was appointed in 1964, expecting voluntary cooperation from the pharmaceutical industry, and its chairman asserted that it was not going to impose unnecessary restraints on the industry. Moreover, a flexible approach was to be taken regarding the efficacy of medicines. The CSD would invite reports on the toxicological testing of drugs, consider whether clinical trials should be undertaken, and assess the results in terms of safety and efficacy. It pledged that information submitted to it by the manufacturers of new drugs would be kept confidential. In its first year the CSD received 600 submissions for new drugs from pharmaceutical manufacturers. Its reviews were rapid and it rejected only a small proportion of the submissions (23). In 1967 the Association of the British Pharmaceutical Industry (ABPI) was facing radical political proposals to abolish brand names of drugs and introduce mandatory labeling with therapeutic classifications on all medicines. To avoid legislation with mandatory rules, the ABPI revised its Code of Practice, so that information on adverse effects, precautions, and contraindications would be incorporated in promotional material (24). When the Medicines Commission was established in 1969 to regulate the quality, safety, efficacy, and promotion

lngar Palmlund

of drugs, the rules of confidentiality regarding data on the effects of drugs remained in place. The Medicines Commission saw its task as integrating consideration of the pharmaceutical industry's interests with the interest of public safety (23). In Sweden public outrage eased the acceptance of proposals for new legislation on drug control, which were pending in the Riksdag (the Swedish Parliament). A new law in 1962 (25), and subsequent regulations issued in 1963 (26), stressed the importance of controlling drug safety and efficacy. Mandatory premarketing testing, with results examined by the Swedish national drug control agency, was to be the main instrument in controlling the drug market. The thalidomide disaster led to other initiafives in many countries to create mechanisms by which doctors could easily alert colleagues to illnesses that they suspected were due to drug exposure. Such national schemes eventually led to the establishment in 1968 of the WHO Collaborating Center for International Drug Monitoting, which receives national data on adverse drug reactions and uses them to issue warnings about hazards to the medical community. Medical devices

A third milestone in the protection of patients in the USA was a wave of reports in the mid 1970s about failing pacemakers and about women who had died or been seriously injured by intrauterine contraceptive devices. The reports led to public demands that medical devices should be covered by the strictest premarketing requirements, and the Medical Device Amendments to the Food, Drug, and Cosmetic Act were enacted in 1976 (27).

Meeting the pharmaceutical industry's needs In many countries the need to ensure the safety and efficacy of drugs in general gradually led to more stringent requirements regarding toxicological testing and clinical trials. The pharmaceutical industry has repeatedly complained over this imposed so-called drug lag-the costly studies necessary to meet slightly different requirements on new drugs in different countries--which delays the introduction of these drugs.

Secrecy hiding harm: case histories from the past that inform the future

At times governments have changed their rules to the benefit of the industry. Soon after the election of a Conservative government in Britain in 1979, several of the requirements for premarketing testing of drugs were relaxed and a clinical trials exemption scheme was introduced (28). In the early 1980s, the political winds also turned in the USA in a way that set a pattern for many countries. The protection of human health and the environment slid down the list of political priorities, and the protection of the freedom of the market rose in a way that some non-governmental organizations called a retreat from safety (29). Deregulation became the watchword of the day. This change in values also had an impact on the control of pharmaceuticals. The FDA's control of the pharmaceutical industry was one of the first deregulation targets. For example, the required submissions to the FDA of detailed toxicological data from the premarketing testing of a drug were replaced by summaries of the data. A program aimed at raising the requirements for pharmaceutical companies to inform patients about the risks of drugs was also stopped (30). The vast majority of new drugs and medicines are developed in Western Europe, Japan, and the USA. In order to harmonize the requirements on data regarding the quality, safety, and efficacy of drugs, the regulatory agencies in the European Union, Japan, and the USA have since 1990 engaged in a negotiation process with the pharmaceutical industry. The process is known as ICH, an abbreviation for The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. The World Health Organization and the Canadian drug regulatory agency have observer status in the ICH process. Even though ICH documents state that it is important that the review of the rules for premarketing testing is carried out in a transparent manner, neither prescribing physicians and other medical professionals nor consumers are directly represented in this process (31).

Secrecy--an obstacle to preventing harmful effects of drugs Access to information regarding the risks of drugs is of key importance in preventing harm. In the governmental control of medicinal drugs

xxvii

across the world, complete data on the safety and efficacy of drugs are often kept secret, in order to protect the commercial interests of the pharmaceutical companies. This secrecy generally covers the results of the testing of efficacy and safety before the drug was approved. In many instances it also covers reports about adverse effects of drugs that the drug regulatory agency has received. There is a striking lack of openness regarding the adverse effects of drugs in most countries (32). Nations such as the USA and Sweden, in which a Freedom of Information law ensures that anyone may partake of information held by public agencies, allow more openness in principle. But in practice, for example in Sweden, rules safeguarding the protection of commercial secrets mean that data owned by a pharmaceutical manufacturer must be kept confidential by the public drug regulatory agency. Substantial summary information for the public about the basis for approving a drug seems to be provided only by the drug regulatory agencies in the USA and Sweden. Another characteristic of the institutionalized public control of drugs is that the performance of the drug regulatory agencies is rarely audited, and so the accountability of its officials is obscure. Only in one of 23 countries, the USA, was an audit of the functioning of the drug regulatory agency publicly available in 1996, according to a recent survey (32). Corruption involving major pharmaceutical companies giving bribes to drug regulatory agency officials in return for speeded up passage of drug approvals is not unknown (33). A third characteristic of the public control of drugs is that patients and consumers have generally been accorded little or no role in the formal decision-making process over whether a drug should be allowed on to the market or not. The doctor-patient relationship, with the patient as a passive receiver of advice and treatment from the active doctor, is institutionalized as a norm in the public control of drugs. Pharmaceutical companies are in many countries required to keep track of the effects of their products. Yet they devote only a small proportion of their research to studies of the effects of approved drugs--as little as 6% of the US pharmaceutical industry's research budget, according to the Pharmaceutical Research and Manufacturers of America (34). In some cases, even in countries such as the USA, where the

xxviii penalties for such secrecy may be high, providers of medical technology have refrained from reporting information about the harmful effects of their products (35, 36). Case reports to national control agencies and to medical journals have been physicians' traditional means of alerting colleagues to suspicious findings. The WHO Collaborating Centre for International Drug Monitoring plays an important role, by alerting the medical community to reports of drug-related injury, especially with regard to new drugs. However, the WHO Centre receives notice of only a small proportion of the observed harmful effects of drugs. Secondary sources, such as encyclopedias and handbooks with data concerning the effects of specific drugs, have been the prescribing physician's main sources of information. However, the time lag of these publications limits their value as sources of knowledge regarding the effects of new drugs on the market. Information resources on the intemet are increasingly used as complements to printed sources. The classical problem with secondary sources is that the selection of data for the compiled information may be dubious. One example of gravely distorted information regarding the effects of diethylstilbestrol used in pregnancy may be an indication of how secondary sources may seriously mislead medical practitioners (37-39). Many accounts of public controversies over products used in medical practice have highlighted scientific and political controversy, in which pharmaceutical companies, prescribing physicians, and drug regulatory agencies have guarded secrecy about the adverse effects of a drug. Officials of regulatory agencies and representatives of pharmaceutical companies have admitted, when pressed about their motives, that they wanted to avoid drawing public attention to a "health scare". An additional motive for secrecy could be to avoid litigation. Several examples illustrate this last point: 9

9

oral contraceptives in various formulations have at different times in different countries been kept on the market without informing women about the risks of thromboembolism and other potentially lethal diseases (40, 41); the benzodiazepine Halcion | (triazolam) caused serious mental effects that were observed in clinical trials in 1973/74 but ac-

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9

9

9

9

knowledged only after court trials in 1990 (42); several reports linked tardive dyskinesia to antipsychotic drugs in 1960-80, but were met with considerable resistance before the illness was recognized as iatrogenic (43); cases of Creutzfeldt-Jakob disease (CJD) have been linked to the administration of growth hormone (44), produced from pituitary glands taken from human cadavers, used as a fertility drug from the late 1950s (45) and also given to children to promote growth; the risk of CJD was first reported in the 1970s (46), but not until 1985 was the use of human-derived growth hormone in children curbed, and not until 1994 were British women at risk of developing drug-related CJD alerted (47); HIV-contaminated blood was given to hemophiliacs and other patients in several countries in the 1980s and 1990s, long after the risks of contaminated blood had been documented (48, 49); more recently, publicity regarding the risks of stroke in young women taking common over-the-counter cold remedies and appetite suppressants containing phenylpropanolamine has shown that the manufacturer had taken measures to prevent evidence of these risks from emerging (50).

Diethylstilbestrol

Diethylstilbestrol provides several illustrations of how societies cope with the risks of harm from a drug. Under different brand names diethylstilbestrol has been given to a wide range of patients over many years, mostly pregnant women and aging men with prostate cancer. The history of iatrogenic disease as a result of the use of diethylstilbestrol in pregnant women shows that patients can play an important role in securing legitimacy for research and the publication of data on the harmful effects of a drug. Diethylstilbestrol was given to pregnant women in many countries, mainly in the 1940s to 1970s, in the mistaken belief that it would prevent miscarriage and provide strong healthy babies (51, 52). The application to market diethylstilbestrol in the USA was the first new drug application submitted to the FDA shortly after the 1938 Food, Drugs, and Cosmetics Act had been passed; permission was grant-

Secrecy hiding harm: case histories from the past that inform the future

ed, although diethylstilbestrol had already been identified as a carcinogen in animals (53). Diethylstilbestrol was especially popular in some maternity clinics in North America, serving middle-class and upper-middle class women, and in the Netherlands, where the Queen's gynecologist promoted it. In other countries it was dispensed through public health maternity centers. In the USA evidence showing that it was ineffective for its intended purpose appeared by the 1950s. However, conclusions based on animal experiments, as well as a major doubleblind controlled clinical trial (54), remained unheeded, partly because prescribing physicians trusted their collegial loyalty more than data that implicitly threw doubt on their practice. In 1971, a rare form of aggressive cancer in the vagina of young girls was attributed to the girls' exposure to diethylstilbestrol in utero in a report that was based on a case-control study of eight young women, one of whom had died, at the Massachusetts General Hospital (55). It was already clear from this small study that monitoring young women exposed to diethylstilbestrol would save lives. However, months and even years were to pass before the discovery led to any public action, at different times in different countries. Only after 5 months, when the risk of cancer in patients exposed to diethylstilbestrol was featured at hearings in the US Congress, did the FDA react. The FDA's Administrator then announced that diethylstilbestrol products were to be labelled with a warning that diethylstilbestrol was contraindicated in pregnancy and should not be given to pregnant women because of risk of the cancer in the offspring (56). Drug regulatory agencies in other countries in which diethylstilbestrol had also been commonly used in pregnancy delayed taking action. In the Netherlands, the first change of labelling to include a warning to physicians that diethylstilbestrol given to pregnant woman might harm the fetus was implemented in 1972. A similar change in labelling was introduced in France in 1977. In many other countries, the news that some daughters of women who had taken diethylstilbestrol while pregnant were at risk of developing a potentially lethal cancer was passed over in silence. In Britain, the medical community was alerted to the risks by an editorial in the British

xxix

Medical Journal in 1971, but it was only in

1973 that the Committee on Safety of Medicines advised against the use of diethylstilbestrol during pregnancy (57). In Britain, drugs were commonly not labelled with information about their contents, nor with warnings of risk until well into the 1990s; thus, patients were kept in ignorance. No measures have yet been taken in Britain to alert the public to the need for medical surveillance of women who have been exposed to diethylstilbestrol in utero. It is estimated that in the USA, the Netherlands, and France, diethylstilbestrol was given to over 5.3 million pregnant women, and it is known that it has been given to pregnant women in most parts of the world. Single cases of clearcell vaginal carcinoma from many countries are known, but systematic studies have not been conducted everywhere. One in a thousand young women exposed to diethylstilbestrol before birth have been estimated to be at risk of developing clear-cell vaginal adenocarcinoma (58). Exposure to diethylstilbestrol in utero also has a range of other effects on exposed women, including malformations of the reproductive organs and difficulties in conception and carrying a pregnancy to term. Some of the men exposed to diethylstilbestrol in utero have urogenital malformations and an increased risk of testicular cancer (59). Most of the women who suspected that they had taken diethylstilbestrol were to learn of the problems from the media, and they had to guess that their daughters might be at risk of developing cancer. When they tried to discover whether they had been given diethylstilbestrol during pregnancy, many of the women found that their obstetricians were not willing to give them access to their own medical records. In a report from a nationwide US survey intended to locate pregnant women who had been given diethylstilbestrol during 1940-72, the investigators complained that at some clinics they had encountered extreme difficulties in getting access to the records (60). Women who have been exposed to diethylstilbestrol sometimes say that never have so many medical files reportedly been lost through fire and inundation, as when they asked for access to records that might document the use of diethylstilbestrol during pregnancy. Many doctors did not notice or did not heed warnings in the early 1970s about the risks of giving diethylstilbestrol to pregnant women. As

xxx late as 1974, according to a prescription audit, some 11000 prescriptions for diethylstilbestrol to be used during pregnancy were written in the USA (61). In 1976, it was observed that diethylstilbestrol was given to unsuspecting pregnant women in several Latin American countries (62). In other countries, prescribing physicians' responses to reports that linked the use of diethylstilbestrol during pregnancy with cancer risks in their daughters were even slower. The latest documented prescription of diethylstilbestrol in Europe was in Spain in 1983 (63). The first batches of educational material for physicians, with warnings and advise regarding health care for women who had been exposed to diethylstilbestrol, were distributed in the USA in 1971, in the Netherlands in 1974, and in France in 1989. No such material has been distributed in Britain. Mothers in the USA who had taken diethylstilbestrol formed an organization, DES Action, to inform the public about the risks and to alert exposed mothers that their daughters needed regular medical examinations, so that potential tumor development would be detected early. Through DES Action they also gave each other mutual support during litigation against the manufacturers and acted politically to ensure that health care would be available for their daughters. DES Action groups outside the USA were formed in Australia, Belgium, Canada, France, Great Britain, Italy, Ireland, and the Netherlands. DES Action was still in the 1990s a prime mover in securing resources for research and follow-up of women who had been exposed to diethylstilbestrol, and in promoting educational programs for those women and for medical professionals. Initiatives by medical researchers, by DES Action, and by the Public Citizen's Health Research Group secured funding in the USA for medical research on the prevalence of cancer and other effects in the young women who had been exposed in utero, and eventually also the men. The US National Institute for Environmental Health Sciences (NIEHS) has been one of the centers for toxicological studies of the effects of diethylstilbestrol. A substantial amount of research on the effects of diethylstilbestrol-animal experiments as well as epidemiological studies--has produced a valuable body of knowledge about how hormones affect the development of the fetus and prime the individual for disease later in life.

Ingar Palmlund

As in the case of thalidomide, the emotional engagement evoked by the harm caused by diethylstilbestrol in pregnancy led to committed action. Some physicians have devoted a major part of their careers to finding out why and how diethylstilbestrol produced adverse effects. The anger over the harm caused by diethylstilbestrol inspired patients to a commitment to prevent further harm by engaging in political action and achieving an effective response from legislators and governmental administrators.

Resistance and denial The above examples tell about a long latency time between observations linking a widely prescribed drug to disease and measures to curb the practices that caused the disease. They prompt questions about patients' rights to know about the origins of iatrogenic disease. All of these case histories from the past reveal a resistance to thinking of drug prescribing as potentially harmful. In each case, prescribing physicians continued to give the drug to their patients, perhaps as ignorant of the risks as the patients were. When a drug had been linked to harmful effects, the burden of providing proof of lack of safety was in case after case placed on those who questioned the wisdom of prescribing the potentially harmful drug. The struggle over controversial scientific evidence of toxicity of a drug is conducted over "truth". But on another level it concerns elusive assets: a reputation, an image of integrity and probity, an advantage in the marketplace, and ultimately money. The important objective for some of the combatants is to keep the evidence of toxicity secret or at least perceived as insignificant. For others, the struggle is over access to information, over good or bad actions, over right or wrong. There have been many attempts to criticize, suppress, or devalue scientific evidence of drug-related harm, both behind closed doors and in scientific and political confrontations in the public domain. In one instance, a German pharmaceutical company even won a Supreme Court injunction for libel against journals that published unfavorable, albeit correct, pharmacological data about one of its products (64). Patients are not likely to understand fully the origin of a drug-related disease that transformed their lives until the evidence is available in the public domain. That is when they can

Secrecy hiding harm: case histories from the past that inform the future

begin to act, organize, and translate their complaints into political demands or private litigation. That is also when mass media may grasp the issue and support them as victims. Eventually, if enough political pressure builds up, measures will be taken to stop the harmful practices, and the issue will be brought to closure, either by removing the drug from the market or by requirements that the labelling of the drug should include warnings of risk.

What does the future hold? The transnational character of the marketplace for pharmaceutical products will become more obvious as national markets in the world coalesce into a small number of trading blocks. The global population will grow from its present 6.2 billion to about 9 billion by 2050, according to UN projections. Even though all will not have access to even basic healthcare, this means a dramatic increase in the number of drug consumers in the world. With increasing proportions of aging and old people in developed as well as developing countries, more patients will have diseases associated with decay of the body and mind, and will probably depend increasingly on medications. The genetic heterogeneity of the growing mass of drug consumers will be manifested in variations in susceptibility to beneficial as well as adverse effects of drugs. Sadly, this means that the number of patients suffering from the harmful effects of drugs is bound to increase in absolute terms. Preventive measures are needed to keep that increase within reasonable bounds. The prevention of drug-related disease is a challenge that policy-makers, as well as the medical community, need to address, as the incidence of identifiable drag-related injury continues to rise and burden the healthcare budgets of individuals, insurance carriers, and nations. The precautionary principle is often invoked in international policies concerning risks to human health and environment. It states that when there are threats of serious or irreversible damage, lack of full scientific certainty shall not be used as a reason for postponing cost-effective measures to prevent environmental degradation (65). In the medical domain, this principle was addressed in a key decision concerning thalidomide by a German court three decades ago: "The scientific uncertainty as to whether a drug causes an adverse effect or not must not be

xxxi

resolved at the patient's expense, because the patient's right to health ranks above the manufacturer's fight to market his product without hindrance" (66). When a drug is marketed, there is genuine scientific uncertainty about its effects in larger, more heterogeneous population groups than those who have participated in clinical trials. The precautionary principle stresses the importance of preventing foreseeable hazards. In the control of drugs, preventive measures can take three forms: 9 9

9

more stringent controls of the efficacy and safety of drugs before they are marketed; more stringent controls of the ways in which drugs are promoted and made available to consumers; more effective monitoring of the effects of drugs on consumers after marketing, and better organized dissemination of information about observed harmful effects of drugs.

The precautionary principle implies that it is not justified to wait for drug disasters to happen before action is taken. The conflicts of interest in premarketing clinical trials of drugs--gains in time and money versus sufficient evidence of a drug's safety and efficacy--point to a need for more efficient auditing of how such trials are organized and implemented. The mechanisms for identifying the risks of adverse effects of drags and for collecting and analyzing reports of drug-related injury will have to be strengthened for effective prevention. Current trends in the pharmaceuticals marketplace set the stage for proactive measures to reinforce the control of drugs during coming decades. Patients' access to drugs and the costs of drugs will continue to be controversial issues. Healthcare providers and governments will be under pressure to ensure that essential drugs are available at reasonable cost. This means that the market for generic drugs must expand. It probably also means that policymakers must become more attentive to how brand-name drugs are promoted and sold in the medical marketplace. Prescribing patterns must be more closely monitored. The pharmaceutical industry already bases some of its promotional activities on computerized prescription data (67); these

xxxii data can also serve in the protection of public health. Although there will never be a pill for every ill, extravagant drug promotion that targets prescribers and healthcare managers is likely to continue to sway medical professionals to prescribe medications. This requires vigilance, not only from regulatory agencies, but also within the medical community, so that basic principles of medical ethics are not set aside. As shown in a series of recent critical articles in US medical journals and newspapers, some of which have been cited among the sources in this essay, the ethics and economics of lavish drug promotion is already controversial. International collaboration is essential, not least to control aggressive drug promotion over the Internet. Patients of the post-war generation are as drug consumers likely to participate more actively than earlier generations in decisions about their medical treatments. They will voice their requests based on the available information-what they can learn from independent sources and their doctors, as well as what they learn from drug merchants via magazines, books, radio, television, the lnternet, and through patients' organizations. As drug consumers get more active, other players in the medical marketplace will adjust. The pharmaceutical industry is already prepared; it financially supports certain patients' organizations that are used as fronts in outreach and lobbying to promote its interests (68). This increase in patients' demands for specific treatments and products will require careful evaluation by healthcare managers and medical professionals authorized to prescribe drugs. Better education for professionals in medical practice in pharmacotherapy and public health is also needed to keep the rates of drug-related injury under control. When the World Health Assembly emphasized health as a fundamental human right and a worldwide social goal, it stressed that people have the right and the duty to participate individually and collectively in the implementation of their health care (69). Consumers constitute a valuable resource that the medical com-

lngar Palmlund

munity should mobilize in the surveillance of the effects of drugs. An organization that already monitors the effects of drugs is Health Action International (HAI), a non-profit-making global network of health, development, consumer, and other public-interest groups in more than 70 countries. HA1 campaigns for better control of drug promotion, and demands that balanced, independent information regarding the safety and efficacy of drugs should be provided to those who prescribe drugs and to consumers. A first intemational conference on Consumer Reports on Medicine, supported by HA1, was held in Sweden in 2000. The conference was a step toward creating an international consumers' pharmacovigilance system, based on consumers' willingness to look out for harmful effects of drugs (70). Also greater transparency is necessary for effective prevention of harm. If the rates of drug-related disease are to be controlled or even reduced, it is of vital importance that prescribing physicians, as well as patients, have access to accurate information about the contents, effects, and risks of pharmaceutical products. Access to information is one of the first demands of patients' and consumers' organizations. Education in public health for the general public is therefore essential in any strategy to reduce the harmful effects of drugs---education about the ways in which nutrition, physical activity, lifestyles, and medical therapies promote healthy living. As Berthold Brecht once wrote: "Put your finger on each post in the bill they give you and ask them 'What is this?' You are the one who will pay!"

Acknowledgements I am grateful to the Wellcome Trust Centre for the History of Medicine at University College London for providing a congenial environment while I wrote this essay. I also thank Naomi Pfeffer and John Henderson for constructive comments.

Secrecy hiding harm: case histories from the past that inform the future

xxxiii

REFERENCES 1. palmlund I. The social construction of menopause as risk. J Psychosomat Obstet Gynecol 1997; 18: 87-94. 2. Palmlund I. The marketing of estrogen drugs. J Psychosomat Obstet Gynecol 1997; 1: 15864. 3. http: //www.kirksnews.com. Accessed 8 September 2000. 4. http://www.cyberhealthservices.com/lycosv.html. Accessed 8 September 2000. 5. Henkel J. Buying drags on line: it's convenient and private, but beware of "rogue sites". FDA Consumer 2000; January/February. 6. Peterson M. When good drugs go gray. The New York Times, 14 December 2000. 7. Kravitz RL. Direct-to-consumer advertising of prescription drags: implications for the patientphysician relationship. J Am Med Assoc 2000; 284: 2244. 8. Gemeperli MP. Rethinking the role of the learned intermediary: the effect of direct-to-consumer advertising on litigation. J Am Med Assoc 2000; 284: 2241. 9. Henney JE. Challenges in regulating direct-toconsumer advertising. J Am Med Assoc 2000; 284: 2241. t0. Gearon CJ. Going online for health: the surfing's great, but use caution. AARP Bulletin 2000; 41: 4, 14. 11. Gearon CJ. Rogue sites make for bad medicine: authorities urge caution when buying drags online. AARP Bulletin 2000; 41: 14-16. 12. US Food and Drag Administration. Buying medicines and medical products online. http://www.fda.gov/oc/buyoniine/default.htm. Accessed 1 January 2001. 13. Ten Hamm M. Advertising, promotion, and sale of medical products across borders using the Internet. http://www.cetp.ipsl.fr/~porteneu/inet98/3d/ 3d-3.htm. Accessed 30 October 2000. 14. Consumer Reports on Medicines----CRM: policy and practice. Consensus Document adopted at the First International Conference on CRM, 29 September-1 October 2000: 10. 15. Pear R. Marketing tied to increase in prescription drug sales. The New York Times, 20 December 2000. 16. US Congress. House Committee on Interstate and Foreign Commerce and Its Subcommittee on Public Health and Environment, 1974. "A Brief Legislative History of the Food, Drug, and Cosmetic Act". Committee Print No. 14. Washington DC: US Government Printing Office, 1974: 1-4. 17. USA, 52 Stat. 1040, 75th Congress, 3rd session, 25 June 1938. 18. USA vs Dotterweich, 1941. 19. USA, 76 Stat. 780, 87th Congress, 2nd session, 10 October 1962. 20. US National Academy of Sciences. Drug efficacy study: a report to the Commissioner of Food

and Drugs. Washington DC: National Academy of Sciences, 1969. 21. Bryan PA. "DESI Who?" FDA Consumer, October 1972. DHEW Publication No 73-3031. 22. PSGB. Industry, safety, Sainsbury and the Bill. Pharm J 1968; 200: 274-5. 23. Abraham J. Science, politics and the pharmaceutical industry: controversy and bias in the drug regulation. New York: St Martin's Press, 1995: 66-80. 24. PSGB. New ABPI code of practice. Pharm J 1967; 198: 692-3. 25. Riksdagen, Sweden. "Kungl Maj:ts l~kemedelsftrordning" Svensk Ftrfattningssamling 1962, No. 701. 26. Riksdagen, Sweden. "Kungl Maj:ts kungtrelse om till~npningen av l~ikemedelsftrordningen den 14 December 1962 (nr 701)". Svensk Ftrfattningssamling 1963, No. 439. 27. USA. Medical Device Amendments of 1976. PL No. 94-295, 21 USC, Sec 360c-360k. 28. Abraham J. Science, politics and the pharmaceutical industry: controversy and bias in the drag regulation. New York: St Martin's Press, 1995: 74-7. 29. Claybrook J and the staff of the Public Citizen's Health Research Group. Retreat from safety: Reagan's attack on America's health. New York: Pantheon Books, 1984. 30. US Department of Health and Human Services, Food and Drag Administration. Prescription drug products; revocation of patient package insert requirements. Federal Register 1982; 47: 173. 31. International Federation of Pharmaceutical Manufacturers Associations. ICH. http:/Iwww.ifpma.orglich. Accessed 15 October 2000. 32. Bardelay D. An ISDB survey to assess the degree of transparency of drug regulatory agencies. Int J Risk Saf Med 1996; 9: 151-5. 33. Anonymous. Time to lift the veil of secrecy. Int J Risk Saf Med 1996; 9: 131-2. 34. Stolberg SG, Gerth J. Drag makers design studies with eye to competitive edge. The New York Times, 23 December 2000. 35. Gerth J, Stolberg SG. Another part of the battle: keeping a drug on the markret. The New York Times, 13 December 2000. 36. Peterson M. Guilty plea by division of drug giant monitors for diabetics found to be defective. The New York Times, 16 December 2000. 37. Chalmers I. Diethylstilbestrol (DES) in pregnancy. In: Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, editors. Cochrane Database of Systematic Reviews: Review No. 02891, 21 April 1994. Published through "Cochrane Updates on Disk". Oxford: Update software, 1994, Disk Issue 1. 38. Bailar JC 3rd. The practice of meta-analysis. J Clin Epidemiol 1995; 48: 149-57.

xxxiv 39. Palmlund I. Dangers of overviews of heath care. Lancet 1995; 346: 852-3. 40. Palmlund I. The case of estrogens: an inquiry into societal risk evaluation. Doctoral dissertation. Ann Arbor: UMI Dissertation Information Service, 1990:200-53 & 317-50. 41. Herxheimer A. Side effects: freedom of information and the communication of doubt. In: Aronson JK, editor. Side Effects of Drugs Annual 19. Amsterdam: Elsevier, 1996: xix-xxvii. 42. Dukes MNG. Drug regulation and the tradition of secrecy. Int J Risk Saf Med 1996; 9: 131220. 43. Brown P, Funk SC. Tardive dyskinesia: barriers to the professional recognition of an iatrogenic disease. J Heath Soc Behav 1986; 27:116-32. 44. Tattam A. Australia announces CJD compensation package. Lancet 1998; 351:1114. 45. Pfeffer N. Pioneers of infertility treatment. In: Conrad L, Hardy A, editors. Women and modem medicine, Amsterdam: Editions Rodopi, 2000: 249~55. 46. Dean M. London: UK human growth-hormone cover up. Lancet 1996; 348: 259. 47. Palmer A. No babies, just mad cow disease. The Spectator 1994; 19 February: 9-10. 48. Leveton LB, Sox HC Jr, Stoto MA, editors. HIV and the blood supply: an analysis of crisis decisionmaking. National Academy Press, 1995. 49. Coulombier D, editor. Le VIH et le SIDA cbez les hdmopniles et les transfuses: situation en France au 31 d6cembre 1998. http://www.rnspsante.fr/actuaite/. Accessed 10 February 2000. 50. Gerth J, Stolberg SG. Another part of the battle: keeping a drug in the store. The New York Times, 13 December 2000. 51. Smith OW, Diethylstilbestrol in prevention of complications of pregnancy. Am J Obstet Gynecol 1948; 56: 821-34. 52. Smith OW, Smith GVS. Influence of diethylstilbestrol on progress and outcome of pregnancy as based on comparison of treated with untreated primigravidas. Am J Obstet Gynecol 1949; 58: 994-1009. 53. Lacassagne A. Apparition d'addnocarcinomes mammaires chez des souris mfiles trait6s par une substance oestrog~ne synthetique. Comptes Rend S6ances Soc Biol 1938; 129: 641-3. 54. Dieckmann WJ, Davis ME, Rynkiewicz LM, Pottinger RE. Does the administration of diethylstilbestrol during pregnancy have therapeutic value? Am J Obstet Gynecol 1953; 66: 1062-81. 55. Herbst AL. Ulfelder H, Poskanzer D. Adenocarcinoma of the vagina. New Engl J Med 1971; 284: 878-81. 56. US Department of Health, Education and Wel-

Ingar Palmlund fare, Food and Drug Administration. Certain estrogens for oral or parenteral use. Drags for human use. Drug efficacy study implementation. Federal Register 1971; 36(217): 21537-8. 57. Mitchell S, producer, Wait J, presenter. Face the Facts. BBC Radio 4, 21 February 2000. 58. Melnick S, Cole P, Anderson D, Herbst AL. Rates and risks of diethylstilbestrol-related clearcell adenocarcinoma of the vagina and cervix: an update. New Engl J Med 1987; 316: 514-16. 59. Palmlund I. Exposure to a xeno-estrogen before birth: the diethylstilbestrol experience. J Psychosomat Obstet Gynecol 1996; 17: 71-84. 60. Nash S, Tilley BC, Kurland LT, et al. Identifying and tracing a population at risk: the DESAD project experience. Am J Publ Health 1983; 73: 253-9. 61. Norwood C. At nighest risk: environmental hazards to young and unborn children. New York: McGraw-Hill, 1980: 141, citing The Wall Street Journal, 23 December 1975. 62. Norwood C. At nighest risk: environmental hazards to young and unborn children. New York: McGraw-Hill, 1980: 141. 63. Direcks A, Figueroa S, Mintzes B, Banta D. DES European Study: DES Action the Netherlands for the European Commission Programme "Europe Against Cancer". Utrecht: DES Action the Netherlands, 1991: 13, 25. 64. Herxheimer A. Side effects: freedom of information and the communication of doubt, citing Oberverwaltungsgerucht MUnster, Judgement of 20 November 1995, Az 13B 619/95. 65. The Rio Declaration on Environment and Development, Principle 15. The Rio Declaration was signed at the United Nations Conference on Environment and Development, Rio de Janeiro, 3-14 June 1992, by more than 178 Heads of State. 66. Herxheimer A. Side effects: freedom of information and the communication of doubt, citing Landgerich Aachen, Contergan, Einstellungsbeschluss, 18 December 1970. Az 4 KMs 1/68, pp. 49-50. 67. Stolberg SG, Gerth J. High-tech stealth being used to sway doctor prescriptions. The New York Times, 16 November 2000. 68. Gerth J, Stolherg SG. Drug industry has ties to groups with many different voices. The New York Times, 5 October 2000. 69. International Conference on Primary H e a t h Care, Alma Ata, USSR, 6-12 September 1978. Declaration of Alma Ata, Principle IV. 70. KILEN--Consumers Institute for Medicines and Health. The First International Conference. Consumer Reports on Medicines at Sigtuna Foundation, Sigtuna, Sweden 29 September-1 October 2000.

Reginald P. Sequeira

1

Central nervous system stimulants, drugs that suppress appetite, and drugs used in Alzheimer's disease

METHYLXANTHINES

(SED-14, 1; SEDA-21, 1; SEDA-22, 1; SEDA-23, 1)

Caffeine Genetic factors can influence caffeine use, intoxication, tolerance, and withdrawal (lC). This conclusion was based on a comprehensive study involving interviews of 486 monozygotic and 335 dizygotic female twins. The wide interindividual variation in preference for caffeine and sensitivity to withdrawal can be explained on genetic factors operating at various levels, such as personality, vulnerability to psychopathology, caffeine metabolism, and variations in adenosine receptors. These findings have implications for the debate over the status of caffeine as a drug of abuse. The relation between coffee drinking and the presence of the K-ras mutation in patients with exocrine pancreas cancer has been investigated in Spain in 121 cases in which tissue specimen were available (2c). In exocrine pancreatic cancer, the K-ras gene may be activated less often among regular coffee drinkers, suggesting that caffeine, or other compounds present in coffee, or other factors with which coffee drinking is associated may modulate Kras activation. While the results of this study may have mechanistic and pathogenic relevance, they have no clinical or health policy implications.

9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

Pregnancy Whether or not the consumption of caffeine during pregnancy increases the risk of spontaneous abortion is controversial. In a nested case-control study 591 women who had a spontaneous abortion at less than 140 days of gestation were compared with 2558 matched women from the same clinic who gave birth to live infants at 28 weeks' gestation and who had serum drawn on the same day of gestation as the women who had abortions (3c). The women were enrolled in the collaborative perinatal project from 1959 to 1966, and the serum paraxanthine concentration was measured 30 years later. Moderate consumption of caffeine was unlikely to increase the risk of spontaneous abortion; only extremely high serum paraxanthine concentrations were associated with spontaneous abortion. D r u g overdose The elimination of caffeine has been described in a neonate weighing 1860 g at 31 weeks of gestation, after the accidental administration of 160 mg/kg. The first serum concentration was 218 mg/1 at 36.5 hours after dosing. The half-life was 81 hours, the clearance 0.01 l/h (0.17 ml/min), and the volume of distribution 1.17 1. Toxic manifestations were hypertonia, sweating, tachycardia, cardiac failure, pulmonary edema, and metabolic disturbances such as metabolic acidosis, hyperglycemia, and raised creatine kinase activity. An unusual feature of this infant's illness was gastric dilatation. These signs resolved by day 7 at a serum concentration of 60-70 mg/1 ( 4A) . Confirmed reports of caffeine overdose are rare. Post-mortem concentrations of caffeine measured in femoral blood were 220 and 190

Chapter 1 mg/1 in two adults (sA). In view of the extensive use of caffeine, the authors emphasized the forensic importance of measuring caffeine.

S T I M U L A N T DRUGS (SED-14,12; SEDA-21, 2; SEDA-22, 2; SEDA-23, 2)

Amphetamines

(SED-14, 16)

Nervous system Methamphetamine toxicity in infants may mimic scorpion (Centruroides sculpturatus) envenomation (6 A, 7A). However, the neurotoxic effect of envenomation can be distinguished from sympathomimetic-induced toxicity by the presence of cholinergic stimulation in scorpion envenomation, producing hypersalivation, bronchospasm, fasciculation of the tongue, purposeless motor agitation, involuntary and conjugate slow and roving eye movements, and often extra-ocular muscle dysfunction (8A). Failure of the antivenin would bring scorpion neurotoxicity into great question

(9~). Psychiatric Psychiatric adverse effects produced by amphetamines have been successfully managed with the atypical antipsychotic drug risperidone (10 A, 11g). A 76-year-old woman, who had taken dexamphetamine since the age of 28 years for narcolepsy, developed an acute schizophreniform psychosis with paranoid delusions and auditory hallucinations. She was initially treated with sulpiride while continuing to take dexamphetaminc. Five months later, sulpiride was withdrawn and her psychotic symptoms recurred. She was given risperidone 3 rag/day and continued to take dexamphetamine 15 mg/day. A 24-year-old man, with a history of intravenous methamphetamine abuse since the age of 19 years, developed psychotic symptoms characterized by auditory hallucinations and persecutory delusions. He had no insight and was given haloperidol and levomepromazine. His symptoms disappeared after 4 months of treatment and he then stopped using methamphetamine. A year and half later, "odd ideas" recurred and he became anxious but had insight. He was treated with bromperidol 9 mg/day for 6 months, but the odd ideas persisted. On referral he was found to fulfil the criteria for obsessive--compulsive disorder according to DSM-IV. No abused substances, including methamphetamine, were identified in his urine. Risperidone 2 mg/day was started and then increased to 5 mg/day. After 3 weeks, the intrusive thoughts and symptoms of "anxious-restless state" gradually subsided and eventually disappeared.

ReginaldP. Sequeira

His symptoms recurred within a week of stopping risperidone and resolved on reintroduction. Musculoskeletal There may be an association between methamphetamine abuse and rhabdomyolysis. In a retrospective review of 367 patients with rhabdomyolysis, 166 were positive for methamphetamine (12 C). They had higher mean initial and lower mean peak activities of creatine phosphokinase. There was no significant difference in the incidence of acute renal insufficiency. The authors suggested screening all patients with rhabdomyolysis of unclear cause for methamphetamine and measuring creatine phosphokinase activity. D r u g abuse The illicit use of methamphetamine is increasing, and there is an association between its illicit use and traumatic accidents. A retrospective review of trauma patients in California showed that methamphetamine rates doubled between 1989 and 1994, while cocaine showed a minimal increase and alcohol a fall. Methamphetamine-positive patients were most likely to be Caucasian or Hispanic and were most commonly injured in motor vehicle collisions. The authors recommended intervention strategies, similar to those used for preventing alcohol consumption and driving, in order to minimize morbidity and mortality (13c). Further evidence concerning increased methamphetamine abuse has come from Taiwan (14c). Between 1991 and 1996, of 3958 deaths with autopsies, 244 were related to methamphetamine (mean age 30.7 years, 73% men). The manner of death was natural (13%), accidental (59%), suicidal (11%), homicidal (14%), or uncertain (3%). Owing to the endemic problem and public hazard created by illicit methamphetamine abuse, the authors urged stronger antidrug programs. Traumatic shock may be complicated by methamphetamine intoxication (15A). Identifying the cause of shock is a key step in the management of patients with severe injuries. This is a challenge, because shock is occasionally caused by more than one mechanism; among the many causes, metabolic derangement attributable to drug abuse should be considered, and masked metabolic acidosis may be a clue to methamphetamine intoxication (16c). With the increased emergence of methamphetamine abuse, clinicians should consider it in the differential diagnosis of any patient exhibiting

Central nervous system stimulants, drugs that suppress appetite violence, psychosis, seizures, or cardiovascular abnormalities.

Doxapram (SED-14, 11; SEDA-21, 4; SEDA-23, 2) The effects of doxapram given enterally or intravenously have been studied in a prospective randomized trial in 15 infants with apnea of prematurity who had not responded to caffeine (17c). Of the nine infants randomized to receive enteral treatment, five had to be changed to intravenous treatment, largely owing to doxapram-induced upper gastrointestinal symptoms (vomiting and large gastric residuals). Doxapram significantly reduced the frequency of attacks of apnea and associated bradycardia and hypoxia in 82% of the infants. The major adverse event was feeding intolerance in one-third of infants given enteral treatment. This was resolved when doxapram was given intravenously. Importantly, some infants responded to and could tolerate enteral treatment, thus avoiding the need for an intravenous line.

Methylphenidate

(SED-14, 19; SEDA-21, 6; SEDA-22, 6; SEDA-23, 7) Nervous system There is continuing concern about the potential for methylphenidate to precipitate tics or Tourette's syndrome, both in subjects with and without tics. In a placebocontrolled cross-over study in 91 children with attention deficit hyperkinetic disorder (ADHD), the usual doses of methylphenidate did not produce significantly more tics than placebo in children with or without pre-existing tics (18CR). This study had limitations of sample size and statistical power. Moreover, these conclusions cannot be generalized to cases in which higher doses of methylphenidate are used, because a dose-dependent relation between methylphenidate and tics has been proposed (19CR). Until the effect of methylphenidate in larger populations has been studied with more exacting measures of tics, it would be wise to monitor for tics, especially if higher doses (0.51.3 mg/kg) of methylphenidate are required. Drug overdose The first reported death due to intranasal abuse of methyli?henidate in a teenager has been reported (20~). The patient presented with the history and physical signs

ChapterI

characteristic of methylphenidate abuse, including hyperpyrexia and tachycardia. The plasma methylphenidate concentration was less than 0.05 mg/1 in the admission sample. However, the concentration of ritalinic acid, the principal metabolite of methylphenidate, was 0.4 mg/1. Ethanol was also found in a concentration of 0.1% w/v. Comparable toxicity with other stimulants is well known (21CR, 22CR). Drug interactions A novel metabolite of methylphenidate, ethylphenidate, has recently been detected in human blood and liver samples obtained from two suicide victims who had taken a large dose of methylphenidate and ethanol (23A). The concentrations of ethylphenidate were small relative to those of methylphenidate and ritalinic acid. Nevertheless, given the frequent occurrence of methylphenidate and ethanol co-ingestion, the detection of ethylphenidate warrants further studies on the extent of its formation, as well as any associated toxicity associated with normal doses. A transesterification reaction, analogous to that known to produce cocaethylene after cocaine and ethanol co-ingestion (24CR), has been described with methylphenidate (25E).

Carbamazepine Carbamazepine can reduce methylphenidate concentrations markedly (26A). Since these drugs are often used together, the authors suggested that the worsening of behavior in a 13-year-old girl with ADHD might have been due to a fall in blood concentration of methylphenidate, resulting from carbamazepine. Clonidine There has been a scare regarding the use of clonidine in combination with methylphenidate, based on frequently cited cases of four children who died, presumably while taking clonidine together with methylphenidate (27 A, 28A). It has been argued that "cases of fatality in people receiving the combination have a paucity of supporting evidence, with prominent mitigating and extenuating circumstances nullifying any scientific attempts at association. Given that no association can be drawn, there are insufficient data to support any 'causal mechanisms' ". Further discussion of the dangers beyond solid evidence does little to provide clarity to our task of thoughtfully using medications in the treatment of children and adolescents with psychopathology (29r).

4

Strychnine

Chapter 1 (SED-14, 12)

Two cases of strychnine poisoning with characteristic signs and symptoms have been described (30A, 31A). Management included gastric lavage, the administration of activated charcoal, sedation with midazolam and phenobarbital, and paralysis with vecuronium, along with respiratory support and forced hydration. In some countries strychnine is available as a pest control agent, resulting in occasional poisoning. Early diagnosis and prompt management can save the patient, despite the consumption of a large dose of strychnine.

DRUGS THAT SUPPRESS APPETITE

Cardiac valvulopathy associated withfenfluramines and phentermine (SEDA-22, 3; SEDA-23, 2) The appetite suppressants fenfluramine and dexfenfluramine, alone or in combination with phentermine, have been implicated as causing valvular heart disease. Criteria It has been proposed that valvular disease can be attributable to appetite suppressants only if the following criteria are satisfied: (a) the macroscopic and microscopic features are consistent with fenfluramine-related valvulopathy, (b) clinical, echocardiographic, and intraoperative findings support the diagnosis, and (c) the history of drug exposure predates the development or exacerbation of valvular dysfunction (32cr). It is obvious that these criteria can be applicable only in cases in which cardiac valves are explanted and are available for histopathological studies. Prevalence Although initially a prevalence of up to 30% was estimated, subsequent reports have suggested much lower rates. There are several reasons for this disparity, including uncontrolled data and the limitations of echocardiography (33 R, 34 R, 35cR). An important issue is to determine the prevalence of valvular regurgitation and abnormal valve morphology in patients exposed to appetite suppressants after withdrawal of the drugs.

Reginald P. Sequeira

The small increase in prevalence of minor degrees of aortic regurgitation and mitral regurgitation in 941 patients treated with dexfenfluramine for 2-3 months was no longer present 3-5 months (median 137 days) after withdrawal (36cR). Echocardiograms were acquired using a standardized protocol and were assessed blindly. These findings suggested that valvular regurgitation in patients who have used dexfenfluramine for a relatively short time does not progress over time. These findings are reassuring for the population of patients treated with dexfenfluramine for 3 months or less, suggesting that progression of valvular regurgitation is unlikely. Nevertheless, patients treated with appetite suppressants who present with a new murmur or clinical symptoms should undergo the evaluation outlined in the guidelines. Based on a prospective study carried out in 226 obese subjects (183 women and 43 men) with a mean body mass index of 39.8 kg/m 2, therapy with fen-phen (fenfluramine + phentermine) was associated with low prevalence of significant valvular regurgitation (37cR). The authors suggested that valvular regurgitation in these subjects may have reflected age-related degenerative changes. Several limitations of this study have been pointed out: (a) there was no control group and not all the subjects had echocardiography, (b) multiple readers interpreted the echocardiograms, rendering the comparison less accurate, (c) inherent inaccuracy in differentiating mild degrees of valvular regurgitation, especially using qualitative scoring systems, (d) selection bias, (e) neither direct inspection nor histopathological confirmation of valvular lesions was performed on any patient. Since this study did not address the development of significant valvular disease at a future date, long- term prospective studies are needed. Clinical course Contrary to recent evidence that anorixigen-induced valvulopathy may be reversible (SEDA-23, 4), progressive valvulopathy has been reported, despite removal of the heart from the offending milieu and surgical debridement of the endocardial plaque (38 a ). Cardiac allograft transplantation was carried out from a 35-year-old hypertensive donor with prolonged exposure to fenfluramine and phentermine. There was non-specific mitral valve thickening, with trivial mitral regurgitation and poor approximation

Central nervous system stimulants, drugs that suppress appetite of the mitral valve leaflets, due to reduced posterior leaflet mobility. There was no evidence of any other valvular lesion. Examination of the donor heart during cardiac implantation showed three discontinuous lesions along the left atrial surface of the mitral valve annulus and anotherfirm nodular lesion of the annular endocardium. Transplantation of the heart was unevenO~uland an intraoperative transesophageal echocardiogram, performed after weaning from cardiopulmonary bypass, showed trivial mitral regurgitation with excellent allograft contractility. The postoperative course was uneventful and patient was discharged on the eighth postoperative day. Histological examination of the specimen showed a glistening appearance with proliferating myofibroblasts and associated fibrinous vegetations. There was no evidence of acute or chronic inflammation, and Gram staining did not show bacterial or fungal elements. A transthoracic echocardiogram 6 weeks after transplantation showed only trivial mitral regurgitation with improved mobility of the posterior leaflet. Hemodynamic data showed normal allografl function. However, after 6 months offollow up, Doppler echocardiography showed worsening of mitral regurgitation to moderate severity, but no adverse effects of this hemodynamic load were noted and the patient has remained stable. Although conclusions based on single cases have limitations, they can often provide useful insights and act as catalysts for further studies. This report illustrates a few important features of cardiac valvulopathy associated with anorexigen use. There was no involvement of chordal apparatus and so the pathological changes within the valve leaflets and annulus represented the earliest site of an anorexigen-induced valvulopathy. This opportunity, to observe a case of "early" valvulopathy visually and histopathologically offered insight into pathogenesis, and may have been helpful in staging the lesions temporally. Mechanisms and risk factors The determinants of valvulopathy in patients treated with dexfenfluramine have been investigated: age and blood pressure may also affect the prevalence of regurgitation (39 cIr 40CR), as may duration of exposure (39CR). Others have found no correlation between valvular disease associated with appetite suppressants and either dose or duration of drug exposure (37CR). Cases of severe diffuse muhivalvular disease associated with fen-phen have been described (41 A, 42A). A 52-year-old woman had a transesophageal echocardiogram one year before starting to take

ChapterI

fen-phen, and had no significant valvular disease. She presented a year later with a new heart murmur and eventually required isolated aortic valve replacement. Pathological evaluation of the excised aortic valve was consistent with that described with fen-phen use. A 44-year-old woman, previously treated with appetite suppressants, developed valvular disease consistent with the effects of fen-phen. She had an identical twin who, despite having been treated with the same anorectic medication, remained symptomfree and without abnormal echocardiogruphy. Both the patient and her sister took fen-phen for 2 years. However, the patient took a daily dose offenfluramine of 60--120 mg (and often as much as 240 rag) and phentermine 90 mg (at times 180 rag), whereas her twin sister adhered to the daily amount prescribed (fenfluramine 60 mg and phentermine 24 mg). This latter case seems to raise the relevance of dosage in the production of the valvular pathology. Mitral and tricuspid insufficiency developed in a 36-year-old woman who had taken f e n phen for 24 months (43A). Transmission electron microscopy o f the mitral and tricuspid valves showed many areas that appeared to contain intracellular, virus-like particles clustered in the cytoplasm, with a mean diameter of 32 nanometers. Whether this finding was incidental or related to the underlying pathology was uncertain. There have been no major breakthroughs in understanding of cardiac valvulopathy induced by appetite suppressants. However, some additional information regarding the natural course of the disease and better estimates of prevalence are now available. Several interesting observations, mostly as case- reports, have been described, but it is too early to draw conclusions based on these reports. These clues should lead towards better insights in understanding valvulopathy associated with appetite suppressant use.

Dexfenfluramine

(SED-14, 21; SEDA-21, 2; SEDA-22, 2; SEDA-23, 2)

Shortly after starting dexfenfluramine 30 mg/day, an 18-year-old woman died with sclerodermal renal crisis (44A). Although there have been reports linking long term fenfluramine use and the development of schleroderma (45A, 46A), this is perhaps the first report implicating dexfenfluramine.

Chapter 1

Phentermine (SED-14, 26; SEDA-21, 2; SEDA-22, 2; SEDA-23, 8) Spontaneous rupture of a retroperitoneal aneurysm occurred in a 70-year-old woman who had been taking phentermine hydrochioride, 30 mg/day, for about 1 month (47A). Other long-term medications included fluoxetine and amitriptyline, and she had no history of coronary artery disease, hypertension, diabetes, or complications of pregnancy. Although it is plausible that phentermine could have contributed to the ruptured aneurysm, other possibilities should be considered, particularly rupture of an anomolous retroperitoneal blood vessel.

Pseudoephedrine and ephedrine (SED-14, 416; SEDA-21, 5; SEDA-22, 6; SEDA-23, 8) The vasoconstrictor action of pseudoephedrine may predispose susceptible patients to ischemic colitis, particularly in the watershed area of the splenic flexure. Perimenopausal women may be more susceptible (48A). Drug interactions Pseudoephedrine--dextromethorphan combinations are used, often in over-the-counter formulations. Although they are generally considered safe, two recent reports have emphasized the potential adverse effect of these cold and cough formulations (49 A, 50or). A 2-year-old child developed hyperirritability, psychosis, and ataxia after being overmedicated with a cough formulation containing pseudoephedrine and dextromethorphan. The child made an uneventful recovery after an observation period of 4 hours in the emergency department. Three cases of acute psychosis associated with the use of similar over-the-counter formulations in adolescent girls have been described. These patients required several days of hospitalization, extensive invasive medical evaluation, and consultations with neurologists, infectious disease specialists, toxicologists, and psychiatrists. They were treated with risperidone.

Propofol A 44-year-old woman was given ephedrine intravenously, to manage hypotension during spinal anesthesia. She developed intracranial hypertension and focal cerebral deficits related to multiple hemorrhagic cerebral infarcts. Angiography showed reversible beading appearance, consistent with the diagnosis

ReginaldP. Sequeira

of cerebral arteritis (51A). Owing to the risk of tachycardia, resulting in myocardial ischemia, the combination of propofol with ephedrine in elderly patients undergoing genitourinary surgery is not recommended (52c). These reports should alert physicians to the potential hazards associated with the use of ephedrine during anesthesia.

Vaccines A hyperthermic event occurred shortly after vaccination with typhoid and Japanese encephalitis vaccines in a service member using an over-the-counter formulation of pseudoephedrine (53A). The patient collapsed, while exercising in mild weather, 75 minutes after vaccination. He presented in asystole, with a core temperature of 42.2~ and there was no evidence of urticaria or angio-edema. The authors suggested that the combined pyrogenic effects of the vaccines, pseudo-ephedrine, exercise, and mild obesity had contributed to a failure of thermoregulation.

DRUGS USED IN ALZHEIMER'S DISEASE (SED-14, 435; SEDA-21, 6; SEDA-22, 7; SEDA-23, 8) Alzheimer's disease is the most common single cause of dementia in our aging society. It is traditionally thought of as an untreatable degenerative condition, but recent advances in drug therapy have challenged this view (54 R, 55R). Given the long history of the therapeutic nihilism towards Alzheimer's disease, it is very encouraging that cholinesterase inhibitors have been shown to produce significant improvement in cognitive performance and clinical ratings (56R). New drugs for Alzheimer's disease are not curative; their effects are probably best described as modest and the cost may be high; however, the human cost of dementia is infinitely higher (57R).

Donepezil

(SED-14, 435; SEDA-23, 9)

Further evidence that donepezil is effective and well tolerated in treating symptoms of mild to moderately severe Alzheimer's disease has emerged from a multinational trial (58c). Common adverse effects were nausea, vomiting,

diarrhea, anorexia, dizziness, and confusion, consistent with previous findings.

Central nervous system stimulants, drugs that suppress appetite Although once-daily donepezil is clinically effective and well tolerated _for the symptoms of mild to moderate Alzheimer s disease (59c), two practical questions are relevant: (a) which patients are too severely affected to be treated with donepezil? and (b) at what point should donepezil be discontinued if the patient continues to deteriorate?

Cardiovascular Symptomatic sinus bradycardia is a possible adverse effect of treatment with donepezil in Alzheimer's disease (60A). An 84-year-old patient with hypertensive cardiomyopathy developed bradycardia, fainting, and left-sided heart failure 3 weeks after starting treatment with donepezil. When donepezil was stopped, the sinus bradycardia disappeared; a 24-hour electrocardiographic recording showed no signs of sinus node disease and no episodes of this type recurred during the next 6 months. It is important to emphasize that disorders of cardiac rhythm associated with the use of donepezil are extremely unusual.

Nervous system Convulsions have been reported during treatment with donepezil (61A). A patient with mild Alzheimer's disease treated with donepezil, 5 mg/day for 2 weeks and then 10 mg/day for 23 days, was admitted with convulsions. His only other medication was aspirin, 100 mg/day. Blood analysis was normal, and a CT scan showed a mild degree of cortical atrophy with no structural lesions. Donepezil was discontinued and no other drug treatment was given. Six weeks later donepezil, 5 mg/day, was restarted. On day 52 he developed loss of consciousness and convulsions, necessitating withdrawal of donepezil. Convulsions in Alzheimer's disease are very rare until late in the illness, and the authors attributed this patient's convulsions to donepezil. Risk factors Three patients with Alzheimer's disease associated with Down's syndrome were treated with donepezil (62A). One patient became agitated and aggressive while the other two developed urinary incontinence. In all three cases donepezil was withdrawn. These results are important, because many individuals with Down's syndrome develop clinical and neuropathological evidence of Alzheimer's disease after the age of 40 years. Also, patients with Down's syndrome were excluded from donepezil clinical trials. Therefore, fewer data,

Chapter1

7

if any, on the efficacy or safety of donepezil are available for this population.

Drug overdose Two cases of donepezil overdose have been reported (63 A, 64A).

A 79-year-old nursing-home patient was given donepezil 50 mg erroneously. She presented to the emergency department with nausea, vomiting, and persistent bradycardia-typical cholinergic adverse effects. She was treated with atropine, 0.2 mg as needed, for bradycardia (total dose 3 mg over 18 hours) and was discharged on the second day. A 74-year-old patient with a history of stroke, myocardial infarction, hypothyroidism, and probable multi-infarct dementia took nine donepezil tablets (a total dose of 45 mg). She developed nausea and vomiting 2 hours later. She fell asleep for 4--5 hours but remained reusable. About 9 hours after ingestion she became flushed and had a bout of diarrhea. Donepezil was withdrawn for 3 days, and there were no adverse effects when it was reintroduced.

Drug interactions A possible drug-drug interaction between donepezil and paroxetine has been described (65A). Two elderly patients with Alzheimer's disease and a mood disorder were treated with donepezil 5 mg/day and paroxetine 20 mg/day One of them became agitated, confused, and aggressive, and donepezil was withdrawn after 8 days. On reintroduction of donepezil she again became rapidly confused, irritable, and verbally aggressive. In another case, while the patient was taking paroxetine, donepezil 5 mg/day resulted in severe diarrhea, flatulence, and insomnia. The dosage of donepezil was reduced to 5 mg on alternate days, but the diarrhea and flatulence persisted. The symptoms resolved when donepezil was stopped. Donepezil is metabolized in the liver by CYP2D6 and CYP3A4. SSRIs, such as paroxetine, are potent inhibitors of CYP2D6. Mood disorders are common in patients with Alzheimer's disease, and SSRIs are used in these patients and can increase the plasma concentration of donepezil, increasing the risk of severe adverse reactions.

Metrifonate (SED-14, 982, 1039; SEDA-23, 10) The pharmacology and pharmacokinetics of metrifonate, and experience with it in Alzheimer's disease have been reviewed (66R). The recently concluded Metrifonate Alzheimer's Trial (MALT) was designed to

8 evaluate a wide range of symptoms and efficacy measures in four main clinical domains of Alzheimer's disease: cognition, psychiatric and behavioral features, activities of daily living, and global functioning (67c). These are considered key targets for antidementia drugs. This prospective, multicenter, randomized, doubleblind, parallel group study was conducted at 71 independent study centers, and 605 patients were randomized to placebo (n = 208), metrifonate 40 or 50 mg/day (n = 200), and metrifonate 60 or 80 mg/day (n = 197); within each treatment group the dose was determined according to body weight. The treatment lasted for 24 weeks. Metrifonate improved a wide range of symptoms across all four clinical domains of Alzheimer's disease in a dosedependent manner, and was well tolerated at both doses studied. One patient withdrew from the study during the high-dose loading phase owing to cholinergic effects, resulting in muscle weakness. Metrifonate was also associated with a slight gradual lowering of hemoglobin, hematocrit, and erythrocyte count in both groups during first 12 weeks. These were non-progressive, stabilized over the 6-month treatment period, and hence were not considered to be clinically relevant. Metfifonate was associated with a higher incidence of bradycardia (under 50 bpm); serious adverse events possibly related to bradycardia (hypotension, postural hypotension, syncope, dizziness, malaise, and accidental injury) occurred in three patients taking placebo, eight taking low-dose metrifonate (three of whom were withdrawn from the study), and two taking high-dose metrifonate.

Chapter 1

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The effect of a loading dose on the adverse events of metrifonate 50 mg/day have been studied in Alzheimer's disease. The regimen without a loading dose was better tolerated during the 4-week study period (68CR).

Rivastigmine

(SED-14, 435)

Rivastigmine (69 R) is the second drug after donepezil in a class of second-generation acetylcholinesterase inhibitors to become commercially available. It is now marketed in over 60 countries worldwide, including those in Europe, South America, and the UK. It has central selectivity, suggesting fewer peripheral adverse effects. These include nausea, vomiting, abdominal pain, and anorexia (70 c, 71c). Daily doses up to 12 mg were tolerated and produced improvement in patients with Alzheimer's disease (72c). Although therapy with newer as well as older cholinesterase inhibitors can prevent cognitive decline, psychiatric and behavioral disturbances, and impaired ability to perform basic activities of daily living, and improve global state of patients with mild to moderately severe Alzheimer's disease, more potent therapies are needed, particularly for modifying the rate of disease progression. Future research efforts need to focus on identifying predictors and better measures of response, timing of treatment, optimum dosage regimens, longer term follow-up, and establishing how and when acetylcholinesterase inhibitors should be stopped (73 r, 74r).

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4. Anderson BJ, Gunn TR, Holford NHG, Johnson R. Caffeine overdose in a premature infant: clinical course and pharmacokinetics. Anaesth Intensive Care 1999; 27: 307-11. 5. Riesselmann B, Rosenbaum E Roscher S, Schneider V. Fatal caffeine intoxication. Forensic Sci Int 1999; 103 Suppl 1: $49-52. 6. Nagorka AR, Bergson PS. Infant methamphetamine toxicity posing as scorpion envenomation. Pediatr Emerg Care 1998; 14: 350-1. 7. Kolecki P. Inadvertent methamphetamine poisoning in pediatric patients. Pediatr Emerg Care 1998; 14: 385-7.

Central nervous system stimulants, drugs that suppress appetite 8. Suchard JR, Currry SC, Nagorka AR, Bergeson PS. Methamphetamine toxicity. Pediatr Emerg Care 1999; 15: 306. 9. Nagorka AR, Bergeson PS. Methamphetamine toxicity. Pediatr Emerg Care 1999; 15: 306. 10. Jha A, Fourie H. Risperidone treatment of amphetamine psychosis. Br J Psychiatry 1999; 174: 366. 11. Iyo M, Sekine Y, Matsunaga T, Tsukamoto T, Takei N, Mori N. Methamphetamine-associated obsessional symptoms and effective risperidone treatment: a case report. J Clin Psychiatry 1999; 60: 337-8. 12. Richards JR, Johnson EB, Stark RW, Derlet RW. Methamphetamine abuse and rhabdomyolysis in the ED: a 5-year study. Am J Emerg Med 1999; 17: 681-5. 13. Schermer CR, Wisner DH. Methamphetamine use in trauma patients: a population based study. J Am Coil Surg 1999; 189: 442-9. 14. Shaw KP. Human methamphetamine-related fatalities in Taiwan during 1991-1996. J Forensic Sci 1999; 44: 27-31. 15. Horiguchi T, Hori S, Shinozawa Y, Fujishima S, Kimura H. A case of traumatic shock complicated by methamphetamine intoxication. Intensive Care Med 1999; 25: 758450. 16. Guharoy R, Medicis J, Choi S, Stalder B, Kusjowski K, Allen A. Methamphetamine overdose: experience with six cases. Vet Hum Toxicol 1999; 41: 28-30. 17. Poets CF, Darraj S, Bohnhorst B. Effect of doxapram on episodes of apnoea, bradycardia and hypoxaemia in preterm infants. Biol Neonate 1999; 76: 207-13. 18. Law SF, Schachar RJ. Do typical clinical doses of methylphenidate cause ticks in children treated for attention~leficit hyperactivity disorders? J Am Acad Adolesc Psychiatry 1999; 38: 944-51. 19. Castellanos FX, Giedd JN, Elia J, Marsh WL, Ritchie GF, Hamburger SD, Rapoport JL. Controlled stimulant treatment of ADHD and comorbid Tourette's syndrome: effects of stimulant and dose. J Am Acad Child Adolesc Psychiatry 1997; 36: 589-96. 20. Masello W 1II, Carpenter DA. A fatality due to intranasal abuse of methylphenidate (Ritalin| J Forensic Sci 1999; 44: 220-1. 21. Hong R, Matsuyama E, Nur K. Cardiomyopathy associated with the smoking of crystal amphetamine. J Am Med Assoc 1991; 265:11524. 22. Rajs J, Falconer B. Cardiac lesions in intravenous drug addicts. Forensic Sci Int 1979; 13: 193-209. 23. Markowitz JS, Logan BK, Diamond E Patrick KS. Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion. J Clin Psychopharmacol 1999; 19: 36245. 24. McCance EF, Price LH, Kosten TR, Jatlow PI. Cocaethylene pharmacology, physiology and beha-

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vioral effects in humans. J Pharmacol Exp Ther 1995; 274: 215-23. 25. Bourland JA, Martin DK, Mayersohn M. Carboxyesterase transesterification of meperidine (Demerol) and methylphenidate (Ritalin | in the presence of [2H6] ethanol: preliminary in vitro findings using rat liver preparation. J Pharm Sci 1997; 86: 1494--6. 26. Schaller JL, Behar D. Carbamazepine and methylphenidate in ADHD. J Am Acad Child Adolesc Psychiatry 1999; 38:112-13. 27. Wilens TE, Spencer TJ. Combining methylphenidate with clonidine. J Am Acad Child Adolesc Psychiatry 1999; 38: 614-16. 28. Fenichel RF. Combining methylphenidate and clonidine: the role of post-marketing surveillance. J Child Adolesc Psychopharmacol 1995; 5: 15545. 29. Cantwell D, Swanson J, Connor D. Case study: adverse response to clonidine. J Am Acad Child Adolesc Psychiatry 1997; 36: 539-44. 30. Oberpaur B, Donoso A, Claveria C, Valverde C, Azocar M. Strychnine poisoning: an uncommon intoxication in children. Pediatr Emerg Care 1999; 15: 264-5. 31. Adam JC, Cheize P, Adam E Strychnine poisoning: about one case. JEUR 1999; 12: 128-30. 32. Steffee CH, Singh HK, Chitwood WR. Histologic changes in three explanted native cardiac valves following use of fenfluramines. Cardiovasc Pathol 1999; 8: 245-53. 33. Weissman NJ. Appetite suppressant valvulopathy: a review of current data. Cardiovasc Rev Rep 1999; 20: 146-55. 34. Adams C, Cohen A. Appetite-suppressant drugs and heart abnormalities. Arch Mal Coeur Vaiss 1999; 92: 1213-19. 35. Ewalenko M, Richard CL, Vandenbossche JL. Fenfluramine and cardiac valvular diseases. Rev Med Brux 1999; 20: 419-26. 36. Kancheda MK, Salti HI, Mulderink TA, Parker M, Bonow RO, Mehlman DJ. Echocardiographic prevalence of mitral and/or aortic regurgitation in patients exposed to either fenfluraminephentermine combination or to dexfenfluramine. Am J Cardiol 1999; 84: 1335-8. 37. Burger A J, Sherman HB, Charlamb M J, Kim J, Asinas LA, Flickner SR, Blackburn GL. Low prevalence of valvular heart disease in 226 phentermine-fenfluramine protocol subjects prospectively followed for up to 30 months. J Am Coil Cardiol 1999; 34: 1153-8. 38. Prasad A, Mehra M, Park M, Scott R, Uber PA, McFadden PM. Cardiac allograft valvulopathy: a case of donor-anorexigen-induced valvular disease. Ann Thorac Surg 1999; 68: 1840-1. 39. Shively BK, Roldan CA, Gill EA, Najarian T, Lora SB. Prevalence and determinants of valvulopathy in patients treated with dexfenfluramine. Circulation 1999; 100: 2161-7. 40. Weissman NJ, Tighe JF Jr., Gottdiener JS, Gwynne JT. Prevalence of valvular regurgitation associated with fenfluramine three to five months

10 after discontinuation of treatment. J Am Coll Cardiol 1999; 34: 2088-95. 41. Mangion JR, Habboub AA, Kamat BR, Tam SKC. Transesophageal echocardiography with pathological correlation in severe valvular disease associated with fenfluramine-phentermine. Echocardiography 1999; 16: 27-30. 42. Tovar EA, Landah DW, Borsari BE. Dose effect of fenfluramine-phentermine in the production of valvular disease. Ann Thorac Surg 1999; 67: 121314. 43. Garon CF, Oury JH, Duran CMG. Virus-like particles in the mitral and tricuspid valves explanted from a patient treated with fenfluraminephentermine. J Heart Valve Dis 1999; 8: 232. 44. Jefferson HG, Jayne DR. Peripheral vasculopathy and nephropathy in association with phentermine. Nephrol Dial Transplant 1999; 14: 1761-3. 45. Korkmaz C, Fresko I, Yazici H. A case of systemic sclerosis that developed under dexfenfluramine use. Rheumatology 1999; 38: 379-80. 46. Aeschiimann A, Truchis P, Khan MF. Scleroderma after therapy with appetite suppressants. Scand J Rheumatol 1990; 19: 88-9. 47. Sobel RM. Ruptured retroperitoneal aneurysm in a patient taking phentermine hydrochloride. Am J Emerg Med 1999; 17: 102-3. 48. Dowd J, Bailey D, Moussa K, Nair S, Doyle R, Culpepper-Morgan JA. Ischemic colitis associated with pseudoephedrine: four cases. J Gastroenterol 1999; 94: 2430-4. 49. Roberge ILl, Hirani KH, Rowland PL, Berkeley R, Krenzelok EE Dextromethorphan and pseudoephedrine induced agitated psychosis and ataxia. Case report. J Emerg Med 1999; 17: 285-8. 50. Soutullo CA, Cottingham EM, Keck PE Jr. Psychosis associated with pseudoephedrine and dextromethorphan. J Am Acad Child Adolesc Psychiatry 1999; 38: 1471-2. 51. Mourand I, Ducrocq X, Lacour JC, Taillandier L, Anxionnat R, Weber M. Acute reversible cerebral arteritis associated with parenteral ephedrine use. Cerebrovasc Dis 1999; 9: 355-7. 52. Gamlin E Freeman J, Winslow L, Berridge J, Vucevic M. The hemodynamic effects of propofol in combination with ephedrine in elderly (ASA groups 3 and 4). Anesth Intensive Care 1999; 27: 477-80. 53. Franklin QJ. Sudden death after typhoid and Japanese encephalitis vaccination in a male taking pseudoephedrine. Mil Med 1999; 164: 157-9. 54. McGleenon BM, Dynan KB, Passmore AP. Acetylcholinesterase inhibitors in Alzheimer's disease. Br J Clin Pharmacol 1999; 48: 471-80. 55. Schachter AS, Davis KL. Guidelines for the appropriate use of cholinesterase inhibitors in patients with Alzheimer's disease. CNS Drugs 1999; 11: 281-8. 56. Bums A, Russell E, Page S. New drugs for Alzheimer's disease. Br J Psychiatry 1999; 174: 476-9.

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57. Sandston TA. Metrifonate for Alzheimer's disease: is the next cholinesterase inhibitor better? Neurology 1999; 52: 675--6. 58. Bums A, Rossor M, Hecker J, Gauthier S, Petit H, Moiler HJ, Rogers SL, Friedhoff LT, and the International Donepezil Study Group. The effects of donepezil in Alzheimer's disease--results from a multinational trial. Dementia Geriatr Cogn Disord 1999; 10: 237-44. 59. Doody RS. Clinical profile of donepezil in the treatment of Alzheimer's disease. Gerontology 1999; 45 Suppl 1: 23-32. 60. Calvo-Romero JM, Ramos-Salado JL. Bradycardia sinusal sintomatica associada a donepecilo. Rev Neurol 1999; 28: 1071-2. 61. Babic T, Zurak N. Convulsions induced by donepezil. J Neurol Neurosurg Psychiatry 1999; 66: 410. 62. Hemingway-Eltomey JM, Lemer AJ. Adverse effects of donepezil in treating Alzheimer's disease associated with Down's syndrome. Am J Psychiatry 1999; 156: 1470. 63. Shepherd G, Klein-Schwartz W, Edwards R. Donepezil overdose: a ten-fold dosing error. Ann Pharmacother 1999; 33: 812-15. 64. Greene YM, Noviasky J, Tariot PN. Donepezil overdose. J Clin Psychiatry 1999; 60: 56-7. 65. Carder L. Donepezil and paroxetine: possible drug interaction. J Am Geriatr Soc 1999; 47: 1037. 66. Ringman JM, Cummings JL. Metrifonate (Trichlorfon): a review of the pharmacology, pharmacokinetics and clinical experience with a new acetylcholinesterase inhibitor for Alzheimer's disease. Expert Opin Invest Drugs 1999; 8: 463-74. 67. Dubois B, McKeith I, Orgogozo JM, Collins O, Meulien D, and MALT Study Group. A multicentre, randomized, double-blind, placebocontrolled study to evaluate the efficacy, tolerability and safety of metrifonate in patients with mild-to-moderate Alzheimer's disease: the MALT Study. Int J Geriatr Psychiatry 1999; 14: 97382. 68. Jann MW, Cyrus PA, Eisner LS, Margolin DI, Griffin T. Efficacy and safety of a loadingdose regimen versus a no-loading-dose regimen of metrifonate in the symptomatic treatment of Alzheimer's disease: a randomized double masked, placebo controlled trial. Clin Ther 1999; 21: 88102. 69. Gottwald MD, Rozanski RI. Rivastigmine, a brain region selective acetylcholinesterase inhibitor for treating Alzheimer's disease: review and current status. Expert Opin Invest Drugs 1999; 8: 1673-82. 70. Corey-Bloom J, Anand R, Veach J, for the ENA 713 B352 Study Group. A randomized trial evaluating efficacy and safety of ENA-713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease. Int J Geriatr Psychopharmacol 1998; 1: 55-65. 71. Rosier M, Anand R, Cicin-Sain A, for the Ex-

Central nervous system stimulants, drugs that suppress appetite elon Study Group. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomized trial. Br Med J 1999; 318: 633-40. 72. Forette F, Anand R, Gharabawi G. A phase II study in patients with Alzheimer's disease to assess the preliminary efficacy and maximum toler-

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ated dose of rivastigmine (Exelon| Eur J Neurol 1999; 6: 423-9. 73. Knopman DS. Metrifonate for Alzheimer's disease: is the next cholinesterase inhibitor better? Neurology 1998; 50: 1203-4. 74. Bayer T. Commentary: another piece of the Alzheimer's jigsaw. Br Med J 1999; 318: 639.

EJ. Cowen

2

Antidepressant drugs

GENERAL TOPICS Drug interactions Interactions of antidepressants with herbal medicines are being reported (lr). Herbal medicines are widely used for their psychotropic properties and patients may take herbal formulations in addition to conventional psychotropic drugs, such as antidepressants. Attention has been drawn to the possible occurrence of symptoms of the serotonin syndrome when St John's Wort is used in combination with serotonin potentiating antidepressants, such as SSRIs, trazodone, and nefazodone. Ginseng has been reported to cause mania, tremor, and headache in combination with conventional MAOIs. Finally, yohimbine can cause hypertension in patients taking tricyclic antidepressants. A drug history should include the use of herbal remedies before conventional treatments are prescribed.

cular disease (2c). These findings suggest that moclobemide at usual therapeutic doses carries a low risk relative to conventional MAOIs of producing significant blood pressure changes. D r u g interactions Rizatriptan is a 5HTIB/1D receptor agonist that is metabolized by MAO type A. In 12 young healthy volunteers moclobemide (300 mg/day for 4 days) potentiated the hypertensive effect of acute rizatriptan (10 mg orally) (3c). This was associated with a significant increase in the area under the curve of rizatriptan and its N-monodesmethyl metabolite (by 2.2- and 5.3-fold respectively). The authors suggested that moclobemide and rizatriptan should not be given together.

TRICYLIC ANTIDEPRESSANTS (SED-14, 44; SEDA-21, 10; SEDA-22, 11; SEDA-23, 16)

MONOAMINE OXIDASE INHIBITORS (MAOIs) (SED-14, 37; SEDA-21, 9; SEDA-23, 15) Cardiovascular Conventional irreversible monoamine oxidase inhibitors (MAOIs) are associated with a significant risk of postural hypotension and spontaneous hypertension. In a prospective drug utilization-observation study in 13 741 patients who received the reversible type A MAOI, moclobemide, in a variety of settings, including general practice, psychiatric out-patients, and psychiatric in-patients, there were few episodes of hypertension (0.11%, 95% CI = 0.06, 0.18%) or hypotension (0.04%, 95% CI = 0.02, 0.10%) and episodes were mostly associated with underlying cardiovas9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

Cardiovascular The diagnosis of depression and the use of antidepressant medication are both associated with an increased risk of myocardial infarction. The relative contribution of these two factors is uncertain. In a case-control study of 2247 subjects, taking antidepressants was associated with a 2.2-fold (CI = 1.3, 3.7) increase in the risk of myocardial infarction (4c). This increased risk seemed to be accounted for entirely by the use of tricyclic antidepressants, because selective serotonin reuptake inhibitors were not associated with an increased risk, although the confidence intervals were wide (relative risk 0.8, CI = 0.2, 3.5). These findings support the usual clinical advice that tricyclic antidepressants are best avoided in those with known cardiovascular disease or significant risk factors. Nervous system The serotonin syndrome is usually associated with the use of combinations

Antidepressantdrugs

Chapter2

of drugs that potentiate brain serotonin function. Rarely the syndrome can be associated with the use of a single agent, such as clomipramine, a tricyclic antidepressant with potent serotonin re-uptake inhibitor properties (5A). A 60-year-old woman with a history of hypertension, type 2 diabetes mellitus, and depression had been taking clomipramine 200 mg/day for 8 months. Three months before admission the dose was increased to 250 mg/day. Her other medication consisted of glibenclamide 7.5 mg/day, lisinopril 5 rag/day, and clonazepam 0.5 mg/day. On the day of admission, without any change in medications or other precipitants, she began to feel confused and weak. She became pyrexial (41.6~ C), confused, and tremulous, with myoclonic jerking. The combined plasma concentrations of clomipramine and desmethylclomipramine were 2230 nmol/1, somewhat greater than the usual target range (below 1900 nmol/l). Within hours of her initial presentation her condition deteriorated, with seizures, ventricular tachycardia, and disseminated intravascular coagulation. Rhabdomyolysis led to acute renal insufficiency, which required dialysis. She remained severely ill over the next 4 weeks and eventually died of opportunistic Gram-negative infections. This case illustrates that the serotonin syndrome can occasionally occur apparently spontaneously in patients taking a single serotonergic medication. The authors were unable to find any reason why the syndrome developed so catastrophically when it did, except for the modestly increased concentrations of clomipramine and its metabolite. The neuroleptic malignant syndrome appears to be clinically related to the serotonin syndrome, in that it features hyperpyrexia and disturbances of consciousness, but patients normally have muscle rigidity rather than myoclonic jerking. The neuroleptic malignant syndrome is classically associated with antipsychotic drugs and is usually attributed to excessive dopamine D2 receptor blockade. However it can rarely occur with other medications, including tricyclic antidepressants. A 62-year-old man was found unresponsive in his apartment. He had a past history of bipolar disorder, for which he was taking nortriptyline and sodium valproate (dosages not stated). On admission to hospital his rectal temperature was 107.1~ F and he had increased muscle tone. He was intubated and cooled with ice packs. His creatine kinase activity was raised (1046 IU/1) but valproate and nortriptyline concentrations were within the target ranges. Extensive investigations, including biochemical screens and

13 brain scans, showed no clear cause for his condition. Shortly afterwards he developed disseminated intravenous coagulation and died. The authors concluded that the features of the illness were consistent with nortriptylineinduced neuroleptic malignant syndrome (6A). However, a contributory role for sodium valproate was also possible. Skin Hyperpigmentation is a recognized adverse effect of the antipsychotic drug, chlorpromazine. Four cases of hyperpigmentation have been described in patients taking the structurally-related tricyclic antidepressant, imipramine (7A). All were women and had been taking imipramine for at least 2 years. The hyperpigmentation occurred in a photodistribution on the face, arms, and the backs of the hands. In two patients who discontinued imipramine the hyperpigmentation resolved within a year. The authors speculated that the pigment might be due to the deposition of melanin in an unusual form, possibly in a complex with a metabolite of imipramine. Fetotoxieity Infants born to mothers taking tficyclic antidepressants may develop "jitterin e s s,' in the first few days of life ( 8A) . A healthy male infant (weight 3370 g) was born to a mother who had been taking clomipramine (100 mg/day) throughout pregnancy. On the second day after delivery, the child was jittery and on the fifth day he developed myoclonic jerking of his arms and legs. There was no epileptic activity on a 10-channel electroencephalogram, and clonazepam and phenobarbital did not suppress the movements. However, the movements were suppressed by a single dose of intravenous clomipramine (0.5 mg). The myoclonus recurred only occasionally over the next 4 days. Examination at 1 month later was normal, apart from mild jitteriness in response to touch. Maternal clomipramine use is associated with seizures in neonates but the present case appears to have been caused by a withdrawal state that was relieved by clomipramine administration.

14

Chapter 2

P.J. Cowen

SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs)

cardiac conduction. There are also a few reports of fluoxetine-induced bradycardia (1 lC).

(SED-14, 67; SEDA-21, 11; SEDA-22, 11; SEDA-23, 17)

Nervous system As noted above, treatment

A meta-analysis of 20 short-term studies of five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) has been published (9M). There were no overall differences in efficacy, but fluoxetine had a slower onset of action. Analysis of tolerability showed the expected adverse effects profile, the most common adverse event being nausea, followed by headache, dizziness, and tremor. The rate of withdrawal from treatment because of adverse effects was significantly greater with fluvoxamine (RR = 1.9; CI = 1.2, 3.0). Additional data available from the UK Committee on Safety of Medicines suggested that withdrawal reactions were most common with paroxetine and least common with fluoxetine (presumably because of the long half-life of its active metabolite norfluoxetine). There were more gastrointestinal reactions to fluvoxamine and paroxetine. This pattern was reflected in prescription-event monitoring data. Citalopram and sertraline were least likely to cause drug interactions, but citalopram had been implicated more often in fatal overdoses. Cardiovascular The effects of fluoxetine (20 mg/day for 12 weeks) on sitting and standing blood pressures have been reported (10c). Fluoxetine modestly but significantly lowered sitting and standing systolic and diastolic blood pressures by about 2 mmHg. Patients with pre-existing cardiovascular disease showed no change. This study confirms that fluoxetine has little effect on blood pressure in physically healthy depressed patients and in those with moderate cardiovascular disease. As noted above, there has been some concern about the cardiovascular safety of citalopram, mainly because of animal studies showing effects on cardiac conduction. Bradycardia (34 bpm) with a prolonged QTc interval of 463 msec occurred in a patient taking citalopram 40 mg/day (11A). The bradycardia resolved when the citalopram was withdrawn. The patient also had alcohol dependence and evidence of cardiomyopathy; presumably this may have potentiated the effect of citalopram on

with serotonin potentiating drugs in usual therapeutic doses can sometimes produce the serotonin syndrome. There are also case reports of this reaction with single doses of SSRIs (12A). An ll-year-old boy was brought to the emergency room about 2 hours after taking a single tablet of fluvoxamine (50 mg) prescribed for treatment of attention-deficit disorder. He was also taking benzatropine and perphenazine (dosages not stated). On arrival he was agitated and unresponsive, with bilateral ankle clonus, muscle rigidity, fasciculations, and profuse sweating. His temperature rose to 39.7~ C. He was paralysed, intubuated, and ventilated, after which his condition improved. Two days after admission he had fully recovered. The dopamine receptor antagonist properties of perphenazine may have played a part in producing the syndrome in this case, but a less severe case of serotonin syndrome after a single dose of sertraline 100 mg has been reported in a 16-year-old girl (13A). The syndrome in this case responded to a single 4 mg dose of the serotonin antagonist, cyproheptadine. The same authors also reported therapeutic benefit from cyproheptadine in a case of serotonin syndrome in a 2-year-old girl who accidentally swallowed ten 50-mg tablets of sertraline (14A). Psychiatric Like other antidepressants SSRIs can sometimes cause mania, but in patients with mood disorders it can be difficult to decide whether or not the mood change reflects a drug-induced effect or a spontaneous upswing. In three children (two aged 9 years and one aged 10 years) who took paroxetine, 10-20 mg/day for the treatment of childhood obsessive-compulsive disorder, symptoms of mania, including overactivity, pressure of speech, irritability, and antisocial behavior, occurred within 3 weeks of starting paroxetine and remitted afterparoxetine withdrawal or dosage reduction (15"). Symptoms of mania are rare in childhood, suggesting that the elevated mood in these cases was a direct effect of the paroxetine.

Hematologic Fluoxetine has been reported to cause neutropenia (SEDA-22, 15) and this has now been reported with paroxetine in a pa-

Antidepressant drugs

Chapter2

tient whose white cell count fell to 2.9 • 109/1 (neutrophils 1.37 x 109/1) (16A). The white count gradually recovered over 6 weeks after paroxetine withdrawal.

15 gest that anecdotal reports of treatment benefit in SSRI-induced sexual dysfunction should be regarded with caution.

Teratogenicity and fetotoxicity

Gastrointestinal SSRIs may predispose to bleeding disorders, perhaps through their ability to block the uptake of serotonin into platelets. In a case--control study, current exposure to SSRIs was associated with an increased risk of upper gastrointestinal bleeding (RR = 3.0; CI --- 2.1, 4.4) (17c). The risk was substantially greater in subjects taking both SSRIs and NSAIDs (RR = 16; CI = 6.6, 37). However, there was also an increased risk of bleeding with trazodone (RR = 8.6; CI = 2.1, 35), which does not block the uptake of 5-HT in therapeutic doses. Thus, while the association between certain kinds of antidepressant drugs and upper gastrointestinal bleeding appears to be real, the mechanism requires further study.

Tricyclic antidepressants appear to be generally free of teratogenetic effects, but the status of newer antidepressants is unclear. Since 1993 four controlled prospective studies of antidepressant exposure during pregnancy have been published, involving about 400 women, most of whom took fluoxetine at various stages during pregnancy (21R). There was no evidence that fluoxetine or other SSRIs caused an increase in intrauterine death, significant birth defects, or growth impairment. Follow-up behavioral studies of infants exposed to SSRIs during pregnancy also showed no difference from controls. Withdrawal effects of SSRI treatment may be apparent in neonates shortly after delivery. These include jitteriness, hypoglycemia, hypothermia, and respiratory distress (22r).

Liver SSRIs are generally believed not to be associated with hepatotoxicity. However, in a post-marketing surveillance study there were some cases in which fluoxetine alone appeared to have precipitated hepatitis, which remitted when treatment was withdrawn (18c). It is recognized that fluoxetine can cause mild increases in liver enzymes, with a rate in clinical trials of about 0.5%. Rarely this can progress to hepatitis. Hepatitis has also been reported with paroxetine (SEDA-21, 12). Skin The Stevens-Johnson syndrome has rarely been described with fluvoxamine and fluoxetine. A case has been reported in a 96year-old woman who had been taking sertraline (dosage not stated) for 3 weeks (19A). The lesions involved the skin, oral mucosa, and conjunctiva. The eruption disappeared within 7 days of sertraline withdrawal. Sexual function SSRIs can cause disturbances in sexual function, including reduced

sexual interest and orgasmic dysfunction. Various treatments have been suggested to be helpful (see SEDA-23, 18), but controlled trials are lacking. In a placebo-controlled, parallelgroup study of buspirone and amantadine in 57 patients with fluoxetine-induced sexual dysfunction, there was an overall improvement in all three treatment groups and no significant differences between them (20c). These data sug-

Drug interactions SSRIs cause numerous drug interactions, because they inhibit the activity of certain cytochrome P450 enzymes to a greater or lesser extent (SEDA-22, 13). In 31 healthy male and female volunteers (mean age 28 years) the ability of four SSRIs (fluoxetine, fluvoxamine, paroxetine, and sertraline) to inhibit CYP2D6 activity was assessed in vivo, as judged by the dextromethorphan test (23c). All were extensive metabolizers of dextromethorphan. After 8 days treatment at therapeutic doses, four of eight paroxetine-treated and five of eight fluoxetine-treated subjects had become poor metabolizers, presumably because of the inhibitory effect of the two SSRIs on CYP2D6 activity. In contrast, none of the eight fluvoxamine-treated or seven sertraline-treated subjects showed this effect. This in vivo study has confirmed the potent inhibitory effect of fluoxetine and paroxetine on CYP2D6 and the relative sparing by fluvoxamine and sertraline. However, fluvoxamine is a potent inhibitor of CYP1A2 and CYP3A3/4 (SEDA-22, 13). In addition, at higher doses (over 100 mg/day at steady state) sertraline can inhibit CYP2D6. As noted above, citalopram appears the least likely of the SSRIs to inhibit CYP enzymes. However, in a 39-year-old man with a schizoaffective disorder, citalopram (40 mg/day) appeared to result in raised plasma clozapine concentrations and increased adverse

16 effects (24A). The adverse effects settled within 2 weeks of a reduction in citalopram dosage to 20 mg/day with a corresponding 25% fall in clozapine concentrations. It is possible that at higher doses, citalopram can increase clozapine concentrations, perhaps through inhibition of CYP1A2 or CYP3A4. Fluvoxamine inhibits CYP1A2, and a low dosage (50 mg/day) produced a 225% increase in plasma thioridazine concentrations in 10 patients with schizophrenia (25c). This was not reflected in an increased incidence of clinical adverse events; however, thioridazine prolongs the QTc interval, which was not measured. Drug interactions leading to the serotonin syndrome usually result from pharmacodynamic mechanisms. However, the antibiotic erythromycin may have precipitated the serotonin syndrome in 12-year-old boy who had been taking sertraline (37.5 mg/day) for 5 weeks for the treatment of obsessivecompulsive disorder (26A). Within 4 days of starting erythromycin (200 mg bd) the child began to feel anxious; this was followed over the next 10 days by panic, restlessness, irritability, tremulousness, and confusion. These symptoms resolved within 72 hours of withdrawal of sertraline and erythromycin. Erythromycin inhibits certain CYP isoenzymes, and the authors proposed that in this case it had inhibited sertraline metabolism by inhibiting CYP3A. This could have led to increased concentrations of sertraline and signs of serotonin toxicity. Unfortunately sertraline concentrations were not measured to confirm this interesting suggestion. Drags used in the treatment of acute migraine, such as sumatriptan and rizatriptan, are 5-HTIB/1D receptor agonists and could theoretically interact with SSRIs to cause serotonin toxicity. Although case series have suggested that sumatriptan can be safely combined with SRRIs, there are occasional reports of toxicity (SEDA-22, 14). Treatment of 12 healthy volunteers with paroxetine (20 mg/day for 14 days) did not alter the pharmacokinetics or pharmacodynamic effects of an acute dose of rizatriptan (10 mg orally) (27c). These data are reassuring, but (as with sumatriptan) it is possible that sporadic cases of 5-HT neurotoxicity could still occur when rizatriptan is combined with an SSRI.

Chapter 2 OTHER

P.J. Cowen

ANTIDEPRESSANTS

Bupropion

(SED-14, 60; SEDA-23, 20)

Bupropion is licensed in the USA for the treatment of depression, and has recently been licensed in the United States and Europe for smoking cessation. The adverse effects profile of bupropion includes insomnia, agitation, tremor, nausea, and dizziness. Randomized controlled trials have shown that bupropion is less likely to cause sexual dysfunction than SSRIs (28 C, 29c). Nervous system Bupropion has been reported to mimic transient ischemic attacks (30"-). A 67-year-old man with a strong history of ischemic heart disease, who had been smoking 20 cigarettes a day for many years, started to take bupropion (100 mg tds) as an aid to smoking cessation. One week later he had episodes of disorientation, a tingling sensation over his body, and roaring sounds in his ears. He ~vas admitted to hospital, where MRI scanning and angiography showed evidence of previous strokes. His current episodes were ascribed to transient ischemic attacks. He had stopped taking bupropion while in hospital and then restarted it 2 days after discharge, when the same symptoms recurred. He then stopped taking bupropion completely and over the next 9 months had no further neurological episodes. It is possible that these symptoms were entirely due to bupropion, but more probably the bupropion interacted in some way with the patient's established cerebrovascular disease. Psychiatric Bupropion potentiates dopamine neurotransmission and at higher doses can cause toxic delirium and psychosis, particularly in patients with a history of psychosis and those taking other dopaminergic medications. A 79year-old man developed a paranoid psychosis with auditory hallucinations during treatment with bupropion (100 mg tds) (31A). The symptoms remitted with reduction of the dose of bupropion and the introduction of haloperidol 5 mg/day. Paranoid ideas and hallucinations can occur during the course of a severe depressive episode, but in this case the patient's mood was gradually improving, so a link with bupropion seems more likely. It seems prudent to dose bupropion conservatively in elderly patients.

Antidepressant drugs Immunologic

Drugs can occasionally cause a

serum sickness-like reaction. Two cases have been reported in association with bupropion when used as an aid to smoking cessation (32 A, 33A). Both patients developed localized swellings of the fingers and hands, urticaria, and arthralgia. In both cases treatment with antihistamines and corticosteroids produced rapid relief of symptoms. Serum sickness reactions to drugs are rare, and it will be important to find out whether bupropion carries an increased risk of this unusual reaction.

Nefazodone

17

Chapter2

(SED-14, 64; SEDA-22, 16;

SEDA-23, 20)

Liver There have been three reports of significant liver toxicity in association with nefazodone. A 27-year-old man developed hepatitis (with raised bilirubin and liver enzymes) without overt jaundice after 12 weeks treatment with nefazodone 200 mg/day (34A). No other cause for the hepatitis could be established and the abnormal liver function tests settled 4 weeks after nefazodone withdrawal They became abnormal again one week after nefazodone rechallenge and settled once again on withdrawal. However, four other female patients, aged 1673 years, developed catastrophic liver failure during nefazodone treatment (35 A, 36A). Two died, one survived after liver transplantation, and one improved sufficiently to obviate the need for transplantation. The duration of nefazodone treatment before the onset of symptoms was 7-28 weeks. The patients had no history of liver disease and other causes were excluded as far as possible. There was a common histological picture of prominent necrosis in centrilobular areas (zone 3). These severe reactions, although rare, cause concern. There are reports to national regulatory agencies of abnormal liver function tests in patients taking nefazodone and one earlier report of an 80-year-old man who developed acute fatal liver failure while taking nefazodone 50 mg/day (35A). Sexual function A 48-year-old woman developed clitoral priapism on the first day of nefazodone treatment (100 mg) (37A). The problem persisted for another day, after which she discontinued the nefazodone and the priapism subsided. Clitoral priapism has been repor-

ted with other antidepressants, including SSRIs both alone and in combination with trazodone. In men, trazodone rather than nefazodone is occasionally associated with priapism (SEDA-21, 14).

Drug withdrawal

Discontinuation of SSRIs causes significant withdrawal symptoms (see SEDA-22, 12). Withdrawal reactions have been less often described after discontinuation of nefazodone. A 22-year-old woman gradually increased her dose of nefazodone to 400 mg/day over 3 weeks (38A). One week later she abruptly discontinued treatment. About 48 hours later she began to have nausea, vomiting, fatigue, headache, myalgia, restlessness, dizziness, nightmares, emotional lability, and anxiety. These symptoms continued unabated for a further 48 hours, after which they remitted a few hours after nefazodone was restarted. The symptoms the patient experienced were very similar to those of severe SSRI-induced withdrawal, as were those described in two further case reports (39 A, 40A). Like SSRIs, it seems prudent to withdraw nefazodone treatment slowly and to be aware of the possibility of SSRI-like withdrawal symptoms.

Drug interactions Combinations of serotonin agents produce serotonin toxicity, and a case of serotonin syndrome occurred when nefazodone (200 mg/day) was combined with fluoxetine (40 mg/day) in a 50-year-old man (41A). The toxic symptoms settled 3 days after withdrawal of both antidepressants. Nefazodone is a potent inhibitor of CYP3A4 (SEDA-22, 13). When nefazodone (400 mg/day for three weeks) was added to clozapine treatment in six patients with schizophrenia there was no significant change in plasma clozapine concentrations (42c). This finding suggests that CYP3A4 does not play a major role in the metabolism of clozapine and that nefazodone may be a suitable adjunctive treatment for depression in clozapine-treated patients. Significant drug interactions between nefazodone and other drugs that are substrates for CYP3A4 have been reported (see SEDA22, 13). These include benzodiazepines, carbamazepine, and ciclosporin (43c). Recently nefazodone has been reported to produce myositis and rhabdomyolysis in patients tak-

18 ing pravastatin and simvastatin (44c). The postulated mechanism involves inhibition of CYP3A4, leading to reduced clearance of the HMG-CoA reductase inhibitors and muscle toxicity.

Reboxetine (SED-14, 64) Drug interactions

Reboxetine, a selective noradrenaline re-uptake inhibitor, is metabolized by CYP3A4. In 11 healthy volunteers ketoconazole, an inhibitor of CYP3A4, increased the plasma area under the curve of reboxetine by about 50% and increased the half-life (45c). The adverse effects profile of reboxetine was not altered by ketoconazole, but the finding suggests that reboxetine should be used with caution in combination with drugs that inhibit CYP3A4, for example nefazodone and fluvoxamine (see above). In the pharmacological management of patients with treatment-resistant depression, it is a common strategy to combine a drug that selectively inhibits noradrenaline re-uptake (for example, reboxetine) with one that selectively inhibits the re-uptake of serotonin (for example, an SSRI). As well as the hoped-for pharmacodynamic interaction, a kinetic interaction can also occur because of the effect of SSRIs on CYP450 enzymes (see above). The effect of combined treatment with reboxetine (8 mg/day) and fluoxetine (20 mg/day) has been compared with each treatment given alone for 8 days in 30 healthy volunteers in a parallel design (46c). There was no potentiation of adverse effects by the combination. Fluoxetine increased the plasma area under the curve of reboxetine by 20%, but this was not statistically significant. The authors suggest that the combination of fluoxetine and reboxetine should have minimal adverse impact in depressed patients. However, the major metabolite of fluoxetine, norfluoxetine, is also an inhibitor of CYP3A4 and would not have reached steady-state concentrations during the time of the study. This suggests that caution might still be needed during longerterm use of this combination in depressed patients.

Trazodone (SED-14, 64) Drug overdose Trazodone is less cardiotoxic than tricyclic antidepressants, although it has rarely been reported to cause ventricular ta-

Chapter 2

P.J. Cowen

chycardia. A patient who took an overdose of trazodone (3 g) had sinus bradycardia (57 bpm) and a prolonged QTc interval (607 msec). The abnormal QTc interval gradually normalized over the next 3 days with supportive hospital treatment (47A). This suggests that overdoses of trazodone (or perhaps therapeutic doses in predisposed individuals) could be associated with QTc prolongation. Drug interactions Trazodone is related to nefazodone (see above) but probably potentiates 5-HT neurotransmission less. Trazodone is often added to MAOIs and SSRIs at low doses (50-150 mg/day) as a hypnotic, but such combinations can rarely provoke the serotonin syndrome. The serotonin syndrome occurred in 60year-old woman when the addition of trazodone 50 mg/day to nefazodone 500 mg/day caused confusion, restlessness, sweating, and nausea after the third day of treatment (48A). The symptoms settled quickly on withdrawal of both antidepressants. In a 53-year-old man trazodone produced a clinically significant increase in carbamazepine concentrations (49A). This suggests that trazodone inhibits CYP3A4, and it should be used with caution in combination with carbamazepine.

Venlafaxine (SED-14, 66; SEDA-21, 13; SEDA-22, 17; SEDA-23, 20)

Cardiovascular In physically healthy subjects venlafaxine has a generally benign cardiovascular profile, although hypotension and dose-related hypertension have been reported (SEDA-23, 20). Venlafaxine is often used in high doses in patients with treatment-resistant depression. If there is continuing failure to respond, ECT might be used, often in combination with venlafaxine. A 73-year-old woman taking venlafaxine (112.5 mg/day) had sustained hypertension for several hours after her first ECT treatment (50A). However, ECT can cause transient hypertension, and the patient had essential hypertension controlled by bendroflumethiazide. It is therefore possible that the reaction observed might have occurred had she not been taking venlafaxine. Nevertheless, the fact that venlafaxine can cause hypertension when used as sole treatment suggests that blood pressure

Antidepressant drugs

Chapter2

should be monitored carefully in patients receiving ECT and venlafaxine together, particularly if there is a history or current evidence of hypertension. Venlafaxine has not been studied systematically in patients with cardiovascular disease, although there are reports that older patients can have clinically significant disturbances of cardiac rhythm (51CR). A 69-year-old woman with stable angina and mild single vessel coronary artery disease developed acute myocardial ischemia within a week of starting venlafaxine (75 mg/day) (5 lCR). Taken together with the information that the authors cited in their review, the current data suggest that venlafaxine should be used with caution in patients with established cardiovascular disease. A 44-year-old woman developed weakness with abnormal liver function tests (AsT activity of 661 IU/L) about 6 months after starting to take venlafaxine (150 mg/day) (52A). Biopsy showed confluent necrosis in zone 3, with unaffected portal tracts. No other cause for the hepatitis could be found. The clinical and biochemical features resolved within 12 weeks of withdrawal of venlafaxine. Raised liver enzymes have been rarely found in patients taking venlafaxine, and it appears that hepatitis may also be rare adverse effect. Liver

Drug overdose Venlafaxine is generally regarded as being reasonably safe in overdose relative to conventional tricyclic antidepressants. Deaths have been described previously in conjunction with venlafaxine overdose, but in combination with other agents and alcohol. However, two fatal cases of overdosage in which venlafaxine was the only agent detected post-mortem have been reported (53A). It therefore appears that venlafaxine can occasionally prove fatal in overdosage, probably through cardiac conduction abnormalities and seizures (53A, 54A). It is possible that poor metabolizers may be especially liable to toxicity (see below). Drug interactions Venlafaxine is metabolized by CYP2D6. In healthy volunteers the oral clearance of venlafaxine (37.5 mg/day for 2 days) was 4-fold less in poor metabolizers (n = 6) than extensive metabolizers (n ---- 8) (55c). Administration of the CYP2D6 inhibitor quinidine, 200 mg/day for 2 days, to the extensive metabolizers reduced the oral clearance of

19 venlafaxine to levels in seen in poor metabolizers. Quinidine had no effect on venlafaxine clearance in subjects who were poor metabolizers before treatment. The authors suggested that poor metabolizers may be at particular risk of venlafaxine toxicity, as could subjects who take inhibitors of CYP2D6. Four depressed patients (age range 21-73 years) had anticholinergic adverse effects when venlafaxine 37.5 mg/day was added to fluoxetine 20 mg/day (56c). Venlafaxine does not have direct anticholinergic effects, but could cause them indirectly as a result of its ability to increase noradrenergic neurotransmission. This effect would be expected only at much higher doses of venlafaxine than those used here, which led the author to suggest that in the presence of CYP2D6 inhibition by fluoxetine, venlafaxine concentrations could have been substantially higher than expected. Unlike SSRIs, venlafaxine only weakly inhibits CYP2D6. Venlafaxine (up to 150 mg/day for 10 days) modestly but significantly increased the plasma area under the curve of a single dose of risperidone (1 mg) in 38 healthy volunteers in an open longitudinal design, but did not affect its active metabolite, 9-hydroxyrisperidone (57c). The authors suggested that their study had shown a small potentiating effect of venlafaxine treatment on risperidone availability, probably through weak inhibition by venlafaxine of CYP2D6. Venlafaxine is therefore less likely to increase risperidone concentrations than fluoxetine and paroxetine. Venlafaxine (150 mg/day) did not alter the disposition of caffeine, a probe of CYP1A2 activity (58c). This suggests that at therapeutic doses venlafaxine, in contrast to fluvoxamine (SEDA-22, 13) does not inhibit CYP1A2. Drugs that potentiate the function of serotonin, such as venlafaxine, can produce pharmacodynamic interactions with dopamine receptor antagonists, perhaps because serotonin pathways can inhibit dopamine neurotransmission. A 44-year-old man who had been taking the dopamine receptor antagonist trifluoperazine (3 mg/day) developed acute neuroleptic malignant syndrome after a single dose of venlafaxine 75 mg (59A). The syndrome resolved 24 hours after the withdrawal of both drugs and subsequently trifluoperazine was re-introduced uneventfully. This case suggests that venlafaxine can rarely increase the risk of neuroleptic

20 malignant syndrome with dopamine receptor antagonists. However, this combination of drugs is often used and it is not understood

Chapter 2

PJ. Cowen

why only very few patients appear to be susceptible to this reaction, and then only on some occasions.

REFERENCES 1. Fugh-Berman A. Herb~lrug interactions. Lancet 2000; 355: 134-8. 2. Delini-Stula A, Baier D, Kohnen, R, Laux G, Philipp M, Scholz, H-J. Undesirable blood pressure changes under naturalistic treatment with moclobemide, a reversible MAO-A inhibitor--results of the drug utilization observation studies. Pharmacopsychiatry 1999; 32: 61-7. 3. Van Haarst AD, Van Gerven JMA, Cohen AF, De Smet M, Sterrett A, Birk KL, Fisher AL, De Puy ME, Goldberg MR, Musson DG. The effects of moclobemide on the pharmacokinetics of the 5HTIB/1D agonist rizatriptan in healthy volunteers. Br J Clin Pharmacol 1999; 48: 190---6. 4. Cohen HW, Gibson G. Alderman MH. Excess risk of myocardial infarction in patients treated with antidepressant medications: association with use of tricyclic agents. Am J Med 2000; 108: 2-8. 5. Rosebush PI, Margetts P, Mazurek ME Serotonin syndrome as a result of clomipramine monotherapy. J Clin Psychopharmacol 1999; 19: 285-7. 6. June R, Yunus M, Gossman W. Neuroleptic malignant syndrome associated with nortriptyline. Am J Emerg Med 1999; 17: 736-7. 7. Ming ME, Bhawan J, Stefanato CM, McCalmont TH, Cohen LM. Imipramine-induced hyperpigmentation: four cases and a review of the literature. J Am Acad Dermatol 1999; 40: 159-66. 8. Bloem BR, Lammers GJ. Clomipramine withdrawal in newborns. Arch Dis Child Fetal Neonatal Ed 1999; 81: F77. 9. Edwards JG, Anderson I. Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs 1999; 57: 507-33. 10. Amsterdam JD, Garcia-Espana E Fawcett J, Quitkin FM, Reimherr FW, Rosenbaum JF, Beasley C. Blood pressure changes during shortterm fluoxetine treatment. J Clin Psychopharmacol 1999; 19: 9-14. 11. Favre M-P, Sztajzel J, Bertschy G. Bradycardia during citaiopram treatment: a case report. Pharmacol Res 1999; 39: 149-50. 12. Gill M, LoVecchio F, Selden B. Serotonin syndrome in a child after a single dose of fluvoxamine. Ann Emerg Med 1999; 33: 457-9. 13. Mullins ME, Horowitz BZ. Serotonin syndrome after a single dose of fluvoxamine. Ann Emerg Med 1999; 34: 806-7. 14. Horowitz BZ, Mullins ME. Cyproheptadine for serotonin syndrome in an accidental pediatric sertraline ingestion. Pediatr Emerg Care 1999; 15: 325-7. 15. Diler RS, Avci A. SSRI-induced mania in obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 1999; 38: 6-7.

16. Moselhy HE Conlon W. Neutropenia associated with paroxetine, lr J Psychol Med 1999; 16: 75. 17. De Abajo FJ, Rodrfguez LAG, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. Br Med J 1999; 319: 1106-9. 18. Capell~i D, Bruguera M, Figueras A, Laporte J-R. Fluoxetine-induced hepatitis: why is postmarketing surveillance needed? Eur J Clin Pharmacol 1999; 55: 545-6. 19. Jan V, Toledano C, Machet L, Machet MC, Vaillant L, Lorette G. Stevens-Johnson syndrome after sertraline. Acta Dermatol Venereol 1999; 79; 401. 20. Michelson D, Bancroft J, Targum S, Kim Y, Tepner R. Female sexual dysfunction associated with antidepressant administration: a randomized placebo-controlled study of pharmacologic intervention. Am J Psychiatry 2000; 157: 23943. 21. Wisner KL, Gelenberg AJ, Leonard H, Zarin D, Frank E. Pharmacologic treatment of depression during pregnancy. J Am Med Assoc 1999; 282: 1264-9. 22. Gerola O, Fiocchi S, Rondini G. Rischi da farmaci antidepressivi in gravidanza: revisione della letteratura e presentazione di un caso di sospetta sindrome da astinenza da paroxetina in neonato. Riv Ital Pediatr 1999; 25: 216-18. 23. Alfaro CL, Lam YWE Simpson J, Ereshefsky L. CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraiine. J Clin Psychophannacol 1999; 19: 155-63. 24. Borba CP, Henderson DC. Citalopram and clozapine: potential drug interaction. J Clin Psychiatry 2000; 61: 301-2. 25. Carrillo JA, Ramos SI, Herraiz AG, Llerena A, Agundez JAG, Berecz R, Duran M, Berdtez J. Pharmacokinetic interaction of fluvoxamine and thioridazine in schizophrenic patients. J Clin Psychopharmacol 1999; 19: 494-9. 26. Lee DO, Lee CD. Serotonin syndrome in a child associated with erythromycin and sertraline. Pharmacotherapy 1999; 19: 894--6. 27. Goldberg MR, Lowry RC, Musson DG, Birk KL, Fisher A, DePuy E, Shadle CR. Lack of pharmacokinetic and pharmacodynamic interaction between rizatriptan and paroxetine. J Clin Pharmacol 1999; 39: 192-9. 28. Coleman CC, Cunningham LA, Foster V J, Batey SR, Donahue RMJ, Houser TL, Ascher JA. Sexual dysfunction associated with the treatment of depression: a placebo-controlled comparison of bupropion sustained release and sertraline treatment. Ann Clin Psychiatry 1999, 11: 205-15.

Antidepressant drugs 29.

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Croft H, Settle E, Houser T, Batey SR, Donahue

RMJ, Ascher JA. A placebo-controlled comparison of the antidepressant efficacy and effects on sexual functioning of sustained-release bupropion and sertraline. Clin Ther 1999; 21: 643-58. 30. Humma LM, Swims MP. Bupropion mimics a transient ischemic attack. Ann Pharmacother 1999; 33: 305-7. 31. Howard WT, Warnock JK. Bupropion-induced psychosis. Am J Psychiatry 1999; 156: 2017-18. 32. Peloso PM, Baillie C. Serum sickness-like reaction with bupropion. J Am Med Assoc 1999; 282: 1817. 33. Tripathi A, Greenberger PA. Bupropion hydrochloride induced serum sickness-like reaction. Ann Allergy Asthma Immunol 1999; 83: 165-6. 34. Schrader GD, Roberts-Thompson IC. Adverse effect of nefazodone: hepatitis. Med J Aust 1999; 170: 452. 35. Lucena MI, Andrade RJ, Gomez-Outes A, Rubio M, Cabello MR. Acute liver failure after treatment with nefazodone. Dig Dis Sci 1999; 44: 2577-9. 36. Aranda-Michel J, Koehler A, Bejarano PA, Poulos JE, Luxon BA, Khan CM, Ee LC, Balistreri WE Weber FL. Nefazodone-induced liver failure: report of three cases. Ann Intern Med 1999; 130: 285-8. 37. Brodie-Meijer CCE, Diemont WL, Buijs PJ. Nefazodone-induced clitoral priapism, lnt Clin Psychopharmacol 1999; 14: 257-8. 38. Rajagopalan M, Little J. Discontinuation symptoms with nefazodone. Aust NZ J Psychiatry 1999; 33: 594-7. 39. Lauber C. Nefazodone withdrawal syndrome. Can J Psychiatry 1999; 44: 285-6. 40. Kotlyar M, Golding M, Brewer ER, Carson SW. Possible nefazodone withdrawal syndrome. Am J Psychiatry 1999; 156:1117. 41. Smith DL, Wenegrat BG. A case report of serotonin syndrome associated with combined nefazodone and fluoxetine. J Clin Psychiatry 2000; 61: 146. 42. Taylor D, Bodani M, Hubbeling A, Murray R. The effect of nefazodone on clozapine plasma concentrations. Int Clin Psychopharmacol 1999; 14: 185-7. 43. Wright DH, Lake KD, Bruhn PS, Emery RW. Nefazodone and cyclosporine drug-drug interaction. J Heart Lung Transplant 1999; 18: 913-15. 44. Alderman CP. Possible interaction between nefazodone and pravastatin. Ann Pharmacother 1999; 33: 871. 45. Herman BD, Fleishaker JC, Brown MT. Ketoconazole inhibits the clearance of the enantiomers

21 of the antidepressant reboxetine in humans. Clin Pharmacol Ther 1999; 66: 374-9. 46. Fleishaker JC, Herman BD, Pearson LK, Ionita A, Mucci M. Evaluation of the potential pharmacokinetic/pharmacodynamic interaction between fluoxetine and reboxetine in healthy volunteers. Clin Drug Invest 1999; 18: 141-50. 47. Levenson JL. Prolonged QT interval after trazodone overdose. Am J Psychiatry 1999; 156: 969-70. 48. Margolese HC, Chouinard G. Serotonin syndrome from addition of low-dose trazodone to nefazodone. Am J Psychiatry 2000; 157: 1022. 49. S~inchez Romero A, Garcia Delgado R, Flores Pena M. Interaction between trazodone and carbamazepine. Ann Pharmacother 1999; 33: 1370. 50. West S, Hewitt J. Prolonged hypertension: a case report of a potential interaction between electroconvulsive therapy and venlafaxine, lnt J Psychiatry Clin Pract 1999; 3: 55-7. 51. Reznik I, Rosen Y, Rosen B. An acute ischaemic event associated with the use of venlafaxine: a case report and proposed pathophysiological mechanisms. J Psychopharmacol 1999; 13: 193-5. 52. Horsmans Y, De Clercq M, Sempoux C. Venlafaxine-associated hepatitis. Ann Intern Med 1999; 130: 944. 53. Jaffe PD, Batziris HP, Van der Hoeven P, DeSilva D, Mclntyre IM. A study involving venlafaxine overdoses: comparison of fatal and therapeutic concentrations in postmortem specimens. J Forensic Sci 1999; 44: 193-6. 54. Blythe D, Hackett LP. Cardiovascular and neurological toxicity of venlafaxine. Hum Exp Toxicol 1999; 18: 309-13. 55. Lessard E, Yessine M-A, Hamelin BA, O'Hara G, LeBlanc J, Turgeon J. Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans. Pharmacogenetics 1999; 9: 435-43. 56. Benazzi E Venlafaxine-fluoxetine interaction. J Clin Psychopharmacol 1999; 19: 96-8. 57. Amchin J, Zarycranski W, Taylor KP, Albano D, Klockowski PM. Effect of venlafaxine on the pharmacokinetics of risperidone. J Clin Pharmacol 1999; 39: 297-309. 58. Amchin J, Zarycranski W, Taylor KP, A1bano D, Klockowski PM. Effect of venlafaxine on CYP1A2-dependent pharmacokinetics and metabolism of caffeine. J Clin Pharmacol 1999; 39: 252-9. 59. Nimmagadda SR, Ryan DH, Atkin SL. Neuroleptic malignant syndrome after venlafaxine. Lancet 2000; 354: 289-90.

J.W. Jefferson

3 The continuing decline of lithium as the favored drug for bipolar disorder in the USA has been reaffirmed by the publication of Medication Treatment of Bipolar Disorder 2000 (1R), a revision of The Expert Consensus Guidelines first published in 1996 (2R). While rankings for lithium remained virtually unchanged in 2000, divalproex (valproate) rose to the level of lithium as a first-line option for euphoric mania, and it continued to be preferred over lithium for mixed or dysphoric mania, mania with psychosis, and rapid cycling. If divalproex was used successfully to treat an acute manic episode, it was also the preferred longterm maintenance treatment, despite a paucity of data to support its long-term efficacy--the recently published 1-year maintenance comparison of divalproex and lithium found no benefit of either drug over placebo (3c). Schou (4R) has argued that "lithium is not an obsolete drug", citing evidence that it is the only drug with demonstrated effectiveness in reducing mortality, particularly from suicide, during long,term use (5c-7c). He has also pointed out the flawed logic used by those who generalize from studies in which lithium failures (efficacy or tolerability) respond to an alternative drug to conclude that the alternative would be a better treatment under all circumstances. Since such a design allows only equal or better outcome for the second treatment, it should not be the basis for generalizations. Preliminary evidence now suggests that valproate treatment failures have a reasonable likelihood of responding to lithium (8c). The adverse effects of lithium have been reviewed in several recent articles, but none provided great detail (9R--12R).

Lithium rial block, and sinus arrest, continue to accumulate in association with both toxic (13 A) and therapeutic (14 A, 15 A) serum lithium concentrations. The rhythm disturbance normalized in some cases when lithium was stopped (13 A, 15A), persisted despite discontinuation (14A), or was treated with a permanent cardiac pacemaker (15A). Of historical interest is the observation that the first patient treated with lithium by Cade developed manifestations of toxicity in 1950, including bradycardia (16A). A study of cardiomyopathies found a specific cause in 614 of 1230 patients (the remainder were diagnosed as idiopathic). One was attributed to lithium but no details were provided (17c). An extension of a previously published study (18 c) added a third comparator group of 18 hypercalcemic non-lithium treated patients and compared them with 12 hypercalcemic lithium patients, 40 normocalcemic lithium patients, and 20 normocalcemic bipolar patients taking anticonvulsant mood stabilizers (19c). Both hypercalcemic groups had more conduction abnormalities than the other two groups but did not differ from each other in this regard. While the authors concluded that both lithium and calcium played important roles in the dysrhythmias, their data suggested that hypercalcemia alone was the critical factor.

Cardiovascular Reports of sinus node dysfunction, as manifested by bradycardia, sinoat-

Respiratory A 37-year-old man who had taken lithium and sulpiride for 14 years and who was a long-time smoker without respiratory symptoms or a history of asthma had lithium withdrawn because of an asymptomatic bradycardia (44 bpm) (14A). Six weeks later he developed symptoms of asthma, including nocturnal cough, exertional wheezing, increased airway resistance, and a low FEVb attributed to lithium discontinuation.

9 2001 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual24 J.K. Aronson, ed.

Ear, nose, throat In two patients profuse paroxysmal rhinorrhea improved when lith-

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ium was withdrawn (20A). The rhinorrhea was thought to be a manifestation of mesotemporal lobe epilepsy that had been worsened by lithium. Nervous system (see also Drug overdose) The complex relation between subsyndromal manifestations of bipolar disorder, particularly cognitive dysfunction, and the role that lithium might play in alleviating or aggravating this problem has been discussed in a thoughtful review (21R). When 67 patients taking lithium who complained of cognitive deterioration were treated with aniracetam, 97% reported subjective improvement (22c). A 65-year-old man taking lithium and doxepin developed moderately severe multidirectional myoclonic jerking of the arms with electroencephalographic findings suggestive of cortical origin shortly after an increase in lithium dosage (23A). A proconvulsive effect of lithium was also suggested in two patients purported to have temporal lobe epilepsy who improved when carbamazepine replaced lithium (20A). Dehydration secondary to lithium-induced nephrogenic diabetes insipidus was thought to be the cause of a superior sagittal sinus thrombosis in a 30-year-old woman who presented with confusion, papilledema, and a left hemiparesis (24A). An 86-year-old man with a serum lithium concentration of 0.7 mmol/l presented with a several month history of asterixis, which resolved fully within 2 weeks of stopping lithium (25A). Symptoms suggestive of toxicity at therapeutic serum concentrations also occurred in a 49-year-old man taking lithium (0.7 mmol/l), carbamazepine, and trifluperidol who developed persistent cerebellar deterioration during a febrile episode of lobar pneumonia (26A). Another patient who developed cerebellar symptoms consistent with lithium neurotoxicity despite a low therapeutic serum concentration (0.5 mmol/1) was more fortunate, as the symptoms resolved promptly when lithium was withdrawn (27A). In a review of the serotonin syndrome, lithium was mentioned as a possible contributing factor when it was combined with various antidepressants (28R). The neuroleptic malignant syndrome in a 49-year-old man was attributed

23 to a combination of lithium and chlorpromazine (29A). Endocrine In 23 women randomized to lithium carbonate 900 mg/day (n = 10) or placebo (n = 13) for one menstrual cycle, there were no significant differences in blood concentrations of prolactin, LH, FSH, 17-/~-estradiol, progesterone, cortisol, dehydroepiandosterone, free testosterone, T4, or leptin, or in glucose tolerance or weight. The only significant effect of lithium was the expected increase in serum TSH, which did not exceed the upper limit of the reference range (30c).

Thyroid In a review of prophylactic lithium therapy, goiter was more common in low iodine countries (e.g. Italy, Germany), and clinical hypothyroidism without goiter was more common in iodine-replete countries (e.g. Canada, Sweden) (31R). A retrospective study of 695 lithium patients from the Aberdeen area found a 10.4% prevalence of clinical hypothyroidism, with the highest risk in women during the first 2 years of treatment and in women started on lithium between ages 40 and 59 years (32r In the US, 30 patients were treated with lithium for 1 year; two developed grade I hypothyroidism (increased TSH, reduced T3 and T4) and nine (31%) developed grade II hypothyroidism (increased TSH, normal T3 and T4). Overall, lower (but not subnormal) free T4 concentrations were associated with more affective episodes, but whether or not supplemental T4 would have stabilized mood was not pursued (33c). In China 46 women taking lithium had thyroid function testing at baseline and at 1 month, and 37 were also tested at 6 months. While all remained clinically euthyroid and none developed antithyroid antibodies, TSH concentrations increased throughout (but did not exceed normal) (34c). A report on two patients suggested that subclinical hypothyroidism played a role in lithium-induced sinus node dysfunction (see also Cardiovascular), although no thyroid function abnormalities were described in the first and the dysrhythmia persisted in the second despite lithium withdrawal and normalization of thyroid function (15A). Two reports have emphasized the lack of consensus about whether or not to use sup-

24 plementary thyroid hormone to treat lithiumrelated subclinical hypothyroidism (35 r, 36r). There have been reports of hyperthyroidism in two patients taking lithium (37 A, 38A), adding to a small but provocative literature on this subject. In contrast, lithium continues to be used in the treatment of hyperthyroidism, with varying degrees of success. Of eight patients with iodine-induced thyrotoxicosis who were treated with methimazole, four also took lithium (39c). Lithium augmentation of 1311 for Grave's disease allowed a 117% reduction in mean 1311 dose and reduced the need for hospitalization, but the degree of treatment failure remained high in small-pool syndrome patients (those with rapid iodine washout) (40c). Another study showed no benefit from adjunctive lithium during 1311 treatment of hyperthyroidism when 50 patients not taking lithium were compared with 50 who took lithium for 3 weeks before and 3 weeks after 131I and 50 who took it for 3 weeks after 131I (41c).

Parathyroid, calcium A 53-year-old woman who had taken lithium for 9 years and carbamazepine for 3 years and had a 3-month history of lethargy was found to be hypercalcemic with a raised concentration of intact parathyroid hormone. She was saved from parathyroid surgery when withdrawal of lithium resolved the hypercalcemia (42A). A clinical study has suggested an association between lithium, hypercalcemia, and dysrhythmias (19 c) (see also Cardiovascular). Metabolism Weight gain A review of psychotropic drugs and weight gain included a brief summary of lithium-related weight gain (43r). A retrospective evaluation of 176 patients taking long-term lithium showed that weight gain was an adverse effect in 18.4%. While 34.2% of the total did not adhere to treatment because of somatic adverse effects, no specific adverse effect (including weight gain) was associated with non-adherence (44c). The prevalence of overweight (BM125-29) and obesity (BMI 30 or more) was determined in 89 euthyroid bipolar patients and 445 reference subjects. The rate of obesity in patients taking only lithium was 1.5 times greater than in the reference population (a non-significant difference), compared with a statistically significant 2.5 times greater rate associated with antipsychotic drugs (45c). In a one-year, placebo-controlled

Chapter 3

J. W. Jefferson

study of bipolar I prophylaxis (n = 372), weight gain with divalproex, but not with lithium, was significantly more common than with placebo (3c). A patient who gained 18.2 kg over 18 months while taking lithium and perphenazine lost 16 kg when the latter was changed to loxapine (she also participated in a weight loss program) (46At). Whether or not lithium played a role in the weight gain was unclear. Finally, a woman with lithium-associated hyperthyroidism lost 2 kg over 3 months, suggesting that lithium may have indirectly caused the weight loss (37A). Hematologic A 16-year-old with severe aplastic anemia failed to respond to treatment with corticosteroids plus an androgen and to antilymphocyte globulin, but had a strikingly positive response to the combination of lithium and an androgen derivative (47A). Leukocytopenia and thrombocytopenia recurred 2 months after lithium was withdrawn and responded to reintroduction of the drug. The potential of lithium to prevent or treat clozapine-induced granulocytopenia has been reviewed (48R). In a study of 38 patients on clozapine for schizophrenia or schizoaffective disorder, the addition of lithium increased the leukocyte count (49c). A 20-year-old man with olanzapine-induced neutropenia on 5 mg/day was able to tolerate 20 mg/day while taking lithium (50A). The immunomodulatory effects of lithium have been reviewed (51 R, 52R). Lithium (a) stimulated the production of proinflammatory cytokines and negative immunoregulatory cytokines or proteins in nine healthy subjects (53c), (b) altered the expression of human leukocyte antigens (HLA) in 11 of 15 subjects (54c), and (c) normalized manifestations of mild immune activation in 17 rapid cycling bipolar patients (55c). The clinical implications of these findings are unclear. Gastrointestinal An 80-year-old woman taking lithium developed constipation, nausea, vomiting, and abdominal pain after starting to take bupropion. A diagnosis of acute paralytic ileus was made and attributed to bupropion, although a bupropion-lithium interaction could not be excluded (56A). An 8-year-old taking lithium citrate for 6 months developed waxing and waning areas of denuded papillae on her tongue, diagnosed as

Lithium

Chapter3

benign migratory glossitis (geographic tongue) and attributed to lithium (57Ar). Urinary tract The effects of lithium on the kidney have been comprehensively reviewed (58 R) and nephrogenic diabetes insipidus has been specifically reviewed in the context of a report of nephrogenic diabetes insipidns that persisted despite withdrawal of lithium (59AR). A 30-year-old woman who became dehydrated secondary to lithium-induced nephrogenic diabetes insipidus developed a superior sagittal sinus thrombosis (24A) (see also Nervous system). A 78-year-old woman who had taken lithium for 25 years had hypotonic polyuria (4.7 1/day), mild renal insufficiency, and hyperparathyroidism attributed to lithium (60AR).

Renal insufficiency was attributed to lithium in a 40-year-old who had had non-toxic concentrations for 15 years (interstitial nephropathy on biopsy) (61 A) and in a 55-year-old woman who had taken lithium for 6 years (serum creatinlne 141 ixmol/1) (62A). In a comparison of patients taking longterm lithium (n = 10) or short-term lithium (n = 9) and bipolar patients not taking lithium (n = 10) there was significantly lower creatinine clearance and renal concentrating ability in the long-term group (63c). Lithium-associated nephrotic syndrome occurred in a 59-year-old woman with lithium toxicity (serum concentration 1.9 mmol/1) whose renal biopsy showed focal segmental glomerulosclerosis. Lithium withdrawal led to resolution of edema and marked improvement in proteinuria and albuminemia (64A). While case reports often fail to establish clear cause-and-effect, the possibility that lithium occasionally impairs kidney function makes periodic monitoring of kidney functioning essential. In one case a psychiatrist and family physician were sued for failing to do just that in a patient who developed renal insufficiency (65A). The distribution of monitoring guidelines in the area of Aberdeen, Scotland, increased the number of lithium patients who had at least once-yearly serum creatinine concentration measurements from 71 to 78%, still leaving 22% without adequate renal functioning monitoring (66c). Skin In a review of acute skin reactions to psychotropic drugs, alopecia, psoriasiform,

25

acneiform, and lichenoid eruptions, and druginduced lupus were attributed to lithium, but critical comment was not provided (67R). Lithium was also mentioned in a review of druginduced alopecia (68r). In a comparison of 51 patients taking lithium with 57 patients taking other psychotropic drugs there were secondary skin reactions in 45% of the former and 25% of the latter. While acne (33% vs 9%) and psoriasis (6% vs 0%) were more common in the lithium group, the only statistically significant association was acne in males (69CR). In a woman who had had keratosis follicularis (Darier's disease) since she was 16 the condition worsened when she was given lithium at age 50 (and improved when she switched to valproate) (70A). Two patients developed halogenoderma (vegetating plaques with peripheral pustules) after taking lithium for 6 and 8 years respectively; whether or not this was more than a coincidence was not established (71A). Lithium had an antiviral effect in a 44-yearold woman whose psychiatric symptoms did not improve but who had complete suppression of herpes labialis for 2 years (after a 30 year history of at least twice-yearly episodes) followed by a recurrence only 5 days after stopping the drug (72A). Sexual function In a cross-sectional pilot study of 22 bipolar women taking lithium (n = 10), divalproex (n = 10), or both (n = 10) there was an increased number of ovarian follicles in one woman taking lithium, but no evidence of hormonal changes suggestive of polycystic ovary syndrome in any patient (73c). The small sample size was a limiting factor. Compared with 13 women taking placebo, 10 women taking lithium carbonate 900 mg/day for one menstrual cycle had no significant alterations in reproductive hormone concentrations (30 c) (see also Endocrine). Drug withdrawal The issue of whether or not postwithdrawal refractoriness to the reintroduction of lithium is a real phenomenon and, if so, how often it occurs, continues to be debated (74r). Three patients were described who failed to respond to the reintroduction of lithium, despite having had sustained beneficial responses before withdrawal (75A). A retrospective study of lithium withdrawal in pregnant and non-pregnant women showed similar rates and times of recurrence, including

Chapter 3

26 a higher risk of early occurrence with rapid withdrawal (1-14 days) vs gradual withdrawal (15-30 days) (76c). How to balance the first trimester fetal risk of greater lithium exposure during gradual withdrawal with the greater maternal risk of potentially devastating relapse after rapid withdrawal remains a challenge. A 37-year-old man had his first attack of asthma 6 weeks after stopping lithium (14 A) (see also Respiratory). Whether or not this was a withdrawal effect of lithium is unknown. Teratogenicity The teratogenic effects of lithium have been reviewed in several articles (77R-79R). The authors concluded that while the risk of cardiovascular malformation is lower than once believed, it is nevertheless increased. Fetal ultrasonography was advised at 18-20 weeks of gestation in cases of first trimester lithium exposure (77R). Also reviewed were reports of fetal goiter and a variety of other lithium-related adverse events in newborus (77R). The higher risk of postpartum recurrence of bipolar disorder in women who had discontinued lithium was verified, and the protective effect of restarting lithium late in pregnancy or soon after delivery was emphasized (76Cr). Lactation Breastfeeding continues to be discouraged if mothers are taking lithium (80R), although the authors of a comprehensive review of the use of mood stabilizers during breastfeeding have pointed out that there is a paucity of information to support adverse effects of lithium in breastfeeding infants--one case of toxicity in a 2-month-old with an intercurrent infection (serum lithium 1.4 mmol/l) and one report of lethargy and cyanosis at days 5 and 6 (infant serum concentration 0.6 mmol/1 on day 5) secondary to fetal and breast milk exposure. The Motherisk Team in Toronto has recommended use of the Exposure Index (the maternal milk/plasma ratio times 100 divided by the infants' clearance in ml/kg/min) to determine the advisability of breasffeeding when a mother is taking lithium (81R). However, this approach does not seem very practical.

Drug overdose (see also Nervous system) The 1998 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System listed three lithiumrelated fatal exposures (two intentional and one

J. W. Jefferson

a therapeutic error) and three other fatalities in which lithium was not the primary cause of death. A total of 4486 lithium-related poison exposure cases were reported, in which the outcome was death in five and a major lifethreatening event or cause-significant residual disability in 212 (82c). A literature review of permanent neurological complications of acute lithium toxicity noted that a cerebellar syndrome is quite common, that neuroleptic drugs may worsen toxicity, as might rapid reduction of raised serum lithium concentrations (83R). The latter point is speculative at best, and hemodialysis remains the treatment of choice for severe lithium poisoning. A study of drug intoxication in the south of Brazil reported 2938 cases of drug ingestion, 25 of which involved lithium (including 14 suicide attempts) (84 c). Anecdotal reports of acute toxicity continue to appear. A 71-year-old woman became lithium toxic (serum concentration 2.1 retool/l) following urinary diversion with ileal conduits for stress incontinence, because of increased absorption of urinary lithium from the bowel (85A). A 29-year-old man who overdosed on 8000 mg of a sustained-release lithium formulation had a serum concentration of 3.12 retool/1 25 hours later, but only became symptomatic (with vomiting and dizziness) 35 hours later; his symptoms resolved with hemodialysis (86A). A 72-year-old woman developed an acute confusional state, gait instability, and blepharospasm and apraxia of eyelid opening (24 hour serum concentration 1.8 mmol/1), which resolved after withdrawal (87A). In the presence of high lithium concentrations (2.6 and 1.6 mmol/l), two patients had high amplitude of the primary complex in median nerve somatosensory evoked potentials, which normalized as concentrations fell (88A).

Drug interactions

There have been two reviews of drug interactions with lithium (89 R, 90R); another review focused on interactions in the elderly (91R).

Angiotensin II receptor type-1 (AT1) antagonists A 51-year-old woman developed symptoms of lithium toxicity (serum concentration 1.4 mmol/1) while taking valsartan, which resolved when the valsartan was replaced by diltiazem (serum lithium concentration 0.8 mmol/1) (92A).

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Chapter3

Anticonvulsants In rats, lithium pretreatment reduced the plasma half-life of valproate by 25% and increased urinary excretion of valproate glucuronide (93E). This has not been studied in humans.

Antidepressants In a review of antidepressants and the serotonin syndrome, a possible contributory role was suggested for lithium, based on case reports with tricyclics, SSRIs, trazodone, and venlafaxine (28R). Lithium augmentation of nefazodone in 13 treatmentresistant depressed patients was associated with a variety of annoying adverse effects, but none led to treatment discontinuation (94c). Anecdotal reports have also appeared. A 65-year-old man taking lithium and doxepin developed myoclohic jerking of his arms after the lithium dose was increased. The low serum concentration at the time (0.3 mmol/l) suggested a possible synergy between lithium and the tricyclic antidepressant (23A). A 20-year-old woman taking lithium and risperidone became catatonic 5-7 days after the addition of paroxetine, leading to speculation that this was due to an interaction between the three drugs (95A).

Antipsychotic drugs The potential benefit and possible risks of using lithium to treat clozapine-induced neutropenia/agranulocytosis have been reviewed (48R). In 34 healthy men, ziprasidone did not alter serum lithium concentrations or renal lithium clearance (96c). In a placebo-controlled trial (n = 24), amisulpride did not alter lithium pharmacokinetics (97c). There was no alteration in steady-state lithium pharmacokinetics when risperidone replaced another neuroleptic drug in 13 patients (98c). On the other hand, an 81-year-old man had an acute dystonic reaction 4 days after lithium was added to a regimen of risperidone, valproic acid, and benzatropine (99A).

27 A patient developed neuroleptic malignant syndrome while taking a combination of lithium and chiorpromazine (29A).

Non-steroidal anti-inflammatory drugs (NSAIDs) The interaction of NSAIDs with lithium has been reviewed briefly (100r). In a review of celecoxib, a selective cyclooxygenase type 2 inhibitor, it was noted that while mean plasma concentrations of celecoxib were higher for the first 6 hours after the dose in the presence of lithium, the AUC was unchanged (101R). Both celecoxib and naproxen, a non-selective cyclo-oxygenase inhibitor, reduced renal clearance of endogenous lithium (used as a measure of proximal tubular sodium reabsorption) (102c). The clinical implications are unclear, since the US package insert for celecoxib describes a study in which 200 mg bd caused an mean increase in serum lithium concentration of only 17% in 24 subjects taking lithium carbonate 450 mg bd.

Interference with diagnostic tests A 33year-old woman was admitted to an intensive care unit after ingesting unknown quantities of a variety of medications, including lithium. She remained asymptomatic, except for drowsiness, despite serum lithium concentrations of 2.7, 3. l, 3.6, and 5.6 mmol/1. The last concentration was discovered to be spuriously high when it was realized that blood had been collected in a lithium-beparin anticoagulant tube. When the test was repeated using the proper collection tube, the concentration was 2.2 mmol/1 (103A). A similar problem occurred in a 20-month-old with recurrent convulsions who had an apparent serum lithium concentration of 3.2 mmol/1. The absence of lithium in the urine prompted further investigation and the source of the lithium was found to be from the use of a lithium-heparin collection tube (104A).

REFERENCES 1. Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JE The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000. Postgrad Med Special Report 2000; April: 1-104. 2. Frances A, Docherty JE Kahn DA. The Expert Consensus Guideline Series: Treatment of Bipolar

Disorder. J Clin Psychiatry 1996; 57 Suppl 12A: 2-88. 3. Bowden CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty E Pope HG, Chou JC-Y, Keck PE, Rhodes LJ, Swann AC, Hirschfeld RMA, Wozniak PJ, for the Divalproex Maintenance Study Group. A randomized, placebo-controlled 12-

28 month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry 2000; 57: 481-9. 4. Schou M. Foreword. Aust NZ J Psychiatry 1999; 33 Suppl: S1-3. 5. Kallner G, Lindelius R, Petterson U, Stockman O, Tham A. Mortality in 497 patients with affective disorders attending a lithium clinic or after having left it. Pharmacopsychiatry 2000; 33: 8-13. 6. Brodersen A, Licht RW, Vestergaard P, Olesen AV, Mortensen PB. Sixteen-year mortality in patients with affective disorder commenced on lithium. Br J Psychiatry 2000; 176: 429-33. 7. Tondo L, Baldessarini RJ, Hennen J, Floris G, Silvetti F, Tohen M. Lithium treatment and risk of suicidal behavior in bipolar disorder patients. J Clin Psychiatry 1998; 59: 405-14. 8. Ghaemi SN, Sachs GS, Goodwin FK. Divalproex vs. lithium in the treatment of bipolar disorder: a naturalistic 1.7 year comparison. Poster presentation, National Institute of Mental Health, New Clinical Drug Evaluation Unit (NCDEU), 39th Annual Meeting, Boca Raton, Florida, 1999: June 1-4. 9. Birch NJ. Inorganic pharmacology of lithium. Chem Rev 1999; 99: 2659-82. 10. Dunner DL. Optimizing lithium treatment. J Clin Psychiatry 2000; 61 Suppl 9: 76-81. 11. Jefferson JW, Greist JH. Lithium. In: Sadock B J, Sadock VA, editors. Kaplan & Sadock's Comprehensive Textbook of Psychiatry, 7th edition. Philadelphia: Lippincott, William & Wilkins, 2000; 2: 2377-90. 12. Schtpf J. Lithium [in German]. Darmstadt: Steinkopff, 1999: 1-89. 13. Lai C-L, Chen W-J, Huang X-H, Lin F-Y, Lee Y-T. Sinus node dysfunction in a patient with lithium intoxication. J Formosan Med Assoc 2000; 99: 66-8. 14. Convery RP, Hendrick DJ, Bourke SJ. Asthma precipitated by cessation of lithium treatment. Postgrad Med J 1999; 75: 637-8. 15. Numata T, Abe H, Terao T, Nakashima Y. Possible involvement of hypothyroidism as a cause of lithium-induced sinus node dysfunction. PACE Pacing Clin Electrophysiol 1999; 22: 954-7. 16. Davies B. The first patient to receive lithium. Aust NZ J Psychiatry 1999; 33 Suppl: $32-4. 17. Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, Baughman KL, Kasper EK. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. New Engl J Med 2000; 342: 1077-84. 18. Wolf ME, Moffat M, Ranade V, Somberg JC, Lehrer E, Mosnalm AD. Lithium, hypercalcemia, and arrhythmia. J Clin Psychopharmacol 1998; 18: 420-3. 19. Wolf ME, Ranade V, Molnar J, Somberg J, Mosnalm AD. Hypercalcemia, arrhythmia, and mood stabilizers. J Clin Psychopharmacol 2000; 20: 260-4.

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20. Berner J. Lithium-treated mood disorders, paroxysmal rhinorrhea, and mesial temporal lobe epilepsy. J Neuropsychiatry Clin Neurosci 1999; 11: 414-15. 21. Miiller-Oerlinghausen B. Does effective lithium prophylaxis result in a symptom-free state of manic-depressive illness? Some thoughts on the fine-tuning of mood stabilization. Compr Psychiatry 2000; 41 Suppl 1: 26--31. 22. Malitas PN, Alevizos B, Christodoulou GN. Aniracetam treatment for lithium-produced cognitive deficits of bipolar patients. Eur Neuropsychopharmacol 1999; 9 Suppl 5: $240. 23. Evidente VGH, Caviness JN. Focal cortical transient preceding myoclonus during lithium and tricyclic antidepressant therapy. Neurology 1999; 52: 211-13. 24. Wasay M, Bakshi R, Kojan S, Bobustuc G, Dubey N. Superior sagittal sinus thrombosis due to lithium: local urokinase thrombolysis treatment. Neurology 2000; 54: 532-3. 25. Stewart JT, Williams LS. A case of lithiuminduced asterixis. J Am Geriatr Soc 2000; 48: 457. 26. Bischof F, Melms A, Fetter M. Persistent cerebellar deterioration in a patient with lobar pneumonia under lithium, carbamazepine, and trifluperidol treatment. Eur Psychiatry 1999; 14: 1756. 27. Kumar R, Deb JK, Sinha VK. Lithium neurotoxicity at therapeutic level--a case report. J Indian Med Assoc 1999; 97: 473-4. 28. Keck PE, Arnold LM. The serotonin syndrome. Psychiatr Ann 2000; 30: 333-43. 29. Leber K, Malek A, D'Agostino A, Adelman HM. A veteran with acute mental changes years after combat. Hosp Pract 1999; 34: 21-2. 30. Baptism T, Lacruz A, De Mendoza S, GuillEn MM, Burguera JL, De Burguera M, Hern~ndez L. Endocrine effects of lithium carbonate in healthy premenopausal women: relationship with body weight reduction. Prog Neuropsychopharmacol Biol Psychiatry 2000; 24: 1-6. 31. Leutgeb U. Overt hypothyroidism and goitre during prophylactic lithium treatment: the influence of ambient iodine supply. A critical review. Neurol Psychiatry Brain Res 1999; 7: 121-30. 32. Johnston AM, Eagles JM. Lithium-associated clinical hypothyroidism. Prevalence and risk factors. Br J Psychiatry 1999; 175: 336-9. 33. Frye MA, Denicoff KD, Bryan AL, SmithJackson EE, Ali SO, Luckenbaugh D, Leverich GS, Post RM. Association between lower serum free T4 and greater mood instability and depression in lithium-maintained bipolar patients. Am J Psychiatry 1999; 156: 1909-14. 34. Lee S, Chow CC, Wing YK, Shek ACC, Mak TWL, Ahuja A, Lee DTS, Leung TYS. Thyroid function and psychiatric morbidity in patients with manic disorder receiving lithium therapy. J Clin Psychopharmacol 2000; 20: 204-9.

Lithium

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35. Panza N, Biondi B, Carella C, Lombardi G. About thyroxine administration during lithium therapy. J Endocrinol Invest 1999; 22: 820-1. 36. Bartalena L, Bogazzi F, Martino E. Is thyroxine during lithium therapy necessary? J Endocrinol Invest 1999; 22: 220-2. 37. Yamagishi S-I, Yokoyama-Ohta M. A case of lithium-associated hyperthyroidism. Postgrad Med J 1999; 75: 188-9. 38. Ripoll Mairal M, Len Abad O, Falc6 Ferrer V, Femfmdez De Sevilla Ribosa T. Hipertiroidismo e hipercalcemia asociados al tratamiento con litio. Rev Clin Esp 2000; 200: 48-9. 39. Henzen C, Buess M, Brander L. Die Jodinduzierte Hyperthyreose (Jodbasedow): ein aktuelles Krankheitsbild. Schweiz Med Wochenschr 1999; 129: 658-64. 40. Brans B, Versijpt J, De Winter O, Monsieurs M, Dierckx RA. Lithium as an adjunct in the treatment of Graves' thyrotoxicosis with small pool syndrome: effect on outcome. Eur J Nucl Med 1999; 26: PS646. 41. Bal CS, Kumar A, Goswami RK. A prospective randomized control trial to evaluate the adjuvant effect of lithium on radioiodine treatment of hyperthyroidism. J Nucl Med 1999; 40: 934. 42. Gama R, Wright J, Ferns G. An unusual case of hypercalcaemia. Postgrad Med J 1999; 75: 769-70. 43. Sussman N, Ginsberg D. Effects of psychotropic drugs on weight. Psychiatr Ann 1999; 29: 580-94. 44. Schumann C, Lenz G, Bergh6fer A, MiillerOerlinghausen B. Non-adherence with long-term prophylaxis: a 6-year naturalistic follow-up study of affectively ill patients. Psychiatry Res 1999; 89: 247-57. 45. Elmslie JL, Silverstone JT, Mann JI, Williams SM, Romans SE. Prevalence of overweight and obesity in bipolar patients. J Clin Psychiatry 2000; 61: 179-84. 46. Cheskin LJ, Bartlett SJ, Zayas R, Twilley CH, Allison DB, Contoreggi C. Prescription medications: a modifiable contributor to obesity. South Med J 1999; 92: 898-904. 47. Amano I, Morii T, Yamanaka T, Tsukaguchi N, Nishikawa K, Narita N, Shimoyama T. Successful lithium carbonate therapy for a patient with intractable and severe aplastic anemia [in Japanese]. Rinsho Ketsueki 1999; 40: 46-50. 48. Oyewumi LK. Does lithium have a role in the prevention and management of clozapine-induced granulocytopenia? Psychiatr Ann 1999; 29: 597603. 49. Wolstein J, Bender S, Hesse A, Jura S, Dittmann-Balqar A. Leukocyte count increases with the addition of lithium to concurrent clozapine treatment. Schizophr Res 2000; 41(NSI): B25. 50. Gajwani P, Tesar GE. Olanzapine-induced neutropenia. Psychosomatics 2000; 41: 150-1. 51. Rybakowski JK. The effect of lithium on the immune system. Hum Psychopharmacol 1999; 14: 345-53.

29 52. Harvey BH, Meyer CL, Gallicchio VS. The hemopoietic and immuno-modulating action of lithium salts: an investigation into the chemotherapy of HIV infection in South Africa. In: Lucas KC, Becker RW, Gallicchio VS, editors. Lithium--50 Years: Recent Advances in Biology and Medicine. Cheshire, Connecticut: Weidner Publishing, 1999: 137-52. 53. Maes M, Song C, Lin A-H, Pioli R, Kenis G, Kubera M, Bosmans E. In vitro immunoregulatory effects of lithium in healthy volunteers. Psychopharmacology 1999; 143: 401-7. 54. Kang B J, Park SW, Chung TH. Can the expression of histocompatibility antigen be changed by lithium? Int J Neuropsychopharmacol 1999; 2 Suppl 1: $55. 55. Rapaport MH, Guylal L, Whybrow P. Immune parameters in rapid cycling bipolar patients before and after lithium treatment. J Psychiatr Res 1999; 33: 335-40. 56. Kales HC, Mellow AM. Ileus as a possible result of bupropion in an elderly woman. J Clin Psychiatry 1999; 60: 337. 57. Gracious BL, Liana M, Barton DD. Lithium and geographic tongue. J Am Acad Child Adolesc Psychiatry 1999; 38: 1069-70. 58. Gitlin M. Lithium and the kidney. An updated review. Drug Saf 1999; 20: 231-43. 59. Stone KA. Lithium-induced nephrogenic diabetes insipidus. J Am Board Fam Pract 1999; 12: 43-7. 60. Kanfer A, Blondiaux I. Complications renales et metaboliques du lithium. Nephrologie 2000; 21: 65-70. 61. Autret L, Meynard JA, Sanchez MF, Bemadet R, Charpin C. Entre efficacit6 et toxicit6: histoire d'un patient gueri par le lithium chez qui l'on dEcouvre une nephropathie iatrog~ne. Enc6phale 1999; 25: 485-7. 62. Lauterbach EC, Abdelhamid A, Annandale JB. Posthalhicinogen-like visual illusions (palinopsia) with risperidone in a patient without previous hallucinogen exposure: possible relation to serotonin 5HT2a receptor blockade. Pharmacopsychiatry 2000; 33: 38-41. 63. Sofuo~lu S, Uta~ C, Aslan SS, Yalqinda~ C, Ba~ttirk M, G6niil AS. Kidney functioning during short and long-term lithium treatment in bipolar patients. Eur Neuropsychopharmacol 1999; 9 Suppl 5: $215-16. 64. Schreiner A, Waldherr R, Rohmeiss P, Hewer W. Focal segmental glomerulosclerosis and lithium treatment. Am J Psychiatry 2000; 157: 834. 65. DiGiacomo JN, Sadoff RL. Managing malpractice risks during psychopharmacologic treatment. Essential Psychopharmacol 1999; 3: 65-89. 66. Eagles JM, McCann I, MacLeod TNN, Paterson N. Lithium monitoring before and after the distribution of clinical practice guidelines. Acta Psychiatr Scand 2000; 101: 349-53. 67. Kimyai-Asadi A, Harris JC, Nousari HC. Critical overview: adverse cutaneous reactions to psy-

Chapter3

30 chotropic medications. J Clin Psychiatry 1999; 60: 714-25. 68. Van den Bemt PM, Brodie-Meijer CC, Krijnen RM, Nieboer C. Haaruitval door gebruik van geneesmiddelen. Ned Tijdschr Geneeskd 1999; 143: 990-4. 69. Chan HHL, Wing Y-K, Su R, Van Krevel C, Lee S. A control study of the cutaneous side effects of chronic lithium therapy. J Affective Disord 2000; 57: 107-13. 70. Ehrt U, Brieger P. Comorbidity of keratosis follicularis (Darier's disease) and bipolar affective disorder: an indication for valproate instead of lithium. Gen Hosp Psychiatry 2000; 22: 128-9. 71. Alagheband M, Engineer L. Lithium and halogenoderma. Arch Dermatol 2000; 136: 1267. 72. Bschor T. Complete suppression of recurrent herpes labialis with lithium carbonate. Pharmacopsychiatry 1999; 32: 158. 73. Rasgon NL, Altshuler LL, Gudeman D, Burt VK, Tanavoli S, Hendrick V, Korenman S. Medication status and polycystic ovary syndrome in women with bipolar disorder: a preliminary report. J Clin Psychiatry 2000; 61: 173-8. 74. Coryell WH, Leon AC, Scheftner W. Lithium discontinuation. Dr Coryell and colleagues reply. Am J Psychiatry 1999; 156:1130. 75. Oostervink F, Nolen WA, Hoenderboom ACG, Kupka RW. Het risico van lithiumresistentie na stoppen en herstart na langdtLrig gebruik. Ned Tijsdchr Geneeskd 2000; 144: 401--4. 76. Viguera AC, Nonacs R, Cohen LS, Tondo L, Murray A, Baldessarini ILl. Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. Am J Psychiatry 2000; 157: 179-84. 77. American Academy of Pediatrics---Committee on Drugs. Use of psychoactive medication during pregnancy and possible effects on the fetus and newborn. Pediatrics 2000; 105: 880-7. 78. Iqbal MM. The effects of lithium on fetuses, neonates, and nursing infants. Psychiatr Ann 2000; 30: 159--64. 79. Warner JP. Evidence-based psychopharmacology. 3. Assessing evidence of harm: what are the teratogenic effects of lithium carbonate? J Psychopharmacol 2000; 14: 77-80. 80. Yoshida K, Smith B, Kumar R. Psychotropic drugs in mothers' milk: a comprehensive review of assay methods, pharmacokinetics and of safety of breast-feeding. J Psychopharmacol 1999; 13: 64-80. 81. Koren G, Moretti M, Ito S. Continuing drug therapy while breastfeeding. Part 2. Common misconceptions of physicians. Can Fam Phys 1999; 45: 1175.

82. Litovitz TL, Klein-Schwartz W, Caravati EM, Youniss J, Crouch B, Lee S. 1998 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1999; 17: 435-87.

J. W. Jefferson

83. Roy M, Stip E, Black DN, Lew V, Langlois R. Srquelles neurologiques secondaires h une intoxication aigu~ au lithium. Can J Psychiatry 1999; 44: 671-9. 84. De Almeida Teixeira A, Machado MF, Ferreira WM, Tortes JB, Brunstein MG, Barros HMT, Barros E. Lithium acute intoxication: epidemiologic study of the causes [in Portuguese]. J Bras Psiquiatria 1999; 48: 399-403. 85. Alhasso A, Bryden AA, Neilson D. Lithium toxicity after urinary diversion with ileal conduit. Br Med J 2000; 320: 1037. 86. Astruc B, Petit P, Abbar M. Overdose with sustainednrelease lithium preparations. Eur Psychiatry 1999; 14: 172--4. 87. Micheli E Cers6simo G, Scorticati MC, Ledesma D, Molinos J. Blepharospasm and apraxia of eyelid opening in lithium intoxication. Clin Neuropharmacol 1999; 22: 176-9. 88. Vollhardt M, Ferbert A. Influence of hypocalcemia and high serum levels of lithium on the amplitude of N20/P25 components of median nerve SEP [in German]. EEG-Labor 1999; 21: 65-70. 89. Miiller-Oerlinghausen B. Drug interactions with lithium. A guide for clinicians. CNS Drugs 1999; 11: 41-8. 90. Janicak PG, Davis JM. Pharmacokinetics and drug interactions. In: Sadock B J, Sadock VA, editors. Kaplan & Sadock's Comprehensive Textbook of Psychiatry, 7th edition. Philadelphia: Lippincott, William & Wilkins, 2000; 2: 2250-9. 91. Sproule BA, Hardy BG, Shulman KI. Differential pharrnacokinetics of lithium in elderly patients. Drugs Aging 2000; 16: 165-77. 92. Leung M, Remick RA. Potential drug interaction between lithium and valsartan. J Clin Psychopharmacol 2000; 20: 392-3. 93. Yoshioka H, Ida S, Yokota M, Nishimoto A, Shibata S, Sugawara A, Takiguchi Y. Effects of lithium on the pharmacokinetics of valproate in rats. J Pharm Pharmacol 2000; 52: 297-301. 94. Hawley C, Sivakumaran T, Ochocki M, Ratnam S, Huber T. A preliminary safety study of combined therapy with nefazodone and lithium. Int J Neuropsychopharmacol 1999; 2 Suppl 1: $30-1. 95. Shad MU, Preskorn SH, Izgur Z. Failure to consider drug-drug interactions as a likely cause of behavioral deterioration in a patient with bipolar disorder. J Clin Psychopharrnacol 2000; 20: 390-3. 96. Apseloff G, Mullet D, Wilner KD, Anziano RJ, Tensfeldt TG, Pelletier SM, Gerber N. The effects of ziprasidone on steady-state lithium levels and renal clearance of lithium. Br J Clin Pharmacol 2000; 49 Suppl 1: $61-4. 97. Chaufour S, Borgstein NG, Van den Eynde W, Bernard F, Canal M, Zieleniuk I, Pinquier JL. Repeated administrations of amisulpride (A) do not modify lithium carbonate (L) pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 1999; 65: 143. 98. Demling J, Huang ML, De Smedt G. Pharmacokinetics and safety of combination therapy with

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lithium and risperidone in adult patients with psychosis. Int J Neuropsychopharmacol 1999; 2 Suppl 1: $63. 99. Durrenberger S, De Leon J. Acute dystonic reaction to lithium and risperidone. J Neuropsychiatry Clin Neurosci 1999; 11: 518-19. 100. Haas DA. Adverse drug interactions in dental practice: interactions associated with analgesics. Part 1II in a series. J Am Dent Assoc 1999; 130: 397-407. 101. Davies NM, McLachlan AJ, Day RO, Williams KM. Clinical pharmacokinetics and pharmacodynamics of celecoxib, a selective cyclo-

31 oxygenase-2 inhibitor. Clin Pharmacokin 2000; 38: 225--42. 102. Rossat J, Maillard M, Nussberger J, Brunner HR, Bumier M. Renal effects of selective cyclooxygenase-2 inhibition in normotensive saltdepleted subjects. Clin Pharmacol Ther 1999; 66: 76-84. 103. Nordt SP, Cantrell FL. Elevated lithium level: a case and brief overview of lithium poisoning. Psychosom Med 1999; 61: 564-5. 104. Van Osch-Gevers M, Draaisma JMTh, Verzijl JM. Een 20 maanden oude peuter met onbegrepen convulsies. Pharm Weekbl 1999; 134:1163-4.

Jayendra K. Patel, Eileen Wong and Alan I. Green

4 AMPHETAMINES

Methylenedioxymethamphetamine (Ecstasy, MDMA) (SED-14,105; SEDA-21, 22; SEDA-22, 29; SEDA-23, 34)

Deaths related to ecstasy MDMA (methylenedioxymethamphetamine), or "ecstasy", and MDEA (3,4-methylenedioxyethylamphetamine), or "eve", have rapidly become popular drugs o f abuse in recent years in Europe and to some extent in other developed countries as welL Over the years, reports of deaths following their use at "rave" parties have generated considerable public concern. A new report from the UK has noted that the annual death rate from ecstasy use is uncertain (lC). A meta-analysis o f surveys o f illegal drug use by 15- to 24-year-old individuals in the UK in 1996 showed that 7% had used ecstasy in the previous year and 3% in the previous month, a rate 44% higher than in 1993-95. But the actual numbers o f ecstasyrelated deaths are more difficult to ascertain. In Scotland, ecstasy-related deaths are defined as "ecstasy found in the body"; in England, on the other hand, it is defined as "ecstasy written on the death certificate". Using these disparate definitions, 11 deaths were reported in Scotland and 18 in England in the 15- to 24-year-old category. Based on all available data, the author o f the report suggested a 26-fold range (0.2-5.3) o f possible ecstasy-related deaths per 10000 within this age group. To make death estimates more reliable, the author recommended that the definition of "ecstasy-related-death" should be unified, and that surveys should ask directly

Death rate

9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed. 32

Drugs of abuse about regular, sporadic, and first-time drug use, so as to determine which group is at most risk. The author expressed concern that these data (poor as they are) may be used by the courts and policy makers as if they were more valid, citing the example o f Switzerland, which has recently liberalized the guidelines on sentencing people who supply ecstasy tablets, in contrast to suppliers o f heroin, based on their interpretation o f the data that the death rate in ecstasy users is at the lower end o f the range. This report generated two responses. One group felt that estimating such death rates is even more complex than noted (2r ). They asked if someone purchases ecstasy but instead gets a contaminated or a very different compound, causing death, would the death be classified as ecstasy-related or as something else? Furthermore, they wondered if the definition o f ecstasy-related death is based on the detection o f MDMA (or its metabolites) in the blood or on detection o f other compounds (consumed under the presumption o f its being ecstasy). Citing their own experience, this group suggested that criteria f o r inclusion should include: "Would the deceased still be alive if (s)he had not abused the substance ?" Thus, even deaths from causes such as traffic accidents when the death was secondary to intoxication with the compound should be included. The second group, while agreeing with the original report, raised the concern that surveys that are more frequent would be economically prohibitive (3r). They noted that in 1997 The National Program on Substance Abuse Deaths (NPSAD) was established to monitor drugrelated-deaths in the UK. It uses a "cause o f death ratio", which looks at the number o f drug-related deaths in specific categories (e.g. 15- to 24-year-olds) and the drugs implicated in these deaths. According to the authors, this method allows rapid surveillance o f the pattern of deaths over time.

Drugs of abuse

Chapter4

Pathology Three deaths have been reported after the ingestion of MDMA/MDEA, in which immunohistological studies further elucidated the causes o f the deaths (4Ag). One death was caused by MDMA intoxication, one was from MDEA, and the third was from combined intoxication. One case had been reported previously (SEDA-22, 31). A 19-year-old man consumed ecstasyfor the entire duration of a discotheque party (lasting until morning) and had respiratory difficulty, uncoordinated movements, generalized hypertonia, and hyperpyrexia (40.6~ He was diagnosed as having disseminated intravascular coagulation and received treatment with heparin, but suffered severe blood loss from the oral cavity and injection wounds. He subsequently developed a cardiac arrest. Another 20-year-old man ingested many ecstasy pills at a discotheque, returned home complaining of feeling feverish (axillary temperature 40~ went to bed, and was found dead 10 hours later, his pillow soaked with blood. The third case involved a 19-year-old man who was found unconscious near a discotheque. His course progressively worsened, with the appearance of diffuse subcutaneous petechiae. While being treated for hypotension, he developed sustained convulsions and uremia and later died. In all cases, amphetamines were detected in the urine; the pathological findings showed diffuse subserous petechiae and polyvisceral stasis. The brains showed massive edema and signs of neuronal hypoxia. In two cases, the heart showed coagulative myocytolysis, while one had areas of subendocardial hemorrhage. The lungs showed subpleural and intra-alveolar hemorrhages with severe edema and in two cases microthrombotic formations inside lung capillaries. In two cases, the liver showed evidence of microvescicular steatosis and in one case centrilobular necrosis. Liver cells in the central zones showed coagulation necrosis with precipitation of fibrin in the whole area affected by necrosis. In the kidney, fibrin thrombi in the renal glomeruli were observed in two of the cases, while acute tubular necrosis was observed in one. The findings from these three cases are similar to those seen in deaths from hyperthermia and disseminated intravascular coagulation. The myocardial necrosis (coagulative myocytolysis) without infarct necrosis is indicative of adrenergic overdrive. In two cases the muscle showed the typical pathological changes observed in deaths due to malignant hyperpyrexia.

33 Myoglobin was detected in the proximal tubules in all three cases. The authors interpreted the clinical histopathological, and toxicological data as indicative of an idiosyncratic response to ecstasy.

Nervous system A report linking ecstasy use and parkinsonism has generated considerable discussion (5At). A 29-year-old man developed difficulty in walking and lost the ability to write or drive 4 weeks after developing clumsiness of his extremities. He was unable to work and live independently. His electroencephalogram, lumber puncture, and MRI and PET scans were normal. Eleven weeks after the onset of symptoms he had disturbed gait and fine motor coordination; his condition deteriorated and 8 weeks later he had bradykinesia of the face and limbs, absence of blinking, hypokinesia in relation to speech, postural instability,and a markedly parkinsonian gait. However, his cognitive function was intact. This patient had ingested ecstasy 10 times during the year before, and his last use was about 3 months before the onset of symptoms. Apart from marijuana, he denied using other substances. He was treated with maximal tolerable doses of levodopa and pramipexole, without improvement. The authors reported that they had no explanation for this patient's symptoms, other than the use of ecstasy. They felt that the parkinsonian symptoms most closely resembled MPTP-induced parkinsonism. They further postulated that this could be a delayed neurotoxic effect of ecstasy on the substantia nigra and striatum and could have occurred as a result of neuronal damage by free radicals. This report brought many responses. The first criticized the authors' conclusion that the neurotoxic effects in their patient were similar to those seen with MPTP (tr). They argued that the PET scan was normal, and that the patient's condition did not respond to the use of antiparkinsonian drugs, unlike MPTP-induced damage, which does respond. They further argued that the extensive animal and human experience involving MDMA has not shown damage to the dopaminergic system. Furthermore, MDMA and MPTP are chemically unrelated and share neither precursors nor metabolites. Although the purity of street drugs is suspect and a contaminant could have been responsible,

34

Chapter 4

they seriously doubted that MPTP was one of the contaminants ingested. Another group expressed the concern that although other amphetamines are known to cause dopaminergic neurotoxicity in animals and are sometimes sold as MDMA, they have not been associated with parkinsonism, despite more than 60 years of worldwide therapeutic and illicit use (7r). Furthermore, they observed that the pattern in this case, in which symptoms began 8 weeks after drug exposure, did not fit the expected pattern of drug toxicity. They proposed that the problem had either been caused by contaminants or by a highly idiosyncratic reaction. However, if the toxicity had been from a contaminant, a cluster of cases would have been expected, as was seen with MPTP. On the other hand, if this had been an idiosyncratic case, the symptoms would have emerged soon after the drug use. They were puzzled by the absence of hair analysis to confirm M D M A use. In their opinion, the urge to implicate adverse health effects to socially disapproved behaviors, such as illicit drug use, with very loose and unconfirmed temporal association is a disservice to science. The authors of the original report responded by citing evidence that M D M A can be toxic to dopaminergic neurons and may cause lasting changes of neuronal responses to dopamine (8r). They further stated that although parkinsonism has not been reported after MDMA, the possibility that such an association exists cannot be excluded. They raised the possibility that clinical evidence of parkinsonism can be missed, particularly when the disorder is mild and, as in their patient, when tremor is absent. They pointed out that with valproate the first full report of parkinsonism did not appear until 18 years after its introduction into the US, even though those who commonly prescribe it (neurologists and psychiatrists) should have noticed it earlier. The authors clarified that they had mentioned MPTP as an example of a substance that may have a delayed neurotoxic effect on monoaminergic neurons, without intending to suggest that M D M A acts chemically in the same manner as MPTP. They agreed that a contaminant could have played a role, and raised a concern that contaminants also put MDMA users at risks of adverse effects. They countered the argument that all idiosyncratic responses have to be immediate, by quoting examples from the literature to suggest that the

JayendraK. Patel, Eileen Wong and Alan L Green

course of a reaction depends on the underlying mechanism. The patient discussed in the case report also responded, alleging that his permission was not obtained before publication (9r). Contradicting the original published report, he stated that he had never used marijuana; the authors defended their data by stating that when the patient's friend, who had accompanied him to the clinic, mentioned cannabis use the patient did not deny it. He also reported using creatine, ephedrine, caffeine, and aspirin, none o f which, the authors noted, has previously been associated with parkinsonian symptoms. Other neurological adverse effects have been reported in a first-time ecstasy user (10AR). A 19-year-old man developed dizziness and loss of consciousness the morning after taking ecstasy for the first time. He was known to use benzodiazepines and heroin occasionally. He was intubated and ventilated. He had a monocular hematoma, pulmonary edema, and cutaneous emphysema, without focal neurological deficits. There was rhabdomyolysis with renal insufficiency, but no rise in temperature. Body fluid toxicological analysis showed only benzodiazepines and amphetamines. After he was weaned from the respirator, although awake, he did not react to noxious stimuli and showed no spontaneous movements. A C T scan of the brain had been normal on admission, but 2 and 3 weeks later it showed multiple hypodense lesions in the white matter. One month after admission, he was in a vegetative state, with marked spasticity, intermittent non-specific reactions to noise, and sustained generalized myoclonus. An electroencephalogram showed generalized slowing with intermittent theta wave activity. An MRI scan showed bilateral severe white matter damage. The brain damage in this patient was restricted to white matter. Although hypoxia was present at the time of admission, the authors did not believe that it was the only etiological factor. By a process of elimination, they concluded that ecstasy might have caused the toxic encephalopathy, although it was not detected by toxicological analysis. They suggested that myelin damage might be an indirect sequelae of MDMA-related metabolic oxidative stress and multiorgan failure due to individual susceptibility. They also entertained the idea of a lipophilic toxic contaminant rather than MDMA as the causative toxic agent. Concerns have been raised about the longterm CNS effects of M D M A use from animal data, which suggest that the dose of MDMA

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used for recreational purposes by humans can cause toxic effects in non-human primates, especially involving the serotonin system. In a case-control study, 10 long-term MDMA users were compared with 10 controls who had not used MDMA but were drug-abusers and were matched for age, sex, education, and premorbid intellect (IlCR). All participated in a SPECT study with the serotonin transporter (SERT) ligand. Dopamine transporter binding was determined from scans acquired 23 hours after injection of the tracer. Hair analysis, which covers about the last 4 weeks of drug use, generally confirmed the drug use history, although two ecstasy users tested negative for both amphetamine and methamphetamine. On neuropsychological testing, both groups showed comparable performances in tests of verbal and spatial memory, psychomotor speed, attention, and executive function. Larger lifetime doses of ecstasy were associated with reduced verbal memory performance on the California Verbal Learning Test and more errors in the Spatial Working Memory Test. Ecstasy users showed a cortical reduction of SERT binding prominently in primary sensory motor cortex, with normal dopamine transporter binding in the lenticular nuclei. There was also an association between the length of the MDMAfree period (mean 18 days) before the scan and ligand binding in the cingulate. Spatial working memory performance and SERT binding in the left calcarine cortex were negatively correlated with the estimated life-time dose of MDMA in the ecstasy users. While these results could be coincidental, or reduced SERT binding could be the imaging correlate of a psychobiological predisposition to heavy use of ecstasy, the authors suggested that this study provided evidence for specific albeit temporary serotonergic neurotoxicity of MDMA in humans. If confirmed, these effects on the serotonergic system could underlie psychiatric morbidity in ecstasy users. Eleetrolyte balance Yet another death from hyponatremia after ecstasy use has been reported from New Zealand, where it is a commonly used recreational drug (12Ar). A 27-year-old woman was admitted to the intensive care unit with coma and respiratory arrest. She had been seen taking two ecstasy tablets while dancing at a nightclub about 5 hours before admission. She had drunk copious amounts of water to cool herself. When she reached the hospital, her Glasgow

35 score was 3 and she was in respiratory arrest with fixed dilated pupils. Her serum sodium concentration was 124 mmol/1 with a low serum osmolarity (267 mmol/1) and normal renal function. Her toxicology screen was positive for ethanol, and MDMA was found in her serum. The electrocardiogram showed a sinus tachycardia without ischemia, and a chest Xray showed gross pulmonary edema. A CT scan of the brain showed generalized cerebral edema, diffuse cerebral swelling, and significantly increased intracranial pressure; the basal cisterns and extracerebral spaces were completely effaced. Brain death was confirmed by cerebral angiography, which showed no intracranial flow in the carotid or vertebral arteries. The post-mortem report confirmed marked cerebral edema with signs of cerebellar tonsillar herniation. The authors reviewed the possible explanations, already discussed extensively in the literature, which include excess water ingestion, the syndrome of inappropriate antidiuretic hormone secretion, and the serotonin syndrome. While many ecstasy users drink water to counter its hyperthermic effects, others do it because of "health advice" given at such parties to prevent toxic effects. However, water intoxication and related death is an important consequence that can occur, albeit infrequently. The authors advised the medical community to consider ecstasy use in the differential diagnosis of hyponatremia and water intoxication in young patients. Immunologic Four healthy male MDMA users volunteered for a randomized, doubleblind, double-dummy, cross-over pilot study in which they took single oral doses of MDMA 75 mg (n = 2) or 100 mg (n = 2), alcohol (0.8 mg/kg), MDMA and alcohol, or placebo to study the effects on their immune system. The doses of MDMA were compatible with those used for recreational use (13 CR). The subjects' baseline immunological parameters were within the reference ranges. Acute MDMA use produced time-dependent immune dysfunction, which paralleled MDMA plasma concentrations and MDMA-induced cortisol stimulation kinetics. The changes in the immune system after MDMA peaked at 1-2 hours. Although the total leukocyte count remained unchanged, there was a fall in the ratio of

CD4 to CD8 T cells and in the percentage of mature T lymphocytes (CD3), probably because of a fall in both the percentage and the absolute number of T helper cells. The fall in CD4 cell count and in the functional

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36

responsiveness of lymphocytes to mitogenic stimulation with phytohemagglutinin A was M D M A dose-dependent. Alcohol produced a decrease in T helper cells, B-lymphocytes, and mitogen-induced lymphocyte proliferation. Combined M D M A and alcohol use produced the greatest suppressive effect on CD4 cell count and mitogen-stimulated lymphoproliferation. Immune function was partially restored at 24 hours. According to the authors, these results provide the first evidence that recreational use of M D M A alone or in combination with alcohol alters immunological status. The reaction of the immune system to M D M A appears to be an alteration of physiological homeostasis, similar to that seen in volunteers exposed to acute physiologic stress, suggesting that M D M A could be a "chemical stressor". Moreover, combined M D M A and alcohol use produced additive effects. This is an important finding, since in the general population the combined use of alcohol and M D M A is common.

CANNABINOIDS

(SED-14, 95;

SEDA-21, 23; SEDA-23, 41) In a recent review, concerns were raised about the possible adverse effects of acute as well as chronic medicinal and recreational use of cannabis on cognition and the body (14R). The author, while acknowledging the therapeutic role of carmabinoids in the management of pain and other conditions, expressed concern that in recent years the prevalence of recreational cannabis use (especially in the young) and the potency of the available products have markedly increased in the UK. C a r d i o v a s c u l a r A case of progressive arteritis associated with cannabis use has been reported (15AR). A 38-year-old Afro-Caribbean man was admitted after 3 months of severe constant ischemic pain and numbness affecting the right foot. The pain was worse at night. He also had intermittent claudication after walking 100 yards. He had a chronic history of smoking cannabis about 1 ounce/day, mixed with tobacco in the early years of usage. However, at the time of admission, he had not used tobacco in any form for over 10 years. He had patchy necrosis and ulceration of the toes and impalpable pulses in the right foot. The serum cotinine concentrations were

JayendraK. Patel, Eileen Wong and Alan 1. Green consistent with those found in non-smokers of tobacco. Angiography of his leg was highly suggestive of Buerger's disease (thromboangiitis obliterans). Remarkably, this patient, despite having abstained from tobacco for more than 10 years, developed a progressiv e arteritis leading to ischemic changes. While arterial pathology with cannabis has been reported before, it has been difficult to dissociate the effects of other drugs. N e r v o u s system An unusual account of transient amnesia after marijuana use has been reported from Europe (16AR). A 40-year-old healthy man with a long history of cannabis use was hospitalized with an acute memory disturbance after smoking for several hours a new, strong type of marijuana called "superskunk". After smoking, he had difficulty recollecting recent events and would ask the same questions repeatedly. While his routine laboratory results were within the reference ranges, his urine and blood toxic screens had very high concentrations of cannabinoids (and no other drugs). He was alert and oriented to his name, address, date, and place of birth, but could not recall his marital status, whether he had children, or the nature of his job. He was disoriented in time. He performed normally in tests of general cognitive functioning (e.g. Raven's matrices, word fluency, Rey's complex figure-copy, etc.) and shortterm memory (e.g. digit span, verbal cues, etc.), but showed severe impairment in verbal and nonverbal long-term components of anterograde memory tests. He had a severe retrograde memory defect mainly affecting autobiographical memory, with a temporal gradient such that remote facts were preserved. These memory impairments lasted 4 days and then rapidly improved, leaving amnesia for the acute episode. Electroencephalography during the anmestic episode was normal, except for brief trains of irregular slow activity in the frontal areas bilaterally. A single photon emission computed tomography (SPECT) scan of his brain was normal. A week later, repeat neuropsychological examination showed normal memory and a normal electroencephalogram and MRI scan of the brain with enhancement. One year later, he had stopped using marijuana and had no further amnestic episodes. The authors found similarities between the memory disorder seen here and transient global amnesia, which consists of anterograde amnesia and a variably graded retrograde amnesia. Such amnesia has been previously reported with a number of substances and medications, but not with marijuana. The authors stated that although memory impairment has been repor-

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ted with marijuana before, it has never involved retrieval of already learned material. They wondered if the memory impairment was due to marijuana-induced changes in cerebral blood flow and ischemia through vasospasm. However, their SPECT data did not support this theory. They considered the possibility that cannabinoid receptors, which are dense in the hippocampus, could have been occupied by marijuana, resulting in such memory loss. They cautioned that the effects of marijuana on memory may be more severe then previously thought.

COCAINE (SED-14, 106; SEDA-21, 23; SEDA-22, 31; SEDA-23, 37) Cardiovascular Cocaine can cause various cardiovascular disorders. Myocardial infarction after cocaine use has been well documented (SEDA-22, 15; SEDA-18, 36). By one estimate, since the first report in 1982, over 250 cases have been reported, mostly in the US. The first report from the UK has recently been published (17AR). Dysrhythmias seem to be the most likely cause of sudden death from cocaine, but cardiac conduction disorders are more common in patients with acute cocaine toxicity. A new report has discussed how severe cocaine toxicity causes acidemia and cardiac dysfunction (18CR). Descriptions of four patients with seizures, psychomotor agitation, and cardiopulmonary arrest were provided. The first two cases are briefly summarized here. A 43-year-old man injected a large dose of cocaine in a suicide attempt and had a seizure and cardiopulmonary arrest, from which he was resuscitated. His arterial blood pH was 6.72 and his electrocardiogram showed a wide complex tachycardia. An infusion of sodium bicarbonate maintained the blood pH at 7.50 and the electrocardiogram became normal. The bicarbonate infusion was discontinued after 12 hours. A 25-year-old man had a cardiac arrest after taking one "knot" or sealed bag of crack cocaine (2.5 g) and was resuscitated. His arterial blood pH was 6.92 and an electrocardiogram showed sinus rhythm, QRS axis 300~ and terminal 40 msec of the QRS axis 285~. After an infusion of sodium bicarbonate, his blood pH was 7.30, his QRS axis 15~ and the terminal 40 msec QRS axis 30~ He passed the bag of cocaine rectally within 12 hours of admission.

37 These patients' initial laboratory values showed acidosis, prolongation of the QRS complex and QTc interval, and right axis deviation. Appropriate treatment included hyperventilation, sedation, active cooling, and sodium bicarbonate, which led to correction of blood pH and of the cardiac conduction disorders. The authors suggested that when intracellular pH is lowered, myocardial contractility is depressed as a result of reduced calcium availability. During acidosis, there are abnormalities of repolarization and depolarization, which potentiate dysrhythmias. The electrocardiographic PR interval increased with increasing abstinence from crack cocaine in a study of 441 chronic cocaine users who had smoked at least 10 g of cocaine in the 3 months before enrollment (19CR). The authors suggested that this may have reflected the normalization of a depolarization defect. Chronic cocaine users have shortened PR intervals, indicative of rapid cardiac depolarization. Nervous system New research in 21 cocaine users and 13 non-drug-using, age-matched controis has suggested that chronic cocaine use may be associated with specific neurochemical changes in the brains of habitual users (20CR). All the subjects underwent a spectral brain scan in a proton MRS scanner. The significant finding was that the concentration of N-acetylaspartate in the left thalamus (but not in the basal ganglia) was significantly lower (17%) in the chronic cocaine users than in the controls. N-acetylaspartate is found in adult neurons and not in glia; it is often used as a marker of neuronal viability; a reduction suggests neuronal damage and/or loss. A new study has provided more information about the cause of cocaine-related stroke and transient ischemic attacks (21CR). Transcranial Doppler sonography, a continuous measure of cerebral blood flow velocity, was used to monitor the course of cerebral hemodynamic changes during acute cocaine administration. Blood flow velocity in seven cocaine abusers was studied during intravenous injections of placebo, and of cocaine I0, 25, and 50 mg. There was a significant increase in mean and systolic velocity (lasting about 2 minutes) with all doses of cocaine, but not with placebo. Cocaine produced an immediate brief period of vasoconstriction (as demonstrated by an in-

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crease in systolic velocity) in the large arteries of the brain. A recent report suggests that even after 4 weeks of abstinence, chronic heavy cocaine users have poor cognitive functioning compared with non-drug-using controls (22r A battery of neuropsychological tests was administered to 30 abstinent chronic cocaine abusers and 21 non-drug-using matched controls. Decrements in areas such as executive functioning, visuoperception, psychomotor speed, and manual dexterity were associated with heavier use of cocaine. Neither frequency nor duration of cocaine use was a strong predictor of performance.

Gastrointestinal Intestinal ischemia is an uncommon complication of cocaine (SEDA-22, 31; SEDA-23, 25). Another case has been reported (23AR). A 36-year-old man who had injected cocaine the day before admission and who occasionally sniffed, smoked, or injected cocaine, presented with a 3-day history of severe abdominal pain and bloody diarrhea. His mid-abdomen was very tender, with rebound tenderness and guarding; bowel sounds were absent. Radiography showed a dilated transverse colon and dilated small bowel loops. He underwent emergency surgery and an edematous dilated transverse colon was removed. The pathology was consistent with ischemic colitis. The blood vessels were dilated but showed no structural abnormalities or thrombosis. U r i n a r y t r a e t Chronic cocaine use can exacerbate pre-existing hypertension, when renal blood vessels narrow secondary to cocaineinduced intimal fibrosis. Acute renal insufficiency with concomitant rhabdomyolysis after cocaine use has been reported before. Acute renal insufficiency in the absence of rhabdomyolysis, which is very rare, has recently been reported (24Ar). A healthy 3 l-year-old man developed acute renal insufficiency 18 hours after inhaling cocaine 5 g. His blood pressure was 150/100 mmHg., his serum creatinine 177 Ixmol/l, the creatine phosphokinase activity was 107 U/l, and the potassium was 3.8 mmol/1. Urinary sodium was 30 mmol/1, and there was a trace of protein and 1-2 red blood cells per high-power field. Immunological studies were unremarkable. On ultrasound, the kidneys were of normal size with hyperechogenity of the right kidney. Over the next 10 days he recovered spontaneously.

Jayendra K. Patel, Eileen Wong and Alan I. Green The authors suggested that intense cocaineinduced renal vasoconstriction was the likely underlying mechanism. Sexual f u n c t i o n Priapism has previously been reported in male cocaine users (SEDA19, 26; SEDA-23, 24) and three new cases have been reported (25AR). Each of the three men had delayed seeking treatment. Cocaine use within the previous 24 hours was the singular contributing factor in all three. Two of the men had had previous episodes of priapism, which had resolved spontaneously. Initial duplex ultrasound tests confirmed low penile blood flow. Manual aspiration and irrigation failed in all three cases. Surgical shunting failed in the first two cases. One man required partial penile amputation for infected, gangrenous, distal penile tissue; one responded to angiographic embolization; and one had only a partial response to angiographic embolization, but then refused further intervention his erection resolved during the next 24 hours. The authors suggested that acute sexual excitement during cocaine intoxication may result in penile erection, with impaired detumescence. Cocaine can inhibit the re-uptake of noradrenaline (by blocking transport in presynaptic sympathetic neurons), thus preventing sinusoidal contraction and the efflux of penile blood. I m m u n o l o g i c A case of urticarial vasculitis, a type III hypersensitivity reaction, has been reported after cocaine use (26AR). A 24-year-old man with acute malaise and fever had a pruritic rash with multiple erythematous circumscribed weals on the trunk, arms, legs, neck, and scalp. He admitted to using intranasal cocaine 6 months, 4 days, and 1 day before the onset of the symptoms. His temperature was 39~ His erythrocyte sedimentation rate was 80 mm in the first hour, C-reactive protein 283 mg/1 (normal <10) and the white blood cell count was 12.4 x 109/1 with 89% neutrophils. A biopsy of an urticarial lesion showed a perivascular inflammatory infiltrate in the upper and middle dermis. The diagnosis was urticarial vasculifts. Bed rest, oral prednisone, oral hydroxyzine, and topical polidocanol led to improvement within 24 hours. Two cases of cocaine-induced anaphylaxis, a type I hypersensitivity reaction, have been reported (27At).

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A 23-year-old woman presented in distress with tongue swelling and difficulty in breathing immediately after having sniffed cocaine. The anterior half of her tongue was edematous with bleeding lesions caused by her fingernails. There were cocaine metabolites in the urine. The diagnosis was angio-edema of the tongue induced by cocaine or its contaminants, and it resolved with subcutaneous adrenaline, Hi-antagonist antihistamines, and intravenous corticosteroids. A 19-year-old man developed generalized urticaria, intense pruritus, and mild bronchospasm 30 minutes after injecting cocaine for the third time. He had weals on the face, neck, arms, and chest, and scattered wheezing in the lungs. Urine toxicology screen was positive for cocaine metabolites. His symptoms resolved several hours after the administration of HI -antagonist antihistamines and intravenous corticosteroids. Careinogenieity Chronic cocaine use, which is associated with immunosuppression, may be carcinogenic. The possible association between chronic cocaine exposure and pancreatic adenocarcinoma has recently been investigated (28CR). A study of hospital records in Brazil for the years 1986--98 showed that of 198 patients diagnosed with pancreatic adenocarcinoma, 13 (6.5%) were younger than 40 years; of these, five had a history of chronic cocaine inhalation; one had abused marijuana. The authors and the editor (29r) were surprised by these findings. Fetotoxicity Research on prenatal cocaine and polydrug exposure has previously focused on several domains of infant outcome, such as physical growth, neurodevelopmental status, and emotional and social functioning (SEDA21, 26; SEDA-22, 32; SEDA-23, 37). A recent study in 105 African-American infants has suggested that infants exposed prenatally to cocaine are at a high risk of significant problems in arousal and attention (30CR). The 8-weekold infants had their heart rates recorded when presented with a series of stimuli. The order of the stimuli was as follows: auditory (rattle), visual (red ring), and social (examiner's face and voice). The infants were categorized in four groups: preterm drug-exposed (n = 25); full-term drug-exposed (n = 32); preterm nonexposed (n = 22); and full-term non-exposed (n = 26). Preterm infants' ages were corrected to match those of the full-term infants. There were significant differences in the responses to social stimuli. Drug-exposed infants had an accelerated heart rate (indicating distress or arousal),

whereas non-drug exposed infants had a slowed response (indicating focused attention). However, there were no heart rate differences among the groups in the auditory or visual conditions. The effects of prenatal maternal cocaine use on neurobehavior have been reported in 2-week-old infants (31CR). The Brazelton Neonatal Behavioral Assessment Scale (BNBAS) was administered to the infants of mothers who had a reported high frequency of cocaine use during pregnancy: (n = 23, >75th percentile reported days of use) or a low frequency (n = 32, <75th percentile). Infants with a high intrauterine exposure had higher scores on the BNBAS excitability cluster than infants with a low exposure. Infants with a high BNBAS excitability score had poorer tone and motor movement, were more irritable and hard to console, and had difficulties in selfquieting. In a meta-analysis of 18 published reports (1985-88, 13 of which failed to meet the inclusion criteria and were excluded) on the effect of in utero exposure to cocaine on infant neurobehavioural outcome, cocaine-exposed infants were compared to non-exposed infants on BNBAS cluster scales at birth and at 3-4 weeks of age (32M). Although the sample size was large enough to detect statistical significance in most of the tests of difference between the two groups, the magnitude of all the effects was small. This was true for differences in the motor performance and abnormal reflex clusters in the infant groups (with a slight trend toward increasing standard differences over time) and in the orientation and autonomic regular clusters (with a trend towards a reduced effect size over time). However, the main finding of the study was the small magnitude of the neurobehavior dysfunction at both times. The authors' cautioned that these data may not be generalizable, since polydrug exposure, the amount of cocaine exposure, and other variables could have confounded the data.

(SED-14, 198; SEDA-21, 33; SEDA-22, 35) (see also Chapter 8) OPIATES

Oral opiates are extensively used worldwide. Codeine, an oral opiate analgesic, and its combination products are among the most widely prescribed classes of psychotropic drugs. Many clinical effects attributed to codeine, which

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Chapter 4

is metabolized through O-demethylation to morphine, probably result from the actions of morphine. Nervous system The Swiss government has developed a program called PROVE, which provides prescriptions of injectable opioids for the treatment of heroin-dependent patients. This program has generally been viewed to be successful in terms of retention in treatment, morbidity and mortality, legal behavior, and costeffectiveness. However, during the 26-month observation period, epileptic seizures occurred in 11% of the 186 patients treated. This finding, along with previous reports of reduced regional blood supply to the brains of opioid users, led the authors to study cerebral deoxygenation after intravenous opioid administration in 10 opioid-dependent subjects and to compare it with intravenous saline in 10 matched controls using Near Infrared Spectroscopy (NIRS) (33CR). Heroin and methadone produced a rapid and dramatic reduction in both respiratory rate and cortical hemoglobin oxygenation, while saline had no effects. The authors suggested that opioid-induced acute deoxygenation of cortical hemoglobin was probably associated with respiratory depression. In one in three subjects, oxygen saturation after intravenous heroin fell rapidly, a finding that has not previously been described in humans. The authors suggested two possible mechanisms for this phenomenon. They discounted the possibility that opioids increase the utilization of oxygenated hemoglobin in the CNS, because PET data from other studies suggest decreased utilization of glucose (indicating reduced brain activity) following opioids. They believed that it was more likely that the increase in cortical reduced hemoglobin was related to opioid-induced respiratory depression, with carbon dioxide retention and resulting vasodilatation. Although preliminary, these data have potential implications for treatment programs involving intravenous opioid maintenance. The authors suggested that intravenous opioids may produce both systemic and cerebral hypoxia, which may at least in part account for the hyperexcitability (as measured by electroencephalography) found after intravenous opioids in other studies. Furthermore, hypoxia may mediate or contribute to the rush sensation, similar to that seen with high altitude or in cases of asphyxiophilia.

Jayendra K. PateL Eileen Wong and Alan L Green

Heroin and progressive spongiform leukoencephalopathy "Chasing the dragon" or inhaling heroin vapor through a straw or tube to produce a "high" is an increasingly popular technique by which heroin users avoid the risks and adverse effects o f parenteral drug use. However, a rare consequence o f inhaling heated heroin is a progressive spongiform leukoencephalopathy. The first three cases in the US were reported in 1996 (SEDA-22, 35). A new reporthas provided more details from physical assessments and laboratory and radiological (MRI and MRS) data, and more information about the course of this heroin-related effect (34AR). The three cases showed raised concentrations o f intracerebral lactate (reflecting mitochondrial dysfunction), which suggests a conversion o f aerobic to anaerobic metabolism seen in hypoxic-ischemic conditions, including stroke. One patient recovered quite well after antioxidant therapy, supporting a metabolic effect o f the heroinrelated toxin; a similar response to co-enzyme Q has been found in other mitochondrial disorders with a high CSF lactate. Thus, the authors recommended that although the role o f antioxidant therapy in this condition is unclear, it may be prudent to administer oral co-enzyme Q supplemented with vitamins C and E to patients with this syndrome. The etiology of the leukoencephalopathy is unclear. Because cases occur in clusters, even though many others who inhale heroin do not get this effect, there is suspicion about the possible role o f contaminants o f small batches o f drug by an unknown substance. In addition, some have suggested that heating could be important, since leukoencephalopathy has not been reported with other means o f heroin use (until this year, as reported in the next case). The authors o f the report postulated that there might be a relation between the amount o f heroin inhaled and the severity o f the illness. Once symptoms develop, progression continues, usually f o r 2-3 weeks, but in some individuals it progresses f o r up to 6 months after exposure. "Coasting", or the phenomenon o f symptom progression after cessation of exposure to toxins, has been observed with other toxins, and it is proposed to result from the storage o f toxin in lipid-rich neural or non-neural body tissues, with subsequent release into the bloodstream. Although the "toxin" involved in this

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condition is unknown, progression could be due to "coasting". Alternatively, oxidative damage could be initiated by the toxin and produce persistent metabolic changes in the affected white matter. Whatever the mechanism, the illness is extremely grave, with no known treatment and with progression to akinetic mutism and death in about 20% of reported cases. Another case of toxic leukoencephalopathy (but with a good outcome) has been reported (35Ar). A 37-year-old male cocaine abuser was admitted with intoxication, mutism, and substupor. His toxicological screening was positive for heroin and cocaine. There was spasticity of all limbs and Babinski reflexes. The cerebrospinalfluid contained some erythrocytes. The electroencephalogram showed generalized slowing, and a CT scan showed bifrontal confluent hypodensities in the deep white matter. The cranial MRI scan showed diffuse bihemispheric white matter lesions dominantly in thefrontal lobe on T2 weighted images. There were abnormal hyperintense lesions in the pyramidal tracts and the corpus callosum. He gradually improved and made a complete recovery within 6 months, as confirmed by neurological and neuropsychological examination. The finding of toxic leukoencephalopathy in this patient's brain imaging studies were similar to those reported in patients who have inhaled impure heroin. However, he had used intravenous heroin and cocaine. This is therefore the first case report of leukoencephalopathy after intravenous use of these drugs. However, it should be noted that the authors did not indicate how the route of drug use was confirmed. They noted that lipophilic substances, such as hexachlorophene or triethylthin, were likely impurities in the abused substances. These two reports raise serious concerns about the possible role of contaminants in the etiology of clinically significant consequences from the use of heroin.

Psychiatric In an exploratory survey among long-term codeine users recruited via newspaper advertisements in Toronto, Canada, more than 300 individuals who used codeine on at least 3 days per week for a minimum of 6 months and were older than 16 years were studied (36CR). Those who used codeine for pain related to malignancy were excluded. The mean age of the respondents included in the final ana-

41 lysis (n = 339) was 44 years and 51% were women. On average, the total years of regular codeine use were 12 with a current mean daily dose of 115 mg. About 60% (n = 213) had sought help for mental health problems, most commonly for depression (70%), followed by generalized anxiety (55%) and panic attacks (24%). One-third of the subjects (n = 339) identified at least one family member as having a mental health problem, with depression as the most frequent. Current antidepressant use was reported by 14% of the whole sample. Men used significantly higher doses of codeine than women, had used the drug for a longer period, and more commonly took it for pleasurable effects and under social pressure. Regular codeine users, in addition to having high rates of drug dependence, had raised scores on general measures of psychological distress and depressive symptoms. From the survey it was not clear to what extent these symptoms preceded codeine use and may have initiated the use and to what extent they were caused by codeine. The authors speculated that many respondents used codeine to modulate mood, particularly dysphoria, in the absence of more appropriate interventions. They suggested that understanding long-term codeine use and its relation to dysphoria may be important in designing both preventive and secondary treatment interventions. The same investigators further analyzed the data according to codeine abuse/dependent and non-dependent status (37CR). There was codeine abuse/dependence in 41% of the subjects. The most common psychological and physical problems attributed to codeine use in the dependent/abuse group (n = 124) were depression (23%), anxiety (22%), gastrointestinal disturbances (15%), constipation (6%), and headache/migraine (5%). The codeinedependent subjects were younger than those who were not dependent. The mean age of the respondents when they first started using codeine was 26 (range 2-78) years. A total of 563 codeine products had been used on a regular basis; the most common combination involved codeine with paracetamol (70%). Codeine was used for headaches (41%), back pain (22%), and other types of pain (25%). Those in the dependent group were more likely to have used codeine initially for other reasons, e.g. pleasure and to relax or reduce stress. Most subjects said that they had obtained their

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Chapter 4

codeine from one physician (66%) or by purchasing it over the counter (54%). Subjects in the dependent group also obtained codeine from friends (32%), from family (11%), "off the street" (19%), and through prescriptions from more than one physician (11%). Overall, more subjects in the dependent group considered themselves to have problems with a larger number of substances (3.3: range 0-15) compared with those in the non-dependent group (1.2: range 0-8). In the dependent group, more subjects said that their physical or mental health problems interfered with normal social activities at least "quite a bit". Significantly more subjects in the dependent group had sought help for a mental health problem, had had an inpatient psychiatric admission, or had sought help for a substance-use disorder, especially alcohol and stimulants. A larger number of subjects in the dependent group identified at least one family member (usually male) with substance-use problems compared with those in the non-dependent group. This study suggests that codeine dependence may be more common in the general population than has been previously thought. The authors suggested that it is important to identify those with codeine abuse or codeine dependence, since they may be using substantial doses of codeine for apparently little benefit compared to the risks. Furthermore, there are also health risks of associated chronic use of paracetamol and a potential for analgesic rebound headache. D r u g withdrawal The relation between the severity of opiate withdrawal and the dose, duration, and route of administration of heroin has been assessed in a retrospective analysis of heroin withdrawal in 22 patients (38 cR). Abrupt withdrawal from opiates resulted in increased symptom severity, peaking on day 2 and then abating after that until day 7. Both the dose and the route of administration were related to the withdrawal score: intravenous heroin was linked to greater total and maximum withdrawal severity than smoking heroin. The authors speculated that the effect of the route of administration may have been due to lower systemic availability of smoked compared with injected heroin. Their data suggested that even the duration of the withdrawal symptoms seemed to increase with higher doses and intravenous use. However, there were several limitations to

Jayendra K. Patel, Eileen Wong and Alan 1. Green

this study. It was retrospective and the period of observation lasted only 7 days, although the withdrawal symptoms lasted much longer. In addition, many subjects took doxepin and benzodiazepines during the observation phase, which may have reduced or suppressed their withdrawal symptoms. Fetotoxidty A new report of death associated with intravenous heroin use has provided insights about the distribution of heroin and its metabolites in the fetus (39A~). A 17-year-old girl with a history of heavy drug abuse for 2 years was found in a public restroom, dead with fresh needle puncture marks. She was 18-20 weeks pregnant with a male fetus, and had massive brain and lung edema from acute intoxication. Analysis of her hair showed that she had used heroin over the previous few months. Drug screening of body fluids showed only opiates (high concentrations of 6-monoacetyl-morphine and morphine) in the maternal and fetal circulation at the time of death. Unexpectedly high amounts of morphine, 6-monoacetyl-morphine, and morphine-3glucuronlde were also found in the amniotic fluid. Only morphine-3-glucuronlde was detected in the fetus, whereas both morphine-3-glucuronlde and morphine-6-glucuronlde were detected in the mother, in the body fluids, and in all investigated organ tissues except the brain. The authors noted that heroin is considered a "pro-drug", with 6-monoacetyl-morphine, morphine, and morphine-6-glucuronide accounting for most of its narcotic activity. In blood, diamorphine is rapidly converted to the active metabolite 6-monoacetyl-morphine, which is presumably converted to morphine in the liver. The majority of the morphine is converted to morphine-3-glucuronide and small amounts are converted to morphine-6glucuronide, which is pharmacologically active. The authors concluded that morphine-3glucurohide can cross the placenta and that high concentrations of heroin and its metabolites can be found in fetal compartments during heroin abuse by the mother. Lastly, heroin and its pharmacologically active metabolites appear to be present in the fetal central nervous system for much longer than in the maternal circulation, because of low fetal drug-metabolizing capacity as well as minimal drug elimination from the amniotic fluid in advancing pregnancy. Pethidine is commonly used in some countries as an analgesic in maternal labor. The

Drugs of abuse

Chapter 4

analgesic and adverse effects of intramuscular pethidine 5 mg plus diamorphine 100 mg in labor have been studied in a randomized, double-blind, controlled study in 64 multiparous and 69 nulliparous women (40CR). There was a significantly higher incidence of low 1minute Apgar scores after pethidine compared with diamorphine. The study also confirmed that for women who requested intramuscular narcotic analgesia, neither diamorphine nor pethidine provided good pain relief, suggesting that there is a need to consider alternatives. Drug interactions Many heroin users use heroin and alcohol together. There has been a new evaluation of the pharmacokinetic interaction between heroin and alcohol and the role of that interaction in the cause of 39 heroin-related deaths that were attributed to either heroin or heroin + ethanol (41CR). The cases were arbitrarily divided into two groups according to blood ethanol concentration (low-ethanol

43 group, under 1000 mg/1, and high ethanol group, over 1000 mg/1). The high-ethanol group was associated with reduced hydrolysis of 6-acetylmorphine to morphine, and there was an inverse correlation between blood ethanol concentration and hydrolysis of 6-acetylmorphine to morphine. The concentration of total morphine was lower in the high-ethanol group. High blood ethanol concentrations were also associated with an increased ratio of unbound to total morphine and with reduced excretion of unbound and total morphine. The relative concentrations of conjugated heroin metabolites were reduced in the presence of a high blood ethanol concentration. The authors hypothesized that alcohol inhibits the glucuronidation of morphine, resulting in less conjugated morphine in the blood. Thus, in patients with high blood ethanol concentrations the additional depressant effects of unconjugated heroin metabolites may contribute to a more acute death.

REFERENCES 1. Gore SM. Fatal uncertainty: death-rate from use of ecstasy or heroin. Lancet 1999; 354: 126545. 2. Ramsey JD, Johnston A, Holt DW. Death rate from use of ecstasy or heroin. Lancet 1999; 354: 2166. 3. Lind J, Oyefeso A, Pollard M, Baldacchino A, Ghodse H. Death rate from use of ecstasy or heroin. Lancet 1999; 354: 2167. 4. Fineschi V, Centini F, Mazzeo E, Turillazzi E. Adam (MDMA) and Eve (MDEA) misuse: an immunohistochemical study on three fatal cases. Forensic Sci Int 1999; 104: 65-74. 5. Mintzer S, Hickenbottom S, Gilman S. Parkinsonism after taking ecstasy. New Engl J Med 1999; 340: 1443. 6. Sewell RA, Cozzi NV. More about parkinsonism after taking Ecstasy. New Engl J Med 1999; 341: 1400. 7. Baggot M, Mendelson J, Jones R. More about parkinsonism after taking Ecstasy. New Engl J Med 1999; 341: 1400-1. 8. Mintzer S, Hickenbottom S, Gilman S. More about parkinsonism after taking Ecstasy. New Engl J Med 1999; 341: 1401. 9. Borg GJ. More about parkinsonism after taking Ecstasy. New Engl J Med 1999; 341: 1400. 10. Bertram M, Egelhoff T, Schwarz S, Schwab S. Toxic leukoencephalopathy following "ecstasy" ingestion. J Neurol 1999; 246:617-18. 11. Semple DM, Ebmeier KP, Glabus ME O'Carroll RE, Johnstone EC. Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA ("ecstasy") users. Br J Psychiatry 1999; 175: 63-9.

12. O'Connor A, Cluroe A, Couch R, Galler L, Lawrence J, Synek B. Death from hyponatremia induced cerebral oedema associated with MDMA ("ecstasy") use. NZ Med J 1999; 112: 25545. 13. Pacifici R, Zuccaro P, Farre M, Pichini S, Di Carlo S, Roset PN, Ortuno J, Segura J, De La Torre R. Immunomodulating properties of MDMA alone and in combination with alcohol: a pilot study. Life Sci 1999; 65: 309-16. 14. Ashton CH. Adverse effects of cannabis and cannabinoids. Br J Anaesth 1999; 83: 637-49. 15. Schneider HJ, Jha S, Burnand KG. Progressive arteritis associated with cannabis use. Eur J Vasc Endovasc Surg 1999; 18: 366-7. 16. Stracciari A, Guarino M, Crespi C, Pazzaglia P. Transient amnesia triggered by acute marijuana intoxication. Eur J Neurol 1999; 6: 521-3. 17. Inyang VA, Cooper AJ, Hodgkinson DW. Cocaine induced myocardial infarction. J Accid Emerg Med 1999; 16: 374-5. 18. Wang RY. pH-dependent cocaine-induced cardiotoxicity. Am J Emerg Med 1999; 17: 364-9. 19. Kajdasz DK, Moore JW, Donepudi H, Cochrane CE, Malcolm RJ. Cardiac and mood-related changes during short-term abstinence from crack cocaine: the identification of possible withdrawal phenomena. Am J Drug Alcohol Abuse 1999; 25: 629-37. 20. Li SJ, Wang Y, Pankiewicz J, Stein EA. Neurochemical adaptation to cocaine abuse: reduction of N-acetyl aspartate in thalamus of human cocaine abusers. Biol Psychiatry 1999; 45: 1481-7. 21. Herning RI, Better W, Nelson R, Gorelick D, Cadet JL. The regulation of cerebral blood flow

44

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during intravenous cocaine administration in cocaine abusers. Ann NY Acad Sci 1999; 890: 489-94. 22. Bolla KI, Rothman R, Cadet JL. Dose-related neurobehavioral effects of chronic cocaine use. J Neuropsychiatry Clin Neurosci 1999; 11: 3619. 23. Papi C, Candia S, Masci P, Ciaco A, Montanti S, Capurso L. Acute ischaemic colitis following intravenous cocaine use. Ital J Gastroenterol Hepatol 1999; 31: 305-7. 24. Amoedo ML, Craver L, Marco MP, Fernandez E. Cocaine-induced acute renal failure without rhabdomyolysis. Nephrol Dial Transplant 1999; 14: 2970. 25. Altman AL, Seftel AD, Brown SL, Hampel N. Cocaine associated priapism. J Urol 1999; 161: 1817-18. 26. Hofbauer GFL, Hafner J, Trueb RM. Urticarial vasculitis following cocaine use. Br J Dermatol 1999; 141: 600-1. 27. Castro-Villamor MA, De Las Heras P, Armentia A, Duenas-Laita A. Cocaine-induced severe angioedema and urticaria. Ann Emerg Med 1999; 34: 296-7. 28. Duarte JGC, Nascimento AF, Pantoja JG, Chaves CP. Chronic inhaled cocaine abuse may predispose to the development of pancreatic adenocarcinoma. Am J Surg 1999; 178: 426-7. 29. Nahrwold DL. Editorial comment. Am J Surg 1999; 178: 427. 30. Coles CD, Bard KA, Platzman KA, Lynch ME. Attentional response at eight weeks in prenatally drug-exposed and preterm infants. Neurotoxicol Teratol 1999; 21: 527-37. 31. Schuler ME, Nair P. Brief Report: frequency of maternal cocaine use during pregnancy and infant neurobehavioral outcome. J Pediatr Psychol 1999; 24: 511-14. 32. Held JR, Riggs ML, Dorman C. The effect of prenatal cocaine exposure on neurobehavioral outcome: a meta-analysis. Neurotoxicol Teratol 1999; 21: 619-25.

Jayendra K. Patel, Eileen Wong and Alan I. Green 33. Stohler R, Dursteler KM, Stormer R, Seifritz E, Hug I, Sattler-Mayr J, Muller-Spahn F, Ladewig D, Hock C. Rapid cortical hemoglobin deoxygenation after heroin and methadone injection in humans: a preliminary report. Drug Alcohol Depend 1999; 57: 23-8. 34. Kriegstein AR, Shungu DC, MiUar WS, Armitage BA, Brust JC, Chillrud S, Goldman J, Lynch T. Leukoencephalopathy and raised brain lactate from heroin vapor inhalation ("chasing the dragon"). Neurology 1999; 53: 1765-73. 35. Maschke M, Fehlings T, Kastrup O, Wilhelm HW, Leonhardt G. Toxic leukoencephalopathy after intravenous consumption o f heroin and cocaine with unexpected clinical recovery. J Neurol 1999; 246: 850-1. 36. Romach MK, Sproule BA, Sellers EM, Somer G, Busto UE. Long-term codeine use is associated with depressive symptoms. J Clin Psychopharmacol 1999; 19: 373-6. 37. Sproule BA, Busto UE, Somer G, Romach MK, Sellers EM. Characterstics of dependent and nondependent regular users of codeine. J Clin Psychopharmacol 1999; 19: 367-72. 38. Smolka M, Schmidt LG. The influence of heroin dose and route of administration on the severity of the opiate withdrawal syndrome. Addiction 1999; 94: 1191-8. 39. Potsch L, Skopp G, Emmerich P, Becker J, Ogbuhui S. Report on intrauterine drug exposure during second trimester of pregnancy in a heroinassociated death. Ther Drug Monit 1999; 21: 593-7. 40. Fairlie FM, Marshall L, Walker JJ, Elboume D. Intramuscular opioids for maternal pain relief in labour: a randomized controlled trial comparing pethidine with diamorphine. Br J Obstet Gynaecol 1999; 106: 1181-7. 41. Polettini A, Groppi A, Montagna M. The role of alcohol abuse in the etiology of heroin-related deaths. Evidence for pharmacokinetic interactions between heroin and alcohol. J Anal Toxicol 1999; 23: 570-6.

Stephen Curran and Shabir Musa

5

Hypnosedatives and anxiolytics

Insomnia and anxiety disorders are common, and the use of hypnotics and sedatives in these conditions is important. For most of these conditions, pharmacological and psychological approaches have an important contribution to make. Patients with insomnia should be carefully assessed before pharmacological treatment and any specific causes of insomnia should be identified and corrected or treated, including physical illness, stress-related disorders, psychiatric illness, disturbances of the sleep-wake cycle, and pharmacological causes, including excessive caffeine. It is also important to consider simple but important factors, such as room temperature, lighting, and noise, as well as day-time sleeping (sleep hygiene). The latter is a very common cause of "insomnia" in older people, ff after a careful assessment and the treatment or management of these problems, when present, the patient still has insomnia, a hypnotic drug can be considered for a short period (2-3 weeks continuously or for longer periods if given intermittently). The choice of drug will depend on individual circumstances, but in general drugs should have relatively short half-lives to avoid next-day psychomotor impairment. This latter point is particularly important for people who have to drive or operate dangerous machinery and in older people, who might be at greater risk of falling. An excellent report on insomnia has been .published by the World Health Organisation (1'~), addressing all of these points. In addition, developments in the pharmacology of this important group of drugs has improved the choice of treatment. Newer drugs have comparable or improved efficacy and significantly improved adverse effects profiles, but they are inevitably more expensive and are therefore not universally available.

AZASPIRONES

(SED-14, 133:

SEDA-21, 39; SEDA-22, 39; SEDA-23, 45)

Buspirone The safety results from two comparisons of buspirone 15 mg bd and buspirone 10 mg tds in patients with persistent anxiety have been subjected to meta-analysis (2M). The incidence of adverse events was similar between the two groups, except for a significantly higher incidence of bouts of palpitation in patients taking buspirone bd (5%) compared with tds (1%). The most frequently reported adverse events for both regimens were dizziness, headache, and nausea. There were no appreciable differences between treatments in vital signs, physical examination, electrocardiography, or clinical laboratory results. A change to twice-dally dosing for buspirone may offer convenience and possibly greater compliance in patients with persistent anxiety, without compromising the excellent safety and tolerability profile of the medication. The effects of hydroxyzine 50 mg/day, buspirone 20 mg/day, and placebo have been studied in 244 patients with generalized anxiety disorder in a double-blind placebo-controlled study (3c). Hydroxyzine (n = 81) was considerably better than placebo (n = 81), with buspirone (n = 82) intermediate. The main adverse effects were headache and migraine with buspirone: 6.1% versus 4.9% with hydroxyzine and 1.2% with placebo. Somnolence occurred in 9.9% with hydroxyzine, 4.9% with buspirone, and none with placebo. Dizziness occurred in 6.1% with buspirone, none with hydroxyzine, and 2.5% with placebo.

Drug interactions 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24

A 49-year-old man had major adverse effects 11 days after taking a combination of sertraline, buspirone, and

J.K. Aronson, ed.

45

46 loxapine (4A). The adverse effects were characteristic of the serotonin syndrome, which is characterized by a constellation of symptoms, including hypomania, agitation, seizures, confusion, restlessness, hyper-reflexia, tremor, myoclonus, ataxia, incoordination, anxiety, double vision, fever, shivering, variable effects on blood pressure, nausea and vomiting, sweating, and diarrhea.

BENZODIAZEPINES

(SED-14, 122; SEDA-21, 37; SEDA-22, 40; SEDA-23, 44)

Alprazolam Cardiovascular A 76-year-old woman with a past medical history of hypertension, valvular heart disease (mitral regurgitation) with chronic atrial fibrillation, chronic obstructive airways disease, diverticular disease of the sigmoid colon, and generalized anxiety disorder developed severe hypotension with associated tachycardia after taking alprazolam for 7 days (5A). In addition, she had severe weakness, depressed mood, and impaired gait and balance, without clinical features of neuromuscular disease.

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aged 22-35 years, and 13 men aged 65-75 years) who received a single intravenous dose of alprazolam 2 mg over 2 minutes (phase I), 15 young and 13 elderly men responded to alprazolam and agreed to participate in phase II of the study, which was a crossover of placebo and alprazolam infusion to plateau for 9 hours (7c). Plasma samples at 0, 1, 4, and 7 hours were assayed for steroid concentrations. Alprazolam produced (a) significant increases in dehydroepiandrosterone concentrations at 7 hours in both the young and elderly men; (b) significant reductions in cortisol concentrations; and (c) no change in dehydroepiandrosterone-S concentrations. The results suggest that alprazolam modulates peripheral concentrations of dehydroepiandrosterone and that dehydroepiandrosterone and/or dehydroepiandrosterone-S may have an in vivo role in modulating GABA receptor-mediated responses. Skin A 65-year-old man developed pruritic erythema on sun-exposed areas (photosensitivity) due to alprazolam (8A). A photopatch test was negative, but an oral photochallenge test with UVA irradiation was positive after he had taken alprazolam for 17 days. Alprazolam, a lipid-soluble drug, may require a long duration of administration to cause photosensitivity.

Nervous system Agoraphobia~panic disorder occurred in 31 patients, 15 of whom had originally been treated with alprazolam and 16 with placebo, who had been previously followedup during an 8-week treatment period, and had alprazolam-induced memory impairment (6c). These patients were reviewed 3.5 years after treatment to determine whether or not the memory impairments persisted. Those who had been treated with alprazolam performed as well as those who had taken placebo on the memory task and other objective tests. The performances in both groups were similar to pretreatment values. However, there were differences in subjective ratings: those who had used alprazolam rated themselves as less attentive and clear-headed and more incompetent and clumsy. Memory impairment found whilst patients were taking alprazolam did not persist 3.5 years later.

Endocrine Alprazolam may cause alterations in dehydroepiandrosterone and cortisol concentrations. Of 38 healthy volunteers (25 men

Drug overdose New cases of alprazolam overdose have been reported (9 A, 10A). A 28-year-old African-American man took alprazolam 12 mg. He denied using alcohol, other prescription medications, over-the-counter medications, or illicit drugs. He denied any suicidal intent. He stated that he had taken this large dose because his usual dose of 1-2 mg failed to relieve his anxiety. He was drowsy and his heart rate was 58 bpm. He had marked first-degree atrioventricular block with a PR interval of 500 msec. A 30-year-old woman, with a history of depression, was found dead after taking an unknown quantity of alprazolam, tramadol, and alcohol. At autopsy only slight decomposition and diffuse visceral congestion were observed. Blood concentrations of alprazolam, alcohol, and tramadol were 0.21 rag/l, 1.29 g/kg, and 38 mg/l respectively. The latter case illustrates that tramadol in overdose can cause death, especially when it is taken in combination with other CNS depressants, such as alprazolam and alcohol.

Hypnosedatives and anxiolytics

Chapter5

Clonazepam Drug interactions The effects of concomitant carbamazepine, phenytoin, sodium valproate, and zonisamide on the steady-state serum concentrations of clonazepam have been investigated in 51 epileptic in-patients under 20 years of age (llC). Serum concentrations of clonazepam correlated positively with the dose of clonazepam and negatively with the doses of carbamazepine and valproic acid, but not with phenytoin or zonisamide. These results confirm that as the oral doses of carbamazepine and sodium valproate increase, the serum concentration of clonazepam falls, but there is no interaction with either phenytoin or zonisamide. In the case of carbamazepine the mechanism of action is thought to be enzyme induction, increasing the metabolism of clonazepam. It is not known what the mechanism is with sodium valproate. In patients with epilepsy, the co-administration of either sodium valproate or carbamazepine will reduce the serum concentration of clonazepam and increase the risk of a seizure. When clonazepam is used in the treatment of epilepsy, sodium valproate and carbamazepine should be avoided; phenytoin and zonisamide would be safer alternatives.

Diazepam Cardiovascular A 51-year-old woman developed gangrene of the fingers after an intraarterial injection of diazepam 10 mg to control an acute claustrophobic anxiety attack (12A). R e s p i r a t o r y Of 94 children who presented with seizures 11 had respiratory depression after intravenous or rectal diazepam (13c). The use of diazepam as first-line therapy for children with acute seizures needs to be reviewed. Nervous system A 23-year-old man developed a brief fugue-like state with retrograde amnesia after short-term oral diazepam (14A), which has not been reported before. There was no other apparent cause for his symptoms, which resolved within 24 hours after diazepam withdrawal. Six patients had untoward effects from excessive rectal diazepam (15A). In three cases seizures reappeared and were interrupted by rectal diazepam, followed by sedation and gradual awakening; the intervals were about 4

47 days. The other three patients had variable and complex symptoms, with serial seizures and altemating states of tension, apathy, and sleepiness. The plasma concentrations of diazepam and desmethyldiazepam showed rapid fluctuations. When rectal diazepam is prescribed, chronic and excessive administration should be avoided. Skin Cutaneous adverse effects of diazepam are very rare. A 50-year-old woman was referred to hospital for chronic depression with alcohol dependence (16A). There was no history of drug allergy. She was given oral thioridazine 100 mg/day and diazepam 10 mg qds. After 2 days she noticed an erythematous eruption on her ankles. Thioridazine was withdrawn, but the eruption became more erythematous and affected both extremities and flanks within a few hours. She was given methylprednisolone 80 mg/day. The next day the eruption became bullous and she became pyrexial (39.4~ C). Urea and creatinine concentrations were normal. Blood cultures were negative. A skin biopsy showed bullous vasculitis with numerous eosinophils in the dermis. Diazepam was then withdrawn, the pyrexia resolved, and the skin lesions healed, although postinflammatory ulcers persisted on both ankles for 2 months. A lymphocyte blast transformation test was positive for diazepam. Fetotoxidty Postnatal, longitudinal, somatic, neurological, mental, and behavioral development has been studied at birth, and at 8, 15, and 24 months of life in children whose mothers had been treated during pregnancy with diazepam (n = 126) or promethazine (n = 127) and in children whose mothers had not been exposed (17c). The children in the diazepam group weighed less at birth, but not at 8 months or subsequently. D r u g interactions The effect of diazepam on the pharmacokinetics of ibuprofen has been studied in eight healthy subjects, who took ibuprofen or ibuprofen plus diazepam at 10.00 or 22.00 hours in a randomized cross-over study (18c). Diazepam significantly prolonged the half-life of ibuprofen at 22.00 hours but not at 10.00 hours. The mean clearance of ibuprofen was therefore reduced by diazepam at night. This time-dependent effect of diazepam on the pharmacokinetics of ibuprofen may be due to circadian variation in the pattern of protein production in the liver and/or competitive protein binding of the two drugs during the night.

48 A 50-year-old man with symptoms of chronic paranoid schizophrenia resistant to typical neuroleptic drugs had a brief syncopal attack with significant electrocardiographic changes (sinus bradycardia and deep anteroseptal inverted T waves and minor ST segment changes) after the dosage of clozapine was increased to 300 mg/day while he was taking diazepam (30 mg/day) (19A).

Lorazepam The value of the Saskatchewan data files in an acute adverse event signalling scheme has been evaluated using two benzodiazepines (20c). The first 20 000 patients taking lorazepam and the first 8525 patients taking alprazolam were followed for 12 months after the initial prescription. The most frequent adverse drug reactions associated with benzodiazepines were drowsiness, depression, impaired intellectual function and memory, lethargy, impaired co-ordination, dizziness, nausea and~or vomiting, skin rashes, and respiratory disturbance. Sleep disorders, depression, dizziness and/or vertigo, respiratory depression, gastrointestinal disorders, and inflammatory skin conditions occurred significantly more often during the first 30 days after the initial prescription than during the next 6 months in both drug groups, indicating that they are important adverse events.

Nervous system The effects of lorazepam (2.5 mg) and diazepam (0.3 mg/kg) on explicit and implicit memory tasks have been examined in 24 men and 24 women randomly allocated to lorazepam, diazepam, or placebo (21c). An implicit word-stem completion task and explicit memory tasks of immediate and delayed word recall and word recognition were administered 90 minutes after drug administration. Both diazepam and lorazepam significantly impaired performance on explicit memory measures. Only lorazepam significantly impaired performance on the implicit memory task. In a separate study, pharmacokineticpharmacodynamic modelling of the psychomotor and amnesic effects of a single oral dose of lorazepam 2 mg was investigated in 12 healthy volunteers in a randomized, doubleblind, placebo-controlled, two-way, cross-over study using the following tasks: choice reaction time, immediate and delayed cued recall of paired words, and immediate and delayed free

Chapter 5

StephenCurran and Shabir Musa

recall and recognition of pictures (22c). The delayed recall trials were more impaired than the immediate recall trials; similar observations were made with the recognition vs recall tasks.

Nitrazepam Between January 1983 and March 1994, 302 patients with intractable epilepsy were entered into a nitrazepam compassionate plea protocol (23c). Nitrazepam increased the risk of death, especially in young patients with intractable epilepsy. The authors suggested that nitrazepam should be used with caution in young children with intractable epilepsy, especially if they have difficulties in swallowing, aspiration, pneumonia, gastroesophageal reflux, or a combination of these.

Temazepam Drug overdose An 83-year-old woman developed coma, respiratory depression, hypotonia with generalized hyporeflexia, bilateral extensor plantar responses, and bullous eruptions containing serous fluid over the medial aspects of the knees after taking seven temazepam tablets (24A).

Triazolam Nervous system Ten healthy men participated in a randomized, double-blind, crossover study involving placebo and tfiazolam 0.125 mg (25c). Resting electroencephalography and event-related potentials under an oddball paradigm were recorded before drug administration, and at 1, 2, 4, 6, and 8 hours after. P300 waveforms were analyzed by peak amplitudes. Triazolam may cause cognitive dysfunction without general sedation or apparent sleepiness, and this effect appeared up to 6 hours after triazolam administration. Psychiatric The subjective and behavioral effects of a commonly used benzodiazepine, triazolam, have been investigated in 20 healthy women, who took triazolam (0.25 mg orally) or placebo at the follicular, periovulatory, and luteal phases of their menstrual cycle in a within-subject design (26c). After triazolam most of them reported the expected increases in fatigue and decreases in arousal and psychomotor performance. Neither plasma concentra-

Hypnosedatives and anxiolytics

Chapter5

tions of triazolam nor mood and performance differed across the three phases. This study shows that the effects of triazolam were highly stable across the menstrual cycle.

OTHER HYPNOSEDATIVES/ ANXIOLYTICS Chloral hydrate (SED-14, 133; SEDA-21, 39; SEDA-22, 42; SEDA-23, 46)

Drug overdose A 27-year-old man with a history of psychiatric illness became unconscious after taking about 20 g of chloral hydrate, 1000 mg of loxapine, and 180 mg of fluoxetine (27 A). He became unresponsive and hypotensive and had intermittent episodes of ventricular tachycardia, which was successfully treated with intravenous propranolol. Chloral hydrate toxicity can cause a number of dysrhythmias, including supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, and torsade de pointes.

Clomethiazole (SED-14, 133) The efficacy and safety of clomethiazole (75 mg/kg by intravenous infusion over 24 hours), as a neuroprotective drug, have been studied in a double-blind placebo-controlled trial in patients with acute hemispheric stroke (28c). Clomethiazole was generally well tolerated and safe. Sedation was the most common adverse event, leading to treatment withdrawal in 16% of patients compared with 4.2% of placebotreated patients.

Zaleplon Zaleplon is a non-benzodiazepine hypnotic, which is effective and well tolerated in the treatment of insomnia. It is a pyrazolopyrimidine hypnotic that binds selectively to the benzodiazepine type I receptor. Initial data suggest that sleep latency is improved and there is no significant next-day psychomotor impairment or memory impairment (29R). After oral administration it is well absorbed (71%) and peak concentrations are reached in about 60 minutes. However, it undergoes presystemic elimination and has a systemic availability of about 30%. Its

49 adverse effects include anterograde amnesia, depression, paradoxical reactions (e.g. restlessness, agitation), dependence, and withdrawal symptoms (related to the dose and duration of treatment). Although the data are limited, it is thought to be relatively safe in overdose, unless it is combined with other CNS depressants. The pharmacokinetics and absolute oral systemic availability of zaleplon have been assessed in a partially randomized, single-dose, cross-over study in 23 healthy subjects, who received intravenous infusions of zaleplon 1 and 2.5 mg during the first and second periods and were then randomly assigned to receive an oral dose of 5 mg or an intravenous infusion of 5 mg in a cross-over design (30c). The oral and intravenous doses of zaleplon were well tolerated. Somnolence, abnormal vision, diplopia, and dizziness were the most commonly reported adverse events. Zaleplon 10 mg, zolpidem 10 mg, or placebo were given double-blind to 36 healthy subjects under standardized conditions in a six-period, incomplete-block, cross-over study (31~). The subjects were gendy awakened and given the medication at predetermined times 5, 4, 3, or 2 hours before morning awakening, which occurred 8 hours after bedtime. When they awoke in the morning, subjective and objective assessments of residual effects of hypnotics were administered. There were no serious adverse experiences during the study; all adverse events were mild to moderate. The most commonly reported adverse events with zaleplon were weakness and somnolence. With zolpidem, weakness, depersonalization, dizziness, and somnolence were the most frequent CNS-related adverse events. The efficacy and safety of three doses of zaleplon have been compared with zolpidem 10 mg and placebo in 615 adult out-patients with insomnia (32c). After a 7-night placebo (baseline) period, the patients were randomly assigned to receive one of five treatments in double-blind fashion for 28 nights (zaleplon 5, 10, or 20 mg; zolpidem 10 mg; or placebo), followed by placebo for 3 nights. Sleep latency, sleep maintenance, and sleep quality were determined from sleep questionnaires each morning. The occurrence of rebound insomnia and withdrawal effects on withdrawal were also assessed. There was no evidence of rebound insomnia or withdrawal symptoms on withdrawal of zaleplon after 4 weeks. However,

50 after withdrawal of zolpidem, the incidence of withdrawal symptoms was significantly greater than after withdrawal of placebo, and there was suggestion of significant rebound insomnia in some patients who had taken zolpidem compared with placebo. The frequency of adverse events in the active treatment groups did not differ significantly from that in the placebo group.

Zolpidern (SED-14, 132; SEDA-21, 40; SEDA-22, 42; SEDA-23, 46) The safety and tolerability of zolpidem have been investigated in two multicenter studies, in which respectively 8.9% and 7.5% of the patients reported an adverse event (33c). The most frequent events were related to the central nervous system (somnolence, headache, confusion, vertigo), but gastrointestinal and cutaneous symptoms were also frequently reported. In a double-blind, placebo-controlled, cross-over study, 10 patients with "probable progressive supranuclear palsy" took single oral doses of zolpidem (5 and 10 rag), cocareldopa (250 mg of levodopa and 25 mg of carbidopa), or placebo in four separate trials in random order (34c). Zolpidem, unlike levodopa or placebo, reduced voluntary saccadic eye movements, and the 5 mg dose produced a statistically significant improvement in motor function. The adverse effects of zolpidem included drowsiness and increased postural instability and were more marked after 10 mg. Liver Liver damage has been attributed to zolpidem (35A). A 53-year-old woman first took zolpidem for insomnia in July 1996. In September 1996 she again took zolpidem (20 mg) and 2 days later had developed sudden epigastric pain associated with pale stools and dark urine but no fever; she stopped taking zolpidem and the abdominal pain resolved spontaneously within 12 hours. In April 1997, she had another episode of abdominal pain after taking zolpidem. Eleven days later her serum A1T and yglutamyltranspeptidase activities were 50 IU/1 and 89 IU/1 respectively. In June 1997 ultrasound showed a normal biliary tract. Viral hepatitis and concurrent infections with Epstein-Barr virus and cytomegalovirus were excluded.

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StephenCurran and Shabir Musa

Risk factors The adverse effects of zolpidem may be enhanced in hepatic cirrhosis (36n). A 41-year-old white man developed postoperative complications 11 months after liver transplantation. His mental status began to deteriorate secondary to hepatic encephalopathy. One day before admission, he was given zolpidem5 mg for sleep and 1 hour later he awoke in a stupor and Was not oriented to place or time. He became increasingly incoherent and verbally abusive. Although this patient's Worsening mental state could have been explained by the natural history of the encephalopathy, it is possible that zolpidem exacerbated his decline. Further research in this area is needed. Drug overdose Two deaths due to acute zolpidem overdose have been reported (37A). A 36-year-old woman with a history of psychiatric illness, including paranoid disorder, depression with panic episodes, and stress disorder, was found dead in bed. Caffeine, risperidone, and zolpidem were found in her urine. A 58-year-old woman with a history of hypertension and mental illness (manic depression and schizophrenia) was found dead in bed, with white foam around her mouth. Zolpidem and carbamazepine were found in her urine. The cause of death in both cases was acute zolpidem overdose, and the manner of death was suicide. Drug interactions Interactions between zolpidem and sertraline have been studied in 28 healthy women, who took a single dose of zolpidem alone and five consecutive doses of zolpidem 10 mg while taking chronic doses of sertraline 50 mg (38c). Co-administration of sertraline 50 mg and zolpidem 10 mg was safe but could result in a shortened onset of action and increased effect of zolpidem. Zopiclolle

(SED-14, 132; SEDA-21, 40;

SEDA-22, 43) The syndrome of inappropriate secretion of antidiuretic hormone has been atEndocrine

tributed to zopiclone (39A). D r u g withdrawal The effects of zolpidem withdrawal are mentioned above under zaleplon (32c).

A woman with a 2-week history of insomnia took zopiclone 7.5 mg nightly, and over the next 9 days be-

Hypnosedatives and anxiolytics

Chapter 5

came confused, lethargic, and depressed, culminating in an overdose of six zopiclone tablets. Her previous medical history included hypertension and two episodes of diuretic-induced SIADH. Her serum sodium was 129 mmol/l and 4 days later fell to 113 mmol/l. Her serum osmolality was low (240 mmol/kg) and her urine sodium was 20 mmol/l, suggesting another

51 episode of SIADH. The serum sodium returned to normal 12 days after withdrawal of zopiclone. The rapid resolution of symptoms and correction of the hyponatremia after withdrawal is consistent with an effect of zopiclone.

REFERENCES 1. World Health Organization. Insomnia. An International Consensus Conference Report, Versailles, 1996. 2. Sramek JJ, Hong WW, Hamid S, Nape B, Cutler NR. Meta-analysis of the safety and tolerability of two dose regimens of buspirone in patients with persistent anxiety. Depression Anxiety 1999; 9: 131-4. 3. Lader M. Anxiolytic effect of hydroxyzine: a double-blind trial versus placebo buspirone. Hum Psychopharmacol 1999; 14 Suppl 1: 94-102. 4. Bonin B, Vandel P, Vandel S, Sechter D, Bizouard P. Serotonin syndrome after sertraline, buspirone and loxapine? Thrrapie 1999; 54: 269-71. 5. Ranieri P, Franzoni S, Trabucchi M. Alprazolam and hypotension. Int J Geriatr Psychiatry 1999; 14: 401-2. 6. Kili~ C, Curran HV, Noshirvani H, Marks IM, Basoglu M. Long-term effects of alprazolam on memory: a 3.5 year follow-up of agoraphobia/panic patients. Psychol Med 1999; 29: 225-31. 7. Kroboth PD, Salek FS, Stone RA, Bertz RJ, Kroboth FJ. Alprazolam increases dehydroepiandrosterone concentrations. J Clin Psychopharmacol 1999; 19: 114-24. 8. Watanabe Y, Kawada A, Ohnish Y, Tajima S, Ishibashi A. Photosensitivity due to alprazolam with positive oral photochallenge after 17 days administration. J Am Acad Dermatol 1999; 40: 832-3. 9. Mullins ME. First-degree atrioventricular block in alprazolam overdose reversed by flumazenil. J Pharm Pharmacol 1999; 51: 367-70. 10. Michaud K, Augsburger M, Romain N, Giroud C, Mangin P. Fatal overdose of tramadol and alprazolam. Forens Sci Int 1999; 105: 185-9. 11. Ikawa K, Eshima N, Morikawa N, Kawashima H, Izumi T, Takeyama M. Influence of concomitant anticonvulsants on serum concentrations of clonazepam in epileptic subjects: an age- and doseeffect linear regression model analysis. Pharm Pharmacol Commun 1999; 5: 307-10. 12. Joist A, Tibesku CO, Neuber M, Frerichmann U, Joosten U. Gangrene of the fingers caused by accidental intra-arterial injection of diazepam. Dtsch Med Wochenschr 1999; 124: 755-8. 13. Norris E, Marzouk O, Nunn A, Mcintyre J, Choonara I. Respiratory depression in children receiving diazepam for acute seizures: a prospective study. Develop Med Child Neurol 1999; 41: 340-3. 14. Simmer ED. A fugue-like state associated with diazepam use. Mil Med 1999; 164: 442-3.

15. Brodtkorb E, Aamo T, Henriksen O, Lossius R. Rectal diazepam: pitfalls of excessive use in refractory epilepsy. Epilepsy Res 1999; 35: 123-33. 16. Olcina GM, Simonart T. Severe vasculitis after therapy with diazepam. Am J Psychiatry 1999; 156: 972-3. 17. Czeizel AE, Szegal BA, Joffe JM, Racz J. The effect of diazepam and promethazine treatment during pregnancy on somatic development of human offspring. Neurotoxicol Teratol 1999; 21: 157--67. 18. Thukaram Bapuji A, Rambhau D, Srinivasu P, Ramesh Rat B, Apte SS. Time dependent influence of diazepam on the pharmacokinetics of ibuprofen in man. Drug Metab Drug Interact 1999; 15: 7181. 19. Tupala E, Niskanen L, Tiihonen J. Transient syncope and ECG changes associated with the concurrent administration of clozapine and diazepam. J Clin Psychiatry 1999; 60: 619-20. 20. Rawson NSB, Rawson MJ. Acute adverse event signalling scheme using the Saskatchewan administrative health care utilization datafiles: results for two benzodiazepines. Can J Clin Pharmacol 1999; 6: 159-66. 21. Le Roi S, Kirby KC, Montgomery IM, Daniels BA. Differential effects of lorazepam and diazepam on explicit and implicit memory. Aust J Psychopharmacol 1999; 9: 48-54. 22. Blin O, Jacquet A, Callamand S, Jouve E, Habib M, Gayraud D, Durand A, Bruguerolle B, Pisano P. Pharmacokinetic-pharmacodynamic analysis of mnesic effects of lorazepam in healthy volunteers. Br J Clin Pharmacol 1999; 48: 510-12. 23. Rintahaka PJ, Nakagawa JA, Shewmon DA, Kyyronen P, Shields WD. Incidence of death in patients with intractable epilepsy during nitrazepam treatment. Epilepsia 1999; 40: 492-6. 24. Verghese J, Merino J. Temazepam overdose associated with bullous eruptions. Acad Emerg Med 1999; 6: 1071. 25. Hayakawa T, Uchiyama M, Urata J, Enomoto T, Okubo J, Okawa M. Effects of a small dose of triazolam on P300. Psychiatry Clin Neurosci 1999; 53: 185-7. 26. Rukstalis M, De Wit H. Effects of triazolam at three phases of the menstrual cycle. J Clin Psychopharmacol 1999; 19: 450-8. 27. Zahedi A, Grant MH, Wong DT. Successful treatment of chloral hydrate cardiac toxicity with propranolol. Am J Emerg Med 1999; 17: 490-1.

52 28. Wahlgren NG, Ranasinha KW, Rosolacci T, Franke CL. Clomethiazole Acute Stroke Study (CLASS): results of a randomized, controlled trial of clornethiazole versus placebo in 1360 acute stroke patients. Stroke 1999; 30: 21-8. 29. Drug and Therapy Perspectives. Does zaleplon help you sleep and wake refreshed? Drug Ther Perspect 1999; 14: 1-4. 30. Rosen AS, Foumi6 P, Darwish M, Danjou P, Troy SM. Zaleplon pharrnacokinetics and absolute bioavailability. Biopharm Drug Disp 1999; 20: 171-5. 31. Danjou P, Paty I, Fruncillo R, Worthington P, Unruh M, Cevallos W, Martin P. A comparison of the residual effects of zaleplon and zolpidem following administration 5 to 2 hours before awakening. Br J Clin Pharmacol 1999; 48: 36774. 32. Elie R, Rtither E, Farr I, Emilien G, Salinas E. Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. J Clin Psychiatry 1999; 60: 536--44. 33. Ganzoni E, Gugger M. Safety profile of

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zolpidem: two studies in 3805 patients with Swiss practitioners. Schweiz Rundsch Med Prax 1999; 88:1120-7. 34. Daniele A, Moro E, Bentivoglio AR. Zolpidem in progressive supranuclear palsy. New Engl J Med 1999; 341: 543--4. 35. Karsenti D, Blanc P, Bacq Y, Metman E-H. Hepatotoxicity associated with zolpidem treatment. Br Med J 1999; 318:1179. 36. Clark A. Worsening hepatic encephalopathy secondary to zolpidem. J Pharm Technol 1999; 15: 139-41. 37. Gock SB, Wong SHY, Nuwayhid N, Venuti SE, Kelley PD, Teggatz JR, Jentzen JM. Acute zolpidem overdose.--report of two cases. J Anal Toxicol 1999; 23: 559~2. 38. Allard S, Sainati SM, Roth-Schechter BE Coadministration of short-term zolpidem with sertraline in healthy women. J Clin Pharmacol 1999; 39: 184-91. 39. Cubbin SA, Ali IM. Inappropriate antidiuretic hormone secretion associated with zopiclone. Psychiatr Bull 1999; 23: 306-7.

Alfonso Carvajal and Luis H. Martin Arias

6

Antipsychotic drugs

GENERAL Several atypical antipsychotic drugs are currently considered to be first-line therapies for schizophrenia. However, choosing one can be difficult, because head-to-head comparisons are just beginning to appear and most published trials are comparisons with typical antipsychotic drugs. Several reviews (1 R, 2 R) and clinical comparisons (3c, 4 C) of atypical antipsychotic drugs have recently been published; a metaanalysis of the efficacy and extrapyramidal effects of the new antipsychotic drugs olanzapine, quetiapine, and risperidone, compared with conventional antipsychotic drugs and placebo deserves particular attention (5M). Only randomized, double-blind, controlled trials in patients with schizophrenia or schizophrenia-like psychoses were selected. Combining all BPRS (Brief Psychiatric Rating Scale) comparisons between all antipsychotic drugs and placebo resulted in a mean effect size of 0.25 (CI = 0.22, 0.28; n = 2477), which is only a moderate treatment effect. Quetiapine (six studies; n = 1414) was as effective as haloperidol. Risperidone (nine studies; n = 2215) and olanzapine (four studies; n = 2914) were statistically superior to haloperidol. However, the latter two effect sizes (0.06 and 0.07) were very small. The new antipsychotic drugs were associated with similar use of antiparkinsonian medications to placebo, and all were clearly superior to haloperidol in this respect; risperidone had the weakest effect (effect size 0.09 vs placebo and 0.12 vs haloperidol). Many of the trials used relatively high doses of haloperidol, favoring the occurrence of extrapyramidal signs. Further comparisons between atypical neuroleptic drugs have been conducted. After a baseline period of treatment with fluphenazine for a minimum of 2 weeks, 29 patients with 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual24 J.K. Aronson, ed.

chronic schizophrenia participated in a randomized, double-blind, 6-week comparison of clozapine and risperidone (3c). Clozapine was superior to risperidone for positive symptoms and parkinsonian adverse effects. In addition, clozapine produced fewer effects on plasma prolactin than risperidone. The mean daily doses during week 6 of the trial were 404 mg of clozapine and 5.9 mg of risperidone. Clozapine has also been compared with risperidone in 60 treatment-resistant patients with schizophrenia in India (4c). There was clinical improvement (a more than 20% reduction from baseline PANSS scale scores) in 80% of the clozapinetreated patients and 67% of the risperidonetreated patients. The predominant adverse effects with clozapine (n = 30) were tachycardia (77%), hypersalivation (60%), sedation (60%), weight gain (43%), and constipation (30%); one patient had a seizure. The adverse effects of risperidone (n = 30) were constipation (50%), dry mouth (47%), weight gain (43%), akathisia (37%), insomnia (33%), tachycardia (30%), and impotence (27%). The final mean daily doses after 16 weeks of treatment were 343 mg for clozapine and 5.8 mg for risperidone. In an open-label comparison of risperidone and olanzapine (mean daily doses at follow-up 4.5 and 13.8 mg respectively) in 42 schizophrenic patients, there was a greater reduction in psychotic symptoms after 6 months of treatment with risperidone, although akathisia was more frequent (6c). Finally, risperidone has been compared with amisulpride in patients aged 18~55 years with an acute exacerbation of schizophrenia who were randomized double-blind to receive risperidone 8 mg/day (n = 113) or amisulpride 800 mg/day (n = 115) for 8 weeks (7c). The two treatments were equally effective. Antiparkinsonian medication was begun in 23% of patients taking risperidone and in 30% of those taking amisulpride. The only notable difference was that patients taking risperidone had signi~q

54

Chapter 6

ficant weight gain (1.4 kg) compared with those taking amisulpride (0.4 kg). Special subgroups have been considered in different studies. Agitated and demented elderly patients should not to be treated with neuroleptic drugs, unless they have pronounced psychotic symptoms (SEDA-23, 48). Having in mind that some studies have reported the lack of a documented diagnosis associated with the use of antipsychotic drugs, a drug utilization study using a chart review has been carried out in Canada to discover the pattern of use of neuroleptic drugs in a long-term care facility (8c). Neuroleptic drugs were prescribed f o r 86 (19.3%) of 446 patients from four units of a 360-bed nursing home, mainly for agitation (n = 21); their mean age was 84 years and the mean length of time they had been receiving neuroleptic drugs was 37 (7-263) months. The authors thought that this was of definite concern, given the modest benefit that has been observed during long periods of treatment in such patients and the risk of tardive dyskinesia and other adverse effects. In the light of evidence from large, randomized, double-blind trials, the authors of a thorough review of the role of atypical antipsychotic drugs in the treatment of psychosis and agitation associated with dementia have concluded that low-dose risperidone (0.25-1.5 rag/day) can be used as first-line treatment (9R). A further comprehensive review on the use of atypical antipsychotic drugs in older adults has also been published (10R). In addition, the medical records of 151 hospitalized elderly psychiatric patients (mean age 71 years) have been analyzed (llC). Of 114 patients treated with risperidone (mean duration of treatment 17 days; mean dose 3 mg/day) 78% responded, as did 75% of 37 patients treated with olanzapine (mean duration of treatment 20 days, mean dose 10 rag/day). Adverse events with risperidone were reported in 20 patients, including newonset extrapyramidal effects in four; tremor in four; sedation in three; hypotension in three; diarrhea in two; tardive dyskinesia in two; and chest pain, anxiety, restlessness, itching, insomnia, and falls in one each. Adverse effects with olanzapine were reported in six patients: sedation in four patients and extrapyramidal signs and postural hypotension in one each. Cardiovascular Hypotension is the most commonly observed cardiovascular adverse

AlfonsoCarvajal and Luis H. Martfn Arias

effect of antipsychotic drugs (SED-14, 141) and it may be particularly hazardous in elderly patients. Severe orthostatic hypotension has been observed in older volunteers (n = 14; aged 65-77 years) who participated in a randomized, double-blind, three-period, cross-over study, in which they took single oral doses of thioridazine (25 mg), remoxipride (50 mg), or placebo (12c). Compared with placebo, there were falls in supine and erect systolic and diastolic blood pressures after thioridazine but not remoxipride. Standing systolic blood pressures fell by a maximum of 26 mmHg. There were similar falls in blood pressure in young volunteers.

QT interval prolongation, torsade de pointes, and sudden death Many antidysrhythmic drugs prolong ventricular repolarization and cause torsade de pointes (SEDA-23, 196). Lately, an increasing number of non-cardiac drugs have been reported to have similar effects (13R); among them, antipsychotic drugs have particularly been associated with conduction disturbances, torsade de pointes being one of the most worrisome (SED-14, 141; SEDA-20, 36; SEDA-21, 43, SEDA-22, 45, SEDA-23, 49). Although the role of antipsychotic drugs in sudden death is controversial (SEDA-18, 47; SEDA-20, 36), and although there are other non-cardiac causes of this syndrome, including asphyxia, convulsions, or hyperpyrexia, QT interval prolongation and torsade de pointes provide a plausible mechanism of sudden death. Recently, a novel atypical antipsychotic drug, sertindole, first introduced in 1997, was withdrawn because of an intolerable risk of cardiac dysrhythmias and sudden death (SEDA-22, 71). Sertindole was associated with 27 deaths (16 cardiac) in 2194 patients who were enrolled in premarketing studies; further fatal cases have been collected, and the Committee on Safety of Medicines has described reports of 36 deaths (including some sudden cardiac deaths) and 13 serious but non-fatal dysrhythmias also associated with sertindole (14c). Pimozide is also known to cause QT interval prolongation and torsade de pointes; a total of 40 reports (16 deaths) of serious cardiac reactions, mainly dysrhythmias, were reported to the Committee on Safety of Medicines from 1971 to 1995 in the UK (15c).

Antipsychotic drugs

Chapter 6

Recently, thioridazine and droperidol have also been associated with QT interval prolongation (SED-14, 141; 16c). On 7 July 2000 doctors and pharmacists in the USA were notified about the addition of extensive new safety warnings, including a boxed warning to the professional product label for the antipsychotic drug thioridazine (Melleril, Novartis Pharmaceuticals). The text of the new boxed warning reads: "Melleril (thioridazine) has been shown to prolong the QTc interval in a dose-related manner, and drugs with this potential, including Melleril, have been associated with torsade de pointes-type arrhythmias and sudden death. Due to its potential for significant, possibly life-threatening, proarrhythmic effects, Melleril should be reserved for use in the treatment of schizophrenic patients who fail to show an acceptable response to adequate courses of treatment with other antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs". The new labeling changes were based primarily on the FDA's review of three published studies. The first of these showed increased blood concentrations of thioridazine in patients with a genetic defect, resulting in the slow inactivation of debrisoquine (17c). In this study, 19 healthy subjects (six poor and 13 extensive metabolizers of debrisoquine) took a single oral dose of thioridazine 25 rag. The poor metabolizers reached higher blood concentrations of thioridazine 2.4 times more quickly than the extensive metabolizers. There was a 4.5fold increase in the absorption of the drug in the poor metabolizers, in whom thioridazine remained in the blood twice as long. The second study showed dose-related prolongation of the QTc interval from 388 (range 370-406) to 411 (range 397-425) ms 4 hours after an oral dose of thioridazine 50 mg (18c). The average maximal increase was 23 ms. This change was statistically greater than that for either placebo or thioridazine 10 mg. In the third study the effect of the selective serotonin re-uptake inhibitor (SSRI) fluvoxamine, 25 mg bd for i week, on thioridazine blood concentrations in 10 hospitalized men with schizophrenia was evaluated (19 c) (see below under Drug interactions). The concentrations of thioridazine and its two active breakdown products, mesoridazine and

55

sulforidazine, increased 3-fold after the administration of fluvoxamine. Mechanism Torsade de pointes, first described in 1966 by Dessertenne (20A), is a potentially fatal ventricular tachydysrhythmia with a characteristic pattern of polymorphous QRS complexes, which appear to twist around the isoelectric line. It is often associated with ventricular extra beats immediately before the dysrhythmia. Torsade de pointes typically occurs in the setting of a prolonged QT interval, which includes depolarization and repolarization times. Conditions or agents that delay ventricular repolarization, causing long QT interval syndromes, can trigger the dysrhythmia. It has been hypothesized that prolongation of the QT interval is caused by early after-depolarization, which in turn may develop in response to abnormal ventricular repolarization (21R-23R ).

Epidemiology The prevalence of QTc prolongation in psychiatric patients has recently been estimated, to assess whether it is associated with any particular antipsychotic drug (16c). Electrocardiograms were obtained from 101 healthy control individuals and 495 psychiatric patients (aged 18-74 years) in various inpatient and community settings in North-East England. Exclusion criteria were atrial fibrillation, bundle-branch block, and a change in drug therapy within the previous 2 weeks (3 months for depot formulations. The threshold for QTc prolongation (456 ms) was defined as 2 SD above the mean value in the healthy controls. Values were abnormal in 40 patients. Significant independent predictors of QTc prolongation in psychiatric patients after adjustment for potential confounding effects were age over 65 years and the use of tricyclic antidepressants, droperidol (RR = 6.7; CI = 1.8, 25), or thioridazine (RR = 5.3; CI = 2.0, 14). Increasing antipsychotic drug dosage was also associated with an increased risk of QTc prolongation. Abnormal QT dispersion or T wave abnormalities were not significantly associated with antipsychotic drug treatment. Based on these results, the authors recommended electrocardiographic screening not only in those patients taking high doses of antipsychotic drugs but also in those taking droperidol or thioridazine, even at low doses. In other studies dose and

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Chapter 6

age were similarly found to be predictive factors (24c), as was carbamazepine (25c).

Management of the conduction disturbances In practice, adverse effects related to QT prolongation can be prevented by avoiding higher doses and by avoiding the following patients at risk: those with organic heart disease, particularly congestive heart failure; those with metabolic abnormalities (such as hypokalemia and hypomagnesemia); and those with sinus bradycardia or heart block. Concomitant administration o f drugs that inhibit drug metabolism should also be avoided, and the potassium concentration should be controlled. I f torsade de pointes is suspected, antipsychotic drugs must be withdrawn. Magnesium sulfate 2 g (20 ml o f a 10% solution intravenously) suppresses torsade de pointes (26c). Most patients report flushing during this injection. A case o f torsade de pointes related to high close haloperidol and treated with magnesium has been reported (2TAr). A 41-year-old woman with liver lacerations, rib fractures, and pneumothorax, due to a motor vehicle accident, was given haloperidol for agitation on day 7. During the first 24 hours she received a cumulative intravenous dose of 15 mg, 70 mg on day 2, 190 mg on day 3, 160 mg on days 4 and 5, and 320 mg on day 6. An hour after the first dose of SO mg on day 7, she had ventricular extra beats followed by 5-beat and 22-beat runs of ventricular tachycardia. The rhythm strips were consistent with polymorphous ventricular tachycardia or torsade de pointes and the QTc interval was 610 ms (normal under 450 in women). She received intravenous magnesium sulfate 2 g. Concurrent medications included enoxaparin, famotidine, magnesium hydroxide, ampicillin/sulbactam, nystatin suspension, midazolam, and 0.45% saline with 20 mmol/l of potassium chloride. She had no further dysrhythmias after haloperidol was withdrawn. Eight days after the episode of torsade de pointes she had a normalized QTc of 426 ms.

Nervous system Extrapyramidal signs In an Australian psychiatric hospital the rating of movement disturbances has been compared with standardized scales (AIMS, SimpsonAngus, and BARS) and the psychiatrists' clinical assessments of such disturbances in 38 consecutive patients (28c). The patients were taking antipsychotic drugs and 47% fulfilled the

Alfonso Carvajal and Luis H. Marffn Arias

Simpson-Angus criteria for the presence of parklnsonian symptoms compared with 39% who were rated as having mild, moderate, or severe parkinsonian symptoms by their psychiatrists. When BARS was used, 11% of the patients scored some degree of akathisia vs 17% identified by the psychiatrists. The corresponding figures for dyskinesia when using AIMS were 11% vs 14%. In the light of these results, the authors suggested that standardized measures should be introduced into routine practice. Parkinsonism has been studied in special groups, such as elderly patients (29c), patients with bipolar disorders (30c), and patients who have received acute medication (31c). The incidence of neuroleptic drug-induced parkinsonism has been examined in 50 older newlymedicated psychiatric patients (29c). After controlling for spontaneous parkinsonism with two groups of 15 unmedicated patients and 49 healthy elderly individuals, 32% of the patients, who were taking an average of 43 mg/day chlorpromazine equivalents of a typical neuroleptic drug, met strict criteria for neuroleptic drug-induced parkinsonism. Among 23 patients with bipolar affective disorder taking neuroleptic drugs, there was a high frequency of akathisia in a preliminary analysis: 15 developed akathisia and 18 had parkinsonism during their entire inpatient treatment (30c). The patients initially received high-potency neuroleptic drugs (maximum 2000 rag/day of chlorpromazine equivalents) and were assessed weekly. Akathisia developed in 44% of the patients with severe headache or nausea who received prochlorperazine 10 mg intravenously (n = 100) within 1 hour (31c). None of the 40 patients receiving other medications, who served as controls, developed akathisia. A nocturnal eating/drinking syndrome secondary to neuroleptic drug-induced restless legs syndrome has been attributed to low-dose haloperidol in a 51-year-old schizophrenic woman (32A), and two further cases of acute neuroleptic drug-induced akathisia in patients with traumatic paraplegia have been published (33A). The authors emphasized the possibility of drug-induced akathisia when patients with traumatic paraplegia or other physical disabilities develop increasing restlessness and an inability to sit or lie still.

Akathisia

Antipsychotic drugs

Chapter6

Tardive dyskinesia Previous neuroleptic drug use at study entry has been shown to be the only significant predictor of tardive dyskinesia (34c). Psychiatric outpatients aged over 45 years, who had taken neuroleptic drugs for 0--30 days (n = 176) were compared with 131 who had taken neuroleptic drugs for more than 30 days. The cumulative incidences of tardive dyskinesia were 23% and 37% at the end of 12 months. In the patients who had never used neuroleptic drugs before (n = 87), the mean cumulative incidence of tardive dyskinesia after the use of typical neuroleptic drugs (median dose, 68 mg/day of chlorpromazine equivalents) was 3.4% at baseline and 5.9% at 1 and 3 months. A case of autoamputation of the tongue in a patient who was taking flupenthixol has been explained as secondary to an acute, atypical, neuroleptic drug-induced orolingual dyskinesia (35A). A 21-year-old man, who had been mentally retarded from birth, was given intramuscular flupenthixol 50 mg/day and oral diazepam 7.5 mg/day for disruptive and inappropriate behavior, and 84 hours later began chewing his tongue repetitively, with resultant edema and bleeding from multiple lacerations. The biting abated within 2 hours after intravenous biperiden 5 mg and diazepam 5 mg; ampicillin, cloxacillin, and metronidazole were also given. One week after admission to hospital, he had an autoamputation of the distal one-third of his tongue. Treatment of tardive dyskinesia is often unsatisfactory, especially in severe cases. A large number of treatments have been proposed, including atypical neuroleptic drugs, tocopherol, benzodiazepines, baclofen, calcium antagonists, valproate, propranolol, opiates, cyproheptadine, tryptophan, lithium, manganese, niacin, and botulinum toxin (SEDA-20, 40). In an open-label study, 20 patients (mean age 65 years) with severe unresponsive tardive dyskinesia (mean duration 44 months, mean exposure 52 months) were treated with tetrabenazine (mean dose 58 mg/day) (36c). The mean score on the AIMS motor subset, determined from videotapes, improved by 54%. Sedation was the only subjective complaint. Vitamin E has been used to treat tardive dyskinesia (SEDA-21, 47) and now the possible involvement of free radicals and treatment with vitamin E has been extensively reviewed

57 (37R). A further study has concluded that the addition of vitamin E to neuroleptic drug medication at the start of treatment can reduce the severity of acute neuroleptic drug-induced parkinsonism (38c). This has been observed by comparing two groups of randomly allocated patients treated with neuroleptic drugs (n = 20) or with neuroleptic drugs plus vitamin E, 600 IU/day (n = 19). From days 0 to 14, there was a mean reduction in SARS scores of 10% in those treated with vitamin E vs an increase of 78% in the comparison group.

Dystonia Laryngeal-pharyngeal dystonia occurs within hours to days of starting therapy with neuroleptic drugs and is characterized by sudden onset of difficulty in breathing and swallowing (SEDA-22, 51). Further reports have illustrated these troublesome reactions (39 A, 40a). A 26-year-old schizophrenic woman developed throat pain and dyspnea while taking haloperidol and a 76-year-old man reported difficulty in starting to swallow after taking haloperidol (6 mg/day), sertraline (200 mg/day), lithium, and temazepam for 6 weeks for recurrent depression.

Pleurothotonus (Pisa syndrome) is currently classified as a tardive dystonia, although it can also occur immediately after the administration of antipsychotic drugs (SED-13, 123). Nine of 20 patients (mean age 40 years) who developed Pisa syndrome while taking antipsychotic drugs (mean duration 12 years) improved within 3 weeks of treatment with trihexyphenidyl 12 mg/day (41c). Reduction or withdrawal of the daily dose of the antipsychotic drugs was beneficial to the remaining patients. Neuroleptic malignant syndrome The neuroleptic malignant syndrome is a rare but potentially fatal disorder characterized by muscle rigidity, hyperthermia, altered consciousness, and autonomic dysfunction (SED-14, 147; SEDA-20, 41). Six further cases successfully treated with ECT have been reported (42 A, 43A).

Sensory systems Antisychotic drugs have been occasionally associated with corneal deposits, cataract, and pigmentary retinopathy (SED-14, 151). A further case of cataract has been reported (44A).

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A 50-year-old woman with schizophrenia had a 1-year history of gradual deterioration of vision in both eyes. For several years she had been taking chlorpromazine 300 mg/day, trifluoperazine 10 mg/day, and trihexyphenidyl 4 mg/day. Slit lamp examination showed fine, discrete, brown refractile deposits on the corneal endothelium in both eyes, and characteristic bilateral stellate cataracts with dense dust-like brown-yellow granular deposits were noted along the suture lines in the anterior pole of the lens and obscured the visual axis.

Hematological Rarely-reported hematological reactions to antipsychotic drugs include agranulocytosis, thrombocytopenic purpura, hemolytic anemia, leukopenia, and eosinophilia (SED-14, 149). Aplastic anemia, defined by the presence of pancytopenia and a hypocellular bone-marrow in the absence of any abnormal blood cells, is a serious reaction that has been now attributed to perphenazine for the first time (45A). A 23-year-old man with schizophrenia treated with perphenazine 4 mg bd, benzatropine mesylate 2 mg/day, lithium carbonate 600 mg each morning and 900 mg at bedtime, and famotidine 40 mg/day developed fatigue, shortness of breath, dizziness, light-headedness, and general debility. He had a pancytopenia, which persisted in spite of blood transfusions. Bone-marrow aspiration showed hypocellularity, absent megakaryocytes, reduced erythropoiesis and myelopoiesis, increased iron storage, and a relative excess of lymphoid cells. All medications were withdrawn and he was given lorazepam 2 mg bd. He recovered after 8 months. Metabolic Whether the relative body weight of individuals with and without schizophrenia is different is of interest. If the distribution of body mass index (BMI) were similar, then even modest weight gains associated with antipsychotic drugs would be of concern, particularly in countries where obesity is common. In fact, many patients with schizophrenia suffer from obesity, which is associated with an increased risk of morbidity from such conditions as diabetes, cardiovascular disease, and locomotor disorders (SED-14, 148). In the USA data from a large health and nutrition survey (n = 17 689) and from schizophrenic patients to be enrolled in a clinical trial (n = 420) showed no differences; the mean BMIs were high and a substantial proportion of the population was obese (46c). In a retrospective chart review of 91 schizophrenic patients (120 treatment episodes; mean

Alfonso Carvajal and Luis H. Marffn Arias

age 38 years) there was weight gain with zotepine (4.3 kg), clozapine (3.1 kg), sulpiride (1.9 kg), and risperidone (1.5 kg), but not in patients treated with classic neuroleptic drugs (mean 0.0-0.5 kg) (47c). The mean duration of treatment was 28-34 days, the maximum weight gain being in the first 3-5 weeks. The mean increases in weight were 4.3% in the patients with normal weight, 3.0% in those with mild obesity, and 1.9% in those with severe obesity (BMI over 30). In another retrospective study, 65 schizophrenic patients who gained weight while taking clozapine for 6 months were followed (48c). After that they were switched to a combination of clozapine with quetiapine for 10 months: clozapine was tapered to 25% of the current dose and quetiapine was added proportionately. During clozapine monotherapy the mean weight gain was 6.5 kg and 13 patients developed diabetes. At the end of the combination period, the mean weight loss was 9.4 kg; patients who developed diabetes showed significant improvement, resulting in a rapid fall in insulin requirements and/or withdrawal of insulin and replacement with an oral hypoglycemic agent. The mechanism of clozapine-associated weight gain is uncertain.

Gastrointestinal Neuroleptic drugs, particularly phenothiazine derivatives, have been reported to cause colitis (SED-14, 150; SEDA-20, 43). The mechanism was thought to be an anticholinergic effect. Two new cases have been reported (49 A, 50A), the latter with positive rechallenge. A 41-year-old man developed acute abdominal pain with profuse diarrhea and fever (39~ C) while receiving intramuscular fluphenazine decanoate 125 mg once every 3 weeks. During the previous 3 months he had also received oral alimemazine 50 mg/day, levomepromazine 50 mg/day, and amitriptyline 100 mg/day. Colonoscopy showed necrotic ulcers in the mucosa of the sigmoid and descending colon. After 3 weeks of parenteral nutrition, there was a marked reduction in the colonic lesions and he recovered. Levomepromazine 50 mg/day and fluphenazine decanoate 100 mg/day were reintroduced. Two days later he complained again of abdominal pain, and tomodensitometry confirmed distension. Pancreas Pancreatitis has been attributed to clothiapine (51A).

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A 49-year-old woman started to take clothiapine 200 mg/day for a severe psychotic episode. On the second day, she complained of abdominal pain and nausea, followed by vomiting. Amylase (1490 U/ml), lipase (3855 U/ml), and urinary amylase activities (3417 U/ml) were increased, suggesting pancreatitis. There was no evidence of gallstones or tumor. She was given perphenazine instead, and her amylase and lipase activities fell to normal. Six months later, when she had a psychotic relapse, she was again treated with clothiapine and 2 days later had a rapid rise in amylase activity (887 U/ml). When switched to perphenazine, she had new peaks in amylase and lipase. A year later, her amylase and lipase were normal and her psychiatric disorder was stabilized on pimozide. Sexual function Priapism can occur with antipsychotic drugs (SEDA-23, 56), and new cases have been reported. Priapism in twins suggests a hereditary predisposition (52A). Identical twin brothers, aged 37 years, had both suffered from bipolar disorder since their early twenties and had been treated with chlorpromazine, haloperidol, lithium, and carbamazepine before developing priapism. One of them developed priapism after taking trazodone 400 mg, and in the 2 years after the initial episode he suffered recurrent painless erections. Initially they occurred daily and lasted 4-5 hours. During a relapse of mania at age 37, he was given oral zuclopenthixol 40 mg/day. On the tenth day he presented with priapism of 4 days duration, which persisted despite zuclopenthixol withdrawal, needle aspiration, and phenylephrine instillation, but subsided 2 weeks later with conservative management. The other twin presented with priapism of 75 hours duration and hypomania at age 31 years. He had been taking lithium and chlorpromazine for the preceding 2 years. Two additional cases of priapism have been published: a 65-year-old man who took a single dose of chlorpromazine 25 mg and a 27-yearold man who took chlorpromazine 200 mg for agitation after a suicide attempt (53A).

59 agitation must be excluded and the nature and frequency of these behaviors must be documented. Non-dangerous agitation, uncooperativeness, wandering, restlessness, insomnia, and impaired memory are insufficient in isolation to justify the use of antipsychotic drugs. With this in mind, the effects of withdrawing haloperidol, thioridazine, and lorazepam have been examined in a double-blind, cross-over study in 58 nursing home residents (43 women and 15 men, mean age 86 years), half of whom continued to take the psychotropic drugs that had been prescribed, while the other half were tapered to placebo (54c). After 6 weeks, the patients were tapered to the reverse schedule and took it for another 6 weeks. There were no differences between drug and placebo in functioning, adverse effects, and global impression. Cognitive functioning improved during placebo. The authors concluded that gradual dosage reductions of psychoactive medications must be attempted, unless clinically contraindicated, in an effort to withdraw these drugs. Similar conclusions have been reached in other studies (SEDA-22, 54).

Pregnancy

Although studies have failed to identify an increased rate of malformations with haloperidol, isolated cases have been reported (SED-14, 152; SEDA-22, 54; SEDA-23, 57). A case ofphocomelia associated with neuroleptic drugs has been reported (55A). A 38-year-old woman was admitted to hospital in the third week after conception and diagnosed as having acute schizophrenia. She was given oral haloperidol 1.5 mg at 12-hour intervals. In the fourth week after conception, an intramuscular formulation of fluphenazine 12.5 was added every 15 days. At eight weeks of gestation, after the diagnosis of pregnancy, haloperidol and fluphenazine were withdrawn and trifluoperazine 5 mg was started and continued until 8 weeks before the baby was born. The child was born with phocomelia of the left ann, with an extremely short humerus and an absent forearm.

Drug withdrawal

The Omnibus Budget Reconciliation Act of 1987 (OBRA '87) regulations (www.elderlibrary.org) specify when neuroleptic drugs can and cannot be used to treat behavioral disturbances in nursing home residents in the USA. Accordingly, antipsychotic drugs may be used in patients with delirium or dementia only if there are psychotic or agitated features that present a danger to the patient or others. Preventable causes of

Risk factors In children and adolescents, antipsychotic drugs are used in general practice to treat psychotic disorders and a variety of nonpsychotic conditions, including autism, Tourette's syndrome, and mental retardation associated with behavioral problems or psychotic disorders. Untoward effects of antipsychotic drugs in children are said to be similar to those seen in adults (56R).

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Drug interactions A large number of substances can interact with antipsychotic drugs (SED-14, 153; SEDA-23, 57). A thorough review of the pharmacokinetics of haloperidol, with special emphasis on interactions, has been published (57R). Specific interactions with

alprazolam, antidepressants, buspirone, carbamazepine, itraconazole, lorazepam, phenobarbital phenytoin, propranolol, quinidine, rifampicin, valproic acid, and dietary factors and smoking have been described. The extent to which smoking, the genotype for CYP2D6, and the concomitant use of enzyme inducers or inhibitors can explain variations in steady-state plasma concentrations of haloperidol has been evaluated in 92 patients (58c). Smokers were treated with higher doses of haloperidol than non-smokers, supporting the view that smokers require larger doses of antipsychotic drugs than non-smokers to achieve therapeutic effects (see SED-14, 154 for further information). Poor metabolizers had higher concentrations of haloperidol metabolites, but not of haloperidol, than extensive metabolizers. Altogether the patients took about 150 different drugs; compared with the rest of the group, there was a tendency for patients taking inducers to be treated with slightly higher doses of haloperidol on average and to have lower dose-normalized plasma concentrations of haloperidol, although the differences were not significant. Based on published data in humans, concomitant medications were classified as potential inhibitors (cimetidine, fluoxetine, levopromazine, paroxetine, and thioridazine) or inducers of haloperidol metabolism (carbamazepine, phenobarbital, and phenytoin). Clarithromycin Clarithromycin may increase the risk of pimozide cardiotoxicity (59c). Twelve healthy volunteers were given oral pimozide 6 mg after 5 days of treatment with clarithromycin (500 mg bd) or placebo. Pimozide significantly prolonged the QTc interval in the first 20 hours in both groups (maximum changes in QTc 16 and 13 ms respectively). Fluvoxamine Fluvoxamine increased thioridazine concentrations 3-fold (19 c) in 10 schizophrenic patients taking steady-state thioridazine who were given fluvoxamine (25 mg bd) for 1 week. Fluvoxamine interferes with the metabolism of thioridazine, probably via CYP2C 19 and/or CYP 1A2.

AlfonsoCarvajaland Luis H. Martfn Arias

ltraconazole Adverse effects can result from increased plasma concentrations of haloperidol during itraconazole treatment. This has been observed in 13 schizophrenic patients treated with haloperidol 12 or 24 mg/day who took itraconazole 200 mg/day for 7 days (60c). Plasma concentrations of haloperidol were significantly increased and neurological adverse effects were more common. Itraconazole is a potent inhibitor of CYP3A4. Grapefruit also inhibits CYP3A4, but, according to a recent report, there is no interaction with haloperidol (61c). Sevoflurane A 19-year-old treated with cyamemazine for schizophrenia had severe dystonia during inhalation of sevoflurane (62A). One minute after taking four or five maximum breaths in a closed system filled with 8% sevoflurane in a 50% N20-O2 mixture, the patient being unconscious, a torticollic posturing began to develop, the stiffness rapidly extending to the left trapezius and scalenus muscles. Then there was severe rotation of the head, tfismus, and opisthotonos. Muscle spasm resolved with an injection of atracurium 30 mg. An interaction of sevoflurane and cyamemazine was suggested as a possible explanation, without precluding a role of N20.

INDIVIDUAL DRUGS

Amisulpride

(SEDA-22, 55;

SEDA-23, 58) The overall safety profile of amisulpride has been assessed, based on the results of 11 studies in 1933 patients with schizophrenia, who were randomly assigned to amisulpride (n = 1247), haloperidol (n = 309), risperidone (n = 113), flupenthixol (n = 62), or placebo (n 202) (63M). Extrapyramidal signs occurred in 15% of those given amisulpride (n = 579), 12% of those given risperidone (n = 113), and 31% of those given haloperidol (n = 214). In contrast, endocrine disorders were more frequent with amisulpride (4%) and risperidone (6%) than with haloperidol (1%). In a subgroup of patients with predominant negative schizophrenia who had at least one electrocardiogram recorded during treatment, there was

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a relative prolongation of the QTc interval of at least 60 ms in 1% (three of 296) of the patients treated with amisulpride versus no cases with both haloperidol (n = 80) and risperidone (n = 91); however, there were no ventricular dysrhythmias. In a randomized double-blind study there were no differences in the numbers of patients with at least one adverse effect with amisulpride 100 mg (24%; n = 18), amisulpride 50 mg (25%; n = 21), or placebo (33%; n = 27) (64c). Few patients had endocrine symptoms (two out of 160 in the amisulpride groups). Amisulpride has been compared with amitriptyline (n = 250; 6 months) (65 C) and with amineptine (n = 323; 3 months) in randomized double-blind trials in the treatment of dysthymia (66c). In both trials amisulpride was more efficacious than placebo but 'equal to amineptine and amitriptyline. Endocrine symptoms (such as galactorrhea and menstrual disorders) and weight gain were more frequent with amisulpride. There was galactorrhea in 8.4% and 11% respectively. In one of the studies (65c), serious adverse events occurred in 13 amisulpride patients (15 events) out of 165. A case of sudden death, probably second to myocardial infarction, occurred in a patient taking amisulpride 7 days after withdrawal. In the other cases, admission to hospital was required for fracture (two cases) and injury, gastric

pain, neuralgia, hyperglycemia, eczema, and an erythematous rash (one case each). Nervous system In a randomized, doubleblind, cross-over study, 21 healthy volunteers who took amisulpride 50 mg/day, amisulpride 400 mg/day, haloperidol 4 mg/day, or placebo, amisulpride 400 mg had several adverse effects

on psychomotor performance and on cognitive performance, similar to those of haloperidol, at the end of the 5-day course of treatment; however, there were no signs of mental disturbances on clinical rating scales or during a structured psychiatric interview (67c).

Clozapine (SED-14, 140; SEDA-21, 52; SEDA-22, 56; SEDA-23, 59) A meta-analysis of 30 randomized controlled comparisons of clozapine with conventional neuroleptic drugs (n = 2530) has been published (68M). Clozapine was more effective in reducing symptoms in patients with both

61 treatment-resistant and non-resistant schizophrenia, although, according to the authors, more community-based long-term trials would be necessary to evaluate the effectiveness of clozapine for global and social functioning in the community. In a subset of 13 trials hematological problems appeared to be more frequent in patients taking clozapine (OR = 1.93, CI = 0.96, 3.87); hypersalivation was also more frequent (OR = 5.50, CI = 4.26, 7.10) ), as were fever (OR = 1.89, CI = 1.38, 2.60), and sedation (OR = 1.94, CI = 1.50, 2.50). Xerostomia (OR = 0.29, CI = 0.20, 0.42) and extrapyramidal symptoms (OR = 0.46, CI = 0.28, 0.75) were more frequent in the patients treated with conventional antipsychotic drugs. There was no difference in weight gain between the two groups (OR = 1.07, CI = 0.37, 3.10), hypotension or dizziness (OR = 1.66, CI = 0.74, 3.71), or seizures (OR = 1.60, CI = 0.84, 3.04). Although there were fewer deaths in the clozapine group, statistical significance was not reached (OR = 0.50, CI = 0.11, 2.30). One of the flaws of this metaanalysis was that there was no information on drop-outs. In this regard, 115 patients out of 518 treatment-resistant schizophrenics on clozapine discontinued medication at 5 years (69c). In this open-label retrospective study, the incidence of agranulocytosis was 0.9% (for reported incidences see Table 1 in SEDA-23, 62). Special subgroups of patients can benefit from clozapine, although they can also present particular risks (SEDA-21, 53; SEDA-23, 59). Fifty special hospitalized patients with schizophrenia associated with serious violence were treated with clozapine (mean dose at 2 years 465 mg) (70c). The most frequent adverse effects were hypersalivation (n = 14), sedation (n = 10), and weight gain (n = 6); two patients had tonic-clonic seizures, two others developed mild neutropenia, and in one case treatment was stopped owing to agranulocytosis. Hypersalivation appears to be one of the most common adverse effects of clozapine. Terazosin alone or benzatropine and terazosin together have been shown to be efficacious in the treatment of clozapine-induced hypersalivation (71C). In 42 elderly patients (mean age 67 years) with schizophrenia randomly assigned to clozapine, titrated to 300 mg/day (n = 24), or chlorpromazine, titrated to a maximum of 600 mg/day (n = 18), both medications were equally

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effective at 5 weeks (72c). In each group there was one patient with a serious and potentially fatal adverse effect: agranulocytosis in the clozapine group and paralytic ileus in the chlorpromazine group; both drugs significantly lowered the white cell count. Rates of hospitalization with different neuroleptic drugs have been reanalyzed by the marketing company, Novartis, based on two retrospective studies of hospitalization among patients with treatment-resistant schizophrenia (73R). All the patients who began clozapine treatment in Texas State psychiatric facilities during the early 1990s (n = 299) were compared with controls who received traditional neuroleptic drugs (n = 223), matched for severity, age, and sex. More patients in the latter group required continuous hospitalization: at 4 years, four times as many patients taking a traditional medication had a 6-month period of continuous hospitalization.

Cardiovascular Cardiomyopathy has been associated with antipsychotic drugs, including clozapine (SED-14, 142; SEDA-21, 52). A thorough study of the risk of myocarditis or cardiomyopathy in Australia detected 23 cases (mean age 36 years; 20 men) out of 8000 patients treated with clozapine from January 1993 to March 1999 (absolute risk 0.29%; relative risk about 1000-2000) (74CR). All accumulated data on previous reports of sudden death, myocarditis, or cardiac disease noted in connection with clozapine treatment were requested from the Adverse Drug Reactions Advisory Committee (ADRAC); there were 15 cases of myocarditis (five fatal) and eight of cardiomyopathy (one fatal) associated with clozapine. All cases of myocarditis occurred within 3 weeks of starting clozapine. Cardiomyopathy was diagnosed up to 36 months after clozapine had been started. There were no confounding factors to account for cardiac illness. Necropsy results showed mainly eosinophilic infiltrates with myocytolysis, consistent with an acute drug reaction. Moreover, the manufacturers analyzed 125 reports of myocarditis with clozapine and found 35 cases with fatal outcomes (75c). A total of 53% occurred in the first month of therapy, and a small number (4.8%) occurred more than 2 years after the start of treatment. In this series, 70% of the patients were men. Since cardiomyopathy is potentially fatal, some precautions must be taken.

AlfonsoCarvajal and Luis H. Martln Arias

If patients taking clozapine present with flu-like symptoms, fever, myalgia, dizziness or faintness, chest pain, dyspnea, tachycardia or palpitation, and other signs or symptoms of heart failure, consideration should always be given to a diagnosis of myocarditis. Suspicion should be heightened if the symptoms develop during the first 6-8 weeks of therapy. It should be noted, however, that flu-like symptoms can also occur during the titration period, supposedly as a result of a-adrenoceptor antagonism by clozapine. Patients in whom myocarditis is suspected should be referred immediately to a cardiac unit for evaluation. Taking into account the results from an epidemiological study of deaths in users and former users of clozapine (76CR), the cardiovascular mortality risk related to clozapine may be outweighed by the overall lower mortality risk associated with its beneficial effects, since the death rate was lower among current users (322 per 100000 person years) than among past users (696 per 100000 person years). The reduction in death rate during current use was largely accounted for by a reduction in the suicide rate compared with past use (RR = 0.25; CI = 0.10, 0.30). The prevalence of clozapine-induced electrocardiographic changes has been estimated at 10%. Cases of tachycardia, the most common cardiovascular adverse effect of clozapine, and atrial fibrillation have previously been reported (SEDA-22, 57; SEDA-23, 60). A patient who developed ventricular fibrillation and atrial fibriUation after 2 weeks of clozapine therapy has been reported (77A). A 44-year-old man with no significant cardiac history was given clozapine and 12 days later had bibasal crackles in the chest and ST segment elevation in leads V2 and V3 of the electrocardiogram. He then developed ventricular tachycardia that needed active resuscitative measures. He also developed atrial fibrillation for 24 hours, which subsequently resolved. The second most common cardiovascular adverse effect of clozapine is hypotension (SEDA-22, 57). A new case has been published of profound hypotension in a 51-year-old man taking maintenance clozapine after cardiopulmonary bypass (78A).

Nervous system Seizures associated with clozapine are said to be dose-dependent (SED-

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14, 142; see also Drug overdose below). A tonic-clonic seizure occurred in a 30-year-old man 4 weeks after he started to take clozapine 400 mg/day (79A). This was followed by a large increase in liver enzymes, which had been normal the week before. The use of clozapine to treat psychosis related to Parkinson's disease has previously been discussed (SEDA-22, 57; SEDA-23, 60). In a randomized, double-blind, placebocontrolled trial of low doses of clozapine (6.2550 mg/day) in 60 patients (mean age 72 years) with idiopathic Parkinson's disease and druginduced psychosis, the patients in the clozapine group had significantly more improvement after 14 months than those in the placebo group in all measures used to determine the severity of psychosis (80c). Clozapine improved tremor and had no deleterious effect on the severity of parkinsonism, but in one patient it was withdrawn because of leukopenia. In addition, in a randomized, double-blind, placebo-controlled, 4-week trial in 60 patients with similar druginduced psychosis in Parkinson's disease, assigned to clozapine (n = 32) or placebo (n = 28), the initial clozapine dose of 6.25 mg/day was titrated over at least 10 days to a maximum of 50 rag/day and was rapidly effective (81c). Somnolence and worsening of parkinsonism were significantly more frequent in the clozapine group, seven of whom reported worsening of Parkinson's disease, usually mild or transient, which was confirmed by aggravation of the Schwab and England score by 10-20% in three patients; however, no-one withdrew for this reason. On the other hand, clozapine has been assessed for the treatment of movement disorders (82c, 83r Six patients who met the criteria for a diagnosis of HIV-associated psychosis, and who had previously developed moderate parkinsonism as a result of typical neuroleptic drugs, were treated with clozapine (82c). Parkinsonism improved by an average of 77%, but one patient did not complete the trial because of a progressive fall in leukocyte count. Clozapine could also be useful for the treatment of essential tremor refractory to the usual drugs (propranolol, primidone, alprazolam, phenobarbital, or botulinum toxin). This was the conclusion of a randomized, double-blind, cross-over study in 15 drug-resistant patients with essential tremor, in whom a single dose of clozapine 12.5 mg was compared with placebo (83c). Responders with more than 50% im-

63 provement after a single dose of clozapine subsequently received 39-50 mg unblinded for a mean period of 16 months. Tremor was effectively reduced by a single dose of clozapine in 13 of 15 patients; sedation was the only adverse effect reported. Neuroleptic malignant syndrome has previously been reported with clozapine (SED-14, 147; SEDA-22, 58; SEDA-23, 60), although some doubts have been expressed about the features of these cases (SEDA-21, 54; SEDA-22, 58). In the light of two new cases, a 35year-old man and a 62-year-old woman, the literature has been comprehensively reviewed and the characteristics of neuroleptic malignant syndrome due to clozapine and traditional antipsychotic drugs compared (84AR). Causation with clozapine was deemed highly probable in 14 cases, of medium probability in five cases, and of low probability in eight cases. The most commonly reported clinical features were tachycardia, changes in mental status, and sweating. Fever, rigidity, and raised creatine kinase activity were less prominent than in the neuroleptic malignant syndrome associated with classical neuroleptic drugs. This suggests that the presentation of clozapine-induced neuroleptic malignant syndrome may be different from that of traditional antipsychotic drugs. Two other cases have also illustrated that possibility (85 At, 86A). It is generally considered that clozapine has little or no potential to cause tardive dystonia; it has even been speculated that clozapine may be an effective therapy for this adverse effect (SEDA-21, 53). The efficacy of clozapine in severe dystonia has been assessed in an open trial in five patients (87c). All five had significant improvement; nevertheless, adverse effects, such as sedation and orthostatic hypotension, developed in all patients: in one subject, persistent symptomatic orthostatic hypotension and tachycardia limited treatment. In contrast, a case of tardive dystonia probably associated with clozapine has also been described (88A). A 37-year-old man, who had taken numerous neuroleptic drugs from 1975 to 1990, was switched to clozapine because of breakthrough psychosis. Clozapine was effective and was his only antipsychotic drug treatment from that time. In 1996, when his clozapine dosage was 825 mg/day, he had left torticollis of 60-70~ mild left laterocollis, and superimposed spasmodic head movements jerking his head to

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the left. He had difficulty rotating his head to the right past the midline. Stuttering, an infrequent adverse effect of antipsychotic medication, has been associated with clozapine (SEDA-22, 58). The pathogenesis of developmental stuttering, as well as acquired or neurogenic stuttering, is unclear. The case of a 49-year-old woman who suffered prominent stuttering before a generalized epileptic seizure and recovered after antiepileptic treatment, has suggested that clozapine-induced stuttering is related to an effect on the brain rather than to a dystonic syndrome, as previously suggested (89Ar).

Psychiatric Obsessive-compulsive symptoms during clozapine therapy have been suggested to be more common than previously reported (SEDA-21, 54). In a retrospective cohort study, the increase or emergence of obsessions has been analyzed in 121 consecutive young patients with recent-onset schizophrenia or other psychotic disorders takinj~ clozapine and other antipsychotic drugs (90'-). More clozapinetreated subjects (21%) had new or worsened obsessions than subjects treated with other antipsychotic drugs (1.3%). However, there was no information on comparability of the groups. Endocrine Hyperglycemia, sometimes leading to ketoacidosis or glycosuria, has been reported in association with clozapine (SEDA21, 54; SEDA-22, 58; SEDA-23, 60). In some cases, the condition has been of new onset, and in others exacerbation of pre-existing diabetes mellitus has occurred. Hyperglycemia appears to be of early onset (2 weeks to 3 months after the start of clozapine treatment) and to occur without predisposing factors. Clozapineinduced hyperglycemia may be serious, leading to coma, but it is reversible if clozapine is withdrawn. In some cases, continuation of clozapine is possible by controlling serum glucose concentrations with the use of hypoglycemic drugs. This approach may be useful in refractory schizophrenia responsive to clozapine. In those with diabetes mellitus, glucose monitoring should be conducted in conjunction with the obligatory hematological monitoring. All patients should be advised to report altered consciousness, polyuria, or increased thirst.

Alfonso Carvajal and Luis H. Marffn Arias

Diabetic ketoacidosis occurred in a 31-yearold man who had taken clozapine 200 mg/day for 3 months for refractory schizophrenia (91A). Clozapine was withdrawn and he remained metabolically stable. Two months later clozapine was restarted, and only 72 hours after drug re-exposure he had increased fasting glycemia and insulinemia, suggesting insulin resistance as the underlying mechanism. Apart from slight obesity, he had no predisposing factors. Hematologic Circadian variation in white cell count, with a dip in the morning, has been misdiagnosed as clozapine-induced neutropenia (92A). A 31-year-old man with resistant schizophrenia was treaWat with clozapine 500 mg/day. Although this was effective, the granulocyte count fell to 1.2 x 109/1 (total count not given) and clozapine was withdrawn. During the subsequent year, several neuroleptic drugs were used, with unsatisfactory results. Careful blood cell monitoring showed a pronounced diurnal variation of total white cell count (2.9--4.2 x 109/1 in the morning and 3.6-7.1 x 109/1 in the afternoon) and granulocytes (0.8-1.4 x 109/1in the morning and 2.9-5.5 x 109/1in the afternoon). Thus, an apparently low white cell count may simply reflect the nadir of the diumal variation and may not indicate a need for withdrawal of clozapine. Pancreas Pancreatitis has been considered to be an uncommon adverse effect of clozapine, although occasional cases have been reported (SEDA-23, 61). Two new cases have been reported in patients with no prior history of alcohol abuse or gallstones (93 Ar, 94A). The authors recommended monitoring serum amylase activity during slow increases in the dosage of clozapine if there is leukocytosis or eosinophilia, which may be associated with asymptomatic pancreatitis. Urinary tract Enuresis has been associated with clozapine (SEDA-21, 54; SEDA-22, 60). In a retrospective study, 27 of 61 Chinese patients treated with clozapine for more than 3 months developed urinary incontinence, persistent in 15 cases (95c). The reaction could not be related to age, sex, clozapine dosage, duration of clozapine use, duration of hospitalization, duration of illness, age at onset

Antipsychotic drugs

Chapter6

of schizophrenia, or concurrent treatment with other psychiatric drugs. A report of clozapine-induced acute interstitial nephritis, claimed to be the first, has been published (96A). A 38-year-old woman developed anorexia, lethargy, and vomiting, and noticed a profound reduction in urine output about 11 days after starting clozapine (125 mg bd). Severe renal insufficiency was confirmed (blood urea 33 mmol/l and creatinine 1200 ixmoUl). There was no history of pre-existing renal or other systemic disease. Sexual function The frequency and course of sexual disturbances associated with clozapine have been studied in a prospective open-label study in 75 men and 25 women, mean age 29 years, and compared with the effects of haloperidol in 41 men and 12 women, mean age 26 years (97c). There were no statistically significant differences between the patients taking haloperidol and those taking clozapine. During 1~5 weeks of treatment with clozapine, the most frequent sexual disturbances among women were diminished sexual desire (28%) and amenorrhea (12%), while among men they were diminished sexual desire (57%), erectile dysfunction (24%), orgasmic dysfunction (23%), ejaculatory dysfunction (21%), and increased sexual desire (15%). The mean daily doses were haloperidol 16 mg and clozapine 261 mg.

Immunologic Allergic reactions associated with clozapine are uncommon; however, a case of rash (SEDA-21, 55) and a case of pleural effusion (SEDA-22, 60) have previously been reported. Both rash and pleural effusion have been recently reported in a 37-year-old woman about 1 week after starting clozapine (98A). Risk factors In a recent review, potential predictors of favorable and adverse outcomes to clozapine treatment have been considered (99M). With data from over 11 000 patients, it was noted that the risk of agranulocytosis is higher in the first 3 months of treatment and is greater among women and elderly patients. Furthermore, an increase in white blood cell count of at least 15% above previous counts is a sensitive, although not specific, predictor for the development of agranulocytosis within 75 days. Clozapine dosage and baseline white cell count do not appear to predict agranulocytosis.

65 Drug overdose A case of clozapine overdose (2.5 g) has been reported in a 67-year-old woman (100A). It resulted in seizures, loss of consciousness, metabolic acidosis, prolonged sedation, and aspiration pneumonia. By 9 days after intoxication she had recovered completely. Drug formulations Since clozapine is expensive, it is interesting that generic clozapine (given as 25 and 100 mg tablets) behaves like Clozaril | the branded formulation; bioequivalence has been observed in 30 patients with schizophrenia (101c).

Drug interactions Serious symptoms due to dangerous interactions with benzodiazepines in patients treated with clozapine have been previously reported (SEDA-19, 55; SEDA-20, 50; SEDA-22, 62). Syncope and electrocardiographic changes (sinus bradycardia of 40/min with deep anteroseptal inverted T waves and minor ST changes in other leads) have been observed with the concurrent administration of clozapine (after the dosage was increased to 300 mg/day) and diazepam (30 mg/day) in a 50-year-old man (102A). Selective serotonin re-uptake inhibitors (SSRls) markedly inhibit the metabolism of clozapine, increasing its plasma concentrations (SEDA-21, 55; SEDA-22, 62; SEDA-23, 63). In 16 patients taking clozapine monotherapy fluvoxamine 50 mg was added, in the hope of ameliorating the negative symptoms of schizoc At steady state the serum conphrenia (103). centrations of clozapine and its metabolites were increased up to 5-fold (average 2- to 3fold). However, adverse effects were almost unchanged in frequency and severity, in spite of the pharmacokinetic interaction. In another study there were similar increases in plasma clozapine concentrations and adverse reactions in 18 patients treated with fluvoxamine 50 mg (week 5, mean dose 97 mg) (104c). The interaction of fluvoxamine with clozapine has also been evaluated in nine men who were given a single dose of clozapine 50 mg on two separate occasions with a 2-week interval (105c). Fluvoxamine increased clozapine plasma concentrations and the total mean clozapine AUC was increased by a factor of 2.6; all the patients were sedated during combined therapy. In contrast, although nefazodone is a potent and specific in vivo inhibitor of CYP3A4, which is thought to play a major role in the metabol-

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Chapter 6

ism of clozapine, there were minimal effects on clozapine metabolism when co-administered in six patients: mean clozapine concentrations rose by 4% and norclozapine concentrations by 16% (106c). Although valproic acid has been reported to increase the sedative effects of clozapine (SEDA-20, 50), a recent study showed only small effects on plasma clozapine concentrations, which were thought to be unlikely to be clinically significant (107c). Inhibitors of CYP1A2 (such as caffeine) and CYP3A4 (such as erythromycin), can theoretically increase plasma clozapine concentrations (SEDA-23, 61). Adverse effects in a patient taking clozapine and erythromycin have previously been reported (SEDA-21, 55). However, in 12 healthy men who took a single dose of clozapine 12.5 mg alone or in combination with a daily dose of erythromycin 1.5 g, the metabolism of clozapine was not altered (108c). This confirms that CYP3A4 is a relatively minor pathway for clozapine metabolism, in contrast to CYP1A2 (see below). Perphenazine doubled clozapine concentrations in a 46-year-old male smoker with paradoxical worsening of psychosis, myoclonus, and hypersalivation (109A). The mechanism of this effect is not known; perphenazine is a substrate for CYP2D6, which is not important in the metabolism of clozapine. Smoking is highly prevalent among patients with schizophrenia, of whom 70-80% smoke. In a before-and-after study, 55 smokers smoked less when treatment was switched to clozapine than when they were being treated with conventional neuroleptic drugs (110c). Nevertheless, it is probable that heavy smoking can induce CYAP1A2, the main enzyme involved in the metabolism of clozapine, and sudden cessation of smoking may cause a rise in plasma clozapine concentrations, and in one case seizures have been reported (111A). A 35-year-old schizophrenic man successfully treated with clozapine 700--725 mg/day for more than 7 consecutive years abruptly stopped chronic heavy cigarette smoking and 2 weeks later suddenly developed tonic-clonic seizures followed by stupor and coma. After recovery, he successfully reduced the daily dose by about 40% before he stopped smoking.

AlfonsoCarvajal and Luis H. Martln Arias

Droperidol

(SEDA-23,64)

Droperidol 5-7.5 mg given during induction of anesthesia was associated with impaired wellbeing scores 6 hours postoperatively in a randomized double-blind comparison of similar doses of droperidol (n = 78) and midazolam (n = 72) for preventing postoperative nausea and vomiting (112c). Nervous system Intramuscular droperidol 2.5 mg was used to treat 23 consecutive patients with acute migraine who had not responded to other drugs (113c). If no relief was achieved by 30-60 minutes after treatment, and no significant adverse effects were reported, a second dose of droperidol 2.5 mg was given. Varying degrees of akathisia after treatment were reported by six patients. Similarly, in a retrospective series of 37 patients who received droperidol 2.5 mg for migraine, three developed mild akathisia and five had drowsiness (114c).

Olanzapine

(SEDA-21, 56; SEDA-22, 64;

SEDA-23, 64) A meta-analysis of four comparisons of olanzapine and haloperidol showed similar efficacy, with fewer extrapyramidal effects with olanzapine (5M). Similar conclusions were reached in another meta-analysis of three randomized, double-blind, controlled comparisons of olanzapine and haloperidol (115M). Only 15% of olanzapine-treated patients (n = 1620, dose 5 20 rag) needed anticholinergic drugs compared with 49% of those treated with haloperidol (n = 786, dose, 5-20 mg). Several recent reviews have not added anything new (116 R-118 R). It has been emphasized that the most common adverse effects are somnolence and weight gain, since about 40% of patients gain weight (especially if on a high starting dose and if they were underweight before treatment); sexual dysfunction can be also a problem for many patients. Since the large trials of olanzapine lasted 6 weeks, long-term efficacy and safety information are still lacking. Likewise, its efficacy in treatment-resistant schizophrenia has not been established, although some inconclusive information has emerged. In 16 patients with treatment-resistant schizophrenia (defined as non-responsiveness to at least three antipsychotic drugs from at least two different

Antipsychotic drugs

Chapter6

67

chemical classes), olanzapine was effective weight gain and self-limited diarrhea. However, treatment in a significant proportion; no serious poor design and small sample size precluded adverse events were associated with mainten- definitive conclusions. ance doses of 10--40 mg/day, and no subjects dropped out (119c). In five consecutive cases, Nervous system Fatal status epilepticus ocolanzapine was also effective for treatment- curred in a patient taking olanzapine with no refractory psychosis in patients previously re- known underlying cause or predisposing factor sponsive to, but intolerant of, clozapine (120c). for seizures (129A). The efficacy and safety of olanzapine in particular disorders have been studied (SEDAA 41-year-old woman developed seizures that 23, 65). Some new uses have been proposed, progressed to status epilepticus, and died from secsuch as the treatment of psychiatric manifest- ondary rhabdomyolysis and disseminated intravascuations of hereditary coproporphyria (121A). In lar coagulation. She had been taking olanzapine 10 mg/day for 5 months. No other toxic, metabolic, or an open-label study, eight patients with Lewy anatomical abnormalities were identified pre- or postbody dementia associated with psychotic and mortem to explain the seizures. However, her medbehavioral difficulties were given olanzapine ications also included levothyroxine 0.15 mg/day, 2.5-7.5 mg (122c). Three of the eight could clonazepam 1.0 mg qds, and propranolol 20 mg tds. not tolerate olanzapine, even at the lowest dose, two had a clear improvement in psychotic and Non-fatal seizures have also been reported behavioral symptoms, and three tolerated olan- in a 31-year-old woman with multiple psychiatzapine but gained only minimal benefit. The ric and medical disorders, including a generalauthors concluded that olanzapine in the doses ized seizure disorder (a probable confounding used conferred little advantage over conven- factor in this case), when she switched from tional neuroleptic drugs and should be given haloperidol to olanzapine (130Ar). Seizures asonly with great caution to patients with Lewy sociated with olanzapine in premarketing studbody dementia. ies have been estimated to occur in 0.88% of Olanzapine has been also compared with patients, a reported incidence probably comhaloperidol in other disorders: cannabis-induc- parable to that found with many conventional ed psychosis (123c), schizoaffective disorder agents. (124c), first-episode psychosis (125M), and Akathisia has previously been reported in treatment resistant schizophrenia (126M); the 16% of patients taking olanzapine (SEDA-21, two last studies were reanalyses of data from 56). A 30-year-old woman with obsessivethe large clinical trials promoted by the man- compulsive disorder, who took olanzapine 10 ufacturers, Eli Lilly. In all cases olanzapine mg/day titrated to 15 mg/day, developed severe was better than haloperidol at reducing BPRS akathisia after 3 weeks; the condition resolved scores, but in patients with cannabis-induced on withdrawal and reappeared on rechallenge psychotic disorders they were similar. Increased (131A). appetite was consistently reported more often Restless legs syndrome shares clinical feain olanzapine-treated patients and extrapyram- tures with akathisia but has not yet been deidal signs more often in those treated with scribed as a adverse effect of olanzapine. A haloperidol. 41-year-old man complained of paresthesia in On the other hand, in a prospective open- both legs at rest, much worse at night, and relabel study for 12 weeks in eight children, lieved by walking around (132A). The reaction adolescents, and adults with developmental dis- occurred during the sixth week of treatment, 36 orders, the most significant adverse effects of hours after an increase in dose from 10 to 20 olanzapine were increased appetite and weight mg/day; no other drug was administered. gain in six patients and sedation in three (127 e). Whether treatment with olanzapine is useful The efficacy and adverse effects of high in psychotic symptoms in patients with Parkindoses of olanzapine have been assessed in pa- son's disease is unclear (SEDA-23, 66). Nine tients with schizophrenia and schizoaffective patients of 12 with drug-induced psychosis in disorder (128c). Seven patients were treated Parkinson's disease had worsening of motor with olanzapine in doses of up to 30 mg/day, function while taking olanzapine (2.5 mg/day and none discontinued olanzapine because of and increased in 2.5 mg increments as needed); adverse effects; the only adverse effects were this worsening was considered dramatic in six

68

Chapter 6

of these patients, and only one was still taking olanzapine at the time of the analysis (12 months) (133c). In addition, two elderly patients, one with and one without pre-existing parkinsonism, had marked rigidity induced by olanzapine 5 mg/day (134A). Two cases of neuroleptic malignant syndrome associated with olanzapine have previously been reported (SEDA-23, 66), and several new cases have emerged (135A--141A). Data from three pivotal trials of olanzapine (SEDA-21, 56) have been reanalyzed by investigators from the manufacturers, Eli Lilly, with a focus on tardive dyskinesia (142R). In a previous study they had presented the percentage of patients developing dyskinesia without regard to the time to development: tardive dyskinesia occurred in 1.0% and 4.6% with olanzapine and haloperidol respectively (SEDA-22, 65). Now they have calculated the number of cases per patient exposure time. When patients were stratified by abnormal involuntary movement scale (AIMS) at baseline, the incidence rate ratios for those with AIMS = 0 was 5.67 (CI = 2.45, 13.1) and for those with AIMS > 0 it was 2.55 (CI = 1.15, 5.68), both favorable to olanzapine. However, since only the highest dosages of olanzapine were as effective as haloperidol in the trials, choosing all the patients treated with olanzapine without regard to the dosages yielded an underestimation of the risk. Since olanzapine has a better profile of extrapyramidal adverse effects, it has been proposed as an alternative in the long-term treatment of schizophrenia (143R). Anecdotal reports of olanzapine-induced tardive dyskinesia are starting to appear. Two cases have been described, purportedly for the first time (144A). Moreover, a 40-year-old woman with bipolar disorder developed tardive dystonia after taking olanzapine 10 mg at bedtime for 7 months (145A). Olanzapine has also occasionally been seen to improve pre-existing tardive dyskinesia (SEDA-23, 66). A new case of marked improvement with olanzapine (2.5 mg/day, titrated within 5 days to 17.5 mg/day) has been reported in a 59-year-old man with a long history of neuroleptic drug exposure (146A). In addition, a case of respiratory dyskinesia, which was conceptualized as a form of tardive dyskinesia, including grunting, tachypnea, and impaired vocalization, also improved after the patient started to take olanzapine 2.5 mg/day (147A).

AlfonsoCarvajal and Luis H. Marffn Arias

Psychiatric Mania has previously been related to olanzapine (SEDA-23, 66), and several new cases have been reported (86 A, 148 A, 149A). Nevertheless, olanzapine has also been proposed as a treatment for acute mania. In a randomized, double-blind, placebo-controlled study for 3 weeks patients were assigned to either olanzapine 10 mg/day (n = 70) or placebo (n = 69) (150c). Significantly more olanzapinetreated patients responded (49%) compared with those assigned to placebo (24%). Somnolence, dizziness, dry mouth, and weight gain occurred significantly more often with olanzapine, but there were no statistically significant differences with respect to measures of Parkinsonism, akathisia, and dyskinesia. In another study, 30 patients with mania were randomized to olanzapine or lithium in a double-blind 4week study (151c). Olanzapine did not differ from lithium in terms of efficacy or of extrapyramidal adverse effects, as measured by the Simpson-Angus Scale. Also, in an open trial to determine the efficacy of olanzapine in the treatment of bipolar mixed state (n = 9), the results showed improvement in acute symptoms and the drug was well tolerated (152c). Finally, two patients, one with treatment-resistant rapid cycling bipolar disorder (153 A) and the other with severe mood changes during corticosteroid therapy (154A), improved with olanzapine. Olanzapine-induced worsening of obsessive-compulsive symptoms has previously been reported (SEDA-23, 67). Now olanzapineinduced de novo obsessive--compulsive disorder has been reported in two cases, claimed to be the first (155A). One of the patients developed de novo obsessive-compulsive symptoms with the introduction of olanzapine, whereas in the other case the patient had undisturbing obsessive symptoms before olanzapine treatment. In contrast, olanzapine was effective in an open-label trial in 10 patients with obsessive-compulsive disorder refractory to selective serotonin re-uptake inhibitors, who were given additional olanzapine; they had minimal adverse effects, primarily sedation (156c). Anxiety has been reported as a common adverse effect (in 36% of patients) associated with olanzapine (SEDA-22, 65). A 36-year-old woman taking olanzapine 5 mg tds had newonset panic attacks, with feelings of severe anxiety, shortness of breath, trembling, palpitation, and sweating, and felt that she was going to die (157A). She had no previous history of

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panic attacks, which responded to the addition of alprazolam. The authors hypothesized that the 5-HT2 antagonist action of olanzapine had triggered the onset of this condition. Hypofrontal symptoms, with problematic discourtesy and socially inconsiderate conduct, occurred in a 31-year-old man shortly after the introduction of olanzapine 20 mg/day; he had taken typical neuroleptic drugs for 13 years without such symptoms (158A). Sensory systems A 37-year-old man who had taken olanzapine 10 mg/day at bedtime for 1 week developed an excessive whitish discharge from the eyes (159c). The authors suggested that in some patients olanzapine may cause heavy mucus secretion in any of the mucus-secreting surfaces of the body.

Endocrine Olanzapine is structurally similar to clozapine, which can worsen diabetes (see SEDA-23, 60). According to the 1999 Physician's Desk Reference, hyperglycemia associated with olanzapine use has a frequency of 1/100 to 1/1000. There has been a previous report of a patient who developed diabetes and required insulin (SEDA-23, 67) and two new cases have drawn attention to this important reaction (160 A, 161A). A 50-year-old man developed acute ketoacidosis with de novo diabetes mellitus after 8 months of adjunctive olanzapine. His dosage was then gradually titrated to 30 mg/day over 6 months, and after withdrawal of olanzapine his diabetes mellitus disappeared completely. A 3t-year-old man taking olanzapine 10 mg/day, who had no family history of diabetes and had never had any laboratory evidence of diabetes or glucose intolerance, developed diabetic ketoacidosis; obesity was the only predisposing factor, his BMI being 40 kg/m2. Olanzapine can also exacerbate pre-existing diabetes (162A). A 45-year-old man with a 4-year history of dietcontrolled diabetes had hyperglycemia with polyuria, polydipsia, and blurred vision associated with the use of olanzapine 10 mg/day. Within 1 week after olanzapine was withdrawn his blood glucose returned to normal and insulin was discontinued. It is recommended that physicians carefully monitor the blood glucose concentration in patients taking olanzapine if they are diabetic or predisposed to diabetes.

69

Metabolic Significant weight gain occurs more often with olanzapine than with either haloperidol or risperidone (SEDA-22, 62; SEDA-23, 67). Further information has come from a retrospective study of 16 patients (seven men, nine women) taking olanzapine (mean dose 14 mg/day, range 10-30) (163r There was weight gain of over 7% in 15 of them; no change in diet, access to food, or change in exercise pattern had occurred. Similarly, weight gain was observed in nine patients (seven men, two women, mean age 41 years) treated with olanzapine (mean dose 19 mg/day, range 1030) (164c). The patients had a mean weight gain of 9.9 kg and tryglyceride concentrations (reference range 0.3-2.3 mmol/1) increased from a mean of 1.9 mmol/1 (range 0.8-4.3) to a mean of 2.7 mmol/1 (range 1.5-4.2). Moreover, weight gain of 38.5 kg occurred in a 15-yearold adolescent who had taken olanzapine 5-10 mg/day for 14 months (165A).

Hematologic Thus far, olanzapine has been believed to cause relatively few hematological adverse effects (SEDA-22, 65; SEDA-23, 67). However, some cases of neutropenia (neutrophil count below 1.5 x 109/1) (166 A) or agranulocytosis (neutrophil count below 0.5 x 109/1) (167 A) have been published. Two cases of olanzapine-induced neutropenia occurred 17 days after the first dose of olanzapine in one case and more than 5 months after the first dose in the other (166A); in this last patient, re-exposure to olanzapine caused the neutrophil count to fall again. In neither case was there evidence of infection and the white blood cell counts increased immediately to the reference ranges after withdrawal of olanzapine, no special treatment being necessary. In addition, two cases of reversible leukopenia during treatment with olanzapine have also been reported (168A). Whether clozapine-induced granulocytopenia or leukopenia predisposes a patient to hematological adverse effects during treatment with olanzapine is unclear: three patients who had previously stopped clozapine owing to hematologic adverse effects had improvement with olanzapine that equated to a 16-31 point reduction in rating scale scores during 1 year of follow-up without any hematological abnormalities (169c). In contrast, one case associated with clozapine worsened when olanzapine was given (170 A).

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Chapter 6

In a 31-year-old woman clozapine monotherapy 75 mg/day caused neutropenia (neutrophil count 1.1 x 109/1); 5 days after elozapine withdrawal the neutrophil count normalized (2.6 x 109/1). Olanzapine was then introduced at 5 rag/day and the next day increased to 10 mg/day. After a week the neutrophil count fell to 0.9 x 109/1 and olanzapine was withdrawn. The neutrophil count was normal 4 weeks after olanzapine withdrawal. In another case olanzapine caused agranulocytosis after clozapine had had no effect on the white cell count (171A). A 27-year-old man taking clozapine, benperidol, and risperidone developed severe extrapyramidal adverse effects and had insufficient antipsychotic effects and was given olanzapine, rapidly increasing to 40 mg/day. After 9 days of treatment with olanzapine, his total white cell count fell from 5.8 • 109/1 to 3.4 x 109/1, and olanzapine was withdrawn; 3 days later his neutrophil count was 0.39 x 109/1. He developed a fever of 39.5 ~ C and was treated with granulocyte colony-stimulating factor. Predisposing factors for neutropenia and agranulocytosis have been investigated in two patients one of whom had neutropenia after taking other drugs and one of whom was also taking amitriptyline (172A). The risk of clozapine-induced agranulocytosis was significantly higher in patients with the HLA haplotypes DQB*01, DQB*05, and DQB*02. One of the patients who had neutropenla had HLADQB*05 and both patients had haplotype HLAA2. Gastrointestinal Increased salivation (SEDA-22, 64) and drooling (SEDA-23, 68) are adverse effects associated with olanzapine.

Excessive, chalky-white, frothy, sticky salivation has now been reported in a 27-year-old man who had taken olanzapine 10 mg/day at bedtime for 4 days (159c). Sexual function Priapism associated with olanzapine has previously been reported (SEDA-23, 68), and a new case occurred in a 27-year-old patient who had taken olanzapine 15 mg at bedtime for 12 days for hallucinations (173A). Partial detumescence was followed by recurrence, and he required an operation to insert a glandular shunt. He subsequently required mechanical support to achieve an erection.

AlfonsoCarvajal and Luis H. Marffn Arias

D r u g overdosage Deaths from overdosage of olanzapine have previously been reported (SEDA-23, 68). Now several non-fatal cases have been published (174A-177A). Profound

central nervous system depression and tachycardia without other dysrhythmias occurred within 2 hours of an olanzapine overdose (800 mg; the highest serum concentration was 991 Ixg/l) (174A). The patient recovered after intubation, gut decontamination, and supportive care. A second patient took an overdose of 1110 mg of olanzapine and had tachypnea,

sinus tachycardia, fluctuating blood pressure, and brief hypoxemia; respiratory and cardiovascular function returned to normal within 16 hours of ingestion with minimal interventions (175 c). The third patient attempted suicide by taking 120 mg of olanzapine, but had no serious clinical adverse effects, and only fatigue, dizziness, and headache (176c). Finally, in four cases of overdose with up to 1000 mg there was significant central nervous system depression and miosis after acute overdosage of olanzapine (177A). Olanzapine concentrations in ng/ml were over 250, 59, 54, and 151 respectively (target range 9-23 ng/ml). All four patients recovered with supportive care and two required advanced airway support. The authors pointed out that all the patients had marked miosis and depressed mental status, findings that are usually associated with intoxication with opioids or a2-adrenoceptor agonists but have not been previously described with neuroleptic drugs. Several cases of olanzapine overdose have recently been reported in children. An 11-kg, l-year-old child developed agitation followed by prolonged lethargy after accidental ingestion of an unknown amount of olanzapine (178A). An 18-month-old boy took 30-40 mg of olanzapine and had respiratory distress and mental status changes (179A). Prolonged central nervous system depression occurred after a medication error in a 17-kg, 6-year-old girl who was given Zypresa (olanzapine 10 mg) instead of Zyrtec (cetirizine 10 rag) (180A). In the light of a dispensing error in a 14year-old boy who was given olanzapine 80 mg/day, eight times the recommended dose in adults, it has been suggested that precautions should be taken when treating children and adolescents with antipsychotic drugs that have only been evaluated in adults (181A).

Antipsychotic drugs

Chapter6

Drug interactions Pharmacokinetic and pharmacodynamic profiles of olanzapine have been extensively reviewed (182R). Olanzapine does not inhibit CYP isoenzymes, and no clinically significant metabolic interactions were found of olanzapine with aminophylline, biperiden, diazepam, ethanol, fluoxetine, imipramine, lithium, or R/S-warfarin. Fluvoxamine, an inhibitor of CYP1A2, increases plasma concentrations of olanzapine; conversely, inducers of CYP1A2, including tobacco and carbamazepine, reduce olanzapine concentrations. There were orthostatic changes when olanzapine and diazepam or ethanol were co-administered. Pharmacodynamic interaction also occurred between olanzapine and

imipramine. The plasma concentration of olanzapine doubled in a patient who also took ciprofloxacin, a potent inhibitor of CYP1A2 (183A), and the magnitude of the interaction was surprising, because available data suggest that CYP1A2mediated oxidation of olanzapine accounts for only a small portion of the biotransformation of olanzapine relative to glucuronidation. Of 56 patients, 22 of whom took olanzapine monotherapy and the rest took other psychotropic drugs, those co-medicated with inhibitors of CYP2D6 and other drugs had a median dose-corrected concentration about 40% higher than those taking monotherapy; the patients co-medicated with carbamazepine had a median dose-corrected concentration 36% lower than those taking monotherapy (184c).

Quetiapine

(SEDA-22, 65; SEDA-23, 68)

The pharmacology, efficacy, and safety of quetiapine, an atypical antipsychotic drug, have been extensively reviewed (185R). Quetiapine interacts with a broad range of neurotransmitter receptors and has a higher affinity for serotonin (5-HT2A) receptors than dopamine (D2) receptors in the brain. In a recent meta-analysis quetiapine was as effective as haloperidol with fewer extrapyramidal adverse effects (5M).

Risperidone

(SEDA-21, 57; SEDA-22, 66;

SEDA-23, 68) A recent review of both core information and new findings concerning risperidone concluded that it can be associated with transient drowsiness (probably no greater than that observed

71 with haloperidol), postural hypotension (which is avoided by dose titration), weight gain, re-

duced sexual interest, and erectile dysfunction. Risperidone can also cause dose-dependent hyperprolactinemia (which may cause amenorrhea, sexual dysfunction, and galactorrhea). Risperidone tends not to cause extrapyramidal signs at therapeutic doses (the optimal dose being 6 mg/day) but they do occur dosedependently (186 ~). In an 8-week open-label prospective study of risperidone in 20 patients, mean age 34 (range 19-53) years, adverse effects included giddiness (n = 3), headache (n = 2), and agitation (n = 2); one woman reported galactorrhea and another developed obsessive-compulsive symptoms; 16 of 20 patients were taking antiparkinsonian drags before the study, compared with 12 patients at the end (187c). Cardiovascular One of two children aged 29 and 23 months with autistic disorder developed a persistent tachycardia and doserelated QTc interval prolongation while receiving risperidone (188A). Cardiotoxicity of risperidone has recently been discussed (189 r) in the light of a death in a patient taking a therapeutic dose (SEDA-22, 68). Nervous system Risperidone produces doserelated extrapyramidal adverse effects (SEDA21, 58; SEDA-22, 68; SEDA-23, 70), although at equieffective doses it has fewer such effects than haloperidol (SEDA-21, 57; SEDA-22, 67; SEDA-23, 68). A recent combined analysis of 12 double-blind studies in schizophrenic patients comparing the use of risperidone (n = 2074) with placebo (n = 140) or haloperidol (n = 517) has further stressed the dose-related extrapyramidal effects associated with risperidone (190CR). After co-variance analysis to adjust for baseline ESRS (Extrapyramidal Symptom Rating Scale) scores, sex, race, age, height, duration of symptoms, age at first hospitalization, hospitalization status, and diagnosis, the effects of the maximum dose of risperidone on the mean shift to worse ESRS total scores were 1.4 (CI = 0.73, 2.03) at 1-4 mg/day (n = 319); 2.1 (CI = 1.65, 2.50) at 4-8 mg/day (n = 932); 3.3 (CI = 2.61, 3.89) at over 8 mg to 12.5 mg/day (n = 439); and 3.8 (CI = 2.99, 4.55) at 13 mg/day or more (n = 361). Similarly, the results showed a significant dose-dependent in-

72

Chapter 6

crease in the use of antiparkinsonian drugs; the percentages of those requiting antiparkinsonian drugs were 14% at 1-4 mg/day (n = 319); 25% at 4-8 mg/day (n = 900); 27% at 8-12.5 rag/day (n = 407); and 31% at 13 rag/day or more (n = 335). Of 882 patients who took risperidone for at least 12 weeks, based on unsolicited reports, two developed tardive dyskinesia. Similar conclusions have been reached in an international, multicenter, double-blind study in 183 patients with a first psychotic episode treated with flexible doses of risperidone or haloperidol for 6 weeks (191c). The severity of extrapyramidal symptoms and the use of antiparkinsonian drugs were significantly lower in patients taking low doses (up to 6 mg/day) than high doses (over 6 rag/day) of risperidone or haloperidol; these findings are consistent with the suggestion that patients with a first psychotic episode may require low doses of antipsychotic drugs. Furthermore, the severity of extrapyramidal symptoms was significantly lower in the risperidone-treated patients. Also, risperidone-treated subjects were significantly less likely than haloperidol-treated subjects to require concomitant anticholinergic drugs after 4 weeks (20% vs 63%); they had significantly less observable akathisia (24% vs 53%) and significantly less severe tardive dyskinesia. This was observed in a randomized double-blind comparison of risperidone 6 mg/day (n = 34) and haloperidol 15 mg/day (n = 33) (192c). A 12-year-old boy developed parkinsonian tremor while taking risperidone (193A). This was claimed to be the first case associated with risperidone. Rabbit syndrome is a late-onset extrapyramidai adverse effect associated with antipsychotic drugs. It is characterized by a rapid tremor of the lips and occasionally of the jaw (SED-14, 146). A case has been reported, supposedly for the first time, in a patient treated with risperidone (194A). A 27-year-old man took risperidone 6 rag/day and after 4 months the dose was reduced to 4 mg; 7 months after the start of treatment he developed fine rapid pouting and puckering of the lips. These movements were accompanied by a strange, irritating, involuntary popping sound. The dosage of risperidone was reduced to 2 mg/day and an anticholinergic drug was added. Within days, there was symptomatic improvement, but a trial withdrawal of the anticholinergic drug resulted in worsening of the symptoms and treatment was renewed.

AlfonsoCarvajal and Luis H. Martin Arias

Catatonia has previously been reported in relation to risperidone (SEDA-23, 72), and a new case has been reported (195A). Catatonia occurred in a 61-year-old woman who was taking risperidone 5 mg/day for prominent paranoid delusions after a postfrontal lobotomy some 35 years ago. The catatonic disorder was dosedependent and resolved immediately after changing to clozapine.

Psychiatric Obsessive-compulsive symptoms associated with risperidone have been previously reported (SEDA-22, 69; SEDA-23, 71), and another case has appeared (196c). A man who had taken risperidone 4 mg/day for 18 months developed an obsessional image of a person's face that repeatedly appeared in his mind as he went about his activities; the recurrent images disappeared after the dosage of risperidone was reduced to 3 mg/day. It has been speculated that the antiserotonergic properties of risperidone could lead to obsessive and depressive symptoms, since a patient taking risperidone 4 rag/day developed major depression and obsessions, which resolved with fluoxetine 29 mg/day, relapsing when fluoxetine was withdrawn (197A). Several cases of anxiety, behavioral stimulation, and mania have been reported in patients taking risperidone (SEDA-21, 59; SEDA22, 69; SEDA-23, 71). Four new cases of risperidone-induced mania (198 A) and a further case of risperidone-induced anxiety in a 35-year-old man (199 c) have been reported. Endocrine The association of hyperprolactinemia and galactorrhea with risperidone has been extensively described (SED-14, 148; SEDA-22, 69; SEDA-23, 71). A recent review has further emphasized this association, which can result in amenorrhea and sexual dysfunction (186R). The relation of prolactin concentrations and certain adverse events has been explored by using data from two large randomized, double-blind studies (n = 2725; 813 women, 1912 men) (200CR). Both risperidone and haloperidol produced dose-related increases in plasma prolactin concentrations in men and women, but they were not correlated with adverse events such as amenorrhea, galactorrhea, or reduced libido in women or with erectile dysfunction, ejaculatory dysfunction, gynecomastia, or

Antipsychotic drugs

Chapter6

reduced libido in men. Nevertheless, in five patients risperidone (1-8 mg/day) caused amenorrhea in association with raised serum prolactin concentrations (mean 122 ng/ml, range 61-230 ng/ml; reference range 2.7-20 ng/ml) (201c). Amenorrhea presumably induced by risperidone has been successfully treated with Shakuyaku-kanzo-to, a Japanese herbal medicine that contains Peoniae radix and Glycyrrhizae radix (202A). Liver Risperidone has been implicated in hepatotoxicity (SEDA-21, 59; SEDA-23, 71). Transient increases in liver enzymes induced by risperidone occurred in two men aged 19 and 22 (203A). Risk factors Adverse effects of risperidone are probably more frequent in elderly patients. The safety, tolerability, and efficacy of risperidone have been assessed in 103 schizophrenic patients (52 men and 51 women) aged 65 years or older in an open-label, multicenter, 12-week study (204c). The mean risperidone dose at endpoint was 2.4 mg/day. Adverse events occurred in 91 patients and included dizziness (n = 23), insomnia (n = 17), agitation (n = 15), somnolence (n = 15), injury (n = 12), constipation (n = ll), and extrapyzramidal disorders (n = 10); l l patients withdrew because of adverse events. Among the 91 patients with normal baseline QTc intervals (below 450 ms), nine had a prolonged QTc interval during the study (range 450-516 ms). Furthermore, adverse effects leading to dosage reduction or discontinuation were also observed in a retrospective study in 57 patients mean age 84 (range 66-97) years, who took fisperidone (doses 0.5-4 mg/day) for more than 1 year (average 2 years) for dementia-related behavioral disturbances (205c). Adverse effects included hypotension (n = 4), agitation (n = 6), and sedation (n = 5), and six patients developed a new movement disorder. Older patients, patients with dementia, and children may develop more extrapyramidal signs. In a retrospective study, a substantial proportion of patients who needed anfiparkinsonian medication while taking fisperidone (mean daily dose 4.4 mg) were identified. Twelve of 55 elderly inpatients (aged over 65 years) treated with risperidone received antiparkinsonian drugs (206Cr). A large proportion of new or worsened extrapyramidal adverse effects (32%)

73 was also observed in a review of the charts of 41 patients with dementia (mean age 75 years) treated with risperidone (mean 1.8 mg/day) (207CR). Similarly, there was a high incidence (44%) of new movement disorders in 36 children and adolescents who were treated with risperidone (the highest dose of risperidone was 6 mg/day and the average maintenance dose was 4 mg/day) (208c). The higher incidence reported in the latter series has been countered by a contrasting report (209 c) that the most common adverse effect was excessive weight gain (n = 10) in a series of 30 children and adolescents (aged 6-21 years) taking risperidone (0.5~5 mg/day) for attention-deficit disorder. Vomiting and drowsiness each occurred in one patient; one patient had withdrawal dyskinesia, but the reintroduction of risperidone and slower withdrawal produced no recurrence. Tardive dyskinesia has previously been associated with risperidone, and the incidence in patients with chronic schizophrenia is said to be 0.34% per year. Advanced age and dementia may be contributing factors (SEDA-21, 59; SEDA-22, 68; SEDA-23, 70). Tardive dyskinesia/dystonia developed in four patients treated with risperidone at an early intervention facility for young people with psychosis (210cr). Other cases that have emerged were in a 13year-old young girl treated with risperidone 6 mg/day (211A), a 21-year-old woman without previous exposure to other neuroleptic drugs or systemic illnesses that affected the central nervous system (212A), and a 58-year-old man with chronic alcoholism who developed tardive dyskinesia after exposure to risperidone that was aggravated by olanzapine (213A). Drug overdose Cardiotoxicity of risperidone in overdosage has previously been reported, including cases of hypotension (SEDA-22, 71; SEDA-23, 72), tachycardia, and dysrhythmias (SEDA-23, 72); a new case has been published (214A). A 41-year-old man who took risperidone 270 mg developed a prolonged QTc interval (480 ms) and sinus bradycardia (44 bpm), without hemodynamic compromise. After 9 hours, he had episodes of asymptomatic supraventricular tachycardia with a maximum frequency of 150 bpm. After 30 hours he was in sinus rhythm with a normal QTc interval (360 ms). He was discharged 72 hours after admission, asymptomatic and with a normal electrocardiogram.

74

Chapter 6

D r u g interactions Dystonia occurred in a 81year-old man who took lithium in addition to risperidone 1 mg/day, valproic acid 2250 mg/day, and benzatropine 4 mg/day (215A). A possible interaction of risperidone with tetracycline has been reported in a 15-year-old adolescent with Asperger's syndrome, Tourette's syndrome, and obsessive-compulsive disorder (216A). Acute exacerbation of motor and vocal tics occurred when tetracycline 250 mg bd was introduced for acne; withdrawal of tetracycline resulted in an improvement in the tics. The possibility of an additive pharmacodynamic interaction between serotonin re-uptake inhibitors and risperidone has previously been discussed (SEDA-23, 72). Now in eight patients with major depressive disorder without psychotic features, who did not respond to serotonin re-uptake inhibitors therapy, when risperidone was added all improved within 1 week. Furthermore, risperidone also seemed to have beneficial effects on sleep disturbance and sexual dysfunction (217c). In an open-label study in 30 healthy subjects who took risperidone 1 mg orally before and after venlafaxine dosing to steady state, the oral clearance of risperidone fell by 38% and the volume of distribution by 17%, resulting in a 32% increase in AUC; renal clearance of 9hydroxyrisperidone also fell by 20% (218c). The authors concluded that these small effects

Alfonso Carvajal and Luis H. Marffn Arias

were consistent with the fact that venlafaxine is unlikely to alter the clearance of risperidone, which is mainly by CYP2D6. Two patients who were hospitalized with a diagnosis of opioid dependence received concomitant treatment with methadone 50 mg/day in one case, and levorphanol 14 mg/day in the other, each in association with risperidone. After several days, both had symptoms of opioid withdrawal despite having no change in their opioid doses (219A). The withdrawal symptoms resolved soon after risperidone was discontinued. According to the authors, this finding suggests that risperidone may precipitate opioid withdrawal in opioid-dependent patients.

Ziprasidone

(SEDA-23, 73)

In a randomized, Phase III, double-blind study, ziprasidone 80 mg/day and 160 mg was more effective than placebo in patients with acute exacerbations of schizophrenia or schizoaffective disorders (n = 302) (220c). After 6 weeks somnolence (19%) and akathisia (13%) were more frequent with ziprasidone 160 mg than with placebo (5 and 7% each). Benzatropine was required at some time during the study by 20% of the patients taking ziprasidone 80 mg/day, 25% of those taking ziprasidone 160 mg/day, and 13% of those taking placebo. The long-term safety of ziprasidone is unknown.

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40. Bulling M. Drag-induced dysphagia. Aust NZ J Med 1999; 29: 748. 41. Suzuki T, Hori T, Baba A, Abe S, Shiraishi H, Moroji T, Piletz JE. Effectiveness of anticholinergics and neuroleptic dose reduction on neurolepticinduced pleurothotonus (the Pisa syndrome). J Clin Psychopharmacol 1999; 19: 277-80. 42. Nisijima K, Ishiguro T. Electroconvulsive therapy for the treatment of neuroleptic malignant syndrome with psychotic symptoms: a report of five cases. J ECT 1999; 15: 158-63. 43. Alao AO, Yolles JC, Armenta W, Michaels AT. Neuroleptic malignant syndrome spectrum: a case report. J Pharm Technol 1999; 15: 162-4. 44. Leung ATS, Cheng ACK, Chan W-M, Lam DSC. Chlorpromazine-induced refractile corneal deposits and cataract. Arch Ophthalmol 1999; 117: 1662-3. 45. Oyewumi LK. Acquired aplastic anemia secondary to perphenazine. Can J Clin Pharmacol 1999; 6: 169-71. 46. Allison DB, Fontaine KR, Heo M, Mentore JL, Cappelleri JC, Chandler LP, Weiden PJ, Cheskin LJ. The distribution of body mass index among individuals with and without schizophrenia. J Clin Psychiatry 1999; 60: 215-20. 47. Wetterling T, MtiBigbrodt HE. Weight gain: side effect of atypical neuroleptics? J Clin Psychopharmacol 1999; 19: 316-21. 48. Reinstein MJ, Sirotovskaya LA, Jones LE, Mohan S, Chasanov MA. Effect of clozapinequetiapine combination therapy on weight and glycaemic control. Clin Drug Invest 1999; 18: 99-104. 49. Capron M, Lafitte B, Benedit M, Camard CN, Nicolas F, Beligon C, Baillet C. Colite ndcrosante chez un homme de 29 ans sous forte dose de neuroleptiques. R~anim Urgences 1999; 8: 701-4. 50. Filloux MC, Mardchal K, Bagheri H, Morales J, Nouvel A, Laurencin G, Montastruc JL. Phenothiazine-induced acute colitis: a positive rechallenge case report. Clin Neuropharmacol 1999; 22: 244-5. 51. Francobandiera G, Rondalli G, Telattin P. Acute pancreatitis associated with clothiapine use. Hum Psychopharmacol Clin Exp 1999; 14:211-12. 52. Michael A, Calloway SP. Priapism in twins. Pharmacopsychiatry 1999; 32: 157. 53. Mutlu N, Ozkurkcugil C, Culha M, Turkan S, Gtikalp A. Priapism induced by chiorpromazine. Int J Clin Pract 1999; 53: 152-3. 54. Cohen-Mansfield J, Lipson S, Werner P, Billig N, Taylor L, Woosley R. Withdrawal of haloperidol, thioridazine, and lorazepam in the nursing home. Arch Intern Med 1999; 159: 173340. 55. Sriram B, Kumar P, Rajadurai VS. A case of phocomelia--drug association revisited. Singapore Paediatr J 1999; 41: 81-3. 56. Campbell M, Rapoport JL, Simpson GM. Antipsychotics in children and adolescents. J Am Acad Child Adolesc Psychiatry 1999; 38: 537-45.

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57. Kudo S, Ishizaki T. Pharmacokinetics of haloperidol: an update. Clin Pharmacokinet 1999; 37: 435-56. 58. Pan L, Stichele RV, Rosseel MT, Berlo JA, De Schepper N, Belpaire FM. Effects of smoking, CYP2D6 genotype, and concomitant drug intake on the steady state plasma concentrations of haloperidol and reduced haloperidol in schizophrenic inpatients. Ther Drug Monit 1999; 21: 489-97. 59. Desta Z, Kerbusch T, Flockhart DA. Effect of clarithromycin on the pbarmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). Ciin Pharmacol Ther 1999; 65: 1020. 60. Yasui N, Kondo T, Suzuki A, Otani K, Mihara K, Fumkori H, Kaneko S, Inoue Y. Lack of significant pharmacokinetic interaction between haloperidol and grapefruit juice. Int Clin Psychopharmacol 1999; 14:113-18. 61. Yasui N, Kondo T, Otani K, Furukori H, Mihara K, Suzuki A, Kaneko S, Inoue Y. Effects of itraconazole on the steady-state plasma concentrations of haloperidol and its reduced metabolite in schizophrenic patients: in vivo evidence of the involvement of CYP3A4 for haloperidol metabolism. J Clin Psychopharmacol 1999; 19: 149-54. 62. Bernard JM, Roux DL, Pdrdon Y. Acute dystonia during sevoflurane induction. Anesthesiology 1999; 90: 1215-16. 63. Coulouvrat C, Dondey-Nouvel L. Safety of amisulpride (Solian| a review of 11 clinical studies. Int Clin Psychopharmacol 1999; 14: 209-18. 64. Danion J-M, Rein W, Fleurot O. Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. Am J Psychiatry 1999; 156: 610-16. 65. Ravizza L. Amisulpride in medium-term treatment of dysthymia: a six-month, double-blind safety study versus amitriptyline. J Psychopharmacol 1999; 13: 248-54. 66. Boyer P, Lecrubier Y, Stalla-Bourdillon A, Fleurot O. Amisulpride versus amineptine and placebo for the treatment of dysthymia. Neuropsychobiology 1999; 39: 25-32. 67. Ramaekers JG, Louwerens JW, Muntjewerff ND, Milius H, Bie De A, Rosenzweig P, Patat A, O'Hanlon JE Psychomotor, cognitive, extrapyramidal, and affective functions of healthy volunteers during treatment with an atypical (amisulpride) and a classic (haloperidol) antipsychotic. J Clin Psychopharmacol 1999; 19: 209-21. 68. Wahlbeck K, Cheine M, Essali A, Adams C. Evidence of clozapine's effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials. Am J Psychiatry 1999; 156: 990-9. 69. Buckman RW, Malan RD. Clozapine for refractory schizophrenia: the Illinois experience. J Clin Psychiatry 1999; 60 Suppl 1: 18-22.

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70. Dalal B, Larkin E, Leese M, Taylor PJ. Clozapine treatment of long-standing schizophrenia and serious violence: a two-year follow-up study of the first 50 patients treated with clozapine in Rampton high security hospital. Crim Behav Ment Health 1999; 9: 168-78. 71. Reinstein MJ, Sirotovskaya LA, Chasanov MA, Jones LE, Mohan S. Comparative efficacy and tolerability of benzatropine and terazosin in the treatment of hypersalivation secondary to clozapine. Clin Drug Invest 1999; 17: 97-102. 72. Howanitz E, Pardo M, Smelson DA, Engelhart C, Eisenstein N, Losonczy ME The efficacy and safety of clozapine versus chlorpromazine in geriattic schizophrenia. J Clin Psychiatry 1999; 60: 41-4. 73. Reid WH. New vs. old antipsychotics: the Texas experience. J Clin Psychiatry 1999; 60 Suppl 1: 23-5. 74. Kilian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999; 354: 1841-5. 75. Warner B, Schadelin J. Clinical safety and epidemiology. Leponex/Clozaril and myocarditis. Novartis Pharm AG, Basel, Switzerland, November 1999. 76. Walker AM, La~aza LL, Arellano E Rothman KJ. Mortality in current and former users of clozapine. Epidemiology 1997; 8: 671-7. 77. Varma S, Achan K. Dysrhythmia associated with clozapine. Aust NZ J Psychiatry 1999; 33: 118-19. 78. Donnelly JG, MacLeod AD. Hypotension associated with clozapine after cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1999; 13: 597-9. 79. Panagiotis B. Grand mal seizures with liver toxicity in a case of clozapine treatment. J Neuropsychiatry Clin Neurosci 1999; 11: 117-18. 80. Friedman J, Lannon M, Cornelia C, Factor S, Kurlan R, Richard I. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease, New Engl J Med 1999; 340: 757-63. 81. Pollak P, Destee A, Tison F, P~r~ JJ, Bordiex I, Agid Y. Clozapine in drug-induced psychosis in Parkinson's disease. Lancet 1999; 353: 2041-2. 82. Lera G, Zirulnik J. Pilot study with clozapine in patients with H1V-associated psychosis and druginduced parkinsonism. Mov Disord 1999; 14: 12831. 83. Ceravolo R, Salvetti S, Piccini P, Lucetti C, Gambaccini G, Bonuccelli U. Acute and chronic effects of clozapine in essential tremor. Mov Disord 1999; 14: 468-72. 84. Karagianis JL, Phillips LC, Hogan KP, LeDrew KK. Clozapine-associated neuroleptic malignant syndrome: two new cases and a review of the literature. Ann Pharmacother 1999; 33: 623-30. 85. Lara DR, Wolf AL, Lobato MI, Baroni G, Kapczinski E Clozapine-induced neuroleptic malignant syndrome: an interaction between dopaminergic and purinergic systems? J Psychopharmacol 1999; 13: 318-19.

77 86. Benazzi E Clozapine-induced neuroleptic malignant syndrome not recurring with olanzapine, a structurally and pharmacologically similar antipsychotic. Hum Psychopharmacol Clin Exp 1999; 14: 511-12. 87. Karp B, Goldstein SR, Chen R, Samii A, BaraJimenez W, Hallett M. An open trial of clozapine for dystonia. Mov Disord 1999; 14: 652-7. 88. Molho ES, Factor SA. Worsening of motor features of parkinsonism with olanzapine. Mov Disord 1999; 14: 1014-16. 89. Supprian T, Retz W, Deckert J. Clozapineinduced stuttering: epileptic brain activity? Am J Psychiatry 1999; 156: 1663-4. 90. De Haan L, Linszen DH, Gorsira R. Clozapine and obsessions in patients with recent-onset schizophrenia and other psychotic disorders. J Clin Psychiatry 1999; 60: 364-5. 91. Colli A, Cocciolo M, Francobandiera G, Rogantin F, Cattalini N. Diabetic ketoacidosis associated with clozapine treatment. Diabetes Care 1999; 22: 176-7. 92. Ahokas A, Elonen E. Circadian rhythm of white blood cells during clozapine treatment. Psychopharmacology 1999; 144: 301-2. 93. Cerulli TR. Clozapine-associated pancreatitis. Hare Rev Psychiatry 1999; 7: 61-3. 94. Bergemann N, Ehrig C, Diebold K, Mundt C, Einsiedel RV. Asymptomatic pancreatitis associated with clozapine. Pharmacopsychiatry 1999; 32: 78-80. 95. Lin CC, Bai YM, Chen JY, Lin CY, Lan TH. A retrospective study of clozapine and urinary incontinence in Chinese in-patients. Acta Psychiatr Scand 1999; 100: 158-61. 96. Elias TJ, Bannister KM, Clarkson AR, Faull D, Faull RJ. Clozapine-induced acute interstitial nephritis. Lancet 1999; 354:1180-1. 97. Hummer M, Kemmler G, Kurz M, Kurzthaler I, Oberbauer H, Fleischhacker WW. Sexual disturbances during clozapine and haloperidol treatment for schizophrenia. Am J Psychiatry 1999; 156: 631-3. 98. Stanislav SW, Gonz~ilez-Blanco M. Papular rash and bilateral pleural effusion associated with clozapine. Ann Pharmacother 1999; 33: 1008-9. 99. Hu RJ, Malhotra AK, Pickar D. Predicting response to clozapine: status of current research. CNS Drugs 1999; 1 l: 317-26. 100. H~igg S, Spigset O, Edwardsson H, Bj/Jrk H. Prolonged sedation and slowly decreasing clozapine serum concentrations after an overdose. J Clin Psychopharmacol 1999; 19: 282-4. 101. Sramek JJ, Anand R, Hartman RD, Schran HF, Hourani J, Barto S, Wardle TS, Shiovitz TM, Cutler NR. A bioequivalence study of brand and generic clozapine in patients with schizophrenia. Clin Drug Invest 1999; 17: 51-8. 102. Tupala E, Niskanen L, Tiihonen J. Transient syncope and ECG changes associated with the concurrent administration of clozapine and diazepam. J Clin Psychiatry 1999; 60: 619-20.

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103. Szegedi A, Anghelescu I, Wiesner J, Schlegel S, Weigmann H, H~tter S, Hiemke C, Wetzel H. Addition of low-dose fluvoxamine to lowdose clozapine monotherapy in schizophrenia: drug monitoring and tolerability data from a prospective clinical trial. Pharmacopsychiatry 1999; 32: 148-53. 104. Lammers CH, Deuschle M, Weigmann H, H~rtter S, Hiemke C, Heese C, Heuser I. Coadministration of clozapine and fluvoxamine in psychotic patients-clinical experience. Pharmacopsychiatry 1999; 32: 76-7. 105. Chang W-H, Augustin B, Lane H-Y, ZumBrunnen T, Liu H-C, Kazmi Y, Jann MW. In-vitro and in-vivo evaluation of the drug-drug interaction between fluvoxamine and clozapine. Psychopharmacology 1999; 145: 91-8. 106. Taylor D, Bodani M, Hubbeling A, Murray R. The effect of nefazodone on clozapine plasma concentrations. Int Clin Psychopharmacol 1999; 14: 185-7. 107. Facciol~tG, Avenoso A, Scordo MG, Madia AG, Ventimiglia A, Perucca E, Spina E. Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders. Ther Drug Monit 1999; 21: 341-5. 108. H~gg S, Spigset O, Mjtrndal T, Granberg K, Persbo-Lundqvist G, Dahlqvist R. Absence of interaction between erythromycin and a single dose of clozapine. Eur J Clin Pharmacol 1999; 55: 221~. 109. Cooke C, De Leon J. Adding other antipsychotics to clozapine. J Clin Psychiatry 1999; 60: 710. 110. McEvoy JP, Freudenreich O, Wilson WH. Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol Psychiatry 1999; 46: 125-9. 111. Skogh E, Bengtsson F, Nordin C. Could discontinuing smoking be hazardous for patients administered clozapine medication.'? A case report. Ther Drug Monit 1999; 21: 580-2. 112. Eberhart LHJ, Seeling W. Droperidolsupplemented anaesthesia decreases post-operative nausea and vomiting but impairs post-operative mood and well-being. Eur J Anaesthesiol 1999; 16: 290-7. 113. Mendizabal JE, Watts JM, Riaz S, Rothrock JE Open-label intramuscular droperidol for the treatment of refractory headache: a pilot study. Headache 1999; 10: 55-7. 114. Richman PB, Reischel U, Ostrow A, Irving C, Ritter A, Allegra J, Eskin B, Szucs P, Nashed AH. Droperidol for acute migraine headache. Am J Emerg Med 1999; 17: 398-400. 115. Lima FB, Cunha RS, Costa LM, Santos-Jests R, De Sena EP, De Miranda-Scippa A, Ribeiro MG, De Oliveira IR. Meta-analysis for evaluate the efficacy and safety of olanzapine compared to haloperidol in the treatment of schizophrenia:

Alfonso Carvajal and Luis H. Martln Arias

preliminary findings. J Bras Psiquiatr 1999; 48: 169-75. 116. Tollefson GD, Kuntz AJ. Review of recent clinical studies with olanzapine. Br J Psychiatry 1999; 174 Snpp137: 30-5. 117. Stephenson CME, Pilowsky LS. Psychopharmacology of olanzapine. Br J Psychiatry 1999; 174 Suppl 38: 52-8. 118. Green B. Focus on olanzapine. Curr Med Res Opin 1999; 15: 79-85. 119, Dursun SM, Gardner DM, Bird DC, Flinn J. Olanzapine for patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study. Can J Psychiatry 1999; 44: 701-4. 120. WeissEL, Longhurst JG, Bowers MB, Mazure CM. Olanzapine for treatment-refractory psychosis in patients responsive to, but intolerant of, clozapine. J Clin Psychopharmacol 1999; 19: 378-80. 121. Strauss J, DiMartini A. Use of olanzapine in hereditary coproporphyria. Psychosomatics 1999; 40: n.nA 5. 122. WalkerZ, Grace J, Overshot R, Satarasinghe S, Swan A, Katona CLE, McKeith IG. Olanzapine in dementia with Lewy bodies: a clinical study. Int J Geriatr Psychiatr 1999; 14: 459--66. 123. Sanger TM, Lieberman JA, Tohen M, Grundy S, Beasley C, Tollefson GD. Olanzapine versus haloperidol treatment in first-episode psychosis. Am J Psychiatry 1999; 156: 79-87. 124. Breier A, Hamilton SH. Comparative efficacy of olanzapine and haloperidol for patients with treatment-resistant schizophrenia. Biol Psychiatry 1999; 45: 403-ll. 125. Tran PV, Tollefson GD, Sanger TM, Lu Y, Berg PH, Beas|ey CM. Olanzapine versus haloperidol in the treatment of schizoaffective disorder. Br J Psychiatry 1999; 174: 15-22. 126. Berk M, Brook S, Trandafir AI. A comparison of olanzapine with haloperidol in cannabisinduced psychotic disorder: a double-blind randomized controlled trial. Int Clin Psychopharmacol 1999; 14: 177-80. 127. Potenza MN, Holmes JP, Kanes SJ, McDougle CJ. Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: an open-label pilot study. J Clin Psychopharmacol 1999; 19: 37--44. 128. Fanous A, Lindenmayer J-P. Schizophrenia and schizoaffectivedisorder treated with high doses of olanzapine. J Clin Psychopharmacol 1999; 19: 275--6. 129. WyderskiRJ, Starrett WG, Abou-Saif A. Fatal status epilepticus associated with olanzapine therapy. Ann Pharmacother 1999; 33: 787-9. 130. Lee JW, Crismon ML, Dorson PG. Seizure associated with olanzapine. Ann Pharmacother 1999; 33: 554--6. 131. Kirrane RM. Olanzapine-induced akathisia in OCD. Ir J Psychol Med 1999; 16: 118. 132. Kraus T, Schuld A, Pollm~icher T. Periodic leg movements in sleep and restless legs syndrome

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probably caused by olanzapine. J Clin Psychopharmacol 1999; 19: 478-9. 133. Molho ES, Factor SA. Possible tardive dystonia resulting from clozapine therapy. Mov Disord 1999; 14: 873-4. 134. Granger AS, Hanger HC. Olanzapine: extrapyramidal side effects in the elderly. Aust NZ J Med 1999; 29: 371-2. 135. Margolese HC, Chouinard G. Olanzapineinduced neuroleptic malignant syndrome with mental retardation. Am J Psychiatry 1999; 156: 1115-16. 136. Levenson JL. Neuroleptic malignant syndrome after the initiation of olanzapine. J Clin Psychopharmacol 1999; 19: 477-8. 137. Apple JE, Van Hauer G. Neuroleptic malignant syndrome associated with olanzapine therapy. Psychosomatics 1999; 40: 267-8. 138. Burkhard PR, Vingerhoets FJG, Alberque C, Landis T. Olanzapine-induced neuroleptic malignant syndrome. Arch Gen Psychiatry 1999; 56: 101-2. 139. Gheorghiu S, Knobler HY, Drumer D. Recurrence of neuroleptic malignant syndrome with olanzapine treatment. Am J Psychiatry 1999; 156: 1836. 140. Hickey C, Stewart C, Lippmann S. Olanzapine and NMS. Psychiatr Serv 1999; 50: 836-7. 141. Marcus E-L, Vass A, Zislin J. Marked elevation of serum creatine kinase associated with olanzapine therapy. Ann Pharmacother 1999; 33: 697-700. 142. Beasley CM, Dellva MA, Tamura RN, Morgenstern H, Glazer WM, Ferguson K, Tollefson GD. Randomised double-blind comparison of the incidence of tardive dyskinesis in patients with schizophrenia during long-term treatment with olanzapine or haloperidol. Br J Psychiatry 1999; 174: 23-30. 143. Kane J. Olanzapine in the long-term treatment of schizophrenia. Br J Psychiatry 1999; 174: 26-9. 144. HerrSn A, V~izquez-Barquero JL. Tardive dyskinesia associated with olanzapine. Ann Intern Med 1999; 131: 72. 145. Dunayevich E, Strakowski SM. Olanzapineinduced tardive dystonia. Am J Psychiatry 1999; 156: 1662. 146. Lykouras L, Malliori M, Christodoulou GN. Improvement of tardive dyskinesia following treatment with olanzapine. Eur Neuropsychopharmacol 1999; 9: 367-8. 147. Gotto J. Treatment of respiratory dyskinesia with olanzapine. Psychosomatics 1999; 40: 257-9. 148. Fitz-Gerald MJ, Pinkofsky HB, Brannon G, Dandridge E, Calhoun A. Olanzapine-induced mania. Am J Psychiatry 1999; 156:1114. 149. Simon AE, Aubry JM, Malky L, Bertschy G. Hypomania-like syndrome induced by olanzapine. Int Clin Psychopharmacol 1999; 14: 377-8. 150. Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa R, Daniel DG, Petty E Centorrino F, Wang R, Grundy SL, Greaney MG, Jacobs

79 TG, David SR, Toma V. Olanzapine versus placebo in the treatment of acute mania. Am J Psychiatry 1999; 156: 702-9. 151. Berk M, Brook S, Trandafir AI. A comparison of olanzapine with haloperidol in cannabisinduced psychotic disorder: a double-blind randomized controlled trial. Int Clin Psychopharmacol 1999; t4: 77-80. 152. Sharma V, Pistor L. Treatment of bipolar mixed state with olanzapine. J Psychiatry Neurosci 1999; 24: 40-4. 153. Ananth J. Is olanzapine a mood stabilizer? Can J Psychiatry 1999; 44: 927-8. 154. Brown ES, Khan DA, Suppes T. Treatment of corticosteroid-induced mood changes with olanzapine. Am J Psychiatry 1999; 156: 968. 155. Mottard J-P, De la Sablonni~re J-E Olanzapine-induced obsessive-compulsive disorder. Am J Psychiatry 1999; 156: 799-800. 156. Weiss EL, Longhurst JG, Bowers MB, Mazure CM. Olanzapine for treatment-refractory psychosis in patients responsive to, but intolerant of, clozapine. J Clin Psychopharmacol 1999; 19: 378-80. 157. Mandalos GE, Szarek BL. New-onset panic attacks in a patient treated with olanzapine. J Clin Psychopharmacol 1999; 19: 191. 158. Swartz C, Walder M. Hypofrontal symptoms from olanzapine: a case report. Ann Clin Psychiatry 1999; 11: 17-19. 159. Wahid Z, Ali S. Side effects of olanzapine. Am J Psychiatry 1999; 156: 800-1. 160. Lindenmayer J-P, Patel R. Olanzapine-induced ketoacidosis with diabetes mellitus. Am J Psychiatry 1999; 156: 1471. 161. Gatta B, Rigalleau V, Gin H. Diabetic ketoacidosis with olanzapine treatment. Diabetes Care 1999; 22: 1002-3. 162. Ober SK, Hudak R, Rusterholtz A. Hyperglycemia and olanzapine. Am J Psychiatry 1999; 156: 970. 163. Gupta S, Droney T, A1-Samarrai S, Keller P, Frank B. Olanzapine: weight gain and therapeutic efficacy. J Clin Psychopharmacol 1999; 19: 273~5. 164. Sheitman BB, Bird PM, Binz W, Akinli L, S~nchez C. Olanzapine-induced elevation of plasma triglyceride levels. Am J Psychiatry 1999; 156: 1471-2. 165. Bryden KE, Kopala LC. Body mass index increase of 58% associated with olanzapine. Am J Psychiatry 1999; 156: 1835~5. 166. Steinwachs A, Grohmann R, Pedrosa F, Rtither E, Schwerdtner I. Two cases of olanzapine-induced reversible neutropenia. Pharmacopsychiatry 1999; 32: 15445. 167. Naumann R, Felber W, Heilemann H, Reuster T. Olanzapine-induced agranulocytosis. Lancet 1999; 354: 566-7. 168. Meissner W, Schmidt T, Kupsch A, Trottenberg T, Lempert T. Reversible leucopenia related to olanzapine. Mov Disord 1999; 14: 872-89. 169. Swartz JR, Ananth J, Smith MW, Burgoyne KS, Gadasally R, Arai Y. Olanzapine treatment

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after clozapine-induced granulocytopenia in 3 patients. J Clin Psychiatry 1999; 60: 119-21. 170. Benedetti F, Cavallaro R, Smeraldi E. Olanzapine-induced neutropenia after clozapineinduced neutropenia. Lancet 1999; 354: 567. 171. Nanmann R, Felber W, Heilemann H, Reuster T. Olanzapine-induced agranulocytosis. Lancet 1999; 354: 566-7. 172. Dettling M, Cascorbi I, Hellweg R, Deicke U, Weise L, Mtiller-Oerlinghausen B. Genetic determinants of drug-induced agranulocytosis: potential risk of olanzapine? Pharmacopsychiatry 1999; 32: 110-12. 173. Gordon M, De Groot CM. Olanzapineassociated priapism. J Clin Psychophannacol 1999; 19: 192. 174. Cohen LG, Fatalo A, Thompson BT, Bergeron GDC, Flood JG, Poupolo PR. Olanzapine overdose with serum concentrations. Ann Emerg Med 1999; 34: 275-8. 175. Gardner DM, Milliken J, Dursun SM. Olanzapine overdose. Am J Psychiatry 1999; 156: 1118-19. 176. Dobrusin M, Lokshin P, Belmaker RH. Acute olanzapine overdose. Hum Psychopharmacol 1999; 14: 355--6. 177. O'Malley GF, Seifert S, Heard K, Daly F, Dart RC. Olanzapine overdose mimicking opioid intoxication. Ann Emerg Med 1999; 34: 279-81. 178. Bonin MM, Burkhart KK. Olanzapine overdose in a 1-year-old male. Pediatr Emerg Care 1999; 15: 266-7. 179. Catalano G, Cooper DS, Catalano MC, Butera AS. Olanzapine overdose in an 18-month-old child. J Child Adolesc Psychopharmacol 1999; 9: 26771. 180. Bond GR, Thompson JD. Olanzapine pediatric overdose. Ann Emerg Med 1999; 34: 292-3. 181. Heimann SW. High-dose olanzapine in an adolescent. J Am Acad Child Adolesc Psychiatry 1999; 38: 496-7. 182. Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM. Olanzapine: pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet 1999; 37: 177-93. 183. Markowitz JS, DeVane CL. Suspected ciprofloxacin inhibition of olanzapine resulting in increased plasma concentration. J Clin Psychopharmacol 1999; 19: 289-91. 184. Olesen OV, Linnet K. Olanzapine serum concentrations in psychiatric patients given standard doses: the influence of comedication. Ther Drug Monit 1999; 21: 87-90. 185. Goldstein JM. Quetiapine fumarate (Seroquel| a new atypical antipsychotic. Drugs Today 1999; 35: 193-210. 186. Keks NA, Culhane C. Risperidone (Risperdal| clinical experience with a new antipsychosis drug. Expert Opin Invest Drugs 1999; 8: 443-52. 187. Chong SA, Yap HL, Low BL, Choo CH, Chan AOM, Wong KE, Mahendran R, Chee KT. Clin-

Alfonso Carvajal and Luis H. Martin Arias

ical evaluation of risperidone in Asian patients with schizophrenia in Singapore. Singapore Med J 1999; 40: 41-3. 188. Posey DJ, Walsh KH, Wilson GA, McDougle CJ. Risperidone in the treatment of two very young children with autism. J Child Adolesc Psychopharmacol 1999; 9: 273-6. 189. Henretig FM. Risperidone toxicity acknowledged. J Toxicol Clin Toxicol 1999; 37: 893--4. 190. Lemmens P, Brecher M, Van Baelen B. A combined analysis of double-blind studies with risperidone vs. placebo and other antipsychotic agents: factors associated with extrapyramidal symptoms. Acta Psychiatr Scand 1999; 99: 16070. 191. Emsley RA and the Risperidone Working Group. Risperidone in the treatment of firstepisode psychotic patients: a double-blind multicenter study. Schizophr Bull 1999; 25: 721-9. 192. Wirshing DA, Marshall BD, Green MF, Mintz J, Marder SR, Wirshing WC. Risperidone in treatment-refractory schizophrenia. Am J Psychiatry 1999; 156: 1374-9. 193. Roberts MD. Risperdal | and parkinsonian tremor. J Am Acad Child Adolesc Psychiatry 1999; 38: 230. 194. Levin T, Heresco-Levy U. Risperidoneinduced rabbit syndrome: an unusual movement disorder caused by an atypical antipsychotic. Eur Neuropsychopharmacol 1999; 9: 137-9. 195. Bahro M, Kiimpf C, Strnad J. Catatonia under medication with risperidone in a 61-year-old patient. Acta Psychiatr Scand 1999; 99: 223-6. 196. Mahendran R, Andrade C, Saxena S. Obsessive-compulsive symptoms with risperidone. J Ciin Psychiatry 1999; 60: 261-3. 197. Panagiotis B, Mafia G, Aris L. Development of obsessive and depressive symptoms during risperidone treatment. Br J Psychiatry 1999; 174: 559. 198. Zolezzi M, Ghany MGA. Risperidone-induced mania. Ann Pharmacother 1999; 33: 380-1. 199. Hod M, Shiraishi H. Risperidone-induced anxiety might also develop 'awakening' phenomenon. Psychiatry Clin Neurosci 1999; 53: 682. 200. Kleinberg DL, Davis JM, De Coster R, Van Baelen B, Brecher M. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999; 19: 57-61. 201. Kim Y-K, Kim L, Lee M-S. Risperidone and associated amenorrhea: a report of 5 cases. J Clin Psychiatry 1999; 60: 315-17. 202. Yamada K, Kanba S, Yagi G, Asai M. Herbal medicine (Shakuyaku-kanzo-to) in the treatment of risperidone-induced amenorrhea. J Clin Psychopharmacol 1999; 19: 380-1. 203. Whitworth AB, Liensberger D, Fleischhacker WW. Transient increase of liver enzymes induced by risperidone: two case reports. J Clin Psychopharmacol 1999; 19: 475-6. 204. Madhusoodanan S, Brecher M, Brenner R, Kasckow J, Kunik M, Negr6n AE, Pomara N.

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Risperidone in the treatment of elderly patients with psychotic disorders. Am J Geriatr Psychiatry 1999; 7: 132-8. 205. Goldberg RJ. Long-term use of risperidone for the treatment of dementia-related behavioral disturbances in a nursing home population. Int J Geriatr Psychopharmacol 1999; 2: 1--4. 206. Cates M, Collins R, Woolley T. Antiparkinsonian drug prescribing in elderly inpatients receiving risperidone therapy. Am J Health-Syst Pharm 1999; 56: 2139-40. 207. Irizarry MC, Ghaemi SN, Lee-Cherry ER, Gomez-Isla T, Binetti G, Hyman BT, Growdon JH. Risperidone treatment of behavioral disturbances in outpatients with dementia. J Neuropsychiarty Clin Neurosci 1999; 11: 336--42. 208. Demb HB, Nguyen KT. Movement disorders in children with developmental disabilities taking risperidone. J Am Acad Child Adolesc Psychiatry 1999; 38: 5-6. 209. Kewley GD. Risperidone in comorbid ADHD and ODD/CD. J Am Acad Child Adolesc Psychiatry 1999; 38: 1327-8. 210. Campbell M. Risperidone-induced tardive dyskinesia in first-episode psychotic patients. J Clin Psychopharmacol 1999; 19: 276-7. 211. Carrol NB, Boehm KE, Strickland RT. Chorea and tardive dyskinesia in a patient taking risperidone. J Clin Psychiatry 1999; 60: 485-7. 212. Hong KS, Cheong SS, Woo J-M, Kin E. Risperidone-induced tardive dyskinesia. Am J Psychiatry 1999; 156: 1290.

81 213. Snoddgrass E Tardive dyskinesia from risperidone and olanzapine in an alcoholic man. Can J Psychiatry 1999; 44: 921. 214. Duefias-Laita A, Castro-Villamor MA, Martfn-Escudero JC, Prrez-Castrillon JL. New clinical manifestations of acute risperidone poisoning. J Toxicol Clin Toxicol 1999; 37: 893-4. 215. Durrenberger S, De Leon J. Acute dystonic reaction to lithium and risperidone. J Neuropsychiatry Clin Neurosci 1999; 11: 518-19. 216. Steele M, Couturier J. A possible tetracyclinerisperidone-sertraline interaction in an adolescent. Can J Clin Pharmacol 1999; 6: 15-17. 217. Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry 1999; 60: 256-9. 218. Amchin J, Zarycranski W, Taylor KP, Albano D, Klockowski PM. Effect of venlafaxine on the pharmacokinetics of risperidone. J Clin Pharmacol 1999; 39: 297-309. 219. Wines JD, Weiss RD. Opioid withdrawal during risperidone treatment. J Clin Psychopharmacol 1999; 19: 265-7. 220. Daniel DG, Zimbroff DL, Potkin SG, Reeves KR, Harrigan EP, Lakshminarayanan M. Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Neuropsychopharrnacol 1999; 20: 491-505.

Emilio Perucca

7

Antiepileptic drugs

GENERAL TOPICS (SED-14,164; SEDA-21, 66; SEDA-22, 81; SEDA-23, 83) Endocrine Serum thyroid hormones have been compared in 148 healthy children and 141 children with epilepsy who had been taking carbamazepine (n = 61), valproate (n = 51) or phenobarbital (n = 29) for at least 1 year (1c). In all the groups mean T4 and free T4 concentrations were lower than in controls, and those taking carbamazepine and valproate also had lower T3 and TBG concentrations and increased mean TSH concentrations. There was subclinical hypothyroidism, defined as a TSH concentration greater than two standard deviations above the control mean, in 26% of the children taking valproate, 8.2% of those taking carbamazepine, 7.1% of those taking phenobarbital, and 3.6% of controls. However, the magnitude of the TSH increase was usually small and the children were clinically euthyroid. Hematologic The combination oflamotligine with valproate has been reported to have caused the production of lupus anticoagulant (2A). A 5-year-old boy with absence epilepsy who had had a moderate reduction in fibrinogen and prolonged partial thromboplastin time while taking valproate was given add-on lamotrigine (2 mg/kg). His seizures disappeared, but the partial thromboplastin time increased and tests for lupus anticoagulant and IgG anticardiolipid antibodies became positive. Serum autoantibody screen and rheumatoid factor were negative. The lupus anticoagulant disappeared after valproate was withdrawn. The authors suggested that lamotrigine may have exacerbated a mild immune response initially induced by valproate, without clinical evidence of systemic disease.

9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed. Q,')

Skin Mild adverse skin reactions to antiepileptic drugs include morbilliform rashes,

fixed drug eruptions, bullous reactions, liehenoid-type reactions, urticaria (excluding angio-edema), alopecia, pigmentation changes, and photosensitivity (3R). There have been reports of positive rechallenge in some patients with exanthems, bullous eruptions, lichenoid-type reactions, and mild urticaria. Corticosteroids may suppress mild carbamazepine-induced eruptions, allowing continuation of treatment in a few patients. Severe and potentially fatal skin reactions include, among others, erythema multiforme,

Stevens-Johnson syndrome, and toxic epidermal necrolysis. Anticonvulsants are among the most important causative agents. The management of severe reactions of any type is controversial, but referral to a bums center is recommended. Essential supportive care includes fluids and nutrition management. Prophylactic antibacterial drugs are not recommended. Most authors advise against the use of corticosteroids, as they increase the risk of infection and sepsis. Several reports have suggested that patients with brain tumors who undergo radiation therapy while taking phenytoin may be at increased risk of developing Stevens-Johnson syndrome. A 47-year-old black man (4A) and four other patients, including one who died (5A), were seen in a 24-month period in one department. Review of 20 similar reported cases showed no relation to the dosage of phenytoin or radiation therapy, or to the histological type of the tumor. Isolated reports have also implicated carbamazepine and phenobarbital in causing Stevens-Johnson syndrome in patients undergoing radiation therapy. In a 53-year-old man taking phenobarbital, eruptions were limited to the sites of radiation, which were multiple (6A). Conversely, a retrospective review of 289 brain tumor patients treated with cranial radiation and anticonvulsant drugs did not identify

Antiepilepticdrugs

Chapter7

an increased incidence of severe skin rashes (7c). Only one patient with Stevens-Johnson syndrome was found in this series, although the incidence of milder skin rashes was higher than expected (18% vs 5-10%). Teratogenieity The rate of congenital malformations in the offspring of 517 mothers exposed to antiepileptic drugs during pregnancy has been examined in a prospective singlecenter study (8Cr). The overall malformation rate was 9.7%. Malformations were classified as structurally severe (5.3%), structurally mild (2.2%), chromosomal genetic (0.4%), and deformities (1.8%). The malformation rate after exposure to polytherapy (9.6%, n = 114) was not higher than after exposure to monotherapy (10.5%, n = 313). Among monotherapy exposures, the rates for structural abnormalities were 16% with valproate (n = 44), 8.6% with primidone (n = 35), 7.1% with carbamazepine (n = 113), 4.8% with phenobarbital (83) and only 3.2% with phenytoin (n = 31). There were no malformations in the offspring of 25 untreated patients. Among women exposed to valproate, the mothers of malformed babies took significantly higher dosages in the first trimester than mothers of non-malformed babies (1712 vs 1008 mg/day). These data confirm that exposure to antiepileptic drugs is associated with an increased risk of fetal malformations, and that the risk may be especially high with high-dose valproate. However, these subgroup analyses should be interpreted cautiously, especially because the numbers were small and the confidence intervals were not calculated. In a retrospective Dutch study, the rate of major congenital anomalies among 1411 children born of mothers who had taken antiepileptic drugs during the first trimester of pregnancy was 3.7% compared with 1.5% among 2000 children born of matched controls not exposed to anticonvulsants (9Cr). Among monotherapies with a denominator higher than 50, the relative risk (RR) was increased significantly only for carbamazepine (RR = 2.6) and valproate (RR = 4.1); for valproate there was a relation with dose. Although the risk was not increased in offspring exposed to phenobarbital monotherapy, it increased significantly (RR = 2.6) when exposures to phenobarbital plus caffeine were added to the phenobarbital monotherapy group. Caffeine intake was also associated with an increased risk among expos-

83 ures to phenobarbital in combination with other anticonvulsants. Among other polytherapies, there was an increased risk for combinations that included clonazepam, and for the combination of carbamazepine with valproate. Cautious interpretation of these data is required, because of retrospective design and the small sample sizes in the subgroup analyses. Fetotoxidty In a prospective study of electroencephalograms, intelligence tests (Wechsler), and neurological findings (Touwen) in 67 school-age and adolescent children born of mothers with epilepsy (risk group) and in 49 controls, focal electroencephalographic changes were more common in the offspring of mothers with primary generalized epilepsy, and pathological electroencephalograms were overall more common after maternal exposure to phenobarbital or primidone (10c). The prevalence of minor neurological dysfunction was also increased in the risk group, especially in the offspring of mothers who had been exposed to polytherapy. Intelligence scores were lower after maternal exposure to polytherapies in which one of the drugs was phenytoin or primidone, but socioeconomic influences also affected the scores. Higher maternal dosages of primidone were associated with lower IQ scores in the children. This study has reinforced the evidence that antenatal exposure to anticonvulsants can adversely affect postnatal intellectual development. However, it is always difficult to control for confounders, such as hereditary and social and family factors. It is also possible that prenatal drug exposure affects neural vulnerability to external influences. A case-control study in 116 children born to epileptic women has suggested that for subjects without inherited factors the risk of developmental disorders is related to antenatal exposure to polypharmacy (OR = 4.8, 95% CI = 1.3-18) and valproate monotherapy (OR = 9.4, 95% CI = 1.7-50) (llC). The findings were presented in abstract form, precluding close scrutiny of methodological aspects. D r u g interactions Choreoathetosis is a rare adverse effect of some anticonvulsants, but has especially been associated with phenytoin. In a retrospective survey, three of 39 adults and one of 38 children developed choreoathetosis acutely when lamotrigine was added to phenytoin or vice versa (12c). The effect was

Chapter 7

84 reversible by withdrawing one of the drugs. It was calculated that the risk of choreoathetosis is increased more than 50-fold when these drugs are combined, possibly owing to a pharmacodynamic interaction.

INDIVIDUAL DRUGS

Benzodiazepines

(SED-14, 186; SEDA-20, 59; SEDA-23, 84) (see also Chapter 5) Respiratory In a prospective study of children admitted to an accident and emergency department because of seizures, there were 122 episodes in which diazepam was administered rectally and/or intravenously. There was respiratory depression in 11 children, of whom eight required ventilation (13c). The authors questioned the use of rectal or intravenous diazepam as first-line therapy for children with acute seizures. Nervous system Two premature neonates, who already had epileptic manifestations related to severe hypoxic ischemic encephalopathy, developed seizures (one tonic and the other tonic-clonic) within a few seconds of receiving intravenous midazolam (0.15 mg/kg) for sedation (14A). In one, the seizure recurred after rechallenge on the same day. Benzodiazepines occasionally cause tonic seizures, especially after intravenous administration to children with Lennox-Gastaut syndrome. This seems to be the first report related to midazolam in newborns. In a randomized double-blind comparison of clobazam, carbamazepine, and phenytoin monotherapy in children with epilepsy, there were no differences in tests of intelligence, memory, attention, psychomotor speed and impulsivity between clobazam and the other drugs after 6 and 12 months of therapy, suggesting that the adverse effects of clobazam on cognition and behavior may be less common than generally thought (15c). However, the authors did not discuss a trend for some scores, particularly items in the Wechsler Intelligence Scale for Children-Revised to improve significantly only in children taking non-benzodiazepine anticonvulsants. Moreover, many children exited

EmilioPerucca

the study before completion of the follow-up, resulting in potential bias.

Carbamazepine (SED-14, 172; SEDA-21, 69; SEDA-22, 85; SEDA-23, 85) When 14 patients taking a brand-named modified-release formulation of carbamazepine were switched to a generic modified-release formulation, nine developed adverse effects such as dizziness, nausea, ataxia, diplopia, and nystagmus, despite the fact that the two formulations met pharmacokinetic criteria for bioequivalence (16c). Mean AUC and Cmax values were about 10% higher with the generic formulation. The authors suggested that standard bioequivalence criteria (90% confidence limits of 80--125% for AUC and 70-143% for Cmax) may be too broad for carbamazepine, which has a relatively narrow therapeutic ratio. While this may be correct, the findings could have been biased by the lack of a control group, lack of randomization in the sequence of the two treatments, and the use of a non-blinded design. Nervous system A study in 10 children with rolandic epilepsy assessed before and after carbamazepine therapy showed an impairing effect of treatment on memory and, possibly, visual search tasks (17c). Evaluation of individual data suggested that some children were especially vulnerable to the adverse effects of carbamazepine on cognition. The authors did not comment on the fact that rolandic epilepsy is regarded as a syndrome for which treatment in most cases is not indicated. Electrolyte balance

Carbamazepine-induced

hyponatremia is not uncommon, but symptomatic cases are relatively rare. Two more cases have been reported (18A). A 72-year-old woman developed somnolence and continuous sharp waves over the left hemisphere when carbamazepine was added to primidone and a diuretic. Her serum sodium concentration was initially 130 mmol/l and fell further to 100 mmol/1. In a 65-year-woman, carbamazepine-induced hyponatremia (127-130 mmol/1) led to serial tonicclonic seizures, somnolence, confusion, and an electroencephalographic misdiagnosis of non-convulsive status. Both patients recovered with normalization of the serum sodium when the carbamazepine dose was tapered.

Antiepilepticdrugs

Chapter7

Gastrointestinal A report of two cases has suggested that carbamazepine can cause colitis as part of the anticonvulsant hypersensitivity syndrome (19 A). A 47-year-old man developed fever, lymphadenopathy, flu-like symptoms, facial edema, a skin rash, and diarrhea after taking carbamazepine 200 mg/day for 3 weeks. Laparatomy because of severe abdominal pain 2 weeks later showed severe colitis with perforations. A 4t-year-old woman had diarrhea, fever, and a skin rash after taking carbamazepine 300 mg/day for 4 weeks. Colitis was confirmed at colonic biopsy. Both patients also had raised liver enzymes, peripheral eosinophilia, and eosinophils in the colonic infiltrate. Persistent recovery occurred after carbamazepine was withdrawn. Hematologic Increased concentrations of P1VKA-H (prothrombin-induced by vitamin K absence for factor II) were found in four of six samples of cord blood collected at parturition from the placenta in mothers exposed to carbamazepine during pregnancy (20c). Prothrombin concentrations were also reduced in the whole group. High PIVKA-II concentrations were also recorded in cord blood from a newborn exposed prenatally to phenytoin and vigabatrin, but not in two exposed to phenytoin alone and one exposed to valproate alone. These results are consistent with evidence that enzyme-inducing anticonvulsants, particularly carbamazepine, interfere with vitamin K metabolism during pregnancy and may result in bleeding disorders in the newborn. Administration of vitamin K is recommended in these newborns at time of birth or in the mother towards the end of pregnancy. The authors also discussed the possibility that vitamin K supplementation in early pregnancy might reduce the risk of fetal facial dysmorphisms caused by enzyme inducing anticonvulsants. Drug overdose There was impaired neuromuscular transmission at high frequency repetitive nerve stimulation in two children who presented in coma with diffuse hypotonia and areflexia after carbamazepine overdose (21A). Both patients recovered with supportive care. This seems to be the first report of a clinically evident neuromuscular transmission defect caused by carbamazepine. D r u g interactions In 25 healthy subjects, carbamazepine (up to 400 mg/day for 25 days) reduced the steady-state AUC of ziprasidone

85 (40 mg/day) by about 35%, presumably through induction of the CYP3A4-mediated metabolism of the antipsychotic (22c). Although the interaction was considered clinically insignificant, the dosage of carbamazepine was relatively low and a greater effect might occur at higher dosages. In a 33-year-old man stabilized on carbamazepine, the addition of fluconazole (150 mg/day) led to severe carbamazepine toxicity associated with high carbamazepine concentrations (104 Ixmol/l) (23A). The condition cleared after withdrawal of both drugs, and carbamazepine was then readministered without recurrence of toxicity. This interaction is likely to be mediated by inhibition of the CYP3A4mediated metabolism of carbamazepine by fluconazole. In one case trazodone increased serum carbamazepine concentrations by about 30% (24A). However, only one sample was taken after adding trazodone, and the rise in carbamazepine concentration might have been caused by random fluctuation.

Felbamate (SED-14, 187; SEDA-21, 70; SEDA-22, 86; SEDA-23, 86) Hematologic Because

felbamate-induced

aplastic anemia might be linked to the formation of atropaldehyde, a urine screening test has been developed that indirectly assesses the formation of this toxic metabolite (25E). The risk of serious toxicity may also be related to HLA status, and HLA typing is being performed in patients entered in the manufacturer's felbamate registry. The potential value of these tests in reducing the risk of toxicity remains to be established. Drug interactions The dose dependency and clinical relevance of the inhibition ofphenytoin metabolism by felbamate has been examined in 10 patients (26c). Phenytoin concentrations increased from 64 Ixmol/1 at baseline to 84 and 107 txmol/1 after felbamate 1200 and 1800 mg/day respectively. Owing to adverse effects, a reduction in phenytoin dosage was required in four patients after felbamate 1800 mglday and in six patients after felbamate 2400 mg/day. Felbamate titration to doses of 3600 mg/day required overall phenytoin dosage reductions of 40% on average (range 20-72%), based on tol-

86 erability. Based on these findings, phenytoin dosage should be reduced by 20% when felbamate is added, and further dosage reductions are likely to be required when felbamate dosage is increased. Requirements for dosage reductions may be predicted by clinical signs of phenytoin intolerance, such as mental slowing, nausea, fatigue, and somnolence. The same study showed that in patients taking phenytoin co-medication serum felbamate concentrations are reduced by about 60% compared with those achieved in monotherapy.

Gabapentin

(SED-14, 188; SEDA-21, 71; SEDA-22, 87; SEDA-23, 87) Nervous system In a double-blind crossover comparison of the cognitive effects of carbamazepine (mean dose 731 mg/day) and gabapentin (2400 rag/day), each given for 5 weeks, in 35 healthy volunteers performance on gabapentin was better than on carbamazepine for eight of 31 variables (visual serial addition test, choice reaction times at initiation and total, memory paragraph I and delayed recall, Stroop Word and Interference, Vigor measure), whereas carbamazepine was better than gabapentin on none (27 c). Although these data suggest that gabapentin produces fewer cognitive effects than carbamazepine, the applicability of the findings to long-term therapy in epileptic patients is uncertain. Gabapentin-induced myoclonus may be more common than initially thought. In a retrospective survey, 13 of 104 consecutive patients developed myoclonus at gabapentin dosages of 800-3200 mg/day (28c). Six of the patients had severe chronic static encephalopathy. Three had focal myoclonus, contralateral to the epileptic focus, and two had exacerbation of pre-existent myoclonus. In all cases the myoclonus was mild and did not interfere with daily activities. The fact that in three patients the electroencephalogram did not show epileptiform discharges suggests that, at least in some cases, the myoclonus is non-epileptic in nature. Psychiatric Gabapentin has rarely been implicated in ps~cchiatric reactions. Two cases, one of mania (29 '~) and one of catatonia (30A), have now been reported. A 35-year-old woman with epilepsy without a history of psychiatric disorders developed elevated mood after being stabilized on gabapentin monother-

Chapter 7

EmilioPerucca

apy (3200 mg/day). After 5 months she developed a manic episode, which remitted when gabapentin was withdrawn. Catatonia was reported in a 48-year-old woman with bipolar disorder within 48 hours of withdrawal of gabapentin, 500 mg/day. The condition lasted for several days and disappeared after treatment with a benzodiazepine. In the first case the presentation was strongly suggestive for a causative role of the drug. In the second it was speculated that the condition might have been provoked by altered GABAergic transmission after gabapentin withdrawal. Endocrine A 28-year-old woman with bipolar depression developed clinical and biochemical evidence of hyperthyroidism, ascribed to thyroiditis, while taking gabapentin (4800 mg/day) in a clinical trial (31A). The condition cleared after withdrawal, and subsequent exposure to a lower dose of gabapentin (1500 mg/day) was uneventful. Whether gabapentin was responsible for the thyroiditis is doubtful. Skin In a 26-year-old woman who had severe Stevens-Johnson syndrome induced by phenytoin and later by carbamazepine, gabapentin resulted in an erythematous pruriginous skin eruption limited to the legs without mucosai involvement (32A). Although gabapentin has a lower allergenic potential than most other anticonvuisants, patients with a history of severe drug-induced idiosyncratic reactions may be at higher risk of gabapentin-induced skin reactions. Sexual function Anorgasmia was reported by a 52-year-old man while he was taking gabapentin, 900-1500 mg/day, for the treatment of neuropathic pain (33A). The condition lasted for over 2 months and remitted when gabapentin was replaced with mexiletine. Anorgasmia is quoted in the Physicians Desk Reference as an infrequent adverse effect. Drug overdose A 30-year-old woman with renal insufficiency on hemodialysis three times a week suffered no significant toxicity after ingesting 600 mg tds of gabapentin for 3 weeks, a large dose in view of her impaired kidney function (34A). The blood gabapentin concentration was 496 ixmol/1. These data suggest that gabap-

Antiepileptic drugs

Chapter7

entin poses no major risk in overdose, partly because high dosages are poorly absorbed.

Lamotrigine (SED-14, 188; SEDA-21, 72; SEDA-22, 88; SEDA-23, 87) A review of the manufacturer's safety database from the adult clinical trial program has been published (35M). In placebo-controlled add-on trials involving a total of 1555 patients, the most common adverse events were dizziness (35% vs 15% on placebo), headache (26% vs 21%), diplopia (25% vs 6%), ataxia (20% vs 6%), nausea (19% vs 9%), blurred vision (14% vs 4%), rhinitis (11% vs 8%), somnolence (10% vs 7%), rashes (10% vs 5%), and vomiting (10% vs 5%). Dizziness and rashes led to withdrawal most commonly, each in 2% of patients. Dizziness, diplopia, nausea, blurred vision, and headache occurred more commonly in patients co-medicated with carbamazepine than in those co-medicated with other drugs. In randomized comparative monotherapy studies, somnolence, weakness, dizziness, and ataxia occurred less often with lamotrigine than with carbamazepine or phenytoin, whereas insomnia was slightly more frequent with lamotrigine. Withdrawals due to adverse events were fewer with lamotrigine than with the other drugs. Rash associated with lamotrigine typically occurred within the first 8 weeks. Exceeding the currently recommended slow dosage escalation guidelines and co-administration of valproate are risk factors for rashes. In adults, the incidence of StevensJohnson syndrome was approximately 1:1000, but higher rates (1 in 50 to 1 in 300) have been reported in children (SEDA-22, 89). In a multicenter, double-blind, monotherapy trial in 150 elderly patients with newly diagnosed epilepsy (mean age 77 years) lamotrigine (median dosage 100 mg/day) was better tolerated than carbamazepine (400 mg/day) (36c). The drop-out rate for adverse events was 18% with lamotfigine compared with 42% with carbamazepine. Patients taking lamotrigine had a lower incidence of skin rashes (3% vs 19%), somnolence (12% vs 29%), and dizziness (10% vs 17%). Lamotrigine may be a better choice for initial treatment in elderly people, although the toxicity of carbamazepine might have been overestimated by giving a non-modified-release formulation twice daily. Seizure control was comparable with the two drugs, but statistical

87 power was insufficient to demonstrate equal efficacy. In an open study, there were adverse events (details not given) in two of 30 patients with serum lamotrigine concentrations between 16 and 39 I~mol/l, and in five of 11 patients with serum concentrations between 39 and 86 Ixmol/l (37c). This is one of the few studies to have provided preliminary evidence for a relation between serum lamotrigine concentrations and the risk of adverse effects. Nervous system Sleep disturbance is a well recognized adverse effect in occasional patients (SEDA-23, 87). In an additional report, two boys aged 6 and 8 years developed severe difficulties in falling asleep and fragmented sleep (in one case associated with scary dreams) after being stabilized on lamotrigine, 8 mg/kg (38A). These disturbances improved when the dosage was reduced. Lamotrigine's ability to cause seizure aggravation in children with severe myoclonic epilepsy was discussed in SEDA-23 (p. 87). Three other reports have suggested that paradoxical seizure aggravation may occur in other types of epilepsy. In a 5-year-old gid with benign rolandic epilepsy, the addition of lamotrigine (0.5-5 mg/kg/day) to valproate resulted in a temporary reduction in seizure frequency (39A). However, her school performance deteriorated insidiously, with poor memory and concentration, clumsiness, stuttering, and emotional lability. After 4 months she developed new daily brief absence-like episodes, with staring, dropping of the head and jaw, and flickering of the eyelids, without loss of consciousness. Ictal electroencephalography showed anterior-predominant 3 Hz sharp slow wave complexes. Withdrawal of lamotrigine resulted in rapid improvement of cognitive function and gradual remission of the new attacks. A 9-year-old girl with Lennox-Gastaut syndrome, who had initially had an improvement in seizure frequency, insidiously developed myoclonic status epilepticus after the lamotrigine dosage was increased from 15 to 20 mg/kg (40A). Withdrawal of lamotrigine resulted in rapid disappearance of status. Two patients (age unspecified) with severe epileptic encephalopathy who had improved on lamotrigine in combination with valproate developed continuous myoclonic jerks after 2-3 years; these were ascribed to high serum concentrations of lamotrigine (65 and 69 I~mol/1)(41A). In the last report, the causative role of the drug is difficult to assess, because no mention

88 was made of whether myoclonus regressed after reducing the dosage. Tics are a rare adverse effect of lamotrigine. Three boys and two girls (mean age 7 years) developed simple motor tics (associated with verbal tics in two cases) within 10 months of starting lamotrigine (maintenance dosage 4-18 mg/kg) (42A). When lamotrigine was withdrawn, the tics resolved within 3 months in three cases (with recurrence after rechallenge in one child) and improved in one. In the fifth child, improvement occurred despite continuation of treatment. Two of the affected patients had acquired epileptic aphasia syndrome, one had expressive and receptive language dysfunction, one had a static encephalopathy, and one had no mental or neurological impairment. These data suggest that children with severe language dysfunction may be at increased risk of developing lamotrigineinduced tics. A 51-year-old man developed blepharospasm 4 months after starting lamotrigine, while taking a maintenance dosage of 500 mg/day (43A). The condition cleared 4 weeks after withdrawal. Lamotrigine (250-324 mg/day) caused Tourette syndrome in three children aged 7, 8, and 12 years; in the 12-yearold boy, the syndrome was accompanied by behavioral abnormalities suggestive of obsessivecompulsive disorder (44"). All the symptoms disappeared when the dosage was reduced to 175-225 rag/day and recurred on rechallenge with higher dosages. Four children developed reversible lamotrigine-associated hepatotoxicity (45A). One had pre-existing encephalitis and the other three had multiple medical and neurological problems, fever and infections, were taking many other drugs, and had very frequent seizures; two had epilepsia partialis continua. The information given was insufficient to assess the role of lamotrigine in the pathogenesis of the hepatic dysfunction. Liver

Lamotrigine-induced serious skin rashes An expert panel has reviewed published and unpublished data on the incidence and risk factors for lamotrigine-induced rash (46M). An allergic skin rash occurs in about 10% of pa-

Chapter 7

Emilio Perucca

tients, usually in the first 8 weeks. In clinical trials, the incidence of rashes leading to hospitalization, including those associated with hypersensitivity syndrome, was about 1:300 in adults (one third as Stevens-Johnson syndrome) and 1:100 in children (50% as Stevens-Johnson syndrome). The risk increased with excessively rapid dosage titration and in patients co-medicated with valproate. Up to March 1997, the manufacturer had received a total of 150 postmarketing reports of possible cases of Stevens-Johnson syndrome o r toxic epidermal necrolysis, and 46 of these were in children aged 12 years or under. Of the 46 pediatric cases, three were reported as toxic epidermal necrolysis, 40 as Stevens-Johnson syndrome, and three as suggestive of Stevens-Johnson syndrome, and two deaths were reported. Rashes associated with one or more symptoms of hypersensitivity reactions occurred in 19 children. 0 f 2 9 patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or hypersensitivity reactions for whom precise details were available, 83% were taking lamotrigine with concomitant valproate and 85% were taking lamotrigine dosages higher than recommended. Although serious skin rashes have been reported with traditional anticonvulsants, the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis with these drugs appears to be lower than with lamotrigine. Data from the Saskatchewan Health Plan suggest that the risk of serious rashes is in the order of 0.9:1000 (1.4:1000 in children) for phenytoin, 0.6:1000 (1.4:1000 in children)for carbamazepine, and O:lO00 for valproate, but Stevens-Johnson syndrome constituted only a small minority of these cases (47(:). The panel agreed on the following conclusions: 9 most skin rashes from lamotrigine are benign and resolve on withdrawal; 9 serious skin rashes occur almost entirely during the first 8 weeks and increased vigilance is recommended during this period; 9 mortality from skin rashes is extremely rare (less than ten known cases); 9 a mild rash may progress to a severe rash or to systemic involvement; fever, lymphadenopathy, facial edema, vomiting, or raised liver enzymes may indicate a hypersensitivity reaction and may precede appearance of a rash;

Antiepileptic drugs 9

9

9

9

9 9

Chapter 7

the following features suggest the development o f a serious rash: mucous membrane lesions, blistering or peeling, facial edema, lymphadenopathy, raised liver enzymes, leukopenia or thrombocytopenia in association with a rash; the risk o f a rash, andpossibly also serious rashes, is increased with excessive initial dosages or too fast rates o f titration, combination with valproic acid (particularly in the absence o f enzyme inducing drugs), and possibly a history of skin or allergic reactions to another anticonvulsant; physicians should follow dosing instructions carefully, and be aware that dosing varies according to whether lamotrigine is added to valproate, an enzyme-inducing antiepileptic drug (such as phenytoin), or both, or is used as monotherapy; potential risks and benefits should be discussed with the patient, who should be informed about symptoms suggestive o f hypersensitivity; if a rash appears, the patient should be seen by a physician within 24 hours and, if necessary, a specialist opinion should be sought; suspected cases o f Stevens-Johnson syndrome and toxic epidermal necrolysis should be hospitalized f o r specialist care; blood chemistry and hematology may be useful to detect systemic involvement; if no alternative explanation exists, the rash should be presumed to be due to lamotrigine and the drug should be withdrawn; in patients with a rash non-typical o f druginduced rashes, lamotrigine may be continued cautiously under close monitoring if its use is deemed essential.

The need f o r a low initial dose and a slow titration rate has been emphasized in another review (48R). For adults taking valproate (with or without other anticonvulsants), the dose escalation rate currently recommended by the manufacturer is 25 mg on alternate days during weeks 1 and 2, followed by 25 mg daily during weeks 3 and 4, with further increments by 25-50 mg every 1-2 weeks up to the usual maintenance dose o f 100-200 mg/day (Europe) or 100--400 mg/day (US). For adults taking enzyme inducers without valproate, the escalation rate is 50 mg/day during weeks 1 and 2followed by 50 mg bd during weeks 3 and 4, with further increments by 100 mg daily every 1-2 weeks

89 up to the usual maintenance dose o f 200-400 mg/day (Europe) or 300-500 mg/day (US). For children aged 2-12 years, starting dosages are O.15 mg/kg/day in the presence o f valproate and 0.3 mg/kg bd in the presence o f enzyme inducers without valproate (49c). Data from the German registry f o r cutaneous reactions seem to confirm that the risk of serious skin rashes is reduced by slower dose escalation (50c). In 1993 there were five cases o f Stevens-Johnson syndrome or toxic epidermal necrolysis, all o f whom were also taking valproate, among 1270 new patients taking lamotrigine, i.e. one per 254 recipients. After the recommended starting dose with valproate was reduced by a factor o f f our, the Stevens-Johnson syndrome or toxic epidermal necrolysis rates fell to two of 15500 recipients in 1994 and two of 34 700 recipients in 1995. However, this apparent change in incidence could be explained in part by additional factors, such as greater risk awareness and consequent more cautious use o f the drug, prompter withdrawal at first appearance o f a rash and possibly changes in ascertainment rates.

Immunologic Systemic hypersensitivity reactions to lamotfigine may be severe. A recent report involved a 27-year-old woman who developed disseminated intravascular coagulation, fever, rash, and hepatic dysfunction 11 days after starting lamotrigine (51A). The drug dosage was not stated.

Teratogenicity There were birth defects in eight of 123 offspring exposed to lamotrigine polypharmacy during the first trimester of pregnancy (95% CI = 3-13%) and in none of 40 exposed to monotherapy (0-11%) (52c). The wide confidence intervals indicate that sample size was not sufficient to determine whether lamotrigine has a lower teratogenic risk than other anticonvulsants. Drug interactions Because valproate inhibits the metabolism of lamotrigine, lamotrigine should be used in lower dosages and with slower titration rates in valproate co-medicated patients. The tolerability of lamotrigine added to valproate has been assessed in 108 mostly adult patients (53c). The median starting dose was 20.8 mg/day and upward titrations were

Chapter 7

90 usually made at 2-week intervals; although these were more cautious than in earlier studies, in many patients the initial dose or titration rate still exceeded those currently recommended by the manufacturer. Adverse events led to withdrawal in 14 patients, including seven of 14 who had a rash. Other adverse events included fatigue (12%), gastrointestinal symptoms (9%), dizziness, headache, and insomnia (3% each). Serious events were hallucinations (two patients), increased liver enzymes (two patients), irritability, and leukopenia (one patient each). These results suggest that, with cautious dosage escalation, lamotrigine can be added to valproate with acceptable safety. In this study, the incidence of rash was not higher than that seen among 310 patients in whom lamotrigine was added to other drug regimens not including valproate (13% vs 14%). In an open prospective trial, patients with partial seizures who had not responded to lamotrigine or valproate given separately, responded well to the combination; this was not due to an effect of valproate on serum lamotrigine concentrations, because after adjusting dosages based on clinical response the serum concentrations of both drugs were lower during combination therapy (54c). Hand tremor developed in all 13 patients given the combination, compared with three of 20 given valproate without lamotrigine and none of 17 given lamotrigine without valproate. These findings confirm that valproate plus lamotrigine is a valuable combination in patients unresponsive to either drug alone, partly because of a pharmacodynamic interaction. Patients co-medicated with valproate should be treated with a lower starting dose of lamotrigine and with slower dosage escalation to minimize the risk of a skin rash. Maintenance lamotrigine dosage requirements are also reduced by valproate co-medication. Although tremor is common, it can be maintained within acceptable limits by adjusting the dosage of either drug.

Drug overdose The manifestations of acute lamotrigine overdose may mimic the anticonvulsant hypersensitivity syndrome (55A). A 49-year-old man with bipolar disorder inadvertently received four daily doses of lamotrigine 2700 mg each. He presented to the hospital with a 2-day history of low-grade fever, skin rash, and periorbital edema. He had a leukocytosis, raised liver enzymes, and acute renal insufficiency. He recovered

EmilioPerucca

fully after lamotrigine withdrawal and steroid therapy.

Levetiracetam

(SED-14, 190)

In a pooled analysis of safety data from doubleblind placebo-controlled add-on trials of levetiracetam (1-3 g/day) in adults with refractory partial seizures, adverse events occurring in at least 3% of patients and with at least 3% higher incidence in the active treatment group were tiredness (14% vs 10%), somnolence (15% vs 10%), dizziness (9% vs 4%), and common cold or upper respiratory tract infections (13% vs 7%) (56M). The proportions of patients requiring withdrawal of treatment or dosage reduction owing to adverse events were 15% with levetiracetam and 12% with placebo.

Oxcarbazepine

(SED-14, 190; SEDA-21, 73; SEDA-23, 88)

Nervous system A 31-year-old man developed oculogyric crises after starting to take oxcarbazepine, and the frequency of these episodes correlated with the dosage of the drug (57A). Similar episodes had occurred in the past after exposure to carbamazepine. The implantation of a vagus nerve stimulator led to the disappearance of the oculogyric crises. Electrolyte balance Hyponatremia occurs in an appreciable proportion of patients taking oxcarbazepine; it is usually asymptomatic. Among 2166 oxcarbazepine-treated patients in the manufacturer's database, the incidence of sodium concentrations below 135 mmol/1 was 21.5% (58c). There was marked hyponatremia (sodium concentrations below 125 mmol/1) in 2.7% overall and the risk increased with age: 0% below 6 years, 0.5% at 6-17 years, 3.4% at 18-64 years, and 7.3% above 65 years. The incidence of adverse events was similar in all sodium categories: the absence of symptoms suggests that the fall in sodium concentrations was not precipitous.

Phenytoin

(SED-14, 180; SEDA-21, 73; SEDA-22, 90; SEDA-23, 89)

Cardiovascular Mild to moderate progressive distal limb edema, discoloration, and pain (purple limb syndrome) was recorded in 20 of

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67 patients who received intravenous phenytoin over a 5-month period (59c). Affected cases tended to be older (median age 70 years vs 57 years in non-affected cases), and all resolved spontaneously within 3 weeks. These data suggest that the incidence of the syndrome may have been underestimated in the past, possibly owing to its delayed onset, frequent occurrence in patients with impaired communication abilities, and its usually mild self-limiting course. In a 49-year-old otherwise healthy woman undergoing craniotomy for aneurysm clipping, inadvertent overdose with phenytoin (1500 mg) by rapid infusion caused intraoperative sinus arrest, which was managed successfully with standard resuscitative measures (60A). This report highlights the cardiovascular risk of intravenous phenytoin, particularly when high infusion rates are used.

Nervous system A 40-year-old man who developed toxic signs and a high serum phenytoin concentration (130 txmol/l) on a low dosage (187.5 mg/day) was found to be heterozygous for the Leu359 allele of CYP2C9 and for the *3 allele of CYP2C19 (61A). Phenytoin is metabolized by both cytochromes and the mutations probably explained the adverse reaction.

Drug interactions In three patients treated with cyclophosphamide, phenytoin comedication increased the formation of the S (but not the R) enantiomer of the dechloroethylated cyclophosphamide metabolite (62c). The findings also suggested that phenytoin increased the clearance of both R- and S-cyclophosphamide to 4-hydroxycyclophosphamide (the activation pathway). The clinical relevance of these findings is unclear. In a 50-year-old woman with familial hypercholesterolemia and epilepsy, the addition of phenytoin caused a marked reduction in the lipid response to simvastatin and atorvastatin, an effect that was reversible after withdrawal of the anticonvulsant (63A). It is likely that phenytoin reduced the efficacy of the statins by inducing their metabolism. A careful study in six patients showed that ticlopidine 250 mg bd caused a two-fold increase in the Michaelis-Menten constant of phenytoin, indicating inhibition of phenytoin metabolism (64c). These results are consistent with the known inhibitory activity of ticlopidine on CYP2C19, and suggest that phenytoin

91 dosage requirements may be reduced by ticlopidine. In a 30-year-old man stabilized on phenytoin, the addition of nelfinavir was associated with a fall in serum phenytoin concentration and seizure recurrence (65A). However, other drugs were also added or withdrawn during the observation period and the role of nefilnavir in this possible interaction is speculative.

Stiripentol Drug interactions After the addition of stiripentol (50 mg/kg) in 20 children treated with clobazam, mean serum clobazam and norclobazam concentrations increased about 2-fold and 3-fold respectively and a mean 25% reduction in clobazam dose was required because of adverse effects (66 c). Serum concentrations of concomitantly administered valproic acid rose by about 20%. These findings are in agreement with evidence that stiripentol is a potent metabolic inhibitor. Sulthiame

(SED-14, 187; SEDA-21, 74)

A 9-year-old boy with rolandic epilepsy developed impaired vigilance, depressed mood, fatigue, loss of drive, and listlessness when given sulthiame 5 mg/kg/day (67A). All his symptoms disappeared within a few days of withdrawal.

Tiagabine (SED-14, 190; SEDA-21, 74; SEDA-22, 91; SEDA-23, 89) In a review of safety data from nearly 3100 patients included in 53 clinical trials, tiagabine had no significant effect on hepatic metabolic processes, serum concentrations of concomitant anticonvulsants, and blood chemistry and hematology tests (68M). Allergic reactions, such as skin rashes, were less common with tiagabine than with most other antiepileptic drugs. Adverse effects were generally mild and affected mainly the central nervous system, the most common being dizziness, weakness, nervous-

ness, tremor, difficulty with concentration and attention, speech disorders, depression, and abdominal pain. About 1% of patients given tiagabine experienced weakness severe enough to cause falls or inability to walk, and some form of weakness occurred in about 9% of

92 patients, especially at high dosages or after stopping a single concomitant enzyme-inducing antiepileptic drug. Nervous system Following initial reports (SEDA-21, 74; SEDA-22, 91) additional cases of tiagabine-associated non-convulsive status epilepticus have been reported. After an increase in tiagabine dose to 32 mg/day, a 28-year-old woman with partial epilepsy developed a prolonged and disoriented state associated with generalized spike-and-wave discharges on the electroencephalogram. Tiagabine was discontinued and the status did not recur. Two similar episodes occurred in a 28-year-old man taking 24 and 32 mg/day (69A). Both patients were co-medicated with a nonenzyme-inducing agent (valproate and lamotrigine respectively), which probably resulted in higher serum tiagabine concentrations than those seen in enzyme induced patients. Although the manufacturer's database suggested that non-convulsive status is rare during tiagabine therapy (68M), the possibility of status needs to be considered in patients who develop episodes of confusion or atypical behavior while taking tiagabine, especially when high dosages are used. A critical analysis of the available literature suggests that misdiagnosis may occur and that some reported cases of putative non-convulsive status epilepticus might in fact have had drug-induced encephalopathy (68 M, 70c). Overall, the risk of tiagabineinduced generalized non-convulsive status is likely to be greater in patients with a history of absence or generalized epileptic discharges, which are known to be aggravated by GABAergic agents, but patients without such a history may be also affected. Generalized non-convulsive status needs to be differentiated not only from non-epileptic encephalopathy, but also from partial nonconvulsive status, which may also be occasionally precipitated by tiagabine (68 c, 70c). Hypoactivity, reduced reactivity, and affective detachment with electroencephalographic features suggestive of frontal non-convulsive status epilepticus developed insidiously in a 12-year-old boy with epilepsy and familial bilateral perisylvian polymicrogyria when the tiagabine dosage was increased from 0.5 to 1 mg/kg/day. The condition cleared after dose reduction (70c). Another case involved a 21-year-old woman with partial epilepsy, who showed seizure aggravation and complex partial status epilepticus after stepwise

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increase of tiagabine to 60 mg/day in addition to carbamazepine and vigabatrin (71A). The electroencephalogram showed bilateral rhythmic slow activity which disappeared, together with clinical signs, when intravenous clonazepam (2 mg) was given. Hematologic A 42-year-old woman developed thrombocytopenia (platelet count of 4 x 109/1), ecchymoses, and petechiae after taking tiagabine 50 mg/day for about 1 month (72A). Bone-marrow biopsy showed a moderate increase in megakaryocytes without signs of disturbed maturation. Withdrawal of tiagabine led to gradual recovery. The authors failed to mention that ecchymoses have been reported before in patients taking tiagabine, as discussed in the manufacturer's prescribing information (73r).

Topiramate (SED-14; 191; SEDA-21, 75; SEDA-22, 91; SEDA-23, 90) In a double-blind, placebo-controlled, add-on trial of topiramate (300 mg/day) in 177 Korean patients with epilepsy, adverse events that were significantly more common in the active treatment group were anorexia (21% vs 6% on placebo), abdominal pain or discomfort (21% vs 2%), speech disturbances (10% vs 1%), psychomotor slowing (9% vs 1%), and weight loss (9% vs 0%) (74cr). The relatively high incidence of gastrointestinal disturbances was not seen in Western trials, suggesting that Koreans may be more sensitive to this type of adverse effect. Of seven patients who withdrew because of adverse events, four did so because of abdominal symptoms, nausea, and/or vomiting.

Psychological In a retrospective survey, behavioral changes occurred in nine of 69 children (median age 12 years) given topiramate (75c). Dosages in the affected children were 2.4-8.5 mg/kg, and three children were taking monotherapy. Manifestations included school difficulties (4), mood swings (2), and aggression, irritability, and hallucinations (one case each). There was no apparent relation to dosage or titration rate. Word-finding difficulties are a known adverse effect of topiramate. Language disturbances (anomia or impaired verbal expression) without other complaints suggestive of impaired cognition were reported by four of 51 patients; five others had language problems as-

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sociated with cognitive dysfunction (76e). One severely retarded patient with a limited vocabulary became mute, although he was otherwise alert. Anomia or dysnomia were also seen in two of eight patients treated with zonisamide, which shares with topiramate a sulfa structure and carbonic anhydrase inhibiting properties.

Psychiatric Psychotic symptoms are a significant adverse effect in occasional patients. In a retrospective survey, five of 80 patients developed psychosis 2--46 days after starting to take topiramate; manifestations included paranoid delusions in four and auditory hallucinations in three (77c). The dosage at the time of onset of symptoms was 50-500 mg/day, and recovery occurred rapidly after drug withdrawal (three patients), dosage reduction (one patient), or neuroleptic drug treatment (one patient). Three of the patients had no significant psychiatric history.

Acid base balance Topiramate lowers serum bicarbonate by inhibiting carbonic anhydrase. In 20 of 29 children there was a greater than 10% fall in serum bicarbonate after starting topiramate (mean absolute reduction 4.7 mmol/l), but none had significant symptoms of metabolic acidosis, except possibly for anorexia in one (78c). In another report, mild to moderate metabolic acidosis (bicarbonate concentrations, 16-21 mmol/l) developed in three topiramatetreated patients aged 25-51 years; the condition was not considered clinically significant, but it led to diagnostic tests to exclude other causes (79A). While the fall in serum bicarbonate is asymptomatic in most cases, special caution is required in patients already at risk of metabolic acidosis, such as those with respiratory acidosis, renal disease, frequent severe infections and sepsis, gastrointestinal disorders with recurrent dehydration, inborn errors of metabolism, or treatment with a ketogenic diet (78c).

Valproate s o d i u m (SED-14, 182; SEDA-21, 76; SEDA-22, 91; SEDA-23, 90) Cardiovascular Hypotension has been attributed to valproate (80A). In an 11-year-old girl treated with intravenous valproate (30 mg/kg over 1 hour) for status epilepticus, the blood pressure fell from 130/80 mmHg to

93 70/55 mmHg after about 40 minutes of infusion. The seizures stopped, but the blood pressure fluctuated for several hours between 90/60 mmHg and 60/30 mmHg, requiring intravenous fluids and pressor therapy. Endotracheal intubation was also performed and she eventually recovered. This seems to be the first case of significant hypotension associated with intravenous valproate in a child: a relatively high dosage of valproate, concurrent varicella infection, and previous use of benzodiazepines might have contributed. Nervous system Valproate rarely causes severe mental deterioration and CT/MRI findings suggestive of cortical atrophy, reversible after withdrawal (SEDA-20, 67). Two possible additional cases have been reported in women with juvenile myoclonic epilepsy aged 22 and 46 years (81A). In one case mental function and brain atrophy regressed over a few months after stopping valproate, while in the other cognitive function improved but CT/MRI abnormalities persisted. The authors suggested that valproateinduced pseudoatrophy of the brain may not be always fully reversible, especially when the interval between onset of the condition and diagnosis is prolonged (2 years in this case). However, the possibility exists that the persistent cortical atrophy had other causes in their patient.

Endocrine Among 45 valproate-treated females aged 8-18 years, hyperandrogenism (serum testosterone concentrations more than two standard deviations above the mean for healthy controls) was seen in 38% of prepubertal girls, 36% of pubertal girls, and 57% of postpubertal girls (82c). Obesity was more common in postpubertal valproate-treated girls than in controls. The authors concluded that valproate may cause hyperandrogenism in girls with epilepsy during the sensitive period of pubertal maturation. The mechanisms involved in valproateinduced weight gain have been assessed in 40 women with epilepsy evaluated before and after 1 year of therapy (83c). At the end of follow-up, 15 patients were obese and had higher serum leptin and insulin concentrations than patients who did not gain weight. The rise in serum leptin is consistent with that observed in other types of obesity.

Chapter 7

94 Fluid balance valproate.

Edema has been attributed to

A 42-year-old man with bipolar disorder developed peripheral edema 14 days after starting treatment with valproate in a dosage of 1400 mg/day (84A). Within 3 weeks he gained 11 kg in body weight, his legs were very swollen, and periorbital edema was present after a night's sleep. Blood chemistry and hematology tests were normal. The diagnosis was avid salt retention by the renal tubules, secondary to treatment with valproate, and recovery occurred when diuretics were given and valproate was substituted with lithium. An 18-year-old woman also developed leg edema while taking valproate 800 mg/day for epilepsy (85A). Although she had taken valproate for 10 years without edema, the lack of alternative explanations and the disappearance of the condition after withdrawal suggested a drug-related effect. She also had dysmenorrea, hirsutism, and obesity, which were thought to have been caused by valproate. There have been eight other published cases of valproate-induced edema, plus two additional cases in whom edema developed when risperidone was added to valproate. Gastrointestinal In a retrospective survey, gastrointestinal adverse effects were less common in 150 patients taking divalproex sodium than in an equal number taking valproic acid (15% vs 29%), despite the fact that serum valproic acid concentrations were comparable in the two groups (86 C). Patients taking divalproex sodium were less likely to discontinue medication because of gastrointestinal adverse effects (4% vs 13%). The difference was ascribed to the enteric-coated formulation of divalproex sodium. Liver Valproate-induced fatal liver failure developed in a 29-year-old woman with Friedreich's disease (87A). The first symptoms (apathy during febrile upper airways infection) occurred after 2 months of therapy at a dosage of 20 mg/kg. The drug was withdrawn 10 days later, when the patient had hepatic encephalopathy and a severe bleeding diathesis; supportive treatment was provided but she died after 4 weeks. This is the third published case of fatal valproate liver toxicity in an adult with Friedreich's disease, suggesting that this condition is a predisposing factor. Although the risk of valproate hepatotoxicity in adults is much lower than in children, adults still represented

EmilioPerucca

over 15% of the cases known to the authors. Overall, a total of 26 other adults (age range 17-62 years) with fatal valproate-induced liver failure have been reported: of these, three were taking monotherapy and 12 had no underlying disease or a clearly non-metabolic and nonhepatic disease. The duration of treatment before the first symptoms varied between 6 days and 6 years. Pancreas In a study of intravenous valproate in status epilepticus, three of 19 patients (age and dosage not specified) developed a rise in serum lipase above 4000 IU/ml within 1-3 weeks (88c), and one of these developed overt exudative pancreatitis. Based on these data, it may be prudent to monitor sertun lipase when using intravenous valproate. Drug interactions In a 34-year-old man with bipolar depression treated with valproate, the addition of sertraline (100 mg/day) was associated with signs of valproate intoxication and an increase in serum valproic acid concentration from 378 to 1127 ixmol/l (89c). The serum valproic acid concentration returned to baseline after sertraline withdrawal. Inhibition of valproic acid metabolism was a probable cause for this interaction.

Vigabatrin

(SED-14, 192; SEDA-21, 77; SEDA-22, 92; SEDA-23, 92)

Nervous system Vigabatrin produces intramyelinic edema (neuronal vacuolization) in rats, mice and dogs, but probably not in non-human primates (90E). These findings have been reassessed on the background of clinical safety data, to determine the potential for a similar effect in man (90CR). In animals intramyelinic edema correlates with changes in multimodality-evoked potentials and MRI, but many studies in patients treated with vigabatrin in dosages of 1~5 g/day for up to 12 years have failed to provide evidence for similar changes in humans. Histological examinations of autopsy brain tissue from 24 patients exposed to vigabatrin for 0.6 months to 9.6 years also failed to show any evidence of astrocytosis or axonal changes similar to those associated with vigabatrin-induced microvacuolization. These findings do not provide any support to

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the hypothesis that intramyelinic edema occurs in patients treated with vigabatrin. That vigabatrin can cause psychosis and depression has been confirmed in an analysis of data from double-blind, controlled, add-on trials (91M). Compared with placebo, vigabatrinexposed patients had a significantly higher incidence of events coded as depression (12% vs 3.5%) and psychosis (2.5% vs 0.3%). Although these events occurred during the first 3 months, most of the studies lasted 12-18 w e e k s and therefore definite conclusions could not be reached about timing.

Vigabatrin-induced visual field defects The occurrence of visual field defects in patients exposed to vigabatrin has been discussed extensively in previous volumes (SEDA-21, 78; SEDA-22, 92) and confirmed in several subsequent publications. In a prospective study in patients evaluated for epilepsy surgery, absolute concentric contraction of the visual field of 10-30 degrees was found in 20 (17%) of 118 patients who had ever taken vigabatrin, compared to none of 39 patients who had never taken vigabatrin (92c). Men were more frequently affected than women (21% vs 6%), and the degree of visual field loss was more severe in patients who had taken vigabatrin for more than 2 years. None of the affected patients complained spontaneously of visual field loss. In a recent more detailed investigation of the incidence and clinical presentation of this disorder, expert review of 25 cases of visual field defects reported to the manufacturer suggested that in 13 of the patients the visual field loss could not be assigned to an alternative known cause and had to be ascribed to vigabatrin (93c). In a cohort open-label extension study in

95

Japan, 29 of 99 patients treated with vigabatrin for 2.7-6. 7 years had visual field defects attributed to vigabatrin. In a reference cohort of 42 patients exposed to other antiepileptic drugs without vigabatrin, seven had visual field defects, but in all of them this could be ascribed to a known cause (93c). The prevalence of visual field loss ascribed to the drug did not differ between patients treated for less than 4 years and those treated for more than 4 years (32% vs 28%), suggesting that the disorder is unlikely to increase with continuous treatment beyond 4 years. Visual field loss occurred in 17 of 45 men (38%) vs 12 of 54 women (22%), indicating that men have a 2-fold increase in risk. Age, body weight, daily or cumulative vigabatrin dose, and concomitant antiepileptic drugs did not predict the occurrence of visual field loss. The appearance in the central field out to 30 ~ eccentricity was typically that of a localized bilateral binasal loss, particularly with static threshold perimetry, extending in an annulus over the horizontal midline, together with a relative sparing of the temporal field. In severe cases, there was a concentric appearance. All cases except one were asymptomatic. The authors concluded that the visual field defect induced by vigabatrin is unique in pattern and profound in terms of frequency of occurrence and location and severity of the loss. Vigabatrin-induced visual field loss is generally considered to be irreversible. Although in a lO-year-old girl a severe visual field defect was said to have reversed after withdrawal (94A), repeat confirmatory testing was not performed before the withdrawal of vigabatrin and the pattern of constriction was suggestive of an artefact related to inadequate compliance with the testing procedure (J. Wild, personal communication, 1999). However, other preliminary reports have suggested that reversibility of the visual field defects may in fact occur following early withdrawal (95 C, 96 a ).

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with repeated AED-induced Stevens-Johnson's syndrome. Ther Drug Monit 1999; 21: 137-8. 33. Clark JD, Elliott J. Gabapentin-induced anorgasmia. Neurology 1999; 53: 2209. 34. Verma A, Miller P, Carwile ST, Husain AM, Radtke RA. Lamotrigine-induced blepharospasm. Pharmacotherapy 1999; 19: 877-80. 35. Messenheimer J, MuUens EL, Giorgi L, Young F. Safety review of adult clinical trial experience with lamotrigine. Drug Saf 1998; 18: 281-96. 36. Brodie MJ, Overstall PW, Giorgi L, The UK Lamotrigine Elderly Study Group. Multicentre, randomized comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. Epilepsy Res 1999; 37: 81-7. 37. Froscher W, Keller F, Kraemer G, Vogt H. Serum level monitoring in assessing lamotrigine efficacy and toxicity. Epilepsia 1999; 40 Suppl 2: 252. 38. Champagne J, Whiting SE. Sleep disturbance on lamotrigine. Epilepsia 1999; 40 Suppl 7: 11819. 39. Catania S, Cross H, De Sousa C, Boyd S. Paradoxic reaction to lamotrigine in a child with benign focal epilepsy of childhood with centrotemporal spikes. Epilepsia 1999; 40: 1657-60. 40. Guerrini R, Belmonte A, Parmeggiani L, Perucca E. Myoclonic status epilepticus following high-dosage lamotrigine therapy. Brain Dev 1999; 21: 420-4. 41. Jansky J, Rasonyi G, Halasz P, Olajos S, Szucs A. Continuous myoclonus during lamotrigine therapy with high serum level. Epilepsia 1999; 40 Suppl 2: 282. 42. Sotero M, Patti M, Cheyette S, Rho JM. Lamotrigine-induced tic disorder: Report of five pediatric cases. Epilepsia 1999; 40 Suppl 7: 123. 43. Verma A, St Clair EW, Radtke RA. A case of sustained massive gabapentin overdose without serious side effects. Ther Drug Monit 1999; 21: 615-17. 44. Lombroso CT. Lamotrigine-induced Tourettism. Neurology 1999; 52:1191-4. 45. Mikati M, Fayad M, Choueiri R, Jbeilie D. Potential hepatotoxicity of lamotrigine in children. Epilepsia 1999; 40 Suppl 2: 233. 46. Guberman AH, Besag FMC, Brodie MJ, Dooley JM, Duchowny MS, Pellock JM, Richens A, Stern R, Trevathan E. Lamotrigine-associated rash: risk/benefit considerations in adults and children. Epilepsia 1999; 40: 985-91. 47. Tennis P, Stern SS. Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine or sodium valproate: a recorded linkage study. Neurology 1997; 49: 542-6. 48. Besag FMC. Approaches to reducing the incidence of lamotrigine-induced rash. CNS Drugs 2000; 13: 21-3. 49. Messenheimer JA. Rash with lamotrigine: dosing guidelines. Epilepsia 2000; 41: 488. 50. Rzany B, Mockenhaupt M, Baur S. Epidemiology of erythema exudativum multiforme majus,

97 Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990--1992): structure and results of a population based registry. J Clin Epidemiol 1996; 49: 769-73. 51. Sarris BM, Wong JG. Multisystem hypersensitivity reaction to lamotrigine. Neurology 1999; 53: 1367. 52. Tennis P, Eldridge R. Six-year interim results of the lamotrigine pregnancy registry. Epilepsia 1999; 40 Suppl 2: 196. 53. Faught E, Morris G, Jacobson M, French J, Harden C, Montouris G, Rosenfeld W, and the Postmarketing Antiepileptic Drug Survey. Adding lamotrigine to valproate: incidence of rash and other adverse effects. Epilepsia 1999; 4 0 : 1 1 3 5 40. 54. Pisani F, Oteri G, Russo MF, Di Perri R, Perncca E, Richens A. The efficacy of valproatelamotrigine comedication in refractory complex partial seizures: evidence for a pharmacodynamic interaction. Epilepsia 1999; 40:1141-6. 55. Mylonakis E, Vittorio CC, Hollik DA, Rounds S. Lamotrigine overdose presenting as anticonvulsant hypersensitivity syndrome. Ann Pharmacother 1999; 33: 557-9. 56. Shorvon SD, Van Rijckevorsel K, Verdru P. Pooled efficacy and safety data of levetiracetam (LEV) used as adjunctive therapy in patients with partial onset seizures. Epilepsia 1999; 40 Suppl 7: 76. 57. Gatzonis SD, Georgaculias N, Singounas E, Jenkins A, Stamboulis E, Siafakas A. Elimination of oxcarbazepine-induced oculogyric crisis following vagus nerve stimulation. Neurology 1999; 52: 1918-19. 58. Sachdeo RC, Wassertein AG, D'Souza J. Oxcarbazepine (Trileptal) effect on serum sodium. Epilepsia 1999; 40 Suppl 7: 103. 59. Meara FM, O'Brien TJ, Cook MJ,Vajda FJ. Prospective study of the incidence of local cutaneous reactions (the purple limb syndrome) in patients receiving i.v. phenytoin. Epilepsia 1999; 40 Suppl 7: 145. 60. Berry JM, Kowalski A, Fletcher SA. Sudden asystole during craniotomy: unrecognized phenytoin toxicity. J Neurosurg Anesthesiol 1999; 11: 42-5. 61. Ninomiya H, Mamiya K, Matsuo S, Ieiri I, Higuchi S, Tashiro N. Genetic polymorphism of the CYP2C subfamily and excessive serum phenytoin concentration with central nervous system intoxication. Ther Drug Monit 2000; 22: 230-2. 62. Williams ML, Wainer 1W, Embree L, Bamett M, Granvil CL, Ducharme MP. Enantioselective induction of cyclophosphamide metabolism by phenytoin. Chirality 1999; 11: 569-74. 63. Murphy M J, Dominiczak MH. Efficacy of statin therapy: possible effect of phenytoin. Postgrad Med J 1999; 75: 359-60. 64. Donahue S, Flockhart DA, Abernethy DR. Ticlopidine inhibits phenytoin clearance. Clin Pharmacol Ther 1999; 66: 563-8.

98 65. Honda M, Yasuoka A, Aoki M, Oka S. A generalized seizure following initiation of nelfinavirin a patient with human immunodeficiency virus type 1 infection, suspected due to interaction between nelfinavir and phenytoin. Intern Med 1999; 38: 302-3. 66. Rey E, Tran A, D'Athis E Chiton C, Dulac O, Vincent J, Ports G. Stiripentol potentiates clobazam in childhood epilepsy: a pharmacological study. Epilepsia 1999; 40 Suppl 7:112-13. 67. Weglage J, Pietsch M, Sprinz A, Feldmann R, Denecke J, Kurlemann G. A previously unpublished side effect of sulthiame in a patient with rolandic epilepsy. Neuropediatrics 1999; 30: 50. 68. Leppik IE, Gram L, Deaton R, Sommerville KW. Safety of tiagahine: summary of 53 trials. Epilepsy Res 1999; 33: 235-46. 69. Ettinger AB, Bernal OG, Andriola MR, Bagchi S, Flores E Just C, Pitocco C, Rooney T, Tuominen J, Devinsky O. Two cases of nonconvulsive status epilepticus in association with tiagabine therapy. Epilepsia 1999; 40:1159-62. 70. Piccinelli E Borgatti R, Perucca E, Tofani A, Donati G, Balottin U. Frontal nonconvulsive status epilepticus associated with high-dose tiagabine therapy in a child with familial bilateral perisylvian polymicrogyria. Epilepsia 2000; 41: 1485-8. 71. Trinka E, Moroder T, Nagler M, Staffen W, Loscher W, Ladurner G. Clinical and EEG findings in complex partial status epilepticus with tiagabine. Seizure 1999; 8: 41-4. 72~ Willert C, Englisch S, Schlesinger S, Runge U. Possible drag-induced thrombocytopenia secondary to tiagabine. Neurology 1999; 52: 889. 73. Adkins JC, Noble S. Tiagabine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of epilepsy. Drugs 1998; 55: 437-60. 74. Lee B-I, Kim W-J, Kim D-K and the Korean Topiramate Study Group. Topiramate in medically intractable partial epilepsies: double-blind placebocontrolled randomized parallel-group trial. Epilepsia 1999; 40: 1767-74. 75. Hamiwka LD, Gerber PE, Connolly MB, Farrell K. Topiramate-associated behavioural changes in children Epilepsia 1999; 40 Suppl 7:116. 76. Ojemann LM, Crawford CA, Dodrill CB, Holmes MD, Kutsy R, Wilensky AJ. Language disturbances as a side effect of topiramate and zonisamide therapy. Epilepsia 1999; 40 Suppl 7: 66. 77. Khan A, Faught E, Gilliam E Kuzniecky R. Acute psychotic symptoms induced by topiramate. Seizure 1999; 8: 235-7. 78. Takeoka M, Holmes GR, Thiele E, Bourgeois B, Helmers SL, Duffy FH, Riviello JJ Jr. Topiramate and metabolic acidosis in pediatric epilepsy. Epilepsia 1999; 40 Suppl 7: 126. 79. Sethi PP, Tulyapronchote R, Faught E, Gilliam E Topirarnate-induced metabolic acidosis. Epilepsia 1999; 40 Suppl 7: 148.

Chapter 7

Emilio Perucca

80. White JR, Santos CS. Intravenous valproate associated with significant hypotension in the treatment of status epilepticus. J Child Neurol 1999; 14: 822-3. 81. La Fiore LA, Jorge CL, Yacubian EMT. Reversible pseudoatrophy of the brain caused by valproate treatment: How reversible is it? Epilepsia 1999; 40 Suppl 2: 129-30. 82. Vainionpaa LK, Rattya J, Knip M, Tapanainen JS, Pakarinen AJ, Lanning P, Tekay A, MyUya VV, Isojarvi/IT. Valproate-induced hyperandrogenism during pubertal maturation in gifts with epilepsy. Ann Neurol 1999; 45: 44430. 83. Verrotti A, Basciani F, Morresi S, De Martino M, Morgese G, Chiarelli E Serum leptin changes in epileptic patients who gain weight after therapy with valproic acid. Neurology 1999; 53: 230-2. 84. Haviv YS, Kuper A. Severe peripheral oedema associated with valproic acid. Clin Drug Invest 2000; 19: 385-7. 85. Basel-Vanagaite L, Zeharia A, Amir J, Mimouni M. Edema associated with valproate therapy. Ann Pharmacother 1999; 33: 1370-1. 86. Zarate CA Jr, Toben M, Narendran R, Tomassini EC, McDonald J, Sederer M, Madrid AR. The adverse effect profile and efficacy of divalproex sodium compared with vaiproic acid: a pharmacoepidemiology study. J Clin Psychiatry 1999; 60: 232--6. 87. Konig SA, Schenk M, Sick C, Holm E, Heubner C, Weiss A, Konig I, Hehlmann R. Fatal liver failure associated with valproate therapy in a patient with Friedreich's disease: review of valproate hepatotoxicity in adults. Epilepsia 1999; 40: 1036-40. 88. Grosse P, Rusch L, Schmitz B. Pancreatitis complicating treatment with intravenous valproate: three case reports. Epilepsia 1999; 40 Suppl 2: 267. 89. Berigan T, Harazin J. A sertraline/valproic acid drug interaction. Int J Psychiatry Clin Pract 1999; 3: 287-8. 90. Cohen JA, Fisher RS, BrigeU MG, Peyster RG, Sze G. The potential for vigabatfin-induced intramyelinic edema in humans. Epilepsia 2000; 41: 148-57. 91. Levinson DE Devinsky O. Psychiatric adverse events during vigabatrin therapy. Neurology 1999; 53: 1503-11. 92. Hardus P, Verduin WM, Postma G, Stilma JS, Berendschot TFJM, Van Veelen CWM. Concentric contraction of the visual field in patients with temporal lobe epilepsy and its association with the use of vigabatrin medication. Epilepsia 2000; 41: 581-7. 93. Wild JM, Martinez C, Reinshagen G, Harding GFA. Characteristics of a unique visual field defect attributed to vigabatrin. Epilepsia 1999; 40: 178494. 94. Versino M, Veggiotti P. Reversibility of vigabatrin-induced visual field defect. Lancet 1999; 354: 486. 95. Krakow K, Polizzi G, Riordan-Eva P, Holder

Antiepileptic drugs

Chapter7

G, MacLeod WN, Fish DR. Recovery of visual field constriction following discontinuation of vigabatrin. Seizure 2000; 9: 287-90. 96. Kramer G, Ried S, Landau K, Harding GFA.

99 Vigabatrin: reversibility of severe concentric visual field defects after early detection and drug withdrawal--a case report. Epilepsia 2001; in press.

A.H. Ghodse and A.M. Baldacchino

8

Opioid analgesics and narcotic antagonists

GENERAL

The prevention of opioid-induced adverse effects Opioids are the mainstay of postoperative analgesia. However opioid analgesia is associated with several adverse effects, including sedation, nausea, and pruritus. Other adverse effects include constipation, sweating, and respiratory depression. Several of this year's literature reviews have described the use of prophylactic drugs to reduce the incidence of sedation, nausea, and pruritus as a result of opioid use. Prevention o f sedation The use and possible mechanism of amphetamines to counteract opioid-induced sedation has been reviewed (1g ). Most studies had methodological problems, including small numbers of patients completing short-term trials (under 1 week) and the small number of randomized, placebo controlled, cross-over trials. The quantitative measure of sedation was highly subjective and no uniform cognitive tests were performed to help compare the results of using amphetamines to reduce opioid induced sedation. The overall conclusion was that more research is needed to determine the exact role of amphetamines. The use of amphetamine and amphetamine derivatives for the treatment of opioid induced sedation is not recommended.

Prevention of emesis Another excellent review has focused on the use of prophylactic antiemetics during patient controlled analgesia (PCA) (2M). A systematic search for rel9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed. lCWI

evant randomized controlled trails identified 14 studies involving 1117 adults published between 1992 and 1998. Without antiemetic drugs the incidence of opioid-induced nausea was on average 48% and of vomiting 55%, with a 67% chance of having an emetic episode. The most frequently studied antiemetic was droperidol added to morphine PCA in six placebo-controlled trials in 642 adults and to tramadol in another trial. A wide range of doses of droperidol was used, with a constant degree of antiemetic efficacy. Based on this review the optimal dose of droperidol is said to be less than O.1 mg of droperidol per mg of morphine or less than 4 mg/day of droperidoL There were few adverse reactions: 56 in 10000 patients had extrapyramidal adverse effects when droperidol was added to morphine PCA. The next most frequently used drugs in the prevention of opioid-induced emesis are the 5HT3 receptor antagonists (ondansetron and tropisetron). There is no evidence that they prevent nausea, but the effect on vomiting is satisfactory enough for these drugs to be regarded as second-line choices after droperidol. However, in 109 patients undergoing day-case oral surgery there was a higher incidence of nausea with tramadol plus ondansetron compared with three other treatments (fentanyl plus metoclopramide, tramadol plus metoclopramide, and fentanyl plus ondansetron) (3cR). There was no difference between the groups in analgesic efficacy. Other prophylactic antiemetic agents include clonidine, promethazine, hyoscine, propofol, and metoclopramide. However, the data on these drugs were either insufficient or non-existent. In a randomized, double-blind, placebocontrolled study of 80 patients who required epidural morphine after abdominal hysterectomy, 40 received intravenous dexamethasone

Opioid analgesics and narcotic antagonists

Chapter 8

(8 mg) (4cR). The incidence of vomiting with dexamethasone group was 5% compared with 25% with placebo; the total incidence of nausea and vomiting was 16% compared with 56%. Prevention o f pruritus The incidence of opioid-induced pruritus varies widely, and depends on the opioid used and its mode of administration. The highest incidence (up to 80%) is associated with intrathecal morphine. The pruritus is usually localized to the area of the face that is innervated by the trigeminal nerve. A central encephalinergic mechanism has been proposed to explain this localization. The pruritus is often difficult to treat and responds poorly to conventional treatments, except for naloxone and propofol; 10-15% remain unresponsive. Naloxone reversibility of opioid-induced pruritus supports the existence of an opioid-medicated central mechanism. However, naloxone will reverse the analgesic effects of the opioids. Three studies have suggested the use of ondansetron, a 5HT3 receptor antagonist, for the treatment of opioid-induced pruritus (5 c, 6 cR, 7c). The articles suggested a possible interaction between the opioid and serotonergic systems. In one prospective, randomized, double-blind, placebo-controlled study (5 c) 80 patients undergoing any type of surgery were given intravenous ondansetron 4 mg or 0.9% saline over 1 minute, with alfentanil as the opioid used in the anaesthetic technique. The study was inconclusive; there was a significant reduction in the incidence of scratching in patients who received ondansetron compared with placebo but a non-significant incidence of itching in the ondansetron group. In a prospective randomized, doubleblind, placebo-controlled study in 100 patients scheduled for elective orthopedic surgery and presenting with pruritus induced by epidural or intrathecal morphine, intravenous ondansetron 8 mg was effective in 70% of cases andplacebo in 30% (6cR). Ondansetron was well tolerated, did not change the degree of analgesia, and was not associated with adverse effects usually associated with ondansetron, such as headache, abdominal pain, and cardiac dysrrhythmias. In a double-blind randomized study of 130 patients given subarachnoid bupivacaine 0.5% with morphine 0.3 mg for surgical and postoperative analgesia, repeated-dose and singledose ondansetron were compared (7c). The

101

overall incidence of pruritus was 73% in the group not given ondansetron, 63% in those who received intravenous ondansetron 4 mg 20 minutes before the spinal analgesia and 2 ml of saline at 12, 24, 26, and 48 hours after surgery, and only 49% in those who received ondansetron 4 mg 20 minutes before the spinal and 12, 24, 36, and 48 hours after surgery. There were methodological problems--the small number of subjects studied and the lack of an objective scoring system--but these results add to the current discussion of pursuing further studies to determine the effective dose of ondansetron in the treatment of opioid-induced pruritus. Further neurobiological research is needed to determine a "human" model of explaining the role and interactions of the central serotinergic system with the opioid system. In a prospective, randomized, controlled study 90 women with moderate to severe pruritus due to intrathecal morphine after cesarean section were given intravenous nalbuphine 2 mg, 3 rag, or 4 mg (8c). Nalbuphine 2-3 mg relieved morphine-induced pruritus without increasing pain scores or causing other adverse effects.

Clinical observations suggest that patients often find adverse effects, particularly nausea and vomiting, more distressing than the postoperative pain for which they are prescribed. Some are even willing to endure pain rather than suffer unpleasant adverse effects. This important aspect of opioid-induced analgesia has been investigated in a randomized, double blind, threeway, cross-over study of between- and withinpatient variability in response to equianalgesic doses of morphine, pethidine, and fentanyl during postoperative patient controlled analgesia (PCA) (9CR). In 82 patients undergoing a variety of surgical procedures the three opioids were equally efficacious from objective measurements in relieving pain and the subsequent incidence and intensity of adverse effects. However, the responses to the three opioids were highly individual, and there were three types of response. One group of patients tolerated all three opioids, another tolerated none, and a third group was sensitive to one or more of the opioids with no preference for any of the opioids used. The authors suggested that it would be good clinical practice to change from one opioid to another in patients who have intol-

102 erable adverse effects during PCA, since there is wide variation in subjective interpretation of pain and adverse effects. Nervous system The pattern of opiate use and the concept of quality of life in achieving analgesia in cancer pain have been reviewed (10R). Opioids are being used in higher doses and at earlier stages of the cancer disease process, and patients are dying with better pain control but with more opioid-induced neurotoxicity. The neuropsychiatric syndrome that results from opioid toxicity consists of cognitive impairment, severe sedation, hallucinations, myoclonic seizures, and hyperalgesia. Opioidinduced neurotoxicity is most often seen in patients receiving high doses of opioids for prolonged periods, often in association with psychoactive medications (e.g. benzodiazepines and tricyclic antidepressants), and in older patients with associated dehydration and renal insufficiency. The authors suggested strategies for reducing the occurrence of opioid-induced neurotoxicity. These primarily include opioid rotation and dosage reduction and circadian modulation techniques. Drugs like amphetamines, amphetamine-like derivatives, and neuroleptic drugs like haloperidol could be used to treat hallucinations and delirium as a result of opioid-induced neurotoxicity and when the minimal dose of opioid that can cause sufficient analgesia also causes excess sedation. Proper assessment of the potential risk factors of opioid-induced neurotoxicity with careful monitoring of early signs still remains the fundamental principle in prevention. The role of opioids in chronic nonmalignant pain has been reviewed (11 oR, 12CR), and reports of randomized, double-blind, controlled studies of opioids in chronic nonmalignant pain have been identified (12CR). Opioids appear to be more effective in patients with well-defined nociceptive pain (i.e. pain associated with clear evidence of tissue damage) than in patients with chronic non-malignant pain of neuropathic origin (i.e. pain associated with injury, disease, or section of the peripheral or central nervous system in the absence of tissue damage) or psychogenic causes (no organic pathology present). Gastrointestinal and CNS adverse effects (sedation, dizziness, cognitive impairment, respiratory depression, myoclonus) were frequent and distressing in most of the studies.

Chapter 8

A.H. Ghodse and A.M. Baldacchino

The need for rational prescription of opioids in patients who have been thoroughly assessed and who have adjunctive cognitive behavioral pain management has been highlighted in a case study series, which included two patients with nociceptive and two with neuropathic pain; all four had received transdermal fentanyl (13c). Opioids and hypnotic drugs are often used to prevent increased intracranial pressure and the subsequent reduction in cerebral perfusion pressure. However, it is still uncertain whether opioids can cause increased intracranial pressure. The effects of a bolus injection and infusion of sufentanil, alfentanil, and fentanyl on cerebral hemodynamics and electroencephalographic activity have been studied in a randomized crossover study in six patients with increased intracranial pressure after severe head trauma (14CR). All three infusions were associated with a significant increase in intracranial pressure (9, 8, and 5.5 mmHg respectively) 3-5 minutes after the bolus opioid injection. Intracranial pressure gradually fell and returned to baseline after 15 minutes. This increase was associated with significant falls in mean arterial pressure and cerebral perfusion pressure throughout the study period. The electroencephalogram changed from a fast to a reduced activity pattern, with an improvement in background activity. It is therefore advisable to avoid using bolus injections of opioids in patients with head injury and to use continuous infusion for sedation.

OPIOID AGONISTS (Seealso Chapter 8)

Obstetric use of opioid analgesics Analgesia during the first stage of labor The 50% and 95% effective doses (ED50 and ED95) of intrathecal sufentanil for analgesia in labor have been characterized in several studies (15 c, 16c). The same criteria have now been applied to fentanyl in 90 women in active early labor (at least 5 cm dilatation), who received a range of doses of intrathecal fentanyl (5-25 l~g) in a double-blind randomized study (17c). Fentanyl induced rapid and effective dose-dependent analgesia in early labor. Pruritus occurred in 66%

Opioid analgesics and narcotic antagonists

Chapter 8

of patients and falls in ventilation were dose related. The ED5o and ED95 values were 5.5 and 17.4 Ixg respectively. Sixty women who requested epidural analgesia during labor were randomized to sufentanil 10 tzg, fentanyl 10 lzg, or saline in addition to intrathecal bupivacaine 2.5 mg (18c). The combination o f sufentanil plus bupivacaine gave a significantly longer duration o f analgesia. Pruritus was more common in women given sufentanil (80%) and fentanyl (47%) than in those given plain bupivacaine. However, there were no differences in the incidences o f gastrointestinal effects, hypotension, or motor blockade between the groups. Adding sufentanil 10 lzg to intrathecal bupivacaine 2.5 mg provided fast onset, better analgesia f o r a longer duration than the other treatments. In another similar study the adverse effects profile, especially in regard to pruritus, improved if intrathecal sufentanil 2.5 lzg was added to bupivacaine 1.25 mg and adrenaline 2.5 lzg, without compromising analgesia in women in the first stage o f labor (19cR ). In 30 women randomized to receive either sufentanil 7.5 Izg plus bupivacaine 2.5 Izg, with or without clonidine 50 lzg, using a combined spinal-epidural technique, analgesia was prolonged in those given clonidine without an increased incidence o f adverse effects or worse pain scores (20c). In a prospective, randomized, double-blind comparison o f nalbuphine with pethidine in 310 women requiring analgesia during labor, nalbuphine produced a lower incidence o f nausea and vomiting (21c). There were no differences between the two groups in the other adverse effects o f the opioids, and nalbuphine did not afford major analgesic benefits. Use in cesarean section The use o f intrathecal or epidural opioids has been recommended f o r the relief of pain after cesarean section, and there have been several comparisons of intrathecal and epidural opioid use. In 50 women randomized to intrathecal diamorphine 0.25 mg or epidural diamorphine 5 mg in addition to intrathecal bupivacaine 10 mg, there was no significant difference in the duration or quality o f analgesia (22cr). The incidence o f nausea and vomiting was higher in the epidural group (24% vs 4%). There was no difference in the incidence o f pruritus, but the

103

incidence was as high as 88% o f patients, and it was severe enough to require treatment in 20%. In a prospective, randomized, double-blind study, 55 women undergoing elective cesarean section were allocated to either epidural diamorphine 3 mg or intrathecal morphine 0.2 mg (23c). There were no significant differences between the two groups in pain assessed by visual analogue scale or in the incidence o f pruritus, sedation, or respiratory depression measured by pulse oximetry during the 28hour postoperative period. Nausea and vomiting were significantly more common in the intrathecal morphine group (73% vs 41%). Patient-controlled analgesia with epidural pethidine or a single bolus o f epidural morphine 4 mg during the 24 hours after cesarean section has been studied in 78 women (24c). There were no differences in the degree of analgesia or opioid adverse effects profiles. In 66 cesarean section patients the effects of sufentanil (2 Izg/ml), tramadol (10 mg/ml), or a mixture of the two were compared using patient controlled extradural analgesia (25c). Nausea and vomiting were closely related to the use of tramadol, whilst pruritus was associated with sufentaniL The combined regimen reduced the dosage requirements of both opioids by 20%. Extradural tramadol cannot be recommended, owing the increased incidence of severe gastrointestinal adverse effects, the high dose required, and inferior analgesia. Patient-controlled epidural fentanyl (20 Izg with 10 minute lock-out) has been compared with patient-controlled intravenous morphine (1 mg with a 5 minute lock-out) in 48 women after cesarean section (26 C). Fentanyl was more efficacious in controlling postoperative pain, with a lower incidence of nausea and drowsiness. Finally, 60 women undergoing cesarean section were randomly given epidural tramadol 100 mg, epidural tramadol 200 mg, or saline (27c). Pain scores and adverse effects were evaluated f o r 24 hours after surgery. In all three groups there were no opioid-related adverse effects and epidural tramadol 100 mg provided adequate postoperative analgesia.

Chapter 8

104

Alfentalfil

(SED-14, 211; SEDA-21, 86; SEDA-22, 97; SEDA-23, 98)

Respiratory A 35-year-old man developed recurrent respiratory depression after being given alfentanil 0.0125 mg/kg for vitreoretinal surgery (28A). General anesthesia was induced with a combination of propofol, rocuronium, and alfentanil, subsequent inhalation of isoflurane, and three additional doses of alfentanil (total 0.04 mg/kg over 2 hours). The pulse oxygen saturation fluctuated and was as low as 89% 180 minutes after extubation. Risk factors

Alfentanil is 90% protein bound,

and variability in protein binding can affect its actions. In 10 patients who received standardized anaesthesia and alfentanil to a target concentration of 150 ng/ml for postoperative analgesia interindividual variation in plasma protein binding explained at least 39% of the interindividual variability in alfentanil requirements (29c). There was a high incidence of adverse effects: seven patients had emesis and five had urinary retention. Drug interactions Eight healthy men participated in a 2-day study in which alfentanil was given to a constant plasma concentration of 50 ng/ml and then ketamine added at escalating plasma concentrations of 50, 100, and 200 ng/ml (30oR). The resting hypoventilation induced by alfentanil was antagonized by ketamine 200 ng/ml, but not 50 ng/ml.

Dextromethorphan

(SED-14, 212; SEDA-21, 87; SEDA.22, 98; SEDA-23, 99)

Psychiatric Dextromethorphan-induced psychotic and/or manic-like symptoms have been previously reported and there have been four further cases (31AR, 32A). A 2-year-old child developed hyperirritability, incoherent babbling, and ataxia after being over-medicated with a pseudoephedrine/dextromethorphan over-the-counter combination cough formulation for upper respiratory symptoms. The symptoms abated after withdrawal of the product. In the other three cases (girls aged 10, 13, and 15 years) severe acute psychosis was associated with the use of an over-the-counter formulation containing ephedrine/pseudophedrine and dextromethorphan combined with other compounds. The psychopatho-

A.H. Ghodse and A.M. Baldacchino

logy included agitation, depressed mood, flat affect, pressure of speech, visual and auditory hallucinations, and paranoia. All three improved dramatically, with residual symptoms of irritability, 2-4 days after withdrawal of the mixture and treatment with risperidone 0.5-2.0 mg/day. Sexual function Spontaneous ejaculation occurred in a 64-year-old man who took dextromethorphan for the common cold (33A). His sexual activity normalized 7 days after stopping the dextromethorphan. He had presented with a similar episode 5 months before, with spontaneous ejaculation starting 3 days after he took dextromethorphan and abating 4 days after discontinuing the product.

Drug interactions Dextromethorphan

is metabolized by CYP2D6 to dextrorphan, which binds to phencyclidine receptors and is thought to account for the toxic effects of hallucinations, tachycardia, hypertension, ataxia, and nystagmus. Individuals who are slow metabolizers, those who take long-acting dextromethorphan formulations, and those who take serotonin re-uptake inhibitors or monoamine oxidase inhibitors are at increased risk of adverse effects. The effects of quinidine sulfate, 50 mg orally, an inhibitor of cytochrome CYP2D6, on the metabolism of dextromethorphan 50 mg has been studied in seven healthy volunteers in a randomized, double-blind, cross-over placebo-controlled study (34R). Quinidine suppressed the conversion of dextromethorphan to dextrorphan in rapid metabolizers to the rate seen in poor metabolizers. The increased concentrations of dextromethorphan increased subjective and objective pain thresholds by 35% and 45% respectively. This result suggests that debrisoquine/sparteine-type polymorphisms account for important differences in the effect of dextromethorphan and the balance between the analgesic effect of dextromethorphan and the hallucinogenic effect of dextrorphan. Concomitant use of quinidine could further affect this balance.

Dextropropoxyphene

(SED-14, 212;

SEDA-23, 99)

Cardiovascular Dextropropoxyphene-induced cardiogenic shock has been described

(35A).

Opioid analgesics and narcotic antagonists

Chapter8

105

A 32-year-old man became deeply comatose, with intraventricular conduction disturbances, after taking dextropropoxyphene 4.6 g. Treatment-resistant seizures lasted for hours. He was treated with an intra-aortic balloon pump and a continuous infusion of milrinone for 7 days and recovered fully.

Delayed onset oculogyric crisis and generalized dystonia occurred in a 19-year-old man

The mechanism of cardiotoxicity of dextropropoxyphene is unknown, but the membranestabilizing effect of its major metabolite, norpropoxyphene, seems to play a central part.

Fentanyl

Respiratory Hypersensitivity

pneumonitis,

not previously reported as an adverse effect of dextropropoxyphene, has been associated with co-proxamol (paracetamol plus dextropropoxyphene) (36A). A 61-year-old man, who was taking prednisolone 20 mg and co-proxamol as required for cranial arteritis, presented with a 2-month history of increasing breathlessness. His chest X-ray showed vague shadowing in both lower zones, consistent with an interstitial abnormality, and a lung biopsy confirmed focal interstitial hypersensitivity pneumonitis. After a diffuse rash appeared the co-proxamol was withdrawn and then reintroduced. The rash recurred and the breathlessness deteriorated. A subsequent challenge with paracetamol did not produce the same symptoms. The dosage of prednisolone was not altered.

Diamorphine (heroin)

(SED-14,214;

SEDA-21, 87)

Nervous system For a discussion of progressive spongiform leukoencephalopathy associated with heroin abuse see Chapter 4. Leukoencephalopathy has been reported after intravenous heroin (37A). A 37-year-old man, with a short history of heroin and cocaine use, presented with spasticity of all limbs, a confusional state, and mutism. The electroencephalogram, CT scan, and MRI scan showed predominantly positive frontal pathology, with other lesions in the pyramidal tracts and corpus callosum. The diagnosis was leukoencephalopathy. The symptoms gradually abated after 4 weeks, and repeat tests after 6 months were normal. Three cases of toxic and progressive spongiform leukoencephalopathy have also been reported as a result of vapour inhalation of heroin (38AR). There were generalized white matter abnormalities and pathology in the cerebellum, internal capsule, corpus callosum, and brain stem.

after intranasal heroin use, possibly due to bilateral hypoxic infarction of the pallidum and pallidothalamic tracts (39A).

(SED-14, 213; SEDA-21; 88; SEDA-22, 98; SEDA-23, 100) The local anesthetic ropivacaine is increasingly being used in combination with fentanyl for postoperative epidural analgesic. The ideal combination strength has been investigated in two studies. In a double-blind randomized study, 30 patients undergoing lower abdominal surgery received one of three solutions for patient controlled analgesia (PCA) after a standardized combined epidural and general anesthetic: ropivacaine 0.2% plus fentanyl 4 Ixg, ropivacaine 0.1% plus fentanyl 2 I~g, or ropivacalne 0.05% plus fentanyl 1 Ixg (40c). All three solutions produced equivalent analgesia. Motor block secondary to the ropivacaine was significantly more frequent and intense with ropivacaine 0.2% plus fentanyl 4 Ixg. Pruritus, nausea, sedation, and hypotension occurred equally often in the three groups and were mild. It was therefore inferred that ropivacaine 0.2% plus fentanyl 4 Ixg is preferable for analgesia after lower abdominal surgery. In a prospective, randomized, doubleblind study, the analgesic effect and adverse effects profile of epidural ropivacaine (2 mg/ml) alone was compared with three different fentanyl/ropivacaine combinations (fentanyl 1, 2, and 4 Ixg/ml) for up to 72 hours of postoperative analgesia in 244 patients after major abdominal surgery, most commonly colorectal surgery (41Cr). Hypotension was significantly more common with fentanyl 4 Ixg (52%) compared with the other three groups (31-34%) in the first 24 hours, but not later. Nausea was not significantly different among the groups, although there was more antiemetic drug use in patients given fentanyl 2 and 4 Ixg by day 3. Pruritus was significantly more common in patients who received fentanyl 4 txg throughout the whole 72 hours. Ropivacaine 2 Ixg/ml plus fentanyl 4 Ixg/ml provided the most effective pain relief over the 3 days. Transdermal fentanyl avoids the discomfort of injections and reduces fluctuations in drug concentrations. In an open-label study of trans-

106 dermal fentanyl patches 50 Ixg for postoperative pain management in 15 thoracotomy patients, two patients had nausea and one had erythema over the site of application of the patch (42c). The analgesic effect of fentanyl 1.5 mg/kg has been compared with that of tramadol 1.5 Ixg/kg in 61 patients receiving standardized anesthetics for day-case arthroscopic knee surgery (43c). Opioid adverse effects and analgesia were similar in the two groups. The analgesic effects and adverse effects profiles of subcutaneous fentanyl and subcutaneous morphine have been compared in a double-blind, cross-over, 6-day study in 23 patients with cancer pain (44cr). There were no significant differences in pain scores between the two drugs and no changes in the level of acute confusion (using the Saskatoon Delirium Checklist) or cognitive impairment (in tests of semantic fluency and trail-making tests). Fentanyl caused significantly less constipation. The patients in this study were highly stable and compliant, and the results cannot be generalized. Drug interactions Ritonavir is an inhibitor of HIV protease and a potent inhibitor of CYP3A4 and CYP2D6. The interaction between ritonavir and intravenous fentanyl has been investigated in 12 healthy volunteers in a double-blind, placebo-controlled, cross-over study (45Cr). The volunteers took ritonavir 600 mg on day 1, ritonavir 900 mg and intravenous 5 mg/kg fentanyl on day 2, and ritonavir 300 mg or placebo on day 3. Ritonavir reduced the clearance of fentanyl by 67% by inhibiting its metabolism. This could result in prolongation of fentanyl-induced respiratory depression in a patient with an already compromised cardiorespiratory system.

Hydromorphone Oral hydromorphone is about 7.5 times more potent than oral morphine. Three randomized double-blind, comparisons of morphine and hydromorphone have been reported. Modifiedrelease hydromorphone hydrochloride 4 mg bd was compared with modified-release morphine sulfate 30 mg bd in 89 patients with cancer pain (46c). In all 88 adverse effects were thought to be directly related to the study medication. Other adverse events were related to the dis-

Chapter 8

A.H. Ghodse and A.M. Baldacchino

ease process, the re-emergence of pain, or not specified. In a comparison of hydromorphone and morphine delivered by continuous subcutaneous infusion in 74 patients with severe cancer pain the number of adverse effects was small and comparable in both groups (47c). When epidural morphine (Duramorph 10 Ixg/kg/hour) was compared with epidural fentanyl (1 lxg/kg/hour) and epidural hydromorphone (1 Ixg/kg/hour) in 90 children undergoing orthopedic procedures, hydromorphone was considered to be safe and efficacious (48CR). The combined incidence of pruritus, nausea, and vomiting was 25% vs 20% vs 10% respectively and for pruritus alone 35% vs 15% vs 8%.

Methadone

(SED-14, 214; SEDA-21, 88;

SEDA-23, 103) Experience with methadone in cancer pain is limited. Its long half-life tends to produce delayed toxicity, especially in older patients, but in chronic renal insufficiency and stable liver disease, methadone is safe, unlike morphine. In a prospective uncontrolled study, 45 patients with advanced cancer were given 0.1% methadone 2-3 times a day as required (49c). Ten had nausea and vomiting, none had drowsiness, and 17 had constipation. In another study, nine of 29 patients in a tertiary level cancer pain clinic could not take opioid analgesics owing to uncomfortable adverse effects: nausea, vomiting, and drowsiness in four and other adverse effects in five (50c). The average daily dose of methadone at the end of the titration phase (range 1-79 days) was 208 (range 15-1520) mg. Twenty patients had methadone toxicity during titration. In 12 patients mild drowsiness was a problem, six patients had nausea, and one patient each had confusion and severe headaches. In a third cross-sectional prospective study 24 patients with advanced cancer pain were rapidly switched form oral morphine to oral methadone using a fixed ratio of 1:5 (51CR). There was a significant reduction in pain intensity and adverse effects intensity within 24 hours of substitution, although five patients required alternative treatments.

Opioid analgesics and narcotic antagonists

Chapter8

Morphine

(SED-14, 215; SEDA-21, 89; SEDA-22, 100; SEDA-23, 103) Intrathecal morphine provides adequate postoperative analgesia in orthopedic surgery, but commonly causes urinary retention, pruritus, and nausea and vomiting. Finding the optimal dose of analgesic effect with minimal adverse effects is still the main objective of most papers published on morphine (52 c, 53CR). In a randomized double-blind study in 143 patients scheduled for total hip surgery the optimal dose of intrathecal morphine was as low as 0.1 mg (54Cr). The patients were allocated to four groups depending on the dose of morphine used (0.025, 0.05, 0.1, and 0.2 mg). The incidence of pruritus, nausea and vomiting, and urinary retention, and the consumption of antiemetics did not differ among the groups Nervous system High dose of chronic morphine can cause hyperalgesia or allodynia (pain caused b y ' a stimulus that does not normally provoke pain) (55A). A 9-month-old girl with an inoperable and partially resected astrocytoma of the hypothalamus had morphine-induced allodynia, and became extremely distressed dtLring routine care, such as nappy changing, feeding, and washing. The allodynia resolved after the dosage of morphine was reduced from 6950 ixg/kg/hour to 280 txg/kg/hour.

Oxycodone

(SED-14, 216; SEDA-23, 104)

Oxycodone has been available in oral form for at least 70 years and is rarely given by other routes. In a study of subcutaneous oxycodone hydrochloride 100 mg/ml for opioid rotation in 63 patients with cancer pain (maximum dose 4.5-660 mg in 24 hours for 1--49 days) there was local toxicity in only two cases, and this included central pallor of the skin at the needle

site with surrounding erythema and bruising; there was no necrosis (56c). The design of the study made it difficult to compare the adverse effects profile of subcutaneous oxycodone with oral oxycodone or other opioids. Randomized controlled trials are needed to support the conclusions that subcutaneous oxycodone is free from adverse effects and is a better vehicle for analgesia in terminal cancer. In a double-blind, randomized, cross-over comparison of the efficacy and safety of

107

modified-release oxycodone bd and immediaterelease oxycodone qds in 57 patients with intervertebral disc disease or osteoarthritis (57 CR) 11 patients withdrew: eight with nausea and constipation while taking modified-release oxycodone and three (one with migraine and two with nausea, vomiting, and headaches) while taking immediate-release oxycodone. There were no statistically significant differences in the adverse effects profiles between the two formulations. The overall incidence of adverse effects fell over the three phases of the study: from 89% (51/57 patients) during titration to 77% (36/47 patients) in stage 1 and 62% (29/47 patients) in stage 2. The most common adverse effects were constipation, nausea, pruritus, somnolence, and dizziness, the frequency of which fell with time; the incidence of constipation remained constant.

Pethidine (meperidine) (SED-14,217; SEDA-21, 89) Finding the ideal analgesic dose of pethidine with minimal adverse effects was the purpose of the following studies. In a double-blind study of 60 patients undergoing elective carpal tunnel release given pethidine 0, 10, 20, 30, 40, or 50 mg in addition to intravenous regional anaesthesia with lidocaine 0.5%, the duration of analgesia increased dose-dependently with 0, 10, 20, and 30 mg (58c). In those given pethidine 30, 40, and 50 mg there was a significantly higher incidence of sedation, pruritus, nausea, vomiting, and respiratory depression with no increase in analgesic effect. These results support an optimal dose of pethidine 30 mg when used with 0.5% lidocaine for postoperative analgesia. In a prospective, randomized, single-blind study in 45 men undergoing lower abdominal surgery using one of three doses of intrathecal pethidine (1.2, 1.5, or 1.8 mg/kg) there was no difference in the incidence of adverse effects among the three groups (59CR). The authors postulated that increasing the dose of pethidine from 1.2 to 1.5 mg/kg increased the duration of analgesia but not the level of sensory block, without an increase in adverse effects. In 40 patients undergoing prostatectomy with spinal anaesthesia with lidocaine 5% (75 mg) intrathecaUy, either alone or coadministered with pethidine 0.15 or 0.30 mg/kg,

108 the higher dose of pethidine reduced the requirement for parenteral analgesics with a nonsignificant incidence of pethidine-related adverse effects (60Cr). Pethidine is metabolized in the liver by hydrolysis and conjugation, either directly or via N-demethylation to norpethidine. Norpethidine is significantly less analgesic, with a longer half-life, and it is twice as likely as pethidine to cause convulsions. The seizures occur at a norpethidine concentration range of 0.389.9 txg/ml, and only few reports have described convulsions within the first 24 hours of pethidine treatment. A 35-year-old woman, who was admitted for elective laparotomy and ileostomy formation, was given patient controlled analgesic with pethidine for postoperative analgesia (61A). The device was set to deliver 20 mg of pethidine with a 5 minute lock-out period and no hourly limit. At 4 hours postoperatively she did not have pethidine-related neurotoxicity, but at 23 hours she had myoclonic jerks and facial twitching followed by a brief generalized tonicclonic seizure and post-ictal sequelae. The pethidine was discontinued and there was no further seizure activity. She had self administered a total of 2700 nag. The norpethidine concentration was 1.8 Ixg/ml.

Remifentanil (SED-14, 217; SEDA-22, 101; SEDA-23, 105) Remifentanil hydrochloride is a selective esterase-metabolized rapidly-acting Ix-opioid receptor agonist that is easily titrated to patient needs with fewer risks than high-dose opioid anesthesia. In a double-blind randomized study a continuous infusion of remifentanil (1 Ixg/kg followed by 0.5 Ixg/kg/min) was compared with alfentanil (25 I~g/kg followed by 1 Ixg/kg/min) during anesthesia in patients undergoing major abdominal surgery (62CR). Both systolic pressure and heart rate were significantly lower with remifentanil, with a higher incidence of hypotension (53% vs 39%) and bradycardia (10% vs 3%). In another double-blind randomized comparison of remifentanil (0.25/0.5 Ixg/kg/min) and alfentanil (50 txg and 0.5 Ixg/kg/min) in 35 patients undergoing total abdominal hysterectomy, remifentanil provided more stable analgesia during anesthesia but caused significantly more hypotension (63c).

Chapter 8

A.H. Ghodse and A.M. Baldacchino

In another double-blind randomized study of 178 patients scheduled for major thoracic, intra-abdominal, and orthopedic surgery a high dose of remifentanil (bolus dose of 1 p~g/kg followed by 1 Ixg/kg/min) was compared with a low dose (bolus dose 1 Ixg/kg followed by 0.5 ixg/kg/min) (64c). In this study the intraoperative hypotension (30% and 27% respectively) and bradycardia (9% and 7% respectively) were equally frequent in the two groups. In conclusion the authors proposed that infusion rates of remifentanil over 0.4 Ixg/kg/min provide satisfactory analgesia throughout surgery but may cause significant hypotension. Prolonged infusion of remifentanil for several hours of surgery does not delay recovery or cause respiratory depression. The analgesic effects of remifentanil and alfentanil have been compared during ophthalmological nerve block in a randomized, doubleblind, parallel-group study in 79 patients (65c). Remifentanil (as a single dose of 1 I~g/kg or as a loading dose of 1 Ixg/kg followed by an infusion of 0.2 ixg/kg/min) was more effective than alfentanil (as a single dose of 7 Ixg/kg). Of the patients given remifentanil, three had mild nausea and three had transient muscle rigidity that resolved spontaneously within 1 minute. There were no adverse effects o f alfentanil. The authors suggested that remifentanil 1 Ixg/kg given over 30 seconds is a useful altemative to alfentanil 7 lxg/kg as an analgesic before ophthalmological nerve block. In a prospective randomized comparison of combined serofluvane plus remifentanil with combined fentanyl plus etomidate for induction of anesthesia in 10 patients with ischemic heart disease, three of the 20 patients given serofluvane plus remifentanil developed severe bradycardia (heart rate less than 40 bpm) and one developed asystole, but the difference between the two groups did not reach statistical significance (66CR). Therefore, in patients with ischemic heart disease remifentanil should be used with caution, and concurrent administration of glycopyrrolate 0.2 mg is advisable to reduce the incidence of bradycardia, hypotension, or both, without increasing the heart rate. The effects of remifentanil on vomiting and the quality of emergence from anesthesia has studied in children undergoing dental restoration and extraction (67CR). The children received desflurane with or without remifentanil

Opioid analgesics and narcotic antagonists

Chapter8

0.2 ixg/kg/min. The two groups did not differ in adverse effects profile or quality of recovery.

Sufentanil (SED-14, 217; SEDA-21, 89; SEDA-22, 101; SEDA-23, 105) In a dose-finding, prospective, double-blind study, 60 men scheduled for unilateral extracorporeal shock-wave lithotripsy were randomized to receive 12.5, 15, 17.5, or 20 txg of intrathecal sufentanil (68c). The results suggested that 15 Ixg of sufentanil may be the optimal intrathecal dose, since 20 Ixg produced significantly more pruritus than the lower doses and those who were given 12.5 Ixg needed significantly more supplementary analgesia.

Tramadol (SED-14, 218; SEDA-21, 90; SEDA-22, 103; SEDA-23, 107) It is now accepted that in addition to a Ix-opioid receptor agonist effect, tramadol inhibits the reuptake of both 5-hydroxytryptamine (5HT) and noradrenaline and stimulates the presynaptic release of 5HT. The atypical analgesic effects of tramadol and its associated adverse effects profile have been reviewed (69R). The incidence of adverse effects is reduced with the use of an oral, modified-release formulation of tramadol in the treatment of chronic pain (70or), starting at the lowest dose, increasing gradually according to the patient's response during chronic oral administration (71 C, 72CR), and using a loading dose immediately after the start of surgery. In mild to moderate postoperative pain rectal tramadol has been compared with standard treatment with co-codamol (paracetamol plus codeine) suppositories in 40 patients who were given either tramadol 100 mg suppositories 6-hourly or 1000/20 mg ofcocodamol 6-hourly (73CR). Nausea and vomiting were significantly more frequent with tramadol (84%) than with co-codamol (31%). The effect of tramadol on postoperative nausea and vomiting after ENT surgery has been studied in a prospective, randomized, double-blind comparison with nalbuphine, pethidine, or saline in 281 patients (74c). The three opioids caused a similar incidence of postoperative nausea and vomiting (40%, 52%, and 37% respectively) and more than placebo (32%). Gastrointestinal

109

Intravenous tramadol 1.5 mg/kg has been compared with a single dose of intravenous ketorolac 10 ng in 60 patients scheduled to undergo day-case laparoscopic sterilization in a prospective, randomized, double-blind comparison (75c). Tramadol was associated with significantly less postoperative pain. There was no difference in the incidence or severity of nausea and vomiting between the two groups. Dry mouth was significantly more common with tramadol (60% vs 27%). When tramadol was compared with codeine in 65 patients undergoing elective intracranial surgery, there was a significantly higher incidence of postoperative nausea, vomiting, and sedation with tramadol 75 mg (76Cr). The patients given codeine had significantly lower pain scores over the first 48 hours postoperatively. Urinary tract The Nethedands Pharmacovigilancy Foundation, LAREB, has reported five cases of transient difficulty in urinating, which spontaneously resolved on withdrawal of tramadol and was suspected to be induced by tramadol; none needed catheterization (77AR). In all five cases tramadol had been prescribed for back pain in relatively healthy individuals in a dose range of 50-150 mg. Skin A maculopapular rash with secondary erythroderma occurred in a 47-year-old man treated with tramadol 100 mg for low back pain; the rash resolved after withdrawal of tramadol (78A). Drug dependence Tramadol abuse has been monitored in the USA during the 3 years (199598) since the drug was marketed there, through the systematic collection and evaluation of reports of suspected abuse in high-risk populations from a network of drug abuse specialists and reports sent through the FDA's Med Watch system (79CR). The overall conclusion was that experimentation with tramadol during the first 18 months of its introduction peaked at two cases per 100000 patients exposed. This figure subsequently fell to less than one case per 100 000 patients in the second 18 months of the study period. Of cases of abuse 97% occurred among individuals with a history of substance abuse.

110 PARTIAL OPIOID AGONISTS

Chapter 8

A.H. Ghodseand A.M. Baldacchino

Nalbuphine

(SED-14,222;

SEDA-22, 104)

Buprenorphine (SED-14,220; SEDA-21, 91; SEDA-22, 103; SEDA-23, 108) Cardiovascular A 27-year-old man injected a 2 mg suspension of crushed oral buprenorphine into his left ulnar artery, leading to acute ischemia of the hand; he was successfully treated with iloprost and dextran-40 (80A). A 22-year-old man snorted an 8 mg crushed tablet of buprenorphine and 2 hours later had crushing chest pain, which resolved within a few minutes (81A). The symptom recurred 3 weeks later after another inhalation of buprenorphine. An electrocardiogram suggested an acute anterior myocardial infarction caused by buprenorphine-induced coronary artery spasm. A 33-year-old man developed severe hepatitis after an oral overdose of buprenorphine tablets 112 mg over 48 hours (82A). He presented with an acute confusional state, including disorientation in time and space. The condition led to anuria and hepatorenal insufficiency. He was successfully treated with hemodialysis. Liver

Drug dependence Sublingual buprenorphine is an alternative to methadone treatment for treating opiate dependence, but its opioid agonist effects pose the risk of intravenous abuse and subsequent dependence. This abuse potential may be limited by using a combination of buprenorphine with naloxone, which will precipitate opiate withdrawal when given intravenously but not sublingually. The effects of three combinations of intravenous buprenorphine and naloxone on agonist effects and withdrawal signs and symptoms in 12 opiatedependent patients have been described (83c). After stabilization with morphine 60 mg intramuscularly the patients were challenged with intravenous doses of buprenorphine 2 mg either alone or in combination with naloxone in ratios of 2:1, 4:1, and 8:1, with morphine alone (15 mg), or with placebo. In those given the combination there was a naloxone dose-dependent increase in opiate withdrawal signs and a reduction in the pleasurable effects that might induce abuse liability. The authors suggested that the combination of buprenorphine with naloxone in a ratio of 2:1 or 4:1 may be useful in the treatment of opiate dependence.

Nalbuphine hydrochloride is equipotent with morphine as an analgesic. However, unlike morphine, it has a "ceiling" effect on respiratory depression, a low incidence of dysphoric effects, and a low addiction potential. Ten patients with a history of cardiac or orthopedic problems who received intravenous nalbuphine (620 mg) required additional doses of morphine (15-70 mg) to relieve pain (84c). However, this report was not supported by objective physiological measures or recognized pain scores.

Pentazocine (SED-14,223; SEDA-23, 109) Musculoskeletal Repeated intramuscular injections of pentazocine cause focal tissue damage. Two case reports have further highlighted this (85 A, 86A). A 26-year-old woman presented with progressive thickening and tightening of the skin over both her shoulders and buttocks, with resulting movement restrictions. She had a 5-year history of multiple intramuscular pentazocine injections for abdominal pain. The site of skin tightening was initially localized to the injection site. The affected areas increased progressively. There was an ill-defined area of hyperpigmented, indurated, "woody hard" skin bound to underlying structures and over her shoulders and buttocks. The diagnosis was pentazocine-induced widespread cutaneous fibrosis and myofibrosis. There was no evidence of scleroderma or dermatomyositis. A 38-year-old man, with a painless progressive restriction of flexion around both knee joints for 4 years, had been injecting pentazocine 1-2 ml intramuscularly for 18-20 years. The diagnosis was pentazocine-induced fibromyositis and contracture.

OPIOID ANTAGONISTS

Nalmefene (SED-14,219; SEDA-22, 104; SEDA-23, 109) In a randomized, placebo-controlled, doubleblind study 120 women undergoing lower abdominal surgery were randomized to receive nalmefene 15 Ixg, nalmefene 25 l~g, or saline intravenously at the end of surgery (87CR). The total consumption of morphine and the subsequent adverse effects profiles were recorded.

Opioid analgesics and narcotic antagonists

Chapter8

Those given nalmefene used significantly less antiemetic and antipruritus medications during the subsequent 24-hours without a change in the quality of analgesia.

Naltrexone (SED-14, 220; SEDA-21, 92; SEDA-22, 104; SEDA-23, 110) Psychiatric The first case of acute psychosis secondary to the use of naltrexone has been reported (88A). A 44-year-old physically healthy woman developed auditory and visual hallucinations and persecutory delusions. She had been given naltrexone hydrochloride 50 mg/day 3 days before the acute

111

psychotic incident in order to prevent relapse of alcohol dependence. Her psychotic symptoms completely resolved 48 hours after withdrawal of naltrexone. Museuloskeletal Rhabdomyolysis has been attributed to naltrexone for the first time (89A). A 28-year-old alcoholic was given naltrexone 50 mg/day on the eighth day of a detoxification regimen. On day 17 there was a marked rise in creatine kinase activity (2654 U/I) but no accompanying symptoms of myalgia, weakness, or chest pain. Naltrexone was withheld immediately. The creatine kinase peaked at over 18000 U/1 on day 19 and then fell to within the reference range by day 25. A diagnosis of rhabdomyolysis without accompanying renal insufficiency was suggested.

REFERENCES 1. Corey PJ, Heck AM, Weathermon RA. Amphetamines to counteract opioid induced sedation. Ann Pharmacother 1999; 33: 136245. 2. Tramer MR, Walder B. Efficacy and adverse effects of prophylactic antiemetics during patientcontrolled analgesia therapy: a quantitative systematic review. Anesth Analg 1999; 88: 1354-61. 3. Broome IJ, Robb HM, Raj N, Girgis Y, Wardall GJ. The use of tramadol following day-case oral surgery. Anaesthesia 1999; 54: 289-92. 4. Wang JJ, Ho ST, Liu YH, Ho CM, Liu K, Chia YY. Dexamethasone decreases epidural morphinerelated nausea and vomiting. Anesth Analg 1999; 89: 117-20. 5. Kyriakide s K, Hussain SK, Hobbs GJ. Management of opioid induced pruritus: a role for 5-HT3 antagonists? Br J Anaesth 1999; 82: 439-41. 6. Borgeat A, Stirnemann HR. Ondansetron is effective to treat spinal or epidural morphine-induced pruritus. Anaesth 1999; 90: 43245. 7. Dimitriou V, Voyagis GS, Kyriakides K. Opioid-induced pruritus: repeated vs single dose ondansetron administration in preventing pruritus after intrathecal morphine. Br J Anaesth 1999; 83: 822-3. 8. Somrat C, Oranuch K, Ketchada U, Siriprapa S, Thipawan R. Optimal dose of nalbuphine for treatment of intrathecal morphine induced pruritus after caesarean section. J Obstet Gynaecol Res 1999 ; 25: 209-13. 9. Woodhouse A, Ward ME, Mather LE. Intra-subject variability in post-operative patientcontrolled analgesia (PCA): is the patient equally satisfied with morphine, pethidine and fentanyl? Pain 1999; 80: 545-53. 10. Daeninck PJ, Bruera E. Opioid use in cancer pain. Is a more liberal approach enhancing toxicity? Acta Anaesthesiol Scand 1999 43: 924-38. 11. Molloy AR. The role of opioids in chronic nonmalignant pain. Mod Med Aust 1999; 42: 52451.

12. Bannwarth B. Risk-benefit assesment of opioids in chronic noncancer pain. Drug Saf 1999; 21: 283-96. 13. Milligan KA, Campbell C. Transdermal fentanyl in patients with chronic, nonmalignant pain: a case study series. Adv Ther 1999; 16: 73-7. 14. Albanese J, Viviand X, Potie F, Rey M, Alliez B, Martin C. Sufentanil, fentanyl, and alfentanil in head trauma patients: a study on cerebral hemodynamics. Crit Care Med 1999; 27:407-11. 15. Herman NL, Calicott R, Van Decar TK, Confin G, Tilton J. Determination of the dose-response relationship for intrathecal sufentanil in laboring patients. Anesth Analg 1997; 84: 1256451. 16. Arkoosh VA, Cooper M, Norris MC, Boxer L, Ferouz E Silverman NS, Huffnagle HJ, Huffnagle S, Leighton BL. Intrathecal sufentanil dose response in nulliparous patients. Anesthesiology 1998; 89: 364-70. 17. Herman NL, Choi KC, Affleck PJ, Calicott R, Brackin R, Singhal A, Andreason A, Gadalla E Fong J, Gomillion C, Hartman JK, Koff HD, Rhim SH, Van Decar TK. Analgesia, pruritus and ventilation exhibit a dose response relationship in parturients receiving intrathecal fentanyl during labor. Anesth Analg 1999; 89: 378-83. 18. Lo WK, Chong JL, Chen LH. Combined spinal epidural for labour analgesia~uration, efficacy and side effects of adding sufentanil or fentanyl to bupivacaine intrathecally vs plain bupivacaine. Singapore Med J 1999; 40: 639-43. 19. Mardirosoff C, Dumont L. Two doses of intrathecal sufentanil (2.5 and 5 microg) combined with bupivacaine and epinephrine for labor analgesia. Anesth Analg 1999; 89: 126345. 20. D'Angelo R, Evans E, Dean LA, Gaver R, Eisenach JC. Spinal clonidine prolongs labor analgesia from spinal sufentanil and bupivacaine. Anesth Analg 1999; 88: 57345.

112 21. Lardizabal JL, Belizan JM, Carroli G, Gonzalez L, Campodonico L, Aguillanme CJ. A randomized trial of nalbuphine vs meperidine for analgesia during labor. Ref Gynecol Obstet 1999; 6: 245-8. 22. Hallworth SP, Fernando R, Bell R, Parry MG, Lim GH. Comparison of intrathecal and epidural diamorphine for elective Caesarean section using a combined spinal-epidural technique. Br J Anaesth 1999; 82: 228-32. 23. Caranza R, Teyapalan I, Buggy DJ. Central neuraxial opioid analgesia after caesarean section: comparison of epidural diamorphine and intrathecal morphine. Int J Obstet Anesth 1999; 8: 90-3. 24. Fanshawe MP. A comparison of patient controlled epidural pethidine versus single dose epiS dural morphine for analgesia after caesarean section. Anaesth Intensive Care 1999; 27: 610-14. 25. Vercauteren MR, Mertens E, Schols G, Van Mol I, Adriaensen HA. Patient-controlled extradural analgesia after caesarean section: a comparison between tramadol, sufentanil and a mixture of both. Eur J Pain 1999; 3: 205-10. 26. Cooper DW, Saleh U, Taylor M, Whyte S, Ryall D, Kokri MS, Desira WR, Day H, McArthur E. Patient-controlled analgesia: epidural fentanyl and i.v. morphine compared after caesarean section. Br J Anaesth 1999; 82: 366-70. 27. Siddik-Sayyid S, Aouad-Maroun M, Sleiman D, Sfeir M, Baraka A. Epidural tramadol for postoperative pain after cesarean section. Can J Anaesth 1999; 46: 731-5. 28. Calenda E, Muraine M. Recurrent respiratory depression after low doses of alfentanil. Eur J Anaesthesiol 1999; 16: 206-7. 29. Van den Nieuwenhuyzen MCO, Engbcrs FHM, Burm AGL, Vletter D. Target-controlled infusion of alfentanil for post-operative analgesia: contribution of plasma protein binding to intra-patient and inter-patient variability. Br J Anaesth 1999; 82: 580-5. 30. Persson J, Scheinin H, Hellstrom G, Bjorkman S, Gotharson E, Gustafsson LL. Ketamine antagonises alfentanil-induced hypoventilation in healthy male volunteers. Acta Anaesthesiol Scand 1999; 43: 744-52. 31. Roberge RJ, Hirani KH, Rowland PL, Berkeley R, Krenzelok EP. Dextromethorphan- and pseudoephedrine-induced agitated psychosis and ataxia: case report. J Emerg Med 1999; 17: 285-8. 32. Soutullo CA, Cottingham EM, Keck PE Jr. Psychosis associated with pseudoephedrine and dextromethorphan. J Am Acad Child Adolesc Psychiatry 1999; 38: 1471-2. 33. Rafols A, Garcia Vicente JA, Farre M, Mas M. Sexual dysfunction because of dextromethorphan. Aten Prim 1999; 24: 495-7. 34. Desmeules JA, Oestreicher MK, Piguet V, Allaz A, Dayer P. Contribution of cytochrome P450 2D6 phenotype to the neuromodulatory effects of dextrometorphan. J Pharmacol Exp Ther 1999; 288: 607-12.

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35. Gillard P, Laurent M. Dextropropoxypheneinduced cardiogenic shock: treatment with intraaortic balloon pump and milrinone. Intensive Care Med 1999; 25: 335. 36. Matusiewicz SP, Wallace WAH, Crompton GK. Hypersensitivity pneumonitis associated with coproxamol (paracetamol and dextropropoxyphene) therapy. Postgrad Med J 1999; 75: 475-6. 37. Maschke M, Fehlings T, Kastrup O, Wilhelm HW, Leonhardt G. Toxic leukoencephalopathy after intravenous consumption of heroin and cocaine with unexpected clinical recovery. J Neurol 1999; 246: 850-1. 38. Kriegstein AR, Shungu DC,Millar WS, Armitage A, Brust JC, Chillrud S, Goldman J, Lynch T. Leukoencephalopathy and raised brain lactate from heroin vapor inhalation ("chasing the dragon"). Neurology 1999; 53: 1765-73. 39. Schoser BGH, Groden C. Subacute onset of oculogyric crises and generalized dystonia following intranasal administration of heroin. Addiction 1999; 94: 431-4. 40. Liu SS, Moore JM, Luo A, Trautman WJ, Carpenter RL. Comparison of three solutions of ropivacaine/fentanyl for postoperative patient controlled epidural analgesia. Anesthesiology 1999; 90: 727-33. 41. Scott DA, Blake D, Buckland M, Etches R, Halliwell R, Marsland C, Merridew G, Murphy D, Paech M, Schug SA, Turner G, Walker S, Huizar K, Gustafsson U, Deam RK, Blyth C, Wallace M, Buckland M, Downey G, Etches R, Bignell S, Pavy T, Orlikowski C, Ryan C, Eugster D, Lim W, Dillenbeck C, Sidebotham D. A comparison of epidural ropivacaine infusion alone and in combination with 1, 2, and 4 microg/ml fentanyl for seventy-two hours of postoperative analgesia after major abdominal surgery. Anesth Analg 1999; 88: 857-64. 42. Pereira B, Jain PN, Kakhandki V, Dasgupta D. Transdermal fentanyl in post-thoracotomy pain. J Anaesthesiol Clin Phannacol 1999; 115: 16972. 43. Cagney B, Williams O, Jennings L, Buggy D. Tramadol or fentanyl analgesia for ambulatory knee arthroscopy. Eur J Anaesthesiol 1999; 16: 182-5. 44. Hunt R, Fazekas B, Thorne D, Brooksbank M. A comparison of subcutaneous morphine and fentanyl in hospice cancer patients. J Pain Symptom Manage 1999; 18:111 - 1 9 . 45. Olkkola KT, Palkama V J, Neuvonen PJ. Ritonavir's role in reducing fentanyl clearance and prolonging its half-life. Anesthesiology 1999; 91: 681-5. 46. Moriarty M, McDonald C J, Miller AJ. A randomised crossover comparison of controlled release hydromorphone tablets with controlled release morphine tablets in patients with cancer pain. J Clin Res 1999; 2: 1-8. 47. Miller MG, McCarthy N, O'Boyle CA, Kearney M. Continuous subcutaneous infusion of morphine

Opioid analgesics and narcotic antagonists

Chapter 8

vs hydromorphone: a controlled trial. J Pain Symptom Management 1999; 18: 9-16. 48. Goodarzi M. Comparison of epidural morphine, hydromorphone and fentanyl for postoperative pain control in children undergoing orthopaedic surgery. Paediatr Anaesth 1999; 49: 419-22. 49. Mercadante S, Casuccio A, Agnello A, Barresi L. Methadone response in advanced cancer patients with pain followed at home. J Pain Symptom Management 1999; 18: 188-92. 50. Hagen NA, Wasylenko E. Methadone: outpatient titration and monitoring strategies in cancer patients. J Pain Symptom Management 1999; 18: 369-75. 51. Mercadante S, Casuccio A, Calderone L. Rapid switching from morphine to methadone in cancer patients with poor response to morphine. J Clin Oncol 1999; 17: 3307-12. 52. Gwirtz KH, Young JV, Byers RS, Alley C, Levin K, Walker SG, Stoelting KR. The safety and efficacy of intrathecal opioid analgesia for acute postoperative pain: seven years' experience with 5969 surgical patients at Indiana University Hospital. Anesth Analg 1999; 88: 599--604. 53. Palmer CM, Emerson S, Volgoropolous D, Alves D. Dose-response relationship of intrathecal morphine for postcesarean analgesia. Anesthesiology 1999; 90: 437-44. 54. Slappendel R, Weber EWG, Dirksen R, Gielen MJM, Van Limbeek J. Optimization of the dose of intrathecal morphine in total hip surgery: a dosefinding study. Anesth Analg 1999; 88: 822-6. 55. Heger S, Maier C, Otter K, Helwig U, Suttorp M. Morphine induced allodynia in a child with brain tumour. Br Med J 1999; 319: 627-8. 56. Gagnon B, Bielech M, Watanabe S, Walker P, Hanson J, Bruera E. The use of intermittent subcutaneous injections of oxycodone for opioid rotation in patients with cancer pain. Supportive Care Cancer 1999; 7: 265-70. 57. Hale ME, Fleischmann R, Salzman R, Wild J, Iwan T, Swanton RE, Kalko RF, Lacoutm'e PG. Efficacy and safety of controlled release versus immediate release oxycodone: randomised, double-blind evaluation in patients with chronic back pain. Clin J Pain 1999; 115: 179-83. 58. Reuben SS, Steinberg BB, Lurie SD, Gibson CS. A dose-response study of intravenous regional anesthesia with meperidine. Anesth Analg 1999; 88: 831-5. 59. Hansen D, Hansen S. The effects of three graded doses of meperidine for spinal anesthesia in African men. Anesth Analg 1999; 88: 827-30. 60. Murto K, Lui AC, Cicutti N. Adding low dose meperidine to spinal lidocaine prolongs postoperative analgesia. Can J Anaesth 1999; 46: 327-34. 61. McHugh GJ. Norpethidine accumulation and generalized seizure during pethidine patientcontrolled analgesia. Anaesth Intensive Care 1999; 27: 289-91. 62. Camu F, Royston D. Inpatient experience with remifentanil. Anesth Analg 1999; 89: S15-21.

113

63. Kovac AL, Azad SS, Steer P, Witkowski T, Batenhorst R, McNeal S. Remifentanil versus alfentanil in a balanced anesthetic technique for total abdominal hysterectomy. J Clin Anesth 1997; 9: 532-41. 64. Hogue CW Jr, Bowdle TA, O'Leary C, Duncalf D, Miguel R, Pitts M, Streisand J, Kirvassilis G, Jamerson B, McNeal S, Batenhorst R.A multicenter evaluation of total intravenous anesthesia with remifentanil and propofol for elective inpatient surgery. Anesth Analg 1996; 83: 27985. 65. Ahmad S, Leavell ME, Fragen RJ, Jenkins W, Roland CL. Remifentanil versus alfentanil as analgesic adjuncts during placement of ophthalmologic nerve blocks. Reg Anesth Pain Med 1999; 24: 331-6. 66. Wang JYY, Winship SM, Thomas SD, Gin T, Russell GN. Induction of anaesthesia in patients with coronary artery disease: a comparison between sevoflurane-remifentanil and fentanyletomidate. Anaesth Intensive Care 1999; 27: 3638. 67. Pinsker MC, Carroll NV. Quality of emergence from anesthesia and incidence of vomiting with remifentanil in a pediatric population. Anesth Analg 1999; 89: 71-4. 68. Lau WC, Green CR, Faerber G J, Tait AR, Golembiewski JA. Determination of the effective therapeutic dose of intrathecal sufentanil for extracorporeal shock wave lithotripsy. Anesth Analg 1999; 89: 889-92. 69. Budd K, Langford R. Tramadol revisited. Br J Anaesth 1999; 82: 493-5. 70. Raber M, Hofmann S, Junge K, Momberger H, Kuhn D. Analgesic efficacy and tolerability of tramadol 100 mg sustained-release capsules in patients with moderate to severe chronic low back pain. Clin Drug Invest 1999; 17: 415-23. 71. Ruoff GE. Slowing the initial titration rate of tramadol improves tolerability. Pharmacotherapy 1999; 19: 88-93. 72. Petrone D, Kamin M, Olson W. Slowing the titration rate of tramadol HCI reduces the incidence of discontinuation due to nausea and/or vomiting: a double-blind randomized trial. J Clin Pharmacol Ther 1999; 24: 115-23. 73. Pluim MAL, Wegener JT, Rupreht J, Vulto AG. Tramadol suppositories are less suitable for postoperative pain relief than rectal acetaminophen/codeine. Eur J Anaesthesiol 1999; 16: 473-8. 74. Van den Berg AA, Halliday E, Kisembo Lule E, Baloch MS. The effects of tramadol on postoperative nausea, vomiting and headache after ENT surgery. A placebo-controlled comparison with equipotent doses of nalbuphine and pethidine. Acta Anaesth Scand 1999; 43: 28-33. 75. Putland AJ, McCluskey A. The analgesic efficacy of tramadol versus ketorolac in day-case laparoscopic sterilisation. Anaesthesia 1999; 54: 382-5.

114 76. Jeffrey HM, Charlton P, Mellor D J, Moss E, Vucevic M. Analgesia after intracranial surgery: a double-blind, prospective comparison of codeine and tramadol. Br J Anaesth 1999; 83: 245-9. 77. Meyboom RHB, Brodie-Meijer CCE, Diemont WL, Van Puijenbroek EE Bladder dysfunction during the use of tramadol. Pharmacoepidemiol Drug Saf 1999; 8: $63-4. 78. Ghislain PD, Wiart T, Bouhassoun N, Legout L, Alcaraz I, Caron J, Modiano P. Tramadol-induced toxic skin reaction. Ann Dermatol Venereol 1999; 126: 38-40. 79. Cicero TJ, Adams EH, Geller A, Inciardi JA, Munoz A, Schnoll SH, Senay EC, Woody GE. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug Alcohol Depend 1999; 57: 722. 80. Gouny P, Gaitz JP, Vayssairat M. Acute hand ischemia secondary to intraarterial buprenorphine injection: treatment with iloprost and dextran-40~ a case report. Angiology 1999; 50: 605-6. 81. Cracowski JL, Mallaret M, Vanzetto G. Myocardial infarction associated with buprenorphine. Ann Intern Med 1999; 130: 537. 82. Houdret N, Asnar V, Azostak-Talbodec N, Leteurtre E, Humbert L, Lecomte-Houcke M, Lhermitte M, Paris JC. Severe hepatonephritis and buprenorphine intoxication. Acta Clin Belg 1999; 54: 29-31.

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83. Mendelson J, Jones RT, Welm S, Baggott M, Fernandez I, Melby AK, Nath RP. Buprenorphine and naloxone combinations: the effects of three dose ratios in morphine-stabilized, opiatedependent volunteers. Psychopharmacology 1999; 141: 37-46. 84. Houlihan KPG, Mitchell RG, Flapan AD, Steedman DJ. Excessive morphine requirements after pre-hospital nalbuphine analgesia. J Accid Emerg Med 1999; 16: 29-31. 85. Jain A, Bhattacharya SN, Singal A, Baruah MC, Bhatia A. Pentazocine induced widespread cutaneous and myo-fibrosis. J Dermatol 1999; 26: 368-70. 86. Das CP, Thussu A, Prabhakar S, Banerjee AK. Pentazocine-induced fibromyositis and contracture. Postgrad Med J 1999; 75: 361-2. 87. Joshi GP, Duffy L, Chehade J, Wesevich J, Gajraj N, Johnson ER. Effects of prophylactic nalmefene on the incidence of morphine-related side effects in patients receiving intravenous patientcontrolled analgesia. Anesthesiology 1999; 90: 1007-11. 88. Amraoui A, Burgos V, Baron P, Alexandre JY. Severe acute auditory and visual hallucinations induced by naltrexone chlorhydrate. Presse M6d 1999; 28: 1361-2. 89. Zaim S, Wiley DB, Albano SA. Rhabdomyolysis associated with naltrexone. Ann Phannacother 1999; 33: 312-13.

A. Del Favero

9

Anti-inflammatory and antipyretic analgesics and drugs used in gout

Do new cyclo-oxygenase (COX-2) inhibitors provide benefits similar to those of traditional NSAIDs with less toxicity? This topic has previously been reviewed in these volumes (SEDA-19, 96; SEDA-22, 109), but it deserves further attention, since data from clinical studies of new selective COX-2 inhibitors have been published, providing important information on the merits and limitations of these drugs.

Experimental background NSAIDs inhibit the cyclo-oxygenase (COX) responsible for prostaglandin synthesis, which exits in two isoforms, COX-1 and COX-2, which differ in their structure, regulation, expression, and function. COX-1 is expressed normally in a constant amount in almost all body tissues and produces prostaglandins important for the maintenance of normal homeostasis. In particular, among other important functions, they help to protect the gastrointestinal mucosa against ulceration and regulate renal function and platelet activity. COX-1 appears to be largely unaffected by inflammatory stimuli. In contrast, the COX-2 isoform is constitutively expressed only in the brain, in bone (associated with osteoblast activity), in the female reproductive tract (associated with both the ovulatory cycle and implantation of fertilized ova), and in the kidney, where it may play an important role in regulating renal function. In many other cells COX-2 is 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

expressed at very low levels or is undetectable, but it is readily induced by inflammatory cytokines, mitogens, and endotoxins. Therefore, prostaglandins generated by COX-2 mediate pain and inflammation in many tissues and probably also have a role in renal brain, and reproductive physiology, and in tissue repair (IR-4R). Traditional NSAIDs inhibit both COX-1 and COX-2, providing benefit at sites of inflammation, but at the cost of potential adverse effects related to COX-1 inhibition, particularly in areas such as the gastrointestinal mucosa, platelets, and the kidney. The development of a drug that inhibits only COX-2 would offer the promise of relieving pain and inflammation without some, if not all of these adverse effects. However, the concept that selective inhibition of COX-2 is only a positive event and inhibition of COX-1 a bad one may be simplistic, as it is flawed by many experimental data that have also implicated COX-2 as an integral component in the maintenance of physiological homeostasis (3R). In particular, COX-2 may reduce inflammation by generating anti-inflammatory prostanoids (5E); COX-2, like COX-l, may be present in normal gastric mucosa (6 E, 7E) and can play a physiological role there in defense mechanisms (8 E, 9E), and there is evidence that prostaglandins derived from COX-2 may be important in the healing of gastric ulcers (10 E 12E). Furthermore, COX-2 inhibition alone may be insufficient to resolve inflammation and pain (13E ), suggesting that COX-1 inhibition may play a role in reducing inflammation as well (14E). Although the relevance of these experimental observations to the possible beneficial role of COX-2 activity is uncertain, they cannot be simply dismissed. 115

116 Therefore, to know whether new drugs that selectively inhibit COX-2 confer real therapeutic advantages over the older NSAIDs, we must wait for confirmation from clinical studies, conducted in populations representative of those treated in clinical practice with the traditional NSAIDs. The new COX-2 inhibitors Nearly all of the traditional NSAIDs are predominantly COX-1 selective. In fact, only two of them, meloxicam and nimesulide (1 R, 2R ), have been shown to have some COX-2 selectivity in humans. Two other NSAIDs, etodolac and nabumetone, may be COX-2 preferential inhibitors, but the evidence is less convincing than for meloxicam or nimesulide. Unfortunately, despite their wide use, clinical and epidemiological evidence that supports the claim of better tolerability of these preferential inhibitors with respect to other NSAIDs, is scanty and even controversial (1 R, 4R ). Furthermore, for both meloxicam and nimesulide there are data consistent with reduced COX-2 selectivity at high doses, those usually used in clinical practice. These considerations have prompted research for new more selective COX-2 inhibitors, and most recently two compounds, celecoxib and rofecoxib, have become available. These compounds are much more selective than previous preferential inhibitors and they have no effect on COX-1 (COX-1 sparing drugs) over the whole range of doses used and concentrations achieved in clinical use. In particular, they have been shown in humans to spare gastric COX-1 to a much greater extent than traditional NSAIDs. Is there convincing evidence that COX-2 selective NSAIDs offer a distinct therapeutic advantage over non-selective ones? To prove

the usefulness of these compounds, clinical studies should show: 9

whether the COX-2 selective inhibitors are as effective as older NSAIDs in the relief of pain and~or inflammation; 9 whether in the effective dosage range there is evidence of less damage to the mucosa of the upper gastrointestinal tract than with conventional NSAIDs; 9 whether there are any effects on platelet in effective doses; 9 whether unexpected adverse drug reactions compromise the safety of these compounds.

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A, Del Favero

Efficacy Both celecoxib and rofecoxib have been evaluated in large randomized trials lasting from weeks to 1 year, for the relief of the signs and symptoms of osteoarthritis or rheumatoid arthritis in adults (1 R, 15c-21c). In all of these studies both compounds have been shown to be more effective than placebo and at least as effective as traditional NSAIDs (i.e. ibuprofen, naproxen, diclofenac, nabumetone). However, there is less information about their efficacy as analgesics. A few randomized double-blind trials have shown that both 9compounds are more effective than placebo; rofecoxib was as effective as non-selective NSAIDs (ibuprofen, naproxen) in relieving the pain of osteoarthritis or after dental surgery, but celecoxib was less effective (22 R, 23 R, 24c-26c). Rofecoxib was also analgesic in patients with primary dysmenorrhea (27c). However, there are no published data on the usefulness of COX-2 selective NSAIDs in other types of acute pain, such as that related to acute gout, migraine, cancer, or biliary or ureteric colic.

Unwanted gastrointestinal

effects Evidence that the COX-2 selective agents cause less damage to the gastrointestinal mucosa than traditional NSAIDs is still limited. Gastrointestinal tolerability has been evaluated by measuring the frequency and severity of gastrointestinal adverse effects during randomized comparative efficacy trials, by performing microbleeding or endoscopic studies, and by evaluating the incidence of severe ulcer complications. Evidence from efficacy trials suggests an incidence of unwanted gastrointestinal effects (dyspepsia, epigastric abdominal pain, nausea, or diarrhea) similar to that caused by the traditional NSAIDs (1 R, 15c-17 c, 20 c, 28c). The withdrawal rate from clinical trials because of unwanted effects (gastrointestinal or as a whole) was also similar, the only exception being one study in which fewer patients with rheumatoid arthritis stopped taking celecoxib than stopped taking diclofenac (16c). However, the clinical importance of the frequency and severity of symptoms is uncertain. In fact, it is well known that symptoms do not necessarily predict the presence of mucosal damage, and it is still unclear if patients who have dyspeptic symptoms associated with NSAIDs are at greater or lesser risk of serious gastrointestinal complications (SEDA15, 92; SEDA-17, 103), the crucial question in evaluating these drugs.

Anti-inflammatory and antipyretic analgesics and drugs used in gout In endoscopic comparisons of the new compounds with placebo or older NSAIDs, in both healthy volunteers and patients with rheumatoid arthritis or osteoarthritis, endoscopically observed lesions (erosions, ulcers) in the stomach and duodenum were undoubtedly fewer with the two COX-2 selective compounds than with non-selective NSAIDs (16 c, 28c-31 c ) and were similar to those found with placebo

(1R).

However, the clinical significance of endoscopicaUy detected erosions and ulcers is still debatable (SEDA-14, 79; SEDA-20, 97), as there is much controversy about whether endoscopic ulcers are surrogates for clinical outcomes such as perforation, obstruction, and gastrointestinal bleeding (31R). Thus, although endoscopic studies are an important step in the evaluation of COX-2 selective inhibitors, large-scale, prospective, randomized outcome studies are necessary before we can definitively determine if these drugs will indeed represent significantly safer alternatives to the older NSAIDs. Unfortunately, these prospective comparative complication trials are difficult to perform, as the absolute rate of serious gastrointestinal complications (perforation, obstruction, and bleeding) is low (about 2% per year) (31 R) and so a large number of patients must be studied. While waiting for the results of these trials, it is worth mentioning that suggestions for improved gastrointestinal safety of COX-2 selective inhibitors have come from two studies, which addressed the problem of sample size by pooling published and unpublished randomized double-blind trials of varying design and duration, comparing rofecoxib, celecoxib, non-selective NSAIDs (ibuprofen, diclofenac, nabumetone), and placebo in patients with osteoarthritis and/or rheumatoid arthritis. In the first study the results of eight studies were pooled (32M). The sample size of 5435 patients was large enough to detect even small differences in rates of complicated ulcers (perforation, symptomatic ulcers, and bleeding ulcers). Over 12 months complicated ulcers occurred at a rate of 1.33 per 100 patient-years with rofecoxib and 2.60 per 100 patient-years with non-selective NSAIDs. The analysis of confirmed upper gastrointestinal perforations, symptomatic ulcers, and upper gastrointestinal bleeding showed a relative risk (RR) with rofecoxib versus NSAIDs of O.51 (95% CI = 0.26,

Chapter 9

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1.00). The difference between rofecoxib and the usual NSAIDs in the incidence of perforation, symptomatic ulcers, and bleeding ulcers became statistically significant as early as 6 weeks and remained so up to 12 months. However, this study has some limitations: first, it was not a prospective analysis or a properly conducted meta-analysis; second, there were only enough patient years of exposure to compare rofecoxib with pooled traditional NSAIDs rather than individual drugs; third, the confidence intervals were wide and compatible with no difference between the two treatment groups; fourth, the time to exposure with any selective drug or placebo was too short to give a good prediction of actual complication rates with typical use. In the second analysis, data from 14 studies of the efficacy of celecoxib in osteoarthritis or rheumatoid arthritis in 11 007 patients were pooled (33 M, 34M). Gastrointestinal complications (bleeding, obstruction, or perforation) occurred in 0.2% of the patients per year of exposure to celecoxib and in 1.7% per year of exposure to traditional NSAIDs. The absolute risk reduction was 1.5% (CI = 0.4, 2.6). This study, too, had some limitations. In fact, ulcer complication was not the specified endpoint of the studies that were pooled, and about 15% of celecoxib treated patients took a dose below that indicated for arthritis. For these reasons we should temper enthusiasm for the results of these studies and wait for the conclusions of current, prospective, long-term, large complications trials to know whether the promise of lower gastrointestinal toxicity of the COX-2 selective inhibitors has been fulfilled (35 R ). In any case, the key issue that will confront prescribers will be whether the reduction in ulcer complications is large enough to warrant prescribing these expensive COX-2 inhibitors. This decision will depend primarily on the individual patient's risk of NSAID-induced ulcer complications. Assuming that a COX-2 selective inhibitor will prevent complicated ulcers in 50% of patients, it has been calculated that the NNT for avoiding one complicated ulcer each year in low-risk patients with rheumatoid arthritis (i.e. with a 0.4% risk of ulcer complications) is 500. On the other hand, in patients at higher risk (i.e. a 5% risk for ulcer complications) the NNT is 40 (35R). It is therefore of paramount importance that studies currently under way confirm the same benefit from COX-

118 2 selective agents in patients with a high risk of ulcer complications (i.e. aged 75 years or older, with a prior history of ulcer and gastrointestinal tract bleeding, taking low-dose aspirin for cardiovascular disease). Two other aspects of gastrointestinal toxicity have yet to be studied. First is the use of COX-2 inhibitors in patients with inflammatory bowel disease, in whom it is likely that COX2 activity is upregulated (36 E) and in whom traditional NSAIDs may exacerbate the disease. Experimental colitis has been induced both in COX-2 deficient mice and in rats treated with COX-2 selective inhibitors (37E). However, in healthy volunteers rofecoxib did not alter intestinal permeability, in contrast to indomethacin, which increased it (38c). Studies in patients with inflammatory bowel disease are necessary before considering COX-2 selective inhibitors to be safe in these patients (39r ). Second, a possible beneficial role of COX2 on the stomach should also be taken into account. In mice COX-2 is expressed at the borders of gastric ulcers and has been implicated as a critical factor in promoting repair (11E). Whether these experimental data have any clinical relevance is unknown, but this issue raises the possibility that individuals with pre-existing peptic ulcers who take COX-2 selective drugs may be at risk of delayed ulcer healing and potential complications. This issue may be of particular concern in patients with ulcers due to Helicobacter pylori infection. In conclusion, clinical trials have shown that COX-2 selective NSAIDs seem to be less toxic to the gastrointestinal mucosa than traditional ones. However, life-threatening ulcer complications have been reported in patients taking both celecoxib (34 M, 40 c, 41 c) and rofecoxib (32M). The FDA and other regulatory authorities require that drug information sheets for celecoxib and rofecoxib carry gastrointestinal ulcer warnings similar to those for older NSAIDs. Only large long-term outcome safety studies and postmarketing surveillance will clarify if these warnings are appropriate. Platelets have only the COX-1 isoform for generating thromboxane to precipitate platelet aggregation. Therefore, selective COX-2 inhibitors have no effect on platelet aggregation or bleeding time (3 R, 42c). On the other hand, COX-2 plays a role in the production of endothelial PGI2. In vitro studEffects on platelets

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ies have shown that COX-2 expression is upregulated in endothelial cells by laminar shear stress (43E). Furthermore, selective COX-2 inhibitors reduce systemic PGI2 production in healthy volunteers (44c). The clinical implications, of these observations are unknown. In theory, COX-2 selective NSAIDs might increase the risk of thromboembolic cardiovascular events because of preferential inhibition of endothelial prostacyclin synthesis without corresponding inhibition of platelet thromboxane synthesis, but no reliable data are available on the occurrence of cardiovascular events in patients treated with COX-2 selective or nonselective NSAIDs. Effects on renal function The effects of NSAIDs on the kidney are heterogeneous, and the relative importance of COX-1 and COX-2 in the human kidney is not yet well defined. Non-selective NSAIDs can cause hemodynamically mediated acute renal insufficiency in predisposed patients and can cause sodium and water retention, causing peripheral edema and hypertension. Whether the COX-2 selective drugs can do the same remains to be seen. It is thought that in healthy kidneys COX-2 plays an important role in the balanc e of water and electrolytes and its activity is up-regulated in patients with reduced left ventricular filling pressure, to help maximize renal blood flow. Efficacy trials have shown a similar incidence of pedal edema, renal adverse effects, and hypertension with COX-2 selective and non-selective NSAIDs (18 c, 28c). However, these data are limited and must be interpreted with caution, since NSAIDs have significant toxic effects on the kidney only in patients at risk (i.e. those with volume depletion, heart failure, cirrhosis, intrinsic renal disease, and hypercalcemia), in whom the secretion of vasodilator prostaglandins is increased in an attempt to counteract the effect of increased renal vasoconstrictors, such as angiotensin II. Two studies in healthy volunteers have shown that the effects of COX-2 inhibitors on renal function are similar to those of traditional non-selective NSAIDs (45 c, 46c). The first was a short-term cross-over study on renal function in healthy elderly subjects treated with rofecoxib and naproxen. Although there was a greater fall in glomerular filtration rate with naproxen, reductions in the urinary excretion of sodium, prostaglandin E2, and 6-keto-

Anti-inflammatory and antipyretic analgesics and drugs used in gout prostaglandin FI=, were similar with the two compounds (45c). In the second study in elderly people taking a low-salt diet, rofecoxib and indomethacin significantly lowered the glomerular filtration to a similar extent (46c). Rare reports o f acute reversible renal function have been recorded in patients with predisposing factors (47 a ). Whether selective COX-2 inhibitors can cause the other types o f renal toxicity that are associated with non-selective NSAIDs (i.e. acute interstitial nephritis, nephrotic syndrome with or without renal insufficiency) is not known. Until additional data are available it seems wise to suggest careful monitoring o f renal function in all patients taking COX-2 selective drugs, especially if they are at risk o f impaired renal function when they take traditional NSAIDs (SEDA-11, 85). Other unwanted effects As the complexity o f diverse physiological and pathophysiological roles f o r COX-2 becomes more clear, we need to achieve a better understanding o f the possible adverse effects o f COX-2 selective inhibitors on other organs and functions. Particular attention should be paid to their potential adverse effects in patients in whom non-selective NSAIDs are contraindicated or who at risk o f serious adverse reactions. Although no studies have been conducted, it seems wise to suggest that the prescription o f COX-2 selective inhibitors should be avoided in asthmatic patients with aspirin sensitivity, because o f the risk o f bronchospasm, in pregnant women in the third trimester o f pregnancy, and in nursing mothers. Concerns that COX-2 inhibitors may be associated with an increased risk o f allergic reactions in patients with a history o f sulfonamide hypersensitivity arise from the molecular structure o f these compounds. A sulfur component is necessary f o r the receptor binding o f both celecoxib and rofecoxib, but their structures differ: celecoxib contains a sulfonamide moiety, whereas rofecoxib contains a sulfone. These structures have different potentials f o r causing allergic reactions. As a result, celecoxib, but not rofecoxib, is thought to be contraindicated in patients who are allergic to sulfonamides. The available data on the immunological tolerability profile o f celecoxib are scanty, as a history o f sulfonamide hypersensitivity was among

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the exclusion criteria in studies o f celecoxib. However, in a meta-analysis that included a small subset of patients with a history o f sulfonamide hypersensitivity reactions, there was a 3to 6-fold higher incidence o f skin reactions than in the entire trial cohort (48M). In contrast, there was no cross-allergenicity between celecoxib and other sulfonamide-containing medications. Recently two case reports have suggested a potential association between the sulfonamide group in celecoxib and the development of acute pancreatitis (49 A, 50A). The cause of acute pancreatitis in patients taking celecoxib is speculative, but sulfonamides are known to cause pancreatitis, and one o f these patients reported an allergy to sulfa medication. Thus, the reaction might have been allergic in nature. Additional research is needed to determine the true incidence o f allergic reactions with celecoxib. There are no clinical data on the effects o f these new compounds on the CNS or on fertility. Conclusions New COX-2 selective inhibitors are as efficacious as traditional NSAIDs in treating inflammation and pain due to osteoarticular diseases. However there are questions to be addressed before COX-2 selective inhibitors can be considered to be definitely safer than traditional NSAIDs (4R). Among these questions the most important relate to the possibility that COX-2 inhibitors may cause complicated ulceration in some subgroup of patients and may retard ulcer healing in others. Therefore whether the of COX-2 inhibitors in place o f non-selective NSAIDs will prove to be costeffective by reducing ulcer-related morbidity, remains to be demonstrated. Moreover, it is likely that such drugs can cause the same renal problems as traditional NSAIDs do. Finally the effect o f COX-2 inhibitors on the incidence o f vascular disease will need strict scrutiny, since vascular disease is a commoner cause o f death than ulcer perforation or bleeding. Only their continuing use and postmarketing surveillance studies will demonstrate their strengths and weaknesses with respect to non-selective NSAIDs. For the present prudent use of these new compounds is wise.

120 Cardiovascular NSAIDs can adversely affect cardiovascular function in many ways (SEDA-13, 27; SEDA-22, 107); in particular, they can cause edema and cause or aggravate congestive heart failure in susceptible patients. Although these are well-known adverse effects, there have been few epidemiological studies on the importance of NSAIDs in the development of congestive heart failure. In a recent matched case-control study the relation between the recent use of NSAIDs and hospitalization with congestive heart failure in elderly patients has been analysed (51c). Cases (n = 365) were patients admitted to hospital with a primary diagnosis of congestive heart failure; controls (n -- 658) were patients without congestive heart failure. Structured interviews were used to obtain information on several possible risk factors, such as a history of heart disease and the type and dosage of NSAIDs used. The use of NSAIDs (other than low-dose aspirin) in the previous week was associated with a doubling of the chance of a hospital admission with congestive heart failure (adjusted OR = 2.5, CI = 1.2, 3.3). The risk was even higher in patients with a history of heart disease, in whom the use of NSAIDs was associated with an OR of 11 (CI = 0.7, 45) for first admission with congestive heart failure, compared with an OR of 1.6 (CI = 0.7, 3.7) in those without a history of heart disease. In contrast to the results of a previous study (52c), the OR for admission to hospital with congestive heart failure was positively related to the dose of NSAID consumed in the previous week and was higher with long half-life NSAIDs than with short half-life NSAIDs. The authors estimated that, assuming that these relations were causal, NSAIDs might be responsible for about 19% of hospital admissions with congestive heart failure. If confirmed, this burden of illness resulting from NSAID-related congestive heart failure may rival that resulting from damage to the gastrointestinal tract and would represent an under-recognized public health problem. In any case, this study reinforces the timely suggestion that NSAIDs should be used with great caution in patients with a history of cardiovascular disease. This recommendation must also include the use of the selective COX-2 inhibitors, until more information is available.

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Adverse effects of NSAIDs on the urinary tract Analgesic nephropathy: a further update This topic has been previously reviewed (SEDA21, 98), but recent epidemiological data merit attention. Abuse of compound analgesics containing phenacetin has been considered to be the main factor responsible for the occurrence of analgesic nephropathy, and this prompted the withdrawal of phenacetin from the market in many countries around the world. Unfortunately, there have been no proper investigations of how the replacement of phenacetin by paracetamal or other analgesics in mixed analgesics has affected the incidence of analgesic nephropathy. The difficulties in conducting such studies are well known. The effect of the withdrawal of phenacetin in Germany in 1986 and its replacement with paracetamol in most analgesic mixtures has been evaluated (53c). There was a significant fall in the incidence of end-stage analgesic nephropathy from 30% in 1981-90 to 21% in 1991-92 and 12% in 1995-97. However, whether this reduction can be taken as proof that only phenacetin and not paracetamol is nephrotoxic in compound analgesics is debatable (54c). In fact, the German authors found that other factors, such as advanced age and an increasing prevalence of type II diabetes mellitus, affected the relative frequencies of primary renal disease in patients with end-stage renal disease to such a degree that the observed relative reduction in analgesic nephropathy may not have been related to a change from phenacetin to paracetamol. Thus, the relative reduction in the incidence of analgesic nephropathy cannot be used as an argument for the non-toxicity of compound analgesics that contain paracetamol. Only a long-term prospective study in patients with abuse of paracetamolcontaining mixed analgesics would clarify the question of the toxicity of this drug. Analgesics and renal tumor-inducing effects: new data Studies on the tumor-inducing effects of heavy use of analgesics, especially those that contain phenacetin, have given contrasting results (SEDA-21, 100; 55 C, 56c). Two case-control studies have been published on the role of habitual intake of analgesics on the

Anti-inflammatory and antipyretic analgesics and drugs used in gout occurrence o f urothelial cancer and renal cell carcinoma. In the first study 647 cases of urothelial cancer (571 bladder, 25 ureter, and51 renal pelvis) and an identical number o f controls were enrolled (57c). Exposure to compound analgesic (at least i kg o f analgesic substances lifelong) showed a substance-specific association, with an increased risk ratio f o r renal pelvis cancer but not f o r ureter or bladder cancers. Among the different analgesics, anilide derivatives (intake over I kg) were associated with the highest risks of renal pelvis cancer, with respective odds ratios o f 5.28 f o r phenacetin (CI = 0.34, 81) and 3.27 f o r paracetamol (CI = 0.25, 43); however, these odds ratios were not statistically significant. This lack of significance was due mainly to two factors, the high proportion o f heavy analgesic use in controls and the low number o f cases with renal pelvis cancer, which had the highest risk. The second study (58 c ) was aimed at clarifying the possible relation between analgesic use and renal cell carcinoma. In previous studies there was a consistent association between phenacetin and renal cell carcinoma, but inconclusive results with respect to non-phenacetin analgesics. In 1024 patients with renal cell carcinoma and an equal number of matched controls regular use of analgesics was a significant risk factor for renal cell carcinoma (OR = 1.6; CI = 1.4, 1.9). The risk was significantly increased by all four major classes o f analgesics (aspirin, NSAIDs, paracetamol, and phenacetin) and within each class o f analgesic, the risk increased with increasing exposure. Individuals in the highest exposure categories had about a 2.5-fold increase in risk relative to non-users or irregular users o f analgesics. However, exclusive users o f aspirin who took aspirin 325 mg/day or less f o r cardiovascular problems were not at an increased risk o f renal cell carcinoma (OR = 0.9; C1 = 0.6, 1.4). In contrast to these results, another large case-control study (59 C) in 1732 patients with renal cell carcinoma and 2039 controls showed no increase in the risk o f renal cell carcinoma among regular users o f phenacetin, paracetamol, and aspirin. There is no clear explanation o f these disparate findings.

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Drug administration route Topical NSA1Ds Despite official approval and wide use as either over-the-counter or prescription drugs, there is skepticism that topical NSAIDs have any action other than as rubefacients (60R). There has been a recent systematic review of the efficacy and safety of these drugs in 86 randomized controlled clinical trials in more than 10000 patients with acute or chronic pain (61M). Topical NSAIDs were significantly more effective than placebo for pain relief. Local tolerability was good: local skin reactions were rare (3.6%) and systemic effects even rarer (less than 0.5%). Local or systemic unwanted effects of sufficient severity to cause withdrawal from the study were also rare (0.5%) and no more common than with placebo. In two case-control studies topical NSAIDs were not significantly associated with upper gastrointestinal bleeding or perforation, after adjustment for the confounding effect of concomitant use of oral NSAIDs (62c), nor with hospitalization for acute renal insufficiency (63t~), although renal adverse effects have been described, albeit rarely, with these topical formulations (SEDA-18, 100).

INDIVIDUAL DRUGS AND CLASSES Acetylsalicylic acid (aspirin) and related compounds (SED-14, 233; SEDA-23, 116) Drug interactions Major hemorrhagic complications, including cerebral hemorrhage, can occur with aspirin (SEDA-23, 116) and the same is also true for thrombolytic therapy of acute ischemic stroke (64c). A post hoc analysis of the Multicenter Acute Stroke Trial-Italy has shown a negative interaction of aspirin and streptokinase in acute ischemic stroke (65c). In 156 patients who received streptokinase plus aspirin and 157 patients treated with streptokinase alone, the combined regimen significantly increased early case fatality at clays 3-10 (53 vs 30; OR = 2.5; CI = 1.2, 3.6). The excess in deaths was solely due to treatment and was not explained by the main prognostic predictors. Deaths in the combination group were mainly cerebral (42 vs 24; OR = 2.0; CI = 1.3, 3.7)

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122 and associated with hemorrhagic transformation (22 vs 11; OR = 2.2; CI = 1.0, 5.0). The data suggest that when thrombolytic agents are used for acute ischemic stroke, aspirin should be avoided.

ANILINE DERIVATIVES

Paracetamol (SED-14, 240; SEDA-23, 116)

Respiratory An observational study, part of a population-based case--control study of dietary antioxidants and asthma, has shown an association between the regular use of paracetamol and the incidence of asthma and rhinitis in adults (66c). After controlling for potential confounding factors the OR for asthma in daily users, compared with never users, was 2.38 (CI = 1.22, 4.64). Not unexpectedly, there was also an association in users and non-users of aspirin, strongest when cases with more severe disease were compared with controls. This adverse effect of paracetamol may be due to depletion of the antioxidant glutathione in the lungs. However, further studies are needed before paracetamol can be blamed for an increase in the prevalence and severity of asthma. D r u g interactions Alcohol abuse can aggravate the risk of severe hepatotoxicity, not only in patients who take excessive doses of paracetamol but also in moderate social drinkers who take therapeutic or modestly excessive doses (67R).

ARYLALKANOIC ACID DERIVATIVES

Amtolmetin guacyl Amtolmetin guacyl (2-[2[1-methyl-5-(4methylbenzoyl)-2-yl] acetamido] acetic acid 2-methoxyphenyl ester) is a non-acid pro-drug of tolmetin. This new NSA1D has recently been introduced in various countries, and its launch has been characterized by claims of better gastrointestinal tolerability than older compounds (68 cR, 69CR). Clinical and endoscopic comparative studies have been carried out in

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patients with various osteoarticular diseases (70 cR, 71 c, 72c). In most of these studies amtolmetin showed similar anti-inflammatory activity to other NSAIDs (ibuprofen, naproxen, diclofenac, flurbiprofen, indomethacin, diflunisal) but less gastrotoxicity at endoscopic evaluation, with no difference in the incidence of gastrointestinal symptoms. Unfortunately, the clinical studies were small and of short duration, and the prognostic value of endoscopic studies with respect to severe gastrointestinal complications (bleeding,. perforation, and obstruction) is debatable. It has been suggested that the possible mechanism of the gastric sparing effect of amtolmetin might be related to the local production of nitric oxide, which can counteract the damaging effects of prostaglandin inhibition (73 E, 74E).

Sulindac (SED-14, 284) Analysis of small renal and biliary stones has shown that sulindac or its metabolite were present in the material (SEDA-15, 99), and labelling of sulindac was revised in 1989 to warn physicians of this phenomenon, whose clinical significance is unknown. However, a recent report has shown that despite the presence of sulindac or its metabolites in some renal stones, patients taking long-term sulindac are not at risk of an increased incidence of renal stone formation compared with those taking other NSAIDs (75c).

OXICAM DERIVATIVES

Lornoxicam (SED-14, 287; SEDA-21, 107) D r u g interactions Lornoxicam interacts differently with different oral anticoagulants. It increased the mean serum concentration of racemic warfarin and correspondingly increased its anticoagulant effect (76c). It also altered the pharmacokinetics of the more potent Sisomer of phenprocoumon and to a lesser extent R-phenprocoumon, with a reduction in factor II and VII activity (77c). In contrast, at the upper limit of the recommended doses lornoxicam did not alter the pharmacokinetics of R-acenocoumarol or the anticoagulant

Anti-inflammatory and antipyreticanalgesics and drugs used in gout activity of acenocoumarol (78c). In conclusion co-administration of lornoxicam with warfarin or phenprocoumon, but not acenocoumarol, requires close monitoring of the prothrombin time.

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good tolerance of the drug in patients with aspirin intolerance (8 lC).

MISCELLANEOUS COMPOUNDS

Meloxicam (SED-14, 288; SEDA-23, 120) Flosulide (SEDA-21, 108) Liver Acute cytolytic hepatitis has been described in a 46-year-old woman who took meloxicam for 4 days (79A). Skin The manufacturers of meloxicam have recently included a warning about the possible occurrence of life-threatening skin reactions in the Summary of Product Characteristics (SEDA-23, 120). Erythema multiforme has been reported in a 19-year-old man 8 days after he started to take meloxicam for tendonitis; withdrawal and therapy with corticosteroids resulted in complete recovery (80A).

PHENYLBUTAZONE AND RELATED COMPOUNDS

Azapropazone (SED-14, 291) Immunologic Patients with aspirin intolerance often react also to many other NSAIDs. Azapropazone seems to be a safe alternative in these patients, according a study which showed

Clinical development of flosulide, a COX-2 selective inhibitor, has been discontinued because of nephrotoxicity (82c). Measurement of renal prostaglandin synthesis did not predict the nephrotoxicity of flosulide in single-dose and short-term studies (83c).

Nilnesulide (SED-14, 294; SEDA-23, 121) Fetotoxicity Various types of nephrotoxicity have previously been described with nimesulide (SEDA-22, 119; SEDA-23, 121). Two reports have illustrated the potential danger of using it as a tocolytic (84 A) or during late pregnancy (85A). In both cases maternal ingestion of nimesulide was accompanied by irreversible neonatal renal insufficiency. In the second case renal biopsy showed abnormal tubular differentiation and sign of tubulointerstitial nephritis. The mechanism of this adverse reaction is not known, but it is probably related to fetal COX-2 inhibition. COX-2 is fundamental for nephrogenesis, and is upregulated in fetal membranes and myometrium at parttLrition.

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ibuprofen in patients with osteoarthritis. Arch Intern Med 2000; 160: 1781-7. 21. Cannon GW, Caldwell JR, Holt P, McLean B, Seidenberg B, Bolognese J, Ehrich E, Mukhopadhyay S, Daniels B. Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized, clinical trial in patients with osteoarthritis of the knee and hip. Rofecoxib phase III protocol 035 study group. Arthritis Rheum 2000; 43: 978-87. 22. Anonymous. Celecoxib for arthritis. Med Lett Drags Ther 1999; 41:11-12. 23. Anonymous. Rofecoxib for osteoarthritis and pain. Med Lett Drugs Ther 1999; 41: 59-61. 24. Morrison BW, Christensen S, Yuan W, Brown J, Amlani S, Seidenberg B. Analgesic efficacy of the cyclooxygenase-2-specific inhibitor rofecoxib in post-dental surgery pain: a randomized, controlled trial. Clin Ther 1999; 21: 943-53. 25. Malmstrom K, Daniels S, Kotey P, Seidenberg BC, Desjardins PJ. Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: a randomized, placebo- and active-comparator-controlled clinical trial. Clin Ther 1999; 21: 1653-63. 26. Ehrich EW, Dallob A, De Lepeleire I, Van Hecken A, Reindeau D, Yuan W, Porras A, Wittreich J, Seibold JR, De Schepper P, Pehlisch DR, Gertz BJ. Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model. Clin Pharmacol Ther 1999; 65: 336-47. 27. Morrison BW, Daniels SE, Kotey P, Cantu N, Seidenberg B. Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhea: a randomized controlled trial. Obstet Gynecol 1999; 94: 504-8. 28. Simon LS, Weaver AL, Graham DY, Kivitz A J, Lipsky PE, Hubbard RC, Isakson PC, Verburg KM, Yu SS, Zhao WW, Geis GS. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis : a randomized controlled trial. J Am Med Assoc 1999; 282: 1921-8. 29. Lanza FL, Rack MF, Simon TJ, Quan H, Bolognese JA, Hoover ME, Wilson FR, Harper SE. Specific inhibition of cyclooxygenase-2 with MK0966 is associated with less gastroduodenal damage than either aspirin or ibuprofen. Aliment Pharmacol Ther 1999; 13: 761-7. 30. Laine L, Harper S, Simon T, Bath R, Johanson J, Schwartz H, Stem S, Quan H, Bolognese J. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Gastroenterology 1999; 117: 776-83. 31. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. New Engl J Med 1999; 340: 1888-99.

Anti-inflammatory and antipyretic analgesics and drugs used in gout 32. Langman M J, Jensen DM, Watson DJ, Harper SE, Zhao PL, Quan H, Bolognese JA, Simon TJ. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. J Am Med Assoc 1999; 282: 1929-33. 33. Goldstein JL, Agrawal NM, Silverstein F, Kaiser J, Burr AM, Verburg KM, et al. Celecoxib is associated with a significantly lower incidence of clinically significant upper gastrointestinal (UGI) events in osteoarthritis (OA) and rheumatoid arthritis (RA) patients as compared to NSAIDs. Gastroenterology 1999; 116: A174. 34. Goldstein JL, Silverstein FE, Agrawal NM, Hubbard RC, Kaiser J, Maurath CJ, Verburg KM, Geis GS. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol 2000; 95: 1681-90. 35. Peterson WL, Cryer B. COX-l-sparing NSAIDs. Is the enthusiasm justified? J Am Med Assoc 1999; 282: 1961-3. 36. Hendel J, Nielsen OH. Expression of cyclooxygenase-2 mRNA in active inflammatory bowel disease. Am J Gastroenterol 1997; 92: 1170-3. 37. Reuter BK, Asfaha S, Buret A, Sharkey KS, Wallace JL. Exacerbation of inflammatoryassociated colonic injury in rat through inhibition of cyclooxygenase-2. J Clin Invest 1996; 98: 207685. 38. Sigthorsson G, Crane R, Simon T, Hoover M, Quan H, Bolognese J, Bjamason I. COX-2 inhibition with rofecoxib does not increase intestinal permeability in healthy subjects: a double blind crossover study comparing rofecoxib with placebo and indomethacin. Gut 2000; 47: 527-32. 39. Bjarnason I, Thjodleifsson B. Gastrointestinal toxicity of non-steroidal anti-inflammatory drugs: the effects of nimesulide compared with naproxen on the human gastrointestinal tract. Rheumatology 1999; 38 Suppl 1: 24-32. 40. Reuben SS, Steinberg R. Gastric perforation associated with the use of celecoxib. Anesthesiology 1999; 91: 1548-9. 41. Mohammed S, Dorwyn WC. Gastropathy due to celecoxib a cyclooxygenase-2 inhibitor. New Engl J Med 1999; 340: 2005-6. 42. Simon LS, Lanza FL, Lipsky PE, Hubbard RC, Talwalker S, Schwartz BD, Isakson PC, Geis GS. Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor. Arthritis Rheum 1998; 41: 1591-602. 43. Topper JN, Cai J, Falb D, Gimbrone MA Jr. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2 manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci USA 1996; 93: 10417-22. 44. McAdam BE Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, Fitzgerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase

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(COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA 1999; 96: 272-7. 45. Whelton A, Shulman G, Wallemark C, Drower EJ, Isakson PC, Verburg KM, Geis GS. Effects of celecoxib and naproxen on renal function in the elderly. Arch Intern Med 2000; 160: 1465-70. 46. Swan SK, Rugy DW, Lasseter KC, Ryan CF, Buechel KL, Lambrecht LJ, Pinto MB, Dilzer SC, Obrda O, Sundblad KJ, Gumbs CP, Ebel DL, Quan H, Larson PJ, Schwartz JI, Musliner TA, Gertz B J, Brater DC, Yao SL. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial. Ann Intern Med 2000; 133: 1-9. 47. Perezella MA, Eras J. Are selective COX-2 inhibitors nephrotoxic? Am J Kidney Dis 2000; 35: 937--40. 48. Patterson R, Bello AE, Lefkowith J. Immunologic tolerability profile of celecoxib. Clin Ther 1999; 21: 2065-79. 49. Godino J, Butani RC, Wong PWK, Murphy FT. Acute drug-induced pancreatitis associated with celecoxib. J Clin Rheumatol 1999; 5: 305-7. 50. Carrillo-Jimenez R, Numberger M. Celecoxibinduced acute pancreatitis and hepatitis: a case report. Arch Intern Med 2000; 160: 4. 51. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 2000; 160: 77784. 52. Heerdink ER, Leufkens HG, Herings RM, Ottervanger JP, Stricker BH, Bakker A. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med 1998; 158:1108-12. 53. Schwarz A, Preuschof L, Zellner D. Incidence of analgesic nephropathy in Berlin since 1983. Nephrol Dial Transplant 1999; 14: 109-12. 54. Fox JM. Doubts about a particularly high nephrotoxicity of combination analgesics. Nephrol Dial Transplant 1999; 14: 2966-8. 55. Dubach UC, Rosner B, Pfister E. Epidemiologic study of abuse of analgesics containing phenacetin. Renal morbidity and mortality (1968-1979). New Engl J Med 1983; 308: 357-62. 56. Dubach UC, Rosner B, Stunner T. An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987). New Engl J Med 1991; 324: 155-60. 57. Pommer W, Bronder E, Klimpel A, Helmert U, Greiser E, Molzahn M. Urothelial cancer at different tumour sites: role of smoking and habitual intake of analgesics and laxatives. Results of the Berlin Urothelial Cancer Study. Nephrol Dial Transplant 1999; 14: 2892-7. 58. Gago-Dominquez M, Yuan JM, Castelao JE, Ross RK, Yu MC. Regular use of analgesics is a risk factor for renal cell carcinoma. Br J Cancer 1999; 81: 542-8.

126 59. McCredie M, Pommer W, McLaughiin JK, Stewart JH, Linblad P, Mandel JS, Mellemgaard A, Schlehofer B, Niwa S. International renal-cell cancer study. II. Analgesics. Int J Cancer 1995; 60: 345-9. 60. Eecles M, Freemantle N, Mason J, for the North of England Non-Steroidal Anti-Inflammatory Drugs Guideline Development Group. North of England evidence based guideline development project: summary guideline for non-steroidal anti-inflammatory drugs versus basic analgesia in treating the pain of degenerative arthritis. Br Med J 1998; 317: 526-30. 61. Moore RA, Tram~r MR, Carrol D, Wiffen PJ, McQuay HJ. Quantitative systematic review of topically applied non-steroidal anti-inflammatory drugs. Br Med J 1998; 316: 333-8. 62. Evans JM, McMahon AD, McGilchrist MM, White G, Murray FE, McDevitt DG, MacDonald TM. Topical non-steroidal anti-inflammatory drugs and admission to hospital for upper gastrointestinal bleeding and perforation: a record linkage case-control study. Br Med J 1995; 311: 22q5. 63. Evans JM, McGregor E, McMahon AD, McGilchrist MM, Jones MC, White G, McDevitt DG, MacDonald TM. Non-steroidal anti-inflammatory drugs and hospitalization for acute renal failure. Q J Med 1995; 88: 551-7. 64. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischemic stroke. Multicentre Acute Stroke Trial--Italy (MAST-I) Group. Lancet 1995; 346: 1509-14. 65. Ciccone A, Motto C, Aritzu E, Piana A, Candelise L. Negative interaction of aspirin and streptokinase in acute ischemic stroke: further analysis of the multicenter acute stroke trial--Italy. Cerebrovasc Dis 2000; 10: 61-4. 66. Shaheen SO, Sterne JA, Songhurts CE, Burney PG. Frequent paracetamol use and asthma in adults. Thorax 2000; 55: 266-70. 67. Draganov P, Durrence H, Coc C, Reuben A. Alcohol-acetaminophen syndrome. Even moderate social drinkers are at risk. Pastgrad Med 2000; 107: 189-95. 68. Marcolongo R, Frediani B, Biasi G, Minari C, Barreca C. Metanalisi sulla tollerabili~ di amtolmetina guacil, un nuovo, efficace farmaco antinfiammatorio non steroideo, confrontato con FANS tradizionali. Clin Drug Invest 1999; 17: 89-96. 69. Caruso A, Cutuli VM, De Bernardis E, Attaguile G, Amico-Roxas M. Pharmaceutical properties and toxicology of MED-15, a prodrug of tolmetin. Drug Exp Clin Res 1992; 18: 4815. 70. Tavella A, Ursini G. A clinical study on the antiinflammatory activity and gastrointestinal tolerability of amtolmetin guacyl, a new NSAID, compared with diclofenac in aged patients with osteoarticular diseases. Clin Ter 1997; 148: 543-8. 71. Montrone E Santandrea S, Caruso I, Gerli R,

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Cesarotti ME, Frediani P, Bassani R. Amtolmetin guacyl versus piroxicam in patients with osteoarthritis. J Int Med Res 2000; 28: 91-100. 72. Bianchi Porro G, Montrone E Lazzaroni M, Manzionna G, Caruso I. Clinical and gastroscopic evaluation of amtolmetin guacyl versus diclofenac in patients with rheumatoid arthritis. Ital J Gastroenterol Hepatol 1999; 31: 378--85. 73. Tubaro E, Belogi L, Mezzadri CM. The mechanism of action of amtolmetin guacyl, a new gastroprotective nonsteroidal anti-inflammatory drug. Eur J Pharmacol 2000; 387: 233-44. 74. Pisano C, Grandi D, Morini G, Coppelli G, Vesci L, Lo Giudice E Pace S, Pacifici L, Longo A, Coruzzi G, Carminati E Gastrosparing effect of new antiinflanunatory drug amtolmetin guacyl in the rat: involvement of nitric oxide. Dig Dis Sci 1999; 44: 713-24. 75. Ita S, Hasegawa H, Nozawa S, Murasawa A, Nakano M, Arakawa M. Sulindac usage may not be associated with an increased incidence of renal stone formation in patients with rheumatoid arthritis. J Rheumatol 1999; 9: 119-21. 76. Ravic M, Johnston A, Turner P, Ferber HP. A study of the interaction between lomoxicam and warfarin in healthy volunteers Hum Exp Toxicol 1990; 9: 413-14. 77. Masche UP, Rentsh KM, Von Felten A, Meier PJ, Fattiger KE. Opposite effects of lomoxicam coadministration on phenprocoumon pharmacokinetics and pharmacodynamics. Eur J Clin Pharmacol 1999; 54: 857--64. 78. Masche UP, Rentsh KM, Von Felten A, Meier PJ, Fattinger K. No clinically relevant effect of lornoxicam intake on acenocoumarol pharmacokinetics and phalmacodynamics. Eur J Clin Pharmacol 1999; 54: 865-8. 79. Staerkel P, Horsmans Y. Meloxicam-induced liver toxicity. Acta Gastro-enterol Belg 1999; 62: 255--6. 80. Nikas SN, Kittas G, Karamaounas N, Drosos AA. Meloxicarn-induced erythema multiforme. Am J Med 1999; 107: 532-4. 81. Gutgesell C, Fuchs T. Azapropazone in aspirin intolerance. Allergy Eur J Allergy Clin Immunol 1999; 54: 897. 82. Kaplan-Machlis B, Klostermeyer BS. The cyclooxigenase-2 inhibitors: safety and effectiveness. Ann Pharmacother 1999; 33: 979-88. 83. Brunel P, Homych A, Guyene TI', Sioufi A, Turri M, Menard J. Renal and endocrine effects of flosulide, after single and repeated administration to healthy volunteers. Eur J Clin Pharmacol 1995; 49: 193-201. 84. Peruzzi L, Gianoglio B, Porcellini MG, Coppo R. Neonatal end-stage renal failure associated with maternal ingestion of cyclo-oxygenase-type-1 selective inhibitor nimesulide as tocolytic. Lancet 1999; 354: 1615. 85. Balasubramaniam J. Nimesulide and neonatal renal failure. Lancet 2000; 355: 575.

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COMPARATIVE STUDIES Vital capacity inhalational induction of anesthesia with sevoflurane has been compared with intravenous induction using propofol in 56 adults undergoing ambulatory anesthesia (1c). The patients were randomized to either sevoflurane 8% plus nitrous oxide 75% mixture at 8 l/min (n = 32), or propofol 2 mg/kg bolus (n = 24), without any premedication. Induction time was significantly shorter with sevoflurane (average 51 seconds) than propofol (average 81 seconds). Adverse effects were different in the two groups: sevofiurane caused cough and hiccups, while propofol caused a fall in blood pressure and reduced movements. The overall incidence of adverse effects was similar. Postoperatively, there was mild nausea in 78% of the patients who received sevoflurane compared with 50% for propofol. However no antiemetics were needed and discharge times were not delayed. The characteristics of sevoflurane anesthesia have been compared with those of targetcontrolled infusion of propofol in 61 day-case adults undergoing surgery (2c). All received nitrous oxide 50% and fentanyl 1 Ixg/kg. After insertion of a laryngeal mask airway the propofol target concentration was reduced from 8 to 4 Ixg/ml and the inspired concentration of sevoflurane was reduced from 8% to 3% and subsequently titrated to clinical effects. Mean times to loss of consciousness and laryngeal mask airway insertion were significantly longer after sevoflurane (73 and 146 seconds respectively) than with propofol (50 and 116 seconds respectively). Sevoflurane was associated with a lower incidence of intraoperative movements 9 2001 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

(10% vs 55%), necessitating less adjustment to the dose. The incidence of movement in the propofol group was comparable to other studies. Emergence was faster after sevoflurane (5.3 vs 7.1 minutes) but sevoflurane was associated with more postoperative nausea (30% vs 17%) and vomiting (3% vs 0%), resulting in delayed discharge times (258 vs 193 minutes) and a higher total cost. The finding of significantly earlier discharge times after propofol anesthesia was unusual. Propofol-alfentanil-nitrous oxide anesthesia has been compared with sevofluranenitrous oxide anesthesia in 44 patients undergoing dilatation and evacuation of the uterus (3c). There was significantly less intraoperative uterine bleeding, as estimated by the gynecologist, with propofol. Above-average bleeding occurred in 5% of the patients with propofol anesthesia and 27% of patients with sevoflurane. This result was not surprising, given that sevoflurane reduces uterine tone while propofol has no effect. The effects of sevoflurane and halothane anesthesia, including the effect of midazolam 0.5 mg/kg premedication on recovery characteristics, have been studied in 100 children aged 6 months to 6 years undergoing myringotomy (4c). Children who received sevoflurane had about 50% faster recovery times and discharge home times than those who received halothane. However, sevoflurane without midazolam premedication was associated with 67% postoperative agitation compared with 40% in the premedicated group. Midazolam delayed early recovery times by about 5 minutes, but bad no effect on discharge times. In view of the very high incidence of postoperative agitation in the control group midazolam was seen as an effective premedicant. 127

128 Sevoflurane 8% plus nitrous oxide 66% has been compared with thiopental 4 mg/kg for induction of anesthesia in brief out-patient procedures (5c). Sevoflurane was safer, more efficacious, and better accepted by 78 unpremedicated adults with laryngeal cancer undergoing direct laryngoscopy for staging and biopsy. All patients received succinylcholine 50 mg on loss of the eyelash reflex and the surgeon then performed the laryngoscopy. Hemodynamic stability was greater and immediate recovery was faster after sevoflurane (9.7 vs 11.4 minutes). The incidence of dysrhythmias was also higher with thiopental (19 vs 12 patients). The dysrhythmias were predominantly ventricular extra beats with sevoflurane and ventricular bigemini with thiopental. The high incidence of dysrhythmias was partly due to the lack of opioid medication as part of the anesthetic.

GENERAL TOPICS Gastrointestinal A simplified risk score for predicting postoperative nausea and vomiting in adult patients undergoing general anesthesia has been developed in a study of 520 adults from Finland, and 2202 patients from Germany who had received anesthesia that included benzodiazepine premedication, thiopental, fentanyl or alfentanil, isoflurane, enflurane or sevoflurane, and non-steroidal or opioid drugs for postoperative analgesia (6c). No antiemetic prophylaxis was given. The final derived score consisted of four predictors: female sex, a history of motion sickness or postoperative nausea and vomiting, non-smoking, and the use of postoperative opioids. The incidence of postoperative nausea and vomiting was 10% when there were no risk factors, 21% (one risk factor), 39% (two risk factors), 61% (three risk factors), and 79% (four risk factors). Only one of the four risk factors related to the drugs used. Postoperative nausea and vomiting in children has been reviewed in detail, including multimodal strategies for management and prevention (7R).

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ANESTHETIC VAPORS (SED-14,318; SEDA-21, 116; SEDA-22, 125; SEDA-23, 126) Cardiovascular The frequency of cardiac dysrhythmias during halothane and sevoflurane inhalation have been compared in 150 children aged 3-15 years undergoing out-patient general anesthesia for dental extraction (8c). The patients were randomized into three groups and received either halothane or sevoflurane in 66% nitrous oxide whilst breathing spontaneously. One group received 0.75% increments of halothane every two to three breaths to a maximum of 3.0% for induction, and then 1.5% for maintenance of anesthesia. One group received sevoflurane in 2% increments to a maximum of 8% and then maintenance of 4%. The final group received 8% sevoflurane for induction and were then maintained on 4%. The children who received halothane had a 48% incidence of dysrhythmias, significantly higher than the 16% incidence in the 8% sevoflurane group and the 8% incidence in the incremental sevoflurane group. The halothane-associated dysrhythmias mainly occurred during dental extraction or emergence from anesthesia, and were usually ventricular. Six children in the halothane group had ventricular tachycardia. The longest run of ventricular tachycardia lasted 5.5 seconds, and one child had 13 separate episodes. Sevoflurane-associated dysrhythmias were mainly single supraventricular extra beats, and did not differ between the two administration methods. Although there was insufficient evidence to suggest that transient dysrhythmias associated with halothane in dental anesthesia can lead to cardiac arrest, sustained ectopic ventricular activity, including ventricular tachycardia, even if self-limiting, results in reduced cardiac output and cannot be ignored. These results imply that sevoflurane may be the preferable agent in this setting. The hemodynamic responses to induction and maintenance of anesthesia with halothane have been compared with those of sevoflurane in 68 unpremedicated children aged 1-3 years undergoing adenoidectomy (9c). The children received either sevoflurane 8% or haiothane 5% plus nitrous oxide 66% for induction of anesthesia and tracheal intubation, without neuromuscular blocking drugs. Anesthesia was maintained by adjusting the inspired concentration of the volatile anesthetic to maintain

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arterial blood pressure within 20% of baseline values, and the electrocardiogram was continuously recorded. The incidence of cardiac dysrhythmias was 23% with halothane and 6% with sevoflurane. Most of the dysrhythmias were short-lasting/self-limiting supraventricular extra beats or ventricular extra beats. Although the overall incidence of dysrhythmias was low in both groups, the result again shows that sevoflurane causes fewer dysrhythmias in children and may be the preferable agent. QT dispersion, defined as the difference between QT(max) and QT(min) in the 12-lead electrocardiogram, is a measure of regional variation in ventricular repolarization (10c). It is greater in patients with dysrhythmias. The effects of halothane and isoflurane on QT dispersion have been studied in 46 adult patients undergoing general anesthesia. QT dispersion was increased in both groups both with and without correction for heart rate. The increase was significantly greater with halothane than isoflurane. The clinical significance of this finding is not known. In isolation QT dispersion reflects an abnormality in ventricular repolarization and correlates with dysrhythmic events. Although there were no overt dysrhythmias in this study, the effect suggests a reason for the variable results of past studies of the QT interval: most studies showed an increase in QT interval, but some showed no change, or a decrease. Larger studies are needed to elaborate on the possible clinical importance of this phenomenon, but it may be a significant cause of dysrhythmias with volatile anesthetics. Nervous system The effects of sevoflurane and isoflurane anesthesia on interictal spike activity have been studied in 12 patients with refractory epilepsy (1 lC). The patients were undergoing insertion of subdural electrodes and were also given fentanyl during surgery. Electroencephalogram spike frequency increased significantly in all patients during 1.5 MAC sevoflurane anesthesia compared with awake recordings; hypocapnia did not change this increased spike activity. The eleetrocortigraphic interictal spike frequency was also significantly higher in all patients during 1.5 MAC sevoflurane anesthesia and in 8 of 10 patients during 1.5 MAC isoflurane anesthesia, compared with 0.3 MAC isotlurane anesthesia. In susceptible individuals, both sevoflurane and isoflurane can provoke interictal spike activity. This effect is

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only well described for enflurane, but it is a dose-dependent feature of most volatile agents. U r i n a r y t r a c t Volatile agents do not cause nephrotoxicity in adults with normal renal function (12c). However, using sensitive urinary markers, both sevoflurane and isoflurane caused mild transient glomerular and tubular functional impairment in 13 patients aged 70 years or over undergoing gastrectomy. The patients received epidural analgesia combined with inhalation anesthesia using 5 l/min fresh gas flow. The mean dose of sevoflurane was 5.1 MAChours and of isoflurane 3.7 MAC-hours. The mean urinary albumin excretion increased from 65 to 148 mg/g creatinine in the sevoflurane group and from 44 to 197 mg/g creatinine in the isoflurane group, and returned to preoperative values on the first postoperative day. The mean urinary o/1 and/~2 microglobulin concentrations also increased markedly in both groups, from 9.3 and 0.8 mg/g to 31.4 and 6.2 mg/g with sevoflurane and from 7.4 and 0.7 mg/g to 44.1 and 10.9 mg/g with isoflurane. These values had returned tonormal by day 7 postoperatively. The mean urinary N-acetyl-/%Dglucosaminidase concentration also increased significantly. These changes suggest transient renal tubular injury in both groups. There has not been any agreement on how these results should be interpreted, and larger studies are warranted. Mutagenieity Genetic damage was demonstrated in 10 non-smoking veterinary surgeons exposed to isoflurane and nitrous oxide compared with 10 non-smoking, non-exposed veterinary physicians acting as controls (13c). The surgeons were monitored for 1 week in a working environment comparable to that of pediatric anesthesia, with the use of uncuffed endotracheal tubes and open circuit breathing systems during operations on small animals. The overall calculated 8-hour time-weighted average exposure of cases was 5.3 ppm for isoflurane and 12.8 ppm for nitrous oxide. The European exposure limits are 10 ppm and 100 ppm respectively, and the corresponding values recommended by USA-NIOSH are 2 ppm and 25 ppm respectively. These values therefore violated the USA-NIOSH limit for isoflurane. The mean frequency of sister chromatid exchanges in peripheral blood lymphocytes was significantly higher in exposed workers than

130 controls (10.2 vs 7.4) and the proportion of micronuclei was also significantly higher in exposed workers (8.7 vs 6.8 per 500 binucleated cells). These measures reflect the mutagenicity of isoflurane and nitrous oxide. The findings are comparable to smoking 11-20 cigarettes a day. However, this study did not distinguish between the potential genotoxic effects of isoflurane and nitrous oxide; nor did it show a dose-dependency of genotoxicity, owing to the small sample size. Further studies are needed.

Desflurane Liver A case of severe hepatotoxicity following desflurane anesthesia has been reported (14A). An obese 37-year-old woman with a past history of allergy to penicillin, nickel, and cobalt, and unexplained mild hepatitis 6 weeks after halothane anesthesia 9 years before, was given an anesthetic including etomidate, alcuronium, metamizole, piritramizide, fentanyl, nitrous oxide, and desflurane. Ten days later she developed the symptoms and signs of hepatitis, an eosinophilia, and raised hepatic enzymes, including AIT 1776 iu/1, AsT 1258 iu/1, yGT 48 iu/1, and bilirubin 503 Ixmol/l.After exclusion of common causes of hepatitis, a liver biopsy confirmed acute hepatitis. There were increased titers of antitrifluroacetylated IgG antibodies, which peaked at 0.159 on day 25 postoperatively. She eventually recovered. This patient had multiple risk factors for anesthesia-induced hepatitis, including obesity, middle age, female sex, a history of drug allergies, and multiple exposures to fluorinated anesthetic agents. Desflurane has a very low rate of hepatic oxidative metabolism (0.02% vs 20% for halothane), and is considered to be one of the safest volatile agents as far as hepatotoxicity is concerned. Nevertheless, this case shows that it can cause severe hepatotoxicity.

Halothane Liver A retrospective review of the casenotes of 44 patients with drug-induced hepatotoxicity diagnosed in 1978-96 found only one case attributable to halothane (15c). Antibiotics, non-steroidal anti-inflammatory drugs, and psychotropic drugs accounted for 73% of the cases.

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Isoflurane Liver The reactive acyl-halide metabolite of tfifluoroacetic acid can trifluoroacetylate liver proteins, resulting in immune-mediated hepatic necrosis (16c). The role of CYP2E1 as the predominant route of metabolism of isoflurane to trifluoroacetic acid and inorganic fluoride ions has been confirmed using the enzyme inhibitor disulfiram as a metabolic probe in 22 adults randomized to either disulfiram 500 mg the evening before surgery or placebo, Anesthesia with 1.5% isoflurane lasted for an average of 8 hours. Postoperative plasma concentrations were increased and urinary excretion of trifluoroacetic acid was inhibited by 80-90% in the disulfiram group. Whether the use of disulfiram would reduce the incidence of hepatitis is unknown.

Sevoflurane Nervous system A case of acute dystonia has been reported during induction of anesthesia with sevoflurane (17A). A 19-year-old schizophrenic, who was taking cyamemazine 75 mg/day, a phenothiazine, and dihydroergotamine 180 mg/day to avoid neurolepticinduced hypotension, had no history of involuntary movements, and neurological examination was normal preoperatively. Anesthesia was induced with midazolam 5 mg oral premedication and an inhalational induction using 4-5 maximum breaths of sevoflurane 8% and nitrous oxide 50% in oxygen. One minute after loss of consciousness, he developed a torticollic posture and stiffness, rapidly extending to the left trapezius and scalene muscles. There was severe rotation of the head accompanied by trismus and opisthotonos. An intravenous injection of the muscle relaxant atracurium 30 mg resolved the muscle spasms. Subsequent anesthesia was uneventful. Cases of dystonia after inhalational anesthetics are rare. They are presumably due to an alteration in the dynamic relation between dopaminergic and other receptors in the brain. Compound A is a product of sevoflurane metabolism by carbon dioxide absorbers that can produce convulsions and neural damage in rats (18E). Peripheral neuropathy has been reported in two healthy men anesthetized with 1.25 MAC sevoflurane at 2 1/min fresh gas flow for 8 hours. Their average concentrations of compound A were 45 and 28 ppm. Both had had previous minor injuries in the regions

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in which the neuropathies were reported. The authors suggested that compound A, or other factors associated with sevoflurane anesthesia, may predispose patients to peripheral neuropathy. Both men were volunteers for earlier published studies comparing the ability of sevoflurane and desflurane to cause nephrotoxicity that were sponsored by Baxter PPD, New Jersey, the manufacturer of desflurane, a rival inhalational anesthetic agent; these reports need to be regarded with caution. Two cases of epileptiform activity during sevoflurane anesthesia have been reported in healthy volunteers (19A). They were taking part in a study of the effects of sevoflurane on regional cerebral blood flow and received twice the minimum alveolar concentration (MAC) of sevoflurane (4.4%). The only other drug administered was rocuronium, a muscle relaxant. Sevoflurane was used at up to twice its MAC, to induce burst suppression of the electroencephalogram. One of the subjects had partial motor seizure activity in the form of slight clonic movements in the right and then later in the left leg. There was an associated increase in heart rate (from 65 to 79 beats/min) and systolic blood pressure (from 85 to 106 mmHg) and rhythmic epileptiform discharges on the electroencephalogram. The second subject had epileptiform activity on his electroencephalogram, consisting of partial and secondarily generalized discharges lasting for 2 and 3 minutes respectively. There were no clinical signs of an epileptic seizure. Burst suppression appeared on the electroencephalogram in both subjects before the seizure activity, and the Bispectral Index increased dramatically during the epileptiform discharge to maximum values of 44 and 73 respectively. As expected, regional cerebral blood flow and regional metabolism of the epileptic focus fell interictally and increased ictally. Although the concentrations of sevoflurane used in this study were high compared with usual anesthetic practice, further human studies are warranted, because prolonged epileptiform discharge is known to be harmful.

Psychiatric Delirium during emergence from sevoflurane anesthesia has frequently been documented. Four patients, an adult and three children aged 3-8 years, who were able to recount the experience have been reported (20A). They had full recall of postoperative events, were terrified, agitated, and distressed, and hence

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presented with acute organic mental state dysfunction which was short-lived. Two were disoriented and had paranoid ideation. They were not in any pain or were not distressed by pain if it was present. The authors hypothesized that misperception of environmental stimuli associated with sevoflurane's particular mode of action may have been the underlying cause of this phenomenon. Anxiolytic premedication and effective analgesia did not necessarily prevent the problem. Urinary tract Sevoflurane is metabolized to compound A by carbon dioxide absorbers. It is nephrotoxic in rats, but nephrotoxicity in humans has not been proven. The accumulation of compound A is greatest with low fresh gas flows and barium hydroxide absorbers, both of which cause higher temperatures in the absorber. Hepatic metabolism of fluoridecontaining volatile anesthetics also results in the production of fluoride ion, which is potentially nephrotoxic. Renal function has been assessed after low fresh gas flow anesthesia (1 1/min or less) with either sevoflurane or isoflurane in a multicenter study of 254 patients (21 c). The mean duration of anesthesia was 3.0 MAC-hours in both groups. Peak serum fluoride concentrations were significantly higher (40 I~mol/1) after sevoflurane compared with isoflurane (3 l~mol/1), and 26 patients had peak fluoride concentrations over 50 Ixmol/1, a concentration that is associated with renal dysfunction after methoxyflurane anesthesia. There were no significant differences in the renal function of the two groups, as measured by serum creatinine, urea, glycosuria, proteinuria, urine pH, or specific gravity. Absence of renal dysfunction, despite high serum fluoride concentrations after sevoflurane anesthesia, was consistent with previous reports. It appears that low fresh gas flow anesthesia with sevoflurane is not associated with clinically significant renal damage. Current anesthetic practice is to use sodium hydroxide for carbon dioxide absorption, because it produces less compound A than barium hydroxide. The effects of sevoflurane, isoflurane, and desflurane on macroscopic renal structure have been studied in 24 patients undergoing nephrectomy (22c). All anesthetics were administered using a fresh gas flow of 1 l/min and a sodium hydroxide absorber and had an average duration of 3 hours. No injury to nephrons

132 was observed by pathologists blinded to which anesthetic agent had been used. Postoperative creatinine concentrations and urine volumes did not differ significantly between the groups. Aquaporin-2 is a protein involved in regulation of water permeability in the kidneys. The effects of sevofurane- and propofol-based anesthesia on urine concentrating ability and aquaporin-2 concentrations have been compared in 30 patients undergoing major surgical procedures given sevofurane/nitrous oxide or propofol/nitrous oxide (23c). Sevoflurane caused a transient 25% fall in aquaporin-2 concentrations 90 minutes after surgery, rather than the usual 40% increase, which occurred in the propofol group. By 3 hours after surgery the aquaporin concentrations in the sevoflurane group had increased and were similar to those in the propofol group. There was a 40% fall in urine osmolarity in the sevoflurane group, but recovery occurred by 3 hours postoperatively. This effect is the likely cause of the occasional cases of polyuria reported in association with sevoflurane anesthesia, rather than nephrotoxicity caused by fuoride ion or compound A. Musculoskeletal There have been reports of rhabdomyolysis after anesthesia with halothane, enflurane, and isoflurane in patients with muscular dystrophy, in which succinylcholine was not used. A case of rhabdomyolysis has now been reported after sevoflurane anesthesia (24A).

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T.G. Short and E. Hedayati

most likely cause of rhabdomyolysis in this patient was thought to be inhalation of sevoflurane. Drug interactions The minimum alveolar concentrations of sevoflurane required to suppress movement and adrcnergic responses to surgery in the presence of the potent opioid fentanyl have been quantified in 226 adults (25c). Fentanyl 3 ng/ml and 6 ng/ml reduced sevoflurane requirements to suppress movement to pain by 61% and 74% respectively and requirements to suppress the adrenergic responses to pain by 83% and 91% respectively. There was no further reduction in sevoflurane requirements at concentrations of fentanyl above 6 ng/ml. The degree of interaction was similar to previous studies of other volatile anesthetic/opioid combinations. In 45 adult patients undergoing elective surgery the ~2-adrenoceptor agonist dexmedetomidine in a concentration of 0.7 ng/ml reduced the minimum alveolar concentration of sevoflurane required to suppress movement to skin incision by 17%, but a plasma concentration of 0.39 ng/ml had no effect (26c). The larger reductions in isoflurane requirements found in earlier studies of dexmedetomidine were probably due to the use of potent opioids and intravenous induction as part of the anesthetic.

Trichloroethylene The carcinogenicity of trichloroethylene has been reviewed (27R).

An l 1-year-old boy with Duchenne's muscular dystrophy underwent strabismus repair. He also had asthma, for which he was taking prednisone 25 mg/day and theophylline. He underwent inhalational induction with sevoflurane 4% and nitrous oxide 64%; tracheal intubation was then performed without the use of a muscle relaxant. Anesthesia was maintained using sevoflurane 1.5-3.0% and nitrous oxide 64%. He also received hydrocortisone 100 mg and diclofenac 25 mg. The operation lasted 51 minutes and anesthesia was uneventful. He suffered heel pain during the first few hours postoperatively, and 3 hours postoperatively passed 300 ml of dark red urine, containing large amounts of myoglobin. His serum enzymes increased from preoperative values, serum AsT from 76 to 458 iu/1, A1T from 136 to 254 iu/1, and creatine kinase from 4430 to 55 700 iu/1. He was treated with dantrolene 1 mg/kg and recovered over the next day. The history and finding in this case are strongly diagnostic of rhabdomyolysis. The

GASES (SED-14, 325; SEDA-21, 121; SEDA-22, 128; SEDA-23, 129)

Nitrous oxide Nervous system Nitrous oxide inactivates the enzyme methionine synthetase, and caution is urged in giving nitrous oxide to patients who may be deficient in vitamin B12. Low serum vitamin B12 concentrations have previously been reported in patients with sickle cell disease, but the reason for this is uncertain. Three cases of peripheral neuropathy have been reported in patients with sickle cell disease who received nitrous oxide (28A-30A). All three had a history of frequent painful sickle crises, for which

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they received nitrous oxide for prolonged periods. Serum vitamin B12 concentrations were slightly reduced in two patients and very low in the third. The patients all presented with difficulty walking and paresthesia. Peripheral sensorimotor neuropathy was confirmed by nerve conduction studies. The patients all responded well to vitamin B12 injections and avoiding further exposure to nitrous oxide. Caution is therefore recommended when using nitrous oxide in patients with sickle cell disease or who are suspected of vitamin B12 deficiency. Two cases of polyneuropathy have also been reported after the use of nitrous oxide for 80 minutes and 3 hours in patients who were subsequently found to have pernicious anemia. They both responded well to hydroxocobalamin.

133

This complication is more common after accidental arterial injection of thiopental. The case illustrates that immediate diagnosis and treatment are required to reduce the damage of intra-arterial injection of drugs such as diazepam.

Nervous system A fugue-like state with retrograde amnesia has been associated with diazepam (32A).

Benzodiazepines

A 23-year-old military officer on active duty took diazepam 5 mg tds and ibuprofen for back spasms. Three days later he was found sitting in a church, and had assumed a previous role from his past life. He identified the date as 14 months previously, and his memory before that time was intact. However, he had no memory of events during the previous 14 months. There were no symptoms suggesting a schizophrenic disorder, and mental function was normal. His symptoms resolved within 24 hours of withdrawal of diazepam, except for amnesia of the event. He assumed his correct identity and was aware of the correct date. He had taken ibuprofen in the past with no adverse effects, and this was his first exposure to a benzodiazepine. No other medications were involved, and a full medical review found no cause for his symptoms other than diazepam use.

Diazepam

Retrograde amnesia with dissociative fugue has not been reported before in association with diazepam.

Drug interactions

For the interaction of nitrous oxide with midazolam see below.

INTRAVENOUS AGENTS (SED-14, 327; SEDA-21, 122; SEDA-22, 129; SEDA-23, 131) (See also Chapter 5)

C a r d i o v a s c u l a r Gangrene of the fingers caused by accidental intra-arterial injection of diazepam has been reported (31A). A 51-year-old woman was accidentally given an intra-arterial injection of diazepam 10 mg to control an acute attack of claustrophobic anxiety. This was associated with a severe knocking pain in the left arm during the injection. On the second day she complained of feeling cold and having paresthesia in the left hand and lower arm, and the area looked red and swollen. On the fifth day, the radial aspect of the palm and her first to third digits became discolored, and thereafter necrotic areas developed in the distal phalanx of the thumb and the proximal phalanx of her index finger. Angiographic examination on the tenth day after the injection confirmed occlusions of the superficial palmar arterial arch and occlusions of the digital arteries of the five fingers. Management included an infusion of heparin 25 000 iu over 24 hours, without success. Eventually on the 24 th day after injection her index finger required amputation, and the distal phalanx of her thumb required debridement and flap-plasty. She made a satisfactory recovery.

I m m u n o l o g i c Hypersensitivity reactions after diazepam are very rare and usually mild. A case of severe vasculitis has been reported (33A). A 50-year-old woman with chronic depression or dysthymic disorder and alcohol dependence was given thioridazine 100 mg/day orally and diazepam 10 mg qds. She had no history of drug allergy. Two days later she noticed an erythematous eruption on her ankles. Thioridazine was withdrawn, but the eruption became more widespread over a few hours. She was given methylprednisolone 80 mg/day, but the following day the eruption progressively became bullous and her condition worsened. She developed a fever of 39.4 ~ C, felt ill, and had a neutrophilia, but blood cultures were sterile and her renal function was normal. A skin biopsy showed bullous vasculitis with numerous eosinophils in the dermis. Diazepam was then withdrawn, which led to resolution of pyrexia and gradual healing of the skin lesions over the next 2 months. The lymphocyte blast transformation test was positive for diazepam.

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T.G. Short and E. Hedayati

This is the first report of severe vasculitis associated with diazepam,

was postulated to be via cold nasopharyngeal stimulation.

Midazolam

Drug interactions Midazolam is selectively metabolized by CYP3A4, with which several drugs interact, influencing its pharmacokinetics and pharmacodynamics. Drugs that do this include the protease inhibitor saquinavir, propofol, and fluconazole (38c-40c), which increase the systemic availability and peak plasma concentrations and prolong the half-life of midazolam, therefore increasing its sedative effects. The dosage of midazolam should be reduced in patients taking these drugs. Glucocorticoids are potent inducers of CYP3A4, and chronic administration of glucocorticoids reduces the sedative effect of midazolam by increasing its clearance; higher doses are therefore required for sedation (41c). The combination of midazolam with nitrous oxide produced retrograde amnesia in 21 women undergoing elective cesarean section (42c). All had spinal anesthesia. After delivery the patients received intravenous midazolam, average dose 94 lxg/kg and inhaled nitrous oxide 50%. At the end of surgery flumazenil was given in 0.1 mg increments until the patient awoke. Another nine women were given only nitrous oxide inhalation after delivery. Of the women who received midazolam and nitrous oxide 33% could not recall their baby's face, while all of the women not given midazolam could. The results suggest that midazolam plus nitrous oxide can produce retrograde amnesia not reversed by flumazenil. The study is interesting in that retrograde amnesia is not a known property of benzodiazepines.

Midazolam was used in a wide range of doses (0.034).6 mg/kg) in 91 children undergoing diagnostic or minor operative procedures with intravenous midazolam sedation (34c). Opioids were co-administered in 84% and oxygen desaturation occurred in 32%, most of whom had received high doses of opioids in addition to the midazolam. Other adverse events included airway obstruction (n = 3) and vomiting (n = 1). The presence of independent appropriate trained personnel not directly involved in performing the procedure, appropriate resuscitation equipment, and monitoring were recommended whenever midazolam and opioids are co-administered for intravenous sedation. Nervous system Involuntary epileptiform movements have been described in three of six premature infants given midazolam for sedation (35c). The infants had been born at 24-26 weeks gestation, were aged 23-32 days, and weighed on average 671 g. They were given midazolam 100 Ixg/kg by slow bolus injection for sedation and then had accentuated myoclonic jerks resembling clonic seizures within 5 minutes. In all cases it was the first dose of midazolam and the cardiorespiratory parameters remained normal. The abnormal movements resolved within 5-10 minutes. There has also been a report of convulsions caused by midazolam in two preterm infants (36A). They were of 26 and 28 week gestation and were given midazolam 100 and 150 Ixg/kg intravenously before tracheal intubation. Both were successfully treated with flumazenil 10 Ixg/kg. The safety of midazolam in very low birth weight neonates is being questioned. In 200 children weighing 3-15 kg premedicated with rectal midazolam 0.5 or 1.0 mg/kg before minor surgery, the incidence of hiccups was 22% and 26% respectively (37c). The mean age of children with hiccups was 6 months and of children without hiccups 20 months. Intranasal ethyl chloride spray was 100% successful in treating the hiccups. The incidence of hiccups was related to age but not dose. The effectiveness of ethyl chloride

Ketamine (SED-14, 329; SEDA-21, 124; SEDA-22, 130; SEDA-23, 130)

Nervous system Oral ketamine is an effective analgesic in patients with chronic pain. In 21 patients with central and peripheral chronic neuropathic pain treated with oral ketamine the starting dose was ketamine 100 mg/day, titrated upwards by 40 mg/day increments every 2 days until a satisfactory effect was achieved, or until adverse effects became limiting (43c). Nine patients discontinued ketamine because of intolerable adverse effects, including psychotomimetic symptoms, such as "elevator" effect or dissociative feelings, somnolence or insomnia,

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and sensory changes such as taste disturbance and somatic sensations. In a similar study of 21 out-patients with refractory neuropathic pain treated with oral ketamine, 17 reported adverse events (44c). The most common were light-headedness, dizzi-

ness, tiredness, headache, a nervous floating feeling, and bad dreams. The adverse effects were sufficient important to prevent 10 patients from continuing with the trial. A case of neurotoxicity due to focal lymphocytic vasculitis has been reported close to the catheter injection site in a patient who received intrathecal ketamine infusion for chronic cancer pain (45c). A 72-year-old woman with abdominal pain due to peritoneal malignant mesothelioma was given patient-controlled analgesia with morphine and then a thoracic epidural infusion of bupivacaine 0.125% and morphine 0.04 mg/ml at a rate of 6-12 ml/hour, with minor success. A thoracic intrathecal catheter was inserted for infusion of bupivacaine 0.25% plus morphine 0.12 mg/ml at a rate of up to 3.5 ml/hour. The morphine concentration was increased to 0.3 mg/ml and then clonidine 3 Ixg/ml was added. Satisfactory pain relief was finally achieved by adding ketamine 1 mg/ml, containing benzethonium chloride preservative. The mean daily intrathecal dose of ketamine was 67 mg. After 7 days she had an acute psychotic reaction and the ketamine was withdrawn. There were no neurological deficits. She died 10 days later. There was focal lymphocytic vasculitis in the spinal medullary tissue, in the nerves, and in the leptomeninges of the thoracolumbar spinal cord. This neurotoxicity could have been due to the preservative benzethonium chloride or to the ketamine. However, several other agents, including bupivacaine, morphine, and clonidine, were also given intrathecally, so causality was not proven, even though the other agents have not been associated with this problem.

Drug

interactions The interaction of ketamine with the respiratory depressant effect of alfentanil has been studied in 8 healthy men, who received alfentanil as a continuous computer-controlled infusion aiming at a plasma concentration of 50 ng/ml and either an infusion of racemic ketamine increasing stepwise through 50, 100, and 200 ng/ml or placebo (46c). Alfentanil caused hypoventilation by reducing respiratory rate, and this was antagonized by ketamine in a concentration-dependent manner. This combination may be effective in

135

overcoming the adverse effects of either agent individually. The interaction of the dopamine antagonist haloperidol 5 mg orally with subanesthetic doses of ketamine has been studied in a placebo-controlled study in 20 healthy volunteers over 4 days (47'~). Haloperidol pretreatment reduced impairment of executive cognitive functions produced by ketamine and reduced the anxiogenic effects of ketamine. However, it failed to block the ability of ketamine to produce psychosis, perceptual changes, negative symptoms, or euphoria, and it increased the sedative and prolactin responses to ketamine. These results imply that ketamine may impair executive cognitive functions via dopamine receptor activation in the frontal cortex, but that the psychoactive effects of ketamine are not mediated via dopamine receptors, but rather via NMDA receptor antagonism.

Propofol

(SED-14, 330; SEDA-21, 125; SEDA-22, 130; SEDA-23, 132)

Propofol is currently formulated as a 1% solution in Intralipid 10% (48c). This formulation has been associated with hyperlipidemia, especially raised triglycerides, when given by prolonged infusion to the critically ill, particularly children or patients with liver disease. A new formulation of propofol 6% in lipofundin (medium- and long-chain triglycerides 10%) has been developed to reduce the risk of hyperlipidemia. In 24 patients who received an induction dose of propofol 2.5 mg/kg over 60 seconds of either the new formulation in 6% or 1% solution and of the original 1% formulation, the pharmacokinetics, induction time, dosage requirements, and safety profile of the three agents were similar. Pain on injection was reported by 17% of the patients, and did not vary between formulations. The 6% solution may be safer for long-term infusion, when reducing the fat load is important. Cardiovascular Propofol causes bradydysrhythmias by reducing sympathetic nervous system activity. A 4-year-old patient developed a nodal bradycardia while on propofol 6 mg/kg/hour and remifentanil 0.25 ixg/kg/min (49A). It responded to atropine 0.3 mg. Complete atrioventricular heart block occurred in a 9-year-old boy with Ondine's curse who re-

136 ceived a single bolus injection of propofol (50A). The authors questioned the safe use of propofol in congenital central hypoventilation syndrome, which is a generalized disorder of autonomic function. The hemodynamic effects of combining ephedrine with propofol in an effort to prevent hypotension and bradycardia have been investigated in 40 elderly patients of ASA grades III and IV, who received ephedrine 15, 20, or 25 mg added to propofol 200 mg (51c). The hypotensive response to propofol was effectively prevented, but marked tachycardia in the majority of patients meant that the technique may not be beneficial, given the high incidence of ischemic heart disease in this age group. Similarly the effects of giving calcium chloride 10 mg/kg after anesthesia induction with propofol, fentanyl, and pancuronium have been investigated in 58 patients undergoing elective coronary artery bypass grafting (52c). Calcium chloride reduced the fall in arterial blood pressure, and prevented the reduction in heart rate, stroke volume index, cardiac index, and cardiac output, compared with placebo. Propofol reduces the availability of calcium to the myocardial cells, and calcium chloride effectively minimizes the hemodynamic effects of propofol. However, given that intravenous calcium can be locally toxic when given via peripheral veins, the technique may have limited applicability. Propofol can cause severe pain on injection, especially when injected into a small vein. A case of severe pain on injection of propofol has been reported in a 36-year-old man with severe Raynaud's phenomenon, including a history of skin ulceration (53A). He received a 2% propofol-lidocaine mixture into a vein on the dorsum of his hand. The author suggested that selecting a larger antecubital vein might be a wiser choice in these patients. There have been several studies of ways of reducing this undesirable adverse effect of propofol. The effectiveness of lidocaine has been confirmed, and a 0.1% strength was optimal (54c). Ondansetron, tramadol, and metoclo,_pramide were less effective than lidocaine (55~--57c). Wanning propofol to 37~ had no effect on the incidence of pain (58c). The kallikrein inhibitor nafamostat mesilate was as effective as lidocaine. Use of the lipid solvent that propofol is dissolved in confirmed that the

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T.G. Short and E. Hedayati

solvent is responsible for this adverse effect (59c). Nervous system Convulsions have been reported in two patients with no history of epilepsy after induction of anesthesia with propofol (60A). However, in a cross-over comparison in 20 epileptic patients undergoing cortical resection, the effects on the electrocorticogram of either propofol or thiopental during isofluranenitrous oxide anesthesia, propofol caused no greater proconvulsive effect, than thiopental, which is used to treat status epilepticus (62c). In spite of occasional reports, a true epileptogenic effect of propofol remains to be proven. Psychiatric The association of propofol with a range of excitatory events is well recognized. Behavioral disturbances with repeated propofol sedation have been reported in a 30-monthold child (61A). Propofol was well tolerated initially, but the patient then became increasingly irritable, aggressive, and uncooperative during awakening from subsequent sedations, including screaming, kicking, hitting, and biting. The next two sedations were performed using methohexital and were not followed by any behavioral disturbances. Pancreas A case of recurrent propofolinduced pancreatitis has been reported (63A). A 51-year-old woman with a past medical history of seizure disorder, schizophrenia, and asthma, who had been admitted with pneumonia was sedated using a propofol infusion to assist mechanical ventilation. Over 7 days she received a total of 26.5 g of propofol at a maximum dose rate of 0.2 mg/kg/min. On diagnosis of pancreatitis, which was associated with hypertriglyceridemia, the propofol infusion was stopped. In addition to raised amylase concentrations, serum triglyceride concentrations peaked at 17 mmol/l and lipase activity at 564 u/l. She recovered over the next 7 days. On day 17 she underwent tracheostomy revision, during which she received propofol 200 mg. The subsequent postoperative period was complicated by another episode of pancreatitis, this time without associated hypertriglyceridemia. She recovered over the next several days. An ultrasound examination ruled out gallstone pancreatitis, despite the presence of cholelithiasis. The association between propofol and pancreatitis has been listed as "probable" in 25 reports of pancreatitis associated with propo-

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Chapter 10

fol to the FDA registry. However, the features of this case, which included resolution of pancreatitis on drug withdrawal and recurrence on rechallenge, suggest that the association should be upgraded to "definite causal". ltelnatologie Fat emulsions affect coagulation and fibrinolysis (64c). In a study of 36 patients undergoing aortocoronary bypass operations with midazolam/fentanyl or propofol/alfentanil based anesthesia, factor XIla con-

137

centrations and kallikrein-like activity were about 30% higher in the propofol group. The authors suggested that there had been stronger activation of the contact phase at the start of recirculation and stronger fibrinolysis in the propofol group. They also found more hypotension in the propofol group, which they assumed to be due to release of kallikrein, resulting in release of bradykinin. Propofol has not been proven to cause increased perioperative bleeding.

REFERENCES 1. Philip BK, Lombard LL, Roaf ER, Drager LR, Calalang I, Philip JH. Comparison of vital capacity induction with sevoflurane to intravenous induction with propofol for adult ambulatory anesthesia. Anesth Analg 1999; 89: 623-7. 2. Smith I, Thwaites AJ. Target-controlled propofol versus sevoflurane: a double-blind, randomised comparison in day-case anaesthesia. Anaesthesia 1999; 54: 745-52. 3. Nelskyla K, Korttila K, Yli-Hankala A. Comparison of sevoflurane-nitrous oxide and propofolalfentanil-nitrous oxide anaesthesia for minor gynaecological surgery. Br J Anaesth 1999; 83: 576-9. 4. Lapin SL, Auden SM, Goldsmith LJ, Reynolds A-M. Effects of sevoflurane anaesthesia on recovery in children: a comparison with halothane. Paediatr Anaesth 1999; 9: 299-304. 5. Nishiyama T, Nakayama H, Hanaoka K. Sevoflurane or thiopental-isoflurane for induction and laryngeal mask insertion? Comparison by side effects, hemodynamics, and spectral analysis of heart rate variability. Anesth Resusc 1999; 35: 99-103. 6. Apfel CC, Laara E, Koivuranta M, Greim C-A, Roewer N. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology 1999; 91: 693-700. 7. Rose JB, Watcha ME Postoperative nausea and vomiting in paediatric patients. Br J Anaesth 1999; 83: 104-17. 8. Blayney MR, Malins AF, Cooper GM. Cardiac arrhythmias in children during outpatient general anaesthesia for dentistry: a prospective randomised trial. Lancet 1999; 354: 186445. 9. Viitanen H, Baer G, Koivu H, Annila P. The hemodynamic and Holter-electrocardiogram changes during halothane and sevoflurane anesthesia for adenoidectomy in children aged one to three years. Anesth Analg 1999; 89: 1423-5. 10. Guler N, Bilge M, Eryonucu B, Kati I, Demirel CB. The effects of halothane and sevoflurane on QT dispersion. Acta Cardiol 1999; 54:311-15.

11. Watts ADJ, Herrick IA, McLachlan RS, Craen RA, Gelb AW The effect of sevoflurane and isoflurane anesthesia on interictal spike activity among patients with refractory epilepsy. Anesth Analg 1999; 89: 1275-81. 12. Hase K, Meguro K, Nakamura T. Assessment of renal effects of sevoflurane in elderly patients using urinary markers. Anesth Analg 1999; 88: 1426-7. 13. Hoerauf K, Lierz M, Wiesner G, Schroegendorfer K, Lierz P, Spacek A, Brunnberg L, Nusse M. Genetic damage in operating room personnel exposed to isoflurane and nitrous oxide. Occup Environ Med 1999; 56: 433-7. 14. Berghaus TM, Baron A, Geier A, Lamerz R, Paumgartner G, Conzen R Hepatutoxicity following desflurane anesthesia. Hepatology 1999; 29: 613-14. 15. Aithal PG, Day CR The natural history of histologically proved drug induced liver disease. Gut 1999; 44: 731-5. 16. Kharasch ED, Hankins DC, Cox K. Clinical isoflurane metabolism by cytochrome P450 2El. Anesthesiology 1999; 90: 766-71. 17. Bernard J-M, Le Roux D, Pereon Y. Acute dystonia during sevoflurane induction. Anesthesiology 1999; 90: 1215-16. 18. Goldberg ME, Larijani GE, Eger II EI. Peripheral neuropathy in healthy men volunteers anesthetized with 1.25 MAC sevoflurane for 8 hours. Pharmacotherapy 1999; 19: 1173~i. 19. Kaisti KK, Jaaskelainen SK, Rinne JO, Metsahonkala L, Scheinin H. Epileptiform discharges during 2 MAC sevoflurane anesthesia in two healthy volunteers. Anesthesiology 1999; 91: 1952-5. 20. Wells LT, Rasch DK. Emergence "delirium" after sevoflurane anesthesia: a paranoid delusion? Anesth Analg 1999; 88: 1308-10. 21. Groudine SB, Fragen RJ, Kharasch ED, Eisenman TS, Frink EJ, McConnell S, Ebert TJ, Muzi M, Hannon V, Jellish WS, Johnson JO, Jones RM, Sebel PS, Vinik HR, Boyd G. Comparison of renal

13 8 function following anesthesia with low-flow sevoflurane and isoflurane. J Clin Anesth 1999; 11: 201-7. 22. Pertek J-P, Le Chaffotec L, Cormier L, Champigneulle J, Omar-Amrani M, Meistelman C. Effects of sevoflurane and isoflurane or desflurane on kidney structure and function in patients undergoing nephrectomy. Cah Anesthesiol 1999; 47: 365-70. 23. Morita K, Otsuka F, Ogura T, Takeuchi M, Mizobuchi S, Yamauchi T, Viakino H, Hirakawa M. Sevoflurane anaesthesia causes a transient decrease in aquaporin-2 and impairment of urine concentration. Br J Anaesth 1999; 83: 734-9. 24. Obata R, Yasumi Y, Suzuki A, Nakajima Y, Sato S. Rhabdomyolysis in association with Duchenne's muscular dystrophy. Can J Anaesth 1999; 46: 5646. 25. Katoh T, Kobayashi S, Suzuki A, Iwamoto T, Bito H, Ikeda K. The effect of fentanyl on sevoflurane requirements for somatic and sympathetic responses to surgical incision. Anesthesiology 1999; 90: 398-405. 26. Fragen R J, Fitzgerald PC. Effects of dexmedetomidine on the minimum alveolar concentration (MAC) of sevoflurane in adults age 55 to 70 years. J Clin Anesth 1999; 11: 466-70. 27. Motohashi N, Nagashima H, Molnar J. Trichloroethylene I. Carcinogenicity of trichloroethylene. In Vivo 1999; 13: 211-14. 28. Ogundipe O, Walker M, Pearson TC, Slater NGP, Adepegba T, Westerdale N. Sickle cell disease and nitrous oxide-induced neuropathy. Clin Lab Haematol 1999; 21: 409-12. 29. Sesso RMC, Iunes Y, Melo ACE Myeloneuropathy following nitrous oxide anesthesia in a patient with macrocytic anaemia. Neuroradiology 1999; 41: 588-90. 30. Alarcia R, Ara JR, Serrano M, Garcia M, Latorre AM, Capablo JL. Severe polyneuropathy after using nitrous oxide as an anaesthetic. Is this pathology preventable? Rev Neurol 1999; 29: 36-8. 31. Joist A, Tibesku CO, Neuber M, Frerichmann U, Joosten U. Gangrene of the fingers caused by accidental intra-arterial injection of diazepam. Dtsch Med Wochenschr 1999; 124: 755-8. 32. Simmer ED, Simmer ED. A fugue-like state associated with diazepam use. Mil Med 1999; 164: 442-3. 33. Olcina GM, Simonart T. Severe vasculitis after therapy with diazepam. Am J Psychiatry 1999; 156: 972-3. 34. Karl HW, Cote CJ, McCubbin MM, Kelley M, Liebelt E, Kaufman S, Burkhart K, Albers G, Wasserman G. Intravenous midazolam for sedation of children undergoing procedures: an analysis of age- and procedure-related factors. Pediatr Emerg Care 1999; 15: 167-72. 35. Waisman D, Weintraub Z, Rotschild A, Bental Y. Myoclonic movements in very low birth weight premature infants associated with midazolam intra-

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T.G. Short and E. Hedayati

venous bolus administration. Pediatrics 1999; 104: 579. 36. Birrell VL, Wyllie JP, Pagan J. Midazolam causing convulsions. Br J Intensive Care 1999; 9: 197. 37. Marhofer P, Glaser C, Krenn CG, Grabner CM, Semsroth M. Incidence and therapy of midazolam induced hiccups in paediatric anaesthesia. Paediatr Anaesth 1999; 9: 295-8. 38. Hamaoka N, Oda Y, Hase I, Mizutani K, Nakamoto T, Ishizaki T, Asada A. Propofol decreases the clearance of midazolam by inhibiting CYP3A4: an in vivo and in vitro study. Clin Pharmacol Ther 1999; 66: 110-17. 39. Palkama VJ, Ahonen J, Neuvonen PJ, Olkkola KT. Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. Clin Pharmacol Ther 1999; 66: 33-9. 40. Ahonen J, Olkkola KT, Takala A, Neuvonen PJ. Interaction between fluconazole and midazolam in intensive care patients. Acta Anaesthesiol Scand 1999; 43: 509-14. 41. Nakajima M, Suzuki T, Sasaki T, Yokoi T, Hosoyamada A, Yamamoto T, Kuroiwa Y. Effects of chronic administration of glucocorticoid on midazolam pharmacokinetics in humans. Ther Drug Monit 1999; 21: 507-13. 42. Takano M, Takano Y, Sato I. The effect of midazolam on the memory during cesarean section and the modulation by flumazenil. Jpn J Anesthesiol 1999; 48: 73-5. 43. Enarson MC, Hays H, Woodroffe MA. Clinical experience with oral ketamine. J Pain Symptom Manage 1999; 17: 384--6. 44. Haines DR, Gaines SP. N of 1 randomised controlled trials of oral ketamine in patients with chronic pain. Pain 1999; 83: 283-7. 45. Stotz M, Oehen H-P, Gerber H. Histological findings after long-term infusion of intrathecal ketamine for chronic pain: a case report. J Pain Symptom Manage 1999; 18: 223-8. 46. Persson J, Scheinin H, Hellstrom G, Bjorkman S, Gotharson E, Gustafsson LL. Ketamine antagonises alfentanil-induced hypoventilation in healthy male volunteers. Acta Anaesthesiol Scand 1999; 43: 744-52. 47. Krystal JH, D'Souza DC, Karper LP, Bennett A, Abi-Dargham A, Abi-Saab D, Cassello K, Bowers MB. Jr, Vegso S, Heninger GR, Charney D.S. Interactive effects of subanesthetic ketamine and haloperidol in healthy humans. Psychopharmacology 1999; 145: 193-204. 48. Knibbe CAJ, Voortman H-J, Aarts LPHJ, Kuks PFM, Lange R, Langemeijer I-IJM, Danhof M. Pharmacokinetics, induction of anaesthesia and safety characteristics of propofol 6% SAZN vs propofol 1% SAZN and Diprivan-10 after bolus injection. Br J Clin Pharmacol 1999; 47: 653-60. 49. Bagshaw O. T1VA with propofol and remifentanil. Anaesthesia 1999; 54: 501-2.

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50. Sochala C, Van Deenen D, De Ville A, Govaerts MJM. Heart block following propofol in a child. Paediatr Anaesth 1999; 9: 349-51. 51. Gamlin F, Freeman J, Winslow L, Berridge J, Vucevic M. The haemodynamic effects of propofol in combination with ephedrine in elderly patients (ASA groups 3 and 4). Anaesth Intensive Care 1999; 27: 477-80. 52. Tritapepe L, Voci P, Marino P, Cogliati AA, Rossi A, Bottari B, Di Marco P, Menichetti A. Calcium chloride minimizes the hemodynamic effects of propofol in patients undergoing coronary artery bypass grafting. J Cardiothorac Vasc Anesth 1999; 13: 150-3. 53. Gilston A. Raynaud's phenomenon and propofol. Anaesthesia 1999; 54: 307. 54. Ho C-M, Tsou M-Y, Sun M-S, Chu C-C, Lee T-Y. The optimal effective concentration of lidocaine to reduce pain on injection of propofol. J Clin Anesth 1999; 11: 296-300. 55. Ambesh SP, Dubey PK, Sinha PK. Ondansetron pretreatment to alleviate pain on propofol injection: a randomized, controlled, double-blinded study. Anesth Analg 1999; 89: 197-9. 56. Pang W-W, Huang P-Y, Chang D-P, Huang MH. The peripheral analgesic effect of tramadol in reducing propofol injection pain: a comparison with lidocaine. Reg Anesth Pain Med 1999; 24: 246-9. 57. Mok MS, Pang W-W, Hwang M-H. The anal-

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gesic effect of tramadol, metoclopramide, meperidine and lidocaine in ameliorating propofol injection pain: a comparative study. J Anaesthesiol Clin Pharmacol 1999; 15: 37-42. 58. Uda R, Kadono N, Otsuka M, Shimizu S, Moil H, Ozturk E, Izdes S, Babacan A, Kaya K. Strict temperature control has no effect on injection pain with propofol. Anesthesiology 1999; 91: 5912. 59. Nakane M, Iwama H. A potential mechanism of propofol-indnced pain on injection based on studies using nafamostat mesilate. Br J Anaesth 1999; 83: 397-404. 60. Yasukawa M, Yasukawa K-I. Convulsion in two non-epileptic patients following induction of anesthesia with propofol. Jpn J Anesthesiol 1999; 48: 271-4. 61. Gozal D, Gozal Y. Behavior disturbances with repeated propofol sedation in a child. J Clin Anesth 1999; 11: 499. 62. Sneyd JR. Propofol and epilepsy. Br J Anaesth 1999; 2: 68-9. 63. Kumar AN, Schwartz DE, Lim KG. Propofolinduced pancreatitis: recurrence of pancreatitis after rechallenge. Chest 1999; 115:1198-9. 64. Schulze H-J, Wendel HP, Kleinhans M, Oehmichen S, Heller W, Elert O. Effects of the propofol combination anesthesia on the intrinsic blood-clotting system. Immunopharmacology 1999; 43: 141-4.

Stephan A. Schug and Deborah Watson

11 GENERAL TOPICS I m m u n o l o g i c Twenty patients with a prior history of generalized and/or local cutaneous reactions after local anesthetics were examined with intradermal testing and patch testing; in 10 of them a lymphocyte transformation test was performed to investigate whether they had T cell sensitization to local anesthetics, which might have been responsible for their symptoms (1CR). Only two had a positive intradermal test, whereas six had a positive patch test and six had a positive lymphocyte transformation test, suggesting that allergic skin symptoms could be mediated by T cells in some patients who do not have evidence of an IgE-mediated reaction. Several immune reactions to local anesthetics have been described. A 20-year-old woman, who had had eight previous uneventful exposures to local anesthetics for dental procedures, received an injection of 1% lidocaine for treatment of an in-growing toenail; 12 hours later she developed widespread urticaria lasting a week accompanied by bronchospasm and abdominal discomfort (2At). A skin prick test gave a slight positive reaction, and later a positive intradermal injection provided evidence of a true type I hypersensitivity reaction. Following negative skin and intradermal tests with prilocaine, subsequent dental treatment 12 months later was performed using prilocaine with no untoward effects. A 70-year-old woman received a peribulbar block using 10 ml of 2% lidocaine, 0.75% bupivacaine (50/50), and hyaluronidase 500 units for cataract extraction; 12 hours later she awoke with a painful, swollen eye (3At). There was marked swelling, erythema, tenderness of the eyelids, and a tense orbit, with reduced visual acuity, marked restriction of eye movements, and conjunctival chemosis. There was no hematoma or evidence of infection, but allergy could not be ruled out. Four days later she received amethocaine eye drops and local infiltration with lidocaine for further suturing and again de9 2001 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed. 1At~

Local anesthetics veloped similar symptoms and signs in that eye, with swelling extending to the cheek; follow-up showed persistent ocular dysfunction. The second patient had had previous exposure to prilocaine, lidocaine, and bupivacaine without problems. The author proposed a diagnosis of lidocaine allergy, although hyaluronidase as the antigen cannot be excluded. For a case of allergy to oxybuprocaine eye drops see Chapter 47. Cross-reactivity between amide local anesthetics is uncommon (in contrast to ester local anesthetics), but has been reported (4A). A 26-year-old woman, 6 months pregnant, developed local redness and itching after exposure to topical agents containing lidocaine, and a further similar reaction to bupivacaine, also with swelling, 8 hours after injection. She had a history of anaphylaxis to an unidentified agent, and a patch test was performed using mepivacaine, lidocaine, and ropivacaine; all resulted in strong reactions after 48 hours, while patch testing was negative with chloroprocaine. She subsequently had a cesarean section under spinal anesthesia with chloroprocaine with no adverse reaction. D r u g f o r m u l a t i o n s Allergic reactions attributed to local anesthetics can be due to excipients in the formulation (5A). A 69-year-old woman developed hypesthesia of all four limbs lasting several hours after three gastroscopies using lidocaine jelly; although the symptom was not typical of an allergic reaction, intradermal tests and nasal provocation tests were performed. The intradermal tests were negative, but the nasal provocation tests were positive for carboxymethylcellulose, a suspending agent used in lidocaine jelly; this caused ipsilateral nasal congestion and dysesthesia of the tongue and the ipsilateral temporal region within 30 minutes. A drug-induced lymphocyte stimulation test was also positive for carboxymethylcellulose. Hypersensitivity to carboxymethylcellulose may have contributed to this patient's unusual symptoms.

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EFFECTS RELATED TO DIFFERENT MODES OF USE Brachial plexus anesthesia The adverse effects of ropivacaine and bupivacaine have been compared in 104 patients who received 30 ml of either 0.75% ropivacaine or 0.5% bupivacaine for subclavian perivascular brachial plexus block (6c). There were similar incidences of nausea (33% and 28%), vomiting (8% and 14%), and Homer's syndrome (8% and 6%), and one patient who received bupivacaine developed a tonic---clonic generalized seizure 8 minutes after injection, suggestive of systemic toxicity. R e s p i r a t o r y Large volumes (30-40 ml) of local anesthetics for interscalene block cause hemidiaphragmatic paresis in nearly all patients. An interscalene brachial plexus block in 11 volunteers using 10 ml of either 0.25% bupivacaine or 0.5% bupivacaine, both with adrenaline 1:200000, resulted in significant impairment of lung function (forced vital capacity fell by 75% and FEV1 by 78%) and in hemidiaphragmatic excursion in those given 0.5% bupivacaine, but not 0.25% bupivacaine (7c). The authors suggested that 10 ml of 0.25% bupivacaine provides adequate anesthesia, with only occasional interference with respiratory function. However, reducing the volume of local anesthetic (1.5% mepivacaine) from 40 to 20 ml, and applying proximal digital pressure, did not reduce the incidence or intensity of diaphragmatic paralysis during interscalene block in 20 patients, in whom arterial oxygen saturation fell significantly (8Cr). Nervous system Ropivacaine is less toxic than bupivacaine. However, there have been three reports of brachial plexus blockade after ropivacaine, associated with unusual symptoms of CNS toxicity; none of the patients recalled the events and there were no subsequent sequelae oAr). A 46-year-old man received an axillary nerve block using 40 ml of 0.5% ropivacaine with 1:200 000 adrenaline and 45 seconds later developed a sinus tachycardia and started screaming, appearing terrified. He struck out violently with all limbs and sat upright, attempting to leave the bed. The

141 pulse oximeter reading (SpO2) fell to 90% and his symptoms were interpreted as a seizure and treated successfully with 100% oxygen, sodium thiopental, and intubation. A 60-year-old woman received an interscalene block using 30 ml of 0.5% ropivacaine with 1:200000 adrenaline. Immediately after the injection, she sat up and began screaming in a loud high-pitched voice, appearing terrified and enraged. She then attempted to get off the stretcher in an uncoordinated manner and became unresponsive to verbal commands. She had a sinus tachycardia and hypotension. Treatment with 100% oxygen and propofol was effective. A 76-year-old woman received an interscalene block using 20 ml of 0.75% ropivacaine with 1:400 000 adrenaline. At the end of the injection, she sat up and appeared extremely terrified; she screamed twice, fell back on the stretcher, and began moving the unblocked ann and both legs in clohic movements, remaining unresponsive to verbal command. She had a sinus tachycardia and hypertension (205/70 mmHg). The seizure abated with thiopental. The authors suggested that these signs of

anxiety, vocalization, and agitation may have been due to the administration of ropivacaine formulated exclusively as the S(-)-enantiomer, which has a spectrum of CNS and cardiovascular toxicity different from the racemic mixture. Reverse arterial flow can cause CNS toxicity, even during peripheral regional blocks with only small volumes of local anesthetic (lOi). A 47-year-old woman received an axillary brachial plexus block with 3 ml of 1% lidocaine after negative aspiration. She became dysphoric 30 seconds later, with muscle twitching in the face and distal arms, became unresponsive, and required ventilation. During a study of 104 adults to compare the efficacy and safety of 40 ml of 0.75% ropivacaine (300 mg) and 40 ml of 0.5% bupivacaine (200 mg) for axillary plexus block, significantly more patients reported postoperative dizziness in the ropivacaine group (5 vs. 0) (11Ar). However, this occurred 4-5 hours after the injection in two patients and the day after in the other three, and was therefore unlikely to have been due to high serum concentrations. One patient developed dizziness, dysarthria, and unconsciousness, with convulsions shortly after an injection of ropivacaine, indicating an intravenous injection.

142 In some cases adjuvants should be considered as well as the local anesthetic after a toxic reaction (12A). A 52-year-old woman received an axillary plexus block with 20 ml of 1% ropivacaine, clonidine 70 Ixg, and 15 ml of 1% mepivacalne with 1:400000 adrenaline. Generalized tonic--clonic seizure activity developed, even though careful incremental aspiration was performed. She was still comatose 90 minutes later, but this was reversed by intravenous naloxone. The authors suggested that clonidine could have been responsible for the maintenance of her unconscious state. Axillary blockade using high-dose mepivacaine with adrenaline was performed in 50 patients, each of whom received 850 mg of mepivacaine; two patients had symptoms of toxicity associated with this combination (euphoria, dizziness, and tinnitus) 13 and 15 minutes after the procedure with doses of 14.1 and 16.4 mg/kg of mepivacaine respectively (13c). One patient who received 10.9 mg/kg developed hypertension and atrial fibrillation, became agitated, and lost consciousness 12 minutes after the block was performed, and required/%blockade and midazolam before waking up 15 minutes later. Another received 6.5 mg/kg, became light-headed, agitated, and hypertensive, and reported whole body numbness 18 minutes later, with resolution of symptoms after 10 minutes with/%blockade. The author thought that adrenaline had probably been responsible for the reaction in the first patient. As high-dose mepivacalne did not greatly improve the quality of the block and can obviously produce serious systemic reactions, it would be prudent to limit the dose to under 10 mg/kg.

Sensory systems An intolerable metallic taste appeared and disappeared in a 48-year-old woman within hours of infusion of bupivacaine via an axillary catheter, and its severity changed with the rate of infusion (14A). The mechanism was postulated to be through sodium channels or taste bud disturbances.

Hematologic A case of methemoglobinemia has been reported in a woman who received a combination of local anesthetics (15AR).

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A 60-year-old woman with medical problems including severe coronary vascular disease and anemia, taking multiple medications including isosorbide dinitrate, received axiUary plexus blockade with bupivacaine 150 mg + 10 ml of 1% lidocaine injected into the operative field; 90 minutes later her SpO2 fell to 85-89% on oxygen 10 l/min. She became drowsy, disoriented, and tachypneic, and an arterial blood gas showed a metabolic acidosis and a methemoglobin concentration of 6.4%. Her mental status improved 10 minutes after methylene blue and sodium bicarbonate; her SpO2 rose to 96% on air, her methemoglobin concentration fell to 1.6%, and her acidosis partly resolved. The authors assumed that displacement of lidocaine from protein binding by bupivacaine, in combination with metabolic acidosis and treatment with nitrates, had caused methemoglobinemia.

Caudal, epidural, and spinal anesthesia Caudal anesthesia Eight episodes of toxic methemoglobinemia occurred in seven premature infants after the combination of caudal anesthesia (5.445.7 mg/kg prilocalne) and EMLA cream (prilocalne 12.5 mg) for hemiotomy; the highest methemoglobin concentration 5.5 hours after anesthesia was 31% (16cR). All the infants were symptomatic, with mottled skin, pallor, cyanosis, and poor peripheral perfusion. The most severe symptoms occurred at 3-8 hours and disappeared within 10--20 hours. The authors stressed the importance of recognizing the poor tolerance of premature infants to methemoglobinemia and that whereas topical prilocaine is relatively safe, caudal administration is not.

Epidural anesthesia In 52 patients who received either epidural bupivacaine (0.10-0.28 mg/kg/h) or lidocaine (0.44--0.98 mg/kg/h), both with epidural morphine, there were no significant differences in the times to mobilize, motor function (as measured by the Bromage grade), and the incidence of hypotension (17 Cr). Mo st of the patients had no motor blockade, and the Bromage grade did not help predict which of them could be mobilized.

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After thoracotomy, 106 patients received a thoracic epidural infusion of either 0.1% or 0.2% bupivacaine, both with fentanyl 10 Ixg/ml, compared with epidural fentanyl alone; there was no difference in the number of episodes of postoperative hypotension (systolic pressure below 90 mmHg) or in the number of interventions for postoperative hypotension, but intraoperative vasopressors were used significantly more in the bupivacaine groups (18c). In addition, two patients given 0.2% bupivacaine reported slight weakness of both hands and another a right-sided Homer's syndrome and weakness of the right hand. There was a similar incidence of nausea and pruritus in all the groups; however, the incidence of respiratory depression with fentanyl was high (4.2%). Random allocation of 150 women in labor to either an intermittent epidural bolus, a continuous epidural infusion, or patient-controlled epidural analgesia with 0.125% bupivacaine and sufentanil 0.5 ~g/ml resulted in significantly more frequent motor blockade with continuous infusion compared with intermittent boluses (22% vs 4%), with similar frequencies of pruritus, hypotension, and high sensory block levels in each group (19c). In 90 parturients who received epidural analgesia during labor with bolus administration of either 10 ml of 0.125% bupivacaine or 0.125% ropivacaine, each with sufentanil 7.5 Ixg, there were comparable onset times and duration of analgesia in the two groups, but patients given ropivacaine had significantly less motor blockade after the third and subsequent epidural injections compared with those given bupivacaine: 93% of those given ropivacaine had no motor impairment compared with 66% of those given bupivacaine (20CR). There were no differences in hemodynamic effects and pruritus. An epidural infusion of 0.2% ropivacaine plus sufentanil has been compared with 0.175% bupivacaine plus sufentanil in 86 patients postoperatively after major gastrointestinal surgery; there was no statistically significant difference in the incidence of adverse effects (respiratory depression, sedation, nausea, vomiting, pruritus, and motor blockade), but those given ropivacaine mobilized more quickly (21Cr). In 60 women who underwent elective cesarean section under epidural anesthesia, 0.5% levobupivacaine or 0.5% bupivacaine (30 ml) were equally efficacious in terms of an-

143 esthesia (22r). The incidence and severity of motor blockade, hypotension, changes in QT interval, nausea, and vomiting were not significantly different, and neither were the neonatal Apgar scores. Cardiovascular In 122 women who received 20 ml of either ropivacaine 7.5 mg/ml or bupivacaine 5 mg/ml for epidural anesthesia during elective cesarean section there were no significant differences in adverse effects, such as the incidence of hypotensive episodes, bradycardia, or nausea and vomiting; however, there was a greater median fall in systolic blood pressure in those given ropivacaine (24% vs 16%) (23c). Efficacy and neonatal tolerability were similar in the two groups. This, together with its less cardiotoxicity, favors ropivacaine as an alternative to bupivacaine in this setting. In a dose-finding study for the combination of 0.2% ropivacaine with fentanyl for thoracic epidural analgesia in 224 patients undergoing major abdominal surgery, each received fentanyl in concentrations of 0, 1, 2 or 4 Ixg/ml; effective pain relief was provided by all the combinations and the degree of motor block was low overall and did not differ significantly among the groups (24Cr). Hypotension was most common during the first postoperative 24 hours and was most frequent in those given fentanyl 4 Ixg/ml. Although the combination with fentanyl 4 p~g/ml improved the quality of analgesia, there was a higher incidence of adverse effects, such as hypotension, nausea, and pruritus. Severe hypotension during a lumbar epidural anesthetic in a 61-year-old woman taking amitriptyline was refractory to high doses of ephedrine and other indirect a-adrenergic agents (25A). It eventually responded to one dose of noradrenaline 200 Ixg, illustrating the importance of the choice of vasopressor for treating hypotension in the presence of chronic tricyclic antidepressant use. Nervous system Transient radicular irritation, a well-established complication of subarachnoid lidocaine, has been reported after epidural use (26A). A 38-year-old woman underwent cystoscopy and urethral dilatation in the lithotomy position under continuous epidural anesthesia at the L3-4 interspace with 3 ml of 1.5% lidocaine with adrenaline

144 1:200000 as a test dose, followed by a total of 15 ml of 2% lidocaine with adrenaline 1:200000 in incremental doses. The operation was uneventful, but 4 hours later she developed severe bilateral buttock and posterior leg pain, described as "deep, aching, and excruciating", worse when immobile and better when standing; there were no other symptoms and ibuprofen gave immediate relief. The authors stressed that transient radicular irritation can occur after epidural administration, despite the lower concentrations of lidocaine in the cerebrospinal fluid. Musculoskeletal Prolonged profound motor block occurred in two patients using patientcontrolled epidural analgesia with 0.1% ropivacaine subsequent to spinal bupivacaine for cesarean section (27AR). One of them developed pressure sores on both heels. The authors hypothesized that epidural ropivacaine may interact with intrathecal bupivacaine to prolong its effects and advised caution when this combination is used, as unexpected motor block may ensue. The optimal concentration of lumbar epidural ropivacaine in terms of adverse effects and quality of analgesia has been studied in 30 patients using patient-controlled epidural analgesia after lower abdominal surgery (28CR). Each solution provided comparable analgesia, but motor block was significantly more common and more intense with 0.2% ropivacaine + 4 Ixg/mi fentanyl than with 0.1% ropivacaine + 2 Ixg/ml fentanyl or 0.05% ropivacaine + 1 txg/ml fentanyl. The amount of ropivacalne used by the 0.1% ropivacaine group was significantly higher than in the other two groups, implying that the concentration rather than the amount of ropivacaine is a primary determinant of motor block with patient-controlled epidural analgesia. The authors recommended the use of ropivacaine in concentrations under 0.2% to reduce motor blockade while still providing effective analgesia. Epidural solutions containing 0.125% levobupivacaine with and without fentanyl 4 txg/mi produced a greater degree of motor blockade only in the first 6 hours of patientcontrolled epidural analgesia compared with fentanyl alone in groups of 22 patients after total hip or knee arthroplasty (29e).

Drug administration route Accidental intravenous injection of a large dose of levobupi-

Chapter 11

StephanA. Schug and Deborah Watson

vacaine (142 mg) has been described during epidural anesthesia (30 AR) A 77-year-old woman had epidural anesthesia, following negative aspiration, with a 3-ml test dose of 0.75% levobupivacaine with 1:200 000 adrenaline and then incremental doses up to a total of 17 ml of 0.75% levobupivacaine. Dm'ing the final 5 ml of injection she became disoriented and drowsy, with slurred speech, immediately followed by excitation with shouting and writhing about. She was given thiopental for seizure prophylaxis with high-flow oxygen, and the excitatory signs abated. The catheter was withdrawn 1 cm and blood was freely aspirated. The serum levobupivacaine concentration 14 minutes later was 2.7 Ixg/ml.

Intratheeal (spinal) anesthesia Spinal anesthesia has been compared with general anesthesia in 33 patients with pre-eclamptic toxemia undergoing cesarean section (31c). The complications after general anesthesia were more serious, with a 4.3% mortality, whereas complications after spinal anesthesia were less serious and easily manageable, notably intraoperative hypotension (47%), difficulty in locating the subarachnoid space (29%), and intraoperative vomiting (6%). Clonidine 300 Ixg was given orally to 30 patients 60 minutes before spinal blockade with lidocaine 40 mg or 80 mg, and 60 other patients received either plain lidocaine 100 mg or lidocaine 40 mg or 80 mg with clonidine 100 Ixg intrathecally (32c). Clonidine, both intrathecally and orally, prolonged the duration of spinal block and allowed a reduction in the dose of lidocaine needed for a given duration of block, but prolongation of motor block, exceeding the duration of sensory block, was a drawback with both routes and doses of clonidine. The smallest hemodynamic changes were seen with lidocaine 40 mg + clonidine 100 Ixg intrathecally, which provided adequate anesthesia for operations lasting up to 140 minutes. All doses of clonidine caused sedation. Hyperbaric ropivacalne 0.25% has been compared with hyperbaric bupivacaine 0.25% in a cross-over study in 18 volunteers who received a spinal anesthetic; the doses were 4, 8, or 12 mg (33c). More patients had lumbosacral back pain after intrathecal ropivacaine compared with bupivacalne (5 vs 1), although this difference was not significant; the back pain lasted 3-5 days and was mild to moderate in intensity.

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Chapter 11

Continuous spinal anesthesia with 10 ml of 0.25% bupivacaine over 24 hours has been compared with continuous epidural anesthesia with 48 ml of 0.25% bupivacaine over 24 hours during the first 2 days after hip replacement in 102 patients (34CR). Continuous spinal anesthesia provided better analgesia and more patient satisfaction, but significantly more patients had motor blockade during the day of surgery and the first postoperative day. There was a significantly higher incidence of nausea and vomiting with continuous epidural anesthesia (39 vs 21). Sameridine is a new compound with both local anesthetic and opioid analgesic properties. An isobaric solution of sameridine given intrathecally in doses of 15, 20, and 23 mg has been compared with hyperbaric lidocaine 100 mg in 100 volunteers (35A). There was one incident of transient paresthesia with sameridine 20 mg and two cases of bradycardia with lidocaine; the incidence of hypotension was more frequent with lidocaine, but pruritus was more common with sameridine. Cardiovascular Bradycardia has been reported to foUow spinal anesthesia in association with urinary retention (36A). A receding spinal block to level L1-2 gave rise to acute bradycardia (34-40 bpm) and transient loss of consciousness in a 31-year-old man 5 hours after spinal anesthesia; on waking he complained of severe low back pain, and although he had no symptoms of urinary retention, urinary catheterization yielded 900 ml of urine with immediate relief of symptoms. The effect of baricity on the hemodynamic effects of intrathecal 0.5% bupivacaine has been measured by recording invasive systolic blood pressure and central venous pressure in 36 men given plain bupivacaine 0.5%, heavy bupivacaine 0.5% (in dextrose 8%), or a mixture of the two (in dextrose 4%) (37CR). Heavy bupivacaine caused more rapid falls in central venous pressure and systolic blood pressure than plain bupivacaine. However, it was subsequently remarked that both 4% and 8% dextrose are significantly hyperbaric relative to adult cerebrospinal fluid, implying that the 4% solution should have behaved more like the 8% solution (38r). In 191 women who had had cesarean sections under spinal anesthesia using hyperbaric bupivacaine 12-15 mg and morphine 0.25 mg

145 who were transferred to the recovery room on a stretcher with the upper body either flexed 30 ~ or supine during transport 10% of each group had a greater than 20% fall in systolic blood pressure unaffected by position (39CR). The authors recommended routine monitoring of the blood pressure and pulse after transfer to the stretcher, and suggested that raising the head for the comfort of the mother during transport does not increase the risk of hypotension. Nervous system Since the cause of transient radicular irritation after lidocaine spinal anesthesia has not been elucidated, and although non-neurotoxic mechanisms must be considered, it has been recommended that the lowest effective doses and concentrations for subarachnoid injection should be used (40R). The continued use of lidocaine for spinal anesthesia if a short-acting anesthetic is desired has been proposed (41R). The incidence of transient radicular irritation has been reported to be as high as 37% in patients who receive 5% lidocaine, but there has only been one obstetric report of transient radicular irritation. In a prospective study of 303 parturients undergoing spinal anesthesia using 0.75% hyperbaric bupivacaine or 5% lidocaine there were no cases of transient radicular irritation after lidocaine (42CR). This is remarkable, as significantly more procedures were performed in the lithotomy position in the lidocaine group; the authors wondered if such a low incidence of transient radicular irritation could have been explained by their use of a 1:1 dilution of lidocaine with cerebrospinal fluid. With the introduction of 25 gauge and 27 gauge spinal needles, it has been suggested that slow injection may be an additional factor predisposing to transient radicular irritation, since layering of the hyperbaric fluid in the dependent portion may lead to areas of highly concentrated local anesthetic (43r). That the concentration of lidocaine is not a contributory factor to transient radicular irritation has been shown in 109 patients who received hyperbaric spinal lidocaine 50 mg, as a 2%, 1%, or 0.5% solution (44CR). The incidence of transient radicular irritation did not differ (16%, 22%, and 17% respectively). Profound musculoligamental relaxation by high doses of local anesthetics may contribute to the development of postoperative musculoskeletal pain. Of 60 patients who received

146 either spinal anesthesia with hyperbaric 5% lidocaine (85-100 mg) or balanced general anesthesia with neuromuscular blockade, there was transient radicular irritation in eight patients who received spinal anesthesia and in one who received general anesthesia, a significant difference (45CR). However, there was nonradiating back pain in 10 of the patients who received spinal anesthesia and in six of those who received general anesthesia. Urinary retention as a true transient neurological symptom developed after accidental total spinal anesthesia with mepivacaine, which is often considered to be the best agent for spinal anesthesia, owing to its low incidence of transient radicular irritation (46A). A 71-year-old man received a spinal anesthetic with 2 ml of 0.3% hyperbaric mepivacaine using a 25-gauge Quincke needle at the L3--4 interspace, before which he had slight hypesthesia in the L5-S1 dermatomes in the right leg, reportedly having originated from the use of local anesthetic in the lumbar spine 16 years before to treat severe lumbago (47A). When he was turned supine he started to complain of severe lightning pain in the region of his hypesthetic segments, which completely resolved 4 hours later.

Cauda equina syndrome is the triad of bilateral paraparesis or paraplegia of the muscles of the legs and buttocks, saddle anesthesia plus sensory deficits below the groin, and incompetence of bladder and rectal sphincters causing incontinence of urine and feces. Cauda equina syndrome after 5% lidocaine via intrathecal microcatheters is well documented; however, six cases of the syndrome have now been reported after "single-shot" spinal anesthesia at the L 3 - 4 interspace with 5% hyperbaric lidocaine (48CR). A 55-year-old man was given 5% hyperbaric lidocaine 100 mg intrathecally in the sitting position for transurethral resection of the prostate in the lithotomy position, with no complications. However, the next day he complained of persistent numbness of the perianal, scrotal, penile, and sacral regions, and both legs. He also had difficulty in defecation and weakness of both quadriceps muscles. Despite normal MRI scanning, electromyography, and electroneurography, he had no neurological improvement, even 1.5 years after the operation. A 59-year-old woman received 5% hyperbaric lidocaine 60 mg for an operation on a toe. That evening she complained of urinary and bowel incontinence; 5 months later she had urinary stress incontinence and bowel incontinence, with absent

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anal reflexes. There was also reduced sensation over the medial side of the foot. A 48-year-old woman had spinal anesthesia for hallux valgus surgery and had pain radiating to the left buttock during insertion of the needle. Hyperbaric 5% lidocaine 100 mg was injected, with no associated paresthesia. One month later, she complained of persistent numbness of the perianal and sacral regions and had sensory loss in these regions, which failed to improve over 6 months. A 31-year-old man had spinal anesthesia with 5% hyperbaric lidocalne 100 mg for fasciotomy. His systolic blood pressure briefly fell to 90 mmHg and he was given ephedrine. He later complained of persistent numbness of the entire right leg, right scrotum, right side of the penis, and right buttock, and had difficulty in micturition; there was no improvement 1 month later, and he had reduced pain and temperature sensation in the right leg, intact touch sensation, and weakness of right hip extension. His neurological state did not improve over a year. A 37-year-old woman had varicose vein surgery under spinal anesthesia with 5% hyperbaric lidocaine 120 mg in two injections followed by a general anesthesia, because the spinal block was inadequate. Postoperatively she complained of persistent numbness in the right buttock, difficulty in micturition, and bowel incontinence. She had reduced sensation in the perianal region and both labia majora, with a large residual urine volume. An MRI scan was normal, but electromyography, electroneurography, and cystometry 4 months later showed denervation of the pelvic muscles, partial denervation of the detrusor muscle, and signs of re-innervation. After 5 months her condition remained much the same. A 59-year-old man had spinal anesthesia for hallux valgus surgery with 5% hyperbaric lidocaine 75 mg. The next day he had persistent perianal numbness, difficulty in micturition, and a large residual urine volume. An MRI scan was normal and he had reduced perianal and scrotal sensation, difficulty in defecation, and erectile impotence. He was no better 5 months later. The authors stated that at least some of the cases had probably resulted from neurotoxicity of hyperbaric lidocaine, most often in the absence of obvious maldistribution. They recommended that hyperbaric lidocaine should be used in concentrations not exceeding 2% and in a total dose no greater than 60 rag. A 75-year-old woman with a history of lumbar laminectomy, but no neurological deficit, received a spinal injection of 4 ml of 0.5% bupivacaine with preservatives at the L4-5 level using a 22-gauge spinal needle for a total knee replacement (49A). Intraoperatively she complained of severe low back pain, which improved 8 hours later. In parallel, she developed persistent sensory loss to L1 and flaccid paralysis of both legs. An MRI scan was normal,

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but myelography showed inflammation of the cauda equina; 2 months later she developed hydrocephalus and had adhesive arachnoiditis of the thoracolumbar region. Her neurological condition did not improve over 2 years. Gastrointestinal Dysphagia has been reported from the cephalad spread of a spinal anesthetic (50AR). A 26-year-old woman underwent cesarean section with an intrathecal injection of 12 mg of 0.75% hyperbaric bupivacaine, fentanyl 25 vtg, and morphine 0.2 mg. After 4 minutes she developed hypotension, which was treated with ephedrine. Another 4 minutes later she became agitated and complained of difficulty in swallowing. At this stage she had a block to T4 with no dyspnea, her facial sensation was normal, and phonation was intact; the dysphagia resolved within 30 minutes.

Dental anesthesia Nervous system An 8-year-old gift received prilocaine for a dental procedure performed under 70% oxygen/30% nitrous oxide (51A). The dose of 288 mg was 2.7 times higher than the recommended safe dose of 6 mg/kg. Towards the end of the procedure she became unconscious and had a convulsion.

Infiltration anesthesia Of 30 volunteers who had subcutaneous slow infusion tumescent anesthesia at 250 ml/hour with three solutions containing lidocaine 2 mg/ml, ropivacaine 0.5 mg/ml mixed with lidocalne 1 mg/ml, and ropivacaine 1 mg/ml alone, all containing adrenaline 1:1 000 000, one had a tingling sensation in the tongue after lidocaine and another went into vasovagal shock (52c). In the same paper, 5020 surgical procedures were reported in 3270 patients using different strengths of ropivacaine alone (0.050.2%) with a maximum dose of 300 mg, or with a mixture of ropivacaine and prilocaine (0.080.3%) with a maximum ropivacaine dose of 160 mg and a maximum prilocaine dose of 300 mg. There was no methemoglobinemia and there were no minor or major adverse effects related to the local anesthetic. The maximum plasma concentrations were low, suggesting that higher maximum doses may be possible, provided adrenaline is added.

147

Cardiovascular Ventricular tachycardia, severe hypertension, and pulmonary edema developed in a 53-year-old woman soon after she had a skin flap infiltrated with 4 ml of 0.5% lidocaine and 0.0005% adrenaline (20 Ixg) (53A). This has been previously described during general anesthesia but not with a local anesthetic alone, and the author emphasized the risk of severe cardiovascular compromise, even with a small dose of adrenaline. Nervous system Five patients with complex regional pain syndrome received a subcutaneous infusion of 10% lidocaine, with successful alleviation of many of their symptoms; initially 200 mg/kg was infused but symptoms of vertigo and slurred speech each occurred in four of them and stuttering in three, so the rate was adjusted to 100-190 mg/hour and serum lidocaine concentrations of 0.1-8.1 Ixg/ml (average 3.7 Itg/ml); other symptoms, such as aphasia, nausea, fatigue, metallic taste, light-headedness, and perioral numbness, each occurred in over half of the patients (54c). Infiltration of even small doses of a local anesthetic in the region of the carotid artery are likely to cause CNS toxicity if injected intra-arterially, as illustrated by a recent report (55Ar). A 76-year-old man had already received a deep and superficial cervical plexus block for an awake carotid endarterectomy. One hour later, during manipulation of the carotid artery discomfort was treated with infiltration of 1 ml of 0.5% lidocaine in that region. Immediately he became unresponsive, with generalized tonic-clonic seizure activity of the face and arms. He was given 100% oxygen and within 30 seconds the seizure terminated spontaneously with no sequelae. This demonstrates the requirement for constant vigilance in a patient undergoing awake carotid endarterectomy.

Hematologic A report has emphasized the severity of methemoglobinemia in infants especially if premature, when even a small dose of prilocaine is used for infiltration ( 5 6A) . A 1.3-kg premature neonate of 30 weeks gestation, having required ventilation over the first 3 days for respiratory distress syndrome, required reintubation on day 12 of life for recurrent apnea. He developed a pneumothorax requiring an intercostal

148 drain; 0.5 ml of 1% prilocaine was used for infiltration, after which his oxygen requirements overnight went from 28% to 100% with an SpO2 of 90% and he turned pale grey. His PaO2 was 170 mmHg (23 kPa) and his methemoglobin concentration was 15%. He was given methylene blue and within 8 hours his methemoglobin concentration was 0.5% and his SpO2 96%.

Intravenous regional anesthesia Chloroprocaine, because of its rapid onset and ester hydrolysis, should be the ideal agent for intravenous regional anesthesia. However, when 20 patients each received 40 ml of 0.5% chloroprocaine or 0.5% lidocaine for intravenous regional anesthesia, chloroprocaine caused significantly higher incidences of a metallic taste (22% vs 0%) and urticaria (28% vs 0%) than lidocaine; when the same study was repeated using alkalinized instead of plain chloroprocaine, there was no significant difference with respect to CNS adverse effects or the incidence of urticaria (57Cr). Nervous system In 15 volunteers ropivacaine 1.2 and 1.8 mg/kg produced intravenous regional anesthesia as quickly as a conventional dose of lidocaine (3 mg/kg), but with more prolonged anesthesia (55 minutes before loss of pinprick analgesia) and motor block (120 minutes before return of hand grip strength) at the higher dose, suggesting that ropivacaine can provide a greater degree of residual analgesia (58c). All the volunteers given lidocaine and only one patient receiving high-dose ropivacaine developed light-headedness and a hearing disturbance when the tourniquet was released after 30 minutes, but with individual peak arterial plasma ropivacaine concentrations lower than the mean values for the group. The authors pointed out the limitations of this study in terms of a small sample size and their inability to determine the safety of ropivacaine for intravenous regional anesthesia.

Ocular anesthesia Lidocaine gel 2% has been compared with 0.5% tetracaine drops for topical anesthesia in cataract surgery in 25 patients (59c). There were no corneal epithelial or ocular surface complications, demonstrating the safety of the gel, which may provide a more practical and efficient method of anesthesia, because it needs

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to be applied only once as opposed to three applications of the drops. A cluster of 25 cases of transient or permanent diplopia occurred after 13 retrobulbar blocks, 10 peribulbar blocks, and two unknown techniques, possibly related to the non-availability of hyaluronidase, highlighting the likely importance of hyaluronidase in preventing anestheticrelated myopathy in the extraocular muscles (60c). Other reports of 21 cases of persistent postoperative diplopia following the peribulbar technique (61 C) and four cases following the retrobulbar technique during the period of non-availability of hyaluronidase support this theory (62Cr). Bupivacaine and lidocaine may be contraindicated for peribulbar or retrobulbar injections without hyaluronidase. Ocular explosion occurred in seven cases after periocular anesthetic injections (63CR). To minimize the incidence of ocular explosion, the authors recommended the following: 9 use a blunt needle and a 12-ml syringe; 9 aspirate the plunger and wiggle the syringe before injection; 9 discontinue the injection if corneal edema or resistance to injection is noted; 9 inspect the globe for evidence of intraocular injection before ocular massage or placement of a Honan balloon. In 60 patients peribulbar blockade was performed with either 8 ml of 0.75% ropivacaine or a 1:1 mixture of 2% lidocaine and 0.5% bupivacaine (64c). Surgical block was achieved after a similar period of time in each group, but ropivacaine provided a better quality of postoperative analgesia, with no pain reported at 24 hours in 26 (87%) compared with 18 (60%) in the lidocaine + bupivacaine group. One patient given ropivacaine reported unbearable pain due to a high intraocular pressure, and the incidence of postoperative nausea and vomiting was under 7% in both groups. In 54 patients who received peribulbar anesthesia with either 1% ropivacaine or a mixture of 0.75% bupivacaine + 2% lidocaine there was no significant difference in akinesia scores or adverse effects reported the following day, notably headache, dizziness, nausea, scalp anesthesia, and diplopia, the latter occurring in 26% and 30% respectively ( 6 5c) .

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Severe sneezing after ocular local anesthetic injection during intravenous sedation has been linked to photic sneezing. However, in 557 patients there was no relation between the two (66ca). Severe involuntary sneezing occurred after ocular blockade under thiopental sedation overall in 5.2% and only in 7.6% of those with a history of photic sneezing; peribulbar block had a significantly higher incidence of involuntary sneezing compared with retrobulbar block (24% vs 4.5%). Sneezing can occur with many hypnotics and after injections inside the muscle cone and outside the orbit, without pupillary dilatation or lid elevation (67c). Awareness of this phenomenon may facilitate recognition and prompt needle withdrawal to avoid serious problems from sudden head movements during injection.

Respiratory

Pulmonary edema has been at-

149

Paravertebral block Among 44 women who received a single paravertebral block with 0.3 ml/kg of 0.5% bupivacaine at the level of T4 for breast surgery, there was one incident of epidural spread of the block with paraparesis for 280 minutes accompanied by unilateral Homer's syndrome for 170 minutes (70A). Post-thoracotomy pain can be treated with thoracic epidural or thoracic paravertebral blockade. In 100 adult patients allocated to receive one of these treatments with preoperative bolus doses of bupivacaine followed by a continuous infusion there was less postoperative respiratory morbidity and significantly better arterial oxygenation in the paravertebral group; nausea (10 vs 2), vomiting (7 vs 2), and hypotension (7 vs 0) were more problematic in the epidural group (71cr).

tributed to lidocaine (68AR).

Sciatic nerve block A 74-year-old woman had peribulbar blockade with 4 ml of 2% lidocaine at the inferotemporal approach and then 3 ml at the medial approach. She had a history of mitral stenosis, occasional angina, and possibly myocardial infarction, but denied breathlessness on exertion, nocturnal dyspnea, or orthopnea. She had breathlessness and sweating 10 minutes after the medial injection. She then developed hypoxia and a few minutes later began to cough up pink frothy secretions, required intubation, and developed a sinus tachycardia without acute electrocardiographic or cardiac enzymes changes. The authors assumed that she had developed neurogenic pulmonary edema, probably worsened by the co-existing myocardial disease.

Nervous system Retrobulbar anesthesia can be complicated by brainstem anesthesia (69At). A 79-year-old man received retrobulbar anesthesia using a 1:1 mixture of 2% lidocaine and 0.5% bupivacaine plus hyaluronidase, which was complicated by brainstem anesthesia presenting as dysarthria. Initially there was some resistance to injection and the syringe was withdrawn slightly before injection of 4 ml of solution; 5 minutes later he complained of a strange sensation in his throat, which progressed to difficulty in swallowing and not being able to speak above a whisper. His blood pressure rose to 210/118 and his pulse to 120 bpm; he also had signs of involvement of cranial nerves 111,VI, and XII. He received glyceryl trinitrate for the hypertension and by 24 hours all the cranial nerve symptoms and signs had resolved.

Cardiovascular Sciatic nerve block cause cardiovascular depression (72AR).

can

A 74-year-old man was to receive a combined sciatic nerve and psoas compartment block for a total hip arthroplasty; the classic Labat's approach was used and 30 ml of 0.75% ropivacaine was injected over 1.5 minutes, after which he suddenly became unresponsive and developed tonic-clonic movements. Propofol was administered and the seizure resolved, but he developed sinus bradycardia with progressive lengthening of the QRS interval, which converted to nodal bradycardia. A ventricular escape rhythm of 20 bpm with T wave inversion was treated with ephedrine 10 mg and adrenaline 0.1 mg, resulting in supraventricular tachycardia with transient atrial fibrillation. The authors pointed out that an equipotent dose of bupivacaine would have resulted in worse cardiovascular depression with less chance of successful resuscitation.

Topical anesthesia Cardiovascular Three of 1648 children who received measles vaccination with EMLA 1 g had adverse reactions 10-20 minutes later; all required adrenaline for similar symptoms of weakness and dizziness with a cold clammy skin and no pulse or a weak pulse (73c). One went on to wheeze markedly and had peripheral cyanosis and shivering, improving with hy-

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150 drocortisone. The authors proposed that these unusual reactions could have been due to a biphasic local reaction to EMLA, with vasodilatation leading to increased absorption and further toxicity.

Nervous system Systemic effects of topical lidocaine have been reported (74A). A 30-year-old woman received two 5 g applications of 40% lidocaine cream with occlusion by plastic wrap during and after laser therapy to areas of her skin. She developed dizziness and headache postoperatively, followed 45 minutes later by lightheadedness, increasing dizziness, and confusion. The dressings were removed. The lidocaine concentration was 2.7 lxg/ml7 hours later. It is recommended that repeat applications of lidocaine, especially in high-concentration formulations, be avoided and the area of application limited. Unilateral mydriasis (anisocoria), suggesting serious neurological injury, has been attributed to topical cocaine (75Ar). A 51-year-old man developed mydriasis in one eye, with loss of the accommodation reflex, immediately after endoscopic sinus surgery, before which 4% cocaine had been applied to the nasal mucosa on cotton pledglets. There were no surgical or anatomical complications. The authors suggested a diagnosis of local anesthetic blockade of the nasociliary nerve. Sensory systems

EMLA cream can cause

severe eye irritation (76Ar). EMLA cream 30 g was applied to both periorbital and proximal nasal sidewall areas for laser treatment in a 20-year-old woman. Despite the use of a fight eye shield for corneal protection, the next day she developed fight eye pain and blurred vision and remembered that EMLA cream had accidentally entered her fight eye before treatment. This caused immediate discomfort, which subsided and then recurred several hours later. She had severe conjunctival injection with loss of epithelium from over 90% of the surface of her cornea, in a pattern more suggestive of chemical than mechanical damage. Treatment with a bandage contact lens and prophylactic antibiotics was effective and her visual acuity returned to baseline.

Acute angle closure glaucoma has been attributed to local cocaine (77AR).

Stephan A. Schug and Deborah Watson

A 46-year-old woman developed acute angle closure glaucoma 24 hours after the application of topical intranasal 25% cocaine (about 200 mg) for an elective antral washout under general anesthesia. She developed a severe headache around the fight eye, with halos and blurring of vision on the same side and associated nausea and vomiting. The next day, when she awoke, she had completely lost the vision in that eye. glands Acute bilateral parotid swelling occurred after upper gastrointestinal Salivary

endoscopy in a 53-year-old woman who had gargled 2% lidocaine solution beforehand; the swelling was associated with difficulty in swallowing and resolved after treatment with intravenous steroids for 4 days (78c). Skin Treatment of 27 HIV-infected patients with distal sensory polyneuropathy (the most common neurological disorder associated with HIV) with 5% lidocaine gel resulted in effective analgesia in 75% of patients; three had dry skin and one had blisters (79c). The analgesic effects of single and repeated applications of EMLA over 6 consecutive days have been studied in 11 patients with postherpetic neuralgia (80c). There was no evidence of systemic adverse effects, but four patients developed mild erythema at 30 minutes, which may have been due to the occlusive dressing, and one patient had pruritus on day 7. Topical 5% lidocaine to 33 patients with postherpetic neuralgia in a cross-over trial provided significantly more pain relief than a vehicle patch placebo (81c). There was no difference in reported adverse effects: skin redness or rash was reported by nine in the lidocaine patch phase and 11 in the placebo phase. One patient stopped using the placebo patch owing to red irritated skin, which resolved after the application of lidocaine patches. There may be a higher incidence of skin sensitization from amethocaine gel than EMLA. At one hospital in a 3-month period there were seven site reactions to amethocaine (82R). While the Summary of Product Characteristics says that significant skin reactions are rare, the authors estimated that seven reactions in their hospital represented a higher rate than 0.01--0.1% (usually regarded as the frequency of rare events). Indeed, the reported incidence of moderate to severe local skin reactions in clinical trials is 0.6-8.8%, compared with 0 1.7% with EMLA. According to the Summary

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of Product Characteristics there is also a risk of sensitization with repeated exposure (four of the seven children who had reactions to amethocaine had had prior exposure to it), which is not known to happen with E M L A .

INDIVIDUAL COMPOUNDS Benzocaine Hematologic Severe

methemoglobinemia

was suspected in a 1-year-old infant after topical application of 10% benzocaine ointment around an enterostomy; on postoperative day 3 the SpO2 was 90% and arterial blood was dark red in color (83A). The authors pointed out the serious potential for toxicity in infants of a local anesthetic that is commonly used for this purpose in adults. However, adult cases have been reported with Cetacaine TM (a proprietary mixture of 14% benzocaine, 2% tetracaine, and 2% butamben) (84 AR, 85 AR) and with benzocaine alone (86Ar). A 77-year-old woman received two sprays of Cetacaine for an attempted emergency nasotracheal intubation. After intubation she became cyanosed. The arterial blood was chocolate brown and the SaO2 by CO oximetry was 54-58%, despite a high PaO2. The methemoglobin concentration was 39% and she was treated with methylene blue. Three weeks later Cetacaine again caused cyanosis with a drop in SpO2 to 76% and a methemoglobin concentration of 24%, which resolved spontaneously. A 74-year-old man received Cetacaine spray to his oropharynx for transesophageal echocardiography. His SpO2 fell to 85%, he became drowsy, then unresponsive, cyanotic, and apneic, and required intubation. His PaO2 was 280 mmHg (37 kPa) with an SaO2 of 40% and a methemoglobin concentration of 60%. Intravenous methylene blue produced an immediate improvement in the cyanosis and the methemoglobin concentration fell to 0.6%. A 71-year-old man received 20% benzocaine spray to the upper airway for bronchoscopy. His SpO2 gradually fell to under 85% and he required intubation. His methemoglobin concentration was 19% with an SaO2 of 75% and a PaO2 of 329 mmHg (44 kPa). After intravenous methylene blue the methemoglobin concentration fell to 1.8%.

Bupivacaine A formulation of bupivacaine called Regibloc TM (bupivacaine HC1; Intramed, South Africa) was the only c o m m o n factor in a

151 series of serious complications after regional anesthesia (87 c). Three consecutive patients had prolonged blockade after retrobulbar block. One had not resolved after 3 months and three others had prolonged mydriasis for 2 weeks. Severe neuralgia developed in eight patients after interscalene blocks lasting 6 to 12 weeks. A 36-year-old woman developed supraclavicular skin necrosis, followed by sloughing of subcutaneous tissue down to the first rib, including the dorsal roots of the brachial plexus, after receiving an interscalene block followed by an infusion; 5 months later she still had complete sensory and motor paralysis of the C5 nerve root requiring nerve grafting. Skin sloughing after a penile ring-block required plastic reconstruction. A 16-year-old gift had a median nerve block followed by an area of skin and fat necrosis at the site of injection and a middle-aged patient received an interscalene block resulting in subsequent fat necrosis at the injection site. No further complications were encountered after the authors changed to another formulation of bupivacaine and stopped using Regibloc. C a r d i o v a s c u l a r An animal study of the mechanism of bupivacaine-induced dysrhythmias has shown that bupivacaine may facilitate early after-depolarization in rabbit sinoatrial nodal cells by blocking the delayed rectifier potassium current (88E).

Cocaine Cardiovascular Substantial systemic absorption of cocaine can cause severe cardiovascular complications (89AR). An 18-year-old man had both nasal cavities prepared with a pack soaked in 3-5 ml of Brompton solution (3% cocaine, about 3 mg/kg, + adrenaline 1:4000) 2 hours preoperatively. In the anesthetic room he was anxious and withdrawn, with a mild tachycardia. Ten minutes later the nasal pack was removed and polypectomy was begun, with immediate sinus tachycardia and marked ST depression on lead II of the electrocardiogram. Increasing the depth of anesthesia and giving fentanyl had little effect, and the procedure was terminated. After extubation a further electrocardiogram showed T wave flattening in leads II, III, aVF, and aVL. Further cardiac investigations ruled out a myocardial infarction, an anatomical defect, or other pathological or metabolic processes. On day 4 a stress electrocardiogram showed no ischemic changes.

152 Absorption of cocaine from the nasal mucosa in eight patients using cotton pledglets soaked in 4 ml of 4% cocaine and applied for 10 or 20 minutes resulted in an absorption rate four times higher than expected, but was not associated with any cardiovascular disturbance; however, one of four patients who received 4 ml of 10% cocaine for 20 minutes developed intraoperative hypertension and another transient ventricular tachycardia (90c). The authors advised against topical use of 10% cocaine.

Lidocaine Cardiovascular In New York City, five of 50 000 deaths over a 5-year period were associated with tumescent liposuction; all had received lidocaine in doses of 10-40 mg/kg in association with general anesthesia and/or intravenous sedation and analgesia (91CR). Three patients died as a result of severe acute intraoperative hypotension and bradycardia with no identified cause, one died of fluid overload, and another died of pulmonary embolism. The authors speculated that lidocalne toxicity or lidocaine-related drug interactions could have contributed to some of the deaths, but other causes could not be ruled out. In California, six cases of cardiac arrest or severe hypoxemia associated with out-patient liposuction resulted in four deaths over a 3.5year period, all in women aged 38-62 years; one had a cardiac arrest after sedation and the administration of local anesthetic but before liposuction was started, four had respiratory difficulties and cardiac arrest after liposuction, and one had respiratory difficulties during liposuction (92A). Whether the cause of morbidity and mortality in any of these cases was related to local anesthetic toxicity was not mentioned. Some have suggested that lidocaine is unnecessary and potentially toxic in liposuction, and that it provides no postoperative pain relief (93CR). Others think that lidocaine toxicity is not a major cause of death during liposuction, stating that all reported deaths after liposuction have been associated with general anesthesia or sedation, including the five in New York, and that doses of lidocalne higher than those used in these cases (10-40 mg/kg) are routinely used in tumescent liposuction, no deaths having been reported (92r, 94R).

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It is possible that adrenaline, high pressure injection, removal of lidocaine by liposuction, and the development of tolerance may all contribute to delay in absorption and lack of toxic symptoms at higher than expected plasma concentrations (95r).

Sensory systems Taste disturbance has been reported with lidocaine (96A). A 73-year-old woman was given a Nadbath Rehman block behind the left pinna to provide motor blockade of cranial nerve VII, before retrobulbar block for cataract surgery. Several minutes later she complained of a metallic taste in her mouth. After surgery she had altered taste sensation on the anterior left side of the tongue, with recovery a day later. The author postulated this to be due to block of the chorda tympani, which runs with cranial nerve VII close to the site of the Nadbath Rehman block. Drug interactions A synergistic interaction of intrathecal fentanyl 100 Ixg and morphine 0.5 mg, given before induction, with systematically administered lidocaine 200 mg 4 hours later for ventricular tachycardia, resulted in potentiation of opioid effects in a 74-year-old man with major heart disease after coronary artery bypass grafting; during the 5 minutes after lidocaine he had a respiratory arrest with loss of consciousness and miotic pupils, all reversed by naloxone (97A). The proposed mechanism was thought to be a reduction in calcium ion concentrations in opioid-sensitive CNS sites.

Proparacaine Skin Proparacaine has been reported to cause contact dermatitis (98A). A 49-year-old ophthalmologist developed fissuring and bleeding of his finger-tips. Skin patch tests using a series of standard and preservative allergens showed only mild reactions to some. Various treatments were attempted, with minimal success, and skin patch testing was repeated using 32 specific formulations that he had contact with in his practice; he had a severe reaction to proparacaine hydrochloride 0.5%. Subsequent removal of proparacaine from his practice resulted in resolution over 6 months.

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15 3

REFERENCES 1. Orasch CE, Helbling A, Zanni MP, Yawalkar N, Hari Y, Pichler WJ. T-cell reaction to local anaesthetics: relationship to angioedema and urticaria after subcutaneous application--patch testing and LTT in patients with adverse reaction to local anaesthetics. Clin Exp Allergy 1999; 29: 1549-54. 2. Ball IA. Allergic reactions to lignocaine. Br Dent J 1999; 186: 224-6. 3. Waiters G, Georgiou T, Hayward JM. Sightthreatening acute orbital swelling from peribulbar local anesthesia. J Cataract Refractive Surg 1999; 25:444 6. 4. Redfern DC. Contact sensitivity to multiple local anesthetics. J Allergy Clin Immnnol 1999; 104: 890-1. 5. Kakuyama M, Toda H, Osawa M, Fnkuda K. An adverse effect of carboxymethylcellulose in lidocaine jelly. Anesthesiology 1999; 91: 1969. 6. Vaghadia H, Chan V, Ganapathy S, Lui A, McKenna J, Zimmer K. A multicentre trial of ropivacalne 7.5 mg.m1-1 vs bupivacaine 5 mg.m1-1 for supraclavicular brachial plexus anesthesia. Can J Anaesth 1999; 46: 946-51. 7. AI-Kaisy AA, Chan VWS, Perlas A. Respiratory effects of low-dose bupivacaine interscalene block. Br J Anaesth 1999; 82: 217-20. 8. Sala-Blanch X, Lazaro JR, Correa J, GomezFernandez M. Phrenic nerve block caused by interscalene brachial plexus block: effects of digital pressure and a low volume of local anesthetic. Reg Anesth Pain Med 1999; 24: 231-5. 9. Klein SM, Benveniste H. Anxiety, vocalization, and agitation following peripheral nerve block with ropivacaine. Reg Anesth Pain Med 1999; 24: 1758. 10. Dominguez E, Garbaccio MC. Reverse arterial blood flow mediated local anesthetic central nervous system toxicity during axillary brachial plexus block. Anesthesiology 1999; 91: 901-2. 11. Raeder JC, Drosdahl S, Klaastad O, Kvalsvik O, Isaksen B, Stromskag KE, Mowinckel P, Bergheim R, Selander D. Axillary brachial plexus block with ropivacaine 7.5 mg/ml. A comparative study with bupivacaine 5 mg/ml. Acta Anaesthesiol Scand 1999; 43: 794-8. 12. Botero M, Enneking FK. Reversal of prolonged unconsciousness by naloxone after an intravascular injection of a local anesthetic and clonidine. Anesth Analg 1999; 88:1185-6. 13. Koscielniak-Nielsen ZJ, Nielsen PR, Nielsen SL, Gardi T, Hermann C. Comparison of transarterial and multiple nerve stimulation techniques for axillary block using a high dose of mepivacaine with adrenaline. Acta Anaesthesiol Scand 1999; 43: 398-404. 14. Lo AB. Bupivacaine-induced metallic taste. J Pharm Technol 1999; 15: 54-5. 15. Schroeder TH, Dieterich HJ, Muhlbauer B. Methemoglobinemia after axillary block with bupivacaine and additional injection of lidocaine in the

operative field. Acta Anaesthesiol Scand 1999; 43: 480-2. 16. Frey B, Kehrer B. Toxic methaemoglobin concentrations in premature infants after application of a prilocaine-containing cream and peridural prilocaine. Eur J Pediatr 1999; 158: 785-8. 17. Rygnestad T, Zahlsen K, Bergslien O, Dale O. Focus on mobilisation after lower abdominal surgery. A double-blind randomised comparison of epidural bupivacaine with morphine vs. lidocaine with morphine for postoperative analgesia. Acta Anaesthesiol Scand 1999; 43: 380-7. 18. Mahon SV, Berry PD, Jackson M, Russell GN, Pennefather SH. Thoracic epidural infusions for post-thoracotomy pain: a comparison of fentanylbupivacaine mixtures vs. fentanyl alone. Anaesthesia 1999; 54: 641-6. 19. Boutros A, Blary S, Bronchard R, Bonnet E Comparison of intermittent epidural bolus, continuous epidural infusion and patient controlledepidural analgesia during labor. Int J Obstet Anesth 1999; 8: 236-41. 20. Gautier P, De Kock M, Van Steenberge A, Miclot D, Fanard L, Hody JL. A double-blind comparison of 0.125% ropivacalne with sufentanil and 0.125% bupivacaine with sufentanil for epidural labor analgesia. Anesthesiology 1999; 90: 772-8. 21. Brodner G, Mertes N, Van Aken H, Pogatzki E, Buerkle H, Marcus MA, Mollhoff T. Epidural analgesia with local anesthetics after abdominal surgery: Earlier motor recovery with 0.2% ropivacaine than 0.175% bupivacaine. Anesth Analg 1999; 88: 128-33. 22. Bader AM, Tsen LC, Camann WR, Nephew E, Datta S. Clinical effects and maternal and fetal plasma concentrations of 0.5% epidural levobupivacaine versus bupivacaine for cesarean delivery. Anesthesiology 1999; 90: 1596~01. 23. Bjornestad E, Smedvig JP, Bjerkreim T, Narvernd G, Kolleros D, Bergheim R. Epidural ropivacaine 7.5 mg/ml for elective caesarean section: a double-blind comparison of efficacy and tolerability with bupivacaine 5 mg/ml. Acta Anaesthesiol Scand 1999; 43: 603-8. 24. Scott DA, Blake D, Buckland M, Etches R, Halliwell R, Marsland C, Merridew G, Murphy D, Paech M, Schug SA, et al. A comparison of epidural ropivacaine infusion alone and in combination with 1, 2, and 4 microg/ml fentanyl for seventy-two hours of postoperative analgesia after major abdominal surgery. Anesth Analg 1999; 88: 857~4. 25. Boada S, Solsona B, Papaceit J, Saludes J, Rull M. Low blood pressure due to sympathetic blockade refractory to ephedrine in a patient receiving long-term treatment with tricyclic antidepressants. Rev Esp Anestesiol Reanim 1999; 46: 36445. 26. Freedman JM, Rudow MP. Bilateral buttock and leg pain after lidocaine epidural anesthesia. Anesth Analg 1999; 88: 1188.

154 27. Buggy DJ, Allsager CM, Coley S. Profound motor blockade with epidural ropivacaine following spinal bupivacaine. Anaesthesia 1999; 54: 895-8. 28. Liu SS, Moore JM, Luo AM, Trautman WJ, Carpenter RL. Comparison of three solutions of ropivacaine/fentanyl for postoperative patient controlled epidural analgesia. Anesthesiology 1999; 90: 727-33. 29. Kopacz D J, Sharrock NE, Allen HW. A comparison of levobupivacaine 0.125%, fentanyl 4 microg/ml, or their combination for patient-controlled epidural analgesia after major orthopedic surgery. Anesth Analg 1999; 89: 1497-503. 30. Kopacz DJ, Allen HW. Accidental intravenous levobupivacaine. Anesth Analg 1999; 89: 1027-9. 31. Ahmed SM, Khan RM, Bano S, Ajmani P. Is spinal anaesthesia safe in pre-eclamptic toxaemia patients? J Ind Med Assoc 1999; 97: 165-8. 32. Dobrydniov I, Samarutel J. Enhancement of intrathecal lidoeaine by addition of local and systemic clonidine. Acta Anaesthesiol Scand 1999; 43: 556-62. 33. McDonald SB, Liu SS, Kopacz DJ, Stephenson CA. Hyperbaric spinal ropivacaine: a comparison to bupivacaine in volunteers. Anesthesiology 1999; 90: 971-7. 34. Mollmann M, Cord S, Holst D, Auf der Landwehr U. Continuous spinal anaesthesia or continuous epidural anaesthesia for post-operative pain control after hip replacement? Eur J Anaesthesiol 1999; 16: 454-61. 35. Mulroy MF, Greengrass R, Ganapathy S, Chan V, Heierson A. Sameridine is safe and effective for spinal anesthesia: a comparative dose-ranging study with lidocaine for inguinal hernia repair. Anesth Analg 1999; 88: 815-21. 36. Coleman MM, Bardwaj A, Chan V. Back pain and collapse associated with receding subarachnoid blockade. Can J Anaesth 1999; 46: 464-6. 37. Critchley LAH, Morley AP, Derrick J. The influence of baricity on the haemodynamic effects of intrathecal bupivacaine 0.5%. Anaesthesia 1999; 54: 469-74. 38. Hallworth S, Fernando R, Critchley LAH, Morley AP, Derrick J. The spread and side-effects of intrathecally administered bupivacaine. Anaesthesia 1999; 54: 1016-17. 39. Bandi E, Weeks S, Carli E Spinal block levels and cardiovascular changes during post-cesarean transport. Can J Anaesth 1999; 46: 736-40. 40. Hampl K, Schneider M, Corbey MP, Bach AB, Dahlgren N. Transient radicular irritation after spinal anaesthesia with Xyloeain. Acta Anaesthesiol Scand 1999; 43: 359-65. 41. Gisvold SE. Lidoeaine may still be an excellent drug for spinal anaesthesia. Acta Anaesthesiol Scand 1999; 43: 369-70. 42. Wong CA, Slavenas P. The incidence of transient radicular irritation after spinal anesthesia in obstetric patients. Reg Anesth Pain Med 1999; 24: 55-8.

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43. Youngs EJ. Rate of injection and neurotoxicity of spinal lidocaine. Anesthesiology 1999; 90: 3236. 44. Pollock JE, Liu SS, Neal JM, Stephenson CA. Dilution of spinal lidocaine does not alter the incidence of transient neurologic symptoms. Anesthesiology 1999; 90: 445-50. 45. Hiller A, Karjalainen K, Balk M, Rosenberg PH. Transient neurological symptoms after spinal anaesthesia with hyperbaric 5% lidocaine or general anaesthesia. Br J Anaesth 1999; 82: 575-9. 46. Adachi Y, Watanabe K, Uchichasi Y, Sato T. Urinary retention as a transient neurologic symptom after acodental total spinal anesthesm w~th mep~vacaine hydrochloride. Jpn J Anesthesiol 1999; 48: 1009-10. 47. Osuga K, Hirabayashi Y, Fukuda H, Shimizu R, Asahara H. Severe lightning limb pain induced by spinal anesthesia. Jpn J Anesthesiol 1999; 48: 679. 48. Loo CC, Irestedt L. Cauda equina syndrome after spinal anaesthesia with hyperbaric 5% lignocaine: a review of six cases of cauda equina syndrome reported to the Swedish Pharmaceutical Insurance 1993--1997. Acta Anaesthesiol Scand 1999; 43: 371-9. 49. Uefuji T. Persistent neurological deficit and adhesive arachnoiditis following spinal anesthesia with bupivacaine containing preservatives. Jpn J Anesthesiol 1999; 48: 176-80. 50. Musch G, Liposky J. Dysphagia following intrathecal local anesthetic--opioid administration. J Clin Anesth 1999; 1l: 413-15. 51. Virts BE. Local anesthesia toxicity review. Pediatr Dent 1999; 21: 375. 52. Breuninger H. Slow infusion tumescent anesthesia. Dermatol Surg 1999; 25: 151-2. 53. Matsumae T. Circulatory disaster following infiltration of epinephrine contained in local anesthetic. Jpn J Anesthesiol 1999; 48: 1020-3. 54. Linchitz RM, Raheb JC. Subcutaneous infusion of lidocaine provides effective pain relief for CRPS patients. Clin J Pain 1999; 15: 67-72. 55. Stoneham MD, Bree SEP. Epileptic seizure during awake carotid endarterectomy. Anesth Analg 1999; 89: 885-6. 56. Ergenekon E, Atalay Y, Koc E, Turkyilmaz C. Methaemoglobinaemia in a premature infant secondary to prilocaine. Acta Paediatr 1999; 88: 236. 57. Lavin PA, Henderson CL, Vaghadia H. Nonalkalinized and alkalinized 2-chloroproeaine vs lidocaine for intravenous regional anesthesia during outpatient hand surgery. Can J Anaesth 1999; 46: 939-45. 58. Chan VWS, Weisbrod MJ, Kaszas Z, Dragomir C. Comparison of ropivacaine and lidocaine for intravenous regional anesthesia in volunteers: a preliminary study on anesthetic efficacy and blood level. Anesthesiology 1999; 90: 1602-8. 59. Barequet IS, Soriano ES, Green WR, O'Brien TP. Provision of anesthesia with single application 9

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of lidocaine 2% gel. J Cataract Refractive Surg 1999; 25: 626-31. 60. Brown SM, Brooks SE, Mazow ML, Avilla CW, Braverman DE, Greenhaw ST, Green ME, McCartney DL, Tabin GC. Cluster of diplopia cases after periocular anesthesia without hyaluronidase. J Cataract Refractive Surg 1999; 25: 1245-9. 61. Hagan IJ, Whittaker TJ, Byars SR. Diplopia cases after periocular anesthesia without hyaluronidase. J Cataract Refractive Surg 1999; 25: 1560-1. 62. Troll G, Borodic G. Diplopia after cataract surgery using 4% lidocaine in the absence of Wydase (sodium hyaluronidase). J Clin Anesth 1999; 11: 615-16. 63. Bullock JD, Warwar RE, Green WR, Cox MS. Ocular explosions from periocular anesthetic injections: a clinical, histopathologic, experimental, and biophysical study. Ophthalmology 1999; 106: 2341-53. 64. Gioia L, Prandi E, Codenotti M, Casati A, Fanelli G, Tom TM, Azzolini C, Torri G. Peribulbar anesthesia with either 0.75% ropivacaine or a 2% lidocaine and 0.5% bupivacaine mixture for vitreoretinal surgery: a double-blinded study. Anesth Analg 1999; 89: 739-42. 65. McLure HA, Rubin AP, Westcott M, Henderson H. A comparison of 1% ropivacaine with a mixture of 0.75% bupivacaine and 2% lignocaine for peribulbar anaesthesia. Anaesthesia 1999; 54: 1178-82. 66. Wessels IF, Wessels DA, Zimmerman GJ. The photic sneeze reflex and ocular anesthesia. Ophthalmic Surg Lasers 1999; 30:208-11. 67. Wessels IF, Najjar ME Paroxysmal sneezing during local anesthesia for ocular surgery with thiopentone hypnosis. Can J Anaesth 1999; 46: 617. 68. Kumar CM, Lawler PG. Pulmonary oedema after peribulbar block. Br J Anaesth 1999; 82: 777-9. 69. Rosen WJ. Brainstem anesthesia presenting as dysarthria. J Cataract Refractive Surg 1999; 25: 1170-1.

70. Pusch F, Freitag H, Weinstabl C, Obwegeser R, Huber E, Wilding E. Single-injection paravertebral block compared to general anaesthesia in breast surgery. Acta Anaesthesiol Scand 1999; 43: 770-4. 71. Richardson J, Sabanathan S, Jones J, Shah RD, Cheema S, Meatus AJ. A prospective, randomized comparison of preoperative and continuous balanced epidural or paravertebral bupivacaine on post-thoracotomy pain, pulmonary function and stress responses. Br J Anaesth 1999; 83: 38792. 72. Ruetsch YA, Fattinger KE, Borgeat A. Ropivacaine-induced convulsions and severe cardiac dysrhythmia after sciatic block. Anesthesiology 1999; 90: 1784--6. 73. Dilraj A, Cutts F-T, Bennett JV, Coovadia HM, Hopkinson C. Adverse reactions possibly associated with the use of EMLA cream. S Afr Med J 1999; 89: 419-20.

15 5 74. Goodwin DP, McMeekin TO. A case of lidocaine absorption from topical administration of 40% lidocaine cream. J Am Acad Dermatol 1999; 41: 280--1. 75. Stewart D, Simpson GT, Nader ND. Postoperative anisocoria in a patient undergoing endoscopic sinus surgery. Reg Anesth Pain Med 1999; 24: 467-9. 76. McKinlay JR, Hofmeister E, Ross EV, MacA1lister W. EMLA cream-induced eye injury. Arch Dermatol 1999; 135: 855-6. 77. Hari CK, Roblin DG, Clayton MI, Nair RG. Acute angle closure glaucoma precipitated by intranasat application of cocaine. J Laryngol Otol 1999; 113: 250-1. 78. Mondardini A, Turco D, Garripoli A, Martinoglio P, Ferrari A. Acute bilateral edema of the parotids after topical anesthesia with lidocaine: an uncommon clinical event. G Ital Endosc Dig 1999; 22: 111-13. 79. Dorfman D, Dalton A, Khan A, Markarian Y, Scarano A, Cansino M, Wulff E, Simpson D. Treatment of painful distal sensory polyneuropathy in H1V-infected patients with a topical agent: results of an open-label trial of 5% lidocaine gel. Aids 1999; 13: 1589-90. 80. Attal N, Brasseur L, Chauvin M, Bouhassira D. Effects of single and repeated applications of a eutectic mixture of local anaesthetics (EMLA TM) cream on spontaneous and evoked pain in postherpetic neuralgia. Pain 1999; 81: 203-9. 81. Galer BS, Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain 1999; 80: 533-8. 82. Clarkson A, Choonara I, O'Donnell K. Localized adverse skin reactions to topical anaesthetics. Paed Anaesth 1999; 9: 553-5. 83. Adachi T, Fukumoto M, Uetsuki N, Yasui O, Hayashi M. Suspected severe methemoglobinemia caused by topical application of an ointment containing benzocaine around the enterostomy. Anesth Analg 1999; 88: 1190-1. 84. Khan NA, Kruse JA. Methemoglobinemia induced by topical anesthesia: a case report and review. Am J Med Sci 1999; 318: 415-18. 85. Stoiber TR. Toxic methemoglobinemia complicating transesophageal echocardiography. Echocardiography 1999; 16: 383-5. 86. Slaughter MS, Gordon PJ, Roberts JC, Pappas PS. An unusual case of hypoxia from benzocaineinduced methemoglobinemia. Ann Thorac Surg 1999; 67: 1776-8. 87. Boezaart AP, Du Toit JC, Van Lill G, Donald R, Van der Spuy G, Bolus M. Urgent local anaesthetic drug alarm. S Afr Med J 1999; 89: 570-2. 88. Matsuda T, Kurata Y. Effects of nicardipine and bupivacaine on early after depolarization in rabbit sinoatrial node cells: a possible mechanism of bupivacaine-induced arrhythmias. Gen Pharmacol 1999; 33: 115-25.

156 89. Laffey JG, Neligan P, Ormonde G. Prolonged perioperative myocardial ischemia in a young male: due to topical intr,masal cocaine? J Clin Anesth 1999; 11: 419-24. 90. Liao BS, Hilsinger RL Jr, Rasgon BM, Matsuoka K, Adour KK. A preliminary study of cocaine absorption from the nasal mucosa. Laryngoscope 1999; 109: 98-102. 91. Rao RB, Ely SF, Hoffman RS. Deaths related to liposuction. New Engl J Med 1999; 340: 1471-5. 92. Ginsberg MM, Gresham L, Vermeulen C, Serra M, Roujeau JC, Talmor M, Bakie PS, Klein JA, Rigel DS, Wheeland RG, et al. Deaths related to liposuction. New Engl J Med 1999; 341: 1000-3. 93. Perry AW, Petti C, Rankin M. Lidocaine is not necessary in liposuction. Plast Reconstr Surg 1999; 104: 1900-2.

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94. Klein JA. Lidocaine is not necessary in liposuction: discussion. Plast Reconstr Surg 1903; 104: 1903-6. 95. Rubin JP, Bierman C, Rosow CE, Arthur GR, Chang Y, Courtiss EH, May JW Jr. The tumescent technique: the effect of high tissue pressure and dilute epinephrine on absorption of lidocaine. Plast Reconstr Surg 1999; 103: 990--1002. 96. Bigeleisen PE. An unusual presentation of metallic taste after lidocaine injections. Anesth Analg 1999; 89: 1239-40. 97. Jensen E, Nader ND. Potentiation of narcosis after intravenous lidocaine in a patient given spinal opioids. Anesth Analg 1999; 89: 758-9. 98. Liesegang TJ, Pemiciaro C. Fingertip dermatitis in an ophthalmologist caused by proparacaine. Am J Ophthalmol 1999; 127: 240-1.

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GENERAL

Neuromuscular blocking agents and skeletal muscle relaxants TOPICS

Neuromuscular function To reduce the incidence of residual paralysis after the administration of non-depolarizing neuromuscular blocking agents, some advocate the routine use of anticholinesterase drugs at the end of surgery. However, it has been suggested that this practice might increase the risk of postoperative nausea and vomiting. Clinical trials have produced contradictory results. A meta-analysis of the available data suggested that omitting routine neostigmine may reduce the incidence of emesis only when a large dose (2.5 mg) is used (1M). With a smaller dose (1.5 mg) there was no difference. The incidence of clinically relevant residual paralysis was 1 in 30 in the control groups. There were no cases of residual curarization in the treatment groups when either edrophonium 500 txg/kg or neostigmine 1.5 mg was given in combination with atropine. Therefore, the question of whether or not routine anticholinesterase administration is beneficial for the patient is still open to debate. Other adverse effects of anticholinesterase drugs, such as bronchial hypersecretion or intestinal hypermotility, could increase morbidity, and we do not know if all of these adverse effects are completely blocked by the concomitant use of a parasympatholytic agent (2R). It should be taken into account that the incidence of residual curarization may be reduced as effectively by the use of neuromuscular transmission monitoring (3 c, 4c). We suggest that anticholinesterase drugs should be used to reverse residual neuromuscular block detected by neuromuscular 9 2001 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

transmission monitoring or producing clinical symptoms. Immunologic After an anaphylactic reaction during anesthesia the drug responsible is usually determined by skin testing. Most often in such cases, a neuromuscular blocking drug is found to be the triggering substance, and since cross-sensitivity between neuromuscular blocking agents can occur, a variety of these drugs should be tested. Neuromuscular blocking agents that produce negative skin results are considered safe for future anesthesia. However, there have been recent descriptions of several patients with previous anaphylactic reactions to neuromuscular blocking agents who had a second severe anaphylactic reaction when skintest negative agents were used (5 a, 6a). The authors assumed that the skin tests had been falsely negative in these patients, but they conceded that newly acquired sensitivity might also have been an explanation. They concluded that all neuromuscular blocking agents should be avoided in patients with previous anaphylaxis to one of these drugs. If that is not possible the patient should be given antiallergic pretreatment and the anesthetic team should be prepared for resuscitation. In addition to standard pretreatment with both Hi and H2 histamine receptor antagonists, monovalent haptens might prove effective in blocking anaphylaxis to neuromuscular blocking agents (7E). Morphine, which has a single substituted quaternary ammonium ion group, binds to antibodies that react with neuromuscular blocking drugs. Morphine radioimmunoassay was more sensitive in detecting IgE antibodies to neuromuscular blocking agents than assays specific for the various agents (8c). Consequently, 157

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158 morphine radioimmunoassay was suggested as a diagnostic tool in cases of suspected anaphylaxis to neuromuscular blocking agents. In addition, IgE-mediated degranulation of basophils after incubation of the patient's serum with a neuromuscular blocking agent may be detected by flow cytometry if a relevant proportion of basophils express the surface marker CD63 (9A, 10A).

DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS

(SED-14, 361; SEDA-21, 141; SEDA-22, 147; SEDA-23, 150)

Succinylcholine Neuromuscular function Recently, a new hypothesis has been offered to explain muscle hyperexcitability in response to succinylcholine (llE). Voltage clamp experiments on alpha subunits of human muscle sodium channels, heterologously expressed in HEK 293 cells, showed that succinic acid, a metabolite of succinylcholine, shifted steady-state activation in the direction of more negative membrane potentials. The ECs0 for this effect was 0.39 mmol/1. This might lead to muscle hyperexcitability in vivo. Clearly it is not currently possible to claim any direct clinical implications of this study, but two facts should be considered. After the administration of a routine dose of succinylcholine, blood concentrations of 0.17 mmol/1 have been reported (12E). ThUS, equimolar concentrations of succinic acid are to be expected, given that cholinesterase activity is not impaired. Moreover, succinic acid is a citric acid cycle intermediate, ubiquitous in body tissues. In conditions of ischemia and hypoxia, tissue and serum concentrations of succinic acid increase up to 0.2 mmol/l (13 E, 14E). Thus, the administration of succinylcholine to a hypoxic patient may well lead to succinic acid concentrations that affect muscle sodium channel excitability in vitro.

Electrolyte

balance Critically ill patients in intensive care units are at risk of succinylcholine-associated life-threatening hyperkalemia and cardiac arrest. Extrajunctional spread of acetylcholine receptors as a result

O. Zuzan and M. Leuwer

of prolonged immobilization is believed to produce a massive release of potassium after succinylcholine administration in these patients. Cardiac arrest after succinylcholine can occur after 5 days of immobilization (15A). In a recent survey of intensive care units in the UK, more than two-thirds of the respondents would have chosen succinylcholine in a clinical scenario requiring re-intubation in a patient with abdominal sepsis and weaning failure after 20 days of ICU stay (16c). The authors concluded that there is a lack of appreciation of the dangers of succinylcholine in critically ill patients in intensive care units. We should like to stress that not only patients with critical illness polyneuropathy but all patients immobilized by critical illness for more than a few days are at risk and should not be given succinylcholine. The use of succinylcholine in patients with renal insufficiency was controversial in the 1970s, after some cases of hyperkalemic cardiac arrest in such patients. As several studies did not show exaggerated potassium release, succinylcholine is now considered safe for patients with renal insufficiency, if preoperative hyperkalemia is excluded. The observation of some cases of postoperative hyperkalemia recently prompted a review of the literature (17R). The authors found sufficient evidence to support the current consensus: succinylcholine may be used in patients with renal insufficiency, but it should not be given if there is pre-existing hyperkalemia; doses of succinylcholine should not be given repeatedly, as this can result in sinus bradycardia. Musculoskeletal The problem of succinylcholine-associated postoperative myalgia has been reviewed (18R). Key statements are"

9 there is no correlation between the severity of muscle fasciculation, changes in serum creatine phosphokinase or serum potassium, and postoperative myalgia; 9 although not proven, mechanical muscle damage is still assumed to be an underlying mechanism; 9 several classes of pretreatment drugs reduce the incidence and severity of myalgia; combining two agents may be the most useful method;

Neuromuscular blocking agents and skeletal muscle relaxants so far, the lowest incidence of postsuccinylcholine myalgia has been reported when a small dose of a non-depolarizing neuromuscular blocking agent was given together with lidocaine as pretreatment. In addition, there was a reduced incidence and intensity of postsuccinylcholine myalgia when anesthesia had been maintained by propofol infusion compared with isoflurane (19c).

NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS (SED-14,371; SEDA-21, 144; SEDA-22, 149; SEDA-23, 150)

Rapacuronium Rapacuronium is a new aminosteroid nondepolarizing neuromuscular blocking agent with a rapid onset and a comparatively short duration of action. It is being investigated as a possible alternative to succinylcholine (20 C, 21c). Cardiovascular A major adverse effect of rapacuronium is an increase in heart rate (22c). Plasma histamine concentrations may increase after rapacuronium injection, but this was not correlated with changes in blood pressure or heart rate (23c). Risk factors Renal insufficiency Rapacuronium plasma clearance was reduced in patients with renal insufficiency, but this did not result in an increased duration of action (24c).

Liver failure Although not completely understood, hepatic uptake is assumed to be the reason for the short duration of action of rapacuronium. However, neither recovery time nor drug half-life after a single bolus of rapacuronium was prolonged in patients with liver cirrhosis compared with healthy controls (25c). Pregnancy Some controversy has been raised by the use of rapacuronium for rapid sequence induction in elective cesarean section (26c). The authors reported that intubating conditions 60 seconds after rapacuronium 2.5 mg/kg were comparable with those after succinylcholine

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1.5 mg. The percentage of the drug crossing the placenta to the fetus was low (umbilical/maternal vein concentration ratio 0.088) compared with other non-depolarizing agents, and there were no adverse effects on the fetus. Others, however, would not use rapacuronium or other non-depolarizing agents for cesarean section, referring to the longer duration of action, which might be a problem in cases of failed intubation (27r). Rapid sequence induction with thiopentone plus succinylcholine is still standard for cesarean section. Rapacuronium should be considered for cesarean section only in patients in whom succinylcholine is contraindicated. In such cases, induction with propofol plus alfentanil without a neuromuscular blocking agent may be an alternative, which still awaits evaluation with regard to maternal and fetal safety.

SKELETAL MUSCLE RELAXANTS Baclofen (SED-14, 390; SEDA-22, 150; SEDA-23, 152) Nervous system Altered consciousness is a major adverse effect of baclofen, because of its GABA-mimetic effects. While this reflects global CNS depression, other adverse effects, such as seizures and dyskinesias, are probably better explained by selective effects on different brain areas. A recent case of akinetic mutism associated with baclofen might be an example of that (28A). A 76-year-old man with a history of cognitive decline of unknown origin had severe contractures with increasing pain in his legs. He was given baclofen 10 mg tds, and 2 days later had difficulty following commands. Another 2 days later he could not speak and would not follow commands, although he was alert with his eyes open. He had no spontaneous movements, but would withdraw to painful stimuli. The electroencephalogram showed intermittent, bilateral, symmetrical, sharp waves. Computed tomography and laboratory tests showed no specific abnormalities. Baclofen was withdrawn and the patient improved over the next 4 days, after which there was no difference to his pre-baclofen condition. The authors explained that akinetic mutism occurs when bilateral frontal lobe or diencephalic-mesencephalic dysfunction inter-

160 rupts the limbic circuitry. As symptoms were observed immediately after the start of treatment and resolved completely after withdrawal, the condition was probably caused by baclofen. It is not known why baclofen in this case impaired neuronal activity specifically in these areas. The authors found only one previous report describing the case of a 57-year-old woman with end-stage renal insufficiency who developed akinetic mutism after a single dose of baclofen (29A). In this case, the symptoms resolved after dialysis. Therefore, adverse effects of baclofen should be suspected if neuropsychiatric symptoms occur after baclofen treatment has been started. Electroencephalography and computerized tomography may be necessary to exclude other causes.

Botulinum toxin A (SED-14, 392; SEDA-21, 147; SEDA-22, 151; SEDA-23, 152) Museuloskeletal For many years botulinum toxin has been used to restore the balance of contraction of the extraocular muscles. Typical adverse effects are ptosis and diplopia, due to local spread of the toxin. Recently, permanent extraocular muscle damage has been reported (30A). A 70-year-old man had increasing difficulty in maintaining binocular vision while reading. There was imbalance of his extraocular muscle activity. Botulinum toxin A 2.5 U was therefore injected into the left inferior rectus muscle under electromyography control using a 27-gauge needle. At the next visit 1 month later he complained of diplopia in all directions of gaze, in keeping with a left inferior rectus muscle palsy. Over the next 10 months there was no improvement. Magnetic resonance imaging then showed atrophy of the left inferior rectus muscle. Inferior transposition of the medial and lateral recti muscles was performed, which produced satisfactory alignment.

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Botulinum-induced atrophy of extraocular muscles of the eye cannot be excluded in this case. This mechanism is supported by the observation that botulinum toxin can cause histological changes in the extraocular muscles in adult monkeys (31E). The authors of the present report also suggested that intramuscular hematoma or direct damage to the nerve to the muscle may have been responsible. So far, permanent extraocular muscle damage after botulinum toxin injection seems to be rare. If additional cases are reported patients should be informed about this possible complication before treatment. Muscle weakness after botulinum toxin injection is usually due to local spread of the agent. Asymptomatic systemic effects have been detected in patients with cervical dystonia after repeated botulinum toxin injections, when muscle biopsies from the vastus lateral muscle were examined (32c). However, generalized neuromuscular symptoms are rare. Patients with a reduced margin of safety with regard to neuromuscular transmission might be considered prone to systemic effects, but even in patients with myasthenia gravis symptoms distal from the injection site have been reported only occasionally (33c). However, generalized muscle weakness can occur if higher doses of botulinum toxin are used, and a recent report has illustrated that this may happen in patients after many uneventful treatment sessions (34c). Electrophysiological findings in these patients were suggestive of mild botulism, with doses of botulinum toxin of 600-900 units. Two similar cases had been reported previously (35A). Therefore, constant long-term monitoring of patients is recommended, even if they have been receiving injections for many years without adverse effects. Special caution is required when botulinum toxin is to be used in patients with systemic neuromuscular disorders.

REFERENCES 1. Tram~r MR, Fuchs-Buder T. Omitting antagonism of neuromuscular block: effect on postoperative nausea and vomiting and risk of residual paralysis. A systematic review. Br J Anaesth 1999; 82: 379-86.

2. Bevan DR, Donati F, Kopman AE Reversal of neuromuscular blockade. Anesthesiology 1992; 77: 785-805. 3. Mortensen R, Berg H, E1-Mahdy A, VibyMogensen J. Perioperative monitoring of neur-

Neuromuscular blocking agents and skeletal muscle relaxants omuscular transmission using acceleromyography prevents residual neuromuscular block following pancuronium. Acta Anaesthesiol Scand 1995; 39: 797-801. 4. Shorten GD, Merk H, Sieber T. Perioperative train-of-four monitoring and residual curarization. Can J Anaesth 1995; 42:711-15. 5. Fisher MM, Merefield D, Baldo B. Failure to prevent an anaphylactic reaction to a second neuromuscular blocking drug during anaesthesia. Br J Anaesth 1999; 82: 770-3. 6. Thacker MA, Davis FM. Subsequent general anaesthesia in patients with a history of previous anaphylactoid/anaphylactic reaction to muscle relaxant. Anaesth Intensive Care 1999; 27: 190-3. 7. Moneret-Vautrin DA, Kanny G, Gu6ant JL, Widmer S, Laxenaire MC. Prevention by monovalent haptents of IgE-dependent leucocyte histamine release to muscle relaxants. Int Arch Allergy Immunol 1995; 107: 172-5. 8. Fisher MM, Baldo BA. Immunoassays in the diagnosis of anaphylaxis to neuromuscular blocking drugs: the value of morphine for the detection of IgE antibodies in allergic subjects. Anaesth Intensive Care 2000; 28: 167-70. 9. Abuaf N, Rajoely B, Ghazouani E, Levy DA, Pecquet C, Chabane H, Leynadier F. Validation of a flow cytometric assay detecting in vitro basophil activation for the diagnosis of muscle relaxant allergy. J Allergy Clin Immunol 1999; 104: 411-18. 10. Monneret G, Benoit Y, Gutowski MC, Bienvenu J. Detection of basophil activation by flow cytometry in patients with allergy to muscle-relaxant drugs. Anesthesiology 2000; 92: 275-7. 11. Haeseler G, Petzold J, Hecker H, Wurz A, Dengler R, Piepenbrock S, Leuwer M. Succinylcholine metabolite succinic acid alters steady state activation in muscle sodium channels. Anesthesiology 2000; 92: 1385-91. 12. Nordgren IK, Forney RB, Jr, Carroll FT, Holmstedt BR, Jaderholm-Ek I, Pettersson BM. Analysis of succinylcholine in tissues and body fluids by ion-pair extraction and gas chromatography-mass spectrometry. Arch Toxicol Suppl 1983; 6: 339-50. 13. Folbergrova J, Ljunggren B, Norberg K, Siesjo BK. Influence of complete ischemia on glycolytic metabolites, citric acid cycle intermediates, and associated amino acids in the rat cerebral cortex. Brain Res 1974; 80: 265-79. 14. lies RA, Barnett D, Strunin L, Strunin JM, Simpson BR, Cohen RD. The effect of hypoxia on succinate metabolism in man and the isolated perfused dog liver. Clin Sci 1972; 42: 35-45. 15. Hansen D. Suxamethonium-induced cardiac arrest and death following 5 days of immobilization. Eur J Anaesthesiol 1998; 15: 240-1. 16. Hughes M, Grant IS, Biccard B, Nimmo G. Suxamethonium and critical illness polyneuropathy. Anaesth Intensive Care 1999; 27: 636-8. 17. Thapa S, Brull SJ. Succinylcholine-induced hyperkalemia in patients with renal failure: an old

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question revisited. Anesth Analg 2000; 91: 23741. 18. Wong SF, Chung F. Succinylcholine-associated postoperative myalgia. Anaesthesia 2000; 55: 14452. 19. Manataki AD, Arnaoutoglou HM, Tefa LK, Glatzounis GK, Papadopoulos GS. Continuous propofol administration for suxamethoniuminduced postoperative myalgia. Anaesthesia 1999; 54: 419-22. 20. Fleming NW, Chung F, Glass PS, Kitts JB, Kirkegaard-Nielsen H, Gronert GA, Chan V, Gan TJ, Cicutti N, Caldwell JE. Comparison of the intubation conditions provided by rapacuronium (ORG 9487) or succinylcholine in humans during anesthesia with fentanyl and propofol. Anesthesiology 1999; 91: 1311-17. 21. Sparr HJ, Mellinghoff H, Blobner M, NoldgeSchomburg G. Comparison of intubating conditions after rapacuronium (Org 9487) and succinylcholine following rapid sequence induction in adult patients. Br J Anaesth 1999; 82: 53741. 22. Osmer C, Wulf K, Vogele C, Zickmann B, Hempelmann G. Cardiovascular effects of Org 9487 under isoflurane anaesthesia in man. Eur J Anaesthesiol 1998; 15: 585-9. 23. Levy JH, Pitts M, Thanopoulos A, Szlam F, Bastian R, Kim J. The effects of rapacuronium on histamine release and hemodynamics in adult patients undergoing general anesthesia. Anesth Analg 1999; 89: 290-5. 24. Szenohradszky J, Caldwell JE, Wright PM, Brown R, Lau M, Luks AM, Fisher DM. Influence of renal failure on the pharmacokinetics and neuromuscular effects of a single dose of rapacuronium bromide. Anesthesiology 1999; 90: 24-35. 25. Duvaldestin P, Slavov V, Rebufat Y. Pharmacokinetics and pharmacodynamics of rapacuronium in patients with cirrhosis. Anesthesiology 1999; 91: 1305-10. 26. Abouleish El, Abboud TK, Bikhazi G, Kenaan CA, Mroz L, Zhu J, Lee J, Abboud TS. Rapacuronium for modified rapid sequence induction in elective caesarean section: neuromuscular blocking effects and safety compared with succinylcholine, and placental transfer. Br J Anaesth 1999; 83: 862-7. 27. Young SJ, Kilpatrick A. Alternatives to succinylcholine at caesarean section. Br J Anaesth 2000; 84: 69545. 28. Rubin DI, So EL. Reversible akinetic mutism possibly induced by baclofen. Pharmacotherapy 1999; 19: 468-70. 29. Parmar MS. Akinetic mutism after baclofen. Ann Intern Med 1991; 115: 499-500. 30. Mohan M, Tow S, Fleck BW, Lee JP. Permanent extraocular muscle damage following botulinum toxin injection. Br J Ophthalmol 1999; 83: 130910. 31. Spencer RF, McNeer KW. Botulinum toxin paralysis of adult monkey extraocular muscle:

162 structural alterations on orbital singly innervated muscle fibres. Arch Ophthalmol 1987; 105: 170311. 32. Ansved T, Odergren T, Borg K. Muscle fiber atrophy in leg muscles after botulinum toxin type A treatment of cervical dystonia. Neurology 1997; 48: 1440-2. 33. Borodic G. Myasthenic crisis after botulinum toxin. Lancet 1998; 352: 1832. 34. Bhatia KP, Munchau A, Thompson PD, Houser

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M, Chauhan VS, Hutchinson M, Shapiro AH, Marsden CD. Generalised muscular weakness after botulinum toxin injections for dystonia: a report of three cases. J Neurol Neurosurg Psychiatry 1999; 67: 90-3. 35. Bakheit AM, Ward CD, McLellan DL. Generalised botulism-like syndrome after intramuscular injections of botulinum toxin type A: a report of two cases. J Neurol Neurosurg Psychiatry 1997; 62: 198.

Michael Schachter

13

Drugs affecting autonomic functions or the extrapyramidal system

The striking feature of this year's review is once again the high level of interest in antiparkinsonian drugs. There is further information on the adverse effects of well-established drugs, and also of course increasing data on the more recent agents, such as the synthetic dopamine receptor agonists. In other areas there are reminders of the hazards of commonly used, often over-the-counter, medications.

DRUGS THAT STIMULATE BOTH or- A N D / % A D R E N O C E P T O R S (SED-14, 414; SEDA-21, 153; SEDA-22, 154; SEDA-23, 155)

Adrenaline (epinephrine) Ventricular dysrhythmias have been reported in a case of adrenaline overdose (1A). A 5-year-old boy was given subcutaneous adrenaline 1:1000 after a severe allergic reaction to a bee sting. Inadvertently, 10 times the correct dose was given. He developed extra beats and two brief runs of ventricular tachycardia, but recovered fully after about 20 minutes. Interestingly, creatine kinase activity, both total and the MB fraction, was slightly raised in this patient (total 603 iu/1, MB fraction 161 iu/1; upper limits of the local reference range 243 and 15 iu/l), suggesting cardiac damage. According to the authors only supraventricular dysrhythmias have previously been described in children given an overdose of adrenaline. 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

Ephedrine and pseudoephrine C a r d i o v a s c u l a r The vascular effects of ephedrine and pseudoephedrine continue to cause severe problems. A group from Yale have described four patients, women aged 35-50 years, who developed ischemic colitis while taking pseudoephedrine (2 A). Three of the patients had taken the drug for about 1 week, the fourth for 6 months. In all cases there was ischemic colitis affecting predominantly the splenic flexure, and there was full recovery after drug withdrawal. Arteritis has been attributed to ephedrine (3A). A 44-year-old Frenchwoman was given intravenous ephedrine during anesthesia and developed hypertension (systolic pressure 180 mmHg) with nausea, vomiting, and progressive drowsiness. She had a history of migraine, antiphospholipid antibodies, mitral valve prolapse, and atrial fibrillation treated with propranolol. Immediately after anesthesia she developed headache, vomiting, and drowsiness. CT scanning showed frontal and parietal hemorrhagic infarcts, and cerebral angiography showed multiple segments of constriction and dilatation consistent with arteritis. She was left with residual visual and memory deficits. This is the first case of this kind associated with ephedrine, and it seems plausible that the patient's previous history indicated a genetic predisposition to vascular disease. Like so much else, ephedrine is now a drug of abuse. It is combined with caffeine and sometimes other substances in a product rather improbably called "Herbal Ecstasy". A 21year-old Canadian man presented with severe headache, nausea and vomiting, hypertension (220/120 m m Hg), and a sinus tachycardia of about 120 bpm with frequent multifocal 163

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ventricular extra beats (4A). He was treated with intravenous sodium nitroprusside and lidocaine and recovered fully within 24 hours. The authors concluded that ephedrine was very largely responsible for the cardiovascular toxicity.

DRUGS THAT PREDOMINANTLY STIMULATE ot-ADRENOCEPTORS

Psychiatric Ephedrine and pseudoephedrine

Oxymetazoline

also have the potential for neuropsychiatric adverse events. Two reports, from Cincinnati and Pittsburgh, have described a total of four cases of acute psychosis in patients who took pseudoephedrine in combination with dextromethorphan (5 A, 6A). All were children, aged 2-15 years. Three had taken the combination for only 2 days and the fourth for a week. The youngest child needed no specific treatment, but the other three (aged 10-15 years) needed antipsychotic medication for several days. It is not clear which was the primary causative drug in these cases or whether there was some degree of synergy or at least additive toxicity. Renal tract Seven patients (four men, three women, aged 21-52 years) taking large doses of over-the-counter formulations containing ephedrine and guaifenesin developed urinary stones (7c). These largely contained guaifenesin metabolites, but presumably dependence on ephedrine was the reason for abuse of these formulations. Body temperature Ephedrine may have played a role in an episode of hyperthermia (8A). A 21-year-old American military recruit, moderately obese, collapsed during a 3-mile run and was asystolic and hyperthermic (rectal temperature 42.2~ C); he could not be resuscitated. Only 75 minutes earlier he had received vaccinations against typhoid and Japanese encephalitis and he was taking over-the-counter pseudoephedrine to promote weight loss. The authors noted that this was only one of the factors predisposing to hyperthermia; one might also wonder whether it was wise to undertake such a run so soon after the vaccinations.

(SED-14, 417; SEDA-21, 153; SEDA-22, 154; SEDA-23, 155)

Oxymetazoline has a vasoconstrictor effect and this has been reported to have caused an ischemic retinopathy (9A). A 43-year-old woman with hypertension and diabetes mellitus used 2-3 puffs of oxymetazoline nasal spray and experienced painless blurring of vision in the right eye, with a corrected acuity of 20/400 (20/50 on the left). Apart from background diabetic retinopathy she had edema of the optic disk. Several weeks later she used the spray again and this time developed blurred vision in the left eye. There was disk pallor on both sides and acuities were 20/400 on the right and 20/70 on the left. There were also segmental inferior field defects in both eyes. After 6 weeks both eyes had recovered somewhat, but only to 20/200 and 20/50 respectively: there was no further improvement after a year. The authors concluded that this was sequential bilateral ischemic retinopathy due to oxymetazoline.

Phenylpropanolamine Nervous system In

October 2000 the FDA announced that formulations containing phenylpropanolamine would be withdrawn in the USA. Case reports had suggested an association between phenylpropanolamine and hemorrhagic stroke, and a very recent epidemiological study has confirmed this association, most notably in women taking phenylpropanolamine-containing appetite suppressants, in whom the odds ratio for increased risk was over 15, albeit with wide confidence limits (10c). In men the link between stroke and cold remedies was undetectable.

Drug interactions A hypertensive crisis has been reported in a patient receiving triple therapy for HIV prophylaxis, including indinavir (llA). A 28-year-old female medical resident was given zidovudine, lamivudine, and indinavir after a needle stick injury involving an HIV-positive patient. She had a long history of sinus complaints and was tak-

Drugs affecting autonomicfunctions or the extrapyramidal system ing a phenylpropanolamine-contalning formulation intermittently. Ten days after starting prophylactic therapy she took phenylpropanolamine, although the dose was not stated, and 6 hours later developed right-sided headache, weakness of the left arm, and a blood pressure of 220/120 mmHg. CT and MRI scans of the brain were normal. Her blood pressure and neurological signs resolved during treatment with nimodipine and aspirin, though the weakness returned briefly. It seems very likely that the protease inhibitor indinavir inhibited the metabolism of phenylpropanolamine by cytochrome P450 (predominantly CYP3A4), increasing circulating concentrations, and causing systemic and cerebral vasoconstriction.

DRUGS THAT PREDOMINANTLY STIMULATE /~I-ADRENOCEPTORS (SED-14,420; SEDA-21, 154; SEDA-22, 155; SEDA-23, 156)

Dobutamine Cardiovascular There is continuing interest in the safety of dobutamine, since it is so widely used in stress echocardiography. An Israeli group has reviewed its hemodynamic and adverse effects in 400 patients, of whom 187 were aged 65-79 years and 49 were 80 years or older (12R). They found a very low incidence (1.5%) of serious adverse effects, even at high-doses of up to 50 Ixg/kg/min, and noted that most problems occur transiently at a lower dose and then resolve. Hypotension and dysrhythmias were the most common adverse effects, and their incidence was not related to age. A 56-year-old woman with dilated cardiomyopathy developed QT interval prolongation and torsade de pointes during infusion of dobutamine in a low dose (2.5 lzg/kg/min). She had no previous documented dysrhythmias (I3A). She was hypokalemic and when her plasma potassium concentration was restored to normal the dysrhythmia disappeared and the QT interval normalized. The authors observed that this was the first case of its kind and emphasized the importance of normokalemia in dobutaminetreated patients.

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DRUGS THAT ACT ON DOPAMINE RECEPTORS (SED-14,421; SEDA-21, 155; SEDA-22, 156; SEDA-23, 156)

Levodopa Nervous system Both common and rare adverse effects of levodopa have been extensively discussed. Two Italian neurologists have described current theories about the pathophysiology of levodopa-associated motor fluctuations and the use of inhibitors of monoamine oxidase (MAO) type B and catechol-O-methyl transferase (COMT), and modified-release levodopa in minimizing this problem (14 R). They have also discussed non-pharmacological approaches, including lesioning or stimulation of the subthalamus and globus pallidus and striatal grafting of dopamine-producing cells. A contribution to this debate about the best method comes from a group in Houston, who have described unilateral stereotactic pallidotomy in 42 patients, with dramatic improvement in dyskinesias at 3 months after surgery: the number of patients with moderate to severe dyskinesias was reduced from 36 to five, although its is not clear whether there was any change in other aspects of the disease (15c). On the other hand, a novel pharmacological approach has been described by a group in Israel, who have used the glutamate receptor antagonist riluzole in six Parkinsonian patients with severe disease and dyskinesias (16c). At a dose of up to 50 mg/day riluzole significantly reduced dyskinesias, did not worsen Parkinsonian symptoms, and was well tolerated. As regards risk factors for the development of levodopa-induced dyskinesias, neurologists from Madrid have studied 168 consecutive patients treated for at least 6 months with levodopa (17c). About 10% of patients per year developed dyskinesias over 7 years. Younger age (less than 50 years) at the onset of the disease and high initial levodopa dosage (more than 600 mg/day) were the most important risk factors identified. A less well defined adverse effect of levodopa is sedation. This has been studied in 22 volunteers given levodopa 200 mg with benserazide 50 mg or triazolam 0.125 mg or placebo in a randomized cross-over design (18c). Both active drugs caused drowsiness, more particularly triazolam. During a further

166 11 days of treatment with levodopa 600 mg/day sedation persisted. Two points are worth noting. First, triazolam was presumably chosen because of its short half-life, but it is a somewhat risky choice, given its known psychiatric adverse effects. Second, the very rapid increase in levodopa dosage, from 200 to 600 mg/day, would be very unrealistic in a clinical context, when dosage titration would be much more gradual. It is therefore difficult to assess the practical relevance of this study. An unusual symptom of Parkinson's disease is apraxia of eyelid opening, a particular aspect of the difficulty in initiating movements (19A). A 76-year-old woman with atypical Parkinsonism had a poor motor response to levodopa and developed apraxia. An increase in dosage (to levodopa 300/day with benserazide 75 mg/day and selegiline 200 mg/day) caused worsening of the apraxia. Drug withdrawal caused no motor deterioration, but the apraxia disappeared. Challenge with subcutaneous apemorphine reinitiated the symptom, strongly supporting its dopaminergic origin in this patient. The authors cited the use of botulinum toxin in a similar case, but this was ineffective in their patient.

Psychiatric The efficacy of the atypical neuroleptic drug clozapine has been described in 60 patients with levodopa-induced neuropsychiatric syndromes (32 assigned to the active drug and 28 to placebo) (20CR). The mean age was 72 years, the mean duration of disease was 12 years (Hoehn and Yahr stage 3.2), and the mean levodopa dosage was 774 mg/day. At a dose of up to 50 mg/day clozapine significantly improved psychotic features, with minimal effects on Parkinsonian symptoms. Clozapine caused somnolence but was otherwise well tolerated.

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gradually resolved without surgical intervention after treatment with vasodilators, anticoagulants, and antiplatelet drugs (none of which were specified). Her serum cholesterol concentration was 8 mmol/1, but she had no other risk factors.

Respiratory Interstitial

pneumonitis occurred in a 65-year-old man who had taken cabergoline in a low dose (1 mg/day) for 4 months (22A). He was given no specific therapy, but withdrawal of the drug resulted in clinical recovery after 3 weeks and radiological resolution within 2 months. Nervous system Eight men aged 54-83 years, who had taken pramipexole 1-4.5 mg/day for Parkinson's disease for an average of 7 months, all fell asleep while driving, resulting in accidents but no injuries (23A). They described sudden irresistible sleepiness, with virtually no warning, and four had had similar episodes during other activities. In six patients pramipexole was withdrawn, and in the other two the dose was reduced. In one patient a similar problem recurred with another synthetic dopamine receptor agonist, ropinirole, in a dosage of 16 mg/day. Such attacks may shed light on the pathogenesis of spontaneous sleep disorders, such as narcolepsy. Bromocriptine has been used successfully in patients with unilateral motor neglect, usually after a stroke. A 58-year-old man had a right middle cerebral artery infarction leading to, among many other neurological deficits, left-sided neglect (24A). When he took bromocriptine 20 mg/day this abnormality worsened and then improved again on withdrawal. The authors suggested that this may have been due to damage to the right putamen, while bromocriptine could still activate the striatum on the left, aggravating the hemispheric bias.

Dopamine receptor agonists Serosae Most of the dopamine receptor agCardiovascular Acute arterial occlusion, a rare complication of bromocriptine, has been described in two women who had been given bromocriptine for the suppression of lactation (21A). A 21-year-old woman had an inferior myocardial infarction, in the absence of cardiovascular risks and with normal coronary arteries on angiography. She made a good recovery but with some persistent posterior wall akinesia. A 38-year-old woman had an acute occlusion of the right popliteal artery, which

onists in current use are ergot derivatives, and these are known to cause serosal fibroinflammatory syndromes. Three men aged 61-70 years, who had taken pergolide 1-3.75 mg/day for 18-24 months for Parkinson's disease developed pericardial, pleural, or retroperitoneal fibrosis (one case of each) (25A). Despite drug withdrawal, one patient needed pericardial exploration, one was left with residual evidence of severe ureteric obstruction, and one was left with persistent pleural disease. A 76-

Drugs affecting autonomic functions or the extrapyramidal system year-old man taking another ergot derivative, cabergoline, 10 mg/day, developed constrictive pericarditis after 11 months (26A). He required pericardiectomy, but cabergoline was continued and a few months later he was found to have pleuropulmonary fibrosis, which did not resolve on drug withdrawal. The authors emphasized the need for a high index of suspicion when patients develop cardiorespiratory symptoms while taking these drugs. Pergolide 3 mg/day has been associated with retroperitoneal fibrosis in an 83-year-old woman after 18 months (27A). She required ureteric stents, which were removed 2 years later, after her renal function had remained stable. Because of deterioration in her Parkinson's disease the non-ergot dopamine receptor agonist ropinirole was started and treatment was uneventful after 12 months. Constrictive pericarditis occurred in two men aged 63 and 69 years treated respectively with bromocriptine 40 mg/day for 4 years and 30 mg/day for 2 years (28c). Pericardiectomy was performed in both cases, but bromocriptine was not suspected at that time. In one case the drug was continued until a pleural effusion occurred 7 months later; in the other withdrawal of bromocriptine was prompted by an episode of confusion just before pericardiectomy. The authors pointed out that this appears to be the first time that this particular fibrotic complication of bromocriptine has been described. Sexual function There have been reports that apomorphine causes penile erections in both Parkinsonian and normal men, and a similar effect has now been described with ropinirole (29A). A 49-year-old man with Parkinson's disease was treated with ropinirole, and the dosage eventually reaching 3 mg tds. He had penile erections 20-30 minutes after each dose, lasting for 10-15 minutes. They were not associated with arousal and were very uncomfortable: he had no history of sexual dysfunction. Their frequency diminished with a reduction in drug dosage, but they only stopped completely on drug withdrawal. Given that this particular adverse effect may not always be unwelcome, the authors recommended that ropinirole should be tested in men with impotence, and analogues are in development for this specific indication.

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OTHER DRUGS THAT INCREASE DOPAMINE ACTIVITY Amantadine (SED-14, 424; SEDA-20, 147) The use of amantadine in Parkinsonian patients is almost certainly declining, but adverse reactions continue to be reported. A 48-yearold woman with a 17-year history of Parkinson's disease developed a sensorimotor peripheral neuropathy after taking amantadine 300 mg/day for 8 years (30A). She had livedo reticularis after only 1 year of treatment and this had become increasingly extensive. Attempts to withdraw the drug resulted in worsening Parkinsonian symptoms. However, after the neuropathy had been diagnosed amantadine was withdrawn, with improvement of the neurological symptoms within 6 weeks and complete resolution after 6 months. However, the livedo reticularis was still present 18 months after withdrawal. This is the first description of peripheral neuropathy in these circumstances, but it suggests that chronic livedo reticularis may be a forerunner of more severe problems.

Drug

withdrawal In four patients amantadine withdrawal was associated with delirium and confusion (31A). The patients, three of them women, were aged 70-83 years and all but one were considered to have early dementia. Amantadine exposure was 1-5 years and the symptoms occurred within a week of drug withdrawal. In all cases they were reversed by reintroduction. The mechanism of the withdrawal reaction is unknown, but it should obviously be borne in mind, especially in elderly patients with long exposure to the drug and with already impaired cognitive function.

CATECHOL-OMETHYLTRANSFERASE INHIBITORS (SED-14, 429) The introduction of the COMT inhibitor tolcapone had a major impact on the management of Parkinson's disease, and within months tens of thousands of patients throughout the world were treated with it. Tolcapone was considered

168 to be useful in prolonging the half-life of levodopa, thereby allowing dosage reduction and possibly smoother therapeutic responses. However, very soon tolcapone was withdrawn in most countries, because of reports of severe hepatotoxicity. The background to these events has been briefly reviewed (32R). Entacapone, a newer COMT inhibitor, has replaced tolcapone and does not appear to be hepatotoxic. Skin Where it is still available, tolcapone may be associated with other adverse effects. Progressive vitiligo occurred in a 50-year-old Caucasian who took tolcapone 300 mg/day in combination with levodopa/carbidopa (33A). The first depigmented lesions appeared a week after starting the drug. The authors speculated that the increased concentrations of dopamine may have interfered with melanin synthesis.

THE ERGOT ALKALOIDS AND RELATED AGENTS (SED-14,431; SEDA-21, 155; SEDA-23, 157) Despite the advent of the triptans, ergotamine is still used in the treatment of migraine, sometimes with predictable adverse effects. Cardiovascular A 44-year-old woman developed claudication and rest pain after gross overuse of ergotamine 100 mg suppositories (up to 6 times a day) for chronic headaches over a period of several years (34A). Angiography showed occlusion of both femoral arteries. Intra-arterial prostaglandin E (presumably El) followed by chemical sympathectomy normalized the circulation in both legs. Drug interactions The combination of ergotamine with sumatriptan has been associated with vasospasm in the cerebral arteries (35 A) and coronary arteries (36A). A 20-year-old woman developed a severe headache 24 hours after a spontaneous normal delivery. She was given sumatriptan 6 mg subcutaneously followed 24 hours later by three tablets of ergotamine. Shortly after this she had a secondarily generalized tonic--clonic seizure, starting in the left ann, and became hemiplegic. A C T scan showed cerebral edema and angiography showed multiple narrowings of the right vertebrobasilar and middle cerebral arteries. After several further seizures she gradually improved

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and was clinically normal after 10 days. An MR[ angiogram was normal two days later. A 43-year-old woman with controlled hypertension, but no other known coronary risk factors, had an acute myocardial infarction. She took two oral doses of methysergide 2 mg 12 hours apart, followed by sumatriptan 6 mg subcutaneously. About 10 minutes after the sumatriptan she complained of chest pain, and on arrival in hospital an anterior myocardial infarction was diagnosed. Subsequent angiography showed a solitary stenosis in the left anterior descending coronary artery, and it was therefore presumed that she had suffered vasospasm associated with this stenosis. She made an excellent recovery after stenting. The danger of combining two cerebral and coronary vasoconstrictors needs no emphasis. Ritonavir has been reported to potentiate the effects of ergotamine (37A). A 28-year-old woman was taking triple therapy for H1V infection, including the protease inhibitor ritonavir. She had also started to take a combined formulation containing ergotamine (0.6 mg/day), phenobarbital (40 mg/day), and belladonna extract (0.4 mg/day). Four days later she noted pain in both legs and all her extremities were cold, pale, and pulseless. She had diffuse arterial spasm in the aorta and all four limbs. Despite intensive vasodilator therapy, she developed bilateral gangrene of the toes, requiring transmetatarsal amputations. Ritonavir is a very potent inhibitor of the CYP3A4 isoform of cytochrome P450, which is responsible for the metabolism of ergotamine, and this interaction obviously led to toxic plasma concentrations of the alkaloid.

AGENTS WITH ANTICHOLINERGIC EFFECTS (SED-14, 436; SEDA-22, 156; SEDA-23, 158) Nervous system The relatively bladderselective antimuscarinic drug tolterodine has been reviewed in relation to efficacy and tolerability (38 CR, 39R). The general conclusion is that tolterodine is better tolerated than the previous standard medication oxybutinin, particularly with regard to the frequency and severity of dry mouth but also comparing other autonomic adverse effects. The rate of adverse effects-related withdrawals was 2-3 times higher with oxybutinin than tolterodine.

Drugs affecting autonomicfunctions or the extrapyramidal system Psychiatric A 64-year-old woman taking co-careldopa, selegiline, and pramipexole for Parkinson's disease, developed hallucinations 10--12 hours after applying a scopolamine transdermal patch to prevent motion sickness (40A). The hallucinations disappeared after the patch was removed and did not recur. Her previous mental state had been entirely normal. Arguably, she was nevertheless at increased risk of this type of reaction, given her co-existing disease and its medication, and this should be

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in mind in giving such patients anticholinergic remedies for motion sickness. Sensory systems Blurred vision can occur in patients given ipratropium by inhaler (41A). A 68-year-old man's visual acuity dramatically improved (20/100 to 20/40) after he discontinued ipratropium bromide, which he had been taking in a dose of two puffs every 6 hours for chronic obstructive pulmonary disease.

REFERENCES 1. Davis CO, Wax PM. Prehospital epinephrine overdose in a child resulting in ventricular dysrhythmias and myocardial ischemia. Pediatr Emerg Care 1999; 15: 116-18. 2. Dowd J, Bailey D, Moussa K, Nair S, Doyle R, Culpepper-Morgan JA. Ischemic colitis associated with pseudoephedrine: four cases. Am J Gastroenterol 1999; 94: 2430-4. 3. Mourand I, Ducrocq X, Lacour JC, Taillandier L, Anxionnat R, Weber M. Acute reversible cerebral arteritis associated with parenterai ephedrine use. Cerebrovasc Dis 1999; 9: 355-7. 4. Zahn KA, Li RL, Purssell RA. Cardiovascular toxicity after ingestion of"herbal ecstasy". J Emerg Med 1999; 17: 289-91. 5. Soutollo CA, Cottingham EM, Keck PE. Psychosis associated with pseudoephedrine and dextromethorphan. J Am Acad Child Adolesc Psychiatry 1999; 38: 1471-2. 6. Roberge RJ, Hirani KH, Rowland PL, Berkeley R, Krenzelok EP. Dextromethorphan- and pseudoephedrine-induced agitated psychosis and ataxia: case report. J Emerg Med 1999; 17: 285-8. 7. Assimos DG, Langenstroer P, Leinbach RF, Mandel NS, Stern JM, Holmes RP. Guaifenesinand ephedrine-induced stones. J Endourol 1999; 13: 665-7. 8. Franklin QJ. Sudden death after typhoid and Japanese encephalitis vaccination in a young male taking pseudoephedrine. Mil Med 1999; 2: 157-9. 9. Fivgas GD, Newman NJ. Anterior ischemic optic neuropathy following the use of a nasal decongestant. Am J Ophthalmol 1999; 127: 104-6. 10. Keman, WN, Viscoli CM, Brass LM, Broderick JP, Brott T, Feldmann E, Morgenstern LB, Wilterdink JL, Horwitz RI. Phenylpropanolamine and the risk of hemorrhagic stroke. New Engl J Med 2000; 343: 1826-32. 11. Khurana V, De la Fuente M, Bradley TP. Hypertensive crisis secondary to phenylpropanolamine interacting with triple-drug therapy for HIV prophylaxis. Am J Med 1999; 106: 118-19. 12. Chenzbraun A, Khoury Z, Gottlieb A, Keren A. Impact of age on the safety and hemodynamic response pattern during high dose dobutamine

echocardiography. Echocardiography 1999; 16: 135-42. 13. La Vecchia L, Ometto R, Finocchi G, Vincenzi M. Torsade de pointes ventricular tachycardia during low dose intermittent dobutamine treatment in a patient with dilated cardiomyopathy and congestive heart failure. PACE Pacing Clin Electrophysiol 1999; 22: 397-9. 14. Colosimo C, De Michele M. Motor fluctuations in Parkinson's disease: pathophysiology and treatment. Eur J Neurol 1999; 6: 1-21. 15. Jankovic J, Lai E, Ben-Arie L, Krauss JK, Grossman R. Levodopa-induced dyskinesias treated by pallidotomy. J Neurol Sci 1999; 167: 62-7. 16. Merims D, Ziv I, Djaldetti R, Melamed E. Riluzole for levodopa-induced dyskinesias in advanced Parkinson's disease. Lancet 1999; 353: 1764-5. 17. Grandas E Galiano ML, Tebernero C. Risk factors for levodopa-induced dyskinesias in Parkinson's disease. J Neurol 1999; 246:1127-33. 18. Andreu N, Chal6 J-J, Senard J-M, Thalamas C, Montastruc J-L, Rascol O. L-dopa-induced sedation: a double-blind cross-over controlled study versus triazotam and placebo in healthy volunteer. Clin Neuropharmacol 1999; 22: 15-23. 19. Defazio G, De Mari M, De Salvia R, Lambert P, Giorelli M, Livrea E "Apraxia of eyelid opening" induced by levodopa therapy and apomorphine in atypical Parkinsonism (possible progressive supranuclear palsy): a case report. Clin Neuropharmacol 1999; 22: 292-4. 20. French Clozapine Parkinsnn Study Group. Clozapine in drag-induced psychosis in Parkinson's disease. Lancet 1999; 353: 2041-2. 21. Matas O, Coppdr6 B, Dupin AC, Richalet F, Ninet J. Accidents ischdmiques art~riels associds la bromocriptine. JEUR 1999; 1: 32. 22. Frank W, Moritz R, Becke B, Pauli R. Low dose cabergoline induced interstitial pneumonitis. Eur Respir J 1999; 14: 968-70. 23. Fmcht S, Rogers JD, Greene PE, Gordon ME Fahn S. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology 1999; 52: 1908-10.

170 24. Barrett AM, Crucian GP, Schwartz RL, Heilman KM. Adverse effects of dopamine agonist therapy in a patient with motor-intentional defect. Arch Phys Med Rehabil 1999; 80: 600-3. 25. Shaunak S, Wilkins A, Pilling JB, Dick DJ. Pericardial, retroperitoneal, and pleural fibrosis induced by pergolide. J Neurol Neurosurg Psychiatry 1999; 66: 79-81. 26. Ling LH, Ahlskog JE, Munger TM, Limper AH, Oh JK. Constrictive pericarditis and pleuropulmonary disease linked to ergot dopamine agonist therapy (cabergoline) for Parkinson's disease. Mayo Clin Proc 1999; 74: 371-5. 27. Lind BC, Neiman RF, Perry PJ. Treatment of Parkinson's disease with ropinirole after pergolideinduced retroperitoneal fibrosis. Pharmacotherapy 1999; 19: 1437-8. 28. Champagne S, Coste E, Peyri~re H, Nigond J, Mania E, Pons M, Hillaire-Buys D, Balmes P, Blayac J-P, Davy J-M. Chronic constrictive pericarditis induced by long-term bromocriptine therapy: report of two cases, Ann Pharmacother 1999; 33: 1050-4. 29. Fine J, Lange AE. Dose-induced penile erections in response to ropinirole therapy for Parkinson's disease. Mov Disord 1999; 14: 7013. 30. Shulman LM, Minagar A, Sharma K, Weiner WJ. Amantadine-induced peripheral neuropathy. Neurology 1999; 53: 1862-5. 31. Miyasaki JM, Grimes D, Lange AE, Factor SA, Molho ES, Brown DL. Acute delirium after withdrawal of amantadine in Parkinson's disease. Neurology 1999; 52: 1720-1. 32. Colosimo C. The rise and fall of tolcapone. J Neurol 1999; 246: 880-2. 33. Sabat6 M, Bosch A, Pedr6s C, Figueras A.

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Michael Schachter

Vitiligo associated with tolcapone and levodopa in a patient with Parkinson's disease. Ann Pharmacother 1999; 33: 1228-9. 34. Rommel J-D, Klee P, Burkard A, Ratthey KP. Normalisierung des GefaBbildes durch Sympathikusblockade bei schwerer arterieller Durchblutungsst/Srung durch Ergotismus. An~isthesiol Intensivmed Notfallmed Schmerzther 1999; 34: 57881. 35. Granier I, Garcia E, Geissler A, Boespflug MD, Durand-Gasselin J. Postpartum cerebral angiopathy associated with the administration of sumatriptan and ergotamine--a case report. Intensive Care Med 1999; 25: 532--4. 36. Liston H, Bennett L, Usher B, Nappi J, The association of the combination of sumatriptan and methysergide in myocardial infarction in a premenopausal woman. Arch Intern Med 1999; 159: 511-13. 37. Liaudet L, Buclin T, Jaccard C, Eckert P. Severe ergotism associated with interaction between ritonavir and ergotamine. Br Med J 1999; 318: 771. 38. Drutz HP, Appell RA, Gleason D, Klimberg I, Radomski S. Clinical efficacy and safety of tolterodine compared to oxybutynin and placebo in patients with overactive bladder. Int Urogynecol J Pelvic Floor Dysfunct 1999; 10: 283-9. 39. Anonymous. Tolterodine offers new hope for those with overactive bladder. Drugs Ther Perspect 1999; 13: 1-4. 40. Minagar A, Shulman LM, Weiner WJ. Transderm-indueed psychosis in Parkinson's disease. Neurology 1999; 53: 433-4. 41. Kizer KM, Bess DT, Bedford NK. Blurred vision from ipratropium bromide inhalation. Am J Health-Syst Pharm 1999; 56: 914.

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

14

Dermatological drugs, topical agents, and cosmetic drugs

Thalidomide (SEDA-16, 36; SEDA-17, 434) Thalidomide was withdrawn from the market in the early 1960s because of major teratogenic effects. Since then, however, it has been found to be effective in the treatment of erythema nodosum leprosum, and in 1997 it was marketed in the USA for this indication. In dermatological practice, thalidomide has also been used to treat patients with various diseases that are unresponsive to conventional therapy. Among these are aphthous stomatitis, Beh~et's disease, discoid and systemic lupus erythematosus, uremic pruritus, actinic prurigo, prurigo nodularis, sarcoidosis, adult Langerhans cell histiocytosis, erosive lichen planus, and pyoderma gangrenosum (1R). Although thalidomide was developed as a sedative, its use in dermatology is based on its immunomodulatory properties. In vitro it inhibits leukocyte chemotaxis and reduces phagocytosis by monocytes and polymorphonuclear leukocytes, without signs of cytotoxicity (2E, 3E). The production of TNF-a in human monocytes is selectively inhibited by enhanced degradation of TNF-o~ messenger RNA (4E). In phytohemagglutinin-activated cultures of peripheral blood mononuclear cells the production of interleukin-4 and interleukin-5 (cytokines for type 2 T-helper cells) is enhanced, while interferon-y production is inhibited by thalidomide (5E). Its anti-angiogenic activity is probably the cause of its teratogenic effects (6E). Cardiovascular Four cases of thrombosis (two arterial, two venous) have been described 9 200t Elsevier Science B.V.All rights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

in three patients with systemic lupus erythematosus and one with severe atopic dermatitis within 10 weeks of starting treatment with thalidomide 50-100 mg/day (7A). All four had at least one risk factor for thrombosis, but none had thrombosis before or after treatment with thalidomide. In a trial of thalidomide in Behqet's disease there was superficial thrombophlebitis in 10 of 32 patients taking thalidomide 100 mg/day, two of 31 patients taking thalidomide 300 mg/day, and three of 32 patients taking placebo (8c). The fact that this apparent increase in the incidence of thrombophlebitis in those taking 100 mg/day was not reproduced at the higher dosage suggests that the effect occurred by chance. Nervous system Sedation, drowsiness, and headache are frequent adverse effects. The sedative effect is possibly through activation of the sleep center in the brainstem. However, even when it is taken in large doses, thalidomide is not associated with lack of coordination or respiratory depression (9R). The incidence of peripheral neuropathy, with symmetrical painful paresthesia of the hands and feet, often accompanied by sensory loss in the legs, seems to vary with the condition that is being treated, and ranges from under 1% in patients with leprosy to over 70% in patients with prnrigo nodularis (10 c, llr). The symptoms do not correlate with either the duration of treatment or the dose. Women and elderly patients seem to have an increased risk of neuropathy (12c). Deterioration of the sensory nerve action potentials more than 40% from baseline may predict the development of neuropathy (13c). Muscle weakness or cramps, mild ataxia, carpal tunnel syndrome, and signs of pyramidal tract involvement have also been described. After withdrawal of thalidomide, symptoms are usually slow to recover, if they 1"71

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eventually do (9R). The first symptoms of peripheral neuropathy can develop even after the withdrawal of thalidomide (8c).

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

Erythroderma and peripheral eosinophilia occurred in two patients with chronic renal insufficiency who were taking thalidomide for prurigo nodularis (18A).

Psychiatric Mood changes are frequent (9R). Endocrine Four of 13 women with cutaneous lupus disease (either discoid or associated with systemic disease) treated with thalidomide (100-300 mg/day) had amenorrhea during the first 4-5 months of treatment (14c). They had high serum concentrations of pituitary gonadotrophins, normal prolactin concentrations, and low estradiol concentrations; antiovary antibodies were not detected. In one woman an ovarian biopsy showed severe ovarian atrophy and absence of ova or follicles. In all four women menstruation resumed 2-3 months after withdrawal of thalidomide. In two women thalidomide was reintroduced: one developed oligomenorrhea again after 5 months with high concentrations of pituitary gonadotrophins; withdrawal of thalidomide resulted in remission. Other cases of ovarian failure in women taking thalidomide for aphthous ulcers have been described (15A).

Metabolism Weight gain and edema have been reported (9R).

Hematologic Neutropenia occurred in 14 of 80 patients treated with thalidomide for refractory chronic graft-vs-host disease (16c). The median thalidomide dose at which neutropenia developed was 200 mg qds. Erythrocyte and platelet counts were not affected. After withdrawal of thalidomide the neutropenia resolved within a month (except in three patients, who died with refractory graft-vs-host disease). Six patients were rechallenged with thalidomide and again became neutropenic.

Xerostomia, nausea, constipation are common (9a, 17RE). Gastrointestinal

Skin

Death A randomized placebo-controlled study of thalidomide in toxic epidermal necrolysis, undertaken because of the potent in vitro TNF-ot-inhibitory properties of thalidomide, was stopped because of excess mortality in the thalidomide group (10 of 12 patients died compared with three of 10 in the placebo group) (19c). There was an insignificant increase in plasma TNF-~ in the thalidomide-treated patients on day 2.

Teratogenicity

Thalidomide should not be used during pregnancy. Birth defects associated with its use during the first trimester include

phocomelia, duodenal stenosis, esophageal fistula, neural tube defects, micro-ophthalmia, deformities of the pinna of the ears, and mid-line hemangiomas (20r). Women of child-bearing age should use reliable contraception during thalidomide therapy. Risk factors The incidence of neuropathy and hypersensitivity reactions seems to be higher in HIV-infectedpatients (17 RE, 21R). Drug interactions Thalidomide enhances the sedative actions of alcohol, barbiturates, chlorpromazine, and reserpine (20R), perhaps by additive effects on their several pharmacodynamic actions (22E), although other mechanisms have been described (23E). In organ bath experiments thalidomide antagonizes the actions of histamine,

5-hydroxytryptamine, acetylcholine, and prostaglandins; neither the mechanisms nor the clinical relevance of these effects are known (24RE).

and

CONTACT A L L E R G Y

Skin reactions to thalidomide include

pustuloderma, erythroderma, exfoliative reactions, and hypersensitivity reactions, including toxic epidermal necrolysis (9R). The frequency of erythema nodosum was increased compared with placebo during the first 8 weeks of thalidomide therapy for Behqet's syndrome, but not thereafter (8~).

Benzoxonium chloride Benzoxonium hydrochloride is a quaternary ammonium compound with antibacterial, antiviral, and antimycotic activity. It may be used in topical disinfection, disinfection of surgical instruments, inhibition of plaque formation, and

Dermatological drugs, topical agents, and cosmetic drugs in veterinary products. Contact allergic reactions have been rarely reported, with potential cross-reactivity with benzalkonium chloride and domiphen bromide (25 A, 26A), and a further case has been reported (27A). A 37-year-old woman developed intense burning and pruritic eczema where she had applied a benzoxonium-containing cream for seborrheic dermatitis for 5 months. The reaction disappeared on withdrawal of the cream. Patch tests were positive to benzoxonium chloride 0.1% aqueous on days 2 and 4. Patch tests with benzalkonium chloride and benzoxonium chloride in 20 controls were negative.

Benzoyl alcohol A patient with a contact allergic reaction to a topical antimycotic that contained benzoyl alcohol showed positive patch tests on day 4 and a positive repeated open application test to benzoyl alcohol 5% in petroleum jelly (28A). The authors noted that although contact allergic reactions to benzoyl alcohol are rarely reported, they may be responsible for contact allergy to topical corticosteroid formulations.

Benzoyl peroxide Benzoyl peroxide is an antimicrobial and keratolytic agent used in the treatment of acne; it is also added to some foods. It is a catalyst for cross-linking in the production of plastics and is occasionally used in acrylic resin systems (e.g. composite dental fillings, dental prostheses) in which it is formed during the cross-linking process. An 80-year-old man developed dermatitis in his leg amputation stump. He had been using stretching tapes containing benzoyl peroxide, and a patch test showed a positive reaction to benzoyl peroxide (1% in petrolatum) on days 2 and 3 (29A).

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A 67-year-old woman was treated with topical carmustine for a stage I cutaneous T-cell lymphoma. A second course was started after 6 months and resulted in severe erosive inflammation at the site of treatment. Patch tests with carmustine 0.1%, 0.5%, and 1% in water all gave positive results; 22 controls were tested with 0.1% carmustine and lomustine and were all negative.

Diethyl sebacate Diethyl sebacate is an emulsifier used in cosmetics and topical medicaments. In contrast to the emulsifying agents stearyl alcohol, stearic acid, and glyceryl stearate, diethyl sebacate is considered to be a rare sensitizer. In a recent case there were positive patch tests to diethyl sebacate (10% and 30% in ether and 1% and 10% in petrolatum) in a 28-year-old woman who had been using a topical antimycotic ointment (32A).

Dibromopropamidine Dibromopropamidine in a cream base is used to treat herpesvirus skin lesions. Contact allergy is infrequently reported. A 40-year-old man with genital herpes and an acute edematous vesicobullous dermatitis on his penile shaft had a positive patch test with dibromopropamidine and not the other ingredients of the cream (33A).

Epirubicin Widespread allergic contact dermatitis occurred in a 73-year-old m a n after intravesical administration of epirubicin; a patch test with an aqueous solution of the drug (0.1%) was positive (34 A).

Fluorouracil

Calcipotriol Contact allergic reactions to calcipotfiol are rarely reported. In a recent case patch tests with Psorcutan Salbe and calcipotriol (its active ingredient) were both positive (30Ar).

Carmustine Topical carmustine can cause hypersensitivity reactions, and three previous cases have been supplemented by a fourth (31A).

The topical use of 5-fluorouracil often leads to skin irritation. However, allergic contact dermatitis is only infrequently reported, although it may be underdiagnosed. A further case has been reported (35A). A 64-year-old man was treated with Efudix ointment (containing 5% 5-fluorouracil) for actinic keratosis. Patch testing with the constituents of the cream showed a doubtful reaction to 5-fluorouracil 5% in petroleum jelly; however, intradermal injection of 5-fluorouracil 10 mg/ml gave a positive reaction.

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Furaltadone Furaltadone, 5-morpholinomethyl-3-(5-nitrofurfurylidenamino)oxazolidin-2-one, is a crystalline antibiotic powder, which is added to animal feeds and can provoke contact allergic reactions (36E). A case of contact allergy to the antibiotic in ear drops, with positive patch tests, has been reported (37A).

1,2,6-hexanetriol 1,2,6-hexanetriol is used as a humectant, solvent, and viscosity-controlling agent in medicaments and cosmetics. A 35-year-old woman had a 3-week history of pruritic erythema, edema, and linear vesiculation of the upper arms where she had applied fluocinonide cream (38A). Patch tests with the cream were positive, but the active ingredient, fluocinonide (0.05% in petrolatum) was negative, while 1,2,6-hexanetriol 5% showed strong positive reactions on days 3 and 7.

Hydroxychloroquine Hydroxychloroquine is well known to cause skin reactions such as urticaria, exanthemata, and porphyria. Allergic contact dermatitis, which progressed to generalized dermatitis and conjunctivitis, followed later by severe asthma, has been described for the first time in a 60-year-old worker in the pharmaceutical industry after exposure to hydroxychloroquine (39A). Patch testing showed delayed sensitivity to hydroxychloroquine. Equivalent tests in five healthy volunteers were negative. The patch test reactions were pustular, and a biopsy was interpreted as multiform contact dermatitis. Bronchial exposure to hydroxychloroquine dust produced delayed bronchial obstruction over the next 20 hours, progressing to fever and generalized erythema (hematogenous contact dermatitis).

lmidazoles Contact allergy to imidazoles is rare, considering how commonly they are used. In a recent case patch testing was positive with clotrimazole (5% in petroleum), itraconazole (1% in ethanol), and croconazole (1% in ethanol) (40At). The authors reviewed the possible crossreactions between the subgroups of imidazoles.

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

A 71-year-old woman had a severe exacerbation of vulval dermatitis for which she had been using Canesten | (clotrimazole) cream (41A). There was a positive patch test reaction with clotrimazole (1% in petrolatum) and patch tests with the other constituents of Canesten | were negative.

lsopalmitate (2-hexyidecanoic acid) and isopalmityl diglyceryl sebacate Allergic reactions to lipsticks have been reported to be caused by a variety of allergens, e.g. azo-dyes, lanolin, castor oil, sunscreens, and paratertiary butylphenol. Palmitate-related substances are viscous oils used in cosmetics and topical medicaments. In lipsticks they replace castor oil, which has been shown to cause contact allergic reactions (42A). A 17-year-old woman developed pruritic edematous erythema on her lips after using a lipstick containing isopalmitate (43A). A patch test with 10% isopalmitate in petrolatum was positive on day 3, with six negative controls. A 27-year-old woman developed papules, scales, and slight swelling of her lips (44 A). A patch test with isopalmityl diglyceryl sebacate, 10% in petrolatum, was positive.

Isopropanolamine Isopropanolamine is used in cosmetics, hair perms, hair sprays, and in tanning lotions as a buffering agent. The first case of contact dermatitis to a gel containing biphenylacetic acid, a non-steroidal anti-inflammatory agent, carbomer, and isopropanolamine has been reported (45A). Patch tests showed a positive reaction to isopropanolamine (1% aqueous) on day 4. Patch testing of 22 patients as controls showed one case of slight irritation.

Non-steroidal anti-inflammatory drugs The topical use of NSAIDs, such as bufexamac, can provoke contact allergic reactions (46 R 48 R) and a case has been reported with bendazac (49 A). A 28-year-old man had been using a bendazaccontaining ointment for his atopic dermatitis for 6 months, together with topical corticosteroids. Patch testing showed positive reactions to bendazac in

Dermatological drugs, topical agents, and cosmetic drugs petrolatum on days 2, 3, and 7 and a positive reaction to alclometasone dipropionate. Contact allergy to topical indomethacin has rarely been reported (50A), but another report has appeared (51A). A 14-year-old boy had contact allergy to indomethacin gel used for a sprained ankle. He had previously taken NSAIDs orally, but not topically. Patch tests with the indomethacin gel and pure indomethacin 1% in petrolatum were positive.

Nystatin Contact allergy due to topical nystatin has been reported in a woman using a combination of clobetasol and nystatin (52A). The contact allergy was demonstrated with a positive patch test on day 4. In another case, the patient developed a maculopapular rash over the trunk and limbs, associated with fever, arthralgia, malaise, and diarrhea; nystatin patch tests were positive on days 2 and 4 (53A).

Povidone-iodine There have only been a few reports of contact allergy to povidone-iodine, despite its widespread use. A further two cases have been reported, with positive patch test reactions on days 2, 3, and 7 to povidone-iodine (5% aqueous) and iodine (0.5% in petrolatum), but with negative reactions to povidone itself (54A).

Polyvinylpyrrolidone eicosene copolymer Polyvinylpyrrolidone (povidone) copolymers are used in cosmetics as antimicrobials, antistatics, binding compounds, stabilizers of emulsions, film-forming agents, viscositycontrolling agents, hair-fixing, skin-condition ing, and skin-protective agents. A third case of a positive patch test to polyvinylpyrrolidone/eicosene (10% in petrolatum on days 2 and 4) in a patient using a sun block has been reported (55 A).

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sodium metabisulfite are rare (56A). In two further cases a sodium metabisulfite-containing topical corticosteroid formulation (Trimovate | cream) caused contact allergy and patch tests were positive with both sodium metabisulfite and Trimovate | cream (57A).

Tribenoside Tribenoside, ethyl-3,5,6-tri-O-benzyl-D-glucofuranoside, is used as an antihemorrhoidal in oral and suppository formulations. A 57-year-old woman developed erythema exsudativum multiforme after using tribenoside 200 mg tds orally for 10 days (58A). Patch tests with tribenoside (1% and 10% in petrolatum) showed erythema on days 2 and 3. Five controls were negative.

CONTACT URTICARIA AND IMMEDIATE REACTIONS Hair dyes Allergic reactions to constituents of hair dyes are not uncommon and are generally due to delayed hypersensitivity. Immediate hypersensitivity reactions have been described, but they are rare and seldom life-threatening. The oxidation product of paratoluenediamine has been identified as a rare cause of a life-threatening immediate hypersensitivity reaction (59A). A 45-year-old woman developed extensive urticarial lesions 30 minutes after the application of a hair dye, starting on the scalp and face, followed by abdominal cramps, watery diarrhea, vomiting, dysphonia, and loss of consciousness. A prick test with a 1/128 dilution of the hair dye showed a positive reaction, but individual dye constituents did not. Prick testing with the oxidation products of the individual dye constituents showed a strongly positive reaction to oxidized paratoluenediamine, which was weaker after addition of an antioxidant to the mixture. Ten healthy controls had negative prick tests with the oxidized paratoluenediamine.

Sodium metabisulfite

Rifamycin

Sodium metabisulfite is used commonly as an antioxidant in foods and drugs. Reports of contact allergy to topical medicaments containing

Another two cases of anaphylactic reactions have been described after topical rifamycin (60A).

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A 36-year-old woman developed generalized urticaria during a second course of treatment with rifamycin-containing eye drops within a month and a 49-year-old man had systemic urticaria, bronchospasm, and hypotension shortly after his surgical wound had been washed with a rifamycin-containing solution. Both patients had positive skin prick tests to rifamycin (1 mg/ml) when tested several weeks after the acute episode, while 10 healthy volunteers had negative tests. The woman also had a positive skin prick test to rifampicin 2 mg/ml, although she had never taken it before.

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

Aciclovir Pre-existing vesicular edematous cheilitis (probably due to contact allergy to the protecting lip salve) was aggravated after application of Zovirax | cream (62A). Patch tests to the lip salve were positive, but in addition there were positive photopatch tests to Zovirax | cream, but not to its separate constituents.

PHOTOCHEMOTHERAPY (PUVA) PHOTOCONTACT DERMATITIS In a review of photopatch testing in 2390 patients with rashes that were confined to sunexposed areas, about 70% of 4374 positive reactions were classified as photo-induced reactions, of which 222 (5%) were photoallergic reactions (61c). NSAIDs, disinfectants, and phenothiazines were the main photoallergens.

Guidelines for topical PUVA therapy, including bath and local immersion PUVA therapy, have recently been published by the British Photodermatology Group (63s). In addition to cases of PUVA-induced pem-

phigus vulgaris and bullous pemphigoid, the first case of PUVA-induced pemphigus foliaceus has been reported (64A). Intermittent flares continued for 2 years after the withdrawal of PUVA.

REFERENCES 1. Stifling DI. Thalidomide and its impact in dermatology. Sem Cut Med Surg 1998; 17: 231-42. 2. Faure M, Thivolet J, Gaucherand M. Inhibition of PMN leukocytes chemotaxis by thalidomide. Arch Dermatol Res 1980; 269: 275-80. 3. Bamhill RL, Doll NJ, Millikan LE, Hastings RC. Studies on the anti-inflammatory properties of thalidomide: effects on polymorphonnclear leukocytes and monocytes. J Am Acad Dermatol 1984; 11: 814-19. 4. Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G. Thalidomide exerts its inhibitory action on tumor necrosis factor a by enhancing mRNA degradation. J Exp Med 1993; 177: 1675-80. 5. McHugh SM, Rifkin IR, Deighton J, Wilson AB, Lachmann PJ, Lockwood CM, Ewan PW. The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Thl cytokine production in mitogen- and antigenstimulated human peripheral blood mononuclear cell cultures. Clin Exp Immunol 1995; 99: 160-7. 6. D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1944; 91: 4082-5. 7. Flageul B, Wallach D, Cavelier-BaUoy B, Bachelez H, Carsuzaa F, Dubertret L. Thalidomide et thromboses. Ann Dermatol Venereol 2000; 127: 171-4.

8. Hamuryudan V, Mat C, Saip S, 0zyazgan Y, Siva A, Yurdakul S, Zwingenberger K, Yazici H. Thalidomide in the treatment of the mucocutaneous lesions of Behqet's syndrome: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1988; 128: 443-50. 9. Tseng S, Pak G, Washenik K, Keltz Pomeranz M, Shupack JL. Rediscovering thalidomide: a review of its mechanism of action, adverse effects, and potential uses. J Am Acad Dermatol 1996; 35: 969-79. 10. Clemmensen OJ, Zander Olsen P, Andersen KE. Thalidomide neurotoxicity. Arch Dermatol 1984; 120: 338-41. 11. Wulff CH, HCyer H, Asboe-Hansen G, Brodthagen H. Development of polyneuropathy during thalidomide therapy. Br J Dermatol 1985; 112: 475-80. 12. Ochonisky S, Verroust J, Bastuji-Gavin S, Gherardi R, Revuz J. Thalidomide neuropathy incidence and clinicoelectrophysiologic findings in 42 patients. Arch Dermatol 1994; 130: 66-9. 13. Gardner-Medwin JMM, Smith NJ, Powell ILl. Clinical experience with thalidomide in the management of severe oral and genital ulceration in conditions such as Behqet's disease: use of neurophysiological studies to detect thalidomide neuropathy. Ann Rheum Dis 1994; 53: 82832.

Dermatological drugs, topical agents, and cosmetic drugs 14. Ordi J, Cortes F, Martinez N, Mauri M, De Torres I, Vilardell M. Thalidomide induces amenorrhea in patients with lupus disease. Arthritis Rheum 1998; 41: 2273-5. 15. Gompel A, Frances C, Piette JC, Blanc AS, Cordoliani E Piette A-M. Ovarian failure with thalidomide treatment in complex aphthosis: comment on the concise communication by Ordi et al. Arthritis Rheum 1999; 42: 2259-60. 16. Parker PM, Chao N, Nademanee A, O'Donnell MR, Schmidt GM, Snyder DS, Stein AS, Smith EP, Molina A, Stepan DE, et al. Thalidomide as salvage therapy for chronic graft-versus-host disease. Blood 1995; 86: 3604-9. 17. Giinzler V. Thalidomide in human immunodeficiency virus (HIV) patients. A review of safety considerations. Drug Saf 1992; 7:116-34. 18. Bielsa I, Teixido J, Ribera M, Ferrandiz C. Erythroderma due to thalidomide: report of two cases. Dermatology 1994; 189: 179-81. 19. Wolkenstain P, Latarjet J, Roujeau J-C, Duguet C, Boudeau S, Vaillant L, Maignan M, Schumacher M-H, Milpied B, Pilorget A, Bocquet H, BrunBuisson C, Revuz J. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet 1998; 352: 1586-9. 20. Beckman DA, Brent RL. Mechanisms of teratogenesis. Ann Rev Pharmacol Toxicol 1984; 24: 483-500. 21. Haslett P, Tramontana J, Burroughs M, Hempstead M, Kaplan G. Adverse reactions to thalidomide in patients infected with human immunodeficiency virus. Clin Infect Dis 1997; 24: 1223-7. 22. Frederickson RCA, Slater IH, Dusenberry WE, Hewes CR, Jones GT, Moore RA. A comparison of thalidomide and pentobarbital--new methods for identifying novel hypnotic drugs. J Pharmacol Exp Ther 1977; 203: 240-51. 23. Somers GE Pharmacological properties of thalidomide (allpha-phtalimido glutarimide), a new sedative hypnotic drug. Br J Pharmacol 1960; 15: 111-16. 24. Hastings RC, Morales MJ, Shannon EJ. Studies on the mechanism of action of thalidomide in leprosy. Pharmacologist 1976; 18: 218. 25. De Groot AC, Conemans J, Liem DH. Contact allergy to benzoxonium chloride (Bradophen). Contact Dermatitis 1984; 11: 324-5. 26. Bruynzeel DP, De Groot AC, Weyland JW. Contact dermatitis to lauryl pyridinium chloride and benzoxonium chloride. Contact Dermatitis 1987; 17: 41-2. 27. Diaz-Ram6n L, Aguirre A, Rat6n-Nieto JA, De Miguel M. Contact dermatitis from benzoxonium chloride. Contact Dermatitis 1999; 41: 53-4. 28. Podda M, Zollner T, Grundmann-Kollmann M, Kaufmann R, Boehnke W-H. Allergic contact dermatitis from benzyl alcohol during topical antimycotic treatment. Contact Dermatitis 1999; 41: 302-3. 29. Greiner D, Weber J, Kaufmann R, Boehncke W-H. Benzoyl peroxide as a contact allergen

Chapter 14

177

in adhesive tape. Contact Dermatitis 1999; 41: 233. 30. Frosch PJ, Rustemeyer T. Contact allergy to calcipotriol does exist. Report of an unequivocal case and review of the literature. Contact Dermatitis 1999; 40: 66-71. 31. Thomson KF, Sheehan-Dare RA, Wilkinson SM. Allergic contact dermatitis from topical carmustine. Contact Dermatitis 2000; 42:112. 32. Kimura M, Kawada A. Contact dermatitis from diethyl sebacate. Contact Dermatitis 1999; 40: 489. 33. Selvaag E. Contact allergy to dibromopropamidine cream. Contact Dermatitis 1999; 40: 58. 34. Ventura MT, Dagnello M, Di Corato R, Tursi A. Allergic contact dermatitis due to epirubicin. Contact Dermatitis 1999; 40: 339. 35. S~inchez-Prrez J, Bartolomd B, Jestls del Rio M, Garcfa-Dfez A. Allergic contact dermatitis from 5-fluorouracil with positive intradermal test and doubtful patch test reactions. Contact Dermatitis 1999; 41: 106-7. 36. Nelder KH. Contact dermatitis from animal feed additives. Arch Dermatol 1972; 106: 722-3. 37. S(mchez-Prrez J, C6rdoba S, Jestis del Rio M, Garcfa-Diez A. Allergic contact dermatitis from furaltadone in eardrops. Contact Dermatitis 1999; 40: 222. 38. Miura Y, Hata M, Yuge M, Numano K, Iwakiri K. Allergic contact dermatitis from 1,2,6-hexanetriol in fluocinonide cream. Contact Dermatitis 1999; 41:118-19. 39. Meier H, Eisner P, Wuthrich B. Occupationallyinduced contact dermatitis and bronchial asthma in an unusual delayed reaction to hydroxychloroquine. Hautarzt 1999; 50: 665-9. 40. Erdmann S, Hertl M, Merk HE Contact dermatitis from clotrimazole with positive patchtest reactions also to croconazole and itraconazole. Contact Dermatitis 1999; 40: 47-8. 41. Cooper SM, Shaw S. Contact allergy to clotrimazole: an unusual allergen. Contact Dermatitis 1999; 41: 168. 42. Sai S. Lipstick dermatitis caused by castor oil. Contact Dermatitis 1983; 9: 75. 43. Kimura M, Kawada A. Contact dermatitis due to 2-hexyldecanoic acid (isopalmitate) in a lipstick. Contact Dermatitis 1999; 41: 99-100. 44. Suzuki K, Matsunaga K, Suzuki M. Allergic contact dermatitis due to isopalmityl diglyceryl sebacate in a lipstick. Contact Dermatitis 1999; 41: 110. 45. Cooper SM, Shaw S. Contact allergy to isopropanolamine in Traxam | gel. Contact Dermatitis 1999; 41: 233. 46. Kr~nke B, Szolar-Platzer C, Komericki P, Derhaschnig J, Aberer W. Epidemiological significance of bufexamac as a frequent and relevant sensitizer. Contact Dermatitis 1997; 36: 212-15. 47. Ophaswonge S, Maibach H. Topical nonsteroidal antiinflammatory drugs: allergic and pho-

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toallergic contact dermatitis and phototoxicity. Contact Dermatitis 1993; 29: 57-64. 48. Guiazdowska B, Rutff E Przybilla B. Delayed contact hypersensitivity to non-steroidal antiinflammatory drugs. Contact Dermatitis 1999; 40: 63-5. 49. Iwakiri K, Hata M, Miura Y, Numano K, Yuge M, Sasald E. Allergic contact dermatitis due to bendazac and alclometasone dipropionate. Contact Dermatitis 1999; 41: 218-19. 50. Belier U, Kaufmann R. Contact dermatitis to indomethacin. Contact Dermatitis 1987; 17: 121. 51. Pulido Z, Gonzfiles E, Alfaya T, ,~lvarez JA, Cefia M, Hoz B. Allergic contact dermatitis from indomethacin. Contact Dermatitis 1999; 41:112. 52. Cooper SM, Shaw S. Contact allergy to nystatin: an unusual allergen. Contact Dermatitis 1999; 4t: 120. 53. Cooper SM, Reed J, Shaw S. Systemic reaction to nystatin. Contact Dermatitis 1999; 41: 345-6. 54. Erdmann S, Herd M, Merk HF. Allergic contact dermatitis from povidone-iodine. Contact Dermatitis 1999; 40: 331. 55. Smith HR, Armstrong K, Wakelin SH, White IR. Contact allergy to PVP/eicosene copolymer. Contact Dermatitis 1999; 40: 283. 56. Heshmati S, Maibach HI. Active sensitization to sodium metabisulfite in hydrocortisone cream. Contact Dermatitis 1999; 41: 166-7. 57. Tucker SC, Yell JA, Beck MH. Allergic contact

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

dermatitis from sodium metabisulfite in Trimovate| cream. Contact Dermatitis 1999; 40: 164. 58. Endo H, Kawada A, Yudate T, Aragane Y, Yamada H, Tezuka T. Drug eruption due to tribenoside. Contact Dermatitis 1999; 41: 223. 59. Pasche-Koo E French L, Piletta-Zanin P-A, Hauser C. Contact urticaria and shock to hair dye. Allergy Eur J Allergy Clin Immunol 1998; 53: 904-5. 60. Garcia R, Blanco J, Carretero E Herrero D, Juste S, GarcEs M, Ptrez R, Fuentes M. Anaphylactic reactions to topical rifamycin. Allergy Eur J Allergy Clin Immunol 1999; 54: 526-33. 61. Neumann NJ, HiSlzle E, Plewig G, Schwarz T, Panizzon RG, Breit R, Ruzicka T, Lehmann E Photopatch testing: the 12-year experience of the German, Austrian, and Swiss Photopatch Test Group. J Am Acad Dermatol 2000; 42: 183-92. 62. Rodriguez-Serna M, Velasco M, Miquel J, De la Cuadra J, Aliaga A. Photoallergic contact dermatitis from Zovirax| cream. Contact Dermatitis 1999; 41: 54-5. 63. Halperu SM, Anstey AV, Dawe RS, Diffey BL Farr PM, Ferguson J, Hawk JLM, Ibbotson S, McGregor JIM, Murphy GM, Thomas SE, Rhodes LE. Guidelines for topical PUVA: a report of a workshop of the British Photodermatology Group. Br J Dermatol 2000; 142:22-31. 64. Aghassi D, Dover JS. Pemphigus foliaceus induced by psoralen-UV-A. Arch Dermatol 1998; 134: 1300-1.

Anthony N. Nicholson

15 Cardiovascular An analysis of spontaneous reports of suspected adverse effects of antihistamines has been carried out (1M). The drugs were divided into two groups, sedative and nonsedative, although it is questionable whether cetirizine should have been included in the nonsedative group. Adverse reaction profiles were broadly similar in the two groups. Terfenadine was associated with the highest incidence of serious cardiac dysrhythmias, sudden death, and death related to disturbances of cardiac rate and rhythm combined. The incidence of ventricular dysrhythrnias associated with non-sedating antihistamines (including cetirizine) has also been assessed using the UK-based General Practice Research Database (2c). There were 18 cases over the period 1992-96. Astemizole was associated with the highest relative risk. The risk associated with terfenadine was no different from that with other non-sedating antihistamines, and there was no single case of ventricular dysrhythmia with the concomitant use of P450 inhibitors and teffenadine. In contrast with astemizole and terfenadine, loratadine is generally believed to be free of adverse cardiac effects. However, there is some evidence that it could be associated with atrial dysrhythmias. In human atrial myocytes loratadine rate-dependently inhibited the transient outward potassium current at therapeutic concentrations, possibly providing a basis for supraventdcular dysrhythmias (3E). However, during prolonged exposure (3 months) of healthy adult men to four times the recommended dally dose (40 mg/day) there was no change in the electrocardiogram that would suggest QTc prolongation or any evidence of cardiac dysrhythmias (4c). Ebastine (10 and 20 mg/day) had no clinically important effect on QTc interval in adults, 9 2001 Elsevier Science B.V.All rights reserved.

Side Effects of Drugs, Annual24 J.K. Aronson, ed.

Antihistamines including elderly people, children, and patients with hepatic or renal impairment. Coadministration with ketoconazole or erythromycin did not lead to significant changes in the QTc interval (5c, 6c). Nervous system Some antihistamines can cause drowsiness and impaired vigilance, but more serious effects on the central nervous system are reported from time to time. Druginduced parkinsonism is an example. It occurs mainly in psychotic patients after exposure to neuroleptic drugs, but can also be caused by cinnarizine (SEDA-22, 178). The prognosis of drug-induced parkinsonism has been discussed (7c, 8c). Negrotri and Calzetti (7c) consider that the results of Marti-Massb and Poza (8c) are over-optimistic. This they ascribe to uncertainty in the collection of their data, which may not have provided adequate evidence of the course of clinical recovery, although differences in cumulative dosages and concurrent use of other drugs could also be involved. The differences in prognosis may be due to the fact that the patients studied by MartiMassb and Poza (2 c) were diagnosed earlier, were less severely affected, and had a good prognosis. Cinnarizine-induced extrapyramidal signs have tended to be associated with old age and prolonged treatment. However, a case of cinnarizine-induced akathisia, parkinsonism, and depression has been reported in a 25-yearold patient after only 11 days of treatment (9A). The neuroleptic malignant syndrome is a rare reaction to butyrophenones and phenothiazines, and usually occurs within the first few weeks of treatment. It involves increased heat generation and reduced heat loss. Promethazine has been implicated in its genesis, although the patients were reportedly taking a neuroleptic drug as well. A report of the neuroleptic malignant syndrome associated with promethazine alone is therefore of interest (10A).

180 A 42-year-old man took promethazine 50 mg every 4---6hours over a 2-day period and presented with hyperthermia (42.4 ~ C). He died 3 days later despite intensive care and treatment with bromocriptine. In another case neuroleptic malignant syndrome was attributed to diphenhydramine (llA). A 39-year-old man presented with a gait disturbance confusion, hyperthermia (38.2 ~ C), and hyperhidrosis after massive ingestion of a formulation containing diphenhydramine. With intensive support, including bromocriptine, he recovered within 12 days. The estimated dose of diphenhydramine was 40 mg • 60 tablets, and each tablet included 26 mg of diprophylline, a xanthine derivative. It has been reported that both promethazine and diphenhydramine modulate dopaminergic transmission. However, the genesis of the second case was less clear. Atropine-like effects occur with diphenhydramine, although signs such as muscle rigidity, akinesia, and hyperhidrosis, cannot be ascribed to anticholinergic activity. Furthermore, the patient had also taken sulpiride, which is a potent dopamine receptor antagonist. Liver H1 histamine receptor antagonists have been associated with liver damage, although often the patients have been taking other drugs. Cholestasis has been reported with cinnarizine (75 mg/day for 4 weeks) in the absence of other drugs ( 1 2A) and liver damage with mequitazine (13A). Skin Cutaneous reactions have been reported with diphenylpyraline hydrochloride (14 A), cetirizine (15A), pheniramine maleate in eye drops (16 A), and ethylenediamine (17 g ). Teratogenicity Antihistamines are generally contraindicated in pregnancy (SEDA-22, 177), because of lack of relevant data, but they are nevertheless widely used. Many years of clinical use have suggested that chlorpheniramine should be the antihistamine of choice, although studies with other antihistamines (18 c, 19c) have failed to provide evidence of teratogenicity. However, the samples may not have been large enough to provide adequate statistical power or to establish the true incidence of individual malformations. A study of the effect of treatment with diazepam and promethazine

Chapter 15

AnthonyN. Nicholson

during pregnancy carried out in the late 1980s has recently been published (20c). The minimal doses for the whole pregnancy were 50 mg and 250 mg respectively. At birth, children of both sexes in the diazepam group had lower birth weights, but did not have lower body weights at 8 months of age. There were no changes in body weight in the promethazine group. The incidence of major malformations with terfenadine (mean dose 30-120 mg/day has been estimated prospectively in women. Rates of major malformations d i d not differ from matched controls amongst those exposed during the first trimester. However, birth weight was lower in babies exposed to terfenadine, but not when babies below 2500 g were compared. The findings emphasize the general value of continued studies on antihistamines during pregnancy, and the findings with terfenadine may be equally applicable to its metabolite fexofenadine (21c). Risk factors Children The long-term safety of cetirizine (0.25 mg/kg bd) has been studied in children with atopic dermatitis (22c). The mean duration of exposure to cetirizine in 399 children was 16.8 months. The frequency of dropouts and serious events did not differ between cetirizine and placebo. There were no clinically important differences in neurological or cardiovascular events, growth, or behavioral or cardiovascular assessments between the groups. No child taking cetirizine had prolongation of the QTc interval. Drug overdose Two cases of overdosage with astemizole (200 mg in a 2-year-old child and 200 mg in a 16-year-old woman) were associated with cardiovascular complications (23R). The authors recommended that patients should be observed for at least 24 hours after overdosage with astemizole. A 35-year-old woman took diphenhydramine 16 g and developed hypertension and QRS prolongation; charcoal hemoperfusion and hemodialysis were used successfully (24A). A 48-year-old woman was found dead after taking guaifenesin, diphenhydramine, and chlorpheniramine with heart blood concentrations of 27, 8.5, and 0.2 mg/l respectively (25A). Drug interactions It is well established that inhibitors of CYP3A4 can lead to accumulation of unchanged terfenadine, causing prolonga-

Antihistamines

Chapter15

tion of the QT interval and ventricular dysrhythmias. However, little is known about the effects of terfenadine on the pharmacokinetics of other drugs, even though it is known that terfenadine itself inhibits CYP3A4 activity in human liver microsomes. Ten healthy volunteers took oral terfenadine 120 mg/day for 3 days and then took buspirone 10 mg; terfenadine had no significant effects on the pharmacokinetics of buspirone (26c). The effect of the concomitant administration of terfenadine and sparfloxacin on the QTc interval has been studied in healthy men aged 18-49 years (27c). Sparfloxacin was given in a dose of 400 mg on the first day and 200 mg/day thereafter for 3 days with terfenadine 60 mg bd. Terfenadine had no effect on the pharmacokinetics of sparfloxacin and there were no apparent effects on the QTc interval.

181 Single doses of erythromycin (333 mg) or ketoconazole (200 mg) were given to healthy men who used levocabastine, two sprays per nostril (0.05 mg/spray) bd for 6 days (28c). There were no changes in the pharmacokinetics of levocabastine or in the QTc interval. Chlorpheniramine enhances the efficacy of chloroquine in acute uncomplicated falciparum malaria, but the disposition of chloroquine in these circumstances is unpredictable. Chloroquine (25 mg/kg) was given orally over 3 days in combination with chlorpheniramine to Nigerian children with parasitemia (29c). The peak whole blood chloroquine concentration was increased and the time to peak concentration shortened. However, in further studies the addition of chlorpheniramine to chloroquine did not amplify the cardiac effects of chloroquine (30c).

REFERENCES 1. Routledge PA, Lindquist M, Edwards IR Spontaneous reporting of suspected adverse reactions to antihistamines: a national and international perspective. Clin Exp Allergy Suppl 1999; 29: 240~. 2. De Abajo FJ, Rodriguez LAG. Risk ofventricular arrhythmias associated with non sedating antihistamine drugs. Br J Clin Pharmacol 1999; 47: 307-13. 3. Crumb WJ. Rate dependent blockade of a potassium current in human atrium by the antihistamine loratadine. Br J Pharmacol 1999; 126: 575-80. 4. Affrime MB, Brannan MD. Lorber RR, Danzig MR. Cuss E A 3-month evaluation of electrocardiographic effects of loratadine in healthy individuals. Adv Ther 1999; 16: 149-57. 5. Moss AJ, Chaikin P, Garcia JD, Gillen M, Roberts DJ, Morganroth J. A review of the cardiac systemic side-effects of antihistamines: ebastine. Clin Exp Allergy Suppl 1999; 29: 200-5. 6. Moss AJ, Morganroth J. Cardiac effects of ebastine and other antihistamines in humans. Drug Saf 1999; 21: 69-82. 7. NegrottiA, Calzetti S. Cinnarizine-induced parkinsonism: ten years later. Mov Disord 1999; 14: 534. 8. Marti-Masso JF, Poza JJ. Reply. Mov Disord 1999; 14: 534-5. 9. Stucchi-Portocarrero S, Vega-Dienstmaier JM, Saavedra JE, Sag~isteguiA. [Akathisia, parkinsonism and depression induced by cinnarizine: a case report]. Rev Neurol 1999; 28: 876-8. 10. Chan-Tack KM. Neuroleptic malignant syndrome due to promethazine. South Med J 1999; 92: 1017-18.

11. Park-Matsumoto YC, Tazawa T. Neuroleptic malignant syndrome associated with diphenhydramine and diprophyllin overdose in a depressed patient. J Neurol Sci 1999, 162: 108-9. 12. Colle I, Renaert H, Naegels S, Hoorens A, Urbain D. Cinnarizine-induced cholestasis. J Hepatol 1999; 30: 553. 13. SasadaT, KoizumiM, Matsumoto M, Takegawa T, Kikukawa M, Oku K, Kitazawa T, Nishimura K, Kosima H, Vemura M, Fukui H. A case of druginduced liver injury caused by mequitazine. Acta Hepatol Jpn 1999; 40: 541-5. 14. Mori Y, Sugihara K, Noda T, Yudate T, Aragane Y, Tezuka T. A case of fixed drug eruption due to diphenylpyraline hydrochloride. Skin Res 1999; 41: 25-9. 15. KaramfilovT, Wilmer A, Hipler U-C, Wollina U. Cetirizine-induced urticarial reaction. Br J Dermatol 1999; 140: 979-80. 16. Parente G, Pazzaglia M, Vincenzi C, Tost A. Contact dermatitis from pheniramine maleate in eyedrops. Contact Dermatitis 1999; 40: 338. 17. Guin JD, Fields P, Thomas KL. Baboon syndrome from i.v. aminophylline in a patient allergic to ethylenediamine. Contact Dermatitis 1999; 40: 170-1. 18. Einarson A, Bailey B, Jung G, Spizzirri D, Baillie M, Koren G. Prospective controlled study of hydroxyzine and cetirizine in pregnancy. Ann Allergy Asthma Immunol 1997; 78: 183-6. 19. Mazzota P, Koren G. Motherisk update. Non sedating antihistamines in pregnancy: considering astemizole. Can Fam Phys 1997; 43: 150911.

182 20. Czeisel AE, Szegal BA, Jotte JM, Racz J. The effect of diazepam and promethazine treatment during pregnancy on the somatic development of human offspring. Neurotoxicol Toxicol 1999; 21: 157-67. 21. Loebstein R, Lalkin A, Addis A, Costa A, Lalkein I, Bonati M, Koren G. Pregnancy outcome after gestational exposure to terfenadine: a multicenter, prospective controlled study. J Allergy Clin lmmunol 1999; 104: 953-6. 22. Simons FER. Prospective, long-term safety evaluation of the Hi-receptor antagonist cetirizine in very young children with atopic dermatitis. J Allergy Clin lmmunol 1999; 104: 433-40. 23. Bosse GM, Matyunas NJ. Delayed toxidromes. J Emerg Med 1999; 17: 679-90. 24. Mullins ME, Pinnick RV, Terhes JM. Life threatening diphenhydramine overdose treated with charcoal hemoperfusion and hemodialysis. Ann Emerg Med 1999; 33: 1194-7. 25. Wogoman H, Steinberg M, Jenkins AJ. Acute intoxication with guaifenesin, diphenhydramine and chlorpheniramine. Am J Forensic Med Pathol 1999; 20: 199-202. 26. Lamberg TS, Kivisto KT, Neuvonen PJ. Lack of

Chapter 15

Anthony N. Nicholson

effect of terfenadine on the pharmacokinetics of the CYP3A4 substrate buspirone. Pharmacol Toxicol 1999; 84: 165-9. 27. Morganroth J, Hunt T, Dorr MB, Magner D, Talbot GH. The effect of terfenadine on the cardiac pharmacodynamics of sparfloxacine. Clin Ther 1999; 21: 1514-24. 28. Pesco-Koplowitz L, Hassell A, Lee P, Zhou H, Hall N, Wiesinger B, Mechlinski W Grover M, Hunt T, Smith R, Travers S. Lack of effect of erythromycin and ketoconazole on the pharmacokinetics and pharmacodynamics of steady state intranasal levocabastine. J Clin Pharmacol 1999; 39: 76-85. 29. Okonkwo CA, Coker HAB, Agomo PU, Ogunbanwo JA, Mafe AG, Agomo CO, Afalabi BM. Effect of chlorpheniramine on the pharmacokinetics of and response to chloroquine of Nigerian children with falciparum malaria. Trans R Soc Trop Med Hyg 1999; 93:306-11. 30. Sowumni A, Fehintola FA, Orundahunsi AT, Off AB. Happi TC, Oduola AMJ. Comparative cardiac effects of halofantrine and chloroquine plus chloropheniramine in children with acute uncomplicated falciparum malaria. Trans R Soc Trop Med Hyg 1999; 93: 78-83.

Tracey D. Robinson, Adrian E Havryk and J. Paul Seale

16 LEUKOTRIENE

Drugs acting on the respiratory tract MODIFIERS

The leukotriene modifiers comprise drugs that interfere with the actions of leukotrienes in two ways:

(1)

(2)

as inhibitors of 5-1ipoxygenase, the first step in the conversion of arachidonic acid to cysteinyl leukotrienes (e.g. zileuton); as antagonists of cysteinyl leukotrienes, which block the CysLT1 receptors (e.g. zafidukast, montehikast, pranhikast).

Several leukotriene modifiers have been launched after extensive preclinical and clinical assessment, and by early 1998 these drugs were available on prescription in many countries. They are indicated for the long-term control of asthma. Comparative studies with inhaled corticosteroids have shown that they are no more potent than beclomethasone dipropionate 400 Ixg/day. All the currently available leukotriene modifiers are taken as oral formulations and they have been generally well tolerated in clinical trials and in postmarketing surveillance studies.

Leukotriene receptor antagonists and Churg-Strauss syndrome Churg-Strauss syndrome is a rare form o f allergic granulomatous vasculitis, in which severe asthma, fever, and eosinophilia are associated with necrotizing granulomata and eosinophilic infiltration o f multiple tissues throughout the body. Eight patients with steroid-dependent asthma, who had been able to either discon-

9 2001 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

tinue or reduce their oral corticosteroid requirement subsequent to starting treatment with zafirlukast, developed Churg-Strauss syndrome (IR). It was postulated that the patients had a primary eosinophilic disorder, which was unmasked by the reduction (or withdrawal) of corticosteroids, which was possible because the addition of zafirlukast had controlled their asthma. A subsequent report o f two patients, who were not taking systemic corticosteroids and developed Churg-Strauss syndrome in association with zafirlukast, raised some doubts about the hypothesis (2A ). However, there must be uncertainty about implicating zafirlukast in one o f these cases, as there appeared to be a delay o f 2 months from the withdrawal o f zafirlukast to the onset o f symptoms, which were subsequently attributed to Churg-Strauss syndrome. There has also been a case report of Churg-Strauss syndrome in a 52-year-old woman some 12 weeks after beginning treatment with pranlukast and 8 weeks after discontinuing low-dose oral prednisolone (5 mg on alternate days) (3A ). Churg-Strauss syndrome has also been reported with montelukast in a patient who had not taken oral corticosteroids. Symptoms developed within 2 days of beginning treatment with montelukast (4 a ). There are now sufficient cases o f ChurgStrauss syndrome to estimate its incidence as probably less than one per 20000 patients. Whilst this may be more than the estimated incidence o f this syndrome in the general population, this apparent increase in incidence does not of itself implicate the drugs as being causal. For example, there may be increased detection related to the increased vigilance associated with the introduction of this new class o f drugs. If the antileukotriene drugs are implicated in some way in the development o f ChurgStrauss syndrome the precise mechanism is unI~

184

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certain. Unmasking pre-existing Churg-Strauss syndrome by permitting corticosteroid withdrawal is one possibility. Another possibility is that the drugs elicit an allergic response that manifests itself as a granulomatous angiitis, a phenomenon that has been reported rarely with other drugs. Current evidence indicates that ChurgStrauss syndrome is rare in patients who take oral leukotriene receptor antagonists. Most patients had to reduce or discontinue oral corticosteroids, raising the distinct possibility that pre-existing Churg-Strauss syndrome was unmasked by corticosteroid withdrawal There remains the unlikely possibility that in some cases there is direct allergy to the drugs, manifesting as a granulomatous angiitis. In any event, clinicians should be aware of this possibility, although it is rare, and discontinue the drugs in cases of suspicion and undertake appropriate investigations. Other case reports of interest include pulmonary eosinophilia in association with montelukast (5A) and the clinical exacerbation of ulcerative colitis in a patient with steroid dependent asthma after the introduction of zafirlukast (6a). Drug-induced lupus syndrome has been reported in a child with an onset 10 days after beginning treatment with zafirlukast. The child had not been taking oral corticosteroids ( 7A).

INDIVIDUAL DRUGS Montelukast Montelukast has been taken by about 2500 patients in over 40 clinical trials. Its adverse events have not been significantly different from those of placebo. Drug interactions Montelukast is extensively metabolized to 21- and 36-hydroxylated and dicarboxylic acid metabolites, which are excreted in the bile. The steady-state plasma concentrations of these metabolites are below the limit of detection in adults and children. In vitro studies have shown that high concentrations of montelukast inhibit CYP3A4 and CYP2C9, but in clinical studies the recommended dose of 10 mg/day did not interfere with metabolism of important cfftochrome P450 substrates, such as warfarin (8'~).

TraceyD. Robinson, Adrian P Havryk and J. Paul Seale

Pranlukast Pranlukast was developed primarily for the Japanese market and there is little international experience of it. To date, adverse events have occurred in under 1% of patients and gastrointestinal effects were the most common, accounting for 4.7% of reported adverse events (9R).

Zafirlukast In the early clinical trials a range of doses of zafirlukast were used. With higher doses (80 mg bd) serum liver enzymes were occasionally raised. In subsequent clinical trials with 20 mg bd a raised AIT was twice as common as in patients taking placebo (10c). Drug interactions Zafidukast has several clinically important drug interactions. It reduces the clearance of warfarin, resulting in a clinically significant prolongation of prothrombin time (11c). The mechanism for this interaction is thought to be inhibition of cytochrome P450 enzymes, such as CYP2C9. Its effects on other substrates of these isozymes, such as calcium antagonists and ciclosporin, have not been formally studied. Zafidukast 20 mg bd for 12 days did not interfere with the metabolism of macrolide antibiotics such as azithromycin or clarithromycin (12 c). The plasma concentrations of zafirlukast are reduced when it is administered concurrently with theophylline or erythromycin.

Zileuton There was an asymptomatic rise in AsT (by a factor of three or more) in 4.6% of patients taking zileuton 600 mg qds compared with 1.6% of patients taking placebo (13c). These rises returned to normal promptly after withdrawal (14c). Based on these findings in clinical trials, it is recommended that serum aminotransferase activities should be measured before starting treatment with zileuton, repeated monthly for 3 months, and then periodically thereafter. Drug interactions Zileuton interacts with warfarin and theophylline (15R). It is thought that it competitively inhibits CYP1A2 and CYP2C9. In view of this drug interaction, pa-

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tients taking warfarin or theophylline require close monitoring when they take zileuton.

improves with continued use of the inhaled corticosteroids, it is likely that the lung bioavailability of inhaled corticosteroid will increase. This likely outcome is a compelling argument for reducing the dose of inhaled corticosteroids to the lowest dose that maintains optimal control of asthma and optimal lung function. The hypothalamic-pituitary-adrenal axis is a readily measurable biological marker of the systemic availability of inhaled corticosteroids, but it is not known whether it correlates with more important indices of clinically relevant outcomes, such as bone mineral density. Since many patients with allergic asthma also have rhinitis, they may be taking both inhaled corticosteroids for their asthma and intranasal formulations for their hay fever. The total systemic availability of corticosteroids has been studied after the addition of intranasal therapy in patients already taking inhaled corticosteroids (21 C) in 12 moderately severe asthmatic subjects (mean FEV1 84% predicted), who were randomized in a placebocontrolled, two-way, cross-over comparison of inhaled fluticasone (880 lzg bd) and intranasal fluticasone (200 lzg od), inhaled triamcinolone (800 Izg bd) and intranasal triamcinolone (220 lzg od), and respective placebos. Both inhaled corticosteroids caused significant suppression of adrenocorticoid activity, although the addition of intranasal formulations did not produce further significant suppression. There were more individual subjects with abnormally low cortisol values when intranasal fluticasone was added. These findings suggest that the dose of intranasal corticosteroids should be taken into account (particularly if used in the long term) when considering the systemic availability of corticosteroids used in the treatment of asthma and hay fever.

INHALED CORTICOSTEROIDS (SED-14, 508; SEDA-21, 187; SEDA-22, 182; SEDA-23, 175)

Systemic availability of inhaled corticosteroids The major interest with respect to adverse effects of inhaled corticosteroids is the extent of systemic absorption. In healthy volunteers high doses of both budesonide and fluticasone were readily absorbed after inhalation from a metered dose aerosol (16c). Fluticasone is extensively metabolized by the liver, so measurable concentrations of parent drug in the systemic circulation reflect efficient absorption across the lung. Lower doses of these inhaled corticosteroids also result in some systemic absorption, reflected in effects on the hypothalamic-pituitary-adrenal axis (17C). Recent studies have shown that the extent of absorption of inhaled corticosteroids tends to be less in asthmatic subjects than in healthy volunteers. In a study of fluticasone (500 Izg via a dry powder device) in asthmatic patients with a wide range of severity there was a highly significant linear correlation between lung function (expressed as percentage predicted FEV1) and the absolute magnitude of adrenal suppression (18c). In 11 patients with moderately severe asthma (mean FEV1 54% predicted), who took fluticasone 1000 I~g daily via a pressurized metered dose inhaler with a spacer, the systemic availability of fluticasone was significantly less (10%) than in 13 healthy controls (21%). The plasma fluticasone concentrations (expressed as AUC) correlated positively with gas transfer (19c). In contrast, there was no difference in plasma concentrations of fluticasone and budesonide between 15 mild asthmatics (mean FEV1 81% predicted) and healthy volunteers after inhalation of 1000 lzg of either drug with single or repeated dosing (20c). Taken together, these studies suggest that patients with severe asthma are protected from the systemic adverse effects of high doses of inhaled corticosteroids, owing to airways obstruction and reduced lung bioavailability. However, as their lung function

Endocrine Deterioration in glucose control has been described in a 64-year-old man with non-insulin-dependent diabetes mellitus (22A). High doses of both fluticasone (2000 ltg/day) and budesonide (2000 Itg/day) had produced glycosuria despite treatment with glibenclamide and metformin 1700 mg/day. On reducing the dose of budesonide there was a commensurate fall in glycosylated haemoglobin and glycosuria. There was no glycosuria at a daily maintenance dose of 800 Ixg and the glycosylated haemoglobin fell from 8.2% to 7.2%.

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This case shows that high-dose corticosteroids can aggravate the control of diabetes in some patients. Skin Since the original observation of the association between high-dose corticosteroids and purpura and dermal thinning, easy bruising o f the skin has become recognized as a systemic adverse effect of inhaled corticosteroids (23c). In a double-blind cross-over study 69 asthmatic subjects received either the usual dose of beclomethasone dipropionate or fluticasone (at half the dose of beclomethasone) each for 4 months (24 C). The frequency and severity of skin bruising were assessed by questionnaire and the numbers of bruises were assessed by direct examination. The dose of fluticasone was selected on the basis of previous studies that showed that it had comparable efficacy when given in half the dose of beclomethasone. This dose of fluticasone had comparable efficacy with respect to the control of asthma, but there was no skin bruising. These findings suggest that the systemic availability of equieffective doses of fluticasone is less than that of beclomethasone. Musculoskeletal Biochemical markers of bone metabolism, such as calcium, hydroxyproline, and pyridinyline cross-links (as markers of bone resorption), and alkaline phosphatase, osteocalcin, and procollagen peptides (as markers of bone formation), have been measured in many studies, but it has been difficult to interpret observed changes (SEDA-22, 178). While these indices may be sensitive to the effects of corticosteroids in the short term, the relation between changes in these markers and intermediate measures, such as bone mineral density, and the more important clinical outcomes of fractures, remains unknown. In a random stratified sample of 3222 women in the perimenopausal age range (47-56 years), including 119 women with asthma, bone mineral density was measured to determine whether asthma was a risk factor of osteoporosis and to investigate the effect of inhaled corticosteroids (25c). The subjects had predominantly adultonset asthma, as the age at diagnosis was over 40 years. There were 26 patients who were treated mainly with inhaled corticosteroids (average dally dose 1000 Ixg). The asthmatic women in this general perimenopausal population had slightly reduced spinal and femoral neck bone mineral density compared with non-

TraceyD. Robinson, Adrian P. Havryk and J. Paul Seale asthmatic women. These differences were more prominent in women who were not taking hormone replacement therapy. The reduction in bone mineral density may be due to corticosteroids, and hormone replacement therapy appears to be protective against bone loss in asthmatics as well as healthy subjects. Cross-sectional studies such as this provide information about association but do not imply causality, for which longitudinal studies are required. Bone mineral density has been measured at 3-year intervals in 51 patients taking inhaled corticosteroids for asthma (26c). The patients were divided into a high-dose group taking over 800 Ixg/day of beclomethasone or budesonide (n = 28, mean dose 983 Ixg/day) and a control group taking no inhaled corticosteroid or less than 500 txg/day (n = 23, mean dose 309 Ixg/day). Whilst there were statistically significant reduction in bone markers, such as serum calcium and phosphorus and osteocalcin, over the 3-year period in each group, there was no significant reduction in bone mineral density in either group of asthmatic patients. Although the change in bone mineral density in the high-dose group was small over the 3-year period and not statistically significant, there was a correlation between bone loss and the daily dose of inhaled corticosteroids. There was no significant correlation between the changes in bone density and either the initial bone density or biomarkers of bone turnover for the level of physical activity. This longitudinal study has shown the unreliability of biomarkers of bone turnover in predicting changes in bone density (and presumably relevant clinical outcomes, such as risk of fracture) and shows the need for measurement of bone mineral density in asthmatic patients who are deemed to be at risk of bone loss. Such patients include those taking oral corticosteroids, perimenopausal women not taking hormone replacement therapy, and patients who need high doses of inhaled corticosteroids. Whilst patients in this study did not have significant changes in bone mineral density over 3 years, the effects of higher doses remain uncertain, so it would be prudent to measure bone mineral density in patients who need higher doses. The long-term effects of inhaled corticosteroids on growth in children have been recently assessed. In the so-called CaAMP Study (27 C) children aged 5-12 years with mild to moderate asthma were randomized to budesonide 200 txg bd (n = 311), nedocromil 8 mg bd (n = 312), or

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placebo (n = 418). At the end of the 4-6 year treatment period, the mean increase in height in the budesonide group was 1.1 cm less than in the placebo group. The difference between budesonide and placebo in the rate of growth was evident primarily within the first year but did not increase thereafter, and all the groups had similar growth velocity by the end of the treatment period. Children taking budesonide (mean daily dose 412 Ixg, range 110-877 Ixg) for periods of 3-13 years have been followed to adulthood to determine their final height (28c). These 142 budesonide-treated children were compared with 18 control patients with asthma who had never taken inhaled corticosteroids and 51 healthy siblings of the patients in the budesonide group. These children, who had taken long term inhaled corticosteroids, attained normal adult height. There was no evidence of a dose-response relation between the mean daily dose of budesonide, the cumulative dose, or the duration of treatment with budesonide and the difference between the measured and target adult heights. These findings suggest that long-term treatment with inhaled corticosteroids in the dosages used in this study do not have any important adverse effects on adult height. These two studies are important, because several previous reports of growth during a period of 1 year after beginning treatment with inhaled corticosteroids (in dally doses of about 400 Ixg of budesonide) identified growth retardation of about 1.5 cm. The mechanism for the termination after 1 year of the effects on growth remains uncertain.

moterol showed a dose-response relation, with maximum protection at the highest dose. This confirmed the authors' hypothesis that salmeterol is a partial agonist at/3-adrenoceptors compared with formoterol. The higher affinity of formoterol for fl-adrenoceptors also produced more adverse effects. There was a significant fall in serum potassium concentration after the 60 Ixg dose of formoterol but not after 250 Ixg of salmeterol. The serum potassium concentration was also significantly lower with the highest dose of formoterol compared with the highest dose of salmeterol (minimum concentration 3.1 mmol/1). The highest dose of formoterol also resulted in more tremor than the highest dose of salmeterol. The increases in heart rate and QTc interval were similar with the two drugs. It should be noted that the doses used in this study were higher than recommended. It remains unclear whether the partial agonist activity of salmeterol is clinically important, but this seems unlikely.

,82-ADRENOCEPTOR AGONISTS (SED-14, 500; SEDA-21, 179; SEDA-22, 188; SEDA-23, 181) The relative efficacy of the long-acting /~2adrenoceptor agonists formoterol and salmeterol has been studied in a randomized, doubleblind, crossover trial in 15 patients with asthma taking regular corticosteroids and salbutamol (29c). The patients had methacholine challenges performed after varying single doses of formoterol (12, 60, and 120 Ixg) and salmeterol (50, 250, and 500 Ixg). The maximal protective effect of salmeterol against methacholine challenge was reached at 250 Ixg, whereas for-

Tolerance to the effects of formoterol and salmeterol Current guidelines recommend the use of formoterol and salmeterol in addition to inhaled corticosteroids for optimal management of asthma. Both drugs are highly selective fieadrenoceptor agonists, with minor pharmacological differences. Several studies have shown that regular use of both formoterol and salmeterol results in the development of tolerance to their bronchoprotective effects, even with treatment periods as short as 1 week. The significance of this tolerance is unclear, but it is potentially important clinically. Previous studies over periods of up to 8 weeks have established that the bronchoprotective effect of salmeterol abates with regular use, even after only 1 week of regular treatment. The effects of longer-term use of salmeterol on airway hyper-responsiveness have been examined in a randomized, double-blind, placebo-controlled trial in 408 patients with mild asthma (30c). These patients were not using inhaled corticosteroids and took salmeterol (42 txg bd) or placebo for 24 weeks. Methacholine challenges were performed at 4, 12, and 24 weeks. At 4 weeks salmeterol provided protection against methacholine of about one doubling dose and there was

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no further change in this protection over the study period. As expected, regular salmeterol produced significant improvements in asthma symptoms. Adverse events were similar in the two groups, apart from headache, which was reported in 14 of 202 patients treated with salmeterol and seven of 206 patients taking placebo. The loss of bronchoprotection that develops with regular salmeterol did not appear to worsen over a 24-week period. The effect of inhaled budesonide on the loss of bronchoprotection with regular salmeterol has been studied in a randomized double-blind trial in 18 patients with mild asthma, taking no regular medications (31c). After 1 week of regular salmeterol (50 Izg bd) 12 patients developed tolerance to its protective effect against airway allergen. After another week of salmeterol combined with either inhaled budesonide (500 lzg bd) or placebo, the patients who took budesonide showed some recovery of the protective effect of salmeterol against airway allergen compared with placebo. The authors suggested upregulation of fl-adrenoreceptors as a potential mechanism. The effect of a bolus of inhaled budesonide on formoterol-induced subsensitivity in airway ~-adrenoreceptors has been studied in a randomized, double-blind, cross-over study in 10 asthmatic patients taking regular inhaled corticosteroids (32c). Challenge testing with AMP was performed at baseline and after 1 week of regular formoterol (24 Izg bd). Before the second challenge the patients were given either a dose of inhaled budesonide (1600 lzg) or placebo via a dry powder inhaler. After I week of formoteroL the PC2o for the second challenge fell significantly (by a factor of 3.9). However, when the second challenge was performed after a bolus of budesonide, there was no fall in the PC2o, suggesting protection against formoterol-induced tolerance. Lymphocyte ~-adrenoceptor density fell with regular formoterol, but not after a bolus of budesonide. These results have implications for the treatment of acute severe asthma in patients taking regular long-acting ~2-adrenoceptor agonists. It may be appropriate to give a bolus dose of inhaled corticosteroids to these patients early in an acute asthma attack, particularly if they are poorly responsive to initial therapy with short-acting bronchodilators.

TraceyD. Robinson, Adrian P. Havryk and J. Paul Seale Drug interactions The interaction of formoterol and salmeterol with salbutamol has been studied in a randomized, double-blind, cross-over study in 16 asthmatic patients (33c). The patients were taking regular inhaled cortieosteroids and were responsive to methacholine challenge, with a PD20 (i.e. the dose of methacholine that produced a fall in FEV1 of 20%) of less than 500 Ixg. The patients had methacholine challenges performed 12 hours after a single dose of formoterol 12 txg, salmeterol 50 Ixg, placebo, and either a low dose (400 Ixg) or a high dose (1600 I~g) of salbutamol. With placebo, challenge after high-dose salbutamol resulted in a higher PD20 than after low-dose salbutamol (as expected). However, after both formoterol and salmeterol, the higher dose of salbutamol did not give as great an increase in PD20 over the lower dose of salbutamol. This suggests that prior treatment with formoterol and salmeterol can antagonize the protective effect of salbutamol against bronchoconstriction. This effect may be important in patients with acute asthma.

INDIVIDUAL DRUGS Bambuterol Bambuterol is an oral prodrug of terbutaline that results in a bronchodilator effect lasting 24 hours. Oral bambuterol (20 mg at night) has been compared with inhaled salmeterol (50 Ixg bd) for persistent nocturnal symptoms in 117 asthmatics already taking inhaled corticosteroids in a randomized, double-blind, placebo controlled trial for 6 weeks (34c). The treatments resulted in significant and equivalent improvements in nocturnal and daytime asthma symptoms, peak flow, and the use of short-acting fl-adrenoceptor agonists. Drug-related adverse events included headache (six with bambuterol, two with salmeterol), tremor (three in each group), cramps (two with bambuterol) and palpitation (three with bambuterol, one with salmeterol). Four patients taking bambuterol withdrew owing to possible drug-related adverse effects (insomnia, headache, flushing, and mental excitation) compared with one patient taking salmeterol (tremor). Bambuterol appears to be a safe and effective alternative to inhaled

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long-acting fl2-adrenoceptor agonists for poorly controlled nocturnal symptoms in asthma. The efficacy of long-acting 132-adrenoceptor agonists in patients with chronic obstructive pulmonary disease remains unclear, but their role in treatment regimens, particularly in comparison with oral theophylline, has recently been reviewed (35R). The authors referred to a comparison of oral bambuterol and salmeterol in patients with chronic obstructive pulmonary disease, in which both drugs resulted in good bronchodilatation but bambuterol alone caused significant and long-lasting tachycardia and tremor. The authors also discussed the potential effects of long-acting fl2-adrenoceptor agonists on the heart in patients with chronic obstructive pulmonary disease, but there have been no studies of this.

50 ktg plus fluticasone 250 Ixg delivered via a combination inhaler and via separate inhalers have been compared in 371 asthmatic patients (37c). There were equivalent improvements in peak flows and asthma symptoms. Candidiasis, dysphonia, and throat irritation were the commonest adverse effects attributed to treatment and occurred equally in the two groups (35%). Palpitation and tremor, which may be related to salmeterol, occurred in 2% (for each symptom) of the combination group and in 1% and under 1% of the separate inhaler group. In both of these studies compliance was measured by dose counters on the inhalers and was equivalent in the two groups. It appears that treatment with fluticasone plus salmeterol delivered via a combination inhaler is as effective as the same drugs given in separate inhalers and has a similar adverse effects profile. Whether treatment with a combination inhaler improves compliance is not yet proven.

Salmeterol plus fluticasone ("Seretide") Combination formulations of fluticasone with salmeterol delivered through a dry powder inhaler have recently become available. These formulations are intended to provide the currently recommended treatment for asthma (a combination of an inhaled corticosteroid and a long-acting fl2-adrenoceptor agonist) in one dose, simplifying the treatment regimen and so possibly improving compliance. Salmeterol 50 txg plus fluticasone 500 Ixg bd delivered via a combination inhaler (plus a placebo inhaler) have been compared with the same drug regimen delivered by separate inhalers in a randomized double-blind trial over 28 weeks in 503 asthmatic patients already taking inhaled corticosteroids (36c). There was also an arm treated with inhaled fluticasone alone. Outcome variables were peak flows and asthma symptoms. Both combination and concurrent therapy with fluticasone plus salmeterol resulted in significantly better symptom control and higher peak flows than fluticasone alone. There were no significant differences in the effects of fluticasone plus salmeterol delivered in a combination inhaler versus separate inhalers. Drug-related adverse effects were similar in all three treatment groups: most were asthma-related, but hoarseness, dysphonia, and throat irritation were the commonest adverse effects attributed to therapy (1-4%). In a similarly designed trial the effects of salmeterol

ANTICHOLINERGIC DRUGS (SED-14, 498; SEDA-21, 187; SEDA-22, 193; SEDA-23, 187) Tiotropium is a specific and potent muscarinic receptor antagonist, which dissociates very slow from its receptors (38R). This property seems to explain its long lasting bronchodilatory effect. In repeated dose studies of 4.5, 9, 18, and 36 Ixg od for 28 days, in 169 patients with chronic obstructive pulmonary disease, each dose was significantly more effective than placebo, as shown by increased effects with increasing dose on FEV1 and peak expiratory flow. At doses of 9 Ixg and above there were detectable concentrations of the drug at peak (5 minutes after inhalation), but a trough plasma concentration was only measurable with the 36 Ixg dose. At the highest dose, three of 34 patients reported a dry mouth compared with none of 35 patients taking placebo. This preliminary study suggests that the anticholinergic activity of tiotropium will cause some systemic adverse effects at high doses.

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NITRIC OXIDE Nitric oxide has been used in the treatment of patients with primary pulmonary hypertension and is now used in subgroups of severely ill and hypoxic children with persistent pulmonary hypertension of the newborn and in adults with acute lung injury and adult respiratory distress syndrome. There are now some reports of its use for intestinal ischemia, reperfusion injury, thrombotic disorders, and sickle cell crises. The role of nitric oxide therapy in infants with severe acute hypoxemic respiratory failure has been reviewed (39R). Inhaled nitric oxide was extremely well tolerated. Inhalation of 80 ppm rapidly improved oxygenation in patients with persistent pulmonary hypertension of the newborn (40c). In three randomized multicenter clinical trials there was a reduction in requirement for extracorporeal membrane oxygenation, with no significant adverse effects. Neither methemoglobinemia, high nitrogen dioxide, nor increased rates of intracranial hemorrhage were noted. In the NINOS trial in 235 term neonates (41 C) the study gas was not withdrawn in any patient because of toxicity. In another study of 58 term neonates receiving inhaled nitric oxide 80 ppm a reduction in the use of extracorporeal membrane oxygenation (from 71% to 40%) was achieved without significant adverse effects (42c).

Cardiovascular The adverse effects and toxicit~ of inhaled nitric oxide have been reviewed (43~). There have been several case reports that high doses of nitric oxide (40--80 ppm) reduce pulmonary vascular resistance and increase pulmonary capillary wedge pressure in some patients with left ventricular dysfunction. The acute increase in left ventricular filling pressure that ensues may cause or exacerbate pulmonary edema. The author concluded that in patients with severe left ventricular dysfunction (pulmonary capillary wedge pressure over 25 mmHg) it would be prudent to avoid the use of inhaled nitric oxide. Systemic hypotension has been reported after the introduction of inhaled nitric oxide (44A). A 72-year-old woman, who underwent emergency resection of a giant left atrial myxoma, had pulmonary hypertension (pulmonary artery pressure 40 mmHg) and a low cardiac output (2.2 l/rain). Inhaled nitric oxide, 40 ppm, before cardiopulmonary

TraceyD. Robinson, Adrian P. Havryk and J. Paul Seale bypass resulted in pulmonary vasodilatation and a fall in pulmonary artery pressure from 39 to 31 mmHg. This was accompanied by a fall in cardiac output from 2.4 to 1.5 1/min and a fall in mixed venous oxygen saturation. After bypass inhaled nitric oxide improved pulmonary and systemic hemodynamics and resulted in a rise in cardiac output from 3.0 to 3.5 1/min. The authors concluded that inhaled nitric oxide had reduced pulmonary hypertension and pulmonary vascular resistance, but that obstruction by the atrial myxoma had caused the low cardiac output, due to a net reduction in transpulmonary pressure.

Respiratory In animal and in vitro studies inhaled nitric oxide has led to surfactant inactivation and promotion of oxidative and nitrosylative lung injury (39E). These effects have not been reported during clinical use of inhaled nitric oxide at concentrations less than 80 ppm. Hematologic Nitric oxide activates guanylate cyclase and increases cGMP concentrations, thus inhibiting platelet aggregation and agglutination in vitro (43 AR, 45R). The apparently high rate (63%) of intracranial hemorrhage in preterm neonates given inhaled nitric oxide (46 c) has not been confirmed in subsequent larger trials or in comparisons with matched controls from a large database (39c). In addition, the frequency of bleeding complications in adults and children treated with inhaled nitric oxide has not been significantly increased in comparison with matched controls (45 R, 46 C). It would seem that impaired platelet function and an increased risk of intracranial hemorrhage in preterm infants have not been substantiated in larger trials. Nitric oxide oxidizes hemoglobin to methemoglobin, two-thirds of which is reduced by nicotinamide adenine dinucleotide (NAD) metbemoglobin rednctase (43AR). Several ethnic groups, such as native Americans have NAD methemoglobin reductase deficiency. There have been reports of methemoglobinemia after accidental overdosage of inhaled nitric oxide in native Americans and others (43AR). A native American woman developed a rise in methemoglobin from 0.9% to 9.4% over 6 hours of inhaled nitric oxide therapy, 80 ppm; with reduction of the dose to 40 ppm, methemoglobin returned to baseline concentration. A patient who received inhaled nitric oxide through an imprecise delivery

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device had a methemoglobin concentration of 67%. Another patient who received a dose of 110 ppm had a methemoglobin concentration of 19%.

tress syndrome treated with inhaled nitric oxide, five developed rebound hypertension and arterial desaturation when inhaled nitric oxide was weaned (49c). In an open-label phase II pilot study of 16 infants over 4 weeks of age with severe bronchopulmonary dysplasia, inhaled nitric oxide, 20 ppm, led to a significant reduction (over 15%) in the concentration of inspired oxygen required to maintain satisfactory arterial oxygen saturation in 11 infants (50c). There were no significant adverse effects at doses of 20 ppm. Of the 11 responders, seven developed episodes of desaturation within 10 minutes of withdrawal of inhaled nitric oxide after being weaned to under 8 ppm. Typically, a transient (30 minute) desaturation from 95% to 81% occurred after withdrawal of inhaled nitric oxide. On reinstituting therapy the desaturation rapidly reversed. The authors postulated that this effect may have been due to downregulation of endogenous nitric oxide synthase. In a retrospective case-control study, 12 children with severe pulmonary hypertension were treated with inhaled nitric oxide followed by prostacyclin 10 nanogram/kg/min for 24 hours before gradual withdrawal of nitric oxide; the 12 matched controls did not receive prostacyclin (51CR). Only one of the patients developed rebound hypertension, indicated by arterial desaturation (a 5% or greater fall in S a t 2 within 4 hours of withdrawal), while eight of 12 controls developed the rebound effect. There have been several case reports on the use of sildenafil to ameliorate rebound pulmonary hypertension (52AR).

In a phase II trial of 177 patients with adult respiratory distress syndrome, four developed a methemoglobin concentration over 5% but none had a concentration over 7%; one received placebo, one received inhaled nitric oxide 40 ppm, and two received 80 ppm. There may also be partial deficiency of methemoglobin reductase in neonates (43AR). In the Neonatal Inhaled NO study (NINOS) the dose of inhaled nitric oxide had to be reduced in 11 of 114 patients (9.6%) because of raised methemoglobin. At doses of 1.2580 ppm, methemoglobinaemia is uncommon; in one study only three of 471 (0.6%) [~atients discontinued therapy for this reason (46K). U r i n a r y t r a c t The effect of inhaled nitric oxide 2, 10, or 40 ppm on the frequency of reversal of acute lung injury in nitric oxide responders has been examined in an open-label randomized trial in 268 patients, of whom 180 were responders (Pat2 increased by more than 20% within 10 minutes) (47c). The patients were randomized into equal groups to receive conventional treatment with or without inhaled nitric oxide. Nitric oxide was given in the lowest effective dose until an end point (reversal of acute lung injury or severe respiratory failure) was reached or for 30 days. There was a significantly higher rate of renal insufficiency requiring renal replacement therapy in those given inhaled nitric oxide (25% vs 12%). The reasons for this were unclear. Although the groups were heterogeneous, both groups were similarly matched for risk of renal insufficiency at the start of the trial. The difference could have been due to a true adverse effect or to investigator bias in an openlabel study. Owing to the absence of preclinical data suggesting renal toxicity and the absence of a known physiological route that could result in renal impairment, it is reasonable to conclude that the effect may have been due to random chance (48R). Drug withdrawal Rebound pulmonary hypertension due to pulmonary vasoconstriction with accompanying deterioration of arterial oxygenation is now well described during weaning or abrupt withdrawal of inhaled nitric oxide. Of 88 patients with adult respiratory dis-

A 6-week-old 3.1-kg girl developed severe pulmonary hypertension and systemic hypotension after the removal of a bilateral pulmonary vein obstruction due to a left atrial membrane. Nitric oxide 20 ppm reduced the pulmonary arterial pressure from 57 to 33 mmHg and plasma cyclic GMP concentrations increased from 12 nmol/l at baseline to 28 nmol/1 with nitric oxide. After three unsuccessful weaning attempts, due to rebound, sildenafil 1 mg was given via a nasogastric tube and nitric oxide was withdrawn 90 minutes later, with minimal increase in pulmonary artery pressure and a rise cGMP concentration to 45 nmol/1. A 3.5-kg newborn girl, who underwent corrective surgery for an infradiaphragmatic totally anomalous pulmonary venous connection, had postoperative systemic hypotension, low cardiac output, and pulmonary hypertension. Inhaled nitric oxide 20 ppm improved her pulmonary hemodynamics but could not be withdrawn by the third postoperative day, owing to reflex pulmonary hypertension. Sildenafil 1

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mg via nasogastric tube again allowed withdrawal of nitric oxide with preservation of plasma cGMP concentrations above baseline. A 4-month-old 4.1-kg boy with severe bilateral pulmonary vein stenosis developed moderate pulmonary hypertension after surgical revision. Sildenafil 1.1 mg via nasogastric tube did not increase the plasma cGMP concentration or reduce the rebound effect. The authors suggested that in this case the effect of sildenafil may have been reduced by impaired gastrointestinal absorption. The authors speculated that exogenous nitric oxide inhibits nitric oxide synthase activity, with a consequent reduction in pulmonary vascular smooth muscle cGMP concentration. Phosphodiesterase type V inhibitors, such as sildenafil, increase cGMP concentration and ameliorate the rebound effect. Severe systemic arterial hypotension has been reported after inadvertent withdrawal of nitric oxide (53A). A 37-year-old woman with acute respiratory failure due to Pneumocystis carinii pneumonia 6 months after allogeneic bone-marrow transplantation developed adult respiratory distress syndrome. Because of deteriorating gas exchange, mechanical ventilation and inhaled nitric oxide 10 ppm were given, with improvement in gas exchange and a reduction in mean pulmonary artery pressure from 46 to 36 mmHg. At times of brief withdrawal of nitric oxide rebound pulmonary hypertension occurred, with rapid reversal after reinstitution of therapy. After 6 days of treatment there was a sudden fall in systemic arterial pressure and pulmonary arterial pressure during interruption of nitric oxide delivery and subsequent measurements showed a fall in cardiac index from 3.3 to 2.11/min/m 2. The authors concluded that after sudden withdrawal of inhaled nitric oxide rebound pulmonary hypertension had contributed to acute right ventricular failure and loss of left ventricular preload, with a fall in cardiac output leading to reduced coronary performance and near cardiac arrest.

NASAL FORMULATIONS Azelastine

(SED-14, 495; see also

Chapter 15)

Azelastine is an H1 histamine receptor antagonist that is used intranasally for allergic rhinitis. It reduces rhinorrhea, sneezing, and nasal congestion. There have been three double-blind,

randomized, parallel-group comparisons of the effects of azelastine nasal spray (1.1 mg/day) with combined treatment with oral loratadine (10 mg/day) and budesonide nasal spray (336 Ixg/day) in 1070 patients with allergic rhinitis unresponsive to monotherapy (54M). The primary outcome measure was the percentage of patients who needed additional therapy for rhinitis after 7 days of treatment, and this was 32-46% across the three studies, with no significant difference between the two treatment groups. The most common adverse event with azelastine was a transient aftertaste (8% compared with 1% in the combined group) and the most common adverse event for combined treatment was headache (6% compared with 5% in the azelastine group). Rhinitis and somnolence were the other commonly reported adverse events, in 3% and 2% with azelastine and 1% and 1% in the combined group. The authors concluded that monotherapy with azelastine is as effective and as well tolerated as combination therapy in improving symptoms in moderate to severe allergic rhinitis, and this seems to be a reasonable claim.

Ipratropium bromide Perennial rhinitis is common in both adults and children and is usually treated with intranasal corticosteroids, intranasal ipratropium bromide, antihistamines, intranasal cromones, and decongestants. Treatment related adverse effects are common and monotherapy is often inadequate. There are few published studies of the comparative efficacy of rhinitis treatments. Ipratropium bromide (42 Ixg per nostril bd) has been compared with budesonide (84 Ixg per nostril bd) for 6 months in a randomized double-blind trial in 146 children with perennial rhinitis (55c). Both treatments resulted in significant improvements in rhinorrhea, sneezing, and congestion (as rated by both patients and physicians) and improved quality of life. Budesonide achieved better control of sneezing than ipratropium throughout the study period and better control of congestion than ipratropium in the later part of the study. Of 36 patients who did not complete the study, largely for administrative reasons, six using ipratropium withdrew owing to lack of efficacy. There were no reports of systemic anticholinergic adverse effects. The commonest nasal adverse events in both groups

Drugs acting on the respiratory tract

Chapter 16

were nasal congestion (23% with ipratropium and 18% with budesonide) and rhinitis (13% with ipratropium and 7% with budesonide). Of nasal adverse events considered to be related to treatment, epistaxis and nasal irritation were more common with budesonide (10% and 4% respectively) than with ipratropium (8% and 0%). Sneezing occurred in 5% of those using ipratropium and in none of those using budesonide, probably reflecting the better efficacy of budesonide for control of sneezing. Overall both drugs were well tolerated. Ipratropium (42 Ixg per nostril tds), budesonide (84 Ixg per nostril bd), and ipratropium plus budesonide for 2 weeks have been studied in a randomized, double-blind, placebo-controlled trial in 533 patients with perennial rhinitis (56c). As monotherapy, both ipratropium and budesonide produced significant reductions in rhinorrhea compared with placebo, and budesonide was more effective than ipratropium in reducing congestion and sneezing. Non-nasal adverse events occurred equally in all three groups. The incidences of epistaxis, nasal congestion, and nasal irritation were similar in all three groups (1-5%) but there was a greater incidence of nasal dryness (3% vs <1%) and blood-tinged mucus (4% vs 2%) with ipratropium. Combination therapy with ipratropium and budesonide reduced the severity and duration of rhinorrhea in 74% and 66% of patients compared with 57% and 50% for ipratropium, 64% and 54% for budesonide, and 47% and 38% for placebo. There were no other advantages for combination therapy over budesonide. Nasal adverse events occurred in all groups, including placebo, but patients who had 2 weeks of budesonide in the monotherapy arm of the study followed by combination therapy had more epistaxis (5%) and more nasal dryness (5%) than patients who had ipratropium before combination treatment. The authors concluded that combination therapy is superior to monotherapy, with no increase in adverse effects. However, the effect of combination therapy over monotherapy in this study is quite small and does not appear to have reached statistical significance. Nevertheless, most adverse effects seem to have been related to budesonide rather than to ipratropium. The addition of ipratropium in a patient already taking budesonide seems to be safe and may increase efficacy.

193

INHALED ANTIBIOTICS Recent studies have shown the efficacy of inhaled tobramycin in the treatment of patients with cystic fibrosis and chronic Pseudomonas lung infection (57c). The efficacy of nebulized tobramycin 300 mg bd for 4 weeks has been studied in a randomized, doubleblind, placebo-controlled trial in 74 patients with bronchiectasis and Pseudomonas infection, without cystic fibrosis. After 4 weeks there was a significant fall in the density of Pseudomonas infection in the sputum of the treated group. This correlated with an improvement in general medical condition, as assessed subjectively 2 weeks later. There was no difference in lung function, and tobramycin resistance (MIC over 16 txg/ml) developed in four patients in the treated group and one patient in the placebo group. Adverse events were reported by 31 of the 37 patients in each ann. There were significantly increased incidences of dyspnea (32%), chest pain (19%), and wheezing (16%) in the treated group compared with placebo (8%, 0%, 0% respectively). Cough increased in 15 patients (41%) in the treated group and 9 (24%) in the placebo group. The investigators felt that the majority of these respiratory adverse events had been related to the drug. They commented that these adverse events did not generally result in withdrawal of the patients from the trial. No more details are given but the apparent adverse effects profile of nebulized tobramycin in this group is of concern.

DORNASE ALPHA

(SEDA-23, 190)

Daily therapy with recombinant human DNase (Pulmozyme, a-dornase) can reduce the frequency of respiratory infections and improve lung function in patients with bronchiectasis due to cystic fibrosis. The effect of daily nebulized domase for 24 weeks has been studied in a randomized, double-blind, placebocontrolled trial in 349 patients with idiopathic bronchiectasis (58R). Three patients withdrew from the trial; two in the placebo group (hemoptysis and sinusitis) and one in the treatment group (increased sputum production, probably an adverse event). The primary outcome measures were the number of infective exacerbations

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and a fall in FEV1. There were more exacerbations in the treatment group, with a relative risk of 1.35 (not statistically significant). The rate of fall in FEV1 and F V C was significantly higher in the treatment group than in the placebo group, and the treatment group required more days of antibiotics and corticosteroids. Four patients died during the study, three in the treatment group. No deaths were considered to have

been due to the treatment. Adverse events occurred equally in both groups, the commonest being non-specific respiratory disorders (10% in the placebo group and 15% in the treatment group). No other adverse events were detailed. These results suggest that dornase is not effective in patients with idiopathic bronchiectasis and may even be detrimental. Dornase should not be used in these patients.

REFERENCES 1. Wechsler ME, Garpestad E, Flier SR, Kocher O, Weiland DA, Polito AK, Klinek MM, Bigby TD, Wong GA, Helmers RA, Drazen JM. Pulmonary infiltrates, eosinophilia and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafiflukast. J Am Med Assoc 1998; 279: 455-7. 2. Green RL, Vayonis AG. Churg-Strauss syndrome after zafirlukast in two patients not receiving systemic steroid treatment. Lancet 1999; 353: 725-6. 3. Kinoshita M, Tsuneaki S, Takeharu K, Mitsuyoshi A, Rikimaru T, Oizumi K. Churg-Strauss syndrome after corticosteroid withdrawal in an asthmatic patient treated with pranlukast. J Allergy Clin Immunol 1999; 103: 534--5. 4. Tuggey JM, Hosker HSR. Churg-Strauss syndrome associated with montelukast therapy. Thorax 2000; 44: 805-6. 5. Franco J, Artes MJ. Pulmonary eosinophilia associated with montelukast. Thorax 1999; 54: 558-60. 6. Kroegel C, Reissig A, Hengst U, Petrovic A, Hafner D, Grahmann RP. Ulcerative colitis following introduction of zafirlukast and corticosteroid withdrawal in severe atopic asthma. Eur Respir J 1999; 14: 243. 7. Finkel TJ, Hunter DJ, Paisley JE, Finkel RS, Larsen GL. Drug-induced lupus in a child after treatment with zafirlukast. J Allergy Clin Immunol 1999; 103: 533-4. 8. Van Hecken A, Depre M, Verbesselt R, Wynants K, De Lepeleire. Effect of montelukast on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. J Clin Pharmacol 1999; 39: 495-500. 9. Barnes NC, De Jong B, Miyamoto T. Worldwide clinical experience with the first marketed leukotriene receptor antagonist. Chest t997; 111 Suppl: 52S-60S. 10. Fish JE, Kemp JP, Lockey RF, Glass M, Hanby LA, Bonuccelli CM, Bronsky M, Condemi J, Golsdtein S, Norton J, et al. Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multicenter study. Clin Ther 1997; 19: 675-90.

11. Kelloway JS. Zafiflukast: the first leukotrienereceptor antagonist approved for the treatment of asthma. Ann Pharmacother 1997; 31: 101221. 12. Garey KW, Peloqnin CA, Godo PC, Nafziger AN, Amsden GW. Lack of effect of zaliflukast on the pharmacokinetics of azithromycin, clarithromycin and 14-hydroxyclarithromycin in healthy volunteers. Antimicrob Agents Chemother 1999; 43:1152-5. 13. Israel E, Rubin P, Kemp JP, Grossman J, Pierson W, Siegel SC, Tinkelman D, Murray JJ, Busse W, Segal AT, et al. The effect of inhibition of 5- lipoxygenase by zileuton in mild to moderate asthma. Ann Intern Med 1993; 119: 1059-66. 14. Israel E, Cohn J, Dube L, Drazen JM. Effect of treatment with zileuton, a 5-1ipoxygenase inhibitor, in patients with asthma: a randomised controlled trial. J Am Med Assoc 1996; 275: 931-6. 15. Lau R. Drug interactions with zileuton. Lancet 1997; 349: 1479-80. 16. Minto C, Li B, Tattam B, Brown KF, Seale JP, Donnelly R. Pharmacokinetics of epimeric budesonide and fluticasone propionate after repeat dose inhalation--intersubject variability in systemic absorption from the lung. Br J Clin Pharmacol 2000; 50: 116-24. 17. Donnelly R, Williams KM, Baker AB, Badcock CA, Day RO, Seale JP. Effects of budesonide and tinticasone on 24-hour plasma cortisol: a dose-response study. Am J Respir Crit Care Med 1997; 156: 1746-51. 18. Weiner P, Berar-Ynanay N, Davidvidovich A, Magaadle R. Nocturnal cortisol secretion in asthmatic patients after inhalation of fluticasone. Chest 1999; 116: 931-4. 19. Brutsche MH, Brntsche IC, Munawar M, Langley SJ, Masterson CM, Daley-Yates PT, Brown R, Custovic A, Woodcock A. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study. Lancet 2000; 35: 556-61. 20. Lofdahl C-G, Thorsson L. No difference between asthmatic patients and healthy subjects in

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lung uptake of flnticasone propionate. Eur Respir J. 1999; 14: 466S. 21. Wilson AM, Lipworth BJ. 24 hour and fractionated profiles of adrenocortical activity in asthmatic patients receiving inhaled and intranasal corticosteroids. Thorax 1999; 54: 2045. 22. Faul JL, Cormican LJ, Tormey V J, Tormey WP, Burke CM. Deteriorating diabetic control associated with high-dose inhaled budesonide. Eur Respir J 1999; 14: 242-3. 23. Capewell S, Reynolds S, Shuttleworth D, Edwards C, Finlay AY. Purpura and dermal thinning associated with high dose inhaled corticosteroids. Br Med J 1990; 300: 1548-51. 24. Malo J-L, Cartier A, Ghezzo H, Mark S, Brown J, Laviolette M, Boulet L-P. Skin bruising, adrenal function and markers of bone metabolism in asthmatics using inhaled beclomethasone and fluticasone. Eur Respir J 1999; 13: 993-8. 25. Laatikainen AK. Kroger HPJ, Tukiainen HO, Honkanen ILl, Saarikoski SV. Bone mineral density in perimenopausal women with asthma: a population-based cross-sectional study. Am J Respir Crit Care Med 1999; 159:1179-85. 26. Boulet L-P, Milot J, Gagnon L, Poubelle PE, Brown J. Long-term influence of inhaled corticosteroids on bone metabolism and density: are biological markers predictors of bone loss? Am J Respir Crit Care Med 1999; 159: 838--44. 27. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. New Engl J Med 2000; 343: 1054-63. 28. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. New Engl J Med 2000; 343: 1064-9. 29. Palmqvist M, Ibsen T, Mellen A, Lotvall J. Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients. Am J Respir Crit Care Med 1999; 160: 244-9. 30. Rosenthal RR, Busse WW, Kemp JP, Baker JW, Kalberg C, Emmett A, Rickard KA. Effect of longterm salmeterol therapy compared with as-needed albuterol use on airway hyperresponsiveness. Chest 1999; 116: 595-602. 31. Giannini D, Bacci E, Dnete FL, Di Franco A, Vagaggini B, Testi R, Paggiaro P. Inhaled beclomethasone dipropionate reverts tolerance to the protective effect of salmeterol on allergen challenge. Chest 1999; 115: 629-34. 32. Aziz I, Lipworth BJ. A bolus of inhaled budesonide rapidly reverses airway subsensitivity and beta-adrenoceptor down-regulation after regular inhaled formoterol. Chest 1999; 115: 623-8. 33. Aziz I, Lipworth BJ. In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol. J Allergy Clin Immunol 1999; 103: 816-22. 34. Wallaert B, Brun P, Ostinelli J, Murciano D, Champel F, Blaive B, Montane F, Godard P. A comparison of two long-acting beta-agonists, oral

bambuterol and inhaled salmeterol, in the treatment of moderate to severe asthmatic patients with nocturnal symptoms. The French Bambuterol Study Group. Respir Med 1999; 93: 33-8. 35. Cazzola M, Donner CF, Matera MG. Long acting beta agonists and theophylline in stable chronic obstructive pulmonary disease. Thorax 1999; 54: 73045. 36. Aubier M, Pieters WR, Schlosser NJJ, Steinmetz K-O. Salmeterol/fluticasone propionate (50/500 mcg) in combination in a Diskus inhaler (Seretide) is effective and safe in the treatment of steroid-dependent asthma. Respir Med 1999; 93: 876-84. 37. Chapman KR, Ringdal N, Backer V, Palmqvist M, Saarelainen S, Briggs M. Salmeterol and fluticasone propionate (50/250 mcg) administered via combination Diskus inhaler; as effective as when given via separate Diskus inhalers. Can Respir J 1999; 6: 45-51. 38. Disse B, Speck GA, Rominger KL, Witek TJ, Hammer R. Tiotropium (SpirivarM): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci 1999; 64: 457-64. 39. Abman SH, Dobyns EL, Kinsella JP. Role of inhaled nitric oxide in the treatment of children with severe hypoxaemic respiratory failure. New Horiz Sci Pract Acute Med 1999; 7: 386-98. 40. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992; 340: 818-19. 41. Ehrenkranz RA, Stork E, Gorjanc E, Verter J, Younes N, Stenzel BA, Powers T, Sokol G, Appel D, Wright LL, et al. Inhaled nitric oxide in fullterm and nearly full-term infants with hypoxemic respiratory failure. New Engl J Med 1997; 336: 597-604. 42. Roberts JD, Fineman J, Morin III FC, Shaul PW, Rimar S, Schreiber MD, Polin RA, Zwass MS, Zayek MM, Gross I, Heyman MA, Zapol WM. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. New Engl J Med 1997; 336: 605-10. 43. Hess DR, Stewart TE, Bigatello LM, Head CA, Roberts JD, Rich, Channick. Adverse effects and toxicity of inhaled nitric oxide. Respir Care 1999; 44: 315-30. 44. Rovira I, Fita G, Suarez S, Gomar C, Cartana R. Effects of inhaled nitric oxide in a patient with pulmonary hypertension and left heart failure secondary to a giant left atrial myxoma. J Cardiothorac Vasc Anaesth 1999; 13: 726-8. 45. Steudel W, Hurford WE, Zapol WM. Inhaled nitric oxide: basic biology and clinical applications. Anesthesiology 1999; 91: 1090-121. 46. Van Meurs KP, Rhine WD, Asselin JM, Durand DJ, Peverinj R, Linda L, Dudell G, Butler S. Response of premature infants with severe respiratory failure to inhaled nitric oxide. Preemie NO Collaborative Group. Pediatr Pulmonol 1997; 24: 319-23.

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47. Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. Intensive Care Med 1999; 25:911-19. 48. Dellinger RP. Inhaled nitric oxide in acute lung injury and acute respiratory distress syndrome. Inability to translate physiologic benefit to clinical outcome benefit in adult clinical trials. Intensive Care Med 1999; 25: 881-3. 49. Mantktelow C, Bigatello LM, Hess D, Hurford WE. Physiologic determinants of the response to inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesthesiology 1997; 87: 297-307. 50. Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J. Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics 1999; 103: 610-18. 51. Hermon M, Golej J, Burda G, Marx M, Trittenwein G, Pollak A. Intravenous prostacyclin mitigates inhaled nitric oxide rebound effect: a case control study. Artif Organs 1999; 23: 975-8. 52. Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999; 91: 307-10. 53. Buratti T, Joannidis M, Pechlaner C, Wiedermann CJ. Systemic hypotension on withdrawal from inhaled nitric oxide in an adult patient with acute respiratory distress syndrome. Crit Care Med 1999; 27: 441.

Tracey D. Robinson, Adrian P.. Havryk and J. Paul Seale 54. Berger WE, Fineman SM, Lieberman P, Miles RM. Double-blind trials of azelastine nasal spray monotherapy versus combination therapy with loratadine tablets and beclomethasone nasal spray in patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol 1999; 82: 53541. 55. Milgrom H, Biondi R, Georgitis JW, Meltzer EO, Munk ZM, Drda K, Wood CC. Comparison of ipratropium bromide 0.03% with beclomethasone in the treatment of perennial rhinitis in children. Ann Allergy Asthma Immunol 1999; 83: 10511. 56. Dockhorn R, Aaronson D, Bronsky E, Cherviusky E Cohen R, Ehtessabian R, Finn A, Grossman J, Howland W, Kaiser H, et al. Ipratropium bromide nasal spray 0.03% alone and in combination for the treatment of rhinorrhoea in perennial rhinitis. Ann Allergy Asthma Immunol 1999; 82: 349-59. 57. Barker AF, Couch L, Fiel SB, Goffried MH, Ilowite J, Meyer KC, O'Donnell A, Sahn SA, Smith LJ, Stewart JO, et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med 2000; 162: 481-5. 58. O'Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. Chest 1998; 113: 1329-34.

J.K. Aronson

17

Positive inotropic drugs and drugs used in dysrhythmias

The use of digitalis and antidysrhythmic drugs to treat or prevent atrial fibrillation The treatment of atrial fibrillation remains problematic. Recent studies have related to three problems: the treatment of chronic atrial fibrillation; the conversion of recent-onset atrial fibrillation to sinus rhythm; and the maintenance of sinus rhythm after conversion. Digitalis In patients with chronic atrial fibrillation digitalis slows the ventricular rate at rest but not during exercise. It is therefore sometimes combined with a calcium antagonist, such as diltiazem; previously combinations with E-blockers have been avoided, because of the risk of excess bradycardia at rest and impaired exercise tolerance (lC ). However, in a recent cross-over study in 12 patients who received digoxin, diltiazem, atenolol, digoxin + diltiazem, and digoxin + atenolol, the most effective control of ventricular rate was achieved with digoxin + atenolol (2c). Nevertheless, the ventricular rate with this regimen varied between about 60 and 70 beats/rain, which may be too slow for most patients with atrial fibrillation, who need a higher rate to maintain a satisfactory cardiac output. Both digoxin and diltiazem produced ventricular rates of between 70 and 90 beats/min, which may be more suitable, despite the larger variability that occurred throughout the day. Of these two regimens, diltiazem produced better control of ventricular rate during exercise. The ventricular response to exercise was similar when the patients took diltiazem alone or diltiazem + digoxin. In my 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

view, digoxin is still the treatment of choice for chronic atrial fibrillation, but if a patient has symptoms during exercise diltiazem can be added or used instead; amiodarone is an alternative. In contrast, the value of digitalis in the treatment of paroxysmal atrial fibrillation is unclear, but it is generally thought that it is at best ineffective in preventing attacks, and may even increase the duration of attacks when they occur (SEDA-16, 173). In a randomized, doubleblind, cross-over, placebo-controlled study of digoxin in 43 patients with frequent symptomatic episodes of atrial fibrillation, digoxin reduced the frequency of episodes, but the effect was very small (3c). The 43patients in this study were highly selected, having been drawn from an original cohort of 190. It is therefore hard to extrapolate even this minimal effect to the general population of patients with paroxysmal atrial fibrillation. The serum digoxin concentration was carefully monitored at an average of 1.3 nmol/l, and adverse effects were limited to gastrointestinal disturbances in two patients. Amiodarone The use of intravenous amiodarone for atrial fibrillation has been reviewed (4R ). The most commonly reported adverse effects in all studies have been hypotension and bradycardia. Other effects include worsening of heart failure, thrombophlebitis at the site of infusion, non-sustained ventricular tachycardia, facial rash, and nightmares. A few studies have also reported the effects and adverse effects of intravenous amiodarone in patients with atrial fbrillation. Of 67 patients with atrial fibrillation, of whom 33 received amiodarone and 34 received placebo, conversion to sinus rhythm occurred in 16 of the patients who received amiodarone and in none of those who received placebo (5c). In 1 ('1"7

198

five patients the systolic blood pressure fell significantly during the first trial of intravenous drug administration. There were no cardiac dysrhythmias. Thrombophlebitis occurred in 12 patients who received amiodarone. In a randomized placebo-controlled trial of 100 patients with paroxysmal atrial fibrillation, intravenous amiodarone 125 mg/hour was compared with placebo (6c). There were no serious adverse effects; five patients given amiodarone developed significant sinus bradycardia, in all cases after conversion to sinus rhythm. In this series there were no significant episodes of hypotension. Thrombophlebitis occurred in eight patients who received amiodarone. The use of amiodarone in the prevention of atrial fibrillation after cardiac surgery has been reviewed (7R ). When an intravenous loading dose of amiodarone was used, bradycardia was a common adverse effect but was rarely severe enough to warrant withdrawal. When only oral amiodarone was used there were no serious adverse reactions.

Amiodarone vs propafenone Amiodarone 30 mg/kg orally for the first 24 hours plus, if necessary, 15 mg/kg over 24 hours has been compared with propafenone 600 mg in the first 24 hours plus, if necessary, 300 mg in the next 24 hours in 86 patients with recent onset atrial fibrillation (8c). Conversion to sinus rhythm occurred faster with propafenone (2.4 hours) than amiodarone (6.9 hours). However, by 24 hours and 48 hours the same proportions of patients were in sinus rhythm; one patient given amiodarone had a supraventricular tachycardia and one a non-sustained ventricular tachycardia. Of 136 patients with atrial fibrillation treated with either amiodarone (n = 96) or propafenone (n = 40), 15 developed subsequent persistent atrial flutter, nine of those taking amiodarone and six of those taking propafenone (9c). In all cases radiofrequency ablation was effective. It is not clear to what extent these cases of atrial flutter were due to the drugs, although the frequency of atrial flutter in previous studies with propafenone have been similar. Atrial enlargement was significantly related to the occurrence of persistent atrial flutter in these patients. Flecainide In 24 patients with atrial fibrillation who underwent elective transvenous car-

Chapter 17

J.K. Aronson

dioversion for atrial fibrillation, flecainide reduced the energy requirements for further defibrillation after induction of atrial fibrillation by atrial pacing (lOt). There were no ventricular dysrhythmias, but transient bradycardia requiring ventricular pacing occurred in two patients. Two patients had transient asymptomatic hypotension after flecainide and one reported transient dizziness and some light-headedness.

Flecainide or propafenone plus radiofrequency ablation In some patients treatment with a class I antidysrhythmic drug converts atrial fibrillation to atrial flutter. Of 187 patients with paroxysmal atrial fibrillation who were treated with flecainide or propafenone, 24 developed atrial flutter, which was typical in 20 cases (11c). These patients underwent radiofrequency ablation, which failed in only one case. All the patients continued to take their pre-existing drugs, and during a mean followup period of 11 months the incidence of atrial fibrillation was higher in patients who were taking combined therapy than in those taking monotherapy. The authors suggested that in patients with atrial fibrillation who developed typical atrial flutter due to class IC antidysrhythmic drugs, combined catheter ablation and continued drug treatment is highly effective in reducing the occurrence and duration of atrial tachydysrhythmias. They did not report adverse effects. Procainamide vs propafenone A comparison between procainamide and propafenone in 62 patients, who had undergone coronary artery bypass grafting or valvular surgery within 3 weeks and developed sustained atrial fibrillation, showed that both drugs converted the dysrhythmia to sinus rhythm in up to 76% of cases, but that propafenone did it more quickly (12c). Symptomatic arterial hypotension occurred more frequently with procainamide (nine of 33 patients) than propafenone (two of 29 patients). Other adverse effects of procainamide were nausea (n = 2) and junctional escape rhythm (n = 2). Other adverse effects of propafenone were hot flushes (n = 1), nausea (n = 3), bronchospasm (n = 1), and junctional escape rhythm (n = 2). Propafenone Three different regimens of oral propafenone have been compared in patients with paroxysmal atrial fibrillation (13c). In 48

Positive inotropic drugs and drugs used in dysrhythmias patients who took 600 mg followed 8 hours later by 150 mg there was a higher rate of early successful cardioversion with a lower incidence of adverse effects than in two other groups who took either 300 mg three times over 8 hours (n = 82) or four doses of 150 mg over 9 hours (n = 58). The rates of conversion were around 80%, similar to those found in other studies. There was QRS prolongation in all three groups, and four of those who took a total of 900 mg developed a broad complex tachycardia.

Propafenone vs quinidine A placebocontrolled study of the use of propafenone 450-600 mg orally, either alone or in combination with digoxin, has been carried out in 176 patients with atrial fibrillation; a further 70 patients were given digitalis plus quinidine (14c). There were no significant differences across the groups in terms of percentage conversion to sinus rhythm, although conversion occurred more quickly in those given digoxin plus propafenone; this catch-up of the other treatments was attributed to spontaneous conversion in those groups. There were no serious adverse effects in this study. The QTc interval was slightly prolonged by digitalis plus quinidine and not by the other treatments. In six patients taking propafenone alone there were mild non-cardiac effects, including sickness in two, headache in one, gastrointestinal disturbances in two, and paresthesia in one. Four patients taking propafenone plus digitalis had either sickness or dizziness, and nine patients taking digitalis plus quinidine had gastrointestinal disturbances, sickness, dizziness, or headache. There were no major dysrhythmias; four of the patients who took digitalis plus propafenone had asymptomatic ventricular extra beats, as did one patient who took digitalis plus quinidine. In nine patients who took digitalis plus quinidine there were asymptomatic short-lasting episodes of atrial flutter with atrial ventricular conduction of at least 2:1 immediately before the restoration of sinus rhythm; this happened in 13 patients who took propafenone, 12 patients who took digitalis plus propafenone, and three patients who took placebo. There were two cases of complete left bundle branch block in patients who took digitalis plus quinidine, in three patients who took propafenone, and in two who took digitalis plus propafenone. In two patients who took digitalis plus quinidine and

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two who took propafenone there was reversible asymptomatic sinoatrial block of Wenckebach type II. Transient mild hypotension occurred in one patient taking digitalis plus quinidine, five taking propafenone, one taking digitalis plus propafenone, and one taking placebo, but the hypotension was transient and not severe. The authors concluded that the addition of digitalis to propafenone hastened cardioversion from atrial fibrillation, although they conceded that the balance of other evidence suggests that digitalis is not effective in restoring sinus rhythm and were unable to explain the efficacy of the combination of digitalis with propafenone.

Quinidine vs sotalol Quinidine and sotalol have been compared in a prospective multicenter trial of 121 patients after conversion of atrial fibrillation (15c). Patients with low left ventricular ejection fractions (below 0.4) or high left atrial diameters (over 5.2 cm) were excluded. After 6 months the percentages of patients remaining in sinus rhythm were similar in the two groups (around 70%), but when the dysrhythmia recurred it occurred later with sotalol than with quinidine (69 vs 10 days). There was also a difference between patients who had been converted from recent-onset atrial fibrillation, in whom sotalol was more effective than quinidine, and in patients who had had chronic atrial fibrillation for more than 3 days, in whom quinidine was more effective. There were significant adverse effects requiring withdrawal of therapy in 17patients, of whom nine were taking quinidine; three patients had gastrointestinal symptoms, two had central nervous symptoms, two had allergic reactions, one had undefined palpitation, and one had QT interval prolongation. One patient taking quinidine, a 65-year-old man, had frequent episodes of non-sustained ventricular tachycardia. Maintenance of sinus rhythm after conversion In some patients with atrial fibrillation conversion to sinus rhythm occurs either spontaneously or after electrical cardioversion. A decision then has to be made as to whether antidysrhythmic drugs should be given in an attempt to prevent further atrial fibrillation, partly because patients with atrial fibrillation are at risk of serious drug-induced dysrhythmias during the loading phase and partly because of the risks of atrial fibrillation itself In 172 patients with sinus rhythm after spon-

200 taneous conversion or electrical cardioversion, cardiac rhythm and symptoms were recorded during antidysrhythmic drug therapy for 10 days (16c). There were six adverse events during the 10 days, none of which occurred before day 4. All occurred in patients without structural heart disease. There were three cases of atrial flutter with one-to-one conduction in patients taking class IC antidysrhythmic drugs; two complained of palpitation and were converted to sinus rhythm; one became syncopal and was also converted. There were two cases of symptomatic bradycardia requiring pacemakers. In one patient sotalol caused prolongation of the QT interval. In addition, 10 asymptomatic events were identified by electrocardiography; in six cases there was sinus bradycardia and in four cases recurrent atrial fibrillation. The authors suggested that out-patient loading with antidysrhythmic drugs, aided by daily electrocardiography, is safe in patients who have converted from atrial fibrillation to sinus rhythm; they did not think that it was necessary to bring patients into hospital for this.

CARDIAC GLYCOSIDES (SED-14, 523; SEDA-21, 194; SEDA-22, 201; SEDA-23, 193) The pharmacology, clinical pharmacology, adverse effects, and interactions of digitalis have again been briefly reviewed (17R). Of 332 residents of a nursing home, 52 had to be admitted to hospital because of adverse drug reactions (18~). The drugs most commonly associated with adverse effects were non-steroidal anti-inflalnmatory drugs (n = 30), psychotropic drugs (n = 14), and digoxin (n =

5). Cardiovascular After an overdose of 300 tablets of digoxin (plasma digoxin concentration 50 ng/ml), recurrent ventricularfibrillation was successfully treated with bretylium tosylate (19A). Digoxin can rarely cause intestinal ischemia through vasoconstriction (SEDA-15, 166). There has now been a report of coronary vasoconstriction in patients who were given acetyldigoxin 0.8 mg intravenously at angiography (20c). Pretreatment with nisoldipine

Chapter 17

J.K. Aronson

10 mg, 2 hours before angiography, prevented the digoxin-induced vasoconstriction. These patients all had pre-existing coronary artery disease, but the vasoconstrictor effect occurred in both normal and abnormal coronary segments. However, the effect on high-grade stenoses was more pronounced. There is other evidence that ischemic damage can occur in patients who have been given digoxin intravenously, including an increase in the activity of serum creatinine kinase (21 C) and impaired left ventricular function after acute myocardial infarction (22c). There is rarely any justification for giving digoxin intravenously, and this route of administration should be restricted to those who have severe atrial fibrillation that requires rapid treatment and in whom cardioversion or other drug therapy is not possible or indicated. Nervous system Progressive stupor has been reported in an 85-year-old woman with mild renal insufficiency who was given digoxin 0.25 mg/day (23A). The plasma digoxin concentration was 7.8 nmol/l. She recovered within 2 weeks after digoxin withdrawal, consistent with the likely half-life of digoxin. A 24-hour electrocardiogram showed one period of asystole for 4 seconds, but that is unlikely to have explained her symptoms. Chorea has occasionally been reported in adults taking digitalis (SEDA-13, 138). It has now been reported in a child (24A). A 7-year-old girl with severe congenital heart disease who was given digoxin 0.125 mg bd developed chorea and had a serum digoxin concentration of 3.8 ng/ml. When digoxin was withheld and the serum concentration fell to 1.5 ng/ml her symptoms resolved. They recurred 4 days after rechallenge, when her digoxin concentration was 2,5 ng/ml, and again resolved after it had fallen to 1.3 ng/ml. The authors hypothesized that digoxin caused chorea by virtue of an estrogenic effect in the basal ganglia, similar to the effect that is occasionally produced by oral contraceptives. Endocrine In three patients with diabetes mellitus, withdrawal of digoxin led to improved blood glucose control, implying that digoxin had impaired glucose tolerance (25A). The authors conceded that the effect may have occurred coincidentally, but in one case glucose tolerance deteriorated again after rechallenge. Insulin increases the cellular uptake of

Positive inotropic drugs and drugs used in dysrhythmias glucose and stimulates the sodium/potassium pump, and it may be that inhibition of the sodium/potassium pump by digoxin has the opposite effect. Death In a retrospective non-randomized study of 484 patients, 90 of whom were taking digoxin, there was an increased death rate (RR = 2.12, CI = 1.21, 3.74) in those taking digoxin (26c). In another non-randomized retrospective analysis of the effects of digoxin in patients with acute myocardial infarction there was a higher rate of mortality in the 243 patients taking digoxin compared with the 1743 patients who were not (27c). The results of these studies are reminiscent of the results of previous similar retrospective analyses. However, the prospective DIG study clearly showed no increase in mortality (SEDA-20, 173), and the results of these more recent non-randomized retrospective studies should be ignored. In a study, 345 patients with heart failure were randomized to either digoxin (n = 175) or captopril (n = 170) and followed for a median of 4.5 years (28c). Since there was no placebo group for comparison it is not clear whether digoxin altered mortality in this study, but the death rate at 48 months was lower with captopill (21%) than with digoxin (32%), although this did not reach conventional significance. Of the numerous adverse effects that were reported, the only one that differed between the two treatments was cough, which was significantly more frequent with captopril. In the absence of a placebo comparison it is impossible to say whether any of the other adverse effects were drug-related.

Risk factors Hypercalcemia The effects of digitalis are enhanced in the presence of hypercalcemia. An 81-year-old woman with congestive heart failure and hypercalcemia secondary to squamous cell carcinoma of the bronchus developed first-degree heart block and symptomatic sinus pauses when her serum digoxin concentration was only 1.5 ng/ml (29A). Children Dosage requirements in children vary greatly with age. The pharmacokinetics of digoxin have been studied in 181 neonates and children with and without congestive heart failure (30c). The clearance rate was lower in

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201

premature neonates than in neonates born at full term. Children with congestive heart failure also had lower digoxin clearance. Drug overdose Accidental overdose of digoxin in a 22-month-old boy caused vomiting, lethargy, and dehydration. The plasma digoxin concentration was 12 ng/ml. There was a relative bradycardia of 90 beats/minute and Mobitz type I second-degree heart block on the electrocardiogram (31A).

The use of activated charcoal in the treatment of digitalis overdose The use of activated charcoal in the treatment of digitalis overdose has been reviewed (32R ). The rationale for its use is that after absorption into the systemic circulation digoxin is secreted into the gut lumen by the action of the P-glycoprotein. Activated charcoal in the gut binds this secreted digoxin and encourages further secretion. In pigs, repeated doses of activated charcoal reduced the half-life of intravenous digoxin significantly from 65 to 17 hours and increased the clearance from 2.3 to 7.1 ml/min/kg (33E). There is evidence of the efficacy of charcoal in healthy volunteers. In six adult volunteers repeated doses of activated charcoal significantly reduced the half-life of digoxin from 23 to 17 hours without a significant increase in clearance; the half-life of digitoxin was also reduced from 110 to 51 hours, and this was accompanied by a significant increase in clearance from 0.24 to 0.47 l/hour (34c). In a volunteer with chronic renal insufficiency charcoal reduced the digoxin half-life from 93 to 29 hours and increased the clearance from 3.6 to 10 l/hour (34c). Similarly, during maintenance therapy in six individuals, daily activated charcoal significantly reduced the mean plasma digoxin concentration by 31% and serum digitoxin concentration by 18% (35c). In 10 healthy volunteers given intravenous digoxin 10 Izg/kg repeated doses of activated charcoal significantly increased the total body clearance from 12 to 18 l/hour and reduced the half-life from 37 to 22 hours (36(:). There have also been reports of the value of multiple doses of activated charcoal in patients with digoxin and digitoxin poisoning. In 23 patients with plasma digoxin concentrations over 2.5 ng/ml multiple doses of activated charcoal

202 increased the mean clearance o f digoxin to 98 ml/min compared with 55 ml/min in 16 patients who were not treated, and reduced the half-life from 68 to 36 hours (37c). Anecdotal reports have also appeared. In a 69-year-old man the plasma digoxin concentration of 8.3 ng/ml fell with a half-life of 14 hours (38A). In a 71-year-old woman with chronic renal insufficiency and a plasma digoxin concentration of 9 ng/ml charcoal shortened the half-lifefrom 7.3 to 1.4 days (39a ). In a 66-year-old man with chronic renal insufficiency whose serum digoxin concentration did not respond to daily hemodialysis, multiple doses of activated charcoal caused a rapid reduction in the serum concentration (40A). In a patient with a peak plasma digoxin concentration of 264 ng/ml multiple doses of activated charcoal reduced the half-life of digitoxin from 162 hours to 18 hours (41A). In a patient on hemodialysis, activated charcoal caused a fall in the plasma digoxin concentration with a half-life of 29 hours (42A). In another patient there was convincing evidence of a change in the digoxin half-life after repeated doses of activated charcoal (43t ). Thus, the use of repeated doses of activated charcoal in patients with digoxin and digitoxin toxicity is a cheap way of increasing the rates of clearance of the drugs. However, in serious intoxication antidigoxin antibody fragments should be used if possible, because they rapidly reverse the effects of digoxin as well as increasing its rate of clearance.

Drug

interactions ct-glucosidase inhibitIn two patients taking steady-state digoxin therapy the addition of acarbose reduced the plasma digoxin concentration (44A). The association was confirmed in both cases by withdrawal of acarbose. The likely mechanism of this interaction is inhibition of the absorption of digoxin by acarbose, although the authors also suggested that acarbose might interfere with the hydrolysis of digoxin before absorption, thus altering the pattern of metabolites in the blood; however, this is a much less likely mechanism. The authors recommended that if acarbose be used in conjunction with digoxin, the doses should be separated by about 6 hours. This absorption interaction has previously been highlighted (45 c, 46A). ors

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J.K. Aronson

In eight healthy men voglibose, another inhibitor of ct-glucosidase, had no effect on the pharmacokinetics of digoxin (47c). This result suggests that inhibition of t~-glucosidase is not the mechanism whereby acarbose alters the absorption of digoxin; however, acarbose also inhibits a-amylase and such inhibition cannot be ruled out as a mechanism of the interaction with acarbose, perhaps by altered gastrointestinal motility. In a randomized study in 18 young men, bosentan caused a small (12%) reduction in the AUC of digoxin, without changing either the Cmax or the Cmin (48c). This was a steady-state study, with plasma concentration measurements for only 24 hours, and so the half-life of digoxin was not measured. Bosentan is an antagonist at endothelin type 1 receptors and could therefore have increased renal blood flow by pre- and postglomerular vasoconstriction, increasing the elimination of digoxin. Furthermore, bosentan is a substrate for Pglycoprotein, which mediates the renal tubular secretion of digoxin, and may induce its expression, increasing digoxin renal clearance. However, whatever the mechanism of this putative interaction, it is clearly unlikely to be of clinical significance. Bosentan

Cerivastatin In 20 healthy men aged 18-45 years, cerivastatin had no effect on the steadystate pharmacokinetics of digoxin (49c). Conversely, digoxin had no significant effect on the phannacokinetics of cerivastatin. Clarithromycin In a 72-year-old woman taking digoxin 0.25 mg/day, the addition of clarithromycin caused a rise in the serum digoxin concentration to 4.6 ng/ml (50A). Interactions of macrolide antibiotics, including erythromycin (SEDA-7, 197), azithromycin (SEDA-21, 195), and clarithromycin (SEDA-23, 194), have previously been reported and attributed to inhibition of the growth of Eubacterium lentum in the gut, reducing the metabolism of digoxin in the gut before its absorption. It has also been reported that clarithromycin reduced the rate of renal digoxin clearance, perhaps by inhibition of P-glycoprotein. Clopidogrel In 12 healthy men steady-state clopidogrel 75 mg/day had no effect on the steady-state plasma concentrations of digoxin (51c).

Positive inotropic drugs and drugs used in dysrhythmias

Gemifloxacin In a cross-over study in 14 healthy elderly individuals gemifloxacin 320 rag/day had no effect on the steady-state pharmacokinetics of digoxin (52c). Itraconazole

Itraconazole

increases

the

digoxin AUCo-72 by about 50%, and reduces its renal clearance by about 20% (53c). Apart from inhibition of the renal secretion of digoxin, which is probably mediated by inhibition of P-glycoprotein, a study in guineapigs also showed significantly reduced biliary excretion of digoxin by itraconazole, suggesting that the interaction between itraconazole and digoxin may be due not only to a reduction in renal clearance, but also to a reduction in the metabolic clearance of digoxin by itraconazole (54E).

Macrogol Macrogol 20 g/day for 8 days caused a 30% reduction in the AUC and a 40% reduction in the Cmax of a single dose of digoxin in 18 healthy volunteers; the tmax and half-life were not affected (55c). This interaction was probably due to reduced absorption of digoxin, perhaps by a physicochemical interaction between the two compounds.

Mibefradil

In 40 healthy subjects mibefradil 50 or 100 mg/day for 6 days had no significant effects on the steady-state pharmacokinetics of digoxin, apart from a very small increase in the Cmax (56'~)-

Rifampicin

Rifampicin induces P-glycoprotein and should therefore increase the clearance of digoxin. Previous reports (57 A, 58A), have suggested that rifampicin reduces the steadystate concentration of digoxin. Another study in eight healthy men has shown that steadystate rifampicin significantly reduced the AUC of oral digoxin but had less of an effect on intravenous digoxin (59c). The authors attributed this to induction of P-glycoprotein in the intestine, with increased secretion of the drug into the gut lumen. Rifampicin has previously been reported to reduce steady-state plasma digitoxin concentrations, an effect that was attributed to induction of the metabolism of digitoxin to digoxin (60A); however, in that study plasma digoxin concentrations were not measured separately, and it may be that rifampicin also increases the secretion of digitoxin into the gut lumen.

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203

Ropinirole In 10 patients with Parkinson's disease steady-state ropinirole treatment caused small reductions in the AUC and Cmax of digoxin at steady-state (10% and 25% respectively) (61c). However, the Cmin was unaffected and overall there was probably no significant effect of ropinirole on digoxin disposition.

Saint John's wort Saint John's wort (Hypericum perforatum) had no effect on the pharmacokinetics of digoxin after a single dose in 25 healthy volunteers, but during steady-state therapy it reduced the AUC of digoxin by 25% (62c). There were also significant reductions in Cmax and Cmin (26% and 33% respectively). This effect was attributed to induction of Pglycoprotein.

Sparfloxacin The interaction of sparfloxacin with digoxin, both at steady state, has been studied in a double-blind, placebo-controlled, cross-over study in 24 healthy men aged 20-49 years. Sparfloxacin had no effect on the steadystate mean plasma concentration, Cmin, tmax, or AUC of digoxin (63c). Conversely digoxin did not alter the steady-state pharmacokinetics of sparfloxacin.

Interference with diagnostic tests Spironolactone is known to interfere with some digoxin radioimmunoassays, because it and its metabolites, such as canrenone and 7-ctthiomethylspironolactone, are immunoreactive with some forms of antidigoxin antibody (64 E, 65E). However, in contrast to this there has been a recent report that canrenoate, the main metabolite of spironolactone, interfered with the immunoassay of digoxin (66EA). The effect was largest with the AxSym MEIA II assay, and there was also some interference with the EMIT assay. However, the TDx assay did not show any interference. Spironolactone also caused some interference in the AxSym assay but less than canrenoate. In this case the failure to measure high digoxin concentrations resulted in clinical toxicity in a 71-year-old man who was given 3.8 mg over 11 days. In a study of the use of the TDx II assay in 80 children and adults, there was apparent digoxin immunoreactivity in 3.7% of healthy subjects (n = 80), 3.6% of pregnant women (n = 28), 10% of patients with renal transplants (n

204 = 31), and 23% of immature infants (n = 40) (67E).

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J.K. Aronson

ventricular dysrhythmias, as described above and in other studies (70c). Acute exacerbation of chronic heart failure has also been reported (71A).

OTHER POSITIVE INOTROPIC DRUGS (SED-14,532; SEDA-21, 196; SEDA-22, 203; SEDA-23, 195)

Milrinone DRUGS USED IN DYSRHYTHMIAS Although the long-term oral use of inhibitors of phosphodiesterase type III, such as milrinone, is associated with an increase in mortality (SEDA17, 217), milrinone continues to be used intravenously in patients with heart failure, both for short-term and longer-term therapy (SEDA21, 196; SEDA-22, 203; SEDA-23, 109). On the premise that phosphodiesterase inhibitors also inhibit the production of cytokines, rnilrinone has also been used in the treatment of nine patients with the systemic inflammatory response syndrome and compared with seven patients with congestive heart failure (68c). In both groups milrinone significantly altered cardiac index, pulmonary capillary wedge pressure, and left ventricular stroke work index. In the patients with cardiac failure it also reduced systemic vascular resistance index, and the dose of adrenaline had to be increased substantially during milrinone infusion to counteract vasodilatation. In a retrospective view of 63 patients who received intravenous milrinone for more than 24 hours for advanced cardiac failtire, the mean dose was 0.43 ixg/kg/min and the mean duration of therapy 12 (range 1-70) days (69c). After 24 hours of therapy there was significant improvement in pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac index. Because of the nature of the study, which was not placebo-controlled, it is impossible to be sure what events could have been attributed to the milrinone. However, the authors reported five cases of asymptomatic non-sustained ventricular tachycardia, six of symptomatic ventricular tachycardia, and three deaths, one in ventricular tachycardia and two in heart failure. There was no difference in the incidence of these adverse events in patients who received milrinone for more than 7 days compared with the others. The main limitation of the short-term use of milrinone is the risk of hypotension and

The effects and adverse effects of some drugs used for the treatment of ventricular tachydysrhythmias have been reviewed (72R). The prodysrhythmic effects of antidysrhythmic drugs have been reviewed in the context of whether patients who are to be given Class I or Class III antidysrhythmic drugs should first be admitted to hospital for observation in the hope of identifying those who are most likely to develop dysrhythmias (73R). The quoted risks of dysrhythmias were: flecainide 30%, quinidine 18%, propafenone 7%, sotalol 6%, and amiodarone 0%. However, the risk of sudden death in patients taking amiodarone was significantly increased in those who had had a prior bout of torsade de pointes. The risk of sotalol-induced torsade de pointes was dose-related and was higher in patients with pre-existing heart failure. As has been reported before (SEDA-18, 199), women were at a greater risk of prodysrhythmic drug effects. The highest risk was in women with heart failure who took more than 320 rag/day (22%); the corresponding figure in men was 8%. The authors delineated certain subgroups whom they considered to be at specific risk of dysrhythmias, listing drugs that should be avoided in those subjects. They recommended avoiding drugs of classes IA and III in women without coronarc artery disease, drugs of class IC in men with coronary artery disease, and drugs of classes IA, IC, and III in men with congestive heart failure and women with coronary artery disease. Class IC antidysrhythmic drugs have been reported to cause the characteristic electrocardiographic changes of the Brugada syndrome, which consists of right bundle branch block, persistent ST segment elevation, and sudden cardiac death, in two patients (74A). Class IA drugs did not cause the same effect.

Positive inotropic drugs and drugs used in dysrhythmias

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205

Table l. The incidence of atrioventricular block with adenosine Type of block

Baseline PR interval over 200 ms (n = 43)

Baseline PR interval under 200 ms (n = 557)

Further prolongation of PR interval Second-degree block Third-degree block

49% 37% 14%

10% 8% 1%

Adenosine (SED-14, 536; SEDA-21, 197; SEDA-22, 203; SEDA-23, 197) In 18 children with aortic valve disease or Kawasaki disease, adenosine stress myocardial perfusion imaging was associated with the usual adverse effects, most commonly flushing and dyspnea (75c). Cardiovascular An infusion of adenosine, 25 Ixg/kg, in 15 women undergoing anesthesia for major gynecological procedures was effective in maintaining hemodynamic stability during operation in addition to conventional anesthesia (76c). It caused a significantly greater fall in systolic blood pressure and increase in heart rate than remifentanil in a comparable group. In four cases ephedrine was required for hypotension that was refractory to intravenous fluids or a temporary reduction in the infusion rate of adenosine. Two patients also required atropine for prolonged bradycardia. The incidence of atrioventricular block has been reported in 600 consecutive patients who underwent stress myocardial perfusion imaging with adenosine (140 Ixg/kg/min for 6 minutes), and of whom 43 had first-degree heart block before adenosine and 557 had a baseline PR interval less than 200 ms (Table 1) (77c). The heart block in all cases was of short duration, was not associated with any specific symptoms, and in no case required specific treatment. The risk of atrioventficular block during adenosine infusion was not increased by the presence of other drugs that might have caused atrioventficular block (digitalis, /3-blockers, diltiazem, verapamil). Adenosine is contraindicated in patients with aberrant conduction pathways, because it can cause cardiac dysrhythmias. There have been three further cases of supraventricutar dysrhythmias in children with Wolff-

Parkinson-White syndrome who were given intravenous adenosine (78A). Adenosine can cause cardiac ischemia by activating adenosine A 1 receptors in the heart. However, in a double-blind placebo-controlled, cross-over study in eight healthy volunteers, adenosine 100 txg/kg/min did not alter ischemic pain in an exercising arm (79c). Otherwise the usual adverse effects were noted, including facial flushing and mild chest tightness.

Respiratory In 94 patients with chronic obstructive pulmonary disease who were given adenosine in an initial dosage of 50 Ixg/kg/min, increasing to 140 txg/kg/min if adverse effects did not occur, there was only a slight and insignificant fall in FEV1 at the highest dose of adenosine (80c). However, four patients had a fall in FEVt of 20% or more, although without shortness of breath or evidence of bronchospasm; in these the dosage of adenosine was reduced to 100 Ixg/kg/min. Two other patients had shortness of breath with no fall in FEVt or bronchospasm, and the dosage was reduced to 100/zg/kg/min. There was no difference in the fall in FEV1 between patients who had a history of asthma and those who did not. Other adverse effects included light-headedness (n = 26), dypsnea (n = 17), headache (n = 14),flushing (n = 8), hypotension (n = 7), chest pain (n = 6), and nausea (n = 2). In a subsequent study in 117 patients, two had symptomatic bronchospasm during adenosine infusion. In two other cases in which bronchospasm was present before treatment, bronchospasm did not develop when adenosine was infused at the highest dosage. Immunologic An anaphylactic reaction has been reported in a 75-year-old woman who was given adenosine 12 mg for a supraventricular tachycardia. She developed bronchospasm and profound inspiratory stridor, her arter-

Chapter 17

206 ial blood pressure fell to 50/30 mmHg from an arterial systolic pressure of 70 mmHg, and she recovered with appropriate treatment (81A).

Ajmaline and derivatives (SED-14, 537; SEDA-17, 219) After an overdose of detajmium bitartrate in a dose of 18 mg/kg, a 36-year-old woman developed ventricular flutter, which responded to treatment with lidocaine, defibrillation, glucagon, noradrenaline, and sodium chloride (82A). Hypokalemia responded to intravenous potassium chloride. Various types of cardiac dysrhythmia have previously been reported after overdosage of ajmaline (SEDA-2, 162).

Amiodarone (SED-14, 537; SEDA-21, 198; SEDA-22, 204; SEDA-23, 198) A meta-analysis of 13 randomized trials has shown that both total mortality and sudden death or dysrhythmic death was less common over 24 months after randomization to amiodarone than in control subjects (83M). In a comparison of amiodarone (n = 23) with sotalol (n = 22) in patients with spontaneous sustained ventricular tachydysrhythmias secondary to myocardial infarction, sotalol was much more effective, 75% of those taking it remaining free of dysrhythmias compared with 38% of those taking amiodarone (84c). Adverse effects requiring withdrawal occurred in 17% of those taking amiodarone at a median time of 3.5 months. The adverse effects included malaise, rash, headaches, flushing, and dyspnea due to pulmonary fibrosis.

Cardiovascular Although amiodarone rarely causes torsade de pointes, a case has been reported within the first 24 hours after the intravenous administration of amiodarone 150 mg followed by 35 mg/hour in a 40-year-old woman (85A). The association with amiodarone was confirmed by subsequent rechallenge. Cardiogenic shock has been reported in 73-year-old woman with a dilated cardiomyopathy who had digitalis and amiodarone toxicity (86A). Respiratory Three further cases of amiodarone-induced lung toxicity have been

J.K. Aronson

reported (87 A, 88A). A 77-year-old man without a history of lung disease was given amiodarone 7 days after bypass surgery because of supraventricular dysrhythmias and nonsustained ventricular tachycardia. He had taken 1600 mg/day for a week followed by a maintenance dosage of 400 mg/day, and 15 days later became pale, sweaty, febrile, and tachypneic. His blood pressure was 100/60 and his heart rate 100/min. There were reduced breath sounds and crackles throughout the lung fields. A chest X-ray showed diffuse interstitial and alveolar infiltrates and small bilateral pleural effusions. A high-resolution CT scan of the chest showed diffuse ground-glass attenuation and patchy peripheral opacities, consistent with an acute hypersensitivity pneumonitis, and other diagnoses were ruled out. He responded to corticosteroids. A 72-year-old man developed hypoxemic respiratory failure while taking amiodarone 300 mg/day. He had no history of lung disease. His CT scan was similar to that of the first patient. He responded to treatment with corticosteroids. In a 79-year-old man with emphysema taking amiodarone 200 mg/day, the diagnosis of amiodarone-induced lung toxicity was complicated by the fact that emphysema has the opposite effect on lung volumes and spirometry from interstitial lung disease. His FEV1, which had been reduced, became normal and then increased. However, the combination of emphysema with amiodarone-induced lung disease led to worsening dyspnea, and a chest Xray showed patchy mixed interstitial and airspace disease, most marked in the mid to upper lung zones bilaterally, and ground-glass opacification in the left lower lobe, suggesting an acute alveolitis. He responded to prednisone after withdrawal of amiodarone. His carbon monoxide diffusing capacity, which had fallen, returned to normal. A C T scan showed marked bullous emphysema and groundglass interstitial changes. The FEV1 almost doubled, from being severely reduced to within the reference range.

Nervous system Periodic ataxia has been attributed to amiodarone in a 67-year-old man taking amiodarone 200 mg/day (89A). The ataxia responded to acetazolamide and eventually to withdrawal of amiodarone. It recurred with rechallenge.

Delirium has rarely been reported with amiodarone (SEDA-13, 140), but another case has now been reported (90A). Psychiatric

A 54-year-old man with no previous psychiatric history took amiodarone 400 mg bd. After a few days he became depressed and paranoid, suffered from insomnia, and had rambling speech. The dosage of amiodarone was reduced to 200 mg bd and he

Positive inotropic drugs and drugs used in dysrhythmias improved. However, 3 days later he became confused, with tangential thinking, labile effect, and a macular rash on the limbs. His serum sodium was reduced at 127 mmol/1 and his blood urea nitrogen was raised. ACT scan of the head was normal. Amiodarone was withdrawn and 4 days later he was alert and oriented. About a week later he started taking amiodarone again and within 4 days became increasingly agitated, confused, and paranoid. He once more recovered after withdrawal of amiodarone.

Depression has been attributed to amiodarone in a 65-year-old woman who was taking amiodarone (dosage not stated) (91A). Because the mode of presentation was atypical in onset, course, duration, and its response to antidepressant drugs, amiodarone was withdrawn, and she improved rapidly. There was no evidence of thyroid disease. Special senses The incidence of optic neuropathy with amiodarone (SEDA-23, 199) has been estimated at 1.8% (SEDA-13, 141). There has been a recent review of 73 cases of optic neuropathy associated with the use of amiodarone, including 16 published case reports and 57 other reports from the National Registry of Drug-Induced Ocular Side Effects, the US FDA, and the WHO (92c). Amiodaroneinduced optic neuropathy is of insidious onset, with slow progression, bilateral visual loss, and protracted disc swelling, which tends to stabilize within several months of withdrawal. These features all distinguish it from non-arteritic ischemic optic neuropathy. The pathology of amiodarone-induced optic neuropathy is associated with lipid deposition, as with other forms of adverse effects of amiodarone. Brown discoloration of implanted lenses has been attributed to amiodarone (93A). A 66-year-old woman, who had had two silicone intraocular lenses inserted because of cataract, developed progressive brown discoloration of the lens while taking amiodarone (dosage not stated). The discoloration progressed markedly after vitrectomy, suggesting that it was due to leakage of the drug into the eye. She also had an amiodarone-induced keratopathy. Endocrine There has been a retrospective study of the frequency of amiodarone-associated thyroid dysfunction in adults with congenital heart disease (94c). Of 92 patients who had taken amiodarone for at least 6 months (mean age 35, range 18-60, years), 36% de-

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veloped thyroid dysfunction--19 became hyperthyroid and 14 hypothyroid. The mean dosage was 194 (100-300) mg/day, and the median duration of therapy was 3 (0.5-15) years. Female sex (OR = 3) and unoperated or palliated cyanotic congenital heart disease (OR = 7) were significant risk factors for thyroid dysfunction. The risk was also dose-related. Although the authors conceded that they may have over-estimated the risk of thyroid dysfunction, because of the selected nature of the population they studied, the risks were markedly higher than in previous studies of older patients with acquired heart disease, despite a lower maintenance dosage of amiodarone. Patients with/%thalassemia major have an increased risk of primary hypothyroidism. In 23 patients with fl-thalassemia amiodarone was associated with a high risk of overt hypothyroidism (33% vs 3% in controls) (95c). This occurred at up to 3 months after starting amiodarone. The risk of subclinical hypothyroidism was similar in the two groups. In one case overt hypothyroidism resolved spontaneously after withdrawal, but the other patients were given thyroxine. After 21-47 months of treatment three patients developed thyrotoxicosis, with remission after withdrawal. There were no cases of hyperthyroidism in the controls. The authors proposed that patients with 15thalassemia may be more susceptible to iodineinduced hypothyroidism, related to a underlying defect in iodine in the thyroid, perhaps associated with an effect of iron overload. Electrolyte balance There has been one previous report of inappropriate secretion of ADH in a patient taking amiodarone (SEDA-21,199). A second case has now been reported (96A). A 62-year-old woman with paroxysmal atrial fibrillation who had taken amiodarone 300 mg/day had a serum sodium concentration of 120 mmol/1 with a normal serum potassium and a reduced serum osmolality (240 mmol/kg); the urinary sodium concentration was 141 mmol/l and the urine osmolality 422 mmol/kg. There was no evident cause of inappropriate secretion of ADH and within 5 days of withdrawal of amiodarone the serum sodium concentration had risen to 133 mmol/1 and rose further to 143 mmol/l 14 days later. There was no rechallenge and no recurrence of hyponatremia during the next 6 months. The mechanism of this effect is not known.

208

Liver Acute severe liver damage has occasionally been reported after intravenous amiodarone (SEDA-14, 149; SEDA-16, 178; SEDA-18, 202; SEDA-22, 206), and another case has been reported (97A). A 69-year-old man was given amiodarone intravenously 1500 mg for multiple coupled ventricular extra beats and 24 hours later developed acute hepatitis, with a 50-fold increase in serum aminotransferase activities and simultaneous increases in LDH, v-glutamyl transferase, bilirubin, and prothrombin time; there was a moderate leukocytosis and mild renal insufficiency.No further amiodarone was given and there was full recovery within 2 weeks. Other causes of acute hepatitis were excluded. The mechanism of this effect is not known, but the histology includes Mallory bodies, steatosis, intralobular inflammatory infiltrates, and fibrosis; electron microscopy suggests phospholipidosis. It has been suggested that liver injury due to amiodarone is either due to a direct biochemical action or perhaps metabolic idiosyncrasy. Because there have been cases in which oral administration has not led to a recurrence, it has also been suggested that the vehicle in which amiodarone is usually dissolved, polysorbate (Tween) 80, is responsible rather than the amiodarone itself (SEDA-18, 202). Chronic liver damage with amiodarone is much more common than acute hepatitis, but cholestatic jaundice is one of the relatively rare presentations (SEDA-19, 193), and another case has been reported (98A). An 84-year-old woman, who had taken amiodarone 400 mg/day for 4-5 years, developed weakness, fatigue, anorexia, and abnormal liver function tests, with an aspartate aminotransferase activity of 234 u/l, alanine aminotransferase 154 u/l, and alkaline phosphatase 316 u/1. She had a normal serum bilirubin and the serum concentrations of amiodarone and desethylamiodarone were both within the usual target ranges. Apart from gallstones, endoscopic retrograde cholangiography and abdominal ultrasound showed a normal biliary tree. After withdrawal of amiodarone her liver function tests improved, but 4 months later she developed a rapidly rising serum bilirubin concentration (142 Ixmol/1), her serum albumin concentration fell to 30 g/l, and her serum cholesterol concentration was high (11 mmol/l). She had bilirubin and urobilinogen in the urine and there was no evidence of viral or immunological hepatitis. Abdominal ultrasonography was normal, as was a liver scan, but a CT scan of the abdomen showed a diffusely hyperdense liver, consistent with

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the effects of amiodarone. Liver biopsy also showed findings consistent with amiodarone-induced cholestatic liver damage, with distorted architecture, portal fibrosis, pericellular sinusoidal fibrosis, and focally irregular lobular sinusoidal fibrosis, but without bridging fibrosis or cirrhosis. There was ductal proliferation and a mild lymphocytic infiltrate but no cholangitis. Electron microscopy showed lamellar inclusions compatible with phospholipidosis. If amiodarone was responsible in this case, it is hard to reconcile the improvement following amiodarone withdrawal with the cholestasis that occurred 4 months later. The patient was also taking felodipine, furosemide, potassium chloride, aspirin (500 mg/day), and cisapride, but the authors argued that the changes were not consistent with liver damage due to any of those drugs. In particular they thought that the felodipine was unlikely to have caused cholestasis, although that has been previously reported, because of the presence of Mallory bodies in the liver biopsy; however, Mallory bodies have previously been reported with felodipine, and although cholestatic liver injury caused by felodipine has not been reported before, that seems as likely a candidate in this case as amiodarone.

Skin Blue-gray discoloration o f the face is an occasional complication of amiodarone therapy (SEDA-15, 171; SEDA-22, 207; SEDA-23, 199), and another case has been reported in a 55-year-old woman who had been taking amiodarone 250 mg/day for about 10 years (99A). Her facial pigmentation responded to treatment with a Q-switched ruby laser at an energy of 8 J/cm 2 and a wave length of 694 ram. Like so many of the adverse effects of amiodarone, this skin pigmentation is thought to be due to long-term deposition of lipofuscin. The authors suggested that the ruby laser had damaged pigment-containing cells. However, the amiodarone was continued, so presumably the laser also destroyed the lipofuscin in situ. Immunologic A case of lupus-like syndrome, which has not previously been attributed to amiodarone, has been reported (100A). A 71-year-old woman, who had been taking amiodarone 200 mg bd for 2 years, developed malaise, intermittent fever, arthralgia, and weight loss. She had a malar rash and hypoventilation at both lung bases. Her erythrocyte sedimentation rate was markedly raised (90 mm/hour), there was a mild nor-

Positive inotropic drugs and drugs used in dysrhythmias mochromic normocytic anemia (10 g/dl), a slight lymphopenia, and otherwise normal routine tests. Her rheumatoid factor was raised in a titer of 1:320, and circulating complexes of IgGqZlq were positive. Antinuclear antibody was positive (1:640), but all other antibodies were negative. There was progressive improvement on withdrawal of amiodarone and all the biochemical tests returned to normal. Reproductive system Non-infective epididymitis has occasionally been reported in patients taking amiodarone (SEDA-10, 148; SEDA-18, 203). Another case has been reported in a 25-year-old man who had taken amiodarone 200 mg bd for 1 year (101A). The epididymitis resolved within 3 months of withdrawal of amiodarone and recurred within 2 months of its reintroduction. This case was unusual in that it involved both testes. The mechanism of this effect is not known, but it has been reported to be dose-dependent, although antiamiodarone antibodies have also been reported (102Ar). The incidence is not known, but has been reported to be as high as 11%. The author of one very brief report (103 e) claimed to have seen 20 cases of epididymitis, some of which were bilateral, since the late 1980s. He claimed that withdrawal produced dramatic resolution of symptoms within 10-20 days, and that amiodarone in a dose of 200 mg/day did not usually cause symptoms, even in patients who had had epididymitis at higher dosages. Fetotoxicity Exposure to amiodarone in utero has only occasionally been described. The major adverse effect on the fetus is altered thyroid function (SEDA-13, 141; SEDA-14, 149; SEDA-19, 194; SEDA-20, 176), although occasionally other adverse effects have been described, including sinus bradycardia (SEDA8, 179) and congenital nystagmus (SEDA-20, 176). In one child there was evidence of mental

delay, hypotonia, hypertelorism, and micrognathia (SEDA-20, 176), although the authors thought that the link between amiodarone and neurotoxicity was speculative. However, there has now been a retrospective study of 10 children who were exposed to amiodarone during pregnancy, compared with matched controls (104c). There was no change in IQ score, but the children who had been exposed to amiodarone had impaired expressive language skills and one child had global developmental delay. However, most of the mothers were not concerned about their children's development, and so any

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effect of amiodarone on neurological development was probably small. One child had transient neonatal hypothyroidism, which responded to a short course of thyroxine; another had mild transient neonatal hyperthyroidism; in neither case was there any difference in development from the other children who had been exposed to amiodarone. One child was born with a congenital jerk nystagmus and had relatively poor reading and comprehension skills for

both words and passages, low scores on several of the verbal subtests of the WISC-R test for information, arithmetic, and vocabulary, and below average spelling. Interactions The interaction of amiodarone with/3-blockers has been reported to be both beneficial and adverse (SEDA-15, 172; SEDA-23, 200). In a recent systematic review, the beneficial interaction has been confirmed (105M). Four groups of patients who had been studied in EMIAT and CAMIAT (SEDA-21, 198) were defined: patients who had taken amiodarone plus /3-blockers, patients who had taken /3blockers or amiodarone alone, and patients who had taken neither. The relative risks for allcause mortality and all forms of cardiac death or resuscitated cardiac arrest were lower in the patients who had taken amiodarone plus /3blockers than in the other three groups. The results of this post hoc analysis should be regarded with caution, but in view of previous similar reports they are suggestive of a beneficial interaction of amiodarone with/3-blockers in patients who have had a previous myocardial infarction. The interaction was statistically significant for cardiac deaths and for dysrhythmic deaths or resuscitated cardiac arrest. In all other cases the relative risk was reduced, although not significantly. The risk was not affected by heart rate. This interaction has also been reviewed (106R).

Indinavir

Ritonavir inhibits CYP3A4, which is responsible for the de-ethylation of amiodarone to desethylamiodarone, and indinavir has now been reported to do the same (107A). A 38-year-old man, who had taken amiodarone 200 mg/day for more than 6 months, was given postexposure prophylaxis for H1V infection after a needle injury; this included zidovudine, lamivudine, and indinavir. During the 4 weeks of therapy his serum amiodarone concentration rose from 0.9 to 1.3 mg/1, with only a small rise in the serum

Chapter 17

210 concentration of desethylamiodarone from 0.4 to 0.5 mg/1. After withdrawal of the prophylactic therapy the plasma amiodarone concentration gradually fell to the pretreatment value, and there was no further change in the concentration of desethylamiodarone. No adverse effects of this interaction were reported.

Meglumine antimoniate

A pharmacodynamic interaction has been described between amiodarone and meglumine antimoniate, both of which prolong the QT interval; the interaction resulted in torsade de pointes (108A).

A 73-year-old man with visceral leishmaniasis was given meglumine antimoniate intramuscularly 75 mg/kg/day. At that time his QTc interval was normal at 0.42 seconds. Three weeks later his QTc interval was prolonged to 0.64 seconds and he was given methyldigoxin 0.4 mg and amiodarone 450 mg intravenously over 8.25 hours; 12 hours later he had a cardiac arrest with torsade de pointes, which was cardioverted by two direct shocks of 300 joules and lidocaine 100 mg in two bolus injections. Because he had frequent episodes of paroxysmal atrial fibrillation, he was given amiodarone 100 mg over the next 40 hours, and developed recurrent self-limiting episodes of torsade de pointes associated with QTc interval prolongation, which responded to intravenous magnesium 1500 mg. After withdrawal of amiodarone there was no recurrence and a week later the QTc interval was 0.48 seconds. The plasma potassium concentration was not abnormal in this case. In view of this report it is probably wise to avoid co-administration of these two drugs.

ZK. Aronson

in this case was unlikely, because the patient had taken both drugs together for 2 years before the increase in response to warfarin, coincident with the emergence of thyrotoxicosis.

Aprindine

(SED-14, 541; SED-18, 203)

The pharmacology, clinical pharmacology, clinical effects, and adverse effects of aprindine have recently been reviewed (112R). Its major adverse effects are neutropenia and cholestatic liver damage, both of which are thought to be non-dose-related reactions. The incidence of neutropenia has been estimated at about 2 per 1000 patient years. Less commonly aprindine can cause adverse effects in the central nervous system (SEDA-1, 156). Pneumonitis has also been reported (SEDA-16, 179). Aprindine is metabolized by CYP2D6, and one would therefore expect interactions with drugs that inhibit this isoenzyme or are metabolized by it.

Cibenzoline (SED-14, 542; SEDA-18, 203; SEDA-20, 177; SEDA-23, 200) The pharmacology, clinical effects, and adverse effects of cibenzoline have recently been reviewed (l12R). Prolongation of the QT interval, leading to cardiac dysrhythmias, is the major adverse effect. Other effects include gastrointestinal disturbances, effects on

Rifampicin

the central nervous system, and hypoglycemia,

Warfarin That amiodarone can potentiate the action of warfarin by inhibiting its metabolism is well known (SEDA-11, 156). However, in a recent case potentiation of the action of warfarin was attributed to amiodarone-induced thyrotoxicosis (111A). A metabolic interaction

perhaps related to inhibition of ATP-dependent potassium channels in the pancreas. Cibenzoline and flecainide have been compared in the prevention of recurrence of atrial tachydysrhythmias in 139 patients (113c). During the study, 27 patients withdrew, in 13 cases with adverse effects, seven of which were due to cibenzoline. Overall there were 26 adverse effects in 23% of the patients taking cibenzoline; these included one case of ventricular dysrhythmia, four minor cardiac events, four cases of nausea or epigastric pain, eight cases of weakness, four cases of depression or insomnia, one skin rash, and one case of hypoglycemia. The QRS complex was prolonged by more than 13% in 14 patients, but the QT interval was not prolonged. Although this was not a placebo-controlled study, the incidence of adverse effects with cibenzoline was probably as one would expect in such a population.

In a 33-year-old woman taking amiodarone 400 mg/day the addition of rifampicin 600 mg/day resulted in paroxysms of atrial fibrillation and atrial flutter, with a very low serum amiodarone concentration and an undetectable concentration of desethylamiodarone (109A). This was attributed to induction of the metabolism of amiodarone and desethylamiodarone, and after withdrawal of rifampicin the concentrations of the two compounds rose to within the target ranges. This interaction has not previously been reported, although it has been demonstrated in human liver microsomes (110E).

Positive inotropic drugs and drugs used in dysrhythmias D r u g o v e r d o s e An overdose of cibenzoline has been reported (114A). An 80-year-old woman who took an unknown number of 300 mg tablets had impaired consciousness, a low blood pressure (58/30 mmHg), coarse crackles in the lung, and a prolonged QTc interval (0.64 seconds). There was mild left ventricular global hypokinesia with a 50% left ventricular ejection fraction, severe mitral regurgitation, and left atrial dilatation. There was a mild partially compensated metabolic acidosis and hypoglycemia (2.9 mmol/1). The plasma concentration of cibenzoline was 2580 ng/ml. She was treated with sodium bicarbonate, dopamine, and noradrenaline. A pre-existing right ventricular pacemaker was not functioning, and the amplitude was increased from 2.5 to 7.5 volts at a rate of 90 per minute. Charcoal perfusion for 5 hours caused a dramatic fall in the plasma cibenzoline concentration in association with a reduction in the QTc interval to 0.48 seconds and improvement in the pacing threshold.

Disopyramide

(SED-14, 543; SEDA-21, 199; SEDA-22, 207; SEDA-23, 200) E n d o c r i n e Hypoglycemia is a well-known adverse effect of disopyramide (SEDA-17, 222), perhaps due to increased secretion of insulin. In six subjects who were being considered for treatment with disopyramide, serum glucose concentrations were measured at 13, 15, 17, and 19 hours after supper, with no further food, with and without the added administration of two modified-released tablets of disopyramide 150 mg with supper and 12 hours later (115c). Disopyramide significantly reduced the serum glucose concentration at all measurement times by an average of 0.54 mmol/1. The fall in serum glucose concentration was not related to the serum concentration of disopyramide or the serum creatinine concentration; it was greater in older patients and in underweight patients.

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has previously been reported to have caused the onset of uterine contractions in eight of 10 patients at term (117c). In view of these reports disopyramide should be avoided in pregnancy. D r u g interactions Some of the macrolide antibiotics have been reported to inhibit the clearance of disopyramide ( S E D A - 2 1 , 2 0 0 ; SEDA22, 207), resulting in serious dysrhythmias. This has again been reported with clarithromycin (118A). A 76-year-old woman developed torsade de pointes 5 days after starting to take clarithromycin 200 mg bd in addition to disopyramide 100 mg tds. Her serum potassium concentration was 2.8 retool/1 and the QTc interval was prolonged to 0.71 seconds. The plasma disopyramide concentration was in the usual target range (3.2 Ixg/ml). The disopyramide and clarithromycin were withheld and potassium was given; 14 hours later the serum potassium concentration was 4.3 mmol/l and there was no further dysrhythmia, despite prolongation of the QTc interval to 0.67 seconds, falling to 0.45 seconds l0 days later. In another case, clarithromycin potentiated the hypoglycemic effect of disopyramide (119A). In a 59-year-old man taking disopyramide 50 mg/day the addition of clarithromycin 600 mg/day caused hypoglycemia, and the serum disopyramide concentration rose from 1.5 to 8.0 ltg/ml. The ratio of plasma insulin concentration to blood glucose concentration was greatly increased, suggesting that hypersecretion of insulin was responsible, confirming the likelihood that the hypoglycemia was due to disopyramide intoxication secondary to inhibition of its metabolism by clarithromycin. There was also slight prolongation of the QTc interval, but no cardiac dysrhythmias. After withdrawal of clarithromycin and disopyramide both the blood glucose concentration and the QTc interval returned to normal.

Flecainide

(SED-14, 545; SEDA-21, 200;

SEDA-22, 207) P r e g n a n c y Disopyramide has previously been reported to cause uterine contractions when given late in pregnancy (SEDA-3, 156), although the association was not clear. However, in a more recent case a 26-year-old woman with Wolff-Parkinson-White syndrome was given two doses of disopyramide at 36 weeks and shortly afterwards went into active labor with prepartum hemorrhage (l16A). The child was delivered by cesarean section and the woman made a full recovery. Disopyramide

D r u g overdose An overdose of flecainide has been reported (120A). A 20-year-old woman took 3-4 g of flecainide and developed circulatory failure unresponsive to pacing, inotropic drags, and sodium bicarbonate. She was then successfully treated with cardiopulmonary bypass for 30 hours. At peak, the plasma flecainide plasma concentration was in excess of 4000 Itg/ml, and although this fell during bypass to below 3.5 Ixg/ml clinical recovery preceded this fall. Other

212 complications included a coagulopathy with intravascular hemolysis, requiring the use of blood products, and renal insufficiency requiring hemodiafiltration. The authors proposed that extracorporeal circulatory support had allowed increased perfusion of the liver and therefore more effective metabolism of the flecainide. A case of fatal flecainide overdose has been reported in a 65-year-old man who probably took 20 tablets of 100 mg each (121A). However, no clinical details were available, because he was found dead. Flecainide was detected in his blood, gastric contents, and liver. Odealkylated flecainide was found in his urine. Of other fatal cases reviewed in the paper, in only one was there a slightly lower blood concentration of flecainide (7.3 compared with 7.7 mg/kg). The authors proposed that pre-existing cardiac damage could have predisposed this man to a dysrhythmic death.

Lidocaine (lignocaine) (SED-14,546; SEDA-21, 201; SEDA-22, 208; SEDA-23, 200) Lidocaine has been used to treat some of the symptoms of multiple sclerosis in 30 patients with painful tonic seizures, attacks of neuralgia, paroxysmal itching, and Lhermitte's sign (122c). Lidocaine was given by intravenous infusion for 5.5 hours in a maintenance dose of 2-2.8 mg/kg/hour after a loading dose, and the mean steady-state concentration was 2.4 txg/ml. Lidocaine almost completely abolished the paroxysmal symptoms and markedly alleviated the persistent symptoms of multiple sclerosis. Adverse effects were not specifically mentioned, but in one case, when the plasma concentration of lidocaine rose above 3.5 Ixg/ml, weakness of the left leg became marked and was associated with an extensor plantar response; this disappeared when the lidocaine was replaced by saline single blind, but subsequently the positive symptoms recurred.

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of thiopental and midazolam. Her ventricular fibrillation responded to procainamide I g intravenously over 10 minutes. The pharmacokinetics of lidocaine are altered by cardiopulmonary bypass, because of hemodilution, changed protein binding, the exclusion of the lungs as an organ for first-pass elimination, altered acid-base balance, and sometimes drug interactions. In particular, reduced protein binding may have contributed in this case to the risk of seizure, but plasma lidocaine concentrations were not measured. However, hypothermia and muscle relaxation may mask the motor manifestations of seizures, masking the true incidence of lidocaine-induced seizures during cardiopulmonary bypass. Risk factors Lidocaine is extensively metabolized in the liver to monoethylglycinexylidide and glycinexylidide, and hepatic cirrhosis therefore increases the risk of lidocaine toxicity by inhibiting this metabolism. The rate of clearance of lidocaine can also therefore be used to assess the degree of impairment of liver function in patients with hepatic cirrhosis (124c), as has been done in 21 patients with cirrhosis, nine patients with acute hepatitis, and nine controls. The patients with cirrhosis had higher concentrations of lidocaine and lower concentrations of monoethylglycinexylidide in the serum compared with the patients with hepatitis and the controls. The half-life was also significantly prolonged from about 3 to 5 hours. There were mild adverse effects (tinnitus, dizziness, drowsiness, and/or perioral paresthesia) in two of the nine controls, seven of the 21 patients with cirrhosis, and five of the nine patients with acute hepatitis. They occurred 90 minutes after the oral administration of lidocaine and resolved spontaneously in 2-3 hours. The adverse effects were not related to differences in the concentrations of lidocaine or monoethylglycinexylidide.

Nervous system Nervous system toxicity is

Mexiletine (SED-14, 547; SEDA-21, 201; SEDA-22, 208; SEDA-23, 200)

the most common adverse effect of lidocaine, and there has been a recent report of a tonicclonic seizure in a 54-year-old woman who was given lidocaine, 200 mg intravenously, for ventricular fibrillation during cardiopulmonary bypass (123A). The seizure occurred immediately after the administration of lidocaine and was relieved by the intravenous administration

In the study of the use of lidocaine in multiple sclerosis mentioned above (122c), mexiletine was also used orally (300-400 mg/day) and produced similar therapeutic effects to lidocaine. In one patient, weakness worsened during the administration of mexiletine. In two patients when mexiletine was replaced by placebo there was

Positive inotropic drugs and drugs used in dysrhythmias a suggestion of some rebound in painful tonic

seizures. In three patients with neuropathic pain, mexiletine added to the analgesic regimen caused some improvement in visual analog scores for pain (125A). All three had some symptoms of nausea, and two became depressed. One patient also reported feeling "trembly and shaky" on occasion, but there was no objective evidence of tremor. Drug interactions A 79-year-old woman who was given mexiletine 125 mg intravenously over 10 minutes during anesthesia, after having been given lidocaine 100 mg intravenously, had a marked drop in blood pressure an hour after the administration of mexiletine (126A). The blood pressure rose when sevoflurane was withdrawn, and the authors proposed that the effect had been brought about by the combination of mexiletine and sevoflurane.

Procainamide (SED-14, 548; SEDA-21, 202; SEDA-22, 208; SEDA-23, 201) Psychiatric Acute psychosis has been attributed to procainamide (127A). A 45-year-old woman developed an acute psychosis within 72 hours of starting to take procainamide 75 mg intravenously followed by a continuous infusion of 2 mg/min for atrial fibrillation. The plasma procainamide concentration was 8.2 t~g/ml and the plasma concentration of the main acetylated metabolite, acecainide, was 4.6 Ixg/ml She was then given oral procainamide 500 mg qds, and 2 days later her trough concentrations of procainamide and acecainide were 4.5 and 4.9 i~g/ml respectively. The following day she had visual hallucinations and was later found wandering the hospital asking about the babies under her bed. She had no previous history of psychiatric illness and she recovered completely 24 hours after withdrawal of procainamide. There have been a few previous reports of similar adverse effects with procainamide in therapeutic dosages, and in most cases the plasma concentrations of procainamide and acecainide have been within the usual target ranges, as in this case. A 70-year-old man developed a maculopapular skin rash on the trunk 10 days after

Skin

starting to take procainamide 1.5 g/day (128A). Resolution occurred soon after the withdrawal

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of procainamide and a similar skin rash occurred on rechallenge. In addition to the maculopapular rash, there was swelling and erythema around the eyes and a purpuric rash on the legs. At the time of rechallenge he also had an eosinophilia. Immunologic IgG antibodies to the (H2AH2B)-DNA complex are common in patients with immunological reactions to procainamide (SEDA-20, 178). In a prospective study of 62 patients who had taken procainamide for a mean duration of 23 months (range 1 month to 16 years), and excluding patients with preexisting systemic lupus erythematosus or who were taking other drugs that have been associated with the lupus-like syndrome, nine developed evidence of lupus-like syndrome and were compared with the other 53 (129c). The mean dosage in the patients with lupus-like syndrome was 3.7 g/day compared with 3 g/day in the others, and the durations of administration were 8.8 and 38 months respectively. All four patients who had polyarticular arthritis and/or pleural effusions were positive for the IgG antibodies and four of the other five, who had significantly lower IgG concentrations, presented with the more typical manifestations of vasculitic rashes, pericarditis, or agranulocytosis. In all cases the symptoms and signs either improved markedly or resolved within 3 weeks of withdrawal of procainamide. Seven asymptomatic patients had IgG concentrations comparable with those seen in the patients with lupus-like syndrome, and high concentrations of antibody, although not as high as the two highest in the latter group. Anti-doublestranded DNA antibodies were not detected in any patients. In 33 control subjects there were no detectable antibodies of any kind. The authors therefore suggested that the (H2A-H2B)DNA IgG antibody is not a useful marker for the occurrence of lupus-like syndrome in patients taking procainamide, although they conceded that the presence of IgG antibody supported the diagnosis of lupus-like syndrome when the main clinical manifestations were arthritis or pleurisy. The significance of the presence of IgG antibodies in asymptomatic patients is not clear, but the authors suggested that it meant that those patients merited careful observation. The lupus-like syndrome in patients taking procainamide is thought to be due to the

214 procalnamide itself, since it has rarely been reported when the main metabolite of procainamide, acecalnide, has been administered itself (SEDA-18, 206). Alternatively, the syndrome may be due to a different metabolite of procainamide, and a hydroxylated derivative has been implicated (SEDA-15, 178). CYP2D6 is the major isoform of cytochrome P450 that is involved in the hydroxylation of procainamide, and in the ,production of some other metabolites (130'~). It remains to be seen whether extensive metabolizers are more likely to develop lupus-like syndrome than poor metabolizers. Body t e m p e r a t u r e Fever occasionally occurs in patients taking procainamide (SEDA-1,155) and has recently been reported again, and attributed to an allergic reaction (131A).

Propafenone

(SED-14, 551; SEDA-21, 202; SEDA-22, 209; SEDA-23, 202) The clinical pharmacology and use of propafenone in patients with atrial fibrillation and some other dysrhythmias have been reviewed (132R). Drug overdose A 24-year-old woman who took an overdose of propafenone 2.7 g had a convulsion and complete heart block (133A). The plasma propafenone concentration 4 hours after ingestion was 2930 Ixg/l (target range 4001600 txg/1). She was given activated charcoal 50 g, mannitol 200 ml, and clonazepam 1 mg intravenously. By 19 hours after ingestion the electrocardiogram was normal and the plasma propafenone concentration was 858 Ixg/1.

Quinidine (SED-14, 552; SEDA-21, 203; SEDA-22, 209; SEDA-23, 202) Immunologic A variety of immune syndromes have occasionally been reported with quinidine, including a lupus-like syndrome, polymyalgia rheumatica, and vasculitis (SEDA20, 179; SEDA-23, 202). There has now been a report of a dermatomyositis-like illness (134 A).

Chapter 17

J.K. Aronson

A previously healthy 63-year-old man, who had taken quinidine gluconate 972 mg/day for 9 months, developed diffuse edematous erythema on the extensor surfaces of the hands, arms, and face, with marked accentuation over the joints. His nail-fold capillaries were dilated and the shoulder abductors were slightly weak. His erythrocyte sedimentation rate was slightly raised (29 mm/h) and there was a positive ANA titer (1:640) with a speckled pattern. There were no antibodies to Sm, ribonucleoprotein, SSA or SSB antigens, or histones. There was no evidence of inflammatory myopathy on electromyography, and a skin biopsy showed a mild, superficial, perivascular, lymphocytic inflammation with positive direct immunofluorescence for IgG and IgM at the dermoepidermal junction. There was no evidence of malignancy. All these abnormalities resolved rapidly after quinidine withdrawal. Drug interactions There is in vitro evidence that the oxidation of quinidine to 3hydroxyquinidine is catalysed by CYP3A4. However, the extent to which other cytochrome P450 isoforms, such as CYP2C9 and CYP2E1, are involved in the oxidation of quinidine is not clear. In 30 healthy young men the pharmacokinetics of a single oral dose of quinidine 200 mg were studied before and during the dally administration of diclofenac 100 mg (a substrate of CYP2C9), disulfiram 200 mg (an inhibitor of CYP2E1), three inhibitors of CYP3A4 (grapefruit juice, itraconazole, and erythromycin), and probes of other enzyme activities, namely caffeine (CYPA2), sparteine (CYP2D6), mephenytoin (CYP2C19), and tolbutamide (CTP2C9) (135c). The clearance of quinidine by N-oxidation was reduced by 27% by diclofenac. Itraconazole, grapefruit juice, and erythromycin all reduced the clearance of quinidine, including its partial clearance by 3hydroxylation and N-oxidation, by up to 84%, confirming the involvement of CYP3A4 in the in vivo oxidation of quinidine. Specifically, itraconazole reduced quinidine total clearance, partial clearance by 3-hydroxylation, and partial clearance by N-oxidation by 61, 84, and 73% respectively. The small effect of diclofenac suggests a small role for CYP2C9, but the other isoforms were not affected. Thus, it is likely that inhibitors of CYP3A4 will cause significant drug interactions with quinidine.

Positive inotropic drugs and drugs used in dysrhythmias

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218 85. Tomcsanyi J, Merkely B, Tenczer J, Papp L, Karlocai K. Early proarrhythmia during intravenous amiodarone treatment. PACE Pacing Clin Electrophysiol 1999; 22: 968-70. 86. Crocco F, Severino M, Scrivano P, Calcaterra R, Cristiano G. Cardiogenic shock in a case of amiodarone intoxication. Gazz Med Ital Arch Sci Med 1999; 158: 159-63. 87. Kanji Z, Sunderji R, Gin K. Amiodaroneinduced pulmonary toxicity. Pharmacotherapy 1999; 19: 1463-6. 88. Cockcroft DW, Fisher KL. Near normalization of spirometry in a subject with severe emphysema complicated by amiodarone lung. Respir Med 1999; 93: 597~00. 89. Onofrj M, Thomas A. Acetazolamideresponsive periodic ataxia induced by amiodarone. Mov Disord 1999; 14: 379-81. 90. Barry JJ, Franklin K. Amiodarone-induced delirium. Am J Psychiatry 1999; 156:1119. 91. Ambrose A, Salib E. Amiodarone-induced depression. Br J Psychiatry 1999; 174: 3667. 92. Macaluso DC, Shults WT, Fraunfelder FF. Features of amiodarone-induced optic neuropathy. Am J Ophthalmol 1999; 127: 610-12. 93. Katai N, Yokoyama R, Yoshimura N. Progressive brown discoloration of silicone intraocular lenses after vitrectomy in a patient on amiodarone. J Cataract Refractive Surg 1999; 25: 451-2. 94. Thorue SA, Barnes I, Cullinan P, Somerville J. Amiodarone-associated thyroid dysfunction: risk factors in adults with congenital heart disease. Circulation 1999; 100: 149-54. 95. Mariotti S, Loviselli A, Murenu S, San F, Valentino L, Mandas A, Vacquer S, Martino E, Balestrieri A, Lai ME. High prevalence of thyroid dysfunction in adult patients with beta-thalassemia major submitted to amiodarone treatment. J Endocrinol Invest 1999; 22: 55-63. 96. Odeh M, Schiff E, Oliven A. Hyponatremia during therapy with amiodarone. Arch Intern Med 1999; 159: 2599-600. 97. Iliopoulou A, Giannakopoulos G, Mayrikakis M, Zafiris E, Stamatelopoulos S. Reversible fulminant hepatitis following intravenous amiodarone loading. Amiodarone hepatotoxicity. Int J Clin Pharmacol Ther 1999; 37: 312-13. 98. Chang C-C, Petrelli M, Tomashefski JF Jr, McCullough AJ. Severe intrahepatic cholestasis caused by amiodarone toxicity after withdrawal of the drug: a case report and review of the literature. Arch Pathol Lab Med 1999; 123: 251-6. 99. Karrer S, Hohenleutner U, Szeimies R-M, Landthaler M, Hruza GJ. Amiodarone-induced pigmentation resolves after treatment with the Qswitched ruby laser. Arch Dermatol 1999; 135: 251-3. 100. Susano R, Caminal L, Ramos D, Diaz B. Amiodarone induced lupus. Ann Rheum Dis 1999; 58: 655-6.

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101. Gabal-Shehab LL, Monga M. Recurrent bilateral amiodarone induced epididymitis. J Uro11999; 161: 921. 102. Sadek I, Biron P, Kus T. Amiodarone-induced epididymitis: report of a new case and literature review of 12 cases. Can J Cardiol 1993; 9: 833-6. 103. Kirkali Z. Re: Recurrent bilateral amiodarone induced epididymitis. J Urol 1999; 162: 808-9. 104. Magee LA, Nulman I, Rovet JF, Koren G. Neurodevelopment after in utero amiodarone exposure. Neurotoxicol Teratol 1999; 21: 261-5. 105. Boutitie F, Boissel J-P, Connolly SJ, Camm AJ, Cairns JA, Julian DG, Gent M, Janse M J, Dorian P, Frangin G. Amiodarone interaction with beta-blockers: analysis of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases. Circulation 1999; 99: 2268-75. 106. Ogunyankin KO, Singh BN. Mortality reduction by antiadrenergic modulation of arrhythmogenic substrate: significance of combining beta blockers and amiodarone. Am J Cardiol 1999; 84 Suppl 1: 76-82. 107. Lohman JJHM, Reichert LJM, Degen LPM. Antiretroviral therapy increases serum concentrations of amiodarone. Ann Pharmacother 1999; 33: 645-6. 108. Segura I, Garcia-Bolao I. Meglumine antimoniate, amiodarone and torsades de pointes: a case report. Resuscitation 1999; 42: 65-8. 109. Zarembski DG, Fischer SA, Santucci PA, Porter MT, Costanzo MR, Trohman RG. Impact of rifampin on serum amiodarone concentrations in a patient with congenital heart disease. Pharmacotherapy 1999; 19: 249-51. ll0. Fabre G, Julian B, Saint Aubert B, Joyeux H, Berger Y. Evidence for CYP3A-mediated Ndeethylation of amiodarone in human liver microsomal fractions. Drug Metab Dispos 1993; 21: 978-85. 111. Woeber KA, Warner I. Potentiation of warfarin sodium by amiodarone-induced thyrotoxicosis. West J Med 1999; 170: 49-51. 112. Kodama I, Ogawa S, Inoue H, Kasanuki H, Kato T, Mitamura H, Hiraoka M, Sugimoto T. Profiles of aprindine, cibenzoline, pilsicainide and pirmenol in the framework of the Sicilian Gambit. Jpn Cire J 1999; 63: 1-12. 113. Babuty D, Malson-Blanche E Fauchier L, Brembilla-Perrot B, Medvedowsky JL, BineScheck E Double-blind comparison of cibenzoline versus flecainide in the prevention of recurrence of atrial tachyarrhythmias in 139 patients. Ann Noninvasive Electrocardiol 1999; 4: 53-9. 114. Aoyama N, Sasaki T, Yoshida M, Suzuki K, Matsuyama K, Aizaki T, Izumi T, Kondo R, Kamijo Y, Soma K, Ohwada T. Effect of charcoal hemoperfusion on clearance of cibenzoline succinate (cifenline) poisoning. J Toxicol Clin Toxicol 1999; 37: 505-8.

Positive inotropic drugs and drugs used in dysrhythmias 115. Hasegawa J, Mori A, Yamamoto R, Kinugawa T, Morisawa T, Kishimoto Y. Disopyramide decreases the fasting serum glucose level in man. Cardiovasc Drugs Ther 1999; 13: 325-7. 116. Abbi M, Kriplani A, Singh B. Preterm labor and accidental hemorrhage after disopyramide therapy in pregnancy: a case report. J Reprod Med Obstet Gynecol 1999; 44: 653-5. 117. Tadmor OP, Keren A, Rosenak D, Gal M, Shaia M, Homstein E, Yaffe H, Graft E, Stem S, Diamant YZ. The effect of disopyramide on uterine contractions during pregnancy. Am J Obstet Gynecol 1990; 162: 482-6. 118. Hayashi Y, Ikeda U, Hashimoto T, Watanabe T, Mitsuhashi T, Shimada K. Torsades de pointes ventricular tachycardia induced by clarithromycin and disopyramide in the presence of hypokalemia. PACE Pacing Clin Electrophysiol 1999; 22: 672--4. 119. fida H, Morita T, Suzuki E, Iwasawa K, ToyoOka T, Nakajima T. Hypoglycemia induced by interaction between clarithromycin and disopyramide. Jpn Heart J 1999; 40: 91-6. 120. Corkeron MA, Van Heerden PV, Newman SMAJ, Dusci L. Extracorporeal circulatory support in near-fatal flecainide overdose. Anaesth Intensive Care 1999; 27: 405-8. 121. Romain N, Giroud C, Michaud K, Augsburger M, Mangin P. Fatal flecainide intoxication. Forensic Sci Int 1999; 106:115-23. 122. Sakurai M, Kanazawa I. Positive symptoms in multiple sclerosis: their treatment with sodium channel blockers, lidocaine and mexiletine. J Neurol Sci 1999; 162: 162-8. 123. Lee DL, Ayoub C, Shaw RK, Fontes ML. Grand mal seizure during cardiopulmonary bypass: probable lidocaine toxicity. J Cardiothorac Vasc Anesth 1999; 13: 200-2. 124. Munoz AE, Miguez C, Rubio M, Bartellini M, Levi D, Podesta A, Niselman V, Terg R. Lidocaine and monoethylglycinexylidide serum determinations to analyze liver function of cirrhotic patients after oral administration. Dig Dis Sci 1999; 44: 789-95. 125. Sloan P, Basta M, Storey P, Von Gunten C.

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Mexitetine as an adjuvant analgesic for the management of neuropathic cancer pain. Anesth Analg 1999; 89: 760-1. 126. Kudo M, Ohke H, Kawai T, Kato M, Kokubu M, Shinya N. Geriatric patient who suffered transitory cardiovascular collapse under sevoflurane anesthesia due to continuous medication with mexiletine hydrochloride. J Jpn Dent Soc Anesthesiol 1999; 27: 614-18. 127. Bizjak ED, Nolan PE Jr, Brody EA, Galloway JM. Procainamide-induced psychosis: a case rcport and review of the literature. Ann Pharmacother 1999; 33: 948-51. 128. Numata T, Abe H, Nakashima Y, Yamamoto O, Kohshi K. Procainamide-induced skin eruption associated with disseminated intravascular coagulation in a patient with sustained ventricular tachycardia. J UOEH 1999; 21: 235~-0. 129. Chi Chi Lau, Clos TD. Anti-[(H2A/2B)DNA] IgG supports the diagnosis of procainamideinduced arthritis or pleuritis. Arthritis Rheum 1999; 42: 1300-1. 130. Lessard E, Hamelin BA, Labbe L, O'Hara G, Belanger PM, Turgeon J. Involvement of CYP2D6 activity in the N-oxidation of procainamide in man. Pharmacogenetics 1999; 9: 683-96. 131. Murray KD, Vlasnik JJ. Procainamideinduced postoperative pyrexia. Ann Thorac Surg 1999; 68: 10724. 132. Valderrabano M, Singh BN. Electrophysiologic and antiarrhythmic effects of propafenone: focus on atrial fibrillation. J Cardiovasc Pharmacol Ther 1999; 4: 183-98. 133. Rambourg-Schepens M-O, Grossenbacher F, Buffet M, Lamiable D. Recurrent convulsions and cardiac conduction disturbances after propafenone overdose. Vet Hum Toxicol 1999; 41: 1534. 134. Gilliland WR. Quinidine-induced dermatomyositis-like illness. J Clin Rheumatol 1999; 5: 39. 135. Damkier P, Hansen LL, Brosen K. Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine. Br J Clin Pharmacol 1999; 48: 829-38.

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

18

fi-adrenoceptor antagonists and antianginal drugs

/~-ADRENOCEPTOR ANTAGONISTS (SED-14, 579; SEDA-21, 207; SEDA-22, 213; SEDA-23, 206)

ORGANS AND SYSTEMS Psyehiatrie Bipolar depression affects 1% of the general population, and treatment resistance is a significant problem. The addition of pindolol can lead to significant improvement in depressed patients who are resistant to antidepressant drugs, such as selective serotonin reuptake inhibitors or phenelzine. Of 17 patients with refractory bipolar depression, in whom pindolol was added to augment the effect of antipressant drugs, eight responded favorably (lC). However, two developed transient hypomania, and one of these became psychotic after the resolution of hypomanic symptoms. In both cases transient hypomanic symptoms resolved without any other intervention, while psychosis required pindolol withdrawal. t-blockers can cause impaired cognitive function. In 27 hypertensive patients

Psychological

aged 65 years or more randomized to continue atenolol treatment for 20 weeks or to discontinue atenolol and start cilazapril, there was a significant improvement in the choice reaction time in the patients randomized to cilazapril (2c). This study has confirmed previous reports that chronic t-blockade can determine adverse effects on cognition in elderly patients. Withdrawal of E-blockers should be considered in any elderly patient who has signs of mental impairment.

9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual24 J.K. Aronson,ed.

Metabolism Propranolol is sometimes used in the treatment of behavioral disorders. Two children in whom propranolol was used to treat attention deficit disorders and anxiety became unarousable, with low heart rate and respiratory rate, due to hypoglycemia (3At). Hypoglycemia can be caused by reduced glucose intake (fasting), increased utilization (hyperinsulinemia), or reduced production (enzymatic defects). One or more of these mechanisms can be responsible for hypoglycemia secondary to drugs. Children treated with propranolol may be at increased risk of hypoglycemia, particularly if they are fasting. Concomitant treatment with methylphenidate can increase the risk of this metabolic disorder. Drug overdose Propranolol intoxication can cause central nervous system depression in the absence of clinical signs of cardiac toxicity. A 16-year-old boy developed central nervous system depression and an acute dilated cardiomyopathy after taking 3200 mg of propranolol in a suicide attempt (4A). He was treated with gastric lavage, activated charcoal, and mechanical ventilation. Echocardiography showed a poorly contracting severely dilated left ventricle. After intravenous isoprenaline hydrochloride and glucagon echocardiography showed normal left ventricular size and function. He became fully alert 20 hours later and made a good recovery without sequelae. Early echocardiographic evaluation is important in t-blocker overdose and can prevent delay in the diagnosis and treatment of cardiac toxicity.

Drug administration route Topical There have been reports of systemic adverse reactions in patients treated with t-blocker eye drops.

fl-adrenoceptor antagonists and antianginal drugs A 58-year-old patient treated with topical timolol maleate for open-angle glaucoma developed cough and dyspnea due to interstitial pneumonitis. Three months after withdrawal of the eye drops, he was asymptomatic with normal lung function, chest Xray, and thoracic CT scan (5A). Continuous 24-hour monitoring of blood pressure has shown that el-blocker eye drops for glaucoma can increase the risk of nocturnal arterial hypotension (6c). Allergic contact dermatitis due to carteolol eye drops occurred in a 61-year-old woman (7A). Withdrawal of carteolol and the use of timolol instead led to improvement within 10 days, suggesting that in some cases there is no cross-reactivity between different/~-blockers.

INDIVIDUAL /~-ADRENOCEPTOR ANTAGONISTS Acebutolol Acebutolol is a E-blocker with membrane stabilizing activity. An overdose of acebutolol (6.4 mg) in a 48-year-old man caused cardiac arrest with ventricular tachycardia (8A). An intravenous bolus of sodium bicarbonate 50 mmol produced sinus rhythm. The membrane-stabilizing activity of E-blockers can play a major role in toxicity. Of 208 deaths, in subjects who had taken E-blockers, 206 occurred with drugs that have membrane-stabilizing activity. This quinidine-like effect can be reversed by sodium bicarbonate, which is also used to counteract the cardiotoxic effects of cyclic antidepressants, which also have membrane-stabilizing activity.

Carvedilol The safety and tolerability profile of carvedilol in heart failure appears to be reassuring (9R). Since the adrenergic system is activated to support reduced contractility of the failing heart, the administration of a E-blocker in a patient with heart failure can cause myocardial depression. This effect is more marked with nonselective first-generation E-blockers, such as propranolol. The third-generation drugs, such as carvedilol, have an acceptable initial tol-

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erability profile, reducing after-load and thus counteracting the negative inotropic properties of adrenoceptor blockade. While these vasodilatory properties can play a favorable role at the start of treatment, it is less likely that vasodilatation can make a substantial contribution to the long-term effects of third-generation /~-blockers. The largest trial of carvedilol in patients with heart failure documented only a 5% withdrawal rate in 1197 patients during the openlabel phase that preceded randomization. The major reasons for withdrawal were worsening heart failure (2%), dizziness (1.1%), bradycardia (0.2%), and death (0.5%). Overall, 78% of the patients who entered the trial and were randomized to carvedilol achieved the target dose of 50 mg/day, and withdrawal rates were comparable with carvedilol and placebo (11-14% over 6.5 months of treatment). The issue of tolerability is particularly important in patients with severe heart failure (NYHA class IV). Unfortunately, so far all trials with carvedilol have failed to recruit a large number of such patients. A retrospective analysis of the tolerability profile of carvedilol in 63 patients with NYHA class IV heart failure showed that non-fatal adverse events while taking carvedilol were more frequent than in class II-III patients (43% vs 24%) and more often resulted in permanent withdrawal of the drug (25% vs 13%) (10c). However 59% of the class IV patients improved by one or more functional class after 3 months of treatment. The conclusion was that carvedilol is a useful adjunctive therapy for patients with NYHA class IV heart failure, but these patients require close observation during the start of treatment and titration of the dose. In patients with heart failure, amiodarone is often required for the treatment of serious ventricular dysrhythmias. The beneficial effects of carvedilol on left ventricular remodeling, systolic function, and symptomatic status were not altered by amiodarone in 80 patients with heart failure. Adverse effects that necessitated withdrawal of carvedilol were no more frequent in patients taking amiodarone than in those taking carvedilol alone (26% vs 25%) (llC).

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NITRATE DERIVATIVES

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

(SED-14, 594; SEDA-21, 208; SEDA-22, 218; SEDA-23, 207)

systemic reaction to topical glyceryl trinitrate was reported as "anaphylactic", without a clear demonstration that it was an allergic reaction (19Ar).

Glyceryl trinitrate (nitroglycerin)

Drug interactions The pressure-lowering ef-

Transdermal glyceryl trinitrate is effective as an analgesic co-adjuvant for cancer pain. In combination with opiates it is well tolerated and reduces the daily consumption of morphine (12c). Transdermal glyceryl trinitrate was safe in potentiating the analgesic effect of spinal sulfentanil analgesia after knee surgery (13c). High-dose transdermal glyceryl trinitrate 50-100 mg given over a period of 12 hours each day for 3 months improved exercise tolerance and left ventricular systolic function in 29 patients with congestive heart failure taking a long-term ACE inhibitor (14cr). The most frequent adverse effects were skin irritation at the site of patch application and headache, which caused premature glyceryl trinitrate withdrawal in three patients. Glyceryl trinitrate has been used as a tocolyric to prolong gestation, reducing the incidence of preterm labor. When compared with a widely used tocolytic, the /~2-adrenoceptor agonist ritodrine, in a randomized multicenter trial, transdermal patches of glyceryl trinitrate 10-20 mg had similar efficacy in 245 women with preterm labor. The main adverse effect of glyceryl Winitrate was headache, while with ritodrine palpitation and tachycardia were significantly more frequent. Headache with glyceryl trinitrate could usually be managed with paracetamol. Therefore, glyceryl trinitrate appears to be an alternative to ritodrine and is devoid of dangerous cardiac adverse effects (15Cr). Glyceryl trinitrate can be used to treat anal fissure, as an alternative to surgery. Although glyceryl trinitrate causes resolution of symptoms in some cases, its local use as ointment is associated with frequent adverse reactions, mostly headache and anal burning (16 cr, 17Cr). The difficulty in adjusting the dose and time of application, the high frequency of adverse reactions (up to 75% of patients), and the high rate of recurrence make the use of glyceryl trinitrate in non-surgical treatment of anal fissures questionable (18R). In one case, a patient reported itching, dyspnea, and hypotension after applying glyceryl trinitrate. This unexplained

fect of a step-wise intravenous infusion of glyceryl trinitrate was significantly increased in 12 healthy volunteers treated for 4 days with sildenafil (Viagra) 25 mg tds; episodes of symptomatic hypotension were also more frequent with sildenafil (20Cr). . When sublingual glyceryl trinitrate was used, the reduction in systolic blood pressure was 4-fold greater in association with sildenafil.

CALCIUM

ANTAGONISTS

(SED-14, 598; SEDA-21, 208; SEDA-22, 215; SEDA-23, 208)

Psychiatric Some reports have suggested that calcium antagonists may be associated with an increased incidence of depression or suicide. However, there is a paucity of evidence from large-scale studies. A study of the rates of depression with calcium antagonists, using data from prescription event monitoring (PEM), involved gathering information on symptoms or events in large cohorts of patients after the prescription of lisinopril, enalapril, nicardipine, and diltiazem by general practitioners (21CR). The crude overall rates of depression during treatment were 1.89, 1.92, and 1.62 per 1000 patient months for the ACE inhibitors, diltiazem, and nicardipine respectively. Using the ACE inhibitors as the reference group, the rate ratios for depression were 1.07 (95% CI = 0.82-1.40) and 0.86 (0.69-1.08) for diltiazem and nicardipine respectively. This study does not support the hypothesis that calcium antagonists are associated with depression. Mouth and teeth Gingival overgrowth is a well-known adverse effect of long-term calcium antagonists; however, its prevalence is still uncertain. Although there have been several studies, the results have been conflicting, with inconsistent estimates. Periodontal condition has been assessed in 911 patients taking calcium antagonists, of whom 442 were taking nifedipine, 181 amlodipine, and 186 diltiazem, and in 102 control subjects (22CR). There was

~-adrenoceptor antagonists and antianginal drugs significant gingival overgrowth in 6.3% of the subjects taking nifedipine, while the prevalence induced by amlodipine or diltiazem was not significantly different than in the controls. The severity of overgrowth in the nifedipine group was related to the amount of gingival inflammarion and also to sex, men being three times as likely to develop overgrowth than women. Drug interactions Calcium antagonists are given to transplant patients for their protective effect against ciclosporin-induced nephrotoxicity. However, some of them have pharmacokinetic interactions: diltiazem, verapamil, nicardipine, and amlodipine increase ciclosporin concentrations, whereas nifedipine, felodipine ,and isradipine do not (SED-14, 604; SEDA-21,210, 212; SEDA-22, 216). Two confirmations of these observations have been published. In a retrospective study of 103 transplant patients verapamil and diltiazem, but not nifedipine or isradipine, caused a significant increase in plasma ciclosporin concentrations (23c). The effect of verapamil and diltiazem on ciclosporin concentrations was independent of dosage. In a cross-over comparison between verapamil, felodipine, and isradipine in 22 renal transplant recipients, verapamil interacted pharmacokinetically with ciclosporin and felodipine and isradipine did not (24c).

INDIVIDUAL CALCIUM ANTAGONISTS

Amlodipine A 3-year-old girl developed telangiectases on the cheeks and gingival hyperplasia while taking furosemide, captopril, and amlodipine for hypertension due to hemolytic-uremic syndrome (25Ar). Both lesions disappeared on withdrawal of amlodipine. A 35-year-old woman with benign intracranial hypertension and high blood pressure was given amlodipine, with good control of her blood pressure (26c). However, her headache worsened and she developed papilledema. The CSF pressure was 30 cm. Her symptoms disappeared shortly after amlodipine withdrawal.

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Drug interactions The effect of sildenafil on arterial pressure has been tested in 16 hypertensive men taking amlodipine 5-10 rag/day (20Cr). Sildenafil did not affect amlodipine pharmacokinetics, but caused a further additive fall in blood pressure. Adverse events with the combination of sildenafil and amlodipine, headache, dyspepsia, and nausea, did not require drug withdrawal.

Diltiazem Drug overdose Several cases of accidental or deliberate self-poisoning with calcium antagonists have been described (SED-12, 452; SEDA-16, 198; SEDA-20, 186) and different approaches to the management of these patients have been proposed. A 52-year-old woman with essential hypertension erroneously took a 7-day supply of modifiedrelease diltiazem, enalapril, and trichlormethiazide, and 30 minutes later complained of nausea (27c). She was treated with gastric lavage, calcium gluconate, activated charcoal, and polyethylene glycol. Her blood pressure and heart rate fell progressively to 120/62 mmHg and 40 bpm respectively, 14 hours after ingestion. Afterwards, her hemodynamic status gradually normalized without further treatment.

Drug interactions

Ciclosporin-induced hypertension and acute renal hypoperfusion are attenuated by the dihydropyridine calcium antagonists and diltiazem. This interaction has now been confirmed with a new microemulsion formulation of ciclosporin in nine patients with renal transplants who took diltiazem 90-120 mg bd for 4 weeks (28c). Diltiazem caused a 51% increase in the AUC of ciclosporin and a 34% increase in peak concentration, without altering the time to peak concentration. However, the ciclosporin microemulsion did not significantly affect the pharmacokinetics of diltiazem. Ciclosporin-induced encephalopathy was precipitated by diltiazem in a 76-year-old white woman with corticosteroid-resistant aplastic anemia and thrombocytopenia, type 2 diabetes, and coronary artery disease, who was taking diltiazem for hypertension (29c). She became comatose after 13 days of therapy with ciclosporin, and clinical examination and electroencephalography showed diffuse encephalopathy of moderate severity. Ciclosporin was withdrawn and she regained consciousness after 36 hours.

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Concomitant diltiazem without proper dosage adjustment of ciclosporin can cause adverse neurological events. The interaction of diltiazem with simvastatin has been investigated in 135 patients attending a hypertension clinic (30 c). Cholesterol reduction in the 19 patients taking diltiazem was 33% compared with 25% in the other 116 patients (median difference 8.6%, 95% CI = 1.1, 12). Multivariate analysis showed that concurrent diltiazem therapy, age, and the starting dose of simvastatin were independent predictors of percentage cholesterol response. The authors concluded that patients who take both diltiazem and simvastatin may need lower doses of simvastatin to achieve the recommended reduction in cholesterol. Nifedipine can increase the blood concentration of the macrolide immunosuppressant tacrolimus (SEDA-21, 392). The same interaction has now been reported with diltiazem (31A). A 68-year-old man developed diarrhea, dehydration, and atrial fibrillation 4 months after liver transplantation. He was taking tacrolimus (blood concentration 13 ng/ml) and was given a continuous infusion of diltiazem for 1 day followed by oral therapy. Three days later he became delirious, confused, and agitated, and the blood concentration of tacrolimus was 55 ng/ml. His mental status gradually improved after withdrawal of both drugs. The concomitant administration of diltiazem with tacrolimus can result in a large increase in tacrolimus concentrations with corresponding toxicity. The mechanism of this interaction is likely to be inhibition of tacrolimus metabolism in the intestine and liver by inhibition of CYP3A4 and P-glycoprotein.

Nicardipine Liver Spider nevi, typical of chronic liver disease, have been seen in patients taking long-term nicardipine (32cr). The lesions disappeared within 2 weeks of drug withdrawal.

Pregnancy Nicardipine has been compared with magnesium sulfate in acute therapy of preterm labor in a randomized trial in 122 women (33Cr). The women treated with nicardipine were less likely to have recurrent preterm labor and adverse effects. Neonatal outcomes were similar in the two groups. The most frequent

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

adverse effect was nausea or vomiting with magnesium sulfate (12/65 women).

Nifedipine Cardiovascular There has been a metaanalysis of 60 published randomized clinical trials that enrolled at least 10 patients with stable angina and that compared any nifedipine formulation, either as monotherapy or combination therapy, with a non-dihydropyridine active drug or a placebo control for at least 1 week (34M). There were 3096 subjects and 5571 treatment exposures. There was an increased risk o f cardiovascular events in patients allocated to nifedipine. The unadjusted odds ratios for nifedipine versus controls were 1.40 (CI = 0.56, 3.49) for major events (death, nonfatal myocardial infarction, stroke, revascularization procedures) and 1.75 (CI = 0.83, 3.67) for increased angina. Episodes of increased angina were more frequent with immediaterelease nifedipine (OR = 4.19; CI = 1.41, 12.49) and with nifedipine monotherapy (OR = 2.61; CI = 1.30, 5.26). This meta-analysis suggests that the adverse effects of nifedipine on cardiovascular events in patients with stable angina are primarily due to more frequent episodes of angina when monotherapy with immediaterelease formulations is used. Modified-release formulations and concurrent/~-blockade do not appear to be associated with an increased risk. Sublingual nifedipine, given for hypertensive crises in elderly patients, can cause adverse effects associated with a precipitous fall in blood pressure, even at low doses. In 93 consecutive hypertensive patients without coronary heart disease, aged 65 years or over, nifedipine reduced blood pressure significantly, increased heart rate, and relieved symptoms associated with raised blood pressure (35c). However, there were electrocardiographic changes consistent with myocardial ischemia in six of 55 patients with left ventricular hypertrophy and in one patient without left ventricular hypertrophy. Treatment of hypertensive emergencies has been the object of a randomized comparison of isosorbide dinitrate aerosol and nifedipine in 60 adults (36c). Two patients taking nifedipine had myocardial ischemia early after administration and four patients had rebound hypertension during the follow-up period. Authors who reviewed the role of nifedipine in hypertensive emergencies reached the con-

fl-adrenoceptor antagonists and antianginal drugs clusion that the use of short-acting sublingual or oral nifedipine is no longer recommended for the treatment of these urgencies because it may precipitate serious adverse reactions. Alternatives, such as captopril, labetalol, clonidine and prazosin, are efficacious and safe for the management of this condition (37R).

Skin Two cases of pemphigus vulgaris, one aggravated and one induced by nifedipine, have been described (38c).

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could have posed an extra risk by causing hypotension and reflex tachycardia.

Drug interactions A pharmacokinetic interaction between fluconazole and nifedipine has been reported (40c). A 16-year-old man with neurofibromatosis type 1, a malignant pheochromocytoma with lung and bone metastases, and candidiasis of the gastrointestinal tract with fungemia was taking nifedipine for arterial hypertension. The fungal infection responded to fluconazole, but three attempts to withdraw the fluconazole resulted in recurrence of headache, palpitation, and increased blood pressure.

A 54-year-old woman with an 8-year history of pemphigus vulgaris had a flare-up of her disease, refractory to oral corticosteroids, after taking nifedipine for 2 years for hypertension. The nifedipine was withdrawn and she was given highdose immunosuppressant treatment with prednisone and azathioprine. The lesions subsided promptly and cleared totally within several weeks. A 68-year-old woman had a bullous eruption of pemphigus vulgaris after antihypertensive treatment with nifedipine. She was given high-dose systemic corticosteroids. However, she was unresponsive and nifedipine was finally withdrawn. Although new lesions did not appear, she died a few days later with uncontrollable sepsis.

After careful pharmacokinetic assessment of the effects of fluconazole withdrawal on 24hour ambulatory blood pressure and nifedipine plasma concentration, the authors concluded that fluconazole can enhance the blood-pressure lowering effects of nifedipine by increasing its plasma concentrations, most likely by inhibiting CYP3A4.

Pregnancy Tocolytic therapy with nifedipine

Drug interactions It has been suggested that

is reportedly as effective as fl2-adrenoceptor agonists, with fewer adverse effects (SEDA-18, 216; SEDA-20, 188; SEDA-22, 217; SEDA23, 211). On the other hand, the possibility that calcium antagonists can cause cardiovascular adverse effects has been widely debated (SED-14, 598; SEDA-20, 185; SEDA-21, 208; SEDA-22, 214). An uncomplicated nonQ wave myocardial infarction has been reported during nifedipine therapy for preterm labor (39e).

calcium antagonists can be used to treat cocaine dependence, and some studies have shown reductions in cocaine-induced subjective and cardiovascular responses with nifedipine and diltiazem. The cardiovascular and subjective responses to cocaine have been evaluated in a double-blind, placebo-controlled, crossover study in five subjects pretreated with two dosage of nimodipine (41c). Nimodipine 60 mg attenuated the systolic, but not the diastolic, blood pressure rise after cocaine. In three subjects nimodipine 90 mg produced greater attenuation than 60 mg. The subjective effects of cocaine were not altered by either dosage of nimodipine.

A 29-year-old woman was admitted because of preterm rapture of membranes and uterine contractions at 29 weeks. She was given ritodrine and 30 hours later reported chest pain. The electrocardiogram was normal. Ritodrine was withdrawn. Oral nifedine was started and 4 hours later she reported chest pain. Her blood pressure was 70/50 mmHg and her heart rate 124 bpm. The electrocardiogram showed T wave inversion in lead lYl and the serum creatine kinase activity was raised. The authors concluded that even if fl2adrenoceptor agonists can cause myocardial ischemia in pregnant women by further increasing oxygen consumption, acute myocardial necrosis is rare; however, in this case nifedipine

Nimodipine

Nitrendipine Nitrendipine had no adverse effect on renal allografts in patients treated for 2 years with ciclosporin (42c). Nitrendipine had a small but significant nephroprotective effect independent of its antihypertensive action. Nitrendipine did not affect blood concentrations of ciclosporin. There were similar results in terms of safety and efficacy in normotensive renal transplant recipients treated for 2 months with amlodipine

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(43c). Thus, nitrendipine and amlodipine, in contrast to other calcium channel blockers, do not affect ciclosporin blood concentrations and can be safely added in transplant recipients.

Verapamil Cardiovascular Severe cardiac conduction disturbances have been reported in patients with chronic renal insufficiency taking verapamil, mainly related to modified-release formulations. A serious bradydysrhythmia with complete atrioventricular block occurred after some months of conventional verapamil at normal doses and dose-adjusted digoxin in a 72-yearold woman with chronic renal insufficiency of unknown cause; the atrioventricular block resolved after 2 hours of hemodialysis (44c). Drug overdose Verapamil poisoning can cause cardiac toxicity with cardiogenic shock, conduction abnormalities (including lifethreatening dysrhythmias), hypotension, and death. The therapy of calcium antagonist poisoning has included several approaches, such as intravenous calcium, atropine, sympathomimetic amines, digoxin, glucagon, glucose combined with insulin, ventricular pacemakers, charcoal hemoperfusion and plasma exchange. Three papers have described different therapeutic approaches in suicide attempts with verapamil. A 41-year-old man who had taken 481XI-X~00 mg of verapamil presented 5 hours later and had a cardiac arrest; cardiopulmonary resuscitation was started and he underwent percutaneous cardiopul-

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

monary by-pass, to maintain adequate tissue perfusion and sufficient cerebral oxygen supply until the drug concentration was reduced and restoration of spontaneous circulation was achieved (45A). Severe poisoning with modified-release verapamil was associated with respiratory failure in a 27-year-old man, who presented 2 hours after taking 24 g, one of the largest reported overdoses (46c). The patient survived after receiving 4 days of partial liquid ventilation as a part of his medical management. Two patients took 2400 mg and 9600 mg of verapamil, resulting in life-threatening hypotension and bradycardia, needing cardiac pacing and resuscitation (47A). Gastric lavage was not carried out in the first patient, owing to clouded consciousness. Both patients underwent plasmapheresis within 4 hours of ingestion, with dramatic improvement. However, the first patient died 38 hours after admission with multiorgan failure, probably because of the long period of cardiogenic shock. The second patient survived without infirmity, despite the higher verapamil dose. The authors of the last report emphasised the role of vigorous gastrointestinal lavage with repeated administration of activated charcoal to reduce gastrointestinal absorption of the drug. A 15-year-old woman survived a total of 65 minutes cardiac arrest after taking 7200 mg of verapamil and 240 mg of paroxetine, which potentiates verapamil toxicity (48AR). Despite the length of cardiopulmonary resuscitation, with evidence of subsequent myocardial damage and renal impairment, she was discharged 17 days after admission, having made a full recovery, without evidence of neurological impairment. The authors considered that the lack of neurological damage may have been related to the possible neuroprotective effect of a large dose of verapamil.

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overgrowth induced by calcium channel blockers: a community-based study. J Periodontol 1999; 70: 63-7. 23. Jacob LP, Malhotra D, Chan L, Shapiro Jl. Absence of a dose-response of cyclosporine levels to clinically used doses of diltiazem and verapamil. Am J Kidney Dis 1999; 33: 301-3. 24. Yildiz A, Sever MS, Ttirkmen A, Ecder T, Tiirk S, Akkaya V, Ark E. Interaction between cyclosporine A and verapamil, felodipine, and isradipine. Nephron 1999; 81: 117-18. 25. Van der Vleuten CJM, Trijbels-Smeulders MAJM, Van de Kerkhof PCM. Telangiectasia and gingival hyperplasia as side-effects of amlodipine (Norvasc) in a 3-year-old girl. Acta Derm Venereol 1999; 79: 323-4. 26. Gurm HS. Calcium channel blockers and bcnign hypertension. Arch Intern Med 1999; 159: 1011. 27. Morimoto S, Sasaki S, Kiyama M, Hatta T, Moriguchi J, Miki S, Kawa T, Nakamura K, Itoh H, Nakata T, Takeda K, Nakagawa M. Sustainedrelease diltiazem overdose. J Hum Hypertens 1999; 13: 643-4. 28. Asberg A, Christensen H, Hartmann A, Carlson E, Molden E, Berg KJ. Pharmacokinetic interactions between microemulsion formulated cyclosporine A and diltiazem in renal transplant rccipients. J Clin Pharmacol 1999; 55: 383-7. 29. Jiang TT, Huang W, Patel D. Cyclosporineinduced encephalopathy predisposed by diltiazem in a patient with aplastic anemia. Ann Pharmacother 1999; 33: 750-1. 30. Yeo KR, Yeo WW, Wallis EJ, Ramsay LE. Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients. J Clin Pharmacol 1999; 48: 610-15. 31. Hebert MF, Lam AY. Diltiazem increases tacrolimus concentrations. Ann Pharmacother 1999; 33: 680-2. 32. Labadie H, Faucher F, Sangla S. Pouss6e d'angiomes stellaires sous traitement par inhibiteurs calciques. Gastroenterol Clin Biol 1999; 23: 788-9. 33. Larmon JE, Ross BS, May WL, Dickerson GA, Fischer RG, Morrison JC. Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor. Am J Obstet Gynecol 1999; 181: 1432-7. 34. Stason WB, Schmid CH, Niedzwiecki D, Whiting GW, Caubet JF, Cory D, Luo D, Ross SD, Chalmers TC. Safety of nifedipine in angina pectoffs. A meta-analysis. Hypertension 1999; 33: 24-31. 35. Ishibashi Y, Shimada T, Yoshitomi H, Sano K, Oyake N, Umeno T, Sakane T, Murakami Y, Morioka S. Sublingual nifedipine in elderly patients: even a low dose induces myocardial ischaemia. Clin Exp Pharmacol Physiol 1999; 26: 404-10. 36. Rubio-Guerra AF, Vargas-Ayala G, LozanoNuevo JJ, Narvaez-Rivera JL, Rodriguez-Lopez L. Comparison between isosorbide dinitrate aerosol

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and nifedipine in the treatment of hypertensive emergencies. J Hum Hypertens 1999; 13: 473-6. 37. Sunderji R, Shalansky KF, Beauchesne MF, Fung A. Is there a role for nifedipine in hypertensive urgencies? Can J Hosp Pharm 1999; 52: 167-70. 38. Brenner S, Golan H, Bialy-Golan A, Ruocco V. Lesion topography in two cases of nifedipinerelated pemphigus. J Eur Acad Dermatol Venereol 1999; 13: 123-6. 39. Oei SG, Oei SK, Brtilmann HAM. Myocardial infarction during nifedipine therapy for preterm labor. New Engl J Med 1999; 340: 154. 40. Kremens B, Brendel E, Bald M, Czyborra P, Michel MC. Loss of blood pressure control on withdrawal of fluconazole during nifedipine therapy. Br J Clin Pharmacol 1999; 47: 707-8. 41. Kosten TR, Woods SW, Rosen MI, Pearsall HR. Interactions of cocaine with nimodipine; a brief report. Am J Addict 1999; 8: 77-81. 42. Rahn K-H, Barenbrock M, Fritschka E, Heinecke A, Lippert J. Effect of nitrendipine on renal function in renal-transplant patients treated with cyclosporin: a randomised trial. Lancet 1999; 354: 1415-20.

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

43. Raman GV, Feehally J, Coates RA, Elliott HL, Griffin PJA. Renal effects of amlodipine in normotensive renal transplant recipients. Nephrol Dial Transplant 1999; 14: 384-8. 44. Martin-Gago J, Pascual J, Rodriguez-Palomares JR, Marc6n R, Teruel JL, Liafio F, Ortufio J. Complete atrioventricular blockade secondary to conventional-release verapamil in a patient on hemodialysis. Nephron 1999; 83: 89-90. 45. Holzer M, Sterz F, Schoerkhuber W, Behringer W, Domanovits H, W e i m a r D, Weinstabl C, Stimpfl T. Successful resuscitation of a verapamilintoxicated patient with percutaneous cardiopulmonary bypass. Crit Care Med 1999; 27: 2818-23. 46. Szekely LA, Thompson BT, Woolf A. Use of partial liquid ventilation to manage pulmonary complications of acute verapamil sustained-release poisoning. Clin Toxicol 1999; 37: 475-9. 47. Kuhlmann U, Schoenemann H, Miiller TF, Keuchel M, Lange H. Plasmapheresis in fatal overdose with verapamil. Intensive Care Med 1999; 25: 1473. 48. Evans JSM, Oram MP. Neurological recovery after prolonged verapamil-induced cardiac arrest. Anaesth Intensive Care 1999; 27: 653-5.

R. V e r h a e g h e

19

Drugs acting on the cerebral and peripheral circulations

DRUGS USED IN THE TREATMENT OF ARTERIAL DISORDERS OF THE BRAIN AND LIMBS

Buflomedil

(SED-14, 630; SEDA-21, 215)

Immunologic An anaphylactic reaction to buflomedil has been reported for the first time (1g). A 53-year-old woman with Raynaud's phenomenon developed an urticarial rash, pruritus, and hypotension 10 minutes after the parenteral administration of buflomedil. She received corticosteroids and recovered within 6 hours. When she later underwent skin tests with buflomedil, there was an immediate positive reaction, suggesting a type 1 hypersensitivity mechanism.

Drug overdose Buflomedil is generally considered innocuous at therapeutic dosages. Acute toxicity is due to accidental or intentional overdosage. A new case of self-poisoning with buflomedil has been reported (2A). A 15-year-old girl took 24 tablets of buflomedil (300 mg) and had a plasma concentration of 93.7 mg/1. She was deeply comatose and in a convulsive state. Shortly after she developed cardiac arrest, from which she did not recover, despite initially successful resuscitation. Central neurological toxicity, combined with negative inotropic and membrane stabilizing effects leading to rhythm and conduction disturbances, was responsible for the fatal outcome. 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual24 J.K. Aronson, ed.

Cilostazol (SED-14, 630; SEDA-22, 221) Cilostazol acts by selectively inhibiting phosphodiesterase type III, an enzyme that breaks down cyclic AME The final result is a lower concentration of intracellular calcium in platelets, which in turn suppresses platelet activity. In addition to its antiplatelet effects, cilostazol acts as an arterial vasodilator: it inhibits the function of contractile proteins by an analogous mechanism. Synthesis of prostaglandins is not affected. Cilostazol was first marketed in Japan for patients with intermittent claudication and ischemic leg ulcers. Recently, six multicenter placebo-controlled trials have been conducted in the USA (3 R, 4R). They involved more than 2000 patients with intermittent claudication and established the efficacy of cilostazol in improving walking distance in these patients. The adverse effects of cilostazol are usually mild. In US trials, headache, diarrhea, loose stools, palpitation, dizziness, and peripheral edema were more frequent than with placebo. Most of these symptoms were transient and responded to symptomatic treatment. They rarely required drug withdrawal.

DRUGS USED IN T H E TREATMENT

OF MIGRAINE

Triptans

(SED-14; 635; SEDA-21, 216; SEDA-22, 222; SEDA-23, 215)

In general, the safety profile of so-called second-generation triptans is similar to that of sumatriptan. The contraindications relating to a history of cardiovascular disease must be respected because of the vasoconstrictor effects of these drugs.

Chapter 19

230 One of the main drawbacks of acute migraine therapies, including 5HT1 receptor agonists, is that headache recurs within 24 hours in about one-third of patients who initially experienced relief after first dosing. Similar recurrence rates and mean time to recurrence are observed for the new triptans as for sumatriptan (5r). An increase in migraine frequency is usually the first sign of a developing drug-induced headache. It occurs with sumatriptan and is also reported with the new triptans (6c).

Rizatriptan The available data on rizatriptan have been reviewed. Only safety aspects are mentioned here. With oral administration adverse effects were mild and transient in placebo-controlled

trials. Digestive intolerance, dizziness, somnolence, weakness and fatigue, and pain or pressure sensations were the most commonly mentioned (7R).

Sumatriptan Cardiovascular Several cases have been reported with a close temporal relation between serious cardiovascular events and subcutaneous administration of sumatriptan; a similar case has now been reported after oral administration (8A). A 41-year-old otherwise perfectly healthy woman developed the typical symptoms of a migraine attack after an aerobics class followed by a sauna and took sumatriptan 100 mg. She collapsed half an hour later and a resuscitation team diagnosed ventricular fibrillation, which was converted to ventricular tachycardia and later to sinus rhythm. Neither the electrocardiogram nor enzyme changes suggested myocardial infarction. She remained comatose and died 6 weeks later. At autopsy there was no evidence of atherosclerotic coronary disease or any other underlying cardiac disorder. The authors considered that the oral sumatriptan may have been responsible for the dysrhythmia. Nervous system The role of sumatriptan and ergotamine in drug-induced headache has been surveyed in over 2000 patients at a regional headache clinic (9CR). About 600 had taken ergot derivatives previously and a similar number had used sumatriptan, while nearly 250 had

R. Verhaeghe

experience of both. Drug overuse was defined as the use of at least one dose of either drug on 18 or more days every month for at least 3 months. By these criteria the rates of ergotamine and sumatriptan overuse were estimated at 14% and 3.5% respectively. Drug-induced headache was much more common among ergotamine overusers than sumatriptan overusers (68% vs 32%). Sensory systems A review of clinical studies with nasal spray sumatriptan in the acute treatment of migraine has pointed to taste disturbance, described as a bad, bitter, unpleasant, or unusual taste, as a specific adverse effect of this route of administration (10R). Drug interactions The use of sumatriptan is discouraged and even considered contraindicated together with or within 24 hours after ergotamine or ergotamine-type medications, such as methysergide. The contraindication is based on the possibility of severe prolonged vasospasm with the combined use of agents with agonist properties at the same receptors. The hazard is illustrated by two recent case reports (11 A, 12A). A 20-year-old woman developed generalized tonic-clonic seizures after she took sumatriptan 6 mg followed by three tablets of ergonovine for postpartum headache. Cerebral angiography 1 day later showed multiple narrowed segments in the vertebrobasiUar and middle cerebral arteries. A myocardial infarction occurred in a 43-yearold woman with no known coronary artery disease who was taking methysergide and injected herself with sumatriptan 6 mg because of persisting headache.

Zolmitriptan The available data on zolmitriptan have been reviewed. Only safety aspects are mentioned here. Orally administered zolmitriptan appears to have been generally well tolerated in placebo-controlled studies (13R). The most commonly reported adverse events are weak-

ness, heaviness or tightness (other than in the chest), dry mouth, nausea, dizziness, somnolence, paresthesia, a sensation of warmth, and chest pain. They were mild to moderate and resolved without the need for intervention or drug withdrawal. Electrocardiographic changes were as frequent with placebo as with

Drugs acting on the cerebral and peripheral circulations zolmitriptan and were not associated with chest tightness or pressure; changes suggesting an ischemic event were not recorded. Nevertheless, zolmitriptan is not recommended in patients with ischemic heart disease.

OTHER PERIPHERAL VASODILATORS Sildenafil (SED-14, 636; SEDA-22, 222; SEDA-23, 215) Risk factors Patients with cardiovascular disease should be cautious in using sildenafil. This recommendation focuses on coronary disease, but should be extended to other cardiac conditions. Cardiac dysrhythmias have been reported (14A). A 54-year-old man with hypertrophic cardiomyopathy, for which he took verapamil, felt unwell after a single tablet of sildenafil. Holter monitoring after repeat sildenatil showed an increase in ventricular premature beats and episodes of non-sustained ventricular tachycardia. On echocardiography, left ventricular dimensions were reduced and the subaortic gradient was markedly increased.

Chapter19

231

Drug interactions A drug interaction between sildenafil and antiretroviral agents (used to treat HIV-infected patients) is suspected since both are metabolized by and act as inhibitors of the same cytochrome P450 isoforms (15r). A pharmacokinetic study of sildenafil in HIV-positive patients taking indinavir has shown that the AUC of sildenafil was 4.4 times higher than data from historical controls (16c). The magnitude of the interaction suggested that a lower starting dose of sildenafil may be more appropriate in patients taking indinavir. Another interaction study has investigated potentiation by sildenafil of the hypotensive effects of glyceryl trinitrate and amlodipine. The fall in systolic blood pressure with glyceryl trinitrate was amplified 4-fold by sildenafil in healthy subjects (both drugs use the same cyclic GMP pathway). These data reinforce the recommendation that the combined use of sildenafil and organic nitrates should be avoided. In contrast, hypertensive patients taking amlodipine had only a minor supplementary fall in blood pressure when challenged with a single dose of sildenafil, and a few had a mild to moderate headache (17c). Retrospective analysis of clinical trials has suggested that the concomitant use of antihypertensive drugs did not lead to an increase of adverse events in patients treated with sildenafil compared with patients taking sildenafil alone (18'-).

REFERENCES 1. Scala E, Guerra EC, Pirrotta L, Giani M, De Pit~ O, Puddu E Anaphylactic reactions to buflomedil. Allergy Eur J Allergy Clin Immunol 1999; 54: 288-9. 2. Tomassini E, Poussel JF, Guyot P. Intoxication mortelle an buflom6dil. Ann Fr Anesth R6anim 1999; 18: 109t-2. 3. Comp PC. Treatment of intermittent claudication in peripheral arterial disease. Recent clinical experience with cilostazol. Today's Ther Trends 1999; 17: 99-112. 4. Sorkin EM, Markham A. Cilostazol. Drags Aging 1999; 14: 63-71. 5. Smith MA, Ross MB. Oral 5-HTI receptor agonists for migraine: comparative considerations. Formulary 1999; 34: 324-28. 6. Limmroth V, Kazarawa Z, Fritsche G, Diener HC. Headache after frequent use of serotonin agonists zolmitriptan and naratriptan. Lancet 1999; 353: 378.

7. Dooley M, Faulds D. Rizatriptan. A review of its efficacy in the management of migraine. Drugs 1999; 58: 699-723. 8. Laine K, Raassaka T, M~ntynen J, Saukko E Fatal cardiac arrhythmia after oral sumatriptan. Headache 1999; 39:511-12. 9. Evers S, Gralow I, Bauer B, Suhr B, Buchheister A, Husstedt I - W , Ringelstein E-B. Sumatriptan and ergotamine overuse and drug-induced headache: a clinicoepidemiologic study. Clin Neuropharmacol 1999; 22:201 6. 10. Dahlof C. Sumatriptan nasal spray in the acute treatment of migraine: a review of clinical studies. Cephalalgia 1999; 19: 769-78. 11. Granier I, Garcia E, Geissler A, Boespflug MD, Durand-Gasselin J. Postpartum cerebral angiopathy associated with the administration of sumatriptan and dihydroergotamine--a case report. Intensive Care Med 1999; 25: 5324.

232 12. Liston H, Bennett L, Usher B Jr, Nappi J. The association of the combination of sumatriptan and methysergide in myocardial infarction in a postmenopausal woman. Arch Intern Med 1999; 159: 511-13. 13. Spencer CM, Gunasekara NS, Hills C. Zolmitfiptan. A review of its use in migraine. Drugs 1999; 58: 347-74. 14. Stauffer JC, Ruiz V, Morard JD. Subaortic obstruction after sildenafil in a patient with hypertrophic cardiomyopathy. New Engl J Med 1999; 341: 700-1. 15. Nandwani R, Gourlay Y. Possible interaction between sildenafil and HIV combination therapy. Lancet 1999; 353: 840.

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R. Verhaeghe

16. Merry C, Barry MG, Ryan M, Tjia JF, Hennessy M, Eagling VA, Mulcahy E Back DJ. Interaction of sildenafil and indinavir when co-administered to HIV-positive patients. AIDS 1999; 13: F1017. 17. Webb DJ, Freestone S, Allen MJ, Muirhead GJ. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol 1999; 83: 21C-28C. 18. Zusman RM, Morales A, Glasser DB, Osterloh IH. Overall cardiovascular profile of sildenafil citrate. Am J Cardiol 1999; 83: 35C44C.

Faiez Zannad

20

Antihypertensive drugs

GENERAL

ANGIOTENSIN CONVERTING ENZYME INHIBITORS

Safety is a major factor in the choice of antihypertensive drugs. It can vary considerably among the various classes of antihypertensive drug. The comparative pattern of adverse effects of drugs is often more comprehensive in ordinary clinical use than in controlled studies of selected groups of patients. The frequency and the profile of adverse effects of five major classes of antihypertensive agents has been assessed in an unselected group of 2586 chronically drug-treated hypertensive patients (1c). This was accompanied by a questionnairebased survey among patients attending a general practitioner. The percentage of patients who reported adverse effects spontaneously, on general inquiry, and on specific questioning were 16%, 24%, and 62% respectively. With ACE inhibitors the figures were 15%, 22%, and 55%. With a-blockers they were 15%, 25%, and 50%. The percentage of patients in whom discontinuation was due to adverse effects was: a-blockers 6.8%, fl-blockers 9.6%, calcium antagonists 5.1%, diuretics 2.8%, and ACE inhibitors 8.1% (significantly higher than diuretics). Compared with fl-blockers, ACE inhibitors were associated with less fatigue (RR = 0.57; 95% CI = 0.38, 0.85), cold extremities (RR = 0.11; CI = 0.07, 0.18), sexual urge (RR = 0.52; CI = 0.33,0.82), insomnia (RR = 0.10; CI = 0.04, 0.26), and dyspnea (RR = 0.38; CI = 0.17, 0.85), and more coughing (RR = 13; CI = 5.6, 30). Likewise, a-blockers were associated with less fatigue, cold extremities, sexual urge, and insomnia, and more bouts of palpitation (RR = 2.5; CI = 1.2, 5.4). The authors did not find a significant effect of age on the pattern of adverse effects. Women reported more effects and effects that were less related to the pharmacological treatment.

(SED-14, 638; SEDA-21, 219; SEDA-22, 225; SEDA-23, 217)

9 2001 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

Indications for ACE inhibitors The indications for using ACE inhibitors continue to expand beyond their uses in hypertension, myocardial infarction, heart failure, and diabetic nephropathy. There is now also evidence of a renal protective effect of ramipril in non-diabetic nephropathies with nephrotic and non-nephrotic proteinuria (2c). Ramipril also improves cardiovascular morbidity and all-cause mortality in patients with some cardiovascular risk (3 c ). The Ramipril Efficacy in Nephropathy (REIN) trial was designed to test whether glomerular protein traffic, and its modification by an ACE inhibitor, influenced disease progression in non-diabetic chronic nephropathies (4c). Patients were stratified before randomization by 24-hour proteinuria. Treatment with ramipril or placebo plus conventional antihypertensive therapy was targeted at the same blood-pressure control. At the second interim analysis, ramipril had slowed the fall in glomerular filtration rate (GFR) more than expected from the degree of blood pressure reduction. In the follow-up study GFR almost stabilized in patients who had been originally randomized to ramipril and had continued to take it for more than 36 months. The combined risk of doubling of the serum creatinine or end-stage renal insufficiency was half that found in those taking placebo plus conventional therapy. In patients with proteinuria of l - 3 g/day the fall in GFR per month was not significantly affected, but progression to end-stage renal insufficiency was significantly less common with ramipril (9/99 vs 18/87) for a relative risk of 2.72 (CI = 1.22, 6.08) (2c); and so was progression to

234 overt proteinuria (15/99 vs 27/87; RR = 2.40; CI = 1.27, 4.52). The results of this trial show that ramipril was well tolerated and even protective in cases of advanced renal insufficiency. One major reason for the current practice of underprescription and of prescription of suboptimal doses of ACE inhibitors, especially in patients with heart failure, is the presence of renal insufficiency (5c). In such patients, not only should ACE inhibitors no longer be avoided, they are indeed indicated for preservation of renal function. The second Swedish Trial in Old Patients with hypertension, STOP-2 was designed to compare the effects of conventional antihypertensive drugs on cardiovascular mortality and morbidity with those of newer antihypertensive drugs, including ACE inhibitors, in elderly patients (6c). The study was prospective, randomized, and open, but with a blinded endpoint evaluation. It included 6614 patients aged 70-84 years with hypertension (blood pressure over 180 mmHg systolic, or over 105 mm Hg diastolic, or both). The patients were randomly assigned to conventional drugs (atenolol 50 mg/day, metoprolol 100 rag/day, pindolol 5 mg/day, or hydrochlorothiazide 25 mg/day plus amiloride 2.5 mg/day) or to newer drugs (enalapril 10 mg/day or lisinopril 10 mg/day, or felodipine 2.5 mg/day or isradipine 2.5 mg/day). Blood pressure fell similarly in all treatment groups. There were equal incidences of the primary endpoints (fatal stroke, fatal myocardial infarction, and other fatal cardiovascular disease combined) in all groups (20 events per 1000 patient years). Subgroup analyses showed that conventional therapy, ACE inhibitors, and calcium antagonists had similar efficacy in preventing cardiovascular mortality and major morbidity. This finding is consistent with the findings of the Captopril Prevention Project (CAPPP), on which I commented in SED-14 (p. 638). It argues against the hypothesis that some classes of antihypertensive drugs have efficacy advantages over others, at least in this population of elderly hypertensive patients. Therefore, the choice of antihypertensive treatment will be related to other factors, such as cost, co-existing disorders, and adverse effects. With respect to the reported adverse effects, since the study was open, causality cannot be established. Nevertheless, the size of the study and its naturalistic design allowed ac-

Chapter 20

FaiezZannad

curate assessment of the incidence of adverse effects in this population of elderly hypertensive patients. With ACE inhibitors the most frequently reported adverse effects were: cough 30%, dizziness 28%, ankle edema 8. 7%, headache 7.7%, shortness of breath 7.3%, and palpitation 5.5%. Actually, little detail was given in the section devoted to safety in the main publication of the results of the trial. The results of the Heart Outcomes Prevention Evaluation study (3 r ) considerably widen the indications for ACE inhibitors (7c). This study showed that virtually all patients with a history of cardiovascular disease, not only those who have had an acute myocardial infarction or who have heart failure, benefitfrom ACE inhibitor therapy. The authors selected 9297 patients at increased risk of cardiovascular disease, defined as a history of a cardiovascular event or evidence of disease, such as angina. People with diabetes but no indication of heart disease were included, but they had to have an additional risk factor. They were allocated to receive the ACE inhibitor ramipril 10 mg/day or placebo. The trial was stopped early, according to the predefined rules, because of an overwhelming effect of ramipril on the primary endpoint, a 22% reduction in a composite measure of myocardial infarction, stroke, and death from cardiovascular causes. Significance was also achieved on outcomes as diverse as myocardial infarction, revascularization, heart failure, cardiac arrest, and worsening angina. Patients with diabetes had a similar 25% reduction for the composite cardiovascular endpoint. Moreover, patients taking ramipril had 16% less overt nephropathy (defined as urine albumin over 300 mg/24 hours, or urine total protein excretion over 500 mg/24 hours, or a urine albumin/creatinine ratio over 36 mg/mmol). They also needed 22% less laser therapy for retinopathy. Since all the patients in the HOPE study were not hypertensive, and since the cardiovascular benefit was greater than that attributable to the fall in blood pressure, the authors suggested that ACE inhibitors are cardioprotective, vasculoprotective, and renal protective, independently of their blood pressure lowering effect. However, with regard to safety, the first reports of the study, as usual for major trials, did not contain detailed information on the type, frequency, and occurrence time of adverse effects. In all 9297 patients, adverse effects

Antihypertensive drugs

Chapter 20

leading to withdrawal of therapy of the ACE inhibitor or placebo were respectively: cough (7.3% vs 1.8%), hypotension or dizziness (1.9% vs 1.5%), and angio-edema (0.4% vs 0.2%). In the diabetic subgroup of 3577 patients, these adverse events did not differ significantly. The dosage issue In heart failure the issue of whether it is justified to use doses of ACE inhibitors substantially smaller than the target doses used in the large-scale studies that established the usefulness of these drugs has been examined in the ATLAS (Assessment of Treatment with Lisinopril and Survival) trial (8c). This trial randomized 3164 patients with New York Heart Association (NYHA) class IIIV heart failure and ejection fractions less than 30% to double-blind treatment with either low doses (2.5-5.0 mg/day) or high doses (32.5-35 mg/day) of the ACE inhibitor lisinopril for 3958 months, while background therapy for heart failure was continued. When compared with the low-dose group, patients in the high-dose group had a non-significant 8% lower risk of death but a significant 12% lower risk of death plus hospitalization for any reason and 24% fewer hospitalizations for heart failure. Dizziness and renal insufficiency were more frequent in the high-dose group, but the two groups were similar in the number of patients who required withdrawal of the study medication. These findings suggest that patients with heart failure shouM not generally be maintained on very low doses of an ACE inhibitor, unless higher doses cannot be tolerated. However, the ATLAS trial did not address this issue properly. The doses in the small-dose arm were actually very small, and much smaller than those used in routine practice, as reported in several other studies (7c). The doses in the large-dose arm may have been unnecessarily high. The recommendation of using target doses proven to be effective in large-scale trials remains unchallenged. Relative to the dosage issue, the dosageplasma concentration relation for enalaprilat (the active metabolite of enalapril) in patients with heart failure and its relation to drugrelated adverse effects has been investigated (9c). In patients taking enalapril for more than 3 months, in dosages of 5-20 mg bd, there were highly variable trough concentrations of enalaprilat. They were affected by serum creatinine, the severity of heart failure, and body weight. Adverse effects, such as cough and

235 rises in serum creatinine and potassium, were more common at high enalaprilat trough concentrations. The authors concluded that these results provide a rationale for individually adjusting ACE inhibitor doses to minimize adverse effects.

Cardiovascular Angio-edema (see below) occurred in a 58-year-old woman 3 hours after biopsy of a hypopharyngeal mass under general anesthesia, and was accompanied by transient electrocardiographic features of anterior myocardial infarction with severe hypokinesis of the anterior wall regions on echocardiography but no significant change in creatinine kinase activity (10A). Only T wave inversion persisted on follow-up. Repeat echocardiography showed significant spontaneous improvement and coronary angiography showed normal coronary arteries. Hypotension and hypoxemia did not seem to occur, and the authors could not therefore speculate on the mechanism of the concomitant cardiac changes. Respiratory The overall frequency of ACE inhibitor-related cough is still a matter of debate and varies widely among published reports. The placebo-controlled randomized HOPE study has provided a remarkable database, with the largest cohort and the longest follow-up ever reported with such therapy (over 9000 patients followed for 5 years on average). Compared with placebo, ACE inhibitor therapy with ramipril caused cough, leading to drug withdrawal in 7.3% of patients (compared with 1.8% for placebo) (4c). Cough in association with ACE inhibitors is thought to be related to bradykinin, and it has been speculated that the risk is genetically predetermined. The possibility that polymorphisms of the human bradykinin Be receptor gene may be involved in ACE inhibitor-related cough has been investigated in a case-control study (llC). The DNA of 60 subjects with and without cough who were treated with ACE inhibitors was compared with that of 100 patients with untreated essential hypertensive and 100 normotensive subjects. The frequencies of the "IT genotype and T allele were significantly higher in the subjects with cough than in subjects without. These tendencies were more pronounced in women. Subjects with the CC genotype were the less susceptible to cough. Accord-

236 ing to the authors, high transcriptional activity of the bradykinin B2 receptor promoter may be related to the risk of ACE inhibitor-related cough. This is the first demonstration that a genetic variant is involved in ACE inhibitorrelated cough. It may therefore be possible to predict the occurrence of cough related to ACE inhibitor use. Endocrine In a matched case-control study of 404 cases of hospitalization for hypoglycemia in diabetic patients and 1375 controls, the risk of hypoglycemia was greater in those who used insulin versus a sulfonylurea and was not influenced by the use of ACE inhibitors (12Cr). However, the use of enalapril was associated with an increased risk of hypoglycemia (OR = 2.4; CI = 1.1, 5.3) in sulfonylurea users. Although the authors emphasized the fact that previous reports of ACE inhibitor-related hypoglycemia were more frequent with enalapril, it is unclear why only enalapril, and not ACE inhibitors as a class, was associated with an increased risk of hypoglycemia and why only in sulfonylurea users. Mineral balance Hyponatremia, defined as plasma sodium concentration of 133 mmol/l or less, has been investigated in a prospective study of elderly patients admitted for hip fracture. ACE inhibitors were the most frequently used drugs (5 of 14 cases) (13c). Of course, this does not prove a cause and effect relation, since in elderly people ACE inhibitors are likely to be among the most frequently prescribed drugs. Immunologie Angio-edema is a well-documented complication of ACE inhibitors. Several new observations are consistent with other reports, in that it can occur the da), after (14 A) as well as many months after (15 ~, 16A) the start of treatment, may be life-threatening (17A), and may need tracheostomy (18A). An unusual presentation with subglottic stenosis has also been reported (19A). For unclear reasons, ACE inhibitor-induced angio-edema was more prevalent among immunosuppressed patients after cardiac or renal transplantation (20Cr). In 156 cardiac patients and 341 adults after renal transplantation, this adverse effect was observed in 4.8% and 1% respectively, 24 times and 5 times higher than in the general population (0.1-0.2%). African-

Chapter 20

FaiezZannad

Americans were even more likely to experience angio-edema. A 74-year-old man with a permanent latex condom catheter developed penile swelling that was non-pitting and involved the subcutaneous tissue of a normal scrotum, after taking lisinopril 5 mg/day for 6 days (21A). Removal of the catheter had no effect. After other possible causes were ruled out, ACE inhibitor-induced angio-edema was suspected and lisinopril was withdrawn. Within a few days, the swelling, which had not spread, resolved. Drug interactions The interaction between aspirin and ACE inhibitors in patients with heart failure is clinically important (22R). Both drugs are often prescribed for a large number of patients with a variety of cardiovascular diseases. These agents have mechanisms of action that interact at the physiological level, and there are consequently many theoretical reasons to expect important clinical consequences. In animals, although not in all experimental models, aspirin can attenuate the beneficial effects of ACE inhibitors on ventricular remodelling after myocardial infarction. Some clinical studies have suggested that there is minimal, if any, adverse peripheral hemodynamic effect. In the most recent such study the acute (4 hours after the dose) and chronic (6 weeks) effects of aspirin 325 mg/day were investigated in 62 patients with mild to moderate heart failure treated with enalapril (more than 10 mg/day for at least 3 months) (23c). This did not produce significant changes in mean arterial pressure or in forearm blood flow and vascular resistance measured by venous plethysmography. In another arm of the study the same results were observed with ifetroban 250 mg/day, a thromboxane A2 receptor antagonist. These conflicting results may be explained by the various mechanisms of the vasodilatory action of ACE inhibitor, which may differ according to the regional peripheral circulation. In none of the studies were central hemodynamics or cardiac output assessed. There is evidence that co-administration of aspirin and ACE inhibitors can be detrimental to renal function in patients with heart failure. In a series of studies of ACE inhibitorinduced improvement in pulmonary function, treatment with aspirin 325 mg/day for 8 weeks in patients with mild to moderate heart failure due to primitive dilated cardiomyopathy did not affect ventilation and peak oxygen consumption during exercise when the patients were not

Antihypertensive drugs

Chapter20

taking an ACE inhibitor but worsened pulmonary diffusion capacity and made the ventilatory response to exercise (tidal volume, ventilation to carbon dioxide production) less effective in those who were, regardless of the duration of ACE inhibition (24c). A series of retrospective analyses of large randomized clinical trials has also shown a counteracting effect of aspirin on ACE inhibitor-induced improvement in survival. However, because of the retrospective and non-randomized nature of these analyses, it is difficult to draw any conclusions about the effect of aspirin in patients taking ACE inhibitors. Although all the evidence supports a clinically relevant interaction between aspirin and ACE inhibitors, it is not clear whether it is safe to use aspirin in patients treated with an ACE inhibitor.

Benazepril Pancreas Benazepril has been associated with pancreatitis (25A). A 70-year-old man with type II diabetes had severe epigastric pain 30 minutes after taking his first dose of 5 mg benazepril and lasting 6-8 hours. The next day he had the same pain, complicated by vomiting. Benazepril was withdrawn and he was unable to eat for 4 days. He later developed severe epigastric pain, nausea, and vomiting 30 minutes after taking a third dose. Laboratory findings confirmed pancreatitis and imaging showed a mildly oedematous inflamed pancreas. He improved progressively with bowel rest and pethidine. He was symptom-free for 2 months after discharge.

Captopril Hematologic Neutropenia (see also below) is a rare and serious adverse effect of captopril. Two new cases have been reported (26A). Agranulocytosis has also been reported in association with toxic epidermal necrolysis (27A). A 59-year-old woman with long-standing hypertension took captopril 200 mg lad plus hydrochiorothiazide 50 mg od, and 3 days later developed nausea, vomiting, malaise, and a severe, pmritic, erythemathous rash, with severe dehydration and orthostatic hypotension. The diuretic was withdrawn and intravenous fluids and diphenylhydramine were given. She recovered within 1 week and remained asymptomatic for 4 weeks. She then developed fever, malaise, a new rash, orthostatic hypotension, and diffuse erythroderma. Her posterior pharynx was

237 erythematous. She had neutropenia (900 x 106/1) and captopril was withdrawn. She was treated empirically with antibiotics and intravenous fluids and subcutaneous granulocyte colony-stimulating factor (G-CSF) for 5 days. The erythroderma progressed to large coalescing blisters, which then ruptured, producing large areas of weeping skin over all her limbs. The bone-marrow and skin recovered fully within 2 weeks.

Drug interactions

It has generally been accepted that ACE inhibitors should be continued up to the time of surgery. The hazards of general anesthesia in the presence of ACE inhibitors have been recognized and reviewed (28R). Patients should be monitored aggressively and hemodynamic instability treated appropriately. An 86-year-old man, who was taking captopri125 mg bd and bendroflumethiazide 25 mg/day for hypertension, had a transurethral resection of the prostate under spinal anesthesia, and developed profound bradycardia and hypotension with disturbances of consciousness during transfer to the recovery room (29At). Initial treatment with atropine produced rapid improvement in cardiovascular and cerebral function. A further hypotensive episode, without bradycardia, occurred about 1 hour later, but responded rapidly to methoxamine. He made a full recovery overnight. The authors suggested that the concomitant administration of captopril may have contributed to the adverse effect, since the r e n i n angiotensin system is important in maintaining blood pressure during anesthesia. Because of a protective effect of angiotensin lI in the presence of sympathetic blockade by presynaptic stimulation of adrenergic neurons, the authors hypothesized that hypotension and bradycardia in this patient may have been magnified by suppression of the renin-angiotensin system, resulting in an enhanced negative Bainbridge effect.

Enalapril Liver Another case of hepatitis has been reported (30A). A 45-year-old man who had taken enalapril (dose not reported) for more than 2 years presented with hepatitis with negative viral serology. Biopsy showed necrosis and cholestasis. He recovered fully after drag withdrawal (timing not reported). S k i n The acantholytic potential of enalapril has previously been shown in vitro in skin cul-

Chapter20

23 8 tures. There has now been a report of in vivo acantholysis without pemphigus.

FaiezZannad

Lisinopril Pancreas

A 66-year-old man, who had taken enalapril 10 mg/day for 1 year, had a basal cell carcinoma removed surgically (31A). Histology showed suprabasal acantholytic clefts in the perilesional epidermis. Direct immunofluorescence did not show intracellular deposits of IgG, IgA, IgM, or C3. Indirect immunofluorescence showed serum anticellular antibodies (titer 1:80). He stopped taking enalapril, and 3 months later his anticellular antibody titer was 1:320. A further biopsy of apparently healthy skin on the back showed new foci of acantholysis. Another biopsy in the same location 2 months later showed no acantholytic changes. Direct immunofluorescence was negative and the anticellular antibody titer was 1:80. HLA typing showed pemphigus-predisposing antigens (DR14, DQ1), which has previously been reported as a predisposing factor for acantholytic changes in the epidermis exposed to enalapril.

Body temperature

Fever has been attributed

to enalapril (32A). A 50-year-old man with heart failure and a valve prosthesis, taking digoxin, furosemide, and spironolactone, was given enalapril 5 mg/day. Two days later, after increasing the dose to 10 mg, he developed a fever with cough and clear sputum, with a normal chest X-ray. Enalapril was withdrawn and 24 hours later the fever resolved. It recurred immediately after rechallenge.

Imidapril Respiratory

The incidences of cough with imidapril and enalapril have been compared in a poorly-designed open-label study in 489 hypertensive patients (33c). The authors claimed a significantly smaller incidence of cough with imidapril. However, because of important methodological flaws, this result cannot be trusted. M i n e r a l b a l a n c e Hyperkalemia is a wellknown adverse effect of ACE inhibitors and can sometimes be severe (34A). An 85-year-old woman with diabetes mellitus and a prior myocardial infarction, who was taking ioxoprofen and imidapril, lost consciousness owing to marked bradycardia caused by hyperkalemia (7.4 mmol/l). An electrocardiogram showed T wave changes compatible with hyperkalemia. After right ventricular pacing she promptly recovered consciousness. She was given glucose and insulin and her plasma potassium fell to 4.1 mmol/l within 3 hours. Simultaneously her heart rate became normal.

Pancreatitis has been reported with lisinopril (35A). A 42-year-old woman, who was taking lisinopril, nicardipine, metoprolol, simvastatin, omeprazole, an estrogen, and sublingual glyceryl trinitrate, presented with epigastric pain and vomiting. Pancreatitis was diagnosed on the grounds of raised activities of lipase (200 iu/l) and amylase (117 iu/1) and diffuse homogeneous enlargement of the head and body of the pancreas on CT scan. The pancreatic enzyme activities normalized 5 days after lisinopril and simvastatin withdrawal. Two months later she was taking estrogen and simvastatin, but not lisinopril. Her amylase and lipase were normal. The temporal relation in this case suggests that lisinopril was causative. The authors raised the possibility that the concomitant use of an estrogen and simvastatin, as well as a history of familial hypertriglyceridemia, may have predisposed her to pancreatitis. S k i n Erythema multiforme has been attributed to lisinopril (36A). A 68-year-old man who had taken lisinopril 10 mg/day for several years stopped taking it temporarily because of a cough. It was then restarted in a dosage of 5 mg/day and a few days later he developed several bean-sized non-pruritic erythemathous plaques with scales over the whole body, particularly on the chest. The appearance was of seborrheic dermatitis, but histology showed the features of erythema multiforme. The eruptions cleared completely a few days after lisinopril withdrawal. Two months later, a rechallenge test was positive.

Quinapril Psychiatric Depressionhas

been attributed to

quinapril (37At). A 90-year-old man with a history of peripheral arterial disease and mild heart failure presented with reduced appetite, insomnia, anhedonia, reduced energy, and suicidal ideation. His symptoms has started a month before, when he had begun to take quinapril 10 mg/day. He was also taking furosemide 20 mg/day and digoxin. He was alert, coherent, and cognitively intact, but depressed with a fiat affect. He had no psychotic symptoms. Quinapril was withdrawn. He improved within 48 hours and recovered fully in 5 days.

Antihypertensive drugs

Chapter20

The authors cited several reports of depression, mania, and psychosis with various ACE inhibitors. Pancreas A possible association between quinapril and pancreatitis has been reported in a 85-year-old woman, very similar to other previously reported cases with other ACE inhibitors (38At).

Ramipril Endocrine Hypoglycemia has been attributed to a complicated sequence of effects (39A). A 64-year-old man with type II diabetes, hypertension, and bilateral renal artery stenosis presented with confusion and dysarthria related to profound hypoglycemia (2.2 mmol/l). He was taking naproxen 500 mg bd, ramipril 2.5 mg/day, glibenclamide 2.5 mg bd, metformin 850 mg bd, and a thiazide diuretic, terazosin, ranitidine, paracetamol, and codeine. His plasma creatinine concentration, previously 185 ixmol/l, was 362 Itmol/1and it fell to 210 Ixmol/lafter the withdrawal of ramipril and naproxen. The authors discussed the possible role of renal insufficiency, resulting from coprescription of naproxen and ramipril in the presence of volume depletion, which may have increased the risk of hypoglycemia related to glibenclamide plus metformin.

Temocapril Drug interactions Temocapril had no effect on the pharmacokinetics or pharmacodynamics of multiple-dose warfarin in 24 healthy subjects (40Cr). There have been similar negative interaction studies with other ACE inhibitors and oral anticoagulants.

Trandolapril Respiratory In 3402 patients with hypertension taking trandolapril, cough, assessed by visual analogue scale, was less common in smokers than in non-smokers (41Or).

239

A N G I O T E N S I N II R E C E P T O R ANTAGONISTS (SED-14, 644; SEDA-21, 222; SEDA-22, 229; SEDA-23, 220) Many new angiotensin II receptor antagonists are now commercially available, including candesartan, eprosartan, irbesartan, losartan, tasosartan, telmisartan, and valsartan. They all have the same pharmacodynamic profile. Variations in chemical structure may lead to marginal but potentially clinically significant differences in the time-effect profile. Noncompetitive antagonists may have longer durations of action than competitive antagonists, because they bind irreversibly to angiotensin II receptors. There have been several reviews of this class of agents (42R). All have emphasized their remarkable tolerance profile. In double-blind placebo-controlled trials, the type and frequency of reported adverse effects was consistently no different from placebo (43c). Several large-scale morbidity/mortality outcome trials are currently assessing the efficacy of angiotensin II receptor antagonists in hypertension, heart failure, myocardial infarction, and a variety of cardiovascular risk factors and diseases. Two such trials have recently been completed. The RESOLVD (Randomized Evaluation of Strategies for Left Ventricular Dysfunction) trial was a pilot study investigating the effects of candesartan, enalapril, and their combination on exercise tolerance, ventricular function, quality of life, neurohormone concentrations, and tolerability in congestive heart failure (44c). Candesartan alone was as effective, safe, and well tolerated as enalapril. The combination of candesartan with enalapril was more beneficial in preventing left ventricular remodelling than either alone. Although the trial was not powered to assess effects on cardiovascular events, it was terminated prematurely because of a trend toward a greater number of events in the candesartan alone and combination groups compared with enalapril alone. In the ELITE study losartan produced greater survival benefit in elderly patients with heart failure than captopril (45c). ELITE II was performed in order to confirm this. It included 3152 patients aged 60 years and over with NYHA class II-IV heart failure and was powered to detect a clinically significant effect on all-cause mortality. Losartan was not superior to captopril in improving survival; however,

Chapter 20

240 it was better tolerated. Significantly fewer patients taking losartan withdrew because of adverse effects, including effects attributed to the study drug, or because of cough.

Respiratory Unlike ACE inhibitors,

angiotensin II receptor antagonists are not thought to be associated with cough. In a PrescriptionEvent Monitoring (PEM) study in 9000 patients cough occurred in 3.1% of patients taking losartan, compared with 3.9%, 14%, and 16% in patients taking enalapril, lisinopril, and perindopril respectively (46Cr). The unusual low rate of cough with enalapril is surprising and emphasizes the limitations of PEM studies. Worthy of remark is a possible confounding effect, discussed by the authors, related to the fact that a large number of patients were given losartan because they had had cough with an ACE inhibitor. Because of a carry-over effect, cough may still be reported, especially in the first week when patients change to losartan. This carry-over effect may have been the cause of cough reported with losartan in other cases (47A).

Candesartan In an open study of 4531 hypertensive patients, the total incidence of adverse effects was 6.1% (48c). Individual adverse effects did not occur in more than 0.8% and were mainly dizziness

and headache. Risk factors

In patients undergoing chronic

hemodialysis, the safety profile did not differ from that reported in other populations, except for some rare cases of hypotension during bemodialysis. Hemodialysis does not affect the kinetics of candesartan. Because of the variability of oral clearance and the pronounced influence of hemodialysis-induced volume contraction on the hemodynamic effects of candesartan, careful monitoring is recommended (49c).

Eprosartan Respiratory In a multicenter controlled study in patients with hypertension and a history of ACE inhibitor-induced cough, eprosartan significantly reduced the risk of cough by 88% compared with enalapril (50c).

FaiezZannad

Irbesartan The pharmacology of irbesartan is the same as that of other angiotensin II receptor antagonists (51R). In the registration studies and other controlled trials adverse effects were not dose-related and not different from placebo. U r i n a r y system Renal insufficiency has been attributed to irbesartan (52Ar). A 77-year-old woman took r 25 mg tds and furosemide 40 mg/day for decompensated heart failure. Irbesartan 75 mg/day then replaced captopril, and 3 days later she developed renal insufficiency. Irbesartan was withdrawn and her renal function normalized within 5 days. It was not stated whether her blood pressure also changed. The authors referred to four cases of renal insufficiency previously reported with losartan.

Losartan Using the method of prescription event monitoring (PEM), the incidence densities of adverse effects per 1000 patient months of exposure have been measured in 14 522 patients (53 c) . Most were hypertensive (63%). During treatment months 2-6, the commonest adverse effects were cough (17%), malaise and lassitude (15%), dizziness (15%), headache or migraine (11%), nausea and vomiting (6.0%), rash (5.0%), dyspnea (4.9%), edema (4.8%), dyspepsia (4.2%), and diarrhea (3.7%). These were also the most common reasons for drug withdrawal. The seemingly high incidence of cough may have been due to carry over from previous use of ACE inhibitors. There was one accidental overdose in an 80year-old patient who took 200 mg/day for 2 months; no ill effects were observed.

Urinary system Renal insufficiency has been reported with losartan ( 5 4A) .

A 69-year-old man with hypertension and heart failure was given losartan 25 mg/day, increasing to 50 mg/day after 2 weeks. He also took spironolactone 50 mg/day, furosemide 40 mg/day, digoxin 0.25 mg/day, acenoucoumarol, and allopurinol. Two weeks later he developed acute renal insufficiency with a plasma creatinine concentration of 725 Ixmol/1 (previously 115 Itmol/l). Within 24 hours after losartan withdrawal (it was not stated whether spironolactone was also stopped) and hemodialysis, he recovered

Antihypertensive drugs

Chapter20

renal function (plasma creatinine 124 mg/1). He was later found to have bilateral renal artery stenosis, which is a contraindication to angiotensin II receptor antagonists. The authors did not discuss the possible aggravating role of spironolactone. Immunologic Two more cases of angioedema with angiotensin II receptor antagonists have been reported (55 At, 56A). An African-American developed swelling of the lips and shortness of breath within 24 hours of starting losartan. However, similar reactions had been noted before, while the patient was taking captopril. It was therefore unclear whether the reaction was related to losartan or was a carry-over reaction to captopril. A 45-year-old white man, who had taken losartan, hydrochlorothiazide, allopurinol, and colchicine for 9 months, developed facial urticaria, eyelid swelling, shortness of breath, and upper chest tightness, which resolved quickly with famotidine, methylprednisolone, and adrenaline. He had a recurrence 7 hours later, not having taken another dose of losartan. The patient had no history of allergy and was well after losartan withdrawal. The late onset and recurrence of symptoms after initial resolution are the unique original features of this case report. Patients with such reactions should be kept under observation after the resolution of initial symptoms. Pregnancy In the study of 14522 patients mentioned above (53 c) three mothers were exposed to losartan during the first trimester of pregnancy. One pregnancy terminated in a spontaneous abortion. The two others were both complicated by hypertension. One baby died with extreme prematurity and growth retardation, and the second survived after having been born prematurely. Drug interactions Indomethacin 50 mg bd for one week did not interfere with the antihypertensive efficacy of losartan 50-100 mg/day in patients with essential hypertension, despite the fact that indomethacin caused significant increases in weight and extracellular fluid volume (57Cr). Glomerular filtration rate remained unchanged. Indomethacin did not adversely influence peripheral hemodynamics. This is in contrast to the reported effects of indomethacin during ACE inhibition, leading to

241 an increase in blood pressure. It suggests that prostaglandins in part mediate vasodilatation during ACE inhibition, a mechanism that is not shared by angiotensin II antagonists. However, the result of this study is in contrast with those of several similar interaction studies with other antihypertensive agents, in which prostaglandin inhibition for 1-4 weeks caused an increase in weight combined with an increase in blood pressure. If indomethacin had been given with losartan for more than 1 week, it may have produced a similar increase in blood pressure. Thus, the results of this study should not be taken as an argument against the recommendation that non-steroidal anti-inflammatory drugs should not be combined with angiotensin II antagonists, a recommendation that should be re-emphasized.

Telmisartan

Respiratory The incidence of cough with telmisartan has been assessed in a multicenter, randomized, parallel-group, double-blind, placebo-controlled study, for 8 weeks using a visual analogue scale in 88 patients with hypertension who had previously had ACE inhibitorrelated cough (58c). Cough was reported in 60% of the patients taking lisinopril 20 mg/day, 16% of those taking telmisartan 80 mg/day, and 9.7% with placebo.

Valsartan In 1378 patients with mild to moderate hypertension valsartan 80 mg/day has been compared with losartan 50 mg/day and placebo for 8 weeks ( 4 3c) . The study confirmed the excellent tolerance profile, not different from placebo, of both angiotensin II receptor antagonists.

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242

FaiezZannad

DRUGS THAT ACT ON THE SYMPATHETIC NERVOUS SYSTEM

dose. Intravenous clonidine 0.150 mg was followed within 30 minutes by a severe, generalized, maculopapular reaction requiring systemic steroids and antihistamines.

IMIDAZOLINE RECEPTOR AGONISTS (SED-14, 648;

The authors interpreted these reactions as being allergic. A patch test was very positive to the commercial formulation. Clonidine is a weak sensitizer, but occlusion and prolonged skin contact during transdermal application may cause delayed hypersensitivity.

SEDA-21, 223; SEDA-22, 230; SEDA-23, 222)

Moxonidine Whereas moxonidine appears to be generally well tolerated in hypertension, in congestive heart failure it was prematurely withdrawn because of adverse outcomes on survival in a major trial, the MOXCON trial in patients with NYHA class II-IV heart failure who were treated with modified-release moxonidine 0.53.0 mg/day or placebo (59c). An interim analysis of the first 2000 patients enrolled showed that 53 patients taking moxonidine, compared with 29 taking placebo, died in the first 6 months. Excess mortality in the moxonidine arm appeared to be related to sudden death. The reason for this adverse outcome has to be fully elucidated. Although it has not been established that moxonidine caused a higher mortality rate, it is no longer being used in patients with heart failure.

Clonidine The number of publications on the use of clonidine in children has increased recently and it has been comprehensively reviewed (60R). Skin

Transdermal clonidine can cause ad-

verse reactions at the patch application site (61c). This has been reported with a frequency of 15% in 357 African-American hypertensive patients. It can lead to drug discontinuation in 4.2% of patients. A case of recurrent maculopapular rash due to both topical and systemic administration of clonidine has been reported (62At). A 47-year-old woman was given transdermal, oral, and intravenous clonidine at different times, separated by several months. The patches were withdrawn after 2 months because of pruritic erythematous vesiculation at the site of application. Oral clonidine (0.3 mg/day) had to be withdrawn when a generalized maculopapular rash appeared on the third day, and was promptly exacerbated by each

POSTSYNAPTIC ADRENOCEPTOR ANTAGONISTS

(SED-14, 648; SEDA-21, 223; SEDA-22, 231; SEDA-23, 222)

Doxazosin The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (63 c) was a multicenter comparison of drugs from each of three classes of antihypertensive agents (amlodipine, lisinopril, and doxazosin) with chlortalidone as an active control, in 24 335 adults with hypertension and at least one other coronary heart disease risk factor. In an interim analysis (median follow-up 3.3 years) there was no significant difference in the rates of fatal coronary heart disease or non-fatal myocardial infarction, or in total mortality between doxazosin and chlortalidone, but doxazosin was associated with higher rates of stroke (RR = 1.19; C! = 1.01, 1.40) and combined cardiovascular disease (RR -- 1.24; CI = 1.17, 1.33). Considered separately, the risk of congestive heart failure was doubled (RR = 2.04; CI = 1.79, 2.32). Mean systolic blood pressure with doxazosin was about 2-3 mmHg higher than with chlortalidone and mean diastolic pressure was similar in the two groups. The authors concluded that the difference in blood pressure control did not account for the differences in cardiovascular endpoints.

Antihypertensive drugs

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243

DIRECT VASODILATORS

(75/40 mmHg) and tachycardia (130 bpm). She was alert and oriented and physical examination was unremarkable. She was given a saline infusion, oral activated charcoal, and sorbitol, and had worsening hypotension (40 mmHg systolic) and bradycardia (20 bpm), developed chest pain and T wave inversion on the electrocardiogram, and lost consciousness. Atropine and dopamine restored a heart rate of 120 bpm, but she remained hypotensive (54/36 mm Hg). Her blood ethanol concentration was 5.64 mmol/1 and other toxicological screening tests were negative. The addition of phenylephrine up to a dose of 200 btg/min restored her systolic blood pressure to 90-100 mmHg.

(SED-14, 649; SEDA-21, 223)

Minoxidil Drug overdose In some countries, an extrastrength solution of minoxidil is available over the counter for hair regrowth treatment in men. Ingestion of a large dose in a suicide attempt has been reported (64At). A 26-year-old woman took 60 ml of minoxidil solution 5% and an hour later developed hypotension REFERENCES 1. Olsen H, Klemetsrud T, Stokke HE Tretli S, Westheim A. Adverse drug reactions in current antihypertensive therapy: a general practice survey of 2586 patients in Norway. Blood Press 1999; 8: 94-101. 2. Ruggenenti E Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari E Schena FP, Remuzzi G. Renoprotective properties of ACEinhibition in non-diabetic nephropathies with nonnephrotic proteinuria. Lancet 1999; 354: 35964. 3. Yusuf S, Sleight E Pogue J, Bosch J, Davies R, Dagenais G, for the Heart Outcomes Prevention Evaluation study investigators. Effects of an angiotensin converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. New Engl J Med 2000; 342: 145-53. 4. Ruggenenti E Pema A, Gherardi G, Gaspari F, Benini R, Remuzzi G, on behalf of Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Lancet 1998; 352: 1252-6. 5. Echemann M, Zannad E Brianqon S, Juilli~re Y, Mert~s PM, Virion JM, Villemot JP, and the EPICAL investigators. Determinants of angiotensinconverting enzyme inhibitor prescription in severe heart failure with left ventricular systolic dysfunction: The EPICAL study. Am Heart J 2000; 139: 624-31. 6. Hansson L, Lindhohn LH, Ekbom T, Dahl6f B, Lanke J, ScherstEn B, Wester P-O, Hedner T, De Faire U. Randomised trial of old and new antihypertensive drugs in elderly partients: cardiovascular mortality and morbidity the Swedish Trial in old patients with hypertension-2 study. Lancet 1999; 354: 1751-6. 7. Gerstein HC, Yusuf S, Mann JFE, on behalf of the Heart Outcomes Prevention Evaluation (HOPE) study investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253-9.

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47. Conigliaro RL, Gleason PP. Losartan-induced cough after lisinophil therapy. Am J Health-Syst Phann 1999; 56: 914-15. 48. Schulte KL, Fischer M, Lenz T, Meyer-Sabellek W. Efficacy and tolerability of candesartan cilexetil monotherapy or in combination with other antihypertensive drugs. Results of the AURA study. Clin Drug Invest 1999; 18: 453-60. 49. Pfister M, Schaedeli F, Frey FJ, Uehlinger DE. Pharmacokinetics and haemodynamics of candesartan cilexetil in hypertensive patients on regular haemodialysis. Br J Clin Pharmacol 1999; 47: 645-51. 50. Oparil S. Eprosartan versus enalapril in hypertensive patients with angiotensin-converting enzyme inhibitor-induced cough. Curr Ther Res Clin Exp 1999; 60: 1-4. 51. Johnston CI. Pharmacology of irbesartan. Expert Opin Invest Drugs 1999; 8: 655-70. 52. Anglada Pintado JC, Gallego Puerto P, Zapata Lopez A, Cayon Blanco M. Acute renal failure associated with irbesartan. Med Clin 1999; 113: 358-9. 53. Mann RD, Mackay F, Pearce G, Freemantle S, Wilton LV. Losartan: a study of pharmacovigilance data on 14,522 patients. J Hum Hypertens 1999; 13: 551-7. 54. Cuxart M, Matas M, Sans R, Garci M. Acute renal failure due to losartan. Nefrologia 1999; 19: 374-5. 55. Cha YJ, Pearson VE. Angioedema due to losartan. Ann Pharmacother 1999; 33: 936-8. 56. Rivera JO. Losartan-induced angioedema. Ann Pharmacother 1999; 33: 933-5. 57. Olsen ME, Thomsen T, Hassager C, Ibsen H,

245 Dige-Petersen H. Hemodynamic and renal effects of indomethacin in losartan-treated hypertensive individuals. Am J Hypertens 1999; 12: 209-16. 58. Lacourciere Y. The incidence of cough: a comparison of lisinopril, placebo and telmisartan, a novel angiotensin II antagonist. Telmisartan Cough Study Group. Int J Clin Pract 1999; 53: 99103. 59. Curel P. Paradoxical findings in halted MOXCON trial. Reactions 1999; 770: 3. 60. Nishina K, Mikawa K, Shiga M, Obara H. Clonidine in paediatric anaesthesia. Paediatr Anaesth 1999; 9: 187-202. 61. Dias VC, Tendler B, Oparil S, Reilly PA, Snarr P, White WB. Clinical experience with transdermal clonidine in African-American and HispanicAmerican patients with hypertension: evaluation from a 12-week prospective, open-label clinical trial in community-based clinics. Am J Ther 1999; 6: 19-24. 62. Crivellaro MA, Bonadonna P, Dama AR, Senna GE, Passalacqua G. Skin reactions to clonidine: not just a local problem. Case report. Allergol Immunopathol 1999; 27: 318-19. 63. Davies BR, Furberg CD, Wright JT, on behalf of the ALLHAT officers and coordinators for the ALLHAT collaborative research group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlortalidone. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Am Med Assoc 2000; 283: 1967-75. 64. Farrell SE, Epstein SK. Overdose of Rogaine Extra Strength for Men topical minoxidil preparation. J Toxicol Clin Toxicol 1999; 37: 781-3.

Gordon T. M c l n n e s

21 GENERAL CONSIDERATIONS

Aldosterone antagonists in heart failure Although widely used in the management of heart failure, loop and thiazide diuretics have not been shown to prolong survival However, with the report from the Randomized Aldactone Evaluation Study (RALES) (lC), spironolactone must be added to the medications that offer improved survival for patients with heart failure. In 1663 patients with New York Heart Association (NYHA) class III (70%) or IV (30%) symptoms and ejection fraction less than 35%, the addition of spironolactone 25 mg/day to conventional treatment (an ACE inhibitor, a loop diuretic, in most cases digoxin, and in 11% a [3-blocker)for an average of 24 months lowered the risk of all-cause mortality by 30% (from 46% to 35%), death from progressive heart failure, and sudden death. There were similar reductions in hospital admissions for worsening heart failure and for all cardiac causes. The magnitude of the overall effect was similar and additional to the proven benefit from ACE inhibition in severe heart failure. Mechanisms Several mechanisms have been postulated to underlie the benefits of aldosterone (2R ). Aldosterone-induced cardiac fibrosis may reduce systolic function, impair diastolic function, and promote intracardiac conduction defects with the potential for serious dysrhythmias. Aldosterone may also increase vulnerability to serious dysrhythmias by other mechanisms. The diuretic and hemodynamic effects of spironolactone in RALES were subtle, and there were no significant changes in body 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed. ~)AA

Diuretics weight, sodium retention, or systemic blood pressure.

Adverse effects The only frequent adverse effects were gynecomastia, breast pain, or both in 10% of men. The rate of discontinuation because of these events was 2%. The risk of gynecomastia should not be an argument against the use of spironolactone in men with severe heart failure, since it reduces both morbidity and death. At the dose of spironolactone used in RALES (1c), there was serious hyperkalemia, defined as a serum potassium concentration over 6.0 mmol/l, in 2% (compared with 1% of controls) and uremia was rare. However, serum potassium concentration over 5 mmol/l and serum creatinine concentration over 220 lzmol/l were exclusion criteria. Although 29% of patients in the spironolactone group used potassium supplements, the benefit of spironolactone in these patients was similar to that in patients who did not. Clinical use The safe and effective dose of spironolactone remains uncertain (2R ). Pilot data from RALES showed that the frequency of hyperkalemia and uremia increased with doses of spironolactone above 50 mg/day (SEDA-20, 202). Doses up to 50 rag/day seem appropriate with adequate monitoring of serum electrolytes and renal function. The optimum strategy in the face of hyperkalemia, uremia, or symptomatic hypotension (reduction in frequency of spironolactone to alternate day dosing, reduction in dose of ACE inhibitor, and/or increased dose of loop diuretics) is unclear, and how frequent such dose adjustments were necessary in RALES was not stated (lC).

The evidence base for the use of low-dose thiazide diuretics as first-line therapy of hypertension is stronger than that for any other

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class of antihypertensive agent (SED-14, 656; SEDA-20, 200; SEDA-22, 233). The benefits of low-dose thiazides extend to regression of left ventricular mass in patients with left ventricular hypertrophy (SEDA-20, 200; SEDA-22, 234), in whom the effect of diuretics appears to be at least equivalent to that of other antihypertensive drugs (SEDA-22, 234). The LIVE (Left ventricular regression, Indapamide Versus Enalapril) study was a I-year, prospective, randomized, double-blind comparison of modified-release indapamide 1.5 mg and enalapril 20 mg in reducing left ventricular mass in 411 hypertensive patients with left ventricular hypertrophy (3c). For equivalent reductions in blood pressure, indapamide was significantly more effective than enalapril in reducing left ventricular mass index. The effectiveness of specific first-line antihypertensive drugs in lowering blood pressure and preventing adverse outcomes has been systematically quantified in a meta-analysis of randomized controlled trials of at least 1 year's duration that provided morbidity and mortality data and compared one of six possible first-line antihypertensive therapies either with another of the six drug therapies or with no treatment (4M). Of 38 trials, 23 involving 50 853 patients met the inclusion criteria. Four drug classes were evaluated: thiazides (21 trials), E-blockers (5), calcium antagonists (4), and ACE inhibitors (1). In five comparisons of thiazides with /%blockers, thiazides were associated with a significantly lower rate of withdrawal because of adverse effects (RR = 0.69; 95% CI = 0.63, 0.76). In the trials that had an untreated control group, low-dose thiazide therapy was associated with a significant reduction in the risk of death (RR = 0.89; CI = 0.81, 0.99), stroke (RR = 0.66; CI = 0.56, 0.79), coronary heart disease (RR = 0.71, CI = 0.60, 0.84), and cardiovascular events (RR = 0.68; CI = 0.62, 0.75). Low-dose thiazide therapy reduced the absolute risk of cardiovascular events by 5.7% (CI = 4.2, 7.2); the number needed to treat (NNT) for approximately 5 years to prevent one event was 18. High-dose thiazide, /~-blocker, and calcium antagonist therapy did not significantly reduce the risk of death or coronary heart disease. Thiazides were significantly better than the other drugs in reducing systolic pressure, but antihypertensive efficacy did not differ between the high- and low-dose thiazide trials.

247 Low-dose thiazide therapy can be prescribed as first-line treatment of hypertension, with confidence that the risk of death, coronary heart disease, and stroke will be reduced. The same cannot be said for high-dose thiazide, /% blocker, calcium antagonist, or ACE inhibitor therapy. These findings support earlier recommendations for the use of low-dose thiazides as the basis of antihypertensive therapy SED-14, 658).

ORGANS AND SYSTEMS Metabolism Hyperuricemia The Issues of whether hyperuricemia is an independent risk factor for cardiovascular disease and the clinical relevance of the rise in serum uric acid caused by diuretic treatment remain controversial (SED-14, 660). In the Systolic Hypertension in the Elderly Program (SHEP), diureticbased treatment in 4327 men and women, aged 60 years or more, with isolated systolic hypertension was associated with significant reduction in cardiovascular events (SED-14, 657). Serum uric acid independently predicted cardiovascular events in these patients (5c). The benefit of active treatment was not affected by baseline serum uric acid. After randomization, however, an increase in serum uric acid of less than 0.06 mmol/l (median change) in the active treatment group was associated with a hazard ratio (HR) of 0.58 (CI = 0.37, 0.92) for coronary heart disease compared with those whose serum uric acid rose by 0.6 mmol/1 or more. This was despite a slight but significantly greater reduction in both systolic and diastolic blood pressures in the latter. Those with serum uric acid increases of 0.6 mmol/1 or more in the active group had a similar risk of coronary events as those in the placebo group. This analysis of the SHEP database confirms the findings of a systematic worksite hypertension program (6c). In 7978 treated patients with mild to moderate hypertension, cardiovascular disease was significantly associated with serum uric acid (HR = 1.22; CI = 1.11, 1.35), controlling for known cardiovascular risk factors. The cardioprotective effect of diuretics increased from 31% to 38% after adjustment for serum uric acid. These observations suggest that persistent elevation of serum uric acid during diuretic-

248 based antihypertensive therapy may detract from the benefit of blood pressure reduction. However, the relation between serum uric acid and cardiovascular disease was independent of the effects of diuretics. Furthermore, current low-dose thiazide regimens have a smaller impact on serum uric acid (SED-14, 660). The recent data are secondary or observational in nature and must be interpreted with caution.

Electrolyte balance Hypokalemia

To assess the clinical relevance of hypokalemia associated with low-dose diuretics, data from 4126 participants in SHEP have been analyzed (7c). After 1 year of treatment, 7.2% of those randomized to treatment based on low-dose chlorthalidone had a serum potassium concentration below 3.5 mmol/l, compared with 1% in the placebo group. After adjustment for known risk factors and drug dose, the hypokalemic group (n = 151) had a risk of cardiovascular events, coronary events, and strokes similar to that in those randomized to placebo (n = 2003) and significantly greater than the risk among active treatment patients with serum potassium of 3.5 mmol/l and more (n = 1951). Although treatment in SHEP was assigned randomly, the dose of chlorthalidone depended on blood pressure response. Significantly more hypokalemic patients took the higher dose (25 mg) of chlorthalidone (53% vs 34%). It is possible that such patients have an increased cardiovascular risk, but adjustment for dose did not alter the findings. A discordant observation was that all-cause mortality rates were higher in normokalemic patients in the active treatment group (24.5 vs 13.5 per 1000 personyears). Even so, and although these results are from a subgroup analysis, the implications cannot be ignored. Maintaining serum potassium concentration at 3.5 mmol/1 or more during the treatment of hypertension seems reasonable. The National Council on Potassium in Clinicai Practice has provided sensible guidelines on potassium replacement (8R). In hypertensive patients with drug-induced hypokalemia, an effort should be made to achieve and maintain the serum potassium concentration at 4.0 mmol/1 or over. Potassium replacement should be considered routinely in patients with congestive heart failure, even if the initial potassium determination is normal. Regular monitoring of serum potassium is essential in these patients,

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because of the risk of hyperkalemia in patients given potassium (or potassium-sparing diuretics) and ACE inhibitors or angiotensin receptor antagonists. Maintenance of optimal potassium concentrations (4.0 mmol/l or over) is critical in patients with cardiac dysrhythmias, and again routine potassium monitoring is obligatory. Although these guidelines recommend the use of potassium supplements, potassium-sparing diuretics are much more effective (SED-14, 662).

Hyperkalemia Several groups of patients are at particularly high risk of developing hyperkalemia if they take potassium-sparing diuretics (9r). These include patients with moderate to severe chronic renal insufficiency, hypoaldosteronism, and diseases associated with impaired response to the potassium secretory effects of aldosterone. Hypoaldosteronism is often seen in elderly patients, those with chronic renal impairment or diabetic nephropathy, those with AIDS, or those with primary adrenal disease. In addition, patients with sickle cell disease, obstructive uropathy, systemic lupus erythematosus with nephropathy, and renal transplants may have tubular resistance to the effects of mineralocorticoids. Spironolactone 300 mg can significantly increase the serum potassium concentration in hemodialysis patients, suggesting that aldosterone may affect the cellular handling and gastrointestinal excretion of potassium. U r i n a r y tract The association of renal calcification with furosemide therapy in pre-term infants is well recognized, but data in fullterm infants are sparse (SED-14, 664). To study the incidence and course of nephrocalcinosis in full-term infants with congestive heart failure receiving long-term furosemide, 36 infants (median age 2.9, range 1.2-8.0 months) and 36 full-term control infants not receiving diuretics (median age 3.4, range 1.1-8.4 months) were studied (10c). Infants with nephrocalcinosis were followed at intervals of 3-6 months up to 2 years of age, or until ultrasound resolution. Nephrocalcinosis was found in five of 36 of the treated infants but in no controls. The average dose of furosemide was significantly higher in the infants with nephrocalcinosis (1.9 vs 1.3 mg/kg/day). There was ultrasonic resolution of nephrocalcinosis in three of the five infants at 12 months, but in the other two it persisted at 24 months.

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Long-term furosemide treatment in fullterm infants with congestive heart failure entails a considerable dose-related risk of nephrocalcinosis. The incidence is considerably less than the 34-93% reported in furosemide-treated infants of very low birth weight. However, renal ultrasonography is warranted in full-term infants within a few months of starting furosemide, and if nephrocalcinosis is found alteration of the diuretic regimen to a thiazide should be considered.

CARBONIC ANHYDRASE INHIBITORS (SED-14,669; SEDA-21, 228; SEDA-22, 236; SEDA-23, 229)

Acetazolamide Adverse events common to diuretics are relatively frequent after the administration of acetazolamide (SED-14, 669). The relation between the concentration of acetazolamide and adverse effects has been examined in 23 patients with glaucoma who took repeated doses of acetazolamide for at least 1 week (llC). Biochemical features suggestive of metabolic acidosis (increased chloride ion concentration) correlated significantly with the acetazolamide concentration in erythrocytes but not with plasma concentrations. There were adverse effects in 13 patients: polyuria (n = 6), polydipsia (n = 5), paresthesia (n = 4), constipation (n = 3), abdominal cramps (n = 1), and fatigue (n = 1). The incidence of adverse effects was greater in those with erythrocyte acetazolamide concentrations over 20 Ixg/ml. Erythrocyte concentrations, rather than plasma concentrations, may reflect accumulation of acetazolamide during chronic administration. Inhibition of carbonic anhydrase isoenzymes in erythrocytes may explain the high incidence of adverse effects with acetazolamide. Periodic monitoring of erythrocyte acetazolamide and plasma chloride ion concentrations in patients with glaucoma treated with long-term acetazolamide may prevent overdosage and adverse effects. A systematic review of randomized placebo-controlled trials has quantified the benefit and harm of pharmacological prevention in acute mountain sickness (12M). Acetazolamide 750 mg/day was effective but acetazolamide

249 500 mg/day was not. Paresthesia (RR = 4.02; CI = 1.71, 9.43) andpolyuria (RR = 4.24; CI = 1.92, 9.37) were the most common adverse effects. The NNTs for these adverse events were 3.0 (CI = 2.0, 6.0) and 3.6 (CI = 2.5, 6.2) respectively. One trial (SED-14, 669; SEDA-15, 219) reported taste disturbance in three of 15 subjects treated with acetazolamide and in none with placebo, but the difference was not significant. The adverse effects of acetazolamide were minor. People climbing or working at high altitude are unlikely to stop using acetazolamide because of paresthesia of the fingertips or

increased diuresis. Nervous system A case of possible Gerstmann syndrome has been attributed to acetazolamide (13c). A 60-year-old woman was admitted with acute confusion 2 days after the removal of a cataract. She had long-standing diabetes mellitus, hypertension, and ischemic heart disease. There had been a minor stroke with complete recovery 2 years earlier. Medication included aspirin, indapamide, enalapril, and oral hypoglycaemic agents. Acetazolamide 500 mg bd was added shortly after the eye operation. Neurological examination showed finger agnosia, nominal and receptive dysphasia, acalculia, astereognosis, and left-right disorientation. Other systems were normal. Withdrawal of acetazolamide resulted in rapid improvement with no residual neurological signs 2 days after admission. A diagnosis of acetazolamide toxicity was suspected, because of the temporal association between drug treatment and the onset of the neurological symptoms, together with metabolic acidosis. Gerstmann syndrome is usually due to an acute stroke. Although brain CT was negative, such an event was likely in this patient, who had a history of cerebrovascular disease and multiple risk factors, and a causal relation to acetazolamide must be considered tenuous. Drug interactions Acetazolamide-induced confusion and lethargy can be provoked by co-administration of salicylates, which inhibit the renal tubular excretion of acetazolamide (SED- 14, 669). A 50-year-old woman with chronic renal insufficiency treated with acetazolamide for simple glaucoma was admitted with confusion, cerebellar ataxia,

250 and metabolic acidosis 2 weeks after starting to take aspirin for acute pericarditis (14A). A diagnosis of salicylism was made despite low serum salicylate concentrations. The authors suggested that acetazolamideinduced acidosis enhances the non-ionized form of salicylate, which crosses membranes more rapidly, and hence explains the cerebral toxicity associated with low serum concentrations of saiicylate. However, an increase in the plasma or erythrocyte concentrations of acetazolamide (not measured) is a much more convincing explanation for this patient's symptoms.

MODERATELY POTENT DIURETICS Thiazide diuretics (SED-14,656; SEDA-21, 229; SEDA-23, 228) Drug interactions Non-steroidal anti-inflammatory drugs (NSAIDs) are often reported to interfere with the blood pressure-lowering action of thiazide diuretics (SED-14, 667). In 17 women with arthritiS and hypertension taking fosinopril and hydrochlorothiazide, ibuprofen, sulindac, and nabumetone, each for 1 month, had no effect on mean arterial pressure (15c). These results suggest that the ACE inhibitor, fosinopril, may neutralize the tendency of NSAIDs to increase blood pressure in thiazide-treated hypertensive patients. However, the design of this study precluded such a conclusion, since no evidence was provided that any of the NSAIDs increased blood pressure in the absence of fosinopril. Furthermore, the patient numbers were small and the precision of the comparison is likely to be low; the 95% confidence intervals of the differences were not provided. Careful monitoring of blood pressure remains necessary when NSAIDs are introduced in thiazide-treated hypertensive patients, even when ACE inhibitors are co-prescribed.

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POTENT DIURETICS (SED-14,670; SEDA-21, 229; SEDA-22, 236; SEDA-23, 229)

Furosemide (frusemide) Skin The first case of linear IgA bulous dermatosis associated with the administration of furosemide has been reported (16A). An 86-year-old woman, with a history of stable schizophrenia, chronic obstructive pulmonary disease, ischemic cardiomyopathy, and type 2 diabetes, was admitted with cardiac insufficiency, which was treated by introduction of enalapril. A chest infection was treated with co-amoxiclav with gradual alleviation of symptoms over 10 days. At this point, furosemide was begun, because of persistent signs of heart failure. After 3 days, erythema and bullae were noted on her palms and soles, and later on the trunk, extremities, hard palate, and buccal mucosa. Biopsy showed the characteristic features of linear IgA bullous dermatosis, with linear deposition of IgA along the basement membrane. Co-amoxiclav and furosemide were withdrawn; no new lesions were noted thereafter. Furosemide has previously been related to other bullous dermatoses, particularly bullous pemphigoid (SED-14, 671) but this is the first association with linear IgA bullous dermatosis. Only a temporal relation was demonstrated, as rechallenge was judged to be unethical. The other putative offending drug, co-amoxiclav, was regarded as unlikely to be causative, because it had been given many times before without noticeable skin lesions. D r u g interactions Furosemide increases steady-state theophylline concentrations (SED11, 428; SED-14, 673). A randomized, controlled study has shown an enhanced diuretic response to furosemide in infants taking theophylline during extracorporeal membrane oxygenation (17c). The underlying mechanism is uncertain, but may be an increase in glomerular filtration rate. Ten pre-term infants receiving regular theophylline for apnea of prematurity who subsequently received vancomycin and furosemide have been studied (18c). When vancomycin was introduced in the infants who were established on furosemide and theophylline, there was a consistent failure to achieve therapeutic concentrations. Starting furosemide in infants who were already receiving vancomycin resul-

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ted in falls in serum vancomycin to subtherapeutic concentrations in all but one case. Serum concentrations fell by a mean of 24% (range 12-43%), in the 24 hours after the start of furosemide treatment. Two of the 10 infants had persistence of coagulase-negative staphylococcal sepsis while vancomycin concentrations were suboptimal. While the mechanism of this interaction is uncertain, the changes in serum vancomycin concentration may indicate acute changes in glomerular filtration rate. Pre-term infants receiving theophylline and furosemide need shorter vancomycin dosage intervals to avoid therapeutic failure.

POTASSIUM-SPARING DIURETICS (SED-14, 674; SEDA-21, 230; SEDA-22, 229; SEDA-23, 239) Drug interactions The interaction between potassium-sparing diuretics and NSAIDs is well documented (SED-14, 674). The major complications are deterioration of renal function and hyperkalemia. The risk associated with non-selective cyclo-oxygenase-2 inhibitors is unknown. However, three recently reported patients had hyperkalemia (8.5, 5.4, and 5.1 mmol/1) after developing acute renal insufficiency while taking these drugs (19a). Co-administration of potassium-sparing diuretics with ACE inhibitors can cause s e v e r e hyperkalemia (SED-14, 674). In a retrospective study, five patients developed extreme hyperkalemia (9.4-11 mmol/1) within 8-18 days of starting combination therapy with co-amilozide and an ACE inhibitor (20~). In eight healthy subjects, treatment with spironolactone and losartan increased mean plasma potassium concentration by 0.8 mmol/1 (up to 5.0 mmol/1) and reduced mean urinary potassium excretion from 108 to 87 mmol/l (21c). Until more data are available, it is prudent to consider angiotensin II receptor antagonists similar to ACE inhibitors as risk factors for hyperkalemia in patients taking potassium-sparing diuretics.

251

Trimethoprim (SED-14, 675) and pentamidine are structurally similar to amiloride and can cause severe hyperkalemia if co-prescribed with potassium-sparing diuretics (9a). This is a particularly important interaction in patients with AIDS.

Eplerenone Eplerenone is an aldosterone antagonist currently undergoing phase III clinical testing. Although similar to spironolactone in its ability to inhibit aldosterone, eplerenone has lesser affinity for androgen and progesterone receptors and may therefore have fewer adverse effects. Eplerenone has recently been compared with spironolactone in patients with heart failure (NYHA classes II-IV). In a dose-finding study, 321 patients maintained on ACE inhibitors and diuretics, with or without digoxin, were randomized to receive eplerenone 25100 mg/day, spironolactone 25 mg/day or placebo (22c). After 12 weeks there was no improvement in heart failure in patients taking either eplerenone or spironolactone. Increases in plasma testosterone were significantly greater in men taking spironolactone than in those taking eplerenone. However, hyperkalemia was more frequent in patients taking eplerenone 100 mg/day (12%) than in those taking spironolactone 25 mg/day (8.7%). The potency of eplerenone relative to spirolactone remains to be established in patients with heart failure, but preliminary results with this new drug are encouraging.

Spironolactone Although the aldosterone receptor antagonist, spironolactone, has been available for more than 30 years, its efficacy and safety in patients with heart failure have only recently been recognized (1c). Based on this and numerous smaller trials, the use of spironolactone, in conjunction with ACE inhibitors, other diuretics, and possibly E-blockers or digoxin, represents a promising strategy for patients with severe heart failure. Its main adverse effects are hyperkalemia and antiadrenergic complications (SED-14, 675).

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REFERENCES 1. Pitt B, Zannad F, Remme W J, Cody R, Castaigne A, Perez A, Palensky J, Wittes J, for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. New Engl J Med 1999; 341: 709-17. 2. Richards AM, Nicolls MG. Aldosterone antagonists in heart failure. Lancet 1999; 354: 78990. 3. Gosse E Sheridan DJ, Zannad E Du-Bourg O, Gu&er TP, Karpov Y, De Leeuw PW, Palma-Gamiz J-L, Pessina A, Motz W, De Gaute J-P, Chastang C, on behalf of the LIVE Investigators. Regression of left ventricular hypertrophy in hypertensive patients treated with indapamide SR 1.5 mg versus enalapril 20 mg: the LIVE Study. J Hypertens 2000; 18: 1465-75. 4. Wright JM, Lee C-H, Chambers GK. Systemic review of antihypertensive therapies: does the evidence assist in choosing a first line drug? Can Med Assoc J 1999; 161: 25-32. 5. Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW, Applegate WB. Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP). J Hypertens 2000; 18: 1149-54. 6. Alderman MH, Cohen H, Madhavan S, Kivlighn S. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension 1999; 34: 141-50. 7. Franse LV, Pahor M, Di Bari M, Somes GW, Cushman WC, Applegate WB. Hypokalaemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly Program. Hypertension 2000; 35: 1025-30. 8. Cohn JN, Kowey PR, Whelton PK, Prisant M. New guidelines for potassium replacement in clinical practice. A contemporary review by the National Council on Potassium in Clinical Practice. Arch Intern Med 2000; 160: 2429-36. 9. Perazella MA. Drug-induced hyperkalemia: old culprits and new offenders. Am J Med 2000; 109: 307-14. 10. Saarela T, Lanning P, Koivisto M, Paavilainen T. Nephrocalcinosis in full-term infants receiving furosemide treatment for congestive heart failure: a study of the incidence and 2-year follow up. Eur J Pediatr 1999; 158: 668-72. 11. Inatani M, Yano I, Tanihara H, Ogura Y, Honda Y, Inui K-I. Relationship between acetazolamide

blood concentration and its side effects in glaucomatous patients. J Ocul Pharmacol Ther 1999; 15: 97-105. 12. Dumont L, Mardirosoff C, Tram& MR. Efficacy and harm of pharmacological prevention of acute mountain sickness:, quantitative systematic review. Br Med J 2000; 321: 267-72. 13. Lee YT, Wu JCY, Chan KFL. Acetazolamideinduced Gerstmann syndrome. Int J Clin Pract 1999; 53: 560-1. 14. Hazouard E, Grimbert M, Jonbille-Berra A-P, DeToffol M-C, Legras A. Salicylism and glaucoma: mutual toxicity enhancement of acetazolamide and acetylsalicylic acid. J Fr Othalmol 1999; 22: 73-5. 15. Thakur V, Cook ME, WaUin JD. Antihypertensive effect of the combination of fosinopril and HCTZ is resistant to interference by nonsteroidal antiinflammatory drugs. Am J Hypertens 1999; 12: 925-8. 16. Cerottini J-P, Ricci C, Guggisberg D, Panizzon RG. Drug-induced linear IgA bullous dermatosis probably induced by furosemide. J Am Acad Dermatol 1999; 41: 103-5. 17. Locham SR, Adeniyi-Jones S, Assadi FK, Frey BM, Marcus S, Baumgart S. Coadministration of theophylline enhances diuretic response to furosemide in infants during extra corporeal membrane oxygenation. A randomized controlled pilot study. J Pediatr 1998; 133: 86-9. 18. Yeung MY, Smyth JP. Concurrent frusemidetheophylline dosing reduces serum vancomycin concentrations in preterm infants. Aust J Hosp Pharm 1999; 29: 269-72. 19. Peratzella MA, Eras J. Are selective COX-2 inhibitors nephrotoxic? Am J Kidney Dis 2000; 35: 93740. 20. Chiu TF, Bullard MJ, Chen JC. Rapid lifethreatening hyperkalemia after addition of amiloride HC1/hydrochlorothiazide to angiotensin-converting enzyme inhibitor therapy. Ann Emerg Med 1997; 30: 612-15. 21. Henger A, Tutt P, Hulter HM, Krapf R. Acidbase effects of inhibition of aldosterone and angiotensin II action in chronic metabolic acidosis in humans. J Am Soc Nephrol 1999; 10: 121A. 22. Pitt B, Roniker B. Eplerenone a novel selective aldosterone receptor antagonist (SARA): dose finding study in patients with heart failure. J Am Coil Cardiol 1999; 33 Suppl A: 188A-189A.

Gijsbert B. van der Voet and Frederik A. de Wolff

22 Aluminium

Metals (SED-14, 683;

SEDA-21, 232; SEDA-22, 242; SEDA-23, 231) Nervous system The hypothesis that aluminium exposure is causally related to Alzheimer's disease has led to much debate (1 R, 2r), and more knowledge is accumulated regarding possible mechanisms of neurotoxicity (3R). A recent study has suggested that researchers looking for a connection between aluminium and Alzheimer's disease may have been ignoring the most important source of aluminium for the average person--foodstuffs that contain aluminium additives (4c). The results implied that aluminium, added to such foods as anticaking agents, emulsifiers, thickeners, leaveners, and stabilizers, may have long-term adverse effects on health. However, the small sample size hampers any definitive conclusions, the odds ratios were very unstable, and the study had limited statistical power to rule out random errors. Aluminium-containing antacids have also been suggested to be the cause of idiopathic Parkinson's disease in a study of 200 patients and 200 age- and sex-matched controls. There was a significantly higher incidence of ulcers (diagnosed by X-ray or surgery) in the patients with Parkinson's disease compared with controls (14% vs 4%) (5c, 6c). The ulcers typically preceded the diagnosis of Parkinson's disease by 10-20 years. Parkinson's disease occurs worldwide, suggesting perhaps that some ubiquitous toxin plays a role in its pathogenesis. Sensory systems Tissue lesions can be caused by local deposition of aluminium, for example in the eye (7A). A 76-year-old man with a history of multiple melanomas noticed a gradually enlarging pigmen9 2001 ElsevierScienceB.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson,ed.

ted mass in his right eye. He had had successful pneumatic cryopexy of a retinal tear in the temporal region of the right eye 4 years before with no reported complications. Slit lamp examination showed a 4 • 2-mm elevated darkly pigmented conjunctival mass surrounding the insertion site of the lateral rectus. An excisional biopsy showed multiple foci of fine, jet-black, granular pigmentation in a perivascular distribution, with additional deposition throughout the conjunctival stroma. There were no melanocyte abnormalities or cellular atypia. Energy dispersive analysis of X-rays showed spectral peaks corresponding to heavy aluminium deposition with trace amounts of silicone. Aluminium is often incorporated in cryoprobe tips for ophthalmic use, providing a possible source of local deposition. Other possibilities include a metallic foreign body and occupational exposure.

Musculoskeletal Osteomalacia due to aluminium-containing antacids has been associated with stainable bone aluminium in a patient with normal renal function (8A). A 39-year-old woman who took high doses of aluminium and magnesium hydroxide for peptic ulcer disease (over 18 kg of elemental aluminium and 15 kg of elemental magnesium over 8 years) developed severe osteomalacia due to profound phosphate depletion. Bone biopsy showed stainable aluminium deposits along 28% of the total bone surface, a unique observation in a patient with normal renal function. Treatment included withdrawal of the antacid and supplementation with phosphate, calcium, and vitamin D. Her bone mineral density increased over the next 2 years. Unexpected persistent aluminium-related

bone disease occurred after renal transplantation following earlier use of aluminium hydroxide (9A). A 59-year-old man presented with end-stage renal insufficiency. While on hemodialysis he had used aluminium hydroxide as a phosphate binder but then used calcium lactate instead after total para9~q

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254

thyroidectomy. Oral vitamin D was discontinued after the parathyroidectomy. However, after he had received a renal transplant he developed aluminiumrelated bone disease and was treated with infusions of deferoxamine. This is the first report of worsening aluminium-related bone disease after renal transplantation. Hyperparathyroidism and aluminium hydroxide lead to aluminium-relatedbone disease; however, total parathyroidectomy does not lead to failure of aluminium mobilization after renal transplantation. This man had satisfactory graft function, and the aluminium excretion that was achieved by deferoxamine suggests that the renal transplant was not the limiting factor for the mobilization of aluminium. The most likely explanation was that he developed adynamic bone through a combination of vitamin D deficiency, hypoparathyroidism, and aluminium deposition. Vitamin D supplementation failed to prevent the osteodystrophy on its own. When aluminium chelation therapy was used, bone healing occurred and his symptoms improved.

Risk factors

Renal insufficiency increases the

risk of aluminium toxicity (10A). A 70-year-old man with advanced obstructive nephropathy began to hemorrhage from the bladder after decompression with a Foley catheter. He developed an encephalopathy after continuous irrigation with 1% alum for 2 days, associated with raised serum aluminium concentrations. Repeated treatment with deferoxamine and hemodialysis removed some aluminium, but he succumbed to bronchopneumonia. At autopsy his brain aluminium content was not excessive. Most reported instances of encephalopathy after alum irrigation have occurred in patients with compromised renal function. The authors recommended that alum should not be used in patients with renal insufficiency.

Antimony Immunologic

(SED-14, 685; SEDA-21, 233)

As an industrial and environmental toxin antimony trioxide may cause disturbances of immune homeostasis. Workers in antimony trioxide manufacture had reduced serum concentrations of cytokines (interleukin2, F-interferon) and immunoglobulin (IgG1, IgE) (1 lC).

GijsbertB. van der Voetand FrederikA. de Wolff Drug resistance The treatment of cutaneous leishmaniasis has been reviewed, including the use of pentavalent antimonials (12R), but no new adverse effects have been reported. However, the emergence of antimony-resistant strains continues (13R), leading to the use of higher dosages of antimonials or combinations of antimonials with other compounds, such as paromomycin or F-interferon (14R).

Arsenic

(SED-14, 686; SEDA-22, 243; SEDA-23, 232) Arsenic trioxide is effective in acute promyelocytic leukemia, achieving a complete remission rate of 60-90% (15 R, 16R). It is particularly used in patients who are resistant to all-trans retinoic acid (17A). The retinoic acid syndrome is the most severe effect of all-trans retinoic acid during treatment of acute promyelocytic leukemia, and a major cause of death. The syndrome causes fever, skin rash, and edema, and more severe symptoms of pleural effusion, pericardial effusion, and acute respiratory failure can also develop. Arsenic trioxide is effective in acute promyelocytic leukemia but can cause a syndrome similar to the retinoic acid syndrome (18A). A 37-year-old woman with acute promyelocytic leukemia was treated with all-trans retinoic acid, idarubicin, and cytosine arabinoside, with complete remission after one course. However, she had an episode of retinoic acid syndrome with fever, edema, and pericardial effusion, which resolved after all-trans retinoic acid was withdrawn. When her leukemia relapsed she was treated with arsenic trioxide 10 mg/day. Leukocytosis again developed, with symptoms (fever, skin rash, and edema) resembling the retinoic acid syndrome, which was quickly relieved by steroids. She received two courses of arsenic trioxide each for 30 days and her complete blood count returned to normal 2 weeks after the second course of treatment. The bone-marrow also reached complete remission.

Cardiovascular Atrioventricular block is very rare after arsenic trioxide treatment for refractory acute promyelocytic leukemia (19A). A 34-year-old woman with acute promyelocytic leukemia was given arsenic trioxide solution 0.1%, 10 ml/day for 7 days. A generalized skin rash appeared, and her serum AsT and A1T rose. An electrocardiogram was normal. A second course of arsenic trioxide was used about 3 months later. She felt palpitation and mild dyspnea and had complete

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Chapter22

atrioventricular block. Echocardiography showed a normal left ventricle. A 2~ myocardial perfusion scan did not show a perfusion defect. Arsenic trioxide was withheld. Sinus rhythm returned 3 days later. Complete atrioventricular block recurred later when arsenic trioxide was readministered, albeit in a lower dosage for a shorter period of time. The heart block due to arsenic trioxide in this case was reversible and did not correlate with the patient's leukemic status.

255 quest for the molecular mechanisms of chromium in relation to diabetes continues (29 R, 30R). Skin Chromium picolinate has been promoted as a nutritional supplement and has received a great deal of interest because of its possible beneficial effects on muscle strength and body composition. However, it has caused

acute generalized exanthematous pustulosis (31A).

Bismuth (SED-14, 686; SEDA-21, 233; SEDA-22, 243; SEDA-23, 232) Bismuth is still used in some Helicobacter pylori eradication regimens (20R, 21R), but no new adverse effects have been reported. Bismuth subsalicylate is also being evaluated in the treatment of microscopic colitis (22R). A uniform technique of tonsillectomy, including the use of bismuth subgallate and reassessment of the tonsillar fossae after a 3-minute observation period, reduced the incidence of primary tonsillar hemorrhage in a retrospective study of 705 children (23c). However, in a randomized study of 204 patients the evidence for the use of bismuth subgaUate as a hemostatic agent in tonsillectomy was weak (24c).

Cadmium Cadmium is an environmental and occupational pollutant that is associated with nephrotoxicity (25 R) and bone toxicity (26R); even low concentrations can impair renal function and/or increase bone fragility. No new observations have been reported regarding cadmium-containing herbal medicines. However, cadmium is a pollutant of infant formulas and weaning foods. Cadmium concentrations were determined in 59 baby food samples, including milk-based cereals and milk-based and soya-based formulas, recommended from 0-18 months of age. The mean weekly intake of dietary cadmium was estimated to be 0.1-3.1 Ixg/kg. Exposure to dietary cadmium from weaning diets can be up to 12 times higher in children fed infant formulas compared with breast-fed children (27c).

Chromium (8ED-14, 683; SEDA-21, 232; SEDA-22, 242; SEDA-23, 231) The general toxicology of chromium compounds has recently been reviewed (28R). The

A 32-year-old previously healthy man developed an extensive rash of sudden onset associated with a tow-grade fever (37.4~ C), a sore throat, and malaise. Four days before he had taken chromium picolinate 1 mg/day. He had a confluent symmetrical erythematous eruption with numerous non-follicular 1-2 mm pustules on the trunk and proximal limbs. The eruption was most prominent in the antecubital and popliteal fossae bilaterally. There was mild pharyngeal erythema and bilateral tender cervical adenopathy, but no tonsillar enlargement or exudate. Chromium picolinate was withdrawn and he was treated with oral prednisone 60 mg/day tapered over 15 days. The acute eruption resolved within 1 week, followed by postinflammatory desquamation. It did not recur during follow-up for 15 months.

Drug interactions

Chromium can potentiate antidepressant pharmacotherapy for manicdepressive disorder. In five patients taking sertraline, chromium picolinate and chromium polynicotinate supplementation led to enhanced remission of dysthymic symptoms (32c). Cobalt

(SED-14, 688)

The toxicity of cobalt has recently been reviewed (33R), without any new findings. Occupational exposure is mainly due to cobalt powders. Its main other uses are in metal alloys and medical devices (e.g. aneurysm clips) (34R). The catastrophic failure of cemented cobaltcontaining femoral stems that had been used in conjunction with the impacting bone-grafting technique has been reported in two cases (35A). A 59-year-old woman with degenerative arthritis of the hip was managed with a bipolar arthroplasty and later with a total hip replacement. A longstem component, manufactured from forged cobaltchromium, was later used for revision. She developed acute pain in the thigh and buttock, with tenderness and swelling in the thigh and hip and pain on move-

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ment. Hip X-rays showed catastrophic failure of the femoral component of the prosthesis, and at operation the prosthesis and the femur were fractured at the same level. A 51-year-old woman sustained a fracture of the left femoral neck, later treated by total hip arthroplasty, which was revised several times with the impaction bone grafting technique and insertion of a prosthesis with cement. She developed a persistent weakness of the hip in flexion and abduction. Later the left hip buckled and she fell while walking. Xrays showed a periprosthetic fracture with bending of the femoral component. It was thought that the mechanism of failure had been cantilever bending secondary to good distal fixation in the presence of poor proximal bone support resulting from poor proximal incorporation of the impacted allograft. In essence, a fatigue fracture had occurred in a forged cobalt chromium stem that did not have an obvious manufacturing defect at the site of failure. Both failures were apparently related to implant design and operative technique rather than to defects introduced during the manufacturing process.

Copper (SED-14, 688; SEDA-21, 234; SEDA-22, 244; SEDA-23, 233) Copper metabolism and toxicity have been reviewed (36R), but no new adverse effects from the medical uses of copper compounds and devices have been reported. The use of coppercontaining intrauterine contraceptive devices has been further discussed (37R). Migration of intrauterine contraceptive devices is relatively rare, although they have been found in the omentum, rectosigmoid, peritoneum, bladder, appendix, small bowel, adnexa, and iliac vein. Most authors have recommended removal of copper-containing devices, because of the potential for inflammatory reactions, which can cause bowel obstruction and perforation (38R). Liver Apart from Wilson's disease and Menke's disease, much attention has been given to copper-associated liver disease in infancy and childhood, in which excessive dietary copper overload and a genetic predisposition can lead to high liver copper concentrations and progressive liver disease (39R).

GijsbertB. van der Voet and FrederikA. de Wolff

Gallium

(SED-14, 690; SEDA-21, 235; SEDA-22, 244; SEDA-23, 234) Gallium-67 is still in use as part of diagnostic nuclear medicine procedures (40R), but it can cause adverse effects (41A). A 40-year-old woman had multiple bone injuries, severe sepsis, and coma after a car accident; a retroperitoneal hematoma caused by lumbar fractures was drained, but she continued to be pyrexial. She had prominent accumulation of 67Ga, which had been used for bone scanning, in hermultiple recent fractures and an area of accumulation in the soft tissue related to a fractured vertebra. Post-traumatic paravertebral calcifications had accumulated 67Ga and simulated the presence of an infected hematoma. Gallium nitrate is still used in anticancer therapy, and its use has been reviewed (42R). Recently it has also been used as an alternative to bisphosphonates in hypercalcemia of malignancy (43R), in which it is effective but associated with a higher frequency of renal toxicity (10%) and of nausea and vomiting (14%) than the bisphosphonates. The use of gallium restorative alloy is being explored. In a pilot study of a direct-placement gallium alloy (Galloy) in nine patients, 30 dental restorations were inserted and assessed over 3 years (44c). The initial 18-month results were encouraging, but at 21 months there was one fractured tooth and within another year two molars had the cracked-tooth syndrome (incomplete tooth fracture). The fractured teeth were restored with amalgam. Tarnish and a rough surface were noted on many of the galllium restorations. These results suggest that Galloy, used with either of two sealing resins, is not a suitable dental restorative material.

Germanium (SED-14, 690; SEDA-21, 235; SEDA-22, 245; SEDA-23, 234) Occupational exposure to inorganic germanium compounds still causes slightly impaired renal function (45 c). Organic germanium compounds are promising as antineoplastic or immunostimulatory agents and are perceived as natural remedies, though they can cause nephrotoxicity and neurotoxicity. Renal and other organ failure has been caused by germanium intoxication (46A).

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A 58-year-old man developed nausea, vomiting, anorexia, and weight loss. He had taken germanium lactate citrate illegally purchased in a pharmacy, recommended as a natural antioxidant, anticancer, and immunostimulatory remedy. He took a total dose of 426 g orally over 6 months and developed renal insufficiency and proteinuria, implying tubular damage. His serum TSH, fasting glucose, glycosylated haemoglobin, and C-peptide were increased. Abdominal ultrasound showed normal kidneys. Cardiac ultrasound showed a pericardial effusion. An electrocardiogram showed a sinus tachycardia. Nerve conduction studies and electromyography showed pathological spontaneous muscular activity and myotonic discharge. The neural conduction velocity was normal in the median nerve and delayed in the peroneal nerve. He received intravenous nutrition, insulin, and electrolytes. The pericardial effusion regressed but the sinus tachycardia continued. The renal dysfunction and the polyneuropathy persisted.

Gold (SED-14, 690; SEDA-21, 236;

257 L i v e r Severe hepatotoxicity occurred during gold therapy for rheumatoid arthritis (48A). A 62-year-old man with rheumatoid factor positive rheumatoid arthritis developed painless icterus, nausea and vomiting, and discoloration of his stools. He had previously been given methotrexate without effect, and he was given aurothioglucose instead, 50 mg/week (cumulative dose 160 rag). He reported sweating, fatigue, and myalgia shortly after each gold injection. The liver was tender but not enlarged, and there were no signs of splenomegaly. Liver function tests showed a cholestatic pattern and predominantly conjugated hyperbilirubinemia. All potentially hepatotoxic drugs (aurothioghicose, naproxen, and aspirin) were withdrawn and his dose of prednisone was increased to 15 mg/day. His liver function tests normalized 4 weeks later. I m m u n o l o g i c Accidental gold administration has reportedly caused an allergic skin rash (49A).

SEDA-22, 245; SEDA-23, 234) No new adverse effects have been reported, although a number of case reports have been published in which previously known adverse effects were confirmed and discussed in more detail. N e r v o u s system An axonal polyneuropathy has been attributed to gold (47A). A 63-year-old man with a 4-month history of rheumatoid arthritis developed progressive malaise, anorexia, weight loss, and had a 2-day history of diarrhea, fever, and chills. He had epigastric and periumbilical pain radiating to the back, associated with nausea, abdominal distension, and jaundice. He was taking prednisone 5 mg bd and diclofenac sodium 100 mg bd. He had recently started weekly gold injections (total dose of gold 150 mg). He received two test doses before starting induction therapy, with no adverse effects. Both gold and diclofenac sodium were withdrawn and 2 weeks later he complained of symmetrical distal paresthesia in a glove and stocking distribution. There was no weakness, parallel reflexes were diminished, and the ankle reflexes were both absent. Nerve conduction studies showed a reduction in sensory nerve action potential amplitude in the sural and median nerves, with normal motor conduction. There was a slightly increased threshold for warm and cold sensations in the foot, with normal results in the hand. A liver needle biopsy showed preserved liver architecture with marked cholestasis mainly in the central and mid zones. A positive lymphocyte transformation test to gold suggested a cell-mediated hypersensitivity reaction.

A 31-year-old woman developed a rash, similar to the rash she had experienced after wearing gold jewelry. The evening before she had taken about 90120 ml of Goldschlager liquor, a cinnamon schnapps that can contain as much as 8-17 mg of gold in 750 ml. The rash was isolated to her neck, upper chest, and hands and was erythematous and pruritic with no borders or margins. Her rash resolved over 2 weeks without desquamation. A 63-year-old woman with rheumatoid arthritis was given intramuscular gold sodium thiomalate and began to have nausea, vomiting, anorexia, and watery diarrhea (50A). A year later the watery diarrhea became more frequent (more than 10 times within a day) and she developed proteinuria. Biopsies from the stomach, duodenum, and kidney showed systemic amyloidosis. This was a rare case of secondary systemic amyloidosis associated with rheumatoid arthritis. It is not clear from the report what the role of gold was in this case.

Iron (SED-14, 697; SEDA-21, 237; SEDA-22, 246; SEDA-23, 235) No new adverse effects of iron have been reported, although the flow of iron-related publications is overwhelming. Gastrointestinal Severe gastrointestinal necrosis and strictures after iron overdose are well described. However, mucosal injury in patients taking therapeutic iron has received

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only scant recognition, despite its widespread use. In 36 upper gastrointestinal tract biopsies from 33 patients (24 gastric, nine esophageal, one gastro-esophageal junctional, and two duodenal) there was characteristic brown crystalline iron material (51R). Most of the biopsies (32 of 36) contained luminal crystalline iron adjacent to the surface epithelium or admixed with luminal fibrinoinflammatory exudate. In 30 biopsies there was crystalline iron deposition in the lamina propria, either covered by an intact epithelium, subjacent to small superficial erosions, or admixed with granulation tissue. Three biopsies showed iron-containing thrombi in mucosal blood vessels. Erosive or ulcerative mucosal injury was present in 30 of 36 biopsies. The amount of iron accumulation in cases with mucosal injury was greater than in the cases without mucosal injury. About half of the patients (17 of 33) also had underlying infectious, mechanical, toxic, or systemic medical conditions that could have initiated or exacerbated tissue injury. Crystalline iron deposition was found in 0.9% of upper gastrointestinal endoscopic examinations (12 of 1300), and iron medication-associated erosive mucosal injury was present in 0.7% (9 of 1300). These resuits suggest that crystalline iron deposition in the upper gastrointestinal tract is not uncommon. It can cause or exacerbate a distinctive histological pattern of erosive mucosal injury, especially in patients with associated upper gastrointestinal disorders. Infection risk In a 10-year consecutive series of 263 allogeneic bone-marrow transplant recipients, there were five cases of invasive mucormycosis (52c). Only one infection occurred within the first 100 days after transplantation, while the rest complicated the late post-transplant course (median day of diagnosis, 343). Sites of infection were considered "non-classical" and included pulmonary, cutaneous, and gastric. There were no cases of fungal dissemination. Mucormycosis was the primary cause of death in three of the five patients. Corticosteroid-treated graft-vs-host disease, either acute or chronic, or severe neutropenia were present in all cases. However, compared with a matched control population, the most striking finding was severe iron overload in each patient. The mean serum ferritin concentration, transferrin saturation, and the number of transfused units of red cells in the

Gijsbert B. van der Voet and Frederik A. de Wolff study group were all significantly higher than in the control group. There was a striking association between the occurrence of mucormycosis in dialysis patients and the use of deferoxamine for the treatment of iron and/or aluminium overload. From experimental work and observational data, it appears that iron overload, either transfusional or due to dyserythropoiesis, may be an important risk factor in the development of mucormycosis in this transplantation patient population. C a r c i n o g e n i d t y Genetic hemochromatosis constitutes a high risk factor for the development of hepatoceUular carcinoma. It is widely accepted that venesection prevents the evolution of cirrhosis in hemochromatosis and indirectly protects against the development of hepatocellular carcinoma. However, three cases did not conform to the "siderosis-cirrhosiscarcinoma" sequence and prompt and adequate iron depletion did not ~rotect against the development of cancer (53~). A 39-year-old army officer had bouts of palpitation and dizziness. There were no risk factors for chronic liver disease apart from a family history of hemochromatosis. His cardiovascular and nervous systems were normal but there was 5 cm hepatomegaly. Percutaneous liver biopsy showed grade 4 siderosis in parenchymal and non-parenchymal liver cells and a mild inflammatory infiltrate with minimal portal fibrosis. He was venesected 45 1 of blood over the next 18 months and a repeat biopsy 3 years later showed a non-cirrhotic liver with no stainable iron. He developed a non-resectable primary hepatocellular clear cell carcinoma 17 years after the initial diagnosis. The other two cases were male siblings. One presented with atypical chest pain and had 3 cm hepatomegaly. Liver biopsy showed parenchymal grade 4 siderosis with normal architecture. He was venesected 170 1 of blood over the next 27 years, but then his iron indices indicated reaccumulation. Ultrasound showed a hyperechoic lesion in the liver due to a moderately differentiated hepatocellular carcinoma. His elder sibling, who had grade 4 siderosis and normal hepatic architecture, also developed a well-differentiated hepatocellular carcinoma.

Lead

(SED-14, 701)

No significant effects have been attributed to lead as a contaminant in herbal medicines, infant formulas, or total parenteral nutrition. In an investigation of the protective effect of calcium supplements against lead absorption,

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Chapter22

103 infants aged 3 . 5 ~ months were randomly assigned to receive an infant formula (ironfortified, containing 465 mg/1 of calcium and 317 mg/1 of phosphate) or the same formula with added calcium glycerophosphate (1800 mg/l of calcium and 1390 mg/1 of phosphate) for 9 months (54c). There was no significant difference between the groups in the mean ratio of urinary calcium to creatinine, serum calcium, or serum phosphorus, nor any change in iron status. At month 4, the median increase was 0.07 Ixmol/l in the control group and 0.04 ixmol/1 in the supplemented group. This significant effect was attenuated during the latter half of the trial, with overall increases in blood lead of 0.12 Ixmol/l in controls and 0.10 Ixmol/l in the supplemented group. Supplementation did not have a measurable effect on urinary calcium excretion, calcium homeostasis, or iron status. The significant effect on blood lead concentration was expected, although it was not sustained during the whole trial, and so no prevention could be concluded. Raised blood lead concentrations in an adult have been attributed to an Asian remedy for menstrual cramps ("Koo Sar" pills) (55A). A Cambodian woman, her husband, and their two children were screened at a free lead-screening event sponsored by a nursing school community health promotion. The husband and children had normal blood lead concentrations, but the woman had a concentration of 440 Ixg/1. She reported no symptoms associated with lead poisoning (e.g. muscle pains or weakness, headaches, or loss of appetite). Samples of any medicines, teas, or cosmetics that she had used that might have been the source of the lead were analyzed. Lead was found only in bottles of red tablets, at concentrations of 3.5 ppm from one bottle and 1.2 ppm in a second bottle. For 3-4 years she had taken six of these tablets per day on 7 days of each month to treat menstrual cramps. She stopped taking them and her blood lead concentrations fell from 280 to 12 Ixg/1 over 6 months. Further laboratory analysis of other bottles showed lead in amounts of 12.5 ppm in tablets from a third bottle and 4.5 ppm in tablets from a fourth bottle. The tablets were traced to a San Francisco-based Hong Kong company who sold them in packages with the brand name listed on the outside of the package as "Koo So Pills" and on the package insert as "Koo Sar Pills". The package literature was written in Chinese. Lead was not among the 11 listed ingredients. The insert stated "These medical pills are good for general debility". The directions for dosage were one pill taken with warm water twice a day (not six per day). The lead content in samples purchased at different shops in San Francisco was 2.7 ppm (0.9 ltg/tablet) and 4.3 ppm (1.4 ixg/tablet).

259 No other cases of lead poisoning have been reported in association with Koo Sar tablets, and it is thought that the varying lead concentrations in the different tablets resulted from varying amounts of lead present during the manufacture of the red dye.

Manganese

(SED-14, 702; SEDA-21, 238; SEDA-22, 246; SEDA-23, 235) No new adverse effects of manganese have been observed. The general toxicity of manganese (56 R) and its neurotoxicity (57 R) have recently been reviewed. N e r v o u s system Two cases of manganese intoxication have been reported during total parenteral nutrition including manganese (58A). A 68-year-old woman developed psychiatric symptoms and gait disturbance. She had received total parenteral nutrition for 3 months for ulcerative colitis, and essential trace elements (Elemenmic | including manganese (20 Ixmol/day) had been added. She was markedly confused and had parkinsonism, with dysarthria, marked rigidity, hypokinesia with a mask-like facies, and a supranuclear vertical gaze palsy. Her manganese concentrations were raised in both serum (4.2 Ixg/1, normal 0.4-2.0 txg/1) and urine (9.0 Ixg/l; normal under 2.0 Ixg/1). Serum concentrations of other trace elements (zinc, copper, iron) were normal. An MRI scan showed symmetrical high intensity Tl weighted images in the basal ganglia, especially the globus pallidus. Trace element supplementation was discontinued, levodopa was given, and her psychiatric symptoms and parkinsonism gradually abated. Calcium EDTA 1 g/day for 5 days produced marked urinary secretion of manganese. The high intensity basal ganglia MRI lesions regressed after supplementation had stopped. A 70-year-old man was given total parenteral nutrition for 4 months, with essential trace elements (Mineralin| including manganese (20 Ixmol/day). After 2 months he had progressive gait disturbance and confusion. His manganese was raised (5. l txg/1 in serum, and 1 ltg/l in the urine). He was markedly confused and had parkinsonism, with marked rigidity, a mask-like facies, hypokinesia, and a slight resting finger tremor. An MRI scan showed symmetrical high intensity signals on TI weighted images of the basal ganglia, especially the globus pallidus, and T2 weighted images showed multiple high intensity spots in the cerebral white matter, suggesting multiple lacunar infarcts. Trace element supplementation was discontinued, levodopa was given, and his parkinsonism gradually improved. Calcium EDTA dally for 5 days produced marked urinary secretion of manganese. The high-intensity basal ganglia lesions regressed after supplementation had stopped.

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GijsbertB. van der Voetand FrederikA. de Wolff

It is difficult to distinguish parkinsonism due to manganese from idiopathic parkinsonism by clinical signs only, but positron emission tomography is helpful in discriminating them.

orthopedic appliances (e.g. nickel alloys) promotes observations related to this sensitizing aspect. The toxicity of nickel has recently been reviewed (63R).

In a 48-year-old welder with parkinsonism an MRI scan showed symmetrical high signal intensities in the globus pallidus (59A). The intensities disappeared almost completely 6 month after cessation of exposure to manganese. Positron emission tomography showed reduced uptake of 18F-dopa in the left putamen, findings which appear in idiopathic parkinsonism. A positron emission tomography study is necessary to distinguish manganism from idiopathic parkinsonism, especially in a working environment with manganese exposure.

Platinum (SED-14, 704; SEDA-22, 248; SEDA-23, 236) More attention has been given to the neurotoxicity of platinum compounds than to their dose-limiting nephrotoxicity (64 R, 65R). Hypomagnesemia has also been reviewed (66R).

Nervous system A n encephalopathy has been attributed to cisplatin (67A).

Another study reports three cases in which positron emission tomography discriminated between idiopathic parkinsonism and parkinsonism due to manganese (60A). A 51-year-old man had a mask-like face, marked postural tremor of the hands, dystonia of the neck and arms, severe retropulsion, and lateropulsion, typical of chronic manganese intoxication. An lSF-dopa scan was normal. Two other patients, a 46-year-old man and a 47-year-old man with tremor at rest, rigidity predominantly on the right side, bradykinesia, stooped posture, and postural instability, all of which were typical of Parkinson's disease, had reduced uptake of 18F-dopa in the striatum, particularly in the posterior putamen, predominantly on the left side. The first patient had pure manganism, while the other two had Parkinson's disease, because loss of nigrostratal fibers was obvious, with asymmetry in the putamen.

Mercury (SED-14, 702; SEDA-21, 239; SEDA-22, 247; SEDA-23, 235) Discussion of the role of amalgams continues (61 R) but seems to become more realistic. Attention is also being given to mercury as a cause of autoimmune responses, especially in the kidney (62R).

Nickel (SED-14, 704; SEDA-21, 240; SEDA-22, 248; SEDA-23, 235) Nickel maintains its reputation as a common sensitizing agent, with a high prevalence of allergic contact dermatitis. Nickel in jewelry continues to cause allergy and contact dermatitis. The growing use of nickel in orthodontic and

A 50-year-old woman with carcinoma of the cervix was treated with radiotherapy and six courses of cisplatin (75 mg/m2 every 3 weeks; total dose 810 mg). The therapy was completed with no obvious acute complications, but 12 weeks after the last course she developed sudden blindness associated with occipital headache. She had mild global cognitive deficits and intermittent myoclonic jerking of both arms. Her visual acuity was limited to light perception in both eyes; her pupils were symmetrical with no afferent pupillary deficit. Anterior segment examination and dilated fundoscopy were normal; no ocular movements were elicited when a large plain mirror was held in front of her. The rest of the neurological examination was normal. Serum magnesium was reduced to 0.1 mmol/l (reference range 0.71.2 mmol/l). Electroencephalography showed diffuse slowing confirming an encephalopathy. Ear, nose, t h r o a t A 67-year-old white woman with a small cell lung cancer was given six courses of cisplatin and etoposide once every 4 weeks and after the last course developed acute shortness of breath, hoarseness, and stridor, due to bilateral vocal cord paralysis (68A).

Selenium (SED-14, 704; SEDA-21, 240; SEDA-22, 249; SEDA-23, 236) The toxicology of selenium and selenium deficiency have recently been reviewed (69R-71R). The major functions of selenium can be attributed to its antioxidative properties and its role in the regulation of thyroid hormone metabolism. Selenium compounds also inhibit tumorigenesis in a variety of animal models, and supplemental selenium in human diets may reduce the risk of cancer. No new data on adverse effects have been reported.

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Silver (SED-14, 705; SEDA-21, 241; SEDA-22, 250; SEDA-23, 236) Despite the supposed anti-infective efficacy of silver-coated medical prostheses, in the majority of studies these prostheses have not been proven to be infection-resistant (72R). The indiscriminate use of over-the-counter products containing colloidal silver or silver salts has resulted in cases of argyria, a permanent blue-grey discoloration of the skin. These "colloidal silver solutions" are being marketed for use in adults and children for diseases including AIDS, cancer, tuberculosis, malaria, lupus erythematosus, syphilis, scarlet fever, herpesvims infections, pneumonia, typhoid, tetanus, and many others. The US Food and Drug Administration has now issued a ruling that a colloidal silver product for any medical use will first have to be approved by the FDA under new drug application procedures (73 s).

Hematologic

A rare adverse effect, namely

methemoglobinemia secondary to topical silver nitrate therapy, has recently been reported (74A). A 12-month-old girl, with necrotizing fasciitis at the site of a cutaneous infection on her left trunk, became unresponsive, lethargic, and in shock, and underwent immediate aggressive tissue debridement. Later wound irrigation was carried out with a solution of silver nitrate 0.5% and 20 days later she became cyanotic and dyspneic. Her methemoglobin concentration was 38%. Intravenous methylene blue restored her oxygen saturation and reduced the dyspnea and cyanosis. Her methemoglobin concentration fell to 0.8%. Titaniunl (SED-14, 706; SEDA-21, 241; SEDA-22, 250; SEDA-23, 237) Titanium continues to be used in a host of orthopedic and othodontic appliances with or without

261 other metals (e.g. nickel, cobalt, chromium), generally without serious adverse effects. Research on the biocompatibility of metal and tissue continues (75c).

Z i n c (SED-14, 706; SEDA-21, 242; SEDA-22, 251; SEDA-23, 237) No explicit new adverse effects of zinc compounds have been published. However, zinc deficiency and toxicity have been reviewed (76R, 77R). Severe depletion of zinc in two patients with advanced cancer and malnutrition was accompanied by cutaneous bleeding, a prolonged bleeding time, and abnormal platelet aggregation (78A). Both had very low serum and urinary zinc concentrations. Oral zinc without any additional therapy was rapidly followed by control of bleeding and normalization of bleeding time and platelet aggregation. Discontinuation of zinc caused the return of the bleeding and abnormal laboratory findings. The efficacy and safety of intravaginal zinc sulfate + usnic acid as adjuvant therapy for human papillomavirus genital infection has been studied before or after radiosurgical treatment in 100 patients (79c). Papillomavirus lesions disappeared in 93% of the patients in the control group and in 100% of the others. Reepithelization after 1 month was complete in only 28% of the control group but in 65% of the treated patients; after 2 months it was complete in 76% of the controls and in 94% of the others. Treatment before radiosurgical treatment resulted in a reduction of the overall area of lesions in 88% of cases. Three months after radiosurgical treatment there was significantly less recurrence in those treated with usnic acid and zinc sulfate. Adverse effects were limited to local pain and irritation and were well tolerated.

REFERENCES 1. Exley C. A molecular mechanism of aluminium-induced Alzheimer's disease? J Inorg Biochem 1999: 76; 133--40. 2. Sjogren B, Ljunggren KG, Basun H, Frech W, Nennesmo I. Reappraisal of aluminosis and dementia. Lancet 1999; 354: 1559. 3. YokelRA, Allen DD, Ackley DC. The distribution of aluminum into and out of the brain. J Inorg Biochem 1999; 76: 127-32.

4. Rogers MAM, Simon DG. Aluminium intake and risk of Alzheimer's disease. Age Ageing 1999; 28: 205-9. 5. Altschuler E. Aluminium-containing antacids as a cause of idiopathic Parkinson's disease. Med Hypotheses 1999; 53: 22-3. 6. StrangeRR. The association of gastroduodenal ulceration and Parkinson's disease. Med J Aust 1965; 52: 842-3.

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7. Linebarger EJ, Kikkawa DO, Floyd B, Granet D, Booth M. Conjunctival aluminum deposition following pneumatic cryopexy. Arch Ophthalmol 1999; 117: 692-3. 8. Woodson GC. An interesting case of osteomalacia due to antacid use associated with stainable bone alunfinum in a patient with normal renal function. Bone 1998; 22: 695-8. 9. Nicholas JCB, Dawes PT, Davies SJ, Freemont AJ. Persisting aluminium-related bone disease after cadaveric transplantation. Nephrol Dial Transplant 1999; 14: 202-4. 10. Phelps KR, Naylor K, Brien TP, Wilbur H, Haqqiw SS. Encephalopathy after bladder irrigation with alum: a case report and literature review. Am J Med Sci 1999; 318: 181-5. 11. Kim H-A, Heo Y, Oh S-Y, Lee K-J, Lawrence DA. Altered serum cytokine and immunoglobulin levels in the workers exposed to antimony. Hum Exp Toxicol 1999; 18: 607-13. 12. Moskowitz PF, Kurban AK. Treatment of cutaneous leihmaniasis: retrospectives and advances for the 21st century. Clin Dermatol 1999; 17: 305-15. 13. Lira R, Sundar S, Makharia A, Kenney R, Gain A, Saraiva E, Sacks D. Evidence that the high incidence of treatment failures in Indian kala-azar is due to the emergence of antimony-resistant strains of Leishmania donovani. J Infect Dis 1999; 180: 564-7. 14. Aggarwal E Handa R, Singh S, Wali JE Kalaazar: new developments in diagnosis and treatment. Indian J Pediatr 1999; 66: 63-71. 15. Lehmann S, Paul C. Arsenik effektivt vid akut promyelocytleukemi. Lakartidningen 1999; 96: 5626-8. 16. Haanen C, Vermes I. Arseentrioxide, een nieuw therapeuticum bij de behandeling van acute promyelocytenleukemie in geval van resistentie tegen tretinoine. Ned Tijdschr Geneesk 1999; 143: 173841. 17. Lin C-E Huang M-J, Chang I-Y, Lin WY. Successful treatment of all-trans retinoic acid resistant and chemotherapy naive acute promyelocytic patients with arsenic trioxide--two case reports. Leuk Lymphoma 2000; 38: 191-4. 18. Lin C-E Huang M-J, Chang IY, Lin W-Y, Sheu Y-T. Retinoic acid syndrome induced by arsenic trioxide in treating recurrent all-trans retinoic acid resistant acute promyelocytic leukemia. Leuk Lymphoma 2000; 38; 195-8. 19. Huang C-H, Chen W-J, Wu C-C, Chen Y-C, Lee Y-T. Complete atrioventricular block after arsenic trioxide treatment in an acute promyelocytic leukemic patient. PACE Pacing Clin Electrophysiol 1999; 22: 965-7. 20. Van der Hulst RW, Van't Hoff BW, Van der Ende A, Tytgat GN. Behandeling van Helicobacter pylori-infectie. Ned Tijdschr Geneesk 1999; 143: 395-400. 21. Houben MHMG, Van de Beek D, Hensen EF, De Craen AJM, Rauws E/El, Tytgat GNJ. A sys-

Gijsbert B. van der Voet and Frederik A. de Wolff tematic review of Helicobacter pylori eradication therapy: the impact of antimicrobial resistance on eradication rates. Aliment Pharm Ther 1999; 13: 1047-55. 22. Schiller LR. Microscopic colitis syndrome: lymphocytic colitis and collagenous colitis. Semin Gastrointest Dis 1999; 10: 145-55. 23. Conley SF, Ellison MD. Avoidance of primary post-tonsillectomy hemorrhage in a teaching program. Arch Otolaryngol Head Neck Surg 1999; 125: 330-3. 24. Sorensen WT, Henrichsen J, Bonding P. Does bismuth subgallate have haemostatic effects in tonsillectomy? Clin Otolaryngol Allied Sci 1999; 24: 72-4. 25. Fels LM. Risk assessment of nephrotoxicity of cadmium. Renal Fail 1999; 21: 275-81. 26. Staessen JA, Roels HA, Emelianov D, Kuznetsova T, Thijs L, Vangronsveld J, Fagard R. Environmental exposure to cadmium, forearm bone density, and risk of fractures: prospective population study. Lancet 1999; 353:1140--4. 27. Eklund G, Oskarsson A. Exposure of cadmium from infant formulas and weaning foods. Food Addit Contam 1999; 16: 509-19. 28. Barceloux DG. Chromium. J Toxicol Clin Toxicol 1999; 37: 173-94. 29. Vincent JB. Quest for the molecular mechanism of chromium action and its relationship to diabetes. Nutr Rev 2000; 58: 67-72. 30. Anderson RA. Chromium in the prevention and control of diabetes. Diabetes Metab 2000; 26: 227. 31. Young PC, Tufiansky GW, Bonner MW, Benson PM. Acute generalized exanthematous pustulosis induced by chromium picolinate. J Am Acad Dermatol 1999; 41: 820-3. 32. McLeod MN, Gaynes BN, Golden RN. Chromium potentiation of antidepressant therapy for dysthymic disorder in 5 patients. J Clin Psychiatry 1999; 60: 237-40. 33. Barceloux DG. Cobalt. J Toxicol Clin Toxicol 1999; 37: 201-6. 34. Steiger HJ, Van Loon JJ. Virtues and drawbacks of titanium alloy aneurysm clips. Acta Neurochir Suppl Wien 1999; 72: 81-8. 35. Jazrawi LM, Della Valle CJ, Kummer FJ, Adler EM, Di Cesare PE. Catastrophic failure of a cemented, collarless, polished, tapered cobalt-chromium femoral stem used with impaction bone-grafting. J Bone Jt Surg Ser A 1999; 81: 844-7. 36. Barceloux DG. Copper. J Toxicol Clin Toxicol 1999; 37: 217-30. 37. Formey JA, Feldblum PJ, Raymond EG. Intrauterine devices. The optimal contraceptive method? J Reprod Med 1999; 44: 269-74. 38. Kassab B, Audra E The migrating intrauterine device. Case report and review of the literature. Contracept Fertil Sex 1999; 27: 696-700. 39. Rodeck B, Kardorff R, Melter M. Treatment of copper associated liver disease in childhood. Eur J Med Res 1999; 4: 253-6.

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40. Gardin J, Farragi M, Le Gudulec D, Bok B. Cell irradiation caused by diagnostic nuclear medicine procedures: dose heterogeneity and biological consequences. Eur J Nucl Med 1999; 26: 1617-26. 41. Lantsberg S, Rachinsky I, Boguslavsky L. False positive Ga-67 uptake in a septic patient after severe automobile trauma. Clin Nucl Med 1999; 24: 890-1. 42. Apseloff G. Therapeutic uses of gallium nitrate: past, present, and future. Am J Ther 1999; 6: 32739. 43. Zojer N, Keck AV, Pecherstorfer M. Comparative tolerahility of drug therapies for hypercalcaemia of malignancy. Drug Saf 1999; 21: 389406. 44. Osborne JW, Summitt JB. Direct-placement gallium restorative alloy: a 3-year clinical evaluation. Quintessence Int 1999; 30: 49-55. 45. Swennen B, Mallants A, Roels HA, Buchet JP, Bernard A, Lauwerijs RR, Lison D. Epidemiological survey of workers exposed to inorganic germanium compounds. Occup Environ Med 2000; 57: 242-8. 46. Ltick BE, Mann H, Melzer H, Dunemann L, Begerow J. Renal and other organ failure caused by germanium intoxication. Nephrol Dial Transplant 1999; 14: 2464-8. 47. Ben-Ami H, Pollack S, Nagachandran P, Lashevsky I, Yarnitsky D, Edoute Y. Reversible pancreatitis, hepatitis, and peripheral polyneuropathy associated with parenteral gold therapy. J Rheumatol 1999; 26: 2049-50. 48. Te Boekhorst PA, Barrera P, Laan RF, Van de Putte LB. Hepatotoxicity of parenteral gold therapy in rheumatoid arthritis: a case report and review of the literature. Clin Exp Rheumatol 1999; 17: 35962. 49. Guenthner T, Stork CM, Cantor RM. Goldschlager allergy in a gold allergic patient. Vet Hum Toxicol 1999; 41: 246. 50. Tahara K, Nishiya K, Yoshida T, Matsubara Y, Matsumori A, Ito H, Kumon Y, Hashimoto K, Moriki T, Ookubo S. A case of secondary systemic amyloidosis associated with rheumatoid arthritis after 3-year disease duration. Ryumachi 1999; 39: 27-32. 51. Abraham SC, Yardley JH, Wu Tr. Erosive injury to the upper gastrointestinal tract in patients receiving iron medication: an unrecognized entity. Am J Surg Pathol 1999; 23: 1241-7. 52. Maertens J, Demuynck H, Verbeken EK, Zach6e P, Verhoef GEG, Vandenberghe E Mucormycosis in allogeneic bone marrow transplant recipients: report of five cases and review of the role of iron overload in the pathogenesis. Bone Marrow Transpl 1999; 24: 307-12. 53. Goh J, Callagy G, McEntee G, O'Keane JC, Bomford A, Crowe J. Hepatocellular carcinoma arising in the absence of cirrhosis in genetic haemochromatosis: three case reports and review of literature. Eur J Gastroenterol Hepatol 1999; 11: 915-19.

263 54. Sargent JD, Dalton MA, O'onnor GT, Olmstead EM, Klein RZ. Randomized trial of calcium glycerophosphate-supplemented infant formula to prevent lead absorption. Am J Clin Nutr 1999; 69: 1224-30. 55. Anonymous. Asian remedy for menstrual cramps ("Koo Sar Pills")--lead poisoning in an adult reported. WHO Pharm Newslett 1999; 5/6 (May-Jun): 6. 56. Barceloux DG. Manganese. J Toxicol Clin Toxicol 1999; 37: 293-307. 57. Pal PK, Samii A, Calne DB. Manganese neurotoxicity: a review of clinical features, imaging and pathology. Neurotoxicology 1999; 20: 227-38. 58. Nagatomo S, Umehara F, Hanada K, Nobuhara Y, Takenaga S, Arimura K, Osame M. Manganese intoxication during total parenteral nutrition: report of two cases and review of the literature. J Neurol Sci 1999; 162: 102-5. 59. Kim Y, Kim JW, Ito K, Lira HS, Cheong HK, Kim JY, Shin YC, Kim KS, Moon Y. Idiopathic parkinsonism with superimposed manganese exposure: utility of positron emission tomography. Neurotoxicology 1999; 20: 24%52. 60. Abe Y, Kachi T, Kato T, Ito K, Yanagisawa N, Sobue G. Diagnostic utility of positron emission tomography for parkinsonism after chronic manganese exposure. Rinsko Shinkeigaku: Clin Neurol 1999; 39: 693-9. 61. Osborne JW, Albino JE. Psychological and medical effects of mercury intake from dental amalgam. A status report for the American Journal of Dentistry. Am J Dent 1999; 12: 151~5. 62. Bigazzi PE. Metals and kidney autoimmunity. Environ Health Perspect 1999; 107 Suppl 5:753 65. 63. Barceloux DG. Nickel. J Toxicol Clin Toxicol 1999; 37: 239-58. 64. Windebank AJ. Chemotherapeutic neuropathy. Curr Opin Neurol 1999; 12: 565-71. 65. Screnci D, McKeage MJ. Platinum neurotoxicity: clinical profiles, experimental models and neuroprotective approaches. J Inorg Biochem 1999; 77: 105-10. 66. Lajer H, Daugaart G. Cisplatin and hypomagnesemia. Cancer Treat Rev 1999; 25: 47-58. 67. A1-Tweigeri T, Magliocco AM, DeCoteau JE Cortical blindness as a manifestation of hypomagnesemia secondary to cisplatin therapy: case report and review of literature. Gynecol Oncol 1999; 72: 120-2. 68. Taha H, Irfan S, Krishnamurthy M. Cisplatin induced reversible bilateral vocal cord paralysis: an undescribed complication of cisplatin. Head Neck 1999; 21: 78-9. 69. Barceloux DG. Selenium. J Toxicol Clin Toxieol 1999; 37: 145-72. 70. Rayman ME The importance of selenium to human health. Lancet 2000; 356: 233-41. 71. Combs GE Chemopreventive mechanism of selenium. Med Klin 1999; 94 Suppl 3: 18-24.

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72. Darouiche RO. Anti-infective efficacy of silvercoated medical prostheses. Clin Infect Dis 1999; 29: 1371-7. 73. Anonymous. Colloidal silver or silver salts-final role: no longer acceptable in over the counter products. WHO Pharm Newslett 1999; 9/12 (Sep-Dec): 1. 74. Chou T-D. Gibran NS, Urdahl K, Lin EY, Heimbach DM, Engrav LH. Methemoglobulinemia secondary to topical silver nitrate therapy--a case report. Bums 1999; 25: 549-52. 75. Parma-Benfenati S, Tinti C, Albrektsson T, Johansson C. Histologic evaluation of guided vertical ridge augmentation around implants in humans. Int J Periodont Restorative Dent 1999; 19: 424-37. 76. Barceloux DG. Zinc. J Toxicol Clin Toxicol 1999; 37: 279-92.

Gijsbert B. van der Voet and Frederik A. de Wolff 77. Abbasi A, Shetty K. Zink: Pathophysiologische Effekte, Mangelzustande und Wirkungen einer Supplementierung bei alteren Personen-ein Forschungsuberblick. Z Gerontol Geriatr 1999; 32 Suppl 1: 175-9. 78. Stefanini M. Cutaneous bleeding related to zinc deficiency in two cases of advanced cancer. Cancer 1999; 86: 866-70. 79. Scirpa P, Scambia G, Masciullo V, Battaglia F, Foti E, Lopez R, Villa P, Malecore M, Mancuso S. Terapia adiuvante con un preparato a base di zinco solfato e acido usnico delle lesioni genitali da Human Papilloma virus (HPV) dopo trattamento chirurgico distruttivo. Minerva Ginecol 1999; 51: 255--60.

R.H.B. Meyboom

23 Deferiprone (SED-14,719; SEDA-21, 249; SEDA-22, 254; SEDA-23, 240) Agranulocytosis is a major concern in the use of the oral iron chelator deferiprone. In 51 children with thalassemia studied in the All India Institute of Medical Sciences some degree of granulocytopenia developed in 12, seven of whom were taking a low dose (50 mg/kg/day) and five a high dose (75 mg/kg/day) (1CR). Four had neutrophil counts well below 1 x 109/1; one developed a serious infection. There was no dose relation. Deferiprone was restarted in 10 of the 12 patients, leading to a relapse of granulocytopenia after 5 months in only one. The mechanism may be different for moderate and severe granulocytopenia. The authors suggested that the high prevalence of granulocytopenia in the Indian study could have been secondary to conditions such as poor transfusion schedules, poor nutritional status, higher serum ferritin concentrations, or genetic factors. On the other hand, in a Lebanese study in 17 patients, mainly with thalassemia major, there were no serious adverse reactions to deferiprone 50-75 mg/kg/day (2CR). Joint pain, stiffness, or swelling occurred in six patients; the symptoms were severe in two and mild in four patients. Seven patients had nausea, especially in the first month of treatment, and two had a reduced appetite. Headache developed in four patients. Mouth ulcers, sore throat, bitter taste, and fatigue occurred in single cases. In one patient there was a weakly positive ANF after 6 months. There were no cases of granulocytopenia and in none of the patients did adverse effects require drug withdrawal. The authors suggested that environmental or hereditary factors might have influenced the results. 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24

Metal antagonists Deferoxamine

(SED-14, 714; SEDA-21, 248; SEDA-22, 254; SEDA-23, 240) Withholding iron is an important protection strategy of the body against microbial and neoplastic cells, and cellular iron depletion plays a prominent role in cell-mediated immune defence (3R). Siderophoric drugs, such as deferoxamine, are likely to play a role in future therapeutic regimens to enhance the ironwithholding defence system. Sensory systems Acute loss of visual acuity has been described after a single test dose of deferoxamine (4Ar). A 58-year-old patient with proliferative glomerulonephritis suddenly suffered loss of visual acuity (320/200 in both eyes) and disturbance of colour vision 2 hours after hemodialysis, during which deferoxamine 10 mg/kg had been given, as a test for aluminium storage. Computerized campimetry showed bilateral central scotomata. Recovery was good but slow: within 3 months visual acuity had increased to 20/30, but bilateral pigmentary macular changes persisted. In a study in China, electroretinographic responses and dark adaptation visual thresholds showed subtle but significant retinal dysfunction in elderly chronically transfused patients with thalassemia receiving deferoxamine (5cr). The authors concluded that the findings suggested that iron accumulation and not deferoxamine toxicity played a major role in these patients.

Hematologic Deferoxamine may have a beneficial effect on impaired erythropoiesis (SED14, 716). In 11 hemodialysis patients who also received recombinant human erythropoietin for anemia secondary to renal failure, deferoxamine increased the proliferation of erythroid precursor cells and had a synergistic in vivo effect on erythropoietin (6CR).

J.K. Aronson, ed. 9Jq~

266

Penicillamine (SED-14, 723; SEDA-21, 251; SEDA-22, 256; SEDA-23, 242) Some 10 years ago, a more aggressive "sawtooth" strategy (early continual serial use) for the treatment of rheumatoid with disease modifying drugs (DMARDs) was advocated (SEDA19, 229). There is now evidence that DMARDs, when carefully monitored, are both less toxic and less effective than previously thought (7CR). Apparently the sawtooth strategy has not changed the balance of benefit and risk of these drugs. No single DMARD or combination of DMARDs stood out favorably with respect to efficacy, toxicity, or survival. Ineffectiveness rather than toxicity was the main reason for drug withdrawal. A Canadian study has added to the evidence that the long-term results of treatment with DMARDs, such as peuicillamine and gold, are disappointing, as well as in patients treated early in the course of their disease (8CR). After 3 years, only 30% were still taking penicillamine. After 6 years only 20% of these had not been withdrawn, with no substantial differences between the drugs. Since the recognition of the superior effectiveness of methotrexate and the publications of the Pediatric Rheumatology Collaborative Study Group, penicillamine has been used infrequently in juvenile rheumatoid arthritis. The maximum dally dose is about 10 mg/kg (750 mg/day) (9R). This dosage is reached in three equal steps, each of 6-8 weeks duration. Perhaps more than gold, penicillamine acts slowly, taking 9 months to 3 years for maximum effectiveness. In a comparison of high doses (750-1000 mg/day) and low doses (125 mg every other day) of penicillamine in the treatment of early diffuse systemic sclerosis, there were no differences in efficacy (10or). However, 16 of the 20 adverse event-related withdrawals were in the high-dose group. Seven of the 34 patients in the high-dose group had proteinuria (over 1 g/day) compared with only one of the 32 patients in the low-dose group. On the other hand, and in accordance with previous experience (SED-14, 723), other recorded adverse reactions, including myasthenia gravis, flu-like illness, thrombocytopenia, stomatitis, and rash, were only slightly more common in the high-dose group.

Hematologic In children with Wilson's disease the importance of early diagnosis has been

Chapter23

R.H.B.Meyboom

emphasized (llCR). Many children have no symptoms or non-specific ones, and Wilson's disease needs to be considered in any child with unexplained persistent liver enzyme abnormalities. In all but one (who required liver transplantation) of 26 children who were treated with penicillamine 20 mg/kg/day, there were fewer adverse reactions than expected: two patients developed a rash, one patient had to stop taking the drug because of a lupus-like syndrome, and another had thrombocytopenia, which resolved after treatment with preduisone. Thrombocytopenia and anemia occurring simultaneously in the same patient have been attributed to penicillamine (12Ar). A 66-year-old woman had taken penicillamine 200 mg/day for 8 months for long-standing systemic sclerosis, together with erythromycin (800 rag/day) for prophylaxis of pulmonary infection. Her platelet count was 39 x 1012/1 and her hemoglobin concentration 7.3 g/dl. The leukocyte count was 3 • 109/1 with a normal differential count. There was no hemolysis. A bone-marrow aspirate showed mild hypoplasia and reduced megakaryopoiesis. Incubation with penicillamine produced inhibition of erythroid and megokaryocyte burst-forming units, but not of granulocyte/macrophage colony-forming units, suggesting a selective effect of penicillamine on erythropoiesis and megakaryopoiesis. The blood cell counts recovered gradually on withdrawal of both penicillamine and erythromycin, treatment with corticosteroids, and a blood transfusion. The authors did not make reference to the effects of incubating the bone-marrow with erythromycin. Urinary tract In a comparison of high doses (750-1000 mg/day) and low doses (125 mg every other day) of penicillamine in the treatment of early diffuse systemic sclerosis, seven of the 34 patients in the high-dose group had proteinuria (over 1 g/day) compared with only one of the 32 in the low-dose group (10c). Rheumatoid arthritis is a risk factor for renal disease, and the distinction from adverse drug reactions may be difficult in these patients (SED-14, 729). Of 44 patients with rheumatoid arthritis, 24 had proteinuria (13CR). Two of these had drug-related nephropathy (penicillamine and gold respectively); both had nonselective tubuloglomerular proteinuria, type V. Penicillamine nephropathy characteristically consists of minimal change glomeronephritis, leading to the nephrotic syndrome, and it has a

Metal antagonists

Chapter23

favorable prognosis (SED-14, 728). Three case reports from Belgium and France have illustrated the fact that rarely proliferative crescent forming extracapiUary glomerulonephritis and renal insufficiency can also occur (14 At, 15Ar). All three patients had taken penicillamine for systemic sclerosis. Antimyeloperoxidase antineutrophil cytoplasm antibodies were found in all three; one patient also had alveolar hemorrhage (i.e. Goodpasture's syndrome). Skin Although it is usually rapidly reversible, penicillamine-induced pemphigus can run a protracted course (SED-14, 730). In a report from the Netherlands, penicillamine-related pemphigus foliaceus was highly resistant to treatment for 7 years (16At). Eventually the intravenous administration of low doses of normal human immunoglobulin (40 mg/kg/day for 5 days in cycles of 3 weeks), together with dexamethasone pulse therapy, led to a remission. Another case of the rare penicillamineinduced elastosis perforans serpiginosa-like skin eruption (SED-14, 730) has been described (17At). The patient was a 37-year-old Japanese woman, who was taking penicillamine (500 mg/day) for systemic sclerosis. She had papules distributed in characteristic arcuate patterns of the skin of her neck. Histologically there was transepidermal elimination of degenerative elastic particles.

267 described the selection of T cell clones specific for the e (rather than the ct or F) subunit, responding to peptide e201-219 (20A). They were restricted to HLA-DR52a (a member of the strongly predisposing HLA A1-B8-DR3 haplotype). Since these T cells had a pathogenic Thl phenotype with the potential to induce complement-activating antibodies, they could be important targets for selective immunotherapy. In another patient penicillamine-related myasthenia gravis developed simultaneously with polymyositis and pemphigus (21 At) (see below). Immunologic The National Taiwan University Hospital has reported successful desensitization with prednisolone in a patient with hypersensitivity to penicillamine (22Ar). A 14-year-old boy with Wilson's disease had a rash, fever, and angio-edema repeatedly after the administration of penicillamine (600 mg/day). He was given prednisolone 30 mg/day for 2 days and then 20 mg/day. He was given penicillamine in an initial dose of 300 mg/day, which was increased to 600 mg/day in increments of 150 mg over 3 days and subsequently to 900 mg/day. Prednisolone was gradually discontinued over a 4 weeks interval, and penicillamine was increased to 1.2 g/day without further problems.

The remarkable potency of penicillamine to induce multiple organ autoimmune reactions was apparent in a patient in whom pemphigus, polymyositis, and myasthenia gravis developed Musculoskeletal Progressive eosinophilic simultaneously (21Ar). fasciitis with muscular involvement in a 35A 67-year-old patient with rheumatoid arthritis year-old Brazilian woman has been attributed had taken penicillamine 600 mg/day for 15 months to penicillamine (250 mg/day) (18At). when a skin emption developed. Although no interPenicillamine-related ocular myasthenia cellular substance or basement membrane antibodgravis has been reported (19At). ies were found, a biopsy showed characteristic intraepidermal blistering. Direct immunofluorescence A 68-year-old woman, with HLA type DRI+, showed anti-IgG and anti-C3 antibodies, and deshad been taking penicillamine (dose not specified) mogleine immunolabelling (32-2B) favored druginduced pemphigus. In addition, acetylcholine refor 9 months for erosive seropositive rheumatoid arthritis. T cell clones were highly specific for D- ceptor antibodies were found. After the withdrawal of penicillamine, but not for L-penicillamine or D- penicillamine there was rapid improvement of pemcysteine, and were restricted to HLA DR1. They phigus and myasthenia. However, polymyositis was responded well to blood mononuclear cells prepulsed progressive, required high doses of corticosteroids with D-penicillamine but not to autologous B cell for about 18 months, and improved only slowly. lines pulsed with D-penicillamine. Apparently penicillamine can couple directly to distinctive peptides resident in surface DR1 molecules on circulating macrophages or dendritic cells. In another article, apparently concerning the same patient, the same group

Tiopronin

(SED-14, 737; SEDA-23, 245)

Tiopronin, also a sulfhydryl-containing compound, has an adverse reactions profile remarkably similar to that of penicillamine and

268 has occasionally been described as a cause of

polymyositis (SED-14, 738). A further case has been described in detail (23At). A 62-year-old woman with rheumatoid arthritis, hypothyroidism, and hypertension, treated for 6 years with tiopronin (dosage not specified), developed severe polymyositis. She had dysphagia and muscle weakness and pain in all limbs; there were no skin abnormalities. Her creatine kinase activity was 12 000 u/l (reference range 25-160) and her LDH 23 000 u/1 (240--480). Her C-reactive protein was 58 mg/l and the erythrocyte sedimentation rate 42

Chapter 23

R.H.B.Meyboom

mm (both raised). Electromyography of her proximal and distal muscles showed pseudomyotonic fibrillations. A biopsy of the deltoid muscle showed necrosis of muscle fibers and interstitial mononuclear infiltrates. There was no evidence of a paraneoplastic syndrome. Tests for toxoplasmosis, trichinosis, picornavirus, H1V, and hepatitis A, B, and C were negative, and there were no autoantibodies (anti-Jo, anti-KU, anti-PM/SCL, anti-DNA, anti-SSA, anti-SSB, antiECT, antithyroid, rheumatoid factor, cryoglobulins), although ANF was positive on one occasion (1/100). Tiopronin was withdrawn, she was given corticosteroids and methotrexate, and made a good recovery.

REFERENCES 1. Pati HP, Choudhry VP. Deferiprone (LI) associated neutropenia in beta thalassemia major: an Indian experience. Eur J Haematol 1999; 63: 267-8. 2. Taher A, Chamoun FM, Koussa S, Abi Saad M, Khoriaty AI, Neeman R, Mourad FH. Efficacy and side effects of deferiprone (L1) in thalassemia patients not compliant with desferrioxamine. Acta Haematol 1999; 101: 173-7. 3. Weinberg ED. Development of clinical methods of iron deprivation for suppression of neoplastic and infectious diseases. Cancer Invest 1999; 17: 507-13. 4, Sanchez Rodriguez A, Martin Oterino JA, Fidalgo Fernandez MA. Unusual toxicity of deferoxamine. Ann Pharmacother 1999; 33: 5056. 5. Jiang C, Hansen RM, Gee BE, Kurth SS, Fulton A. B Rod and rod mediated function in patients with beta-thalassemia major. Documenta Ophthalmol 1999; 96: 333-45. 6. Aucella E Vigilante M, Scalzulli P, Musto P, Prencipe M, Valente GL, Carotenuto M, Stallone C. Synergistic effect of desferrioxamine and recombinant erythropoietin on erythroid precursor proliferation in chronic renal failure. Nephrol Dial Transplant 1999; 14: 1171-5. 7. Sokka T, Hannonen E Utility of disease modifying antirheumatic drugs in "sawtooth" strategy. A prospective study of early rheumatoid arthritis patients up to 15 years. Ann Rheum Dis 1999; 58: 618-22. 8. Galindo-Rodriguez G, Avin-Zubieta JA, Russell AS, Suare-Almazor ME. Disappointing longterm results with disease modifying antirheumatic drugs. A practice based study. J Rheumatol 1999; 26: 2337-43. 9. Cassidy JT. Medical management of children with juvenile rheumatoid arthritis. Drugs 1999; 58: 831-50. 10. Clements PJ, Furst DE, Kong W-K, Mayes M, White B, Wigley E Weisman MH, Barr W, Morel LW, Medsger TA Jr, Steen V, Martin RW, Collier D, Weinstein A, Lally E, Varga J, Weiner S, An-

drews B, Abeles M, Seibold JR. High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial. Arthritis Rheum 1999; 42: 1194-203. 11. Sanchez-Albisua I, Garde T, Hierro L, Camarena C, Frauca E, De la Vega A, Diaz MC, Larrauri J, Jara P. A high index of suspicion: the key to an early diagnosis of Wilson's disease in childhood. J Pediatr Gastroenterol Nutr 1999; 28: 18690. 12. Katayama Y, Kohriyama K, Matsui T. In vitro inhibition of hematopoiesis in a patient with systemic sclerosis treated with D-penicillamine. J Rheumatol 1999; 26: 2493-5. 13. Niederstadt C, Happ T, Tatsis E, Schnabel A, Steinhoff J. Glomerular and tubular proteinuria as markers of nephropathy in rheumatoid arthritis. Rheumatology 1999; 38: 28-33. 14. Kyndt X, Ducq P, Bridoux F, Reumaux D, Makdassi R, Gheerbrant JD, Vanhille Ph. Extracapillary glomerulonephritis with anti-myeloperoxidase antibodies. Presse Mrd 1999; 28: 67-70. 15. Marlier S, Gisserot O, Yao N, Hecht M, Paris JF, Carli P, Chagnon A. Extracapillary glomerulonephritis in a patient treated with D-penicillamine. Presse Mrd 1999; 28: 689-90. 16. Toth GG, Jonkman ME Successful treatment of recalcitrant penicillamine-induced pemphigus foliaceus by low-dose intravenous immunoglobulins. Br J Dermatol 1999; 141: 583-5. 17. Matsushita A, Hiruma M, Ogawa H, Watanabe S, Saeki T. A case of D-penicillamine-induced elastosis perforans serpiginosa in a woman with systemic sclerosis. Nishinihon J Dermatol 1999; 61: 451-4. 18. Dulcine M, Borges C, Vianna MADAG, Neto EFB. Eosinophilic fasciitis with subclinical myopathy with exacerbated myositis after using the d-penicillamine. Rev Bras Reumatol 1999; 39: 303-6. 19. Hill M, Beeson D, Moss P, Jacobson L, Bond A, Corlett L, Newsom-Davis J, Vincent A, Willcox N. Early-onset myasthenia gravis: a recurring T-cell

Metal antagonists

Chapter 23

epitope in the adult-specific acetylcholine receptor epsilon subunit presented by the susceptibility allele HLA-DR52a. Ann Neurol 1999; 45: 224-31. 20. Hill M, Moss P, Wordsworth P, Newsom-Davis J, Willcox N. T cell responses to D-penicillamine in drug-induced myasthenia gravis: recognition of modified DRl:peptide complexes. J Neuroimmunol 1999; 97: 146-53. 21. Jan V, Callens A, Machet L, Machet MC, Lorette G, Vaillant L. Pemphigus, polymyositis and

269 myasthenia gravis associated with pcnicillaminc treatment. Ann Dermatol Vencreol 1999; 126:153 6. 22. Hsu H-L, Huang F-C, Ni Y-H, Chang M-H. Steroids used to desensitize penicillamine allergy in Wilson disease. Acta Paediatr Taiwan 1999; 40: 448-50. 23. Cacoub P, Sbai A, Azizi P, Gatfosse M, Godeau P, Piette JC. Tiopronine-induced polymyositis. Presse M6d 1999; 28: 911-12.

Pam Magee

24

Antiseptic drugs and disinfectants

BISBIGUANIDES Chlorhexidine (SED-14, 764; SEDA-22, 262; SEDA-23, 247) Musculoskeletal Chondrolysis in the knee has been reported after accidental irrigation of a 1% aqueous chlorhexidine solution during arthroscopy (SEDA-23, 247). Even very dilute solutions of chiorhexidine can cause marked chondrolysis of articular cartilage, leading to severe permanent damage of the knee (lC). A 20-year-old woman, a 30-year-old man, and a 62-year-old woman all had arthroscopic reconstruction of the anterior cruciate ligament performed by the same surgeon. The only difference in technique in these three cases, compared with the rest of his cases, was the use of chlorhexidine 0.02% for irrigation throughout the procedure. All had good immediate postoperative recovery with no sign of infection, and none had preceding rheumatoid or other inflammatory joint disease, systemic disease, or chronic use of drugs. However, they all developed pain, swelling, stiffness, and loud crepitus at 2-4 months after the procedure and had radiological evidence of loss of joint space, especially in the medial compartment. Arthroscopy in all three cases showed a large amount of loose chondral material, a "snowstorm" appearance, which could be washed out. Severe erosion of the articular cartilage and a mild synovitis were also demonstrated. The ligaments were all intact and culture of the synovial fluid was sterile. Histopathology of the fragments of cartilage showed non-viable chondrocytes, with an absence of acute inflammatory cells and very few chronic inflammatory cells. The synovial biopsies showed evidence of fibrosis. All three patients had severely damaged knees which required total knee replacement.

These cases of chondrolysis did not result from accidental use of relatively concentrated solutions of chlorhexidine, but from the use of a very low concentration, 0.02%, which is widely used as an irrigation solution during surgical procedures. Chlorhexidine has a damaging effect on the articular cartilage of the knee, and should not be used, even in low concentrations, to irrigate exposed articular cartilage. Immunologic In 1998 the FDA issued a public health notice to inform healthcare professionals about the potential for serious hypersensitivity reactions to medical devices impregnated with chlorhexidine (SEDA-23, 248). A meta-analysis of the clinical and economic effects of chlorhexidine and silver sulfadiazine antiseptic impregnated catheters has been undertaken (2M). The costs of hypersensitivity reactions were considered as part of the analysis, and the use of catheters impregnated with antiseptics resulted in reduced costs. The analysis used the higher estimated incidence of hypersensitivity reactions occurring in Japan, where the use of chlorhexidine impregnated catheters is still banned (3R). Severe anaphylactic shock continues to be reported with chlorhexidine products (4A). A 64-year-old man had severe anaphylaxis induced by intraurethral chlorhexidine gel 0.05%. Previous hypersensitivity reactions during urethral dilatation had been thought to be due to lidocaine. Chlorhexidine-specific IgE antibodies were demonstrated, and the chlorhexidine gel had been used in all the proceeding urological procedures the patient had undergone. The authors suggested that chlorhexidine anaphylaxis is probably under reported.

9 2001 ElsevierScienceB.V. All fights reserved.

Side Effectsof Drugs, Annual24 J.K. Aronson,ed.

Antiseptic drugs and disinfectants

ETHYLENE OXIDE (SED-14,761; SEDA-21, 254; SEDA-23, 248)

Sensory systems Ethylene oxide is most extensively used for sterilizing heat-sensitive medical supplies. In the sterilization units in which it is widely used the toxicity of ethylene oxide varies according to the degree of exposure (SEDA-21,254). Its major acute health effects are respiratory and neurological disorders and, in cases of high-dose exposure, cataracts. Of 16 hospital sterilization operators who had been exposed to ethylene oxide and underwent medical and ocular examinations, 14 had lens opacities and 12 had abnormal contrast vision (an abnormality that is non-specific to cataracts but which often supports the diagnosis)

(5c).

Mutagenicity While recognized as an animal carcinogen for nearly 20 years the potential of ethylene oxide as a human carcinogen has not been established. The International Agency for Research on Cancer has classified ethylene oxide as category 1 ("carcinogenic in humans"), based primarly on sufficient evidence in animals and genotoxic considerations. An ethylene oxide cancer risk assessment based on epidemiological data showed no increase in leukemia (6c). However, both animal and human studies suggest that the incidence of cancers of the lymphopoietic tissues warrants additional epidemiological follow-up.

IODOPHORS

271

Chapter24

(SED-14, 768;

SEDA-22, 263)

containing antiseptic cream for external use only. She had inserted povidone iodine into the rectum by means of a cannula. The iodine-containing cream was suspended, and a /%blocker prescribed. The palpitation resolved within 2 weeks, and plasma thyroid hormone concentrations normalized within 1 month. Hyperthyroidism in this patient was probably triggered by improper long-term use of an over-the-counter cream. U r i n a r y tract Povidone iodine given by any route can result in systemic absorption of iodine. In two cases of acute renal insufficiency metabolic acidosis may have been a characteristic associated with iodine toxicity (8 A, 9A). A 65-year-old man with second- and third-degree bums covering 26% of his body was given intravenous lactated Ringer solution and topical silver sulfadiazine in addition to debridement and skin grafting. However, he developed a wound infection with Pseudomonas aeruginosa, which was treated successfully with topical povidone iodine gel. Persistent nodal bradycardia with hypotension, metabolic acidosis, and renal insufficiency occurred 16 days later. Iodine toxicosis was suspected and the serum iodine concentration was 206 mg/1 (reference range 20-90 [xg/1). The povidone iodine gel was therefore withdrawn immediately, and hemodialysis was scheduled. However, the patient's family refused hemodialysis and he died 44 days after admission. A 57-year-old man developed renal insufficiency after triple coronary bypass grafting, in association with povidone iodine mediastinal irrigation. The acute renal insufficiency occurred on day 26 (7 days after the povidone iodine irrigation) and required 3 days of renal replacement therapy. Complete resolution occurred within 8 days and followed a short non-oliguric phase (4 days). Although other common causes of acute renal insufficiency were present in this case, the only significant change in this patient's management at the time of onset of renal insufficiency was the use of povidone iodine.

Povidone iodine Endocrine Hypothyroidism has been repor-

PHENOLIC COMPOUNDS

ted with povidone iodine antiseptics (SEDA-20, 226; SEDA-22, 263). Hyperthyroidism is rarer (SEDA-20, 226), but a history of long-term use of iodine-containing medications should be considered when investigating the cause of hyperthyroidism (7A).

(SED-14, 773; SEDA-21, 255; SEDA-22, 264; SEDA-23, 248)

A 48-year-old woman was referred because of palpitation and insomnia. The clinical history, physical examination, and laboratory tests supported hyperthyroidism. Since July 1994 she had been combating constipation by improper use of an iodine-

The use of phenol as an antiseptic is limited by its severe adverse effects. It is still occasionally used as a disinfectant. A phenol solution of 89% was mistakenly sprayed into the nostrils of a 79-year-old man (10A). Immediately, blanching and local erythema developed. It was expected that the patient would develop a significant local bum and possibly systemic toxicity, but

272 neither developed. This may have been due to the amount sprayed or the relatively small body surface area covered by the phenol. The New Zealand Ministry of Health has issued a public statement concerning the safety of phenol solutions after the death of a patient from a cardiac dysrhythmia that was possibly associated with the use of a chemical face peeling solution containing phenol (11A). This product appears to be marketed under two brand names: Exoderm | and Exoderm Lift | It is manufactured in Israel and is distributed to dermatologists and plastic surgeons. Exoderm | is not approved as a medicine in New Zealand or Israel.

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Pam Magee

Phenol-containing face-peeling solutions are regarded as medicines in New Zealand. The safety and efficacy profile of these products has not been assessed, and the Minister has not given consent to the distribution of Exoderm | or any other phenol-containing face-peeling solutions. In view of the Ministry's concerns about the safety of these products, the Medicines Safety Division has recommended that practitioners should not use phenol-containing face-peeling solutions and should check the legal status of any similar product that they may want to use. They should also be aware that they are required to inform patients fully of the risks and benefits of any proposed treatment.

REFERENCES 1. Van Huyssteen AL, Bracey DJ. Chlorhexidine and chondrolysis in the knee. J Bone Jt Surg Ser B 1999; 81: 995-6. 2. Veenstra DL, Saint S, Sullivan SD. Costeffectiveness of antiseptic-impregnated central venous catheters for the prevention of catheterrelated bloodstream infection. J Am Med Assoc 1999; 282: 554-60. 3. Raad I, Hanna H. Intravascular catheters impregnated with antimicrobial agents: a milestone in the prevention of bloodstream infections. Supportive Care Cancer 1999; 7: 386-90. 4. Wicki J, Deluze C, Cirafici L, Desmules J. Anaphylactic shock induced by intraurethral use of chlorhexidine. Allergy Eur J Allergy Clin Immunol 1999; 54: 768-9. 5. Sobaszek A, Hache JC, Frimat P, Akakpo V, Victoire G, Furon D. Working conditions and health effects of ethylene oxide exposure at hospital sterilization sites. J Occup Environ Med 1999; 41: 492-9. 6. Teta M J, Sielken RL Jr, Valdez-Flores C. Ethylene oxide cancer risk assessment based on epidemi-

ological data: application of revised regulatory guidelines. Risk Anal 1999; 19: 1135-55. 7. Pagliaricci S, Lupattelli G, Mannarino E. An unusual case of iodine-induced hyperthyroidism. Ann Ital Med Intern 1999; 14: 124--6. 8. Aiba M, Ninomiya J, Furuya K, Arai H, Ishikawa H, Asaumi S, Takagi A, Ohwada S, Morishita Y. Induction of a critical elevation of povidoneiodine absorption in the treatment of a burn patient: report of a case. Surg Today 1999; 29: 157-9. 9. Ryan M, A1-Sammak Z, Phelan D. Povidoneiodine mediastinal irrigation: a case of acute renal failure. J Cardiothorac Vasc Anesth 1999 13: 72931. 10. Durback-Morris LF, Scharman El. Accidental intranasal administration of phenol. Vet Hum Toxicol 1999; 41: 157. 11. Geddes AD, D'Souza SM, Ebetino FH, Ibbotson KJ. Bisphosphonates: structure-activity relationships and therapeutic implications. In: Heersche JNM, Kanis JA, editors. Bone and Mineral Research, Amsterdam, the Netherlands: Elsevier Science, 1994: 265-74.

T. Midtvedt

25

Penicillins, cephalosporins, other/3-1actam antibiotics, and tetracyclines

Antibiotic resistance As we enter a new millennium, it is of interest to look back through the scientific and therapeutic mirrors. As mentioned before (SEDA-23, 250) the 20th century can be characterized as the century of antibiotics. Taking a glance in the mirror, it is salutary that many of the principles underlying the prudent use of antimicrobials (the term antibiotic was introduced into medicine by the Nobel laureate Selman Waksman in around 1940) were proposed at the beginning of the century. I shall cite some statements made by another Nobel Laureate, Paul Ehrlich (1R ).

Targets "Parasites possess a whole series of chemoreceptors which are specifically different from one another. If we can succeed in discovering among them a grouping which has no analogue in the organs o f the body, then we should have the possibility of constructing an ideal remedy". It is a well-established fact that ~-lactams fulfil these criteria and thereby also Ehrlich's dream: " L e t us hope that it will be possible chemotherapeutically to hit the bull's eye . . . ". Stumbling stones

" .. in men exist idiosyncrasies, forms of supersensitiveness". Allergic reactions after antibiotics are certainly too common (SEDA-23, 251). "... the destroyed bodies of bacteria which may occur in sterilized water are capable of bringing about a series of serious and unpleasant phenomena".

Endotoxins are still of major concern in antimicrobial therapy. Development o f resistance "... parasites which are settled in dead corners of the organism are not reached by the medicine... ". "... possible explanation of the deficient sterilization, that among the large number of parasites there may be some which are unaffected by certain drugs, thus resisting sterilization". We should have learned by now that microbes strike back. The path to success "... it is in my opinion necessary to allow the therapeutic treatment to come into action as early as possible ". "... the most important questions are dosology, indications and contraindications". Nowadays we are paying an exorbitant price for having neglected most of these simple basic principles. As I have stated several times before in these volumes, steadily increasing resistance to more and more antimicrobials among more and more microbial species is their most important adverse effect. Therefore--as outlined before in greater detail (SEDA-23, 250)--we need a shift in paradigm: we have to look on microbes not as enemies but as friends. Nowadays we have molecular methods to unmask the steady cross-talk between our own cells and the microbial world--whether they are there as friends or enemies. By listening to this cross-talk we shall be able to survive in the microbial world as well as "hit the bull's-eye "far more precisely than before.

9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed. 97q

274

Postmarketing surveillance for reporting adverse effects~ friend or foe? Spontaneous reporting of suspected adverse drug reactions has formed the key element of postmarketing surveillance in many countries for several decades. Over the years, this approach has identified a number of unexpected adverse drug reactions and has assisted in raising awareness. Consequently, it has achieved a high degree of acceptance among drug agencies and doctors. Why then be worried? Simply put, it is more and more clear that a postmarketing surveillance system based on spontaneous reports of suspected adverse drug reactions certainly does not represent "the truth, the whole truth, and nothing but the truth". The value of such systems has recently been challenged by several authors (2R-4R ), and I shall comment on one of these articles (4 R) in some detail. Flucloxacillin, an isoxazolyl penicillin to be used against staphylococci, has been widely used in many countries. Reports from some countries, especially Australia, have suggested the likelihood of an unacceptable risk of flucloxacillin-associated jaundice (5R ; SEDA22, 266). Countries with an apparently similar use of the drug, such as New Zealand and the UK, had insufficient data to confirm or refute this proposition, whereas data from Sweden supported the risk associated with flucloxacillin (61~). There were 2.9 per million cases of possible drug-induced jaundice with flucloxacillin, compared with 1.6 for dicloxacillin and cloxacillin. The severity and frequency of cholestatic hepatitis after the use of flucloxacillin made a strong case for regulatory action in some countries. Some of the Australian reactions are outlined in (4R ). Based on the mere fact that there are major differences in the reports from different countries, the authors reviewed current spontaneous postmarketing reporting systems in some detail. They discussed their strengths and weaknesses and stated that "despite the many successes attributed to these schemes, they can reliably detect only a small fraction of the range of possible drug-related events and provide virtually no useful quantitative data". They advocated

Chapter 25

T. Midtvedt

that "spontaneous monitoring should be supplemented by the systematic monitoring of users of cohorts of new drugs, using record linkage to track their subsequent health". It goes without saying that these statements were challenged in letters to the journal. In one letter valuable, new information on the flucloxacillin~licloxacillin story was given (7r). In 1997-98, flucloxacillin was prescribed about three times more often than dicloxacillin, but the number of reports to the Adverse Drug Reactions Advisory Committee was nearly the same (138 vs 127 reports for flucloxacilln and dicloxacillin respectively). However, hepatic reactions were reported about three times more often for flucloxacillin than for dicloxacillin (55 vs 17 reports respectively). These data can be interpreted in several ways. In their comments, McNeil and coworkers (8r) stated that "spontaneous monitoring schemes alone may provide an illusion of diligent safety monitoring. Unless they are supplemented by more rigorous methods, we will continue to risk missing some important adverse reactions and raising false alarms of others". It seems reasonable to assume that the debate on the relative hepatotoxicity of flucloxacillin and dicloxacillin, and on the relative values of various postmarketing surveillance systems, will continue. In the meantime, liver function should be closely monitored in patients taking antimicrobials.

Antibiotics, the pill, and pregnancy In a previous review I focused on male fertility and antibiotics (SEDA-16, 262). Here I shall focus on antimicrobials and the effects of oral contraceptives. Over the years this has been a matter of some concern and the problem can be considerable. Worldwide, hundreds of millions of women take oral contraceptives, and the number of women who take antimicrobials is certainly not smaller. As early as 1971 it was observed that there was an increased incidence of intermenstrual bleeding in women who were reliably taking oral contraceptives and rifampicin for tuberculosis (9c). Subsequent studies showed that pregnancy was a possible adverse effect of the combined use of antibiotics and oral contraceptives, the most commonly involved antimicrobial drugs being ampicillin, co-trimoxazole,

Penicillins, cephalosporins, other fl-lactam antibiotics, and tetracyclines and tetracyclines (1OR). In an analysis based on reports to the Committee on Safety of Medicines in the UK between 1968 and 1984, 63 pregnancies were identified in women taking this combination of drugs (l lR ). Tetracyclines and penicillin were the drugs most often involved. However, the question of under-reporting was underlined. Over the years, a few reports have appeared describing the possibility of ineffectiveness of oral contraceptives during the use of antimicrobial drugs. A typical example is that of a healthy 21-year-old woman, using an oral contraceptive, who became pregnant while taking minocycline 1O0 mg/day for acne (12 A ). How can that happen ? From a theoretical point of view, at least three different mechanisms have to be taken into consideration. 1. Antibiotics, for example rifampicin (SEDA8, 256), may interfere with the hepatic metabolism of the compounds in oral contraceptives. 2. Antibiotics may increase gastric emptying and small intestinal motility. This in turn may alter gastrointestinal absorption (and reabsorption) of oral contraceptives (probably both estrogens and progestogens). Increased gastrointestinal motility has been best studied in the macrolide group (SEDA18, 269). However, I am not aware of any evidence of reduced efficacy of oral contraceptives through an effect of macrolides on gastrointestinal motility, which is in any case an unlikely mechanism. 3. Antibiotics may interfere with the normal flora in the gastrointestinal tract, thereby also interfering with the normal enterohepatic circulation of the compounds that are included in oral contraceptives, This is a complex story. Oral contraceptives contain estrogens and progestogens. There are several different derivatives in each group and the amounts of each compound vary from formulation to formulation. However, most (if not all) of the compounds have an enterohepatic circulation--they are excreted into the bile, usually as conjugates, and are reabsorbed from the intestinal tract. The efficacy of their absorption and reabsorption depends on physicochemical factors in the gut (such as pH, conjugated versus unconjugated compounds, and adsorption to microbes and dietary constituents). In addition to this basic physiological circulation,

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intestinal microbes interact with the compounds, most often by splitting conjugates, but also by acting on double bonds, hydroxyl groups, and keto groups, present in the original compounds. These derivatives may have different absorption rates from the original ones. Partly because of their complexity, these microbial interactions have been very little studied. However, it is well known that microbes interfere with the enterohepatic circulation of other molecules with similar structures, such as androgens (SEDA-13, 215; SEDA-16, 262) and bile acids (13r). A similar effect can take place in patients with gastrointestinal bacterial infections. In addition, and at least from a theoretical point of view, an effect on this enterohepatic circulation may also occur in individuals with a high load of living microbes, as is the case when ingesting probiotics (products that contain live bacteria such as Bifidobacterium and Lactobacillus). To the best of my knowledge, this possibility has not been adequately addressed by any of the companies that sell tons of probiotics to fertile women taking oral contraceptives. Given the problems of under-reporting, the lack of proper investigations, and the possibility of an unwanted pregnancy, the concern can be reduced to a practical one: what should women be told? An excellent recommendation was recently published in the UK (14R ): "Your doctor has prescribed antibiotics which are necessary to treat [your] infection. However, the antibiotics can interfere with the pill and make it less effective. This means that you may not be protected from pregnancy if you have sex, even though you are taking the pill. You are advised that you should take precautions, that is use of a condom, during the time you are taking the antibiotics, and for 7 days after completing the course of antibiotics... ". For the time being, this might be the best advice. However, more investigations in this important field are needed.

Chapter 25

276 PENICILLINS (SED-14, 810; SEDA-21, 259; SEDA-22, 266; SEDA-23; 252)

Co-amoxiclav Hepatotoxic reactions in patients taking coamoxiclav continue to be reported (15 C, 16A 19 A) and it is reasonably well established that it is clavulanic acid rather than amoxicillin that is responsible for this high incidence. The importance of HLA antigens in the pathogenesis of some liver diseases (autoimmune hepatitis, primary biliary cirrhosis, primary cholangitis) is also reasonably well established (20R). This was the background to a recent study in which 35 patients with biopsy-documented liver damage due to co-amoxiclav and 300 controls (volunteer bone-marrow doors) were investigated for HLA class antigens (21c). HLA-A and HLA-B were typed using alloantisera and HLA-DBR and HLA-DWB were typed by PCR. The patients with hepatitis were characterized by a higher frequency of DRB 1" 1501*DRB5-DRB5*0101-DQB 1"0602 haplotype (57% vs 12% in controls). Patients with that haplotype tended to have a cholestatic rather than a hepatocellular type of hepatitis. However, these data also suggest that other factors must act concurrently. These factors may involve heterogeneity of the formed antigens and/or polymorphism of the T call receptor. A reaction to (unknown) metabolites of clavulanic acid also has to be kept in mind. The authors suggested that "metabolic factors may play a greater role in the pathogenesis of hepatocellular cases, whereas immunological factors may be more involved in the pathogenesis of cholestatic ones". The importance of taking a careful history in patients in whom drug-related hepatitis is suspected has recently been underlined (22R). It seems reasonable to assume that HLA characterization will be implemented in a future diagnostic armamentarium. It goes without saying that "a high index of suspicion should be maintained for any drug taken by a patient with evidence of liver injuries, as failure to recognize and subsequently discontinue the offending agent is associated with a high risk of liver damage persisting even after the drug is eventually stopped".

T. Midtvedt

Flucloxacillin Hepatitis after the use of flucloxacillin is a matter of some concern, especially in Australia, where it has been reported with a frequency varying from 1:10000 to 1:100000 prescriptions. A recent report has focused on a possible future problem: chronic hepatitis in patients with a history of flucloxacillin-induced hepatitis (23A). A 55-year-old woman with psoriasis was treated with oral 5-methoxypsoralen and UVA photochemotherapy. After 40 treatments over 5 months she became unwell and complained of headaches, nausea, and abdominal pain. Laboratory tests confirmed a diagnosis of hepatitis. Six years earlier she had had flucloxacillin-induced hepatitis. Hepatitis after 5-methoxypsoralen is supposed to be very rare, and the authors gave only one reference, although there have been several more reports after the use of 8methoxypsoralen. Without discussing possible mechanisms underlying this difference, it might be wise to remember that a previous history of drug-induced hepatitis should be a reminder of the need to consider hepatotoxic reactions in any patient who develops unexplained symptoms while using another drug.

Piperacillin Hematologic Hemolytic anemia is a wellrecognized complication of penicillin therapy, and has been related to several derivatives. That any derivative can cause this adverse effect is emphasized by the following case (24A). A 34-year-old woman with cystic fibrosis took piperacillin 6 g tds for respiratory distress. She had no known allergies, although she had previously had pruritus while taking ceftazidime and tingling in her hands with azlocillin. She had completed courses of amoxicillin and flucloaxcillin without adverse effects. After about 2 weeks she complained of headache and nausea and passed pink mine. A diagnosis of hemolytic anemia was established and piperacillin was withdrawn. She was given a blood transfusion, prednisone, and folic acid, with good effect. A panel of antibiotics, including piperacillin, tazobactam, azlocillin, ticarcillin, temocillin, flucloxacillin, imipenem, meropenem, aztreonam, cefuroxime, ceftazidime, chloramphenicol, gentamicin, and colistin, were incu-

Penicillins, cephalosporins, other fl-lactam antibiotics, and tetracyclines bated with this patient's serum. Of these drugs, only piperacillin and pipercillin/tazobactam caused agglutination in an indirect agglutination test. The authors concluded that her hemolytic anemia had been caused by the piperacillin.

CEPHALOSPORINS

(SED-14, 821; SEDA-21, 260; SEDA-22, 267; SEDA-23, 254)

Cefotetan Cefotetan-induced hemolytic anemia has been discussed in a review of 35 cases, eight of which were discussed in greater detail (25R). All eight cases were associated with the prophylactic use of cefotetan in gynecological or obstetric procedures. The patients had received 1-4 doses of cefotetan, and they left hospital in good shape, but all were readmitted with hemolytic anemia within 2 weeks after the last dose. All needed several blood transfusions and two underwent plasmapheresis twice. They all survived, but the authors underlined the seriousness of this adverse effect. Of 43 cases of drug-induced hemolytic anemia that had been referred to their laboratory in the previous 8 years, 35 had been caused by cefotetan and three by ceftriaxone; 11 had a fatal outcome, eight and three caused by cefotetan and ceftriaxone respectively.

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type cephalosporins, i.e. they had a common structural formula at the C7 position on 7aminocephalosporinic acid. This antibody did not show any cross-reactivity with five kinds of penicillins (ampicillin, aspoxicillin, carbenicillin, piperacillin, sulbenicillin). The authors asked a difficult question: why did anaphylactic shock accompany acute hemolysis? Their answer was that the complex of ceftizoxime with IgM anticeftizoxime might act like anti-A or anti-B. This hypothesis will surely be further tested. In the meantime, it would be wise not to use the newer cephalosporins too freely.

Ceftriaxone Hematological Ceflriaxone has previously been associated with several cases of hemolytic anemia, sometimes fatal (SEDA-23, 255), and new reports continue to appear (27 A, 28A). A 38-year-old man with no known disease rapidly developed disturbed consciousness 4 days after having taken co-amoxiclav for sinusitis. On admission, he was given intravenous ceftriaxone 2 g bd for purulent meningitis. On the tenth day of therapy, he developed icterus and hemolytic anemia. Despite vigorous resuscitative efforts, he died with evidence of multiple organ failure on day 5. A 48-year-old women who had been given ceftriaxone 2 g/day intravenously for 7 days for Lyme disease developed severe hemolytic anemia. She had previously been given ceftriaxone twice without any adverse effects. An immune complex mechanism was suggested.

Ceftizoxime Ceftizoxime is one of the latest cephalosporins on the market, but the first case of hemolytic anemia has already occurred (26c). A 76-year-old Japanese man, who had been given 23 courses of intravenous antibiotic therapy over 2 years for chronic bronchitis, was given intravenous ceflizoxime 1 g/day. He developed anaphylactic shock and hemolysis. Despite very extensive therapy he died 2 weeks later. The patient's serum was tested for antibodies against five penicillins and 30 different cephems (i.e. all types of cephalosporins), using protocols to detect drug adsorption as well as immune-complex mechanisms. His serum contained an IgM antibody that formed immune complexes with 10 of the 30 cephems. The 10 drugs were classified as oxime-

In previous cases of hemolytic anemia associated with ceftriaxone, the effector antigen has been ceftriaxone itself. However, a case has been reported in which the causative antibodies appeared to be stimulated solely by a degradation product of ceftriaxone (29A). A 16-year-old girl with craniofacial dysplasia was given ceftriaxone 4 g/day for pneumococcal meningitis. On the seventh day of therapy she developed neck muscle spasms, dizziness, and tachypnea immediately after the administration of ceftriaxone. On the next day the same symptoms occurred about 30 minutes after the end of the infusion of ceftriaxone. Her plasma was red and her hemoglobin had fallen to 2.4 g/dl. A direct antiglobulin test was positive only for C3d and no ceftriaxone-dependent antibodies were detected. Her serum reacted strongly with erythrocytes in the presence of ex vivo antigen related to ceflriaxone (urine samples from patients receiving ceftriaxone). All therapeutic attempts were

Chapter 25

278 unsuccessful and she developed renal insufficiency and died. The authors concluded that this was the first reported case in which the causative an-

tibodies appeared to be stimulated solely by a degradation product of ceftriaxone. Unfortunately, they were not able to characterize the degradation products. They ended their report by advising that degradation products should be taken into account in all suspected cases of drug-dependent hemocytopenia in which the antibody remains undetectable.

TETRACYCLINES (SED-14, 906; SEDA-20, 261; SEDA-22, 268; SEDA-23, 255)

Therapeutic effects of tetracyclines on microbes or enzymes As I briefly commented last year, tetracyclines have many effects on cells involved in inflammatory reactions. Here I shall comment on the effects of tetracyclines on periodontal disease, rheumatoid arthritis, and acne. Periodontal disease Periodontal disease is caused by micro-organisms, but host responses are in large part responsible for destruction of the periodontal support structures. In these patients pathological activity of host-derived matrix metalloproteinases occurs in response to the bacterial infection in the periodontal tissues, causing destruction of collagen, the primary structural component of periodontal matrix. This in turn leads to gingival recession, pocket formation, and increased tooth mobility. The final outcome is loss of the tooth. Tetracyclines inhibit collagenolytic activity in gingival tissue (SEDA-23, 256; 30 R, 31 R, 32c). Based on these findings, a large clinical development program was initiated to demonstrate the potential of a subantimicrobial dose of doxycycline to augment and maintain the beneficial effects afforded by conventional nonsurgical periodontal therapy in adult periodontitis. A summary of these studies has recently been published (33R ). A number of different dosage regimens and placebo were compared in patients who had had a variety of adjunctive non-surgical procedures. Of the various para-

T. Midtvedt

meters studied the following are worthy of mention: collagenase activity in gingival crevicular fluid and gingival specimens, so-called clinical attachment levels, probing pockets depths, bleeding on probing, and subtraction radiographic measurements of alveolar bone height. Subantimicrobial doses of doxycycline reduced collagenase activity in both gingival crevicular fluid and gingival biopsies, augmented and maintained gains in clinical attachment levels and reductions in pockets depths, reduced bleeding on probing, and prevented loss of alveolar bone height. These clinical effects occurred in the absence of any significant effects on the subgingival microflora and without evidence of an increase in the incidence or severity of adverse reactions relative to the controls. The authors proposed that the main mechanism underlying these effects is inhibition of pathologically high matrix metalloproteinase activity in neutrophils (MMP-8) and bone cells (MMP-13). Rheumatoid arthritis Two perspectives on the use of tetracyclines in rheumatoid arthritis have recently been published (34 R, 35R). The mechanisms by which tetracyclines have their therapeutic effects in rheumatoid arthritis are far from well defined. Tetracyclines have a large variety of effects in mammalian cells, and it is likely that it is a combination of such discrete actions that contribute to their overall therapeutic effects in rheumatoid arthritis. In addition to an effect on matrix metalloproteinases, the authors focused on a potential antiarthritic action of tetracyclines by their effects in the interaction between the generation of nitric oxide, matrix metalloproteinase release, and chondrocyte apoptosis. Recent data suggest that both minocycline and doxycycline inhibit the production of nitric oxide from human cartilage and murine macrophages (36 E) in concentrations that are achieved in vivo. The authors suggested that tetracyclines may have several potential chondroprotective effects---direct inhibition of matrix metalloproteinase activity and, by inhibition of nitric oxide production, further reduction of matrix metalloproteinase activity, reversal of reduced matrix synthesis, and reduced chondrocyte apoptosis. Over the years, there have been several proposals for long-term antibacterial treatment of rheumatoid arthritis (SEDA-23, 255). With current knowledge in mind, a reasonable sum-

Penicillins, cephalosporins, other fl-lactam antibiotics, and tetracyclines ming up is that the observations were right but the explanations wrong. Most probably the therapeutic effects of tetracyclines in rheumatoid arthritis are not mediated by their antimicrobial effects, but by their discrete effects on mammalian cells and function. It is to be hoped that new tetracyclines with refined antiinflammatory and enzyme inhibitory (and reduced antimicrobial) effects will be marketed. They are already in experimental laboratories (37r). It will certainly not be the first time that potential adverse effects will have become useful ones. Ache Over the years, various tetracyclines have been used in the treatment of acne, but it has never been possible to link their therapeutic effects definitively with an effect on the microbes found in sebaceous glands. It is tempting to speculate that the tetracyclines have their beneficial effect not (only) on the microbes, but on the tissues of the sebaceous glands. If that is so, the new tetracyclines mentioned above will have another market, reducing the use of real antibiotics.

Gastrointestinal Tetracycline-induced esophageal damage is a well-known adverse effect in adults (SEDA-23, 256). In three previous studies of more than 600 children with chest pain, none had tetracycline-induced esophagitis as a cause of their pain (38c-40c). However, two reports of esophagitis in children have been reported (41A). A 12-year-old boy developed lower chest pain, having taken doxycycline for 7 days for presumed epididymitis. He had a normal chest X-ray and electrocardiogram and no signs of infection. Doxycycline was withdrawn, but the chest pain persisted. After 4 days endoscopy showed two very large ulcerated craters measuring about 5 x 12 mm in the distal esophagus. A 15-year-old gid developed chest pain and difficulty in swallowing after having taken five doses of doxycycline. Physical examination was normal and she had a normal chest X-ray and electrocardiogram. Doxycycline was withdrawn and she was given sucralfate 10 ml tds, omeprazole having been ineffective. Gastroscopy was not performed. Her pain began to improve 2 days later. The authors stated that it is important to inquire about the use of tetracyclines in chil-

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279

dren with chest pain, and to consider them as a possible cause of the pain. Drug interactions Doxycycline can be added to the long list of drugs (SEDA-18, 262; SEDA23, 253) that can interact with methotrexate (42A). A 17-year-old girl with a femoral osteosarcoma received her 11th cycle of methotrexate and simultaneously oral doxycycline 100 mg bd for a palpebral abscess. As in previous cycles, pharmacokinetic monitoring of methotrexate was performed. On this occasion the half-life of methotrexate was more than doubled. She developed hematological and gastroenterological toxicity. The authors recommended that in patients receiving methotrexate an alternative to doxycycline should be used. An interaction of tetracycline with risperidone and/or sertraline has been described (43A). A 15-year-old man with Asperger's syndrome, Tourette's syndrome, and obsessive-compulsive disorder was stabilized on risperidone 1.5 mg bd and sertraline 100 mg od and had marked improvement in his social skills and tics, until he was given tetracycline 250 mg bd for acne. Within 2 weeks his tics were acutely exacerbated with pronounced neck jerking and guttural sounds. The sertraline was increased to 150 mg/day, but the tics did not resolve. The tetracycline was withdrawn after 1 month, and the tics improved within a few weeks. The authors reviewed the major metabolic pathways of the three drugs used in this case. Tetracycline may have accelerated the hepatic metabolism of risperidone, but to the best of my knowledge it has never been shown that tetracycline induces CYP2D6, the major hepatic enzyme involved in the metabolism of risperidone. The authors claimed that it was more likely that tetracycline binds to risperidone or its active metabolite, making them inactive. They supported this suggestion by citing evidence that clozapine, which has similar pharmacology to ris]~eridone, interacts with tetracycline in vitro (44=). They also commented on the possibility that the effect could have come from increased concentrations of sertraline, which can increase tics (45R). Tetracycline may inhibit the hepatic enzymes that metabolize sertraline; however, adequate evidence is lacking. Another possibility is a protein

280 binding interaction, because all three drugs are highly protein bound. However, the observation that the tics were not worsened by an increase in sertraline dosage makes this possibility less likely. The mere fact that the withdrawal of tetracycline resulted in an improvement in the tics supports an interaction between tetracycline and risperidone.

Minocycline The adverse effects of minocycline are reported far more often than adverse effects of other tetracycline derivatives. Whatever the mechanisms underlying this larger number of rep6rts might be, they continue to appear. With increasing use of minocycline in acne and other conditions, adverse reactions may become increasingly common; early recognition is important to prevent further deterioration, to hasten recovery, and to avoid invasive investigations and treatment (46R). The authors of this review recommended that safer alternatives be considered in the treatment of acne. S k i n Fixed drug eruptions are characterized by solitary or multiple, round or oval, erythematous patches of variable size; some of them develop into bullae or superficial erosions. Characteristically they appear in the same site each time the responsible drug is given, usually 30 minutes to 8 hours after administration, and with itching or burning as the first symptoms. Over a period of 1-2 weeks they fade, often with crusting and scaling, followed by hyperpigmentation, which can persist for months. Antimicrobial drugs, especially cotrimoxazole, ampicillin, and tetracyclines, can cause fixed drug eruptions (47R), and cases have been attributed to doxycycline (48 A) and minocycline (49A). Hitherto lack of crossreactivity has been emphasized (50r). However, a case of fixed drug eruption has now been

Chapter 25

T. Midtvedt

reported after minocycline in a patient with a previous eruption due to doxycycline (51A). A 48-year-old man with urethritis took doxycycline 100 mg bd and developed a fixed drug eruption on the glans penis. Doxycycline was withdrawn and the eruption healed with symptomatic treatment. Eight months later he took minocycline 100 mg/day for rosacea. A few hours after taken the first tablet he became aware of oval erythematous patches on the glans, prepuce, and scrotum. The patches rapidly became violaceous and developed into superficial erosions. He stopped taking minocycline and the lesions faded. According to the authors, this is the first report of a fixed drug eruption after minocycline in a patient with a previous eruption due to doxycycline. They advised clinicians to be aware of this potential cross-reactivity when prescribing these two drugs. I m m u n o l o g i c Necrotizing vasculitis of the skin and uterine cervix has been reported in a patient taking minocycline (52A). A 35-year-old woman developed an asymptomatic, erythematous, subcutaneous nodule on the anterior aspect of her left leg. She had been taking minocycline 50-100 mg bd for acne for 2 years, and her only other medication was an oral contraceptive. A presumptive diagnosis of erythema nodosum was made. The nodule was injected twice with triamcinolone acetonide and she was given indomethacin 50 mg tds but continued to take minocycline. Some weeks later, after a routine gynecological examination, pathological examination of a cervical biopsy showed necrotizing arteritis of the cervix. A biopsy of the pretibial nodule showed a necrotizing vasculitis with fibrinoid necrosis of the vessel walls and thrombosis. Her serum AsT and A1T activities were increased, and an antinuclear antibody test was positive at 1:60 with a nucleolar pattern. Minocycline was withdrawn, and over the next 3 months her liver function tests normalized, the antinuclear antibody became negative, and the pretibial nodule and uterine cervix vasculitis resolved. There was no recurrence over the next 2 years.

REFERENCES 1. Ehrlich E Address in Pathology at the International Congress of Medicine 1913. Lancet 1913; 2: 447-51. 2. Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions; current perspectives and future need. J Am Med Assoc 1999; 281: 824-9.

3. Temple R. Meta-analysis and epidemiological studies in drug development and postmarketing surveillance. J Am Med Assoc 1999; 281: 841--4. 4. McNeill JJ, Grabsch EA, McDonald MM. Postmarketing surveillance: strength and limitations. The flucloxacillin-dicloxacillinstory. Med J Aust 1999; 170: 270-3.

Penicillins, cephalosporins, other ~-lactam antibiotics, and tetracyclines 5. Adverse Drug Reaction Advisory Committee of the Australian Drug Evaluation Committee. Fatal hepatic reactions to flucloxacillin. Adv Drug React Bull 1994; 13: 10-11. 6. Olsson R, Wiholm B-E, Sand C, Zettergren L, Hultcrantz R, Myrhed M. Liver damage from flucloxacillin, cloxacillin and dicloxacillin. J Hepatol 1992; 15: 154-451. 7. Boyd IW. Postmarketing surveillance: strengths and limitations. The flucloxacillin~licloxacillin story. Med J Aust 1999; 171: 219. 8. McNeill J, Grabsch E, McDonald M. Reply. Med J Aust 1999; 171: 219. 9. Reimers D, Jezek A. Simultaneous use of rifampicin and other antituberculous agents with oral contraceptives. Prax Pneumol 1971; 25: 25562. 10. Szoka PR, Edgren RA. Drug interactions with oral contraceptives: complication and analysis of adverse experience data base. Fertil Steril 1988; 49: 315-18. 11. Back DJ, Grimmer SFM, Orme MLE. Evaluation of Committee on Safety of Medicine yellow card reports on oral contraceptive-drug interactions with anticonvulsants and antibiotics. Br J Clin Pharmacol 1988; 25: 527-32. 12. De Groot, Eshuis H, Stricker BH. Inefficacy of oral contraception during use of minocycline. Ned Tijdschr Geneesk 1990; 134: 1227-9. 13. Midtvedt T. Microbial functional activities. In: Probiotics, other nutritional factors, and intestinal microflora. Hanson LA, Yolken RH, editors. Philadelphia: Lippincott-Raven, 1999: 79-96. 14. Mastrantonio M, Minhas H, Gammon A. Antibiotics, the pill, and pregnancy. J Accid Emerg Med 1999; 16: 268-79. 15. Maggini M, Raschetti R, Agostini L, Cattarruzzi C, Troncon MG, Simon G. Use of amoxicillin and ampicillin--clavulanic acid and hospitalization for acute liver injury. Ann Ist Sup Sanita 1999; 35: 429-33. 16. Soza A, Riquelme F, Alvarez M, Duarte I, Glasinovic JC, Arrese M. Hepatotoxicity by amoxicillin/clavulanic acid: case report. Rev Med Chile 1999; 127: 1487-91. 17. Ma C, Bayliff CD, Ponich T. Amoxicillinclavuanic acid-induced hepatotoxicity. Can J Hosp Pharm 1999; 52: 30-2. 18. Richardet JP, Mallat A, Zafrania ES, Blazquez M. Bognel J. Prolonged chotestasis with ductopenia after administration of amoxicillin/clavulanic acid. Dig Dis Sci 1999; 44: 1997-2000. 19. Limauro DL, Chan-Thomkins NH, Carter RW, Brodmerkel GJ. Amoxicillin/clavulanateassociated hepatic failure with progression to Stevens-Johnson syndrome. Ann Pharmacol 1999; 33: 560--4. 20. Berson A, Freneanx E, Larrey D, Lepage V, Douay C, Mallet C, Fromenty B. Benhamou JP, Pessayre D. Possible role of HLA in hepatotoxicity: an explorative study in 71 patients with drug-

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induced idiosyncratic hepatitis. J Hepatol 1994; 20: 336--42. 21. Hautekeete ML, Horsmans Y, Van Waeyenberge C, Demanet C, Henrion J, Verbist L, Brenard R, Sempoux C, Michielsen PP, Yap PSH, Rahier J, Geubel AP. HLA association of amoxicillinclavulanate-induced hepatitis. Gastroenterol 1999; 117: 1181-6. 22. Aithal PG, Day CP. The natural history of histologically proven drug induced liver damage. Gut 1999; 44: 731-5. 23. Stephens RB, Cooper A. Hepatitis from 5methoxypsoralen occurring in a patient with previous flucloxacillin hepatitis. Aust J Dermatol 1999; 40:217 19. 24. Thickett KM, Wildman MJ, Fegan CD, Stableforth DE. Hemolytic anemia following treatment with piperacillin in a patient with cystic fibrosis. J Antimicrob Chemother 1999; 43: 435-6. 25. Garratty G, Leger RM, Arudt PA. Severe immune hemolytic anemia associated with prophylactic use of cefotetan in obstetric and gynecologic procedures. Am J Obstet Gynecol 1999; 181: 103-4. 26. Endoh T, Yagihashi A, Sasaki M, Watanabe N. Cefizoxime-induced hemolysis due to immune complexes: case report and determination of the epitope responsible for immune complex-mediated hemolysis. Transfusion 1999; 39: 306-9. 27. Punar M, Ozsiit H, Eraksoy H, Calangu S, Dilmenen M. An adult case of fatal hemolysis induced by ceftriaxone. Clin Microbiology Infection 1999; 5: 585-6. 28. Maraspin V, Lotric Fudan S, Stale E Ceftriaxone associated hemolysis. Wien Klin Wochenschr 1999; 111: 368-70. 29. Meyer O, Hackstein H, Hoppe, Grbel FJ, Bein G, Salama A. Fatal immune haemolysis due to a degradation product of ceftriaxone. Br J Haematol 1999; 105: 1084-9. 30. Golub LM, Ryan ME, Williams RC. Modulation of the host response in the treatment of periodontitis. Dent Today 1998; 17: 102-6. 31. Sorsa T, Montyla E Ronka H. Kallio E Kallis GB, Lundquist C, Kinana DE Salo T, Gohib LM, Teronen G, Tikanoja S. Scientific basis of a matrix metalloproteinase-8-specific chair-side test for monitoring periodontal and peri-implant health and disease. Ann NY Acad Sci 1999; 878: 130-40. 32. Garrett S, Johnson L, Disko CH, Adams DF, Bandt C, et al (36 authors). Two multi-center studies evaluating locally delivered doxycycline hyclate, placebo control, oral hygiene, and scaling and root planing in the treatment of periodontitis. J Periodont 1999; 70: 490-503. 33. Ashley RA. Clinical trials of a matrix metalloproteinase inhibitor in human periodontal disease. SDD Clinical Research Team. Ann NY Acad Sci 1999; 878: 335-46. 34. Cooper SM. A perspective on the use of minocycline for rheumatoid arthritis. J Clin Rheumatol 1999; 5: 233-6.

282 35. Alarcon GS. Antibiotics for rheumatoid arthritis? Minocycline shows promise in some patients. Postgrad Med 1999; 105: 95-8. 36. Attur MG, Patel RN, Patel PD, Abramson SB, Amin AR. Tetracycline up-regulates COX-2 expression and prostaglandin E2 production independent of its effect on nitric oxide. J Immunol 1999; 162: 3160-7. 37. Golub LM, Ramamurthy NS, Llavaneras A, Ryan ME, Lee HM, Liu Y, Bain S, Sorsa T. A chemically defined modified nonantimicrobial tetracycline (CMT-8) inhibits gingival matrix metalloproteinases, periodontal breakdown, and extraoral bone loss in ovariectomized rats. Ann NY Acad Sci 1999; 878: 290-310. 38. Pantell RH, Goodman BW. Adolescent pain: a prospective study. Pediatrics 1983; 71: 881-7. 39. Selbdt SM, Ruddy RM, Clark BJ. Pediatric chest pain: a prospective study. Pediatrics 1988; 82: 319-23. 40. Zavares-Angekidou KA, Weinhouse E, Nelson DB. Review of 180 episodes of chest pain in 134 children. Pediatr Emerg Care 1992; 8: 189-93. 41. Palmer KM, Selbst SM, Shaffer S, Proujansky R. Pediatric chest pain induced by tetracycline ingestion. Pediatr Emerg Care 1999; 15: 200-1. 42. Tortajada-Ituren JJ. Ordovas-Baines JP, LlopisSalvia P, Jimenez-Torres NV. High-dose methotrexate-doxycycline interaction. Ann Pharmacother 1999; 33: 804-8. 43. Steele M, Couturier J. A possible tetracyclinerisperidone-sertraline interaction in an adolescent. Can J Clin Pharmacol 1999; 6: 15-17.

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44. Csik V, Molnar J. Possible adverse interaction between clozapine and ampicillin in an adolescent with schizophrenia. J Child Adolesc Psychopharmacol 1994; 4: 123-8. 45. Hauser RA, Zesiewicz TA. Sertraline-induced exacerbation of tics in Tourette's syndrome. Mov Disord 1995; 10: 682--4. 46. Somech R, Arav-Boger R, Assia A, Spirer Z, Jurgenson U. Complications of minocycline therapy for acne vulgaris: case reports and review of the literature. Pediatr Dermatol 1999; 16: 46972. 47. Gaffor PMA, George VM. Fixed drug eruptions occurring on the male genitals. Curls 1990; 45: 242-4. 48. Alanko K. Topical provocation of fixed drug eruption. Contact Dermatitis 1994; 31: 25-7. 49. LePaw Mi. Fixed drug eruption to minocycline--report of one case. J Am Acad Dermatol 1983; 8: 263-4. 50. Bargman H. Lack of cross-sensitivity between tetracycline, doxycycline and minocycline with regard to fixed drug sensitivity to tetracycline. J Am Acad Dermatol 1984; 11: 900-1. 51. Correla O, Delgado L, Pol6nia J. Genital fixed drug eruption: cross-reactivity between doxycycline and minocycline. Clin Exp Dermatol 1999; 24: 137. 52. Schrodt B J, Kulp-Shorten CL, Callen JP. Necrotizing vasculitis of the skin and uterine cervix associated with minocycline therapy for acne vulgaris. South Med J 1999; 92: 502-4.

R. Walter

26

Miscellaneous antibacterial drugs

(SED-14, 837; SEDA-21, 265; SEDA-22, 274; SEDA-23, 264) AMINOGLYCOSIDES

Pharmacoeconomics A pharmacy-based active therapeutic drug monitoring service has been examined in a prospective study (1c). In the patients that were not monitored, the gentamicin dosage regimen was determined by the physician; in the patients that were monitored, the regimen was calculated using a population model and measured serum gentamicin concentrations. This resulted in significantly different mean dosage intervals: 19 hours in the monitored patients and 14 hours in the others. Active monitoring resulted in higher peak concentrations of aminoglycosides, lower trough concentrations, a reduction in the length of hospitalization, a reduced duration of aminoglycoside therapy, reduced nephrotoxicity, and a trend towards reduced mortality that was significant for patients with an infection on admission. Costs were lower with active monitoring. Although all patients treated with an aminoglycoside profited from active monitoring, it was most beneficial in patients who were admitted to the hospital with a suspected or proven Gram negative infection. Nervous system Aminoglycoside antibiotics can cause neuromuscular blockade. The mechanisms involved include reduced release of acetylcholine prejunctionally and an interaction with the postjunctional acetylcholine receptorchannel complex. While neomycin interacts with the open state of the receptor, streptomycin blocks the receptor (2R).

9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

Sensory systems The A1555G mutation in the human mitochondrial 12S RNA, which has been associated with hearing loss after aminoglycoside administration (3 C) and has been implicated in maternally inherited hearing loss in the absence of aminoglycoside exposure in some families, can now be identified by a simple and rapid method for large-scale screening that uses one-step multiplex allele-specific PCR (4E). A second pathogenic mutation that could predispose to aminoglycoside ototoxicity has been identified in an Italian family, of whom five members became deaf after aminoglycoside exposure (5c). In the mitochondrial 12S ribosomal RNA gene, the deletion of nucleotide 961 thymidine was associated with a varying number of inserted cytosines. Transient evoked oto-acoustic emission has been suggested as a sensitive measure for the early effects of aminoglycosides on the peripheral auditory system and may be useful as a tool for the prevention of permanent ototoxicitiy (6 C). The possible mechanisms underlying aminoglycoside-induced ototoxicity or assessed associated risk factors have been investigated in several studies. Differences between sera from patients with resistance or susceptibility to aminoglycoside ototoxicity have been described in vitro (7c). Sera from sensitive but not from resistant individuals metabolized aminoglycosides to cytotoxins, whereas no sera were cytotoxic when tested without the addition of aminoglycosides. This effect persisted for up to 1 year after aminoglycoside treatment. Aminoglycoside-induced ototoxicity may be in part a process that involves the excitatory activation of cochlear NMDA receptors (8c). In addition, the uncompetitive NMDA receptor antagonist dizocilpine attenuated the vestibular toxicity of streptomycin in a rat model, 283

Chapter 26

284 further stressing that excitotoxic mechanisms mediated by NMDA receptors also contribute to aminoglycoside-induced vestibular toxicity (9E). In two studies in guinea pigs, nitric oxide and free radicals, demonstrated by the beneficial effect of the antioxidant/free radical scavenger ot-lipoic acid, have been suggested to be involved in aminoglycoside-induced ototoxicity (10E, llE). In contrast, insulin, transforming growth factor-a, or retinoic acid may offer a protective potential against ototoxicity caused by aminoglycosides. However, they do not seem to promote cochlear hair cell repair (12c). In guinea pigs, brain-derived neurotrophic factor, neurotrophin-3, and the iron chelator and antioxidant 2-hydroxybenzoate (salicylate), at concentrations corresponding to anti-inflammatory concentrations in humans, attenuated aminoglycoside-induced ototoxicity (13 E, 14E). In rats, concanavalin A attenuated aminoglycoside-induced ototoxicity, and kanamycin increased the expression of the glutamate-aspartate transporter gene in the cochlea, which might play a role in the prevention of secondary deaths of spiral ganglion neurons (15 E, 16E). Finally, 4-methylcatechol, an inducer of nerve growth factor synthesis, enhanced spiral ganglion neuron survival after aminoglycoside treatment in mice (17E). Metabolism Aminoglycosides can stimulate the formation of reactive oxygen species (free radicals) both in biological and cell-free systems (18c, 19c).

R. Walter

In a prospective, randomized, doubleblind study of once-daily versus twice-daily aminoglycoside therapy in 123 patients (of whom 83 received treatment for over 72 hours), once-dally administration of aminoglycosides had a predictably lower probability of causing nephrotoxicity than twice-dally administration. In a Kaplan-Meier analysis, once-dally dosing provided a longer time of administration until the threshold for nephrotoxicity was met. The risk of nephrotoxicity was modulated by the dally AUC for aminoglycoside exposure, and the concurrent use of vancomycin significantly increased the probability of nephrotoxicity and shortened the time to its occurrence (21CR). In another study, once-dally aminoglycoside in 200 patients was prospectively compared with a retrospectively evaluated group of 100 patients treated with individualized traditional dosing. Patients with a baseline creatinine clearance below 40 ml/min, meningitis, bums, spinal cord injury, endocarditis, or enterococcal infection were excluded. Clinical and microbial outcome was similar in the two groups. Nephrotoxicity occurred in 7.5% of the patients treated with once-daily aminoglycosides compared with 14% of the others. The cumulative AUC was significantly larger in patients on traditional dosing. Minimum serum concentrations, length of aminoglycoside therapy, and AUC over 24 hours were related to nephrotoxicity. Whereas vancomycin and concurrent nephrotoxic agents were independent~ related to toxicity, sex and age were not

(23'-). Mineral balance In children with cystic fibrosis, aminoglycosides can cause hypomagnesemia due to excessive renal loss (20c). Urinary tract Aminoglycoside nephrotoxicity is thought to be centered in the proximal renal tubular epithelial cells. The uptake of aminoglycosides into these cells is limited to the luminal cell border and is saturable. Less frequent administration of doses larger than needed for saturation of this uptake may therefore reduce drug accumulation in the renal cortex (21CR). In vitro and in vivo data have provided evidence that partially reduced oxygen metabolites (superoxide anion, hydrogen peroxide, and hydroxyl radical), which are generated by renal cortical mitochondria, are important mediators of aminoglycoside-induced acute renal insufficiency (22'~).

In patients undergoing peritoneal dialysis, intraperitoneal or intravenous aminoglycosides can increase the rapidity of the fall in residual renal function. In an observational, nonrandomized study, 72 patients on peritoneal dialysis were followed for 4 years (24c). Patients who had been treated for peritonitis with intraperitoneal or intravenous aminoglycosides for more than 3 days had a more rapid fall in renal creatinine clearance and a more rapid fall in dally urine volume than patients without peritonitis or patients treated for peritonitis with antibiotics other than aminoglycosides. However, the use of other nephrotoxins or agents that may improve renal function was not quantified. Musculoskeletal Aminoglycosides have a moderate capacity for diffusion into bone tissue (25R).

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Drug resistance In a prospective surveillance study in France, the development of resistance to aminoglycosides and fluoroquinolones among Gram negative bacilli was assessed in 51 patients with a second infection due to Gram negative organisms at least 8 days after a first Gram negative infection (26c). Treatment of the first infection with a fl-lactam antibiotic plus an aminoglycoside significantly reduced the susceptibility to amikacin (the most prescribed antibiotic). When the first infection was treated with a fl-lactam plus a fluoroquinolone, susceptibility to ciprofloxacin, pefloxacin, netilmicin, and tobramycin, but not gentamicin and amikacin, fell significantly. A multidrug efflux system that appears to be a major contributor to intrinsic high-level resistance to aminoglycosides and macrolides has been identified in Burkholderia pseudomallei (27c). Out of 1102 consecutive clinical Gram negative blood isolates from Belgium and Luxembourg, 157 were "not susceptible" to aminoglycosides (28c). The resistance levels were 5.9% for gentamicin, 7.7% for tobramycin, 7.5% for netilmicin, 2.8% for amikacin, and 1.2% for isepamicin. In a large European multinational study on 7057 Gram negative bacterial isolates, resistance levels were 0.43% for amikacin, 2-13% for gentamicin, and 2.5-15% for tobramycin among Enterobacteriaceae; 75% of Staphylococcus aureus isolates, but only 21% of enterococcal strains were susceptible to gentamicin (29E). In a study from Spain, 9% of 1014 clinical Pseudomonas aeruginosa isolates were resistant to amikacin or tobramycin (30E). In the same country, resistance to amikacin rose from 21% to 84% and to tobramycin from 33% to 72% between 1991 and 1996 (31E). In a leading cancer center in Houston, 24% of 758 Gram negative clinical isolates were resistant to tobramycin and 12% were resistant to amikacin (32E). In 3144 bacterial isolates causing urinary tract infections in Chile, 74% were identified as Escherichia coli; 4.2% of these strains were resistant to gentamicin, and 1.3% were resistant to amikacin (33E). In contrast, the resistance levels were 30% and 17% respectively, in the other enterobacterial strains. In Brazil, all isolates of methicillin-resistant S. aureus were also resistant to gentamicin, amikacin, kanamycin, neomycin, and tobramycin (34E), and 97% of such

strains from Spain were resistant to tobramycin (35E).

Drug dosage regimens Compared with traditional dosing regimens, once-daily administration of aminoglycosides has resulted in a small reduction in nephrotoxicity and a slight overall improvement in efficacy. However, how therapy should be monitored is still unclear. The traditional concept of peak and trough concentration measurements has become obsolete for once-daily treatment. Alternatively, mid-dosage interval plasma concentration monitoring has been suggested to estimate the AUC, aiming to limit overall drug exposure (36R). In controlled trials of once-daily aminoglycoside regimens patients with endocarditis have often been excluded, and therefore few clinical data are available on this topic. Based on pharmacokinetic data in experimental endocarditis and integrative computer modeling, it has been hypothesized that drug penetration into vegetations would be enhanced by oncedally aminoglycoside administration, resulting in a long residence time in the vegetations and a beneficial effect in providing synergistic bactericidal action in combination with another antibiotic (37R). With the exception of two early studies using enterococci, results from animal studies have been promising in once-daily aminoglycoside treatment of endocarditis. Only two human studies of once-daily aminoglycoside therapy in streptococcal endocarditis were identified. The regimen was efficacious and safe. The authors concluded that there appeared to be sufficient promising evidence to justify large trials to further investigate oncedaily aminoglycoside in the treatment of endocarditis due to viridans streptococci, whereas more preliminary investigations were needed for enterococcal endocarditis.

Amikacin Sensory systems Preretinal hemorrhages developed in a 58-year-old man who was treated with two intravitreal injections of amikacin (0.4 mg) and cefazolin (2.25 mg) 48 hours apart for postoperative endophthalmitis following routine extracapsular cataract extraction (38A). Risk factors In an open-labeled study in eight young healthy Japanese women, the pharma-

286 cokinetics of amikacin were affected by the phase of the menstrual cycle (39c). In patients with hematological malignancies, bodyweight, renal function, acute myeloblastic leukemia, and hypoalbuminemia were the most important co-variates for the interindividual variability in amikacin pharmacokinetics (40 c).

Drug resistance In Spain, an epidemic strain of A. baumannii with resistance to amikacin was isolated in eight different hospitals (41E).

Gentamidn Sensory systems The characteristics of ototoxicity of topical gentamicin has been studied retrospectively in 16 patients (42c). All used ear drops for more than 7 days before the development of symptoms, and all had some degree of vestibulotoxicity, but only one had a worsening of cochlear reserve.

Skin Erythema multiforme developed in a 4year-old girl after treatment with topical aural gentamicin sulfate (0.3%) plus hydrocortisone acetate (1%) prescribed for otorrhea (43A).

Drug interactions In guinea pigs, metronidazole augmented gentamicin-induced ototoxicity, determined by the measurement of compound action potentials (44E).

Neomycin Nervous system In rats, neomycin inhibited striatal dopaminergic and serotoninergic systems by as yet unclear mechanisms (45E). In bovine adrenal chromaffin cells, neomycin inhibited catecholamine secretion by direct binding to the nicotinic acetylcholine receptor, resulting in blockage of this signalling pathway (46E).

Sensory systems In mice, the bacterial neomycin phosphotransferase gene, which confers resistance to aminoglycoside antibiotics, prevented the loss of hair cells after neomycin treatment (47E).

Immunologic In 927 patients undergoing patch testing, two or more positive reactions occurred in 37% (48c). Concomitant reactions to pairs of allergens (ethylenediamine + neomycin sulfate or potassium dichromate + neomycin

Chapter 26

R. Walter

sulfate) in individual patients occurred at a rate greater than would be predicted by chance. The authors suggested that this reflected crosssensitization or co-sensitization. Neomycin was one of the most frequent culprits in positive patch tests in 359 patients with venous and/or arterial leg ulcers (49c). In a prospective hospital-based study from the United Arab Emirates, 5.1% of 224 patients with positive patch tests were sensitized to neomycin (50c). In 137 children with atopic dermatitis, 43% tested positive for contact sensitiziation, and in 2.6% patch tests for neomycin were positive (51c).

Streptomycin and dihydrostreptomycin Drug resistance The aminoglycoside adenylyltransferase (aadA) genes that mediate resistance to streptomycin and spectinomycin are found in Gram negative and Gram positive bacteria. Two new genes have now been described. In a pathogenic porcine E. coli, aadA5 has been found integrated with a trimethoprim resistance gene (52E). The novel aadA6 has been sequenced from P. aeruginosa and mediates high-level resistance in E. coli (53E). Several studies from all parts of the world have reported resistance of mycobacteria to streptomycin. In Morocco, 26% of M. tuberculosis and 40% of atypical mycobacteria were resistant to this antibiotic alone, whereas 18% of M. tuberculosis and 25% of atypical mycobacteria strains were resistant to the combination isoniazid/rifampicin/streptomycin (54E). In Pakistan, 28% of M. tuberculosis strains were resistant to streptomycin (55E). In Russia 14% of 50 clinical isolates of M. tuberculosis were resistant to streptomycin, and most of these strains were resistant to two or more drugs (56E). In Uganda, 13% of M. tuberculosis strains had primary and 22% acquired resistance to streptomycin (57E). In Spain, only 1.1% had primary resistance to streptomycin (58E). In New Caledonia, no primary resistance against streptomycin was found in 105 strains isolated from 1995-96, and only one of 12 strains isolated from patients with relapsing disease had acquired resistance to streptomycin (59E). In Italy, the incidence of multidrug resistant M. tuberculosis to streptomycin was 80% (60E).

Miscellaneous antibacterial drugs

Chapter26

The strains that caused the outbreak of cholera in West Bengal in 1998 were resistant to several antibiotics, including streptomycin (61E). In Vietnam, 94% of Vibrio cholerae O1 strains isolated after 1990 were resistant to streptomycin. Class I integrons containing a gene cassette mediated resistance to streptomycin and spectinomycin (62E). A class I integron was also identified in multidrug-resistant V. cholerae O1 strains isolated in Albania and Italy in 1994 (63E). In Northern California, two outbreaks, including a total of 110 culture confirmed cases of salmonellosis, were ascribed to the DT104 strain, and raw milk products were identified as an important risk factor for the development of disease (64E). In Ethiopia 18 of 39 foodborne Salmonella isolates were resistant to streptomycin, whereas gentamicin was effective against all isolates and kanamycin showed intermediate resistance to two isolates and was otherwise fully effective (65E). In Tajikistan, 27 of 29 Salmonella typhi isolates that caused a total of 8901 cases of typhoid fever were resistant to streptomycin (66E). In Greece, enterococci with high-level resistance to streptomycin were recovered from tap water, treated water, and dialysate in several renal units (67E). In Germany 28% of 730 clinical enterococcal isolates had high-level resistance to streptomycin (68E).

Tobramycin Drug resistance Intermittent administration of inhaled tobramycin has been recommended in patients with cystic fibrosis, as it improves pulmonary function, reduces the density of P. aeruginosa in sputum, and reduces the risk of hospitalization. The proportion of patients with P. aeruginosa isolates with higher minimal inhibitory concentrations of tobramycin may increase (69c). Treatment with inhaled tobramycin does not increase isolation of Burkholderia cepacia, Stenotrophomonas maltophilia, or Alcaligenes xylosoxidans; however, isolation of Candida albicans and Aspergiltus species may increase (70c). Risk factors Reduced tobramycin clearance can be associated with a normal creatinine clearance in serum concentration-adjusted

287 dosage of once-daily tobramycin therapy in critically ill patients (71 c). The pharmacokinetics of tobramycin in patients with cystic fibrosis are significantly altered after lung transplantation, and early and close drug monitoring is recommended (72c). Hydrophilic contact lenses may increase the penetration of tobramycin into the aqueous humor (73c). Drug overdose Multiple-dose activated charcoal does not increase the elimination of tobramycin and is therefore not recommended for treatment of poisoning (74R).

C H L O R A M P H E N I C O L AND THIAMPHENICOL (SED-14, 848; SEDA-23, 268) Drug resistance S. typhimurium DT104 is usually resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline. An outbreak of 25 culture-confirmed cases of multidrug-resistant S. typhimurium DT104 has been identified in Denmark. The strain was resistant to the above mentioned antibiotics and nalidixic acid and had reduced susceptibility to fluoroquinolones. A swine herd was identified as the primary source (75c). The DT104 strain was also found in cases of salmonellosis in Washington State, and soft cheese made with unpasteurized milk was identified as an important vehicle of its transmission (76c). A high rate of resistance of non-typhoid Salmonella to commonly used antimicrobial agents was found in Taiwan; 67% of the isolated strains were resistant to chloramphenicol (77E). Streptococcus pneumoniae was isolated in 30% of 40 HIV-infected and 50% of 162 HIV-negative children living in a Romanian orphanage (78c). Multidrug-resistant streptococci were highly prevalent, and 21% of the isolates were resistant to chloramphenicol. Drug interactions Ciclosporin possibly interacts with chloramphenicol (79A). A morbidly obese 17-year-old Hispanic with a cadaveric renal transplantation 5 years before who took ciclosporin and prednisone for immunosuppression was treated with chloramphenicol 875 mg qds and ceftazidime 2 g tds for vancomycin-resistant enterococcal sinusitis. Ciclosporin concentrations in-

288 creased markedly after chloramphenicol was added. Normalization was achieved after withdrawal of chloramphenicol. An interaction between warfarin and ocular chioramphenicol (5 mg/ml; one drop qds in each eye), which led to an increase in INR, has been suspected in a 83-year-old white woman (80A). The authors suggested that the effect may have been due to inhibition by chloramphenicol of CYP2C9, since the pharmacologically active enantiomer S-warfarin is metabolized by this enzyme.

Interference with diagnostic tests Esterases in serum from rabbits and to a lesser extent humans can convert diacetyl chloramphenicol back to an active antibiotic. Therefore, in vitro findings may not accurately reflect the level of chloramphenicol resistance by chloramphenicol acetyltransferase-bearing bacteria in vivo, when growth media supplemented with serum are used (81E).

FUSIDIC ACID (SED-14,912) Fusidic acid has a narrow antibiotic spectrum, with a bacteriostatic or slow bactericidal effect mainly directed at both coagulase-negative staphylococci and S. aureus (82R). Mechanisms of resistance to fusidic acid include alterations in elongation factor G (whose inhibition at the ribosome level mediates the effect of fusidic acid), altered drug permeability, binding by chloramphenicol acetyltransferase type 1, and enhanced efflux. Elimination of fusidic acid is primarily by non-renal mechanisms, and a proportion is metabolized to several breakdown products detectable in bile. Systemic clearance is increased by hypoalbuminemia, reduced by severe cholestasis, and is unchanged in renal insufficiency (83R). Most common adverse effects are minor and are related to the gastrointestinal tract (discomfort, diarrhea). Rare adverse events include granulocytopenia, thrombocytopenia, venous spasm, and skin reactions (84R).

Chapter 26

in more detail whether there is any therapeutic usefulness (85R). D r u g resistance Most studies show low levels of resistance in staphylococci, with a slighdy higher rate in methicillin-resistant S. aureus strains (86R): This has been confirmed in recent studies. Only one of 106 isolates of methicillin-resistant Staphylococcus aureus was also resistant to fusidic acid (87E). And only very little resistance to fusidic acid has been reported from Wales (88E). However, clonal spread of fusidic acid resistant methicillin-resistant Staphylococcus aureus has been documented in Norway (89E). And a resistance rate of about 50% has been found in coagulase-negative staphylococci isolated in eight Swedish intensive care units between 1995 and 1997 (90E). A high rate of resistance to fusidic acid was also found in bacteria that were cultured from blood after dental treatment (91E). Pathogenic nocardia may inactivate fusidic acid (92c). In an in vitro study, salicylate and related compounds increased the MIC in strains of S. aureus both resistant and susceptible to fusidic acid (93E). Risk factors The half-life of fusidic acid was shortened in 10 patients with severe burns treated with 500 mg tds intravenously (94c). This effect may be explained by translesional extra-hepatic clearance and an increase in hepatic clearance.

Drug interactions

Activation of the CYP450 enzyme system, demonstrated by an increase in the metabolism of antipyrine, has been found in 30 HIV-positive drug abusers (95c). This activating effect was demonstrated after 28 but not after 14 days of treatment with fusidic acid 500 mg/day, suggesting time dependency.

GLYCOPEPTIDES (SED-14, 858; SEDA-21, 276; SEDA-22, 276; SEDA-23, 269)

Pharmacoeconomics Immunologic

Fusidic acid may have an immunomodulatory effect that seems to be partly mediated by suppression o f cytokine production. The effect on several diseases has been investigated, but it remains to be characterized

R. Walter

In a randomized prospective cost-effectiveness study both teicoplanin and vancomycin were assessed as second-line therapy in 66 neutropenic patients after the failure of empirical treatment with a combination of piperacillin/tazobactam

Miscellaneous antibacterial drugs

and amikacin (96c). The primary success of second-line therapy was equivalent, and the direct total costs were similar. Acquisition costs per dose were in favor of vancomycin, but costs derived from administering vancomycin and serum concentration monitoring led to similar costs for both regimens. With the exception of the red man syndrome, which occurred in 10% of vancomycin-treated patients but none of the teicoplanin-treated patients, toxicity (renal, liver, and ear toxicity, diarrhea, phlebitis) was also similar. In a retrospective cost analysis, the records of 527 patients with acute leukemia were studied (97c). They had been treated in a multicenter randomized trial for febrile neutropenia with ceftazidime and amikacin plus either teicoplanin (6 mg/kg in a single dose; n = 275) or vancomycin (30 mg/kg/day in 2 doses; n = 252). Clinical responses were equivalent. Again the nigher acquisition costs for teicoplanin were counterbalanced by the lower incidence of adverse events and easier administration, resulting in overall similar costs for both regimens. A total of 8% of patients treated with vencomycin reported adverse events compared with 3.2% of patients treated with teicoplanin. Skin rashes occurred in 6.0% vs 1.4% respectively. Nephrotoxicity, ototoxicity, fever, and hypotension occurred in very few patients.

Urinary tract

289

Chapter 26

There was a fall in residual renal function during episodes of peritonitis in a propective multicenter study in 152 children with peritoneal dialysis-associated peritonitis (98c). The study evaluated the efficacy, safety, and clinical acceptance of combination treatment, including a glycopeptide (teicoplanin or vancomycin) and ceftazidime, each given either intermittently or continuously. Irreversible anuria developed in 19% of the patients with residual diuresis. In patients who retained residual renal function, there was a strong trend towards a decreased residual glomerular filtration rate (-11%). There was no difference with respect to the type of glycopeptide or the mode of use. Aminoglycosides were used concomittantly in only 12 patients and did not seem to affect the evolution of residual renal function. Underdosing/non-compliance or overdosing occurred in 8.2% of continuously treated vs 4.9% of intermittently treated patients. In one patient with vancomycin intoxication, a 20-30 dB increase in hearing threshold was

documented. Intermittent and continuous intraperitoneal treatment with glycopeptides and ceftazidime were equally efficious and safe when measured by objective clinical criteria.

Teicoplanin Only three of 422 patients treated with a single dose of teicoplanin for antimicrobial prophylaxis during hip or knee arthroplasty (400 mg by intravenous bolus at the time of anesthesia) reported adverse events compared with nine of 424 patients treated with five doses of cefazoline: one had nausea, and two had erythema (99c). Six patients given teicoplanin had surgical wound infections, and 57 had proven or suspected infections involving other body systems. In another study, a single dose of teicoplanin (6 mg/kg intravenously) was compared with three doses of cefradine plus metronidazole as prophylaxis for vascular surgery. Efficacy was similar with the two regimens. Adverse events were reported by 40 of 136 patients treated with teicoplanin (vs 39 of 139 treated with cefradine plus metronidazole), and 19 (vs 15) were considered to be related to the study drug; however, none was considered definitely related (100 c). In a study of the effects of teicoplanin (612 mg/day intravenously), 166 of 342 patients reported one or more adverse events, and in 119 they were thought to be associated with teicoplanin (101c). Most had some form of hypersensitivity response (fever, rash, chills, or pruritus), and treatment was withdrawn in 59 patients. There was a clinically significant abnormality of liver function tests in 123 patients, but in only 33 was it judged to be possibly associated with teicoplanin. There was a rise in serum creatinine in 28 patients, in five of whom an association with teicoplanin was suggested. Cell wall agents, such as glycopeptides, have concentration-independent bactericidal activity, and the time over which the antibiotic serum concentration persists over the minimal inhibitory concentration of the pathogen is a main pharmacodynamic determination of the outcome. In a two-way, randomized, openlabel, two-period, crossover study in ten healthy adults, teicoplanin given in two 200 mg doses intramuscularly produced steady-state trough concentrations even higher than those after

290 once-dail)~ intravenous administration of 400 mg (102'-). Conversion from intravenous to intramuscular administration may therefore allow better compliance with preserved efficacy. Intramuscular teicoplanin was well tolerated. Adverse effects reported were mild local pain for 2-3 hours, headache, and backache. Musculoskeletal Teicoplanin diffuses well into bone tissue (25R). Immunologic Previous case reports have suggested cross-reactivity between vancomycin and teicoplanin in the induction of the red man syndrome. A new case seems to corroborate this association, although the underlying mechanism remains elusive (103Ar). A swinging pyrexia (peaking at 39--40~ during the day but settling overnight) developed after the 5th day of teicoplanin treatment in a 35-year-old man with infective endocarditis due to S. mitis. Two days after stopping the drug he became apyrexial. Therapy with vancomycin had previously had to be interrupted because of an extensive purpuric rash and erythema, which progressed to exfoliative dermatitis and was subsequently identified as red man syndrome secondary to vancomycin.

Vancomycin Vancomycin is a glycopeptide antibiotic with a narrow spectrum and primary activity against Gram positive organisms, including staphylococcus and streptococcus species. Owing to the increased prevalence of methicillin-resistant staphylococci and penicillin-resistant S. pneumoniae, the use of vancomycin has grown significantly over the last years. Improvement in manufacturing has resulted in a purer product and fewer toxic effects, but vancomycin is still associated with potentially serious adverse reactions (104r). Sensory systems In a consecutive series of 118 patients undergoing cataract surgery, the use of supplementary prophylactic vancomycin in the irrigating solution during extracapsular lens extraction was significantly associated with an increased incidence of angiographic and clinical cystoid macular edema (105c). Hematologic Vancomycin-induced neutropenia occurs in about 2% of treated patients, and complete recovery takes place in 2-5 days

Chapter 26

R. Walter

after withdrawal. An immune-mediated mechanism (antineutrophil antibodies, sensitized lymphocytes) seems to be implicated. A typical case of vancomycin-induced neutropenia has been reported in a 39-year-old woman with sickle cell SS disease treated with vancomycin for methicillin-resistant coagulase-negative staphylococcal bacteremia (106A). However, in addition to neutropenia, the clinical course was defined by a febrile period characteristic of drug fever, with delayed onset and resolution 48 hours after vancomycin was withdrawn. In this case, fluconazole and cefazoline were also administered, but their contribution to neutropenia was jugded unlikely (negative rechallenge with fluconazole, withdrawal of cefazoline after less than 5 days of therapy). Thrombocytopenia is a rare adverse effect of vancomycin and may be associated with the presence of vancomycin-dependent antiplatelet IgG antibodies. Vancomycin-associated thrombocytopenia has been reported in a 72-year-old woman who was treated with gentamicin and vancomycin for infectious endocarditis due to C. pseudodipheriticum (107A). On the 4th day of treatment, the platelet count fell and reached a nadir of 14 • 1012/1 on day 7. Two days after withdrawal of vancomycin (day 8) the platelet count began to rise and reached 150 x 1012/1 within 5 days. Vancomycin-dependent antiplatelet IgG antibodies were not detected 10 days after vancomycin. Thrombocytopenia also developed in a 72-year-old man who was treated with vancomycin for staphylococcal sepsis after treatment with gemcitabine for metastatic pancreatic cancer (108A). On day 12 thrombocytopenia developed, reached a nadir on day 18 (13 x 101a/l), and did not respond to platelet transfusions. Bone-marrow megakaryocytes were adequate. Platelet-associated IgG and IgM were increased. Vancomycin was withdrawn on day 28, with prompt recovery of the platelet count to 136 x 1012/1 in 10 days. Vancomycin was also associated with the subsequent development of thrombocytopenia in a retrospective study that included 193 patients in a surgical trauma intensive care unit (109c). Urinary tract Of 69 neonates (including eight with peak vancomycin concentrations over 40 Ixg/ml) with culture-proven S. aureus or coagulase-negative staphylococcal septicemia

Miscellaneous antibacterial drugs

Chapter26

who received vancomycin for more than 3 days, six had a doubling of serum creatinine concentration during vancomycin treatment, and all were in the group with peak serum vancomycin concentrations under 40 Ixg/ml (110c). Skin Linear lgA buUous disease is an autoimmune subepidermal disorder, characterized by a linear deposition of IgA along the blister base, with a predominantly neutrophilic dermal infitrate. Most often idiopathic, a subset of linear IgA bullous disease is induced by drugs, and intravenous vancomycin is the best-documented drug that triggers it. A new case induced by intravenous vancomycin has been reported ( I l l A) and two cases have been added, with further identification of another 14 previous cases (ll2AR). The features of these 17 cases were: mean age 65 years; 11 men/6 women; eruption latency 1-15 days; normal trough concentrations (when reported); cutaneous manifestations included bullous, urticarial, erythematous, and targetoid erythema multiforme-like lesions favoring the trunk, extremities, palms, and soles and sparing the head and neck; six patients had mucosal involvement. The gold standard for diagnosis is direct immunofluorescence of the perilesional skin. Circulating antibasement membrane zone antibodies were identified only in a minority of patients. Therapies included drug withdrawal, prednisone, and dapsone. No spontaneous recurrences were reported. Musculoskeletal Vancomycin diffuses moderately well into bone tissue (25R). Immunologic Vancomycin can cause a chemically mediated anaphylactoid reaction, clinically recognized as "red man" or "red neck" syndrome. It most often occurs after rapid intravenous administration. However, it has been stressed that near-fatal reactions can also occur after slow administration (113A). An 83-year-old white man became distressed and had nausea and facial flushing after 10 minutes of a slow infusion of vancomycin (1 g scheduled over 2 hours). Despite interruption, he developed suffocating respiratory distress requiring intubation and mechanical ventilation. Uncharacteristic of anaphylactoid reactions, he became severely hypertensive. Subsequently, his condition rapidly normalized. During the acute event, there was an increase in serum troponin concentration.

291 Pretreatment with H 1 and H2 receptor antagonists (diphenhydramine 1 mg/kg and cimetidine 4 mg/kg) intravenously serially over 3 minutes, starting 10 minutes before the infusion of vancomycin, permitted rapid vancomycin administration (1 g over 10 minutes) in 17 of 19 patients compared with eight of 19 patients treated with placebo in a prospective, randomized, double-blind, placebo-controlled study of patients undergoing elective arthroplasty (114c). Hypotension occurred in 2 vs 12 of the patients, and 12 vs 19 of the patients had a rash. Serum histamine concentrations were raised after vancomycin administration in both groups. Possible synergism between vancomycin and narcotics in the induction of anaphylactold shock due to histamine release has been suggested in a 19-year-old woman treated with fentanyl and vancomycin during orthopedic surgery (l15A). Evidence from an animal study has suggested that the risk of anaphylactoid reactions to vancomycin may be enhanced by the co-administration of muscle relaxants, resulting in enhanced release of histamine (116E). Drug resistance The emergence of bacterial resistance to vancomycin has raised widespread concern. In 1986, the first vancomycin-resistant enterococcal strains were reported. Since then such strains have been recognized all over the world, and the incidence has been steadily increasing during the last decade. Recently, vancomycin/glycopeptide intermediately resistant and methicillin-resistant S. aureus have been described in Japan, Europe, the Far East, and the USA. Some vancomycin-susceptible S. aureus strains contain subpopulations with intermediate resistance to vancomycin (heterogenous strains), and these may escape laboratory detection (117c-119 C, 120R, 121R). Numerous risk factors have been identified for infection with vancomycin-resistant enterococci. In a recent study, the severity of mucositis in cancer patients was also significantly associated with vancomycin-resistant enterococci (122c). Previous vancomycin therapy was also believed to be a risk factor. However, a recent meta-analysis concluded that the reported strong association between vancomycin treatment and hospital-acquired vancomycinresistant enterococci results from selection bias, confounding by duration of hospitalization, and publication bias (123M).

292 Glycopeptide resistance in a cluster of three clinical isolates of vancomycin-resistant E. faecium was due to vanD, which was located on the chromosome and was not transferable to other enterococci. These isolates were indistinguishable but differed from the strain in which vanD-mediated resistance has been reported previously (124E). A new type of acquired glycopeptide resistance, named vanE, has been characterized in E. faecalis BM 4405. It results in low-level resistance of vancomycin but susceptibility to teicoplanin (125E). Defects in penicillin-binding protein 4 result in a distorted peptidoglycan composition of the cell of vancomycin-resistant and teicoplanin-resistant laboratory mutants of S. aureus and are suggested to be part of the mechanism of glycopeptide resistance in these microbes (126E). Vancomycin-dependent enterococci growing only in the presence of vancomycin may best be treated by withdrawing vancomycin (127c). However, vancomycin-independent revertants can rapidly emerge in vitro, endangering the cure of patients treated by interruption of vancomycin only (128c). Drug overdose Two preterm twins, born in the 35th week of gestation, accidentally received an overdose of vancomycin as an intravenous bolus injection (129A). Both were treated from the day of birth with piperacillin (100 mg/kg/day) and cefotaxime (100 mg/kg/day) for congenital pneumonia. On the 6th day of antibiotic therapy, vancomycin (38 and 35 mg/kg respectively) was given over 1 minute. A few minutes later the twins developed flushed faces and trunks and peripheral cyanosis. Other findings were a prolonged capillary refill time, apnea and hypoxemia, bradycardia (40--60 bpm), a fall in systolic blood pressure of 10 mmHg, and metabolic acidosis (pH 7.29 and 7.24 and base excess -10.5 and -10.9 respectively). Metabolic acidosis and the red man syndrome disappeared after 30 minutes. Serum vancomycin concentrations were 32 and 34.5 mg/1 respectively 9 hours after administration. Fundoscopy and repeated otoacoustic emissions were normal. There was minimal reduction in creatinine clearance. Tubular proteinuria, paralleled by increased activity of N-acetyl-~-D-glucosaminidase in the urine, resolved completely within 1 week. Hemodialysis with high-efficiency dialysis membranes resulted in a removal of plasma vancomycin of about 60% (calculated half-life 2 hours) in two children with initial plasma vancomycin concentrations of 238 and 182 Ixg/ml

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R. Walter

(130A). In a 6-day-old neonate with a solitary hypodysplastic kidney, suspected sepsis, and acute renal insufficiency, venovenous hemodia filtration with a high-flux membrane was successfully used to treat a 10-fold overdose of vancomycin (131A). In contrast, multiple-dose activated charcoal did not increase the elimination of vancomycin and is therefore not recommended for detoxification of acute poisoning (74R). D r u g interactions Preterm infants often receive theophylline for apnea of prematurity and furosemide to improve dynamic lung compliance and to reduce total pulmonary resistance. In 10 preterm infants receivingfurosemide plus theophylline, vancomycin was introduced according to the generally recommended dosing schedules but failed to achieve anticipated therapeutic concentrations (132CR). In nine infants the addition of furosemide to vancomycin plus theophylline resulted in a fall in serum vancomycin concentrations to subtherapeutic within 24 hours, and only in one did vancomycin concentrations remain within the target range. The addition of furosemide reduced the serum creatinine concentration by 24% (range 12-43). These data suggest that furosemide enhances the excretion of vancomycin, and an acute and transient increase in glomerular illtration rate and creatinine clearance may be the explanation. Co-administration of fosfomycin or imipenem-cilastatin may reduce the nephrotoxicity of vancomycin, as suggested by a study in rats (133E). Intravitreal application of dexamethasone may reduce the elimination of intravitreal vancomycin and may enhance this therapy, as suggested by an in vivo study in rabbits (134E). Lactoferrin, a protein contained in tears, increases the activity of vancomycin against biofilms of S. epidermidis strains and may be therapeutically helpful in the treatment of infections such as endophthalmitis associated with intraocular lenses (135E). Interference with diagnostic tests Fluorescence polarization immunoassay determination of serum vancomycin concentrations can result in falsely high vancomycin concentrations in excess of 30-80% in patients with renal dysfunction. This is due to the formation of a non-toxic, non-microbiologically active

Miscellaneous antibacterial drugs

Chapter26

pseudometabolite, the vancomycin crystalline degradation product (136R). A report on a 48year-old man underlines the significance of resuiting underdosing and eventually suboptimal clinical response (137 Ar).

LINCOSAMIDES (SED-14, 871; SEDA-21, 268; SEDA-22, 278; SEDA-23, 273)

Drug resistance

The erythromycin ribosomal methylase (erm) genes encode 23S ribosomal RNA methylases. This modification results in reduced binding of all known macrolides, lincosamide, and streptogramin B to the ribosome (MLS resistance). Novel triazine-containing methyltransferase inhibitors that may reverse erm-mediated resistance are under development (138c). MLS resistance was found in four of 137 consecutive clinical S. pyogenes isolates (139E). In two, both ermB and ermTR genes were present. In the other two, these genes were not identified, suggesting a new mechanism of high-level resistance to these antibiotics. Erm genes were detected in 45% of 173 S. pneumoniae strains isolated from surveillance studies in day-care centers in Central Italy (140E). From 387 clinical strains of erythromycin-resistant S. pyogenes strains isolated in Italian laboratories from 1995 to 1998, 31% were assigned to the inducible and 17% to the constitutive MLS resistance phenotype (141E). Resistance to erythromycin increased to 33% in 1997 among community-acquired S. pneumoniae isolates from Central Italy (142E). Most carried an erm gene and were also resistant to clindamycin. Regulatory regions located upstream of the erm genes were amplified and sequenced in clinical isolates of enterococci and streptococci with either inducible or constitutive resistance. Expression of constitutive resistance in two strains of S. pneumoniae and E. faecalis could be accounted for by a large deletion or a DNA duplication within the regulatory regions respectively (143E). In 294 macrolide-, lincosamide-, and/or streptogramin-resistant clinical isolates of S. aureus and coagulase-negative staphylococci isolated in 1995 from 32 French hospitals, ermA or ermC genes were found in 88% (144E). Genes related to linA/linAI and conferring resistance to lincomycin were detected

293 in one strain of S. aureus and 7 strains of coagulase-negative staphylococci. A new resistance gene, named linB, which encodes a lincosamide nucleotidyltransferase catalysing the adenylation of the hydroxyl group in position 3 of the molecules of lincomycin and clindamycin has been characterized in a clinical isolate of E. faecium (145E). Expression of linB was also observed in E. coli and S. aureus, and the spread of this gene in other clinical isolates of E. faecium has been suggested. In Brachyspira hyodysenteriae (formerly Serpulina hyodysenteriae) isolates, resistance to clindamycin was associated with a transversion mutation in the nucleotide position homologous with position 2058 of the E. coli 23S rRNA gene (146 E).

Clindamycin Clindamycin is effective in the treatment of most infections involving anaerobes and Gram positive cocci. Adverse drug reactions may be well below 1%. In a tertiary care center, adverse drug reactions to clindamycin were reported in 0.47% of 3896 courses, and in half of these events an effect of other medications could not be excluded (147 C). Cardiovascular Clindamycin can cause QT interval prolongation and ventricular fibrillation (148A). Nervous system Lincosamide antibiotics can produce neuromuscular block postjunctionally by interacting with the open state of the acetylcholine receptor-channel complex. Lipophilicity, rather than stereochemistry of the molecule, is important for open-channel blockade affecting primarily the "off" rate of channel blocking (2c). A case of neuromuscular block after clindamycin has been reported (149A). A 44-year-old woman with mild asthma and mitral valve prolapse was given intravenous clindamycin 300 mg, methylprednisolone 125 mg, and midazolam 2 mg 30 minutes before surgery. Succinylcholine 120 mg was given and general anesthesia was induced with fentanyl 0.1 mg and propofol 120 mg, and maintained with 60% nitrous oxide in oxygen, desflurane, and a single dose of propofol 80 mg. Five hours after uneventful surgery and about 20 minutes after another intravenous dose of clindamycin 600 mg, she complained of profound weakness

Chapter 26

294 and had bilateral ptosis, difficulty in speaking, and rapid shallow respiration. Her weakness rapidly became more profound, and she was given neostigmine 4 mg and glycopyrrolate 0.8 mg, after which her muscle strength returned to normal. An electromyogram showed no evidence of neuromuscular disease, and acetylcholine receptor antibodies were negative. An in vitro study has shown a direct effect of clindamycin on nicotinic but not muscarinic acetylcholine receptors (150E). This may explain improvement of tremor on treatment with clindamycin in a patient with Parkinson's disease. On each of three occasions, the tremor almost completely disappeared shortly after the start of therapy with clindamycin but reappeared within 1-3 days after withdrawal. Gastrointestinal Clindamycin is one of the antibiotics most often associated with diarrhea due to C. difficile, and restricting clindamycin has been successful in terminating outbreaks of C. difficile diarrhea associated with its use (151R). Between 1989 and 1992, outbreaks of diarrhea due to a clindamycin-resistant strain of C. difficile occurred in different parts ot the USA. Resistance was mediated by the ermB gene. The use of clindamycin was a specific risk factor for diarrhea due to this strain (152c). Clindamycin can rarely cause antibiotic-associated diarrhea after short-term use as vaginal cream (153c). There was reduced susceptibility of C. difficile to clindamycin in 80% of French isolates in 1997 (154E). Skin In a 38-year-old non-atopic man, a generalized pruriginous maculopapular eruption with lip edema and facial erythema developed after 10 days of treatment with oral clindamycin phosphate (300 mg qds) and amoxicillin (500 mg qds) for bronchopneumonia (155A). A patch test was positive 2 months later for clindamycin phosphate but negative for penicillin, amoxicillin, ampicillin, and erythromycin. Prick tests and intradermal tests were all negative. Oral rechallenge with clindamycin phosphate 300 mg was positive. Drug resistance There was a significant increase in the rate of resistance in clinical strains of B. fragilis from Canada (20% in 1997) (156E). This trend was also observed in a prospective multicenter survey from the USA (157c).

R. Walter

Among P. acnes isolated from acne lesions, a resistance level of 4% (of 50 strains) and 6.8% (of 70 strains) were found in Japanese and German studies respectively (158 E, 159E). Of 302 clinical S. pyogenes isolates from Portugal, 108 were resistant to erythromycin, and 86 also had a constitutive resistance to clindamycin (MLSB phenotype) (160E). Four isolates had a phenotype characterized by lowlevel erythromycin resistance and high-level clindamycin resistance. In another European study of 286 S. pneumoniae strains, 7% were resistant to penicillin, and 35% were also resistant to clindamycin (161E). Of 3205 group A streptococcal strains from Canada, only 18 and 2 strains respectively showed inducible and constitutive resistance to clindamycin (162E). Among 180 strains of the S. milleri group isolated in Spain, 17% were resistant to clindamycin (163E). An increase in resistance to clindamycin has been found in group B streptococcal strains causing neonatal infection (164E). Drug formulations Whereas only about 4% of clindamycin from a vaginal cream was systemically absorbed, systemic absorption was in the range of 30% when clindamycin was intravaginally administered as a phosphate ovule (165~).

Drug interactions

In two patients who had lung transplants and were taking an immunosuppressive regimen that included ciclosporin, the addition of clindamycin (600 mg tds) resulted in a significant reduction in ciclosporin concentrations (166A).

Lincomydn Gastrointestinal

Lincomycin was among the antibiotics that were most often associated with the development of antibiotic-associated diarrhea in a Turkish study of 154 patients; other associated antibiotics were azithromycin and ampicillin (167c).

KETOLIDES Ketolides are semisynthetic derivatives of 14membered-ring macrolide antibiotics, but they differ from macrolides by having a 3-keto group

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instead of a L-cladinose group on the erythronolide A ring. In a study of the efficacy of the ketolides HMR 3004 (previously RU 004) and HMR 3647 (previously 66647) against 1% lactamase-producing H. influenzae, the in vitro activity of both ketolides against 30 clinical isolates was comparable to that of azithromycin and superior to clarithromycin and erythromycin A. Furthermore, HMR 3004 and HMR 3647 were both active in a murine model of experimental pneumonia, as assessed by pulmonary clearance of/3-1actamase producing H. influenzae (168E).

MACROLIDES (SED-14, 873; SEDA-21, 269; SEDA-23, 273) Immunologic Immunomodulatory effects of macrolides have been repeatedly reported; for example, suppression of the release of chemotactic mediators may be important for the clinical effect of roxithromycin in patients with chronic lower respiratory tract infections (169c). Both clarithromycin and azithromycin altered cytokine production in human monocytes in vitro (170E). The suppressive activity of macrolide antibiotics on pro-inflammatory cytokine production has also been shown in mice, in which Oxithromycin inhibited the in vitro production of intedeukin-1/~ and tumor necrosis factorc~ from human peripheral blood monocytes (171E). It also suppressed cytokine production after a prolonged pretreatment period. In another mouse model both roxithromycin and clarithromycin inhibited angiogenesis and enhanced the antitumor activity of some cytotoxic agents, suggesting a beneficial effect when combined with such drugs against solid tumors (172 E, 173E). Furthermore, growth suppression of human fibroblasts by roxithromycin has been demonstrated both in vitro and in vivo (174c). Drug resistance An area of increasing concern and clinical importance is the increasing macrolide resistance that has been reported over the last several years with some of the common pathogens, particularly S. pneumoniae, group A streptococci, and H. influenzae, and may result in failure of therapy of pneumonia, pharyngitis, and skin infections (175R). High rates of resist-

295 ance of several groups of streptococci to macrolides have been reported from all parts of the world (142 E, 160E, 162E, 164E, 176c-181c). Risk factors Allergic reactions to antimicrobials are frequent in patients with Sjtgren's syndrome. They are especially prone to reactions to penicillins, cephalosporins, and sulfonamides, but reactions to macrolides and tetracyclines also seem to be overrepresented in these patients (182c). Drug interactions Rhabdomyolysis is a rare disorder that mostly results from adverse drug effects. Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are among the most important drugs causing this disorder, and the risk is increased when gemfibrozil or macrolide antibiotics are concurrently administered. Rhabdomyolysis requiring short-term dialysis occurred in a 57-year-old man with chronic renal insufficiency treated with lovastatin 40 mg/day, gemfibrozil 600 mg bd, and clarithromycin 500 mg tds (183AR). Six previous reports of rhabdomyolysis associated with the combination of HMG-CoA reductase inhibitors and macrolide antibiotics were cited. All cases developed within 2 weeks of combination therapy with macrolide antibiotics. Diabetes mellitus and chronic renal insufficiency seem to be predisposing factors. The patients presented with myalgia and muscle weakness. Treatment included drug withdrawal, intravenous fluids, urine alkalinization, and eventually short-term dialysis.

Interference with diagnostic routines

Incubation of respiratory tract pathogens in a 5% carbon dioxide-enriched atmosphere results in a loss of activity of macrolide antibiotics; this effect can be reduced by adjusting the bioassay medium to pH 8.4 (184E).

Azithromycin Compared with tetracycline, azithromycin had a favorable short-term effect on childhood morbidity in a mass trial for trachoma in rural Gambian villages, and adverse effects were limited (185c).

Sensory systems Sensorineural hearing loss has been attributed to azithromycin (186AR).

296 A 35-year-old Caucasian man with AIDS and multiple opportunistic infections, including Mycobacterium kansasii and Mycobacterium avium complex (MAC) disease developed moderate to severe primary sensorineural hearing loss after 45 months of therapy with oral azithromycin 500 mg/day. Other medications included ethambutol, isoniazid, rifabutin, ciprofloxacin, co-trimoxazole, fluconazole, zidovudine (later switched to stavudine), lamivudine, indinavir, methadone, modified-release oral morphine, pseudoephedrine, diphendydramine, megestrol acetate, trazodone, sorbitol, salbutamol by metered-dose inhaler and nebulizer, ipratropium, and oral morphine solution as needed. Significant improvement of the hearing impairment was documented 3 weeks after drug withdrawal. A literature review identified several cases of ototoxicity in HIV-positive patients treated with azithromycin for MAC infection. In four series, ld d 1% of such patients had some degree of heating loss. However, some patients were also taking other potentially ototoxic drugs, which may have contributed to the high frequency of hearing loss reported. Hearing loss improved markedly after withdrawal of azithromycin. Hearing loss may be more common and probably more severe with high-dose azithromycin than with high-dose clarithromycin. Severe ototoxicity has also been attributed to azithromycin (187AR). A 47-year-old woman who had a left lung transplantation 3 months earlier and who was taking ticarcillin-clavulanate and aztreonam for sinusitis, was given co-trimoxazole, ticarcillinclavulanate, azithromycin (500 mg od intravenously), and ganciclovir for presumed pneumonia. Other drugs included tacrolimus, mycophenolate, prednisone, lansoprazole, diltiazem, itraconazole, warfarin, alendronate, ipratropium bromide, folic acid, and nystatin. The next day, rimantadine and vancomycin were added, and co-trimoxazole was reduced. A neurological examination to assess symptoms of peripheral neuropathy noted no hearing deficit. On day 3, vancomycin, ticarcillin-clavulanate, and ganciclovirwere withdrawn. On the 5th day, mild tinnitus and reduced heating developed and gradually progressed to complete deafness. After eight doses, azithromycin was withdrawn, and 20 days later her hearing was back to baseline. Even a single oral dose of azithromycin altered the conjunctival bacterial flora of children from a trachoma endemic area (188c). However, the clinical significance is not yet clear.

Chapter 26

R. Walter

Gastrointestinal Gastrointestinal symptoms were the most common adverse effects reported in a trial of azithromycin in disseminated Mycobacterium avium complex in 62 patients with AIDS (189c). Drug resistance Clinical isolates of N. gonorrhoeae with reduced susceptibility to azithromycin are commonly found in Uruguay, and one of the mechanisms involved included mutations in the mtrR gene (190c). D r u g interactions The first case of a possible interaction of azithromycin with warfarin has been reported in a 71-year-old woman who was taking maintenance warfarin for a prosthetic heart valve and took a 5-day course of azithromycin; 6 days later her INR rose from 2.5-3.5 to 15 (191A). The authors discussed several possible explanations for this rise in INR, but were "unable to explain" it. However, it seems likely that azithromycin inhibited the metabolism of warfarin. Although zafirlukast inhibits CYP3A, it did not have any significant pharmacokinetic effect on single doses of azithromycin or clarithromycin in 12 healthy volunteers (192c).

Clarithromycin Sensory systems Abnormal taste developed in 17 of 175 patients treated with clarithromycin 250 mg bd for 10 days for community-acquired pneumonia, compared with three of 167 patients treated with sparfloxacin (193c). Mild to moderate gastrointestinal disturbances were the most common adverse events and were reported in 13% and 11%, respectively. Topical clarithromycin may induce selfresolving corneal deposits (194c). Psychiatric Two women, aged 49 and 50 years, developed altered mental status a few days after starting to take clarithromycin for eradication of H. pylori (195A). There was incoherent speech with perseveration, inability to sustain attention, impaired ability to comprehend, coprolalia, euphoria, restlessness, visual hallucinations, anxiety, and inappropriate affect. Similarly, in three cases, a 46-year-old man, a 39-year-old woman, and a 4-year-old boy, treatment with clarithromycin was followed by CNS and psychiatric symptoms that included euphoria, insomnia, aggressive be-

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Chapter26

havior, hyperactivity, and emotional lability (196A). Gastrointestinal Like erythromycin, clarithromycin is proldnetic, as shown in 16 patients with functional dyspepsia and H. pylori gastritis (197c).

Urinary tract A 77-year-old man taking regular captopril, furosemide, salbutamol inhaler, vitamin C, and nasal beclomethasone diproprionate took clarithromycin 250 mg bd for sinusitis and bronchitis and 5 days later developed abdominal pain and intermittent fever (198A). Laboratory findings included raised serum creatinine and blood urea nitrogen, AsT, amylase, lactate dehydrogenase, and creatine kinase (not of the MB isoenzyme). The cause of the nonoliguric renal insufficiency was diagnosed by renal biopsy as interstitial nephritis with eosinophilic infiltrates. During the course of illness he also developed thrombocytopenia. Immunologic Henoch-Sch6nlein purpura developed in an 84-year-old Indian woman 10 days after she started to take clarithromycin (250 mg bd) for pneumonia (199Ar). She was otherwise healthy and taking no regular medications. Histology confirmed a leukocytoclastic vasculitis of superficial vessels with extravasation of erythrocytes, and direct immunofluorescence showed iinmunoglobulin A in superficial dermal vessels. Treatment with prednisone (1 mg/kg/day) was required. Most of the symptoms and signs resolved within a few days, but renal function remained impaired. The authors identified two previous case reports of clarithromycin-induced leukocytoclastic vasculitis. Drug resistance Resistance of H. pylori to clarithromycin appears to have increased in proportion to clarithromycin use. Clarithromycin resistance arises through mutations that lead to base changes in 23S ribosomal RNA subunits. A rapid PCR hybridization assay with a sensitivity of 97% for the detection of clarithromycin resistance of H. pylori strains has been described (200E). Resistance to clarithromycin has a serious impact on the efficiency of eradicating regimens that include clarithromycin (201R-203R). The reported incidences of primary resistence of H. pylori to clarithromycin are 6.1% in the USA, 8% in Austria, 8.7%

297 in Bulgaria, 9.5% in Japan, 10% in Spain, 11% in France, 13% in Nigeria, and 23% in Italy (204c-211c). Drug interactions A concomitant clarithromycin-associated interaction with digoxin and warfarin has been reported (212A). A 72-year-old man was taking regular digoxin (0.25 mg/day) and warfarin (22.5 rag/week) for chronic atrial fibrillation; other medications included furosemide, enalapril, glyceryl trinitrate paste, and a beclomethasone inhaler. He developed signs of digoxin intoxication after taking clarithromycin (500 mg tds) for 12 days and a raised serum digoxin concentration was confirmed. In addition, the INR was well above the target range (7.3 instead of 2.0-3.0). An interaction with CYP450 enzymes was thought to be involved in the interaction with warfarin, and alteration of gut flora may have been involved in digoxin intoxication. Inhibition of P-glycoprotein by clarithromycin may also have contributed to the interaction with digoxin (213A).

Cisapride Torsade de pointes occurred in a 77-year-old woman taking cisapride and clarithromycin (214A). Disopyramide

In a 76-year-old woman severe prolongation of the QTc interval and selfterminating torsade de pointes were induced by the combined use of clarithromycin and disopyramide; concomitant hypokalemia may have contributed to the cardiac dysrhythmia (215A). Symptomatic hypoglycemia developed in a 59-year-old man treated with a combination of disopyramide (50 mg/day) and clarithromycin (600 mg/day) (216A). Additional investigations suggested enhanced insulin secretion induced by toxic disopyramide concentrations as the probable mechanism.

Itraconazole In three patients with pulmonary Mycobacterium avium complex and aspergillosis infections, itraconazole was suggested to increase the plasma concentration of clarithromycin as well as the clarithromycin:14hydroxyclarithromycin ratio (217A). This effect may have been due to inhibition of CYP3A4 by intraconazole.

Methylprednisolone

In an open label study in six adults with mild to moderate asthma,

Chapter 26

298 clarithromycin significantly reduced methylprednisolone clearance, thereby increasing the risk of steroid-induced adverse effects (218c). In contrast, prednisolone clearance and mean prednisolone plasma concentrations were unaffected.

Omeprazole In 21 healthy volunteers, clarithromycin (400 mg bd) for 3 days before omeprazole (20 mg/day) significantly inhibited the metabolism of omeprazole (219 C). Pimozide Owing to inhibition of the metabolism of pimozide by clarithromycin, pimozide plasma concentrations increase and may result in an increased risk of cardiotoxicity presenting as prolongation of the QT interval and fatal ventricular dysrhythmias (220 c).

Tacrolimus In two women aged 37 and 69, acute and reversible tacrolimus nephrotoxicity developed after the addition of clarithromycin for an upper respiratory tract infection (221A).

TheophyUine Clarithromycin increases the serum concentration of theophylline by inhibiting CYP450 enzymes. In a 72-year-old man, the administration of clarithromycin (400 mg/day) plus modified-release theophylline (200 mg/day) resulted in acute rhabdomyolysis with renal insufficiency requiring hemodialysis after 5 days of combined treatment (222A).

Erythromycin Cardiovascular In 35 women and 28 men erythromycin caused QTc interval prolongation after the first few doses (223c). Similarly, in a prospective, comparative study in 19 patients with uncomplicated community-acquired pneumonia, a single dose of intravenous erythromycin 500 mg increased the heart rate and prolonged the QTc interval. These effects were seen after 15 minutes of infusion and disappeared 5 minutes after the infusion had been stopped (224c). Owing to prolongation of the QT interval, a newborn with congenital AV block developed ventricular extra beats and nonsustained ventricular tachycardia after intravenous erythromycin; the QT interval normalized after withdrawal (225 c).

R. Walter

Only a modest increase in QTe interval has been observed with concomitant use of erythromycin and the antihistamine ebastine (226c).

Gastrointestinal The use of erythromycin in post-exposure prophylaxis for pertussis in 200 infants was followed b y an increased number of cases of infantile hypertrophic pyloric stenosis, and all seven cases had taken erythromycin prophylactically (227c). A case review and cohort study supported these preliminary findings (228c). Liver A young woman developed severe cholestasis and jaundice after taking erythromycin stearate (229A). A second severe episode of jaundice and malaise occured after treatment with erythromycin succinate 2 years later pointing to erythromycin itself as the culprit. Skin

A

31-year-old

woman

developed

Stevens-Johnson syndrome after she had taken oral erythromycin 333 mg tds for otitis media (230A). After two doses she developed oral ulcers, tongue swelling, and a generalized erythematous rash. The diagnosis was confinned histologically. She recovered slowly after withdrawal of erythromycin. Immunologic A 39-year-old man developed acute angio-edema and urticaria 6 hours after taking erythromycin base 500 mg in entericcoated pellets for acute sinusitis (231A). He remembered having taken erythromycin once before without any problem. He had no known allergies and was taking no regular medications, but he had had chemotherapy for nonHodgkin's Lymphoma several years earlier. The authors identified five previous reports of erythromycin-associated urticarial reactions. However, it was not possible to exclude a reaction to the ingredients of the coated pellets.

Teratogenidty In a large case-control surveillance study from Hungary in 38 151 pregnant women, oral erythromycin during pregnancy did not present a detectable teratogenic risk to the fetus (232c). Drug interactions Many of the adverse effects that are observed with the use of erythromycin are explained by the inhibitory effect on CYP3A4. The following drug-drug inter-

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Chapter26

actions have each been suggested to be due to inhibition of CYP3A4.

Acenocoumarol Erythromycin may potentiate acenocoumarol anticoagulant treatment, as reported in a 68-year-old man on stable anticoagulation with acenocoumarol 3 mg/day who took erythromycin ethylsuccinate 1.5 g/day (233A).

Atorvastatin In 12 healthy volunteers, erythromycin increased both the maximal plasma concentration and AUC of the co-administered HMG-CoA reductase inhibitor atorvastatin (234c).

Buspirone

Co-administration of erythromycin with the anxiolytic drug buspirone increases the plasma concentration of buspirone (235 c).

Cilostazol

When erythromycin was given to 16 healthy non-smoking male volunteers taking cilostazol, the Cmax and AUC of cilostazol increased significantly by 47% and 73% respectively, and the unbound clearance of the major metabolite of cilostazol, OPC- 13015, fell by about 50% (236c).

Cisapride Cisapride can prolong the QT interval, with a risk of ventricular dysrhythmias (237 or, 238R). Halofantrine

Erythromycin inhibited halofantrine metabolism in vitro, suggesting that increased cardiotoxicity might be clinically important (239E).

Lidocaine Erythromycin may increase the plasma concentration and toxicity of oral lidocaine, as shown in a cross-over study in nine volunteers who took erythromycin orally (500 mg tds) for 4 days and 1 mg/kg of oral lidocaine on day 4 (240c).

Quinidine Erythromycin reduced the total clearance of quinidine, reduced its partial clearance by 3-hydroxylation, and increased its maximal serum concentration in an open study in 30 healthy young volunteers (241c). Quinine Erythomycin is a competitive in vitro inhibitor of quinine 3-hydroxylation and may therefore interact with quinine (242E).

299

Risperidone

Drugs that inhibit CYP3A may significantly alter risperidone concentrations, especially in patients with CYP2D6 deficiency (243c).

Sertraline

A 12-year-old boy developed the serotonin syndrome, which is normally associated with the interaction of two or more serotonergic agents, after the co-administration of erythromycin and sertraline; this could have been due to erythromycin-induced inhibition of sertraline metabolism by CYP3A (244A).

Josamycin Liver Josamycin can cause cholestatic hepatitis (245A).

Roxithromycin Cardiovascular In 202 patients with unstable angina pectoris, roxithromycin prevented death and re-infarction for at least 6 months after initial treatment (246c). However, these findings could not be confirmed in another study in 302 patients with coronary heart disease and a seropositive reaction to C. pneumoniae who were treated with azithromycin. While global tests of markers of inflammation improved, there were no differences in antibody titers and clinical events (247c).

Troleandomycin Drug interactions Troleandomycin is an in vitro competitive inhibitor of quinine 3-hydroxylation, which is mediated by CYP3A4, and may therefore interact when co-administered with quinine (242E). Troleandomycin may also inhibit the metabolism of ecabapide and alprazolam by inhibition of CYP3A4 (248 E, 249E). Other drugs that may be affected include gallopamil, the watersoluble artemisinin analogue artelinic acid, nefazodone, and lovastatin (250E-253E).

Tylosin Tylosin is a polyketide lactone substituted with three deoxyhexose sugars. It is used as an antimicrobial growth promoter in animals. Acquired resistance has been observed in potentially human pathogenic strains isolated from animals (254E). Of further concern is the fact

300

Chapter 26

that tylosin confers cross-resistance on erythromycin (255r).

POLYMYXINS

(SED-14, 887)

Polymyxins are cationic, basic, and amphipathic polypeptides that interact with lipopolysaccharides in the outer membrane of bacilli. They potently neutralize endotoxin, reduce blood endotoxin concentrations in patients with septic shock during direct hemopeffusion over immobilized polymyxin B fibers, and are bactericidal for many Gram negative rods. Because of their poor tissue distribution and their substantial nephrotoxicity and neurotoxicity, they are mainly restricted to topical use. However, polymyxins may be considered for serious systemic infections caused by multidrug resistant Gram negative bacteria (256 R, 257 c, 258 c, 259R). For life-threatening meningitis due to such organisms, polymyxins can also be given intrathecally as adjunctive therapy (260eR). Polymyxins are also used in regimens of selective decontamination of the digestive tract (261R). Sensory systems A food additive (flavored BMI-60) may help to mask the bitter taste of polymyxin B sulfate tablets (262c). Drug resistance The Gram negative organism Burkhoderia pseudomallei is the pathogen that causes melioidosis. This bacterium is intrinsically resistant to the killing action of cationic antimicrobial peptides, including polymyxins. An in vitro study has now identified genetic loci that are associated with resistance to polymyxins in a virulent clinical isolate (263E). In patients with cystic fibrosis P. aeruginosa synthesized specific lipid A structures containing palmitate and aminoarabinose, which were associated with resistance to cationic antibiotics and increased inflammatory responses (256c). A two-component regulatory system has been characterized that is involved in the resistance of P. aeruginosa in response to external magnesium concentrations (264E). Similarly, the PmrA/PmrB two-component system of S. enterica that mediates modifications in the lipopolysaccharide, resulting in resistance to polymyxins, has been characterizied in

R. Walter

more detail (265E). The pqaB locus affected polymyxin B resistance in S. typhi (266E). All hemolytic and cytotoxic Aeromonas species that have been isolated from water samples from various sources were resistant to polymyxin B (267E). Resistance to polymyxin B was also found in V. vulnificus (268E).

STREPTOGRAMINS Pristinamycin Pristinamycin is a synergistic combination of streptogramin A (pristinamycin IIA) and streptogramin B (pristinamycin IB). It is active against the main bacteria that cause respiratory tract infections and could be useful in the treatment of acute or recurrent sinusitis, community-acquired pneumonia, or periodontal infection with Actinobacillus actinomyectomcomitans (269 R, 270 R, 27 lC-273c). Skin Patch tests may be used to confirm pristinamycin-induced drug eruptions. In 11 patients with cutaneous drug reactions after oral pristinamycin, patch tests (with pristinamycin diluted to 20% aqueous and 20% petrolatum) were performed 1-3 months after treatment with pristinamycin. There were positive patch tests in nine, and there was no relapse of the drug eruption during patch testing; 30 control patients had negative tests (274 c). Drug resistance The relative frequency of resistance to macrolides, lincosamides, and streptogramins (MLS resistance) has been assessed in a series of 2091 staphylococcus isolates collected during a 3-week period in 1995 in 32 French hospitals. A total of 294 strains (144 S. aureus, 150 coagulase-negative staphylococci) exhibited resistance to at least one of these groups of antibiotics. Resistance to pristinamycin was phenotypically detected in 10 S. aureus strains (seven isolates from the same hospital and possibly of the same clone) and three coagulase-negative staphylococcus isolates. It was associated with resistance to type A streptogramins encoded by vat or vatB genes and was associated with the erm genes (144E). A short report demonstrated the absence of a reliable correlation between killing kinetics and normal laboratory tests for pristina-

Miscellaneous antibacterial drugs

Chapter26

mycin susceptibility testing of some pneumococci (275c). Eight selected multiresistant clinical isolates and two reference pristinamycinresistant S. pneumoniae strains were studied. Dish diffusion susceptibility and MICs were determined by the agar dilution method, and all clinical isolates appeared to be susceptible to pristinamycin, whereas the two reference strains were not. In contrast, time-kill experiments identified a limited bactericidal effect of pristinamycin in three clinical and both reference strains. These three strains had been classified as pristinamycin-resistant by the VitekII system, which uses a kinetic turbidimetric measurement of bacterial growth. Epidemiological infomation is hindered by the use of highly selected strains for the study.

Quinupristin + dalfopristin Quinopristin and dalfopristin are two semisynthetic pristinamycin derivatives that are given in combination parenterally. The combination has a broad spectrum of activity against Gram positive bacteria, including multidrug resistant bacilli. A comprehensive review has been published (276R). In a small, open, phase II pilot study, lowdose quinupristin + dalfopristin (5 mg/kg intravenously every 8 hours; n = 11) and high-dose quinupristin + dalfopristin (7.5 mg/kg intravenously every 8 hours; n = 15) were compared with vancomycin (1 g intravenously every 12 hours; n = 13) in the treatment of catheterrelated staphylococcal bacteremia (277c). In patients with a baseline pathogen, the outcome was comparable in all groups. Adverse clinical events in the quinupristin + dalfopristin group consisted of arm and chest pain, chills, fever,

arthritis, and phlebitis or pain at the injection site; quinupristin + dalfopristin was withdrawn in 12% of patients (compared with 15% of vancomycin-treated patients). The pooled results of two multicenter, phase III, randomized comparisons of quinupristin + daifopristin (7.5 mg/kg intravenously every 12 hours; n = 450) with established comparators (cefazolin, oxacillin, vancomycin; n = 443) for complicated skin and skin structure infections have been reported (278c). The success rate was equivalent in the two groups: 63% of patients given quinupristin + dalfopristin (vs 54%) reported at least one adverse event, most commonly nausea, vomiting, rash, pain, or pruritus. A1-

301 though most of the adverse events were mild to moderate, the drug was withdrawn in 19% of patients treated with quinupristin + dalfopristin (vs 4.7%) owing to an untoward event. Adverse venous events (atrophy, edema, hem-

orrhage, hypersensitivity, inflammation, thrombophlebitis, pain) were reported by 66% of patients treated with quinupristin + dalfopristin (vs 28%) and required withdrawal of the drug in 12% of these patients (vs 2%). Risk factors The disposition of quinupristin, dalfopristin, and their primary metabolites was similar in eight non-infected patients on peritoneal dialysis compared with eight matched healthy volunteers after the administration of quinupristin + dalfopristin 7.5 mg/kg (279c). Since dialysis clearance was insignificant, the combination was thought to be inadequate for the therapy of dialysis-associated peritonitis.

OTHER ANTIMICROBIAL DRUGS

Bacitracin (SED-14, 911; SEDA-22, 279; SEDA-23, 268)

Immunologic Bacitracin is one of the most important clinical allergens (280c). Lifethreatening anaphylactic reactions after topical bacitracin have previously been reported. A new case occurring after bacitracin nasal packing has been reported (28 IA). A 48-year-old man underwent uneventful septorhinoplasty, after which his right nostril was packed with 6 ft of vaseline gauze placed in the finger of a latex glove coated with bacitracin ointment. Within seconds, his oxygen saturation fell from 97% to 94% (and increased to 97% with 100% oxygen), but blood pressure and heart rate were unchanged. After the left nostril had been packed, his oxygen saturation fell to 89%, no pulse wave was registered and an electrocardiogram showed a heart rate of 39 bpm with firstdegree atrioventricular block, and the blood pressure was not obtainable by non-invasive measurement. Cardiopulmonary resuscitation was successful, but the patient remained intubated for 2 days because of concerns about facial and upper airway edema. Later he gave a history of an episode of irritation and swelling after nasal application of polymyxin B and bacitracin ointment 2-3 weeks before surgery. Skin prick testing was positive for bacitracin but negative for latex, polymyxin, cefazolin, and saline.

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302 Drug resistance Although there is evidence of acquired resistance to bacitracin in enterococci and staphylococci isolated from animals (254E), a review of the current literature found no evidence that the prevalence of such resistance has increased over time or in relation to the use of bacitracin in man or in animals (in which bacitracin is used as a growth promoter) (282R). Interference with diagnostic tests In forensic medicine, the detection of semen may be critical, and identification due to Wood's lamp-induced fluorescence has been suggested to be helpful. In a study to investigate whether semen can be distinguished from other products, none of 41 physicians was able to differentiate semen from other products using a Wood's lamp; however, some ointments and creams that contained bacitracin were mistaken for semen (283c).

Fosfomycin

(SED-14, 911)

In a multicenter trial in 749 ambulatory women aged at least 12 years with an acute uncomplicated urinary tract infection, a single dose of fosfomycin tromethamine 3 g had an equivalent bacteriological and clinical cure rate as a 7-day course of nitrofurantoin (284c). Adverse events were reported by 5.3% of fosfomycintreated patients (vs 5.6%). The most common adverse effects were diarrhea (2.4%), vaginitis (1.8%), and nausea (0.8%), and 1.9% of fosfomycin-treated patients were withdrawn owing to adverse events (vs 4.3%). Urinary tract In Japanese children the use of fosfomycin within the first two days for treatment of illness caused by E. coli O157 reduced the risk of subsequent hemolytic-uremic syndrome (285c). However, treatment with oral fluoroquinolones may be preferrable (286c). In rats, co-administration of fosfomycin significantly reduced the nephrotoxicity of vancomycin (133 E). Musculoskeletal Fosfomycin diffuses moderately well into bone tissue (25R).

R. Walter

Immunologic The immunomodulatory effect of fosfomycin may in part be explained by an effect on cytokine production, as shown in mice in vivo (287E).

Novobiocin Drug interactions The permeabilizer sodium polyphosphate may enhance the activity( of novobiocin against P. aeruginosa (288=), and lactoferrin can potentiate the activity of novobiocin against some E. coli strains (289E).

Spectinomycin

(SED-14, 912)

Drug resistance Aminoglycoside adenylyltransferase (aadA) genes mediate resistance to streptomycin and spectinomycin. In a pathogenic porcine E. coli, the novel aaA5 has now been described integrated with a trimethoprim resistance gene (52E). The aadA6 gene has been sequenced from P. aeruginosa and can confer high-level resistance to spectinomycin in E. coli (53E). All strains of multidrug resistant V. cholerae O1 E1 Tot isolated in Albania were resistant to spectinomycin, and resistance to this antibiotic was mediated by the aadA1 gene cassette located in the bacterial chromosome within a class 1 integron (63E). Another class 1 integron that contained aadA2 was found in pathogenic S. typhimurium isolates from France and was also chromosomally located (290E). An aadA gene has also been described in E. faecalis (291E). Resistance of E.coli isolates from chicken in Saudia Arabia was 96% compared with 71% among human isolates (292E). Serotyping showed an overlap between human and chicken strains, suggesting that these animals may serve as a resistance pool for humans.

Virginiamycin Drug resistance Acquired resistance to virginiamycin, which is active against Gram positive lactic acid-producing bacteria, can be detected in E. faecium and E. faecalis strains isolated from animals and food (254E).

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303

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caused by clindamycin. Am J Cardiol 1999; 83: 813-5, A11. 149. Best JA, Marashi AH, Pollan LD. Neuromuscular blockade after clindamycin administration: a case report. J Oral Maxillofac Surg 1999; 57: 600-3. 150. Schulze J, Toepfer M, Schroff KC, Aschhoff S, Remien J, Muller FW, Endres S. Clindamycin and nicotinic neuromuscular transmission. Lancet 1999; 354: 1792-3. 151. Samore MH. Epidemiology of nosocomial Clostridium difficile diarrhoea. J Hosp Infect 1999; 43 Suppl: S183-90. 152. Johnson S, Samore MH, Farrow KA, Killgore GE, Tenover FC, Lyras D, Rood JI, DeGirolami P, Baltch AL, Rafferty ME, Pear SM, Gerding DN. Epidemics of diarrhea caused by a clindamycinresistant strain of Clostridium diflicile in four hospitals. New Engl J Med 1999; 341: 1645-51. 153. Vikenes K, Lund TS, Schreiner A. Clostridium difficile-associated diarrhea after short term vaginal administration of clindamycin. Am J Gastroenterol 1999; 94: 1969-70. 154. Barbut F, Decre D, Burghoffer B, Lesage D, Delisle E Lalande V, Delmee M, Avesani V, Sano N, Coudert C, Petit JC. Antimicrobial susceptibilities and serogroups of clinical strains of Clostridiurn difficile isolated in France in 1991 and 1997. Antimicrob Agents Chemother 1999; 43:2607-11. 155. Vicente J, Fontela JL. Delayed reaction to oral treatment with clindamycin. Contact Dermatitis 1999; 41: 221. 156. Labbe AC, Bourgault AM, Vincelette J, Turgeon PL, Lamothe E Trends in antimicrobial resistance among clinical isolates of the Bacteroides fragilis group from 1992 to 1997 in Montreal, Canada. Antimicrob Agents Chemother 1999; 43: 2517-19. 157. Snydman DR, Jacobus NV, McDermott LA, Supran S, Cuchural GJ Jr, Finegold S, Harrell L, Hecht DW, Iannini P, Jenkins S, Pierson C, Rihs J, Gorbach SL. Multicenter study of in vitro susceptibility of the Bacteroides fragilis group, 1995 to 1996, with comparison of resistance trends from 1990 to 1996. Antimicrob Agents Chemother 1999; 43: 2417-22. 158. Fluhr JW, Gloor M, Dietz P, Hoffler U. In vitro activity of 6 antimicrobials against propionibacteria isolates from untreated acne papulopustulosa. Zentralbl Bakteriol 1999; 289: 53-61. 159. Kurokawa I, Nishijima S, Kawabata S. Antimicrobial susceptibility of Propionibacterium acnes isolated from acne vulgaris. Eur J Dermatol 1999; 9: 25-8. 160. Melo-Cristino J, Fernandes ML. Streptococcus pyogenes isolated in Portugal: macrolide resistance phenotypes and correlation with T types. Portuguese Surveillance Group for the Study of Respiratory Pathogens. Microb Drug Resist 1999; 5: 219-25. 161. Fluit AC, Schmitz FJ, Jones ME, Acar J, Gupta R, Verhoef J. Antimicrobial resistance

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311 225. Brixius B, Lindinger A, Baghai A, Limbach HG, Hoffmann W. Ventrikul~e Tachykardie nach Erythromycin-Gabe bei einem Neugeborenen mit angeborenem AV-Block. Klin Padiatr 1999; 211: 465-8. 226. Moss AJ, Chaikin P, Garcia JD, Gillen M, Roberts DJ, Morganroth J. A review of the cardiac systemic side-effects of antihistamines: ebastine. Clin Exp Allergy 1999; 29 Suppl 3: 200-5. 227. Hypertrophic pyloric stenosis in infants following pertussis prophylaxis with erythromycin-Knoxville, Tennessee, 1999. Morb Mortal Wkly Rep 1999; 48: 1117-20. 228. Honein MA, Paulozzi LJ, Himelright IM, Lee B, Cragan JD, Patterson L, Correa A, Hall S, Erickson JD. Infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromcyin: a case review and cohort study. Lancet 1999; 354: 2101-5. 229. Horn S, Aglas F, Horina JH. Cholestasis and liver cell damage due to hypersensitivity to erythromycin stearate--recurrence following therapy with erythromycin succinate. Wien Klin Wochenschr 1999; 111: 76-7. 230. Sullivan S, Harger B, Cleary JD. StevensJohnson syndrome secondary to erythromycin. Ann Pharmacother 1999; 33: 1369. 231. Gallardo MA, Thomas I. Hypersensitivity reaction to erythromycin. Cutis 1999; 64: 375-6. 232. Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A population-based case-control teratologic study of oral erythromycin treatment during pregnancy. Reprod Toxicot 1999; 13: 531-6. 233. Grau E, Real E, Pastor E. Macrolides and oral anticoagulants: a dangerous association. Acta Haematol 1999; 102:113-14. 234. Siedlik PH, Olson SC, Yang BB, Stern RH. Erythromycin coadministration increases plasma atorvastatin concentrations. J Clin Pharmacol 1999; 39: 501-4. 235. Mahmood I, Sahajwalla C. Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug. Clin Pharmacokinet 1999; 36: 277-87. 236. Suri A, Forbes WP, Bramer SL. Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet 1999; 37 Suppl 2: 61-8. 237. Evans ME, Feola DJ, Rapp RP. Polymyxin B sulfate and colistin: old antibiotics for emerging multiresistant gram-negative bacteria. Ann Pharmacother 1999; 33: 960-7. 238. Tonini M, De Ponti F, Di Nucci A, Crema E Review article: cardiac adverse effects of gastrointestinal prokinetics. Aliment Pharmacol Ther 1999; 13: 1585-91. 239. Baune B, Flinois JP, Furlan V, Gimenez E Taburet AM, Becquemont L, Farinotti R. Halofantrine metabolism in microsomes in man: major role of CYP 3A4 and CYP 3A5. J Pharm Pharmacol 1999; 51: 419-26. 240. Isohanni MH, Neuvonen PJ, Olkkola KT. Effect of erythromycin and itraconazole on the phar-

312 macokinetics of oral lignocaine. Pharmacol Toxicol 1999; 84: 143-6. 241. Damkier P, Hansen LL, Brosen K. Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine. Br J Clin Pharmacol 1999; 48: 829-38. 242. Zhao X J, Ishizaki T. A further interaction study of quinine with clinically important drugs by human liver microsomes: determinations of inhibition constant (Ki) and type of inhibition. Eur J Drug Metab Pharmacokinet 1999; 24: 272-8. 243. Bork JA, Rogers T, Wedlund PJ, De Leon J. A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A. J Clin Psychiatry 1999; 60: 469-76. 244. Lee DO, Lee CD. Serotonin syndrome in a child associated with erythromycin and sertraline. Pharmacotherapy 1999; 19: 894-6. 245. Lavin I, Mundi JL, Trillo C, Trapero A, Fernandez R, Lopez MA, Cervilla E, Quintero D, Palacios A. Hepatitis colestasica por josamicina. Gastroenterol Hepatol 1999; 22: 160. 246. Gurfinkel E, Bozovich G, Beck E, Testa E, Livellara B, Mautner B. Treatment with the antibiotic roxithromycin in patients with acute non-Qwave coronary syndromes. The final report of the ROXIS Study. Eur Heart J 1999; 20: 121-7. 247. Anderson JL, Muhlestein JB, Carlqnist J, Allen A, Trehan S, Nielson C, Hall S, Brady J, Egger M, Home B, Lim T. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: the Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) study. Circulation 1999; 99: 1540o7. 248. Fujimaki Y, Arai N, Inaba T. Identification of cytochromes P450 involved in human liver microsomal metabolism of ecabapide, a prokinetic agent. Xenobiotica 1999; 29: 1273-82. 249. Gorski JC, Jones DR, Hamman MA, Wrighton SA, Hall SD. Biotransformation of alprazolam by members of the human cytochrome P4503A subfamily. Xenobiotica 1999; 29: 931-44. 250. Suzuki A, Iida I, Tanaka F, Akimoto M, Fukushima K, Tani M, Ishizaki T, Chiba K. Identification of human cytochrome P-450 isoforms involved in metabolism of R(+)- and S(-)gallopamil: utility of in vitro disappearance rate. Drug Metab Disp 1999; 27: 1254-9. 251. Grace JM, Skanchy D J, Aguilar AJ. Metabolism of artelinic acid to dihydroqinghaosu by human liver cytochrome P4503A. Xenobiotica 1999; 29: 703-17. 252. Von Moltke LL, Greenblatt DJ, Granda BW, Grassi JM, Schmider J, Harmatz JS, Shader RI. Nefazodone, meta-chlorophenylpiperazine, and their metabolites in vitro: cytochromes mediating transformation, and P45003A4 inhibitory actions. Psychopharmacol Berl 1999; 145:113-22. 253. Jacobsen W, Kirchner G, Hallensleben K, Mancinelli L, Deters M, Hackbarth I, Benet LZ,

Chapter 26

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Sewing KF, Christians U. Comparison of cytochrome P--450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and pravastatin in the liver. Drug Metab Disp 1999; 27: 173-9. 254. Butaye P, Devriese LA, Haesebrouck E Phenotypic distinction in Enterococcus faecium and Enterococcus faecalis strains between susceptibility and resistance to growth-enhancing antibiotics. Antimicrob Agents Chemother 1999; 43: 2569-70. 255. Pedersen KB. Some growth promoters in animals do confer antimicrobial resistance in humans. Br Med J 1999; 318: 1076. 256. Ernst RK, Yi EC, Gu0 L, Lim KB, Burns JL, Hackett M, Miller SI. Specific lipopolysaccharide found in cystic fibrosis airway Pseudomonas aeruginosa. Science 1999; 286: 1561-5. 257. Asanuma Y, Furuya T, Tanaka J, Sato T, Shibata S, Koyama K. The application of immobilized polymyxin B fiber in the treatment of septic shock associated with severe acute pancreatitis: report of two cases. Surg Today 1999; 29:1177-82. 258. Nakamura T, Ebihara I, Shoji H, Ushiyama C, Suzuki S, Koide H. Treatment with polymyxin B-immobilized fiber reduces platetet activation in septic shock patients: decrease in plasma levels of soluble P-selectin, platelet factor 4 and betathromboglobulin. Inflamm Res 1999; 48: 171-5. 259. Hellman J, Warren HS. Antiendotoxin strategies. Infect Dis Clin North Am 1999; 13: 371-86, ix. 260. Segal-Maurer S, Mariano N, Qavi A, Urban C, Rahal JJ Jr. Successful treatment of ceftazidimeresistant Klebsiella pneumoniae ventriculitis with intravenous meropenem and intraventricular polymyxin B: case report and review. Clin Infect Dis 1999; 28:1134-8. 261. Rommes JH, Zandstra DE Van Saene HK. Selectieve darmdecontaminatie voorkomt sterfte bij intensive-carepatienten. Ned Tijdschr Geneeskd 1999; 143: 602-6. 262. Saito M, Hoshi M, Igarashi A, Ogata H, Edo K. The marked inhibition of the bitter taste of polymyxin B sulfate and trimethoprimsulfamethoxazole by flavored BMI-60 in pediatric patients. Biol Pharm Bull 1999; 22: 997-8. 263. Burtnick MN, Woods DE. Isolation of polymyxin B-susceptible mutants of Burkholderia pseudomallei and molecular characterization of genetic loci involved in polymyxin B resistance. Antimicrob Agents Chemother 1999; 43: 264856. 264. Macfarlane EL, Kwasnicka A, Ochs MM, Hancock RE. PhoP-PhoQ homologues in Pseudomonas aeruginosa regulate expression of the outermembrane protein OprH and polymyxin B resistance. Mol Microbiol 1999; 34: 305-16. 265. Wosten MM, Groisman EA. Molecular characterization of the PmrA regulon. J Biol Chem 1999; 274: 27185-90. 266. Baker SJ, Gunn JS, Morona R. The Salmonella typhi melittin resistance gene pqaB affects intra-

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cellular growth in PMA-differentiated U937 cells, polymyxin B resistance and lipopolysaccharide. Microbiology 1999; 145: 367-78. 267. Alavandi SV, Subashini MS, Ananthan S. Occurrence of haemolytic and cytotoxic Aeromonas species in domestic water supplies in Chennai. Indian J Med Res 1999; 110: 50-5. 268. Ghinsberg RC, Dror R, Nitzan Y. Isolation of Vibrio vulnificus from sea water and sand along the Dan region coast of the Mediterranean. Microbios 1999; 97: 7-17. 269. I.~,clercq R. Activit6 in vitro de la pristinamycine sur les germes respiratoires. Presse M6d 1999; 28 Suppl 1: 6-9. 270. Klossek JM, Mayaud C. Conclusions: quelle stratEgie antibiotique dans les infections respiratoires de l'adulte? Presse M6d 1999; 28 Suppl 1: 16-18. 271. Poirier R. La place de la pristinamycine dans les pneumopathies aiguEs communautaires de l'adulte. Presse MEd 1999; 28 Suppl 1: 13-15. 272. Pessey JJ. Place de la pristinamycine dans le traitement des sinusites aiguEs de l'adulte en ville. Presse MEd 1999; 28 Suppl 1: 10-12. 273. Madinier IM, Fosse TB, Hitzig C, Charbit Y, Hannoun LR. Resistance profile survey of 50 periodontal strains of Actinobacillus actinomyectomcomitans. J Periodontol 1999; 70: 88892. 274. Mayence C, Dompmartin A, Verneuil L, Michel M, Leroy D. Value of patch tests in pristinamycin-induced drug eruptions. Contact Dermatitis 1999; 40: 161-2. 275. Schlegel L, Sissia G, Fremaux A, Geslin P. Diminished killing of pneumococci by pristinamycin demonstrated by time-kill studies. Antimicrob Agents Chemother 1999; 43: 2099-100. 276. Lamb HM, Figgitt DP, Faulds D. Quinupristin/dalfopristin: a review of its use in the management of serious Gram-positive infections. Drugs 1999; 58: 1061-97. 277. Raad I, Bompart E Hachem R. Prospective, randomized dose-ranging open phase II pilot study of quinupristin/dalfopristin versus vancomycin in the treatment of catheter-related staphylococcal bacteremia. Eur J Clin Microbiol Infect Dis 1999; 18: 199-202. 278. Nichols RL, Graham DR, Barriere SL, Rodgers A, Wilson SE, Zervos M, Dunn DL, Kreter B. Treatment of hospitalized patients with complicated gram-positive skin and skin structure infections: two randomized, multicentre studies of quinupristin/dalfopristin versus cefazolin, oxacillin or vancomycin. Synercid Skin and Skin Structure Infection Group. J Antimicrob Chemother 1999; 44: 263-73. 279. Johnson CA, Taylor CA, III, Zimmerman SW, Bridson WE, Chevalier E Pasquier O, Baybutt RI. Pharmacokinetics of quinupristin-dalfopristin in continuous ambulatory peritoneal dialysis patients.

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Antimicrob Agents Chemother 1999; 43: 1526. 280. Maouad M, Fleischer-AB J, Sherertz EE Feldman SR. Significance-prevalence index number: a reinterpretation and enhancement of data from the North American contact dermatitis group. J Am Acad Dermatol 1999; 41: 573-6. 281. Gall R, Blakley B, Warrington R, Bell DD. Intraoperative anaphylactic shock from bacitracin nasal packing after septorhinoplasty. Anesthesiology 1999; 91: 1545-7. 282. Phillips I. The use of bacitracin as a growth promoter in animals produces no risk to human health. J Antimicrob Chemother 1999; 44: 725-8. 283. Santucci KA, Nelson DG, McQuillen KK, Duffy SJ, Linakis JG. Wood's lamp utility in the identification of semen. Pediatrics 1999; 104: 1342-4. 284. Stein GE. Comparison of single-dose fosfomycin and a 7-day course of nitrofurantoin in female patients with uncomplicated urinary tract infection. Clin Ther 1999; 21:1864-72. 285. Ikeda K, Ida O, Kimoto K, Takatorige T, Nakanishi N, Tatara K. Effect of early fosfomycin treatment on prevention of hemolytic uremic syndrome accompanying Escherichia coli O157:H7 infection. Clin Nephrol 1999; 52: 357-62. 286. Shiomi M, Togawa M, Fujita K, Murata R. Effect of early oral fluoroquinolones in hemorrhagic colitis due to Escherichia coli O157:H7. Pediatr int 1999; 41: 228-32. 287. Matsumoto T, Tateda K, Miyazaki S, Furuya N, Ohno A, Ishii Y, Hirakata Y, Yamaguchi K. Fosfomycin alters lipopolysaccharide-induced inflammatory cytokine production in mice. Antimicrob Agents Chemother 1999; 43: 697-8. 288. Ayres HM, Furr JR, Russell AD. Effect of permeabilizers on antibiotic sensitivity of Pseudomonas aeruginosa. Lett Appl Microbiol 1999; 28: 13-16. 289. Sanchez MS, Watts JL. Enhancement of the activity of novobiocin against Escherichia coli by lactoferrin. J Dairy Sci 1999; 82: 494-9. 290. Poirel L, Guibert M, Bellais S, Naas T, Nordmann P. Integron- and carbenicillinase-mediated reduced susceptibility to amoxicillin-clavulanic acid in isolates of multidrug-resistant Salmonella enterica serotype typhimurium DT104 from French patients. Antimicrob Agents Chemother 1999; 43: 1098-104. 291. Clark NC, Olsvik O, Swenson JM, Spiegel CA, Tenover FC. Detection of a streptomycin/spectinomycin adenylyltransferase gene (aadA) in Enterococcus faecalis. Antimicrob Agents Chemother 1999; 43: 157-60. 292. A1 Ghamdi MS, El Morsy F, A1 Mustafa ZH, A1 Ramadhan M, Hanif M. Antibiotic resistance of Escherichia coli isolated from poultry workers, patients and chicken in the eastern province of Saudi Arabia. Trop Med Int Health 1999; 4: 278-83.

Andreas H. Groll, Christine Chiou and Thomas J. Walsh

27 (SED-14, 937; SEDA-21, 288; SEDA-22, 290; SEDA-23, 298) ALLYLAMINES

Terbinafine In a randomized, double-blind comparison of terbinafine 250 mg/day (n = 146) with itraconazole 200 mg/day (n = 146), administered for 12 weeks for toenail onychomycosis, mycological cure rates at the 36-week followup endpoint (67% vs 61%) and the proportion of patients with adverse effects (23% vs 22%) were similar in both study arms. However, more patients taking terbinafine stopped treatment permanently because of treatment-related adverse events (8% vs 1%) (1c). In a double-blind, randomized, multicenter comparison of terbinafine (250 mg/day for 12 or 16 weeks) or itraconazole capsules (200 mg bd for 1 week every 4 weeks for 12 or 16 weeks), 236 patients reported at least one adverse event. All were within the known safety profle of both drugs, and there were no significant differences among the four treatment regimens. Continuous terbinafine was significantly more effective than intermittent itraconazole (mycological cure rates at week 72: 76%, 81%, 38%, and 49%; significant for all comparisons between terbinafine and itraconazole) (2C, 3c). Hematologic Granulocytopenia is a rare adverse effect of terbinafine. A 42-year-old man presented with fever and granulocytopenia (absolute neutrophil count: 340 x 106/1; temperature: 39.5 ~ C) after a 30 day course of oral terbinafine 250 mg/day for presumed onychomycosis (4A). The granulocyte count recovered promptly after withdrawal of the drug and administration of G-CSF for 2 days.

9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual24 J.K. Aronson, ed. ql/I

Antifungal drugs Skin Cutaneous adverse effects reportedly occur in 1-3% of patients taking terbinafine. The overwhelming majority of these reactions consist of mild to moderate macular exanthems. More serious skin disorders, such as eryth-

ema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema toxicum, cutaneous lupus erythematosus, and generalized pustular eruptions are rare. A 62-year-old diabetic man on stable oral medication with glibenclamide, metformin, Zestoretic (lisinopril + hydrochlorothiazide), gemfibrozil, and aspirin developed febrile generalized pustular eruptions after 44 days of therapy with oral terbinaline 250 mg/day (5A). Withdrawal of terbinafine and symptomatic treatment with hydrotherapy and topical and systemic steroids resulted in complete resolution of fever and pustulosis within 4 days. The erythematous component responded more slowly, and mildly pruritic erythematous plaques persisted for more than 40 days. A 74-year-old woman developed inverse psoriasis after 14 days of therapy with terbinafine 250 rag/day for onychomycosis (6A). The lesions resolved almost completely on withdrawal of terbinafine and topical therapy. Probable psoriatic onychodystrophy, misdiagnosed as onychomycosis and treated with terbinafine, induced inverse psoriasis, underscoring the importance of mycological confirmation of onychomycosis before therapy. Risk factors Children In an open noncomparative study of the use of terbinafine for 14 days to treat tinea capitis in 50 children and adolescents (mean age 7.6 years; range 24 months to 18 years) the clinical and mycological cure rates were 86%. The drug appeared to be well tolerated. Two children had reversible neutropenia, thought to be due to a preceding viral illness; other adverse effects were not observed (7c).

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AMPHOTERICIN B FORMULATIONS (SED-14, 922; SEDA-21, 282; SEDA-22, 285; SEDA-23, 289)

Amphotericin B deoxycholate (D-AmB) Liver Hepatotoxicity, a rare adverse effect of amphotericin, has recently been reported (8At).

315 Risk factors Children Data on the safety of D-AmB have been reported for 50 therapeutic courses in 44 children and adolescents with cancer and a median age of 6.8 years (range 9 months to 18 years) (10c). D-AmB was given in a dose of at 1 mg/kg over 2 hours for a mean duration of 7.8 days. Most of the patients received the drug as empirical antifungal therapy in the setting of persistent fever and neutropenia. Nephrotoxicity, defined as a 100% increase in the serum creatinine from baseline, was observed in only one patient. Infusionrelated reactions (fevers and/or rigors) occurred in 24% of treatment courses. Thus, D-AmB was relatively well tolerated in this population, although the mean duration of therapy was comparatively short.

A 26-year-old previously healthy man with life threatening pulmonary blastomycosis developed increased hepatic transaminases to a maximum of 10 times (AsT) and 20 times (A1T) the upper limit of the reference ranges 10 days after the addition of arnphotericin (0.5 mg/kg) to his initial itraconazole therapy (200 mg bd). The serum transaminase activities returned to normal within 4 days after withdrawal of amphotericin, and the blastomycosis was success- Individuals in developing countries Amphofully treated with itraconazole alone. A liver biopsy tericin is highly effective in the treatment of showed mild focal fatty changes but no evidence of visceral leishmaniasis (llC). In a prospective blastomycosis. s t u d y of 938 patients from Bihar, India, who received the drug in a dosage of 1 mg/kg/day The authors speculated that amphotericin infused over 2 hours for 20 days, serum cremay have facilitated the uptake of itraconazole atinine values over 177 #mol/1 were noted in into mammalian cells by its membrane6.3%, and acute renal insufficiency developed damaging action, leading to increased inter- in three patients. Two patients died possibly action of itraconazole with CYP450 enzymes related to amphotericin, one with renal insufand hepatocellular damage. ficiency, and one with hypokalemia and cardiac arrest. Infusion-related chills occurred in 92% and fever in 40% of patients. The parasitoloU r i n a r y tract The nephrotoxicity of amphotericin B deoxycholate has been investigated gical cure rate (no relapse within 6 months) exceeded 99%. in a retrospective multicenter study in 239 immunosuppressed patients with suspected or proven aspergillosis for a median duration of 15 Aerosolized amphotericin B days (9c). The serum creatinine concentration doubled in 53% of the patients and exceeded In a prospective, randomized, multicenter trial 221 Ixmol/l in 29%; 15% underwent dialysis, inhalation of aerosolized amphotericin (10 mg and 60% died. Multivariate Cox proportional bd) has been investigated as prophylaxis against hazards analysis showed that patients whose invasive aspergillosis in 382 cancer patients creatinine concentration exceeded 221 Ixmol/1, with an anticipated duration of neutropenia of and patients with allogeneic and autologous at least 10 days (12c). While there was no bone-marrow transplants were at greatest risk difference in the incidence of invasive asperof requiring hemodialysis. The use of hemo- gillosis, infection-related mortality, and overall dialysis, the duration of amphotericin therapy, mortality, 31% of the patients discontinued amand the use of nephrotoxic agents were asso- photericin B prophylaxis prematurely owing to ciated with a greater risk of death, whereas adverse effects (55%; most commonly cough, patients who underwent solid organ transplant- bad taste, nausea), inability to cooperate further ation were at lowest risk. The findings of this (30%), violation of the study protocol (11%), study suggest that raised creatinine concentra- and non-compliance (4%). tions during therapy with amphotericin are associated with a substantial risk of hemodialysis and a higher mortality rate, but these risks vary in different patients.

316

Chapter 27

Andreas H. Groll, Christine Chiou and Thomas J. Walsh

Amphotericin B Colloidal Dispersion (ABCD) The safety of amphotericin B colloidal dispersion (ABCD) has been reviewed using data from 572 irnmunocompromised patients refractory to or intolerant of standard therapies enrolled in five phase I/II clinical trials (13R). The mean daily dose of ABCD was 3.85 (median 3.8; range 0.1-9.1) mg/kg and the mean duration of treatment was 25 (median 16; range 1-409) days. Overall, the principal adverse events associated with ABCD therapy were chills (52%), fever (39%), and hypotension (19%). These infusion-related reactions were dose dependent and were the dose-limiting adverse events, defining the maximum tolerated dosage at 7.5 mg/kg. ABCD did not adversely affect renal function, as measured by overall changes in serum creatinine from baseline to the end of therapy, even in patients with pre-existing renal impairment; only 3.3% of patients discontinued therapy because of nephrotoxicity. Complete or partial responses to treatment were reported in 149 of 260 evaluable patients (57%). The safety and efficacy of ABCD in 220 bone-marrow transplant recipients enrolled in the five phase I/II trials have been published separately (14R). The median dose in this population was 4 (range 0.4-8.0) mg/kg, and the median duration of treatment was 16 (range 1409) days. Overall, 37 (19%) of the patients had nephrotoxicity, defined as a doubling of serum creatinine from baseline, an increase of 88 txmol/l from baseline, or at least a 50% fall in calculated creatinine clearance. There were no significant changes in hepatic transaminases, alkaline phosphatase, or total bilirubin. Fever and chills were reported by 12% and 11% of patients respectively. Other acute, severe, infusion-related adverse events were hypoxia (4.1%), hypertension (2.7%), and hypotension (2.7%)9

Amphotericin B Lipid Complex (ABLC) Safety data have been published in a retrospective analysis of 551 patients with invasive fungal infections intolerant of or refractory to conventional antifungal therapy, 73 of whom received ABLC initially at 3 mg/kg/day in-

stead of 5 m g/kg/day, as recommended in the protocol (15~). There were no notable differences in adverse events (increased serum creatinine, infusion-related chills) between the two groups9 Serum creatinine values were improved or stable at the end of therapy in 78% and 70% of patients respectively. Two smaller series have addressed the safety of ABLC in immunocompromised patients (16 c, 17c). Each included about 30 patients who were treated with median dosages of 4.8 and 5.0 mg/kg for a median of 8 and 14 days. In contrast to a previous retrospective analysis that showed a 74% withdrawal rate, mostly 9 due to infusion-related reactions (18 R C ), ABLC was well tolerated, with a withdrawal rate of 6% and 0% and an overall trend for stable or improved serum creatinine values at the end of therapy. Similarly, 13 infusion-related reactions have been reported among 308 infusions in four of 10 patients with hematological malignancies receiving ABLC 3 mg/kg/day (19c). These reactions (fever, rigors, myalgias) occurred during the first infusions, were judged to be mild, and resolved during later infusions. ABLC was well tolerated by 30 persistently febrile neutropenic patients with hematological malignancies who received it in a low dosage of 1 mg/kg/day for a median of 7.5 (range 2-19) days (20c). Seven patients (23%) had mild to moderate infusion-related reactions, and no patient had nephrotoxicity. In one patient, ABLC was discontinued owing to intolerable infusion-related fever and chills. Cardiovascular Severe hypertension associated with the use of amphotericin B deoxycholate has been reported (21a). A 67-year-old man with multiple intraperitoneal and urinary fungal pathogens and a history of wellcontrolled chronic hypertension developed severe hypertension associated with an infusion of ABLC (22A). He received a 5 mg test dose, which was tolerated without incident. About 60 minutes into the infusion (5 mg/kg), his blood pressure rapidly increased to 262/110 mmHg from a baseline of 150/80 mmHg. His temperature increased to 39.8 ~ C, and tachycardia developed (up to 121 bpm). The infusion was stopped, and he was given morphine, propanolol, and paracetamol. His blood pressure returned to baseline over the next 2 hours. Rechallenge with ABLC on the next day resulted in an identical reaction despite premedication with pethidine, diphenhydramine, and morphine. ABLC was permanently withdrawn,

Antifungal drugs

Chapter27

and the infection was managed with high dosages of fluconazole. The etiology of amphotericin-associated hypertension has not been elucidated, but it may be related to vasoconstriction. Of note, the traditional test dose appears not to identify individuals predisposed to hypertensive reactions; four of six cases of amphotericin-associated hypertension received test doses without incident. Risk factors Children The safety and efficacy of amphotericin B lipid complex (ABLC) have been studied in an open-label, emergency use, multicenter study in 111 treatment episodes in children with invasive mycoses refractory to or intolerant of conventional antifungal drugs (23c). The mean dally dosage was 4.85 (range, 1.1-9.5) mg/kg, and the mean duration of therapy was 33 (range 1-191) days. While the proportion of patients with deteriorating renal function was not mentioned, the mean serum creatinine concentration in the entire study population did not change significantly between baseline (109/zmol/1) and withdrawal of ABLC (117 Ixmol/l) over 6 weeks. Similarly, there were no significant differences between initial and end-of-therapy concentrations of serum potassium, magnesium, AsT, A1T, alkaline phosphatase, and hemoglobin. However, there was a significant increase in mean total bilirubin (from 63 to 91 txmol/1) at the end of therapy. ABLC was withdrawn owing to toxicity in seven of the 11 l children; adverse events leading to withdrawal included intolerable infusion-related reactions and allergic reactions. Among the 54 evaluable patients, a complete or partial therapeutic response was obtained in 38.

Liposomal amphotericin B

(L-AmB) The results of a randomized, double-blind, multicenter comparison of liposomal amphotericin (3.0 mg/kg/day) with conventional amphotericin (0.6 mg/kg/day) for empirical antifungal therapy in patients with persistent fever and neutropenia have been reported (24c). The mean duration of therapy was 10.8 days for liposomal amphotericin (343 patients) and 10.3 days for conventional amphotericin (344 patients). While the composite rates of successful treatment were similar (50% for liposomal

317 amphotericin and 49% for conventional amphotericin), significandy fewer of the patients who received the liposomal preparation had infusion-related fever (17% vs 44%), chills or rigors (18% vs 54%), or other reactions, including hypotension, hypertension, and hypoxia. Nephrotoxicity (defined by a serum creatinine concentration twice the upper limit of normal) was significantly less frequent among patients treated with liposomal amphotericin (19%) than among those treated with conventional amphotericin (34%). In a smaller randomized, double-blind, placebo-controlled study liposomal amphotericin (2 mg/kg three times weekly) was investigated as prophylaxis against fungal infections in 161 patients undergoing chemotherapy or bone-marrow transplantation for hematological malignancies (25c). There were no statistically significant differences between the two study arms in the incidences of the most frequently reported adverse events or in changes in renal and hepatic laboratory parameters. Despite a sizable rate of suspected or documented fungal infections in the placebo arm, prophylactic therapy with liposomal amphotericin did not lead to a significant reduction in fungal infections or the requirement for systemic antifungal therapy. Skin An allergic skin reaction to amphotericin has been reported (26A).

A 3-year-old child had a severe allergic reaction during treatment with liposomal amphotericin for persistent neutropenic fever following unrelated allogeneic cord blood stem cell transplantation. The patient developed an extensive maculopapular rash and severe itching that was unresponsive to antihistamine and corticosteroid medication and resolved only after drug withdrawal. Continuation of therapy with conventional amphotericin for 20 days was well tolerated, suggesting that the lipid carrier was responsible for the adverse event.

Amphotericin B formulated in parenteral lipid emulsions The adverse effects of amphotericin prepared in nutritional fat emulsion (a non-approved mode of amphotericin administration) have been compared with those of amphotericin prepared in 5% dextrose in two studies. While one of the studies showed a significantly lower frequency of infusion-related reactions and hypokalemia in patients receiving the fat emulsion

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(27c), there were no differences in safety and tolerance between the two formulations in the other study (10c). The safety of arnphotericin B prepared in nutritional fat emulsions has been discussed in past volumes (SEDA-21,282; SEDA-22, 285). Because of stability concerns and lack of systematic safety data, this form of amphotericin cannot be recommended.

after vaginal administration of miconazole capsules to two postmenopausal patients (30A) and after oral administration of miconazole gel in three elderly patients with oral candidiasis (31A). In both instances there were no major bleeding complications. However, it appears prudent to consider the use of non-azole topical antifungal agents in patients who are taking CYP3A4 metabolized drugs with a narrow therapeutic index.

AZOLE DERIVATIVES (SED-14,928; Antihistamines Ebastine (10 and 20 mg/day) SEDA-21, 282; SEDA-22, 293; SEDA-23, 295)

Drug interactions with antifungal azole derivatives Drug interactions with the antifungal azoles are common for several reasons: 9 they are substrates of CYP3A4, but also interact with the heme moiety of CYP3A, resulting in non-competitive inhibition of oxidative metabolism of many CYP3A substrates; to a lesser extent they also inhibit other CYP450 isoforms; 9 although fluconazole undergoes minimal CYP-mediated metabolism, it nevertheless inhibits CYP3A4 in vitro, albeit much more weakly than other azoles; however, fluconazole also inhibits several other CYP isoforms in vitro and interacts with enzymes involved in glucuronidation (281r 9 interaction of antifungal azoles and other CYP3A substrates can also result from inhibition of P-glycoprotein-mediated efflux; P-glycoprotein is extensively colocalized and exhibits overlapping substrate specificity with CYP3A (28R); 9 the systemic availability of the antifungal azoles depends in part on an acidic gastric environment and the activity of intestinal CYP3A4 and P-glycoprotein. Alfentanil In a randomized, double-blind, placebo-controlled, cross-over study in nine subjects fluconazole 400 mg reduced the clearance of alfentanil 20 Izg/kg by 55% and increased alfentanil-induced subjective effects (29c). Anticoagulants Potentiation of the anticoagulatory effects of acenocoumarol was noted

had no clinically important effect on QTc interval in adults, including elderly people, children, and patients with hepatic or renal impairment, and coadministration with ketoconazole or erythromycin did not lead to significant changes in the QTc interval (32 C, 33c). Similarly, when single doses of erythromycin (333 rag) or ketoconazole (200 rag) were given to healthy men who used levocabastine, two sprays per nostril (0.05 rag~spray) bd for 6 days, there were no changes in the pharmaeokinetics of levocabastine or in the QTc interval (34c ).

Benzodiazepines Alprazolam and triazolarn In a double-blind, cross-over kinetic and dynamic study of the interaction of ketoconazole with alprazolam and triazolam, two CYP3A4 substrate drugs with different kinetic profiles, impaired clearance by ketoconazole had more profound clinical consequences for triazolam than for alprazolam (35c). Midazolam The pharmacokinetics and pharmacodynamics of midazolam are significantly affected by antifungal azoles. The effects offluconazole (400 mg loading dose followed by 200 rag~day) on the kinetics of midazolam have been studied in 10 mechanically ventilated adults receiving a stable infusion of midazolam (36c). Concentrations of midazolam were increased up to 4-fold after the start of fluconazole therapy; these changes were most marked in patients with renal insufficiency. During the study, the ratio of ct-hydroxymidazolam to midazolam progressively fell. The authors concluded that in ICU patients receiving fluconazole, reduction of the dose of midazolam should be considered if the degree of sedation is increasing. Similarly, in a study of the pharmacokinetics and pharmacodynamics of oral midazolam 7.5-15 mg, switching from inhibition of metabolism by itraconazole 200 rag~day to induction

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of metabolism by rifampicin 600 mg/day caused an up to 400-fold change in the AUC of oral midazolam (37c).

319 flux. However, the rate of absorption increased, suggesting inhibition by ketoconazole of the gut wall metabolism of (R/S)-verapamil by CYP3A4 (41c).

Buspirone The interaction of itraconazole with the active 1-(2-pyrimidinyl)-piperazine metabolite of buspirone, a non-benzodiazepine anxiolytic agent, has been studied after a single oral dose of buspirone 10 mg (38c). Itraconazole reduced the mean AUC of the metabolite by 50% and the Cmax by 57%, whereas the mean AUC and Cmax of the parent drug were increased 14.5 and lO.5-fold respectively. Thus, itraconazole caused relatively minor changes in the plasma concentrations of the active piperazine metabolite of buspirone, although it had major effects on the concentrations of buspirone after a single oral dose.

Calcium antagonists Nifedipine Fluconazole can enhance the blood pressure lowering effects of the calcium antagonist nifedipine by increasing its plasma concentrations, most likely by inhibition of CYP3A4. This interaction has been elegantly documented in a 16-year-old patient with malignant pheochromocytoma taking chronic nifedipine for arterial hypertension who was given fluconazole for Candida septicemia (39A). The authors correctly pointed out that this drug interaction may also occur with other dihydropyridine calcium channel blockers, and that it may be even more pronounced with other antifungal azoles. The effects of ketoconazole 200 mg on the pharmacokinetics of nisoldipine 5 mg have been investigated in a randomized crossover trial (40c). Pretreatment with and concomitant administration of ketoconazole resulted in 24- and 11-fold respective increases in the AUC and Cmax of nisoldipine. The ketoconazole-induced increase in plasma concentrations of the metabolite M9 was of similar magnitude. Thus, ketoconazole and other potent inhibitors of CYP3A should not be used concomitantly with nisoldipine. Nisoldipine

In an intestinal perfusion study of the effect of ketoconazole 40 mg/l on the jejunal permeability and first-pass metabolism of (R)and (S)-verapamil 120 mg/l in six healthy volunteers, ketoconazole did not alter the jejunal permeability of the isomers, suggesting that it had no effect on the P-glycoprotein mediated efVerapamil

Carbamazepine Fluconazole can cause carbamazepine toxicity, presumably by inhibition of CYP3A4 (42 A ). A 33-year-old man on stable therapy with carbamazepine (400 mg tds) for a seizure disorder became stuporose due to carbamazepine toxicity after taking fluconazole 150 mg/day for 3 days. Withdrawal of both drugs resulted in a fall in carbamazepine concentrations (maximum concentration 25 Izg/ml) and return of the patient's baseline mental status. Carbamazepine was restarted and the patient had no further adverse events. Table 1. Changes in ciclosporin kinetics during coadministration of fluconazole Parameter

Day0

AUC (ng.tdml)

2887 4750 4052 2330 701 941 768 498 207 274 293 174 17 13 12 30 3.0 2.0 2.5 3.0

Cmax (ng/ml) Cmin (ng/ml) CL (ml/min/kg) tmax (h)

Day4

Day7

Day 14

Ciclosporin Fluconazole can increase concentrations of ciclosporin by inhibiting CYP3A4. This effect is dose-dependent, with no interaction at a fluconazole dosage of 100 rag~day. The effects of higher dosages of fluconazole on ciclosporin immunosuppression have been investigated in six renal transplant patients in a prospective, unblinded, crossover study (43c). Baseline renal function, ciclosporin AUC, Cmax, Cmin, tmax, and clearance were compared with those 2, 4, and 7 days after starting fluconazole orally in a dosage of 200 mg/day. From day 8 onwards the ciclosporin dose was reduced by 50% and the above parameters were repeated on day 14. The results are shown in Table 1. On repeated-measures ANOVA only the AUC and Cmax on day 4 of fluconazole were significantly higher than on day O. There were no significant changes in ciclosporin clearance and tmax. The authors concluded that changes in Cmin may not be sensitive enough to detect the described interaction and suggested monitoring

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the AUC near day 4 of treatment to guide ciclosporin dosage adjustments in all patients taking concomitant fluconazole. Clarithromycin A report of three HIVnegative but nevertheless polymedicated patients has suggested that concomitant therapy with itraconazole and clarithromycin can lead to increased clarithromycin exposure, with an increased metabolic ratio, possibly related to itraconazole's effect on CYP3A4 (44A). Nevertheless, in none of the three reported individuals were clinical adverse effects from this presumed interaction noted. Clozapine ltraconazole 200 mg had no significant effect on serum concentrations of clozapine (200-550 mg/day) or desmethylclozapine in seven schizophrenic patients (45c). Cyclophosphamide A retrospective study in 22 children with cancers has addressed the potential interaction between fluconazole and cyclophosphamide. Cyclophosphamide is a prodrug that is metabolized by CYP450 enzymes to produce alkylating species, which are cytotoxic, and the extent of cyclophosphamide metabolism correlates with both treatment efficacy and toxicity. Children with an established profile of cyclophosphamide metabolism who were not receiving other drugs known to affect drug metabolism were selected; nine were taking fluconazole and 13 were controls. The plasma clearance was significantly lower in patients taking concomitant fluconazole (2.4 vs 4.2 l/h/m2 ). In vitro studies in six human liver microsomes showed that the IC5o offluconazole for reduction of 4-hydroxycyclophosphamide production was 9--80 lzmol/l (46E). It is unclear whether this interaction is associated with a reduction in the therapeutic efficacy of cyclophosphamide. Digoxin Itraconazole increases the digoxin AUCo-72 by about 50%, and reduces its renal clearance by about 20% (47c). Apart from inhibition of the renal secretion of digoxin, which is probably mediated by inhibition of P-glycoprotein, a study in guinea pigs also showed significantly reduced biliary excretion of digoxin by itraconazole, suggesting that the interaction between itraconazole and digoxin may not only be due to a reduction in renal clearance, but also to a reduction in the

metabolic clearance of digoxin by itraconazole (48~). Donepezil Donepezil 5 mg produced no change in plasma concentrations of ketoconazole 200 mg (49c). Famotidine Famotidine (40 mg/kg/day) reduced the peak and trough concentrations of itraconazole 200 mg/kg/day by about 35% in 18 patients undergoing chemotherapy for hematological malignancies (50c).

Fentanyl Fentanyl

is metabolized by CYP3A4. However, the pharmacokinetics and pharmacodynamics of fentanyl 3 Ixg/kg were similar after both itraconazole 200 mg and placebo in 10 healthy volunteers (51c). Grapefruit juice The effect of grapefruit juice on the systemic availability of itraconazole capsules has been investigated in a randomized, two-way, cross-over design in 11 healthy volunteers (52c). Grapefruit juice reduced the mean itraconazole AUCo-48by 43% and the mean hydroxyitraconazole AUCo-72 by 47%. Grapefruit juice also significantly delayed the mean itraconazole tmax from 4 to 5.5 hours. The mechanisms for the impaired absorption of itraconazole in the presence of grapefruit juice remain to be elucidated; however, grapefruit juice is acidic and an inhibitor of CYP3A4. Unexpectedly, in another study, grapefruit juice did not affect the pharmacokinetics of itraconazole in 22 healthy men while orange juice reduced the Cmax, trnax, and AUC (53c). Halofantrine Halofantrine, a highly lipophilic antimalarial drug with poor and erratic absorption, is metabolized to its equipotent metabolite, desbutylhalofantrine, and this is inhibited by oral ketoconazole (54c). Haloperidol The effects of itraconazole (200 mg/day for 7 days) on the steady-state plasma concentrations of haloperidol and its reduced metabolite have been investigated in schizophrenic patients receiving haloperidol 12 or 24 rag~day (55c). Itraconazole significantly increased trough plasma concentrations of both haloperidol and reduced haloperidol (17 vs 13 ng/ml and 6.1 vs 4.9 ng/ml respectively). There was no change in clinical symptoms, but neurological adverse effects of haloperidol were

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significantly increased during itraconazole coadministration. Similar findings in a similar study were reported for bromperidol and its reduced metabolite, although there were no differences in clinical symptoms or neurological adverse effects during concomitant itraconazole therapy (56c). H I V protease inhibitors Amprenavir The effects of coadministration of ketoconazole 400 mg and amprenavir 1200 mg, an HIV-1 protease inhibitor that is mostly metabolized by CYP3A4, have been studied in an openlabel, randomized, balanced, single-dose threeperiod, cross-over study in 12 healthy men (57c). Coadministration of the two drugs increased the amprenavir AUC by 31% and reduced its Cmax by 16%. Amprenavir increased the AUC of ketoconazole by 44% and increased its half-life and Cmax by 23% and 16% respectively. Thus, coadministration of amprenavir and ketoconazole result in statistically significant increases in the AUCs of both agents, but the clinical significance of these changes remains to be investigated. Indinavir The pharmacokinetic interaction of fluconazole 400 mg od and indinavir 1000 mg tds has been evaluated in a placebo-controlled, cross-over study for 8 days; there was no significant interaction (58c).

HMG-CoA reductase inhibitors Antifungal azoles can increase the systemic exposure to certain HMG-CoA reductase inhibitors by inhibiting CYP3A in the liver and perhaps the intestine (28R), potentially leading to hepatotoxicity and rhabdomyolysis. However, the inhibitory effects of azoles on the metabolism of these drugs varies, as studies with itraconazole have shown. Atorvastatin In a randomized, double-blind, placebo-controlled, cross-over study in 10 healthy volunteers given atorvastatin 40 mg, itraconazole 200 mg increased the AUCo-7e and the half-life of atorvastatin acid about 3fold, without a change in Cmax (59c). The AUCo-72 of atorvastatin lactone was increased about 4-fold, and the peak serum concentration and half-life were increased more than 2-fold. Itraconazole significantly reduced the Cmax and AUCo-7e of 2-hydroxyatorvastatin acid and 2-hydroxyatorvastatin lactone and in-

321

creased the half-life of 2 hydroxyatorvastatin lactone. Cerivastatin Cerivastatin uses a secondary CYP2C8-mediated metabolic pathway, which is unaffected by itraconazole (28R). The effects of itraconazole on the pharmacokinetics of cerivastatin and its major metabolites have been investigated in a randomized, doubleblind, cross-over study (60c). Inhibition of the CYP3A4-mediated M-1 pathway led to raised serum concentrations of cerivastatin, cerivastatin lactone, and metabolite M-23, resulting in increased concentrations of active HMG-CoA reductase inhibitors. However, the effect was modest. Fluvastatin The effects of itraconazole 100 mg on the pharmacokinetics of fluvastatin 40 mg have been studied in a randomized, placebocontrolled, cross-over study in 10 healthy volunteers (61c). Itraconazole had no significant effect on the Cmax or total AUC of fluvastatin, but slightly prolonged its half-life. Lovastatin The effects of itraconazole 100 mg on the pharmacokinetics of lovastatin 40 mg have been studied in a randomized, placebocontrolled, cross-over study in 10 healthy volunteers (61c). Itraconazole, even in this low dosage, greatly increased plasma concentrations of lovastatin and its active metabolite, lovastatin acid. It increased the Cmax of Iovastatin about 15-fold and the total AUC by more than 15-fold; similarly, the Cmaxand total AUC of lovastatin acid were increased about 12- and 15-fold respectively. Pravastatin The effects of itraconazole 200 mg on the pharmacokinetics of pravastatin have been studied in a randomized, double-blind, cross-over study in 10 healthy volunteers (62c). Itraconazole slightly increased the AUC and Cmax of pravastatin, but the changes were not statistically significant; the half-life was not altered. Simvastatin The effects of itraconazole 200 mg on the pharmacokinetics of simvastatin have been studied in a randomized, double-blind, cross-over study in 10 healthy volunteers (62 C ). Itraconazole increased the Cmax and AUC of simvastatin and simvastatin acid at least 10fold. The Cmax and AUC of total simvastatin

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acid (naive simvastatin acid plus that derived by hydrolysis of the lactone) were increased 17and 19-fold respectively, and the half-life was increased by 25%. Two cases have been reported in which rhabdomyolysis occurred after coadministration of simvastatin (20 mg/day) and ketoconazole (63 a ). The authors of these papers concluded that concomitant use of atorvastatin, lovastatin, and simvastatin with itraconazole should be avoided or that the doses should be reduced, but that fluvastatin and pravastatin have much less potential than other statins for clinically significant interactions with itraconazole and other CYP3A4 inhibitors. The effects of cerivastain are intermediate.

Local anesthetics

Bupivacaine The interaction of itraconazole (200 mg orally od for 4 days) with a single dose of intravenous racemic bupivacaine (0.3 mg/kg given over 60 minutes) has been examined in a placebocontrolled cross-over study in 10 healthy volunteers (64c). Itraconazole reduced the clearance of R-bupivacaine by 21% and that of S-bupivacaine by 25%, but had no other significant effects on the pharmacokinetics of the enantiomers. Reduction of bupivacaine clearance by itraconazole is likely to increase steady-state concentrations of bupivacaine enantiomers by 20-25%, and this should be taken into account in the concomitant use of itraconazole and bupivacaine. Ropivacaine Ketoconazole 400 mg caused only a minor reduction in the clearance of ropivacaine, a local anesthetic, which is mostly metabolized by CYPIA2 (65c). Methadone In a randomized, double-blinded, placebo-controlled study in 25 patients fluconazole 200 mg/day increased methadone concentrations, but patients treated with fluconazole did not have signs or symptoms of significant narcotic overdose (66 c ).

placebo, increased the Cmax 1.9-fold, and prolonged the half-life 2.4-fold, probably by inhibition of CYP3A4. Similar effects were found in a study of the effects of itraconazole on the kinetics of intravenous methylprednisolone in a double-blind, randomized, cross-over study in nine healthy volunteers (68c). Itraconazole (200 mg for 4 days) increased the AUC of methylprednisolone (16 mg on day 4) 2.6-fold, and the AUC12-24 12-fold. The systemic clearance of methylprednisolone was reduced to 40% by itraconazole and the half-life was increased from 2.1 to 4.8 hours. The mean morning plasma cortisol concentration was only 9% of that during the placebo phase. Thus, concomitant itraconazole greatly increased exposure to methylprednisolone during the night-time, probably by inhibition of CYP3A4-mediated metabolism of methylprednisolone, and led to enhanced adrenal suppression. Omeprazole In 11 healthy volunteers omeprazole 40 mg reduced the systemic availability of itraconazole 200 mg; these two drugs should therefore not be taken together (69c).

Oral contraceptives

Itraconazole can delay withdrawal bleeding in women using oral contraceptives (70c). An analysis using data from a spontaneous adverse drug reaction reporting system in the Netherlands and logistic regression analysis showed an odds ratio of 85 (CI = 32, 230) for delayed withdrawal bleeding in women who used both drugs concomitantly compared with woman who used neither oral contraceptives nor itraconazole. Nine of the 10 reports of delayed withdrawal bleeding concerned oral contraceptives containing desogestreL In an open cross-over study in lO young healthy subjects fluconazole 150 mg increased the serum concentrations of ethinylestradiol at a dose of 30-35 lzg/day (71c).

Quinidine In vitro studies suggest that the oxMethylprednisolone

The interaction of itraconazole with oral methylprednisolone has been examined in a randomized, double-blind, cross-over study in 10 healthy volunteers taking either oral itraconazole 200 mg od or placebo for 4 days followed by methylprednisolone 16 mg (67c). Itraconazole increased the total AUC of methylprednisolone 3.9-fold compared with

idation of quinidine to 3-hydroxyquinidine is a specific marker reaction for CYP3A4 activity. In six young healthy men the pharmacokinetics of a single oral dose of quinidine 200 mg were studied before and during daily administration of intraconazole 100 mg (72c). Itraconazole reduced quinidine total clearance, partial clearance by 3-hydroxylation, and par-

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Chapter 27

tial clearance by N-oxidation by 61, 84, and 73%, respectively.

Reboxetine Reboxetine, a selective noradrenaline re-uptake inhibitor, is metabolized by CYP3A4. In 11 healthy volunteers ketoconazole increased the AUC of reboxetine by about 50% and increased its half-life (73c). The adverse effects profile of reboxetine was not altered by ketoconazole.

Rifampicin Rifampicin 600 mg/day for 14 days had a very strong inducing effect on the metabolism of a single dose of itraconazole 200 mg, indicating that these two drugs should not be used concomitantly (74c).

Tacrolimus Since tacrolimus (FK506) is metabolized by intestinal and hepatic CYP3A4, drugs that inhibit CYP3A4 may reduce the metabolism of tacrolimus and increase tacrolimus blood concentrations (75A). The effect of fluconazole on the blood concentrations of tacrolimus have been investigated in eight liver transplant patients in whom prophylactic fluconazole (200 mg/day) was withdrawn because of rises in hepatic transaminases (n = 6), renal dysfunction, or eosinophilia (n = i each) (76c). Calculated FK506 concentrations fell by 1381% (median 41%) between the fourth and ninth days after withdrawal of fluconazole. Tacrolimus blood concentrations should be carefully monitored and dosages increased as necessary after withdrawal of fluconazole. Individual case reports have also appeared. A 17-year-old man with cystic fibrosis who took itraconazole after a lung-liver transplant had high trough concentrations of tacrolimus, despite the relatively low dosage (0.1-0.3 mg/kg/day) (77c). A patient taking tacrolimus 0.085 mg/kg bd with itraconazole 20~400 mg/day, developed ketoacidosis, neutropenia, and thrombocytopenia, requiring the withdrawal of both drugs (78c). A 34-year-old renal transplant recipient taking a stable regimen of tacrolimus and methylprednisolone was given itraconazole 100 m~g bd for a yeast infection of the urinary tract (79A). Concomitant therapy with itraconazole led to a marked increase in tacrolimus trough concentrations on the second day of therapy (from 13 to 21 rig~rot) and an increase in serum creatinine concentrations, necessitating dosage reduction of tacrolimus by 50%. When itraconazole was withdrawn the effect of itraconazole on the kinetics of tacrolimus took 12 days to reverse.

323

The inhibitory effect of itraconazole occurred quickly, while the time of disappearance was much longer, which is important for clinical management. Thus, during coadministration of itraconazole with tacrolimus, close monitoring of tacrolimus blood concentrations and careful dosage adjustments are essential to avoid toxicity. Tolterodine Tolterodine is an antimuscarinic drug for the treatment of patients with an overactive bladder. It is eliminated by two different oxidative metabolic pathways: hydroxylation, catalysed by CYP2D6, and D-alkylation, catalysed by CYP3A. The pharmacokinetics and safety of tolterodine and its metabolites in the absence and presence of ketoconazole have been investigated in healthy volunteers with deficient CYP2D6 activity (poor metabolizers) (80c). Clearance of tolterodine fell by 60% during coadministration of ketoconazole, resulting in a 2.1-fold increase in AUC. Thus, caution is needed when ketoconazole and other potent inhibitors of CYP3A are used concomitantly with tolterodine. Vincristine Two adults with acute lymphoblastic leukemia developed unusually severe neurotoxicity caused by vincristine, which was probably the result of an interaction with itraconazole suspension (81A). Zidovudine Zidovudine glucuronidation in human hepatic microsomes in vitro was inhibited more by the combination of fluconazole with valproic acid than with other drugs, such as atovaquone and methadone (82E). Zolpidem Zolpidem is a short-acting imidazole-pyridine non-benzodiazepine hypnotic which is mainly transformed by CYP3A4. Ketoconazole 200 mg bd impaired the clearance of zolpidem 5 mg and enhanced its" benzodiazepine-like pharmacodynamic effects (83c). In contrast, itraconazole 100 mg bd and fluconazole 100 mg bd had small effects on zolpidem kinetics and dynamics (83r and in another study in 10 healthy volunteers itraconazole 200 mg did not alter the pharmacokinetics and pharmacodynamics of zolpidem 10 m g (84c).

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Fluconazole Cardiovaseular Fluconazole has been reported to cause torsade de pointes (85A). A 59-year-old woman with liver cirrhosis and Candida peritonitis developed long QT syndrome

and torsade de pointes after intravenous therapy with 400-800 mg/day of fluconazole for 65 weeks, followed by intraperitoneal administration (150 mg/day). One day after the second intraperitoneal administration, she developed palpitation, multifocal ventricular extra beats, and syncope. In contrast to a normal electrocardiogram on admission, electrocardiography showed polymorphic ventricular extra beats, T wave inversion, alternating T wave amplitude, and a prolonged QTc interval of 606 ms. Torsade de pointes required cardiopulmonary resuscitation. The fluconazole plasma concentration was 216 I~g/ml (usual target range at 400-800 mg/day: 18-28 p.g/ml). Fluconazole was withdrawn and all conduction abnormalities reversed fully within 3 weeks. This patient was not taking any concomitant drugs that prolong the QT interval, suggesting that fluconazole can prolong the QT interval.

with the gastrointestinal tract (7.7%), the skin (1.2%), or the liver and biliary system (0.5% or three patients). Overall, 18 patients discontinued treatment owing to adverse effects, mainly gastrointestinal. Dosage and age did not affect the incidence and pattern of adverse effects. Treatment-related laboratory abnormalities included transiently raised AlT (4.9%), AsT (2.7%), and alkaline phosphatase (2.3%). Although 99% of patients were taking concomitant drugs, there were no clinical or laboratory interactions. The safety profile of fluconazole was compared with those of other antifungal agents, mostly oral polyenes, by using a subset of data from five controlled studies. Adverse effects were reported by more patients treated with fluconazole (45 of 382; 12%) than by patients treated with comparator agents (25 of 381; 6.6%); vomiting and diarrhea were the most common events in both groups. The incidence and type of treatment-related laboratory abnormalities were similar in the two groups. Fluconazole was well tolerated, mirroring the favorable safety profile seen in adults.

Teratogenicity Liver Fluconazole can cause liver damage (86A). A 45-year-old woman with protracted cryptococcal meningoencephalitis developed fulminant hepatic failure secondary to high fluconazole serum concentrations, possibly precipitated by renal dysfunction induced by concomitant amphotericin therapy or concomitant therapy with lisinopril, atenolol, or amlodipine. Four days after the withdrawal of fluconazole, 400 mg/day, the serum concentration of fluconazole was 40 Ixg/ml. This and the previous case point to the potential risks of fluconazole therapy in the setting of renal insufficiency, particular in with higher dosages (400 mg/day and more). Risk factors Children The safety profile of fluconazole has been assessed in 562 children (aged 0-17 years; 323 boys and 239 girls), enrolled into 12 clinical studies of prophylactic or therapeutic fluconazole in predominantly immunocompromised patients (87c). Most of the children received multiple doses of fluconazole 1-12 mg/kg, given as oral suspension or intravenously. Overall, 58 children reported 80 treatment-related adverse effects. The most common adverse effects were associated

The risk of malformations and other outcomes in children exposed to fluconazole in utero has been examined in 165 women who had taken fluconazole just before or during pregnancy, mostly in the form of a single dose of 150 mg to treat vaginal candidiasis (88c). Birth outcomes (malformation, low birth weight, and preterm delivery) were compared with the outcomes among 13 327 women who did not receive any prescriptions during their pregnancies. The prevalence of malformation was 3.3% (four cases) among the 121 women who had used fluconazole in the first trimester, and 5.2% (697 cases) in offspring to controls (OR = 0.65; CI = 0.24, 1.77). The risks of preterm delivery (OR = 1.17; CI = 0.63, 2.17) and low birth weight (OR = 1.19; CI = 0.37, 3.79) were not significantly increased in association with fluconazole. Thus, the study showed no increased risk of congenital malformations, low birth weight, or preterm birth in offspring to women who had used single dose of fluconazole before conception or during pregnancy. The potential ability of fluconazole to modulate phenytoin teratogenesis has been studied in Swiss mice (89E). Pretreatment with a nonembryotoxic dosage of fluconazole (10 mg) potentiated phenytoin teratogenesis; combined treatment of fluconazole 50 mg with phenytoin

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resulted in a significant increase in embryo deaths. The mechanism of this teratological interaction remains to be established.

Itraconazole The safety of continuous itraconazole (50-200 mg/day for up to 3 months) in the treatment of onychomycosis and dermatomycosis has been reviewed, using published and unpublished data from clinical trials (90c). The overall incidence of adverse events in patients who took continuous itraconazole (21%) differed little from that in patients who took either topical miconazole or oral placebo (18%). The most frequently reported adverse events were gastrointestinal disorders (6.7%), headache (4.2%), and skin disorders (2.7%). No data were given on the incidence of serious adverse events attributed to itraconazole. Among laboratory abnormalities, clinically significant rises in liver function tests occurred in 3.4% of 527 patients treated with itraconazole (2.6% in patients treated with 50-200 mg/day for dermatomycosis vs 6.6% in patients treated with 200 mg/day for 3 months for onychomycosis). Gastrointestinal The oral cyclodextrin formulation of itraconazole enhances its systemic availability, but may have gastrointestinal adverse effects when used in escalating dosages exceeding 400 mg/day. A dose-ranging study of itraconazole in antifungal prophylaxis in 123 neutropenic patients with hematological malignancies has been reported (91c). The dosing regimens included itraconazole capsules 400, 600, or 800 mg/day and itraconazole cyclodextrin solution 400 and 800 mg/day (with an additional loading with 800 mg of the capsule formulation for 7 days). Ten of 28 patients taking 800 mg/day as a solution withdrew after 1-6 days with severe nausea and vomiting in temporal relation to ingestion of the drug. All the patients who discontinued the solution continued medication with itraconazole capsules in the same dosage without gastrointestinal adverse effects. Pseudomembranous colitis has been reported in association with exposure to itraconazole (92A). A 54-year-old man developed new abdominal pain and non-bloody diarrhea l month after exposure to a 7-day course of oral itraconazole 200 mg/day.

325 He was taking stable chronic sertraline, valproic acid, and perphenazine, and had not taken antimicrobial drugs for 6 months. Flexible sigmoidoscopy after clinical progression showed pseudomembranes, and subsequent evaluation excluded other causes of diarrhea. Although Clostridium difficile culture and toxin assay were eventually negative, possibly because of delayed stool sampling, he responded to a 10-day course of anti-anerobic drug therapy and was discharged with completely resolved symptoms. The authors proposed that itraconazole had disrupted the resident fungal flora of the colon. Risk factors Children The safety and efficacy of oral cyclodextrin itraconazole (5 mg/kg/day) as antifungal prophylaxis has been assessed in an open trial in 103 neutropenic children (median age 5 years; range 0-15 years) (93c). Prophylaxis was started at least 7 days before the onset of neutropenia and continued until neutrophil recovery. Of the 103 patients, only 47 completed the course of prophylaxis; 27 withdrew because of poor compliance, 19 because of adverse events, and 10 for other reasons. Serious adverse events (other than death) occurred in 21 patients, including convulsions (7), suspected drug interactions (6), abdominal pain (4), and constipation (4). The most common adverse events considered definitely or possibly related to itraconazole were vomiting (12), abnormal liver function (5), and abdominal pain (3). Tolerability of the study medication at endpoint was rated as good (55%), moderate (11%), poor (17%), or unacceptable (17%). There were no unexpected problems of safety or tolerability. Diabetes mellitus Adverse effects due to drug-drug interactions are not expected in diabetic patients using insulin and oral hypoglycemic drugs that are not metabolized by CYP3A4 (e.g. tolbutamide, gliclazide, glibenclamide, glipizide, and metformin). The pharmacokinetic and safety data from clinical trials and postmarketing surveillance have been reviewed to assess the safety of itraconazole in diabetic patients with onychomycosis or dermatomycosis (94c). Postmarketing surveillance, including all adverse event reports in patients taking itraconazole concomitantly with insulin or an oral hypoglycemic drug, revealed 15 reports suggestive of hyperglycemia and nine reports suggestive of hypoglycemia. In most patients there was no change in antidia-

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betic effect. From clinical trials in 189 diabetic patients taking itraconazole for various infections, one itraconazole-related adverse event was recorded; this was a case of aggravated diabetes in a renal transplant patient who was also taking ciclosporin.

Ketoconazole Liver A cohort study of the risk of acute liver injury among users of oral antifungal drugs has been performed in the general population of the General Practice Research Database in the UK (95c). The cohort included 69830 patients, free from liver and systemic disease, who had received at least one prescription for

oral griseofulvin, fluconazole, itraconazole, ketoconazole, or terbinafine between 1991 and 1996. Five cases of acute liver injury occurred during the use of oral antifungal drugs. Two were using ketoconazole, another two itraconazole, and one terbinafine. The incidence rates of acute liver injury were 134 (CI = 37, 488) per 100 000 person-months for ketoconazole, 10 (CI = 2.9, 38) for itraconazole, and 2.5 (CI = 0.4, 14) for terbinafine. One case was associated with past use of fluconazole. Ketoconazole was the antifungal drug that was associated with the highest relative risk, 228 (CI = 34, 933) compared with the risk among nonusers, followed by itraconazole and terbinafine, with relative risks of 17.7 (CI = 2.6, 73) and 4.2 (CI = 0.2, 25) respectively.

REFERENCES 1. Degreef H, Del Palacio A, Mygind S, Ginter G, Pinto Soares A, Zuhiaga De Cadena A. Randomized double-blind comparison of short-term itraconazole and terbinafine therapy for toenail onychomycosis. Acta Dermatol Venereol 1999; 79: 221-3. 2. Evans EG, Sigurgeirsson B. Double blind, randomised study of continuous terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis. The LION Study Group. Br Med J 1999; 318: 1031-5. 3. Sigurgeirsson B, Billstein S, Rantanen T, Ruzicka T, di Fonzo E, Vermeer BJ, Goodfield MJD, Evans EGV. LION Study: efficacy and tolerability of continuous terbinafine (Lamisil) compared to intermittent itraconazole in the treatment of toenail onychomycosis. Br J Dermatol Suppl 1999; 141 Suppl 56: 5-14. 4. ShapiroM, Li LJ, Miller J. Terbinafine-induced neutropenia. BrJ Dermatol 1999; 140: 1196-7. 5. Bennett ML, Jorizzo JL, White WL. Generalized pustular eruptions associated with oral terbinafine. Int J Dermatol. 1999; 38: 596-600. 6. Pauluzzi P, Boccucci N. Inverse psoriasis induced by terbinafine. Acta Dermatol Venereol 1999; 79: 389. 7. Krafchik B, Pelletier J. An open study of tinea capitis in 50 children treated with a 2-week course of oral terbinafine. J Am Acad Dermatol 1999; 41: 60-3. 8. Gill J, Sprenger HR, Ralph ED, Sharpe MD. Hepatotoxicity possibly caused by amphotericin B. Ann Pharmacother 1999; 33: 683-5. 9. Wingard JR, Kubilis P, Lee L, Yee G, White M, Walshe L, Bowden R, Anaissie E, Hiemenz J, Lister J. Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis. Clin Infect Dis 1999; 29: 1402-7.

10. Nath CE, Shaw PJ, Gunning R, McLachlan AJ, Earl JW. Amphotericin B in children with malignant disease: a comparison of the toxicities and pharmacokinetics of amphotericin B administered in dextrose versus lipid emulsion. Antimicrob Agents Chemother 1999; 43: 141723. 11. Thakur CP, Singh RK, Hassan SM, Kumar R, Narain S, Kumar A. Amphotericin B deoxycholate treatment of visceral leishmaniasis with newer modes of administration and precautions: a study of 938 cases. Trans R Soc Trop Med Hyg 1999; 93: 319-23. 12. Schwartz S, Behre G, Heinemann V, Wandt H, Schilling E, Aming M, Trittin A, Kern WV, Boenisch O, Bosse D, Lenz K, Ludwig WD, Hiddemann W, Siegert W, Beyer J. Aerosolized amphotericin B inhalations as prophylaxis of invasive Aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial. Blood 1999; 93: 3654-61. 13. Herbrecht R, Letscher V, Andres E, Cavalier A. Safety and efficacy of amphotericin B colloidal dispersion. An overview. Chemotherapy 1999; 45 Suppl 1: 67-76. 14. Noskin G, Pietrelli L, Gurwith M, Bowden R. Treatment of invasive fungal infections with amphotericin B colloidal dispersion in bone marrow transplant recipients. Bone Marrow Transplant 1999; 23: 697-703. 15. Linden P, Lee L, Walsh TJ. Retrospective analysis of the dosage of amphotericin B lipid complex for the treatment of invasive fungal infections. Pharmacotherapy 1999; 19: 1261-8. 16. Singhal S, Hastings JG, Mutimer DJ. Safety of high-dose amphotericin B lipid complex. Bone Marrow Transplant 1999; 24:116-17. 17. Cook G, Franklin IM. Adverse drug reactions associated with the administration of amphotericin

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B lipid complex. Bone Marrow Transplant 1999; 23: 132545. 18. Ringden O, Jonsson V, Hansen M, Tollemar J, Jacobsen N. Severe and common side-effects of amphotericin B lipid complex. Bone Marrow Transplant 1998; 22: 733-4. 19. Martino R, Subira M, Sureda A, Sierra J. Amphotericin B lipid complex at 3 mg/kg/day for treatment of invasive fungal infections in adults with haematological malignancies. J Antirnicrob Chemother 1999; 44: 569-72. 20. Martino R, Subira M, Domingo-Albos A, Sureda A, Brunet S, Sierra J. Low-dose ampbotericin B lipid complex for the treatment of persistent fever of unknown origin in patients with hematologic malignancies and prolonged neutropenia. Chemotherapy 1999; 45: 205-12. 21. 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. 22. Rowles DM, Fraser SL. Amphotericin 13 lipid complex (ABLC)-associated hypertension: case report and review. Clin Infect Dis. 1999; 29: 1564-5. 23. Walsh TJ, Seibel NL, Arndt C, Harris RE, Dinubile MJ, Reboli A, Hiemenz J, Chanock SJ. Amphotericin B lipid complex in pediatric patients with invasive fungal infections. Pediatr Infect Dis J 1999; 18: 702-8. 24. Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, Pappas P, Seibel N, Greenberg RN, Dummer S, Schuster M, Holcenberg JS. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. New Engl J Med. 1999; 340: 764-71. 25. Kelsey SM, Goldman JM, McCann S, Newland AC, Scarffe JH, Oppenheim BA, Mufti GJ. Liposomal amphotericin (AmBisome) in the prophylaxis of fungal infections in neutropenic patients: a randomised, double-blind, placebo-controlled study. Bone Marrow Transplant 1999; 23: 163-8. 26. Cesaro S, Calore E, Messina C, Zanesco L. Allergic reaction to the liposomal component of liposomal amphotericin B. Supportive Care Cancer 1999; 7: 284-6. 27. Nucci M, Loureiro M, Silveira F, Casali AR, Bouzas LF, Velasco E, Spector N, Pulcheri W. Comparison of the toxicity of amphotericin B in 5% dextrose with that of amphotericin B in fat emulsion in a randomized trial with cancer patients. Antimicrob Agents Chemother 1999; 43: 1445-8. 28. Gubbins PO, McConnell SA, Penzak SR. Antifungal Agents. In: Piscitelli SC, Rodvold KA, editors. Drug Interactions in Infectious Diseases. Totowa, NJ: Humana Press Inc, 2001: 185-217. 29. Palkama V J, Isohanni MH, Neuvonen PJ, Olkkola KT. The effect of intravenous and oral fluconazole on the pharmacokinetics and pharmaco-

327 dynamics of intravenous alfentanil. Anesth Analg 1998; 87: 190-4. 30. Lansdorp D, Bressers HP, Dekens-Konter JA, Meyboom RH. Potentiation of acenocoumarol during vaginal administration of miconazole. Br J Clin Pharmacol 1999; 47: 22545. 3l. Ortin M, Olalla JI, Muruzabal MJ, Peralta FG, Gutierrez MA. Miconazole oral gel enhances acenocoumarol anticoagulant activity: a report of three cases. Ann Pharmacother 1999; 33: 175-7. 32. Moss AJ, Chaikin P, Garcia JD, Gillen M, Roberts DJ, Morganroth J. A review of the cardiac systemic side-effects of antihistamines: ebastine. Clin Exp Allergy Suppl 1999; 29: 200-5. 33. Moss AJ, Morganroth J. Cardiac effects of ebastine and other antihistamines in humans. Drug Saf 1999; 21: 69-82. 34. Pesco-Koplowitz L, Hassell A, Lee P, Zhou H, Hall N, Wiesinger B, Mechlinski W, Grover M, Hunt T, Smith R, Travers S. Lack of effect of erythromycin and ketoconazole on the pharmacokinetics and pharmacodynamics of steady state intranasal levocabastine. J Clin Pharmacol 1999; 39: 76-85. 35. Greenblatt DJ, Wright CE, von Moltke LL, Harmatz JS, Ehrenberg BL, Harrel LM. Ketoconazole inhibition of triazolam and alprazolam clearance: differential kinetic and dynamic consequences. Clin Pharmacol Ther 1998 ; 64: 23747. 36. Ahonen J, Olkkola KT, Takala A, Neuvonen PJ. Interaction between fluconazole and midazolam in intensive care patients. Acta Anaesthesiol Scand 1999; 43: 509-14. 37. Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ. The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin. Eur J Clin Pharmacol 1998; 54: 53-8. 38. Kivisto KT, Lamberg TS, Neuvonen PJ. Interactions of buspirone with itraconazole and rifampicin: effects on the pharmacokinetics of the active 1-(2-pyrimidinyl)-piperazine metabolite of buspirone. Pharmacol Toxicol 1999; 84: 94-7. 39. Kremens B, Brendel E, Bald M, Czyborra P, Michel MC. Loss of blood pressure control on withdrawal of fluconazole during nifedipine therapy. Br J Clin Pharmacol 1999; 47: 707-8. 40. Heinig R, Adelmann HG, Ahr G. The effect of ketoconazole on the pharmacokinetics, pharmacodynamics and safety of nisoldipine. Eur J Clin Pharmacol 1999; 55: 57450. 41. Sandstrom R, Knutson TW, Knutson L, Jansson B, Lennernas H. The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)-verapamil in humans. Br J Clin Pharmacol 1999; 48: 180-9. 42. Nair DR, Morris HH. Potential fluconazoleinduced carbamazepine toxicity. Ann Pharmacother 1999; 33: 790-2. 43. Sud K, Singh B, Krishna VS, Thennarasu K, Kohli HS, Jha V, Gupta KL, Sakhuja V. Un-

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predictable cyclosporin-fluconazole interaction in renal transplant recipients. Nephrol Dial Transplant 1999; 14: 1698-703. 44. Auclalr B, Beruing SE, Huitt GA, Peloquin CA. Potential interaction between itraconazole and clarithromycin. Pharmacotherapy 1999; 19: 143944. 45. Raaska K, Neuvonen PJ. Serum concentrations of clozapine and N-desmethylclozapine are unaffected by the potent CYP3A4 inhibitor itraconazole. Eur J Clin Pharmacol 1998; 54: 167-70. 46. Yule SM, Walker D, Cole M, McSorley L, Cholerton S, Daly AK, Pearson AD, Boddy AV. The effect of fluconazole on cyclophosphamide metabolism in children. Drug Metab Dispos 1999; 27: 417-21. 47. Jalava KM, Partanen J, Neuvonen PJ. Itraconazole decreases renal clearance of digoxin. Ther Drug Monit 1997; 19: 609-13. 48. Nishihara K, Hibino J, Kotaki H, Sawada Y, Iga T. Effect of itraconazole on the pharmacokinetics of digoxin in guinea pigs. Biopharm Drug Dispos 1999; 20: 145-9. 49. Tiseo PJ, Perdomo CA, Friedhoff LT. Concurrent administration of donepezil HCI and ketoconazole: assessment of pharmacokinetic changes following single and multiple doses. Br J Clin Pharmacol 1998; 46 Suppl 1: 30-4. 50. Kanda Y, Kami M, Matsuyama T, Mitani K, Chiba S, Yazaki Y, Hirai H. Plasma concentration of itraconazole in patients receiving chemotherapy for hematological malignancies: the effect of famotidine on the absorption of itraconazole. Hematol Oncol 1998; 16: 33-7. 51. Palkama VJ, Neuvonen PJ, Olkkola KT. The CYP 3A4 inhibitor itraconazole has no effect on the pharmacokinetics of iv. fentanyl. Br J Anaesth 1998; 81: 5 9 8 ~ 0 . 52. Penzak SR, Gubbins PO, Gurley BJ, Wang PL, Saccente M. Grapefruit juice decreases the systemic availability of itraconazole capsules in healthy volunteers. Ther Drug Monit 1999; 21: 304-9. 53. Kawakami M, Suzuki K, Ishizuka T, Hidaka T, Matsuki Y, Nakamura H. Effect of grapefruit juice on pharmacokinetics of itraconazole in healthy subjects. Int J Clin Pharmacol Ther 1998; 36: 306-8. 54. Khoo SM, Porter JH, Edwards GA, Charman WN. Metabolism of halofantrine to its equipotent metabolite, desbutylhalofantrine, is decreased when orally administered with ketoconazole. J Pharm Sci 1998; 87: 1538--41. 55. Yasui N, Kondo T, Otani K, Furukori H, Mihara K, Suzuki A, Kaneko S, Inoue Y. Effects of itraconazole on the steady-state plasma concentrations of haloperidol and its reduced metabolite in schizophrenic patients: in vivo evidence of the involvement of CYP3A4 for haloperidol metabolism. J Clin Psychopharmacol 1999; 19: 149-54. 56. Furukori H, Kondo T, Yasui N, Otani K, Tokinaga N, Nagashima U, Kaneko S, Inoue Y. Effects

of itraconazole on the steady-state plasma concentrations of bromperidol and reduced hromperidol in schizophrenic patients. Psychopharmacology 1999; 145: 189-92. 57. Polk E, Crouch MA, Israel DS, Pastor A, Sadler BM, Chittick GE, Symonds WT, Gouldin W, Lou Y. Pharmacokinetic interaction between ketoconazole and amprenavir after single doses in healthy men. Pharmacotherapy 1999; 19: 137884. 58. De Wit S, Debier M, De Smet M, McCrea J, Stone J, Carides A, Matthews C, Deutsch P, Clumeck N. Effect of fluconazole on indinavir pharmacokinetics in human immunodeficiency vires-infected patients. Antimicrob Agents Chemother 1998; 42: 223-7. 59. Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64: 58-65. 60. Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on cerivastatin pharmacokinetics. Eur J Clin Pharmacol 1999; 54: 851-5. 61. Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol 1998; 46: 49-53. 62. Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 1998; 63: 332--41. 63. Gilad R, Lampl Y. Rhabdomyolysis induced by simvastatin and ketoconazole treatment. Clin Neuropharmacol 1999; 22: 295-7. 64. Palkama V J, Neuvonen PJ, Olkkola KT. Effect of itraconazole on the pharmacokinetics of bupivacaine enantiomers in healthy volunteers. Br J Anaesth 1999; 83: 659-61. 65. Arlander E, Ekstrom G, Aim C, Carrillo JA, Bielenstein M, Bottiger Y, Bertilsson L, Gustafsson LL. Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors. Clin Phannacol Ther 1998; 64: 484-91. 66. Cobb MN, Desai J, Brown LS Jr, Zannikos PN, Rainey PM. The effect of fluconazole on the clinical pharmacokinetics of methadone. Clin Pharmacol Ther 1998; 63: 655-62. 67. Varis T, Kaukonen KM, Kivisto KT, Neuvonen PJ. Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole. Clin Pharmacol Ther 1998; 64: 3638. 68. Varis T, Kivisto KT, Backman JT, Neuvonen PJ. Itraconazole decreases the clearance and enhances the effects of intravenously administered methylprednisolone in healthy volunteers. Pharmacol Toxicol 1999; 85: 29-32. 69. Jaruratanasirikul S, Sriwiriyajan S. Effect of omeprazole on the pharmacokinetics of itraconazole. Eur J Clin Pharmacol 1998; 54: 159-61.

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70. Van Puijenbroek EP, Egberts AC, Meyboom RH, Leufkens HG. Signalling possible drug--drug interactions in a spontaneous reporting system: delay of withdrawal bleeding during concomitant use of oral contraceptives and itraconazole. Br J Clin Pharmacol 1999; 47: 689-93. 71. Sinofsky FE, Pasquale SA. The effect of fluconazole on circulating ethinyi estradiol levels in women taking oral contraceptives. Am J Obstet Gynecol 1998; 178: 300~. 72. Damkier P, Hansen LL, Brosen K. Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine. Br J Clin Pharmacol 1999; 48: 829-38. 73. Herman BD, Fleishaker JC, Brown MT. Ketoconazole inhibits the clearance of the enantiomers of the antidepressant reboxetine in humans. Clin Pharmacol Ther 1999; 66: 374-9. 74. Jaruratanasirikul S, Sriwiriyajan S. Effect of rifampicin on the pharmacokinetics of itraconazole in normal volunteers and AIDS patients. Eur J Clin Pharmacol 1998 ; 54: 155-8. 75. Moreno M, Latorre A, Manzanares C, Morales E, Herrero JC. Clinical management of tacrolimus drug interactions in renal transplant patients. Transplant Proc 1999; 31: 2252-3. 76. Hairhara Y, Makuuchi M, Kawarasaki H, Takayama T, Kubota K, Ito M, Tanaka H, Yoshino H, Hirata M, Kita Y, Kusaka K, Sano K, Saiura A, Ijichi M, Matsukura A, Watanabe M, Hashizume K, Nakatsuka T. Effect of fluconazole on blood levels of tacrolimus. Transplant Proc 1999; 31: 2767. 77. Billaud EM, Guillemain R, Tacco F, Chevalier P. Evidence for a pharmacokinetic interaction between itraconazole and tacrolimus in organ transplant patients. Br J Clin Pharmacol 1998; 46: 271-2. 78. Furlan V, Parquin F, Penaud JF, Cerrina J, Le Roy Ladurie E Dartevelle P, Taburet AM. Interaction between tacrolimus and itraconazole in a heartlung transplant recipient. Transplant Proc 1998; 30: 187-8.

79. Capone D, Gentile A, Imperatore P, Palmiero G, Basile V. Effects of itraconazole on tacrolimus blood concentrations in a renal transplant recipient. Ann Pharmacother 1999; 33: 1124-5. 80. Brynne N, Forslund C, Hallen B, Gustafsson LL, Bertilsson L. Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity. Br J Clin Pharmacol 1999; 48: 564-72. 81. Gillies J, Hung KA, Fitzsimons E, Soutar R. Severe vincristine toxicity in combination with itraconazole. Clin Lab Haematol 1998; 20: 123-4. 82. Trapnell CB, Klecker RW, Jamis-Dow C, Collins JM. Glucuronidation of 3t-azido-31deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole,

329 methadone, and valproic acid. Antimicrob Agents Chemother 1998; 2: 1592-6. 83. Greenblatt DJ, Von Moltke LL, Harmatz JS, Mertzanis P, Graf JA, Durol ALB, Counihan M, Roth-Schechter B, Shader RI. Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole. Clin Pharmacol Ther 1998; 64: 661-71. 84. Luurila H, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem. Eur J Clin Pharmacol 1998; 54: 163-6. 85. Wassmann S, Nickenig G, Bohm M. Long QT syndrome and torsade de pointes in a patient receiving fluconazole. Ann Intern Med 1999; 38: 797. 86. Crerar-Gilbert A, Boots R, Fraenkel D, MacDonald GA. Survival following fulminant hepatic failure from fluconazole induced hepatitis. Anaesth Intensive Care 1999; 27: 650-2. 87. Novelli V, Holzel H. Safety and tolerability of fluconazole in children. Antimicrob Agents Chemother 1999; 43: 1955-60. 88. Sorensen HT, Nielsen GL, Olesen C, Larsen H, Steffensen FH, Schonheyder HC, Olsen J, Czeizel AE. Risk of malformations and other outcomes in children exposed to fluconazole in utero. Br J Clin Pharmacol 1999; 48: 234-8. 89. Tiboni GM, Iammarrone E, Giampietro E Lamonaca D, Bellati U, Di Ilio C. Teratological interaction between the bis-triazole antifungal agent fluconazole and the anticonvulsant drug phenytoin. Teratology 1999; 59: 81-7. 90. Nolting SK, Gupta A, Doncker PD, Jacko ML, Moskovitz BL. Continuous itraconazole treatment for onychomycosis and dermatomycosis: an overview of safety. Eur J Dermatol 1999; 9: 540-3. 91. Glasmacher A, Hahn C, Molitor E, Marklein G, Sauerbruch T, Schmidt-Wolf IG. Itraconazole though concentrations in antifungal prophylaxis with six different dosing regimens using hydroxypropyl-beta-cyclodextrin oral solution or coated-pellet capsules. Mycoses 1999; 42: 591-600. 92. Nguyen A J, Nelson DB, Thuru JR. Pseudomembranous colitis after itraconazole therapy. Am J Gastroenterol 1999; 94: 1971-3. 93. Foot AB, Veys PA, Gibson BE. Itraconazole oral solution as antifungal prophylaxis in children undergoing stem cell transplantation or intensive chemotherapy for haematological disorders. Bone Marrow Transplant 1999; 24: 1089-93. 94. Verspeelt J, Marynissen G, Gupta AK, De Doncker P. Safety of itraconazole in diabetic patients. Dermatology 1999; 198: 382-4. 95. Garcia Rodriguez LA, Duque A, Castellsague J, Perez-Gutthann S, Stricker BH. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol 1999; 48: 847-52.

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ANTIMALARIALDRUGS (SED-14, 799; SEDA-21, 293; SEDA-22, 302; SEDA-23, 304)

Adjunctive treatments in malaria The mainstay of effective treatment in malaria is the administration of an effective antimalarial drug by the safest and quickest route. However, mortality from complications of treated severe malaria is still high. There is therefore a potential role for adjunctive treatments in malaria aimed at reducing mortality from complications. Some potential adjunctive therapies (such as the use of steroids in cerebral malaria) have been tested and rejected, whereas others have not yet been adequately evaluated by appropriately powered clinical trials. The use of phenobarbital (3.5 mg/kg) as a prophylactic anticonvulsant in cases of strictly defined cerebral malaria has been standard practice in many units since the publication of a small trial in adults in 1978 (lC). A recent much larger randomized placebo-controUed trial in 340 Kenyan children has shown that phenobarbital prophylaxis (20 mg/kg) in cerebral malaria was associated with a doubling of mortality when it was used with diazepam (18% vs 8% mortality, OR = 2.39; CI = 1.28, 4.64) (2c). Although there were fewer fits in those given the anticonvulsant, there was a higher incidence of respiratory arrest in patients who did not have access to ventilatory support. Phenobarbital prophylaxis in this dose can no longer be recommended routinely for children with cerebral malaria (up to 80% of whom may have seizures) if ventilatory support is unavailable. The use of lower doses of phenobarbital and the relevance of these findings to adults (in whom the incidence of postadmission seizures is much lower) need further study. 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed. qqfl

The use of exchange transfusion as adjunctive therapy is another area in which there may be a difference between children and adults. The potential hazards of blood transfusion, particularly in areas where there are high viral carriage rates (e.g. for HIg, hepatitis B, or hepatitis C), are obvious. Unless the benefits of transfusion are clear-cut, blood and its products should not be used. In adults with severe malaria (for example, returning travellers) there is no consensus (3 R, 4 R) and recent small studies have only added to the sense of uncertainty regarding the use of exchange transfusion (5 c, 6r In children, a recent study has shown that when hyperparasitemia was the only risk factor almost all children with even 70% parasitemia survived without exchange transfusion (7c). This observation makes it less likely that exchange transfusion will be a useful adjunct in semi-immune children, especially in areas in which the incidence of H1V is high. Some risks associated with exchange transfusion can be significantly reduced by using automated exchange (8 c, 9R), although this technology is not available in the parts of the world in which HIV incidence is highest. Equally controversial is the role of micronutrients as adjunctive therapy, particularly the value of iron supplementation for anemia, and the use of iron-chelating agents for cerebral malaria. Some studies have suggested that iron supplementation is beneficial in reducing the incidence of malaria and mortality from malaria in children (10 c, 11R). Although several small studies have suggested that deferoxamine may reduce mortality from malaria, a recent meta-analysis showed no significant difference between those given iron chelators and placebo (12M). Indeed, there may have been an increased mortality in recipients of deferoxamine (32/175 compared with 19/177 placebo recipients; OR = 1.86; CI = 1.02, 3.4) (13 R, 14c).

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Other micronutrients may also have potential as adjunctive therapies. Malaria infection depletes vitamin A reserves and recent evidence has suggested that vitamin A supplementation significantly reduced mortality (15 c, 16r). Thiamine (vitamin B1) defic&ncy is associated with malaria and is more marked in severe disease in Southeast Asian adults (17c), although no interventional study has been reported. Small trials or animal studies provide some evidence for the beneficial effects of several other B vitamins and possibly for vitamins D and E, fish oils, and zinc (18 c, 19E), although these are exploratory in nature.

ENDOPEROXIDES

331 quine monotherapy (22e). In the 126 patients who took artemether-benflumetol there were no adverse effects attributed to drug treatment. However, less than 70% of patients were cured at 28 days. Benflumetol may be more effective at higher concentrations (23 c) but toxicity studies are lacking. Although neurological adverse effects of artemisinin derivatives have been reported in dogs, extensive trials in humans have failed to identify similar toxicity. In one case of an inadequately-treated non-immune subject who developed neurological symptoms after relapse and retreatment, the symptoms were ascribed to artemether (24A), although the well-recognized postmalaria neurological syndrome seems a much more likely cause, which the authors did not discuss (25R).

Artemisia derivatives (SED-14,966; SEDA-21, 293; SEDA-22, 302; SEDA-23, 305) Artemisinin is an antimalarial isolated from sweet wormwood. It has been used in traditional Chinese medicine for many years. Antimalarial drugs from this class are sesquiterpene lactones with an endoperoxidase bridge, structurally distinct from other antimalarials. Recent studies have reinforced the impression there is little to choose between parenteral formulations (artemether, artesunate) in terms of clinical response. Artemisinin derivatives are as effective as quinine in areas in which parasites are fully quinine sensitive, and are probably superior to quinine when quinine resistance is established. These drugs are limited by an unacceptable incidence of recrudescence with monotherapy, and they therefore need to be used in combination. A recent summary of prospective trials that looked specifically for adverse effects showed that artemisinins alone are very well tolerated (20R). The same study showed no evidence of adverse interactions of artesunate with mefloquine, with an incidence of adverse effects similar to that expected from malaria and mefloquine (25 mg/kg) together. Reducing doses of mefloquine increases recrudescence rates to unacceptable levels (21c). Combinations of artemisinins with quinine, co-trimoxazole, and doxycycline are well tolerated. A large trial of the first fixed-dose combination of an artemsinin derivative likely to be licensed (artemether-benflumetol) had disappointing relapse rates compared with meflo-

CHLOROQUINE AND CONGENERS (SED-14,950; SEDA-21, 294; SEDA-22, 303; SEDA-23, 305)

Chloroquine Chloroquine is highly effective against virtually all non-falciparum malaria, but of very limited use against falciparum malaria because of the spread of resistance. Most new data on adverse effects of chloroquine monotherapy come from its use in rheumatological conditions, in which higher doses are used for longer than in malaria, and so are of doubtful relevance to the management of acute disease. Combining chloroquine with the histamine H1 receptor antagonist chlorpheniramine seems to reverse chloroquine insensitivity in vivo, and has been mooted as a potential replacement. In small trials there does seem to be an increase in QTc interval with this combination, but less than with halofantrine (26c).

Halofantrine Halofantrine has fallen out of favor in many parts of the world because it commonly prolongs the QT interval and predisposes to polymorphous ventricular dysrhythmias such as torsade de pointes in Southeast Asian adults and more recently in Africa (26c). Halofantrine is still widely used, especially in francophone

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areas. There have been recent reports in the French medical press of further cases of significant QTc prolongation in children returning to France, and caution in its use has been urged (27c). A small trial in non-immune adults in the Netherlands and France also showed increased QTc dispersion with halofantrine but not artemether/lumefantrine (28c). Gastrointestinal adverse effects are also more common with halofantrine than other antimalarial drugs (29c).

ChristopherJ.M. Whitty and Sanjeev Krishna

risk of mefloquine in pregnancy compared with other antimalarial drugs, a recent study of 208 pregnant women on the Thai-Burmese border showed a significantly increased incidence of still-births compared with 1565 women treated with other antimalarial drugs (35c). Other adverse effects were no more common than with other antimalarial drugs. The study was performed during a period of emerging mefloquine-resistant malaria, and the findings may also reflect the effect of suboptimal malaria treatment.

Mefloquine The adverse effects of mefloquine have been extensively reviewed both for prophylaxis (when rare neuropsychiatric adverse effects makes its use controversial) and in treatment doses, when it has been linked to an increased incidence of the postmalaria neurological syndrome. Recent large studies that have added to the literature on adverse effects of prophylactic mefloquine include a retrospective review of 5120 Italian soldiers, which showed an overall chemoprophylaxis curtailment rate of less than 1%, which was not significantly different from the combination of chloroquine and proguanil (30c). A recent semi-systematic review has also suggested no significant difference in tolerability compared with other antimalarial drugs (31R). Mefloquine is an excellent antimalarial, but any reduction in neurological and neuropsychiattic adverse effects profile would enhance its usefulness. Penetration into the brain of the (+) enantiomer is much higher than that of the (-) enantiomer (32 c) whilst plasma concentrations are greater for the (-) enantiomer, potentially providing a way of minimizing neurological adverse effects (often significantly overstated (33R)) by using the less toxic enantiomer. However, chiral separation technology is not sufficiently well developed to be economically realistic for clinical practice in the foreseeable future. Sensory systems Three cases of previously well patients who developed persisting highfrequency sensorineural hearing loss and tinnitus whilst taking mefloquine have been reported (34c). Pregnancy In contrast to the review reported last year, which suggested no increased

Drug interactions Recent reports that there was a possible interaction between concurrent mefloquine administration and intradermal rabies vaccination have not been substantiated. Four cases in which rabies vaccine and mefloquine were accidentally given concurrently all led to good antirabies antibody responses (36C).

PRIMAQUINE AND CONGENERS (SED-14, 958; SEDA-21, 296; SEDA-22, 305; SEDA-23, 306) Hematologic That primaquine can cause hemolysis in patients with G6PD deficiency is well-recognized and is a major limitation to its use. Pdmaquine still remains important as the only antimalarial licensed for the radical cure of relapsing forms of malaria. In those without G6PD deficiency it is well tolerated as a prophylactic at doses of 15 mg/day (37c), with only 1/106 patients withdrawing because of gastrointestinal upset in one study. The operational limitations of having to test for G6PD concentrations before use make primaquine less attractive, but a recently developed analogue, tafenoquine, has a better safety profile, and it has been effective and safe in early trials (38c). However, although it may well be safer, patients were also excluded from this trial if they had G6PD deficiency, so it remains to be seen whether tafenoquine can overcome the most important practical problem with primaquine. Further widespread use will be needed before rare adverse effects, if any, emerge.

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333

Proguanil

(SED-14, 959; SEDA-21, 297; SEDA-22, 306; SEDA-23, 306)

Quinine (SED-14, 962; SEDA-21, 297; SEDA-22, 306; SEDA-23, 307)

Proguanil is not used as monotherapy in conventional practice, but is important in combination with either chloroquine or atovaquone in malaria prophylaxis, and with atovaquone in malaria treatment. Most new data relate to combinations that rely on proguanil (and are covered here under the more active drug). The major limitation of proguanil is that in most ethnic groups there are individuals who have limited ability to metabolize proguanil to the active metabolite cycloguanil. Consequently, poor proguanil metabolizers treated with combination drugs are effectively taking monotherapy. Recent work suggests that poor-metabolizers also have an increased incidence of adverse effects with [~roguanil, especially gastrointestinal effects (39~).

Quinine remains the mainstay of malaria treatment in most parts of the world. It is not pleasant to take, and adverse effects, including

Drug interactions There has been a new report of a drug interaction that is potentially clinically important. Cimetidine co-administration increased the Cmax of proguanil, and significantly reduced the Cmax and AUC of cycloguanil, presumably by inhibiting the metabolism of proguanil; co-administration is probably inadvisable (40c).

Proguanil + atovaquone Atovaquone used alone has for some time been an important drug in the treatment and prophylaxis of Pneumocystis carinii and other opportunistic infections in HIV. The recent demonstration that it is a highly effective antimalarial when used in combination with proguanil (currently marketed as Malarone) expands the indications for atovaquone. When atovaquone is used alone for malaria, relapse rates are very high. Proguanil + atovaquone is useful in the treatment of uncomplicated malaria (41c), including against multidrug resistant forms, and in prophylaxis (42c). It has not yet been widely marketed, so data on rare adverse effects are currently sparse. An in-patient study of 79 patients given proguanil + atovaquone compared with 79 patients given mefloquine showed no malaria-independent adverse effects (43c). Although there was a significant transient increase in liver enzymes this was probably of limited clinical importance.

nausea, tinnitus, dizziness, and hypoglycemia, are well recognized and common compared with other antimalarial drugs (44 C) in the doses used to treat malaria, although not in the smaller doses used to prevent leg cramps, when classical hypersensitivity reactions can still occur (45R). Most serious adverse effects are due to the pro-dysrhythmic properties of quinine, and its effects as an hypoglycemic agent, especially in pregnant women with severe malaria.

Hematologic D&seminated intravascular coagulation has been attributed to quinine (46~). A 79-year-old woman developed disseminated intravascular coagulation. She had taken a dose of quinine for leg cramps 3 months before and on the day before admission. Her only other medication was bendroflumethiazide. Investigations showed a platelet-associated immunoglobulin with positive immunofluorescence on exposure to quinine sulfate. This case presents strong indirect evidence that disseminated intravascular coagulation can occur as a consequence of quinine administration. Whilst these idiosyncratic adverse effects are rare and not obviously dose-related, both the debilitating but non-fatal effects of cinchonism, and the rare but potentially dangerous cardiovascular adverse effects are dose related. It has been standard practice in many Westem centres to measure quinine concentrations in those receiving intravenous quinine, especially if they have renal insufficiency. An important pharmacokinetic study in adults with renal insufficiency showed that concentrations of the main metabolite, hydroxyquinine, rose to 45% of the concentrations of the parent compound, and may contribute up to 25% of the cardiac effects of quinine (47c). The current practice of measuring quinine concentrations with high-performance liquid chromatography would have failed to detect this.

Liver Cholestatic jaundice has been attributed to quinine (48A).

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A 57-year-old native American with nocturnal leg cramps was given quinine 260 mg/day. She had known type 2 diabetes, hyperlipidemia, and coronary artery disease. She was already taking insulin, lisinopril, amlodipine, aspirin, furosemide, multiple vitamins, and occasional paracetamol. She did not consume alcohol. The day after her first dose she became unwell with nausea, chills, rigor, and a fever of 39.5~ C. She was given ceftriaxone, tobramycin, and vancomycin, and her usual drugs were continued. She had abnormal liver function tests, with raised AsT, LDH, alkaline phoshatase, and bilirubin. Over the next 8 days her alkaline phosphatase continued to rise to 642 in/l, while the AsT remained stable and below 300 iu/l. Quinine was withdrawn on day 5 and recovery occurred after day 8. This case provides circumstantial, but by no means definitive, evidence of an association between cholestatic jaundice and quinine. Multiple other drugs and significant pyrexia, with clinical resolution beginning before quinine was stopped, raise the possibility of alternative explanations.

DRUGS USED FOR PNEUMOCYSTIS CARINII (SED-14, 970; SEDA-21, 298; SEDA-22, 307; SEDA-23, 307) PNEUMONIA

Atovaquone Of 39 patients who had bone-marrow transplants and who were randomized to receive either co-trimoxazole or atovaquone as prophylaxis in an open-label trial, eight taking co-trimoxazole withdrew because of presumed drug reactions, although in five of these the reported neutropenia and thrombocytopenia could have been a consequence of transplantation itself or of other drugs (49r None of 16 patients treated with atovaquone withdrew. This rate of reported adverse effects with cotrimoxazole is higher than usually reported in clinical practice with prophylactic dosages.

Azithromycin Azithromycin, alone or in combination with atovaquone, has been suggested as suitable for the prophylaxis of Pneumocystis carinii pneumonia. The pharmacokinetic interaction between the two may be complex, and azith-

ChristopherJ.M. Whittyand Sanjeev Krishna

romycin concentrations may be reduced by coadministration of atovaquone (50c). However, a prospective study of 804 children specifically designed to examine the adverse effects profile of azithromycin monotherapy used as mass prophylaxis (against trachoma) showed it to be very safe (51c).

Co-trimoxazole (trimethoprim + sulfamethoxazole) Co-trimoxazole remains a first-line drug for treatment in most cases, being effective and cheap and having a long track record. It is undoubtedly the easiest prophylactic in those known to be immunosuppressed, especially with HIV disease. Adverse effects seems to occur most quickly in those with the lowest CD4+ lymphocyte counts (52c). Liver, pancreas

A report of simultaneous

hepatitis and pancreatitis with co-trimoxazole is the second such report, although each adverse effect has been reported as occurring more frequently in isolation (53A). A 34-year-old woman developed simultaneous pancreatitis and hepatitis after exposure to cotrimoxazole. She had had an episode of hepatitis after co-trimoxazole 4 years previously. No other convincing cause was identified. She made a full recovery after the drug was withdrawn. Immunologic Desensitization to co-trimoxazole and the usefulness of subsequent patch testing have been studied in 19 patients with cotrimoxazole hypersensitivity (type IV) (54c). Fifteen patients were successfully desensitized when rechallenged with treatment doses. No reactor was identified by patch testing, showing that there is probably no useful role for patch testing in this context.

Dapsone Dapsone is usually used in combination therapies in the treatment of malaria and leprosy, and as monotherapy for prophylaxis of Pneumocystis carinii pneumonia. Two adverse effects are widely known: methemoglobinemia and "dapsone syndrome". The development of methemoglobinemia is highly reproducible after dapsone in certain individuals. To illustrate this, a case of Mun-

Antiprotozoal drugs

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chausen's syndrome has recently been reported in which the patient repeatedly presented with methemoglobinemia thought to be secondary to surreptitious abuse of dapsone, which had been prescribed for leukocytoclastic vasculitis (55A). Dapsone syndrome, a multiorgan hypersensitivity reaction involving liver and skin, has recently been associated with hepatitis B infection, although the evidence rests on a case series (56c). A more systematic prospective study compared the adverse effects profile of dapsone in weekly (n = 46) and daily (n = 48) regimens used to prevent Pneumocystis carinii pneumonia in children. There was a trend towards fewer hematological adverse effects with the weekly regimen, although this was at the expense of a higher frequency of breakthrough Pneumocystis carinii pneumonia (57c). A comparison between high- and low-dose dapsone in daily treatment (1 or 2 mg/kg) paradoxically showed more adverse effects with the low-dose regimen, although the numbers were too small to make a valid comparison.

DRUGS USED IN OTHER PROTOZOAL INFECTIONS

Metronidazole

(SED-14, 977; SEDA-21, 301; SEDA-22, 311; SEDA-23, 309) Metronidazole is important for the treatment of several protozoal infections, including amebiasis, giardiasis, and Trichomonas infections. A metallic taste and the disulfiram-like reaction with alcohol are common, and peripheral neuropathy is well recognized.

Sensory systems Two recent reports of moderate to severe sensorineural deafness after metronidazole therapy which resolved slowly after therapy ended may indicate this is an additional adverse effect (58A). Both cases of deafness were preceded by tinnitus, which may be a warning to withdraw the drug. Teratogenicity The safety of metronidazole in pregnancy has been debated. In a retrospective cohort study using the national birth registry in Denmark comparing 124 women who took the drug with 13 327 who did not, there was

335 no evidence of any increased risk to the unborn child (59c).

Drug interactions A possible interaction with metronidazole recently reported is that it significantly increased blood ciclosporin and tacrolimus concentrations in two patients (60A). Since both of these immunosuppressive drugs are toxic in overdosage, and since patients taking them are prone to infection, this is potentially a serious interaction.

DRUGS USED IN TRYPANOSOMIASIS

Melarsoprol

(SED-14, 981;

SEDA-23, 310) Nervous system Melarsoprol is the only available drug proven to be effective against African trypanosomiasis (both the West and East African varieties) once CNS invasion has taken place. Unfortunately it is an arsenical, and morbidity and mortality directly from the encephalopathy attributable to the drug is high. The last large-scale review estimated that encephalopathic syndromes occur in 5-10% of patients, and that 10-50% of these die as a result (61R). Safer drugs are urgently needed, but none is currently in production; ethornithine, the only other drug that is definitely effective in this disease, is no longer made. The efficacy and safety of two regimens of melarsoprol have been compared in patients with CNS involvement from Trypanosoma b. gambiense: a conventional regimen lasting 26 days, starting at 1.2 mg/kg and rising to 3.6 mg/kg (n = 259), and a regimen of 2.2 mg/kg for 10 days (n = 250) (62c). Parasitological cure 24 hours after treatment was 100% in both groups. Disappointingly, the rates of encephalopathy were no better (in fact marginally worse) with the new schedule, despite using 30% less drug overall, and there were six drug-related deaths in each arm. However, the new schedule is quicker and cheaper, and treatment deviations were significantly fewer in the new schedule arm. In a further detailed prospective study of the drug in eight patients with advanced leukaemia, three developed seizures attributable to the drug at doses broadly comparable to those used in trypanosomiasis.

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DRUGS USED IN VISCERAL LEISHMANIASIS Pentavalent antimonial drugs (SED-14, 984; SEDA-23, 310) The standard treatment of most South American cutaneous leishmaniasis is systemic, because of the propensity of the parasites to spread to mucous membranes. The drugs in common use remain parenteral, and are fairly toxic. Sodium stibogluconate remains the gold standard, with liposomal amphotericin a possible alternative. Both drugs are also the preferred choice for all strains of visceral leishmaniasis. In a prospective open trial conventional treatment with sodium stibogluconate (n = 69) was compared with meglumine antimoniate (n = 58) for cutaneous Leishmania braziliensis (63c). The trial was too small and of too short a duration to compare efficacy reliably, but significantly fewer patients on meglumine antimoniate developed the myalgia/arthralgia, headache, and abdominal pain that are the most common adverse effects of the drug, and that tend to increase as treatment continues. About 30% developed significant adverse effects early in treatment and 70% late when stibogluconate was used, while 12% had early and 45% late adverse effects for antimoniate. Unfortunately, QTc intervals were not monitored; a fatal dysrhythmia, usually preceded by increased QTc dispersion, is the complication of sodium stibogluconate therapy most likely to lead to death. There has been a single case report of torsade de pointes and cardiac arrest after QTc prolongation due to meglumine antimoniate

(04A).

ChristopherJ.M. Whitty and Sanjeev Krishna

A 73-year-old man with visceral leishmaniasis received 15 days of intramuscular meglumine antimoniate (75 mg/kg). At the start of treatment he had a normal electrocardiogram with a QTe interval of 0.42 seconds. Some days later he developed chest tightness, and was in fast atrial fibrillation with a QTc of 0.64 seconds. Electrolytes were normal. The antimonial was withdrawn, and the patient received metildigoxin as a bolus and an amiodarone infusion was started. He had a cardiac arrest 12 hours later with a polymorphous ventricular dysrhythmia. Successful resuscitation was performed. The electrocardiogram returned to its pretreatment form and the patient made an uneventful recovery over the next 4 weeks having stopped taking antimonials. Torsade de pointes has occasionally been described with amiodarone, but it is likely that the antimonial was the cause of this arrest. Because of concerns regarding the cardiac adverse effects of antimonials, it is good practice to admit patients for the duration of therapy whenever practicable. This may mean admitting otherwise fit young patients for several weeks for treatment of a non-healing ulcer. To address the safety of out-patient management, a recent small study of 13 marines in the U K showed that they could be safely managed as out-patients with daily stibogluconate injections, provided there was close monitoring of electrocardiograms and blood tests to provide early warning of bone-marrow toxicity (65c). Three patients developed minor electrocardiographic changes and one developed thrombocytopenia. All these adverse effects resolved when treatment was withdrawn. Patients with a predisposition to dysrhythmias (such as some with ischemic heart disease) are best treated with pentavalent antimonials as in-patients to identify and manage adverse effects early when resources allow.

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32. Pham YT, Nosten F, Farinotti R, White NJ, Gimenez F. Cerebral uptake of mefloquine enantiomers in fatal cerebral malaria. Int J Clin Pharmacol Ther 1999; 37:58~51 [erratum 1999; 37: 316]. 33. Reid AJ, Whitty CJ, Ayles HM, Jennings RM, Bovill BA, Felton JM, Behrens RH, Bryceson AD, Mabey DC. Malaria at Christmas: risks of prophylaxis versus risks of malaria. Br Med J 1998; 317: 1506-8. 34. Fusetti M, Eibenstein A, Corridore V, Hueck S, Chiti-Batelli S. [Mefloquine and ototoxicity: a report of 3 cases]. Clin Ter 1999; 150: 37982. 35. Nosten E Vincenti M, Simpson J, Yei P, Thwai KL, De Vries A, Chongsuphajaisiddhi T, White NJ. The effects of mefloquine treatment in pregnancy. Clin Infect Dis 1999; 28: 808-15. 36. Lau SC. Intradermal rabies vaccination and concurrent use of mefloquine. J Travel Med 1999; 6: 140-1. 37. Schwartz E, Regev-Yochay G. Primaquine as prophylaxis for malaria for nouimmune travelers: a comparison with mefloquine and doxycycline. Clin Infect Dis 1999; 29: 1502-6. 38. Lell B, Faucher JF, Missinou MA, Bomnann S, Dangelmaier O, Horton J, Kremsner PG. Malaria chemoprophylaxis with tafenoquine: a randomised study. Lancet 2000; 355: 2041-5. 39. Kaneko A, Bergqvist Y, Taleo G, Kobayakawa T, Ishizaki T, Bjorkman A. Proguanil disposition and toxicity in malaria patients from Vanuatu with high frequencies of CYP2C19 mutations. Pharmacogenetics 1999; 9: 317-26. 40. Kolawole JA, Mustapha A, Abdul-Aguye I, Ochekpe N, Taylor RB. Effects of cimetidine on the pharmacokinetics of proguanil in healthy subjects and in peptic ulcer patients. J Pharm Biomed Anal 1999; 20: 737-43. 41. Shapiro TA, Ranasinha CD, Kumar N, Barditch-Crovo P. Prophylactic activity of atovaquone against Plasmodium falciparum in humans. Am J Trop Med Hyg 1999; 60: 831-6. 42. Bustos DG, Canfield C J, Canete-Miguel E, Hutchinson DB. Atovaquone-proguanil compared with chloroquine and chloroquine-sulfadoxinepyrimethamine for treatment of acute Plasmodium falciparum malaria in the Philippines. J Infect Dis 1999; 179: 1587-90. 43. Looareesuwan S, Wilairatana P, Chalermarut K, Rattanapong Y, Canfield CJ, Hutchinson DB. Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 1999; 60: 526-32. 44. Birku Y, Makonnen E, Bjorkman A. Comparison of rectal artemisinin with intravenous quinine in the treatment of severe malaria in Ethiopia. East Afr Med J 1999; 76: 154-9. 45. Beyens MN, Guy C, Ollagnier M. [Adverse effects of quinine in the treatment of leg cramps]. Th6rapie 1999; 54: 59-62.

Christopher J.M. Whitty and Sanjeev Krishna

46. Kedia RK, Wright AJ. Quinine-mediated disseminated intravascular coagulation. Postgrad Med J 1999; 75: 429-30. 47. Newton P, Keeratithakul D, Teja-Isavadharm P, Pukrittayakamee S, Kyle D, White N. Pharmacokinetics of quinine and 3-hydroxyquinine in severe falciparum malaria with acute renal failure. Trans R Soc Trop Med Hyg 1999; 93: 69-72. 48. Farver DK, Lavin MN. Quinine-induced hepatotoxicity. Ann Pharmacother 1999; 33: 32-4. 49. Colby C, McAfee S, Sackstein R, Finkelstein D, Fishman J, Spitzer T. A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 1999; 24: 897-902. 50. Ngo LY, Yogev R, Dankner WM, Hughes WT, Burchett S, Xu J, Sadier B, Unadkat JD. Pharmacokinetics of azithromycin administered alone and with atovaquone in human immunodeficiency virus-infected children. The ACTG 254 Team. Antimicrob Agents Chemother 1999; 43: 1516-19. 51. Whitty CJ, Glasgow KW, Sadiq ST, Mabey DC, Bailey R. Impact of community-based mass treatment for trachoma with oral azithromycin on general morbidity in Gambian children. Pediatr Infect Dis J 1999; 18: 955-8. 52. Morikawa SJ, Cortese LM, Walker JS, Dster CN, Stoute JA. The risk of hypersensitivity reactions to trimethoprim/sulfamethoxazole as a function of the CD4+ count in HIV-infected patients. J Pharm Technol 1999; 15: 165-9. 53. Brett AS, Shaw SV. Simultaneous pancreatitis and hepatitis associated with trimethoprimsulfamethoxazole. Am J Gastroenterol 1999; 94: 267-8. 54. Gompels MM, Simpson N, Snow M, Spickett G, Ong E. Desensitization to co-trimoxazole (trimethoprim-sulphamethoxazole) in HIVinfected patients: is patch testing a useful predictor of reaction? J Infect 1999; 38: 111-15. 55. Cart KM, Elias L, Caruana LC, Rabinowitz I. Factitious methemoglobinemia. Am J Hematol 1999; 62: 196-7. 56. Pavithran K, Bindu V. Dapsone syndrome: hepatitis-B infection a risk factor for its development? Int J Lepr Other Mycobact Dis 1999; 67: 171-2. 57. McIntosh K, Cooper E, Xu J, Mirochnick M, Lindsey J, Jacobus D, Mofenson L, Yogev R, Spector SA, Sullivan JL, Sacks H, Kovacs A, Nachman S, Sleasman J, Bonagura V, McNamara J. Toxicity and efficacy of daily vs. weekly dapsone for prevention of Pneumocystis carinii pneumonia in children infected with human immunodeficiency virus. ACTG 179 Study Team. AIDS Clinical Trials Group. Pediatr Infect Dis J 1999; 18: 432-9. 58. Iqbal SM, Murthy JG, Banerjee PK, Vishwanathan KA. Metronidazole ototoxicity--report of two cases. J Laryngol Otol 1999; 113: 355-7.

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59. Sorensen HT, Larsen H, Jensen ES, Thulstrup AM, Schonheyder HC, Nielsen GL, Czeizel A. Safety of metronidazole during pregnancy: a cohort study of risk of congenital abnormalities, preterm delivery and low birth weight in 124 women. J Antimicrob Chemother 1999; 44: 854-6. 60. Herzig K, Johnson DW. Marked elevation of blood cyclosporin and tacrolimus levels due to concurrent metronidazole therapy. Nephrol Dial Transplant 1999; 14: 521-3. 61. Anonymous. WHO Control and surveillance of African trypanosomiasis. WHO Tech Rep Ser 1998; 881: 1-114. 62. Burri C, Nkunku S, Merolle A, Smith T, Blum J, Brun R. Efficacy of new, concise schedule for melarsoprol in treatment of sleeping sickness

339 caused by T~,panosoma brucei gambiense: a randomised trial. Lancet 2000; 355: 1419-25. 63. Saldanha ACR, Romero GAS, MerchanHamann E, Magalhaes AV, Macedo O. Comparative study between sodium stibogluconate BP 88R and meglumine antimoniate for cutaneous leishmaniasis treatment: I. Efficacy and safety. Rev Soc Bras Med Trop 1999; 32: 383-7. 64. Segura I, Garcia-Bolao I. Meglumine antimoniate, amiodarone and torsades de pointes: a case report. Resuscitation 1999; 42: 65-8. 65. Seaton RA, Morrison J, Man I, Watson J, Nathwani D. Out-patient parenteral antimicrobial therapy--a viable option for the management of cutaneous leishmaniasis Q J Med 1999; 92: 65967.

M.N.G. Dukes

29 DRUGS ACTIVE AGAINST CYTOMEGALOVIRUS Cidofovir (SED-14, 989; SEDA-21, 306; SEDA-23, 314) Sensory systems Iritis has been previously described as a complication of intravenous cidofovir (SED-14, 989), and a recent observation in two patients has confirmed the link (IA). Both had cytomegalovirus retinitis, and the drug association with the iritis was demonstrated by withdrawal and rechallenge. Both had also taken probenecid, but it is not clear whether or not that was involved. The evidence is that in such cases the cidofovir should be withdrawn; treatment should be with a mydriatic and corticosteroids. Uveitis (2 c) and cystoid macular edema (3c) are other recognized risks associated with cidofovir treatment for cytomegalovirus retiniris. The latter is almost certainly an immune recovery phenomenon, since it is apparently encountered only in eyes with inactive CMV retinitis; the unaffected contralateral side never develops cystoid macular edema. The time range of appearance (3-48 weeks after administration) also makes a direct toxic effect of cidofovir unlikely. Risk factors The risk of renal tubular damage with cidofovir is well recognized and continues to be stressed as new cases are reported (4cR). However, in some cases the drug is much needed, despite pre-existing renal insufficiency. In an acute study designed to examine its kinetics under these unfavorable conditions, 24 subjects with varying degrees of renal insufficiency were given a single intravenous dose of cidofovir 0.5 mg/kg over 1 hour (5c). Those who 9 2001 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual24 J.K. Aronson, ed. 2A/~

Antiviral drugs were not receiving dialysis were given intravenous hydration and concomitant oral probenecid. Mean cidofovir clearance in control subjects (normal renal function; n = 5) was 1.7 ml/min/kg, and this fell markedly with falling renal function. The mean steady-state volume of distribution did not change significantly in those with kidney disease, but cidofovir halflife was significantly prolonged in those with severe renal insufficiency. Cidofovir was not significantly cleared during continuous ambulatory peritoneal dialysis, but high-flux hemodialysis resulted in the removal of 52% of the dose. The authors concluded that very considerable aggressive dosage reduction of cidofovir would be necessary in subjects with kidney disease to ensure comparable drug exposure in terms of serum concentrations.

Fomivirsen Fomivirsen (ISIS 2922) is an antisense oligonucleotide that specifically inhibits replication of human cytomegalovirus; it is being developed in the hope that it will be of value in the treatment of cytomegalovirus retinitis. The most common adverse events reported in clinical trials to date have been increased intraocular pressure and mild to moderate intraocular inflammation (6R). These events were generally transient or reversible with topical corticosteroids.

Foscarnet (SED-14, 989; SEDA-21, 307) While renal problems during foscarnet treatment can usually be prevented by adequate hydration before and during therapy (SED-14, 989), irreversible renal damage continues to be reported. Patients who have undergone renal transplantation and then require treatment for cytomegalovirus infection are obviously at special risk. One such recipient developed the nephrotic syndrome with microscopic hema-

Antiviral drugs

Chapter29

turia and non-oliguric acute renal insufficiency within 15 days after starting foscarnet therapy for cytomegalovirus infection (7A). A kidney biopsy showed crystals in all glomeruli and in the proximal tubules. The crystals consisted of several forms of foscarnet salts. Renal function and proteinuria nevertheless improved progressively, and a second transplant biopsy 8 months after the first one showed fibrotic organization of half of the glomeruli and of the interstitial tissues, and a reduction in the amount of crystals. The renal damage caused by foscarnet can itself alter the drug's kinetics; the dosage needs to be substantially reduced when renal complications occur, and appropriate guidelines have been developed (8cr).

Ganciclovir (SED-14, 990; SEDA-21, 307) Until recently most work with ganciclovir related to parenteral use, but it is also being used orally. Particularly bearing in mind the fact that the neutropenia the drug causes is dose-dependent, it is important under these conditions to ensure that food intake does not result in an unacceptable fluctuation in blood concentrations. A recent well-controlled investigation using high doses of oral ganciclovir in HIV- and CMV-seropositive subjects has shown that food markedly increases the systemic availability of ganciclovir. For example, there is a doubling of blood concentrations and AUC if the drug is given within 30 minutes after a meal rather than on an empty stomach (9c). Whatever dosage instructions are given, it seems clear that the relation to meal times should be explained, for example with a firm recommendation to take the drug consistently with food. Nervous system Effects on the central nervous system, which occur in some 5% of patients, are generally mild and involve only aspects of mental function (SED-14, 990). However, a very clear case of encephalopathy has been described in a patient who had received a bone-marrow transplant; the problem resolved on withdrawal (10Cr). Drug interactions The interaction kinetics and safety profile of oral ganciclovir when co-administered with trimethoprim have been

341 investigated in HIV- and CMV-seropositive patients (llC). Trimethoprim significantly reduced the renal clearance of ganciclovir and prolonged its half-life, although the changes are unlikely to be clinically important. Ganciclovir did not alter trimethoprim pharmacokinetics, with the exception of a 13% increase in Cmin. Ganciclovir was well tolerated when given alone or in this combination.

Ribavirin (SED-14, 992; SEDA-23, 315) A well-documented photoallergic reaction has been described in a woman who was taking both ribavirin and interferon-or (12CR). The case provided evidence that ribavirin is a potential photosensitizer for UVB, a problem that may become increasingly relevant in patients with chronic hepatitis C taking combination therapy for 6-12 months with interferon-c~ and ribavirin.

DRUGS ACTIVE AGAINST HEPATITIS VIRUSES The decision to provide aggressive drug treatment for chronic hepatitis C must still depend on a careful assessment of the risks of therapy set against the current or anticipated risks of the disorder itself. As Foster has pointed out in a balanced review of the issue (13R), there is a growing body of evidence that patients with chronic hepatitis C virus infection without major disease-related complications perceive themselves to be unwell and have significant changes in their physical and mental wellbeing. These abnormalities cannot be attributed to the mode of acquisition of the infection or to the severity of liver damage. The mechanism of these changes is unknown, but the symptoms remit after successful therapy, suggesting that the presence of the virus plays a role. These symptoms require careful evaluation and may be sufficiently severe to justify therapy in the absence of advancing liver damage. Treatment of chronic hepatitis C nevertheless significantly impairs a patient's quality of life. The decision as to whether an individual patient's symptoms are sufficient to justify therapy to prevent progressive liver damage is one that must be based on an assessment of the individual's current and

342 likely future status, as well as their ability to tolerate current therapy.

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS Sensory systems One possible consequence of the use of potent anti-HIV regimens, such as HAART (Highly Active Antiretroviral Therapy), is that as the immune response is restored some of the clinical manifestations of AIDS (and its secondary infections) may change, demanding particular care in clinical monitoring. Cytomegalovirus retinitis can present atypically: the host immune response can be responsible for an increase in ocular inflammation and there may even be hypopyon, intense vitritis, and a frosted angiitis syndrome. Severe macular edema can be present and need treatment with local corticosteroid injections. The differential diagnosis of ocular lesions must include endogenous uveitis (14R). Drug interactions Illicit drugs Bearing in mind that a proportion of HIV-carriers have acquired their infection as a result of self-injecting illicit drugs, it is important to realize that if such drugs continue to be used during antiretroviral treatment they may seriously complicate the use of the latter. Most antiretroviral agents are potent inhibitors (and occasionally inducers) of hepatic and intestinal cytochrome P450 isozymes and therefore have the potential to alter the elimination of any substances, licit or illicit, that use these metabolic pathways, for example amphetamines. A patient infected with HIV-1 who was taking ritonavir and saquinavir had a prolonged effect from a small dose of methylenedioxymetamphetamine (MDMA, Ecstasy) and a near-fatal reaction from a small dose of y -hydroxybutyrate (15 c).

Phenylpropanolamine

Since two or three drugs are normally used in combination in HIVinfected patients, there is a high likelihood of interactions with whatever other drugs may be taken. In one case the use of phenylpropanolamine with triple drug therapy for HIV prophylaxis led to a hypertensive crisis (16A). As the patient had previously tolerated phenylpropanolamine well, one must suspect that

Chapter 29

M.N.G.Dukes

one or more of the anti-HIV drugs (probably indinavir) had interfered with the metabolic breakdown of the phenylpropanolamine. NUCLEOSIDE ANALOG REVERSE TRANSCRIPTASE INHIBITORS (NRTI)

(SED-14, 996; SEDA-23, 319) Metabolism Some light has been thrown on the complexity of the metabolic adverse effects of the nucleoside analog reverse transcriptase intfibitors by a well-controlled French comparison of changes in body composition, body fat distribution, and insulin secretion in patients taking stavudine (n = 27) or zidovudine (n = 16) compared with controls (n = 15) (17c). The zidovudine group and the control group had similar body composition and regional fat distribution. Stavudine was associated with a significantly lower percentage of body fat than zidovudine (13% vs 15%), a markedly lower ratio of subcutaneous to visceral fat, and a higher mean intake of fat and cholesterol. Triglyceride concentrations were significantly higher with stavudine than in the controls, but did not differ between stavudine and zidovudine or between zidovudine and controls. Free fatty acids tended to be higher with stavudine. Lipodystrophy was observed in 17 patients taking stavudine, and in three taking zidovudine after a median time of 14 months. The relative risk of fat wasting with stavudine compared with zidovudine was 1.95. Five of 12 patients had a major or mild improvement in their lipodystrophy after stavudine was withdrawn. The authors concluded that lipodystrophy may be related to long-term NRTI therapy, particularly if it includes stavudine.

Abacavir (SED-14, 29) Abacavir, another NRTI, has been the subject of highly enthusiastic conclusions based on the manufacturers' clinical studies, conclusions that have to be taken with the usual reservations until there has been a reasonable amount of clinical use. Abacavir has good oral systemic availability and penetrates the CNS; since its metabolism does not depend on cytochrome P450, drug interactions may not be a problem. It has antiviral potency comparable to that of protease inhibitors and to dual nucleoside combinations. There is also evidence that it is effective in reducing viral load and increasing the CD4

Antiviral drugs

Chapter29

count in HIV-infected patients. To date it has been claimed that abacavir has an acceptable safety profile, although hypersensitivity reactions lead to withdrawal of therapy in about 3% of patients (18r). The latter can be severe, and anaphylaxis has been reported after rechallenge in a patient with an apparent allergic reaction to abacavir (19A). It is wise to avoid rechallenge when hypersensitivity is suspected (20c). In a recent study nausea and vomiting occurred in 38-57% of patients, headache in 27-41%, malaise and fatigue in 28%, diarrhea in 18-23%, and weakness in 29% (21c). There was also one case of agranulocytosis accompanied by a skin

rash.

Didanosine (SED-14, 995; SEDA-21, 307; SEDA-23, 319) There has been a report of a patient in whom

pancreatitis, fulminant hepatic failure, and persistent lactic acidosis occurred, culminating in death from liver failure (22c).

Lamivudine (SED-14, 995;

343 the large toes as a result of Candida albicans and Escherichia coli infection (26A). The paronychia resolved after treatment with oral fluconazole and topical antiseptics. It may be noted in this connection that paronychia of the large toes has also been observed when illgrastim (recombinant granulocyte colony stimulating factor) was used alongside chemotherapy in poor-risk patients with myelodysplastic syndrome (27c), and there is some evidence that paronychia (even in the absence of blood disorders) can occur as an independent adverse reaction to various antiretroviral drugs, including indinavir and lamivudine (28Cr). Closely similar is the strong evidence from case-control studies that ingrowing toenails are associated with the use of indinavir (29 c) and possibly other similar compounds, but not lamivudine.

Multiorgan failure A well-documented case has shown that zidovudine can cause type B lactic acidosis and acute respiratory and hepatic failure (30nr).

SEDA-21, 310; SEDA-23, 320)

A 34-year-old obese woman developed nausea, vomiting, and intermittent diarrhea. Her current medications included zidovudine. She had tachypnea and tender hepatomegaly, and a CT scan of the abdomen showed hepatomegaly with fatty infiltration. The serum bicarbonate concentration was low and the lactate concentration three times normal. The tachypnea and dyspnea worsened as the lactate concentration rapidly increased to 15 times normal, and she died in acute respiratory and hepatic failure with multiorgan dysfunction.

Hematologic Despite the better tolerance of

Pregnancy Despite

SEDA-21, 308; SEDA-23, 319) A case report has provided strong evidence that lamivudine can on rare occasions cause severe anemia; the mechanism is unclear (23A).

Zidovudine (SED-14, 994;

zidovudine with the reduced doses now in use, constant alertness is called for. Besides reactions reported earlier, red cell aplasia has now been described (24c). Achieving a well-tolerated dosage is particularly difficult in neonates. Skin Besides cases of skin hypersensitivity and occasional cases of Lyell's syndrome, zidovidine can occasionally cause unusual pigmentation, probably depending on the individual's pigmentary pattern (25c). Nails In one case the presenting sign of neutropenia in a neonate treated with zidovudine prophylaxis for reduction of perinatal transmission was, unusually, severe paronychia of

earlier forebodings (SED-14, 995; SEDA-23, 320), the use of zidovudine in pregnancy, in order to reduce maternal-infant transmission of HIV-1, does not as a rule seem to harm the fetus. However, it is still necessary to follow the children born of these pregnancies to exclude late adverse effects. There has been a randomized cohort study in the USA of children from 122 pregnancies in which zidovudine was given and of children from 112 pregnancies in which only a placebo was used (31c). The median age of the children at the last follow-up visit was 4.2 years. There were no significant differences between children exposed to zidovudine and those who received placebo in terms of sequential data on lymphocyte subsets, weight, height, head cir-

344 cumference, and cognitive/developmental function. There were no deaths or malignancies. Two children (both exposed to zidovudine) were still being followed for unexplained abnormal fundoscopy. One child exposed to zidovudine had a mild cardiomyopathy on echocardiography at the age of 48 months but was clinically asymptomatic. Lactation Since zidovudine seems to be relatively well tolerated both in pregnancy and in neonates, there is also much reason to consider its use during lactation in order to reduce vertical transmission of HIV. Indeed, many would regard it as highly preferable to abandoning breastfeeding by H1V-infected women. In a critical double-blind West African study the effects of a 6-month course of treatment in prenatal and lactating mothers were examined (32CR). Eligible participants were women aged 18 years or older who had confirmed HIV-1 infection, were 36-38 weeks pregnant, and gave written informed consent. Exclusion criteria were severe anemia, neutropenia, abnormal liver function, and sickle cell disease. They were randomly assigned to zidovudine (n = 214; 300 mg bd until labor, 600 mg at the start of labor, and 300 mg bd for 7 days) or to matching placebo (n = 217). The Kaplan-Meier probability of HIV infection in the infant at 6 months was 18% in the zidovudine group and 28% in the placebo group, a relative efficacy of 0.38. In current and follow-up observations over 6 months, no major adverse biological or clinical events were reported in excess among women or children in the zidovudine group. The authors concluded that a short course of oral zidovudine given during the peripartum period is well tolerated and provides significant reduction in early vertical transmission of HIV-1 infection despite breastfeeding. A second related study showed similar results (33Cr), and the two papers together provide impressive evidence that it is proper and defensible to use zidovudine in breastfeeding mothers. Drug interactions Atovaquone can potentiate the activity of zidovudine by inhibiting its glucuronldation ( 3 4c) . Clarithromycin has an unpredictable effect on the absorption of zidovudine; blood concentrations may rise or fall (35 c, 36c).

Chapter 29

M.N.G.Dukes

There was a striking incidence of headache in a small series of patients when zidovudine was given with oxazepam (37c). Paracetamol (acetaminophen) increased the clearance (andpossibly reduced the effects) of zidovudine (38 '~, 39c). Relatively recently, a study in Italy has sought to define the effect of antineoplastic drug therapy on the kinetics of zidovudine given simultaneously; there was no clinically significant interaction (40c). However, rifampicin, a well-known enzyme inducer, increased the metabolism of zidovudine, and the effect persisted for 2 weeks after rifampicin had been withdrawn (41Cr). NON-NUCLEOTIDE REVERSE TRANSCR1PTASE INHIBITORS (NNRTI)

Delavirdine (SED-14, 996) While hypersensitivity to delavirdine is generally mild, resulting only in a transient rash (SED-14, 996), severe hypersensitivity reactions, including anaphylaxis (42c), can occur and may necessitate drug withdrawal.

Efavirenz (SEDA-14, 996) Additional evidence is emerging that efavirenz is in some respects better tolerated than certain of the alternatives used in HIV infection. However, comparisons remain difficult, since it will generally be used with drugs of other types in order to avoid the rapid development of resistance. An approach in which it is combined with nucleoside analogs seems promising in terms of reduced toxicity (43R). A similarly positive impression has been obtained in a recent open-label comparison of efavirenz and indinavir (plus two nucleoside analogs) in predominantly treatment-naive patients (44CR). The authors concluded that the efavirenz-based triple therapy provided at least similar antiviral effects over 48 weeks. Furthermore, fewer patients discontinued efavirenzbased triple therapy than indinavir-based therapy because of adverse events. Adverse effects associated with efavirenz included a maculopapular rash and central nervous system disturbances (dizziness, vivid dreams, poor concentration, sleep disturbances), which generally occurred (but later resolved) within the first weeks of therapy.

Antiviral drugs

345

Chapter29

Nevirapine

(SED-14, 997; SEDA-21, 308; SEDA-22, 318; SEDA-23, 320)

PROTEASE INHIBITORS

Metabolism Lipodystrophy, well recognized

Endocrine Protease inhibitors can also causes a rise in blood glucose concentration, although only a few cases have been reported. Patients with a family history of diabetes mellitus may be at a greater risk, and they demand especially close monitoring, for example with both baseline and quarterly glucose determinations, at least during the 6-12 months of treatment (52 R, 53A). Two recent case reports seem to suggest that where a protease inhibitor is used with a corticosteroid the tendency to adverse corticosteroid effects may be potentiated (54 A, 55A). Two HIV-positive patients developed severely disfiguring skin striae within 3 months of starting indinavir therapy (56At).

with stavudine (see above), has now also been reported in nine of 56 patients taking combined HAART therapy including nevirapine, although there must be some doubt as to which drug or combination was responsible (45c).

Liver

The hepatic risks associated with nevirapine (SEDA-23, 320) have been underlined by a severe case of hepatic failure, which resolved on withdrawal and in which there was no other obvious cause than the use of nevirapine (46A). Skin While skin reactions to nevirapine are apparently not uncommon (9-32% of cases), and clearly cannot be prevented by the use of corticosteroids (47cr), it is possible to induce tolerance to them, enabling treatment to continue (48c). All the same, very severe skin reactions, with characteristics of both StevensJohnson syndrome and Lyell's syndrome, have occasionally been reported (49c).

Drug

interactions Nevirapine induces CYP3A4 and therefore interacts with drugs such as protease inhibitors and oral contraceptives. When methadone is used in HIV infection (for pain or treatment of opioid dependence) nevirapine given simultaneously can reduce methadone blood concentrations, the effect being sufficient to cause methadone withdrawal symptoms (50c).

Trecovirsen Trecovirsen is a 25-met antisense phosphorothioate oligonucleotide, which is targeted at the gag site of the HIV gene. In an early clinical experiment it has been given to HIV-positive volunteers by intravenous infusion in single escalating doses of 0.1-2.5 mg/kg in groups of 6 12 subjects (51c). The only significant adverse event was an isolated transitory increase in activated partial thromboplastin time at doses of 2.0 mg/kg or more; it was related to plasma trecovirsen concentrations and was attributed to the polyanionic character of the molecule. Headache occurred in 12% of subjects, and there were some cases of abdominal pain, back

pain, diarrhea, and weakness.

(SED-14, 997;

SEDA-23, 316)

Metabolism Lipodystrophy has been recognized as an adverse effect of protease inhibitors since they started to be used, and despite careful monitoring reports of various fat distribution disorders continue to appear. In one recent case "buffalo neck" was described in a middleaged man taking indinavir who developed a lipomatous formation in the retrocervical area; abdominal fat also increased in volume, while the subcutaneous fat on the lower limbs decreased (57A). These effects may be related to a corticosteroid-like action (see above). While abnormal concentrations of circulating lipids are common in patients with HIV infection (usually hypercholesterolemia and moderate hypertriglyceridemia), there is no doubt that members of this group of drugs can cause much more marked changes. The possible differences between various protease inhibitors as regards their effects on the lipid spectrum have been characterized in 93 HIV-infected adults taking ritonavir, indinavir, or nelfinavir, alone or in combination with saquinavir (58c). There was a rise in plasma cholesterol concentration in all those who took a protease inhibitor, but it was more pronounced with ritonavir than with indinavir or nelfinavir. Plasma HDL cholesterol was unchanged. Ritonavir, but not indinavir or nelfinavir, was associated with a marked rise in plasma triglyceride concentrations. The combination of ritonavir or nelfinavir with saquinavir did not further alter plasma lipid concentrations. There was a 48% increase in plasma concentrations of lipoprotein(a) in

Chapter 29

346 those taking a protease inhibitor, with pretreatment values exceeding 200 mg/1. There were similar changes in plasma lipid concentrations in six children taking ritonavir. The risk of pancreatitis and premature atherosclerosis as a consequence of such dyslipidemia remains to be established. A 35-year-old HIV-positive man developed a serum cholesterol of 38 mmol/1 and a fasting serum triglyceride of 98 mmol/l after he started to take ritonavir, saquinavir, nevirapine, and didanosine (59AR). All other medications had been stable during this time; the condition resolved with antiretroviral drug withdrawal and lipid-lowering therapy. It was striking that the raised cholesterol and triglyceride concentrations did not recur when therapy was restarted in modified form with nelfinavir, saquinavir, nevirapine, and didanosine; the hyperlipidemia was therefore attributed to ritonavir. In 19 consecutive HIV-positive men examined before and during treatment with a protease inhibitor (nelfinavir, ritonavir, or indinavir) and two nucleoside analog reverse transcriptase inhibitors (NRTI), median treatment duration 22 (range 7-40) weeks, the predominant feature of dyslipidemia was an increase in triglyceride-containlng lipoproteins (60CR). This observation is in accordance with the hypothesis of increased apoptosis of peripheral adipocytes, release of free fatty acids, and subsequent increased synthesis of VLDL cholesterol. The lipid profile, based on the ratio of total cholesterol to HDL cholesterol and the ratio HDL2 to HDL3, is significantly more atherogenic than normal.

Hematologic There is still no clear explanation for a series of seven patients in whom treatment with various protease inhibitors was associated with early thrombosis (61or). Hematological or vascular effects conducive to thrombosis are not recognized as a complication with this group of compounds; the only previous similar cases were associated with prolonged therapy. However, a detailed report on a large series of patients has provided impressive evidence that the use of protease inhibitors in HIV-infected patients with hereditary bleeding disorders can lead to an increased bleeding tendency (62c). This effect, which is most likely to occur when ritonavir is used, is also unexplained.

M.N.G.Dukes

Indinavir (SED-14, 998; SEDA-21, 308; SEDA-23, 316)

Hematologic Indinavir has now in at least one well-documented case been associated with thrombocytopenia (63 A) and there has been a report of severe hemolytic anemia (64AR). U r i n a r y t r a c t When one considers the increasing number and diversity of renal complications reported with antiviral drugs of various classes, it seems doubtful how specific these are to any particular drug. However, indinavir is known to promote the formation of renal calculi (SED-14, 998; 65A). The incidence of urolithiasis with indinavir has been estimated at 9% (66 cR) but, according to some, may be as high as 20%. Indinavir calculi are often radiolucent and may be missed on CT scan rather than by using a contrast medium (which is itself not without risk) (67 cr, 68Cr). It may therefore be that in some cases in which other renal complications with indinavir have been described there was in fact undetected renal stone formation. Any patient taking indinavir who develops renal colic should be suspected of having renal stones (69CR). In two recent cases long-term use of indinavir appeared to have been responsible for renal atrophy (70c), and again one wonders whether crystals may have been present but radiologically invisible. Reversible renal insufficiency (which again can be due to crystalluria) has been reported with indinavir (71At). A 38-year-old man developed renal insufficiency while taking indinavir. His serum creatinine increased over a period of about 1 year, but urinalysis was persistently normal. A renal biopsy showed marked tubular crystal deposition. The indinavir was withdrawn, and after 2 months his serum creatinine returned to normal. Since the basic problem in many such cases is probably crystalluria, it should be possible to treat it with rehydration, perhaps supplemented by brief interruption of therapy; this has been the conclusion of a study in which the unwanted renal effects of indinavir were prominent (72Cr). Of 74 individuals infected with HIV-1 and taking indinavir 2.4 g/day orally, 15 had indinavir-related urological adverse effects (19 episodes), most commonly dull flank pain and dysuria. Microhematuria occurred in

Antiviraldrugs

Chapter29

347

16 of the 19 episodes. Four patients had urinary tract distension on ultrasonography as a possible indirect sign of urolithiasis and one passed a stone. In four patients treatment had to be stopped permanently, but in the other 11 it was continued. Some patients required dosage reduction and/or interruption of treatment: only conservative therapeutic measures were required, consisting of rehydration (fluid intake of at least 1.5 l/day) and analgesics. Skin HIV-positive/AIDS patients using indinavir are repeatedly found to develop rashes early in treatment, a finding that is familiar with various other drugs used in this condition. This problem has been quantified in a study using data from postmarketing surveillance (73c). Of 110 HIV/AIDS patients with a rash, 67% reported that it had occurred within 2 weeks of the start of indinavir therapy. The rash was initially localized in all cases, but in the majority it went on to spread to other body areas, involving all parts of the body in no less than 44%. It was usually pruritic but not accompanied by fever. Relief was often obtained by use of topical antihistamines or oral or topical corticosteroids. More than half the patients decided to continue therapy despite the rash. Hair While alopecia has been reported before with ganciclovir, a brief report of its occurrence during indinavir treatment in 10 men appears to be the first of its type (74c). The authors remarked on the similarity between some of these localized adverse effects (alopecia and paronychia) and those seen with retinoids, a point worth considering when work is undertaken into the mechanism of these effects. Musculoskeletal

Three

recent reports

of

frozen shoulder in patients taking indinavir seem too similar to be coincidental, especially since there have been seven earlier instances involving triple therapy, but the mechanism underlying them remains unexplained (75Ar). An adhesive capsulitis seems to be present. Drug interactions There is good evidence that indinavir can substantially increase plasma concentrations of sildenafil (76Cr). Since HIV infection commonly leads to erectile dysfunction, the drugs may well be used together and it will then be prudent to use a lower dose of sildenafil.

Nelfinavir (SED-14, 998; SEDA-22, 317; SEDA-23, 317) Pancreas Pancreatitis,if it occurs, can be serious; any doubt as to the causal link has been largely dispelled by a case in which there was positive rechallenge (77A). Drug interactions While one might expect nelfinavir to reduce blood concentrations of certain other drugs by inducing their metabolism, it has on occasion been suggested that it might actually increase circulating concentrations of simultaneously administered phenytoin. However, a Japanese case has suggested that phenytoin concentrations can indeed be reduced; when the two drugs were co-administered a patient previously stabilized on phenytoin had a generalized convulsion (78A).

Ritonavir (SED-14, 998; SEDA-21, 309; SEDA-22, 318; SEDA-23, 317) Ritonavir does not have a broad therapeutic margin, and patients with higher ritonavir concentrations are at a higher risk of neurological or gastrointestinal adverse effects. It is feasible to individualize the dosage regimen with the aid of plasma concentration measurement and close observation of adverse effects, and there is a close relation between the two; this may enable one to increase substantially the percentage of patients who tolerate ritonavir without risking underdosage (79Cr). Cardiovascular In the light of a case with positive dechallenge and rechallenge it has been concluded that edema of the lower limbs may be an adverse effect of ritonavir in some HIVpositive patients (80Ar). The authors suspected a relation to the drug's vasodilatory activity. However, it should also be borne in mind that ritonavir has caused reversible renal insufficiency (SED-14, 998), which should be looked for in any patient who develops edematous changes. Reproductive system A recent report of four women with hypermenorrhea has strongly suggested that this can occur as a complication of ritonavir treatment (8 lcr). Infrequent periods and amenorrhea have been reported before.

348

Drug interactions In patients taking both ritonavir and ergotamine, ischemia of the lower limbs or elsewhere in the periphery has been reported, the suggestion being that the drugs interact (82c-84c). The complication is well recognized with ergot derivatives, and it is very likely that ritonavir potentiates this effect by interfering with the metabolism of ergotamine. Kinetic work has shown that by inhibiting CYP3A4, ritonavir can significantly inhibit the metabolism of fentanyl, and considerable caution is needed (85c). Similarly, there is evidence that ritonavir can dangerously increase warfarin concentrations (86c).

Chapter29

M.N.G.Dukes

Drug interactions As noted above, the protease inhibitors as a group can interfere with the metabolism of other drugs. The recent kineric finding that saquinavir substantially potentiates the effects of midazolam by raising its blood concentrations must therefore being regarded as a warning of a parallel interaction that could occur with other protease inhibitors (and no doubt certain other benzodiazepines) in a similar combination (88c).

DRUGS ACTIVE AGAINST INFLUENZA VIRUSES Zanamivir (SED-14, 999; SEDA-23, 321)

Saquinavir (SED-14, 998; SEDA-21, 310; SEDA-23, 318) Endocrine

Gynecomastia has been reported in a series of men taking saquinavir (87c). In these cases the association was clear (particularly since there was positive dechallenge), but this is a rare effect and has not previously been reported with either this or other protease inhibitors.

A recent review of the use of zanamivir in 6000 patients in clinical studies (89 M) seems to have confirmed its favorable safety profile, although the outcome of wider clinical use is awaited, particularly since if the drug is well accepted the scale of use is likely to be massive. To date there is still an optimistic impression that the adverse reactions pattern is no different from that of placebo and that interactions too are unlikely.

REFERENCES 1. Neau D, Renaud-Rougier MB, Viallard JE Dutronc H, Cazorla C, Ragnaud JM, Dupon M, Lacut JY. Intravenous cidofovir-induced iritis. Clin Infect Dis 1999; 28- 156-7. 2. Ambati J, Wayne KB, Angerame MC, Robinson MR. Anterior uveitis associated with intravenous cidofovir use in patients with cytomegalovirus retinitis. Br J Ophthalmol 1999; 83: 1153-8. 3. KerstenAJM, Althans C, Best J, Sundmacher R. Cystoid macular edema following immune recovery and treatment with cidofovir for cytomegalovirus retinitis. Graefe's Arch Clin Exp Ophthalmol 1999; 237: 893~5. 4. Skiest DJ, Duong M, Park S, Wei L, Keiser E Complications of therapy with intravenous cidofovir: severe nephrotoxicity and anterior uveitis. Infect Dis Clin Pract 1999; 83: 151-7. 5. Brody SR, Humphreys MH, Gambertoglio JG, Schoenfeld E Cundy KC, Aweeka FT. Pharmacokinetics of cidofovir in renal insufficiency and in continuous ambulatory peritoneal dialysis or highflux hemodialysis. Clin Pharmacol Ther 1999; 65: 21-8. 6. Perry CM, Barman Balfour JA, Johnson DW, De Clercq E. Fomivirsen. Drugs 1999; 57:375-81.

7. Zanetta G, Maurice-Estepa L, Mousson C, Justrabo E, Daudon M, Rifle G, Tanter Y. Foscarnetinduced crystalline glomerulonephritis with nephrotic syndrome and acute renal failure after kidney transplantation. Transplantation 1999; 67: 1376-8. 8. Aweeka Fr, Jacobson MA, Martin-Munley S, Hedman A, Schoenfeld P, Omachi R, Tsunoda S, Gambertoglio JG. Effect of renal disease and hemodialysis on foscarnet pharmacokinetics and dosing recommendations. J Acquired Immune Defic Syndr Hum Retrovirol 1999; 20: 350-7. 9. Jung D, (}fifty K, Dorr A. Effect of food on high-dose oral ganciclovir disposition in HIVpositive subjects. J Clin Pharmacol 1999; 39: 161-5. 10. Sharathkumar A, Shaw PJ. Ganciclovir-induced encephalopathy in a bone marrow transplant recipient. Bone Marrow Transplant 1999; 24: 421-3. 11. Jung D, Abdel Hameed MH, Hunter J, Teitelbaum P, Dorr A, Griffy K. The pharmacokinetics and safety profile of oral ganciclovir in combination with trimethoprim in HIV- and CMVseropositive patients. Br J Clin Pharmacol 1999; 47: 255-9.

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12. Stryjek-Kaminska D, Ochsendorf F, Roder C, Wolter M, Zeuzem S. Photoallergic skin reaction to ribavirin. Am J Gastroenterol 1999; 94: 1686-8. 13. Foster GR. Hepatitis C virus infection: quality of life and side effects of treatment. J Hepatol 1999; 31 Suppl 1: 250-4, 14. Guex-Crosier Y. Effect of highly active antiretroviral therapy (HAART) on cytomegalovirus retinitis. Klin Monatsbl Augenheilkd 1999; 214: 317-20. 15. Harrington RD, Woodward JA, Hooton TM, Horn JR. Life-threatening interactions between H1V-1 protease inhibitors and the illicit drugs MDMA and gamma-hydroxybutyrate. Arch Intern Med 1999; 159: 2221-4. 16. Khurana V, De la Fuente M, Bradley TP. Hypertensive crisis secondary to phenylpropanolamine interacting with triple-drug therapy for HIV prophylaxis. AIDS Reader 1999; 106:118-19. 17. Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang J-M, Gastaut J-A, Touraine J-L. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 1999; 13: 1659--67. 18. Staszewski S. Coming therapies: abacavir. Int J Clin Pract Suppl 1999; 103: 35-8. 19. Walensky RP, Goldberg JH, Daily JE Anaphylaxis after rechallenge with abacavir. AIDS 1999; 13: 999-1000. 20. Escaut L, Liotier LY, Albengres E, Cheminot N, Vittecoq D. Abacavir rechallenge has to be avoided in case of hypersensitivity reaction. AIDS 1999; 13: 1419-20. 21. Tikhomirov V, Namek K, Hindes R. Agranulocytosis induced by abacavir. AIDS 1999; 13: 14201. 22. Calegari J, Lorenzana R, Cheyer C, Gang DL, Higgins TL. Lactic acidosis and fulminant hepatic failure in a patient treated with didanosine, nelfinavir and stavudine. Clin Intensive Care 1999; 10: 61-3. 23. Weitzel T, Plettenberg A, Albrecht D, Lorenzen T, Stoehr A. Severe anaemia as a newly recognized side-effect caused by lamivudine. AIDS 1999; 13: 2309-11. 24. Blanche P, Silberman B, Barrett L, Gombert B, Sicard D. Reversible zidovudine-induced pure red cell aplasia. AIDS 1999; 13: 1586-7. 25. Zazo-Hernanz V, Sanchez-Herreros C, Gonzalez-Beato-Merino MJ, Lazaro-Ochaita P. Zidovudine pigmentation. Med Oral 1999; 4: 441. 26. Russo E Collantes C, Guerrero J. Severe paronychia due to zidovudine-induced neutropenia in a neonate. J Am Acad Dermatol 1999; 40 Suppl II: 322-4. 27. Kang-Birken SL, Prichard JG. Paronychia of the great toes associated with protease inhibitors. Am J Health-Syst Pharm 1999; 56: 1674-5. 28. Tosti A, Piraccini BM, D'Antuono A, Marzaduri S, Bettoli V. Paronychia associated with

349 antiretroviral therapy. Br J Dermatol 1999; 140: 1165-8. 29. Bourezane Y, Thalamy B, Viel J-F, Bardonnet K, Drobacheff C, Gil H, Vuitton D-A, Hoen B. Ingrown toenail and indinavir: case-control study demonstrates strong relationship. AIDS 1999; 13: 2181-2. 30. Acosta BS, Grimsley EW. Zidovudineassociated type B lactic acidosis and hepatic steatosis in an HIV-infected patient. South Med J 1999; 92: 421-3. 31. Culnane M, Fowler M-G, Lee SS, McSherry G, Brady M, O'Donnell K, Mofensen L, Gortmaker SL, Shapiro DE, Scott G, Jiminez E, Moore EC, Diaz C, Flynn PM, Cunningham B, Oleske J. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. J Am Med Assoc 1999; 281: 151-7. 32. Dabis F, Msellati P, Meda N, Welffens-Erka C, You B, Manigart O, Leroy V, Simonon A, Cartoux M, Combe P, et al. Six-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Ctte d'Ivoire and Burkina Fast: a double-blind placebo-controlled multicentre trial. Lancet 1999; 353: 786-92. 33. Wiktor SZ, Ekpini E, Karon JM, Nkengasong J, Maurice C, Severin ST, Roels TH, Kouassi MK, Lackritz EM, Coulibaly I-M, Greenberg AE. Shortcourse oral zidovudine for prevention of motherto-child transmission of HIV-1 in Abidjan, C6te d'Ivoire: a randomised trial. Lancet 1999; 353: 781-5. 34. Lee BL, Tauber MG, Sadler B, Goldstein D, Chambers HE Atovaquone inhibits the glucuronidation and increases the plasma concentrations of zidovudine. Clin Pharmacol Ther 1996; 59: 14-21. 35. Gustavson LE, Chu S-Y, Mackenthun A, Gupta MS, Craft JC. Drug interaction between clarithromycin and oral zidovudine in H1V-1 infected patients. Clin Pharmacol Ther 1993; 53: 163. 36. Vance E, Watson-Bitar M, Gustavson L, Kazanjian P. Pharmacokinetics of clarithromycin and zidovudine in patients with AIDS. Antimicrob Agents Chemother 1995; 39: 1355--60. 37. Mole L, Israelski D, Bubp J, O'Hanley P, Merigan T, Blaschke T. Pharmacokinetics of zidovudine alone and in combination with oxazepam in the HIV infected patient. J Acquired Immune Defic Syndr 1993; 6: 56-60. 38. Sattler FR, Ko R, Antoniskis D, Shields M, Cohen J, Nicoloff J, Leedom J, Koda R. Acetaminophen does not impair clearance of zidovudine. Ann Intern Med 1991:114: 937-40. 39. Shriner K, Goetz MB. Severe hepatotoxicity in a patient receiving both acetaminophen and zidovudine. Am J Med 1992: 93: 94-45. 40. Toffoli G, Errante D, Corona G, Vaccher E, Bertola A, Robieux I, Aita P, Sorio R, Tirelli U, Boiocchi M. Interactions of antineoplastic chemotherapy with zidovudine pharmacokinetics in patients with

350 HIV-related neoplasms. Chemotherapy 1999; 45: 418-28. 41. Gallicano KD, Sahai J, Shukla VK, Seguin I, Pakuts A, Kwok D, Foster BC, Cameron DW. Induction of zidovudine ghicuronidation and amination pathways by rifampicin in HIV-infected patients. Br J Clin Pharmacol 1999; 48: 16879. 42. Mills G, Morgan J, Hales G, Smith D. Acute hypersensitivity with delavirdine. Antiviral Ther 1999; 4: 51. 43. Gazzard BG. Efavirenz in the management of H1V infection. Int J Clin Pract 1999; 53: 60--4. 44. Moyle GJ. Efavirenz: shifting the HAART paradigm in adult HIV-1 infection. Expert Opin Invest Drugs 1999; 8: 473-86. 45. Aldeen T, Wells C, Hay P, Davidson F, Lau R. Lipodystrophy associated with nevirapinecontaining antiretroviral therapies. AIDS 1999; 13: 865-7. 46. Cattelan AM, Erne E, Salatino A, Trevenzoli M, Carretta G, Meneghetti F, Cadrobbi P. Severe hepatic failure related to nevirapine treatment. Clin Infect Dis 1999; 29: 455-6. 47. Rey D, Partisani M, Krantz V, KempfG, Nicolle M, De Mautort E, Priester M, Bernard-Henry C, Lang J-M. Prednisolone does not prevent the occurrence of nevirapine-induced rashes. AIDS 1999; 13: 2307. 48. Demoly P, Messaad D, Fre J, Reynes J, Bousquet J. Nevirapine-induced cutaneous hypersensitivity reactions and successful tolerance induction. J Allergy Clin Immunol 1999; 104: 504-5. 49. Wetterwald E, Le Cleach L, Michel C, David F, Revuz J. Nevirapine-induced overlap StevensJohnson syndrome/toxic epidermal necrolysis. Br J Dermatol 1999; 140: 980-2. 50. Heelon MW, Meade LB. Methadone withdrawal when starting an antiretroviral regimen inchiding nevirapine. Pharmacotherapy 1999; 19: 471-2. 51. Sereni D, Tubiana R, Lascoux C, Katlama C, Taulera O, Bourque A, Cohen A, Dvorchik B, Russell Martin R, Tournerie C, Gouyette A, Schlechter PJ. Pharmacokinetics and tolerability of intravenous trecovirsen (GEM-91), an antisense phosphorothioate oligonucleotide, in H1V-positive subjects. J Clin Pharmacol 1999; 39: 47-54. 52. Kaufman MB, Simionatto C. A review of protease inhibitor-induced hyperglycemia. Pharmacotherapy 1999; 19: 114-17. 53. Rodriguez-Rosado R, Soriano V, Blanco F, Dona C, Gonzalez-Lahoz J. Diabetes mellitus associated with protease inhibitor use. Eur J Clin Microbiol Infect Dis 1999; 18: 675-7. 54. Chen F, Kearney T, Robinson S, Daley-Yates PT, Waldron S, Churchill DR. Cushing's syndrome and severe adrenal suppression in patients treated with ritonavir and inhaled nasal fluticasone. Sex Transm Infect 1999; 75: 274. 55. HiUebrand-Haverkort ME, Prummel MF, Ten Veen JH. Ritonavir-induced Cushing's syndrome in

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a patient treated with nasal fluticasone. AIDS 1999; 13: 1803. 56. Darvay A, Acland K, Lynn W, Russell-Jones R. Striae formation in two HIV-positive persons receiving protease inhibitors. J Am Acad Dermatol 1999; 41: 467-9. 57. Milpied-Homsi B, Krempf M, Gueglio B, Raffi F, Stalder J-E Buffalo neck in HIV-positive patients receiving protease inhibitor therapy. Ann Dermatol Venereol 1999; 126: 254-6. 58. Periard D, Telenti A, Sudre E Cheseaux J-J, Halfon E Reymond MJ, Marcovina SM, Glauser MP, Nicod P, Darioli R, Mooser V. Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. Circulation 1999; 100: 700-5. 59. Echevarria KL, Hardin TC, Smith JA. Hyperlipidemia associated with protease inhibitor therapy. Ann Pharmacother 1999; 33: 859-63. 60. Berthold HK, Parhofer KG, Ritter MM, Addo M, Wasmuth JC, Schliefer K, Spengler U, Rockstroh JK. Infuence of protease inhibitor therapy on lipoprotein metabolism. J Intern Med 1999; 246: 567-75. 61. George SL, Swindells S, Knudson R, Stapleton JT. Unexplained thrombosis in HIV-infected patients receiving protease inhibitors: report of seven cases. Am J Med 1999; 107: 624--6. 62. Wilde JT, Lee CA, Collins E Giangrande PLE Winter M, Shiach CR. Increased bleeding associated with protease inhibitor therapy in HIV-positive patients with bleeding disorders. Br J Haematol 1999; 107: 556-9. 63. Durand JM. Indinavir and thrombocytopenia. AIDS 1999; 13: 148-9. 64. Morrison-Griffiths S, Newman M, O'Mahony C, Pirmohamed M. Haemolytic anaemia associated with indinavir. Postgrad Med J 1999; 75: 313-15. 65. Tsao JW, Kogan SC. Indinavir crystalltwia. New Engl J Med 1999; 340: 1329. 66. Hermieu J-F, Prevot M-H, Ravery V, Sty L, Moulinier E Delmas V, Bouvet E, Boccon-Gibod L. Urolithiasis and the protease inhibitor indinavir. Eur Urol 1999; 35: 239-41. 67. Schwartz BE Schenkman N, Armenakas NA, Stoller ML. Imaging characteristics of indinavir calculi. J Urol 1999; 161: 1085-7. 68. Sundaram CE Saltzman B. Urolithiasis associated with protease inhibitors. J Endourol 1999;13: 309-12. 69. Kohan AD, Arrnenakas NA, Fracchia JA. Indinavir urolithiasis: an emerging cause of renal colic in patients with human immunodeficiency virus. J Urol 1999; 161: 1765-8. 70. Hanabusa H, Tagami H, Hataya H. Renal atrophy associated with long-term treatment with indinavir. New Engl J Med 1999; 340: 392-3. 71. Grabe DW, Eisele G, Miller C, Singh J, Stein D. Indinavir-induced nephropathy. Clin Nephrol 1999; 51: 181-3. 72. Hug B, Naef M, Bucher HC, Sponagel L, Lehmann K, Battegay M. Treatment for human

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immunodeficiency virus with indinavir may cause relevant urological side-effects, effectively treated by rehydration. BJU Int 1999; 84: 610-14. 73. Gajewski LK, Grimone AJ, Melbourne KM, Vanscoy GJ. Characterization of rash with indinavir in a national patient cohort. Ann Pharmacother 1999; 33: 17-21. 74. Boscarat F, Prevot M-H, Matheron S. Alopecia associated with indinavir therapy. New Engl J Med 1999; 341: 618. 75. Peyriere H, Mauboussin J-M, Rouanet I, Rouveroux P, Hillaire-Buys D, Balmes P. Frozen shoulder in HIV patients treated with indinavir: report of three cases. AIDS 1999; 13: 2305-6. 76. Merry C, Barry MG, RyanM, Tjia JF, Hennessy M, Eagling VA, Mulcahy F, Back DJ. Interaction of sildenafil and indinavir when co-administered to HIV-positive patients. AIDS 1999; 13: F101-7. 77. Di Martino V, Ezenfis J, Benhamou Y, Bernard B, Opolon P, Bricaire F, Poynard T. Severe acute pancreatitis related to the use of nelfinavir in HIV infection: report of a case with positive rechallenge. AIDS 1999; 13: 1421-3. 78. Honda M, Yasuoka A, Aoki M, Oka S. A generalized seizure following initiation of nelfinavir in a patient with human immunodeficiency virus type 1 infection, suspected due to interaction between nelfinavir and phenytoin. Intern Med 1999; 38: 302-3. 79. Gatti G, Di Biagio A, Casazza R, De Pascalis C, Bassetti M, Cruciani M, Vella S, Bassetti D. The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring. AIDS 1999; 13: 2083-9.

351 80. Dol L, Geffray L, E1 Khoury S, Cevallos R, Veyssier E Lower-limb edema in an HIV+ patient: an adverse effect of ritonavir? Presse M6d 1999; 28: 75. 81. Nielsen H. Hypermenorrhoea associated with ritonavir. Lancet 1999; 353: 811-12. 82. Montero A, Giovannoni AG, Tvrde PL. Leg ischemia in a patient receiving ritonavir and ergotamine. Ann Intern Med 1999; 130: 329-30. 83. Liaudet L, Buclin T, Jaccard C, Eckert E Drug points. Severe ergotism associated with interaction between ritonavir and ergotamine. Br Med J 1999; 318: 186. 84. Rosenthal E, Sala F, Chichmanian R-M, Batt M, Cassuto J-E Ergotism related to concurrent administration of ergotamine tartrate and indinavir. J Am Meal Assoc 1999; 281: 987. 85. Olkkola KT, Palkama VJ, Neuvonen PJ. Ritonavir's role in reducing fentanyl clearance and prolonging its half-life. Anesthesiology 1999; 91: 681-5. 86. Newsham G, Tsang P. Ritonavir and warfarin interaction. AIDS 1999; 13: 1788-9. 87. Donovan B, Bodsworth NJ, Mulhall BE Allen D. Gynaecomastia associated with saquinavir therapy. Int J STD AIDS 1999; 10: 49-50. 88. Palkama VJ, Ahonen J, Neuvonen PJ, Olkkola KT. Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. Clin Pharmacol Ther 1999; 66: 33-9. 89. Freund B, Gravenstein S, Elliott M, Miller I. Zanamivir. A review of clinical safety. Drug Saf 1999; 21: 267-81.

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30

Drugs used in tuberculosis and leprosy

Dapsone

(SED-14, 1021; SEDA-22, 321; SEDA-23, 326)

Dapsone is an alternative drug for Pneumocystis carinii pneumonia prophylaxis in individuals who cannot tolerate co-trimoxazole, and although this has become less of a problem since the advent of highly active antiretroviral drug therapy in countries able to afford these regimens, further data on the toxicity of dapsone in children are welcome. In a multicenter study from the USA daily and weekly dapsone regimens have been compared in 94 HIV-infected children, monitoring hematological and liver toxicity and the incidence of skin rashes, Pneumocystis carinii pneumonia, or death (IC). They concluded that the weekly regimen produced less hematological toxicity, but that this advantage was offset by a trend toward higher breakthrough rates of Pneumocystis carinii pneumonia.

Hematologic A patient who had been taking dapsone inappropriately instead of an antispasmodic that had been prescribed for a spinal condition, because of incorrect labelling in a pharmacy, developed methemoglobinemia (2A). Methylene blue was given intravenously and may have contributed to the severe hemolysis that followed.

9 2001 Elsevier ScienceB.V. All rights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed. q52

Isoniazid

(SED-14, 1009; SEDA-23, 324)

Toxicity of prophylactic isoniazid in healthcare workers An Australian group has investigated the safety o f prophylaxis against tuberculosis using isoniazid in healthcare workers with strongly positive tuberculin skin tests (3c). They started by pointing out that tuberculosis is a well recognized occupational risk in healthcare workers, but added that this risk must vary considerably in different parts o f the world. For example, in the West Midlands, UK, a 4-year prospective study showed that doctors and nurses had a higher rate o f tuberculosis than the general public, but all but one o f the doctors in whom tuberculosis was diagnosed over a 5-year period had almost certainly acquired the infection abroad, so that the risk to doctors from occupationally acquired tuberculosis in the UK is probably extremely small (4c). Nurses may be at rather greater risk. A second important consideration is whether BCG immunization should be used to protect healthcare workers. In the USA it is not, and a positive tuberculin test in an American healthcare worker makes it reasonably likely that that individual has recently been infected with M. tuberculosis and is at risk o f developing the disease. In Australia, as in the UK, BCG is used, and in this study 89% o f the 878 healthcare workers who were tuberculin tested had a definite history o f BCG immunization, lsoniazid was offered to 291 workers with a definite history o f BCG and a tuberculin test result of more than 15 mm, and to eight who were not immunized and who had a test result o f more than 10 mm. Heavy drinkers and those with chronic liver disease were not offered prophylaxis, and 299, all o f whom had normal baseline liver

Drugs used in tuberculosis and leprosy

Chapter 30

function tests, actually received isoniazid with the intention of continuing for 6 months. All also received pyridoxine. During the 6-month treatment period adverse effects considered to be related to isoniazid were reported by 34 (41%), of whom 26 had adverse effects that were considered sufficiently severe to require withdrawal of therapy. The most common was an over 4-fold increase in transaminases, with malaise, nausea, and arthralgia the next most common. The authors concluded by stating that preventive therapy with isoniazid has an important role, and they referred to guidelines issued by the American Thoracic Society. However, one must question whether such guidelines are appropriate in healthcare systems in which BCG is widely used, since it is certain that in such circumstances some healthcare workers would be offered prophylaxis because they happened to respond briskly to tuberculin after immunization rather than because they had actually been infected with tubercle bacilli. To my mind, a high rate of adverse effects supports the view that isoniazid prophylaxis should be confined to TB contacts who have positive tuberculin tests only if they had never received a BCG or if they are judged to be at a particularly high risk of progression to clinical infection.

A strikingly different incidence of hepatotoxic reactions to isoniazid prophylactic Liver

therapy has been reported from Seattle, USA, where only 11 patients of 11 141 had hepatotoxic reactions (5c). The rate was 0.1% of those starting and 0.15% of those completing the course of therapy. The duration of therapy was not stated, but ten of the 11 episodes occurred within 3 months of starting. The definition of hepatotoxicity was the same as in the earlier study. Why the Australian study should have had a much higher incidence of hepatotoxicity (6% overall by the same criteria) is unclear. In most studies, increasing age has been identified as a risk factor for hepatotoxicity, but the median age in the American group was actually less (34 years) than in the Australian group (39 years). A difference in the extent of compliance with therapy must be a possibility. Skin A case of pellagra has been reported in a patient taking isoniazid, despite concomitant pyridoxine prophylaxis (6A).

353 A 52-year-old man developed pellagra with a classical photosensitive distribution after taking isoniazid for 14 months, the first 6 months being treatment for possible tuberculous meningitis, the rest to provide antituberculous protection while steroids were given for possible neurosarcoidosis. He was said to take alcohol only occasionally and took pyridoxine throughout the entire period of treatment. He improved rapidly on withdrawal of isoniazid and supplementation with nicotinamide. The authors noted that isoniazid-induced pellagra was first described in 1956, shortly after the introduction of isoniazid for the treatment of tuberculosis, but that subsequent reports have been very uncommon. Isoniazid has also been reported to cause subepidermal blistering (7A). A 63-year-old man developed bullous lesions on the trunk and limbs and a 6-fold rise in liver enzymes 15 days after treatment for tuberculosis. His skin recovered and his liver enzymes returned to normal within 2 weeks of withdrawal of all treatment, but the abnormalities recurred when treatment was resumed. At this point a skin biopsy showed subepidermal blistering. Once again withdrawal of treatment led to improvement, and when treatment was resumed without isoniazid the improvement continued.

Rifampicin

(SED-14, 1014; SEDA-21, 313; SEDA-22, 322; SEDA-23, 324) Immunologic The authors of a comprehensive review of the adverse effects of rifampicin (8 R) have made the point that these are likely to increase, because reactions such as hemo-

lysis, thrombocytopenia, and flu-like syndromes are more likely in patients who take rifampicin intermittently, a pattern of treatment that is becoming recognized as the best way to manage tuberculosis in developing countries and in patients everywhere whose compliance cannot be relied upon, since it is impractical to administer directly observed therapy (DOTS) more often than two or three times a week. Furthermore the flu-like syndrome is certainly more common in HIV-infected patients even with daily regimens. A possible explanation of the association with intermittent therapy is that during daily regimens the antigen-antibody complexes are continuously cleared from the plasma without reaching a critical concentration, whereas in intermittent regimens antibody titers can increase markedly during the drug-free days. This is supported by the observation that antirifampicin

354 antibodies, measured by the indirect Coombs' test, developed more commonly during intermittent than during daily therapy and that antibodies may disappear from the serum when patients change from intermittent to daily regimens. Curiously, rifampicin-induced rash often resolves spontaneously, even without drug withdrawal, although in others it may be severe and may be accompanied by systemic symptoms, in some cases amounting to anaphylaxis. The authors made the point that while the usual procedure with any adverse drug reaction is to withdraw the incriminated drug, options may become increasingly limited in the treatment of mycobacterial infections, given the rising prevalence of isoniazid resistance. Desensitization protocols may be helpful in patients who have anaphylactic reactions, and the detection of IgE antibodies to rifampicin may possibly be helpful in clarifying pathogenesis, but a switch to a daily regimen, when administration was previously intermittent, may allow resumption of rifampicin without further problems. However, the flu-like syndrome, hemolytic and thrombocytopenic crises, and acute renal insufficiency are not IgE mediated, and when rifampicin is thought to be indispensable a course of treatment may be completed under corticosteroid cover. Finally, the authors reported an HIV-infected patient who developed an anaphylactic reaction to rifampicin but who tolerated treatment with the similarly active rifamycin, rifabutin, without any adverse event. In a separately reported series (9c), four patients with reactions to rifampicin, one with rash, fever, and lymphadenopathy and one with hepatitis, completed courses of antituberculous therapy for CNS infections under corticosteroid cover.

Drug interactions Rifampicin is a potent inducer of hepatic microsomal drug metabolizing enzymes and has been implicated in reducing the effectiveness of many drugs that are metabolized in the liver (SEDA-21, 313). Interactions continue to be recognized, reflecting the extension of the use of rifampicin from an antituberculous agent to an antistaphylococcal drug, particularly useful in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) and when prostheses are infected.

Chapter 30

C.J. Ellis

Amiodarone Rifampicin has been reported to reduce the effects of amiodarone (10A). A 33-year-old woman was given rifampicin to suppress an MRSA infection of a pacing system that could not be removed. She was already taking amiodarone which, with the pacing system, was intended to manage her complex dysrhythmias. The introduction of antibiotic therapy was followed by an increase in bouts of palpitation and in shocks from her defibrillator. Her amiodarone concentrations had fallen and returned to the target range, with disappearance of her symptoms, when the rifampic!n was withdrawn. The authors discussed the possible reasons for this interaction, including a reduction in systemic availability of amiodarone or induction of metabolism by rifampicin. Digoxin In eight healthy volunteers administration of rifampicin reduced digoxin plasma concentrations (11c), mirroring clinical experience. The authors hypothesized that this effect may be brought about by induction of P-glycoprotein, which increases excretion of digoxin into the gut lumen; however, renal digoxin clearance, which is also mediated by Pglycoprotein, was not affected. In these healthy volunteers rifampicin reduced digoxin concentrations by about 50%, so the interaction is likely to be clinically important. Oral contraceptives A possible interaction between rifampicin and oral contraceptives has been previously described and the effects of rifampicin have been compared with those of rifabutin (increasingly used for the treatment of atypical mycobacterial infections) in a double-blind cross-over study in 12 woman who were taking a stable oral contraceptive regimen containing ethinylestradiol and norethindrone (12c). Rifampicin had the greater effect in reducing the mean AUC, but none of the subjects ovulated during the cycle in which either of the rifamycins was administered. Thyroxine Induction of cytochrome P-450 may be the explanation for a modest increase in the clearance of thyroxine (10-15%) which may necessitate an increase in dosage. Two cases have been reported in which rifampicin led to significant increases in TSH concentrations in patients being treated for hypothyroidism (13A).

Drugs used in tuberculosis and leprosy

Chapter30

355

REFERENCES 1. Mclntosh K, Cooper E, Xu J, Mirochnick M, Lindsey J, Jacobus D, Mofenson L, Yogev R, Spector SA, Sullivan JL, et al (95 authors). Toxicity and efficacy of daily vs weekly dapsone for prevention of Pneumocystis carinii pneumonia in children infected with human immunodeficiency virus. Paediatr Infect Dis J 1999; 18: 432-9. 2. Southgate HJ, Masterson R. Lessons to be learned: a case study approach: Prolonged methaemoglobinaemia due to inadvertent dapsone poisoning; treatment with methylene blue and exchange transfusion. J R Soc Health 1999; 119: 52-5. 3. Stuart RL, Wilson T, Grayson ML. Isoniazid toxicity in health care workers. Clin Infect Dis 1999; 28: 895-7. 4. Hill A, Burge A, Skinner C. Tuberculosis in hospital staff in the West Midlands region of England, 1992--95. Thorax 1997; 52: 994-7. 5. Nolan CM, Goldbert SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey. J Am Med Assoc 1999; 281: 1014-18. 6. Darvay A, Basarab T, McGregor JM, RussellJones R. Isoniazid-induced pellagra despite pyridoxine supplementation. Clin Exp Dermatol 1999; 24: 167-70. 7. Scheid P, Kanny G, Trehot Ph, Rosner V,

Menard O. Isoniazid-induced bullous skin eruption. Allergy Eur J Allergy Clin Immunol 1999; 54: 294-6. 8. Martinez E, Collazos J, Mayo J, Hypersensitivity reactions to rifampicin: pathogenetic mechanisms, clinical manifestations, management strategies, and review of the anaphylactic-like reactions. Medicine 1999; 78: 361-9. 9. Morris H, Muckerjee J, Akhtar S, Abdullahu, Harrison M. Use of corticosteroids to suppress drag toxicity in complicated tuberculosis. J Infect 1999; 29: 23740. 10. Zarembski DG, Fischer SA, Santucci PA, Porter MT. Impact of rifampicin on serum amiodarone concentrations. Pharmacotherapy 1999; 19: 24951. 11. Greiner B, Eichelbaum M, Fritz P, Kreichgauer HP. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampicin. J Clin Invest 1999; 104: 147-53. 12. Borditch-Crovo P, Trapnell CB, Ette E, Azcur HA, Coresh J. The effects of rifampicin and rifabutin on the pharmacokinetics of a combination oral contraceptive. Clin Pharmacol Ther 1999; 65: 428-38. 13. Nolan SR, Self TH, Norwood JM. Interaction between rifampin and levothyroxine. South Med J 1999; 92: 529-31.

A.G.C. Bauer

31

Antihelminthic drugs

BENZIMIDAZOLES

(SED-14, 1030; SEDA-21, 315; SEDA-22, 324; SEDA-23, 327)

ity and frequency of the usually mild adverse effects are comparable.

Albendazole and mebendazole

Liver That all benzimidazoles can cause liver damage is illustrated by a case of granulomatous hepatitis with eosinophilia probably caused by mebendazole (2A).

The use of albendazole and mebendazole in patients with hydatidosis has recently been evaluated in 448 patients with Echinococcus granulosis hydatid cysts who received oral albendazole 10-12 mg/kg/day or mebendazole 50 mg/kg/day for 3 - 6 months (lCR). At the end of treatment, 82% of the cysts treated with albendazole and 56% of the cysts treated with mebendazole showed degenerative changes. During long-term follow-up 25% of these cysts showed relapse, which took place within 2 years in 78% of cases. Further treatment with albendazole induced degenerative changes in over 90% of the relapsed cysts, without induction of more frequent or more severe adverse effects, as observed during the first treatment period. Adverse effects during the first treatment period consisted of raised transaminases with albendazole (67 of 323 patients) and mebendazole (16 of 125 patients), and abdominal pain in 12% and 11% respectively. Headache occurred in eight patients taking albendazole and three taking mebendazole, abdominal distension in seven and five patients, vertigo in five and one, urticaria in five and three, jaundice in one and one, thrombocytopenia in two and none, fever in three and none, dyspepsia in two and four, and tachycardia in two and none. Six of 323 patients taking albendazole withdrew because of adverse effects compared with eight of 125 patients taking mebendazole. It appears that albendazole is more effective than mebendazole in the treatment of hydatid cysts caused by Echinococcus granulosis and that both the intens-

9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual24 J.K. Aronson, ed.

A 52-year-old man with ascariasis took two 3day cycles of mebendazole 100 mg bd with a 2-week interval. Within 48 hours of the second course he developed fever (39 ~ C), diarrhea, anorexia, and prostration. Ten days later he had tender hepatomegaly. His liver function tests were abnormal (AsT 466 iu/1, A1T 458 iu/1). The serum alkaline phosphatase and bilirubin were normal and the F-glutamyltransferase mildly raised. The white blood cell count was 12.7 x 106/1 with 18% eosinophils. Coagulation was normal. Tests for Hepatitis A, B, and C, cytomegalovirus and Epstein-Barr virus infections were all negative. Serum ACE was not raised. Antimitochondrial antibodies were negative but antinuclear antibodies (1:60) and antibodies against smooth muscle (1:160) were positive. Extensive tests to exclude other causes of granulomatous hepatitis were all negative. A liver biopsy showed multiple granulomata consisting of epithelioid cells, multinucleated giant ceils, plasma cells, and lymphocytes. There was slight fibrosis around the granulomata. There was no evidence of cholestasis. No helminthic ova were found. ZiehlNielsen and periodic acid Schiff stains were both negative. After 2 days the fever had subsided without treatment and he felt better. The serum transaminases returned to normal over the next 10 weeks and the eosinophilia disappeared. Liver damage has been described after treatment with most benzimidazoles, but it is usually cholestatic. The liver damage described in this case was granulomatous. Liver damage after mebendazole in the low dose used in this case is rare, probably because of its poor absorption. It is more frequent, although still rare, in the higher doses used in the treatment of human echinococcosis.

Antihelminthicdrugs

Chapter31

Diethylcarbamazine

(SED-14, 1034)

Diethylcarbamazine is effective in several types of filariasis. Although ivermectin is now the preferred drug in many cases, diethylcarbamazine is still widely used, especially in Loa Loa infections and in lymphatic filariasis, in which diethylcarbamazine can cause systemic reactions, such as fever, arthralgia, headache, and malaise, and local reactions such as swollen and painful lymph nodes. All of these reactions are thought to be caused by an allergic reaction to antigens from the dying microfilaria and not to a toxic effect of the drug itself. This causal relation is further emphasized by a study from Indonesia, in which adverse reactions to treatment with diethylcarbamazine were studied in patients with Brugia Malayi filariasis--26 microfilaria-positive patients (mean 235 mf/10 ml), 12 "endemic" controls (from the endemic area, but microfilaria counts negative), and 17 patients with elephantiasis, of whom three had high microfilaria counts (3c). Adverse effects, mainlyfever, headache, and body aches, started 2-24 hours after the administration of diethylcarbamazine 6 mg/kg/day for 12 days. Of the patients with positive pretreatment microfilaria counts 15% had severe adverse reactions, 19% moderate reactions, and 65% mild reactions. There was a direct relation between the severity of the adverse effects and the height of pretreatment microfilaria counts, and the more severe adverse effects occurred in the patients with the highest pretreatment microfilaria counts. In the endemic controls there were no reactions or only mild ones. In the patients with elephantiasis there were no reactions or only mild ones in all but two patients, both of whom had moderate reactions and had high pretreatment microfilaria counts. That diethylcarbamazine may still be the more effective drug in Brugia Malayi infections, despite these adverse effects, is suggested in a study from India, in which the efficacy and safety of several single-dose drug combinations, including albendazole, diethylcarbamazine, and ivcrmectin were compared in 51 microfilaria positive patients with Brugia Malayi and in which diethylcarbamazine was more effective in reaching a sustained reduction in microfilaria counts after 1 year than ivermectin, although the study was small (4c). Adverse reactions (fever, headache, myalgia, and chills) occurred in all of the 16 patients

357 treated with a combination of ivermectin (200 Ixg/kg as a single dose) and diethylcarbamazine (6 mg/kg as a single dose), in 15 of the 16 patients treated with albendazole (400 mg as a single dose) and diethylcarbamazine (6 mg/kg as a single dose), and in 12 of the 16 patients treated with ivermectin and albendazole.

Ivermectin (SED-14, 1035; SEDA-21, 315; SEDA-22, 326; SEDA-23, 328) Ivermectin is a very effective microfilaricidal drug in the treatment of strongyloidiasis, all types of filariasis (except Dipalonema perstans), and in scabies. Ivermectin and onchocerciasis Ivermectin has been successfully used in the treatment of onchocerciasis and is now considered to be the drug of choice. Because of its low incidence of adverse effects it can be used in mass treatment campaigns. Observations that proteinuria and hematuria may occur in patients with filariasis bancrofti and loiasis, which may exacerbate after treatment with diethylcarbamazine or ivermectin, led to the study of kidney function in patients with onchocerciasis before and after treatment with ivermectin (5c). The occurrence of renal abnormalities was studied in a population-based study in a meso-endemic village (40% microfilaria carriers), in a group of patients with a generalized or hyper-reactive form of onchocerciasis, and in 46 patients treated with ivermectin in a single oral dose of 150 Ixg/kg. All individuals in all three study groups were examined clinically and had skin snips, serological testing for onchocerciasis, and nodulectomy (when relevant). Tests for malaria, schistosomiasis, intestinal nematodes, and hepatitis B, and serum glucose, creatinine, IgE, and electrophoresis were also performed. The urine was tested for erythrocytes, leukocytes, protein, nitrites, pH, glucose, ketone bodies, urobilinogen, and creatinine. All the patients underwent renal ultrasound examination. There was no difference in renal function and renal ultrasound between patients with and without onchocerciasis. A raised urinary protein concentration (over 70 mg/g of creatinine) was common and occurred in 47% of the patients with onchocerciasis and 63% of the patients without onchocerciasis. In the 46 patients treated for onchocerciasis with a single dose

358 of 150 I~g/kg there was a slight but statistically significant increase in total urine protein after 2 and 5 days, especially in 16 patients with high pretreatment skin microfilaria counts. The abnormalities were minor and insignificant. Neither onchocerciasis itself nor treatment with ivermectin was associated with abnormalities of renal function. Ivermeetin and scabies There have been two recent trials of the efficacy of ivermectin in scabies (6C, 7c). In a randomized double-blind comparison of the efficacy of oral ivermectin and topical lindane 53 patients were randomly allocated to either a single oral dose of ivermectin 150-200 I~g/kg and a placebo topical solution, or a single dose of lindane topical solution 1% and placebo tablets (6c). Patients who did not fulfil the criteria for clinical cure within 15 days, defined as the absence of both pruritus and clinical lesions or a reduction in signs and symptoms to a mild degree, repeated the initial treatment. Of the 53 patients 43 completed the study (19 of those treated with ivermectin and 24 of those treated with lindane). After 15 days 74% of the patients treated with ivermectin and 54% of the patients treated with lindane were considered to be cured. At 29 days both treatments were equally effective, with cure rates of 95% and 96% respectively. Adverse effects were mild and transient in both groups. One of the patients treated with ivermectin had hypotension, one had abdominal pain, one had vomiting, and one complained of headache. There were no abnormalities on routine laboratory testing. In another uncontrolled open-label study 101 patients with scabies were treated with a single oral dose of ivermectin 200 Ixg/kg and then followed at 3 days and at 2 and 4 weeks (7c). Two weeks after the start of treatment 89 patients were completely free of scabies, while another three had only mild lesions and pruritus with negative skin scrapings. The other nine patients had persistent pruritus and new lesions and were treated with a second dose, with a complete cure in all cases after 4 weeks. Twelve patients reported minor adverse effects, consisting of drowsiness (4), arthralgia and bone aches (2), dyspnea (3), headache (1), nausea (1), and blurred vision (1). The adverse effects were mostly reported at the first follow-up and were easily tolerated. Ivermectin appears to be a safe and effective treatment for scabies in a

Chapter 31

A.G.C.Bauer

dose of 200 Ixg/kg, although a second dose is necessary for complete cure in a few patients.

Levamisole (SED-14, 1037; SEDA-21, 317; SEDA-22, 328; SEDA-23, 330) Although it was originally developed as an antihelminthic drug, levamisole is now mainly used as an immunomodulating drug in the treatment of nephrotic syndrome in children and in the adjuvant chemotherapy of Dukes B and C colorectal cancer. Adverse effects include granulocytopenia, mild elevation of

hepatic transaminases, arthralgia, rashes and skin discoloration, neuropsychiatric abnormalities (such as insomnia and depression), and neurological syndromes (especially inflammatory cerebral demyelination, which presents with confusion, ataxia, dysarthria, diplopia, focal neurological signs, and seizures). Another two cases of this syndrome have recently been presented and the syndrome has been extensively discussed and reviewed (8AR). A 65-year-old man developed impaired cognition and a disturbed gait 6 months after the removal of a Dukes C colon cancer with adjuvant chemotherapy with fluorouracil and levamisole. Three months later he developed arthralgias in the hands, elbows, and knees, followed 1 month later by intermittent monocular diplopia, an ataxic gait, and deteriorating cognitive function. An MRI scan of the brain showed multiple small round and oval hyperintense lesions in the periventricular white matter, without surrounding edema or mass effect. Most of the lesions showed ring enhancement after intravenous gadolinium. The cerebrospinal fluid protein content was raised, but cytology was normal. A stereotactic biopsy of one of the lesions showed marked cellularity of the white matter, with mononuclear cells in both the parenchyma and perivascular areas, and severe demyelination of the white matter with relative preservation of the axons. Most of the parenchymal cells were macrophages, containing myelin debris. All the findings were consistent with a diagnosis of multifocal inflammatory leukoencephalopathy after treatment with levamisole. The adjuvant therapy was discontinued and he was treated with methylprednisolone 1 g/day intravenously for 3 days, followed by dexamethasone 4 mg qds orally. Within weeks he started to improve, with resolution of the ataxia and improved cognitive function. However, there was residual mild left hemiparesis and he remained moderately unsteady on his feet. The corticosteroids were slowly tapered and an MRI scan several weeks later still showed multiple patchy areas of bright signal, corresponding to the previous demyelination, but

Antihelminthic drugs

Chapter 31

without enhancement. A further MRI scan after 1 year showed complete resolution. His neurological condition and performance had further improved, but there was residual impairment of sbort-term memory. The authors suggested that this syndrome may be more common than supposed, and that it is likely that levamisole is the main causal factor, since the same symptoms have been described after treatment with high-dose levamisole alone, but that the effect may be enhanced by the co-administration of fluorouracil, which potentiates the immunostimulatory action of levamisole. Although there is no conclusive evidence of the value of corticosteroids in this syndrome, an adequate course of corticosteroids is advised, comparable to the treatment of multiple sclerosis. A 57-year-old man had a Dukes C colon cancer removed and was given adjuvant chemotherapy with fluorouracil and levamisole at 4-week intervals (9c). Four months later he developed insomnia, diplopia, and a reduced level of consciousness. He was disoriented in time and place, but there were no focal neurological defects. The cerebrospinal fluid protein concentration was slightly raised. A provisional diagnosis of fluorouracil/levamisole-induced neural toxicity was made and he was treated with dexamethasone 4 mg qds. There was an improvement in orientation after 3 days of treatment, but he remained mentally dull. After 28 days of therapy the corticosteroids were tapered. An MRI scan showed multiple focal hyperintensities, with involvement of both deep and subcortical white matter. The lesions were not associated with a mass effect and were mildly enhanced by gadolinium. At 30 months follow-up the patient was well without evidence of relapse. An MRI scan at 24 months showed small, residual, hyperintense lesions, which were not further enhanced by gadolinium, consistent with gliotic scars. This neurological syndrome, although severe, fortunately appears to be rare. Fluorouracil plus leucovorin has been compared with fluorouracil plus levamisole and combined fluorouracil plus leucovorin and levamisole in 2151 patients with Dukes B and C colon cancers (10c). The regimens were as follows: fluorouracil plus leucovorin: six 8-week cycles of leucovorin 500 mg/m 2 as a 2hour infusion repeated weekly for six doses and fluorouracil 500 mg/m 2, given as an intravenous bolus 1 hour after the start of the leucovorin infusion, also weekly for six

359 doses; the cycle was repeated after a rest period of 2 weeks; fluorouracil plus levamisole: fluorouracil 350 mg/m2 as an intravenous bolus daily for five consecutive days, then once weekly starting on day 29 and levamisole orally tds for 3 days and repeated every 14 days; fluorouracil plus leucovorin plus levamisole: the same fluorouracil plus leucovorin treatment as described above, with the addition of levamisole in the dose used in the fluorouracil plus levamisole group. There was a small prolongation of the disease-free interval and overall survival in favor of fluorouracil plus leucovorin, although of borderline statistical significance. Information on toxicity was obtained in 98% of the patients. Eighteen died while on chemotherapy, four in the fluorouracil plus leucovorin group, three in the fluorouracil plus levamisole group, and 11 in the fluorouracil plus leucovorin and levamisole group. Grade 3-4 toxicity was reported equally in the three groups: fluorouracil plus leucovorin 35%, fluorouracil plus leucovorin and levamisole 36%, and fluorouracil plus levamisole 28%. They consisted mainly of adverse effects attributed to fluorouracil, such as diarrhea, vomiting, and stomatitis. Hematological toxicity was minimal (<2% grades 3-4) and not significantly different across the groups. Neurotoxicity was rare. Ataxia was the most frequent neurological disorder, in 2% of the patients who received fluorouracil plus levamisole and in 1% of the patients in the other two groups combined. In an extensive review of the treatment of minimal lesion glomemlonephritis the use of levamisole was briefly mentioned (llr). The author concluded that levamisole has a beneficial effect in this disorder, although no new studies have appeared in recent years and wellcontrolled studies are scarce. Levamisole appears to be well tolerated in this condition. The adverse effects were neutropenia, rash, and

raised liver transaminases. Immunologic Disseminated autoimmune disease has been described during treatment with levamisole for nephrotic syndrome (12A). An 8-year-oldboy had a 5-year history of steroiddependent nephrotic syndrome. After half a year of steroid treatment he was given levamisole 2.5 mg/kg

Chapter 31

360 on alternate days for 1 year, with complete suppression of the proteinuria. The proteinuria reappeared after withdrawal of levamisole, and corticosteroids and levamisole were reintroduced as before. Two years later, while still taking levamisole, he developed hepatosplenomegaly, a low-grade fever, and a Coombs' negative hemolytic anemia. The anticardiolipin IgM titer was high, p-ANCA antibodies were positive, C3 was moderately low. and antinuclear anti-DNA antibodies were negative. Levamisole was withdrawn. Two weeks later the clinical parameters had normalized and 4 weeks later the liver enlargement had disappeared. Although p-ANCA antibodies persisted at 1 month the anticardiolipin IgM titer had returned to normal. After 6 months there still was splenomegaly but no other symptoms, and proteinuria was absent. The same group of authors have also described a distinctive vasculitis with circulating antibodies in children with nephrotic syndrome associated with long-term levamisole, presenting with purpura of the ears (13c). Four boys and one girl (mean age 10 years) had had nephrotic syndrome for 2-8 years and had taken levamisole orally in doses of 1.7-2.5 mg/kg/day for 16 ~A months (mean 24 months). All had a sudden onset of rapidly enlarging purpuric and erythematous macules progressing to the formation of necrotic areas, purpuric plaques, and hemorrhagic bullae. The pinnae were involved in all five. In three there were also lesions on the cheek or lower limbs. One had fever and another complained of arthralgia. Routine laboratory tests were all normal. Antibodies to extractable nuclear antigen, cryoglobulin, rheumatoid factor, Coombs' test, circulating immune complexes, and complement and components were all negative or normal. However, antiphospholipid antibodies and/or anticardiolipin IgG and IgM were positive in three patients, p-ANCA was positive in three, and c-ANCA in one. Antinuclear antibodies were positive in two patients and anti-double-stranded DNA antibodies were positive in one. Biopsies of the skin lesions in four patients showed vasculitis, ranging from a leukocytoclastic and thrombotic vasculitis to vascular occlusive disease without true vasculitis. Two patients had a hypersensitivity vasculitis in the superficial and deep dermis, with neutrophilic infiltration of the vessel walls and fibrinoid necrosis. Features of panniculitis with occlusion of deep and superficial blood vessels by fibrin-platelet thrombi were found in one patient. The lesions completely resolved in all patients within 2-3 weeks after the withdrawal of levamisole. The serum autoantibodies had disappeared in all cases after 2-14 months. Although leukocytoclastic immunecomplex vasculitis induced by levamisole is well known, this specific presentation with

A.G.C.Bauer

involvement of the ears has not been described before.

Praziquantel

(SED-14, 1041; SEDA-21, 318; SEDA-22, 329)

Praziquantel is considered to be safe and effective in all types of human schistosomiasis, for which it is the treatment of choice, and in a wide range of other helminthic infections. The efficacy and adverse effects of treatment with a single oral dose of praziquantel 40 mg/kg, in relation to egg counts and morbidity, have been studied in 611 primary school children infected with Schistosoma mansoni in Northeastern Ethiopia (14c). Before treatment 40% of the patients had no symptoms and 3 0 40% complained of nausea, abdominal cramps, and/or bloody diarrhea. The symptoms before treatment were not related to nutritional status, intensity of S. mansoni egg excretion, or the presence of concomitant intestinal parasites. In the first 4--6 hours 90 children (15%) developed severe gastrointestinal symptoms, with vomiting, abdominal cramps, and/or bloody diarrhea. They had higher mean pretreatment egg counts than the children who did not have these symptoms. The day after treatment 529 children (87%) were reviewed. Adverse effects were reported by 92% and consisted of abdominal cramps (87%), bloody diarrhea (50%), dizziness (31%), and vomiting (29%). Skin rashes and edema were observed in four individuals. The combination of abdominal cramps with vomiting, bloody diarrhea, and general weakness was significantly more common in the malnourished children and in the children with higher pretreatment egg counts. The overall cure rate after treatment with praziquantel was 83% after 5 weeks, but this rate fell with increasing pretreatment egg counts. These findings confirm that praziquantel is effective in the treatment of S. mansoni infections but that treatment may be associated with severe abdominal adverse effects, which may reduce drug compliance in population chemotherapy. This point has been further evaluated in a larger double-blind placebo-controlled study of the concurrent administration of albendazole and praziquantel in over 1500 children with high prevalences of schistosomiasis and other helminthic diseases in China and the Philip-

Antihelminthic drugs

Chapter31

pines, including two strains of S. japonicum, and two different areas of Kenya, one each with S. mansoni or S. hematobium (15c). There was no difference between the rate of adverse effects after treatment with albendazole compared with placebo, but after treatment with praziquantel the children had significantly more nausea, abdominal pain, and headache. These adverse effects, although considered mild, were more common in children with schistosomiasis, which suggests a reaction to dying schistosoma rather than a toxic effect of the drug itself. There was a very high rate of complaints in Kenya, but both the history and the reactions after placebo suggested that many of the adverse effects reported after treatment reflected complaints before treatment. In all four sites there was a significant increase in hemoglobin after 6 months in the children treated with praziquantel. This beneficial effect strongly supports population-based mass treatment for schistosomiasis and other helminthic diseases, although it may be accompanied by adverse abdominal effects, which may be severe in a small minority of patients, especially in S. mansoni infections.

Praziquantel and neurocysticercosis

Praziquantel 100 mg/kg in three divided doses has been compared to albendazole 15 mg/kg/day for 1 week in the treatment of neurocysticercosis in 20 patients (16c). In the patients treated with albendazole the number of cysts fell from 64 to 7 and in the patients treated with praziquantel it fell from 59 to 24. The difference was not statistically significant. All the patients were concomitantly treated with high doses of corticosteroids. Nine of the 10 patients treated with praziquantel had seizures, headache, and dizziness, and two had hemiparesis before treatment. A few hours after the last dose of praziquantel six patients had adverse reactions, including headache and vomiting in five patients, seizures in one patient, and worsening of the pre-existing motor deficit in one. Analgesics and antiemetics improved the symptoms in four patients. In two patients treatment with mannitol was needed to relief symptoms of increased cranial pressure. The results suggested that single-day treatment with praziquantel of neurocysticercosis may be a useful option. The observed adverse effects were considered to be the result of the inflammatory reaction follow-

361 ing the dying of worms and not a toxic effect of the drug itself.

Praziquantel and teniasis In a report from India the efficacy and safety of treatment of Tenia saginata infections, resistant to niclosamide, has again been confirmed in 185 consecutive patients with niclosamide-resistant infection treated with praziquantel 10/mg/kg orally (17c). Follow-up stool examinations at 4 and 12 weeks showed a cure rate of 96%. Eleven patients were lost to follow-up, and 8 still produced proglottides at the end of 12 weeks. None passed the worm in their stools, since praziquantel destroys the worm, after which the scolex and worm are digested. Thirty patients (16%) reported minimal adverse effects, such as nausea (4), abdominal discomfort (10), and giddiness (16).

Suramin (SED-14, 1042; SEDA-21, 318; SEDA-22, 330; SEDA-23, 332) Suramin is rarely used as a macrofilaricidal drug in the treatment of onchocerciasis, but is now mainly used in the treatment of hormonerefractory prostate cancer, in which it has some antitumor effect, although accompanied by extensive and sometimes severe adverse effects, especially in the higher dosage regimens necessary. The efficacy and adverse effects of treatment with suramin for hormone-refractory prostate cancer have been evaluated in 27 patients (18Cr). The treatment regimen consisted of a loading phase, targeted to reach suramin serum concentrations of 180-250 Ixg/ml using a dose of 1.4 g/m 2 at 3-day intervals. Constant suramin concentrations were obtained with a dose of 0.5-1 g/m 2 every 7-10 days. Six patients did not complete the suramin loading phase because of adverse effects and were withdrawn. About one-third of the assessable patients had a more than 50% reduction in prostate specific antigen and/or serum alkaline phosphatase. Two of these also had a reduction in metastases on bone scan. Another 48% of the patients had unchanged prostate specific antigen or serum alkaline phosphatase during treatment with suramin, suggesting stable disease. The mean survival time was 41 weeks. Responders had a survival of 70 weeks compared with 12 weeks among non-responders.

362 However, the adverse effects were substantial. The most common adverse effects were renal impairment (18 patients), 10 of whom had a mild increase in serum creatinine and seven had a moderate increase. One patient died of multiorgan failure, including renal shutdown. Suramin treatment was interrupted for 7-14 days when the creatinine clearance was under 40 ml/min, which resulted in improvement in renal function. A sensimotor polyneuropathy occurred in 18 patients and typically presented as paresthesia involving the limbs, combined with reduced nerve conducting velocity. Mild and moderate sensorimotor polyneuropathy occurred in 14 patients. Severe polyneuropathy occurred in two cases and led to the withdrawal of suramin. These effects were only partially reversible. Eleven patients had no neurotoxic symptoms. Allergic rashes occurred in 30% of patients and consisted of a moderate, diffuse, morbilliform rash during the loading phase of suramin treatment, usually disappearing within a few days without further therapy. Two patients with more severe and prolonged rashes were treated with high-dose corticosteroids with a beneficial effect. Hematological toxicity consisted of anemia in 22% of the patients, who all needed blood transfusions, leukopenia in 15%, of whom one with a severe leukopenia was successfully treated by granulocyte-macrophage colony stimulating factor, and thrombocytopenia, which occurred in 15% of patients and led to spontaneous bleeding in two. The platelet count returned to normal in both cases after the withdrawal of suramin. Vortex keratopathy occurred in 15% of the patients. Corneal changes were always minimal and vision was not affected. One pa-

Chapter 31

A.G.C.Bauer

tient had a retinal bleed, which led to withdrawal. Severe infections occurred in 26% of the patients, and also led to the withdrawal of suramin and required intravenous antibiotics. These results have further confirmed that suramin has a limited but statistically significant effect in the treatment of hormonerefractory prostate cancer. Although the severity of adverse effects were somewhat less than in previous studies they were still substantial. The toxicity of suramin seems to be closely related to the cumulative dose, peak concentration, and treatment regimen, and toxicity may be reduced by reducing daily doses and giving additional treatment-free intervals. Suramin has been combined with epirubicin in 26 patients with hormone-refractory prostate cancer (19c). No additional therapeutic effect was found compared with suramin or epirubicin alone. Suramin was given in an initial daily dose of 350 mg/m 2, with weekly infusions thereafter, targeted to maintain suramin plasma concentrations at 200-250 Ixg/ml for a maximum of 6 months. Cortisone acetate was added after 4 weeks in order to prevent adrenal insufficiency. Epirubicin was given as a weekly intravenous bolus from the start, also for a maximum of 6 months. The median duration of therapy with suramin and epirubicin was 9 (2-29) weeks. The toxic effects of this combined treatment included grade 1-2 nausea and vomiting (54%), fatigue (54%), anorexia (58%), stomatitis (52%), diarrhea (8%), mild rash (11%), neutropenia, usually mild (65%), low-grade fever (26%), mild increases in serum creatinine concentrations (27%), proteinuria (58%), and peripheral neurotoxicity(mild 23%, severe 4%); alopecia was caused by the epirubicin in 58%.

REFERENCES 1. Franchi C, Di Vico B, Teggi A. Long-term evaluation of patients with hydatidosis treated with benzimidazole carbamates. Clin Infect Dis 1999; 29: 304-9. 2. Colle I, Naegels S, Hoorens A, Hautekeete M. Granulomatous hepatitis due to mebendazole. J Clin Gastroenterol 1999; 28: 44-5. 3. Haarbrink M, Terhell AJ, Abadiz GK, Mitsui Y, Yazdanbakhsh M. Adverse reactions following diethylcarbamazine (DEC) intake in "endemic normals", microfilaraemics and elephantiasis patients. Trans R Soc Trop Med Hyg 1999; 93: 9145.

4. Shenoy RK, Dalia S, John A, Suma TK, Kuraswami V. Treatment of the microfilaraemia of asymptomatic Brugian filariasis with single doses of ivermectin, diethylcarbamazine or albendazole, in various combinations. Ann Trop Med Parasitol 1999; 93: 643-51. 5. Burchard GD, Kubica T, Tischendorf FW, Kruppa T, Brattig NW. Analysis of renal function in onchocerciasis patients before and after therapy. Am J Trop Med Hyg 1999; 60: 980-6. 6. Chouela EN, Abeldano AM, Pellerano G, La Forgia M, Papale R, Garsd A, Del Carmen Balian

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M, Battista V, Poggio N. Equivalent therapeutic efficacy and safety of ivermectin and lindane in the treatment of human scabies. Arch Dermatol 1999; 135: 651-5. 7. Elmogy M, Fayed H, Marzok H, Rashad A. Oral ivermectin in the treatment of scabies. Int J Dermatol 1999; 38: 926--8. 8. Recht LD, Primavera JM. Neurologic disorder in a 65-year-old man after treatment of colon cancer. New Engl J Med 1999; 341: 512-19. 9. Yeo W, Tong M, Chan YL. Multifocal cerebral demyelination secondary to fluoronracil and levamisole therapy. J Clin Oncol 1999; 17: 431-3. 10. Wolmark N, Rockette H, Mamounas E, Jones J, Wieand S, Wickerham DL, Bear HD, Atldns JN, Dimitrov NV, Glass AG, Fisher ER, Fisher B. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 1999; 17: 3553-9. 11. Bargman JM. Management of minimal lesion glomerulonephritis: evidence-based recommendations. Kidney Int Suppl 1999; 55: $3-16. 12. Barbano G, Ginevri F, Ghiggeri GM, Gusmano R. Disseminated autoimmune disease during levamisole treatment of nephrotic syndrome. Pedriatr Nephrol 1999; 13: 602-3. 13. Rongioletti E Ghio L, Ginevri F, Bleidl D, Rinaldi S, Edefonti A, Gambini C, Rizzoni G, Rebora A. Purpura of the ears: a distinctive vasculo-

363 pathy with circulating autoantibodies complicating long-term treatment with levamisole in children. Br J Dermatol 1999; 140: 948-51. 14. Berhe N, Gundersen SG, Abebe F, Birrie H, Medhin G, Gemetchu T. Praziquantel side effects and efficacy related to Schistosoma mansoni egg loads and morbidity in primary school children in North-East Ethiopia. Acta Trop 1999; 72: 53-63. 15. Olds GR, King C, Hewlett J, Olveda R, Wu G, Ouma J, Peters P, McGarvey S, Odhiambo O, Koech D, Liu CY, Aligui G, Gachihi G, Kombe Y, Parraga I, Ramirez B, Whalen C, Horton R J, Reeve P. Double-blind placebo-controlled study of concurrent administration of albendazole and praziquantel in schoolchildren with schistosomiasis and geohelminths. J Infect Dis 1999; 179: 996-1003. 16. Fel Brutto OH, Campos X, Sanchez L, Mosquera A. Single-day praziquantel versus 1-week albendazole for neurocysticercosis. Neurology 1999; 52: 1079-81. 17. Koul PA, Waheed A, Hayat M, Soft B A. Praziquantel in niclosamide-resistant Taenia saginata infection. Scand J Infect Dis 1999; 31: 603-4. 18. Garcia-Schurmann JM, Schulze H, Haupt G, Pastor J, Allolio B, Senge T. Suramin treatment in hormone- and chemotherapy-refractory prostate cancer. Urology 1999; 53: 535-41. 19. Falcone A, Antonuzzo A, Danesi R, Allegrini G, Monica L. Pfanner E, Masi G, Ricci S, Del Tacca M, Conte P. Suramin in combination with weekly epirubicin for patients with advanced hormone-refractory prostate carcinoma. Cancer 1999; 86: 470-6.

S. Dittmann

32 Editor's note: Abbreviations used in this chapter include: 9

9 9 9 9

9

9 9 9 9 9 9 9

9

9

DT: diphtheria + tetanus toxoids; DTP: diphtheria + tetanus toxoids + pertussis; DTaP: diphtheria + tetanus toxoids + acellular pertussis; DTwP: diphtheria + tetanus toxoids + whole-cell pertussis; HB: hepatitis B; HbOC (also called PRP-CRM): Hib-PRP (polyribosylphosphate: capsular antigen of Hemophilus influenzae) linked to the nontoxic diphtheria variant CRd~197; Hib: Hemophilus influenzae type b; IPV: inactivated poliomyelitis vaccine; OPV: oralpoliovirus vaccine; OspA: Borrelia burgdorferi outer surface protein A; PPV: pneumococcal polysaccharide vaccine; PRP-CRM: see HbOC; PRP-D-Hib: conjugated Hib vaccine (a mutant polypeptide o f diphtheria toxin covalently linked to Hib capsular polysaccharide); PRP-T-Hib: conjugated Hib vaccine (tetanus toxoid linked to Hib capsular polysaccharide ); MMR: measles + mumps + rubella.

Vaccines Adverse events after immunizationm the need for improved research, surveillance, and communication In modem medicine, adverse effects o f preventive and therapeutic agents receive high priority. This is particularly the ease with immunization, because it involves healthy individuals. The success o f vaccines is not only impressive and convincing but also makes immunization its own worst enemy. When natural disease is disappearing, concerns about vaccine safety become increasingly prominent in such a successful immunization program, particularly since we know that no vaccine can be regarded as being completely safe. Some are very much safer than others, but none is completely free from adverse effects o f one sort or another. Progress in the development, manufacture, and control o f modem vaccines has contributed to the safety of current vaccines. However, it is absolutely necessary to know what the true complications of immunization are, what the gaps in our current knowledge are, and when there is no evidence linking immunization and a suspected adverse effect. We have to remember that our current knowledge about vaccine risks is incomplete, as noted in extensive reviews in the early 1990s by the Institute o f Medicine in the USA (1 R, 2R ). Two-thirds of the 76 vaccine adverse events evaluated by the Institute of Medicine had either no evidence or inadequate evidence to assess the causal role o f a vaccine. Specifically, the reviews identified the following limitations: -

9 200t Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

inadequate understanding of the biological mechanisms that underlie adverse events; insufficient or inconsistent information from case reports and case series; inadequate size or length of follow-up o f many population-based epidemiological studies;

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limitations of existing surveillance systems to provide persuasive evidence of causation; few experimental studies published relative to the total number of epidemiological studies published.

Therefore, a concerted effort is needed to improve both research and surveillance regarding the risks associated with immunization, as well as better benefit and risk communication in order to reassure health-care providers, parents, and the public (including the media) about the steps taken to ensure vaccine safety and the overwhelming safety record of vaccines. The medical community still has pre-eminence as the purveyor of advice to the public on matters of immunization and should play a key role in improving communication. Nothing will strengthen our ability to communicate risk more than ensuring that there is adequate capacity and funding for vaccine safety infrastructure and research (3R ). The response to a newly published adverse event due to immunization must be rapid. First, if the reported association is correct, urgent re-evaluation of the immunization program is necessary. Otherwise, if the reported association is false, a credible countermessage must be sent to minimize the negative impact on the immunization program (4R ). The pros and cons of the (US) Vaccine Adverse Events Reporting System (VAERS; SEDA14, 919) have been critically reviewed (SEDA23, 336; 5R). Among the many new developments in the communication of adverse events, the increasing role of the Internet should be mentioned. Many national bodies (e.g. the Food and Drug Administration, Rockville, Maryland, USA, www.fda.gov, or the Centers for Disease Control and Prevention, Atlanta, Georgia, USA, www.vaers.org) and intergovernmental health authorities responsible for licensure of vaccines (e.g. the European Agency for the Evaluation of Medicinal Products, EMEA, www.eudra.org/emea.html), and/or vaccine safety (e.g. the World Health Organization (WHO), www. who.int/vaccinesdiseases/safety/) as well as vaccine manufacturers (through postmarketing surveillance of their products, e.g. SmithKline Biologicals, www.worldwidevaccines.com), universities, and private organizations have also launched

365

Web sites providing information on vaccine safety and immunization risks.

BACTERIAL VACCINES

Hemophilus influenzae type b (Hib) vaccine (SED-14, 1065; SEDA-21, 329; SEDA-22, 337; SEDA-23, 337) Three different types of conjugated Hib vaccines have been used extensively in Scandinavia: (a)

PRP-D-Hib vaccine (a mutant polypeptide of diphtheria toxin covalently linked to PRP), e.g. ProHIBit, produced by Connaught Laboratories, Philadelphia; (b) HbOC vaccine (Hib oligosaccharides linked to the non-toxic diphtheria toxin variant CRM197), e.g. HibTITER, produced by Lederle-Praxis Biologicals, Pearl River, NY; (c) PRP-T-Hib vaccine (tetanus toxoid linked to PRP), e.g. ActHIB or OmniHIB, produced by Pasteur Merieux, Lyon, France. The effectiveness and safety of these different vaccines and immunization strategies has been evaluated in Denmark, Finland, Iceland, Norway, and Sweden (6c). Few places outside Scandinavia have collected data on Hib immunization programs for a long time (more than a decade has elapsed since universal Hib immunization was initiated in Scandinavia) and with similar accuracy. Phase 3 studies with PRPD-Hib vaccine were undertaken in Finland in the late 1980s, and PRP-D-Hib vaccine has been the only vaccine used in Iceland. HbOC vaccine was first compared with PRP-D-Hib vaccine in Finland and then reintroduced to the primary health-care system as the only Hib vaccine used. Finally, PRP-T-Hib vaccine was first temporarily used in Finland, and then as almost the only vaccine in Denmark, Norway, and Sweden. Besides the different conjugate vaccines, the immunization programs have differed in other aspects, such as immunization schedule and administration of vaccines (separate versus simultaneous administration with other vaccines, such as DT, DTP, DTaP, IPV, or MMR).

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Effectiveness Notwithstanding the different approaches taken in the various Scandinavian countries, the results are similar: before vaccination against invasive Hemophilus influenzae type b (Hib) diseases, first introduced in Finland in 1986, the incidence of cases in the five Scandinavian countries was 49/100 000 per year in 0- to 4-year-olds and 3.5/100 000 overall. During the next decade, Hib conjugates given to young children had about 95% effectiveness, regardless of which conjugate was used, whether two or three primary doses were used, and no matter at what age in early infancy the first vaccination was given. Invasive diseases due to Hemophilus influenzae have thus been nearly eliminated. Adverse reactions Comparisons of adverse reactions to different vaccines are difficult, because the vaccines have virtually always been administered together with other vaccines. However, the general experience is that adverse reactions are mild. Most reactions develop when the vaccine is given simultaneously with DTP vaccine. There have been no deaths or permanent sequelae attributable to Hib immunization. Experience with PRP-D derives from Finland and Iceland. In Finland, 14.1 adverse reactions per 100000 doses were reported in all, consisting respectively of 5.3, 6.3, 4.4, and 2.9 per 100 000 doses of local reactions, fever, rash, and irritability. These rates probably underestimate the true rates. In Iceland, adverse effects have not been monitored, but no serious events have been reported. For PRPCRM, there were 17.8 per 100000 doses in all, of which 7.7 were due to local reactions, 8.9 fever, and 8.3 rash. PRP-T currently enjoys the largest use in Scandinavia, being the routine choice in three countries. Of 115 reactions reported in Denmark, none was of serious concern; most were local reactions, fever, or rash. In Norway, the incidence of systemic reactions was 1/550 doses; again, fever and other symptoms and signs similar to those after DTP vaccination were the most common complaints. However, two findings were characteristic of Norway, where local reactions were reported with an overall frequency of 1/1500 doses: (a)

immediate mild allergic reactions were more common than if DTP or IPV was

(b)

S. Dittmann

given alone; their incidence was 1/35 000 doses of PRP-T; large swellings at the vaccination site, with edema and sometimes bluish or other discoloration of the lower limbs were reported in 18 children, suggesting an incidence of about 1/30000 doses; this reaction developed within hours after vaccination and subsided within 24 hours; all the vaccinees recovered spontaneously without treatment or sequelae.

About 1.5 million doses Of PRP-T have been used in Sweden. Similar concerns about adverse reactions have been raised as in Norway, and further elucidation has recently begun. In Finland (where PRP-T was used in 1990-93), there were 15.9 reports per 100000 doses; 6.2 per 100000 doses were local reactions, 5.9 fever, 2.8 rash, and 2.4 irritability (6c).

Lyme disease vaccine In December 1998, the first Lyme disease vaccine (LYMErix | manufactured by the then SmithKline Beecham) was licensed by the Food and Drug Administration for individuals aged 15-70 years old (7 R) and has since become commercially available in the USA. In 1999, the Advisory Committee on Immunization Practices (ACIP) made recommendations for Lyme disease vaccine (8R), including data on efficacy and safety (SEDA-23, 338). Lyme disease prevention and prophylaxis has been reviewed (9R).

Lyme disease vaccine and autoimmune disease The hypothesis that LYMErix could cause a treatment-resistant form of autoimmune arthritis has been previously mentioned (SEDA-23, 339). The premarketing trials for the vaccine were assessed by an independent advisory committee and no link between Lyme disease immunization and autoimmune arthritis was found. However, the committee underlined the need for long-term surveillance and further studies of the possible development of autoimmunity. Recently, the FDA has received some reports of arthritis and Lyme disease after the use of the vaccine (1OR). On 31 January 2001,

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the FDA's Vaccines and Related Biological Products Advisory Committee held a meeting to evaluate safety data o f LYMErix. Among other information, the experts considered a manufacturer's briefing document as well as safety data reported to the VAERS. A postmarketing assessment cohort study using automated record linkage has been initiated at Harvard Pilgrim Health Care (HPHC) in order to address the theoretical concern that immunization with a vaccine containing OspA might cause an autoimmune arthritis, and to evaluate whether exposure to the vaccine is a risk factor f o r Lyme disease, treatment-resistant Lyme disease, rheumatoid arthritis, certain neurological diseases, allergic events, hospitalization, and death. The study involves 25 000 HPHC members who are expected to receive the vaccine and 75000 non-immunized controls. For the most recent report, matched data were available f o r 2568 vaccinees and 7497 controls. At this preliminary stage, the available results do not suggest that the outcomes o f interest (see above) were more frequent among vaccinees than non-vaccinees. Having recognized that enrollment into the database is at a slower rate than anticipated, two additional Health Maintenance Organizations in countries where Lyme disease is endemic have been identified and will contribute. Up to 30 November 2000, 1.4 million doses o f vaccine had been distributed. From January 1999 to the time o f the database query, no evidence has been found that the incidence o f these arthritic conditions was higher than reported in the general population or that they were associated with an autoimmune process (11s). LYMErix safety data reported to the VAERS from 21 December 1998 to 31 October 2000 mentioned reports of adverse events associated with Lyme vaccine in pre-licensure trials, including injection site reactions, transient arthralgia and myalgia within 30 days o f vaccination, fever, and a flu-like illness. For other reported adverse events, causal relations with Lyme vaccine have not been established. Hypersensitivity reactions were reported to the VAERS and some can be plausibly linked to the vaccine because of the short latency between vaccination and reaction onset. No clear patterns in age, sex, time to onset, or vaccine dose have been identified, although the unexpected predominance o f reports o f arthrosis in

367 men may warrant further consideration. From reports containing information on HLA types, clinical descriptions o f adverse events are similar in people with DR4 and non-DR4 HLA haplotypes and do not suggest more inflammatory arthritis in people o f DR4 haplotype. The characteristics o f adverse events in people with a self-reported history o f Lyme disease do not differ substantially from all adverse events after Lyme vaccine. To address further the question o f a possible link between Lyme vaccine and arthritis, the FDA is conducting a telephone survey of individuals who have reported arthritic conditions to the VAERS after receiving the vaccine. This survey is a census o f available and willing individuals who submitted reports that have been coded as arthritis, arthrosis, rheumatoid arthritis, joint disease, and arthralgia. The goals o f the survey are to describe the characteristics o f these adverse events, to identify concomitant factors that might influence the characteristics o f these events, and to describe the relationship o f the events o f vaccination. After this survey phase is complete, the VAERS will identify cases o f arthritis and conduct a case-control study to examine the hypothesis that Lyme vaccine causes arthritis. It is planned to compare people who report arthritis after Lyme disease vaccine with two control groups: people reporting arthritis to the VAERS after other vaccines and those reporting adverse events to the VAERS other than arthritis after Lyme vaccine. All cases will be age-, sex-, and race-matched with controls. All three groups will be tested f o r DR HLA haplotypes at the allele level and f o r peripheral blood lymphocyte responses to OspA and leukocyte function-associated antigen-1 (LFA-1). This is an attempt to determine if people who report arthritis after Lyme vaccine have a higher prevalence o f certain HLA alleles that are known to be associated with rheumatoid arthritis and have the same third common hypervariable region, while simultaneously having greater peripheral T-cell reactivity to OspA and LFA-1. Given the relatively small number o f arthritis cases reported after Lyme vaccine, probably only a very high risk will be detectable (l lS ). The Associated Press Report from 31 January 2001 on the FDA meeting on Lyme vaccine read (in part) as follows: "Vaccine Safety experts found no proof that the LYMErix vaccine is dangerous--the rare cases o f arthritis and

368 other symptoms could be coincidence. Many reports are of minor complaints or are not believed to have been caused by the vaccine, but the FDA is studying 133 reports of severe arthritis-like symptoms. That's because of a theory that the vaccine might set off an autoimmune reaction where the body attacks its own tissues, particularly in people who carry a certain gene called HLA-4". The panel said ultimately "no convincing evidence exists that the vaccine causes serious problems", but the experts urged the FDA and the manufacturer to expedite new safety studies and demanded that the Government should act to ensure that patients are told about the possible risks before inoculation. They also urged that the CDC should aggressively distribute a patient-friendly safety fact sheet about LYMErix (12s).

Meningococcal vaccine (SED-14, 1080; SEDA-21, 329; SEDA-22, 338; SEDA-23, 339) Polysaccharide vaccines are available in various combinations against meningococcal disease caused by meningococci of groups A, C, W135, and Y. Meningococcal group B polysaccharide vaccine is poorly immunogenic in humans and is therefore not available commercially. Studies mostly using a bivalent serogroup A + C vaccine have been carried out in about 15 countries, in some millions of people, and have shown efficacy of 61-99%. Meningococcal group A vaccine is more immunogenic than group C vaccine in infants and small children. However, infants under 6 months of age produce a weak response, and meningococcal group C vaccine should not be used before the age of 2 years. In association with the quadrivalent vaccine used in Canada, fever was reported in less than 1%, local reactions in 6.3%, and rash in 1.6% among those aged 11 years or older. Local reactions were also the most frequent adverse effect in other reports. Non-polysaccharide group B meningococcal vaccines Considering the poor immunogenicity of polysaccharide group B vaccines, different vaccines have been developed: a Norwegian outer membrane complex group B vaccine and a Cuban vaccine, in which the group C

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polysaccharide is added to a mixture of high molecular weight B outer membrane proteins and proteoliposomes. Both vaccines have been used in clinical trials, mainly in Latin America, but more conclusive studies with these two products have been awaited, particularly in children below the age of 4 years, because efficacy data in these age cohorts were very poor. From studies in 370 infants and children and 171 adults aged 18-30 years, who received three doses of outer membrane protein meningococcal vaccine developed in either Cuba or Norway or a control vaccine (Hib vaccine), the vaccines are promising candidates for the control of epidemics caused by homologous epidemic strains (13c). However, the vaccines would not confer protection during a heterologous epidemic. All vaccinees had more pain, induration, and erythema at the injection site than did Hib vaccine recipients; there were no serious adverse events, and 95% of individuals who reported symptoms said that the symptoms did not interfere with their normal activities. A new genetically engineered vaccine containing six meningococcal class I (PorA) outer membrane proteins, representing 80% of group B meningococcal strains prevalent in the UK, has been assessed in 103 infants who received the vaccine at ages 2, 3, and 4 months with routine infant immunization, and a fourth dose at 12-18 months (14c). The vaccine was well tolerated, and after the fourth dose there were larger bactericidal responses to all six strains. Conjugated meningococcal vaccines Success with protein conjugate formulations of Hemophilus influenzae vaccines has facilitated research into and development of conjugated meningococcal vaccines with preference for monovalent group C or bivalent group A/group C vaccines. When clinical trials confirmed the efficacy and safety of the vaccine, conjugated meningococcal group C vaccines of various manufacturers were first licensed in 1999 in the UK and then (at the end of 2000) in some other member states of the European Union (Belgium, Germany, Greece, Luxembourg, Ireland, Portugal, Spain). Further results of clinical trials with conjugated meningococcal vaccines have been published. Vaccine containing oligosaccharides derived from group C meningococcal capsular polysaccharide coupled to CR]VI197, a nontoxic mutant diphtheria toxin (manufactured by

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Chapter32

Table 1. Numbers•finfantswith••cal•rsystemicreacti•nswithin7days•fmening•c•ccalc•njugatevaccineand DTP/Hib vaccines at 2, 3, and 4 months Reaction

Conjugated meningococcal group C vaccine Low dose (2 txg/ml) High dose (10 Ixg/ml)

DTP/Hib vaccine

Erythema >2.5 cm Swelfing >2.5 cm Fever >38 ~ C (up to 3 days) Systemic reactions in first 24 h Crying >1 h in first 24 h

4/171 (2.3%) 2/171 (1.2%) 7/171 (4.1%) 26/171 (12%) 3/156 (1.9%)

38/344 (12%) 64/344 (19%) No data No data No data

Wyeth Lederle Vaccines and Pediatrics, Pearl River, NY) was given to 114 infants at 2, 3, and 4 months of age; 57 received a vaccine containing 2 Ixg of oligosaccharide and 5 Ixg of CRM197, and 57 received a vaccine containing 10 Ixg of oligosaccharide and 25 Ixg of CRMj97. The infants received DTP and Hib vaccine at the same time. In each group, 25 infants received a polysaccharide vaccine booster at median age of 83 weeks. Antibody concentrations required for protection are estimated to be 1-2 Ixg/ml. All the infants achieved a concentration of 2 Ixg/ml by age 4 months after two doses of conjugated meningococcal vaccine, and concentrations of bactericidal antibodies were much higher than after meningococcal polysaccharide vaccines. Antibody concentrations fell significantly by age 14 months. After boosting with polysaccharide vaccine all the children achieved antibody concentrations over 2 Ixg/ml. Local and systemic reactions were rare after meningococcal conjugate vaccines and significantly less common at the site of DTP/Hib immunization for all three doses. The high-dose cohort had more systemic reactions than the low-dose cohort (Table 1). One infant required hospitalization for a viral illness soon after the second injection (15c). A somewhat different conjugated meningococcal vaccine (purified group C meningococcal polysaccharide coupled to purified tetanus toxoid, manufactured by North American Vaccine, Columbia, Maryland, U S A ) h a s been evaluated in 30 healthy adults (16c). One dose containing 10 Ixg of polysaccharide and 15.5 t~g of tetanus toxoid was given intramuscularly. All the volunteers developed a four-fold or greater increase in serum bactericidal antibody to group C meningococcus. Most of the local and systemic reactions were mild (Table

5/173 (3.9%) 6/173 (3.5%) 8/173 (4.6%) 53/173 (31%) 2/153 (1.3%)

Table 2. Frequencyof adverse events within 7 days of meningococcus C-tetanus toxoid conjugate vaccine in healthy adults Reaction

Number

Tenderness Erythema Pain Induration Fever >38 ~ C Headache Myalgia Arthralgia

15/30 15/30 13/30 8/30 1/30 2/30 1/30 0/30

2). The only significant local erythema and swelling (over 3 cm) was related to an injection site hematoma, which resolved rapidly.

Pertussis vaccine (including diphtheria-tetanus-pertussis vaccine [DTP]) (SED-14, 1083; SEDA-21, 329; SEDA-22, 338; SEDA-23, 340) Acellular pertussis vaccines Quality control of acellular pe~ussis vaccines presents particular problems related to the various methods used for preparation of the active components, the different compositions of the final formulations, and different amounts of antigen (the various acellular pertussis vaccines were described in SED-14, 1085). Researchers in the National Institute for Biological Standards and Control in the UK have presented a strategy capable of addressing the key problem areas likely to be encountered with all existing types of acellular pertussis vaccines and combina-

370

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Table 3. Reactions after the fourth dose of DTaP given at 2 or 3 years of age Local and systemic reactions Pain Erythema Swelling Induration Tenderness Fever >38 ~ C Fever >38.3 ~ C

ACEL-IMUNE

Tripedia

Infanrix*

Certiva

10% >2.4 cm

19% 30% >2.54 cm 29% ->2.54 cm

26% 14% _>2 cm 11% >2 cm

19% 6% > 3 cm 5% > 3 cm

9% >2.4 cm 26%

26%

6.3%

5.5%

* To be compared with reactions after the first dose: pain 2%, erythema 0%, swelling 0%, fever _>38~ C 6.3%.

Table 4. Reactions after the fifth dose of DTaP administered at entry to school Local and systemic reactions Pain Erythema Swelling Induration Tenderness

ACEL-IMUNE

Tripedia

Infanrix

20% >2-2.4 cm

2.1% severe pain 31% > 5 cm 25% > 5 cm

1.6% severe pain 30% >5 cm 21% >5 cm

14% 38%

tions (17c). Their proposal could be considered as a starting point for improvement of quality control programs for these vaccines. Data on the use of a single DTaP vaccine for four- or five-dose series are limited, but the available data show a substantial increase in the frequency and magnitude of local reactions with successive doses. The accompanying tables show reactions after the fourth dose (Table 3) and the fifth dose (Table 4). The original data and references are included in the supplementary recommendations of the Advisory Committee on Immunization Pracrices (ACIP) on the use of DTaP vaccines in a five-dose series (18R). Limb swelling after booster doses o f DTaP Swelling involving the entire thigh or upper ann has been reported after booster doses of different acellular pertussis vaccines, e.g. in a German study during April 1993 to November 1994 using a fourth dose of lnfanrix. There was an increase in thigh circumference in 1.2-3.2% of children; swelling began within 48 hours of a booster dose and the mean duration

was 3.9 (range 1-7) days; the mean increase in circumference was 2.2-5 cm; in a few children, the swelling interfered with walking. Similar swelling and substantial local reactions have been observed in fourth- and fifthdose follow-up studies from the Multicenter Acellular Pertussis Trial, which examined 12 different DTaP vaccines, and in recent studies of the fifth dose of Tripedia and Infanrix in Germany. The pathogenesis of both substantial local reactions and limb swelling is unknown. Associations with pertussis toxoid, diphtheria toxoid, or aluminium in the vaccine have been discussed. Because reports to date have suggested that the reactions are self-limited and resolve without sequelae, and in recognition of the benefits of a fifth dose of DTaP, the ACIP has recommended that a history of extensive swelling after the fourth dose should not be considered to be a contraindication to a fifth dose of DTaP. Parents or carers of children who receive fourth and fifth doses of a DTaP series should be informed of the increases in reactogenicity that have been observed ( 1 8R) .

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Combination vaccines: DTaP or DTwP vaccine combined with other antigens such as HaemophUus influenzae type b (Hib) or inactivated poliovirus (IPV) or simultaneous administration of these vaccines (SEDA-14, 1086; SEDA-21, 330; SEDA-22, 342; SEDA-23, 341) On the request of the French Drug Agency, the Regional Pharmacovigilance Center of Tours has analyzed the adverse events that occurred in 1986-90 with the use of three different tetravalent DTwP-IPV vaccines produced by French vaccine manufacturers (19c). The most frequent adverse events were local reactions (43% of the 631 events reported). Serious adverse events represented 25% of all reported events, including 23 reports of persistent crying, 12 febrile seizures, 14 apyretic seizures, and three reports of shock-like events. This analysis could be used in future comparisons with pentavalent and hexavalent combination vaccines. Immunological interference, particularly to the Hemophilus influenzae (Hib) response, has been assessed in 135 infants at 2, 4, 6, and 18 months of age in studies of two different types of administration of DTaP and Hib vaccines: combined administration of the two vaccines mixed in the same syringe and simultaneous administration of separate injections at different sites (20c). The vaccines were well tolerated and there were no differences in the rates of local and systemic reactions. Immune responses were also comparable between the two groups. Four-, five- and six-component combination vaccines based on DTaP or DTwP vaccine, and including other antigens such as hepatitis B or Hib or IPV, will play an important role in future worldwide immunization programs. Some of these combination vaccines have already been licensed in some countries and others are expecting licensnre soon or being evaluated in clinical trials. Recently, the first hexavalent combination vaccines (DTaPIPV-HB-Hib) have been licensed in Germany; two hexavalent vaccines are available, manufactured by SmithKline Beecham and Aventis Pasteur.

371

Pneumocoecal vaccine (SED-14, 1086; SEDA-21, 330; SEDA-22, 344; SEDA-23, 343) Polysaccharide

vaccine The question of whether revaccination with 23-valent pneumococcal polysaccharide vaccine (PPV) at least 5 years after the first vaccination is associated with more frequent or more serious adverse events than those after the first vaccination has been studied in patients aged 50-74 years who had never been vaccinated with PPV (n = 901), or who had been vaccinated once at least 5 years before enrollment (n = 513) (21c). After one dose of PPV, local injection site reactions and prevaccination concentrations of type-specific antibodies were measured. Those who were revaccinated were more likely than those who received their first vaccinations to report a local injection site reaction of at least 10.2 cm (4 in) in diameter within 2 days of vaccination (55/513 vs 29/901, or 11% vs 3%). The reactions resolved by a median of 3 days after vaccination. The highest rate was among revaccinated patients who were immune competent and did not have chronic illnesses: 15% (33/228) compared with 3% (10/337) among comparable patients receiving their first vaccinations. The risk of these local reactions correlated significantly with prevaccination geometric mean antibody concentrations. The authors concluded that physicians and patients should be aware that self-limited local injection site reactions occur more often after revaccination compared with a first vaccination. However, this risk does not represent a contraindication to revaccination with PPV in recommended patients. Conjugated pneumococcal polysaccharide vaccines Pneumococcal polysaccharide vaccines are not immunogenic in infants, but improved immunogenicity of polysaccharideprotein conjugates has been demonstrated. In 2000, the first heptavalent conjugate pneumococcal vaccine, Prevnar (containing polysaccharides of pneumococcal serotypes 4, 6B, 9V, 14, 19E and 23E and oligosaccharide of serotype 18C, conjugated to the protein carrier CRM197 [non-toxic variant of diphtheria toxin]), has been licensed in the USA (covering 90% of pneumococcal serotypes found in young children in the USA). Licensnre of the vaccine in other countries is

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Table 5. Local reactions within 48 hours of injection in infants receiving DTwP-Hib and pneumococcal vaccines and toddlers receiving DTaP + Hib vaccine and pneumococcal vaccine Reaction

No. of children

Infants Pneumococcal vaccine(%)

Redness dose 1 dose 2 dose 3 dose 4

183 159 160 110

17 18 16 9.1

18 29 22

Swelling dose 1 dose 2 dose 3 dose 4

183 159 160 110

10 11 9.0 6.4

19 20 21

Tenderness dose 1 dose 2 dose 3 dose 4

183 159 160 110

24 21 23 16

27 26 28

expected in 2001. Furthermore, 9- and l l valent vaccines (covering 80-90% of serotypes found worldwide) are under development or assessment in clinical trials. In a randomized double-blinded study, 302 healthy infants in the Northern California Kaiser Permanente Health Plan received either the pneumococcal vaccine (later called Prevnar) or the meningococcal group C conjugate vaccine as a control at 2, 4, and 6 months of age and as a booster at 12-15 months of age (22c). The immunogenicity and safety of simultaneous administration of vaccines used in the routine immunization program of children (DTwP or DTaP, Hib and OPV or hepatitis B vaccine) were also evaluated. Local reactions after pneumococcal, DTwP-Hib, and DTaP plus Hib vaccine were statistically less severe at the pneumococcal vaccine site than at the DTwP-Hib sites (Table 5). There were 12 emergency room visits and eight hospitalizations that occurred soon after immunization (otitis, febrile illness, urinary tract infection, bums), but none was thought to be related to the vaccine. One hypotensive-hyporesponsive episode 15 minutes after pneumococcal vaccine, DTwP-Hib/HB, and OPV, with complete recovery within 1 hour, was considered to have

DTwP-Hib (%)

Toddlers DTaP+ Hib (%)

6.1

3.7

9.8

been vaccine related. After the booster dose of pneumococcal vaccine, the geometric mean titers of all seven serotypes increased significantly (compared with the values after dose 3 and before dose 4) to antibodies considered as protective. When vaccine was administered at the same time as the booster dose of DTaP and Hib vaccines, there were lower antibody titers for some of the antigens than the antibody response when the pneumococcal vaccine was given separately. Because the geometric mean titers of the booster responses were all generally high, and all subjects achieved similar percentages above predefined antibody titers, these differences were considered to be not probably clinically significant. Summarizing their results the authors concluded that the pneumococcal vaccine was safe and immunogenic.

Typhoid fever vaccine

(SED-14, 1096;

SEDA-23, 343) A previous meta-analysis of studies of the efficacy and toxicity of typhoid fever vaccines (SEDA-23, 343) has been criticized as an in-

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teresting mathematical exercise but of little practical relevance (23r). The meta-analysis had lumped together different parenteral wholecell vaccines (alcohol-inactivated, formalininactivated, acetone-inactivated, and dried whole-cell vaccines), but the only parenteral killed whole-cell vaccine that is available is the heat-inactivated phenol-preserved vaccine. Therefore, the analysis should have been limited to heat-phenolized vaccine. It was also mentioned that the quoted data on the occurrence of adverse reactions failed to include the largest clinical trial of Ty21a vaccine. Last but not least, the authors of the meta-analysis failed to relate the severity of reactions connected with the use of parenteral whole-cell vaccine. These adverse reactions, including high fever, malaise, and nausea, make the killed wholecell vaccine among the most reactogenic vaccine ever licensed. In contrast, oral Ty21a and parenteral Vi vaccines are well tolerated.

VIRAL VACCINES Infection risk Varicella zoster There have been three case reports of suspected reactivation of Varicella zoster through hepatitis A vaccine, influenza vaccine, and simultaneous administration of rabies and Japanese encephalitis vaccine (24A). A 53-year-old woman without signs of immunodeficiency developed Herpes zoster in the left T10 dermatome 14 days after influenza immunization. The rash resolved without sequelae. Five months later she received another injection of influenza vaccine and 12 days later developed Herpes zoster in the left T1 dermatome. Recovery was prolonged. An 80-year-old woman with carcinoma developed long-lasting left thoracic herpes zoster 6 days after influenza immunization. Influenza vaccination before and after the event had no adverse effect. A 27-year-old man developed Herpes zoster in the second and third branches of the trigeminal nerve 1 day after immunization against rabies and Japanese encephalitis.

Bovine spongiform encephalitis Since the problem of bovine spongiform encephalitis (BSE) emerged in Europe around 1987, the WHO and ministries of health have been alert to the danger that BSE-contaminated materials might be used in biological products, including vaccines. Guidelines were created that en-

373 sured that when bovine materials were needed in a biological product, the materials were obtained from countries that were free from BSE. Bovine products are used in the production of certain vaccines, in creating seed lots, or in amplifying the seed lot into working lots. The material is generally calf serum, which, even if it came from an infected animal, is extremely unlikely to transmit the prions that cause the disease. An exceptional situation arose on 20 October 2000, when the UK withdrew one manufacturer's OPV because of the possibility that the vaccine had been manufactured using serum from calves from a BSE-infected country. Even though the risk was extremely remote, the health authorities decided to have the vaccine withdrawn. This particular product was not the main OPV used in the UK. To clarify the situation in the UK, and to reassure countries throughout the world that there were no implications for OPV used in the eradication of poliomyelitis, the WHO issued the following position statement (25s): "On 20 October 2000, Evans/Medeva Oral Polio Vaccine (OPV), which to the knowledge of the World Health Organization has only been used in the United Kingdom and Republic of Ireland, was recalled in the UK. This vaccine has never been used in the immunization campaigns that are ongoing as part of the Global Polio Eradication Initiative. The recall was prompted by evidence that the Evans/Medeva vaccine was manufactured in contravention of European Union guidelines, and was not based on any adverse events related to the vaccine. The specific concern is that fetal bovine calf serum (FCS) from the UK was used in the manufacture of the Evans/Medeva vaccine, at a time when there was a risk of bovine spongiform encephalopathy (BSE) in that country. WHO endorses the recall step as a precaution, even though FCS is removed in the manufacturing process of the vaccine and there is no evidence that FCS could transmit BSE. Due to this breach of EU guidelines and acting on a precautionary basis, the Health Departments in the UK have withdrawn remaining shelf stocks of the Evans/Medeva brand of polio vaccine, which had already ceased production. The World Health Organization imposes strict production and quality controls to ensure the safety and efficacy of OPV. WHO recommends that manufacturers use the safest source of materials from countries which have not reported

374 indigenous BSE cases and have a compulsory BSE notification system, compulsory clinical and laboratory verification of suspected cases and a surveillance program. The Global Polio Eradication Initiative only distributes vaccine supplied by vaccine manufacturers who follow National Control Authorities' criteria provided by WHO". Two advisory committees of the US Food and Drug Administration, the Transmissible Spongiform Encephalopathies Advisory Committee and the Vaccines and Related Biologicals Product Advisory Committee, said at a joint meeting on 3 August 2000 that vaccines made from bovine-derived materials from countries with a known or uncertain risk of BSE carry only an infinitesimal risk of new variant Creutzfeldt-Jakob disease, and that no change in US immunization practice is indicated (Evans G, personal communication, 3 August 2000).

Drug formulations Thiomersal as a preservative in vaccines Questions and answers on thiomersal have been provided by the WHO, which has underlined the fact that the risk of adverse effects of thiomersal is theoretical, uncertain, and at most extremely small (26s). However, the WHO aims to replace thiomersal with other preservatives in the long term. Combination vaccines can reduce the amount of mercury to an absolute minimum.

Gelatine as a stabilizer in vaccines There has been a report of an allergic reaction after MMR vaccine (27AR). The author concluded that gelatin seems to be far more often the cause of allergic reactions to MMR vaccine than egg allergy. In vaccinees who receive DTaP vaccine (some brands contain gelatin) before MMR vaccine, the prior injection of gelatin-containing DTaP may be the cause of sensitization to gelatin and the subsequent reaction to other gelatin-containing vaccines.

H e p a t i t i s B v a c c i n e (SED-14, 1067; SEDA-21, 331; SEDA-22, 346)

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Is there a causal link between hepatitis B vaccine and multiple sclerosis? The hypothesis that hepatitis B vaccine could cause multiple sclerosis has been extensively reviewed (SED-14, 1069" SEDA-22, 346; SEDA23, 345). In summary, hepatitis B vaccine is still among the safest and most powerful vaccines in immunization programs. The latest statement from the Viral Hepatitis Prevention Board (8 June 2000), working closely together with the WHO, is worth repeating: the data available to date do not show a causal association between hepatitis B immunization and central nervous system demyelinating disease, including multiple sclerosis. No evidence presented indicates a need to change public health policies with respect to hepatitis B immunization. Therefore, based on demonstrated important benefits (including prevention of liver cirrhosis and primary liver cancer) and a purely hypothetical risk, the Viral Hepatitis Prevention Board supports the recommendation of the WHO that all countries should have universal infant and/or adolescent immunization programs and should continue to immunize adults at increased risk of hepatitis B infection as appropriate (28s). However, the French Ministry of Health has already compensated 14 patients on the basis of a link between hepatitis B vaccine and neurological effects (multiple sclerosis, retrobulbar neuritis) or rheumatological symptoms. According to a press release from the French Ministry of Health, the decision was taken in the interest of the patients, and despite the fact that even the experts from the Agence franqaise de securitd sanitaire des produits, who were charged with regularly re-evaluating the safety profile of hepatitis B vaccine, have not yet been able to conclude whether there is an actual association between the vaccine and the development of multiple sclerosis or autoimmune disorders. It also stated that the decision in no way challenges the benefit:harm evaluation of hepatitis B vaccine and recommendations with respect to national immunization policies (29s). In the USA, following public discussions on the safety of hepatitis B vaccine, health officials, testifying in 1999 before the Government Reform Subcommittee on Criminal Justice, Drug Policy, and Human Resources, said that use of the vaccine has been monitored for 15 years,

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that it has not been proven to be the cause o f deaths, and is only rarely linked to serious adverse effects ( 30s ). Case reports o f CNS diseases However, in addition to current epidemiological studies, case reports o f diseases o f the central nervous system, temporally related to hepatitis B immunization, should be carefully collected. Eight cases o f CNS diseases suspected to be either recurrent disseminated encephalitis or multiple sclerosis after hepatitis B immunization have been reported (31c). Symptoms started in four cases at 4--14 days after vaccination, and in the other four cases 42-70 days after vaccination. There was a familial history o f multiple sclerosis in two patients, one o f whom had had symptoms compatible with optic neuritis before immunization. In a third patient, there was a history o f an episode compatible with Lhermitte's sign. The authors concluded that the risk o f demyelinating CNS diseases is unknown. They recommended avoiding hepatitis B immunization in individuals with a personal or familial history of symptoms suggestive o f an inflammatory or demyelinating disease o f the CNS. A 45-year-old woman with a history of epilepsy developed a lumbosacral acute demyelinating polyneuropathy I month after her second hepatitis B immunization (32A). She had an uncommon syndrome that combined demyelinating and axonal features confined to the lumbosacral roots whose relation to Guillain-Barrd syndrome was unclear, l,fral or bacterial causes of the disease could not be found. The authors concluded that a relation between immunization and disease could not be excluded. A 44-year-old female health worker developed bilateral optic neuritis 7 days after immunization against poliomyelitis (OPV) and hepatitis B (33A). All hematological biochemical bacterial and virological investigations were normal and there was no evidence of demyelination on MRI scanning.

Immunologic A case of arthritis (34 A) and three cases of vasculitis (35 A) have been described 7-20 days after immunization with hepatitis B. A causal relation in such very rare cases is unclear, and these events probably do not occur more than could be expected by chance (see also SED-14, 1067).

375 The first case of erythermalgia (paroxysmal attacks of bilateral pain in the extremities, with an acute increase in local heat in the affected parts, the production and aggravation of the distress by heat, relieved by cold) probably caused by hepatitis B vaccine has been reported (36A). A 17-year-old boy developed the symptoms of erythermalgia 2 days after a third dose of hepatitis B vaccine. He was severely ill and recovered only 2 months after treatment with immunoglobulin and hypnotherapy. During hospitalization it was learned that he had had transient moderate pain of both feet for 3 nights after the second dose of vaccine. The disease that followed the third dose of hepatitis B vaccine therefore met the criteria for positive rechallenge. Influenza vaccine (SED-14, 1072; SEDA-21, 334; SEDA-22, 349; SEDA-23, 347) Currently, inactivated vaccine is the vaccine of choice in immunization against influenza. Influenza vaccine viruses are propagated in chick embryos. The virus-containing extraembryonic fluid is harvested, purified, and inactivated with formalin. Inactivated influenza vaccine is produced either as whole-virus vaccine or ether-disrupted split or subunit preparations. However, many other new or modified influenza vaccines are already available or are expected to appear in the near future, e.g. vaccines containing new adjuvants, live attenuated vaccines, and vaccines administered by alternative routes. The safety and immunogenicity of an inactivated subunit influenza vaccine containing MF59 (oil-in-water emulsion, squalene, and Tween 80 and sorbitan tfioleate as stabilizers) as an adjuvant has been described in two studies of 92 and 211 elderly persons (65 years of age and over) (37 C, 38c). Investigations were carried out during three consecutive influenza seasons. Compared with a commercial nonadjuvant subunit vaccine containing the same influenza strains recommended by the WHO, geometric mean titers and seroconversion rates were higher after the use of the newly developed vaccine. The adjuvant vaccine caused more local reactions than the conventional vaccine. However, the reactions were mild and limited to the first 2-3 days after immunization. Systemic reactions were not significantly different, except for mild transient malaise. Considering the better immunogenicity of the adjuvant vaccine, the authors recommended it

376 is used particularly for elderly people, who are at greatest risk of developing severe influenza disease. The vaccine manufactured by Chiron Behring has been already licensed for persons of 65 years of age and over in Italy and Germany. The results of several clinical trials with a liposomal influenza vaccine have been reviewed (39M). This trivalent liposomal influenza vaccine consists of purified influenza hemagglutinin inserted into a membrane of phosphatidylcholine and phosphatidylethanolamine; it contains 15 txg of hemagglutinin per viral strain per dose. The triMs included two randomized studies (in 126 healthy nursing-home residents aged 63-102 years and 72 elderly individuals aged 60-98 years) and four double-blind studies (in a total of 831 elderly persons aged 67-71 years and younger adults aged 28-38 years); further studies included 24 children and adults with cystic fibrosis and 49 children at high risk of influenza. In all of these studies, the liposomal vaccine was compared with commercially available whole and subunit influenza virus vaccines. In general, seroconversion rates were significantly higher with the liposomal vaccine than with the commercially available vaccines. Local adverse reactions, such as pain at the injection site (up to 62% of children and up to 11% of adults), local induration and swelling (33% of all vaccine recipients), or redness (5% of adults and 20% of children) were transient and usually mild. One child with cystic fibrosis and two elderly persons had severe pain. Between 68 and 100% of children with cystic fibrosis reported at least one systemic reaction (fatigue, cough, coryza, headache) after the liposomal vaccine compared with 23-50% after the commercially available subunit vaccine. Fatigue (up to 19%), malaise (up to 14%), headache (up to 10%), and cough (up to 8%) were the most common systemic reactions reported by young adults and elderly people. There were single cases of severe fatigue, cough, and diarrhea in children with cystic fibrosis, young adults, and elderly people. Liposomal influenza vaccine did not induce a mean antiphospholipid antibody response in the elderly volunteers. In a randomized double-blind study, trivalent, live, attenuated, cold-adapted intranasal influenza vaccine (FhiMist) has been compared with intranasal placebo plus a trivalent injected inactivated influenza vaccine (40c). The

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200 patients were aged 65 years and over and had chronic cardiovascular or pulmonary conditions, or diabetes mellitus. During the 7 days after immunization, sore throat was reported on at least 1 day by significantly more of the FhiMist recipients (15% vs 2%). The increased frequency of sore throat may have been attributable to the direct or indirect effects of vaccine virus replication. No other symptom was associated with FhiMist. These findings were consistent with evaluations of other live, attenuated, cold-adapted influenza vaccine formulations in older adults. However, further studies of the safety of FhtMist are warranted. Sensory systems Four patients with corneal transplants developed ocular manifestations (bilateral graft rejection in two cases, uveitis, and epithelial and stromal herpetic kerato-uveitis) at 3 days to 6 weeks after the receipt of inactivated influenza vaccine (41A). Whereas case reports of ocular manifestations after influenza immunization are known, this is perhaps the first report of vaccine-related herpetic recurrence. The authors advised caution when influenza immunization is considered for patients who have had a corneal transplant.

Japanese encephalitis vaccine (SED-14, 1075; SEDA-21, 334; SEDA-22, 350; SEDA-23, 347) A supplementary volume of the journal Vaccine has dealt with the results presented at a WHO meeting held in Bangkok, Thailand in 1998 (42 c -45 c ). Comprehensive data were provided on the epidemiological and virological situation in South-East Asia and Australia, control measures, vaccine production capacities, and different vaccines against Japanese encephalitis. Adverse events after the use of inactivated mouse-brain vaccine (the only vaccine currently licensed for international use) have been reviewed in detail (42c). Hypersensitivity reactions reported from Denmark and other countries have previously been discussed (SED-14, 1075). Now two deaths from acute anaphylaxis and four cases of acute encephalopathy or acute disseminated encephalomyelitis (two fatal), temporally related to Japanese encephalitis immunization, have been reported from the Republic of Korea (42c). The live attenuated vaccine developed and used in China had

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98% efficacy in a two-dose schedule. Concern that a live vaccine derived from an encephalitogenic virus might lead to vaccine-associated encephalitis could not be addressed satisfactorily, even in a study of 26 000 children. During efficacy studies in different geographic areas of China and in different years, the observations were combinable: the average encephalitis risk after live attenuated Japanese encephalitis vaccine was 1.59 per 100 000 vaccinees. Postmarketing surveillance data of adverse events after Japanese encephalitis immunization in Japan and the USA have been compared (46'-). The rates of total reported adverse events were 2.8 per 100 000 doses in Japan and 15.0 per 100000 doses in the USA. In Japan, 17 neurological disorders were reported from April 1996 to October 1998 (0.2 per 100000 doses), whereas in the USA there were no serious neurological adverse events temporally associated with Japanese encephalitis vaccine from January 1993 to June 1999. Rates for systemic hypersensitivity reactions were 0.8 and 6.3 per 100 000 doses in Japan and the USA, respectively.

Measles vaccine (SED-14, 1076; SEDA-21, 335; SEDA-23, 348) The immunogenicity and safety of two live attenuated measles vaccine strains (Schwarz strain and AIK-C strain) have been compared in 9-month-old Taiwanese infants in order to find a candidate for an effective measles immunization in the first year of life (47c). Because of persisting maternal measles antibody, the commercially available measles vaccines do not produce a sufficient antibody response when given during the first year of life. However, early protection is particularly required in developing countries with high measles morbidity and mortality in infants. Attempts to find suitable candidates for early immunization, including the use of the high-titer Edmonston-Zagreb measles vaccine strain, failed (SED-14, 1078). The Japanese AIK-C measles vaccine strain (derived from the Edmonston strain) has been given to 67 infants and a measles vaccine based on the Schwarz strain was given to 68 infants. The AIK-C strain vaccine caused seroconversion in 65 infants (97%), whereas only 52 infants (77%) seroconverted with the Schwarz strain vaccine. Adverse effects of the two vac-

377 cines were comparable: fever 8.8% (Schwarz strain) vs 19% (AIK-C strain); skin rash 13% vs 13%; rhinorrhea 8.8% vs 12%; cough 7.4% vs 6%; diarrhea 2.9% vs 4.5%; poor appetite 2.9% vs 1.5%; irritability 2.9% vs 6%.

Nervous system Epilepsyhas been attributed to measles vaccine (48c). A 23-month-old boy developed Lennox-Gastaut syndrome (an epileptic syndrome caused by an acquired organic brain insult) 14 days after measles immunization with Japanese FL vaccine, based on AIK-C live attenuated measles vaccine strain. The child's prenatal and perinatal histories and his development until 23 months of life were uneventful. His monozygotic twin brother had no epileptic seizures, but it is not clear from the original paper whether or not the twin received the same vaccine. The controversy about measles vaccine and

encephalopathy continues. A review of claims regarding encephalopathy followed by permanent brain injury or death associated with measles immunization submitted to the US National Vaccine Injury Compensation Program (SEDA-23, 348) has been criticized as an attempt to establish an adverse event of a vaccine, without a specific laboratory finding, without a specific syndrome, without comparable data for non-immunized children, and by ignoring or minimizing years of descriptive epidemiology on reactions (49r). In reply, the original authors reminded their critic that the US Congress had set up the Vaccine Injury Table to avoid disagreements over causation by making temporal association an important eligibility element for listed conditions (50r). Although biologic plausibility is an important standard for assessing causation in medicine, it is less important in law. In the case of the National Vaccine Injury Compensation Program, the statute provided for a legal presumption of causation, if encephalopathy began 5-15 days after measles immunization.

Measles-mumps-rubella (MMR) vaccine (including measles-mumps and measles-rubella vaccines) (SED-14, 1078; SEDA-21, 335; SEDA-22, 351; SEDA-23, 348) The hypothesis that MMR vaccine can cause autism and Crohn's disease, mainly sugges-

378 ted by Andrew Wakefield, a researcher in the Royal Free Hospital in London, UK, has previously been discussed at length (SEDA-23, 350). Summarizing the discussion, no evidence has been found to establish such a causal relation. However, particularly in the UK, because of Wakefield's activities many parents have become concerned about the safety of MMR vaccine, and MMR coverage has fallen. Recently, The Lancet has once more reviewed the developments in the discussion (51r), with emphasis on evidence that contradicts the alleged association and new data presented by Wakefield. The last part of the editorial reads as follows: "In a new twist, Wakefield's crusade fuelled further anxiety among parents when he and John O'Leary, director of pathology at Coombe Women's Hospital, Dublin, Ireland, presented unpublished data to the US Senate's congressional oversight committee in Washington on April 6 [2000]. The hearing was called by the chairman, Dan Burton, an Indiana Republican, whose grandson has autism and visited the Royal Free Hospital in November last year. At the hearing, six parents of children with autism gave moving testimonies of their children's illness . . . . Scientific evidence was presented by six chosen 'experts'. According to Wakefield's testimony, he has now studied more than 150 children with 'autistic enterocolitis'--an unproven association had become a disease-and a detailed analysis of the first 60 cases is to be published in the American Journal o f Gastroenterology later this year. Wakefield presented uninterpretable fragments of results only and concentrated on refuting studies that had contradicted his findings. His conclusions were surprisingly noncommittal: 'the virological data indicate that this may be measles virus in some children'; he added that it would be imprudent to interpret the temporal relationship with MMR as a chance finding, in the absence of thorough investigation. O'Leary explained that gut-biopsy material from 24 of 25 children with autism was positive for measles virus compared with one of 15 controls, and that this material was presented to him by Wakefield using 'blinded protocols'. Since the controls are not further described and the details of these findings remain unpublished, this evidence raises far more questions than it answers. Autism is a poorly understood neurodevelopmental-disease spectrum with a heart-

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breaking personal story behind every case. But parents of such children have not been served well by these latest claims made well beyond the publically [sic] available evidence. A congressional hearing, like a press conference, is no place to make controversial scientific assessments. And if scientists question the safety of vaccines without making their evidence fully transparent, harm will be done to many more children than they purport to protect".

Poliomyelitis vaccine

(SED-14,1087; SEDA-21, 336; SEDA-22, 352; SEDA-23, 352) Oral poliovirus vaccine is safe and effective, and it is the recommended vaccine in the global effort to eradicate polio by 2005. It is the only vaccine proven to stop transmission of the virus in developing countries. Using this vaccine, the global campaign to eradicate polio has achieved a more than 90% reduction in the number of polio cases worldwide in the 11 years since it was launched, and is on track to eradicate polio (25R). Polio vaccine and SV40 virus The problem of early polio vaccines produced in the 1950s and early 1960s, and, in some instances, contaminated with the monkey virus SV40 (simian virus 40) has been discussed (52R; see also SED14, 1089). The authors concluded that critical assessment of virological and epidemiological data suggest a probable causative role for SV40 in certain human cancers, but that additional studies are necessary to prove etiology. To help answer these issues, the WHO has provided the following statement (53s): "Investigations from several medical research institutions have detected the presence of simian virus 40 (SV40) genome in certain rare human tumors, notably mesotheliomas, osteosarcomas, and brain tumors. SV40, which is known to induce tumors in laboratory rodents, is a polyomavirus identified in 1960 as a contaminant of some batches of primary rhesus monkey kidney cells used to produce polio vaccine in the 1950s. Soon after its discovery, measures to exclude the virus from polio and other vaccines were rapidly introduced into WHO Requirements for the Manufacture and Quality Control of Polio Vaccines, and these have been rigorously applied by vaccine manufacturers. For over 30 years now, polio vaccines made in primary monkey

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kidney cells have been shown to be free of live SV40". The use of new and highly sensitive polymerase chain reaction (PCR) techniques for the detection of SV40 genome in batches of oral polio vaccines from several manufacturers has confirmed that the measures taken have been effective in excluding SV40 from the vaccines. There is no doubt that the early batches of polio vaccine that were used between 1955 and 1963 contained SV40. Epidemiological studies between 1960 and 1974 failed to show an association between exposure to SV40-contaminated vaccines and human tumors. More recent epidemiological data from tumor registers, involving more than 60 million person years of observation, have likewise found no differences in tumor incidence that could be attributable to SV40-contaminated polio vaccines. The latest data published in

the Journal of the National Cancer Institute, USA, suggest that SV40 may be present in humans more commonly than had previously been thought, and raises the possibility of transmission of the virus among humans. Whether the antibodies that have been detected are due to exposure to SV40 or to cross-reacting human polyomaviruses is not known. Neither is it certain that SV40 strains now present in the human population originated from the use of the early polio vaccines. Despite almost 40 years of observafion, there is still no evidence that SV40 contamination of some early batches of polio vaccine has had any adverse effect on human health. In contrast, widespread immunization has drastically reduced the incidence of paralytic polio worldwide. Indeed, with over 150 million neonates being vaccinated globally each year, WHO-led immunization campaigns are nearing their goal of the complete global eradication of polio. It is to be expected that in a few years both poliomyelitis and polio vaccines will be confined to history books and science museums. Polio immunization will stop for good.

R o t a v i r u s vaccine (SEDA-14, 1091; SEDA-20, 292; SEDA-21, 337; SEDA-23, 354) The safety, immunogenicity, and efficacy of a live oral human rotavirus vaccine 89-12 has been assessed in 213 US infants in a randomized, placebo-controlled, double-blind, multicenter trial (54c). The infants received two

doses of vaccine or placebo and were followed up through one rotavirus season. There was an immune response to vaccine in 94.4% of vaccinees, and vaccine efficacy was 89%. Adverse reactions were mild. Low-grade fever after the first dose was the only adverse effect that was significantly more common with the vaccine than with placebo.

Gastrointestinal Tetravalent rhesus-based rotavirus vaccine and intussusception has been previously discussed at length (SED-14, 1091; SEDA-23, 354). In an editorial in the journal Emergency and Office Pediatrics, the critical role of physicians in the early detection of adverse events has been stressed. Despite the demands of busy clinical practice, all physicians are obliged to be alert to unusual circumstances and to seek answers when unexpected findings---especially related to new drugs, vaccines, or procedures--seem to be more than just coincidence. It is incumbent on them to report these findings and to learn if their experience can be confirmed by colleagues

(55R).

Natural rotavirus itself is a causative agent for intussusception (56R). In rotavirus disease in Japan, hyperplasia of the intestinal lymphoid tissue is a common pathological finding in necropsy cases, and is identical with that observed in patients who receive the tetravalent rhesus-based rotavirus vaccine.

Rubella vaccine (SED-14, 1092; SEDA-21, 337; SEDA-22, 353)

Nervous system Neurological complications after rubella vaccine have only been reported in a few cases. It has been suggested that there is insufficient evidence to indicate either the presence or absence of a causal relation between RA 27/3 rubella vaccine and radiculoneuritis and other neuropathies (1c). However, the case of a 23-year-old woman who developed a mild distal demyelination neuropathy 4 weeks after rubella immunization has been reported (57c). Immunological studies showed the presence of antibodies to the rubella virus proteins and to the myelin basic protein. The authors suspected that a virus-induced immune response caused an autoaggressive reaction responsible for demyelination.

380

Tickborne encephalitis vaccine (SED-14, 1095; SEDA-20, 292; SEDA-22, 354) Following the use of tickborne encephalitis vaccine ("Ticovac", produced by Baxter) in German children, there was a sudden increase in the number of cases of high fever, and 20-30% of vaccinees, primarily those 3 years of age and younger, reacted with a high fever (39~ or more) after the first dose (58c). The increased number of cases of high fever was observed after changes in the production of tickborne encephalitis vaccine were made: the vaccine no longer contains thiomersal and human albumin. Currently, according to the German licensing authority, the Paul Ehrlich institute, the vaccine is no longer recommended for children under 3 years; children aged 3-15 years should only receive half a dose of Ticovac, and the vaccine should only be used when strongly indicated. The reason for the changed reactogenicity is still unclear.

Varicella v a c c i n e (SED-14, 1096; SEDA-21, 338; SEDA-22, 354; SEDA-23, 355) In 1995, live virus Varicella vaccine (Oka strain) was licensed in the USA. Of the 6574 reported adverse events 4% (67.5 per 100 000

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doses) after immunization were serious, while the majority were minor reactions, such as rash, redness, or injection sitepain (59R). About 10% of immunized children developed mild chickenpox. A total 193 vaccinees reported neurological symptoms, including Bell's palsy, con-

vulsions, and demyelinating syndromes; febrile seizures accounted for half of the cases of convulsions. There were 14 deaths, but a role for the vaccine was not proven. Infection risk Zoster in childhood has been reported (60c). It is an unusual event and probably even less common after varicella immunization. A 6-year-old boy developed a zoster infection (with a vesicular rash in a left second thoracic dermatome pattern on his back extending to the back of his left arm) 15 days after the receipt of Varicella vaccine (Oka strain). Molecular biological analysis of the virus isolated from the vesicles showed a pattern consistent with wild-type Varicellazoster virus. The authors felt that this case mandates a careful review of all cases of zoster after Varicella immunization. Zoster induced by Varicella immunization could have implications for the use of immunization to prevent zoster in the eldedy, a population with almost uniform Varicella zoster latent virus and at higher risk of zoster.

REFERENCES 1. Howson CP, Howe CJ, Fineberg HV, editors. Adverse effects of pertussis and rubella vaccines. Washington DC: National Academy Press, 1991: 8. 2. Stratton KR, Howe CJ, Johnston RB, editors. Adverse events associated with childhood vaccines. Washington DC: National Academy Press, 1994: 37. 3. Chen RT. Vaccine risks: real, perceived, and unknown. Summaries of speeches. Fourth European Conference on Vaccinology, Brighton, UK, 17-19 March 1999. 4. Duclos P, Ward BJ. Measles vaccines. A review of adverse events. Drug Saf 1998; 19: 435-54. 5. Singleton JA, Lloyd JC, Mootrey GT, Salive ME, Chen RT. An overview of the VaccineAdverse Event Reporting System (VAERS) as a surveillance system. Vaccine 1999; 17: 2908-17. 6. Peltola H, Aavitsland P, Hansen KG, Jonsdottir KE, Nokleby H, Romanus V. Perspective: a five-country analysis of the impact of four different Haemophilus influenzae type b conjugates and vaccination strategies in Scandinavia. J Infect Dis 1999; 179: 223-9.

7. Anonymous. Lyme disease vaccine. Med Lett Drugs Ther 1999; 41: 29-30. 8. Advisory Committee on Immunization Practices (ACIP). Recommendations for the use of Lyme disease vaccine. Morb Mortal Wkly Rep 1999; 48(RR-7): 1-25. 9. Hayney MS, Grunske MM, Boh LE, Da Camada CC, Perreault MM. Lyme disease prevention and vaccine prophylaxis. Ann Pharmacother 1999; 33: 723-9. 10. Noble HB. Concerns over reactions to Lyme shots. New York Times, 21 November 2000. 11. FDA.Vaccines and Related Biological Products Advisory Committee. LYMErix. Lyme Disease Vaccine Safety Update, 31 January 2001. htpp://www.fda.gov/ohrms/dockets/ac/01/briefing/ 3680b2.htm (accessed 10 February 2001). 12. Associated Press Report, 31 January 2001. Warnings urged for Lyme vaccine. htpp://www.fda.gov (accessed 1 February 2001). 13. Tappero JW, Lagos R, Ballesteros AM, Plikaytis B, Williams D, Dykes J, Gheesling LL, Carlone GM, Hoiby EA, Hoist J, Nokleby H, Rosenqvist E, Sierra G, Campa C, Sotolongo F,

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Vega J, Garcia J, Herrera P, Poolman JT, Perkins BA. Immunogenicity of two serogroup B outermembrane protein meifingococcal vaccines: a randomized controlled trial in Chile. J Am Med Assoc 1999; 281: 1520-7. 14. Cartwright K, Morris R, Rurnke H, Fox A, Borrow R, Begg N, Richmond P, Poolman J. Immunogenicity and reactogenicity in UK infants of a novel meningococcal vesicle vaccine containing multiple class 1 (PorA) outer membrane proteins. Vaccine 1999; 17: 2612-19. 15. Richmond E Borrow R, Miller E. Clark S, Sadler F, Fox A, Begg N, Morris R, Cartwright K. Meningococcal serogroup C conjugate vaccine is immunogenic in infancy and primes for memory. J Infect Dis 1999; 179: 1569-72. 16. Richmond P, Goldblatt D, Fusco PC. Fusco JDS, Heron I, Clark S, Borrow R, Michon E Safety and immunogenicity of a new Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine in healthy adults. Vaccine 1999; 18: 6416. 17. Corbel MJ, Xing DKL, Bolgiano B, Hockley DJ. Approaches to the control of acellular pertussis vaccines. Biologicals 1999; 27: 133-41. 18. Use of diphtheria toxoid-tetanus toxoidacellular pertussis vaccine as a five-dose series. Supplemental recommendations of the Advisory Committee on Immunization Practices (ACIP). Morb Mort Wkly Rep 2000; 49(RR-13): 1-8. 19. Jonville-Bera AP, Autret-Leca E, Radal M. Adverse effects associated with diphtheria, tetanus, pertussis, and poliomyelitis vaccinations (Tetracoq, IPAD/DTCE DTCP). Arch Pediatr 1999; 6: 51015. 20. Lee CY, Thipphawong J, Huang LM, Lee PI, Chiu HH., Lin W, Debois H, Harrison D, Xie E Barreto L. An evaluation of the safety and immunogenicity of a five-component acellular pertussis, diphtheria, and tetanus toxoid vaccine (DTaP) when combined with a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine (PRP-T) in Taiwanese infants. Pediatrics 1999; 103: 2530. 21. Jackson LA, Benson P, Sheller VP, Butler JC, Thompson RS, Chen RT, Lewis .S, Carlone G, DeStefano E Holder P, Lezhava T, Williams WW. Safety of revaccination with pneumococcal polysaccharide vaccine. J Am Med Assoc 1999; 281: 243-8. 22. Shinefield HR, Black S, Ray P, Chang I, Lewis N, Fireman B, Hackell J, Paradiso PR, Siber G, Kohberger R, Madore DV, Malinowski FJ, Kimura A, Le C, Landaw I, Aguilar J, Hansen J. Safety and immunogenicity of heptavalent pneumococcal CR/VI197 conjugate vaccine in infants and toddlers. Pediatr Infect Dis J 1999; 18: 75763. 23. Clemens J, Hoffman S, Ivanoff B, Klugman K, Levine MM, Neira M, Pang T. Typhoid fever vaccines. Vaccine 1999; 17: 2476-8.

3 81 24. Walter R, Hartmann K, Fleisch F, Reinhart WH, Kuhn M. Reactivation of herpesvirus infections after vaccinations? Lancet 1999; 353: 810. 25. World Health Organization. Bovine spongiform encephalitis and oral polio vaccine. Position statement. October 2000. http://www.who.int/vaccinesdiseases/safety/hottop/bse.htm (accessed 10 November 2000). 26. World Health Organization. Questions and answers on thiomersal. July 1999. http:// www.who.int/vaccines-diseases/safety/hottop/ thiomersal.htm (accessed 15 November 2000). 27. Kelso JM. The gelatin story. J Allergy Clin Immunol 1999; 103: 200-2. 28. WHO. Press release. Hepatitis B and multiple sclerosis. Geneva, 8 June 2000. http:// www.who.int/vaccines-diseases/safety/hottop/ hepb.htm (accessed 20 August 2000). 29. French Ministry of Health. Press release, 23 May 2000. Compensation for hepatis B vaccination, http://www.who.int/vaccines-diseases/ safety/pressreleasenglish.html (accessed 2 August 2000). 30. Associated Press. Press release, 15 April 1999. Hepatitis vaccine safety questioned in the United States. http://www.who.int/vaccinesdiseases/safety/hottop/HBV_Press.html (accessed 2 August 2000). 31. Tourbah A, Gout O, Liblau R, Lyon-Caen O, Bougniot C, Iba-Zizen M, Cabanis EA. Encephalitis after hepatitis B vaccination: recurrent disseminated encephalitis or MS? Neurology 1999; 53: 396--401. 32. Creange A, Temam G, Lefaucheur JP. Lumbosacral acute demyelinating polyneuropathy following hepatitis B vaccination. Autoimmunity 1999; 30: 143-6. 33. Stewart O, Chang B, Bradbury J. Simultaneous administration of hepatitis B and polio vaccines associated with bilateral optic neuritis. Br J Ophthalmol 1999; 83: 1200-1. 34. Casals JL, Vasquez MA. Arthritis after hepatitis B vaccination. Ann Med Interna 1999; 16: 601-2. 35. Le Hello C, Cohen P, Bousser M-G, Letellier P, Guillevin L. Suspected hepatitis B vaccination related vasculitis. J Rheumatol 1999; 26: 191-4. 36. Rabaud C, Barbaud A, Trechot P. First case of erythermalgia related to hepatitis B vaccination. J Rheumatol 1999; 26: 233-4. 37. Minutello M, Senatore E Cecchinelli G, Bianchi M, Andreani T, Podda A, Crovari P. Safety and immunogenicity of an inactivated subunit influenza virus vaccine combined with MF59 adjuvant emulsion in elderly subjects, immunized for three consecutive influenza seasons. Vaccine 1999; 17: 99-104. 38. De Donato S, Granoff D, Minutello M, Lecchi G, Faccini M, Agnello M, Senatore F, Verweij P, Fritzell B, Podda A. Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly. Vaccine 1999; 17: 3094-101.

382 39. Holm KJ, Goa KL, Oxford JS, McElhaney JE. Liposomal influenza vaccine. Biodrugs 1999; 11: 137--46. 40. Jackson LA, Holmes SJ, Mendelman PM, Huggins L, Cho I, Rhorer J. Safety of a trivalent live attenuated intranasal influenza vaccine, FluMist, administered in addition to parenteral trivalent inactivated influenza vaccine to seniors with chronic medical conditions. Vaccine 1999; 17: 1905-9. 41. Solomon A, Siganos CS, Frucht-Pery J. Adverse ocular effects following influenza vaccination. Eye 1999; 13: 381-2. 42. Tsai TF. New initiatives for the control of Japanese encephalitis by vaccination: minutes of a WHO/CVI meeting, Bangkok, Thailand, 13-15 October 1998. Vaccine 2000; 18 Suppl 2: 1-25. 43. Markoff L. Points to consider in the development of a surrogate for efficacy of novel Japanese encephalitis viral vaccines. Vaccine 2000; 18 Suppl 2: 26-32. 44. Kurane I, Takasaki T. Immunogenicity and protective efficacy of the current inactivated Japanese encephalitis vaccine against different Japanese encephalitis virus strains. Vaccine 2000; 18 Suppl 2: 33-5. 45. Tsarev SA, Sanders ML, Vaughn DW, Innis BL. Phylogenetic analysis suggests only one serotype of Japanese encephalitis virus. Vaccine 2000; 18 Suppl 2: 36--43. 46. Takahashi H, Pool V, Tsai TF, Chen RT, The VAERS Working group. Adverse events after Japanese encephalitis vaccination: review of postmarketing surveillance data from Japan and the United States. Vaccine 2000, 18: 2963-9. 47. Tsai H-Y, Huang L-M, Shih Y-T, Chen J-M, Jiang T-M, Tsai C-H, Lee C-Y. Immunogenicity and safety of standard-titer AIK-C measles vaccine in nine-month-old infants. Viral Immunol 1999; 12: 343-8. 48. Ishikawa T, Ogino C, Chang S. Lennox-Gastaut syndrome after a further attenuated live measles vaccination, Brain Dev 1999; 21: 563-5.

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49. Sepkowitz S. Letter to the editor. Pediatrics 1999; 103: 694-5. 50. Weibel RE, Caserta V, Benor DE, Evans G. Reply. Pediatrics 1999; 103: 695-6. 51. Measles, MMR, and autism: the confusion continues. Lancet 2000; 355: 1379. 52. Butel J, Lednlcky JA. Cell and molecular biology of SV40: implications for human infections and diseases. J Natl Cancer Inst 1999; 91: 11934. 53. World Health Organization. Hot topics: statement on simian virus (SV40) and polio vaccine, http://www.who.int/vaccines-diseases/ safety/hottop/sv40.htm (accessed 14 September 2000). 54. Bernstein DI, Sack DA, Rothstein E, Reisinger K, Smith VE, O'Sullivan D, Spriggs DR, Ward RL. Efficacy of live, attenuated, human rotavirus vaccine 89-12 in infants: a randomised placebocontrolled trial. Lancet 1999; 354: 287-90. 55. Liebert PS. Reporting vaccine complications. Emerg Off Pediatr 1999; 12: 125. 56. Suzuki H, Katsushima N, Konno T. Rotavirus vaccine put on hold. Lancet 1999; 354: 1390. 57. Cusi MG, Bianchi S, Santini L, Donati D, Valassina M, Valensin PE, Cioe L, Mazzocchio R. Peripheral neuropathy associated with anti-myelin basic protein antibodies in a woman vaccinated with rubella virus vaccine. J Neurovirol 1999; 5: 209-14. 58. Statement of the Paul Ehrlich Institute. Use of Ticovac TBE vaccine. Langen, Germany. http:llwww.pei.delticovacinfo.htm (accessed 14 September 2000). 59. Wise RP, Salive ME, Miles BM. Postlicensure safety surveillance for Varicella vaccine. J Am Med Assoc 2000; 284: 1271. 60. Kohl S, Rapp J, La Russa P, Gershon AA, Steinberg SP. Natural Varicella-zoster virus reactivation shortly after varicella immunization in a child. Pediatr Infect Dis J 1999; 18:1112-13.

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33

BloOd~nblOOdad

plasma, ALBUMIN (SED-14, 1123; SEDA-21, 342; SEDA-23, 359) Cardiovascular Albumin infusion during resuscitation can result in hypervolemia, due to overfilling of the circulation (1R). It has been postulated that cardiac pump function can be reduced owing to binding of free calcium to albumin (1R). Albumin infusions can increase capillary permeability (2R). ltematologie Albumin can inhibit platelet aggregation (1R). In addition, coagulation defects can result from dilution after albumin administration (1a). Drug contamination The production process of albumin excludes transmission of viruses, such as hepatitis B and C and HIV (1R). However, there is little information on the safety of albumin with respect to hepatitis A and parvovirus (2R). Risk factors A meta-analysis of virtually all existing randomized controlled studies of albumin or plasma protein fraction showed excess mortality of about 6% in combined groups of patients with hypovolemia, burns, or hypoproteinemia who received albumin either instead of or in addition to crystalloid solutions (SEDA23, 360; 3R). It was stated that albumin should not be given to critically ill patients outside of rigorously conducted randomized controlled trials. However, other authors do not agree with the outcome and conclusions of this metaanalysis. They have stated that a meta-analysis is not exact and that in this specific study three

9 2001 Elsevier Science B.V. All fights reserved.

Side Effectsof Drugs, Annual24 J.K. Aronson, ed.

c o m p o n e n t s ~

plasmaproducts separate indications have been studied, which were not comparable (2R). An Expert Working Party of the Committee on Safety of Medicines was set up to examine these findings and to advice on any necessary regulatory action. The Working Party concluded that there is insufficient evidence of harm to warrant withdrawal of albumin products from the market and that the effect of albumin on mortality can only be discovered by conducting large, purpose-designed, randomized, controlled trials (4R). It was recommended that a number of changes be made to the product information for human albumin. Specifically, the Expert Working Party recommended that the indication for human albumin solutions should be focused on the use of albumin to replace lost fluids, rather than the underlying illness that resulted in hypovolemia, and that albumin deficiency in itself was not an appropriate indication. The product information should contain warnings about the risks of hypervolemia and cardiovascular overload and emphasize that hemodynamic monitoring in patients who receive albumin should be undertaken to avoid these complications. A warning that special care should be taken when administering albumin in pathological states that affect capillary integrity should also be included.

BLOOD SUBSTITUTES (SED-14, 1703; SEDA-21, 346; SEDA-23, 359) Perfluorocarbon emulsions are oxygen carriers with a transport capacity that is greater than that of blood under hyperoxic conditions (5c). The available formulations include perfluoro-octyl bromide, perfluoro-octylethane, perfluorodichloro-octane, Fluoso-DA | (70% 383

384 perfluorodecalin and 30% perfluorotripropylamine), OxygenTM (perflubron, perfluoro-octyl bromide), and LiquiVent | (perflubron). The characteristics of an ideal emulsion for use as a blood substitute are absence of incompatibility and risk of transmission of infectious diseases, a long duration of conservation, easy access, and rheological parameters similar to those of blood (5c). Second-generation perfluorocarbons are now used in anemia, trauma, high blood loss surgery, perioperative hemodilution, ischemia, and organ conservation for transplantation. Phase III studies of one of the perfluorocarbons, OxygenTM, are proceeding in cases in which tissue oxygenation is required and when it is desirable to avoid allogeneic blood transfusion. Adverse effects of perfluorocarbon emulsions include a dose-dependent flu-like illness 4-6 hours after infusion (5c). The symptoms include fever, arterial hypotension, tachycardia, a high leukocyte count, and thrombocytopenia. The most important adverse effect of LiquiVent | is the risk of intravascular passage of the perfiuorocarbon. Phagocytosis by alveolar macrophages has been demonstrated by cytology. Larger doses of emulsion particles can lead to hepatic engorgement and temporary impairment of immune defences (5C). Third-generation emulsions are currently in early preclinical development (5c). The absence of toxicity of these new emulsions has been demonstrated in endothelial cell cultures and in animal organ preservation studies. Cardiovascular One of the modified hemoglobin solutions, DCLHb, has been associated with an increase in mean arterial pressure. The authors suggested that this was due to "inhibition of nitric oxide", stimulation of the production of endothelin, and sensitization and/or potentiation of ill- and/~2-adrenoceptor responses to catecholamines (5c). Other adverse effects of modified hemoglobin solutions include abdominal discomfort and increases in creatinine kinase and iso-LDH5. Another hemoglobin substitution product, liposome-encapsulated tetrameric hemoglobin, can exacerbate the manifestations of septic shock (5c). Respiratory In premature neonates and children with respiratory distress syndrome treated

Chapter 33

H.W. Eijkhout and W.G. van Aken

with perfluorocarbon, pneumothorax has been observed (5c). Sensory systems Corneal epithelial damage has been attributed to a perfluorocarbon (6A). An elderly man underwent vitreoretinal surgery for retinal detachment. Perfluorodecalin was used to repair the retina and was left in situ for 8 weeks and removed via the pars plana. One month later he developed a non-healing corneal epithelial defect associated with limbitis. Perfluorodecalin was found under the superior conjunctiva. A biopsy showed vacuoles in the conjunctival strorna surrounded by inflammatory cells. On surgical removal of the perfluorodecalin from the subconjunctival space, the epithelial defect healed. Urinary tract Compared with erythrocytes, hemoglobin solutions have a more efficient microcirculatory transport of oxygen. Purification of hemoglobin has been improved, which was necessary to avoid free hemoglobin, resulting in nephrotoxicity (5c). Immunologic Hemoglobin solutions do not have the antigenic properties of the blood groups. Drug contamination Three sources of hemoglobin can be distinguished: human, bovine, and recombinant. The main limitation of bovine hemoglobin is the risk of transmission of bovine spongiform encephalopathy and the development of antibodies to bovine proteins (5c).

FRESH FROZEN PLASMA (SED-14, 1123) Cardiovascular Thirteen patients with warfarin-related intracranial hemorrhage were treated with either fresh frozen plasma or prothrombin complex product to achieve rapid correction of anticoagulation (7c). In five of the eight patients treated with fresh frozen plasma there were complications of fluid overload. In two of these patients congestive heart failure developed, resulting in myocardial infarction and renal insufficiency respectively. Two patients had supraventricular tachydysrhythmias and one developed pulmonary edema.

Blood, blood components, plasma, and plasma products

Respiratory The incidence of transfusion-related acute lung injury is 0.164).24% per transfusion of blood products and is the cause of 15% of all fatal complications of blood transfusion (8A). Specific antigen-antibody reactions involving donor antibodies specific for leukocyte antigens of the recipients cause activation of neutrophils and aggregation in small pulmonary vessels (8A). The complement and cytokine cascade is activated, leading to capillary leakage. In a 58-year-old man transfusion of a unit of fresh frozen plasma resulted in acute lung injury, caused by antibodies of the donor specific for the neutrophil antigen NB1 (8A). NB 1 has a phenotype frequency of 97%.

INTRAVENOUS (SED-14, 1123; SEDA-21, 344; SEDA-22, 363; SEDA-23, 360) IMMUNOGLOBULIN

The efficacy and safety of intravenous immunoglobulin have been reported in primary and secondary immunodeficiency, as well in some immune disorders such as idiopathic thrombocytopenic purpura, Kawasaki disease, and Guillain-Barr6 syndrome (9c). Higher dosages of intravenous immunoglobulin are used for autoimmune indications (400-2000 mg/kg) than in immunodeficiency diseases (10(0-400 mg/kg). Minor adverse effects, such as headache, myalgia, chest discomfort, and fever, occur in 10% of patients (10c). Most adverse effects are related to the rate of administration and can be attenuated by slowing the rate of the infusion (1 lC). Cardiovascular Thrombosis in elderly patients with an increased risk of thrombosis, such as hypertension or previous episodes of infarction, has been described (12R). Transient hypertension occurred in a patient with dermatomyositis during therapy with intravenous immunoglobulin (13A). In the past his diastolic blood pressure had been 104-106 mm Hg, but he was normotensive with antihypertension medication. Several mechanisms for the transient hypertension were postulated, e.g. stimulation of the vascular endothelium to secrete endothelin to inhibit nitric oxide synthesis.

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385

Respiratory A 35-year-old woman with idiopathic thrombocytopenic purpura treated with high dosages of intravenous immunoglobulin developed a recurrent lymphocytic pleural effusion (14A).

Nervous system Headache occurred in 25% of all patients who received an infusion of intravenous immunoglobulin, probably related to larger volumes and fluid shifts, protein loads, and infusion rates (15c). Aseptic meningitis has been reported in association with the administration of intravenous immunoglobulin (16c). Aseptic meningitis is characterized by headache, photophobia, nausea, vomiting, and meningism, and is confirmed by cerebrospinal fluid pleocytosis and negative cultures (15c). Possible mechanisms of aseptic meningitis include hypersensitivity reactions, stabilizing products, cytokines, cerebrovascular sensitivity, and direct meningeal irritation. Stroke and ischemic encephalopathy, probably caused by cerebral vasospasm after intravenous immunoglobulin, have been reported as possible complications of intravenous immunoglobulin (17A). Hematologic Neutropenia after intravenous immunoglobulin is frequent and seems to be transient and self-limiting (18c). Neutropenia is not dose-dependent. Hemolysis after intravenous immunoglobulin infusion is due to acquisition of red cell aUoantibodies from donor serum (12R). Specifications in pharmacopeial monographs and product licences require intravenous immunoglobulin products to be free from significant amounts of anti-A and anti-B antibodies (19 C). It has been advised that a specification be adopted that will prevent the use of batches of intravenous immunoglobulin with abnormally high anti-D titers (over 1: 64) (19c). Various immunoglobulin products contain IgG of molecular weight of a dimer or greater (over 300 kDa), which in the presence of serum can mimic immune complexes and bind to erythrocytes via CR1 (20c). Especially in young adults, the immune complex-like moieties in intravenous immunoglobulin bind to erythrocytes and serve as opsonins in the mediation of erythrocyte sequestration, resulting in significant drops in hematocrit and hemoglobin concentrations (20c). It has been suggested that

386 the presence of immune complex-like moieties bound to erythrocyte CR1 after intravenous immunoglobulin treatment is correlated with in vivo hemolysis. Urinary tract So far, the FDA has received about 114 reports worldwide of renal dysfunction and/or renal insufficiency associated with intravenous immunoglobulin infusions (llC). Renal insufficiency has been attributed to the large amount of sucrose, a stabilizer, in the product (21c). The high solute load in the kidney can cause osmotic damage (llC). Renal tubular injury from the intracellular accumulation of sucrose by pinocytosis leads to the osmotic flow of fluid into the cells and causes cellular swelling and vacuole formation (1 lC). In most cases the acute renal insufficiency is reversible and recovery occurs after 7-15 days

(9c).

Risk factors for renal insufficiency include increased age, impaired renal function, dehydration, and high dosages of intravenous immunoglobulin (9 C, 1 lC). To avoid renal insufficiency patients should be adequately hydrated and potent diuretics should be avoided (9c). Skin Skin reactions to intravenous immunoglobulin, e.g. urticaria, pruritus, and petechiae, are rare. Pompholyx has been observed 5-7 days from the last day of therapy in three of 23 neurological patients treated with intravenous immunoglobulin (10c). Pompholyx is characterized by small papules, subdermal vesicles, desquamation, and crusting. Alopecia after intravenous immunoglobulin has been reported (22A).

Immunologic Anaphylaxis has been observed in patients with IgA deficiency and antibodies to IgA (10A). In recipients of left ventricular assist devices awaiting cardiac transplantation treated with intravenous immunoglobulin clinical manifestations of immune complex disease occurred during four of 27 (15%) monthly courses (23c). The immune complex disease was characterized by fever, arthralgia, and maculopapular rashes. Drug contamination Transmission of hepatitis B and HIV after infusion of intravenous immunoglobulin has never been reported (12R).

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H.W. Eijkhoutand W.G. van Aken

However, 112 cases of hepatitis C virus were reported in 1994. Modification of the manufacturing process, e.g. the use of a solvent detergent, eliminates hepatitis C virus transmission (12 R, 24c). Interference with diagnostic tests In a 38year-old man with end-stage renal insufficiency and thrombocytopenia secondary to systemic lupus erythematosus, pseudohyponatremia occurred after treatment with intravenous immunoglobulin 1 g/kg for 2 days (25A). This phenomenon is explained by the fact that intravenous immunoglobulin increases the non-aqueous phase of the plasma, resulting in a relative loss of plasma water volume. Sodium is virtually restricted to serum water, so each volume of plasma measured will contain less sodium and be interpreted as hyponatremia. Using the direct ion-selective electrode method prevents this.

CLOTTING FACTORS (SED-14, 1125; SEDA-21, 342; SEDA-22, 36; SEDA-23, 362) Hemophiliacs are traditionally treated with bolus injections of factor VIII or IX. This kind of administration is associated with peak and trough concentrations of these factors, with a risk of bleeding when the concentration of factor VIII or factor IX falls below a critical concentration (26c). Several studies of continuous infusions of factor VIIa, VIII, and IX in hemophiliacs undergoing surgery have shown that this mode of administration is safe and effective when steady plasma concentrations of the clotting factors can be achieved (26 c, 27 c, 28 c, 29c). The total dosage of clotting factor concentrates is reduced, and so continuous infusions are cost effective (26 c, 29c). Cardiovascular Activated prothrombin complex products, which contain factors II, VII, IX, and X, and which bypass the need for factor VIII in the clotting cascade, are indicated for the treatment of bleeding episodes in hemophiliacs with inhibitors of factor VIII (30c). Myocardial necrosis has been described after the administration of one of these products, probably owing to an excessive amount of kininogen in the product.

Blood, blood components, plasma, and plasma products Thromboembolic events in relation to activated prothrombin complex products include

deep venous thrombosis and pulmonary embolism (31 R, 32r, 33r). So far, the exact mechanism of how thromboembolic events are stimulated by prothrombin complex products is not known. It has been postulated that the presence of activated clotting factors VII, IX, and X, as well as procoagulatory phospholipids in prothrombin complex products are responsible for the development of thrombosis (34R). Thrombophlebitis has been noted after infusion of factor VIIa (34 a, 35c). Hematologic Porcine factor VIII, used for the treatment of patients with inhibitors of factor VIII, can cause thrombocytopenia, which is dose-related and occurs during intensive treatment for severe bleeding or surgery (31 a, 36c). Hypofibrinogenemia has been observed immediately after infusion of one of the activated prothrombin complex products (such as Autoplex| It has been advised that antifibrinolytic substances should be avoided in conjunction with Autoplex |

Disseminated intravascular

coagulation

has been described as an adverse effect of activated prothrombin complex products (30c). Recombinant factor VIIa acts through the extrinsic pathway via expressed tissue factor allowing local hemostasis (33r). Compared with activated prothrombin complex products the risk of disseminated intravascular coagulation and other thrombolic events appears to be reduced (33 r, 36c). However, one case of disseminated intravascular coagulation and myocardial infarction after infusion of recombinant factor VIIa has been reported (31R). Skin An erythematous pruritic eruption has been described after infusion of Autoplex| (31R).

Immunologic One of the most important adverse effects of factor VIII substitution therapy is the development of antibodies to factor VIII, which occurs in about 10-16% of patients

(30c). Risk factors for developing an inhibitor are the severity of the hemophilia, age (under 30 years), genetic predisposition, antigenicity of factor replacement therapy, and race (increased prevalence among black people) (31a). In addi-

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tion, it has been suggested that changing from one product to another can also stimulate the development of inhibitors (37c). Patients with a low inhibitor concentration can be treated with high-dose infusions of factor VIII, while patients with high antifactor VIII titers require products such as activated prothrombin complexes (30c). It has recently been shown that recombinant factor VIIa is both effective and safe in the treatment of inhibitors directed to either factor VIII or IX (32 r, 33r). In patients with hemophilia A and B with inhibitors, treated with recombinant factor VIIa, there was no evidence of antigenicity of recombinant factor VIIa (38c). However, antibodies to factor VII in factor VII-deficient patients treated with recombinant factor VIIa have been demonstrated (38c). Novel molecular defects, Arg2163His and Phe2101Cys, were held responsible for inhibitor formation in two patients (39c). Two patients (aged 60 and 73 years) with mild and moderate hemophilia respectively, without a family history of inhibitor formation, were exposed to factor VIII for more than 50 days. An inhibitor developed in both patients after an intermediate factor VIII product was replaced by a high purity factor VIII product, which was given by continuous infusion during a surgical procedure. In 58 previously treated patients with hemophilia treated with a recombinant factor VIII product for more than 5 years, there were no allergic reactions to murine or hamster proteins (40c). Nor was there any de novo formation of inhibitors of factor VIII. In two studies of previously untreated patients who were given two different recombinant factor VIII products, the incidence of development of an inhibitor was comparable to that in patients with severe hemophilia (+30%) (41R). The prevalence of inhibitors in hemophilia B is very low (about 4%) compared with that in hemophilia A, and it has been postulated that there is a correlation between mutation type and inhibitor risk (42c). Of the patients with gross deletion, nonsense, or frameshift mutations, 11% developed inhibitors compared with 0% and 0.36% of patients with hemophilia B with mis-sense or other mutations. Anaphylaxis in conjunction with inhibitor development has been described. Patients with hemophilia B with complete gene deletions

388 have the greatest risk of anaphylaxis, with a minimum risk of 26%, whereas the risk in patients with null mutations was 2.4% and nearly zero for mis-sense mutations (43c). Predisposing factors for the development of anaphylaxis, besides mutation type, are genetic predisposition and environmental experience, such as the type and frequency of factor IX product (43c). It has been recommended that nonhemophiliacs with autoantibodies be treated with porcine factor VIII products (31R). Drug contamination In the past plasma factor VIII products have exposed hemophiliacs to foreign proteins as well as blood-borne viruses, including hepatitis B, hepatitis C, human Parvo B 19, and human immunodeficiency virus (40c). However, since viral inactivation methods, such as solvent detergent and heat pasteurization, have been implemented in the production process, the risk of HIV and hepatitis has virtually been eliminated (SEDA-23, 363). Nevertheless, most of the currently used viral inactivation methods do not eliminate certain (non-enveloped) viruses, e.g. parvovirus and hepatitis A. Bacterial growth in infusion bags has not been detected, and complications such as infections during thepostoperative period has not been observed (26'~). Drug interactions Small doses of heparin are used for the prophylaxis of infusion-related thrombophlebitis (28c). Low molecular weight heparin should be added to recombinant factor VIIa to prevent a 50% loss of activity of factor VII within 4 hours of storage (34R). In one case, however, precipitation of reconstituted factor VIIa and low molecular weight heparin in syringes has been observed (27e). The authors therefore suggested that a parallel saline infusion be used instead of heparin to prevent thrombophlebitis.

EPOETIN (ERYTHROPOIETIN) (SED-14, 1128; SEDA-21, 347; SEDA-22, 366; SEDA-23, 364) For several years recombinant human erythropoietin has been widely used for the treatment of anemia in patients undergoing chronic dialysis, and it improves the quality of life of chronic uremic patients (44 c, 45c).

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Epoetin is also indicated for the prevention of anemia in surgical patients, for chemotherapy-induced anemia, and for anemia induced by zidovudine in H1V-infected patients and patients with multiple myeloma (SEDA-23, 364). While epoetin is not of benefit in patients receiving autologous bone-marrow transplantation, in patients receiving allogeneic bonemarrow transplantation epoetin results in accelerated erythroid engraftment, increased hemoglobin concentrations, a reduced requirement for erythrocyte transfusions, and a shortened time to transfusion independence (46R). In a prospective, randomized, double-blind, placebo-controlled, multicenter study in 80 critically ill patients, epoetin led to a 45% reduction in the number of erythrocyte units transfused. There were no epoetin-related adverse effects (47c). The most common adverse effects that occur after intravenous injection of epoetin are bone and muscle pain, chills, and fever, and they can be avoided by injecting epoetin subcutaneously rather than intravenously (46R). Other mild adverse effects include headache, conjunctival infection, nausea, vomiting, and diarrhea. There is an inadequate response to epoetin therapy in iron deficiency, hematological diseases, vitamin deficiencies, chronic blood loss, osteitis fibrosa, infection/inflammation, and aluminium toxicity (48 R, 49r). During treatment of renal hypertension or heart failure with ACE inhibitors the response to epoetin therapy is reduced; this can be avoided by the use of angiotensin-II receptor antagonists (49r). Epoetin causes or aggravates hypertension in about 20-35% of dialysis patients (50 r, 51 c, 52c). In 44 children with chronic renal insufficiency treated with epoetin 150 U/kg/week, hypertension was mostly observed in patients on hemodialysis (66%) compared with peritoneal dialysis (33%) and predialysis patients (16%) (53c). The induction of hypertension by epoetin has been attributed to increased blood viscosity after a rapid increase in hematocrit and a loss of hypoxia-induced vasodilatation (51c). Another pathogenic mechanism for the induction of hypertension by epoetin is enhanced endothelin production by endothelial cells (51c). Cardiovascular

Blood, blood components, plasma, and plasma products Antiplatelet therapy reduces the incidence of epoetin-induced hypertension in predialysis patients (52c). Risk factors for the development or worsening of hypertension are pre-existing hypertension, the presence of native kidney, a rapid increase in hematocrit, a low baseline hematocrit, a high dosage of epoetin, and intravenous administration (SEDA-23, 364). The use of epoetin is associated with an increased risk (about 7.5%) of thrombogenicity of vascular prosthetic arterial access for hemodialysis (45 c, 48R). In addition, an increase in cardiac-related deaths has been noted. It has been recommended that in patients with congestive heart failure or ischemic heart disease the hematocrit should not be raised above 42% (45c). Nervous system Hypertension caused by epoetin can result in hypertensive encephalopathy. Reversible posterior leukoencephalopathy syndrome, in which imaging abnormalities are present in the parieto-occipital regions of the brain, is reversible after blood pressure control and withdrawal of epoetin (51 c, 54c). Monitoring of the blood pressure is indicated and the hematocrit should be increased slowly, with a target of not more than 30%. If hypertension and seizures are under control, epoetin therapy can be resumed (5 lC). Seizures have been observed in 3% of patients treated with epoetin (48R). Seizures occur most often during the correction of anemia and are associated with a rapid increase in hemoglobin concentration and poor control of hypertension (48R). Psychiatric Visual hallucinations have been reported (5 lC). Reversible neutropenia and have been observed after epoetin. Iron supplementation is necessary during epoetin treatment. In premature infants treated with enteral epoetin, there was a significant fall in ferritin concentrations despite iron supplementation (55c). Iron deficiency was also a common adverse effect (30%) in children with chronic renal insufficiency treated with epoetin and iron supplementation (53c). In a prospective controlled study, epoetin for elective hip surgery did not activate coagulation and fibrinolysis (56c). Hematologic

lymphocytopenia

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Immunologic Anaphylaxis has been observed after the administration of epoetin that contained bovine gelatine as a stabilizer (44A). Antibovine gelatine IgE antibodies were found. No anaphylactic reaction was observed after the administration of epoetin that contained human serum albumin as a stabilizer in the same patient. Antibodies to epoetin are rare (48R).

Drug administration route It has been advised that epoetin be given subcutaneously rather than intravenously. After subcutaneous administration the systemic availability of epoetin is not complete (20%) and lower plasma concentrations are observed than after intravenous administration. However, pharmacokineric data show that the half-life of epoetin is prolonged after subcutaneous injection, and this allows the use of lower doses to obtain an equivalent hemoglobin concentration (48R). Subcutaneous injections are more effective when given thrice weekly rather than once weekly (48R). Patients with a skin-fold thickness of less than 20 mm at the injection site have a mean reduction in the maintenance dose of 36% when treatment is changed from two injections a week to daily injections (57c). In patients with a thin layer of subcutaneous fat, the diffusion distance of epoetin to bloodstream is shorter than in patients with a thicker layer of subcutaneous fat. Therefore, the diffusion time in lean patients is shorter and the increase in plasma epoetin concentration is more pronounced but of shorter duration after each injection. More frequent injections of reduced amounts of epoetin creates an absorption curve whose area is more congruent with the area of the therapeutic plasma concentration. Usually epoetin is given parentally, but it can also be given orally in premature infants, resulting in a significant increase in plasma epoetin concentration, increased peak reticulocyte counts, and reduced blood transfusion requirements (53 c, 55e). In children undergoing peritoneal dialysis, epoetin is usually given intraperitoneally, resuiting in a similar systemic availability and dosages compared with subcutaneous administration. A follow-up study is required to determine if the risk of peritonitis is increased by intraperitoneal epoetin (58c).

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REFERENCES 1. Tioeng MM, Bartelink AKM, Thijs LG. Exploding the albumin myth. Pharm World Sci 1999; 21: 17-20. 2. Drummond GB, Ludlam CA. Is albumin harmful? Br J Haematol 1999; 106: 266-9. 3. Roberts I, Berger A. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Cochrane Injuries Group Albumin Reviewers. Br Med J 1998; 317: 235-40. 4. Anonymous. Albumin (human)--review of safety: conclusions. WHO Pharm Newslett 1999; 7/8 (Jul-Aug): 1. 5. Remy B, Deby-Dupont G, Lamy M. Red blood cell substitutes: fluorocarbon emulsions and haemoglobin solutions. Br Med Bull 1999; 55: 277-98. 6. Ramaesh K, Bhagat S, Wharton SB, Singh J. Corneal epithelial toxic effects and inflammatory response to perfluorocarbon liquid. Arch Ophthalmol 1999; 117: 1411-13. 7. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999; 45: 1113-19. 8. Leger R, Palm S, Wulf H, Vosberg A, Neppert J. Transfusion-related lung injury with leukopenic reaction caused by Fresh Frozen Plasma containing Anti-NB1. Anesthesiology 1999; 91: 1529-32. 9. Gras V, Andrdjak M, Decocq G. Acute renal failure associated with intravenous immunoglobulins. Pharmacoepidemiol Drug Saf 1999; 8 Suppl 1: 73-8. 10. Iannaccone S, Sferrazza B, Quattrini A, Smirne S, Ferini-Strambi L. Pompholyx (vesicular eczema) after IV immunoglobulin therapy for neurologic disease. Neurology 1999; 53:1154-5. 11. Haskin JA, Warner DJ, Blank DU. Acute renal failure after large doses of intravenous immune globulin. Ann Phannacother 1999; 33: 800-3. 12. Clark AL. Clinical uses of intravenous immunoglobulin in pregnancy. Clin Obstet Gynecol 1999; 42: 368-80. 13. Keohane SG, Kavanagh GM, Gordon PM, Hunter JAA. Transient hypertension during infusion of intravenous gammaglobulin for dermatomyositis. J Dermatol Treat 1999; 10: 2878. 14. Bolanos-Meade J, Keung YK, Cobos E. Recurrent lymphocytic pleural effusion after intravenous immunoglobulin. Am J Hematol 1999; 60: 248-9. 15. Kishiyama JL, Valacer D, CunninghamRundles C, Sperber K, Richmond GW, Abramson S, Glovsky M, Stiehm R, Stocks J, Rosenberg L, Shames RS, Corn B, Shearer WT, Bacot B, DiMaio M, Tonetta S, Adelman DC. A multicenter, randomized, double-blind, placebo-controlled trial of high dose intravenous immunoglobulin for oral corticosteroid-dependent asthma. Clin Immunol 1999; 91: 126-33.

16. A1-Ghamdi H, Mustafa MM, AI-Fawaz I, A1Dowaish A. Acute aseptic meningitis associated with administration of immunoglobulin in children: a case of report and review of the literature. Ann Saudi Med 1999; 19: 362-4. 17. Sztajzel R, Le Floch-Rohr J, Eggimann P. High-dose intravenous immunoglobulin treatment and cerebral vasospasm: a possible mechanism of ischemic encephalopathy? Eur Neurol 1999; 41: 153-8. 18. Berkovitch M, Dolinski G, Tauber T, Aladjem M, Kaplinsky C. Neutropenia as a complication of intravenous immunoglobulin 0VIG) therapy in children with immune thrombocytopenic purpura: Common and non-alarming. Int J Immunopharmacol 1999; 21:411-15. 19. Turner CE, Thorpe SJ, Brasheer MDR, Thorpe R. Anti-Rh D activity of commercial intravenous immunoglobulin preparations. Vox Sang 1999; 76: 55-8. 20. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H. In vivo administration of intravenous immunoglobulin (Wig) can lead to enhanced erythrocyte sequestration. J Autoimmun 1999; 13: 129-35. 21. Laidlaw S, Bainton R, Wilkie M, Makris M. Acute renal failure in acquired haemophilia following the use of high intravenous immunoglobulin. Haemophilia 1999; 5: 270-2. 22. Leclech C, Maillard H, Penisson-Besner I, Lain~-Cessac P, Verret JL. R6action cutan6e inhabitueUe apr~s perfusion intraveineuse d'immunoglobulines polyvalentes. Presse M6d 1999; 28: 531. 23. John R, Lietz K, Burke E, Ankersmit J, Mancini D, Sucik-Foca N, Edwards N, Rose E, Oz M, Itescu S. Intravenous immunoglobulin reduces anti-HCA alloreactivitty and shortens waiting time to cardiac transplantation in highly sensitized left ventricular assist device recipients. Circulation 1999; 100 Suppl 2: 229-35. 24. Chidwick K, Matejtschuk P, Gasco'fgne E, Briggs N, More JE, Dash CH. Clinical experience of a new solvent detergent-treated intravenous immunoglobulin free of hypotensive effects. Vox Sang 1999; 77: 204-9. 25. Ng SKB. Intravenous immunoglobulin infusion causing pseudohyponatremia. Lupus 1999; 8: 48890. 26. Tagariello G, Davoli PG, Gajo GB, De Biasi E, Risato R, Baggio R, Traldi A. Safety and efficacy of high-purity concentrates in haemophiliac patients undergoing surgery by continuous infusion. Haemophilia 1999; 5: 426-30. 27. Lorenzo JI, Montoro JM, Aznar JA. Postoperative use of rFVIIa by continuous infusion in a haemophilic boy. Haemophilia 1999; 5: 135-8. 28. Rochat C, McFadyen ML, Schwyzer R, Gillham A, Cruickshank A. Continuous infusion of intermediate-purity factor VIII in haemophilia A

Blood, blood components, plasma, and plasma products patients undergoing elective surgery. Haemophilia 1999; 5: 181-6. 29. Schulman S, Wallensten R, White B, Smith OP. Efficacy of a high purity, chemically treated and nanofiltered factor IX concentrate for continuous infusion in haemophilia patients undergoing surgery. Haemophilia 1999; 5: 96-100. 30. DellaCroce FJ, Kountakis S, Aguilar III EF. Manifestations of factor VIII inhibitor in the head and neck. Arch Otolaryngol Head Neck Surg 1999; 125: 1258-61. 31. Penner JA. Management of haemophilia in patients with high-titre inhibitors: focus on the evolution of activated prothrombin complex concentrate Autoplex. Haemophilia 1999; 5 Suppl 3: 1-9. 32. Roberts HR. The use of agents that by-pass factor VIII inhibitors in patients with haemophilia. Vox Sang 1999; 77 Suppl 1: 38-41. 33. Shapiro AD. Recombinant factor VIIa: A viewpoint. BioDrugs 1999; 12: 78. 34. Barthels M, Clinical efficacy of prothrombin complex concentrates and recombinant factor VIIa in the treatment of bleeding episodes in patients with factor VIII and IX inhibitors. Thromb Res 1999; 95 Suppl 1: 31-8. 35. Scharrer I. Recombinant factor VlIa for patients with inhibitors to factor VIII or IX or factor VII deficiency. Haemophilia 1999; 5: 253-9. 36. Santagostino E, Gringeri A, Mannucci PM. Home treatment with recombinant activated factor VII in patients with factor VIII inhibitors: the advantages of early intervention. Br J Haematol 1999; 104: 22-6. 37. Zanon E, Zerbinati P, Girolami B, Bertomoro A, Girolami A. Frequent but low titre factor VIII inhibitors in haemophilia A patients treated with high purity concentrates. Blood Coagul Fibrinolysis 1999; 10:117-20. 38. Dunn C J, Spencer CM. Recombinant factor VIIa. Biodrugs 1999; 12: 71-7. 39. Yee Tr, Lee CA. Is a change of factor VIII product a risk factor for the development of a factor VIII inhibitor? Thromb Haemostasis 1999; 81: 852. 40. Seremetis S, Lusher JM, Abildgaard CF, Kasper CK, Allred R, Hurst D, The Kogenate Study Group. Human recombinant DNA-derived antihaemophilic factor (factor VIII) in the treatment of haemophilia A: conclusions of a 5-year study of home therapy. Haemophilia 1999; 5: 9-16. 41. Berntorp E. Other ongoing rFVIII PUP studies. Vox Sang 1999; 77 Suppl 1: 10-12. 42. Parquet A, Laurian Y, Rothschild C, Navarro R, Gu6rois C, Gay V, Durin A, Peynet J, Sultan Y. Incidence of factor IX inhibitor development in severe haemophilia B patients treated with only one brand of high purity plasma derived factor IX concentrate. Thromb Haemostasis 1999; 82: 1247-9. 43. Thorland EC, Drost JB, Lusher JM, Warrier I, Shapiro A, Koerper MA, Dimichele D, Westman J, Key NS, Sommer SS. Anaphylactic response to

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factor IX replacement therapy in haemophilia B patients: complete gene deletions confer the highest risk. Haemophilia 1999; 5: 101-5. 44. Sakaguchi M, Kenada H, Inouye S. A case of anaphylaxis to gelatin included in erythropoietin products. J Allergy Clin Immunol 1999; 103: 349-50. 45. Mingoli A, Sapienza P, Puggioni A, Modini C, Cavallaro A. A possible side-effect of human erythropoietin therapy: thrombosis of peripheral arterial reconstruction. Eur J Vasc Endovasc Surg 1999; 18: 273-4. 46. Klaesson S. Clinical use of rHuEPO in bone marrow transplantation. Med Oncol 1999; 16:2 7. 47. Corwin HL, Gettinger A, Rodriguez RM, Pearl RG, Gubler KD, Enny C, Colton Th, Corwin MJ. Efficacy of recombinant human erythropoietin in the critically ill patient: a randomized, double-blind, placebo-controlled trial. Crit Care Med 1999; 27: 2346-50. 48. Cameron JS, Barany P, Barbas J, Carrera F, Chanard J. European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. Nephrol Dial Transplant 1999; 14: 1-50. 49. Schiffl H, Bergner A. Angiotensin-II, renal anaemia and hyporesponsiveness to recombinant human erythropoietin. Int J Artif Organs 1999; 22: 672-5. 50. Buemi M, Allegra A, Aloisi C, Corica F, Frisina N. Hemodynamic effects of recombinant human erythropoietin. Nephron 1999; 81: 1-4. 51. Van den Bent MJ, Bos GMJ, Sillevis Smitt PAE, Comelissen JJ. Erythropoietin induced visual hallucinations after bone marrow transplantation. J Neurol 1999; 246: 614-16. 52. Kuriyama S, Tomonari H, Hosoya T. Antiplatelet therapy decreases the incidence of erythropoietin-induced hypertension in predialysis patients. Clin Exp Hypertens 1999; 21: 21322. 53. Brandt JR, Avner ED, Hickman RO, Watkins SL. Safety and efficacy of erythropoietin in children with chronic renal failure. Pediatr Nephrol 1999; 13: 143-7. 54. Rodrigo E, San Mill~ha JCR, Heras M, Pifiera C, Fresnedo F, Sanz de Castro S, Martin de Francisco YM, Arias AL. Posterior leukoencephalopathy in erythropoietin induced hypertensive encephalopathy. Neurologica 1999; 19: 3604. 55. Ballin A, Bilker-Reich A, Arbet E, Davidovitz Y, Kohelet D. Erythropoietin, given enterally, stimulates erythropoiesis in premature infants. Lancet 1999; 353: 1849. 56. Hasegawa Y, Takamatsu J, Iwase T, Iwasada S, Kitamura S, Iwata H. Effects of recombinant human erythropoietin on thrombosis and fibrinolysis in autologous transfusion for hip surgery. Arch Orthop Trauma Surg 1999; 119: 384-7. 57. Brahm M. Subcutaneous treatment with recom-

392 binant human erythropoietin: the influence of injection frequency and skin-fold thickness. Scand J Urol Nephrol 1999; 33: 192-6. 58. Kausz AT, Watkins SL, Hansen C, Godwin DA,

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Palmer RB, Brandt JR. Intraperitoneal erythropoietin in children on peritoneal dialysis: A study of pharmacokinetics and efficacy. Am J Kidney Dis 1999; 34: 651-6.

M.C. Allwood

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Intravenous infiasions: solutions and emulsions

PLASMA SUBSTITUTES (SED-14, 1145; SEDA-21, 351; SEDA-22, 371; SEDA-23, 368)

Dextrans Respiratory One of the least common adverse effects of dextrans is characterized by non-cardiogenic pulmonary edema and/or respiratory distress syndrome. A case has been reported postoperatively (1A). A 43-year-old woman underwent delayed breast reconstruction 9 months after modified radical mastectomy and received 4.4 1 of crystalloid intraoperatively. Postoperatively she was given an infusion of dextran 40 preceded by a small dose of dextran 1. On the next two days she was febrile, with no respiratory symptoms, although her oxygen saturation was 83%. On the third day, she was febrile and dyspneic, with a respiratory rate of 29 breaths per minute. Her oxygen saturation fell to 70%. A chest X-ray showed diffuse alveolar infiltration. Dextran was withdrawn. Her lungs worsened, and on day 6 she required intubation for worsening hypoxia, dyspnea, and tachypnea. A chest X-ray showed bilateral alveolar consolidation and other signs consistent with respiratory distress syndrome. Her oxygenation slowly improved and extubation was possible on day 11. Dextran is a polysaccharide that reduces platelet adhesion and aggregation in vivo and has other properties that make it suitable for improving flap survival in microsurgery. However, this case illustrates the risk of adult respiratory distress syndrome, and the authors suggested that the serious nature of this complication in an elective operation calls into question the continued routine use of dextran in microsurgery. 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

Skin Icodextrin and maltodextrin glucose polymer are increasingly being used in continuous ambulatory peritoneal dialysis (CAPD). Until recently, no adverse events relating to icodextrin had been reported. However, a case of severe cutaneous hypersensitivity in a diabetic patient receiving CAPD has now been published (2~). A 50-year-old insulin-dependent diabetic developed end-stage renal insufficiency secondary to diabetic nephropathy, and was treated with standard CAPD containing glucose. About 20 months later she was given 2 1 of icodextrin 7.5% postoperatively and 11 days later complained of pruritus on the lateral aspects of the thigh with erythroderma, which quickly spread to the back, abdomen, arms, hands, and head, followed by a widespread pruritic erythematous macopapular rash, which became exfoliated and psoriasiform. Icodextrin was withdrawn 5 days later and there was rapid healing of the dermatitis, almost completely within 7 days. Rechallenge resulted in recurrence within 2 days. The authors pointed out that previous cases of scaly and exfoliative rashes have been reported several days after starting icodextrin, but these have regressed without the need to withdraw icodextrin, except in one case. They concluded that, given the therapeutic advances made possible by icodextrin, and the extreme rarity of such adverse events, there should be no hesitation in using it in CAPD. The possibility of cutaneous adverse events 10-12 days after starting peritoneal exchange should be borne in mind, although the normal transient nature of such reactions rarely requires withdrawal.

Haemaccel An IgE-mediated anaphylactic reaction to a polygeline (Haemaccel, Hoechst Marion Roussel) has been reported (3A). 393

394 A 33-year-old woman with supraventricular tachycardia and a history of cadaveric renal transplantation for end-stage renal insufficiency, who was taking an immunosuppressant, enalapril, and simvastatin, was given intravenous adenosine and Haemaccel 500 ml. After 30 minutes she developed generalized urticaria. Promethazine and hydrocortisone did not ameliorate her symptoms and an hour later she developed angio-edema of the lips and tongue, but no airway obstruction, bronchospasm, or hypotension. The reaction resolved with subcutaneous adrenaline. Skin prick tests 2 weeks later showed hypersensitivity to Haemaccel but not to latex (a possible contaminant). The authors suggested that the positive skin prick reaction showed that the cause was an IgE-mediated anaphylactic reaction, rather than an anaphylactoid reaction, although this was not confirmed by independent tests.

Hydroxyethyl starch (hetastarch) Hematologic A recent survey of formulations containing hydroxyethylstarch, and particularly Elohes | 6% (molecular weight approximately 200 000) carded out by the French Agency for Health Products has identified eight cases of acquired von Willebrand disease (4c). Three cases were fatal and in two cases there were hematomas with prolongation of the activated cephalin clotting time. All these effects were observed during the administration of Elohes | for vasospasm secondary to meningeal hemorrhage due to rupture of a cerebral aneurysm in patients with no relevant previous history. Duration of treatment of more than 4 days appears to be a risk factor. Nine cases of hepatic overload were also reported, and could cause or aggravate portal hypertension The Agency has announced that the product information for products containing hetastarch will be revised with a contraindication to the use of Elohes | in patients with severe hepatic insufficiency, the stipulation of a maximum dose, a restriction on the duration of treatment, and instructions on the monitoring of hemostasis. Skin Severe intractable pruritus can be a major adverse effect of high doses of hydroxyethyl starch. It is assumed that this effect is caused by large amounts of tissue deposition of hydroxyethyl starch. However, it is not clear if the duration of this tissue storage of hydroxyethyl

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starch is dose-dependent or even if elimination from affected tissues occurs. This latest point has been explored in 26 patients who had received hydroxyethyl starch (varying widely in both dose and duration), including the examination of biopsies from a range of organs (5c). The storage of hydroxyethyl starch was dose- dependent, and fell in all organs over time; tissues deposits were greater in patients with pruritus. The authors concluded that tissue deposition is transitory and dose-dependent, but varies widely between subjects in both severity and duration. This issue has also been investigated using a retrospective postal questionnaire in 100 consecutive intensive care patients who had previously received hydroxyethyl starch (6c). Of 73 patients who replied, 34% had pruritus after discharge, of whom 44% had persistent pruritus that did not resolve with conventional treatments. There was a significant relation between the volume of hydroxyethyl starch infused and the occurrence of pruritus.

Pentastarch Starch derivatives are relatively safer in terms of adverse reactions than other colloid plasma substitutes, although they do carry a small risk of anaphylactoid reactions. What is thought to have been the first such reaction to pentastarch has been reported (7A). A 43-year-old male non-smoker, with a history of asthma, hypertension, and angina pectoris, was admitted to an intensive care unit for mechanical ventilation for acute severe asthma. He was given an inhaled bronchodilator, aminophylline, and prednisolone. His condition improved slowly but he became hypovolemic. Within 60 seconds of a fluid challenge with pentastarch 200 ml he had a severe anaphylactoid reaction. Patients with allergy and atopy have an exaggerated response to chemical mediators released during adverse reactions. The incidence of allergy, atopy, and asthma in patients who have anaphylactic reactions is substantially greater than in non-reacting controls, which may explain this incident. This sudden unanticipated severe reaction demanded immediate intervention and its occurrence in a patient with pre-existing bronchospasm posed problems in maintaining ventilation and oxygenation.

Intravenous infusions: solutions and emulsions

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CONTINUOUS AMBULATORY PERITONEAL DIALYSIS (SED-14, 1149) Serosae One complication of long-term CAPD is peritoneal calcification. The cause is unclear, but it may be associated with multiple bouts of peritonitis combined with hyercalcemia. In one case there was evidence that the effect may be reversible (8A). A 48-year-old women undergoing CAPD had several bouts of peritonitis, with four admissions for treatment between 1988 and 1993. In 1993, moderate amounts of calcification surrounding the small bowel were identified by CT scan, and this progressively increased over the following year. CAPD was discontinued and hemodialysis with a low dialysate calcium concentration was used instead. After a further admission 4 months later, parenteral nutrition was begun. Over the following 3 years, CT scans showed a progressive reduction in the extent of peritoneal calcification surrounding the small bowel. The authors speculated that hemodialysis and long-term parenteral nutrition may result in reversal of peritoneal calcification caused by CAPD.

P A R E N T E R A L NUTRITION (SED-14, 1150; SEDA-21, 353; SEDA-22, 373; SEDA-23, 369) Liver, biliary tract Cholestatic liver disease is a frequent complication of prolonged parenteral nutrition, especially in preterm infants, with an occurrence rate that can approach 60% after 2 weeks of parenteral nutrition. Risk factors include high baseline serum bile acids, reduced hepatic extraction, and an underdeveloped ileal transport system for conservation of bile acids. These lead to a reduced pool of bile acids and consequent exposure of the liver to toxic bile acids. It is aggravated by sepsis, ischemia, necrotizing enterocolitis, or surgery. Parenteral nutrition causes a fall in bile flow and physiological cholestasis, due to less efficient enterohepatic circulation. There is no effective treatment, except for using enteral nutrition as soon as possible. However, the benefits of ursodeoxycholic acid, a naturally occurring non-toxic hydrophilic bile acid, have been evaluated in a retrospective chart review of

395

six infants who received oral ursodeoxycholic acid 15-30 mg/kg/day for at least 1 month (9c). Ursudeoxycholic acid was safe and led to some early reduction in bilirubin concentrations, although there was no improvement in other markers of liver function. Clearly, the possible benefits have yet to be firmly established. Other recent studies have underlined the current importance of this adverse effect of parenteral nutrition. In a retrospective survey of the incidence of liver dysfunction in 94 children (mean age 5 years) receiving parenteral nutrition over 2 years, liver disease was identified in over 50% of cases, with a nadir during the second week of parenteral nutrition (10c). The most closely associated factors were length of parenteral nutrition and sepsis. In premature low birth-weight infants hepatobiliary dysfunction with histological changes has been attributed to parenteral nutrition (1 leE). Nutrition Linoleic acid and t~-linoleic acid are essential fatty acids that are provided in any long-term parenteral nutrition by administering fat emulsions at least twice a week. Fatty acid deficiency is a common complication of severe end-stage liver disease. The ability of short-term intravenous lipid supplementation to reverse fatty acid deficiencies has been studied in patients with chronic liver disease and low plasma concentrations of fatty acids (12c). Short-term supplementation failed to normalize triglycerides.

Glutamate Animal studies have shown that raised plasma glutamate concentrations increase cerebral edema whenever the bloodbrain barrier is disturbed. In a prospective study of 23 neurosurgical patients requiting parenteral nutrition, glutamine-containing regimens were compared with parenteral nutrition regimens that excluded glutamine (13c). The former doubled plasma glutamine concentrations compared with controls, and the authors concluded that glutamine-containing solutions cannot be recommended for patients with a disturbed blood-brain barrier. Thiamine Another case of thiamine deficiency has been reported (14A). Parenteral nutrition was used to support a patient requiring autologous blood stem-cell transplantation, but vitamins were excluded (the reason was not identi-

396 fled). After about 28 days, the patient suddenly developed severe metabolic acidosis, heart failure, and deep coma. Thiamine was immediately infused, with rapid improvement. The authors were unsure if the associated graft failure was due to the acute metabolic acidosis or thiamine deficiency, since the absence of thiamine in the diet leads to poor glucose oxidation, resulting in accumulation of lactic acid and metabolic acidosis, which is refractory to any treatment except thiamine supplementation. Electrolyte balance Electrolyte deficiencies are a constant concern for patients with chronic renal insufficiency who receive parenteral nutrition. Such patients commonly require reduced phosphate or even no phosphate in their diet, and so hypophosphatemia is common. This subject has received continued attention recently, resulting in the need to recognize the importance of maintaining awareness of the possibility of low phosphate concentrations, monitoring phosphate concentrations closely during the first week of therapy, and supplementing with phosphate cautiously while serum concentrations remain in the reference range (15 c, 16c). Metal metabolism Copper Copper deficiency has been reported in a patient with Crohn's disease after removal of copper from the parenteral nutrition because of severe cholestasis (17A). The patient developed pantocytopenia with severely depressed serum copper concentrations after 8 weeks. Bonemarrow biopsy confirmed the cause as copper deficiency. Although intravenous replacement of copper improved the patient's anemia and other markers, he suddenly died of cardiac tamponade.

Manganese Concerns about high serum manganese concentrations in patients receiving parenteral nutrition continue to be voiced. Hypermanganesemia after parenteral nutrition was first reported about 5 years ago and was linked to portosystemic encephalopathy. Patients with liver disease were particularly at risk. Manganese deposition in the brain has been reported after 28 days of parenteral nutrition including manganese 20 Ixmol/day (18At). The serum manganese concentration was raised (4.9 Ixmol/1) 34 days postoperatively, 13 days after stopping parenteral nutrition. MRI scans

Chapter 34

M.C.Allwood

showed symmetrical hyperintense lesions in the globus pallidus, which gradually improved as serum manganese concentrations fell to normal. The authors concluded that even short-term perioperative parenteral nutrition can result in manganese deposition, especially if there is liver impairment. The relation between dose and erythrocyte concentrations of manganese has been studied in patients receiving parenteral nutrition for periods varying from a few days to many months (19c). All the patients received manganese 500 ixmol/day. While concentrations during short-term parenteral nutrition were normal, patients who had been receiving parenteral nutrition for up to 30 days showed evidence of raised concentrations. Of 21 patients who had been receiving parenteral nutrition for over 1 month, 15 had raised erythrocyte manganese concentrations, although in this group there was no clear relation with liver test abnormalities or renal function. In three patients there was evidence of neurological damage. The authors recommended ~hat all patients receiving parenteral nutrition for more than 30 days should be monitored for serum manganese concentrations, that the recommended dose of manganese should not exceed 100 Ixg/day, and that manganese should be eliminated from nutrition solutions when the serum concentration is raised. The authors also recommended that manganese should not be added to parenteral nutrition solutions for patients with chronic liver disease. The possible link between hypermanganesemia and cholestasis has been investigated in patients receiving long-term parenteral nutrition (20c). The author concluded that cholestatic liver disease does not contribute to increased blood manganese concentrations in such patients, and that plasma concentrations reflect recent manganese exposure and impaired excretion when cholestasis is present. They also emphasized that sermn concentrations are a poor marker and that erythrocyte manganese concentrations should be used instead.

Selenium The signs of selenium deficiency include skeletal myopathy and cardiomyopathy, and selenium deficiency continues to be reported in cases in which this essential element has not been added to parenteral nutrition solutions during long-term administration (21c).

Intravenous infusions: solutions and emulsions

Chapter 34

D r u g interactions Infants of very low birth weight have reduced tolerance to intravenous fat emulsions, with consequent hyperlipidemia. Since glucocorticoids are often used to prevent or treat chronic lung disease, and since they can cause hypedipidemia, this potential drug interaction has been investigated in a randomized

397

double-blind trim (22c). The results supported the hypothesis that dexamethasone increases triglyceride serum concentrations, and the authors recommended that low birth-weight infants who are receiving both dexamethasone and fat emulsion should be monitored carefully for signs of impairment of lipid tolerance.

REFERENCES 1. Hein KD, Wechsler ME, Schwartzstein RM, Morris DJ. The adult respiratory distress syndrome after dextran infusion as an antithrombotic agent in free TRAM flap breast reconstruction. Plast Reconstr Surg 1999; 103: 1706-8. 2. Queffeulou G, Bernard M, Vrtovsnik F, Skhiri H, Lebrun-Vigne B, Hufnagel G, Michel C, Mignon E Severe cutaneous hypersensitivity requiring permanent icodextrin withdrawal in a CAPD patient. Clin Nephrol 1999; 51: 18445. 3. Chew GY, Phan TG, Quin JW. Anaphylactic or anaphylactoid reaction to Haemaccel? Med J Aust 1999; 171: 387-8. 4. Anonymous. Hetastarch (hydroxyethylstarch)--fatal haemorrhages. WHO Pharm Newslett 1999; 7/8 (Jul-Aug): 2. 5. Sirtl C, Laubenthal H, Zumtobel V, Kraft D, Jurecka W. Tissues deposits of hydroxyethyl starch (HES): dose-dependent and time related. Br J Anaesth 1999; 82: 510-15. 6. Sharland C, Huggett A, Nielson MS, Friedmann PS. Persistent pruritus after pentastarch infusions in intensive care patients. Anaesth 1999; 54: 500-1. 7. Kannan S, Milligan KR. Moderately severe anaphylactoid reaction to pentastarch (200/0/5) in a patient with severe asthma. Intensive Care Med 1999; 25: 220-2. 8. Najem ES, Webel M, Ailinani JM. Reversibility of peritoneal calcification in a dialysis patient maintained on hemodialysis and total parenteral nutrition. Am J Roentgenol 1999; 172: 247-8. 9. Levine A, Maayan A, Shamir R, Dinari G, Sulkes J, Sirotta L. Parenteral nutrition-associated cholestasis in preterm neonates: evaluation of ursodeoxycholic acid treatment. J Pediatr Endocrinol Metab 1999; 12: 549-53. 10. Moreno Villares JM, Gomis Munoz, P, Galiano Segovia MJ, Serrano Garrote O, Leon Sanz M. Complicaciones hepaticas asociadas a nutricion parenteral de corto duracion en nifios. Ann Esp Pediatr 1999; 51: 2245. 11. Loft S, Kranxlin B, Moghadam M, Dzakovic A, Wessel L, Back W, Hosie S, Witth H, Waag K-L. Parenteral nutrition-induced hepatobiliary dysfunction in infants and prepubertal rabbits. Pediatr Surg 1999; 15: 479-82. 12. Duerksen DR, Nehra V, Palombo JD, Ahmad A, Bistrian BR. Essential fatty acid deficiencies in patients with chronic liver disease are not reversed by

short-term intravenous lipid supplementation. Dig Dis Sci 1999; 44: 1342-8. 13. Stover JF, Kemski OS. Glutamate-containing parenteral nutrition doubles plasma glutamate: a risk factor in neurosurgical patients with bloodbrain barrier damage? Crit Care Med 1999; 27: 225245. 14. Sawada M, Tsurumi H, Hara T, Goto H, Yamada T, Oyama M, Moriwaki H. Graft failure of autologous peripheral blood stem cell transplantation due to acute metabolic acidosis associated with total parenteral nutrition in a patient with relapsed breast cancer. Acta Haematol 1999; 102: 1579. 15. Druml W, Kleinberger G. Hypophosphatemia in patients with chronic renal failure during total parenteral nutrition. J Parenter Enter Nutr 1999; 23: 45. 16. Duerksen DR, Papineau N. Response to Drs Druml and Kleinberger. J Parenter Enter Nutr 1999; 23: 46. 17. Spiegel JE, Willenbucher E Rapid development of severe copper deficiency in a patient with Crohn's disease receiving parenteral nutrition. J Parenter Enter Nutr 1999; 23: 169-72. 18. Kondoh H, Iwase K, Higaki J, Tanaka Y, Yoshikawa M, Hori S, Osuga K, Kamike W. Manganese deposition in the brain following parenteral manganese administration in association with radical operation for esophageal cancer: report of a case. Surg Today 1999; 29: 77345. 19. Fitzgerald K, Mikalunas V, Rubin H, McCarthy R, Vanagunas A, Craig RM. Hypermanganesemia in patients receiving total parenteral nutrition. J Parenter Enter Nutr 1999; 23: 33345. 20. Wardle CA, Forbes A, Roberts NB, Jawhari AV, Shenkin A. Hypermanganesemia in long-term intravenous nutrition and chronic liver disease. J Parenter Enter Nutr 1999; 23: 350-5. 21. Ishihara H, Kanda F, Matsushita T, Chihara K. White muscle disease in humans: myopathy caused by selenium deficiency in anorexia nervosa under long term total parenteral nutrition. J Neurol Neurosurg Psychiatry 1999; 67: 829-30. 22. Sentipal-Walerius J, Dollberg S, Mimouni F, Doyle J, Gilmour C. Effect of pulsed dexamethasone therapy on tolerance of intravenously administered lipids in extremely low birth weight infants. J Pediatr 1999; 134: 229-32.

K. Peerlinck and J. Vermylen

35

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

COUMARIN CONGENERS (SED-14, 1181; SEDA-21, 358; SEDA-22, 386; SEDA-23, 377) Liver Hepatotoxicity due to oral anticoagulants is rare. Only a few cases, generally presenting as cholestatic hepatitis, have been reported. Subacute liver failure necessitating orthotopic liver transplantation after treatment with phenprocoumon in a 39-year-old woman has been reported (1A ). A 39-year-old woman developed idiopathic thrombosis of the posterior tibial vein. Oral contraceptives and resistance to activated protein C were identified as risk factors. After initial treatment with intravenous heparin, she was given phenprocoumon and the oral contraceptive was withdrawn. After 4 months she developed subacute liver failure and phenprocoumon was withdrawn immediately. Autoimmune disease, viral hepatitis, toxic causes, and Budd~hiari syndrome were excluded. Despite symptomatic treatment she deteriorated further and orthotopic liver transplantation was performed. Histopathology of the explanted liver further excluded ischemic liver cell necrosis and Budd42hiari syndrome. Drug interactions Interactions between coumarin derivatives and miconazole have been reported, although the mechanism of the interaction is not known. Two separate reports of potentiation of the anticoagulant effect of acenocoumarol by nonsystemic administration of miconazole have appeared. Three patients taking long-term acenocoumarol who used miconazole gel for oral candidiasis had significant rises in INR (2A). In two other patients vaginal miconazole potentiated the anticoagulant effect of acenocoumarol (3A). 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed. 398

DRUGS THAT ALTER PLATELET FUNCTION

Dipyridamole

(SED-14, 1698;

SEDA-22, 387) The Food and Drug Administration has withdrawn conditional approval for certain drug products containing dipyridamole, because there is a lack of sufficient evidence that these drugs are effective in the long-term therapy of angina pectoris (4R). Cardiovascular

Two

cases

of

severe

bradydysrhythmias (one complete heart block, one sinus bradycardia) have been described after intravenous dipyridamole (5c). Nervous system In the Second European Stroke Prevention Study headaches associated with dipyridamole (in 8% of patients taking dipyridamole or dipyridamole + aspirin vs 2% of patients taking aspirin alone or placebo) frequently led to discontinuation of therapy. The predicting factors for headaches have been explored in a recent study of the bioequivalence of two formulations of dipyridamole 200 mg in a modified-release combination with aspirin 25 mg (6r). The conclusion was that the rapid fall in the incidence of headaches over time implied that most patients quickly develop tolerance to dipyridamole-associated headaches. However, in the European Stroke Prevention Study 2, headache was the most common adverse event, and it occurred more often in dipyridamole-treated patients (7R). Immunologic Infusion of dipyridamole caused an acute allergic reaction during myocardial scintigraphy (8A).

Drugs affectingbloodcoagulation,fibrinolysis, and hemostasis A 56-year-old man with a history of allergy to aspirin, tetracycline, and penicillin, including angioedema and dyspnea, was given a dipyridamole stress test. About l minute after the infusion was started he reported periorbital pruritus. The infusion was completed uneventfully with the administration of 99mtechnetium sestamibi at 7 minutes. Twenty minutes later he had tightness in the neck, dyspnea, and generalized facial swelling. He was given oxygen and intravenous promethazine hydrochloride and hydrocortisone. He improved over the next 2 hours, with residual periobital edema but complete recovery from the respiratory symptoms. The cardiac study was completed without further events. The result was normal.

Clopidogrel (SED-14, 1194; SEDA-21, 359; SEDA-22, 387; SEDA-23, 378) By active surveillance by medical directors of blood banks, hematologists, and the manufacturers of clopidogrel, 11 patients were identified in whom thrombotic thrombocytopenic purpura developed during or soon after treatment with clopidogrel (9c). Ten of the 11 patients had taken clopidogrel for 14 days or less before the onset. From this study it is not possible to calculate the frequency of thrombotic thrombocytopenic purpura, since the size of the population from which the 11 cases were drawn is unknown.

Ticlopidine (SED-14, 1193; SEDA-21, 359; SEDA-22, 387; SEDA-23, 378) In 43 322 patients treated with coronary stents and ticlopidine for 1 year there were nine cases of thrombotic thrombocytopenic purpura (0.02%) (10c). The risk of thrombotic thrombocytopenic purpura during the use of ticlopidine after coronary stenting was 50-fold higher than in the general population. Ten other cases of thrombotic thrombocytopenic purpura related to ticlopidine were identified from the participating centers. Four of the 19 patients died, and all four deaths occurred in patients who were not treated with plasmapheresis. The authors stressed that early recognition and treatment is crucial for minimizing mortality.

Chapter35

399

ANTIFIBRINOLYTIC DRUGS

Aprotinin

(SED-14, 1209; SEDA-22, 387; SEDA-23, 378) The sera of 150 patients who had undergone cardiac surgery and were receiving aprotinin for the first time have been studied before and after the operation. At 3.5 months after surgery the prevalence of aprotinin-specific IgG antibodies was 33% (15/45) after local, 28% (13/46) after intravenous, and 69% (41/59) after combined exposure (11c). The authors concluded that local administration of aprotinin induces a specific immune response and reinforces that of intravenous exposure; they therefore recommended that any exposure in a patient should be documented.

Epsilon-aminocaproic acid (SED-14, 1193) Two different case reports have dealt with previously unreported adverse effects of aminocaproic acid in patients with renal insufficiency. One patient with underlying chronic renal insufficiency, who underwent coronary bypass artery grafting and was treated with intravenous aminocaproic acid, developed hyperkalemia (6.7 mmol/l) (12A). There was no other obvious cause for the acute increase in serum potassium. The authors suggested that the structural similarity between aminocaproic acid and lysine and arginine underlies the mechanism of hyperkalemia; intravenous arginine can cause hyperkalemia (13 A, 14A). Furthermore, aminocaproic acid infusion in anephric dogs caused a rapid rise in serum potassium (15E). A patient has also been described with a nigh anion gap metabolic acidosis related to infusion of aminocaproic acid, which temporarily corrected during bemodialysis and resolved on withdrawal of the drug (16A).

THROMBOLYTIC AGENTS (SED-14, 1187; SEDA-21, 359; SEDA-22, 387; SEDA-23, 378) A case of an anaphylactic reaction to intravenous alteplase has been described (17 A).

400 A 70-year-old woman was treated with intravenous alteplase for thrombolysis in acute ischemic stroke and 30 minutes later had acute sinus tachycardia and hypotension, followed by cyanosis and loss of consciousness. Serum samples analyzed by ELISA were positive for IgE antibodies to alteplase.

Chapter 35

K. Peerlinck and J. Vermylen

This is the first report of an anaphylactic reaction to alteplase that has been confirmed by identification of specific IgE antibodies. Such reactions are very r a r e - - f o u r reported cases in over 1 million administrations.

REFERENCES 1. Mix H, Wagner S, Boker K, Gloger S, Oldhafer KJ, Behrend M, Flemming P, Manns ME Subacute liver failure induced by phenprocoumon treatment. Digestion 1999; 60: 579-82. 2. Ortin M, Olalla JI, Muruzabal MJ, Peralta FG, Gutierrez MA. Miconazole oral gel enhances acenocoumarol anticoagulant activity. Ann Pharmacother 1999; 33: 175-7. 3. Lansdorp D, Bressers HPHM, Dekens-Konter JAM, Meyboom RHB. Potentiation of acenocoumarol during vaginal administration of miconazole. Br J Clin Pharmacol 1999; 47: 225-6. 4. Anonymous. Dipyridamole--withdrawn. WHO Pharm Newslett 1999; 5/6 (May-Jun): 2. 5. Bielen M, Karsera D, Melon E Kulbertus H. Severe bradyarrhythmias after dipyridamole injection. Rev Med Liege 1999; 54: 105-8. 6. Theis JGW, Deichsel G, Marshall S. Rapid development of tolerance to dipyridamole-associated headaches. Br J Clin Pharmacol 1999; 48: 750-5. 7. Diener H, Cunha L, Forbes C, Sirenius J, Smets P, Lowenthal A. European stroke prevention study 2. Nervenheilkunde 1999; 18: 380-90. 8. Angelidis S, Van der Wal H, Freedman SB. Acute reaction to dipyridamole during myocardial scintigraphy. New Engl J Med 1999; 340: 394. 9. Bennett CL, Connors JM, Carwile JM, Moake JL, Bell W, Tarantolo SR, McCarthy LJ, Sarode R, Hatfield AM, Feldman MD, Davidson CJ, Tsai

H-M. Thrombotic thrombocytopenic purpura associated with clopidogrel. New Engl J Med 2000; 342: 1773-7. 10. Steinhubl SR, Tan WA, Foody JM, Topoi EJ. Incidence and course of thrombotic thrombocytic purpura due to ticlopidine following coronary stenting. J Am Med Assoc 1999; 281: 806-10. 11. Scheule AM, Beierlein W, Wendel HP, Jurmann M J, Eckstein FS, Ziemer G. Aprotinin in fibrin tissue adhesives induces specific antibody response and increases antibody response of high-dose intravenous application. J Thorac Cardiovasc Surg 1999; 118: 348-53. 12. Perazella MA, Biswas P. Acute hyperkalemia associated with intravenous epsilon-aminocaproic acid therapy. Am J KidneyDis 1999; 33: 782-5. 13. Hertz P, Richardson JA. Arginine-induced hyperkalemia. Arch Intern Med 1972; 130: 778-80. 14. Buchinsky DA, Gennari FJ. Life-threatening hyperkalemia induced by arginine. Arch Intern Med 1978; 89: 632--4. 15. Caroll HJ, Tice DA. The effects of epsilon aminocaproic acid upon potassium metabolism in the dog. Metabolism 1966; 15: 449-57. 16. Budris WA, Roxe DM, Duvel JM. High anion gap metabolic acidosis associated with aminocaproic acid. Ann Pharmacother 1999; 33: 30811. 17. Rudolf J, Grond M, Prince WS, Schmulling S, Heiss W-D. Evidence of anaphylaxy after alteplase infusion. Stroke 1999; 30: 1142-3.

H.J. De Silva

36

Gastrointestinal drugs

ANTIEMETICS

Cisapride

(SED-14, 1223; SEDA-21, 361; SEDA-22, 389; SEDA-23, 380) The effect of cisapride 20 mg bd for 7 days in preventing symptoms of gastro-esophageal reflux disease induced by a provocative meal has been assessed in 122 patients who had had symptoms suggestive of gastro-esophageal reflux for at least 3 months (lC). Cisapride prevented or reduced the symptoms of heartburn and related symptoms, such as belching and regurgitation. Mild to moderate diarrhea was the main adverse effect. Cardiovascular Several studies have corroborated the finding of QT interval prolongation during cisapride therapy in children. The effects of cisapride on the QTc interval, heart rate, and cardiac rhythm have been reported in a controlled study of 83 infants aged 2-54 months receiving cisapride for a minimum of 4 days for gastro-esophageal reflux and 77 controls, using continuous bipolar limb lead electrocardiography for 8 hours (2c). The QTc interval was significantly prolonged by cisapride in infants under 3 months old. There was no significant difference in heart rates and there were no dysrhythmias. None of the infants was receiving drugs that inhibit the hepatic metabolism of cisapride via CYP3A4. Prolongation of the QT interval by cisapride can result in life-threatening dysrhythmias, and over 30 drugs and other substances (e.g. grapefruit juice) can cause interactions that can enhance this effect. Despite regulatory action, including strengthened warnings in the product information, reports of dysrhythmias have continued to appear. The Medicines Con-

9 2000 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual23 J.K. Aronson, ed.

trol Agency in the UK has therefore suspended the product licences for cisapride; the European Committee for Proprietary Medicinal Products is also reviewing what the indications for cisapride should be, if any (3r).

Clebopride

(SED-14, 1223)

Clebopride can cause extrapyramidal syndromes, ranging from transient dyskinesia to persistent parkinsonism and tardive dykinesia. Extrapyramidal symptoms associated with clebopride have been reported in two 17year-old patients within 10-16 hours of taking clebopride 0.5 mg tds (4A).

Domperidone

(SED-14, 1224; SEDA-22, 389; SEDA-23, 381)

The efficacy and adverse effects of domperidone and metoclopramide have been compared in a double-blind, multicenter, randomized trial in 93 insulin-dependent diabetics with symptomatic gastroparesis (5c). Domperidone 20 mg qds and metoclopramide 10 mg qds, for 4 weeks, were equally effective in alleviating symptoms of gastroparesis. Somnolence, akathisia, anxiety, and depression were more severe with metoclopramide. Of the spontaneously reported adverse effects, nausea, vomiting, headache, insomnia, and diarrhea occurred in 6-10% of patients treated with domperidone and in up to 4% of patients treated with metoclopramide. The incidence of prolactin-related adverse effects was similar in the two groups (6%).

5-HT3 receptor antagonists (SED-14, 1225; SEDA-22, 390; SEDA-23, 381) The safety and efficacy of the selective 5HT3 receptor antagonist alosetron in the treatment of irritable bowel syndrome has been reviewed (6R). In patients with irritable bowel 41)1

402 syndrome alosetron increases colonic transit time and colonic compliance. It produces significant improvements in abdominal pain, stool consistency, frequency, and urgency in nonconstipated women with irritable bowel syndrome, but not in men. Alosetron appears to be safe and well tolerated. Constipation is the most common adverse effect. It occurs more commonly at higher doses and is more common in women, which is consistent with reported bowel function data. The antiemetic efficacy of tropisetron has been confirmed in 22 children (median age 14 years) who received a total of 125 courses of highly emetogenic chemotherapy (7c). The only reported adverse effects attributable to tropisetron were mild diarrhea during two treatment courses and dry mouth during three courses.

Chapter 36

H.J. De Silva

was significantly more effective than placebo and provided prompt relief of heartburn lasting up to 12 hours. The most common adverse effects were nausea, diarrhea, and headache, which occurred in under 2% of patients in each group. Different doses of ~'anitidine (150 mg bd and 300 mg bd for 8 weeks) have been compared in resolving heartburn in 271 patients with gastro esophageal reflux disease who had been symptomatic after 6 weeks of therapy with ranitidine 150 mg bd (1 lC). Less .than 20% of the patients in either group had complete resolution of heartburn at 4 and 8 weeks; there was no significant difference in the efficacy between the two treatment groups. At least one adverse event was reported by 38% of the patients in each group. They included sinusitis, nausea,

abdominal pain, dyspepsia, constipation, and increased liver enzymes.

HISTAMINE H2 RECEPTOR (SED-14, 1225; SEDA-21, 362; SEDA-22, 391; SEDA 23, 382) ANTAGONISTS

Cimetidine Cimetidine has rarely been reported to cause hepatic encephalopathy. Cimetidine-induced hyperammoniacal encephalopathy has been reported in a previously healthy 44-year-old man who had taken cimetidine 400 mg/day for four days; he recovered completed after drug withdrawal (8A).

Drug interactions Cimetidine can interact with other drugs by inhibiting hepatic cytochrome P450. A 41-year-old man developed an intramural hematoma of the small bowel through potentiation of the action of acenocoumarol by cimetidine 800 mg/day for esophagitis (9A). He had been stable while taking acenocoumarol 2 mg/day for a prosthetic aortic valve for several years.

Ranitidine The efficacy of low-dose ranitidine for the relief of heartburn has been studied in a double-blind placebo-controlled trial (10c). Subjects with heartburn were randomized to ranitidine 75 mg (n = 491), ranitidine 25 mg (n = 504), or placebo (n = 494), to be taken as needed up to four times a day for 2 weeks. Ranitidine 75 mg

PROTON PUMP INHIBITORS (SED-14, 1230; SEDA-21, 363; SEDA-22, 391; SEDA 23, 383) Lansoprazole 15 mg/day and omeprazole 10 mg/day for 4 weeks have been compared in the relief of heartburn and epigastric pain in a randomized, double-blind, parallel-group study in 609 patients with acid-related dyspepsia (12c). Low-dose lansoprazole was more effective in controlling symptoms. There were no significant differences in adverse events between the two groups, although there was a trend towards a higher incidence of more severe adverse events with omeprazole. Most of the reported adverse events were difficult to relate to the treatments. An unblinded questionnaire survey has been carried out to determine patients' perceptions of differences in the efficacy, adverse effects, and value of omeprazole vs lansoprazole for gastroesophageal reflux disease maintenance therapy (13c). The patients had been taking omeprazole for at least 2 months and then switched to lansoprazole for a minimum of 2 months. There was no significant difference between median symptom scores with the two drugs, but 64% of patients preferred omeprazole to lansoprazole. The most commonly reported adverse effects with both drugs were flatulence, headache, and diarrhea. Significantly more patients repor-

Gastrointestinal drugs

Chapter36

ted adverse effects with lansoprazole than with omeprazole. Rabeprazole 20 mg/day has been compared with omeprazole 20 mg/day in a randomized, double-blind, multicenter study in 205 patients with active duodenal ulcers (14c). Rabeprazole produced healing rates equivalent to omeprazole at 2 and 4 weeks of treatment (69 vs 61% and 98% vs 93% respectively) and greater improvement in day-time pain. Both drugs were well tolerated; adverse effects were similar, and included headache, infections,

diarrhea, gastritis, stomatitis, rash, and sweating. Serum gastrin concentrations increased over time in both groups. There was a statistically significant difference between the groups in the mean change in fasting serum gastrin from baseline to endpoint; +39.8 pg/ml with rabeprazole and +18.9 pg/ml with omeprazole. However, mean values at the end of the study were in the reference range in both groups. Rabeprazole 20 mg/day and omeprazole 20 mg/day have been compared in the treatment of erosive or ulcerative esophagitis in a double-blind multicenter study in 202 patients (15 C). Overall healing rates for rabeprazole and omeprazole at 4 and 8 weeks of treatment were equivalent (81% vs 81% and 92% vs 94% respectively), as was symptom relief. Both drugs were well tolerated, and there was no significant difference in reported adverse events, except for flatulence, which was only reported by patients taking omeprazole (4%). Other adverse effects included headache, diarrhea,

rash, flu-like syndrome, gastroenteritis, raised AsT and gammaglutamyltransferase, weakness, myalgia, somnolence, and hypertension. Serum gastrin concentrations increased over time in both groups; however, there was no significant difference between the treatment groups in the mean change in fasting serum gastrin concentrations from baseline to endpoint. Omeprazole produces a higher intragastric pH in the presence of Helicobacter pylori than after eradication. The mechanism of this effect is unclear, but possible explanations are reduced production of ammonia or other neutralizing substances after eradication of the infection or the development of gastritis during omeprazole therapy in the presence of H. pylori, leading to reduced acid secretion. In a doubleblind, cross-over study in 13 subjects with H. pylori, pumaprazole (BY841) 100 mg bd, a reversible proton pump inhibitor, which (unlike

403 omeprazole) does not require activation in the acid compartment of the parietal cell, produced a similar rise in intragastric pH to that produced by omeprazole before and after eradication of H. pylori (16c). Adverse events during the study were mild and assessed as probably not related to the drugs. They included headache,

abdominal pain, and diarrhea. Serum gastrin concentrations rose during pumaprazole therapy and were higher than during omeprazole therapy, both before and after eradication of H.

pylori. Lansoprazole 30 mg/day, lansoprazole 15 mg/day, and ranitidine 150 mg/day have been compared in a randomized, double-blind, multicenter trial in the prevention of relapse of duodenal ulcer and symptom control over 12 months in 359 patients (17c). Both doses of lansoprazole were superior to ranitidine. There was no significant difference between the two lansoprazole groups, although there was a trend in favor of lansoprazole 30 mg/day. There were no differences in adverse effects profiles in the three groups. The adverse effects included

diarrhea, abdominal pain, viral infections, headache, and vomiting.

Omeprazole Liver Acute hepatitis has been attributed to omeprazole (18A). A 34-year-old woman developed jaundice 11 days after starting to take omeprazole for ulcer dyspepsia. Her liver function tests suggested acute hepatitis with large rises in transaminases. Investigations excluded virus infections, autoimmune disorders, copper overload, and alpha 1 antitrypsin deficiency. On withdrawal of omeprazole, A1T and AsT activities gradually normalized.

Hematologic Cases of agranulocytosis in a kidney transplant recipient (19 A) and of

neutropenia (20 A) have been associated with omeprazole. Immunologic Two cases of angio-edema and two cases of anaphylaxis due to omeprazole have previously been documented and anaphylaxis has again been reported (21A). A 35-year-old alcoholic with pancreatitis developed anaphylaxis after an intravenous infusion of omeprazole. He had raised serum tryptase activity 6 hours after the onset of anaphylaxis. Total serum IgE concentrations were also raised. Intradermal tests 2

Chapter 36

404 months later were positive for both omeprazole and lansoprazole, suggesting cross reactivity.

OTHER ULCER-HEALING AGENTS

Sucralfate

(SED-14, 1233; SEDA-21, 364;

SEDA-22, 392) Sucralfate is a drug that can form bezoars. The French System of Pharmacovigilance on sucralfate has reported bezoars in 16 adults and five neonates (22CR). All the children were of low birth weights and developed bezoars in the stomach. Adults developed esophageal bezoars around nasogastric tubes. The risk factors for bezoar formation were severe illness, gut hypomotility, dehydration, overdosage with sucralfate, and nasogastric tube feeding. At a pH below 4, there is extensive polymerization of sucralfate, and a sticky viscid gel is formed, which may lead to the formation of a bezoar. In view of this report, it has been recommended that sucralfate be used with caution in premature babies and in adults in intensive care who are being fed via a nasogastric tube.

H e l i c o b a c t e r p y l o r i eradication regimens (SEDA-21, 362; SEDA-22, 392; SEDA 23, 384) Although the best regimen for the eradication of H. pylori is yet to be established, there is wide agreement that eradication is best achieved with a combination of gastric acid suppression (a proton pump inhibitor or an H2 receptor antagonist) and two antibiotics from among metronidazole, amoxicillin, clarithromycin, and tinidazole--so-called triple therapy regimens. Bismuth can also be used in combination with antibiotics instead of a proton pump inhibitor. The duration of treatment is usually lweek. Adverse effects relate to the individual drugs. The MACH-2 study has assessed the role of omeprazole in triple therapy in 539 patients with duodenal ulcers associated with H. pylori (23c). The addition of omeprazole resulted in significantly higher eradication rates (over 90%) than antibiotics alone (amoxicillin plus clarithromycin about 25%; clarithromycin plus metronidazole 70%), and reduced the impact of primary resistance to metronidazole. About

H.J. De Silva

one-third of the patients who took amoxicillin reported diarrhea/loose stools. The frequency of taste disturbance was dose-dependent with clarithromycin. Increased liver enzymes were more commonly reported in those taking metronidazole. The addition of omeprazole did not increase the frequency of reported adverse effects. The DU-MACH study assessed the efficacy of two omeprazole-based triple therapies (omeprazole, amoxicillin, clarithromycin vs omeprazole, metronidazole, clarithromycin) given for 1 week to 149 patients for eradicating H. pylori, healing duodenal ulcers, and preventing ulcer relapse over 6 months after treatment (24c). Both regimens achieved high eradication rates (about 90%) and were well tolerated. Adverse effects were similar in the two groups, and included diarrhea, taste disturbance, headache, nausea, and dyspepsia. Ranitidine 300 mg bd and omeprazole 20 mg bd have been compared as components of triple therapies (combining them with either amoxicillin plus clarithromycin or amoxicillin plus metronidazole) in 320 patients with H. pylori (25c). Omeprazole and ranitidine combined with two antibiotics for 1 week were equally effective in eradicating H. pylori. This result questions the role of profound acid suppression in the eradication of H. pylori. There was no difference in the reported adverse effects, which included nausea, vomiting, diarrhea, metallic taste, skin rashes, and headache. In a similar study in 221 patients with peptic ulcer disease associated with H. pylori, rabeprazole has been compared to omeprazole and lansoprazole (combining them with amoxicillin plus clarithromycin for 1 week) (26c). Rabeproazole was as effective as omeprazole and lansoprazole in eradicating H. pylori (8488% each). There were no differences in reported adverse events. Common adverse effects were soft stools, glossitis, taste disturbances, and skin rashes. Dual therapy (omeprazole plus clarithromycin) for 2 weeks has been compared with triple therapy (omeprazole plus amoxicillin and clarithromycin) for 1 week in the eradication of H. pylori in 145 patients with duodenal ulcers (27c). Triple therapy was significantly more effective in eradicating H. pylori (71 vs 48%). There were no significant differences in compliance or adverse effects. The most frequent

Gastrointestinal drugs

Chapter 36

adverse effects were metallic taste and nausea in the dual-therapy group and metallic taste, miM abdominal pain, and diarrhea in the tripletherapy group. Quadruple therapy (omeprazole, amoxicillin, roxithromycin, and metronidazole for 1 week) has been studied in an open trial in 169 patients with H. pylori (28c). This regimen achieved an eradication rate of 92%. It was also beneficial in patients infected with pretreatment resistant strains to the antibiotics, in which cases the eradication rates achieved (over 90%) were similar to eradication rates in patients infected with sensitive strains. Compliance was good and there was only one serious adverse effect---anaphylaxis, probably due to amoxicillin. Frequent adverse effects were abdominal distension (10%), glossitis (9%), and diarrhea (8%). There is a relatively low incidence of duodenal ulcers in children. Studies of the relation between treatment of H. pylori infection and duodenal ulcer disease in children are therefore limited. The efficacy of triple therapy with bismuth plus amoxicillin and metronidazole has been assessed in an open trial in 26 children with duodenal ulcers associated with H. pylori (29c). H. pylori was eradicated in 25 children and the ulcer was healed in 24. During a mean follow up of nearly 2 years, the annual ulcer relapse rate was 9% (compared with 56% in historical controls, in whom the infection was not eradicated). Adverse events were reported by 13% of the children, and included diarrhea, dizziness, nausea, and vomit-

ing. The prevalence of both H. pylori infection and functional dyspepsia increases with age. Triple therapy with bismuth plus amoxicillin and metronidazole for 2 weeks has been compared with dual therapy with omeprazole plus amoxicillin for 2 weeks in 126 patients over the age of 60 years, who were H. pylori positive and had functional dyspepsia ( 3 0c) . Eradication rates were similar in the two groups 2 months after the end of therapy (66% with triple therapy and 64% with dual therapy), and there was a significant reduction in dyspeptic symptoms in patients in whom H. pylori was eradicated compared with those in whom infection persisted. Adverse effects were reported by 15% of patients who took triple therapy (nausea and metallic taste) compared with 4% of those who took dual therapy (nausea and headache). In all

405 cases no adverse effect was severe enough to interrupt therapy. The effect of adding compliance-enhancing measures to triple therapy with omeprazole plus amoxicillin and metronidazole for 10 days has been studied in 119 Australian patients with H. pylori infection (31c). The complianceenhancing measures were: the provision of the medication in a dose-dispensing unit, the use of a medication chart, the provision of an information sheet about the treatment, and a reminder by telephone 2 days after the start of therapy. Ten days of triple therapy was effective for H. pylori eradication (85-90%) and patient compliance was excellent in both groups (97%). Attempts to improve compliance had no impact on outcome and adverse effects were common and were significantly associated with treatment failure and poor compliance in both groups. There were no significant differences in the adverse effects profiles. Female sex predicted more adverse effects. Two patients reported severe adverse effects, 19 reported moderate adverse effects, and 75 reported mild adverse effects. Common adverse effects included anorexia and nausea (35%), vomiting (7%), constipation (16%), diarrhea~flatulence (37%), abdominal pain~cramps (27%), a metallic taste (44%), headache/dizziness (48%), rash~itch (3%), lethargy/confusion (9%), and insomnia~agitation (4%). The authors attributed the unusually high prevalence of adverse effects to comprehensive reporting.

ACTIVATED CHARCOAL (SED-14, 1241) Activated charcoal is established as standard therapy for gut decontamination in most emergency departments. Frequent vomiting after ingestion can be a problem. Two formulations of activated charcoal 50 g (Carbomix, which was made into a slurry with 400 ml of tap water, and Actidose-Aqua, which came as a 240 ml suspension) have been compared in a prospective, randomized, single-blind study in 97 patients (32c). The mean dose of Carbomix (26.5 g) was significantly higher than the mean dose of Actidose-Aqua (19.5 g); the reasons for this difference were not stated. The rates of vomiting did not differ between patients who received Carbomix (6%) or Actidose-Aqua (8%),

406

Chapter 36

H.J. De Silva

and were low compared with previous reports (13%).

Carcinogenesis The carcinogenic potential of phenolphthalein and danthron has been discussed (37r).

LAXATIVES (SED-14, 1235; SEDA-21,361; SEDA-22, 393; SEDA 23, 384)

AMINOSALICYLATES

Low-dose polyethylene glycol electrolyte solution and lactulose have been compared in chronic constipation in a randomized multicenter study in 115 patients with chronic constipation (33c). After 4 weeks the patients who took polyethylene glycol had a higher number of stools, a lower median dally score for straining at stool, and greater overall improvement than patients who took lactulose. Except that significantly fewer patients who took polyethylene glycol reported flatus, other adverse effects were similar in the two groups and included

liquid stools, abdominal pain, bloating, and rumbling. Picolax (sodium picosulfate plus magnesium citrate) plus clear fluids has been compared with bisacodyl tablets plus an unrestricted diet and a phosphate enema just before investigation in a randomized single-blind trial in bowel preparation for colonoscopy in 66 children aged 18 months to 16 years (34c). Bowel cleansing was significantly better with Picolax. Compliance with both regimens was excellent. Bisacodyl produced significantly more abdominal pain. Some children given Picolax reported vomiting (n = 3) and were distressed because of lack of solid food (n = 6). The other adverse effects included abdominal discomfort and fecal

incontinence. Gastrointestinal Two cases of esophageal obstruction after ingestion of laxatives have been reported (35 A, 36A). A 91-year-old man presented with complete esophageal obstruction after taking a tablespoonful of sterculia granules (Normacol) without water. There was no predisposing esophageal disease. The severity of obstruction was such that endoscopic clearance was not possible, and the patient required gastrotomy and manual disimpaction of the lower esophagus. A 69-year-old man with Parkinson's disease developed severe dysphagia after taking granules of the bulk laxative Perdiem (82% psyllium and 18% senna formulated as granules). Disimpaction of the bezoar was performed via a rigid endoscope under general anaesthesia.

(SED-14, 1237; SEDA-21, 364; SEDA-22, 393; SEDA-23, 386) There have been several reports of nephrotoxicity in patients with ulcerative colitis treated with 5-aminosalicylic acid (5-ASA) formulations. The effects of mesalazine and olsalazine in delivering active 5-ASA to the colon and in producing a systemic load as a basis for potential long term-toxicity have been compared in a single-blind, randomized, crossover study in 15 patients with ulcerative colitis (38c). The patients took either olsalazine 500 mg bd or mesalazine 500 mg tds, with a crossover after 7 days. Plasma and urine concentrations of 5-ASA and acetyl-5-ASA were assayed. Olsalazine caused loose stools in one patient and diarrhea in two, whereas mesalazine caused diarrhea in one. The systemic load of active 5-ASA was significantly higher after mesalazine than olsalazine, based on both therapeutically recommended doses and when calculated on an equimolar basis. Some patients treated with mesalazine had very high plasma and urinary concentrations of 5-ASA and acetyl-5-ASA, which may have long-term safety implications. Short-chain fatty acids, especially butyrate, are a preferred source of energy for the colonic epithelium. There is evidence to suggest that butyrate enemas are effective in the treatment of ulcerative colitis. The seeds of Plantago ovata (a source of fermentable dietary fiber) increase fecal concentrations of butyrate and acetate. In a randomized, open-label, parallel-group, multicenter study in 105 patients with ulcerative colitis, Plantago ovata seeds 10 mg bd were as effective as mesalazine 500 mg tds in maintaining remission over 12 months (39c). Adverse effects were similar in the two groups, and included constipation, fatulence, nausea, and

diarrhea. In a randomized multicenter study in 94 patients, mesalazine 4 g/day for 12 weeks in a microgranular formulation was as effective as a standard dose of a corticosteroid (6methylpredisolone 40 mg/day) in mild to mod-

Gastrointestinal drugs

Chapter36

erate Crohn's ileitis (Crohn's Disease Activity Index 180-350) (40c). The group treated with methylpredisolone had a higher number of adverse events than those given mesalazine. The only adverse effect related to mesalazine was acute pancreatitis, which resolved on withdrawal.

Mesalazine (mesalamine) The use of oral enteric-coated mesalazine, a formulation that releases mesalazine in the terminal ileum and colon, has been reviewed (41R). About 74% of patients with mild to moderate ulcerative colitis improve with entericcoated mesalazine 2.4-4.8 g/day. There is a trend towards a better response with higher doses. Oral enteric-coated mesalazine 0.8--4.4 g/day appears to be as effective as sulfasalazine 2 - 4 g/day, modified-release mesalazine 1.5 g/day, and balsalazide 3 g/day in maintaining remission in ulcerative colitis. There is limited evidence that in patients with Crohn's disease enteric-coated mesalazine 0.4-4.8 g/day is effective in active disease (achieving remission in up to 45% of patients) and in maintaining remission (relapse rate 34% over 12 months) (41R). Oral enteric-coated mesalazine appears to be well tolerated in children aged 4 - 1 9 years and in adults who are intolerant of sulfasalazine. The most c o m m o n adverse effects are headache, gas, nausea, diarrhea, and dyspepsia. The adverse effects can be severe enough to require withdrawal of the drug in up to 11% o f patients. In a 4-week randomized trial in 103 patients with mild to moderate left-sided ulcerative colitis or proctosigmoiditis, mesalazine gel enema 2 g/day was as effective as mesalazine foam enema 2 g/day in inducing remission (42c). Patients in the foam group had significantly more difficulty in retention and more abdominal bloating and discomfort during administration of the drug. C a r d i o v a s c u l a r The time between the start of treatment and the onset of mesalazineassociated pericarditis has previously been reported to range from a few days to 7 months. In a new case the delay was longer ( 4 3A) . A 53-year-old man with Crohn's disease, who had taken mesalazine 500 mg/day for the past 8 years, developed pericarditis with an effusion. The

407 pericarditis resolved rapidly on drug withdrawal. Investigations excluded other common causes of pericarditis. R e s p i r a t o r y Adverse respiratory effects of mesalazine have recently been reported. A 35-year-old woman with ulcerative colitis who had taken mesalazine 1.5 g/day for about 40 days developed a low-grade fever with bilateral eosinophilic pulmonary infiltrates (confirmed by transbronchial lung biopsy) (44A). Spontaneous clinical and radiological resolution occurred on withdrawal. A drug lymphocyte stimulation test was positive for mesalazine. A 29-year-old woman with ulcerative colitis taking mesalazine l g tds developed respiratory distress (45A). Her respiratory symptoms (chest pain and respiratory distress, especially exertional dyspnea) occurred 48 hours after she started to take mesalazine and disappeared immediately on withdrawal. Similar symptoms recurred on rechallenge 3 weeks later in a lower dose of 500 mg bd. Chest X-ray and white cell count a day later were normal. L i v e r Mesalazine-induced chronic hepatitis and liver fibrosis, with raised serum IgG concentrations and autoantibodies, has been reported for the first time (46A). A 57-year-old man with an unspecified abdominal complaint (later confirmed not to be inflammatory bowel disease), and who was also taking simvastatin, developed abnormal liver function tests and antinuclear and antismooth muscle antibodies 13 months after starting to take mesalazine. Simvastatin hepatotoxicity was suspected and that drug was withdrawn, but there was no improvement in liver function. Mesalazine was withdrawn 21 months after the start of therapy, with rapid normalization of liver enzymes and serum IgG concentrations and disappearance of the autoantibodies. Pancreas

Two cases of mesalazine-induced

acute pancreatitis have been reported (47 At, 48At). A 29-year-old man with Crohn's disease who had taken mesalazine 2 g/day for 3 days developed acute pancreatitis. Clinical and biochemical improvement occurred on drug withdrawal. Acute pancreatitis recurred on rechallenge. A 23-year-old man with ulcerative colitis developed acute pancreatitis after taking mesalazine 1.5 g/day for 4 days. Resolution occurred on withdrawal but rechallenge was not performed. U r i n a r y t r a c t Serious renal impairment occurs in under 1 in 500 recipients of enteric-

408 coated mesalazine (41R), and early recognition and withdrawal (after up to 10 months of administration) has been reported to have resulted in complete recovery of renal function in five out of six patients. Monitoring renal function in patients taking mesalazine formulations is recommended. Oral enteric-coated mesalazine should not be used in patients with renal sensitivity to sulfasalazine, a history of hypersensitivity to salicylates, severe renal impairment, and children under 2 years old.

CHOLELITHOLYTIC AGENTS

Chapter 36

fibrosing colonopathy due to pancreatins have been reported in children with cystic fibrosis in the UK, USA, and continental Europe. The disorder is not affected by age or sex, and the age at diagnosis is 9 months to 13 years. Evidence implicates high-strength formulations, which provide at least 22 000-25 000 international units of lipase per capsule (compared with low- and medium-strength formulations which provide up to 10 000 iu), and the association between pancreatins and colonopathy is clearly dose related--the higher the dose greater the risk of colonopathy. The are several hypotheses about the pathogenesis of the condition. They include the following:

Bile acids (SED-14,1240; SEDA-22, 395; SEDA-23, 387)

9

In a randomized placebo-controlled study in 219 patients with histology-proven chronic hepatitis (44 HbsAg-positive and 149 antiHCV antibody-positive) and persistently raised transaminases, oral ursodeoxycholic acid 300 mg bd for 6 months produced significant improvement in clinical and biochemical markers (49c). Apart from diarrhea, which was reported by a few patients, the drug was well tolerated.

9

PANCREATIC ENZYME SUPPLEMENTS (SED-14, 1242; SEDA-21,366; SEDA-22, 395; SEDA-23, 387) Colonic toxicity due to pancreatic enzyme supplements in children with cystic fibrosis has been reviewed (50R). Since it was first reported in 1994, an increasing number of cases of

H.J. De Silva

9

toxicity due to the enteric coating (Eudragit L-30D-55) used in high-strength pacreatin capsules; prolonged exposure of the colon to highstrength pancreatins because of the abnormally low small intestinal pH in cystic fibrosis, causing delay in dissolution of the enteric coating of the capsule (which occurs only above pH 5.5) until the enzymes reach the distal small intestine or even the large intestine; a colon-specific immune-mediated disorder or primary dysregulation of collagen synthesis in the colonic wall.

Having reviewed the available epidemiological data, the UK Medicines Control Agency has recommended that high-strength pancreatins coated with Eudragit L-30D-55 should be contraindicated in children under 15 years, that all high-strength pancreatins should be available only on prescription, and that no pancreatin formulation should be used in a dosage higher than 10 000 iu/kg/day.

REFERENCES 1. Castell D, Silvers D, Littlejohn T, Orr W, Napolitano J, Oleka N, Jokubaitis L, and the CISUSA-89 study group. Cisapride 20 mg lad for preventing symptoms of GERD induced by a provocative meal. Aliment Pharmacol Ther 1999; 13: 787-94. 2. Benatar A, Feenstra A, Decraene T, Vandenplas Y. Cisapride and proarrhythmia in childhood. Paediatrics 1999; 103: 856-7. 3. Committee on Safety of Medicines, Medicines Control Agency. Cisapride (Prepulsid) withdrawn. Curt Probl Pharmacovig 2000; 26: 9-10.

4. Serrano-Serrano ME, Alvare-Frejo M, Taberner-Garcia J, Marti-Martin S. Sindrome extrapyramidal por cleboprida. Aten Prim 1999; 23: 50-1. 5. Patterson D, Abell T, Rothsten R, Koch K, Barnett J. A double blind multicenter comparison of domperidone and metoclopramide in the treatment of diabetic patients with symptoms of gastroparesis. Am J Gastroenterol 1999; 94: 1230-4. 6. Mangel AW, Northcutt AR. Review article: the safety and efficacy of alosetron, a 5-HT3 receptor antagonist, in female irritable bowel syndrome pa-

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tients. Aliment Pharmacol Ther 1999; 13 Suppl: 77-82. 7. Uysal KM, Olgun N, Sarialioglu E Tropisetron in the prevention of chemotherapy induced acute emesis in paediatric patients. Turk J Paediatr 1999; 41: 207-18. 8. Duval L, Hautecoeur P, Mahieu M. Encephalopathie hyperammoniemique apr~s prise de cimetidine. Presse Mrd 1999; 28: 582-3. 9. Cappelli J, Lenaerts A, Lamy V, Ramdani B, Moisse R. Hematome intramural du gr~le associ6 aux anticoagulants, potentialisrs par interaction avec la cimrtidine. Med Chir Dig 1999; 28: 712. 10. Pappa KA, Gooch WM, Buaron K, Payne JE, Giefer EE, Sirgo MA, Ciociola AA. Low-dose ranitidine for relief of heart burn. Aliment Pharmacol Ther 1999; 13: 459-65. ll. Kahrilas PJ, Fennerty MB, Joelsson B. High versus standard dose ranitidine for control of heartburn in poorly responsive acid reflux disease: a prospective controlled trial. Am J Gastroenterol 1999; 94: 92-7. 12. Jones R, Crouch SL. Low dose lansoprazole provides greater relief of heartburn and epigastric pain than low dose omeprazole in patients with acid related dyspepsia. Aliment Pharmacol Ther 1999; 13: 413-19. 13. Condra LJ, Morreale AP, Stolley SN, Marcus D. Assessment of patient satisfaction with a formulary switch from omeprazole to lansoprazole in gastro-oesophageal reflux disease maintenance therapy. Am J Managed Care 1999; 5: 631-8. 14. Dekkers CPM, Beker JA, Thjodleifsson B, Gabryelewicz A, Bell NE, Huphries TJ, and the European Rabeprazole Study Group. Comparison of rabeprazole 20 mg versus omeprazole 20 mg in the treatment of active duodenal ulcer: a European multicentre study. Aliment Pharmacol Ther 1999; 13: 179-86. 15. Dekkers CPM, Beker JA, Thjodleifsson B, Gabryelewicz A, Bell NE, Huphries TJ, and the European Rabeprazole Study Group. Double blind placebo controlled comparison of rabeprazole 20 mg versus omeprazole 20 mg in the treatment of erosive or ulcerative gastro-oesophageal reflux disease. Aliment Phannacol Ther 1999; 13: 49-57. 16. Martinek J, Blum AL, Stolte M, Hartmann M, Verdu EF, Luhmann R, Dorta G, Wiesel P. Effects of pumaprazole (BY841), a novel reversible proton pump antagonist, and of omeprazole on intragastric acidity before and after cure of Helicobacterpylori infection. Aliment Pharmacol Ther 1999; 13: 2734. 17. Bardhan KD, Crowe J, Thompson RPH, Trewby PN, Keeling PN, Weir D, Crouch SL, on behalf of the UK-Eire Lansoprazole Group. Lansoprazole is superior to ranitidine as maintenance treatment for the prevention of duodenal ulcer relapse. Aliment Pharmacol Ther 1999; 13: 827-32.

409 18. Romero Gomez M, Suarez Garcia E, Garcia Diaz E. Acute hepatitis related to omeprazole. Am J Gastroenterol 1999; 94:1119-20. 19. Gabutti L, Stoller R, Vogt B. Omeprazoleinduced agranulocytosis in a kidney transplant recipient. Nephrol Dial Transplant 1999; 14: 523--4. 20. Holt TL, Coombes ID, Pillans PI, Scott IA. Neutropenia associated with omeprazole. Med J Aust 1999; 170: 141-2. 21. Galindo PA, Borja J, Feo F, Gomez E, Garcia R, Cabrera M, Martinez C. Anaphylaxis to omeprazole. Ann Allergy Asthma Immunol 1999; 82: 52-4. 22. Guy C, Ollagnier M. Sucralfate et bezoard: bilan de l'enquete officielle de pharmacovigilance et revue de la literature. Thrrapie 1999; 54: 55-8. 23. Lind T, Megraud F, Unge P, Bayerdorffer E, O'Morain C, Spiller R, Van Zanten SV, Bardhan KD, Heltblom M, Wrangstadh M, Zeijlon L, Cederberg C. The MACH-2 Study: role of omeprazole in eradication of Helicobacter pylori with 1-week triple therapies. Gastroenterology 1999; 116: 248-53. 24. Van Zanten SJOV, Bradette M, Farley A, Leddin D, Lind T, Unge P, Bayerdorffer E, Spiller R, O'Morain C, Sipponen P, Wrangstadh M, Zeijlon L, Sinclair P. The DU-MACH Study: eradication of Helicobacter pylori and ulcer healing in patients with acute duodenal ulcer using omeprazole based triple therapy. Aliment Pharmacol Tber 1999; 13: 289-95. 25. Savarino V, Zentilin P, Bisso G, Pivari M, Mele MR, Mela GS, Mansi C, Vigneri S, Termini R, Celle G. Head to head comparison of 1-week triple regimens combining ranitidine or omeprazole with two antibiotics to eradicate Helicobacter pylori. Aliment Pharmacol Ther 1999; 13: 643-9. 26. Miwa H, Ohkura R, Murai T, Sato K, Nagahara A, Hirai S, Watanabe S, Sato N. Impact of rabeprazole, a new proton pump inhibitor, in triple therapy for Helicobacter pylori infection-comparison with omeprazole and lansoprazole. Aliment Pharmacol Ther 1999; 13: 741-6. 27. Calvet X, Lopez-Lorente M-T, Cubells M-J, Bare M, Galvez E, Molina E, for the Sabadell Primary Care Study Group. Two-week dual vs one-week triple therapy for cure of Helicobacter pylori infection in primary care: a multicentre, randomised trial. Aliment Pharmacol Ther 1999; 13: 781-6. 28. Okada M, Nishimura H, Kawashima M, Okabe N, Maeda K, Seo M, Ohkuma K, Takata T. A new quadruple therapy for Helicobacter pylori influence of resistant strains on treatment outcome. Aliment Pharmacol Ther 1999; 13: 769-74. 29. Huang FC, Chamg MH, Hsu HY, Lee PI, Shun CT. Long term follow up of duodenal ulcer in children before and after eradication of Helicobacter pylori. J Paediatr Gastroenterol Nutr 1999; 28: 76-80. 30. Catalano F, Brachiforte G, Brogna A, Bentivegna C, Luca S, Terranova R, Michalos A, Dawson

410 BK, Chodash HB. Helicobacter pylori positive functional dyspepsia in elderly patients. Dig Dis Sci 1999; 44: 863-7. 31. Henry A, Batey RG. Enhancing compliance not a prerequisite for effective eradication of Helicobacter pylori the HelP Study. Am J Gastroenterol 1999; 94:811-15. 32. Boyd R, Hanson J. Prospective single blinded randomised controlled trial of two orally administered activated charcoal preparations. J Accid Emerg Med 1999; 16: 24-5. 33. Attar A, Lemann M, Ferguson A, Halphen M, Boutron MC, Flourie B, Alix E, Salmeron M, Guillemot E Chaussade S, Menard AM, Moreau J, Naudin G, Barthet M. Comparison of low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation. Gut 1999; 44: 226-30. 34. Pinfield A, Stringer MD. Randomised trial of two pharmacological methods of bowel preparation for day case colonoscopy. Arch Dis Child 1999; 80: 181-3. 35. Brown DC, Doughty JC, George WD. Surgical treatment of oesophageal obstruction after ingestion of a granular laxative. Postgrad Med J 1999; 75: 106. 36. Shulman LM, Minagar A, Weiner WJ. Perdiem causing oesophageal obstruction in Parkinson's disease. Neurology 1999; 52: 670-1. 37. Anonymous. Laxatives containing dantron and phenolphthalein--unacceptable ingredients in OTC drug products. WHO Pharm Newslett. 1999; 3,4 (Mar-Apt): 3. 38. Stoa-Berketvedt G, Florholmen J. The systemic load and efficient delivery of active 5aminosalicylic acid in patients with ulcerative colitis on treatment with olsalazine or mesalazine. Aliment Pharmacol Ther 1999; 13: 357-61. 39. Fernandez Banares E Hinijosa J, Sanchez Lombrana JL, Navarro E, Martinez Salmeron JE Garcia Puges A, Gonzalez Huix E Riera J, Gonsalez-Lara V, Dominguez Abascal F, Gine JJ, Moles J, Gomollon E Gassull MA, for the Spanish Group for the Study of Crohn's Disease and Ulcerative Colitis. Randomized clinical trial of Plantago ovata seeds (dietary fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. Am J Gastroenterol 1999; 94: 427-33.

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40. Prantera C, Cottone M, Pallone E Annese V, Franze A, Cerutti R, Porro GB, and a Cooperative Study Group. Mesalamine in the treatment of mild to moderate active Crohn's disease: results of a randomised, multicenter trial. Gastroenterology 1999; 116: 521-6. 41. Prakash A, Markham A. Oral delayed release mesalazine. Drugs 19~9; 57: 383--408. 42. Gionchetti P, Ardizzone S, Benvenuti ME, Porro GB, Biasco G, Cesari E D'Alhasio G, De Franchis R, Monteleone G, Pallone E Ranzi T, Trallori G, Valpiani D, Vecchi M, Campieri M. A new mesalazine gel enema in the treatment of left sided ulcerative colitis: a randomised controlled multicenter trial. Aliment Pharmacol Ther 1999; 13: 381-8. 43. Vayre E Vayre-Oundjian L, Monsuez JJ. Pericarditis associated with longstanding mesalazine administration in a patient. Int J Cardiol 1999; 68: 243-5. 44. Tanigawa K, Sugiyama K, Matsuyama H, Nakao H, Kohno K, Komuro Y, Iwanaga Y, Eguchi K, Kitalchi M, Takagi H. Mesalazine induced eosinophilic pneumonia. Respiration 1999; 66: 69-72. 45. Guslandi M. Respiratory distress during mesalazine therapy. Dig Dis Sci 1999; 44: 48-9. 46. Deltenre P, Berson A, Marcellin P, Degott C, Biour M, Passayre D. Mesalazine (5-aminosalicylic acid) induced chronic hepatitis. Gut 1999; 44: 886-8. 47. Decocq G, Gras-Champel V, Vrolant-Mille C, Delcenserie R, Sauve L, Masson H, Andrejak M. Pancreatites alguSs induites par les medicaments deriv6s de l'acide 5-aminosalicylique: un cas et revue de la litterature. Th6rapie 1999; 54: 41-8. 48. Mari B, Brullet E, Campo R, Bustamante E, Bombardo J. Pancreatitis aguda pot acido 5aminosalicilico. Gastroenterol Hepatol 1999; 22: 28-9. 49. Berlotti M, Morselli-Labate AM, Rusticali AG, Loria P, Carulli N, and the Investigators of the Italian Multicenter Study on UDCA in Chronic Hepatitis. Ursodeoxycholic acid improves liver tests in chronic hepatitis. Results of a randomised controlled trial. Clin Drug Invest 1999; 17: 425-34. 50. Powell CJ. Colonic toxicity from pancreatins: a contemporary safety issue. Lancet 1999; 353:91115.

Thierry Vial and Jacques Descotes

37

Drugs acting on the immune system

(SED-14, 1246; SEDA-21, 369; SEDA-22, 399; SEDA-23, 391) INTERFERONS

Interferon-u Considerable efforts have been made to improve the efficacy of interferon-c~ in patients with chronic hepatitis C. Currently used regimens, including long-term interferon-a alone or in combination with ribavirin, produce a sustained response rate of 40-50%. Other possibly effective strategies include a longer duration of treatment, higher fixed doses, and high-dose induction (1R). A longer duration of treatment has been evaluated in patients with chronic hepatitis B. In 118 patients, a treatment duration of 32 rather than 16 weeks enhanced the virological response to hepatitis B without increasing the severity of adverse effects, except for hair loss, which was more frequent during prolonged therapy (2c). Low daily doses of interferon-a have been used with small doses of cytarabine in the treatment of early chronic myelogenous leukemia (3c). With doses sufficient to obtain a good cytogenetic response (e.g. 3.7 MU/m2/day plus cytarabine 7.5 mg/day) toxicity was considered acceptable. There was significant fatigue in 43% of cases, significant neurological changes in 27%, weight loss in 19%, and oral ulcers in 4%. Cardiovascular Cardiovascular complications are very seldom reported in patients without risk factors. Cardiomyopathy has been reported for the first time in an infant (4A).

9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual24 J.K. Aronson, ed.

A 3-month-old boy was given interferon-a (2.55.5 MU/m 2) for chronic myelogenous leukemia. After 7.5 months he developed progressive respiratory distress, with anorexia, irritability, and nocturnal sweating. A chest X-ray showed cardiomegaly, an echocardiogram showed a markedly dilated left ventricule, and an electrocardiogram showed left ventricular hypertrophy with abnormal repolarization. Viral cultures and serology for cytomegalovirus, B19-parvovirus, and enterovirus were negative. Infectious diseases and metabolic disturbances were excluded. Interferon-a was withdrawn and digoxin, furosemide, and an angiotensin converting inhibitor were given. One year later, he was asymptomatic without further cardiac treatment.

Respiratory Interferon-a-induced pneumonitis and exacerbation of asthma have already been described (SED-14, 1248). Sustained and isolated dry cough has more recently been attributed to interferon-a in a 49-year-old woman (5A). This case report was highly convincing, because her symptoms disappeared after withdrawal, recurred on readministration, and again resolved after withdrawal. Furthermore, no other cause was found after thorough investigation. Nervous system There was diffuse electroencephalographic slowing, suggesting mild encephalopathy, in a prospective study of the effect of interferon-ct (56 MU/day for 4 weeks then 27 MU/week for 20 weeks) on brain function in 56 patients with chronic hepatitis C, using blinded evaluation of quantitative electroencephalography performed at baseline, at 2 and 4 weeks of treatment, and after the completion of treatment (6c). These changes completely reversed after withdrawal. However, the dosage used in this Japanese study was relatively high compared with the dosages currently used in Western countries. In addition, the clinical relevance of these electroencephalographic changes was not investigated. /111

412 Tonic-clonic seizures are continually reported during both low- and high-dose interferon-a treatment. In three further patients, seizures occurred after a cumulative dose of 266-900 MU (7 A, 8A). Two patients were retreated with a lower dose and remained free of seizures, so that the strength of the causal relation is debatable (7A). However, a dose-dependent effect is still possible. Another patient with a history of bipolar mood disorder had his first four episodes of seizures with a prolonged delirious state 1 week after withdrawal of interferon-a (8% Persistent neurotoxicity induced by interferon-~ has been poorly investigated. This issue has been addressed in a report of severe refractory akathisia (9A). A 28-year-old man received interferon-a (5 MU/day for 28 days) for chronic hepatitis B. At the end of treatment he developed a slight parkinsonian gait, and 8 days later had a fever with vomiting, insomnia, restlessness, and raised serum creatine phosphokinase activity (4946 iu/1). He had severe akathisia with psychomotor excitement and parkinsonism. Despite treatment with clonazepam, thioridazine, propranolol, trihexyphenidyl, and bromocriptine, his condition progressively worsened. He was finally given intravenous levodopa for 8 days and recovered dramatically within the next few days. This report, together with previous experimental data, suggests that levodopa might be useful in alleviating some of the manifestations of persistent interferon-a-induced neurotoxicity. Psychological The neuropsychological adverse effects of long-term treatment have been assessed in 14 patients with myeloproliferative disorders using a battery of psychometric and electroneurological tests before and after 3, 6, 9, and 12 months of treatment (median dose 25 MU/week) (10c). In contrast to several previous studies, there was no significant impairment of neurological function, and attention and short-term memory improved during treatment. Despite the small number of patients, these results suggest that prolonged interferon-or treatment did not cause severe cognitive dysfunction, at least in patients with cancer.

Psychiatric The reported rate of depressive symptoms associated with interferon-t~ ranges

Chapter 37

ThierryVial and Jacques Descotes

from none to more than 50%, but most investigators have found rates of 10-20% (11 R, 12R). Unfortunately, depression was not carefully investigated in many studies and validated measures of depression were used in only a few instances. In addition, there is no clear evidence yet as to whether a previous history of psychiatric symptoms constitutes an additional risk. Recent there have been several attempts to assess these issues. The occurrence of psychiatric disorders has been prospectively investigated in 63 patients who received a 6-month course of interferon-c~ (9 MU/week) for hepatitis C (13c). All were assessed at baseline with the Structured Clinical Interview for DSMIII-R (SCID) and monitored monthly with the Hopkins Symptoms Checklist (SCL-90). Most had a history of alcohol or polysubstance dependence, and 12 had a lifetime diagnosis of major depression. There were no significant changes in the SCL-90 scores during the 6month period of survey in the 49 patients who completed the study, even in those who had a lifetime history of major depression. At 6 months, there was probable minor depression in eight patients and major depression in one; none had attempted suicide. In another prospective study 50 patients with chronic hepatitis B or C who received 18-30 MU/week of natural or recombinant interferon-or were followed for 12 months (14c). The SCID before starting interferon-t~ identified 16 patients with a current psychiatric diagnosis and eight with a previous psychiatric disorder; 26 patients free of any psychiatric history constituted the control group. Psychiatric manifestations during treatment occurred in 11 patients (five from the control group), major depression in five, depressive disorders in three, severe dysphoria in two, and generalized anxiety disorder in one. Most of them were successfully treated with psychological support and drug therapy. Overall, 20 patients interrupted interferon-c~ (10 in each group), including three for psychiatric adverse effects, but patients with a pre-existing or recent psychiatric diagnosis were no more likely to withdraw from treatment than the controls. These studies have confirmed that previous psychiatric disorders are not necessarily a contraindication to a potentially effective treatment. However, as strong predictors of psychiatric morbidity remain to be identified, pa-

Drugs acting on the immune system

Chapter 37

tients with depressive symptoms immediately before treatment are still regarded at risk of severe psychiatric deterioration with treatment (llR). Finally, and although psychiatric manifestations usually appeared during interferon-a therapy, a delayed reaction remains possible in some patients, as has been described in a 37year-old man without a previous psychiatric history, who developed major depression with severe psychotic features within days after the discontinuation of a 1-year course of interferona2b (15A). Suggested approaches for assessing and managing interferon-a-induced depression have been discussed (12R), but there have been no studies of the careful management of such disorders, despite the large body of data on interferon-a-induced depression. Selective serotonin re-uptake inhibitors have been advocated as the drugs of choice to allow completion of interferon-a treatment (11R), but that was based on very limited experience and the unproven assumption that SSRIs are safe in patients with underlying liver disease. Based on preliminary results from a doubleblind placebo-controlled study, 2 weeks of pretreatment with paroxetine significantly reduced the occurrence of major depression in 16 patients on high-dose interferon-a for malignant melanoma (16 c ). Endocrine Although sporadic cases of diabetes mellitus have previously been reported, the effect of interferon-a on glucose metabolism has been little examined. A 75 g oral glucose tolerance test was performed before and after 3 months of interferon-a treatment in 32 patients with chronic hepatitis C, of whom 15 also had an intravenous glucose test (17c). Baseline evaluation showed that five patients had mild diabetes mellitus, three had impaired glucose tolerance, and 24 were normal. After 3 months of treatment, two patients with diabetes mellitus shifted to impaired glucose tolerance, and all patients with impaired glucose tolerance had normal glucose tolerance. Only three initially normal patients developed impaired glucose tolerance and none had newly diagnosed diabetes mellitus. From these results, and in contrast to previous reports (SED-14, 1250), it appears that interferon-a did not have any adverse effects on insulin sensitivity and glucose tolerance after 3 months of treatment.

413 Thyroid disorders have been reported at various times with interferon-a, but generally in the form of thyroiditis and hypothyroidism (SEDA-14, 1249). Hyperthyroidism is much less common and it is not clear how it could be induced. However, a case in a middle-aged woman pointed strongly to a causal association with subacute thyroiditis which was present by the sixth month of treatment (18A). She also had the classic symptoms of hyperthyroidism, although it is clear that these could easily be mistaken for adverse effects of interferon-a itself, e.g. weakness, weight loss, and palpitation. Thyroid complications can be symptomatic, but they are also likely to be reversible if the diagnosis is made in good time and appropriate measures are taken.

Hematologic Prior interferon-a treatment lasting for more than 6 months and withdrawn for 2-3 months was one of the most significant factors to explain a reduced yield of peripheral blood stem cells in 88 previously autografted patients with myeloma undergoing G-CSF stimulation for future autotransplantation (19c). As suggested by this study, the myelosuppressive effects of interferon-a may be prolonged to such an extent that a minimum delay of more than 2-3 months after interferona withdrawal should be considered before harvesting bone-marrow cells. There have been further reports of interferon-a-induced hemolytic anemia, sometimes with an autoimmune origin (20 A, 21A). A 33-year-old man developed a delayed hemolytic reaction 7 days after red cell transfusion (22A). Additional investigations showed the presence of an anti-M antibody, the production of which was supposedly caused by chemoimmunotherapy (interferon-a, IL-2, and 5-fluorouracil) begun 24 hours after transfusion. Interferon-a can sometimes aggravate hepatitis C-related cryoglobulinemia. Fatal exacerbation, preceded by rapid deterioration of neurological status, massive upper gastrointestinal bleeding, and diffuse hemorrhagic gastritis with vasculitic changes on gastroscopy, has been reported within the first 3 weeks of interferon-a treatment in a 5 I-year-old woman (23A). Gastrointestinal Celiac disease was observed after 2-3 months of interferon-a treatment in two patients with chronic hepatitis C aged 34 and 38 years (24A). Both had total

414

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ThierryVialand Jacques Descotes

villous atrophy on distal duodenal biopsy, were positive for antiendomysial antibodies, and responded to a gluten-free diet.

a review of drug-associated pancreatitis spontaneously reported to the Dutch adverse drug reaction system (28A).

Liver The first case of interferon-aassociated macrovesicular steatosis has been reported (25A).

Urinary tract Interferon-a-induced thrombotic microangiopathy is rare but extremely

A 50-year-old woman without a history of liver disease, dyslipidemia, diabetes, obesity, or alcoholism, started interferon-~ (7.5 MU/day) for chronic myelogenous leukemia together with allopurinol and hydroxyurea for 2 weeks. Her liver tests were normal before treatment but AsT and AIT activities were greatly increased after 2 weeks. Serological tests for hepatitis B and C and HIV were negative, as was screening for serum antitissue antibodies. Liver biopsy showed severe macrovesicular steatosis (80% of hepatocytes) without steatohepatitis. Liver tests completely normalized on interferon-~ withdrawal. A few weeks after interferon-a was restarted in a lower dose (3-5 MU/day), she again had a rise in liver enzymes, and a second liver biopsy showed unchanged findings. Liver tests remained stable despite treatment continuation. Acute exacerbation of hepatitis has been reported in patients treated for chronic hepatitis B. It is an extremely rare complication of chronic hepatitis C treatment but has again been described (26A). A 43-year-old man had a moderate rise in hepatic transaminase activities after 4 weeks of interferont~ treatment. His liver tests normalized after withdrawal, but the AsT increased dramatically shortly after treatment was restarted. His condition rapidly deteriorated, with a diagnosis of hepatorenal failure, and he finally required liver transplantation. Histological examination of the liver showed advanced micronodular cirrhosis, a feature not found on pretreatment liver biopsy.

severe, and is almost exclusively reported in patients treated for chronic myelogenous leukemia and with a delayed onset (29r). From these data and three recently reported cases (30 At, 31A), a total of 15 cases have now been reported. The diagnosis was made after 7 months to 10 years of treatment (median 50 months) with weekly doses of 15-70 MU. Renal prognosis was poor, with early death in four patients, chronic hemodialysis in eight, and chronic renal failure in three. S k i n Telogen effluvium is a common adverse effect of interferon-a. Injection-site alopecia has now been reported in three patients, affecting the thighs in two patients and the abdomen in one (32A). A reversible focal telogen effluvium secondary to high local concentrations of interferon-a was the most likely cause, indicating that rotating injections sites are needed to prevent this adverse effect. One case of alopecia areata after 7 months of interferon-a, slowly reversible on withdrawal, has also been reported in a 36-year-old woman (33A). Musculoskeletal Polymyositis has very rarely been associated with interferon-a, but has again been reported together with autoimmune thyroiditis in a 48-year-old woman after treatment for 5 months for malignant melanoma (34A).

Immunologic

Systemic lupus erythematosus

A 54-year-old man developed abdominal pain from the beginning of interferon-or treatment. Two weeks later his serum amylase and lipase peaked at about three times the upper limit of normal. Careful radiological investigations ruled out pancreatic calcification and biliary or pancreatic lithiasis and showed only pancreatic enlargement. Complete improvement occurred after treatment withdrawal. As in the very few previous cases, there was no hypertriglyceridemia in this patient.

has been reported in two patients given interferon-a for chronic hepatitis C (35 A, 36A). However, it is not known whether this complication was coincidental or treatment related. The management of chronic hepatitis C patients with associated features of autoimmune disease carries the risk of exacerbating the underlying disease. Different treatment strategies, including interferon-a alone or combined with ribavirin or corticosteroids or no treatment, have been discussed (37R).

A definite case of pancreatitis proven by positive rechallenge was also briefly cited in

Risk factors Children In chronic viral hepatitis, the safety profile of interferon-a is con-

Pancreas Acute pancreatitis, which is rare with interferon-a, has been reported (27A).

Drugs acting on the immune system

Chapter 37

sidered to be very similar in children and adults. Although infants treated for severe hemangiomas may also benefit from this treatment, careful periodic neurological examination should be considered, because spastic diplegia can occur. This complication has been again observed in one of 53 infants treated for a median of 51 weeks (38c).

Transplantation A debate as to whether previous interferon-c~ adversely affects the outcome of bone-marrow transplantation in chronic myelogenous leukemia has arisen in the past few years. Of eight studies, five showed no harmful effect and three suggested an increased risk of post-transplant complications or mortality (SEDA-22, 403; SEDA-23, 395). To address this issue, the outcome of bone-marrow transplantation in 152 patients (86 on interferon-c~, 66 on chemotherapy) included in two consecutive randomized trials, has been analyzed prospectively (39Cr). Whereas the duration of interferon-c~ treatment did not influence the outcome of transplantation, there was a significant reduction in survival: the 5-year survival was 45% in the 50 patients who were still receiving interferon-a within 3 months before bone-marrow transplantation and 71% in the 36 patients who were not. According to the authors, interferon-c~ should not be prescribed in patients who are likely candidates for early bone-marrow transplantation. D r u g interactions The combination of interferon-c~ with ribavirin is now commonly used. There was an increased incidence of adverse skin effects, mostly eczema, malar erythema, and lichenoid eruptions, in 33 patients who received this combination compared with 35 treated with interferon-a alone (40c). Depending on the timing of exposure, interferon-or may adversely affect the pharmacokinetic and hematological effects of cyclophosphamide. In 10 patients with multiple myeloma, interferon-t~ given 2 hours before cyclophosphamide infusion significantly reduced cyclophosphamide clearance and produced less exposure to its metabolite 4hydroxycyclophosphamide compared with interferon administration 24 hours after cyclophosphamide (41c). This resulted in a significantly greater fall in white blood cell count in

415 patients who received interferon-or after cyclophosphamide.

Interferon-fl Clinically relevant adverse effects associated with interferon-/~ and their management have been lengthily reviewed (42R). Interferon-/~la and/~lb, the two recombinant available forms of interferon-/~, have not been directly compared. From the results of a randomized cross-over study in 12 healthy volunteers, a single injection of interferon-/~la 6 MU (Rebif~ ) was suggested to produce less frequent and less severe fever than interferon-/~lb 8 MU (Betaseron| but identical pharmacodynamic effects (43c).

Cardiovascular Severe

reactions to interferon-~6 are very rare, and fatal capillary leak syndrome has been reported for the first time (44A). A 27-year-old woman had a 8-month history of relapsing-remitting neurological symptoms and a monoclonal gammopathy. She started to take interferon-fllb for multiple sclerosis, but had marked somnolence 30 hours after a single injection. She rapidly became unresponsiveness, and hemodynamic tests showed low central venous and pulmonary capillary wedge pressures with generalized peripheral edema, ascites, and bilateral pleural effusions. She died within 80 hours after injection from multiple organ failure. At post-mortem she was found to have C 1 esterase inhibitor deficiency. In the light of the possible effects of interferon-/~ on cytokine release and complement activation, a cytokine-mediated reaction was discussed as the cause of this capillary leak syndrome in a patient with C 1 esterase inhibitor deficiency.

Psychiatric The debate over the respective roles of interferon-fl and multiple sclerosis in the occurrence of depressive symptoms has not been resolved, and it is unclear whether interferon-fl has a direct psychotropic effect. Depression has been quantified by telephone interview in 56 patients with relapsing multiple sclerosis 2 weeks before treatment, at the start of treatment, and after 8 weeks of treatment (45c). Patients with a high depressive score 2 weeks before treatment significantly improved on starting treatment and returned to baseline within 8 weeks, whereas the depression score

416 in non-depressed patients remained essentially unchanged. The investigators therefore suggested that patients' expectations had temporarily resulted in improvement of depression, and that increased depression during treatment is more likely to reflect posttreatment depression. Urinary tract Whereas proteinuria, nephrotic syndrome, and various forms of renal lesions can be caused or exacerbated by interferon-or (SED-14, 1252), this has not been clearly described with interferon-el. The clinicopathological features ofproteinuria have been investigated in 23 patients with chronic hepatitis C who had new or worsened proteinuria during interferon treatment (interferon-c~ 6-10 MU/day in three patients and interferon-c] 6 MU/day in 20 patients (46c). Renal function and urinary findings were normal before treatment in 21 subjects. Proteinuria appeared after a mean of 12 (range 5-30) days after the start of treatment, and the mean value was 2.1 g/day. There was low selective proteinuria in 78% of the patients. Renal histopathology in 11 patients showed IgA glomerulonephritis in five, mesangial proliferative glomerulonephritis in four, membrano-proliferative glomerulonephrifis in one, and nephrosclerosis in one. There was only trace deposition of hepatitis C virus core antigen in three of nine patients, suggesting that hepatitis C was not the primary cause of these glomerulopathies. Skin Injection site reactions to interferon-c]la are infrequent and usually not severe compared with those sometimes described with interferon-c]lb. However, severe necrotizing cutaneous lesions have also been attributed to subcutaneous interferon- c]la (47A).

(SED-14, 1260; SEDA-21, 375; SEDA-22, 406; SEDA-23, 398) INTERLEUKINS

Interleukin-2 (IL-2) The use, benefits, and adverse effects of IL-2 in HIV-infected patients have been extensively reviewed (48R). IL-2 significantly increased the CD4+ cell count without an increase in viral load. However, many questions remain unanswered. In particular, it is still not known whether immunological improvements translate

Chapter 37

ThierryVialand Jacques Descotes

into clinical benefit. Regardless of how IL-2 is administered--intravenously, subcutaneously, or as polyethylene glycol-modified (pegylated) IL-2--adverse effects are generally not treatment limiting. As the duration of adverse effects was shorter with the subcutaneous route, these patients may be treated as out-patients (49c). In an analysis of data from 270 patients with metastatic melanoma in eight clinical trials, high-dose IL-2 (8.4-9.8 MU/kg during each cycle) produced an overall objective response rate of 16%, with 17 complete responses and 26 partial responses (50c). Although the response rate was low, there was a durable response for at least 24 months in 10 of 17 complete responders. Adverse effects were primarily the same as those previously described in patients with metastatic renal cell carcinoma, and severe hypotension (64%) was the most frequent. Six patients died from bacterial sepsis, but none was taking prophylactic antibiotics. In a randomized trial, 102 patients with metastatic melanoma had more frequent treatment-related adverse effects, particularly hematological suppression in patients treated with tamoxifen, cisplatin, and dacarbazine followed by interferon-or and IL-2, than in patients treated with chemotherapy alone, but there was no increase in survival (51c).

Respiratory Pulmonary infiltrates and respiratory failure during IL-2 treatment are usually attributed to vascular leak syndrome. From one report in a 49-year-old woman with breast cancer who received IL-2 and interferon-y after autologous stem cell transplantation, activation of eosinophils within the lung and subsequent deposition of the eosinophil major basic protein have been suggested to result in direct lung toxicity and a localized vascular leak syndrome (52A). Dose-dependent cough has been reported as the most frequent adverse effect of inhaled IL-2 (53c). Urinary tract Risk factors for renal dysfunction have been analyzed in 72 patients with metastatic renal cell cancer treated with highdose IL-2 (18 MU/m2/day), interferon-c~ (5 MU/m2/day), and lymphokine-activated killer lymphocytes (54c). There was some type of renal dysfunction in 97%, of whom 69% developed renal toxicity of grade 2 (creatinine 260-525 Ixmol/1) or grade 3 (creatinine 525-

Drugs acting on the immune system

Chapter 37

1050 Ixmol/1). Although renal function commonly resolved between successive treatment courses, six patients had a persistently raised creatinine concentration (more than 20% above baseline). Among the various potential risk factors, a multivariate analysis showed that the significant risk factors for severe renal dysfunction were male sex, posttreatment hypertension, and sepsis during treatment.

Drug interactions There are very few data on possible pharmacokinetic interactions with IL2, and this potential has been investigated in 18 patients who underwent surgical resection of hepatic metastases (55cE). Compared with seven control patients not receiving IL-2 before surgery, six patients receiving 9 or 12 MU/m 2 from days 7 to 3 before hepatectomy had a significant fall in the activities of total cytochromes and several mono-oxygenases. No such effect was found in five patients treated with 3 or 6 MU/m 2 before hepatectomy. This suggests that high-dose IL-2 might cause drug interactions.

lnterleuldn-3 (IL-3) The benefit of IL-3 in promoting hemopoietic reconstitution after autologous bone-marrow transplantation has been investigated in 198 patients with malignant lymphoma who received either IL-3 (10 txg/kg for 4 weeks, 130 patients) or placebo (68 patients) (56c). There was no significant advantage of IL-3 over placebo in regard to the number of platelet transfusions before engraftment, the time to platelet engraftment, or the incidence of hemorrhagic complications. This confirms that IL-3 alone has limited clinical effects. In contrast, significantly more patients who received IL-3 had to discontinue treatment because of adverse events (26% vs 7%). Adverse events that were significantly more frequent with IL-3 than with placebo were mucositis (69% vs 44%), headache (38% vs 13%), and rash (25% vs 12%). It is not yet known whether the initial route of administration (continuous intravenous infusion for 7 days followed by subcutaneous administration for 21 days) might account for these findings. The clinical and hematological effects of PIXY321, a genetically engineered GMCSF/IL-3 fusion protein, have been evaluated in 71 women with breast cancer (57c). In addition to chemotherapy (four cycles of fluorouracil, doxorubicin, and cyclophosphamide), the pa-

417 tients received either PIXY321 or placebo from days 3 to 15. Although the incidence and/or duration of chemotherapy-induced severe neutropenia was significantly reduced by PIXY321, there were more frequent systemic adverse effects (fever, chills, abdominal pain, arthralgia, and injection-site reactions) and more severe thrombocytopenia during cycles 3 and 4. Based on these results and the lack of a demonstrable advantage of PIXY321 over GM-CSF (58R), the development of PIXY321 as an adjuvant treatment in cancer was halted.

Immunologic An anaphylactoid reaction to recombinant human IL-3 (rHulL-3) has been described (59A): A 66-year-old man with radiation-induced aplastic anemia and myelodysplastic features failed to respond to multiple therapeutic regimens. A trial of rHulL-3 was begun, but he had transient shortness of breath and hypotension after the first subcutaneous injection. On the next day, 2 hours after the second dose, he had restlessness, dyspnea, spasticity, wheezing, cyanosis, hyperthermia, tachycardia, and hypotension (70/50 mmHg). Full recovery was obtained with fluids, adrenaline, promethazine, and corticosteroids. Histamine release from circulating basophils was the suggested mechanism.

COLONY STIMULATING FACTORS (SED-14, 1270; SEDA-21, 377; SEDA-22, 407; SEDA-23, 399)

Granulocyte colony-stimulating factor (G-CSF) The use of G-CSF in healthy donors of peripheral blood progenitor cells is considered to be reasonably safe. This has been confirmed in an analysis of adverse effects in 737 evaluable patients included in three independent databases from Spain, the USA, and Japan (60c-62c). In one study, the overall incidence of adverse effects was 67%. The most common adverse effects were bone pain (71-90%), headache (17-54%), fatigue (6-33%), insomnia (up to 14%), nausea~vomiting (3-13%), and low-grade fever (6%). Although most adverse effects were rated as moderate, about two-thirds of the patients required analgesics for bone

418 pain or headache. Other adverse events, such as non-cardiac chest pain, paresthesia, itching, or minor injection site reactions, were rare. Very few patients discontinued G-CSF because of clinical toxicity. Moderate thrombocytopenia was common after apheresis; there was more severe, but asymptomatic and promptly reversible thrombocytopenia (below 50 x 1012/1) in up to 3.9% of patients (61 C, 62c). However, the respective contribution of apheresis and G-CSF in thrombocytopenia is difficult to assess. There was also a fall in the absolute neutrophil count to less than 1 • 109/1 in 3% of patients 9-16 days after G-CSF withdrawal (62~). Serum alkaline

phosphatase and lactate dehydrogenase activities were increased about 2-fold compared with posttreatment, a finding explainable by G-CSFinduced neutrophilia (61 c, 62c). Doses higher than 8.8 txg/kg/day, patients younger than 35 years of age, and female sex were significant risk factors for bone pain, headache, and nausea~vomiting respectively (62c). Sufficient data on the potential long-term effects of GCSF in healthy volunteers is still lacking. In 20 donors followed for 6-12 months after peripheral blood progenitor cell collection, there were no particular symptoms or hematological abnormalities (62c). Because there have been isolated reports of arterial thrombosis in patients or donors treated with G-CSF, hemostatic changes have been investigated in 22 healthy donors (63Cr). The patients received G-CSF 5 txg/kg bd for 5 days and underwent a series of laboratory tests before and 96 hours after G-CSF administration, i.e. immediately before leukapheresis. The results suggested possible hypercoagulability, including significant increases in von Willebrand factor and factor VIII and evidence of thrombin generation. The clinical relevance of these findings and of the previously reported effects of G-CSF on platelet aggregation (SED-14, 1270) is unknown, but it should be taken into account in patients with a history of risk factors for atherosclerotic disease, as illustrated by the following report (64A). A 46-year-old donor denied pre-existing cardiac symptoms, but smoking and a family history of coronary artery disease were noted as possible risk factors. The pretreatment electrocardiogram was normal. Six hours after the second and the third doses of G-CSF 10 I~g/kg before peripheral blood progenitor cell collection, he developed symptoms and signs of cardiac ischemia, including palpitation, chest

Chapter 37

ThierryVial and Jacques Descotes

discomfort, trigeminy, and T wave inversion. However, troponin was unchanged. Cardiac catheterization showed severe coronary artery occlusion and he underwent percutaneous transluminal coronary angioplasty. He finally admitted mild exertional chest discomfort 2 weeks before the first dose of G-CSF. Endocrine G-CSF had no effect on thyroid function in 33 patients with cancer, even in patients with pre-existing antibodies (65e). Subclinical and spontaneously reversible hyperthyroidism occurred in eight patients without thyroid antibodies and w i t h normal thyroid function before treatment, but this was felt to be related to stressful procedures. Skin G-CSF caused a lichenoid reaction at an injection site (66A). A 40-year-old woman with metastatic breast cancer received cyclic subcutaneous G-CSF for chemotherapy-induced neutropenia. After 5 months she had a pruritic rash at the injection sites. She did not change the injection sites and the lesions recurred after each injection. Biopsy showed a lichenoid reaction and the lesions healed with residual pigmentation after topical steroid application and G-CSF discontinuation. GM-CSF was well tolerated. Carcinogenesis Although G-CSF mobilization of peripheral blood progenitor cells can be safely achieved in patients with multiple myeloma receiving concomitant effective chemotherapy, G-CSF-induced rapid disease progression and extramedullary tumor growth has been reported in a 47-year-old woman with stable multiple myeloma (67A). Risk factors G-CSF can cause pulmonary complications. A hemodialysis patient developed refractory pleural effusion with prolonged leukopenia and thrombocytopenia, and another developed sudden cyanotic dyspnea with subsequent death after G-CSF administration for drug-induced neutropenia (68A). The authors suggested that hemodialysis patients receiving G-CSF may have an increased risk of adverse effects.

Drugs acting on the immune system

Chapter37

Granulocyte-macrophage colony-stimulating factor (GM-CSF) Nervous system Very few neurological adverse effects have been associated with GMCSE A 49-year-old woman with chronic hepatitis C received filgrastim (G-CSF) for interferon-u-induced leukopenia (69A). Filgrastim was discontinued after 3 months because of leg cramps and back pain. She later received sargramostim (GM-CSF) 500 Ixg twice weekly and she noticed gait unsteadiness and headaches within 2 weeks. During the following 3 months, she developed progressive confusion, forgetfulness, and lethargy, and both interferon-or and sargramostim were withdrawn. She rapidly deteriorated and died from central hypoventilation 6 days later. Autopsy showed atypical, perivascular, lymphoid infiltrates in the white matter, basal ganglia, hypothalamus, brain stem, cerebellum, and spinal cord. Serum hepatitis C virus DNA sequences were not detected. This case of fulminant perivascular lymphocytic proliferation suggests that some of the effects of GM-CSF on white blood cell proliferation can sometimes produce unexpected adverse effects.

Immunologic Immediate hypersensitivity reactions have been rarely reported with both G-CSF and GM-CSF, but cross-sensitivity and possible desensitization have not been documented. A 42-year-old woman with defective immunological function had generalized pruritus, flushing, shortness of breath, and general discomfort within 30 minutes of her 16th intravenous injection of molgramostim (70A). Her symptoms resolved with adrenaline, hydrocortisone, and promethazine. Despite the prophylactic use of corticosteroids and antihistamines, she developed a similar reaction after molgramostim readministration and 4 hours after the fourth injection of filgrastim. Positive skin prick tests to molgramostim and filgrastim suggested IgEmediated hypersensitivity. An acute desensitization protocol starting with molgramostim 0.0008 txg increasing to 320 txg was successful, and molgramostim was later continued uneventfully.

Stem cell factor (SCF) Stem cell factor, added to other recombinant hemopoietic cytokines, is used to increase the mobilization of peripheral blood progenitor cells.

419 In 102 patients with multiple myeloma, stem cell factor plus G-CSF produced more frequent injection site reactions and more frequent skin reactions (25% vs 2%), namely rash, erythema,

urticaria, pruritus, and abnormal pigmentation, compared with G-CSF alone (71c). These reactions occurred despite systemic prophylactic antihistamines. Other adverse effects occurred with similar frequency in the two groups of patients.

MONOCLONAL ANTIBODIES (SED-14, 1308; SEDA-21, 379; SEDA-22, 409; SEDA-23, 401) The clinical uses of monoclonal antibodies are expanding year by year. Various antibodies have now been approved, and many others are still under investigation. The main fields of interest are related to transplantation, the treatment of autoimmune or chronic inflammatory disorders, and various malignancies. Various monoclonal antibodies have been developed to be used as carrier molecules or as immunoconjugates to target drugs, enzymes, isotopes, or toxins to tumor cells. In a recent review some of the available data have been summarized (72R). There is still insufficient evidence of clinical benefit.

Alemtuzumab (campath-lH) Alemtuzumab, a humanized monoclonal antibody targeted against the CD52 antigen of lymphocytes and monocytes, is being investigated for the treatment of chronic lymphocytic leukemia. It has also been used to deplete circulating lymphocytes in patients with multiple sclerosis (73c). Nine of 27 patients with multiple sclerosis developed clinical and/or biological features of Graves' disease 6-31 months after a 5-day pulse of alemtuzumab, a finding that was not reported in patients treated for other disorders.

Basiliximab Important warnings have recently been released by the manufacturers of basiliximab regarding the possible risk of severe hypersensitivity reactions within 24 hours of initial exposure or after re-exposure after several months, based on

420 17 reports that included cardiac and/or respiratory failure, bronchospasm, urticaria, cytokine release syndrome, and capillary leak syndrome.

Etanercept Although included here for convenience, etanercept is not an antibody, but a dimeric fusion protein consisting of two recombinant p75 TNF receptors fused with the Fc portion of human IgG1. It inhibits the binding of TNF-c~ to its receptor, and thereby neutralizes TNFot biological activity. It has been approved for the treatment of moderate to severe active rheumatoid arthritis in patients who have failed to respond to previous disease-modifying antirheumatic drugs. The therapeutic use and safety of etanercept has been reviewed (74R). Mild-to-moderate injection site reactions were the most common adverse effects (42-49%), with a frequency 3.8 to 6 times greater than with placebo. Non-neutralizing antibodies to etanercept were rarely detected. As regards the development autoantibodies and compared with placebo recipients, etanercept-treated patients more often developed new antinuclear antibodies or antidouble-stranded DNA antibodies, but no patient developed symptoms suggestive of an autoimmune disease during clinical trials. Important postmarketing warnings that have recently been issued by the regulatory agencies and the manufacturers are related to a possible risk of aplastic anemia and pancytopenia (10 reported cases of which five ended in fatal sepsis) and to a possible increased risk ofdemyelinating disorders, such as multiple sclerosis, myelitis, and optic neuritis, in patients with pre-existing or a recent history of demyelinating disorders. The latter risk was in keeping with the results obtained in a placebo-controlled trial of lenercept, another recombinant TNF receptor immunoglobulin fusion protein, in 168 patients with multiple sclerosis (75c). Compared with placebo, significantly more patients randomized to lenercept had exacerbation of multiple sclerosis, and exacerbation also occurred earlier. Etanercept caused widespread skin reactions in two women with rheumatoid arthritis aged 58 and 78 years (76A). Skin biopsies showed discoid lupus erythematosus in one and a necrotizing vasculitis with eosinophils in the other. Skin

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Infliximab (cA2) Infliximab, a monoclonal chimeric human/murine antibody directed against TNF-ct, has recently been approved for the treatment of severe active Crohn's disease (77r, 78R). It is alSO being investigated in the treatment of rheumatoid arthritis (79c). From the available data submitted for Crohn's disease to the US and European regulatory agencies, the most significant acute adverse reactions were infusion reactions, defined as symptoms within 2 hours after intravenous infusion. The symptoms consisted of fever, chills, urticaria, dyspnea, chest pain, or hypotension, and occurred in 16% of infliximab-treated patients versus 6-7% of placebo-treated patients. Several adverse effects, such as upper respiratory tract infections, headaches, rash, or cough, were more common than with placebo, but severe adverse effects were only slightly more frequent (3.6% vs 2.6%). Clinical trims also showed an increase

in the prevalence of antinuclear antibodies or the development of double-stranded DNA antibodies (9% of patients). Although there were clinical features suggestive of the lupuslike syndrome in only very few patients, this issue needs to be further investigated. Also of great concern is the report in several patients of lymphoma (80 c) or severe opportunistic infections (81c). Patients taking concomitant ilnmunosuppressive drugs should be carefully observed for such complications.

Immunologic Whereas antibodies to infliximab were rarely found in patients with rheumatoid arthritis also taking methotrexate, low titers were detected in about 13% of patients with Crohn's disease. Their presence increased the risk of infusion reactions, and they might also predispose to the occurrence of serum sickness-like reaction after delayed retreatment. Of 40 patients who had received multiple doses of an investigational liquid formulation of infliximab 2-4 years before, 10 had a severe delayed hypersensitivity reaction within 3-12 days after the first or the second re-infusion (82c). This reaction mostly included myalgia, rash, fever, polyarthralgia, and pruritus. Although the six patients tested were negative for antibodies to infliximab before re-infusion, these antibodies were consistently raised after the reaction.

Drugs acting on the immune system

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Orthoclone (OKT3) Nervous system Orthoclone-induced aseptic meningitis is relatively common and is usually benign, with prompt recovery despite continuation of treatment. In a 28-year-old man the clinical features of aseptic meningitis were prolonged over 1 month after orthoclone administration, and persistent severe headaches resolved only after several aspirations of cerebrospinal fluid (83A). This case was described as a syndrome of headache with neurological deficits and CSF lymphocytosis (HaNDL syndrome).

421 the introduction of rituximab. First-dose reactions mostly occurred in patients with high numbers of circulating blood tumor cells and were ascribed to a rapid tumor lysis syndrome (86 C, 87cr). In 11 patients with malignant B cell leukemia, first-dose reactions were significantly more severe in patients whose baseline lymphocyte count was higher than 50 • 106/1 and were also associated with raised peak serum concentrations of TNF-c~ and IL-6 (88c). Desquamative alveolitis has also been reported in a 55-year-old woman with mantle-cell lymphoma (89c).

Trastuzumab Immunologic Rare anaphylactic reactions with antiorthoclone IgE antibodies have been previously reported (SED-14, 1309). An anaphylactoid reaction to orthoclone is also possible (84A). A 15-year-old girl underwent uneventful renal transplantation. On the third postoperative day she received her first dose of orthoclone for a presumptive diagnosis of graft rejection. Despite premedication with diphenhydramine, paracetamol, and high-dose methylprednisolone, within 20 seconds after intravenous orthoclone, she developed shortness of breath, digital paresthesia, facial edema, laryngeal stridor, reduced oxygen saturation, and a fall in blood pressure. She recovered after intubation and appropriate vasopressor administration, but required transplant nephrectomy for hemorrhagic and coagulative necrosis of the transplanted kidney.

Trastuzumab is a recombinant humanized monoclonal antibody that binds to the HER2 receptor, which is expressed in 25-30% of primary breast cancers. It has been approved for the treatment of selected patients with metastatic breast cancer whose tumors overexpress the HER2 protein (90R). Adverse effects mostly consisted of infusion-related constitu-

tional symptoms, digestive disorders (diarrhea, vomiting), pain, cough, headache, dyspnea, mild infections, and insomnia. Compared with

This acute reaction was supposedly mediated by non-immunologic mast cell degranulation, as screening for IgE antiorthoclone antibodies was negative.

chemotherapy alone, the addition of trastuzumab more often produced moderately severe adverse hematological effects (leukopenia and anemia) and diarrhea. Severe congestive cardiac failure is a major consequence of trastuzumab treatment. According to the product labelling, severe cardiac failure was observed in 5-19% of patients (trastuzumab alone versus trastuzumab plus anthracycline and cyclophosphamide).

Carcinogenesis An analysis of the Australia

Other antibodies

and New Zealand Dialysis and Transplant Registry (7953 patients with 9460 renal transplants) has confirmed that immunosuppression with polyclonal and monoclonal orthoclone antibodies independently increases the risk of virus-mediated cancer (85c). The increased risk was about 60% for non-Hodgkin's lymphoma and 75% for non-Hodgkin's lymphoma plus carcinoma of the cervix, vagina, and vulva in women.

Rituximab Severe and sometimes life-threatening firstdose reactions were recognized shortly after

Several humanized CD3 antibodies have been produced and tested, with the aim of reducing the adverse effects associated with the murine orthoclone antibody. The first results in renal transplant patients are encouraging, with promising clinical results, no evidence of antiglobulin response, and no or very few and minimal adverse effects attributable to various humanized monoclonal CD3 antibodies (91 C, 92c). In particular, careful patient monitoring failed to identify any significant cytokine release syndrome.

422

IMMUNOSUPPRESSIVE DRUGS Azathioprine and mercaptopurine (SED-14, 1280; SEDA-21, 381; SEDA-22, 409; SEDA-23, 401) The relation between thiopurine methyltransferase (TPMT) activity, clinical effects, and the occurrence of azathioprine-associated adverse effects continues to be investigated. In 22 children with renal transplants, high erythrocyte TPMT activity, measured 1 month after transplantation, correlated positively with rejection episodes during the first 3 months, and this was probably due to more rapid azathioprine catabolism (93c). As suggested in a study of 180 patients with acute lymphoblastic leukemia, determination of genetic polymorphisms in TMPT may be useful in predicting potential toxicity and in optimizing the determination of an appropriate dose in patients who are homozygous or heterozygous for TMPT deficiency (94c).

Hematologic Myelosuppression due to the direct toxic effects of mercaptopurine is common. Although prospective identification of TPMT polymorphism aimed at detecting patients at risk of severe hematological disorders, it failed to identify a number of patients who developed neutropenia or abnormal liver function tests during the course of azathioprine treatment, suggesting that factors other than TPMT polymorphism are likely to be involved in these cases. This has again been suggested in 78 patients treated with azathioprine for systemic lupus erythematosus, of whom 10 developed azathioprine-associated reversible neutropenia (95c). Only one of these patients was homozygous for TPMT deficiency, but it should be noted that he had the most severe episode (aplastic anemia). The first case of immune hemolytic anemia has been reported in a 67-year-old man treated with mercaptopurine for chronic myelomonocytic leukemia (96A). Serology showed a positive direct antiglobulin test and confirmed the presence of mercaptopurine drug-dependent antibodies. The patient improved and the direct antiglobulin test was no longer positive 20 days after mercaptopurine withdrawal.

Gastrointestinal Diarrhea may be isolated or part of the azathioprine hypersensitivity

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ThierryVialand Jacques Descotes

syndrome. In two patients with azathioprineinduced diarrhea proven by positive rechallenge, the period of sensitization ranged from 1 week to 1 year (97A).

Liver Azathioprine has recently been suggested as an additional risk factor for severe liver disease outcome in transplant patients with chronic viral hepatitis (SEDA-20, 341; SEDA23, 402). Fatal fibrosing cholestatic hepatitis has been reported in a 63-year-old cardiac transplant patient with acquired post-transplant hepatitis C virus infection whose immunosuppressive regimen included azathioprine (98A). Histology showed several features of azathioprine hepatotoxicity, namely veno-subocclusive lesions and nodular regenerative diffuse hyperplasia, suggesting a pathogenic role of azathioprine.

Pancreas

In a review of definite or probable drug-associated pancreatitis spontaneously reported to the Dutch adverse drug reactions system during 1977-98, azathioprine was the suspected drug in four of 34 patients, two of whom had positive rechallenge (28c). Although most of the carefully described reports of azathioprine-induced pancreatitis were found in patients with inflammatory bowel disease, transplant recipients might also suffer this complication. Over a year after renal transplantation, a 48-year-old man, who took azathioprine, ciclosporin, and prednisolone, developed acute necrotizing pancreatitis (99A). Improvement was obtained after azathioprine withdrawal, but he again took azathioprine and had similar symptoms within 30 hours after a single dose. Musculoskeletal In two patients with Crohn's disease, azathioprine was suspected to have caused severe gait disorders with an incapacity to walk (100A). Within 1 month of treatment both had joint pains or diffuse arthralgias that were the presumed cause of pseudoparalysis of the legs. In one patient other causes were carefully ruled out and similar symptoms recurred shortly after azathioprine was reintroduced.

Immunologic Hypersensitivity reactions to mercaptopurine or azathioprine are well described, but a true immunoallergic reaction has never been convincingly demonstrated. Desensitization has been successfully performed

Drugs acting on the immune system

Chapter 37

in isolated patients (101A), and this has been more extensively addressed in a retrospective analysis of the charts of patients treated for inflammatory bowel disease (102c). Of 591 patients observed over a 28-year period, 16 (2.7%) developed allergic reactions, which mostly consisted of fever (14 patients), joint pains (six patients), or severe back pain (five patients). Symptoms commonly appeared within 1 month and lasted 5 days on average. All nine patients rechallenged with mercaptopurine had similar but less severe symptoms. Further rechallenge with azathioprine in six of these patients caused symptoms in five of them. Careful desensitization with mercaptopurine or azathioprine was attempted in five patients, and resulted in tolerance and therapeutic success in four. The last patient, who had a previous history of mercaptopurine-induced sepsis-like syndrome with renal insufficiency, had a similar reaction after only one-quarter of the dose of azathioprine. This study suggests that a direct switch from mercaptopurine to the parent drug azathioprine cannot be recommended in patients who developed allergic reactions to mercaptopurine, and that desensitization should not be attempted in patients with previous lifethreatening hypersensitivity reactions. Carcinogenesis Mercaptopurine is not considered to be leukemogenic, but this assumption has been disputed in a study of 439 children who received mercaptopurine as part of their maintenance therapy for acute lymphoblastic leukemia (103c). Five patients developed secondary myelodysplasia or acute myeloid leukemia 23-53 months after diagnosis, a consequence that was attributed to mercaptopurinc. These five patients had significantly lower TPMT activity, and two were classified as heterozygous for TPMT deficiency on genotype analysis. Although the number of evaluable patients was small, the suggestion was that a subset of patients with low TMPT activity might have an increased leukemogenic risk when exposed to mercaptopurine with other cytotoxic agents. Whether these findings can be extrapolated to patients without cancers is not known. Of 550 patients treated for inflammatory bowel disease for a mean of 8 years, 25 (4.5%) developed a malignancy, with an overall incidence of 2.7 neoplasms per 1000 years of follow-up (104c). The numbers of the most

423 commonly observed cancers, such as bowel cancers (eight patients), breast cancers (three patients), or single cases of other cancers, did not seem to be higher than expected in the general population or in the inflammatory bowel disease population. Although mercaptopurine was suspected in two cases of testicular carcinoma, two cases of lymphoma, and one case of leukemia, the authors emphasized the small risk of malignancies compared with the beneficial results of mercaptopurine in inflammatory bowel disease. Teratogenicity There are very few data on the possible reproductive effects of purine analogs in men. The consequences of paternal mercaptopurine exposure on the outcome of pregnancies have been retrospectively studied in 57 men with inflammatory bowel disease; 23 men had fathered 50 pregnancies and had taken mercaptopurine before conception--of these, 13 pregnancies were conceived within 3 months of paternal mercaptopurine use (group 1A) and 37 pregnancies were conceived at least 3 months after paternal mercaptopurine discontinuation (group 1B); the other 34 men, who fathered 90 pregnancies, had not been exposed to mercaptopurine before conception (group II) (105c). Of the 140 conceptions, two resulted in congenital anomalies in group 1A, whereas there were no congenital anomalies in the other groups. One child had a missing thumb and the other had acrania with multiple digital and limb abnormalities. The overall number of complications (spontaneous abortion and congenital anomalies) was significantly higher in group 1A (4/13) compared with both group IB (1/37) and group II (2/90). Although the retrospective nature of this study and the limited number of evaluable patients precluded any definitive conclusion, the observed congenital anomalies were similar to those found in the offspring of female rabbits treated with mercaptopurine during pregnancy, and suggested that patemal mercaptopurine treatment should ideally be discontinued at least 3 months before planned conception. Whereas neutropenia and immune deficiencies can affect neonates born to transplant patients, the exact role of azathioprine is difficult to establish. A recent report has suggested that such effects should also be expected in neonates bom to patients taking azathioprine for other conditions (106k).

Chapter 37

424 A 27-year-old woman who took azathioprine (125 mg/day) and mesalamine (3 g/day) during her whole pregnancy, delivered a normal boy who had febrile respiratory distress after 36 hours. Chest Xray showed interstitial pneumonitis and thymus hypoplasia. There was severe neutropenia (20 • I06/I), lymphopenia (24 x 106/1), and hypogammaglobulinemia. His clinical condition improved over the next 26 days with immunoglobulin treatment and antibiotics, but B lymphocytes and IgM were still undetectable. Drug interactions The effect of azathioprine or mercaptopurine on the anticoagulant effects of warfarin or acenocoumarol has again been discussed (107 A, 108A). Both patients required an approximate 3-fold increase in the weekly anticoagulant dosage while taking azathioprine or mercaptopurine. A pharmacokinetic interaction was the most likely cause, but the mechanism (impaired absorption or enhanced anticoagulant metabolism) is unknown.

Ciclosporin

(SED-14,1286;

SEDA-21, 382; SEDA-22, 411; SEDA-23, 402) In renal transplantation, ciclosporin maintenance monotherapy can be effectively achieved in a subset of patients with the aim of reducing adverse effects associated with corticosteroids or azathioprine, but this should be carefully balanced against the risks of acute or chronic allograft rejection. This approach has again been emphasized based on data from 100 adult patients and a review of the most recent literature (109CR). According to the authors, clinical predictors of successful ciclosporin maintenance therapy included compliant patients over 25 years old with a donor age younger than 40 years, patients with later azathioprine withdrawal, patients with serum creatinine concentrations of 125 Ixmol/1 or less, patients without a history of rejection (or one rejection episode responding favorably to corticosteroids), and patients who have successfully discontinued corticosteroids 6 months before. Nervous system Although ciclosporin neurotoxicity is a well described complication after transplantation, there is still debate about whether or not it crosses the blood-brain barrier and enters the cerebrospinal fluid. Ciclosporin could not be identified in the cerebrospinal fluid from 14 patients with liver transplants

ThierryVialand Jacques Descotes

who had various neurological complications (110c). Ciclosporin metabolites were measurable in the cerebrospinal fluid in only four patients, who had evidence of acute renal insufficiency, cholestasis, and raised blood concentrations of ciclosporin metabolites but identical ciclosporin parent drug blood concentrations compared with 10 patients with undetectable concentrations of ciclosporin metabolites in the cerebrospinal fluid. Ciclosporin metabolites enter the cerebrospinal fluid, and direct neurotoxicity is therefore possible in at least some patients with renal or hepatic dysfunction. Severe ciclosporin neurotoxicity has mostly been reported in transplant patients, but should also be considered in non-transplanted patients. A 87-year-old patient with resistant nodular prurigo was successfully treated with ciclosporin (3 mg/kg/day) and prednisone (10 mg/day) (lllA). Bilateral numbness and distal limb weakness developed after 18 months. Clinical examination, electromyography, and nerve conduction studies confirmed a diffuse axonal neuropathy which rapidly progressed over the next 2 months. Ciclosporin alone was withdrawn and complete remission was observed within 3 months. Unfortunately, ciclosporin blood concentrations and renal function at the time of diagnosis were not reported. Mineral balance Hypomagnesemia in the early post-transplant period is sometimes due to ciclosporin, and this has been cited as a possible risk factor for acute ciclosporin neurotoxicity. Ciclosporin-induced sustained magnesium depletion has been investigated in 109 ciclosporin-treated patients with renal transplants who had been stable for more than 6 months (112c). Total and ionized plasma magnesium concentrations were significantly lower than in 21 healthy volunteers and in 15 patients with renal transplants who were not taking ciclosporin. Ciclosporin-treated patients who were also taking hypoglycemic drugs had lower plasma magnesium concentrations, but patients taking diuretics did not. U r i n a r y t r a c t The contribution of ciclosporin to chronic nephrotoxicity in patients with renal allografts is a matter of continuing investigation. Of 91 consecutive patients with renal transplants with a minimum graft survival of 1 year who were followed for 7-8 years, 65% had

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Chapter37

stable renal function despite ciclosporin serum concentrations of 200-250 ng/ml (113c). In addition, none of the 26 patients with worsening renal function had features of ciclosporin nephrotoxicity on renal biopsy. Thrombotic microangiopathy is a wellknown complication of ciclosporin therapy after transplantation. The contributory factors have been retrospectively investigated in 50 of 188 patients with kidney or kidney + pancreas allografts who underwent graft biopsies and in 19 control patients who had never had renal graft dysfunction or a biopsy (114c). There were definite histological features of thrombotic microangiopathy 4 days to 6 years after transplantation in 26 patients, of whom 24 were taking ciclosporin and two were taking tacrolimus, showing that this complication can occur at any time after transplantation. Eight patients had graft loss, but only two had associated systemic evidence of microangiopathy, i.e. thrombocytopenia and intravascular hemolysis, suggesting that thrombotic microangiopathy should be considered in any patients with renal graft dysfunction, even if there are no suggestive systemic symptoms. Although the more frequent use of the microemulsion form of ciclosporin (Neoral | in patients with confirmed thromboric microangiopathy than in controls suggested a possible role of this formulation, this issue remained to be further investigated, because the number of evaluable patients was small. None of the other investigated variables (age, sex, race, living-related or cadaveric donor status, the degree of HLA mismatch, type of allograft, or the incidence of urinary tract infections after transplantation) were significantly associated with the occurrence of thromboric microangiopathy compared with patients without thrombotic microangiopathy. Finally the most successful strategy was a switch from ciclosporin to tacrolimus, which resulted in normalization of graft function in 81% of these patients.

Hair, nails, and sweat #ands

Nail changes sometimes occur in ciclosporin-treated patients. Marked pitting with Mees' lines (homogeneous transverse white lines in the nail plates) in the fingernails, a disorder that has not been previously reported, was attributed to ciclosporinassociated kidney dysfunction in a 41-year-old man who inadvertently took ciclosporin 300 mg/day for psoriasis (115A).

425 Musculoskeletal Muscle disorders attributed to ciclosporin have been mostly described in anecdotal case reports (SED-14, 1291). This topic has been reanalyzed in a systematic review of published papers, in which relevant information from a total of 34 patients was identified (116M). All but two patients were also taking concomitant drugs known to affect the muscles, among which corticosteroids, simvastatin, lovastatin, colchicine, and pyrazinamide were the most frequently cited. Ciclosporin is therefore difficult to implicate in most patients, but at least one case with positive ciclosporin readministration supported a causative role. The clinical picture was nonspecific, with myalgias, cramps, and muscle weakness, sometimes associated with raised serum creatine kinase activity, and heterogeneous histopathology. Finally, skeletal muscle abnormalities have rarely been described in patients without muscle symptoms. Drug interactions As many drug interaction studies or case reports involving ciclosporin are published each year, only those that add significant information will be cited here. Drugs that reduce ciclosporin blood concentrations Clindamycin In two lung transplant patients aged 39 and 48 years, blood ciclosporin concentrations fell after the addition of oral clindamycin (1.8 g/day), and both patients required temporary increases in daily ciclosporin dose until clindamycin withdrawal (117A). Hypericum perforatum St John's wort (Hypericum perforatum), which is used for mild depression, is a recently recognized inducer of cytochrome P450. This herbal drug has been reported to cause a rapid dramatic fall in ciclosporin blood concentrations, resulting in acute heart transplant rejection in two patients aged 61 and 63 years (l18A). Later on, Hypericum perforatum was confirmed to produce an average 50% reduction in ciclosporin blood concentrations (119c). Orlistat There was a 2-fold reduction in blood ciclosporin concentrations 2 weeks after odistat was given to a 61-year-old patient with a heart transplant (120A). The FDA has received six reports of subtherapeutic blood ciclosporin con-

426 centrations soon after transplant recipients started to take orlistat (121A). Reduced absorption of ciclosporin was the most likely mechanism. Sulfasalazine In a 51-year-old woman with a renal transplant who had been stable for the past 13.5 months with ciclosporin (9.6 mg/kg) and sulfasalazine (1.5 g/day) for ulcerative colitis, sulfasalazine withdrawal resulted in an almost 2-fold increase in ciclosporin blood concentrations over the next 10 days (122A). Ticlopidine Although there was no interaction between ciclosporin and ticlopidine in a previous phannacokinetic study, a 64-year-old patient with a renal transplant had a reduction in the concentration:dose ratio of ciclosporin after each of two successive courses of ticlopidine (123A). Drug that increase ciclosporin blood concentrations Chloramphenicol Chloramphenicol was suspected of causing a dramatic increase in ciclosporin blood concentrations in a single patient (124A). However, multiple concomitant confounding factors made this interaction purely speculative. Protease inhibitors Interactions of ciclosporin with protease inhibitors have been poorly explored but should be expected, particularly with ritonavir, a known potent inhibitor of CYP3A. Despite a prophylactic reduction in the dose of ciclosporin (100 mg/day) before antiretroviral treatment, a 40-year-old woman had an acute increase in ciclosporin trough concentrations (over 1000 ng/mi) and serum creatinine concentration (from 84-228 Ixmol/1) after taking zidovudine (600 mg/day), saquinavir (800 mg/day), and ritonavir (800 mg/day) for 11 days (125A). Despite ciclosporin withdrawal, ciclosporin and creatinine blood concentrations remained high for over l0 days until triple drug therapy was withdrawn. Ritonavir was the most likely suspect. Pharmacodynamic interactions Imipenem/cilastatin In contrast to what has previously been stated, there was no significant increase in the frequency of seizures among 77 patients with bone-marrow trans-

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plants who were taking ciclosporin alone (three seizures), 45 patients taking ciclosporin plus imipenern/cilastatin (two seizures), and 44 patients taking imipenem/cilastatin alone (no seizures) (126c). NSAIDs NSAIDs combined with ciclosporin carry a theoretical risk of enhanced nephrotoxicity. In an 8-year-old girl with rheumatoid arthritis, this combination was suggested to have caused biopsy-proven non-specific colitis, because her symptoms occurred only when both drugs were used together (127A). Indomethacin and diclofenac were the NSAIDs used. Effects of ciclosporin on other drugs HMG-CoA reductase inhibitors Patients taking concomitant ciclosporin and conventional dosages of lovastatin or simvastatin may develop acute muscular toxicity (SED-14, 1296). Among 110 ciclosporin-treated patients with heart transplants, four of 18 patients taking simvastatin 20 mg/day developed rhabdomyolysis, whereas none of the patients taking simvastatin 10 mg/day (26 patients) or pravastatin 20 mg/day (66 patients) had similar symptoms (128c). Inhibition of CYP3A by ciclosporin was the most likely mechanism. In another study there was a 5-fold higher AUC of lovastatin (10 mg/day for 10 days) in 16 patients taking ciclosporin compared with 13 patients not taking ciclosporin (129c). In accordance with this mechanism, similar interactions are expected with other HMG-CoA reductase inhibitors that are metabolized by CYP3A, namely atorvastatin and cerivastatin. Indeed, the addition of atorvastatin (10 mg/day) to a multidrug regimen including ciclosporin in a 40-year-old patient with a renal transplant resulted in rhabdomyolysis within 2 months (130A). Ciclosporin also produced a 3- to 5fold increase in the plasma concentrations of cerivastatin and its metabolites in 12 patients with renal transplants who took cerivastatin 0.2 mg/day for 7 days compared with a single dose in 12 healthy controls (131c). Dosages of atorvastatin, cerivastatin, lovastatin, and simvastatin should therefore be reduced in patients taking ciclosporin. Idarubicin In 27 patients ciclosporin caused a marked increase in the AUC of idarubicin and its main metabolite idarubicinol, perhaps

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427

due to inhibition of the multidrug transporter P-glycoprotein (132 c).

species and several inactive by-products, but very few metabolic interactions involving cyclophosphamide have been reported. In a retrospective study of 22 children treated with cyclophosphamide for cancer or bone-marrow transplantation, cyclophosphamide clearance was significantly lower in nine patients taking fluconazole compared with 13 patients not taking it (137CE). In vitro studies in human liver microsomes confirmed that the rate of 4-hydroxylation of cyclophosphamide was inhibited by fluconazole. In another study daily prednisolone significantly reduced the total clearance of cyclophosphamide and the peak concentration and AUC of 4-hydroxycyclophosphamide (138c). It is not known whether these previously unreported interactions have clinical consequences.

Mycophenolate mofetil Although an interaction between ciclosporin and mycophenolate mofetil had not been previously described, this possibility was investigated in 52 renal transplant patients taking triple therapy (ciclosporin, mycophenolate mofetil, and prednisone), who continued taking the same treatment (19 patients) or underwent elective ciclosporin withdrawal (19 patients) or prednisolone withdrawal (14 patients) 6 months after transplantation (133c). Median mycophenolate mofetil trough concentrations 3 months later were about 2fold higher in patients who had discontinued ciclosporin compared with patients who continued to take triple therapy and patients who had discontinued prednisone. No clear mechanism readily explains these changes.

Methotrexate (SED-14, 1297;

Cyclophosphamide

(SED-14, 1283; SEDA-21, 386; SEDA-22, 410; SEDA-23, 405)

SEDA-21, 387; SEDA-22, 416; SEDA-23, 406; see also Chapter 45)

Carcinogenesis Cyclophosphamide-induced bladder toxicity is well known, but data on the possible consequences on the upper urinary tract are sparse. In a few cases normal cystoscopy did not rule out renal tract toxicity.

Respiratory Based on a report of nine cases

A 72-year-old woman who received 1400 mg cyclophosphamide over 2 weeks for Wegener's granulomatosis had gross hematuria and dysuria (134A). Cystoscopy was normal, but there was marked irregularity of the mucosa of the upper ureteric mucosa, the renal pelvis, and the renal calyces on retrograde ureteropyelography. Nephroscopy showed a gray necrotic uroepithelium with dystrophic calcification. Renal adenocarcinoma has been reported in a 50-year-old man after 3 years of cyclophosphamide treatment for hepatic sarcoidosis (135A).

Teratogenicity Based on one case and a review of six previous reports of malformations after in utero exposure to cyclophosphamide in the first trimester, a distinct embryopathy due to cyclophosphamide has been suggested (136Ar). The proposed phenotype included growth defi-

ciency, developmental delay, craniosynostosis, blepharophimosis, flat nasal bridge, abnormal ears, and distal limb defects. Drug interactions Cyclophosphamide is a prodrug that requires cytochrome P450-dependent hepatic activation to produce alkylating

and a careful reanalysis of 123 previously published cases, the clinical spectrum and histopathology of methotrexate-induced pneumonitis have been reviewed (139CR). The authors again stressed that methotrexate pneumonitis should be promptly recognized to avoid a severe outcome, although no specific features could be identified compared with other druginduced adverse lung effects and no definite pathological findings compared with rheumatoid lung. Diagnostic criteria therefore mostly included a history of exposure, the exclusion of other pulmonary diseases, especially infections, and the presence of pulmonary infiltrates on the chest X-ray. Once methotrexate pneumonitis developed, 13% of the patients died from respiratory failure, clearly underlining the fact that methotrexate pneumonitis is potentially life-threatening. Methotrexate reintroduction should also be strongly discouraged in such cases, because about 25% of patients experience recurrence. Even though methotrexate pneumonitis was first described about 30 years ago, very little is known about the mechanism, and whether it is due to direct cumulative toxicity, hypersensitivity, or an idiosyncratic reaction. In a recent case, IL-8 was speculated to play an important role in the pathogenesis of methotrexate-induced pneumonitis (140c).

428

Hematologic Impaired renal function is an obvious risk factor for methotrexate-induced pancytopenia. This has been clearly illustrated in a 57-year-old man who had been on hemodialysis for the past 5 years and who developed severe pancytopenia 12 days after a single dose of methotrexate 5 mg (141A). Liver Methotrexate-associated liver disorders have often been described. The incidence and risk factors of rises in serum transaminases have been detailed from a retrospective analysis of 66 patients with rheumatoid arthritis (142c). There was an asymptomatic increase in serum AsT and A1T in 42 and 49% of patients respectively, an incidence 4-5 times greater than that found in 21 patients taking other diseasemodifying antirheumatic drugs. Although most of the rises in transaminases were transient and spontaneously reversible, 14 patients had sustained rises. There was a close relation between the incidence of high transaminases and the weight-adjusted dose of methotrexate. In a multivariate regression analysis, only obesity, methotrexate dose (over 0.15 mg/kg/week), and the concomitant presence of gastrointestinal adverse effects were significantly and independently associated with the likelihood of a rise in A1T. In the 14 patients who had persistently high transaminases, weekly folic acid 5 mg produced a sustained fail in serum A1T within 3 months, but three patients had to be withdrawn because of exacerbation of rheumatoid arthritis. Skin Persistent hyperpigmentation is an unusual manifestation of weekly administration of methotrexate (143A). Severe cutaneous reactions after low-dose methotrexate are infrequent. One report has described severely ulcerated psoriatic plaques and acute extensive exfoliative dermatitis in a 37-year-old man who had taken methotrexate for 5 years for psoriasis (144A). There was a characteristic clinical and histopathological spectrum of skin lesions, distinct from rheumatoid papules, in four patients who took low-dose methotrexate for acute flares of collagen vascular disease (145c). These socalled methotrexate-induced rheumatoid papules developed shortly after methotrexate administration, consisted of erythematous indurated papules mostly affecting the proximal limbs, and disappeared after methotrexate was

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ThierryVial and Jacques Descotes

withdrawn or tapered. Histology showed inflammatory infiltrates of interstitially arranged histiocytes and a few neutrophils, but no features of leukocytoclastic vasculitis. Musculoskeletal There are still uncertainties about the possible effects of methotrexate on bone metabolism and bone loss, and this has again been discussed in the context of two adults (146 A) and in relation to a study in children with juvenile rheumatoid arthritis (147 C) who had delayed bone healing after surgery. The two adults, aged 52 and 62 years, had been taking methotrexate (7.5 and 15 mg/week) for 14 and 15 months when they underwent metatarsal and tibial osteotomy. Because X-ray examination 5 and 6 months after surgery showed non-union, methotrexate was withdrawn; the bone healed promptly in both patients within 2 months. The authors thought that the outcome in these patients without risk factors for bone fragility suggested that temporary methotrexate withdrawal should be considered in cases of delayed bone healing after surgery. In contrast, in a longitudinal study of 32 patients with juvenile rheumatoid arthritis, there was no evidence of deleterious effects of longterm, low-dose methotrexate on bone mass density (147c). The cumulative dose of corticosteroids, weight, and height were the main determinants of bone mass changes. Immunologic Immediate hypersensitivity reactions have not previously been reported after low-dose methotrexate. A 53-year-old woman had three episodes of angio-edema while taking methotrexate, with no recurrence after withdrawal (148A).

Carcinogenesis There is still no clear evidence that low-dose methotrexate increases the risk of cancer in patients with rheumatoid arthritis (149R), but a relation between methotrexate treatment and lymphoma cannot be ruled out. Two patients developed lymphomas within 3 years of methotrexate treatment, and the authors suggested that an increase in serum IgE concentrations might anticipate the development of lymphoma in patients with rheumatoid arthritis treated with methotrexate (150c). Teratogenicity The developmental effects of in utero exposure to methotrexate have recently been reviewed, including a brief mention of

Drugs acting on the immune system

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three original cases (151AR), and a series of pregnancy outcomes in four patients exposed to low-dose methotrexate during early pregnancy has been reported more extensively (152 c). When taking into account all the previously published data on low-dose methotrexate exposure during pregnancy, no more than 24 cases are available for evaluation. These patients took 2.5-35 mg/week and were accidentally exposed from the beginning of pregnancy up to 19 weeks gestation. Pregnancy ended in spontaneous abortion in four patients and elective abortion in three (including one case of major malformation). Of the 17 neonates, three had major malformations. The malformations mostly consisted of central nervous system or craniofacial abnormalities and skeletal defects. Three patients had been exposed up to 8 weeks of gestation and one from 8 to 10 weeks, and the methotrexate doses were 12.5-35 mg/week. This is consistent with the threshold dose of 10 mg/week and the timing of exposure previously suggested for fetal methotrexate syndrome. Unfortunately, little is known about the possible long-term effects of methotrexate on physical and mental development of the offspring of patients exposed during the early phase of pregnancy. A 3-year-old infant born to a woman who had taken methotrexate 37.5 mg/week throughout the first 8 weeks after conception had significant developmental delay with mental retardation, which might therefore be a feature of the fetal methotrexate syndrome (153 A).

Mycophenolate mofetil (SED-14, 1303; SEDA-21, 389; SEDA-22, 418; SEDA-23, 406) Apart from its use in patients with transplants, this potent suppressor of lymphocyte proliferation has been studied in various chronic inflammatory disorders, such as rheumatoid arthritis, pemphigus vulgaris, and psoriasis. In 70 patients with chronic active Crohn's disease, mycophenolate plus corticosteroids produced benefit on disease activity comparable to azathioprine plus corticosteroids (154c). Two of the 35 patients randomized to mycophenolate had significant adverse effects that required drug withdrawal, namely rashes and vomiting. Skin The first case of mycophenolate mofetilinduced eczema has been reported (155A).

A 45-year-old woman with a liver transplant began to take mycophenolate mofetil (2 g/day) before planned ciclosporin withdrawal. After 3 days she developed pruritus and a bullous eruption on her hands and feet. The lesions improved after mycophenolate mofetil was withdrawn, but soon reappeared after readministration of a lower dose (500 mg/day). A skin biopsy showed dyshidrotic eczema and a skin test with mycophenolate mofetil produced recurrence.

Infection risk

As with many other immunosuppressive drugs, regimens that contain mycophenolate mofetil are associated with an increased risk of opportunistic infections or reactivation of latent infections. A retrospective study in 19 children with renal transplants identified three who developed disseminated varicella, despite a prior history of chicken pox in two and post-transplant varicella vaccination in one ( 1 5 6c) . The clinical disease was mild and responded promptly to oral aciclovir. Although this was based on very few patients, the incidence of 16% was thought to be unexpectedly high compared with that reported in historic controls (0.7-1.9%), and might have resulted from the higher degree of immunosuppression achieved with mycophenolate mofetil. This latter view was shared by other investigators, who reported two cases of intestinal microsporidiosis (157 A) and 1 case of Nocardia asteroides brain abscess (158 A) in adult patients.

Carcinogenesis Kaposi's sarcoma has been reported after a mean of 7 months of treatment in three renal transplant patients whose immunosuppressive regimen included mycophenolate mofetil ( 1 5 9c) . As a result, these investigators found that the incidence of Kaposi's sarcoma in patients taking regimens containing mycophenolate mofetil was 0.8% (3/371 patients) compared with 0.1% in patients not taking it (2/1464). Although this requires further data, it was suggested that mycophenolate mofetil might increase the susceptibility to Kaposi's sarcoma. Risk factors Children The adverse effects of mycophenolate mofetil in children have been reviewed from the retrospective data of 24 renal transplant patients (mean age 14.4 years) switched from azathioprine to mycophenolate mofetil a mean of 4.8 years after transplantation (160c). The mean dose of mycophenolate mofetil was 560 mg/m 2. After a mean

430 of 9.6 months, 13 had to discontinue treatment because of adverse effects, namely severe and partially reversible anemia (10 patients, of whom three required transfusions), neutropenia (one patient) and diarrhea (two patients). The anemia was normocytic and normochromic in nine patients, and such a high incidence of severe anemia was unexpected from the available adult data. Although patients who discontinued treatment had a lower pretreatment calculated creatinine clearance, this was not significant and probably not the major cause of anemia. The author speculated that the anemia resulted from a disproportionately high unbound plasma concentration of mycophenolate mofetil, due to reduced protein binding and impaired renal clearance.

Drug interactions Patients taking tacrolimus have higher mycophenolate mofetil plasma trough concentrations than patients taking ciclosporin (SEDA-21,390; 161c). In addition, ciclosporin can lower mycophenolate mofetil trough concentrations (133 c ).

Sirolimus Sirolimus recently became available in the USA for the prophylaxis of renal transplant rejection. It is recommended for use in combination with ciclosporin and corticosteroids, but it has also been investigated as a replacement for ciclosporin in primary immunosuppression. In a 12-month study in 719 patients with renal transplants, the combination of sirolimus, ciclosporin, and prednisone in 558 patients (284 taking sirolimus 2 mg/day and 274 taking 5 mg/day) produced significantly more acne, diarrhea, dyslipidemia, headache,

hirsutism, hyperkalemia, hypertension, lymphocele formation, and thrombocytopenia compared with 161 patients who took azathioprine, ciclosporin, and prednisone (162c). Serum cre-

atinine concentrations were significantly higher at 6 and 12 months in those who took sirolimus. Most of these adverse effects were thought to represent exacerbation of ciclosporin adverse effects, except for diarrhea (8-32%), dyslipidemia (30-42%), lymphocele formation ( t 2 15%) and thrombocytopenia (9-18%), which were more probably related to sirolimus. That the adverse events profile of sirolimus is different from that of ciclosporin has been further suggested in 83 patients taking

Chapter 37

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a primary immunosuppressant regimen containing sirolimus (41 patients) or ciclosporin (42 patients) (163c). Arthralgia (20%), hypercholesterolemia (44%), hypertriglyceridemia (51%), leukopenia (39%), thrombocytopenia (37%), and pneumonia (17%) were significantly more frequent in patients taking sirolimus, particularly during the first 2 months of treatment, i.e. until sirolimus trough concentrations were carefully monitored. Serum creatinine concentrations were lower in the sirolimus group, confirming that this new immunosuppressant probably has no direct nephrotoxic effect.

Respiratory Progressive diffuse interstitial pneumonitis has been reported as a possible adverse effect of sirolimus in three patients with renal transplants (164A). All three patients were negative for other causes of pneumonitis and improved only after sirolimus withdrawal.

SDZ-RAD SDZ-RAD is an immunosuppressive macrolide that also has synergistic actions with ciclosporin and interrupts the proliferative responses of vascular and bronchial smooth muscle cells. In a phase I trial the safety profile and pharmacokinetics were assessed during a 4-week course of once-daily, sequential ascending doses (0.75, 2.5, or 7.5 mg/day) in renal transplant recipients on a stable regimen of cyclosporin and prednisone (165c). Pharmacokinetic data showed dose proportionality, a good correlation between trough and AUC concentrations, and moderate accumulation (2.5-fold). Absorption was within 2 hours, and the halflife was 16-19 hours. There was no evidence of a pharmacokinetic interaction of ciclosporin with SDZ-RAD. Virtually every patient in this study had at least one adverse event and 43% of patients treated with 7.5 mg SDZ-RAD had serious adverse events. In all SDZ-RAD groups there was an increased incidence of infectious episodes (Herpes simplex, upper respiratory

infections, pharyngitis, pneumonia, and sinusitis). Similarly, adverse events involving the gastrointestinal system (diarrhea, nausea, and vomiting) were more common. Serum concentrations of triglycerides and total cholesterol increased significantly over time. Individuals treated with 7.5 mg SDZ-RAD had significant

falls in white cell count (-2.6%) and falls in

Drugs acting on the immune system

Chapter37

431

platelet count (-51%); the nadir occurred on

and mild to moderate sensorineural hearing loss. Her hearing improved on tacrolimus dosage reduction and after the tacrolimus blood concentration reached 15 ng/ml.

day 19 and cell counts recovered spontaneously without withdrawal of the drug. Serum creatinine concentrations and blood pressure did not change in the SDZ-RAD group.

Tacrolimus In 14 patients with renal transplants, there was a close relation between individual tacrolimus whole blood trough concentrations and the occurrence of adverse effects (166c). The incidence of tacrolimus adverse effects was 76% with tacrolimus concentrations above 30 ng/ml and only 5.3% with concentrations below 10 ng/ml. This relation was found in all separate groups of adverse effects analyzed, i.e. nephrotoxicity, neurotoxicity, infections, and others. In contrast, there was no relation between tacrolimus concentrations and rejection episodes. Accordingly, the authors stressed that tacrolimus whole blood trough concentrations should be strictly kept under 20 ng/ml. Cardiovascular Few reports have cited intravenous tacrolimus as a cause of severe dysrhythmias (SED-14, 1305). In 37 patients with liver transplants there was no difference between the pre- and post-transplant QT interval in the 25 taking oral ciclosporin and the 12 taking oral tacrolimus (167c). Nervous system Severe neurological complications of tacrolimus are infrequent. A chronic inflammatory demyelinating polyneuropathy was considered to have been caused by tacrolimus in a 62-year-old patient (168A). The presence of significant tacrolimus concentrations (5.2 and 1.3 ng/ml at 8 and 72 hours after the last dose) in the cerebrospinal fluid of a 64-year-old woman with a renal transplant who developed an extremely severe form of encephalopathy after 21 months of treatment suggested that tacrolimus can cross the blood-brain barrier (169A). Sudden hearing loss has not been previously reported (170A). A 38-year-old woman was switched from ciclosporin to tacrolimus 44 days after a kidney and pancreas transplantation and 17 days later had sudden hearing loss with tinnitus. Her tacrolimus blood concentration 3 days later was 28 ng/ml and peaked at 35 ng/ml 8 days later. Audiograms showed bilateral hearing loss--80% for speech perception

Although she was taking many other drugs, including orthoclone, which was withdrawn I month before heating loss, the role of tacrolimus was supported by its chemical similarity to erythromycin, which is ototoxic when given intravenously. The risk of post-transplant diabetes mellitus is greater with tacrolimus than

Endocrine

with ciclosporin, but this was mostly true in black patients and durin~ the initial months after transplantation (171'~). In one study, insulin sensitivity, a and /3 cell function, and /3 cell reserve were studied in 14 hepatitis C positive patients with liver transplants, who took tacrolimus or ciclosporin maintenance for 1 year (172c). The patients were matched for low prednisolone dosage (1.1 mg/day vs 1.3 mg/day), body mass index, lean body mass, and sex, and compared with eight controls. Insulin sensitivity and insulin secretory reserve were significantly different from controls, but there was no significant difference between ciclosporin and tacrolimus. Hematologic The prothrombin time was prolonged to 36 seconds, with isolated factor V deficiency (5%), 2 weeks after a 46-year-old patient with a liver transplant was given tacrolimus and oxacillin (173AE). Factor V antigen was lower than 5%. In vitro investigations of the patient's plasma showed dose-dependent factor V inhibitory activity in the presence of tacrolimus. Factor V activity and the coagulation profile returned to normal after withdrawal. The development of this transiently acquired inhibitor of coagulation factor V may have been due to either tacrolimus or oxacillin. Microangiopathy and the resulting throm-

botic thrombocytopenic purpura-like syndrome has been again reported in three transplant patients taking tacrolimus, including one patient with a severe form (174c). Microangiopathy was associated with high trough tacrolimus concentrations (over 24 ng/ml) and raised concentrations of endothelin and various cytokines, namely IL-8, IL-10, IL-12, TNF-t~, and interferon-F.

432

Urinary tract Tacrolimus nephrotoxicity has been reviewed (175 R) and is considered to be very similar to that described with ciclosporin. The clinical and histological characteristics of acute tacrolimus nephrotoxicity have been described from a retrospective analysis of 67 patients with renal transplants, of whom 27 developed acute nephrotoxicity, in seven of whom underlying moderate-to-severe renal arteriosclerosis might have predisposed to tacrolimus nephrotoxicity (176c). Sexual function The first case of priapism has been described in a patient with a liver transplant (177 A). One month after transplantation, a 19-year-old man who was taking tacrolimus, azathioprine, and prednisone, developed nausea and vomiting. He reported a 2-week history of painful spontaneous penile erections lasting 2-3 minutes and had had no previous episodes of priapism. An episode of spontaneous erection was confirmed during a medical examination that found no physical abnormalities. The tacrolimus blood concentration was 28 ng/ml. The digestive symptoms and priapism resolved after the tacrolimus concentration had fallen. Sickle cell disease was ruled out. The authors discussed several mechanisms, including tacrolimus-induced vasodilatation, platelet aggregation, an increase in serotonin, or a fall in endothelin concentrations, based on in vitro data only. Musculoskeletal Severe bone pain, previously reported in ciclosporin-treated patients (SED-14, 1291), also occurred as a possible consequence of tacrolimus treatment in a 50year-old woman (178A). Bilateral knee pain occurred within 2 months after renal transplantation and bone scintigraphy showed increased uptake in both knees. Calcitonin was ineffective, and she improved only after the dose of tacrolimus was reduced.

Immunologic

A possible link between tacrolimus and food hypersensitivity in an infant has previously been discussed (SEDA-21,391). The sudden occurrence of fish allergy with increased IgE total concentrations and specific IgE antibodies against various fish products has been reported in two children with liver transplants (179A). Even though both patients had a personal or familial history of allergy, this

Chapter 37

ThierryVial and Jacques Descotes

again suggested a possible relation between tacrolimus and food allergy.

Infection risk An increasing blood eosinophil count was associated with Pneumocystis carinii pneumonia in patients taking tacrolimus (180c). The mean absolute eosinophil count was significantly higher and absolute eosinophilia (over 350 x 106/1) was more frequent in six patients who developed Pneumocystis carinii pneumonia while receiving tacrolimus compared with six patients with Pneumocystis carinii pneumonia who were taking ciclosporin and eight patients without Pneumocystis carinii pneumonia who were taking tacrolimus. A retrospective analysis also showed that the increase in eosinophil count preceded the diagnosis of Pneumocystis carinii pneumonia. D r u g interactions Although initially based on theoretical grounds, an accumulating number of reports or studies has now clearly confinned that tacrolimus and ciclosporin share a similar drug interaction profile. Among antibiotics, clarithromycin, erythromycin, ketoconazole, and itraconazole have been confirmed to cause a rapid increase in blood tacrolimus concentration, but only a moderate rise in serum creatinine concentration (181A-183A). A new potential interaction with pristinamycin has been described in a 41-year-old renal transplant patient who had an approximate 5fold increase in tacrolimus trough concentrations within 4 days of pristinamycin treatment (184A). In contrast, a 10-fold increase in tacrolimus dosage was required in a 61-year-old patient with a renal transplant who took concomitant rifampicin (185A). This drug interaction has been convincingly confirmed in six healthy volunteers who took a single oral or intravenous dose of tacrolimus (186c). Rifampicin 600 mg/day for 18 days produced a significant 47% increase in tacrolimus clearance after intravenous administration and a 51% reduction in its oral systemic availability, consistent with induction by rifampicin of both hepatic and intestinal metabolism of tacrolimus. Although strongly suspected, but not previously shown, a 3-day course of diltiazem (90 mg/day) produced a 4-fold increase in tacrolimus trough concentrations in a 68-year-old patient with a liver transplant (187A).

Drugs acting on the immune system

Chapter37

Various protease inhibitors are metabolic inhibitors and are predicted to have deleterious effects on tacrolimus metabolism. In a 52-yearold liver transplant patient with HIV infection, successive treatment with various antiretroviral combinations containing nelfinavir, ritonavir, or saquinavir increased tacrolimus blood concentrations and caused severe prolonged neurological symptoms suggestive of tacrolimus toxicity (188"). The patient was finally stabilized with a regimen containing nelfinavir, stavudine, and lamivudine, and a more than 95% reduction in the dosage of tacrolimus.

IMMUNOENHANCING DRUGS

Bropirimine

(SED-14, 1312)

Oral bropirimine (3 g/day thrice weekly for 1 year) has been compared with weekly intravesical Bacillus Calmette-Gu6rin (2 cycles of 6 weeks) in 55 patients with newly diagnosed bladder carcinoma (189c). Whereas the response to treatment was not significantly different between the two groups, adverse effects resulted in more frequent treatment discontinuation in the BCG than in the bropirimine group (14% vs 4%). Bropirimine produced more frequent systemic reactions (in particu-

lar diarrhea, fever, flu-like syndrome, headache, nausea~vomiting) but less frequent and less severe local complications.

433

lmiquimod Imiquimod is an immune response enhancer that induces production of interferon and several other cytokines. It has been approved for the treatment of external genital and perianal warts/condyloma acuminata in adults (190R). The most common adverse effects were inflammatory reactions at the injection site (mostly erythema and itching), which usually occurred after 2-5 weeks of treatment. These local reactions were rarely severe enough to warrant withdrawal. Trials of imiquimod have failed to identify any particular systemic or laboratory abnormalities. There was also no deleterious effect on disease progression in HIV-infected patients (191c).

Ribonucleic acid Ribonucleic acid has been used to enhance immune function in patients with cancer. Of 83 patients who received subcutaneous injections of ribonucleic acid (10 mg every other day) for various skin diseases, three developed an

erythematous edematous reaction around the injection sites after the seventh to 15th injection (192c). Although patch tests were negative in all three patients, lesions were reproduced after intradermal injection in one patient.

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436 60. Anderlini E Donato M, Chan KW, Huh YO, Gee AP, Lauppe M J, Champlin RE, Ktrbling M. Allogeneic blood progenitor cell collection in normal donors after mobilization with filgrastim: the M.D. Anderson Cancer Center experience. Transfusion 1999; 39: 555-60. 61. De la Rubia J, Martinez C, Solano C, Brunet S, Cascon P, Arrieta R, Alegre A, Bargay J, De Arriba E Canizo C, Lopez J, Serrano D, Verdeguer A, Torrabadella M, Diaz MA, Insunza A, De la Serna J, Espigado I, Petit J, Martinez M, Benlloch L, Sanz MA. Administration of recombinant human granulocyte colony-stimulating factor to normal donors: results of the Spanish National Donor Registry. Bone Marrow Transplant 1999; 24: 723-8. 62. Murata M, Harada M, Kato S, Takahashi S, Ogawa H, Okamoto S, Tsuchiya S, Sakamaki H, Akiyama Y, Kodera Y. Peripheral blood stem cell mobilization and apheresis: analysis of adverse events in 94 normal donors. Bone Marrow Transplant 1999; 24: 1065-71. 63. LeBlanc R, Roy J, Demers C, Vu L, Cantin G. A prospective study of G-CSF effects on hemostasis in allogenic blood stem cell donors. Bone Marrow Transplant 1999; 23: 991-6. 64. Vij R, Adkins DR, Brown RA, Khoury H, DiPersio JF, Goodnough T. Unstable angina in a peripheral blood stem and progenitor cell donor given granulocyte-colony-stimulating factor. Transfusion 1999; 39: 542-3. 65. Duarte R, De Luis DA, Lopez-Jimenez J, Roy G, Garcia A. Thyroid function and autoimmunity during treatment with G-CSE Clin Endocrinol 1999; 51: 133-4. 66. Viallard AM, Lavenue A, Balme B, Pincemaille B, Raudrant D, Thomas L. Lichenoid cutaneous drug reaction at injection sites of granulocyte colony-stimulating factor (filgrastim). Dermatology 1999; 198: 301-3. 67. Kobbe G, Germing U, Soehngen D, Aul C, Heyll A. Massive extramedullary disease progression in a patient with stable multiple myeloma during G-CSF priming for peripheral blood progenitor mobilization. Oncol Rep 1999; 6: 11512. 68. Nakamura M, Sakemi T, Fujisaki T, Matsuo S, Ikeda Y, Nishimoto A, Ohtsuka Y, Tomiyoshi Y. Sudden death or refractory pleural effusion following treatment with granulocyte colony-stimulating factor in two hemodialysis patients. Nephron 1999; 83: 178-9. 69. Riggs JE, Mansmann PT, Cook LL, Schochet SS, Hogg JP. Fulminant CNS perivascular lymphocytic proliferation: association with sargramostim, a hematopoietic growth factor. Clin Neuropharmacol 1999; 22: 288-91. 70. Shahar E, Krivoy N, Pollack S. Effective acute desensitization for immediate-type hypersensitivity to human granulocyte-monocyte colony stimulating factor. Ann Allergy Asthma Immunol 1999; 83: 543-6.

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71. Facon T, Harousseau JL, Maloisel E Aual M, Odriozola J, Alegre A, Schroyens W, Hulin C, Schots R, Matin P, Guilhot E Granena A, De Waele M, Pigneux A, MEresse V, Clark E Reiffers J, SCFMultiple Myeloma Study Group. Stem cell factor in combination with filgrastim after chemotherapy improves peripheral blood progenitor cell yield and reduces apheresis requirements in multiple myeloma patients: a randomized, controlled trial. Blood 1999; 94: 1218-25. 72. Panousis C, Pietersz GA. Monoclonal antibodydirected cytotoxic therapy. Potential in malignant diseases of aging. Drugs Aging 1999; 15: 113. 73. Coles AJ, Wing M, Smith S, Coraddu F, Greet S, Taylor C, Weetman A, Hale G, Chatterjee VK, Waldmann H, Compston A. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 1999; 354: 16915. 74. Jarvis B, Faulds D. Etanercept. A review of its use in rheumatoid arthritis. Drugs 1999; 57: 94566. 75. Arnason BGW, for the Lenereept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebocontrolled multicenter study. Neurology 1999; 53: 457-65. 76. Brion HP, Mittal-Henkle A, Kalunian KC. Autoimmune skin rashes associated with etanercept for rheumatoid arthritis. Ann Intern Med 1999; 131: 634. 77. Bell S, Kamm MA. Antibodies to tumor necrosis factor alpha as treatment for Crohn's disease. Lancet 2000; 355: 858-9. 78. Wall GC, Heyneman C, Pfanner TE Medical options for treating Crohn's disease in adults: focus on antitumor necrosis factor-alpha chimeric monoclonal antibody. Pharmacotherapy 1999; 19: 1138-52. 79. Maini RN, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P. Infliximab (chimeric anti-tumour necrosis factor alphamonoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase HI trial. Lancet 1999; 354: 1932-9. 80. Bickston SJ, Lichtenstein GR,Arseneau KO, Cohen RB, Cominelli E The relationship between infliximab treatment and lymphoma in Crohn's disease. Gastroenterology 1999; 117: 1433-7. 81. Morelli J, Wilson FA. Does administration of infliximab increase susceptibility to listeriosis? Am J Gastroenterol 2000; 95: 841-2. 82. Hanauer SB, Rutgeerts PJ, D'Haens G, Targan SR, Kam L, Present DH, Wagner C, LaSorda J, Sands B, Livingstone RA. Delayed hypersensitivity to infliximab (Remicade) re-infusion after a 2--4 year interval without treatment. Gastroenterology 1999; 116: A731.

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83. Thomas MC, Walker R, Wright A. HaNDL syndrome after "benign" OKT3-induced meningitis. Transplantation 1999; 67: 1384-5. 84. Berkowitz RJ, Possidente C J, McPherson BR, Guillot A, Braun SV, Reese JC. Anaphylactoid reaction to muromonab-CD3 in a pediatric renal transplant recipient. Pharmacotherapy 2000; 20: 1(KI--4. 85. Hibberd AD, Trevillian PR, Wlodarzcyk JH, Gillies AHB, Stein AM, Sheil AGR, Disney APS. Cancer risk associated with ATG/OKT3 in renal transplantation. Transplant Proc 1999; 31: 1271-2. 86. Byrd JC, Waselenko JK, Maneatis TJ, Murphy T, Ward FT, Monahan BP, Sipe MA, Donegan S, White CA. Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. J Clin Oncol 1999; 17: 791-5. 87. Yang H, Rosove MH, Figlin RA. Tumor lysis syndrome occurring after the administration of rituximab in lymphoproliferative disorders: high-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Am J Hematol 1999; 62: 247-50. 88. Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A. Cytokine-release syndrome in patients with beta-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 1999; 94: 221724. 89. Zerga M, Cerchetti L, Cicco J, Constantini P, De Riz M. Desquamative alveolitis: an unusual complication of treatment with mabthera. Blood 1999; 94 Suppl 1: 271. 90. Goldenberg MV. Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. Clin Ther 1999; 21: 309-18. 91. Friend PJ, Hale G, Chatenoud L, Rebello P, Bradley J, Thiru S, Phillips JM, Waldmann H. Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection. Transplantation 1999; 68: 1632-7. 92. Woodle ES, Xu D, Zivin RA, Auger J, Charrette J, O'Laughlin R, Peace D, Jolliffe LK, Haverty T, Bluestone JA, Thistlethwalte JR. Phase I trial of a humanized, Fc receptor nonbinding OKT3 antibody, huOKT3gamma-1 (Ala-Ala) in the treatment of acute renal allograft rejection. Transplantation 1999; 68: 608-16. 93. Dervieux T, Mddard Y, Baudoin V, Maisin A, Zhang D, Broly F, Loirat C, Jacqz-Aigrain E. Thiopurine methyltransferase activity and its relationship to the occurrence of rejection episodes in paediatric renal transplant recipients treated with azathioprine. Br J Clin Pharmacol 1999; 48: 793800. 94. Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, Pui CH, Evans WE. Mercaptopurine therapy intolerance and bet-

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43 8 activity of warfarin. Ann Phannacother 2000; 34: 120-1. 109. Touchard G, Verove C, Bridoux E Bauwens. Cyclosporin maintenance monotherapy after renal transplantation. What factors predict success? BioDrugs 1999; 12: 91-113. ll0. Bronster DJ, Chodoff L, Yonover L, Sheiner PA. Cyclosporine levels in cerebrospinal fluid after liver transplantation. Transplantation 1999; 68: 1410-13. 111. Braun RE Arechalde A, French LE. Reversible ascending motor neuropathy as a side effect of systemic treatment with ciclosporine for nodular prurigo. Dermatology 1999; 199: 372-3. 112. Vannini SDP, Mazzola BL, Rodoni L, Truttmann AC, Wermnth B, Bianchetti MG, Ferrari E Permanently reduced plasma ionized magnesium among renal transplant recipients on cyclosporine. Transplant Int 1999; 12: 244-9. 113. Lipkowitz GS, Madden RL, Mulhern J, Braden G, O'Shea M, O'Shaughnessy J, Nash S, Kurbanov A, Freeman J, Rennke H, Germain M. Long-term maintenance of therapeutic cyclosporine levels leads to optimal graft survival without evidence of chronic nephrotoxicity. Transplant Int 1999; 12" 202-7. 114. Zarifian A, Meleg-Smith S, O'Donovan R, Tesi RJ, Batuman V. Cyclosporine-associated thrombotic microangiopathy in renal allografts. Kidney Int 1999; 55: 2457~a6. 115. Siragusa M, Alberti A, Schepis C. Mees' lines due to cyclosporin. Br J Dermatol 1999; 140: 1198-9.

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124. Bui LL, Huang DD. Possible interaction between cyclosporine and chloramphenicol. Ann Pharmacother 1999; 33: 252-3. 125. Smak Gregoor PJH, Van Gelder T, Van der Ende ME, Ijzermans JNM. Weimar W. Cyclosporine and triple-drug treatment with human immunodeficiency virus protease inhibitors. Transplantation 1999; 68: 1210-11. 126. Turhal NS. Cyclosporin A and imipenem associated seizure activity in allogeneic bone marrow transplantation patients. J Chemotherapy 1999; 1 l: 410-13. 127. Constantopoulos A. Colitis induced by interaction of cyclosporine A and non-steroidal antiinflammatory drugs. Pediatr Int 1999; 41: 184-6. 128. Rodriguez JA, Crespo-Leiro MG, Paniagua M J, Cuenca JJ, Hermida LE Juff6 A, Casto-Beiras A. Rhabdomyolysis in heart transplant patients on HMG-CoA reductase inhibitors and cyclosporine. Transplant Proc 1999; 31: 2522-3. 129. Gullestad L, Nordal KP, Berg KJ, Cheng H, Schwartz MS, Simonsen S. Interaction between lovastatin and cyclosporine A after heart and kidney transplantation. Transplant Proc 1999; 31: 2163-5. 130. Maltz HC, Balog DL, Cheigh JS. Rhabdomyolysis associated with concomitant use of atovastatin and cyclosporine. Ann Pharmacother 1999; 33: 1176--9. 131. Miack W, Mai I, Fritsche L, Ochmann K, Rohde G, Unger S, Johne A, Bauer S, Budde K, Roots i, Neumayer HH. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther 1999; 65: 25161. 132. Pea E Damiani D, Michieli M, Ermacora A, Baraldo M, Russo D, Fanin R, Baccarani M, Furlant M. Multidrug resistance modulation in vivo: the effect of cyclosporin A alone or with dexverapamil on idarubicin pharmacokinetics in acute leukemia. Eur J Clin Pharmacol 1999; 55: 361-8. 133. Smak Gregoor PJI-I, De S6vanx RGL, Hen6 RJ, Hesse CJ, Hilbrands LB, Vos P, Van Gelder T, Hoitsma AJ, Weimar W. Effect of cyclosporine on mycopbenolic acid trough levels in kidney transplant recipients. Transplantation 1999; 68: 1603~5. 134. Aviles RJ, Vlahakis SA, Elkin PL. Cyclophosphamide-associated uroepithelial toxicity. Ann Intern Med 1999; 131: 549. 135. Das D, Smith A, Warnes TW. Hepatic sarcoidosis and renal carcinoma. J Clin Gastroenterol 1999; 28: 61-3. 136. Enns GM, Roeder E, Chan RT, Catts ZAK, Cox VA, Golabi M. Apparent cyclophosphamide (Cytoxan) embryopathy: a distinct phenotype? Am J Med Genet 1999; 86: 237-41. 137. Yule SM, Walker D, Cole M, McSorley L, Cholerton S, Daly AK, Pearson ADJ, Boddy AV. The effect of fluconazole on cyclophosphamide

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metabolism in children. Drug Metab Dispos 1999; 27: 417-21. 138. Belfayol-Pisant6 L, Guillevin L, TOd M, Fauvelle E Possible influence of prednisone on the pharmacokinetics of cyclophosphamide in systemic vasculitis. Clin Drug Invest 1999; 18: 22531. 139. Imokawa S, Colby TV, Leslie KO, Helmers RA. Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients. Eur Respir J 2000; 15: 373-81. 140. Yoshida S, Onuma K, Akahori K, Sakamoto H, Yamawaki Y, Shoji T, Nakagawa H, Hasegawa H, Amayasu H. Elevated levels of IL-8 in interstitial pneumonia induced by low-dose methotrexate. J Allergy Clin Immunol 1999; 103 : 9524. 141. Nakamura M, Sakemi T, Nagasawa K. Severe pancytopenia caused by a single administration of low dose methotrexate in a patient undergoing hemodialysis. J Rheumatol 1999; 26: 1424-5. 142. Suzuki Y, Uehara R, Tajima C, Noguchi A, Ide M, Ichikawa Y, Mizushima Y. Elevation of serum hepatic aminotransferases during treatment of rheumatoid arthritis with low-dose methotrexate. Risk factors and response to folic acid. Scand J Rheumatol 1999; 28: 273-81. 143. Tousirrot E, Wendling D. Methotrexateinduced hyperpigmentation in a rheumatoid arthritis patient. Clin Exp Rheumatol 1999; 17: 751. 144. Peters T, Tehile-Ochel S, Chemnitz J, St~hngen D, Hunzelmann N, Scharffeter-Kochanek K. Exfoliative dermatitis after long-term methotrexate treatment of severe psoriasis. Acta Derm Venereol 1999; 79: 391-2. 145. Goerttler E, Kutzner H, Peter HH, Requena L. Methotrexate-induced papular eruption in patients with rheumatic diseases: a distinctive adverse cutaneous reaction produced by methotrexate in patients with collagen vascular diseases. J Am Acad Dermatol 1999; 40: 702-7. 146. Gerster JC, Bossy R, Dudler J. Bone nonunion after osteotomy in patients treated with methotrexate. J Rheumatol 1999; 26: 2695-7. 147. Bianchi ML, Cimaz R, Galbiati E, Corona F, Cherubini R, Bardare M. Bone mass change during methotrexate treatment in patients with juvenile rheumatoid arthritis. Osteoporosis Int 1999; 10: 20-5. 148. Freeman AM, Dasgupta B. Angio-neurotic oedema associated with methotrexate treatment in rheumatoid arthritis. Rheumatology 1999; 38: 908. 149. Beauparlant P, Papp K, Haraoui B. The incidence of cancer associated with the treatment of rheumatoid arthritis. Semin Arthritis Rheum 1999; 29: 148-58. 150. Kono H, Inokuma S, Matsuzaki Y, Nakayama H, Yamazaki J, Hishima T, Maeda Y. Two cases of methotrexate induced lymphomas in rheumatoid arthritis: an association with increased serum IgE. J Rheumatol 1999; 26: 2249-53.

439 151. Lloyd ME, Carr M, McElhatton P, Hall GM, Hughes RA. The effects of methotrexate on pregnancy, fertility and lactation. Q J Med 1999; 92: 551-63. 152. Ostensen M, Hartmann H, Salvesen K. Low dose weekly methotrexate in early pregnancy. A case series and review of the literature. J Rheumatol 2000; 27: 1872-5. 153. Del Campo M, Kosaki K, Bennett FC, Jones KL. Developmental delay in fetal aminopterin/methotrexate syndrome. Teratology 1999; 60: 10-12. 154. Neurath ME Wanitschke R, Peters M, Krummenauer F, Meyer zum Btischenfelde KH, Schlaak JF. Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn's disease. Gut 1999; 44: 625-8. 155. Semhoun-Ducloux S, Ducloux D, Miguet JE Mycophenolate mofetil-induced dyshidrotic eczema. Ann Intern Med 2000; 132: 417. 156. Rothwell WS, Gloor JM, Morgenstern BZ, Milliner DS. Disseminated Varicella infection in pediatric renal transplant recipients treated with mycophenolate mofetil. Transplantation 1999; 68: 158-61. 157. Guerard A, Rabodonirina M, Cotte L, Liguory O, Piens MA, Daoud S, Picot S, Touraine JL. Intestinal microsporidiosis occuring in two renal transplant recipients treated with mycophenolate mofetil. Transplantation 1999; 68: 699-707. 158. Magee CC, Halligan RD, Milford EL, Sayegh MH. Nocardial infection in a renal transplant recipient on tacrolimus and mycophenolate mofetil. Clin Nephrol 1999; 52: 44-45. 159. Eberhard OK, Kliem V, Brunkhorst R. Five cases of Kaposi's sarcoma in kidney graft recipients. Possible influence of the immunosuppressive therapy. Transplantation 1999; 67: 180-4. 160. Butani L, Palmer J, Baluarte HJ, Polinsky MS. Adverse effects of mycophenolate mofetil in pediatric renal transplant recipients with presumed chronic rejection. Transplantation 1999; 68: 83-6. 161. Htibner GI, Eismann R, Sziegoleit W. Drug interaction between mycophenolate mofetil and tacrolimus detectable within therapeutic mycophenolic acid monitoring in renal transplant patients. Ther Drug Monit 1999; 21: 536-9. 162. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomized multicentre study. Lancet 2000; 356: 194-202. 163. Groth CG, B~ickman L, Morales JM, Calne R, Kreis H, Lang P, Touraine JL, Claesson K, Campistol JM, Durand D, Wramner L, BrattstrSm C, Charpentier B. Sirolimus (rapamycin)-based therapy in human renal transplantation. Similar efficacy and different toxicity compared with cyclosporine. Transplantation 1999; 67: 1036-42. 164. Morelon E, Stern M, Kreis H. Interstitial pneumonitis associated with sirolimus therapy in renaltransplant recipients. New Eng J Med 2000; 343: 225-6.

440 165. Kahan BD, Wong RL, Carter C, Katz SH, Von Fellenberg J, Van Buren CT, Appel DS. A phase I study of a 4-week course of SDZ-RAD (RAD) quiescent cyclosporine-prednisone-treated renal transplant recipients. Transplantation 1999; 68:1100-6. 166. BOttiger Y, Brattstrtm C, Tyden G, Sawe J, Groth CG. Tacrolimus whole blood concentrations correlate closely to side-effects in renal transplant recipients. Br J Clin Pharmacol 1999; 48: 445-8. 167. Gonzalez MG, Hemandez-Madrid A, Santoman AL, Monge G, De Vicente E, Barcena R. Comparison of posfliver transplantation electrocardiographic alterations between cyclosporine- and tacrolimus-treated patients. Transplant Proc 1999; 31: 2423-4. 168. Haviv YS, Friedlaender M, Dranitzki-Elhallel M. Chronic inflammatory demyelinating polyneuropathy possibly associated with tacrolimus. Clin Drug Invest 1999; 18: 169-72. 169. Grimbert P, Azema C, Pastural M, Dhamane D, Remy P, Saiomon L, Schortgen F, Baron C, Lang P. Tacrolimus (FK506)-induced severe and late encephalopathy in a renal transplant recipient. Nephrol Dial Transplant 1999; 14: 2489-91. 170. Min DI, Ku YM, Rayhill S, Corwin C, Wu YM, Hunsicker LG. Sudden hearing loss associated with tacrolimus in a kidney-pancreas allograft recipient. Pharmacotherapy 1999; 19: 891-3. 171. Weir MR, Fink JC. Risk for posttransplant diabetes mellitus with current immunosuppressive medications. Am J Kidney Dis 1999; 34: 1-13. 172. Fernandez LA, Lehmann R, Luzi L, Battezzati A, Angelico MC, Ricordi C, Tzakis A, Alejandro R. The effects of maintenance doses of FK506 versus Cyclosporin A on glucose and lipid metabolism after orthotopic liver transplantation. Transplantation 1999; 68: 1532-41. 173. Leroy-Matheron C, Mallat A, Duvoux C, Mttreau JIM, Cherqui D, Dhumeaux D, GouaultHeilmann M. Inhibitor against coagulation factor V after liver transplantation. Possible role of the FK506 imunosuppressive drug. Transplantation 1999; 68: 1054-6. 174. Burke GW, Ciancio G, Cirocco R, Markou M, Olson L, Contreras N, Oth D, Esquenazi V, Tzakis A, Miller J. Microangiopathy in kidney and simultaneous pancreas/kidney recipients treated with tacrolimus: evidence of endothelin and cytokine involvement. Transplantation 1999; 68: 133642. 175. Finn WF. FK506 nephrotoxicity. Renal Fail 1999; 21: 319-29. 176. Shimizu T, Tanabe K, Tokumoto T, Ishikawa N, Shinmura H, Oshima T, Toma H, Yamaguchi Y. Clinical and histological analysis of acute tacrolimus (TAC) nephrotoxicity in renal allografts. Clin Transplant 1999; 13 Suppl 1: 48-53. 177. Harmon JD, Ginsberg PC, Nachmann MM, Manzarbeita C, Harkaway RC. Stuttering priapism in a liver transplant patient with toxic levels of FK506. Urology 1999; 54: 366.

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ThierryVial and Jacques Descotes

178. Villaverde V, Cantalejo M, Balsa A, Mola EM, Sanz A. Leg bone pain syndrome in a kidney transplant patient treated with tacrolimus (FK506). Ann Rheum Dis 1999; 58: 653-60. 179. Inui A, Komatsu H, Fujisawa T, Matsumoto H, Miyagawa Y. Food allergy and tacrolimus. J Pediatr Gastroenterol Nutr 1999; 28: 355-6. 180. Dickenmann MJ, Tamm M, Tsinalis D, Binet I, Thiel G, Steiger J. Blood eosinophilia in tacrolimus-treated patients. An indicator of pneumocystis carinii pneumonia. Transplantation 1999; 68: 1606-8. 181. Capone D, Gentile A, lmperatore P, Palmiero G, Basile V. Effects of itraconazole on tacrolimus blood concentrations in a renal transplant recipient. Ann Pharmacother 1999; 33:1124-5. 182. Gomez G, Alvarez ML, Errasti P, Lavilla FJ, Garcia N, Ballester B; Garcia I, Purroy A. Acute tacrolimus nephrotoxicity in renal transplant patients treated with clarithromycin. Transplant Proc 1999; 31: 2250-1. 183. Moreno M, Latorre A, Manzanares C, Morales E, Herrero JC. Clinical management of tacrolimus drug interactions in renal transplant patients. Transplant Proc 1999; 31: 2252-3. 184. Billaud EM, Chebassier C, Antoine C, Glotz D. Tacrolimus-pristinamycin drug interaction in renal transplant patient. Fundam Clin Pharmacol 1999; 13: 354. 185. Chenhsu RY, Loong CC, Chou MH, Lin MF, Yang WC. Renal allograft dysfunction associated with rifampin-tacrolimus interaction. Ann Pharmacother 2000; 34: 27-31. 186. Hebert ME Fisher RM, Marsh CL, Dressier D, Bekersky I. Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers. J Clin Pharmacol 1999; 39: 91-6. 187. Hebert ME Lam AY. Diltiazem increases tacrolimus concentrations. Ann Pharmacother 1999; 33: 680-2. 188. Sheikh AM, Wolf DC, Lebovics E, Goldberg R, Horowitz HW. Concomitant human immunodeficiency vires protease inhibitor therapy markedly reduces tacrolimus metabolism and increases blood levels. Transplantation 1999; 68: 3079. 189. Witjes WPJ, Ktnig M, Boeminghaus FP, Hall RR, Schulman CC, Zudo M, Fittipaldo A, Riggi M, Debruyne FMJ. Results of a European comparative randomized study comparing oral bropirimine versus intravesical BCG treatment in BCG-naive patients with carcinoma in situ of the urinary bladder. Eur Urol 1999; 36: 57681. 190. Czelusta AJ, Evans T, Arany I, Tyring SK. A guide to immunotherapy of genital warts. Focus on interferon and imiquimod. BioDrugs 1999; 11: 319-32. 191. Gilson RJC, Shupack JL, Friedman-Kien AE, Conant MA, Weber JN, Nayagam AT, Swann RV, Pietig DC, Smith MH, Owens ML, Imiquimod Study Group. A randomized, controlled, safety

Drugs acting on the immune system

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study using imiquimod for the topical treatment of anogenital warts in H1V-infected patients. AIDS 1999; 13: 2397-404.

441 192. Li LE Erythematous skin reaction to subcutaneous injection of ribonucleic acid. Contact Dermatitis 1999; 41: 239.

H.D. Reuter

38 Alcohol, vitamin A, and ~-carotene: adverse interactions, including hepatotoxicity and carcinogenicity Ethanol and retinol are converted to their corresponding aldehydes by isozymes of alcohol dehydrogenase and other dehydrogenases. Recently, new pathways of retinol metabolism have been described in hepatic microsomes, partly involving cytochrome P450 isozymes, which can also metabolize various drugs. Multiple interactions of retinol, ethanol, and other drugs can therefore occur (1R ). It is not therefore surprising that prolonged use of alcohol, drugs, or both, not only results in reduced dietary intake of retinoids and carotenoids, but also accelerates the breakdown of retinol through cross-induction of degradative enzymes. There is also competition between ethanol and retinoic acid precursors. Depletion of retinol and retinoic acid precursors is associated with hepatic and extrahepatic pathology, including carcinogenesis and fetal defects. Unfortunately, correction of vitamin A deficiency by supplementation is complicated by the intrinsic hepatotoxicity of retinol, which is potentiated by concomitant alcohol consumption. Furthermore, the precursor of vitamin A, B-carotene, has recently been found to interact with ethanol, interfering with the conversion of B-carotin to retinoL while the combination of B-carotene with ethanol results in hepatotoxicity. In smokers who also consume alcohol, Bcarotene supplementation promotes pulmonary cancer and possibly cardiovascular complications. It was already known in 1987 that foods that provide large amounts of retinol increase the risk of cancer of the esophagus (2 R, tic). And 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

442

Vitamins in an epidemiological study the increased risk of cancer associated with the use of cigarettes and alcohol was enhanced by the ingestion of foods containing retinol (4c). The hepatotoxic effects of vitamin A have been reported after consumption of doses of about 100 000 IU/day for periods ranging from weeks to months, as well as after daily supplementation with 25 000 IU for a couple of years, accompanied by an increase in plasma vitamin A concentration to 10 times normal in users of health foods. The smallest daily supplement of vitamin A reported to be associated with liver cirrhosis is 25 000 IU taken for 6 years (5c). In recent years the effect of alcohol abuse, one of the most common aggravating factors of vitamin A toxicity, has been elucidated. Vitamin A toxicity was potentiated in patients who took 10 000 IU/day for sexual dysfunction, and this effect was attributed to excess alcohol consumption (6c). In animals potentiation of vitamin A toxicity by ethanol resulted in striking hepatic inflammation and necrosis accompanied by a rise in serum glutamate dehydrogenase and AsT (7 E ). Alcohol may also act indirectly by causing liver disease, which in turn might affect the capacity of the liver to export vitamin A, thereby enhancing its local toxicity. In alcoholics the carrying capacity of retinol binding protein was increased, even in those with low serum retinol concentrations (8r In such cases, caution in the amount of vitamin A used for therapy is recommended. Similarly, diets that are severely deficient in protein can affect the capacity of the liver to export vitamin A and enhance its hepatotoxicity. In contrast to retinoids, carotenoids were considered non-toxic, even when taken chronically in large amounts, until recently, when it was found that ethanol interacts with carotenoids, interfering with their conversion to retinol. In baboons, the consumption of ethanol together with B-carotene resulted in more striking

Vitamins

Chapter38

hepatic injury than consumption of either compound alone (9E ). This interaction occurred at a total dose of 7.2-10.8 mg of E-carotene per Joule of diet. This dose is common in people who take supplements and is the same order of magnitude used in the E-Carotene and Retinol Efficacy Trial (CARET) (30 mg/day) (10c) and in another study (20 mg/day for 12 weeks) (llC ). The amount of alcohol given to the baboons was equivalent to that taken by an average alcoholic. The well-known toxicity of ethanol was potentiated by large amounts of ~carotene, and the concomitant administration of both 16-carotene and alcohol resulted in striking liver lesions, characterized by increased activity of plasma liver enzymes, an inflammatory response, and striking autophagic vacuoles and alterations in the endoplasmatic reticulum and mitochondria (12c). Besides its hepatotoxic effects, E-carotene supplementation can also cause cardiovascular complications in smokers and potentiate carcinogenicity. The ot-TocopheroL 1S-Carotene and Cancer Prevention Study (ATBC) (13c) and CARET (10c) showed that supplementation of E-carotene in smokers increased the incidence of death from coronary artery disease. Recent results suggest that E-carotene participates as a pro-oxidant in the oxidative degradation of LDL, and that raised LDL concentrations may cancel the protective effect of ot-tocopherol (14c). The two trials also showed that E-carotene supplementation increased the incidence of pulmonary cancer in smokers. Because heavy smokers are commonly heavy drinkers it was supposed that alcohol might have contributed to the increased incidence of lung cancer. Subsequent analysis showed that there was indeed a relation between the incidence of pulmonary cancer and the amount of alcohol consumed. As detrimental effects result from deficiency as well as an excess of retinoids and carotenoids, and since both have similar adverse effects in terms of fibrosis, carcinogenesis, and possibly embryotoxicity, therapeutic measures must pay attention to the narrow therapeutic window, especially in drinkers, in whom alcohol narrows the therapeutic window even further by promoting the depletion of retinoids and by potentiating their toxicity.

443

VITAMIN A (RETINOL) (SED-14, 1340; SEDA-21, 405; SEDA-22, 433; SEDA-23, 418) Teratogenieity The potential teratogenicity of high doses of vitamin A in humans has been presented in case reports and analyzed in both cohort and case-control studies (see also SEDA23, 418). To get further information about the teratogenicity of high doses of vitamin A, the European Network of the Teratology Information Services (ENTIS) has prospectively evaluated data from 423 pregnancies exposed during the first 9 weeks of gestation to 10 000 IU/day or more (15c). The presence of major structural malformations, excluding chromosomal and genetic diseases, was evaluated in 311 infants exposed to a median daily dose of vitamin A of 50000 (range 10000-300 000) IU/day. Three infants had a major malformation: pulmonary stenosis, stenotic anus with fistula, and bilateral inguinal hernia. There were no congenital malformations among 120 infants exposed to more than 50000 IU/day. When the birth prevalence rate of major malformations in the study group was compared with two internal control groups of infants exposed to "high" doses of vitamin A later in pregnancy, and nonteratogenic doses, the respective rate ratios were 0.28 (CI = 0.06, 1.23) and 0.50 (CI = 0.14, 1.76). There was no evidence for an increased risk of major malformations, associated with high vitamin A doses during organogenesis. The incidence of the acute adverse effects of an oral dose of vitamin A 400 000 IU given to a newly delivered mother and a oral dose of 50 000 IU given at the same time to her baby has been assessed in a randomized, double-blind, placebo-controlled study, with follow-up 1 or 2 days after dosing in 839 mothers and babies, of whom 788 were assessed (16c). The incidence of reported adverse effects was low. Only two mothers in each group spontaneously reported bulging fontanelles in their babies. One of these babies (in the placebo group) was reported to have been vomiting. The rates of bulging fontanelles found on examination were 1.5% and 1.0% in the treatment and control groups respectively (OR 1.48; CI = 0.35, 7.19) Only one baby (in the vitamin A group) of the 11 who had bulging fontanelles on examination had a symptom (vomiting, possibly attributable

444 to raised intracranial pressure). Maternal symptoms did not differ between the groups. Other reported symptoms in the vitamin A group (n = 398) compared with the controls (n = 390) were vomiting (6% vs 4.8%) and irritability (7.5% vs 5.4%). From these results it can be concluded that these large doses of vitamin A are well tolerated by newly delivered mothers and babies.

Cis-refinoic acid Urinary tract Two cases of bone-marrow transplant nephropathy that developed coincident with retinoid therapy have been reported (17A). A 3-year-old boy with a neuroblastoma was given cisplatin, adriamycin, and cyclophosphamide for five induction cycles and radiation to sites of residual bony metastases 1 month before autologous bonemarrow transplant, which resulted in an absolute neutrophil count of 500 x 106/1 on day 9 and a selfsustaining platelet count over 50 x 1012/1on day 72. He was randomized to receive retinoids 80 mg/m2 bd by mouth, beginning on day 100 after bonemarrow transplant. Before beginning cis-retinoic acid his highest serum creatinine concentration was 44 I~mol/1 on day 8. When cis-retinoic acid was begun, his hemoglobin was 9.8 g/dl and his platelet count 97 x 1012/1. At the end of the second 2-week cycle of retinoic acid he developed a severe headache and diastolic hypertension (BP 120/108 mmgHg), a blood urea nitrogen concentration of 4 mmol/l, serum creatinine of 133 ILmol/1, hemoglobin of 5.8 g/dl, and platelet count of 57 • 1012/1. Urinanalysis showed erythrocytes and protein. Renal biopsy showed mesangiolysis, wide capillary loops, focal intimal thickening, and vacuolization of glomerular and tubular cells. His hematuria and proteinuria persisted for 4 weeks, and his blood urea nitrogen and serum creatinine gradually improved, as did the hypertension. A 5-year-old boy with a neuroblastoma was treated in the same way. On day 105 after bonemarrow transplantation he developed hypertension (BP 140/92 mm Hg), hematuria, proteinuria, and a raised serum creatinine. His hemoglobin and platelet count fell. His mine contained protein 800 mg/1, a few hyaline casts, and 25-30 erythrcoytes per high power field. When nephritis developed, cis-retinoid acid was withdrawn. He gradually improved, and his mine cleared of casts, erythrocytes, and protein within 4 weeks.

All-trans retinoic acid (ATRA) All-trans retinoic acid has been evaluated in 26 patients with histologically confirmed adeno-

Chapter 38

H.D. Reuter

carcinoma of the prostate and manifestations of progressive metastatic disease (18c). They received a single oral dose of all-tram retinoic acid 45 mg/m2/day for 7 days followed by no treatment for 7 days before starting to take alltrans retinoic acid again. Toxicity was mostly mild. There was cheilosis in 11 patients and vomiting in one. In eight patients there were transient rises in serum triglyceride concentrations up to three times normal, returning to normal within 3 - 6 weeks, despite continuation of all-trans retinoic acid. One patient had a severe headache with vomiting on day 1 and required a 30% dosage reduction. No patient withdrew because of toxicity. Fatal adverse effects have been reported in patients given all-trans retinoic acid for acute promyelocytic leukemia (19c). Of 82 patients with acute promyelocytic leukemia 35 developed leukocytosis and 22 had fatal adverse effects (15 with the all-trans retinoic acid syndrome and seven with intracranial bleeding). Leukocytosis was a risk factor for fatal adverse effects. The authors suggested that the combination of all-trans retinoic acid with lowdose harringtonine can reduce the incidence of leukocytosis-related intracranial bleeding and corticosteroids can reduce mortality from the retinoic acid syndrome. In another study of 413 patients with acute promyelocytic leukemia treated with all-trans retinoic acid plus daunorubicin, all-trans retinoic acid syndrome occurred in 64 cases, of which five were fatal (20c).

Respiratory Respiratory distress has been attributed to all-trans retinoic acid in a patient with acute promyelocytic leukemia (21A). A 56-year-old woman with acute promyelocytic leukemia developed a fever of unknown origin, weight gain of 5 kg, and respiratory distress 9 days after the start of treatment with all-trans retinoic acid 45 mg/m2. Her white cell count rose to 21 x 109/1 despite treatment with cytosine arabinoside and idarubicin. A chest X-ray showed bilateral alveolar opacities. She recovered fully after 5 days of treatment with dexamethasone 10 mg bd. Nervous system A case of multiple mononeuropathies has been attributed to alltrans retinoic acid (22A). The neurological symptoms resembled atypical pseudotumor cerebri with focal neurological signs.

Vitamins

Chapter 38

A 23-year-old woman with acute promyelocytic leukemia was given all-trans retinoic acid (45 mg/m2/day) together with daunorubicin and cytarabine. She had a slight headache after the administration of all-trans retinoic acid. On the 17th day an acute subdural hematoma required operation. Her headache persisted and she complained of diplopia, and burning pain and contact dysesthesia of the back of the left hand and the right foot, with accompanying weakness on day 21. Electrophysiology showed reduced conduction velocity and amplitude in the right peroneal nerve. She also had a right abducens nerve palsy and visual disturbance. There was no papilledema. MRI scan of the brain was normal. On day 51 all-trans retinoic acid was discontinued. Her symptoms of peripheral neuropathy and the electrophysiological findings gradually improved as did her headache and dry skin, despite continued chemotherapy. The right abducens nerve palsy partly resolved.

Extramedullary relapse of acute promyelocytic leukemia, which is rare Hematologic

after chemotherapy alone, was more common after all-trans retinoic acid, but it is not clear whether it truly increases the risk of extramedullary recurrence and what the risk factors are. In a retrospective analysis of the incidence of extramedullary relapse in patients after prior treatment with all-trans retinoic acid and in patients previously treated with chemotherapy alone (23 c) three of the 13 patients who received all-trans retinoic acid had extramednllary involvement compared with none of the 11 patients previously treated with chemotherapy alone (RR = 2.1; CI = 1.34, 3.29). The retinoic acid syndrome during prior induction treatment was significantly associated with extramedullary relapse (three of five patients with the retinoic acid syndrome vs none of eight without the syndrome; R R = 5.0; CI = 1.4, 17). Thus, all-trans retinoic acid may predispose patients with acute promyelocytic leukemia to extramedullary involvement at relapse and the retinoic acid syndrome is a risk factor. G a s t r o i n t e s t i n a l Vasculitis and necrosis o f the ileum developed in a patient with acute promyelocytic leukemia treated with all-trans retinoic acid (24A). A 29-year-old woman with acute promyelocytic leukemia was given all-trans retinoic acid 45 mg/m 2. On day 20 she developed pain in both hands and wrists, feet and ankles, with erythema and edema. On day 24 her fever increased to over 38 ~ C and the white blood cell count was 10.9 • 109/1. She was given

445 dexamethasone (8 mg i.v. on three consecutive days) and all her symptoms quickly resolved, but on day 37 she developed a low-grade fever and polyarthralgia, which persisted. On day 42 she had a profuse bloody stool and her abdominal pain worsened and spread all over the abdomen. At emergency operation there was segmental necrosis in several parts of the ileum, with inflammation invading the serosa. Histology of the ileum showed a leukocytoclastic vasculitis. After operation all-trans retinoic acid was withdrawn and she had no fever, edema, arthralgia, or abdominal pain therafter. Skin

Skin adverse effects associated with all-

trans retinoic acid are relatively common, including dry skin, itching, xerostomia, and cheilitis, but acute febrile neutrophilic dermatosis (Sweet's syndrome) has rarely been reported. Sweet's syndrome is characterized by five cardinal features: fever, neutrophilia, multiple raised painful asymmetric erythematous cutaneous plaques, dermal infiltrates consisting of mature neutrophils, a rapid response to steroid therapy. In up to 10-20% of cases it precedes or coincides with a diagnosis of malignancy, most commonly acute myelogenous leukemia. In cases associated with all-trans retinoic acid the symptoms come on at 7 - 3 4 days and the skin lesions are seen on the face, limbs, and back. A new case has been described (25A). A 58-year-old woman was given all-trans retinoic acid 45 mg/m2/day for acute promyelocytic leukemia and after 9 days developed symptoms of upper respiratory tract infection and fever (38.2 ~ The next day multiple erythematous and painful cutaneous plaques appeared on her limbs. Her white cell count was 5.71 x 109/1. A skin biopsy showed a normal epidermis with subepidermal edema and dense diffuse perivascular aggregates composed of granulocytes and scattered eosinophils, compatible with Sweet's syndrome. Prednisolone 20 mg/day had no effect, but after 2 days treatment with cytarabine and daunorubicin the rash started to fade and gradually disappeared. Remission was achieved after one course and all-trans retinoic acid was subsequently renewed without complications.

Leukemia cutis is very rare in acute myelocytic leukemia. A case of cutaneous relapse in acute promyelocytic leukemia has been reported during a period of complete hematological remission after treatment with all-trans retinoic acid (26A). A 51-year-old man with acute promyelocytic leukemia was given induction chemotherapy and alltrans retinoic acid 45 mg/m2. After 1 month he

Chapter 38

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H.D. Reuter

developed discrete erythematous papules, although marrow biopsy suggested hematological remission. The papules were disseminated on all his limbs, trunk and scalp, and were scattered, discrete, and 2-3 mm in diameter. Biopsy showed a moderate perivascular infiltration of medium to large atypical cells, mainly in the upper dermis, suggesting infiltrating promyelocytes. The clinical, histological and histochemical findings were compatible with leukemia curls. One week later, a bone-marrow biopsy still showed hematological remission.

Vitamin B6 (pyridoxine)

VITAMINS OF THE B GROUP

Syncope was induced by intramuscular injection of hydroxocobalamin in a paraplegic patient (31A).

(SED-14, 1344; SEDA-21, 407; SEDA-22, 436; SEDA-23, 419)

Nicotinic acid (niacin), nicotinamide Liver Niacin-induced hepatitis is a rare complication in patients treated with modifiedrelease niacin formulations to control hyperlipidemia and hypercholesterolemia. A "starry sky liver" has been reported in a patient with niacin-induced hepatitis (27A). A 50-year-old man developed recurrent sharp lower abdominal pain and nausea, having taken modified-release niacin 500-2000 mg/day for 8 weeks for hypercholerolemia. He had a low-grade fever, tachycardia, and hypotension. Abdominal ultrasonography showed a markedly hypoechoic liver of normal size, with relatively echogenic conspicuous portal triads. AsT and prothrombin time were raised. Niacin was withdrawn and the signs and symptoms resolved within several days. Niacin can cause hepatic steatosis and clinical hepatic abnormalities that together stimulate the presentation of hepatobiliary neoplasia. A case of niacin-induced hepatotoxicity has been reported (28A).

In a systematic review on the efficacy of vitamin B6 in the treatment of premenstrual syndrome, adverse effects were reported in 63 patients (6.7%) (see Table 1) (29R). In another study of 940 w o m e n one had a neuropathy associated with pyridoxine toxicity (30c).

Vitamin B12 (hydroxocobalamin, cyanocobalamin)

An 81-year-old man who had been a prisoner of war 58 years before and had been fed mainly rice had developed complete loss of power and sensation in the right leg, weakness in the left leg, and weakness and impaired sensation in the right arm; he had become almost blind and deaf in both ears. When he was given vitamin B tablets his sight became almost normal within 1 month, but recovery of motor power was slower. In 1945 he returned home and was given injections of vitamin B12 on and off without adverse effects. In 1997 he had a serum vitamin B12 concentration of 91 ng/1 (reference range 223-1132), a normal folate concentration, a hemoglobin of 15.7 g/dl, and an MCV of 95 ft. He was given intramuscular vitamin B12 1 mg every 4-6 weeks. In 1998 he fainted about 10 min after an injection of vitamin B12. His blood pressure was 60/30 mmHg. Soon after the next injection he patient fainted again and developed red patches and blisters over his arms, chest, and legs. Oral vitamin B12 without intrinsic factor resulted in 3.47% excretion in 24 hours. Vitamin B12 with intrinsic factor led to an urinary excretion of 1.49%. No reactions to oral vitamin B12 were reported.

VITAMIN D (CALCIFEROL) AND ANALOGS (SED-14, 1351; SEDA-21, 408; SEDA-22, 438; SEDA-23, 423)

A 52-year-old man with long-standing tetraplegia, who had been taking oral niacin 2 g/day for several months, developed nausea, vomiting, and fever, raised liver enzymes and total and indirect bilirubin. Ultrasonography showed several hyperechoic intrahepatic lesions and CT scan showed several hypoattenuating lesions, some of which were associated with interrupted vessels and had convex borders, suggestive of a tumor. Other lesions had CT features typical of fatty infiltration of the liver. Nicacin was withdrawn. The liver function tests normalized within 4 days and the nausea and vomiting abated. The hepatic lesions on CT scan improved within 1 month and resolved after 9 months.

Alfacalcidol The prevalence and etiology of ectopic calcification due to alfacalcidol and the risk factors have been examined in 60 patients with systemic lupus erythematosus (32c). The prevalence of ectopic calcification was 40%. Localization of calcification was in peripheral arteries (6.7%), in periarticular areas (33%), and in other soft tissues (17%). The incidence of lupus

Vitamins

447

Chapter 38 Table 1. Adverse effects of pyridoxine in the treatment of premenstrual syndrome

Number taking Pyridoxine

Placebo

204 49 46 14

230 70 59 8

Dosage and duration

Number with adverse effects Pyridoxine Placebo

10-200 mg/day 200 mg/day*, 4 cycles 100 mg/day*, 4 cycles 600 mg/day, 3 cycles

11 8 5 1 5 2 1 0 Tingling in the fingers 5 Gastrointestinal 15 Indigestion (7), nausea (5), breast soreness (3) 21 Nausea (8), dizziness (5), mild tingling or numbness (6)

31

150-600 mg/day*

630

4-200 mg/day

336

Over 200 mg/day

* In a multivitamin formulation.

nephritis and nephrotic syndrome were significantly higher in those with ectopic calcification. Total protein concentrations in patients with ectopic calcification (70 g/l) were significantly lower than in patients without calcification (75 g/l). Significantly more of the patients with ectopic calcification had received alfacalcidol (63% vs 19%). The authors concluded that alfacalcidol therapy and lupus nephritis increase the risk of ectopic calcification in patients with systemic lupus erythematosus.

area of suppurative, aseptic, subcutaneous necrosis in the left upper leg perforated. At 2 years of age he was well.

Calcitriol (1,25-dihydroxycholecalciferol)

Doxercalciferol

Vitamin D intoxication occurred in a 7-weekold infant after an overdose of calcitriol (33A). A 7-week-old boy lost weight, became dehydrated and apathetic, and developed muscular hypotonia and mild leukocyturia. His serum calcium was 4.05 mmol/1, his urine calcium 3.1 mmol/1, and his serum phosphate 51 mg/l. He had been given vitamin D 200 000 U/day for 30 days in error, instead of the usual 500 U/day. Parathormone was unmeasureably low. The serum concentration of 1,25-dihydroxycholecalciferol on day 1 was 61 pg/ml (reference range 20-135), 25-hydroxycholecalciferol was 980, 2660, and 8280 ng/1 (reference range 100620) on days 8, 20, and 34 respectively. He was treated with a calcium-free diet, prednisolone, phenobarbital, fluids, and furosemide for 8 weeks. His nephrocalcinosis persisted and after 8 months a large

As routine prophylaxis with vitamin D is not entirely safe, because of errors of prescription or dispensing, and because of its narrow therapeutic range, one should remember that the daily requirements of 100-400 U are usually met by the fortification of formula milk with 40 U/100 g alone.

Doxercalciferol (Hectorol TM)is a new synthetic analog of vitamin D (34r). Unlike calcitriol, which acts in the small intestine to stimulate absorption, it remains inactive until it reaches the liver, where it undergoes transformation to active vitamin D. As a result, doxercalciferol minimizes the risk of hypercalcemia by 67-80%. The manufacturers claim that doxercalciferol is as potent as calcitriol in lowering parathormone concentrations. In two placebo-controlled trials, 90% of dialysis patients with moderate to severe secondary hyperparathyroidism who received doxercalciferol for 16-24 weeks had about a 70% reduction in parathormone concentrations. The most frequently reported adverse effects include edema, headache, and malaise.

448

VITAMIN K (PHYTOMENADIONE)(SED-14, 1356; SEDA-21, 409; SEDA-22, 439; SEDA-23, 423) Skin A severe localized and subsequently generalized dermatitis occurred after the intramuscular injection of vitamin K1 (35A). A 40-year-old woman with no pre-existing hepatic disease was given intramuscular vitamin K1 (Konakion) 1 ml/day (10 mg/ml) on 4 days before open cholecystectomy for gallstones. She then noticed a pruritic erythematous patch on her anterior left thigh, and over the next 4 weeks four patches appeared on her thighs and became larger (maximum diameter 15 cm), vesicular, weeping, hot, indurated, and intensely itchy. Topical calamine lotion, 1% hydrocortisone cream, and Paxyl cream (lignocaine and benzalkonium chloride) and oral cefalexin had no effect. The eruption then spread to the operation wound site, the face, neck, and arms. Oral prednisolone resulted in gradual improvement over the next 4

Chapter 38

H.D. Reuter

weeks, but residual erythema persisted for nearly 6 months. I m m u n o l o g i c The recommendation that prolongation of the international normalised ratio (INR) to over 6 should be corrected with parenteral vitamin K (36 r, 37 r ) is not accompanied by the caveat that t h e intravenous route entails the risk of life-threatening anaphylactoid reactions and even death, due to the use of polyethoxylated castor oil (Cremophor EL) as a solvent (38c). A severe.reaction to intravenous vitamin K has been reported (39A). A 74-year-old woman, taking warfarin, presented with an INR of 6.2. She was given a slow intravenous injection of vitamin K (Konakion, Roche Products Ltd) 0.25 ml (500 Ixg) over about 60 seconds, and soon after felt profoundly unwell and complained of severe backache. She was given chlorpheniramine 10 mg by rapid intravenous injection and adrenaline 1 mg in 10 ml of water over 30 minutes, with a good result.

REFERENCES 1. Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr 1999; 69: 1071-85. 2. Tuyns AJ, Riboli E, Doornbos G, Pequinot G. Diet and esophageal cancer in Calvados (France). Nutr Cancer 1987; 9: 81-92. 3. DeCarli A, Liati, P, Negri E, Franceschi S, La Vechhia C. Vitamin A and other dietary factors in the etiology of esophageal cancer. Nutr Cancer 1987; 10: 29-37. 4. Graham S, Marshall J, Haughey B, Brasure J, Freudenheim J, Zielezny M, Wilkinson G, Nolan J. Nutritional epidemiology of cancer of the esophagus. Am J Epidemiol 1990; 131: 454--67. 5. Geubel AP, DeGalocsy C, Alves N, Rahier J, Dive C. Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases. Gastroenterology 1991; 100: 1701-9. 6. Worner TM, Gordon G, Leo MA, Lieber CS. Vitamin A treatment of sexual dysfunction in male alcoholics. Am J Nutr 1988; 48: 1431-5. 7. Leo MA, Lieber CS. Hepatic fibrosis after long term administration of ethanol and moderate vitamin A supplementation in the rat. Hepatology 1983; 3: 1-11. 8. Chapman KM, Prubhudesai M, Erdman JW Jr. Vitamin A status of alcoholics upon admission and after two weeks of hospitalization. J Am Coil Nutr 1993; 12: 77-83. 9. Leo MA, Kim CI, Lowe N, Lieber CS. Interaction of ethanol with beta-carotene: delayed glood clearance and enhanced hepatotoxicity. Hepatology 1992; 15: 883-91.

10. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass, A, Keogh JP, Meyskens FL Jr, Valanis B, Willimas JH Jr, Baarnahrt S, Hammar S. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. New Engl J Med 1996; 334: 1150-5. 11. Rust P, Eichler I, Renner S, Elmadfa I. Effects of long-term oral beta-carotene supplementation on lipid peroxidation in patients with cystic fibrosis. Int J Vitam Nutr Res 1998; 68: 83-7. 12. Leo MA, Aleynik S, Aleynik M, Lieber CS. Beta-carotene beadlets potentiate hepatotoxicity of alcohol. Am J Clin Nutr 1997; 66: 1461-9. 13. The Alpha-Tocopherol, Beta-Carotene and 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. Bowen HAT, Omaye ST. Oxidative changes associated with beta-carotene and alpha-tocopherol enrichment of human low-density lipoproteins. J Am Coil Nutr 1998; 17: 171-9. 15. Mastroiacovo P, Mazzone T, Addis A, Elephant E, Carlier P, Vial T, Garbis H, Robert E, Bonati M, Ornoy A, Finardi A, Schaffer C, CarameUi L, Rodriguez-Pinilla E, Clementi M. High vitamin A intake in early pregnancy and major malformations: a multicenter prospective controlled study. Teratology 1999; 59:7-11. 16. lliff PJ, Humphrey JH, Mahomva AI, Zvandasara P, Bonduelle M, Malaba L, Nathoo KJ. Tolerance of large doses of vitamin A given to mothers and their babies shortly after delivery. Nutr Res 1999; 19: 1437-46.

Vitamins

Chapter38

17. Turman MA, Hammond S, Grovas A, Ranck AM. Possible association of retinoic acid with bone marrow transplant nephropathy. Pediatr Nephrol 1999; 13: 755-8. 18. Culine S, Kramar A, Droz JP, Theodore C. Phase II study of all-trans retinoic acid administered intermittently for hormone refractory prostate cancer. J Urol 1999; 161: 173-5. 19. Junjie Y, Zhaoping H, Minfei P. Fatal sideeffects of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Bull Hum Med Univ 1999; 24: 293-5. 20. Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomised comparison of alltrans retinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukaemia. Blood 1999; 94; 1192200. 21. Van de Loosdrecht AA, Van Imhoff GW. Images in clinical medicine. All-trans-retinoic acid related pulmonary syndrome in acute promyelocytic leukemia. Neth J Med 1999; 54: 1312. 22. Yamaji S, Kanamori H, Misnima A, Fujisawa S, Motomura S, Mohri H. All-trans retinoic acidinduced multiple mononeuropathies. Am J Hematol 1999; 60: 311. 23. Ko B-S, Tang J-L, Chen Y-C, Yao M, Wang C-H, Shen M-C, Tien H-F. Extramedullary relapse after all-trans retinoic acid treatment in acute promyelocytic leukemia--the occurrence of retinoic acid syndrome is a risk factor. Leukemia 1999; 13: 1406-8. 24. Yamada K, Sugimoto K, Matsumoto T, Narumi K, Oshimi K. All-trans retinoic acid-induced vasculitis and hemonecrosis of the ileum in a patient with acute promyelocytic leukemia. Leukemia 1999; 13: 647-8. 25. Levi I, Raanani P, Shalmon B, Schiby-Brilliant R, Ben-Bassat I. Acute neutrophilic dermatosis induced by all-trans-retinoic acid treatment for acute promyelocytic leukemia. Leuk Lymphoma 1999; 34: 401-4.

449 26. Chang SE, Huh J, Choi JH, Sung K-J, Moon K-C, Koh J-K. Cutaneous relapse in acute promyelocytic leukaemia following treatment with alltrans retinoic acid. Br J Dermatol 1999; 141: 586-7. 27. Scheer MS, Perlmutter S, Ross W, Katz DS. U1trasonographic findings in niacin-induced hepatitis. J Ultrasound Med 1999; 18: 321-3. 28. Kristensen T, Olcott EW. Effects of niacin therapy that simulate neoplasia: Hepatic steatosis with concurrent hepatic dysfunction. J Comput Assisted Tomogr 1999; 23: 314-17. 29. Wyatt KM, Dimmock PW, Jones PW, O'Brien PMS. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. Br Med J 1999; 318: 1375-81. 30. London RS, Bradley L, Chiamori NY. Effect of a nutritional supplement on premenstrual symptomatology in women with premenstrual syndrome: a double blind longitudinal study. J Am Coil Nutr 1991; 10: 494-9. 31. Vaidyanathan S, Soni BM, Oo T, Watt JWH, Sett P, Singh G. Syncope following intramuscular injection of hydroxocobalamin in a paraplegic patient: indication for oral administration of cyanocobalamin in spinal cord injury patients. Spinal Cord 1999; 37: 147-9. 32. Okada J, Nomura M, Shirataka M, Kondo H. Prevalence of soft tissue calcifications in patients with SLE and effects of alfacalcidol. Lupus 1999; 8: 456-61. 33. Muhlendahl KEV, Nawracala J. Vitamin D intoxication. Eur J Pediatr 1999; 158: 266. 34. Portyansky E. New vitamin D analog arrives for hyperparathyroid patients. Drug Topics 1999; 143: 16. 35. Wong DA, Freeman S. Cutaneous allergic reaction to intramuscular vitamin K1. Australas J Dermatol 1999; 40: 147-52. 36. Hirsh J, Dalen JE, Deykin D, Poller L, Bussey H. Oral anticoagulants mechanism of action, clinical effectiveness, and optimal therapeutics. Chest 1995; 108 Suppl 4: 231S-246S. 37. Routledge PA. Practical prescribing: warfarin. Prescr J 1997; 37: 173-9. 38. Martin JC. Anaphylactoid reactions to vitamin K. Med J Aust 1991; 155: 851. 39. Jolobe OMP, Penny E. Severe reaction to i.v. vitamin K. Pharm J 1999; 262:112.

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39

Corticotrophin ,, corticosteroids, and prostaglandins

CORTICOTROPHINS

(SED-14, 1365; SEDA-21, 412; SEDA-22, 442)

apart from inhalation and nasal administration, which are dealt with in Chapter 16.

Pneumocystis carinii pneumonia has been at-

Cardiovascular Intravenous bolus therapy with corticosteroids is often used in standard immunosuppression after organ transplantation and to treat acute graft rejection. Although this regimen in generally is safe, recurrent cardiocirculatory arrest has been reported (2A).

tributed to high-dose A C T H (1A). An infant girl was given ACTH 80 u/day for infantile spasms. After 5 weeks she became increasingly lethargic, with reduced oral intake, cough, an increased respiratory rate (50 breaths/min), and a fever of 38.6 ~ C. Investigations were consistent with pneumonia and she was given intravenous ceftriaxone. She initially improved, but 36 hours later her respiratory distress worsened and she required intubation and mechanical ventilation. The diagnosis of Pneumocystis carinii pneumonia was confirmed and she was given intravenous co-trimoxazole and corticosteroids. Her respiratory distress resolved and she was extubated 10 days later. Immunological testing after the withdrawal of corticotrophin did not show any abnormalities that could have predisposed her to Pneumocystis carinii pneumonia. The authors commented that a transient immunodeficiency related to corticotrophin may have predisposed to the development of Pneumocystis carinii pneumonia.

SYSTEMIC GLUCOCORTICOSTEROIDS (SED-14,1369; SEDA-21, 412; SEDA-22, 442; SEDA-23, 427) Note: In this section adverse effects that arise from the oral or intravenous administration of corticosteroids are covered. Other routes o f administration are dealt with in the next section, 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed. 450

A 60-year-old white man was admitted for kidney transplantation. Immediately after reperfusion and intravenous methylprednisolone 500 mg, he developed severe bradycardia with hypotension and then cardiac arrest. After resuscitation, his clinical state improved quickly, but on the moming of the first postoperative day directly after the intravenous administration of methylprednisolone 250 mg, he had another episode of severe bradycardia, hypotension, and successful cardiopulmonary resuscitation. A third episode occurred 24 hours later after intravenous methylprednisolone 100 mg, again followed by rapid recovery after resuscitation. Two weeks later, during a bout of acute rejection, he was given intravenous methylprednisolone 500 mg, after which he collapsed and no heartbeat or breathing was detectable; after cardiopulmonary resuscitation he was transferred to the intensive care unit, where he died a few hours later. If patients at risk are identified, corticosteroid bolus therapy should be avoided or, if that is not possible, should only be done under close monitoring. Postnatal exposure to steroids has been associated with hypertrophic cardiomyopathy in neonates. Such an effect has not previously been described in infants born to mothers who received antenatal corticosteroids. Three neonates (gestational ages 36, 29, and 34 weeks) whose mothers had been treated with betamethasone prenatally in doses of 12 mg

Corticotrophins, corticosteroids, and prostaglandins twice weekly for 16 doses, 8 doses and 5 doses respectively, developed various degrees of hypertrophic cardiomyopathy diagnosed by echocardiography (3A). There was no maternal evidence of diabetes, except for one infant whose mother had a normal fasting and postprandial blood glucose before corticosteroid therapy, but an abnormal I-hour postprandial glucose after 8 weeks of betamethasone therapy, with a normal H b A l c concentration. There was no family history of hypertrophic cardiomyopathy, no history of maternal intake of other relevant medications, no hypertension, and none of the infants received corticosteroids postnatally. Follow-up echocardiography showed complete resolution in all infants. The authors suggested that repeated antenatal maternal corticosteroids might cause hypertrophic cardiomyopathy in neonates. These changes appear to be dose- and duration-related and are mostly reversible. Respiratory Dexamethasone has been used in ventilator-dependent preterm infants to reduce the risk and severity of chronic lung disease. Usually it is given in a tapering course over a long period (42 days). The effects of dexamethasone on developmental outcome at 1 year of age has been evaluated in 118 infants of very low birth weights (47 boys and 71 girls, aged 15-25 days), who were not weaning from assisted ventilation (4c). They were randomly assigned double-blind to receive placebo or dexamethasone (initial dose 0.25 mg/kg) tapered over 42 days. A neurological examination, including ultrasonography, was done at 1 year of age. Survival was 88% with dexamethasone and 74% with placebo. Both groups obtained similar scores in mental and psychomotor developmental indexes. More dexamethasone-treated infants had major intracranial abnormalities (21% vs 11%), cerebral palsy (25% vs 7%; OR = 5.3; CI = 1.3, 21), and unspecified neurological abnormalities (45% vs 16%; OR = 3.6; CI = 1.2, 11). Although the authors suggested an adverse effect, they added other possible explanations for these increased risks (improved survival in those with neurological injuries or at increased risk of such injuries). Although there have been several trials of early dexamethasone to determine whether it would reduce mortality and chronic lung disease in infants with respiratory distress, the

Chapter39

451

optimal duration and adverse effects of such therapy are unknown. The purpose of one study was: (a) to determine if a 3-day course of early dexamethasone therapy would reduce chronic lung disease and increase survival without chronic lung disease in neonates who received surfactant therapy for respiratory distress syndrome and (b) to determine the associated adverse effects (5c). This was a prospective, placebo-controlled, multicenter, randomized study of a 3-day course of early dexamethasone therapy, beginning at 24--48 hours of life in 241 neonates, who weighed 5001500 g, had received surfactant therapy, and were at significant risk of chronic lung disease or death. Infants randomized to dexamethasone received a 3-day tapering course (total dose 1.35 mg/kg) given in six doses at 12-hour intervals. Chronic lung disease was defined by the need for supplementary oxygen at a gestational age of 36 weeks. Neonates randomized to early dexamethasone were more likely to survive without chronic lung disease (RR = 1.3; CI = 1.0, 1.7) and were less likely to develop chronic lung disease (RR = 0.6; CI = 0.3, 0.98). Mortality rates were not significantly different. Subsequent dexamethasone therapy was less in early dexamethasone-treated neonates (RR = 0.8; CI = 0.70, 0.96). Very early (before 7 days of life) intestinal perforations were more common among dexamethasone treated neonates (8% vs 1%). The authors concluded that an early 3-day course of dexamethasone increases survival without chronic lung disease, reduces chronic lung disease, and reduces late dexamethasone therapy in high-risk, low birth weight infants who receive surfactant therapy for respiratory distress syndrome. The potential benefits of early dexamethasone therapy in the regimen used in this trial need to be weighed against the risk of early intestinal perforation. In another randomized clinical trial the effects and adverse effects of early dexamethasone on the incidence of chronic lung disease have been evaluated in 50 high-risk preterm infants (6c). The treated infants received dexamethasone intravenously from the fourth day of life for 7 days (0.5 mg/kg/day for the first 3 days, 0.25 mg/kg/day for the next 3 days, and 0.125 mg/kg/day on the seventh day). The incidence of chronic lung disease at 28 days of life and at 36 weeks of postconceptional age was significantly lower in the infants who

452 were given dexamethasone, who also remained intubated and required oxygen therapy for a shorter period. Hyperglycemia, hypertension,

growth failure, and left ventricular hypertrophy were the transient adverse effects associated with early steroid administration. Early dexamethasone administration may be useful in preventing chronic lung disease, but its use should be restricted to preterm high-risk infants. A systematic review of randomized controlled trials has been performed to determine whether dexamethasone therapy in the first 15 days of life prevents chronic lung disease in premature infants (7M). Studies were identified by a literature search using Medline (1970-97) supplemented by a search of the Cochrane Library (1998, issue 4). Inclusion criteria were: (a) prospective randomized design with initiation of dexamethasone therapy within the first 15 days of life; (b) report of the outcome of interest; and (c) less than 20% cross-over between the treatment and control groups during the study period. The primary outcomes were mortality at hospital discharge and the development of chronic lung disease at 28 days of life and 36 weeks postconceptional age. The secondary outcomes were the presence of a patent ductus arteriosus and treatment adverse effects. Dexamethasone reduced the incidence of chronic lung disease by 26% at 28 days (RR = 0.74; CI = 0.57, 0.96) and 48% at 36 weeks postconceptional age (RR = 0.52; CI = 0.33, 0.81). These reductions were more significant when dexamethasone was started in the first 72 hours of life. The 24% relative risk reduction of deaths was marginally significant (RR = 0.76; CI = 0.56, 1.04). The 27% reduction in patent ductus arteriosus and the 11% increase in infections were not statistically significant, nor were any other changes. The conclusion from this meta-analysis was that systemic dexamethasone given to at-risk infants soon after birth may reduce the incidence of chronic lung disease. There was no evidence of significant short-term adverse effects. Persistent hiccupping has been described in a 30-year-old man after the administration of a single intravenous dose of dexamethasone (16 mg) (8A). The symptom was resistant to metoclopramide and resolved spontaneously after 4 days. On rechallenge, the hiccups recurred within 2 hours and disappeared after 36 hours.

Nervous system Benign intracranial hyper-

Chapter 39

J. Costa and M. Farrd

tension, with the risk of permanent visual loss, is a complication that is under-recognized in children (9A~). A 6-year-old girl, who had taken prednisone for 2.5 years for nephrotic syndrome with seven relapses in 3 years, developed symptoms of benign intracranial hypertension after oral corticosteroid dosage reduction over 10 months from 30 mg/day to 2.5 mg/every other day. Laboratory studies and head CT scan were normal, but there was bilateral papilledema and the cerebrospinal fluid pressure was increased. She was given prednisone 1 mg/kg/day initially, with acetazolamide and 25 ml of cerebrospinal fluid was removed. All her symptoms resolved and treatment was gradually withdrawn. She developed no further visual failure. All patients taking large doses of corticosteroids who complain of headache or blurred vision, particularly after a reduction in dosage, should have an ophthalmoscopic examination to exclude this complication. Spinal epidural lipomatosis has been attributed to long-term corticosteroid therapy (10A). A 57-year-old man took prednisone 20-30 mg/day for 13 years for rheumatoid arthritis. He had been treated unsuccessfully with gold, azathioprine, hydroxychloroquine, and sulfasalazine; tapering his corticosteroid dosage had been unsuccessful. He developed worsening back pain in his thoracic spine and lateral leg weakness. He was unable to walk. He was Cushingoid and had marked thoracic kyphosis associated with multiple vertebral body fractures in T5-8. An MRI scan at T5~i showed displacement and compression of the spinal cord by high-signal epidural fat, which had caused anterior thecal displacement and total effacement of cerebrospinal fluid. The authors commented that because of the lower doses of corticosteroids that are generally used, spinal epidural lipomatosis has only rarely been described as a complication of treatment in rheumatoid arthritis. Cerebral venous thrombosis associated with corticosteroid treatment has rarely been reported. A relation between corticosteroids and venous thrombosis has already been suggested but has never been clearly understood. Three cases of young patients, two women (aged 28 and 45) and one man (aged 38 years), developed cerebral venous thrombosis after intravenous highdose corticosteroids (11At). All presented with probable multiple sclerosis according to clinical, CSF, and MRI criteria. All had a lumbar puncture and were then treated with methylprednisolone 1 g/day for 5 days. All the usual

Corticotrophins, corticosteroids, and prostaglandins causes of cerebral venous thrombosis were systematically excluded. The authors proposed that corticosteroids interfere with blood coagulation and suggested that the administration of corticosteroids after a lumbar puncture carries a particular risk of complications.

Chapter 39

453

with visual hallucinations, disorientation, agitation, and attempts to leave the floor. Her mother refused treatment with haloperidol. Steroids were withdrawn and lorazepam was given as needed. Nine days later the symptoms had not improved. She was given risperidone 1 mg/day; within 3 days the psychotic reaction began to improve and by 3 weeks the symptoms had completely resolved.

Sensory systems Intravitreal triamcinolone given for subretinal neovascularization has been associated with a rise in ocular pressure (12c). A total of 113 patients with angiographically proven subretinal neovascularization were enrolled into a prospective study of the effects of intravitreal triamcinolone. About 30% developed a significant rise in intraocular pressure (at least 5 mmHg) above baseline during the first 3 months.

Psychiatric Mania has been attributed to corticosteroids (13A). A 46-year-old man, with an 8-year history of cluster headaches and some episodes of endogenous depression, took corticosteroids 120 mg/day for a week and then a tapering dosage at the start of his latest cluster episode. His headaches stopped but then recurred after 10 days. He was treated prophylactically with verapamil, but a few days later, while the dose of corticosteroid was being tapered, he developed symptoms of mania. The steroids were withdrawn, he was given valproic acid, and his mania resolved after 10 days. Verapamil prophylaxis was restarted and he had no more cluster headaches. The authors commented that the manic symptoms had probably been caused by the steroids or steroid withdrawal. They concluded that patients with cluster headache and a history of affective disorder should not be treated with corticosteroids, but with valproate or lithium, which are effective in both conditions. Lamotrigine, an anticonvulsive drug with moodstabilizing effects, may prevent steroid-induced mania in patients for whom valproate or lithium are not possible (14A). A case report has suggested that risperidone, an alternative to classical antipsychotic drugs, can be useful in treating adolescents with steroid-induced psychosis and may hasten its resolution ( 1 5A) . A 14-year-old African-American girl with acute lymphocytic leukemia was treated with dexamethasone 24 mg/day for 25 days. Four days after starting to taper the dose she had a psychotic reaction

Glucocorticoids can regulate hippocampal metabolism, physiological functions, and memory. Despite evidence of memory loss during glucocorticoid treatment (SEDA-23, 428), and correlations between memory and cortisol concentrations in certain diseases, it is unclear whether exposure to the endogenous glucocorticoid corfisol in amounts seen during physical and psychological stress in humans can inhibit memory performance in otherwise healthy individuals. In an elegant experiment on the effect of cortisol in memory 51 young healthy volunteers (24 men and 27 women) participated in a double-blind, randomized, cross-over, placebo-controlled trial of cortisol, 40 mg/day or 160 mg/day for 4 days (16c). The lower dose of cortisol was equivalent to the cortisol delivered during a mild stress and the higher dose to major stress. Cognitive performance and plasma cortisol were evaluated before and until 10 days after drug administration. Cortisol produced a dose-related reversible reduction in verbal declarative memory without effects on non-verbal memory, sustained or selective attention, or executive function. Exposure to cortisol at doses and plasma concentrations associated with physical and psychological stress in humans can reversibly reduce some elements of memory performance. Children have marked increases in behavioral problems during treatment with high-dose prednisone for relapse of nephrotic syndrome, according to the results of a study conducted in the USA (17c). Ten children aged 2.9-15 years (mean 8.2 years) received prednisone 2 mg/kg/day, tapering at the time of remission, which was at week 2 in seven patients. At baseline, eight children had normal behavioral patterns and two had anxious/depressed and aggressive behavior using the Child Behaviour Checklist (CBCL). During high-dose prednisone therapy, five of the eight children with normal baseline scores had CBCL scores for anxiety, depression, and aggressive behavior above the 95th percentile for age. The two children with high baseline CBCL scores had

454 worsening behavioral problems during highdose prednisone. Behavioral problems occurred almost exclusively in the children who received over 1 mg/kg every 48 hours. Regression analysis showed that prednisone dosage was a strong predictor for increased aggressive behaviour. Endocrine A 26-year-old woman with a monochorionic monoamniotic twin pregnancy developed hyperadrenalism after she received five courses of betamethasone to enhance fetal lung maturation during preterm labour at 27 weeks of gestation (see Use in pregnancy) (18A). Acute withdrawal led to adrenal insufficiency. Hyperadrenalism has never been reported after the sequential use of corticosteroids for fetal lung maturation. Metabolic In the past two decades dexamethasone has gained wide acceptance in routine practice for the postnatal treatment of prevention of chronic lung disease. Although dexamethasone is commonly associated with transient adverse effects, several randomized trials have shown that it rapidly reduces oxygen requirements and shortens the duration of ventilation. A randomized study was designed to evaluate the effects of two different dexamethasone courses on growth in preterm infants (19c). The first phase included 30 preterm infants at high risk of chronic lung disease, of whom 15 (eight boys) were given dexamethasone for 14 days, from the tenth day of life, and received a total dose of 4.75 mg/kg; 15 babies were assigned to the control group (eight boys). The second phase included 30 preterm infants at high risk of chronic lung disease, of whom 15 babies (seven boys) were treated with dexamethasone for 7 days, from the fourth day of life, and received a total dose of 2.38 mg/kg; 15 babies were assigned to the control group (nine boys). Infants given dexamethasone had significantly less weight gain than controls, but they caught up soon after the end of treatment. At 30 days of life the gains in weight and length in each group were similar to those in control infants, but those given dexamethasone had significantly less head growth. There were no differences between the groups at discharge. The longer term impact of postnatal dexamethasone on mortality and morbidity is less clear. Better data from larger clinical trials with longer follow-up will determine whether this kind of

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J. Costa and M. Farr~

treatment enhances lives, makes little difference, causes significant harm, or does several of these things (20r). Nutrition Most premature neonates need intravenous lipids during the first few weeks of life to acquire adequate energy intake and prevent essential fatty acid deficiency before they can tolerate all nutrition via enteral feeds. Dexamethasone is associated with multiple adverse effects in neonates, including poor weight gain (see above) and impairment of glucose and prorein metabolism. In 10 neonates (four boys, mean age 17.3 days) taking dexamethasone for bronchopulmonary dysplasia, intravenous lipids (3 g/kg/day) caused hypertriglyceridemia in the presence of hyperinsulinemia and increased free fatty acid concentrations (21c). Because of concomitant hyperinsulinemia, the authors speculated that dexamethasone reduced fatty acid oxidation, explaining poor weight gain. Metal metabolism Corticosteroids increase chromium losses and steroid-induced diabetes can be reversed by chromium supplementation (22c). Doses of hypoglycemic drugs were also reduced by 50% in all patients when they were given supplementary chromium. Liver Although hepatic steatosis is a potential adverse effect of prednisolone, liver damage is rarely severe. Fatal liver failure has been reported (23A). A 53-year-old woman who took prednisolone 20 mg/day for systemic lupus erythematosus for 38 days developed increased AsT and A1T (175 and 144 iu/1 respectively on day 38 and 871 and 658 iu/1 on day 69). She denied taking hepatotoxic drugs. Serological tests for hepatitis viruses were all negative. Autoantibodies against mitochondria and smooth muscle were not detected. Ultrasound and CT scan were consistent with fatty infiltration. Histology showed macrovesicular fat infiltration, periportal cell infiltration with fibrosis, and a few Mallory bodies. The corticosteroid was gradually tapered and the AsT and A1T gradually fell. Pancreas Two new cases of glucocorticoidinduced pancreatitis have been reported (24A). A 74-year-old woman with seronegative rheumatoid arthritis was given sulfasalazine followed by methotrexate, both of which were withdrawn because of adverse effects. She also took prednisone 10 mg/day. She developed acute abdominal pain and

Corticotrophins, corticosteroids, and prostaglandins fever (38.7~ C) with no chills. Her serum amylase was 269 iu/1, serum lipase 300 iu/l, and urinary amylase 2895 iu/1. There was no evidence of tumor, hypertriglyceridemia, or lithiasis. In addition to prednisone, she was taking amlodipine, bromazepam, and omeprazole, none of which have been reported to cause pancreatitis. A marked improvement was noted after prednisone withdrawal. A 68-year-old woman who had taken prednisone 30 mg/day for polymyalgia rheumatica for 6 months developed sharp stabbing abdominal pain, fever (39~ C), and vomiting. Her serum amylase was 310 iu/1, serum lipase 340 iu/1, and urinary amylase 1560 iu/1. Other causes of pancreatitis were ruled out. She had been taking a thiazide diuretic therapy for the past 10 years. Her symptoms improved noticeably after prednisone withdrawal. U r i n a r y tract Prednisolone can cause an abrupt rise in proteinuria in patients with nephrotic syndrome. A placebo-controlled study in 26 patients aged 18-68 years with nephrotic syndrome has clarified the mechanisms responsible for this (25c). Systemic and renal hemodynamics and urinary protein excretion were measured after prednisolone (125 mg or 150 mg when body weight exceeded 75 kg) and after placebo. Prednisolone increased proteinuria by changing the size-selective barrier of the glomerular capillaries. Neither the reninangiotensin axis nor prostaglandins were involved in these effects of prednisolone on proteinuria. Skin Budesonide is advocated as a marker molecule for corticosteroid contact allergy. When patch testing corticosteroids, one must consider both their sensitizing potential and their anti-inflammatory properties, as well as the possibility of different time courses of such properties. The dose-response relation for budesonide has therefore been investigated with regard to dose, occlusion time, and reading time in 10 patients (ages not stated) who were patch tested with budesonide in ethanol in serial dilutions from 2.0% down to 0.0002%, with occlusion times of 48, 24, and 5 hours (26c). Readings were on days 2, 4, and 7. The 48-hour occlusion detected most positive reactors (8/10) at a reading time of 4 days and 0.002% detected most contact allergies. The "edge effect" (reactions with a peripheral ring due to suppression of the allergic reaction under the patch because of the intrinsic anti-inflammatory effect of the corticosteroid itself) was noted with several concentrations at early readings. That

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lower concentrations can detect budesonide allergy better at early readings and that patients with an "edge reaction" can have positive reactions to lower concentrations can be explained by individual corticosteroid reactivity, the doseresponse relation, and the time-courses of the elicitation and the anti-inflammatory capacity. A 14-year-old girl with newly diagnosed systemic lupus erythematosus developed a pruritic bullous eruption while taking prednisone 20 mg/day (27A). She was given a single daily dose of intravenous methylprednisolone 60 mg with rapid improvement. In preparation for discharge, the steroid was changed to oral prednisone 60 mg/day to which she developed a pruritic bullous eruption consistent with erythema multiforme. She underwent immediate and delayed hypersensitivity tests. Intradermal and patch tests to liquid prednisone were positive. She was given oral methylprednisolone 48 rag/day and has not had recurrence of the skin lesions. Musculoskeletal Osteoporosis induced by chronic glucocorticoid therapy in patients with obstructive lung diseases has recently been reviewed (28R). The authors presented guidelines regarding the identification of patients at risk of developing bone loss and discussed therapeutic altematives. In patients with secondary hypoadrenalism, hydrocortisone 30 mg/day for replacement produced a significant fall in osteocalcin, indicating bone loss. Lower doses of hydrocortisone (10 mg and 20 mg) produced similar efficacy in terms of quality of life but smaller effects on osteocalcin concentrations and therefore a reduction in bone loss (29c). Aseptic necrosis of the femoral head has been described for first time in a pregnant woman (see Use in pregnancy) (30A). Accelerated bone loss, with an increased risk of first hip fracture, occurred in elderly women taking oral corticosteroids (31c). At baseline, 122 (1.5%) women were taking inhaled corticosteroids only (median dose equivalent to inhaled beclomethasone 168 txg/day), 228 (2.8%) were taking oral corticosteroids (median dose equivalent to prednisone 5 mg/day) with or without inhaled corticosteroids, and 7718 were not taking any corticosteroids. The women who were taking oral corticosteroids had lower mean bone mineral density at 3.6 years than non-users, with an interim fall that was twice as fast. First hip fracture occurred in 4.8% of the women who were taking oral corticosteroids and in 2.8% of

456 the women who were not (RR = 2.1; CI = 1.0, 4.4). The researchers said that the power of the study was not sufficient to determine the relative risk of hip fracture in w o m e n taking inhaled corticosteroids. I m m u n o l o g i c An anaphylactoid reaction occurred in a 35-year-old man with multiple sclerosis who became allergic to methylprednisolone (dose not stated) after starting treatment with interferon-/3lb (32A). He had previously been treated with different courses of methylprednisolone. Clinicians should be aware that the complexity of the effects of interferon-t31b on the immune system can lead to unexpected outcomes. It is uncertain whether the sequence of events here was due to an effect of interferon-fllb or to coincidence. Anaphylaxis has also been reported with methylprednisolone alone (33A). A 17-year-old boy, with an ll-year history of asthma, had anaphylaxis with respiratory distress shortly after he received intravenous methylprednisolone for an exacerbation of asthma while taking a tapering course of oral prednisone 15 mg/day. He had been corticosteroid-dependent for at least 1 year. He reported having received intravenous corticosteroids previously. He was treated with inhaled salbutamol and then intravenous methylprednisolone 125 mg over 15-30 seconds and 3 4 minutes later became flushed and dyspneic, and developed diffuse urticarial lesions on his trunk and face and an undetectable blood pressure. He was treated with adrenaline, but required intubation. Sinus bradycardia developed and then asystole. He was successfully resuscitated and a 10-15 second period of generalized tonic-clonic activity was treated with diazepam. He remained unresponsive to stimulation for 30 minutes. However, he awoke 1 hour after his respiratory arrest and was extubated and discharged the following day taking a tapering dosage of prednisone. Cross-reactivity between corticosteroids and progestogens has been described (34A). A 68-year-old woman, with a prolonged history of pityriasis lichenoides chronica treated with topical corticosteroids, including hydrocortisone, took a formulation containing conjugated estrogens 0.625 mg and hydroxyprogesterone acetate 5 mg (frequency of administration not stated) for late menopausal syndrome. Years later she started to have pruritus, a maculopapular rash, and flu-like symptoms for several days before menstruation. On this occasion, she presented with a severe, pruritic, papulovesicular eruption on her chest, back, abdomen, and legs. The eruption had developed after treatment for 7

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days with the estrogen-progestogen formulation; she had developed similar symptoms on several previous occasions after taking the same medication. She was treated with antihistamines and her skin eruption resolved within a few days. Patch tests were positive to 17-OH-progesterone, tixocortol pivalate, and budesonide. The authors hypothesized that this patient, who had taken topical corticosteroids for several years, had become sensitive and that the recurrent episodes of autoimmune progestogen dermatitis were related to endogenous progestogen sensitivity following cross-sensitivity to corticosteroids. This hypothesis was supported by the development of recurrent eczema several times after she took an estrogen-progestogen preparation. A hypersensitivity reaction to intravenous hydrocortisone has been reported (35A). A 64-year-old woman with a history of bronchial asthma developed increasing shortness of breath after an upper respiratory tract infection. Her medication included inhaled salbutamol as necessary, theophylline 300 mg bd, and aspirin 325 mg/day. She was given nebulized salbutamol and ipratropium and hydrocortisone 200 mg intravenously. Within 30 minutes, she developed a generalized rash, fever (38.3 ~ C), and respiratory distress. She was promptly intubated and mechanical ventilation was started. No further doses of corticosteroid were given. Skin testing with various parenteral formulations of corticosteroids produced a 5-mm wheal at the site of hydrocortisone and methylprednisolone injections. She was subsequently given a challenge dose of triamcinolone using a metered-dose inhaler with no reaction, and was therefore continued on this medication.

Contact allergy to budesonide in a breathactuated inhaler has been described (36A). A 40-year-old woman had a flare-up of her eczema. She had had previous negative patch tests 10 years before. She had taken topical corticosteroids and emollients for a few months, but had not used budesonide. Patch testing with the European standard series showed a positive reaction to budesonide 0.1% at 3 days. All other allergens were negative. The only antecedent exposure was that she had three children with asthma, all of whom regularly used inhaled budesonide and occasionally nebulizers. She had not used the inhaler but had helped her children to manage the devices. A subsequent patch test with powdered budesonide from the inhaler was positive. Dexamethasone significantly affected the antibody response of preterm infants with

Corticotrophins, corticosteroids, and prostaglandins chronic lung disease to immunization against

Hemophilus influenzae (37c). Serum samples were obtained before and after immunization from an unselected cohort of 59 preterm infants (30 boys; gestational age 175-208 days). Hemophilus influenzae antibodies were measured using ELISA. Before and after immunization IgG antibody concentrations in 16 infants who received no dexamethasone were 0.16 and 4.63 tzg/ml. The corresponding values for those who received dexamethasone were 0.10 and 0.51 lzg/ml. Infection risk Patients who take corticosteroids have an increased risk of infections, including those produced by rare pathogens. The use of betamethasone for the treatment of premature rupture of membranes during pregnancy is associated with an increased prevalence of maternal and neonatal infections. Two reports have described the risk of infections associated with the use of corticosteroids during pregnancy. Of 374 patients with preterm premature rupture of membranes, 99 received a single course of corticosteroid, 72 received multiple courses, and 203 were not treated with corticosteroids (38c). Only multiple courses of betamethasone increased the incidence of early-onset neonatal sepsis, chorioanmionitis, and endometritis in mothers. A single course of corticosteroid was not significantly associated with any maternal or neonatal infectious complications. The incidence of maternal infections in 37 patients who received three or more courses of betamethasone (median 6, range 3-10) because risk of preterm delivery has been evaluated, with 70 healthy pregnant women as controls (39c). Of those treated with betamethasone 65% developed infectious diseases compared with 18% of controls. Symptomatic lower urinary tract infections (35% vs 2.7%) and serious bacterial infections (24% vs 0%) were more frequent in treated mothers. Eight of nine serious infections occurred in patients exposed to five or more courses of steroids. Scedosporium apiospermum infection occurred in the left forearm of an 81-year-old man who was taking chronic oral prednisone (increased to 40 mg/day 1 month before presentation) for lung fibrosis (40A). The use of corticosteroids in patients with hematological diseases is a factor that facilitates the occurrence of Legionella pneumophila

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pneumonia, and 10 episodes of this infection were possibly related to corticosteroids in a series of 67 cases of Legionella sp pneumonia diagnosed in a single institution during 2.5 years (41c). Pregnancy Prenatal corticosteroid therapy to enhance fetal lung maturation reduces neonatal morbidity and mortality. However, adverse effects of serial courses of betamethasone on mother and fetus can occur. Osteonecrosis of the femoral head can occur with corticosteroids in non-pregnant individuals, but has not previously been reported in pregnancy (30A). A 37-year-old white woman was given a course of betamethasone (two doses of 12 mg over a day) at 24 weeks of a twin pregnancy, because of a history of growth restriction in her first pregnancy. At 25 weeks Doppler of the umbilical vessels suggested a reduction in end-diastolic flow in one twin. Betamethasone was prescribed again and was repeated weekly to a total of six courses because of the high risk of preterm delivery. At 30 weeks she complained of pain in the right hip exacerbated by weight bearing, which increased over the following 7 days until standing was impossible. An MRI scan showed avascular necrosis of the femoral head. Maternal hyperadrenalism occurred after five courses of betamethasone to enhance fetal lung maturation (18A ). A 26-year-old woman was given intravenous salbutamol 0.3 mg/hour for preterm labor, and intramuscular betamethasone 12 mg/day for 2 days. Daily oral tocolysis (salbutamol 2 mg every 6 hours plus nicardipine 50 mg every 12 hours) and betamethasone every week were continued at home for 3 weeks. The mother developed amyotrophy, acne on the face and trunk, moon face, hirsutism with whiskers, and thin skin. Free urinary cortisol was less than 5 mg/day (reference range 25-90), plasma cortisol was less than 10 ng/ml (100-200), and the salivary cortisol was less than 0.6 ng/ml (2.34.7). One hour after intramuscular tetracosactide 250 Irg, her plasma cortisol was 102 ng/ml (reference range over 210) and the salivary cortisol was 3.1 ng/ml (13-25), indicating no adrenocortical response. She was given hydrocortisone 20 mg/day and 2 months later, adrenocortical insufficiency persisted, with a plasma cortisol of 152 ng/ml after ACTH stimulation. One year later, she still required hydrocortisone 10 mg/day.

A reduction in fetal response to vibroacoustic stimulation (vibroacoustic startle reflex) has

458 been reported during 48 hours after the administration to pregnant women of two doses of betamethasone (12 mg 2 days apart) (42c). The authors recommended that this test should not be used to evaluate well-being in fetuses exposed to corticosteroids. Teratogenicity Congenital malformations that may be associated with inhaled budesonide in pregnancy have been evaluated using the Swedish Medical Birth Registry (43c). Of 2014 infants whose mothers started to use inhaled budesonide in early pregnancy, 75 (3.7%) had a congenital malformation; the corresponding rate among all infants born in 1995-97 was 3.5%. Five infants had chromosomal anomalies that were unlikely to have been caused by drugs. This study did not identify teratogenic properties of inhaled budesonide.

Fetotoxicity Betamethasone, two doses of 12 mg a day apart, in 40 pregnant women (2734 weeks) caused important changes in fetal physiology (44c). Fetal breathing (the number of breathing episodes and the total breathing time in 30 minutes) fell by 83% and fetal limb and trunk movements fell by 53% and 49% respectively. These changes were transient and returned to the range of normality 96 hours after administration. There were no changes in Doppler velocimetry of the umbilical and middle cerebral arteries. Awareness of these effects may prevent unnecessary iatrogenic delivery of preterm infants who present abnormal biophysical profile scores 2 days after corticosteroid exposure.

Drug contamination

Unregulated Chinese herbal products adulterated with corticosteroids have been detected (45c). Dexamethasone was present in eight of 11 Chinese herbal creams analyzed by UK dermatologists. The creams contained dexamethasone in concentrations inappropriate for use on the face or in children (64-1500 Ixg/g). The cream with the nighest concentration of dexamethasone was prescribed to treat facial eczema in a 4-month-old baby. In all cases it had been assumed that the creams did not contain corticosteroids. The authors were concerned that these patients received both unlabelled and unlicensed topical corticosteroids. They wrote that "greater regulation and restriction needs to be imposed on herbalists,

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and continuous monitoring of side effects of these medications is necessary". Drug interactions Drug interactions that affect the efficacy of corticosteroids have been reviewed (46R). Clarithromycin (500 mg bd for 2 days) reduced the clearance of methylprednisolone by 65% and significantly increased its plasma concentrations (47c). Clarithromycin did not influence the clearance or plasma concentrations of prednisone. The mechanism could be related to the inhibitory action of clarithromycin on CYP3A4. The effect of prednisone 1 mg/kg on the pharmacokinetics of cyclophosphamide and its initial metabolites 4-hydroxycyclophosphamide and aldophosphamide has been studied between the first and sixth cycles in seven patients (two men) with systemic vasculitis receiving intravenous cyclophosphamide 0.6 g/m e as a 1-hour intravenous infusion every 3 weeks for six cycles (48c). (Aldophosphamide is the acyclic tautomer of 4-hydroxycyclophosphamide.) Prednisone reduced the clearance of cyclophosphamide from 5.8 to 4.0 1/hour, reducing the amount of initial metabolites formed. Although the clinical significance of this interaction is unclear, 4-hydroxycyclophosphamide and aldophosphamide are probably responsible for the cytotoxic activity of cyclophosphamide, and increased cyclophosphamide dosages should be considered in patients taking prednisone. Itraconazole 200 mg/day orally for 4 days markedly reduced the clearance and increased the half-life of intravenous methylprednisolone from 2.1 to 4.8 hours in a double-blind, randomized, two-phase, cross-over study in nine healthy volunteers (SEDA-23, 430; 49c). The volume of distribution was not affected. The mean morning plasma cortisol concentration during the itraconazole phase, measured 24 hours after methylprednisolone, was only 9% of that during the placebo phase (11 vs 117 ng/ml). The authors recommended that care be taken when methylprednisolone is prescribed in combination with itraconazole or other potent inhibitors of CYP3A4.

Corticotrophins, corticosteroids, and prostaglandins

SPECIAL ROUTES OF ADMINISTRATION OF CORTICOSTEROIDS (SED-14, 1387; SEDA-21, 419; SEDA-22, 451; SEDA-23, 431) Epidural and intrathecal administration

Spinal epidural lipomatosis secondary to exogenous administration of steroids is a rare condition that has been reported almost exclusively in association with systemic treatments. A second case after local epidural corticosteroids has now been published (50A). I n h a l a t i o n The use of corticosteroids by inhalation and nasal administration is covered in Chapter 16.

Intra-articular administration

The first report of hiccups after intra-articular administration has been published (51A). A 38-year-old man had an intra-articular injection of betamethasone dipropionate (dose not stated) into his right ankle, and the day after had hiccups that lasted for 24 hours and then resolved without treatment. Some months later, because of persistent arthritis, he received a further injection of betamethasone dipropionate into his right ankle. Once again, he had hiccups the following day. On this occasion, the hiccups resolved after 2 weeks, following treatment with levomepromazine.

Intranasal administration Cushing's syndrome has been attributed to nasal fluticasone in an interaction with ritonavir (52A). A 30-year-old man who was using an intranasal formulation of fluticasone (therapeutic indication not stated), developed Cushing's syndrome about 5 months after starting ritonavir 600 mg bd, zidovudine, and lamivudine for HIV infection. His plasma cortisol concentrations were undetectable, his corticotrophin was low (under 2 pmol/1), and his 24-hour urinary cortisol excretion was under 30 nmol/l. Further investigations were consistent with secondary adrenal failure or with corticosteroid use. He admitted to having used a topical corticosteroid cream for 2 months. However, 6 weeks after he stopped using this cream, his plasma cortisol concentrations were still undetectable. It was then established that he had used nasal fluticasone propionate 200 Itg/day for about 1 year before starting ritonavir. Ritonavir was replaced by nevirapine, and he continued to use fluticasone nasal spray. Three weeks later, his plasma cortisol concentration had increased to 290 nmol/l. Ritonavir was then added and his plasma cortisol concentration fell rapidly. Ritonavir was stopped again and his

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cortisol concentration normalized and his Cushingoid facies improved. The authors thought it likely that inhibition of cytochrome P-450 by ritonavir increased the systemic availability of fluticasone and thus caused Cushing's syndrome in this patient.

Topical administration

Although corticosteroids are used to treat eczema, they can sometimes exacerbate it (53A). A 74-year-old man developed worsening eczema 24 hours after he applied clobetasol (Decloban | to treat chronic eczema of his external ear. Twelve years earlier he had noted exacerbation of a cutaneous lesion after he had applied a topical corticosteroid. He had also had generalized erythema after an intraarticular injection of paramethasone. Patch tests to a series of corticosteroids were positive for all drugs except flupametasone, fluocortine, and tixocortol. In addition, intradermal tests were positive to hydrocortisone and prednisolone, despite negative patch tests. The authors commented that most corticosteroid-sensitized patients react to several of the same group and less frequently of different groups. No case of hypersensitivity to corticosteroids of all four classes has previously been reported.

(SED-14, 1396; SEDA-21, 420; SEDA-22, 452; SEDA-23, 432) PROSTAGLANDINS

Alprostadil (prostaglandin ED There is a high dropout rate from selfinjection therapy for erectile dysfunction. O f 86 patients aged 36-76 years who had been using home treatment for at least 3 months, 17 had discontinued treatment (54c). The patients were evaluated by interview and clinical examination. Patients still in the program used one injection every 2 weeks, and those who had given up treatment had used one injection in 3 weeks. They were in the program for 39 and 16 months respectively, and had used a mean of 50 vs 12 injections respectively. There was no difference in the number of injections that produced unsatisfactory penile rigidity, prolonged erections, hematomas at the injection site, corporal fibrosis, secondary penile deviation, or mean

460 estimated duration of a drug-induced erection. Patient satisfaction, estimated partner satisfaction, increase in self-esteem, and negligible effort in performing injections were all significantly better for those still in the program. The authors commented that the reasons for dropout from self-injection therapy were not based on objective adverse effects and discomfort. Patients who leave the program are less motivated, less satisfied with the quality of drug-induced sexuality, consider the effort of giving the injections to be substantial, and have not achieved improved self-esteem. There has been a report of a long4erm follow-up program for treatment of erectile dysfunction in 32 patients who used alprostadil for a minimum of 5 years under standardized protocol conditions (55c). All the patients had organic erectile dysfunction, and their mean age was 59 years. The period of observation was on average 75 months, and the mean dose of alprostadil was 14 Ixg. In all 6799 injections were registered. The average number of injections was 213 per patient, 2.8 injections per month per patient. As regards adverse effects, hematomas occurred in 1.9% of the patients and there were five cases of prolonged erection (0.07%) caused by unauthorized redosing. Three patients developed reversible penile nodules. In 10 patients, the initial dosage had to be increased. Five patients dropped out after 5 years, none of them because of treatment complications.

Dinoprostone (prostaglandin E2) Uterine rupture occurred after labor had been induced with dinoprostone at 10 days after term; the baby was born dead (56A). A 26-year-old woman, whose first child had been delivered by elective cesarean section at 38 weeks of gestation because of a breech presentation, was given two doses of dinoprostone vaginal gel 1 mg 6 hours apart; 8 hours after the second dose her cervix was soft, fully effaced, and dilated to 3 cm. Since her uterine contractions were only mild and irregular, she underwent amniotomy and an infusion of oxytocin was begun. Fetal tachycardia occurred 4 hours later, with recurrent decelerations. Prolonged deceleration of the fetal heart then occurred and there was fresh vaginal bleeding. Uterine rupture was suspected and the neonate was delivered by emergency cesarean section, but could not be resuscitated. The mother required a blood transfusion, hut subsequently made a good recovery.

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The authors commented that induction with prostaglandins in women with a previous lower segment cesarean scar is associated with a risk of symptomatic scar rupture no greater than 0.6%, and the vaginal delivery rate is about 75%, i.e. similar to rates quoted for spontaneous labor in women with a cesarean scar. At present, faced with the lack of comparative evidence, clinicians can only provide women with the best estimate of risk based on uncontrolled observational data.

Latanoprost The use of latanoprost and unoprostone in the treatment of open-angle glaucoma and ocular hypertension has recently been reviewed (57R). More data on safety are needed to calculate its benefit:harm ratio.

Respiratory Latanoprost seems to cause systemic effects rarely. Latanoprost aggravated respiratory symptoms in a patient with chronic bronchitis and emphysema, with improvement after latanoprost was withdrawn (58").

Sensory systems Iris pigmentation has been reported in patients treated with latanoprost. The mechanism is unknown. In an in vitro experiment using uveal melanocytes, the addition of latanoprost increased melanin content, melanin production, and tyrosinase activity (59E). ot-methyl-para-tyrosine, an inhibitor of tyrosinase (the enzyme that transforms tyrosine to l-dopa), completely prevented the latanoprost-induced stimulation of melanogenesis. Iris cyst associated with latanoprost has been described in a 76-year-old woman (60A). Latanoprost was given for 5 weeks and during a re-examination a large iris cyst was observed in her right eye. The cyst disappeared 3 weeks after latanoprost withdrawal. The fine structure of an iridectomy specimen from a 65-year-old woman treated with latanoprost has been reported (61A). She received latanoprost for 13.5 months and the drug was withdrawn because of iris color change. She underwent cataract surgery 16 months after stopping the drug and a sector iridectomy was obtained. The authors found some melanocytes with atypical features, including nuclear chromatin margination, prominent nucleoli, and invagination of the nucleoli. These character-

Corticotrophins, corticosteroids,and prostaglandins

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istics are also seen in precancerous lesions, in the normal ageing iris, and in patients with glaucoma. A case of bilateral optic disc edema has been described (62A).

ation with other substances (e.g. mifepristone). The most common adverse effects during misoprostol use in labor include pyrexia (temperature over 38 ~ C), shivering, postpartum hemor-

A 64-year-old woman was included in a randomized double-blind trial of drugs used in the treatment of ocular hypertension. After 3 months examination of the optic nerve showed bilateral edema. She had been using latanoprost 0.0005% eye drops at night to both eyes. Latanoprost was withdrawn and the disc edema resolved at 1 week.

first-second trimester for pregnancy termination, its adverse effects included fever, chills, vomiting, diarrhea, moderate and severe ab-

Four patients treated with latanoprost developed dendritiform epitheliopathy, a sign of corneal toxicity; the lesions reversed in 1-4 weeks after latanoprost withdrawal (63A). New cases of cystoid macular edema have been reported (64 c, 65A). A possible explanation is enhanced disruption of the b l o o d aqueous barrier induced by latanoprost (64c).

Infection risk Three cases of Herpes simplex keratitis developed during latanaprost therapy (66A). One of the patients with a history of Herpes simplex keratitis had recurrence with latanoprost (4 months); the infection resolved on withdrawal but recurred on rechallenge. The second patient, with a history of Herpes simplex keratitis, had bilateral recurrence with latanoprost (1 month); antiviral therapy did not eradicate the infection until latanoprost was withdrawn. The third patient developed the infection after 1 month; the keratitis cleared on withdrawal of latanoprost and antiviral therapy; reinstitution of latanoprost with prophylactic antiviral medication (valaciclovir) kept the cornea clear, but as soon as the antiviral drug was discontinued, Herpes simplex virus keratitis reappeared. Although the mechanism is unclear, it is known that inhibitors of prostaglandin synthesis reduce recurrence of epithelial Herpes simplex infections and prostaglandins may stimulate their occurrence.

Misoprostol (methylprostaglandin El) Misoprostol is used in the prevention and treatment of peptic ulcer caused by NSAIDs. It is an effective myometrial stimulant of the pregnant uterus and is used for the induction of labor and as abortifacient, both alone or in combin-

rhage, nausea, vomiting, diarrhea, hot flushes, headache, and vertigo. When it is used in the

dominal pain, profuse bleeding, dysfunctional uterine bleeding, dizziness, and headache. A systematic review of the use of misoprostol for induction of labor has been published (67M). The meta-analysis included all randomized clinical trials registered in the Cochrane Pregnancy and Childbirth Group. Vaginal misoprostol was associated with increased uterine hyperstimulation, both without fetal heart changes (RR = 1.67; CI = 1.30, 2.14) and with associated fetal heart rate changes (RR = 1.45; CI = 1.04, 2.04). There was also an increase in meconium-stained amniotic fluid (RR = 1.38; CI = 1.06, 1.79).

Reproductive system

Seven pregnant women had uterine rupture after intravaginal administration of misoprostol for induction of labor (SEDA-23, 436); all seven had undergone cesarean section in previous pregnancies (68 c). The first four women (aged 26-36 years) underwent induction of labour at 3 7 4 0 weeks of gestation. They received 1-2 doses of intravaginal misoprostol 25 Ixg; three of the women then received intravenous oxytocin. Soon after the first woman began pushing, there was fetal heart rate deceleration and the fetal head could not be palpated in the vagina. Emergency laparotomy showed that the baby was free in the abdominal cavity and the woman had a bladder defect. The bladder and uterine defects were repaired successfully and the mother received a transfusion of packed erythrocytes. In the second case, there was sudden fetal bradycardia. Laparotomy showed a large clot overlying the previous uterine incision. Dissection through the hematoma showed complete separation of the uterine incision. After delivery, the uterine rupture site and a cervical laceration were successfully repaired. The third woman had sudden onset severe abdominal pain and fetal decelerations were detected. Emergency laparotomy showed complete separation of the uterine scar; both the fetus and the placenta were free in the abdominal cavity. The uterine defect was repaired and the woman recovered. However, the baby subsequently died. The fourth woman began to have extreme pain and fetal bradycardia then occurred. Uterine rupture from the previous incision was found at emergency

462 cesarean section, with the baby's arm extending through the lacerated area. The uterine defect was successfully repaired. Uterine rupture also occurred in another three women (ages not stated) after misoprostol (dosages not stated) was used to induce labor. One underwent cesarean section because labor did not progress. During the procedure, the fetal hand and head were outside the uterine cavity (maternal and fetal outcome not stated). The other two women underwent emergency cesarean deliveries because of fetal bradycardia. Both had complete uterine wall separation; one had a stellate laceration involving the previous incision, and the other had a hematoma associated with the scar disruption. Outcomes were good in both cases. Misoprostol is not approved by the FDA for any obstetric indication. In view of these cases, the authors recommended that there be a moratorium on the use of misoprostol in the setting of a scarred uterus until the relative risks have been thoroughly investigated in appropriately controlled trials. B o d y t e m p e r a t u r e A case of severe hyperthermia has been reported after misoprostol (69A).

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A 23-year-old woman took oral misoprostol 600 txg/day twice when she was 7 weeks pregnant to induce an abortion. At 12 weeks she developed varicella. At 15 weeks ultrasound showed a fetus of 14.5 weeks size with several abnormalities. After amniocentesis at 17 weeks an elective abortion was performed. The fetus had amputation deformities at the proximal interphalangeal joints of four fingers, with distal fusion of the proximal finger stumps by thin strands of tissue; the index finger was normal. The left leg had an amputation deformity at the mid-tibial/fibular level. There was an omphalocele. Histological examination of the placenta showed an absence of amnion on the chorionic surface, with reactive changes in the superficial chorionic stroma and "vernix granulomas" on the chorionic surface. These findings are diagnostic of early amnion rupture. There were no features of varicella embryopathy.

Sulprostone Sulprostone is a synthetic prostaglandin analog of dinoprostone, used for inducing uterine contraction. In large series it has had good tolerability and a very low complication rate. The most severe complication is myocardial infarction secondary to coronary spasm, with a frequency of 1 in 20 000, usually in smokers and women over 35 years of age with cardiovascular disease (SEDA-23, 436).

A 31-year-old primigravida had a missed abortion after 12 weeks of amenorrhea and was admitted for evacuation of the uterus. Preoperative cervical priming was done with intravaginal misoprostol 600 Ixg. Within 30 minutes of insertion of the misoprostol tablets she had chills and rigors, felt unwell, and started to have lower abdominal cramps. She was febrile (39.5 ~ C) and her pulse rate was 90 beats/minute. The undissolved misoprostol tablets were removed digitally and her vagina was douched. Ice sponging lowered her temperature. A rectal suppository of diclofenac (25 rag) and an intramuscular injection of promethazine (25 mg) were given. Her temperature remained high at 38 ~ C for 3 hours and normalized after 5 hours.

A 30-year-old woman developed uterine atony and bleeding after induced abortion because of fetal death at 17 weeks of gestation (72A). Sulprostone was given intravenously at a rate of 500 txg/hour. When additional sulprostone was injected into the uterine cervix the patient sustained a myocardial infarction, with ventricular fibrillation and cardiocirculatory arrest, most probably due to coronary artery spasm. She was resuscitated and recovered completely.

Teratogenicity The use of misoprostol by women in an unsuccessful attempt to terminate pregnancy has been associated with the Miibius' syndrome (congenital facial paralysis) in their infants (SEDA-23, 435). A case of MObius' syndrome in association with congenital central alveolar hypoventilation has been described in Brazil (70A). A case of multiple malformations has been described associated with the use of misoprostol (71A).

Unoprostone

Sulprostone should be used with care, particularly in patients with cardiac risk factors, and only in settings equipped to manage complications.

Unoprostone is a prostaglandin-related compound used in the treatment of open-angle glaucoma and ocular hypertension. Its mechanism of action is believed to be by enhancing uveoscleral outflow, like latanoprost. Most of the literature on unoprostone is in Japanese. Its adverse effects are similar to those of latanoprost: conjunctival hyperemia, iris pig-

mentation, hypertrichosis and hyperpigmenta-

Corticotrophins, corticosteroids, and prostaglandins tion of eyelashes, and rarely systemic effects (57R).

PROSTACYCLIN ANALOGS (SED-14, 1398; SEDA-22, 454; SEDA-23, 436)

Epoprostenol Epoprostenol has become the preferred long-term treatment for patients with primary pulmonary hypertension who continue to have symptoms in spite conventional therapy (SEDA-23, 436). Respiratory Pulmonary edema has been attributed to epoprostenol (73A). A 61-year-old woman developed pulmonary edema during treatment with epoprostenol for severe pulmonary hypertension associated with limited scleroderma. She received an infusion of epoprostenol 1 ng/kg/min, and the dosage was increased by 1-2 ng/kg/min every 15 minutes. At a dosage of 6 ng/kg/min, her pulmonary vascular resistance had fallen by 60% and her cardiac output had increased by 55%. However, at this dosage, she became acutely dyspneic. Epoprostenol was withdrawn, she was treated with furosemide and high-flow oxygen, and her symptoms resolved. Because no other therapy was available, she agreed to restart epoprostenol therapy the next day, 1 ng/kg/min, increasing by 1 ng/kg/min every 24 hours to 3 ng/kg/min at discharge. Over the next 6 months, the dosage of epoprostenol was gradually increased to 20 ng/kg/min. She had a significant improvement in her exercise tolerance and there was no evidence of pulmonary edema. However, after about 7 months of marked clinical

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improvement, she developed right ventricular decompensation. Increased doses of epoprostenol were ineffective and she died. Autopsy showed severe obliterative and plexogenic pulmonary arteriopathy. This is the first case in which epoprostenol has been successfully restarted. The authors commented that pulmonary edema during acute infusion of epoprostenol is considered a contraindication to its further use. They theorized that the pulmonary edema could have occurred secondary to the dramatic increase in pulmonary perfusion at 6 ng/kg/min of epoprostenol and subsequent rapid shifts in vascular hydrostatic pressure. The slow increase in dosage during reinstitution may have averted the dramatic increase in pulmonary perfusion. Patients with end-stage liver failure, portal hypertension, and associated pulmonary artery hypertension (portopulmonary hypertension) have a high mortality when undergoing liver transplantation. Successful transplantation in these patients may depend on efforts to reduce pulmonary artery pressure. To this end, some centers are using a continuous intravenous infusion of epoprostenol, which has been shown to improve symptoms, extend life span, and reduce pulmonary artery pressure in patients with primary pulmonary hypertension. There have been four cases in which treatment of portopulmonary hypertension with continuous intravenous epoprostenol was followed by the development of progressive splenomegaly, with worsening thrombocytopenia and leukopenia (74A). This finding may limit the usefulness of epoprostenol in portopulmonary hypertension and influence the timing of transplantation in such patients.

REFERENCES 1. Dunagan DE Rubin BK, Fasano MB. Pneumocystis carinii pneumonia in a child receiving ACTH for infantile spasms. Pediatr Pulmonol 1999; 27: 286-9. 2. Schult M, Lohmann D, Knitsch W, Kuse ER, Nashan B. Recurrent cardiocirculatory arrest after kidney transplantation related to intravenous methylprednisolone bolus therapy. Transplantation 1999; 67: 1497-8. 3. YunisKA, Bitar FF, Hayek P, Mroueh SM, Mikati M. Transient hypertrophic cardiomyopathy in the newborn following multiple doses of antenatal corticosteroids. Am J Perinatol 1999; 16: 17-21.

4. O'Shea TM, Kothadia JM, Klinepeter KL, Goldstein DJ, Jackson BG, Weaver HI RG, Dillard RG. Randomized placebo-controlled trial of a 42day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics 1999; 104: 15-21. 5. Garland JS, Alex CP, Pauly TH, Whitehead VL, Brand J, Winston JF, Samuels DP, McAuliffe TL. A three-day course of dexamethasone therapy to prevent chronic lung disease in ventilated neonates: a randomized trial. Pediatrics 1999; 104: 91-9.

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6. Romagnoli C, Zecca E, Vento G, De Carolis ME Papacci P, Tortorolo G. Early postnatal dexamethasone for the prevention of chronic lung disease in high-risk preterm infants. Intensive Care Med 1999; 25: 717-21. 7. Arias-Camison JM, Lau J, Cole CH, Frantz HI ID. Meta-analysis of dexamethasone therapy started in the first 15 days of life for prevention of chronic lung disease in premature infants. Pediatr Pulmonol 1999; 28: 167-74. 8. Ross J, Eledrisi M, Casner E Persistent hiccups induced by dexamethasone. West J Med 1999; 170: 51-2. 9. Lorrot M, Bader-Meunier B, Sebire G, Dommergues JP. Benign intracranial hypertension: An unrecognized complication of oral corticosteroid therapy. Arch Pediatr 1999; 6: 40-2. 10. Parker CT, Jarek MJ, Finger DR. Corticosteroid-associated epidural lipomatosis. J Clin Rheumatol 1999; 5: 141-2. 11. Albucher JE Vnillemin-Azais C, Manelfe C, Clanet M, Guiraud-Chaumeil B, Chollet E Cerebral thrombophlebitis in three patients with probable multiple sclerosis. Cerebrovasc Dis 1999; 9: 298-303. 12. Wingate RJB, Beaumont PE. Intravitreal triamcinolone and elevated intraocular pressure. Aust NZ J Ophthalmol 1999; 27: 431-2. 13. Evers S, Luttmann R, Hetzel G, Erffurht A, Frese A, Husstedt IW. Acute mania induced during a cluster headache episode. Cephalalgia 1999; 19: 434. 14. Preda A, Fazeli A, McKay BG, Bowers MB, Mazure CM. Lamotrigine as prophylaxis against steroid-induced mania. J Clin Psychiatry 1999; 60: 708-9. 15. Kramer TM, Cottingham EM. Risperidone in the treatment of steroid-induced psychosis. J Child Adolesc Psychopharmacol 1999; 9: 315-16. 16. Newcomer JW, Selke G, Melson AK, Hershey T, Craft S, Richards K, Alderson AL. Decreased memory performance in healthy humans induced by stress-level cortisol treatment. Arch Gen Psychiatry 1999; 56: 527-33. 17. Soliday E, Grey S, Lande MB. Behavioral effects of corticosteroids in steroid-sensitive nephrotic syndrome. Pediatrics Electronic Pages (serialonline) 1999; 104: e51. 18. Schmitz T, Goffinet E Barrande G, Cabrol D. Maternal hypercorticism from serial courses of betamethasone. Obstet Gynecol 1999; 94: 849. 19. Romagnoli C, Zecca E, Vento G, Maggio L, Papacci P, Tortorolo G. Effect on growth of two different dexamethasone courses for preterm infants at risk of chronic lung disease. A randomized trial. Pharmacology 1999; 59: 266-74. 20. Tarnow-Mordi W, Mitra A. Postnatal dexamethasone in preterm infants. Br Med J 1999; 319: 1385-6. 21. Amin SB, Sinkin RA, McDermott MP, Kendig JW. Lipid intolerance in neonates receiving dexa-

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methasone for bronchopulmonary dysplasia. Arch Pediatr Adolesc Med 1999; 153: 795-800. 22. Ravina A, Slezak L, Mirsky N, Bryden NA, Anderson RA. Reversal of corticosteroid-induced diabetes mellitus with supplemental chromium. Diabet Med 1999; 16: 164-7. 23. Nanki T, Koike R, Miyasaka N. Subacute severe steatohepatitis during prednisolone therapy for systemic lupus erythematosis. Am J Gastroenterol 1999; 94: 3379. 24. Scotto Di Fazano C, Messica O, Quennesson S, Quennesson ER, Inaoui R, Vergne P, Bonnet C, Bertin P, Treves R. Two new cases of glucocorticoid-induced pancreatitis. Rev Rhum Engl Ed 1999; 66: 235. 25. Reichert LIM, Koene RAP, Wetzels JFM. Acute haemodynamic and proteintLdc effects of prednisolone in patients with a nephrotic syndrome. Nephrol Dial Transplant 1999; 14: 91-7. 26. Isaksson M, Bruze E, Goossens A, Lepoittevin JE Patch testing with budesonide in serial dilutions: the significance of dose, occlusion time and reading time. Contact Dermatitis 1999; 40: 24-31. 27. Betty Lew D, Higgins GC, Skinner RB, Snider MD, Myers LK. Adverse reaction to prednisone in a patient with systemic lupus erythematosus. Pediatr Dermatol 1999; 16: 146-50. 28. Goldstein MF, Fallon JJ Jr, Haming R. Chronic glucocorticoid therapy-induced osteoporosis in patients with obstructive lung disease. Chest 1999; 116: 1733-49. 29. Wichers M, Springer W, Bidlingmaier E Klingmuller D. The influence of hydrocortisone substitution on the quality of life and parameters of bone metabolism in patients with secondary hypocortisolism. Clin Endocrinol 1999; 50: 759-65. 30. Spencer C, Smith P, Rata N, Weatherell R. Corticosteroids in pregnancy and osteonecrosis of the femoral head. Obstet Gynecol 1999; 94 Suppl 1: 848. 31. Baltzan MA, Suissa S, Bauer DC, Cummings SR, for the Study of Osteoporotic Fractures Group. Hip fractures attributable to corticosteroid use. Lancet 1999; 353: 1327. 32. Clear D. Anaphylactoid reaction to methyl prednisolone developing after starting treatment with interferon beta-lb. J Neurol Neurosurg Psychiatry 1999; 66: 690. 33. Schonwald S. Methylprednisolone anaphylaxis. Am J Emerg Med 1999; 17: 583-5. 34. Ingber A, Trattner A, David M. Hypersensitivity to an oestrogen-progesterone preparation and possible relationship to autoimmune progesterone dermatitis and corticosteroid hypersensitivity. J Dermatol Treat 1999; 10: 139-40. 35. Vaghjimal A, Rosenstreich D, Hudes G. Fever, rash and worsening of asthma in response to intravenous hydrocortisone. Int J Clin Pract 1999; 53: 567-8. 36. O'Hagan AH, Corbett JR. Contact allergy to budesonide in a breath-actuated inhaler. Contact Dermatitis 1999; 41: 53.

Corticotrophins, corticosteroids, and prostaglandins 37. Robinson M J, Campbell F, Powell P, Sims D, Thornton C. Antibody response to accelerated Hib immunisation in preterm infants receiving dexamethasone for chronic lung disease. Arch Dis Child Fetal Neonatal Ed 1999; 80: F69-71. 38. Vermillion ST, Soper DE, Chasedunn-Roark J. Neonatal sepsis after betamethasone administration to patients with preterm premature rupture of membranes. Am J Obstet Gynecol 1999; 181: 320-7. 39. Rotmensch S, Vishne TH, Celentano C, Dan M, Ben-Rafael Z. Maternal infectious morbidity following multiple courses of betamethasone. J Infect 1999; 39: 49-54. 40. Bower CPR, Oxely JD, Campbell CK, Archer CB. Cutaneous Scedosporium apiospermum infection in an immunocompromised patient. J Clin Pathol 1999; 52: 846-8. 41. Feru~ndez-Avilrs E Batlle M, Ribera JM, Matas L, Sabri~ M, Feliu E. Legionella sp pneumonia in patients with hematologic diseases. A study of l0 episodes from a series of 67 cases of pneumonia. Haematologica 1999; 84: 4745. 42. Rotmensch S, Celentano C, Liberati M. Sadan O, Glezerman M. The effect of antenatal steroid administration on the fetal response to vibroacoustic stimulation. Acta Obstet Gynecol Scand 1999; 78: 847-51. 43. K~llrn B, Rydhstroem H, Aberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol 1999; 93: 3925. 44. Rotmensch S, Liberati M, Celentano C, Efrat Z, Bar-Hava I, Kovo M, Golan A, Moravski G, Ben-Rafael Z. The effect of betamethasone on fetal biophysical activities and Doppler velocimetry of umbilical and middle cerebral arteries. Acta Obstet Gynecol Scand 1999; 78: 768-73. 45. Keane FM, Munn SE, Du Vivier AW, Taylor NF, Higgins EM. Analysis of Chinese herbal creams prescribed for dermatological conditions. Br Med J 1999; 318: 563-4. 46. Feldweg AM, Leddy JE Drug interactions affecting the efficacy of corticosteroid therapy. A brief review with an illustrative case. J Clin Rheumatol 1999; 5: 143-50. 47. Fost DA, Leung DY, Martin RJ, Brown EE, Szefler SJ, Spahn JD. Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy. J Allergy Clin Immunol 1999; 103: 1031-5. 48. Belfayol-Pisant6 L, Guillevin L, Tod M, Fauvelle E Possible influence of prednisone on the pharmacokinetics of cyclophosphamide in systemic vasculitis. Clin Drug Invest 1999; 18: 225-31. 49. Vails T, Kivisto KT, Backman JT, Neuvonen PJ. Itraconazole decreases the clearance and enhances the effects of intravenously administered methylprednisolone in healthy volunteers. Pharmacol Toxicol 1999; 85: 29-32.

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50. Sandberg DI, Lavyne MH. Symptomatic spinal epidural lipomatosis after local epidural corticosteroid injections: case report. Neurosurgery 1999; 45:162-5. 51. Gutierrez-Urena S, Ramos-Remus C. Persistent hiccups associated with intra-articular corticosteroid injection. J Rheumatol 1999; 26: 760. 52. Hillebrand Haverkort ME, Prummel ME Ten Veen JH. Ritonavir-induced Cushing's syndrome in a patient treated with nasal fluticasone. AIDS 1999; 13: 1803. 53. Marcos C, Allegue F, Luna I, Gonzalez R. An unusual case of allergic contact dermatitis from corticosteroids. Contact Dermatitis 1999; 41: 2378. 54. Lehmann K, Casella R, Blochlinger A, Gasser TC. Reasons for discontinuing intracavernous injection therapy with prostaglandin El (alprustadil). Urology 1999; 53: 397-400. 55. Hauck EW, Altinkilic BM, Schroeder-Printzen I, Rudnick J, Weidner W. Prostaglandin El longterm self-injection programme for treatment of erectile dysfunction--a follow-up of at least 5 years. Andrologia 1999; 31 Suppl l: 99-103. 56. Vause S, Macintosh M. Use of prostaglandins to induce labour in women with a caesarean section scar. Br Med J 1999; 318: 1056-8. 57. Eisenberg DL, Camras CB. A preliminary riskbenefit assessment of latanoprost and unoprostone in open-angle glaucoma and ocular hypertension. Drug Saf 1999; 20: 505-14. 58. Veyrac G, Chiffoleau A, Cellerin L, Laurosse C, Bourin M. Latanoprost (Xalatan | et effect systrmique respiratoire? A propos d'un cas. Thrrapie 1999; 54: 49445. 59. Drago E Marino A, La Manna C. Alphamethyl-p-tyrosine inhibits latanoprost-induced melanogenesis in vitro. Exp Eye Res 1999; 68: 85-90. 60. Krohn J, Hove V. Iris cyst associated with topical administration of latanoprost. Am J Ophthalmol 1999; 127: 91-3. 61. Grierson I, Lee W, Albert D. The fine structure of an iridectomy specimen from a patient with latanoprost-induced eye color change. Arch Ophthalmol 1999; 117: 394-6. 62. Stewart O, Walsh L, Pande M. Bilateral optic oedema associated with latanoprost. Br J Ophthalmol 1999; 83: 1092-3. 63. Sudesh S, Cohen E, Rapuano C, Wilson RP. Corneal toxicity associated with latanoprost. Arch Ophthalmol 1999; 117: 539-40. 64. Miyake K, Ota I, Maekubo K, Ichihashi S, Miyake S. Latanoprost accelerates disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema in early postoperative pseudophakias. Arch Ophthalmol 1999; 117: 34-40. 65. Moroi SE, Gottfredsdottir M, Schteingart M, Elner S, Lee C. Schertzer R, Abrams G, Johnson M. Cystoid macular edema associated with latanoprost therapy in a case series of patients with

466 glaucoma and ocular hypertension. Ophthalmology 1999; 106: 1024-9. 66. Wand M, Gilbert M, Liesegang T. Latanoprost and Herpes simplex keratitis. Am J Ophthalmol 1999; 127: 602--4. 67. Hofmeyr GJ, Giilmezoglu AM, Alfirevic Z. Misoprostol for induction of labour: a systematic review. Br J Obstet Gynaecol 1999; 106: 798-803. 68. Plaut MM, Schwartz ML, Lubarsky SL. Uterine rupture associated with the use of misoprostol in the gravid patient with a previous cesarean section. Am J Obstet Gynecol 1999; 180: 1535-42. 69. Fong YF, Singh K, Prasad RNV. Severe hyperthermia following use of vaginal misoprostol for pre-operative cervical priming. Int J Gynaecol Obstet 1999; 64: 74-5. 70. Lahorgue-Nunes M, Friedrich MAG, FernandoLoch L. Association of misoprostol, Moebius syndrome and congenital central alveolar hypoventilation. Arq Neuropsiquiatr 1999; 57: 88-91.

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71. Genest DR, Di Salvo D, Rosenblatt MJ, Lewis BH. Terminal transverse limb defects with tethering and omphalocele in a 17 weeks fetus following first trimester misoprostol exposure. Clin Dysmorphol 1999; 8: 53-8. 72. Kulka PJ, Quent P, Wiebalck A, Jager D, Strumpf M. Myocardial infarction after sulprostone therapy for uterine atony and bleeding: a case report. Geburtshilfe Frauenheild 1999; 59: 634-7. 73. Farber HW, Graven KK, Kokolski G, Korn JH. Pulmonary edema during acute infusion of epoprostenol in a patient with pulmonary hypertension and limited scleroderma. J Rheumatol 1999; 26: 1195-6. 74. Findlay JY, Plevak DJ, Krowka MJ, Sack EM, Porayko MK. Progressive splenomegaly after epoprostenol therapy in portopulmonary hypertension. Liver Transplant Surg 1999; 5: 3625.

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Sex hormones and related compounds, including hormonal contraceptives

(SED-14, 1448; SEDA-21, 426; SEDA-22, 458; SEDA-23, 440)

ESTROGENS

Teratogenidty The

best-known secondgeneration effects of estrogens are the genital complications that result from the formerly widespread use of diethylstilbestrol in pregnancy, mainly between 1940 and 1975. Although it remains difficult to reconstruct medical histories dating back to this period, evidence continues to emerge. Records available in Finland have been used to seek correlations between hormonal treatment (with diethylstilbestrol, steroidal estrogens, or progestogens) and adverse effects, inchiding cancers in the mother or infant. A retrospective cohort of 2052 hormone-drug exposed mothers, 2038 control mothers, and their 4130 infants was collected from maternity centers in Helsinki covering the period from 1954 to 1963 (1ca). Cancer cases were searched for in national registers through record linkage. Exposures were examined by the type of the drug (estrogen plus progestogen or progestogen only) and by timing (early in pregnancy or only late in pregnancy). There were no statistically significant differences between the groups with regard to maternal cancers, whether total or specified hormone-dependent cancers. However, the total number of malformations recorded, as well as malformations of the genitals in male infants, were higher among exposed children. The number of cancers among the offspring was small and none of the differences between groups was statistically significant. The authors 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

suggested that their study supported the conclusion that estrogen or progestogen therapy during pregnancy causes malformations among children who were exposed in utero, but not the hypothesis that it causes cancer later in life in the mother; the power to study cancers in offspring was too low to draw finn conclusions. Non-existence of the risk, negative confounding, weak exposure, or low study power may have explained the negative findings. The use of diethylstilbestrol in pregnant women may have had other adverse effects on the offspring than those which are usually recognized. A study in the USA has produced some evidence that in the population with amblyopia those who were exposed to diethylstilbestrol before birth may be more likely to develop myopia (2CR). Even the classic genital manifestations of diethylstilbestrol in women who have been exposed to it in fetal life may be overlooked unless one is alert to them; vaginal discharge with ectropion should cause one to enquire as to possible diethylstilbestrol exposure before birth (3CR).

Natural estradiol Particularly in Scandinavia, the "natural" estrogen 17-/%estradiol has become popular rather than the synthetic alternative. The micronized form has been most widely used, in order to ensure adequate oral availability. Some recent work relates to intranasal administration by means of a spray, used for relief of menopausal symptoms. There were no local complications, except for mild irritation leading to sneezing (4c). A67

468

Hormone replacement therapy (HRT) Cardiovascular One of the most serious aspects of the thromboembolic complications now widely acknowledged as being associated with HRT is that their emergence coincides with the development of the conclusion that the role of HRT in reducing the risk of coronary heart disease is at best unproven. A form of treatment that was originally viewed as potentially beneficial to the cardiovascular system is at present on balance perhaps harmful (5R). The mechanisms of thrombotic complications with estrogens may be multiple (SED-14, 1462). While it has previously been reported that estrogen treatment raises fibrinogen concentrations, it has now been suggested that during HRT the greatest risk of thromboembolism may lie with patients with low fibrinogen concentrations. A US group examined potential risk factors for venous thromboembolic events in women assigned to HRT in the Postmenopausal Estrogen/Progestin Interventions (PEPI) study, a 3year double-blind study in 875 postmenopausal women designed to assess the effects of HRT on heart disease risk factors (HDL cholesterol, fibrinogen, blood pressure, and insulin) (6CR). Women with a history of estrogen-associated venous thromboembolic events were excluded. Ten women, all assigned to HRT, had a venous thromboembolic event during the study. Only baseline fibrinogen varied significantlybetween those who had a venous thromboembolic event while assigned to HRT (mean 2.49 g/l) and those who did not have an event (mean 2.81 g/l). Adjusting for covariates did not affect this finding. As the authors remarked, the lower fibrinogen concentrations among women who subsequently reported venous thromboembolic events may be a marker for a specific, but as yet undefined, coagulopathy that is magnified in the presence of exogenous hormones. However, larger studies are needed to confirm this hypothesis. Since much of the evidence of thromboembolic complications with HRT relates to the use of conjugated equine estrogens, the degree of risk when natural 17-fl-estradiol was used instead has been examined in Norway in a population-based case-control study involving consecutive women, aged 44 70 years, discharged from a University Hospital between

Chapter 40

M.N.G.Dukes

1990 and 1996 with a diagnosis of deep venous thrombosis or pulmonary embolism (7CR). Women with cancer-associated thrombosis were excluded. Random controls were used. The material comprised 176 cases and 352 controls, i.e. two controls for each case. All the women who received HRT had been given estradiol. The frequency of HRT use was 28% (50/176) in cases and 26% (93/352) in controls. The estimated matched crude odds ratio was 1.13 (CI -- 0.71, 1.78), which indicates no significant association of overall use of estradiol-based HRT and thromboembolism. However, when the duration of exposure to HRT was taken into account by stratification, there was an increased risk of thromboembolism during the first year of use, with a crude odds ratio of 3.54 (CI = 1.54, 5.2). This effect was reduced by extended use to a crude odds ratio of 0.66 (CI -- 0.39, 1.10) after the first year of use. The authors concluded that the use of estradiol for HRT was associated with a 3-fold increase in the risk of venous thromboembolism, but that this increased risk was restricted to the first year of use. One is bound to wonder whether this shift in risk was genuine or reflects only the limitations of the study. Among the less common forms of thromboembolism that have been reported are occlusion of the retinal vein, familiar with the oral contraceptives but unusual with HRT (8c). Drug dependence While the effects of estrogen treatment on mental function and mood are generally assessed as positive, work in Britain has raised the possibility of some form of psychological dependence. The starting point was the finding in various studies that a proportion of women in whom hormone replacement therapy was terminated had a return of psychological symptoms, such as low mood and tiredness, despite the fact that their circulating estrogen concentrations were high. A questionnairebased study was therefore carded out in 600 women, mean age 46 years; in most of them, HRT with implants had been undertaken after hysterectomy, and the mean duration of use was 5 years. Among those with high circulating estradiol concentrations (more than 500 pmol/l) 40% reported a need to use top-up doses of HRT to cope with daily activities, 78% spoke of low mood and tiredness (apparently when estrogen concentrations were falling), 80% experienced a "buzz" (which was undefined) 1-2 weeks

Sex hormones and related compounds, including hormonal contraceptives

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after receiving a new implant, and 75% claimed that life without an implant would be "terrible". These effects, interpreted as evidence of dependence, were almost absent in women with lower circulating estrogen concentrations. The authors were of the opinion that circulating concentrations of some 300 pmol/1, which are sufficient to maintain bone mass, should be the therapeutic aim, and that there will then be much less of a dependence problem than when higher concentrations are attained (9CR, 10CR).

cific breast cancers occurred in the at-risk cohort of 37 105 women, it was concluded that exposure to HRT was associated most strongly with an increased risk of invasive breast cancer with a favorable prognosis. There was a more modest increase in the risk of invasive ductal or lobular carcinoma of the breast (11CR). Setting these data against those in the Table presented in SED-14, many of which are comparable, one must conclude that there is now a great deal of consensus on the problem.

Carcinogenicity Ovarian cancer While the risk that HRT may induce endometrial tumors has been widely discussed, less attention has been given to the possibility that it could increase the risk of epithelial ovarian cancer. Since cancer of the ovary has some risk factors in common with endometrial cancer (notably low parity and obesity), this possible risk needs to be considered, especially in view of the fact that the endometrioid epithelial type of ovarian tumor is histologically so similar to adenocarcinoma of the endometrium. A large Australian case-control study has now examined the issue. A total of 793 eligible incident diagnoses of epithelial ovarian cancer in 1990-93 among women living in Queensland, New South Wales, and Victoria were identified. These were compared with 855 eligible female controls selected at random. Standard questionnaires were used to obtain histories. There were no clear associations between the use of hormone replacement therapy overall and the risk of ovarian cancer. However, unopposed estrogen replacement therapy was associated with a significant increase in the risk of endometrioid or clearcell epithelial ovarian tumors. In addition, the risk associated with estrogen replacement therapy was much larger in women with an intact genital tract than in those with a history of either hysterectomy or tubal ligation. The authors therefore suggested that postmenopausal estrogen replacement may be a risk factor associated with endometrioid and clear-cell tumors in particular.

Estrogens with or without progestogens

Breast cancer There is a complex association between hormone replacement therapy and breast cancer (SED-14, 1454-5). The most important single piece of recent evidence is the 1999 report on the Iowa Women's Health Study. On the basis of observations of postmenopausal women over 11 years, during which 1520 spe-

Recent cases have underlined the need to use an estrogen in combination with a progestogen, rather than unopposed estrogen, when treating women who have undergone radical surgery (removal of both the ovaries and uterus) for endometriosis. It has become clear that, if unopposed estrogen replacement is given, any residual area of endometriosis will rapidly expand (12CR).

Transdermal estrogen therapy When estrogens are given by means of transdermal patches, allergic reactions and systemic contact dermatitis can occur. While in some cases these are clearly attributable to the patch material or to excipients, it is certain that even natural estradiol when administered in this way can occasionally cause hypersensitivity reactions, as determined by patch tests (13CR).

Fosfestrol Fosfestrol is an unusual agent used in Japan for the treatment of prostatic carcinoma but not accepted by experts in Europe. Described as an estrogen, in European studies it had a high incidence of complications, includingfluid retention (16%), myocardial infarction (10%), and thromboembolism (6.3%). A case of adrenocortical insufficiency has now been documented in Japan, involving a 59-year-old man who had taken the drug for 10 years (14AR).

470

(SED-14, 1468; SEDA-21, 431; SEDA-22, 462; SEDA-23, 442) PROGESTOGENS

Cardiovascular Since thromboembolic complications can occur with progestogens, there may be a danger in using them in patients in whom other risk factors for thromboembolism are also present. A Spanish group had to deal with patients with AIDS in whom megestrol acetate seems to be helpful in countering AIDSrelated anorexia or cachexia. However, advanced HIV infection is itself a known risk factor for thromboembolism, as is tuberculosis, which readily occurs in this population. Of 199 patients with AIDS followed for 2 years, 25 were treated with megestrol 320 mg/day. Deep vein thrombosis was observed in seven patients in the entire series, four of them being in the megestrol group and three having tuberculosis. The duration of hormonal therapy up to the moment of thrombosis averaged 98 days. Tuberculosis was an independent risk factor. Statistical analysis led to the conclusion that in this high-risk population the use of megestrol had increased the risk of thrombosis by a factor of 7.6 (15c). Skin Progestogens have very occasionally been reported to cause hypersensitivity reactions or skin disorders. Pemphigus has now been reported (16 AR). A 34-year-old woman with a 3-month history of dysphagia, odynophagia, and conjunctivitis with bulbar injection, who had been taking an oral contraceptive containing a progestogen for 7 months, developed typical bullous lesions on her trunk and nose, typical of pemphigus. Ceftriaxone and ampicillin, which are known to aggravate pemphigus, exacerbated the lesions. There was reason to believe that the patient had a genetic predisposition to the disorder. The circumstances pointed strongly to a drug association, but the identity of the oral contraceptive was not stated; it is likely to have contained a synthetic progestogen and not progesterone itself. However progesterone-induced dermatitis certainly does occur. A recent case involved a formulation containing hydroxyprogesterone acetate (alongside conjugated estrogen) taken for late menopausal syndrome in a 68-year-old woman who had for many years had autoimmune progesterone dermatitis (17 C).

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D r u g formulations As with estradiol, a case has been made for using natural progesterone for treatment, rather than synthetic analogs, largely because it is assumed that as a physiological substance it will be safer. The fact that progesterone when given by mouth has poor systemic availability can be largely overcome by micronization, and the first product based on this concept was marketed in France as long ago as 1980. Studies and reviews have appeared, particularly since 1997, suggesting that it is indeed less likely to cause adverse effects than the synthetic progestogens are (18R). The most frequently reported adverse reactions are stated to be mere dizziness or drowsiness, which could be related to the pregnenolone metabolites and do not seem to reflect vasoactive changes. The theoretical argument has been raised that there might be altered sodium metabolism, but no hypertensive effects have been seen. Unusually high doses of micronized progesterone given in pregnancy (in the hope of avoiding premature labor) have been suspected of causing intrahepatic cholestasis, at least in women with a genetic predisposition, but these doses are much higher that those in normal use. No changes in lipid profile appear to occur. With these very positive conclusions it is not clear why micronized progesterone has not been more widely used; commercial factors may well have played a role in maintaining the overwhelming dominance of the patented synthetic progestogens. On the other hand, despite the fact that there are estimated to be 500 000 current users of micronized progesterone in France alone, the scope of experience worldwide is still limited compared with that of the synthetic analogs, and one must be prepared for surprises if this product should ever be used more widely. It is a fact that in the 1970s, when studies in beagle dogs gave rise to much concern regarding progestogens and the induction of mammary tumors, that the same effect was also observed with natural progesterone if sufficient doses were administered; even a natural substance can have unpleasant effects when used in a manner not foreseen in nature. It may be noted that natural progesterone is now also being used in forms other than the micronized oral product; recent work describes modified-release vaginal gel containing polycarbophil-based progesterone; no adverse reactions have been reported (19c).

Sex hormones and related compounds, including hormonal contraceptives

HORMONAL CONTRACEPTIVES (SED-14, 1405; SEDA-21, 433; SEDA-22, 462; SEDA-23, 442) Cardiovascular A massive amount of material continues to appear to fill in the details of the problem of thromboembolic complications. Some primarily serves to confirm, on the basis of larger series, conclusions that are already well accepted, such as the better safety record of products that contain 35 Ixg or less of estrogen. It is, however, significant that within the scope of this general conclusion, as advanced through extensive work from the Planned Parenthood Federation of America, there is some variation in the level of risk, depending on the accompanying progestogen; the figures ranged from 1895 events per 100000 women-years when norgestimate was used to 3969 per 100000 women-years when desogestrel was used (20CR). Although the authors did not find the difference statistically significant, it runs parallel to findings from other work regarding a higher risk when third-generation progestogens are used. The Medicines Commission of the UK has reviewed all currently available relevant data and has confirmed that the incidence of venous thromboembolism is about 25 per 100 000 women per year of use (21R). The incidence of venous thrombembolism in users of second-generation combined oral contraceptives is about 15 per 100 000 women per year of use. This indicates a small excess risk of about 10 per 100 000 women-years for women using third-generation combined oral contraceptives containing desogestrel or gestodene, which has not been satisfactorily explained by bias or confounding. However, the absolute risk of venous thromboembolism in women taking combined oral contraceptives containing desogestrel or gestodene is very small and is much less than the risk of venous thromboembolism in pregnancy. The Summaries of Product Characteristics (data sheets) and patient information leaflets for combined oral contraceptives containing desogestrel or gestodene will be updated to include the following statements:

Contraindications A history of confirmed venous thromboembolism. A family history of idiopathic venous thromboembolism. Other

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known risk factors for venous thromboembolism.

Warnings An increased risk of venous thromboembolic disease associated with the use of oral contraceptives is well established but is smaller than associated with pregnancy, which has been estimated at 60 cases per 100000 pregnancies. Some epidemiological studies have reported a greater risk of venous thromboembolism for women using combined oral contraceptives containing desogestrel or gestodene (the so-called third-generation formulations) than for women using formulations containing levonorgestrel (the so-called secondgeneration formulations). The spontaneous incidence of venous thromboembolism in healthy non-pregnant women (not taking any oral contraceptive) is about 5 cases per 100 000 women per year. The incidence in users of secondgeneration formulations is about 15 per 100 000 women per year of use. The incidence in users of third-generation formulations is about 25 per 100000 women per year of use: this excess incidence has not been satisfactorily explained by bias or confounding. The risks of venous thromboembolism increase with age and is likely to be increased in women with other known factors for venous thromboembolism, such as obesity. While the overwhelming bulk of the evidence still points to a substantially higher risk of thromboembolism with the third-generation hormonal contraceptives than with their predecessors, some groups continue to produce data from their own systems that fall to confirm this. Some of these studies, including unpublished data circulated to experts for purposes of special pleading, have used selected material, and one can only consider them flawed. On the other hand, Jick et al. may be entirely right in their finding that, insofar as the special risk of idiopathic cerebral hemorrhage is concerned, no material difference in risk has been demonstrated between products of the second generation and those of the third generation (22CR). A special aspect of the debate about thromboembolism is the effect of the oral contraceptives in smokers in whom another risk factor is present. Appropriately, this has been investigated on a large scale in Denmark, where the incidence of smoking among women is much

472 higher than in many other countries (23CR). Evidence has emerged that the combination of smoking with oral contraceptive use may have a synergistic effect on the risks of acute myocardial infarction and cerebral thromboembolism (but not of venous thromboembolism), particularly among users of high doses of estrogen (50 Ixg). The authors therefore suggested that the very low-dose products, which in Denmark contain 20 Ixg of ethinylestradiol, should be preferred in smokers. While this conclusion is clear and defensible, the situation is somewhat complicated by the fact that in Denmark the only products that contain this low dose of estrogen are those in which it is combined with either desogestel or gestodene, i.e. third-generation progestogens, which are themselves suspected of increasing the risk of thromboembolic complications. It could well be that the safest combined oral contraceptives for smokers will prove to be those in which the 20 Ixg dose of estrogen is combined with a more traditional progestogen. Incidental reports continue to appear of thrombotic incidents in relatively unusual forms, including a further case of mesenteric thrombosis leading to intestinal necrosis (24 AR) and a report of fatal pulmonary embolism following intravenous injections of conjugated estrogens ( 2 5 ~ ) . Gastrointestinal Acute abdominal symptoms in users of hormonal contraceptives suggest embolus or infarction at some site, but there can be unusual explanations. In one case of right lower abdominal pain in a 15-year-old girl, which had in fact been present throughout the 3 months that she had used the product but which had now become so severe as to demand emergency care, the problem was traced to cutaneous nerve entrapment in the abdominal wall (26~a~). It is not clear how this could have resulted from the treatment, but it might have entailed fluid redistribution in or around an old appendicectomy scar. It may be noted that nerve entrapment is recognized as a possible adverse effect of oral contraceptives in the carpal tunnel syndrome.

Formulations of oral contraceptives Many papers continue to describe general preor postmarketing studies o f products that differ only slightly or not at all from those already widely used. The findings are as a rule only

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what one would expect, and this account will be limited to those papers that seem to introduce truly new elements into the discussion.

New dosage schemes Any dosage scheme f o r estrogens and progestogens administered to prevent conception can represent no more than an approximation to the physiological processes during a normal cycle that result in feedback to the pituitary and hence in suppression o f ovulation. The original (excessively) highlydosed products were progressively replaced by formulations that treat the endocrine system with rather greater respect; doses in the fixed twenty-tablet combinations were progressively reduced, and modified schemes o f administration include "sequential" and "normophasic" products, as well as progestogen-only contraceptives. Experience seems to confirm that there is a place f o r all o f these alternatives, in view o f individual variance in tolerance and need, with many women trying a series of dosage schemes in turn until they find a program that they tolerate best. The latest arrival is the " estrophasic" form o f administration, in which 20 Izg o f ethinylestradiol are given on days 1-5 o f the cycle, 30 txg on days 6-12, and 35 txg on days 1321. Norethisterone acetate 1 mg is also given throughout this period. The literature to date does not show that the new product, though claimed to be more "physiological" in its composition, is in fact better tolerated than a comparable combination in which ethinylestradiol is given in a dose o f 30 I~g throughout (27cR). However, the reduction in what may at some phases o f the cycle be an unnecessarily high estrogen dose, Le. more than is needed to maintain cycle control is a healthy step, and it may be useful to have a further alternative product f o r women who do not find any existing formulation fully satisfactory.

Alternative estrogen components As noted above there is continued interest in natural 17fl-estradiol (see also under HRT above) in a form suitable f o r oral use, in view o f the likelihood that it will produce fewer adverse effects than the synthetic estrogens used in most oral contraceptives. The particular problem where the oral contraceptives are concerned has been to secure adequate cycle control with the natural substance, which is rapidly metabolized to estrone in the intestinal wall and liver; the

Sex hormones and related compounds, including hormonal contraceptives degradation process is actually accelerated by progestogens. One approach under development in Germany (28 cR ) involves combining this estrogen with dienogest, a progestogen that is reported to have no antiestrogenic activity. Preliminary work suggests that this can be successful, but one must be cautious in assuming that the end-product will be safer in all respects. There is evidence of a lesser effect of the natural estrogen on fibrinolysis, liver function, and lipid metabolism, but one must bear in mind that the true incidence of thromboembolic and other complications of the existing oral contraceptives is only now coming to the fore after many years of worldwide use. Injectable formulations The degree to which women tolerate the adverse effects of longacting injectable contraceptives seems to vary from one population to another, and it can be important to examine the frequency and severity of complaints in different environments. Particularly in developed countries, these products are often stated to induce mood changes, weight gain, and demineralization, but in developing countries they are very widely used. A recent worldwide review has surveyed the incidence of these conditions in users and has compared some of the figures with those found with an implantable product (Norplant, see also below) (29R). Perhaps surprisingly, a consensus seems to be emerging that depot medroxyprogsterone acetate injections do not in fact result in a rise in the incidence of depression (or the severity of pre-existent depression), even after 1 or 2 years, nor do they cause significant weight gain. Norplant, similarly, was not found to cause depression. Subgroups of users of depot medroxyprogsterone acetate may have reduced spinal bone density, but this seems to be reversible after withdrawal. Bearing in mind, however, that the product will be used in the long term, it may in this respect be wise to await the outcome of a lO-year follow-up in the USA, which is due to be completed in 2004.

Subdermal contraceptive implants As with injectable formulations, willingness to tolerate the adverse effects of implants has differed regionally, with considerable resistance to them in some industrialized countries (SED14, 1433). In some developing countries the method has been widely used, but there too one finds a tendency to early withdrawal. In

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Burkina Faso experience in 1660 women over 4 years has been critically reviewed (30c). There were 247 withdrawals before the fourth year, for various reasons, including cycle disorders (60 withdrawals), unspecified medical reasons (53), personal objections (47), weight gain (14), and contraceptive failure (2). Menstrual disorders, including amenorrhea, spotting, and hypermenorrhea, occurred in 51% of the cases. The investigators stressed the need for a good information and sensitization campaign to reduce the number of implant withdrawals before the fourth year of use, since the product often seems to be withdrawn for insufficient reasons. A study in Senegal produced similar findings over 5 years; the method was safe and effective, but dissatisfaction with cycle control was again a prominent reason for requesting removal of the implant (31c).

Hormonal intrauterine devices Intrauterine contraceptive devices that release either hormones or copper ions to potentiate their contraceptive effects have been in use for a generation. A more recent development is a device that releases both copper and norgestrel ( "GynefixNorgestrel"). Preliminary experience in 22 women has suggested that the product is well tolerated and that the amount of menstrual bleeding is less than with the conventional "Gynefix" product, which is based on copper alone (32c1r

GONADOTROPINS AND OVULATION-INDUCING DRUGS (SED-14, 1464; SEDA-22, 465; SEDA-23, 444) The risk of ovarian hyperstimulation, in which the administration of an ovulation-inducing drug is followed by rapid ovarian enlargement with peritoneal effusion, is well recognized. However, it has generally been thought that this complication would not occur when treating cases of "empty follicle syndrome". Nevertheless, there has now been a report of the case of a 33-year-old woman in whom a dose of 10 000 iu of urinary HCG for this purpose did cause severe symptomatic ovarian hyperstimulation (33A). This suggests that even when dealing with such patients, particularly if there is any reason to think that they are at risk of ovarian hyperstimulation, it is wise to take the usual precautions, using a much Endocrine

474 lower dose of HCG and adding progesterone for luteal support. The dangers of ovarian hyperstimulation should not be underestimated. Quite apart from the risks of abdominal complications and even myocardial infarction (see under Tamoxifen below), one recent although unusual report concerns a case in which it apparently led to marked changes in liver function tests (34A). It has been suggested that ultrasonographic monitoring is a means of detecting impending ovarian hyperstimulation, so that treatment can be suspended in good time (35c). Carcinogenesis In a prospective study of 1200 infertile women in Israel, including a subgroup who developed breast cancer, there was no statistical association between the occurrence of this cancer and the use of fertilityinducing drugs (36CR).

Can fertility drugs cause ovarian cancer? The hypothesis that the use o f fertility drugs, including human gonadotropins and clomiphene, which increase the endogenous secretion o f gonadotrophins, might increase the risk of ovarian cancer appears to have come first clearly into the open in 1996 (37R). However one can distil similar suggestions from other work from 1992 onwards (38 R, 39 R, 40CR), and anecdotal reports o f an association have accumulated. The hypothesis has emerged that the increased number o f ovulations (or the high concentrations o f estrogen and gonadotrophin) induced by drugs given to treat infertility could promote the development o f ovarian cancers. Ovarian cancer is much less common in married women, and during the last 30 years a direct inverse association has been found between the number o f pregnancies and the duration o f use o f oral contraception on the one hand and the occurrence o f ovarian cancer on the other. In 1971 a Lancet reviewer suggested that incessant ovulation might well be a causal factor f o r the development of cancer o f the ovary, in that the repeated rupture of foUicles involved a cycle o f damage to the surface epithelium, alternating with repair involving mitogenic activity and thereby in turn a risk o f mutations (41R). On the other hand, as has been pointed out, no correlation has been

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found between the risk o f ovarian cancer and the age at menarche and menopause, i.e. the length o f the fertile period, which might be anticipated if the so-called "ovulation hypothesis" is correct. An alternative suggestion has been that gonadotrophins, by enhancing the transformation of ovarian epithelial cells, also increase the risk o f malignant transformation in this tissue. This idea is compatible with the inverse relations between ovarian cancer and pregnancy or oral contraception, since the latter processes suppress the secretion o f gonadotrophins. Both the hypothesis o f ovarian injury and that o f gonadotrophic influence seem to provide tempting explanations f o r any relation that there may be between infertility treatment and ovarian cancer, since such treatment both induces further ovarian "injury" by ovulation (sometimes multiple) and increases circulating gonadotrophin concentrations. However, the existence o f a possible mechanism does not prove that there actually is an association. The stumbling block in either proving or disproving a link between the drugs and the cancers is the fact that infertility itself proves to be a risk factor f o r ovarian cancer. Women who fail to become pregnant have a higher risk o f ovarian malignancy than other women, irrespective o f whether they are taking drugs or not. A study from Denmark in 1997 showed that among infertile women the overall risk o f ovarian cancer was not influenced by the use (or otherwise) o f treatment with antifertility drugs (42cR). There is also American work that shows that among infertile women with a high risk o f ovarian cancer circulating gonadotrophin concentrations are low, which is what one would expect in such a group, but which does not tally well with the theory of gonadotrophic causation (43CR). Given current evidence, and with anecdotal reports that add nothing to the discussion of a possible cause-and-effect relation, one can discern considerable polarization in the discussion. It is not irrelevant, nor is it uncharitable, to point out that whereas fully independent academic workers have been most vocal in expressing concern, the papers that seek to dismiss an association between the drugs and the cancers have tended to emerge from groups that acknowledge support from pharmaceutical companies that produce the drugs used in this field. That is natural, and it results in the sort

Sex hormones and related compounds, including hormonal contraceptives of argument and counter-argument that may do something to promote the emergence of the truth. It is currently unhelpful to the physician who is treating women for infertility and who is anxious to know what to tell the concerned patient, as well as finding some way of reducing whatever risks treatment may carry. However, bearing in mind the fact that the use of high-doses of fertility drugs certainly brings with it other risks (e.g. that of sometimes dangerous overstimulation, considered later in this chapter), this could be a reason for applying some of the more restrained available dosage schemes, and for avoiding persisting with this inherently abrasive treatment when it has failed to produce results on two or more occasions.

Clomiphene Teratogenicity

Fertility-inducing drugs are often--almost inevitably---continued for a short period after pregnancy has been induced and before it is recognized (SED-14, 1466). The question has often been raised as to whether this might not adversely affect early development. An unusual condition that has now been tentatively ascribed to clomiphene is persistence of the hyperplastic primary vitreous, i.e. fetal ophthalmic tissue that normally resolves before birth. If more than a trace of the material persists, ocular complications, including cataract and retinal detachment, can result. In a case reported from Canada, there had been an estimated 3 weeks of exposure to high doses of clomiphene (100 mg/day) after gestation, and the child's vision was severely impaired (44AR). This is probably not a mere chance association, since several cases of visual defects of various types after to exposure clomiphene have been described before, and in some animal studies the drug does adversely affect ocular development.

ANTIESTROGENS (SED-14, 1466; SEDA-21, 426; SEDA-23, 443)

Tamoxifen There is currently a move to use tamoxifen to prevent mammary carcinoma in women who

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have never had the disease but are believed to be at high risk; one published trial involved treatment for up to 5 years. The merits of this type of prophylaxis have been disputed (45R), but it is clear that it would involve very long treatment and that one's view of the adverse effects might need to be revised for this class of users.

Endocrine

When tamoxifen is used to treat mammary carcinoma there is a small but widely recognized risk that it may cause ovarian hyperstimulation, with multiple follicles and cyst formation. In one recent case reported from Japan, torsion of such an ovarian cyst occurred (46A), while in a German case it led to myocardial infarction (47A). In a study from Israel to explain the mechanism and frequency of this complication, hormone concentrations in 20 premenopausal women taking tamoxifen (20 mg/day) were compared with those in untreated controls (48CR). Ovarian cysts were found in 80% of the treated patients but only in 8% of controls, and 17-~-estradiol concentrations were significantly raised. Dutch workers concluded that patients who were still having a menstrual cycle had a high chance (81%) of developing ovarian cysts during tamoxifen treatment, but that postmenopansal women taking tamoxifen only developed ovarian cysts if their ovaries were able to respond to FSH stimulation, as shown by serum estradiol production (49CR). Differences in patient populations might explain why some workers (50 CR) still find no association in their patients between tamoxifen and ovarian pathology.

Liver

While both liver dysfunction and peliosis hepatis are recognized as occasional complications of tamoxifen, cirrhosis with fatty liver seems to have been recognized only recently, following reports from several centers. Several of these cases involved women to whom the drug was being given after surgery for breast cancer. The condition is reversible, and liver tests are advisable so that the tamoxifen can be promptly withdrawn if necessary (51AR).

Sexual function

Loss of libido is a reported adverse effect of tamoxifen, and a US study has sought to examine sexual function as a whole in 57 such patients (52c). Sexual desire, arousal, and the ability to achieve orgasm were unaffected. There was a 54% incidence of dyspareunia, but this seemed to be a consequence

476 of co-administration of chemotherapy, which can induce vaginal dryness and loss of libido, rather than an effect of tamoxifen.

Careinogenicity Some further support for the belief that tamoxifen can promote the development of endometrial carcinoma is provided by six cases reported from France and supported by a literature review in 1999 (53CR). With a total of 36 such cases published up to the time of that review (and others appearing concurrently (54 C)) the hypothesis is now emerging that in women aged over 55 tamoxifen can indeed have this adverse effect, whereas in younger women the effect is more likely to be an additive one attributable to use of both tamoxifen and pelvic irradiation in the same subject. A recent report has added a case of pure uterine rhabdomyosarcoma (55AR). A closely associated problem with tamoxifen is the formation of endometrial polyps and the occurrence of polypoid endometriosis; these polyps ("basilomas") can themselves become malignant (56.cR, 57CR), perhaps because of their lack of progesterone receptors and their consequent exposure to unopposed estrogen (58CR). Whether one should routinely screen patients for endometrial changes is disputed; there seems to be no correlation between endometrial thickness and endometrial pathology, and complications could be easily overlooked (59CR).

Raloxifene Raloxifene is a so-called "selective estrogen receptor modulator" (SERM), i.e. it binds to estrogen receptors, but this binding produces agonistic effects at some sites and antagonistic effects at others (60R). The drug thus has both estrogenic and antiestrogenic activity, and has been studied for its ability to reduce bone loss in postmenopausal women (61R). It has shown some promise, although most of the evidence is limited to premarketing studies. LDL cholesterol and total cholesterol concentrations fell significantly compared with placebo, but there was no change in HDL cholesterol or triglyceride concentrations, nor was endometrial thickness affected; the incidence of vaginal bleeding was not increased. However, in one published study there was a 2- to 3-fold rise in the incidence of thromboembolism, similar to that seen with estrogen treatment. There

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were also some cases of leg cramps and hot flushes. In a critical review of raloxifene published in France it was concluded that the compound has no advantages compared with a traditional estrogen, and that in view of certain findings in animal studies there is a possibility that it might increase the risk of ovarian cancer; there is also a need to determine whether it is sufficiently safe in women with a history of (or predisposition to) breast cancer (62R). One also finds a critical view expressed, in the USA, where a survey of the literature up to end of 1999 concluded that while raloxifene might carry a lesser risk of breast cancer than estrogenic HRT, it was also less effective in maintaining bone density, and that as regards cardiovascular risk the estrogenic treatment produced a more favorable outcome (63R).

ANDROGENIC AND ANABOLIC STEROIDS AND RELATED COMPOUNDS (SED-14, 1471; SEDA-21, 434; SEDA-22, 463; SEDA-23, 444)

Hormonal contraception in men The use of combined hormonal contraceptive products in men was proposed at the beginning of the oral contraceptive era. Delays in putting the concept into practice have related variously to difficulties in finding an effective combination, complaints of reduced libido or potency, and the long delay between the start of treatment and the attainment of azoospermia. One combination currently under study, with promising results to date, comprises the progestogen desogestrel and testosterone. Doses are still the subject of experimentation, and a recent study used various combinations, including a sequential pattern. The optimal dosage to induce azoospermia seemed to be desogestrel 300 Ixg daily by mouth and testosterone enanthate 50 mg weekly by intramuscular injection. Among 24 subjects, there were no withdrawals clearly related to the treatment. During weeks 1-3 adverse effects were reduced sex drive (4), tiredness (1), and a sensation of depression (1); during weeks 4-24 they included mild acne (10), increased sexual interest (3), emotional lability (2), tiredness (2), night sweats (1), and headache (1). However,

Sex hormones and related compounds, including hormonal contraceptives laboratory studies showed that desogestrel had clear effects on lipid metabolism in dosages of 150 I~g/day or more, with reductions in HDL cholesterol, apolipoprotein, A1 lipoprotein, sex hormone binding globulin, and to some extent total cholesterol and LDL cholesterol. If this approach can be developed to provide a more convenient dosage scheme, these biochemical changes will be amonAg those that need to be followed carefully (64').

Misuse of androgens and anabolic steroids in s p o r t The publicity accorded to the disqualification of some participants in the 2000 Olympic Games because of their use of nandrolone provides a reminder that evidence of the serious health risks of this form of misuse has not put an end to it. While hepatic and cardiac complications are most prominent, other risks continue to emerge. Some cases are detailed below. Poststeroid balance disorder was diagnosed in a 20-year-old Polish athlete who had been given two courses of metandienone, oxymetholone, and nandrolone phenylproprionate (65A). Vertigo occurred twice just after "doping" and persisted in spite of a 1.5-year break in taking anabolic steroids. There was positional nystagmus, the eye-tracking test was abnormal, and there were abnormal responses in caloric tests. In computed dynamic posturography the incidence and degree of body sway were increased and consequently the field of the outspread area was enlarged. These findings pointed to a permanent poststeroid disorder of the central part of the equilibrium organ. A German report of a 22-year-old male body-builder who had taken both testosterone propionate and nandrolone decanoate in rising doses over a period of 4 months has detailed the emergence of fulminant acne, a sternoclavicular bone lesion, and loss o f libido (66AR). Severe acne after excessive androgen use has been reported before, and the apparently osteoarthritic complication in this case was probably secondary to the acne. Erythrocytosis has come to the fore only recently, though increases in hemoglobin have been known for a long time, and anabolic steroids have actually been used in refractory anemias. A Texas group observed erythrocytosis in a young body-builder taking androgens and followed up this observation by examining hematological measures in nine male com-

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petitive body-builders who admitted to using these steroids illicitly (67AR). Although erythropoietin concentrations were normal (and even tended to be low), six subjects had a raised hematocrit with erythrocytosis. Cholestasis and renal insufficiency occurred together in a German body-builder who had been taking two anabolic steroids together over a period of 80 days (68h). A large hepatic hematoma led to intraabdominal hemorrhage in a 24-year-old man who for 2 years had taken two anabolic steroids as well as clomiphene and HCG (69AR). The authors obtained information from health clubs that users commonly took some 300 mg of nandrolone weekly, whereas the recommended dose was only 50 mg monthly. Suicide----or attempted suicide--in eight users of anabolic steroids has been described in Germany; the cases were related variously to hypomanic states during use of anabolic steroids or depression after withdrawal (70A). Some of the users had committed acts of violence while using the drugs. In all cases, there were risk factors for suicidality and the drugs may simply have triggered the suicidal decision.

Nervous system Androgens can produce euphoria and even occasionally a toxic confusional state (SED-14, 1473), but psychotic mania is rare. A recent case was particularly unusual in that it involved a 28-year-old man with AIDS who was given a testosterone patch to counter progressive weight loss (71h). He had a history of bipolar disorder, but had never required hospitalization for it. He now developed worsening mania with an elevated mood, racing thoughts, grandiose delusions, and auditory hallucinations. His condition improved in hospital after removal of the patch and the administration of antipsychotic treatment. No cause for the psychosis, other than the use of testosterone, was detected.

The use of androgens in women There are clear differences o f opinion about the use o f androgens in women. An Australian reviewer has argued that women may have symptoms secondary to androgen deficiency and that "prudent" androgen replacement can be effective in relieving both the physical and psychological symptoms of such insufficiency

478

(72R). The reviewer suggested that testosterone replacement for women is safe, with the caveat that doses should be restricted to the "therapeutic" window for androgen replacement in women, such that the beneficial effects on well-being and quality of life are achieved without incurring undesirable virilizing effects. The predominant symptom of women with androgen deficiency is claimed to be loss of sexual desire after a premature or natural menopause, while other indications for androgens include premenopausal iatrogenic androgen deficiency states, corticosteroid-induced bone loss, management of wasting syndromes, and possibly premenopausal bone loss, premenopausal loss of libido, and the treatment of the premenstrual syndrome. Some reservations about this approach arise when one considers the possible adverse effects and the doubts that have been raised as to whether there is in fact a safe therapeutic window when treating women with androgens. This comes clearly to the fore in a thoughiful paper by another Australian author, a speech therapist (73cR). For women treated with androgens or related compounds for any reason, virilization of the voice, which soon becomes permanent, is a distressing complication that has not received a great deal of specific study. This review provides some pointers for clinical practice. She reports on four women aged 2758 years who sought otolaryngological examination because of significant alterations to their voices, the primary concerns being hoarseness, lowering of habitual pitch, difficulty in projecting their speaking voices, and loss of control over their singing voices. Otolaryngological examination with a mirror or flexible laryngoscope showed no apparent abnormality of vocal fold structure or function, and the women were referred for speech pathology with diagnoses of functional dysphonia. Objective acoustic measures using the Kay Visipitch showed significant lowering of the mean fundamental frequency for each woman, and perceptual analysis of the patients' voices during quiet speaking, projected voice use, and comprehensive singing activities showed a constellation of features typically noted in pubescent men. The original diagnosis offunctional dysphonia was queried, prompting further exploration of each woman's medical history. In each case the vocal symptoms had started shortly after the beginning of treatment with medications containing virilizing agents,

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M.N.G.Dukes

notably danazol, nandrolone decanoate, and testosterone. Although some of the vocal symptoms abated in severity with 6 months of voice therapy and after withdrawal of the drugs, a number of symptoms remained permanent, suggesting that each subject had suffered significant alterations i n vocal physiology, including muscle tissue changes, muscle coordination dysfunction, and propioceptive dysfunction. The study showed that both the projected speaking voice and the singing voice proved highly sensitive to virilizing effects. It has been known for more than 30 years that some 50% of women have voice changes with anabolic steroids. While it has sometimes been thought that safe doses can be identified, studies of individual patients, including one of the cases documented here, throw doubt on this. The effects can be disastrous for any woman and incapacitating to a singer; clearly the use in women of any product having any androgenic potency must be undertaken with great reticence.

Androgens a n d ageing men Interest in the use of androgens in elderly men continues, with on the one hand the long-standing hope that potency and libido may be restored and on the other hand the belief that cardiovascular prospects might be improved. The uncertainties that exist in this latter respect have been well reviewed in a paper that merits reading in full; it is best summarized in the author's own conclusion that " . . . overall, the androgens are as likely to prevent arterial disease as they are to cause i t . . . " (74R). D r u g formulations Transdermal androgens The transdermal route for administering testosterone to hypogonadal men ("Andropatch") seems logical and convenient, but a British study in 50 treated patients showed that patient acceptance was surprisingly poor (75c). There were adverse effects in 84%, mostly skin problems; 72% requested a return to depot injections, and 5% returned to oral therapy. The reservoir patches, 6 cm in diameter, were, to quote the report literally, judged to be too large, uncomfortable, and visually obtrusive, while the noise they made on bodily movement distracted dogs, wives, and Children; they fell off in showers and attracted ribald remarks from sports partners; they could only be re-

Sex hormones and related compounds, including hormonal contraceptives moved with difficulty and left bald red marks on the body. The nature of the complaints suggests that they might be accommodated by further technical development of the product.

Danazol As a very weak androgen capable of inhibiting secretion of gonadotrophins, danazol continues to be used in endometriosis and certain other conditions. However, it can cause liver damage, and hepatocellular tumors have been reported (SED-14, 1474). In 87 cases of hereditary angio-edema treated with danazol over a number of years, there were three cases of hepatocellular adenoma (76AR), and another case has now been reported (77AR). A 44-year-old woman with acromegaly who took danazol (600 mg/day) for uterine fibroids and an ovarian cyst developed an acute abdomen after 6 months, and a large typical hepatic adenoma was found, with areas of hemorrhage and necrosis. It was removed, but a smaller one was left in place. During the next 6 months, despite withdrawal of danazol, there was further growth of adenomas in the liver, presumably from small tumors not detected at laparotomy. Hepatic adenomas have been associated with both oral contraceptives and anabolic steroids, but not previously with danazol. It is possible that in this patient acromegaly played a predisposing role, since growth hormone can promote the development of tumors, as shown in animal studies; the major liver resection that was carded out could have promoted the subsequent growth of the other adenomas. D r u g interactions Danazol and ciclosporin have been used together in aplastic anemia, and danazol increases ciclosporin blood concentrations, which can in turn in some instances cause a raised serum creatinine, some derangement of hepatic function, or a moderate rise in blood pressure (78A).

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479

ANTIANDROGENS (SED-14, 1475; SEDA-22, 464; SEDA-23, 445)

Biclutamide It is still not clear whether there is a significant difference in adverse effects between biclutamide and its congeners. Most of the work available up to 1999 was from preregistration studies, and while it has been asserted that tolerance is somewhat better on all fronts than with other antiandrogens (79R), this is a relatively recent product and it needs to be examined in the field over a longer period.

Finasteride Bearing in mind that finasteride has proved useful in treating hirsutism, it is at first sight remarkable to find it advocated for treating malepattern hair loss. In both cases, however, use is made of the drug's ability to block the conversion of testosterone to dihydrotestosterone, the substance that is considered responsible for male-pattem hair loss. The oral dose that appears to be sufficient (1 mg/day) does not affect the hypothalamic-pituitary axis or corticosteroid concentrations, but some slight increases in serum estradiol have been noted. To date, no adverse effects have been recorded on measures of semen production or quality, on lipid or bone metabolism, or on prostate volume, although serum prostate-specific antigen was somewhat reduced (80R). These provisionally favorable conclusions need to be monitored in the field, since a drug for this indication is likely to be used for long periods and the temptation to increase doses will be considerable.

Flutamide

Respiratory Fatal interstitialpneumonitis occurred in an elderly man undergoing treatment with flutamide and leuprorelin for prostatic carcinoma (81AR). While one might be inclined to attribute this primarily to the use of leuprorelin, cases of this complication with the antiandrogen nilutamide have been reported before, and it is therefore possible that flutamide had some involvement in this case. Hematologic Since androgens have a hemopoietic effect, it is not surprising to en-

Chapter40

480 counter instances of anemia during treatment with antiandrogens. One case involving flutamide was reported as early as 1991 and there has been a recent report of the consistent occurrence of significant anemic changes in 19 men taking both finasteride (5 mg/day) and flutamide (750 mg/day) for 6 months or more to treat advanced prostatic cancer (82CR). The significance of this adverse effect, which did not result in clinical symptoms, will in further work need to be weighed against the merits of using this combination of drugs in such patients.

M.N.G.Dukes

A 75-year-old man with prostatic carcinoma, who had taken flutamide for 18 months, developed blisters on the back of the hands and fingers after sun exposure. The bullae were associated with skin fragility and atrophic scarring. Histological examination and direct immunofluorescence showed ultrastructural features close to those described in porphyria cutanea tarda. Laboratory blood tests and quantitative analysis of porphyrins in the urine were normal. Flutamide was withdrawn, leading to healing of the lesions, with no relapse after 11 months.

MISCELLANEOUS COMPOUNDS Liver Incidents of serious (83 A, 84A) or even fatal (85 A) hepatotoxicity continue to be reported. The incidence of hepatotoxicity varies. In one recent series it occurred in two of 22 patients (86c). In a retrospective Japanese study of 123 patients there was a 26% incidence of liver disorders, and the incidence was particularly high in men with a history of liver conditions and in those with raised AIT activity, but rather lower in smokers (87CR). In a recent severe case from Japan (88A), serial serum concentrations of flutamide and its metabolites were very high and there was delayed elimination of flutamide, suggesting reduced metabolic oxidation of the drug. The authors went on to monitor flutamide concentrations and liver function in 37 other treated men. In two patients, AsT and A1T were raised to over 100 iu/1, and flutamide was withdrawn. Slight rises in AsT and A1T of 40-100 iu/l were also detected in five patients, and flutamide was withdrawn. Liver function recovered in all cases. The above work appears to show that the risk of liver complications is most marked in men with impaired metabolism of the drug, and this should be monitored. Skin Skin complications, other than some dryness of the skin, have only very rarely been described, but recently a case of pseudoporphyria has been described in France (89AR).

Tibolone Tibolone is a steroid with intrinsic estrogenic, progestogenic, and androgenic properties, which has been used in a range of conditions, including hormone replacement therapy. A group of 113 postmenopausal women treated with tibolone for 6 years were followed in order to examine its long-term effects on the genital tract (90c). The rate of amenorrhea between 6 months and 6 years was 90% with tibolone and 91% in the controls. There was improvement in pre-existing vaginal symptoms with tibolone but not in the controls. Median endometrial thickness increased slightly with tibolone, and two women had temporary endometrial hyperplasia early in treatment, but there was no evidence of cellular abnormalities. Both the vaginal karyopyknotic index and the maturation index increased significantly with tibolone over 6 years, but not in the control group. Vaginal bleeding was cited by only two women as a reason for abandoning treatment. The authors concluded that tibolone was effective in maintaining an inactive endometrium while providing estrogenization of the lower genital tract over a 6-year period. Other studies have presented a similar picture, but there does seem to be a small incidence of acne, mild hypertension, and (unspecified) venous problems (91CR), matters that should be borne in mind as the product comes into use on a wider scale.

Sex hormones and related compounds, including hormonal contraceptives

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16. Lo Schiavo A, D'Avino M. Progesterone, an unsuspected pemphigus inductor. G Ital Dermatol Venereol 1999; 134: 331-4. 17. Ingber A, Trattner A, David M. Hypersensitivity to an oestrogen-progesterone preparation and possible relationship to autoimmune progesterone dermatitis and corticosteroid hypersensitivity. J Dermatol Treat 1999; 10: 139-40. 18. De Lignieres B. Oral micronized progesterone. Clin Ther 1999; 21: 41-60. 19. Warren MP, Biller BMK, Shangold MM. A new clinical option for hormone replacement therapy in women with secondary amenorrhea: effects of cyclic administration of progesterone from the sustained-release vaginal gel Crinone (4% and 8%) on endometrial morphologic features and withdrawal bleeding. Am J Obstet Gynecol 1999; 180: 42-8. 20. Burnhill MS. The use of a large-scale surveillance system in Planned Parenthood Federation of America clinics to monitor cardiovascular events in users of combination oral contraceptives. Int J Fertil Women's Med 1999; 44: 19-30. 21. Anonymous. Oral contraceptives containing gestodene or desogestrel--up-date: revised product information. WHO Pharm Newslett 1999; 7/8 (JulAug): 3. 22. Jick SS, Myers MW, Jick H. Risk of idiopathic cerebral haemorrhage in women on oral contraceptives with differing progestagen components. Lancet 1999; 354: 302-3. 23. Lidegaard O. Smoking and use of oral contraceptives: impact on thrombotic diseases. Am J Obstet Gynecol 1999; 180: $357-63. 24. Hassan HA. Oral contraceptive-induced mesenteric venous thrombosis with resultant intestinal ischemia. J Clin Gastroenterol 1999; 29: 90-5. 25. Zreik TG, Odunsi K, Cass I, Olive DL, Sarrel P. A case of fatal pulmonary thromboembolism associated with the use of intravenous estrogen therapy. Fertil Steril 1999; 71: 373-5. 26. Peleg R. Abdominal wall pain caused by cutaneous nerve entrapment in an adolescent girl taking oral contraceptives pills. J Adolesc Health 1999; 24: 45-7. 27. Rowan JP. Estrophasic dosing: a new concept in oral contraceptive therapy. Am J Obstet Gynecol 1999; 180: $302-6. 28. Hoffmann H, Moore C, Kovacs L, Teichmann AT, Klinger G, Graser T, Oettel M. Alternatives for the replacement of ethinylestradiol by natural 17 beta-estradiol in dienogest-containing oral contraceptives. Drugs Today 1999; 35 Suppl C: 105-13. 29. Kaunitz AM. Long-acting hormonal contraception: assessing impact on bone density, weight and mood. Int J Fertil Women's Med 1999; 33:110-17. 30. Kone B, Lankoande J, Ouedraogo CMR, Ouedraogo A, Bonane B, Dao B, Sanou J. Contraception through subcutaneous implants of levonorgestrel (Norplant); African experience of

482 Burkina Faso. Contracept Fertil Sex 1999; 27: 162-3. 31. Ba MG, Moreau JC, Sokal D, Dunson R, Dao B, Kouedou D, Diadhiou E A 5-year clinical evaluation of Norplant implants in Senegal. Contraception 1999; 59: 377-81. 32. Wildemeersch D, Dhont M, Temmerman M, Delbarge W, Schacht E, Thiery M. GyneFix-LNG: preliminary clinical experience with a copper and levonorgestrel-releasing intrauterine system. Eur J Contracept Reprod Health Care 1999; 4: 15-19. 33. Evbuomwan IO, Fenwick JD, Shiels R, Herbert M, Murdoch AP. Severe ovarian hyperstimulation syndrome following salvage of empty follicle syndrome. Hum Reprod 1999; 14: 1707-9. 34. Borgaonkar MR, Marshall JK. Marked elevation of serum transaminases may be associated with ovarian hyperstimulation syndrome. Am J Gastrocnterol 1999; 94: 3373. 35. Grio R, Patriarca A, Ramondini L, Ferrara L, Curti A, Piacentino R. Ultrasonographic monitoring as a method of preventing the risks of ovarian hyperstimulation during pharmacological treatment. Minerva Ginecol 1999; 51: 15-17. 36. Potashnik G, Lemer-Geva L, Genkin L, Chetrit A, Lunenfeld E, Porath A. Fertility drugs and the risk of breast and ovarian cancers: Results of a long-term follow-up study. Fertil Steril 1999; 71: 853-9. 37. Shushan A, Paltiel O, Iscovich J, Elchalal U, Peretz T, Schenker JG. Human menopausal gonadotrophin and the risk of epithelial ovarian cancer. Fertil Steril 1996; 65: 13-18. 38. Whittemore AS, Harris R, Itnyre J, Cassagrande JT, Cramer D, Hartage P, Kelsey JL, Lee M, Lee NC, Lyon JL, et al. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-controlled studies. Part II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 1992; 136: 1184-203. 39. Banks E, Beral V, Reeves G. The epidemiology of epithelial ovarian cancer: a review. Int J Gynecol Cancer 1997; 7: 425-38. 40. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumours in a cohort of infertile women. New Engl J Med 1994; 331: 771--6. 41. Fathalla ME Incessant ovulation--a factor in ovarian neoplasia? Lancet 1971; 2: 163. 42. Mosgaard B J, Lidegaard O, Kjaer SK, Schou G, Andersen AN. Infertility, fertility drugs and invasive ovarian cancer. A case-control study. Fertil Steril 1997; 67: 1005-12. 43. Helzlsouer KJ, Alberg AJ, Gordon GB, Longcope C, Bush TL, Hoffman SC, Comstock GW. Serum gonadotrophins and steroid hormones and the development of ovarian cancer. J Am Med Assoc 1995; 274: 1926-30. 44. Bishai R, Arbour L, Lyons C, Koren G. Intrauterine exposure to clomiphene and neonatal persistent hyperplastic primary vitreous. Teratology 1999; 60: 143-5.

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45. Kaufman CS, Bear HD. Another view of the Tamoxifen Trial. J Surg Oncol 1999; 72: 1-8. 46. Nasu K, Miyazaki T, Kiyonaga Y, Kawasaki F, Miyakawa I. Torsion of a functional ovarian cyst in a premenopausal patient receiving tamoxifen. Gynecol Obstet Invest 1999; 48: 200-2. 47. Ludwig M, Tolg R, Richardt G, Katus HA, Diedrich K. Myocardial infarction associated with ovarian hyperstimulation syndrome. J Am Med Assoc 1999; 282: 632-3. 48. Cohen I, Figer A, Tepper R, Shapira J, Altaras MM, Yigael D, Beyth Y. Ovarian overstimulation and cystic formation in premenopausal tamoxifen exposure: comparison between tamoxifen-treated and nontreated breast cancer patients. Gynecol Oncol 1999; 72: 202-7. 49. Mourits MJE, De Vries EGE, Willemse PHB, Ten Hoor KA, Hollema H, Sluiter WJ, De Bruijn HWA, Van Der Zee AGJ. Ovarian cysts in women receiving tamoxifen for breast cancer. Br J Cancer 1999; 79: 1761-4. 50. McGonigle KF, Vasilev SA, Odom-Maryon T, Simpson JF. Ovarian histopathology in breast cancer patients receiving tamoxifen. Gynecol Oncol 1999; 73: 402~i. 51. Oien KA, Moffat D, Curry GW, Dickson J, Habeshaw T, Mills PR, MacSween RNM. Cirrhosis with steatohepatitis after adjuvant tamoxifen. Lancet 1999; 353: 36-7. 52. Mortimer JE, Boucher L, Baty J, Knapp DL, Ryan E, Rowland JH. Effect of tamoxifen on sexual functioning in patients with breast cancer. J Clin Oncol 1999; 17: 1488-92. 53. Treilleux I, Mignotte H, Clement-Chassagne C, Guastalla P, Bailly C. Tamoxifen and malignant epithelial-nonepithelial tumours of the endometrium: report of six cases and review of the literature. Eur J Surg Oncol 1999; 25: 477-82. 54. Ramondetta LM, Sherwood JB, Dunton CJ, Palazzo JP. Endometrial cancer in polyps associated with tamoxifen use. Am J Obstet Gynecol 1999; 180: 340-1. 55. Okada DH, Rowland JB, Petrovic LM. Uterine pleomorphic rhabdomyosarcoma in a patient receiving tamoxifen therapy. Gynecol Oncol 1999; 75: 509-13. 56. Schlesinger C, Silverberg SG. Tamoxifenassociated polyps (basalomas) arising in multiple endometriotic foci: a case report and review of the literature. Gynecol Oncol 1999; 73:305-11. 57. Cohen I, Bemheim J, Azaria R, Tepper R, Sharony R, Beyth Y. Malignant endometrial polyps in postmenopausal breast cancer tamoxifen-treated patients. Gynecol Oncol 1999: 75: 136--41. 58. Maia H Jr, Maltez A, Calmon LC, Moreira K, Coutinho EM. Endometrial carcinoma in postmenopausal patients using hormone replacement therapy: a report on four cases. Gynaecol Endosc 1999; 8: 235-41. 59. Seoud M, Shamseddine A, Khalil A, Salem Z, Saghir N, Bikhazi K, Bitar N, Azar G, Kas-

Sex hormones and related compounds, including hormonal contraceptives par H. Tamoxifen and endometrial pathologies: a prospective study. Gynecol Oncol 1999; 75: 15-19. 60. Young RL. An introduction to SERMs and their gynecologic effects. Am J Managed Care 1999; 5 Suppl: S 146-55. 61. Vignot E, Meunier PJ. Effects of raloxifene on bone loss and fracture risk in postmenopausal woman. Contracept Fertil Sex 1999; 27: 858-60. 62. Anonymous. Raloxifene. Prescrire Int 1999; 8: 165-7. 63. Umland EM, Rinaldi C, Parks SM, Boyce EG. The impact of estrogen replacement therapy and raloxifene on osteoporosis, cardiovascular disease, and gynecologic cancers. Ann Pharmacother 1999; 33: 1315-28. 64. Wu FCW, Balasubramanian R, Mulders TMT, Coelingh-Bennink HJT. Oral progestogen combined with testosterone as a potential male contraceptive: additive effects between desogestrel and testosterone enanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipid metabolism. J Clin Endocrinol Metab 1999; 84: 112-22. 65. Bochnia M, Medras M, Pospiech L, Jaworska M. Poststeroid balance disorder--a case report in a body builder. Int J Sports Med 1999; 20: 407-9. 66. Assmann T, Arens A, Becker-Wegerich PM, Schuppe H-C, Lehmann E Acne fulminans with sternoclavicular bone lesions and azoospermia after abuse of anabolic steroids. H G Z Hautkr 1999; 74: 570-2. 67. Dickerman RD, Pertusi R, Miller J, Zachariah NY. Androgen-induced erythrocytosis: is it erythropoietin? Am J Hematol 1999; 61: 154-5. 68. Habscheid W, Abele U, Dahm HH. Anabolic steroids as a cause of severe cholestasis and renal failure in a body builder. Dtsch Med Wochenschr 1999; 124: 1029-32. 69. Habscheid W, Abele U, Dahm HH. Large hepatic hematoma and intraabdominal hemorrhage associated with abuse of anabolic steroids. New Engl J Med 1999; 340: 1123-4. 70. Thiblin I, Runeson B, Rajs J. Anabolic androgenic steroids and suicide. Ann Clin Pyschiatry 1999; 11: 223-31. 71. Weiss EL, Bowers MB Jr, Mazure CM. Testosterone-patch-induced psychotic mania. Am J Psychiatry 1999; 156: 969. 72. Davis SR. The therapeutic use of androgens in women. J Steroid Biochem Mol Biol 1999; 69: 177-84. 73. Baker J. A report on alterations to the speaking and singing voices of four women following hormonal therapy with virilizing agents. J Voice 1999; 13: 496-507. 74. Crook D. Androgen therapy in the aging male: assessing the effect on heart disease. Aging Male 1999; 2: 151-6. 75. Parker S, Armitage M. Experience with transdermal testosterone replacement therapy for hypogonadal men. Clin Endocrinol 1999; 50: 57-62.

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76. Bork K, Pitton M, Harten P, Koch E Hepatocellular adenomas in patients taking danazol for hereditary angio-oedema. Lancet 1999; 353: 10667 77. De Menis E, Tramontin P, Conte N. Danazol and multiple hepatic adenomas: peculiar clinical findings in an acromegalic patient. Horm Metab Res 1999; 31: 476-7. 78. Borras-Blaseo J, Rosiqu-Robles JD, Peri-Marti J, Navarro-Ruiz J, Gonzalez-Delgado M, ConesGarcia V. Possible cyclosporin-danazol interaction in a patient with aplastic anemia. Am J Hematol 1999; 62: 63-4. 79. Schellhammer E An update on bicalutamide in the treatment of prostate cancer. Expert Opin Invest Drugs 1999; 8: 849-60. 80. McClellan KJ, Markham A. Finasteride. A review of its use in male pattern hair loss. Drugs 1999; 57:111-26. 81. Azuma T, Kurimoto S, Mikami K, Oshi M. Interstitial pneumonitis related to leuprorelin acetate and flutamide. J Urol 1999; 161: 221. 82. Ornstein DK, Beiser JA, Andriole GL. Anaemia in men receiving combined finasteride and flutamide therapy for advanced prostate cancer. BJU Int 1999; 83: 43~5. 83. Nicolas D, Perez-Ebri ML, Sarrion JV, Nos E Acute hepatitis due to flutamide. Gastroenterot Hepatol 1999; 22: 262-3. 84. Andrade R J, Lucena MI, Fernandez MC, Suarez F, Montero JL, Fraga E, Hidalgo E Fulminant liver failure associated with flutamide therapy for hirsutism. Lancet 1999; 353: 983. 85. Okaneya T, Murata Y, Kinebuchi Y. Fatal hepatic failure following hepatitis caused by flutamide: a case report. Jpn J Urol 1999; 90: 590-3. 86. Cetin M, Demirci D, Unal A, Altinbas M, Guven M, Unluhizarci K. Frequency of flutamide induced hepatotoxicity in patients with prostate carcinoma. Hum Exp Toxicol 1999; 18: 137-40. 87. Wada T, Ueda M, Abe K. Risk factor of liver disorders caused by flutamide--statistical analysis using multivariate logistic regression analysis. Acta Urol Jpn 1999; 45: 521-6. 88. Nakagawa Y, Koyama M, Matsumoto M. Flutamide-induced hepatic disorder and serum concentrations of flutamide and its metabolites in patients with prostate cancer. Acta Urol Jpn 1999; 45: 821-6. 89. Mantoux F, Bahadoran P, Perrin C, Bermon C, Lacour J-Ph, Ortonne J-P. Flutamide-induced pseudoporphyria. Ann Dermatol Venereol 1999; 126: 150-2. 90. Morris EP, Wilson POG, Robinson J, Rymer JM. Long term effects of tibolone on the genital tract in postmenopausal women. Br J Obstet Gynaecot 1999; 106: 954-9. 91. Egarter C, Sator M, Berghammer P, Huber J. Efficacy, tolerability, and rare side effects of tibolone treatment in postmenopausal women. Int J Gynecol Obstet 1999; 64: 281-6.

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Thyroid hormones and antithyroid drugs

THYROID HORMONES (SED-14, 1485; SEDA-21, 437; SEDA-22, 469; SEDA-23, 451)

Drug interactions with thyroxine Thyroxine (T4) remains one of the most widely prescribed medications. It is readily absorbed from the small intestine, peak serum concentrations being reached after 6-12 hours. Noncompliance is by far the commonest cause of persistent hypothyroidism despite adequate prescription of thyroxine, but it is recognized that severe gastrointestinal disease can affect absorption and hence result in a reduced effect of thyroxine. It has also been reported, although it is not widely recognized, that drugs can affect absorption, including cholestyramine and aluminium hydroxide. Two patients with hypothyroidism treated with fixed doses of thyroxine developed a rise in serum thyrotrophin (TSH) after the introduction of aluminium hydroxide and magnesium oxide for dyspepsia and constipation (ICE). The serum TSH returned to norreal when these medications were withdrawn. The authors also performed in vitro experiments, in which minced tablets of antacids or laxatives were mixed with radiolabelled thyroxine and the adsorption of thyroxine to the tablet suspension was examined. They reported that a mixture of aluminium hydroxide, magnesium hydroxide, and magnesium carbonate, but not magnesium oxide, resulted in significant adsorption of thyroxine. Since antacids and laxatives are widely used, and often selfadministered without prescription, their role should be considered in patients in whom there 9 2001 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed. 4R4

is an inadequate biochemical and clinical response to standard doses of thyroxine. Two previous reports have demonstrated induction of a hypothyroid state in patients taking concomitant thyroxine and ferrous sulphate (2 3, 33). A similar interaction with ferrous fumarate has now been described in a patient who took both medications simultaneously (43). Separation of thyroxine from iron may be prudent, since this interaction may reflect the formation of a non-absorbable complex in the gut (33). In addition to interference with the absorption of thyroxine, various drugs induce enzymes involved in thyroid hormone metabolism. In one case (5c) there was a modest rise in serum TSH concentration when rifampicin was given to a patient previously stabilized on thyroxine replacement. Rifampicin is believed to increase the metabolic clearance of both thyroxine and the inactive compound reverse tri-iodothyronine and in healthy volunteers it reduces circulating concentrations of total and free thyroxine, although in subjects without thyroid disease it has no effect on serum TSH (6c).

ANTITHYROID DRUGS (SED-14, 1489; SEDA-21, 437; SEDA-22, 468; SEDA-23, 451)

Hematologic

The most feared complication of thionamide drugs is bone-marrow suppression. Agranulocytosis has a reported incidence of 0.1-0.3%. Although full recovery usually follows drug withdrawal, the treatment of this complication is controversial. There have been at least 15 reports of the use of granulocytecolony stimulating factor (G-CSF) in severe cases (granulocyte count under 100 • 106/1)

Thyroid hormones and antithyroiddrugs

Chapter41

of thionamide-induced agranulocytosis with the objective of shortening the period of neutropenia and hence the risk of infection (7CR). A further case was reported in which the use of G-CSF in thionamide-induced agranulocytosis was associated with a number of iatrogenic complications (7CR). A review of the literature of subjects treated with G-CSF has shown that the average time to recovery from agranulocytosis is 8.2 days, not obviously different from the reported range of 7-14 days without the drug, leading the authors to argue against its routine use in afebrile patients, even in the face of a severe reduction in granulocyte count.

485

Not all of the systemic complications of thionamides are associated with the appearance of antineutrophil cytoplasmic antibodies, as the following reports show: chronic tubulointerstitial nephritis with renal insufficiency due to propylthiouracil (14A), delayed cholestatic hepatitis due to methimazole (15A), and acute pancreatitis and parotitis due to methimazole (16A).

IODINE AND THE IODIDES (SED-14, 1492; SEDA-21, 438;

SEDA-22, 470; SEDA-23, 452) Immunologic The other group of important adverse effects of the thionamides is vasculitis. Antineutrophil cytoplasmic antibody (ANCA)associated vasculitis is a well described complication, particularly with propylthiouracil and to a lesser extent with carbimazole, and has been most often described in patients with Graves' disease. Cutaneous vasculitis is often a feature of such cases, although severe systemic manifestations are often also apparent. Two patients with propylthiouracil hypersensitivity presented with skin manifestations but also had renal, rheumatological, and hematological features (8AR). A review of the literature showed that the symptoms and signs in patients with ANCA-associated thionamideinduced vasculitis are diverse. Acral purpuric skin lesions are typically seen; recognition of these classical clinical features may allow early diagnosis and limit associated morbidity and the requirement for other therapies, particularly immunosuppression. A further case of ANCA-positive vasculifts in a patient with multinodular goiter has been described, together with a review of the clinical features in a further 26 cases (9AR). Renal involvement, typically with crescentic or necrotizing glomerulonephritis on biopsy, and arthralgia were the most common manifestations. Further new cases of ANCA-associated disease in patients have also been reported, including subjects presenting with neutrophilic dermatosis (10A), pyoderma gangrenosum, secondary sterile pyoarthrosis (llA), and purpura fulminans (12 A). Small vessel vasculitis leading to pulmonary alveolar hemorrhage and crescentic glomerulonephritis has also been described (13A).

It has been estimated that in 1994 some 1.5 billion people in 118 countries were at risk of iodine deficiency, this being regarded as the world's most significant cause of preventable brain damage and mental retardation. Fortification of all salt for animal and human consumption has been chosen as the preferred method for the prevention of iodine deficiency disorders, and this approach is effective in reducing the incidence of such disorders. However, iodine supplementation is not without risk, particularly iodine-induced hyperthyroidism. Because of reports of severe hyperthyroidism after the introduction of iodized salt in two severely iodine-deficient African counties (Zimbabwe and the Democratic Republic of the Congo), a multicenter study has been conducted in seven countries in the region to evaluate whether the occurrence of iodine-induced hyperthyroidism after the introduction of iodized salt was a generalized phenomenon or corresponded to specific local circumstances in the two affected countries (17CR). Iodine deficiency had been successfully eliminated in all of the areas investigated and the prevalence of goiter had fallen markedly. However, it was clear that some areas were now exposed to iodine excess as a result of poor monitoring of the quality of iodized salt and of the iodine intake of the population. In these areas, iodineinduced hyperthyroidism occurred only when iodized salt had been recently introduced. This complication of iodine administration is not confined to those receiving dietary supplements. Two of 788 unselected patients from a relatively iodine-deficient area of Germany who underwent coronary artery angiography with an iodine-containing radiographic contrast

486 agent developed hyperthyroidism within 12 weeks (despite the absence of the typical risk factors of advanced age, preceding nodular goiter, or a low serum TSH) (18CR). While

Chapter 41

J.A. Franklyn

this represents a relatively low incidence, this series highlights the importance of recognizing the role of iodine containing drugs in inducing hyperthyroidism, even in developed countries.

REFERENCES 1. Mersebach H, Rasmussen AK, Kirkegaard L, Feldt-Rasmussen U. Intestinal adsorption of levothyroxine by antacids and laxatives: case stories and in vitro experiments. Pharmacol Toxicol 1999; 84: 107-9. 2. Shakir KM, Chute JP, Aprill BS, Lazarus AA. Ferrous sulfate-induced increase in requirement for thyroxine in a patient with primary hypothyroidism. South Med J 1997; 90: 637-9. 3. Campbell NR, Hasinoff BB, Stalts H, Rao B, Wong NC. Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism. Ann Int Med 1992; 117: 1010-13. 4. Leger CS, Chye T. Ferrous fumarate-induced malabsorption of thyroxine: Endocrinologist 1999; 9: 493-5. 5. Nolan SR, Self TH, Norwood JM. Interaction between rifampin and levothyroxine. South Med J 1999; 92: 529-31. 6. Ohnhaus EE, Studer H. A link between liver microsomal enzyme activity and thyroid hormone metabolism in man. Br J Clin Phannacol 1983; 15: 71~i. 7. Hirsch D, Luboshitz J, Blum I. Treatment of antithyroid drug-induced agranulocytosis by granulocyte colony-stimulating factor: a case of primum non nocere. Thyroid 1999; 9: 1033-5. 8. Chastain MA, Russo GG, Boh EE, Chastain JB, Falabella A, Millikian LE. Propylthiouracil hypersensitivity: report of two patients with vasculitis and review of the literature. J Am Acad Dermatol 1999; 41: 757--64. 9. Gunton JE, Stiel J, Caterson RJ, McElduff A. Antithyroid drugs and antineutrophil cytoplasmic antibody positive vasculitis. A case report and review of the literature. J Clin Endocrinol Metab 1999; 84: 13-16.

10. Miller RM, Darben TA, Nedwich J, Savige J. Propylthiouracil-induced antineutrophil cytoplasmic antibodies in a patient with Graves' disease and a neutrophilic dermatosis. Br J Dermatol 1999; 141: 943-4. 11. Darben T, Savige J, Prentice R, Paspaliaris B, Chick J. Pyoderma gangrenosum with secondary pyarthrosis following propylthiouracil. Australas J Dermatol 1999; 40: 144~. 12. Park KEJ, Chipps DR, Benson EM. Necrotizing vasculitis secondary to propylthiouracil presenting as purpura fulminans. Rheumatol 1999; 38: 790-2. 13. Dhillon SS, Singh D, Doe N, Qadri AM, Ricciardi S, Schwarz MI. Diffuse alveolar hemorrhage and pulmonary capiUaritis due to propylthiouracil. Chest 1999; 116: 1485-8. 14. Nakahama H, Nakamura H, Kitada O, Sugita M. Chronic drug-induced tubulointerstitial nephritis with renal failure associated with propylthiouracil therapy. Nephrol Dial Transplant 1999; 14: 1263-5. 15. Hung YT, Yu WK, Chow E. Delayed cholestatic hepatitis due to methimazole. Hong Kong Med J 1999; 5: 200-1. 16. Tagachi M, Yokata M, Koyano H, Endo Y, Ozawa Y. Acute pancreatitis and parotitis induced by methimazole in a patient with Graves' disease. Clin Endocrinol 1999; 51: 667-70. 17. Delange F, De Benoist B, Alnwick D. Risks of iodine-induced hyperthyroidism after correction of iodine deficiency by iodized salt. Thyroid 1999; 9: 545-56. 18. Hintze G, Blombach O, Fink H, Burkhardt U, Kobberling J. Risk of iodine-induced thyrotoxicosis after coronary angiography: an investigation in 788 unselected subjects. Eur J Endocrinol 1999; 140: 264-7.

H.M.J. Krans

42

Insulin, glucagon, and hypoglycemic drugs

INSULIN (SED-14, 1501; SEDA-22, 472; SEDA-23, 454) Recommendations for the treatment of type 2 diabetes, including problems with and contraindications to various forms of therapy in France have been reviewed (1 ~ ). Metabolism Hypoglycemia In a review of 102 consecutive drug-induced hospital-related cases of coma, 23 were caused by insulin only, 14 by insulin + glibenclamide (glyburide), and three by insulin + metformin (2R). The likelihood of readmission for hypoglycemia after a previous admission was 2.9 times greater. For details see under Sulfonylureas. A case of hypoglycemic coma due to insulin with extensive mental changes has been reported, including a review of six comparable cases in patients aged 37-56 years, whose coma lasted from 36 hours to 31 days ( 3 ~ ) . A 37-year-old man could not be wakened in the morning. He had injected insulin without eating. His blood glucose was 1.5 mmol/1 and he did not improve with intravenous glucose 16 g. In hospital he remained unconscious with a blood glucose of 12.2 mmol/1. There was no alcohol in the blood, his pH was 7.35, and he had a normal anion gap (18 mmol/1). His serum creatinine concentration was 288 izmol/1 and his creatine kinase activity was high, suggesting rhabdomyolysis. A brain CT scan was normal and repeated electroencephalography showed slow waves with reduced voltages but no focal changes or irritation. He gradually recovered and was discharged after 6 days. Because of the dissociation between physical and mental improvement he was checked after 6 months and still had antegrade memory loss and problems with memory, complaining that he needed reminders on paper, and had less vitality and reduced emotionality. 9 2001 Elsevier Science B.V. All fights reserved.

Side Effects of Drugs, Annual 24

Of the six reviewed patients two died in coma; the other four had neuropsychological problems that did not improve after 6 months and up to 2 years. They had comparable electroencephalographic changes. During coma there was hypokalemia and hypocalcemia combined with increased lipolysis; this may have accounted for the permanent cerebral changes. Of 20 patients with severe hypoglycemic coma and 20 with no or light coma, those with hypoglycemia had chronic depression and anxiety and performed persistently more poorly in several cognitive tests (4c). In 42 patients with at least two episodes of severe hypoglycemia in the previous 2 years and 51 patients with no episodes, low blood glucose, hypoglycemia-impaired ability to do mental subtractions, and awareness of neuroglycopenia and hypoglycemia predicted future severe attacks of hypoglycemia (5c). In another study blood glucose awareness training increased adrenaline responses to hypoglycemia (6c). However, in a reanalysis of data from the Diabetes Control and Complications Study, a large study relating the development of secondary complications to less strict control of blood glucose (7c), there was no effect of repeated hypoglycemia (8c). In 29 prepubertal children, with diabetes for at least 12 months and using twice-daily mixed insulin, observed for two nights, asymptomatic hypoglycemia occurred in 13 children on the first night and in 11 children on the second night (9c). Cognitive performance was not altered, but mood was reduced. Of 546 Spanish diabetic children and teenagers, 14% had one period of hypoglycemia and 21% had more than one episode (10c). The highest incidence was in the moming, possibly related to the frugal Spanish breakfast and abundant food intake in the evening.

J.K. Aronson, ed. ~R7

488 A 19-year-old woman with diabetes developed hypoglycemia with pulmonary edema (11A). This has previously been seen as a complication of insulin shock therapy for psychiatric illnesses. In 37 drivers with type 1 diabetes, fewer corrective actions were taken when the blood glucose was below 2.8 mmol/l (12c). This was related to increased neuroglycopenic symptoms and increased electroencephalographic thetawave activity. The authors suggested that diabetics should not begin to drive when the blood glucose concentration is in the 4.5-4.0 mmol/l range. In two editorials the possibility of further restricting driving licenses in people with diabetes has been discussed (13 r, 14r). However, there is no evidence of higher accident rates in drivers with diabetes. A rise in C reactive protein has been observed during spontaneous attacks of hypoglycemia in diabetics and after experimental hypoglycemia in healthy controls (15r).

Fat metabolism A 14-year-old adolescent girl who had only used regular insulin developed lipoatrophy (16A). Histology showed lipoblastoma-like cells, a possible sign of dedifferentiation. Skin tests showed no signs of allergy. The concentrations of immunoglobulins and TNF-t~ were normal. Liver Hepatic damage by regular human insulin has been reported (17A). A 45-year-old man, who drank alcohol 60 g/day until diabetes was diagnosed, had mild liver function test abnormalities 6 months earlier, but only the y-glutamyltranspeptidase was raised (167 iu/1). When insulin was given the aminota'ansferases also increased. Liver function normalized after withdrawal of insulin. Reinstitution of insulin and a switch to another human insulin formulation again increased the liver enzymes. He was managed with glibenclamide and liver biopsy was not performed. Lymphocyte stimulation tests gave negative results to all insulin formulations. All hepatitis-related virus markers were negative. As the changes in this case were seen with different types of insulin, it is improbable that additions to the formulation were responsible. It is possible that the use of alcohol made the liver more sensitive to the damaging effects of exogenous insulin.

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H.M.J.Krans

Immunologic Allergy has been reported to human insulin and protamine (18 A) and to human insulin (19 A, 20A). A 41-year-old woman became allergic to all types of insulin (beef, pork, human, lente, etc.). She had used insulin for the first time during pregnancy and was intermittently treated unsatisfactorily with oral agents. She used lispro insulin for more than 6 months without an allergic reaction.

In India insulin antibodies have been investigated in 25 patients with type 1 diabetes, 19 patients with so-called malnutrition-related diabetes, and eight patients with fibrocalculous pancreatopathy, who used bovine insulin because it was cheaper (21r). Antibodies appeared within 3 months of treatment. The development of antibodies was not related to the type of diabetes. There was a fall in antibody titer with increased duration of treatment. There was no correlation between dally insulin requirement and antibody titers. D r u g administration route Insulin pumps The various types of pumps, the insulin and other substances involved, and the associated problems have been reviewed (22R), as has the use of pumps in children (23R). In a randomized cross-over study in 10 children aged 7-10 years who used subcutaneous insulin pumps only in the evening and the night, fasting and 0300 h blood glucose and fructosamine concentrations were improved (24c). There was a better quality of life and a reduced fear of hypoglycemia. Children of this age may not be capable of handling a pump during the day. Continuous subcutaneous insulin infusion in 75 youths aged 12-20 years has been compared with multiple daily injections over 12 months (25c). HbAlc was lower, and the number of attacks of hypoglycemia in the pump group was 50% less. Ketoacidosis seldom occurred--once during intensive therapy and twice during pump therapy. Weight increased more during pump treatment. Coping with diabetes was less difficult with pump therapy. When insulin delivery stops during continuous subcutaneous insulin infusion, ketoacidosis can develop rapidly, but it can be easily corrected if ketoacidosis has developed recently, although exceptions occur (26A).

Insulin, glucagon, and hypoglycemic drugs

Chapter 42

A 32-year-old woman with well-regulated diabetes, using about 35 units/day of insulin by continuous subcutaneous infusion, tried a sauna for the first time when her blood glucose was 7 mmol/1. She stayed for about 45 minutes and the temperature reached 70~ C for 10 minutes. The blood glucose concentration rose to 11 and 17 mmol/1,despite a bolus of insulin 6 units. She felt sick and vomited during the night; the next morning her blood glucose was 21 mmol/1and she had ketomtria, abdominal cramps, and extreme fatigue. Insulin 25 units by pump produced no improvement, but after opening a new vial the situation improved; within 6 hours she was normoglycemic, and her ketonuria disappeared within 16 hours. It is not clear in this case whether insulin had formed aggregates and fibrils due to the high temperature or if the action of counterregulatory hormones induced by hyperthermia was increased, or both. Lispro is sometimes less beneficial in continuous subcutaneous insulin infusion (27A). A 58-year-old man with diabetes and unawareness of hypoglycemia had 53 emergency hospital admissions in 2 years before he started regular continuous subcutaneous insulin infusion. His attacks of hypoglycemia were reduced to one every 2-3 weeks. His mean blood glucose was 7.0 mmol/1.When lisPro was introduced in the pump he had an attack every 2-3 days for 68 days and hospital admission was required seven times. The mean blood glucose was 6.3 mmol/l. After he used soluble insulin instead of lispro the number of attacks of hypoglycemia fell substantially. The mean blood glucose was 6.4 mmol/l. It may be that the more rapid diffusion and absorption of lispro in diabetics who achieve tight metabolic control and have hypoglycemia unawareness destabilizes glycemic control. Problems with insulin delivery in implanted pumps are difficult to correct. A change in Hoechst 21 pH-neutral semisynthetic insulin 400 U/ml in accordance with new regulations of the European Pharmacopoeia (SEDA-20, 397) resulted in more frequent clogging when this insulin was used in the Minimed 2001 implantable Pump (MIP 2001). From October 1995 to October 1996, 17 pumps were implanted ( 2 8c) . The refilling period was reduced from 90 to 3045 days and the reservoirs were washed with insulin-free buffer before each refill. Backflow was seen in 13 pumps after a mean period of 7.2 months. Modification of the manufacturing process produced 21PH ETP insulin (human semisynthetic insulin, Genapol stabilized)

489

400 U/ml, Hoechst, with improved stability since July 1997. All pumps were specifically cleaned before the new insulin was used for refill. The refill period was increased from 38 to 78 days. In 16 pumps only one backflow was seen after 14 months. The incidence of catheter blockage did not change. The better stability of this insulin for implantable pumps has been confirmed in a study in which 88 pumps were refilled every 45 days and 108 pumps every 90 days (29c).

Insulin pens

Long acting NPH insulin in pens is often insufficiently resuspended before an injection, resulting in a great variation in the dose of insulin per injection (30CE). NPH content ranged from 5-214%. Only 10% of 109 patients tipped and rolled the pen more than 10 times. There was no relation between inadequate suspension and the number of attacks of hypoglycemia. It was mechanically proven that 20 cycles are necessary for good suspension. After education, suspension errors were less frequent in 80% of the patients. They had fewer attacks of hypoglycemia, but HbAlc did not change. After injecting insulin the pen has to be kept in place for some time. Many pens leak from the tip of the needle when the pen is removed from the injection site 7 seconds after the injection is finished (31R). Only the Novopen 1.5 ml and Novolet 1.5 ml showed no leakage; eight of twenty 3 ml BD pens and Novo pens, 16 of 20 Novolets 3 ml and 19 of 20 Saline Pens 3 ml (Lilly) leaked 4.0, 4.7, 5.9, and 9.2 mg respectively. It is necessary to keep the needle in place 10-30 seconds after injection. Measured by ultrasonography, 86% of injections with needles of 12.7 mm and 38% of injections with needles of 8 mm in diabetic children with a BMI below the 60 percentile were intramuscular instead of subcutaneous (32r). The injection changed from intramuscular to subcutaneous in half of the injections in the ann and in two-thirds of injections in the thigh when 8-mm needles were used. Nowadays 6 mm needles are available in many countries.

New synthetic insulin analogs Varieties In recent years, using biotechnology, various analogs with shorter or longer durations of action than regular insulin have been developed. The shorter-acting analogs are

490

lispro (in which the aminoacids proline on site 28 of the B-chain and lysine on site 29 have been interchanged) and insulin aspart (in which proline on B 28 has been replaced by the negatively charged aspartic acid). They have a tendency to reduced polymerization and act more rapidly but have a shorter duration of action than human insulin. Glargine (Hoe 901) is a new longer-acting analog, in which phenylalanine is removed from site 30 of the B-chain (the C-terminal side), and two arginine molecules are bound, adding two positive charges. Asparagine on site 21 of the A-chain is replaced by the more stable glycine to avoid deamination. In an other analog, insulin detemir (NN 304), the epsilon-amino group of lysine at position B 29 is acylated with a fatty acid and the B 30 phenylalanine is removed. This stimulates binding to albumin and increases the half-life, extending its duration of action. Older long-acting insulins, such as NPH and lente, had a maximal hypoglycemic effect after 5 hours (in the beginning of the night), and the glucose-lowering action then abated gradually. The newer analogs have a more constant profile of action. The new insulins have been extensively reviewed

Chapter 42

H.M.J.Krans

ability was high. This means that the clinical role of insulin detemir still has to be established. Duration o f action In single-dose, doubleblind, euglycemic clamp studies glargine had a smoother metabolic effect with a peakless profile of action starting at 2-4 hours and continuing over 24 hours compared with NPH insulin, whose peak occurred at 4 hours and whose activity subsequently fell (37c).

The binding of these analogs to insulin and IGF-I receptors and their metabolic and mitogenic properties have been evaluated in vitro (34E). In general the metabolic potencies correlated with insulin receptor binding and the mitogenic properties correlated with IGFI receptor binding. The rapid acting analogs resembled insulin, except that the binding of lispro to the IGF-I receptor was slightly increased. Insulin glargine had a 6- to 8-fold greater affinity for IGF-I and mitogenic potency than human insulin (suggesting greater growthstimulating potential). In insulin detemir the balance between the metabolic and mitogenic potency was not changed, but receptor affinity was reduced, which may explain its lower efficacy on a molar base in humans.

Beneficial effects A regimen of regular insulin + NPH compared with a mixture of 75% lispro and 25% neutral protamine lispro had no effect on HbAlc, the frequency of hypoglycemia, or treatment satisfaction (38 c ). During Ramadan lispro reduced the number of attacks of hypoglycemia and reduced postprandial blood glucose (39c). It also reduced postsnack raised blood glucose concentrations when sugar-rich snacks were used (4or). Insulin aspart had an increased maximal effect compared with regular insulin in euglycemic clamps in non-diabetics (41c). In an open-label comparison of insulin aspart and regular human insulin for 6 months in 882 patients with type i diabetes and extended to 714 patients for another 6 months, postprandial glucose concentrations were lower with insulin aspart (42c). HbAlc was slightly but significantly lower (7.78% vs 7.93%). There were no differences in hypoglycemic periods or adverse events. Six children were treated with glargine and six with NPH as the long-acting insulin component (43r). After 3 months free insulin concentrations were lower during the night with glargine. There were three cases of hypoglycemia with NPH and one with glargine. In an editorial the current position of glargine was compared to that of lispro in 1996: the pharmacodynamic data are promising but evidence of a beneficial effect on HbAlc may take some years (44 r ).

Absorption The absorption of insulin glargine was delayed compared with NPH insulin in a study using radioactive tracers (35c). In healthy volunteers there was a dosedependent increase in total insulin detemir concentrations in blood, more linear than with NPH (36c). However, there was no clear doseresponse metabolic effect and individual vari-

Metabolism Hypoglycemic events in 24 controlled trials of rapid-acting insulin analogs have been analyzed (45M). In 22 trials insulin lispro was used, 19 studies were open and unblinded, and five were double-blind. In five of 22 studies there was a significant reduction in mild hypoglycemia, but there were no changes in the frequency of severe hypoglycemia in 10 of

(33R).

Insulin, glucagon, and hypoglycemic drugs

Chapter 42

12 studies that reported these events; there was a fall in nocturnal hypoglycemia in six studies, but in 18 studies there was no fall. The author stated that rapid-acting insulins are only appropriate in intensive therapy, which involves well-educated and well-motivated patients. The use of lispro instead of regular insulin reduced the frequency of nocturnal attacks of hypoglycemia but did not change HbAlc (46c). This was confirmed by the UK Prospective Diabetes Study (47c), which also found a fall in postprandial glucose with an increase in fasting and preprandial glucose. A cross-over comparison of regular insulin + NPH at bedtime with lispro + multiple NPH showed no effect on overall hypoglycemia but there was less frequent severe hypoglycemia with the second treatment (48c). The reduction in HbAlc was small and not significant. Insulin doses were the same. Patients preferred the second treatment. In a randomized parallel-group study there were fewer episodes of nocturnal and serious hypoglycemia when glarginine was compared with once- or twice-daily NPH insulin (49 c, 50c). Other adverse reactions and reactions at the injection sites were identical. Pregnancy In a comparison of premeal regular insulin and premeal lispro in gestational diabetes there were fewer attacks of hypoglycemia with lispro, but fasting glucose, postprandial glucose, and HbAlc were similar in the two groups (51c). There were no fetal or neonatal abnormalities.

Insulin-like growth factor (IGF-I) Recombinant human IGF-I, which has 54% identity to proinsulin, is used as an adjunct to insulin therapy in patients with large daily variations in insulin effect. It is sometimes given in insulin resistance syndromes caused by changes in the insulin receptor or in type B insulin resistance syndrome caused by antibodies to the insulin receptor.

Sensory systems Of 199 patients 16 developed significant worsening of retinopathy including neovascularization over 12 weeks; 12 of the 16 had optic disc swelling, which ne-

491

cessitated laser therapy in three of them (52Cr). This was mostly seen in patients using a high dose of IGF-I, but a long-term effect of lowdose IGF-I cannot be excluded.

Immunologic IGF-I can cause allergic reactions (53A). A 75-year-old man had glucose intolerance, severe hyperinsulinemia, and extreme insulin resistance with anti-insulin receptor antibodies. His HbAlc rose to 13.8%. Plasmapheresis to remove the antibodies and immunosuppressive therapy had no lasting success. Treatment with hrlGF-I, 0.4 mg/kg/day, reduced HbAIr to 8.0%. After 5 months he developed a generalized skin eruption 20 minutes after the injection. When IGF-I was withdrawn the HbAlc rose again. After careful desensitization with hrlGF-I, 0.1 mg three times a week, IGF-I was continued, with good effect on HbAlc. Carcinogenicity I have previously reported the results of a study of the effect of adding IGF to insulin therapy (SEDA-23, 457) including adverse effects. In a reaction to this, one of the investigators has deplored the fact that the report had omitted to mention the development of non-Hodgkin's lymphoma in the right femur of a 58-year-old male participant who had used 40 Ixg bd (54A).

ORAL HYPOGLYCEMIC DRUGS (SED-14, 1508; SEDA-21, 443; SEDA-22, 475; SEDA-23, 457) New oral drugs--the sulfonylurea glimepiride, the meglitinide repaglinide, the biguanides mefformin (only recently introduced into the USA), the ct-glucosidase inhibitors acarbose and miglitol, and the thiazolidinediones---have been briefly reviewed, including adverse effects and contraindications (55R). Other reviews of oral hypoglycemic drugs have appeared (56 R, 57R). Recommendations for and contraindications to the various oral drugs in France have been published (1R). Metabolism In patients with maximal oral therapy plasma homocysteine concentrations were raised during secondary failure with poor metabolic control, which may indicate increased vascular risk (58c). The concentrations

Chapter 42

492 correlated inversely with endogenous insulin concentrations. Prompted by reports about the hepatotoxicity of troglitazone, the relation of liver Liver

disease to oral hypoglycemic drugs has been investigated in 44 406 patients, of whom 605 had liver disease (59c). When 185 patients with mild and transient disorders, 249 with a predisposing condition, and 113 with another cause were excluded, 57 cases with possibly druginduced liver changes were left. Of these, 11 could be attributed to other drugs and eight were attributed to fatty liver disease caused by diabetes. In 51 patients oral drugs were continued without worsening of the liver enzymes. In two cases (a 58-year-old woman, whose liver function improved after discontinuing metformin, and an 86-year-old woman, who developed jaundice and died shortly after metformin and glibenclamide were prescribed) a causal relation could not be excluded. Risk factors Exercise training can force a reduction in the dose of various drugs in the treatment of diabetes (60r). The hypoglycemic action of exercise in combination with sulfonyhirea on postabsorptive glucose concentration is mainly caused by greater inhibition of glucose production in the liver (61r).

H.M.J.Krans

R e s p i r a t o r y A 76-year-old man who had taken glibenclamide for 2 weeks, having switched from voglibose, developed pneumonitis (65A). A lymphocyte stimulation test was positive for glibenclamide. Metabolism Hypoglycemia Reported cases again illustrate that hypoglycemia induced by tablets tends to relapse and that long-term observation after normalizing the blood glucose concentration is necessary. Hypoglycemia can cause bemiplegia and a bilateral case has been reported (66A). A 68-year-old man started to take glibenclamide and 1 week later developed a blurred voice and fightsided hemiplegia with a blood glucose of 1.4 mmol/1. Ten minutes after intravenous glucose 50 g his motor function returned to normal. Six hours later he developed slurred speech and left-sided hemiplegia; his blood glucose was 1.9 mmol/l. During glucose administration his deficit resolved.

Hematologic Glibenclamide can cause hemolysis by a non-immune mechanism (67A). A 68-year-old man with a long history of type 2 diabetes and a slowly progressive myelodysplastic syndrome for 2 years took glibenclamide 5 mg/day for more than a year, buformin 150 mg/day, and voglibose 0.6 mg/day. His hemoglobin was 8.4 g/dl. No other cause of hemolysis was found and glibenclamide was withdrawn. His hemoglobin rose to 11.1

g/dE (SED-14, 1508; SEDA-21, 443; SEDA-22, 475; SEDA-23, 457) SULFONYLUREAS

The ATP-sensitive channels in the t-cells and other tissues have been reviewed, including a discussion of the effects of various sulfonylureas (62R). Enhanced action on t-cells by the addition of ADP suggests that the action of sulfonylureas varies with the metabolic state of the islet. Chlorpropamide and glibenclamide have great islet binding specificity, while glibenclamide also binds with high affinity to extrapancreatic binding sites. The UK Prospective Diabetes Study did not find different mortality in patients treated with insulin, glibenclamide, or chlorpropamide (63c). Cardiovascular

Glibenclamide prevents the

increase in tolerance to myocardial ischemia normally observed during the second of two sequential exercise tests (64c).

Skin Erythema multiforme has been attributed to glibenclamide (68A). A 69-year-old woman, who had taken gliclazide 40 mg/day for 3 months, was switched to glibenclamide 2.5 mg/day. She had malaise for 2 days, followed by anorexia, fever, and 2 days later erythema multiforme over her whole body. She also had liver dysfunction, renal impairment, and rhabdomyolysis. A lymphocyte stimulation test was positive for glibenclamide, which was withdrawn; the rash improved and the laboratory tests normalized within 4 days.

Pigmented purpuric dermatosis has been attributed to glipizide (69A). A 66-year-old man took glipizide for 4 weeks and developed brownish, non-pruritic, purpuric, scaling patches on his upper legs and buttocks. Biopsy showed dilated capillaries with surrounding extravasated erythrocytes, perivascular lymphocytic in-

Insulin, glucagon, and hypoglycemic drugs

Chapter42

filtrates, and areas of hemosiderin deposition. After withdrawal of glipizide the rash cleared. Risk factors Drug-induced hypoglycemia in 102 non-alcoholic non-epileptic patients has been reviewed (2R). There were risk factors for hypoglycemia in 94; 84 were over 60 years old, of whom 70 were over 70 years; 66 had renal impairment, of whom 28 also had reduced energy intake, 10 had reduced energy intake, 30 had infections, five had liver cirrhosis, and 10 had malignant neoplasia; 14 had used hypoglycemia-potentiating drugs, such as /%blockers (8), cimetidine (2), co-trimoxazole (2), and aspirin (2). Forty patients had protracted hypoglycemia lasting 12-72 hours. Head trauma (4), skeletal injury (3), seizures (8), transient asymptomatic myocardial ischemia (2), and transient right hemiplegia (1) were seen. Five patients died. Ten used glibenclamide + mefformin, 14 used glibenclamide + insulin, and 53 used only glibenclamide. Glimepiride (55R), which is metabolized in the liver, was given for 3 months to diabetic patients with renal impairment; two groups with creatinine clearances of 30-60 ml and 10-30 ml were distinguished (70c). The goal was to reach fasting blood glucose below 10 mmol/1. Recurrent hypoglycemia occurred in one patient who did not need further drug therapy. One "silent" myocardial infarct occurred. There were no other adverse effects. Serum insulin and C-peptide concentrations did not change. There was increased clearance of glimepiride in the group with low creatinine clearances, probably caused by altered protein binding, increasing the unbound fraction available for hepatic metabolism. D r u g overdose A suicide attempt with chlorpropamide has been reported (71Ar). A 23-year-old woman took chlorpropamide 510 g. She needed assisted respiration and cardiac pacing for bradycardia (probably due to blockade of potassium channels), fluid infusion, and forced diuresis for 3 days. Notwithstanding continuous glucose infusion and glucose boluses she relapsed into severe hypoglycemia with convulsions. Only on day 27 was her urine free of chlorpropamide and her blood glucose normal. Chlorpropamide is the longest acting sulfonylurea. The high doses of glucose she was given may have stimulated further insulin secre-

493

tion, thus contributing to the long period of fluctuating hypoglycemia. In the preceding 5 years 12 fatal cases of chlorpropamide poisoning with 3-15 g were seen in the same institution. Drug interactions In a retrospective casecontrol study a primary diagnosis of hypoglycemia was identified in 413 patients registered as diabetic in 1993 (72c). Five controls of the same age and sex, without hypoglycemia, were selected for each case from the same cohort. The relative risks of hypoglycemia with ACE inhibitors, t-blockers, calcium antagonists, and salicylates were determined. There was an association between enalapril and sulfonylureas. However, other ACE inhibitors could not be identified as a risk factor. There was no interaction with t-blockers, calcium antagonists, or salicylates. The interaction of ACE inhibitors with sulfonylureas has also been illustrated in case reports (73 A, 74A). A 67-year-old man using corticosteroids for asthma, ranitidine 300 mg/day, and enalapril 5 mg/day developed a low blood glucose (1.2 mmol/1) within 48 hours of starting to take glibenclamide 5-10 mg/day. A 64-year-old man, who used, amongst other drugs glibenclamide 2.5 mg and metformin 850 mg bd, lost consciousness after a week of dwindling appetite and lose stools. His blood glucose was 2.2 mmol/1. He had renal impairment (creatinine 362 Ixmol/l). He also used ranitidine and ramipril 2.5 mg/day, which could have contributed to both the hypoglycemic effect and renal insufficiency. In the second case, renal insufficiency could have reduced the clearance of the active metabolites of glibenclamide. The interaction of tolbutamide with diltiazem has been studied in eight healthy men (75c). Tolbutamide had no effect on diltiazem, but diltiazem increased the AUC of tolbutamide by 10% without an effect on blood glucose concentrations. Low doses of alcohol (4.35 mmol/l/kg, comparable to one or two drinks) given to fasting diabetics taking glibenclamide 20 mg/day in a randomized, double-blind, placebo-controlled study caused a greater fall in blood glucose concentrations than saline and increased counterregulatory hormone concentrations (76c).

494

MEGLITINIDES The meglitinides are benzoic acid derivatives, which contain the non-sulfonylurea moiety of glibenclamide. They bind with high affinity to a receptor, distinct from the sulfonylurea receptor, on the ATP-sensitive potassium channels in/~-cells and stimulate insulin secretion.

Nateglinide The phenylalanine derivatives, like nateglinide, are still experimental. In a randomized, double-blind, placebo-controlled, multicenter study 289 patients took nateglinide in doses of 30 mg (n = 51), 60 mg (n = 58), 120 mg (n = 63), 180 mg (n = 57), or placebo (n = 60) before main meals (77c). Meal-time insulin increased rapidly and meal-time glucose excursions were reduced. HbAlc concentrations were significantly reduced after 12 weeks in those taking 60 mg and more. Fasting plasma glucose was only significantly reduced in those taking 120 mg. The drug was withdrawn in one patient taking 180 mg because of increased liver enzymes; at the next visit the enzymes were normal. There were mild symptoms of hypoglycemia, such as increased sweating, tremor, dizziness, weakness, and increased appetite. Blood glucose concentrations were between 2.7 and 3.3 mmol/l in three patients taking 120 mg/day. In 12 patients with type 2 diabetes a combination of nateglinide 120 mg or placebo with metformin 500 mg before each meal on two separate days was well tolerated (78c). One patient taking nateglinide had a headache. One patient was withdrawn because of a myocardial infarction and had multivessel coronary artery disease on catheterization.

Repaglinide Repaglinide, which is registered in various countries, has recently been reviewed (55 R, 79R). It stimulates glucose-dependent insulin secretion, amplifying insulin bursts without changing burst frequency, but it does not restore disrupted pulsatile secretion in type 2 diabetes (80cE). It is rapidly absorbed. It is metabolized by the liver and is 90% excreted in the feces. It has a half-life of 32 minutes. Its pharmacokinetics do not differ in young or older healthy persons (81c). It can be given as monotherapy (82c), and the effective dose is 0.5-8

Chapter 42

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mg/day, starting with 0.5 mg/day. It has to be given before each meal and can be adapted to irregular food intake or missed meals (83c). The most frequent adverse effect is hypoglycemia, followed by respiratory disorders, with a frequency not different from the general population. In renal impairment the half-life is prolonged. Reasons for withdrawal were hyperglycemia, hypoglycemia, and myocardial infarction (84c). A 14-week, double-blind, multicenter, randomized, parallel-group trial of repaglinide and glibenclamide has been performed in patients with type 2 diabetes with borderline or poor control but still responsive to oral hypoglycemic drugs (85c). In all, 83 patients taking repaglinide and 78 taking glibenclamide completed the trial, and about 90% reached the maximum dose. HbAlc fell at the same rate in both groups. The 2-hour postprandial blood glucose concentration was lower with repaglinide, but fasting and mean glucose concentrations did not differ. Repaglinide was associated with 20 hypoglycemic episodes in nine patients and glibenclamide with 15 episodes in nine patients. There were no serious adverse effects. Of 82 patients insufficiently controlled by mefformin, 27 continued to take metformin with placebo, 28 took titrated repaglinide with placebo, and 27 took metformin with titrated repaglinide for 4-5 months (86c). There were no serious adverse effects. Nine patients taking mefformin + repaglinide reported 30 hypoglycemic events and three patients taking repaglinide reported nine events. In an open trial 256 patients with type 2 diabetes with inadequate hypoglycemic control (HbAlc over 7.0% during previous therapy) took repaglinide (0.5--4 mg at meals), troglitazone (200-600 mg/day), or a combination of the two for 22 weeks (87c). Combination therapy was most effective. Repaglinide only was more effective than troglitazone only. Mean body weight increased in both groups. Serious adverse events were chestpain,

cerebrovascular disorders, malignancies, dysrhythmias, electrocardiographic changes suggesting myocardial infarction, and increased AsTactivity (in one patient taking troglitazone). The serious adverse effects were similar in the different groups. Hypoglycemia occurred in 4% of the patients taking combined therapy, in 16% of those taking troglitazone only, and in 27% of those taking repaglinide only; none needed

Insulin, glucagon, and hypoglycemic drugs

Chapter42

assistance. There were changes in liver function tests in three patients in the combined group and in one patient each in the two other groups; the drugs were withdrawn in the affected patients and liver function normalized. There were no differences in adverse effects in the different groups. Hypoglycemia occurred in 11 patients taking repaglinide, in seven taking combination therapy, and in one taking troglitazone. Anemia occurred in four patients taking combined therapy and in two taking troghtazone only.

BIGUANIDES (SED-14, 1512; SEDA-21, 445; SEDA-22, 475; SEDA-23, 459)

Cardiovascular In a retrospective study, cardiovascular deaths in patients using a sulfonylurea only (n = 741) were compared with deaths in patients taking a sulfonylurea + mefformin (n = 169) (88c). In patients taking the combination the adjusted odds ratios were: for overall mortality 1.63 (CI -- 1.27, 2.09); for mortality from ischemic heart disease 1.73 (1.17, 2.55); and for stroke 2.33 (1.17, 4.63). The patients taking the combination were younger, had had diabetes for longer, were more obese, and had higher blood glucose concentrations. Metabolism Hypoglycemia In 102 consecutive patients with drug-induced hospitalrelated hypoglycemic coma, 13 were taking mefformin + glibenclamide and three were taking mefformin + insulin; for details see under sulfonylureas (2R).

495

Risk factors Of 308 patients 73% had contraindications, risk factors, or intercurrent illnesses necessitating withdrawal of metformin (93c): 19% had renal impairment, 25% heart failure, 6.5% respiratory insufficiency, and 1.3% hepatic impairment; 51% had advanced coronary heart disease, 9.8% atrial fibrillation, 3.3% chronic alcohol abuse, 2% advanced peripheral arterial disease, and 0.7% were pregnant. Four fatal cases in 18 months in a community hospital were reported; three had clear contraindications (94A). A 45-year-old woman with liver cirrhosis, a 64-year-old man with coronary artery disease, a 65-year-old man with peripheral arterial disease and asthma, and a 74-year-old man had renal insufficiency. The effect of age on the response to metformin has been studied in 174 patients aged over 70 years not well controlled on glibenclamide 7.5 mg/day or gliclazide 120 mg/day (95c). They were given either maximal sulfonylurea doses (glibenclamide 15 mg/day or gliclazide 240 mg/day) or a sulfonylurea + mefformin (1700 mg/day). Renal function and liver function were normal. There were nine cases of non-severe hypoglycemia in the first group. In the second group there were two cases of hypoglycemia after delayed meals and 35% had transient mild gastrointestinal discomfort. There were no increases in lactic acid. Lipid concentrations were a little lower in the second group. The authors concluded that age as such is not a contraindication to mefformin, provided that contraindications, such as renal impairment, are absent and that blood glucose is measured regularly.

Drug overdose A 37-year-old woman took Lactic acidosis In retrospective studies neither the degree of hyperlactatemia nor accumulation of metformin had prognostic significance, but mortality was linked to the underlying disease (89 c, 90c). The authors stated that mefformin must not be considered to be a toxic drug. The same opinion has been expressed elsewhere (91R), provided that the recommended guidelines are strictly followed. Gastrointestinal In 43 patients with poorlycontrolled type 2 diabetes using insulin the addition of metformin improved HbA1c and reduced the dose of insulin (92c). Seven patients in the metformin group and four in the placebo group had nausea; nine vs four had diarrhea.

mefformin 10 g on purpose (96A). She did not develop hypoglycemia but the serum lactate increased to 3.2 mmol/1 (reference range under 2.1 mmol/l) and she became nauseated. She recovered.

ot-GLUCOSIDASE INHIBITORS (SED-14, 1513; SEDA-21, 446; SEDA-22, 477; SEDA-23, 460) Acarbose and miglitol have recently been reviewed (52R, 97R). Their major adverse effects areflatulence, abdominal discomfort, diarrhea, and bloating.

Chapter 42

496 In a double-blind, placebo-controlled study in 74 patients for 2 years, acarbose 100 mg tds, after a stepwise increase in dosage over 5 weeks, improved HbAlc (-1.71%) more than placebo (98c). Two patients taking acarbose withdrew with drug-related adverse effects. Of 1027 patients, 283 used acarbose as the treatment of choice (99c). In 250 cases the physician was not sure of the benefit; 124 of these patients took acarbose and 126 patients took placebo besides regular therapy. In those taking acarbose HbAlc fell. The adverse effects were bloating, flatulence, abdominal cramps, and diarrhea; there were moderate increases in A1T and AsT. The effects of acarbose in 18 studies in diabetic animals have been reviewed (100EM). All had reduced postprandial glucose and reduced glycosylation of proteins, and secondary complications were delayed or prevented. Gastrointestinal Although acarbose often causes abdominal complaints, dietary manipulation has not been used to reduce the complaints (101c). In 120 patients with type 1 diabetes, acarbose lowered postprandial glucose but did not reduce HbAlc (102c). Four patients taking acarbose withdrew because of gastrointestinal effects, which improved after withdrawal. One of the placebo group withdrew because of gastrointestinal problems and one other patient taking acarbose withdrew with a Bell's palsy, which was not considered to be related to acarbose. Liver Acute hepatitis has been reported (103A). A 58-year-old man taking gliclazide 80 mg/day, atenolo1100 mg/day, and pravastatin 10 mg/day started to take acarbose 150 mg/day and benazepril 10 mg/day. After 2 weeks he developed weakness and myalgia and 1 week later his A1T was 22 times higher and AsT nine times higher than the upper limit of the reference range. Benazepril and pravastatin were withdrawn and his antidiabetic therapy was changed to insulin. No viral or other antibodies related to liver disease were found. He improved and was given glibenclamide and acarbose instead of insulin. His enzymes increased 3 weeks later without subjective signs and he had an eosinophilia. A liver biopsy showed intralobular and periportal necrosis of liver cells and mononuclear infiltrates. Acarbose was withdrawn and he improved.

H.M.J.Krans

This appears to have been an idiosyncratic reaction to acarbose. Comparable reports have prompted a questionnaire investigation of 770 patients with type 2 diabetes at the start of acarbose therapy (104c). Patients with one or more risk factors regarding the liver underwent ultrasonography and autoantibody assays. There was silent liver disease in 13% and 20 patients had a fatty liver without hepatic disease. In 15% of these patients there were slight reversible changes in aminotransferase activity after acarbose. This supports the supposition that severe hepatotoxic reactions to acarbose are idiosyncratic. Skin

Erythema multiforme has been reported

(105A).

The skin biopsy of a 58-year-old man showed necrosis of keratinocytes with lymphocytic and eosinophylic infiltration. Liver enzymes were normal. After withdrawal the erythema disappeared. After 3 weeks rechallenge with acarbose 50 mg caused the skin changes to reappear.

THIAZOLIDINEDIONES (SED-14, 1514; SEA-21, 446; SEDA-22, 478; SEDA-23, 461) Three thiazolidinediones have been developed: troglitazone, rosiglitazone, and pioglitazone; ciglitazone is still in development. They reduce insulin resistance and are sometimes designated as insulin sensitizers. They promote glucose utilization in peripheral tissues by stimulating non-oxidative glucose metabolism and suppressing gluconeogenesis. They activate the socalled Peroxisome Proliferator Activated Receptor Gamma (PPARy), a nuclear hormone receptor that enhances a number of genes encoding enzymes involved in glucose and fat metabolism. PPARy is essential for normal insulin sensitivity (106 r, 107 E, 108R). In some systems troglitazone behaves as a partial agonist; in fat ceils it behaves as a full agonist. The transcriptional activities of troglitazone and rosiglitazone differ (109E). The thiazolidinediones can be prescribed as single drugs or in combination with other hypoglycemic drugs (55R). Their adverse effects are comparable: weight gain, hypoglycemia (mostly in combination with other hypoglycemic drugs), small clinically unimportant falls

Insulin, glucagon, and hypoglycemic drugs

Chapter 42

in hematocrit and hemoglobin, and in animals edema and cardiac hypertrophy. However, troglitazone causes liver complications, sometimes fatal, and this has led to its withdrawal from the market. In a parallel-group study in patients starting on hypoglycemic therapy with thiazolidinediones, 35 took troglitazone 600 mg/day, 36 took rosiglitazone 8 mg/day, and 30 took pioglitazone 45 mg/day (ll0C). At 2 and 4 months there was an equal effect on glucose lowering and greater weight gain with pioglitazone; pioglitazone had the largest beneficial effect on lipids and rosiglitazone the least.

Troglitazone Troglitazone was the first drug of this group (registered in 1997). It has been recently reviewed (111R-113R). In general it lowers fasting glucose and postprandial glucose. Its effects persist for 2-3 weeks after withdrawal (114c). It is also effective in insulin-resistant glucocorticoid-induced diabetes (115c). It has a greater insulin sparing effect than biguanides when given to patients on continuous subcutaneous insulin infusion (116c). In 1998 there were 21 fatal cases of liver failure and three liver transplantations in patients taking troglitazone (l17A). Monitoring of liver function was intensified and in 1998 troglitazone was withdrawn for monotherapy. In 1999 the FDA received 61 reports of fatal hepatic toxicity and seven cases requiring liver transplantation (118 c ) and in spring 2000 troglitazone was withdrawn in America and in Japan. Late hepatic damage has also been reported (119 A, 120A). A 62-year-old woman started to take troglitazone 400 rag/day in addition to other drugs. Her liver function became abnormal 9 months later and deteriorated suddenly 10 months after that. Troglitazone was withdrawn immediately. No other causes for changed liver function could be found. A biopsy 3 weeks after withdrawal showed hepatic necrosis. A 76-year-old man took troglitazone 400 mg in addition to glimepiride 4 mg/day, metformin 1 g/day, aspirin, and pravastatin. After 18 months his liver function deteriorated and improved after withdrawal of troglitazone. Museuloskeletal Rhabdomyolysis has been attributed to troglitazone in combination with alcohol (121A).

497

A 59-year-old man took troglitazone 400 mg/day for 6 months and alcohol about 40 g/day. He developed weakness and muscle pain. He had mild liver damage. His HbAlc concentration was 9.0%. All his muscles were tender, his creatine kinase activity was 10 570 iu/ml, and his myoglobin, aldolase, and AsT were raised. Troglitazone was withdrawn. He improved biochemically and clinically. Drug interactions Troglitazone has been reported to reduce the effect of simvastatin, probably by induction of CYP3A4 (122A).

Rosiglitazone Rosiglitazone has recently been reviewed (123 R, 124R). Increases in liver enzymes were comparable to those in patients taking placebo, a sulfonylurea, or metformin. Hemoglobin and

hematocrit were slightly reduced and diastolic blood pressure fell by 2.3 mmHg, as assessed by 24-hour ambulatory monitoring. In 12 healthy people meals did not affect absorption (125c). In a parallel-group, double-blind, placebocontrolled, dose-ranging (4, 8, and 12 mg/day) study of 369 patients for 8 weeks after a run-in period, hematocrit and hemoglobin, C pep-

tide, fasting blood glucose, and fructosamine all fell (126c). Hepatotoxicity, significant cardiac events, or hypoglycemia were not different from placebo. In 574 patients taking a sulfonylurea, twicedaily placebo (n = 192 patients) was compared with rosiglitazone 1 mg/day (n = 199 patients) or rosiglitazone 2 mg/day (n = 183 patients) for 26 weeks (127c). Rosiglitazone improved HbAlc. With the higher dose of rosiglitazone there were more cases of hypoglycemia and a small increase in mean body weight; some patients complained of headache and upper

respiratory tract infections. Hematologic In 303 patients who took placebo or rosiglitazone for 8 weeks after a run-in period, rosiglitazone 4 mg bd had the same effect as 6 mg bd, but hemoglobin and hematocrit were lower with 6 mg bd (128c).

MEDICAL DEVICES USED IN DIABETES Insulin pumps and insulin pens are discussed above. For blood glucose meters see Chapter 49.

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32. Tubiana-Rufi N, Belarbi N, Du PasquierFediaevsky L, Polak M, Kakou B, Leridon L, Hassan M, Czernichow E Short needles (8 ram) reduce the risk of intramuscular injections in children with type 1 diabetes. Diabetes Care 1999; 22: 1621-5. 33. Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia 1999; 42:1151-67. 34. Kurtzhals E Sch~ffer L, S0rensen A, Kristensen C, Jonassen I, Schmid C Triib T. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000; 49: 999-1005. 35. Owens D, Coates PA, Luzio SD, Tinbergen JP, Kurzhals R. Pharmacokinetiks of 125I-labeled insulin glargine (Hoe 901) in healthy men. Diabetes Care 2000; 23: 813-19. 36. Heinemann L, Sinha K, Weyer C, Loftager M, Hirschberger S, Heise T. Time-action profile of the soluble, fatty acid acylated, long-acting insulin analogue NN304. Diabetic Med 1999; 16: 332-8. 37. Heinemann L, Linkeschova R, Rave K, Hompesch B, Sedlak M, Heise T. Time-action profile of the long-acting insulin analog insulin glargine (Hoe901) in comparison with those of NPH insulin and placebo. Diabetes Care 2000; 23: 644-9. 38. Janssen MMJ, Snoek FJ, Masurel N, Hoogma RPLM, DevilM WL, Pop-Snijders C, Heine RJ. Optimized basal-bolus therapy using a fixed mixture of 75% lispro and 25% NPL insulin in type 1 diabetes patients. Diabetes Care 2000; 23: 62933. 39. Akram J, De Verga V, Ramadan Study Group. Insulin lispro (Lys(B28), Pro(B29)) in the treatment of diabetes during the fasting month of Ramadan. Diabetic Med 1999; 16: 861-6. 40. Kong N, Kitchen MM, Ryder REJ. The use of lispro for high sugar content snacks between meals in intensive insulin regimens. Diabetic Med 2000; 17: 331-2. 41. Mudaliar SR, Lindberg FA, Joyce M, Beerdsen P, Strange P, Lin A, Henry RR. Insulin aspart (B28 Asp-insulin): a fast-acting analog of human insulin. Diabetes Care 1999; 22: 1501-6. 42. Ruskin P, Guthrie RA, Leiter L, Riis A, Javanovic L. Use of insulin aspart, a fast-acting insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes. Diabetes Care 2000; 23: 583-8. 43. Mohn A, Strang S, Wemicke-Panten K, Lang AM, Edge JA, Dunger DB. Nocturnal glucose control and free insulin levels in children with type 1 diabetes by use of the long-acting insulin HOE 901 as part of a three-injection regimen. Diabetes Care 2000; 23: 557-9. 44. Buse J. Insulin Glargine (HOE901). Diabetes Care 2000; 23: 576-8. 45. Heinemann L. Hypoglycemia and insulin analogues: is there a reduction in incidence? J Diabetes Complications 1999; 13: 105-14.

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46. Heller SR, Amiel SA, Mansell P, UK Lispro Study Group. Effect of the fast-acting insulin analog lispro on the risk of nocturnal hypoglycemia during intensified insulin therapy. Diabetes Care 1999; 22: 1607-11. 47. Gale EAM. A randomized, controlled trial comparing insulin lispro with human soluble insulin in patients with type 1 diabetes on intensified insulin therapy. Diabetic Med 2000; 17: 209-14. 48. Colombel A, Murat A, Krempf M, KuchlyAnton B, Charbonnel B. Improvement of blood glucose control in type 1 diabetic patients treated with lispro and multiple NPH injections. Diabetic Med 1999; 16: 319-24. 49. Pieber TR, Eug~ne-Jolchine I, Derobert E. Efficacy and safety of Hoe 901 versus NPH insulin in patients with type 1 diabetes. Diabetes Care 2000; 23: 157-62. 50. Rather RE, Hirsch IB, Neifing JL, Garg SK, Mecca TE, Wilson CA. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care 2000; 23: 639-43. 51. Jovanovic L, Ilic S, Pettitt D J, Hugo K, Gutierfez M, Bowsher RR, Bastyr HI El. Metabolic and immunologic effects of insulin lispro in gestational diabetes. Diabetes Care 1999; 22: 1422-7. 52. Lanzetta P, Malara C. Co-therapy with recombinant human IGF-I and insulin improves glycemic control in type 1 diabetes. Diabetes Care 2000; 23: 436-7. 53. Yamamoto T, Sato T, Mori T, Yamakita T, Hasegawa T, Miyamoto M, Hosoi M, Ishii T, Yoshioka K, Tanaka S, Fujii S. Clinical efficacy of insulin-like growth factor-1 in a patient with autoantibodies to insulin receptors: a case report. Diabetes Res Clin Pract 2000; 49: 65-9. 54. Mayer-Davis EJ. Cancer in a patient receiving IGF-I therapy. Diabetes Care 2000; 23: 433-4. 55. Parulkar AA, Fonseca VA. Recent advances in pharmacological treatment of type 2 diabetes mellitus. Compr Ther 1999; 25: 418-26. 56. DeFronzo RA. Pharmacological therapy for type 2 diabetes mellitus. Ann Intern Med 1999; 131: 281-303. 57. Lebovitz HE. Insulin secretagogues: old and new. Diabetes Rev 1999; 7: 139-153. 58. Drzewoski J, Czupryniak L, Chwatko G, Bald E. Total plasma homocysteine and insulin levels in type 2 diabetic patients with secondary failure to oral agents. Diabetes Care 1999; 22: 2097-9. 59. Jick SS, Stender M, Myers MW. Frequency of liver disease in type 2 diabetic patients treated with oral antidiabetic agents. Diabetes Care 1999; 22: 2067-7 I. 60. Fujinuma H, Abe R, Yamazaki T, Seino H, Kikuchi H, Hoshino T, Hirano R, Yoshida S. Effect of exercise training on doses of oral agents and insulin. Diabetes Care 1999; 22: 1754-5. 61. Larsen JJ, Dela F, Madsbad S, Vibe-Petersen J, Galbo H. Interaction of sulfonylureas and exercise on glucose hemostasis in type 2 diabetic patients. Diabetes Care 1999; 22: 1647-54.

500 62. Ashcroft FM, Gribble FM. ATP-sensitive K + channels and insulin secretion: their role in health and disease. Diabetologia 1999; 402: 903-10. 63. Turner RC, Holman RR, Cull CA, Stratton IM, Matthews DR, Frighi V, Manley E, Neil A, McEIroy H, Wright D, Kohner E, Fox C, Hadden D. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 83753. 64. Tomai F, Danesi A, Ghini AS, Crea E Perino M, Gaspardone A, Ruggeri G, Chiariello L, Goiffr~ PA. Effects of KATPchannel blockade by glibenclamide on the warm-up phenomenon. Eur Heart J 1999; 20: 196-202. 65. Ishibashi R, Takagi Y, Ozaki S. A case with glibenclamide induced pneumonitis [in Japanese]. Jpn J Chest Dis 1999; 58: 758-62. 66. Wattoo MA, Liu HH. Alternating transient dense hemiplegia due to episodes of hypoglycemia. West J Med 1999; 170: 170-1. 67. Noto H, Tsukamoto K, Kimura S. Glyburideinduced hemolysis in myelodysplastic syndrome. Diabetes Care 2000; 23: 129. 68. Aoki T, Sobajima H, Suzuki Y, Sassa H. A case of erythema multiforme and rhabdomyolysis induced by Daonil (glibenclamide) 2.5 mg tablet [in Japanese]. J Jpn Diabetes Soc 1999; 42: 759-63. 69. Adams BB, Gadenne A-S. Glipizide-induced pigmented purpuric dermatosis. J Am Acad Dermatol 1999; 41: 827-9. 70. Profozic V, Mrzljac V, Nazar I, Metelko Z, Rosenkranz B, Lange C, Malerezyk V. Safety, efficacy, and pharmacokinetics of glimepiride in diabetic patients with renal impairment over a 3-month period. Diabetol Croat 1999; 28: 25-32. 71. Ciechanowski K, Borowiak KS, Potocka BA, Nowacka M, Dutkiewicz G. Chlorpropamide toxicity with survival despite 27-day hypoglycemia. J Toxicol Clin Toxicol 1999; 37: 869-71. 72. Thamer M, Ray NF, Taylor T. Association between antihypertensive drug use and hypoglycemia: a case-control study of diabetic users of insulin or sulfonylureas. Clin Ther 1999; 21: 1387400. 73. Parlapiano C, Paoletti V, Campana E, Giovanniello T, Pantone E Increased risk of hypoglycemia from enalapril plus ranitidine with glibenclamide: a clinical case. Adv Ther 1999; 16: 130-2. 74. Collin M, Mucklow JC. Drug interactions, renal impairment and hypoglycemia in a patient with type II diabetes. Br J Clin Pharmacol 1999; 48: 134-7. 75. Dixit AA, Rao YM. Pharmacokinetic interaction between diltiazem and tolbutamide. Drug Metab Drug Interact 1999; 15: 269-77. 76. Burge MR, Zeise T-J, Sobhy TA, Rassam AG, Schade DS. Low-dose ethanol predisposes elderly fasted patients with type 2 diabetes to sulfonylureainduced low blood glucose. Diabetes Care 1999; 22: 2037-43.

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77. Hanefeld M, Bouter KP, Dickinson S, Guitard C. Rapid and short-acting mealtime insulin secretion with nateglinide controls both prandial and mean glycemia. Diabetes Care 2000; 23: 2027. 78. Hirschberg Y, Karara AH, Pietri AO, McLeod JF. Improved control of mealtime glucose excursions with coadministration of nateglidine and metformin. Diabetes Care 2000; 23: 349-53. 79. Ratner RE. Repaglinide therapy in the treatment of type 2 diabetes. Today's Ther Trends 1999; 17: 57-66. 80. Juhl CB, PCrksen N, Hollingdale M, Stuffs J, Pincus S, Veldhuis JD, Dejgaard A, Schmitz O. Repaglinide acutely amplifies pulsatile insulin secretion by augmentation of burst mass with no effect on burst frequency. Diabetes Care 2000; 23: 675-81. 81. Hatorp V, Huang W-C, Strange P. Repaglinide pharmacokinetics in healthy young adult and elderly subjects. Clin Ther 1999; 21: 702-10. 82. Gomis R. Repaglinide as monotherapy in type 2 diabetes. Exp Clin Endocrinol Diabetes 1999; 107 Suppl 4: S133-5. 83. Damsbo P, Marbury TC, Hatorp V, Clauson E MUller PG. Flexible prandial glucose regulation with repaglinide in patients with type 2 diabetes. Diabetes Res Clin Pract 1999; 45:31-9. 84. Schatz H. Preclinical and clinical studies on safety and tolerability of repaglinide. Exp Clin Endocrinol Diabetes 1999; 107 Suppl 4: S1448. 85. Landgraf R, Bilo HGJ, Miiller PG. A comparison of repaglinide and glibenclamide in the treatment of type 2 diabetic patients previously treated with sulphonylureas. Eur J Clin Pharmacol 1999; 55: 165-71. 86. Moses RG. Repaglinide in combination therapy with metformin in type 2 diabetes. Exp Clin Endocrinol Diabetes 1999; 107 Suppl 4: S136-9. 87. Raskin P, Jovanovic L, Berger S, Schwartz S, Woo V, Ratner R. Repaglinide/troglitazone combination therapy. Diabetes Care 2000; 23: 979-83. 88. Olson J, Lindberg G, Gotts~iter M, Lindwall K, SjCistrand /~, Tisell A, Melander A. Increased mortality in type II diabetic patients using sulphonylurea and metformin in combination: a population-based observational study. Diabetologia 2000; 43: 558-60. 89. Lalau J-D, Race J-M. Lactic acidosis in metformin therapy. Drugs 1999; 58 Suppl 1: 55-60. 90. Lalau J-D, Race J-M. Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf 1999; 20: 377-84. 91. Chan NN, Brain HPS, Feher MD. Metforminassociated lactic acidosis: a rare or a very rare clinical entity. Diabetic Med 1999; 16: 273-81. 92. AvilEs-Santa L, Sinding J, Raskin E Effect of metformin in patients with poorly controlled insulin-treated type 2 diabetes mellitus. Ann Intern Med 1999; 31: 182-8.

Insulin, glucagon, and hypoglycemic drugs

Chapter 42

93. Holstein A, Nahrwold D, Hinze S, Egberts EH. Contra-indications to metformin therapy are largely disregarded. Diabetic Med 1999; 17: 6926. 94. Beis SJ, Goshman LM, Newkirk GL. Risk factors for metformin-associated lactic acidosis. Wisc Med J 1999; 98: 56-7. 95. Gregorio F, Ambrosi F, Manfrini S, Velussi M, Carle F, Testa R, Merante D, Filipponi P. Poorly controlled elderly type 2 diabetic patients: the effects of increasing sulphonylurea dosages or adding metformin. Diabetic Med 1999; 16: 1016-24. 96. Bates D, Caton B. Metformin overdose. Can J Hosp Pharm 1999; 52: 173-5. 97. Lebovitz HE. Alpha-glucosidase inhibitors as agents in the treatment of diabetes. Diabetes Rev 1998; 6: 132-45. 98. Hasche H, Mertes G, Bruns C, Englert R, Genthner P, Heim D, Heyen P, Mahla G, Schmidt C, Schulze-Schleppinghof B, Steger-Johannsen G. Effects of acarbose treatment in type 2 diabetic patients under dietary training: a multicentre, doubleblind, placebo-controlled, 2-year study. Diabetes Nutr Metab Clin Exp 1999; 12: 277-85. 99. Scorpiglione N, Belfiglio M, Carinci F, Cavaliere D, De Curtis A, Franciosi M, Mad E, Sacco M, Tognoni G, Nicolucci A. The effectiveness, safety and epidemiology of the use of acarbose in the treatment of patients with type II diabetes mellitus. Eur J Clin Pharmacol 1999; 55: 23949. 100. Creutzfeld W. Effects of the alpha-glucosidase inhibitor acarbose on the development of long-term complications in diabetic animals: pathophysiological and therapeutic implications. Diabetes Metab Res Rev 1999; 15: 289-96. 101. Lindstrtm J, Tuomilehto J, Spengler M. Acarbose treatment does not change the habitual diet of patients with type 2 diabetes. Diabetic Med 2000; 17: 20-5. 102. Riccardi G, Giacco R, Padllo M, Turco S, Rivellese AA, Ventura MR, Contadini S, Marra G, Monteduro M, Santeusanio F, Brunetti P, Librenti MC, Pontiroli AE, Vedani P, Pozza G, Bergamini L, Bianchi C. Efficacy and safety in the treatment of type 1 diabetes mellitus: a placebo-controlled, double-blind, multicentre study. Diabetic Med 1999; 16: 228-32. 103. Mennecier D, Zafrani ES, Dhumeaux D, Mallat A. Htpatite aigu~ induite par l'acarbose. Gastroenterol Clin Biol 1999; 23: 1398-9. 104. Gentile S, Turco S, Guarino G, Sasso FC, Torella R. Aminotransferase activity and acarbose treatment in patients with type 2 diabetes. Diabetes Care 1999; 22: 1217-18. 105. Kono T, Hayami M, Kobayashi H, Ishii M, Taniguchi S. Acarbose-induced generalised erythema multiforme. Lancet 1999; 354: 396-7. 106. Schwartz MW, Kahn SE. Insulin resistance and obesity. Nature 1999; 402: 860-1. 107. Barroso I, Gurnell M, Crowley VEF, Agostini M, Schwabe JW, Soos MA, Maslen GL, Willi-

501

ams TDM, Lewis H, Schafer AJ, Chatterjee VKK, O'Rahily S. Dominant negative mutations in human PPAR-gamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1999; 402: 880-3. 108. Auwerx J. PPAR-gamma, the ultimate thrifty gene. Diabetologia 1999; 42: 1033-49. 109. Camp HS, Li O, Wise SC, Hong YH, Frankowski CL, Shen X-Q, Vanbogelen R, Leff T. Differential activation of peroxisome proliferatoractivated receptor-gamma by troglitazone and rosiglitazone. Diabetes 2000; 49: 539-47. 110. King AB. A comparison in a clinical setting of the efficacy and side effects of three thiazolidinediones. Diabetes Care 2000; 23: 557. 111. Scheen AJ, Lef'ebvre PJ. Troglitazone: antihyperglycemic activity and potential role in the treatment of type 2 diabetes. Diabetes Care 1999; 22: 1568-77. 112. Saleh YM, Mudaliar SR, Henry RR. Metabolic and vascular effects of the thiazolidinedione troglitazone. Diabetes Rev 1999; 7: 55-76. 113. Plosker GL, Faulds D. Troglitazone: a review of its role in the treatment of type 2 diabetes mellitus. Drugs 1999; 57: 409-38. 114. Frias JP, Yu JG, Kruszynska YT, Olefsky JM. Metabolic effects of troglitazone therapy in type 2 diabetic, obese, and lean normal subjects. Diabetes Care 2000; 23: 64-9. 115. Fujibayashi K. Nagasaka S. Itabashi N, Kawakami A, Nakamura T, Kusaka I, Ishikawa S-E, Saito T. Troglitazone efficacy in a subject with glucocorticoid-induced diabetes. Diabetes Care 1999; 22: 2088-9. 116. Yu JG, Kruszynska YT, Mulford MI, Olefsky JM, A comparison of troglitazone and metformin on insulin requirements in euglycemic intensively insulin-treated type 2 diabetic patients. Diabetes 1999; 48: 2414-21. 117. Misbin RI, Troglitazone-associated hepatic failure. Ann Intern Med 1999; 130: 330. 118. Bailey CJ. The rise and fall of troglitazone. Diabetic Med 2000; 17: 414-15. 119. Iwase M, Yamaguchi M, Yoshinari M, Okamura C, Hirahashi T, Tsuji H, Fujishima M. A Japanese case of liver dysfunction after 19 months of troglitazone treatment. Diabetes Care 1999; 22: 1382-4. 120. Bell DSH, Ovalle E Late-onset troglitazoneinduced hepatic dysfunction. Diabetes Care 2000; 23: 128-9. 121. Yokoyama M, Izumiya Y, Yoshizawa M, Usuda R. Acute rhabdomyolysis associated with troglitazone. Diabetes Care 2000; 23: 421-2. 122. Lin JC, Ito MK. A drug interaction between troglitazone and simvastatin. Diabetes Care 1999; 22: 2104-5. 123. Barman Balfour JA, Plosker GR. Rosiglitazone. Drugs 1999; 57: 921-30. 124. Caspi A. The promise of a new generation: rosiglitazone for the treatment of type 2 diabetes. P&T 1999; 24: 313-22.

502 125. Freed MI, Allen A, Jorkasky DK, DiCicco RA. Systemic exposure to rosiglitazone is unaltered by food. Eur J Clin Pharmacol 1999; 55: 53---6. 126. Nolan JJ, Jones NP, Patwardhan R, Deacon LF. Rosiglitazone taken once daily provides effective glycaemic control in patients with type 2 diabetes mellitus. Diabetic Med 2000; 17: 287-94. 127. Wolffenbuttel BHR, Gomis R, Squatrito S, Jones NP, Patwardhan RN. Addition of low-dose

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rosiglitazone to sulphonylurea therapy improves glycaemic control in type 2 diabetic patients. Diabetic Med 2000; 17: 40-7. 128. Raskin P, Rappaport EB, Cole ST, Patwardhan R, Freed MI. Rosiglitazone short-term monotherapy lowers fasting and postprandial glucose in patients with type lI diabetes. Diabetologia 2000; 43: 278-84.

E Coates

43

Miscellaneous hormones

Calcitonin (SED-14, 1520; SEDA-21, 451; SEDA-22, 483; SEDA-23, 466)

of pneumonitis associated with GnRH agonist therapy.

Calcitonin has anti-inflammatory properties in addition to its antiresorptive activity in bone. Adverse effects are common but usually mild, and include nausea, cramps, flushing, dizzi-

Psychiatric A 32-year-old woman had psychotic symptoms of persecutory delusions, agitation, and auditory hallucinations a few days after her second injection of triptorelin (4A). Her symptoms recurred after a pregnancy, suggesting that they were due to the rapid fall in estrogen in both instances.

ness, headache, frequent urination, and local reactions. They are dose-related, which probably explains why the intranasal form is associated with fewer adverse effects than the subcutaneous form. In 40 patients there was nausea and dizziness in 37% of patients given rectal salmon calcitonin compared with 6% given placebo (lC). Respiratory Salmon calcitonin 100 iu was given intravenously to 18 patients with atopic asthma in a randomized, double-blind, crossover study, to assess any potential antiinflammatory effect (2c). Calcitonin infusion caused a significant decrease in FEV1 and FVC, which lasted less than 1 hour. Three subjects had dyspnea that did not require specific treatment.

Gonadotrophin-releasing hormone (GnRH, gonadorelin) and analogs (SED-14, 1523; SEDA-21, 451; SEDA-22, 483; SEDA-23, 466) Respiratory A 75-year-old man developed a high fever and cough immediately after an injection of leuprorelin acetate 3.75 mg, and 8 days after starting flutamide 375 mg/day (3A). He died of respiratory failure after a month, and interstitial pneumonitis was confirmed postmortem. There have been two other reports 9 2001 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

Endocrine Hypogonadal adverse effects, for example hot flushes, mood changes, and reduced libido, are extremely common with gonadorelin and its analogs. In a randomized, multicenter, double-blind comparison of intranasal nafarelin bd with depot leuprolide acetate monthly for 6 months in 192 young women with endometriosis, nafarelin caused fewer hypo-estrogenic symptoms, although the difference between the two groups was statistically significant only after 3 months of therapy (5c). Ovarian hyperstimulation syndrome (characterized by multiple ovarian follicles, ascites, vomiting, headache, and reduced urine output) has been described in a few women after ovulation induction with GnRH agonists and various combinations of gonadotrophins (SED14, 1524). Obesity and pre-existing polycystic ovary syndrome are the major recognized risk factors. A 32-year-old woman who was not obese developed benign intracranial hypertension in association with ovarian hyperstimulation syndrome after ovulation induction using goserelin, FSH, and human chorionic gonadotrophin (hCG) (6A). The syndrome did not recur during a second pregnancy in which FSH and hCG were not used. It is unclear which of the hormonal agents used was responsible for this complication.

Metabolism There were mild increases in serum triglyceride and cholesterol concen5fl~

504 trations in 13 hirsute women treated with triptorelin and a triphasic oral contraceptive, in a randomized comparison of triptorelin with flutamide + cyproterone acetate (7c). Altered lipid profiles have not been described before in patients receiving GnRH agonists and oral contraceptives.

Gonadotrophin-releasing hormone antagonists Gonadorelin agonists suppress gonadotrophin release after an initial surge: pituitary suppression takes up to 2 weeks to develop. Competitive antagonists at gonadorelin receptors cause an immediate inhibition of gonadotrophin secretion without down-regulating the receptor. This class of agents would therefore be preferable to gonadorelin agonists when a rapid clinical effect is desired, for example in controlled ovarian stimulation. Early generation gonadorelin agonists had low potency and tended to cause histamine release (8R). The adverse effects of ganirelix, a third-generation antagonist, are usually mild and include minor injection site reactions, mild nausea, and malaise (8R). Endocrine In a small controlled study of 10 healthy men, cetrorelix increased concentrations of insulin, leptin, and apolipoprotein A-I compared with placebo (9c). The clinical significance of these findings has yet to be determined.

Growth hormone (human growth hormone, hGH, somatotropin) (SED-14, 1520; SEDA-21, 451; SEDA-22, 484; SEDA-23, 467) The therapeutic use of human growth hormone is being extended to include adults with growth hormone deficiency and children with idiopathic short stature, as well as the established indications of childhood growth hormone deficiency, Tumer's syndrome, and chronic renal insufficiency. Body composition, respiratory muscle function, physical strength, and height improved in a 12-month trial of hGH

Chapter 43

P Coates

for 54 children with Prader-Willi syndrome (10c). Adverse effects are commoner in patients using higher doses. Men are more sensitive to growth hormone than women, and they have more adverse effects. Starting at a low dose, increasing the dose gradually, and titrating individual doses against age-specific IGF-I concentrations may minimize adverse events. One recommended regimen is to start with 0.15 mg/day and titrate upward (SED-14, 1521). Very high doses (0.1-0.2 mg/kg/day, 10-20 times higher than replacement doses given to adults with growth hormone deficiency) were given to 532 critically ill patients in intensive care units in two placebo-controlled trials (llC). Mortality was significantly higher in the treated group than in the placebo group (42% vs 18%). Morbidity was also increased in growth hormone recipients, who needed longer ventilator times. Cardiovascular Fluid retention, edema, and hypertension are common adverse effects of human growth hormone. In an open study of five patients with severe dilated cardiomyopathy given high dose human growth hormone 4 iu/day (1.3 mg/day) for 3 months, ventricular dysrhythmias worsened in all patients during treatment, from Lown class 2 or 3 to 4A or 4B, and returned to baseline when treatment was stopped (12 c). Nervous system Headache is a common adverse effect, often occurring early in treatment and usually responding to temporary dosage reduction followed by gradual re-escalation (10C, 13c). It can be an early indicator of the rare complication pseudotumor cerebri (idiopathic intracranial hypertension), particularly in highrisk groups, such as children with renal insufficiency, and may require further investigation.

Human growth hormone and insulin resistance Hyperinsulinemia is common in recipients of human growth hormone, but the long-term effects are controversial. This issue is becoming increasingly important as more adult patients are treated and the duration of therapy is extended. Growth hormone deficiency is itself asso-

Miscellaneous hormones

Chapter 43

ciated with insulin resistance (14c). The effect of human growth hormone on cardiovascular risk is complex, as growth hormone reduces visceral fat and total cholesterol and increases HDL cholesterol concentrations (15c-17c). In a postmarketing review of over 20 000 patients, type H diabetes was three times more common than expected, probably because atrisk individuals became diabetic at an earlier age than predicted (18 R ). In a double-blind study of 24 growth hormone-deficient adults treated for 4 months with growth hormone 2 iu/day or placebo, the treated patients had a significant increase in fasting plasma glucose and insulin concentrations, and increased insulin resistance, determined by insulin AUC during oral and intravenous glucose tolerance testing (17c). Similarly, a group of 30 non-growth hormone-deficient adolescents treated for a mean of 7.9 years had significantly reduced insulin sensitivity and raised plasma glucose concentrations during treatment, returning to control concentrations after human growth hormone was withdrawn (19c). One of these patients developed glucose intolerance. In a study of high-dose human growth hormone (0.1 mg/kg/day) in 20 patients with severe burns (a condition known to cause insulin resistance), 60% of the treated patients required insulin therapy for hyperglycemia compared with 25% of controls (20c). This study was limited by the fact that the treated patients had more severe burns than the controls. Acanthosis nigricans, which is characterized by dark velvety thickening of the skin on the nape of the neck and in the groin and axillae, has been described in a non-obese 10year-old boy with achondroplasia who received human growth hormone 3--4 iu/week for 7years (21A). There has been one previous report of acanthosis nigricans in a woman who received human pituitary extract ( 2 2A) . This condition is usually seen in hyperinsulinemic states, including diabetes mellitus and acromegaly: overstimulation at the IGF-I receptor is probably the final common pathway.

505

Growth hormone release-inhibiting hormone (somatostatin) and

analogs

(SED-14, 1522; SEDA-21, 453; SEDA-22, 486; SEDA-23, 469)

Cardiovascular Both somatostatin and octreotide cause a transient increase in mean arterial pressure and mean pulmonary pressure when given intravenously to cirrhotic patients, more marked with bolus administration than with continuous infusion (23R). This is not usually associated with significant clinical effects. There has been one report of a patient who developed acute pulmonary edema during octreotide and intravenous fluid therapy for variceal bleeding (24A). Endocrine In an open retrospective comparison of octreotide and lanreotide in 38 patients with acromegaly, one patient in each group stopped therapy because of worsening glycemic control (25c). Although both hyperglycemia and hypoglycemia have been reported with somatostatin analogs, these effects are not usually of clinical importance.

Gastrointestinal Diarrhea is a common adverse effect of octreotide therapy. It usually resolves after the first 1-2 weeks of treatment. Lanreotide has a similar effect (25 c, 26c). Biliary Up to 50% of patients with acromegaly treated with octreotide have gallstones, compared with 10-25% of the general population. However, only a few patients are symptomatic. Patients treated with octreotide have impaired meal-stimulated gall-bladder emptying and altered bile chemical composition, similar to "spontaneous" cholelithiasis. In 16 patients with acromegaly the serum deoxycholic acid concentration increased in proportion to large bowel transit time (27c). Gall-bladder emptying was slower in patients given octreotide LAR than lanreotide SR in a study of 11 patients, but was impaired in both groups compared with pretreatment values (28CR). Skin Reversible hair loss has been reported in a few patients after both octreotide (29 C) and lanreotide (30c).

Pregnancy Octreotide is a small peptide that can pass the placental barrier, and it is not re-

506

Chapter 43

P. Coates

commended for use in pregnant women. There have been seven reports of women taking somatostatin analogs during pregnancy, five of whom stopped taking it when the pregnancy was diagnosed (31R). One woman had a single injection of modified-release lanreotide before pregnancy was diagnosed, with no apparent adverse effects on the infant (32A). No fetal malformations or delay in postnatal development have been reported.

Pituitary apoplexy is the most serious TRHrelated complication, and is probably due to its vasoactive properties. A case has recently been described of a patient who developed severe headache, nausea and vomiting, visual disturbance, and altered mental function 88 hours after a TRH/GnRH stimulation test to investigate a pituitary macroadenoma (36A). Bleeding into the tumor was seen on CT scan. The patient died 9 days later of pneumonia.

Oxytocin and analogs (SED-14,1523)

VASOPRESSIN AND ANALOGS

Oxytocin is in common use during induction of labor and in the third stage of labor to prevent uterine atony and postpartum hemorrhage. Carbetocin, a synthetic analog with a half-life 4-10 times longer than the native hormone, has been studied in clinical trials (33c). Both agents cause a small transient fall in blood pressure (less than 4 mmHg). Common mild adverse effects of both drugs include headache, flush-

ing, a feeling of warmth, a metallic taste, and abdominal pain. In a retrospective analysis of 2774 women who had had one prior cesarean delivery there was a 1% incidence of uterine rupture in women who were given oxytocin, compared with 0.4% in non-augmented controls with spontaneous labor (34~). Six women needed emergency hysterectomy. The odds ratio for uterine rupture in the oxytocin treated women was 4.6 by logistic regression analysis (CI = 1.5, 14). The small number of events limited the study: it had only a 30% power to detect changes of that magnitude. However, it is reasonable to proceed cautiously, with close clinical observation, given the potentially severe outcome.

Thyrotropin-releasing hormone (TRH, protirelin) (SED-14, 1523; SEDA-21, 454; SEDA-22, 486) Nervous system A woman developed severe bifrontal headache and visual blurring 5 minutes after the intravenous administration of TRH 200 Ixg to investigate her pituitary macroadenoma (35A). The symptoms resolved in less than 2 hours without sequelae.

(SED-14, 1522; SEDA-21, 454; SEDA-22, 487; SEDA-23, 469)

Desmopressin (N-deamino-8-Darginine vasopressin, DDAVP) Cardiovascular DDAVP causes a significant increase in plasma concentrations of von Willebrand factor and factor VIII, potentiating primary hemostasis. A recent meta-analysis of placebo-controlled trials of desmopressin in 702 cardiac surgery patients showed a significantly increased risk of myocardial infarction in treated patients (RR = 2.39, CI = 1.02, 5.60) (37M). Overall mortality was not different from placebo. DDAVP was less efficacious in reducing perioperative blood loss than either aprotinin or lysine analogs. Ear, nose, throat Nasal irritation and rhinitis are common adverse effects of nasal DDAVP: treatment does not normally have to be altered as a result (38 c, 39c). Electrolyte balance DDAVP has a potent antidiuretic action. It is increasingly being prescribed for enuresis and urinary incontinence in children and for patients with neurological diseases, such as multiple sclerosis. Fluid intake needs to be controlled to prevent hyponatremia. A recent meta-analysis identified 14 studies of serum sodium in 529 patients treated with DDAVP; mild asymptomatic hyponatremia occurred in up to 10% of patients (40M). In a long-term open study of 245 Swedish children given intranasal desmopressin 20-40 ~g at night for enuresis, five had an asymptomatic fall in plasma sodium, consistent with this finding (38c).

Miscellaneous hormones

Chapter 43

In children particularly, a minimal positive balance of hypotonic fluid can cause fatal hyponatremia when extrarenal electrolyte loss is high, for example postoperatively. Warning signs include progressive lethargy, weakness, nausea and vomiting, and headache. Cerebral edema and tentorial herniation was the cause of death in the few fatal cases reported. A 13-kg 3-year-old boy given 40 txg of DDAVP intravenously and 1.6 1 of hypotonic fluid over 12 hours had convulsions and a respiratory arrest: his plasma sodium fell to 114 mmol/l (41AR). There have been 11 other reported cases of convulsions after DDAVP administration, six associated with excessive fluid intake. In a 12-year-old boy taking DDAVP for nocturnal enuresis, hyponatremia and cerebral edema developed after high fluid intake before a urodynamic procedure (42A). In a double-blind cross-over study, 20 men aged 52-80 years were given DDAVP for nocturia. Three of them had symptoms due to fluid retention, particularly bloating, headache, and reversible weight gain, and two of these had a significant fall in plasma sodium (43c).

Hematologic Desmopressin causes a significant but transient reduction in platelet count in patients with von Willebrand disease. There are no reports of increased thrombotic complications in this disorder (44C).

507

Ornipressin Cardiovascular Ornipressin is a selective agonist at vasopressin V1 receptors and has weaker antidiuretic activity than the native hormone. Of l0 patients with hepatorenal syndrome one had to be withdrawn 2 hours after ornipressin 6 iu/hour and a dopamine infusion 2-3 Ixg/kg/min was started, because of a ventricular tachydysrhythmia (45c). Gastrointestinal Tongue ischemia and ischemic colitis have been described after 4-9 days of treatment with ornipressin 6 iu/hour combined with plasma volume expansion (46c).

Terlipressin (triglycyl-lysine vasopressin) Musculoskeletal Rhabdomyolysis has been attributed to terlipressin (47A). A 36-year-old man with nephrotic syndrome was given a terlipressin infusion (2 mg intravenous bolus followed by 2 mg over 24 hours) to treat diffuse gastric bleeding, and 12 hours later developed acute pain and livedo reticularis in both legs. High plasma concentrations of myoglobin and creatine kinase confirmed the diagnosis of toxic rhabdomyolysis, thought to be due to the vasoconstrictor action of terlipressin. He made a gradual recovery over the next few weeks after terlipressin was withdrawn. Pre-existing blood vessel disease due to amyloidosis may have contributed to the outcome in this patient.

REFERENCES 1. Lyritis GP, Ioannidis GV, Karachalios Th, Roidis N, Kataxaki E, Papaioannou N, Kaloudis J, Galanos A. Analgesic effect of salmon calcitonin suppositories in patients with pain due to recent osteoporotic vertebral crush fractures: a prospective double blind, placebo-controlled clinical study. Clin J Pain 1999; 15: 284-9. 2. Kawalski H, Polanowicz U, Jonderko G, Kucharz EJ, Krol W, Klimmek K, Gina AR, Pieczyrak R, Slifirski J, Shani J. Immunological parameters and respiratory functions in patients suffering from atopic bronchial asthma after intravenous treatment with salmon calcitonin. Immunol Lett 1999; 70: 15-19.

3. Azuma T, Kurimoto S, Mikami K, Oshi M. Interstitial pneumonitis related to leuprorelin acetate and flutamide. J Urol 1999; 161: 221. 4. Mahe V, Nartowski J, Montagnon F, Dumaine A, Gluck N. Psychosis associated with gonadorelin agonist administration. Br J Psychiatry 1999; 175: 290-1. 5. Zhao SZ, Kellerman LA, Francisco CA, Wong JM. Impact of nafarelin and leuprolide for endometriosis on quality of life and subjective clinical measures. J Reprod Med Obstet Gynecol 1999; 44: 100045. 6. Lesny P, Maguiness SD, Hay DM, Robinson J, Clarke CE, Killick SR. Ovarian hyperstimulation

508 syndrome and benign intracranial hypertension in pregnancy after in-vitro fertilization and embryo transfer. Hum Reprod 1999; 14: 1953-5. 7. Pazos F, Escobar-Morreale I-IF, Balsa J, Sancho JM, Varela C. Prospective randomized study comparing the long-acting gonadotropin-releasing hormone agonist triptorelin, flutamide, and cyproterone acetate, used in combination with an oral contraceptive, in the treatment of hirsutism. Fertil Steril 1999; 71: 122-8. 8. Gillies PS, Faulds D, Balfour JAB, Perry CM. Ganirelix. Drugs 2000; 59:107-11. 9. Buchter D, Behre HM, Kliesch S, Chirazi A, Nieschlag E, Assmann G, Von Eckardstein A. Effects of testosterone suppression in young men by the gonadotropin releasing hormone antagonist cetrorelix on plasma lipids, lipolytic enzymes, lipid transfer proteins, insulin, and leptin. Exp Clin Endocrinol Diab 1999; 107: 522-9. 10. Carrel AL, Myers SE, Whitman BY, Allen DB. Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: a controlled study. J Pediatr 1999; 134: 215-21. 11. Takala J. Ruokonen E. Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ. Increased mortality associated with growth hormone treatment in critically ill adults. New Engl J Med 1999; 341: 785-92. 12. Frustaci A, Gentiloni N, Russo M. Growth hormone in the treatment of dilated cardiomyopathy. New Engl J Med 1996; 335: 672-3. 13. Toogood AA, Shalet SM. Growth hormone replacement therapy in the elderly with hypothalamic-pituitary disease: a dose-finding study. J Clin Endocrinol Metab 1999; 84: 131-6. 14. Johansson JO, Fowelin J, Landin K, Lager I, Bengtsson BA. Growth hormone-deficient adults are insulin-resistant. Metabolism 1995; 44:11269. 15. Weaver JU, Monson JP, Noonan K, John WG, Edwards A, Evans KA. The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivity, and cardiovascular risk factors in hypopituitary adults. J Clin Endocrinol Metab 1995; 80: 153-9. 16. Attanasio AE Lamberts SW, Matranga AM, Birkett MA, Bates PC, Valk NK, Hilsted J, Bengtsson BA, Strasburger CJ. Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. J Clin Endocrinol Metab 1997; 82: 82-8. 17. Rosenfalck AM, Fisker S, Hilsted J, Dinesen B, Volund A, Jorgensen JO, Christiansen JS, Madsbad S. The effect of the deterioration of insulin sensitivity on beta-cell function in growth-hormonedeficient adults following 4-month growth hormone replacement therapy. Growth Horm IGF Res 1999; 9: 96-105. 18. Frisch H. Pharmacovigilance: the use of KIGS (Pharmacia and Upjohn International Growth Data-

Chapter 43

P. Coates

base) to monitor the safety of growth hormone treatment in children. Endocrinol Metab 1997; 4 Suppl B: 8345. 19. Bareille P, Azcona C, Matthews DR, Conway GS, Stanhope R. Lipid profile, glucose tolerance and insulin sensitivity after more than four years of growth hormone therapy in non-growth hormone deficient adolescents. Clin Endocrinol 1999; 51: 347-53. 20. Demling RH. Comparison of the anabolic effects and complications of human growth hormone and the testosterone analog, oxandrolone, after severe burn injury. Burns 1999; 25: 215-21. 21. Downs AMR, Kennedy CTC. Somatotrophininduced acanthosis nigricans. Br J Dermatol 1999; 141: 390-1. 22. Nordlund JJ, Lerner AB. Cause of acanthosis nigricans. New Engl J Med 1975; 293: 200. 23. Hadengue A. Somatostatin or octreotide in acute variceal bleeding. Digestion 1999; 60 Suppl 2: 31-41. 24. Jenkins SA, Shields R, Davies M, Elias E, Turnbull AJ, Bassendine ME James OF, Iredale JP, Vyas SK, Arthur MJ, Kingsnorth AN, Sutton R. A multicentre randomised trial comparing octreotide and injection sclerotherapy in the management and outcome of acute variceal haemorrhage. Gut 1997; 41" 526-33. 25. Razzore P, Colao A, Baldelli R, Gaia D, Marzullo P, Ferretti E, Ferone D, Jaffrain-Rea ML, Tamburrano G, Lombardi G, Camanni F, Ciccarelli E. Comparison of six months therapy with octreotide versus lanreotide in acromegalic patients: a retrospective study. Clin Endocrinol 1999; 51: 159--64. 26. Lin J-D, Lee S-T, Weng H-E An open, phase IH study of lanreotide (Somatuline PR) in the treatment of acromegaly. Endocr J 1999; 46: 193-8. 27. Veysey MJ, Thomas LA, Mallet AI, Jenkins PJ, Besser GM, Wass JAH, Murphy GM, Dowling RH. Prolonged large bowel transit increases serum deoxycholic acid: a risk factor for octreotide induced gallstones. Gut 1999; 44: 675-81. 28. Turner HE, Lindsell DRM, Vadivale A, Thillainayagam AV, Wass JAH. Differing effects on gall-bladder motility of lanreotide SR and octreotide LAR for treatment of acromegaly. Eur J Endocrinol 1999; 141: 590--4. 29. Vecht J, Lamers CBHW, Masclee AAM. Longterm results of octreotide-therapy in severe dumping syndrome. Clin Endocrinol 1999; 51: 619-24. 30. Suliman M, Jenkins R, Ross R, Powell T, Battersby R, Cullen DR. Long-term treatment of acromegaly with the somatostatin analogue SR-lanreotide. J Endocrinol Invest 1999; 22: 409-18. 31. Herman-Bonert V, Seliverstov M, Melmed S. Pregnancy in acromegaly: successful therapeutic outcome. J Clin Endocrinol Metab 1998; 83: 72731. 32. De Menis E, Billeci D, Marton E, Gussoni G. Uneventful pregnancy in an acromegalic patient

Miscellaneous hormones

Chapter 43

treated with slow-release lanreotide: a case report. J Clin Endocrinol Metab 1999; 84: 1489. 33. Dansereau J, Joshi AK, Helewa ME, Doran TA, Lange IR, Luther ER, Farine D, Schulz ML, Horbay GLA, Griffin P, Wassenaar W. Doubleblind comparison of carbetocin versus oxytocin in prevention of uterine atony after cesarean section. Am J Obstet Gyneeol 1999; 180: 670-6. 34. Zelop CM, Shipp TD, Repke JT, Cohen A, Caughey AB, Lieberman E. Uterine rupture during induced or augmented labor in gravid women with one prior cesarean delivery. Am J Obstet Gynecol 1999; 181: 882-6. 35. Sachmeni I, Bitton RN, Patel D, Schneider BS. Transient headache and impaired vision after intravenous thyrotropin-releasing hormone in a patient with pituitary macroadenoma. Mt Sinai J Med 1999; 66: 330-3. 36. Dokmetas HS, Selcuklu A, Colak R, Unlluhizarci K, Bayram F, Kelestimur F. Pituitary apoplexy probably due to TRH and GnRH stimulation tests in a patient with acromegaly. J Endocrinol Invest 1999; 22: 698-700. 37. Levi M, Cromheecke ME, De Jonge E, Prins MH, De Mol BJM, Briet E, Buller HR. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999; 354: 1940-7. 38. Tullus K, Bergstrom R, Fosdal I, Winnergard I, Hjalmas K. Efficacy and safety during long-term treatment of primary monosymptomatic nocturnal enuresis with desmopressin. Acta Paediatr 1999; 88: 1274-8. 39. Chiozza ML, Del Gado R, Di Toro R, Ferrara P, Fois A, Giorgi P, Giovannini M, Rottoli A, Segni G, Biraghi M. Italian multicentre open trial on DDAVP spray in nocturnal enuresis. Scand J Urol Nephrol 1999; 33: 42-8.

509 40. Robson WLM, Norgaard JP, Leung AKC. Hyponatraemia in patients with nocturnal enuresis treated with DDAVP. Eur J Paediatr 1996; 155: 959-62. 41. Francis JD, Leary T, Niblett DJ. Convulsions and respiratory arrest in association with desmopressin administration for the treatment of a bleeding tonsil in a child with borderline haemophilia. Acta Anaestesiol Scand 1999; 43: 870-3. 42. Brodzikowska-Pytel A, Giembicki J. Hyponatremia as a complication of nocturnal enuresis treatment with desmopressin in a child. Pediatr Pol 1999; 74: 79-83. 43. Cannon A, Carter PG, McConnell AA, Abrams P. Desmopressin in the treatment of nocturnal polyuria in the male. BJU Int 1999; 84: 2 0 ~ . 44. Casonato A, Steffan A, Pontara E, Zucchetto A, Rossi C, De Marco L, Girolami A. Post-DDAVP thrombocytopenia in type 2B von Willebrand disease is not associated with platelet consumption: failure to demonstrate glycocalicin increase or platelet activation. Thromb Haemostasis 1999; 81: 224-8. 45. Gulberg V, Bilzer M, Gerbes AL. Long-term therapy and retreatment of hepatorenal syndrome type I with ornipressin and dopamine. Hepatology 1999; 30: 870-5. 46. Guevera M, Gines P, Fernandez-Esparrach G, Sort P, Salmeron JM, Jimenez W, Arroyo V, Rodes J. Reversibility of hepatorenal syndrome by prolonged administration of omipressin and plasma volume expansion. Hepatulogy 1998; 27: 3541. 47. Rolla D, Cannella G, Ravetti JL. Toxic rhabdomyolysis induced by terlipressin infusion in a uraemic patient suffering from AA-type amyloidosis. Nephron 1999; 83: 167-8.

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Drugs affecting lipid metabolism

Fibrates (SED-14, 1527; SEDA-21, 458; SEDA-22, 490; SEDA-23, 472) Pancreas For the first time pancreatitis has been attributed to bezafibrate. A 75-year-old white woman had fever and raised amylase on three consecutive occasions after taking a tablet of bezafibrate (1n). After stopping the drug, she remained free of symptoms. Museuloskeletal Two women, 55 and 57 years old, with renal insufficiency, had rhabdomyolysis after taking micronized fenofibrate in dosages a little higher than recommended (2A). Notably both had mild hypothyroidism. Low-dose bezafibrate was associated with myositis in a patient with mild chronic renal insufficiency (serum creatinine 210 t~mol/1) (3A). The patient was a 58-year-old obese diabetic with isolated hypertriglyceridernia. Reduced renal function in the elderly appears to be a risk factor for myopathy (SEDA-23, 472).

HMG coenzyme-A reductase inhibitors (SED-14, 1530; SEDA-22; 490; SEDA-23, 472) Nervous system Peripheral neuropathy occurs with statins, perhaps with all cholesterollowering drugs, and may be related to reduced production of ubiquinone, as suggested by a recent review (4AR). Moreover, it appears that once a statin produces a neuropathy, rechallenge with any other statin is likely to cause recurrence of symptoms. This is reported to occur 1-3 weeks after rechallenge, whereas 9 2001 Elsevier Science B.V. All rights reserved.

SideEffectsofDrugs, Annual24 J.K. Aronson, ed. 510

resolution occurs 4-6 weeks after withdrawal (4AR). Altogether 14 cases of neuropathy have now been reported. The last series of seven cases were all axonal peripheral neuropathies and both thick and thin nerve fibers were affected (5AR). No cause of peripheral neuropathy other than statin treatment could be identified. In this series at least four of the cases were irreversible, probably due to long exposure to statins (4-7 years vs 1-2 years in previous reports). Besides an effect on ubiquinone, interference with cholesterol synthesis may alter nerve membrane function, since cholesterol is a ubiquitous component of human cell membranes. Neuropathy has not been observed in extensive long-term trials of lipid-lowering drugs. It could be due to patient selection, a low frequency of the adverse effect, or lack of attention to symptoms of peripheral neuropathy. The observed association may also not be causal. A case-control study on this subject might be informative. With the present level of information, it is prudent to consider withdrawal of statins in patients with symptoms compatible with polyneuropathy.

Metabolism Although the statins seem to be similar in their ability to lower LDL, there are also dissimilarities. For instance, simvastatin increases HDL cholesterol with increasing doses, whereas atorvastatin does not (6R). The clinical significance of this is unknown. Liver Of 224 atorvastatin-treated patients two had clinically significant rises in AlT activity in a comparison of atorvastatin with pravastatin (7c). The two patients recovered during the next 4 months, one after withdrawal of atorvastatin and the other after a dosage reduction. Withdrawals due to adverse effects were similar in the two groups. The overall probability of having an increase in transaminase activ-

Drugs affecting lipidmetabolism

Chapter44

ity above three times the top of the reference range is 0.7% (8R). The probability might be increased in patients with pre-existing minor hepatic changes, as has been seen in one patient with systemic lupus erythematosus (9c). One patient developed hepatitis while taking atorvastatin, but was able to tolerate simvastatin (10A). The authors concluded that this adverse effect was not a class effect. Eosinophils in a liver-biopsy specimen pointed to an immunological mechanism. Skin Adverse effects on the skin are rarely seen, even though statins can affect cutaneous lipid content. Life-threatening toxic epidermal necrolysis in one patient and symptoms diagnosed as porphyria cutanea tarda in another have been described (SEDA-23, 472). In a 54-year-old Chinese man ichthyosiform skin lesions developed during treatment with lovastatin (11A).

Diplopia may be an early sign of drug-induced, generalized muscle dysfunction. Altogether 71 cases of diplopia, possibly related to various HMG-CoA inhibitors, have been collected from adverse drug reactions reporting databases. The information was mostly too scanty to judge a causal relation, but improvement occurred in 33 on withdrawal, and two patients had positive rechallenge data (12R). Exercise-induced muscle pain, without myopathy and a rise in creatine kinase activity, can probably be caused by statins. This has been described in seven cases with heterozygous familial hypercholesterolemia and consisted of pain during exercise and cramps in the following hours (13A). Musculoskeletal

Drug interactions With the exception of fluvastatin and pravastatin, the statins are metabolized by CYP3A4. This and other mechanisms of drug-drug interactions involving statins have been reviewed (14R). Other drugs metabolized by CYP3A4 can greatly enhance statin concentrations in the body and thereby precipitate rhabdomyolysis. Selective inhibition of CYP3A4 or of P-glycoprotein (14R) in the small intestine probably increases the systemic availability of CYP3A4 substrates. CYP3A4 is inhibited by grapefruit juice. Accordingly, serum concentrations of atorvastatin but not pravastatin increased after two days administra-

511 tion of double-strength grapefruit juice 200 ml tds for 2 days (15c). Similarly, diltiazem interacts with lovastatin but not with pravastatin (16c). The azoles, which are liable to cause rhabdomyolysis when taken with statins, now ineludes both ketokonazole and itraconazole and this interaction is described for both lovastatin and simvastatin (17c). Concomitant use of atorvastatin with itraconazole should also be avoided (18c). A 73-year-old woman had rhabdomyolysis, cholestatic hepatitis, and slight renal insufficiency 14 days after starting to take the centrally-acting muscle relaxant chlorzoxazone while taking simvastatin (19A). Withdrawal of the causal medication and conservative therapy with volume substitution and forced diuresis was followed by almost complete resolution of the symptoms. The authors believed that either the two drugs had interacted by metabolism through the same hepatic enzyme, or that chlorzoxazone had caused cholestasis which then increased the blood concentration of simvastatin.

INDIVIDUAL HMG COENZYME-A REDUCTASE INHIBITORS Atorvastatin Drug interactions Atorvastatin, although a substrate of CYP3A4, does not affect blood terfenadine concentrations to a clinically significant degree (20c). Rhabdomyolysis occurred when atorvastatin was combined with ciclosporin for 2 months in a woman with systemic lupus erythematosus and a renal transplant (21A).

Cerivastatin A pooled analysis of studies with at least 8 weeks treatment with cerivastatin 0.1-0.4 mg/day showed no differences in drugrelated adverse events between cedvastatin and placebo (22M). There was no association between plasma transaminase or creatine phosphokinase activities and cerivastatin dosages. A summary of phase 2b/3 studies of this drug has shown a similarity to other statins in hep-

512 atic and renal toxicity. With doses of 0.3-0.4 mg/day after 8 weeks in 349 patients there were no increases in creatine kinase above 10 times the top of the reference range (23R). This agrees with the observation of no cases of myalgia in 94 patients taking cerivastatin 50-300 Ixg/day for 72 weeks, whereas in the same study two of 59 patients taking simvastatin had myalgia (24c). Similar observations are needed with higher doses of cerivastatin. Hitherto cerivastatin has been tested in a dosage of 0.8 mg/day for 4 weeks with only mild and transient adverse effects (25c). Drug interactions Cerivastatin 0.2 mg/day was well tolerated when given together with ciclosporin, although there was a 3- to 5-fold increase in plasma concentrations of the drug and its metabolites. Possibly ciclosporin affected both the distribution and biotransformation of the statin in the liver (26c). Myalgia and a marked increase in creatine kinase was precipitated a 74-year-old woman with normal renal function who took gemfibrozil 1200 mg/day 3 weeks after she had started to take cervastatin 0.3 mg/day (27A). Thus, although cerivastatin is degraded by two different isoforms of P450 in the liver, and so is less liable to be involved in drug interactions than most of the other statins, clinically important interactions can occur.

Fluvastatin Hepatotoxicity has been reported with fluvastatin for the first time. Cholestatic hepatitis developed in a 71-year-old man with nephrotic syndrome (28A). Hepatic function was normal after several months of fluvastatin 20 mg/day. Some weeks after the dose was increased to 40 mg/day, his yglutamyltransferase activity rose from normal to 1818 iu/1, with negative serology for viruses. After normalization, reintroduction of fluvastatin 20 mg/day was not tolerated, but the patient tolerated simvastatin 20 mg/day. Thus, monitoting hepatic function is important, even with fluvastatin. Liver

Pravastatin Endocrine Gynecomastia has not previously been reported with statins, but one patient taking pravastatin 20 mg/day for 3 months re-

Chapter 44

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ported changes that regressed after withdrawal of the drug; he was also taking allupurinol (29A). Mechanisms of liver damage by statins are unknown. Acute cholestatic hepatitis occurred after 7 weeks of pravastatin 20 mg/day. There was no evidence of allergy (30A). It is possible that pravastatin enhances the toxicity of simultaneously administered drugs, as for instance metoprolol in the present case. Liver

Although myopathy is rarely seen with pravastatin in clinical trials, it does occur; rhabdomyolysis was suspected in a 67-year-old obese man with an acute myocardial infarction (31A). A 37-year-old man with sarcoidosis developed marked myotonia during several years while he was taking pravastatin 20 mg/day (32A). On drug withdrawal his symptoms improved after 2 months. This association does not prove a causal relation. The authors pointed to previous observations of myotonia both in sarcoidosis and during the administration of various drugs. Musculoskeletal

Simvastatin (SED-14, 1533; SEDA-23, 474) Musculoskeletal Simvastatin 5 mg/day caused rhabdomyolysis in a 61-year-old man not taking interacting drugs (33A). Thus, all patients should be warned about this potentially serious adverse effect. Drug interactions In a meta-analysis of megatrials with simvastatin, the overall incidence of myopathy was 0.025% (34M). The authors suggested that potent inhibitors of CYP3A4 greatly increase the risk, but weak inhibitors do not. They found the same proportion of patients using calcium antagonists in the group with myositis as the proportion overall, suggesting that there is no important interaction between these two groups of drugs. An interaction with warfarin with resulting acute rhabdomyolysis has been observed in a patient taking simvastatin (35A). This has not been observed with other statins. The authors argued that the INR tends to rise when the two drugs are combined. A reduction in the wafarin dosage follows, and serious rises of simvastatin concentrations are avoided.

Drugs affecting lipid metabolism

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513

REFERENCES 1. Gang N, Langevitz P, Livneh A. Relapsing acute pancreatitis induced by re-exposure to the cholesterol lowering agent bezafibrate. Am J Gastroenterol 1999; 94: 3626-8. 2. Ciouatre Y, Leblanc M, Ouimet D, Pichette V. Fenofibrate-induced rhabdomyolysis in two dialysis patients with hypothyroidism. Nephrol Dial Transplant 1999; 14: 1047-8. 3. Gotsman I, Haviv YS, Nir-Paz R. Low-dose bezafibrate-associated myositis in a patient with chronic renal failure. Clin Drug Invest 1999; 18: 481-3. 4. Ziajka PE, Wehmeier T. Peripheral neuropathy and lipid-lowering therapy. South Med J 1998; 91: 667-8. 5. Jeppesen U, Gaist D, Smith T, Sindrup SH. Statins and peripheral neuropathy. Eur J Clin Pharmacol 1999; 54: 835-8. 6. Mikhailidis DE Wierzbicki AS. HDLcholesterol and the treatment of coronary heart disease: contrasting effects of atorvastatin and simvastatin. Curr Med Res Opin 2000; 16: 13946. 7. Assmann G, Hiiwel D, Schussman K-M, Smilde JG, K6sling M, Withagen AJAM, Wunderlich J, Stoel I, Van Dormaal JJ, Neuss J, et al. Efficacy and safety of atorvastatin and pravastatin in patients with hypercholesterolemia. Eur J Intern Med 1999; 10: 33-9. 8. Black DM, Bakker-Arkema RG, Nawrocki JW. An overview of the clinical safety profile of atorvastatin (Lipitor), a new HMG-CoA reductase inhibitor. Arch Intern Med 1998; 158: 577-84. 9. Jimbnez-Alonso J, Osorio JM, Guti~rrezCabello F, Osa AL, L~on L, Garcia JD. Atorvastatin-induced cholestatic hepatitis in a young woman with systemic lupus erythematosus. Arch Intern Med 1999; 159: 1811-12. 10. Nakad A, Bataille L, Hamoir V, Sempoux C, Horsmans Y. Atorvastatin-induced acute hepatitis with absence of cross-toxicity with simvastatin. Lancet 1999; 353: 1763-4. 11. Park JH, Oh KS, Lee HJ, Whang KU. Ichthyosiform skin eruptions possibly due to lovastatin (Mevacor). Korean J Dermatol 1999; 37: 535-7. 12. Fraunfelder FW, Fraunfelder FT, Edwards R. Diplopia and HMG-CoA reductase inhibitors. J Toxicol Cutaneous Ocul Toxicol 1999; 18: 287-9. 13. Sinzinger H, Schmid E O'Grady J. Two different types of exercise-induced muscle pain without myopathy and CK-elevation during HMG-Coenzyme-A-reductase inhibitor treatment. Atherosclerosis 1999; 143: 459-60. 14. Horsmans Y. Differential metabolism of statins: importance in drug-drug interactions. Eur Heart J Suppl 1999; 1 Suppl T: T7-12. 15. Lilja JJ, KivistO KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999; 66:118-27.

16. Azie NE, Brater DC, Becker PA, Jones DR, HaU SD. The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 1998; 64: 36977. 17. Gilad R, Lampl u Rhabdomyolysis induced by simvastatin and ketoconazole treatment. Clin Neuropharmacol 1999; 22: 295-7. 18. Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64: 58-65. 19. Bielecki JW, Schraner C, Briner V, Kuhn M. Rhabdomyolysis and cholestatic hepatitis under treatment with simvastatin and chlorzoxazone. Schweiz Med Wochenschr 1999; 129: 514-18. 20. Stern RH, Smithers JA, Olson SC. Atorvastatin does not produce a clinically significant effect on the pharmacokinetics of terfenadine. J Clin Pharmacol 1998; 38: 753-7. 21. Maltz HC, Balog DL, Cheigh JS. Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporine. Ann Pharmacother 1999; 33: 1176-9. 22. Stein E, Schopen U, Catagay M. A pooled efficacy analysis of cerivastatin in the treatment of primary hyperlipidaemia. Clin Drug Invest 1999; 18: 433--44. 23. Davignon J, Hanefeld M, Nakaya N, Hunninghake DB, Insull W Jr, Ose L. Clinical efficacy and safety of cerivastatin: Summary of pivotal phase lib/Ill studies. Am J Cardiol 1998; 82: 32J-39J. 24. Leiter LA, Hanna K, Canadian Cerivastatin Study Group. Efficacy and safety of cerivastatin in primary hypercholesterolemia: a long term comparative titration study with simvastatin. Can J Cardiol 1999; 15: 545-55. 25. Stein E, Isaacsohn J, Stoltz R, Mazzu A, Liu MC, Lane C, Heller AH. Pharmacodynamics, safety, tolerability, and pharmacokinetics of the 0.8-mg dose of cerivastatin in patients with primary hypercholesterolemia. Am J Cardiol 1999; 83: 1433-6. 26. Muck W, Mai I, Fritsche L, Ochmann K, Rohde G, Unger S, Johne A, Bauer S, Budde K, Roots I, Neumayer H-H, Kuhlmann J. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Clin Pharmacol Ther 1999; 65:251-61. 27. Pogson GW, Kindred LH, Carper BG. Rhabdomyolysis and renal failure associated with cerivastatin-gemfibrozil combination therapy. Am J Cardiol 1999; 83: 1146. 28. Gascon A, Zabala S, Iglesias E. Acute cholestasis during long-term treatment with fluvastatin in a nephrotic patient. Nephrol Dial Transplant 1999; 14: 1038. 29. Aerts J, Karmochkine M, Raguin G. Gyn6comastie attributable ~ la pravastatine. Presse M6d 1999; 28: 787. 30. Hartleb M, Rymarczyk G, Januszewski K. Acute cholestatic hepatitis associated with pravastatin. Am J Gastroenterol 1999; 94: 1388-90.

514 31. Offman EM, Sabawi N, Melendez LJ. Suspected pravastatin-induced rhabdomyolysis in a patient experiencing a myocardial infarction. Can J Hosp Pharm 1998; 51: 233-5. 32. Riggs JE, Schochet SS Jr. Myotonia associated with sarcoidosis: marked exacerbation with pravastatin. Clin Neuropharmacol 1999; 22: 180-1. 33. Pershad A, Cardello FP. Simvastatin and rhabdomyolysis--a case report and brief review. J

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Pharm Technol 1999; 15: 88-9. 34. Gruer PJ, Vega JM, Mercuri ME Dobrinska MR, Tobert JA. Concomitant use of cytochrome P450 3A4 inhibitors and simastatin. Am J Cardiol 1999; 84: 811-15. 35. Mogyorosi A, Bradley B, Showalter A, Schubert ML. Rhabdomyolysis and acute renal failure due to combination therapy with simvastatin and warfarin. J Intern Med 1999; 246: 599602.

Andrew Stanley

45

Cytostatic drugs

Author'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 an overview of adverse reactions in this field as the Annual gives in others. For this reason, in this chapter I present only salient points that appear to provide entirely new data, or increase the understanding of known but uncommon adverse effects. I have paid particular attention to incidents in which it seems possible to attribute particular effects to individual agents. Because of the methods used to identify adverse effects for inclusion, far fewer potential sources of information have been reviewed; thus, the information in this year's chapter may not be as comprehensive as in some previous years. Finally, I should like to thank those clinicians and researchers who have sent me copies of their original research papers.

Recent good reviews, which have helped in the development of a better understanding of the toxicity profile of either individual drugs or a group of drugs, have dealt with taxanes (1 R) and chemotherapy for advanced hormonerefractory prostrate cancer (2R).

and isosorbide dinitrate 40 mg/day, and after 42 hours into the second cycle had the same chest pain and electrocardiographic changes. These were only controlled by withdrawal of the 5-fluorouracil and the intravenous administration of glyceryl trinitrate.

Cardiovascular Congestive heart failure and cardiomyopathy induced by anthracyclines, and particularly doxorubicin, have been well documented. Of 682 patients, 144 who were over 65 years of age all had doses up to but not exceedin~ the usual cumulative dose for doxorubicin (3'-). The authors concluded that older patients without cardiovascular co-morbidity are at no greater risk of congestive heart failure. The cardiotoxic effects of 5-fluorouracil can result in angina or ischemia. However, some doubt has been cast on this following the failure of both oral nitrates and calcium antagohists to prevent chest pain associated with 5-fluorouracil (4A).

Three patients developed acute cardiopulmonary toxicity after vinorelbine therapy (5A). The symptoms mimicked acute cardiac ischemia but with no electrocardiographic changes or raised cardiac enzymes. In two patients tachypnea, r~les, wheezing, and severe dyspnea responded to inhaled salbutamol. One patient developed pulmonary edema and bilateral pleural effusions, which contained no malignant cells when drained.

About 48 hours after starting her first course of 5-fluorouracil (1000 mg/m2/day) a woman developed anginal chest pain and electrocardiographic changes that eventually normalized. She was readmitted for her second cycle whilst taking amlodipine 10 mg/day 9 2001 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

Nervous system Oxaliplatin, the most recent platinum-containing anticancer drug, seems to cause less neurological toxicity than both cisplatin and carboplatin, with a cumulative incidence of grade 2 peripheral sensory neuropathy of 19% (6c). Sensory systems Transient, non-infectious, crystalline, intrastromal corneal deposits have been reported after subconjuctival administration of 5-fluorouracil (7A). The deposits were treated with corticosteroids and completely resolved in 4 days. SI'~

516

Chapter 45

A 52-year-old patient with glioblastoma developed severe ocular and orbital toxicity after receiving intracarotid etoposide phosphate and carboplatin (8A). Acutely non-pupillary block angle-closure glaucoma developed secondary to uveal effusion in the ipsilateral eye. Four days later, severe orbital inflammation resulted in reduced visual acuity, proptosis, optic neuro-

pathy, and total external ophthalmoplegia. Auditory brainstem responses have been used to detect ototoxicity from cisplatin and carboplatin when used in combination therapy (9c). The method described is capable of detecting early high frequency damage due to these drugs up to two or three cycles earlier than conventional audiometry. Endocrine Hyperosmolar non-ketotic hyperglycemia occurred in a 61-year-old patient 6 days after a first cycle of cisplatin therapy (10A). The patient recovered with conventional conservative management. There have been cases of acute tumor lysis syndrome in patients with melanMetabolism

oma (11Ar ) and light-chain amyloidosis (12At). The authors also reviewed the incidence of acute tumor lysis syndrome in these diseases, which are less typically associated with it. Hematologic The idea that toxicity (the degree of leukocyte suppression) can be used to predict the success of adjuvant chemotherapy has been applied to combined treatment with cyclophosphamide, methotrexate, and 5fluorouracil for breast cancer; the lower the nadir leukocyte count the greater the incidence of metastatic disease-free survival (13). Gastrointestinal

A new scoring system for

AndrewStanley

falls in both glomerular filtration rate to 22 ml/min and serum magnesium concentration to 0.17 mmol/1 (17c). The authors were convinced that the fall in glomerular filtration rate, although statistically significant, was not clinically significant, but they were unsure about the long-term clinical effects of the low magnesium. Whilst hemolytic-uremic syndrome is a well documented if rare adverse effect of mitomycin C, cisplatin, and bleomycin, it had not previously been noted in association with the nucleoside analog gemcitabine. However, a single case has been reported (18A), and after the manufacturers received a further 12 reports they reviewed their database of 78 800 patient exposures, which confirmed that although it is a very rare complication, gemcitabine should be added to the list of causative drugs, with a crude overall incidence rate of 0.015% (19c). Another case of hemolytic-uremic syndrome, this time in association with thrombotic thrombocytopenic purpura, in a patient receiving pentostatin (deoxycoformycin) has been reported after exposure to only 15 mg/m 2 given over 3 days (20A). Skin Leg ulcers occurred in 41 patients taking hydroxyurea (21c). They had a mean age of 67 years and mean therapy duration of 5 years, and none had any underlying vascular disease. There were megaloblastic erythrocytes trapped in the capillary beds, causing local tissue anoxia, and the authors postulated that the megaloblastic erythrocytes had resulted from hydroxyurea and that the ulcers were due to consequent impaired circulation and cutaneous atrophy; they also commented that there was no major vascular disease that could have accounted for the leg ulcers.

mucositis has been proposed and validated (14 C) and multivariate analysis has been used to identify contributory factors (15c). A diagnosis of leukemia, the use of total body irradiation or allogenic transplantation in treatment, or delayed neutrophil recovery were associated with an increased incidence of oral mucositis. It has also been proposed that a change in serum diamine oxidase activity is a very sensitive surrogate for early signs of upper gastrointestinal tract mucositis (16c). Urinary tract During a 2-year follow-up of 23 children receiving carboplatin there were

Musculoskeletal Bone mineral density has been used to help predict which children who have had chemotherapy may subsequently develop osteoporosis (22c). Immunologic There was a 12% incidence rate of hypersensitivity reactions in 205 women who received carboplatin as part of their treatment for gynecological malignancies (23c). In trying to characterize these reactions the authors noted that in about a half of the patients the reaction developed after more than half of their carboplatin had been infused, with a me-

Cytostatic drugs

Chapter 45

dian number of exposures to carboplatin of eight cycles before the reaction. Carcinogenicity The nucleoside analogs fludarabine, pentostatin, and cladribine have not traditionally been associated with secondary malignancies. Long-term follow-up for 5-7.5 years of 2014 patients who had received these agents for chronic lymphoid leukemia and hairy cell leukemia has been reviewed (24R). Of 111 malignancies that were detected, the three most common were lymphoma (25 patients), prostate cancer (19 patients), and lung cancer (15 patients). While these incidences suggested significant additional risks beyond those in the normal population, the authors could not conclude beyond a reasonable doubt that the increased risks were greater than expected. In 550 patients who had taken 6-mercaptopurine 12.5-100 mg/day for up to 22 years for inflammatory bowel disease, 25 had malignancies, but only leukemia/lymphoma rates were greater than expected in this population (25c). While there is a small but well documented risk of endometrial tumors with tamoxifen five cases of carcinoma arising within tamoxifenassociated endometrial polyps have been reported (26A). In four of the five cases there were no other changes in the endometrium.

517 In another study of 604 women who were given six cycles of epimbicin after 4 years of tamoxifen, there were 12 non-breast second malignancies (27c). Although the authors did not analyze these in respect to population expectation, they did believe that the incidence rate was relatively high. The anthracycline idarubicin in combination with etoposide (total doses 180 mg and 5760 mg respectively) have been associated with a case of acute promyelocytic leukemia (28A). What is believed to be the first case of chemotherapy-related myelodysplastic syndrome has been reported in association with adult T cell leukemia (29A).

Pregnancy The FDA has classified cyclophosphamide as a pregnancy risk factor D drug. It is teratogenic in animals, but population studies have not conclusively shown teratogenicity in humans. However, in a study of in utero first trimester exposure to four doses of cyclophosphamide 20 mg/kg it was concluded that cyclophosphamide is a human teratogen, that there is a distinct embryopathic phenotype, and that there are serious doubts about the safety of cyclophosphamide in pregnancy (30c).

REFERENCES 1. Vaishampayan U, Parchment RE, Jasti BR, Hussain M. Taxanes: an overview of the pharmacokinetics and pharmacodynamics. Urology 1999; 54 Suppl 1: 22-9. 2. Petrylak DP. Chemotherapy for advanced hormone refractory prostrate cancer. Urology 1999; 54 Suppl 1: 30-5. 3. Ibrahim NK, Hortobagyi GN, Ewer M, Ali MK, Asmar L, Theriault RL, Fraschini G, Frye DK, Buzdar AU. Doxorubicin-induced congestive heart failure in elderly patients with metastatic breast cancer, with long-term follow-up: the MD Anderson experience. Cancer Chemother Pharmacol 1999; 43: 471-8. 4. Akpek G, Hartshorn KL. Failure of oral nitrate and calcium channel blocker therapy to prevent 5-fluorouracil-related myocardial ischemia: a case report. Cancer Chemother Pharmacol 1999; 43: 157~1. 5. Karminsky N, Merimsly O, Kovner F, Inbar M. Vinorelbine-relatedacute cardiopulmonary toxicity. Cancer Chemother Pharmacol 1999; 43: 180-2.

6. Levi E Zidani R, Brienza S, Dogliotti L, Perpoint B, Rotarski M, Letourneau Y, Llory J-E Chollet P, Le Rol A, Focan C. A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin, 5-fluorouracil and leucovorin as initial treatment of patients with metastatic colorectal carcinoma. Cancer 1999; 85: 2532-40. 7. Rothman RF, Liebmann JM, Ritch R. Noninfectious crystalline keratopathy after postoperative subconjunctival 5-fluorouracil. Am J Ophthaltool 1999; 128: 236-7. 8. Lauer AK, Wobig JL, Shults WT, Neuwelt EA, Wilson MW. Severe ocular and orbital toxicity after intracarotid etoposide phosphate and carboplatin therapy. Am J Ophthalmol 1999; 127: 230-3. 9. De Lauretis A, De Capua B, Barbieri MT, Bellussi L, Passali D. ABR evaluation of ototoxicity in cancer patients receiving cisplatin carboplatin. Scand Audiol 1999; 28: 139-43. 10. SakakuraC, Hagiware A, Kin S, Yamamoto K, Okamoto K, Yamaguchi T, Sawai K, Yamagishi H. A case of hyperosmolar nonketotic coma oc-

518 cutting during chemotherapy using cisplatin for gallbladder cancer. Hepato-Gastroenterology 1999; 46: 2801-3. 11. Castro MP, Van Auken J, Spencer-Cisek P, Legha S, Sponzo RW. Acute tumour lysis syndrome associated with concurrent biochemotherapy of metastatic melanoma: a case report and review of the literature. Cancer 1999; 85: 1055-9. 12. Akasheh MS, Chang CP, Vesole DH. Acute tumour lysis syndrome: a case in AL amyloidosis. Br J Haematol 1999; 107: 386--7. 13. Poikonen P, Saarto T, Lundin J, Joensuu H, Blomqvist C. Leucocyte nadir as a marker for chemotherapy efficacy in node-positive breast cancer treated with adjuvant CME Br J Cancer 1999; 80: 1763-6. 14. Sonis ST, Ellers JP, Epstein JB, LeVeque FG, Liggett WH, Mulagha MT, Peterson DE, Rose AH, Schubert MM, Spijkervet FK, Wittes JP. Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Cancer 1999; 85: 2103-13. 15. Rapoport AP, Watelet LFM, Linder T, Eberly S, Raubertas RF, Lipp J, Duerst R, Abboud CN, Constine L, Andrews J, Etter M, Spear L, Powley E, Packman C, Rowe J, Schwertschlag U, Bedrosian C, Liesveld J. Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants. J Clin Oncol 1999; 17: 2446-53. 16. Tsujikawa T, Uda K, Ihara T, Inoue T, Andoh A, Fujiyama Y, Bamba T. Changes in serum diamine oxidase activity during chemotherapy in patients with haematological malignancies. Cancer Lett 1999; 147: 195-8. 17. English MW, Skinner R, Pearson ADJ, Price L, Wyllie R, Craft AW. Dose-related nephrotoxicity of carboplatin in children. Br J Cancer 1999; 81: 336-41. 18. Serke S, Riess H, Oettle H, Huhn D. Elevated reticulocyte count--a clue to the diagnosis of haemolytic-uraemic syndrome (HUS) associated with gemcitabine therapy for metastatic duodenal papillary carcinoma: a case report. Br J Cancer 1999; 79: 1519-21. 19. Fung MC, Storniolo AM, Nguyen B, Aming M, Brookfield W, Vigil J. A review of haemolytic uremic syndrome in patients treated with gemcitabine therapy. Cancer 1999; 85: 2023-32. 20. Leach JW, Pham T, Diamandidis D, George JN. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) following treatment

Chapter 45

Andrew Stanley

with deoxycoformycin in a patient with cutaneous T-cell lymphoma (Sezary syndrome): a case report. Am J Hematol 1999; 61: 268-70. 21. Sirieix M-E, Debure C, Baudot N, Dubertret L, Roux M-E, Morel P, Frances C, Loubeyres S, Beylot C, Lambert D, Humbert P, Ganthier O, Dandurand M, Guillot B, Vaillant L, Lorettte G, Bonnetblanc J-M, Lok C, Denoeux J-P. Leg ulcers and hydroxyurea: forty-one cases. Arch Dermatol 1999; 135: 818-20. 22. Arikoski P, Komulainen J, Riikonen P, Jurvelin JS, Voutilainen R, Kroger H. Reduced bone density at completion of chemotherapy for a malignancy. Arch Dis Child 1999; 80: 143-8. 23. Markman M, Kennedy A, Webster K, Elson P, Peterson G, Kulp B, Belinson J. Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol 1999; 17: 1141-5. 24. Cheson BD, Vena DA, Barrett J, Freidlin B. Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukaemia. J Clin Oncol 1999; 17: 2454-60. 25. Korelitz BI, Mirsky FJ, Fleisher MR, Warman JI, Wisch N, Gleim GW. Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine. Am J Gastroenterol 1999; 94: 3248-53. 26. Ramondetta LM, Sherwood JB, Dunton C J, Palazzo JP. Endometrial cancer in polyps associated with tamoxifen use. Am J Obstet Gynecol 1999; 180: 340-1. 27. Wils JA, Bliss JM, Marty M, Coombes G, Fontaine C, Morvan F, Olmos T, Perez-Lopez FR, Vassilopoulos P, Woods E, Coombes RC. Epirubicin plus tamoxifen versus tamoxifen alone in node-positive postmenopausal patients with breast cancer: a randomised trial of the International Collaborative Cancer Group. J Clin Oncol 1999; 17: 1988-98. 28. De Renzo A, Santoro LFE, Notaro R, Pane F, Buonaiuto MR, Luciano L, Rotoli B. Acute promyelocytic leukaemia after treatment for nonHodgkin's lymphoma with drugs targeting topoisomerase II. Am J Hematol 1999; 60: 300-4. 29. Kawabata H, Utsunomiya A, Hanada S, Makino T, Takatsuka Y, Takeuchi S, Susuki S, Suzumiya J, Ohshima K, Horiike S. Myelodysplastic syndrome in a patient with adult T-cell leukaemia. Br J Haematol 1999; 106: 702-5. 30. Enns GM, Roeder E, Chan RT, Catts ZA, Cox VA, Golabi M. Apparent cyclophosphamide (Cytoxan) embryopathy: a distinct phenotype? Am J Med Genet 1999; 86: 237-41.

Sameh K. Morcos and Peter Brown

46

Radiological contrast agents

Iodinated water-soluble contrast media are of four types: 9 9 9 9

high-osmolar ionic monomers; low-osmolar ionic dimers; low-osmolar non-ionic monomers; iso-osmolar non-ionic dimers.

They are mainly administered intravascularly but can also be given orally for opacification of the gastrointestinal tract, and some, such as Gastrografin, are suitable only for oral or rectal administration. There are also contrast agents that enhance the diagnostic information provided by ultrasound imaging and magnetic resonance imaging (MRI); these are mainly gadolinium-based, but new non-gadolinium paramagnetic contrast agents have recently become available for clinical use. Barium sulfate formulations are widely used for imaging the gastrointestinal tract. Adverse reactions to all types of contrast media are generally few, and serious reactions are uncommon. Ultrasound contrast agents, which are microbubbles that provide acoustic enhancement, are extremely safe.

INTRAVASCULAR IODINATED CONTRAST AGENTS (SED-14, 1596; SEDA-21, 476; SEDA-22, 498; SEDA-23, 494) of acute reactions Adverse reactions to the intravascular use of iodinated agents are usually classified into minor, intermediate, or severe life-threatening. All types of reactions to low-osmolar contrast media are five times less common than reactions to highosmolar contrast agents. However, there is no significant difference in the incidence of deaths Incidence

9 20Ol Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

between the low-osmolar and high-osmolar agents (SEDA-22, 489; SEDA-23, 494). An analysis of adverse reactions associated with drugs in Poland (1997-1998) has shown that 11.5% of these reactions were due to radiographic contrast media. People aged 36455 were the largest group to have adverse drug reactions (1c). In 1798 Indian patients the prevalence of adverse reactions to high-osmolar ionic iodinated contrast media was 21% (mild 19%, moderate 1.3%, and severe 0.3%) and there was only one death. The incidence of adverse effects was significantly higher in patients with risk factors, such as a history of previous contrast reactions (46%), bronchial asthma (69%), and diabetes mellitus (60%), compared with patients with no risk factors (21%). The authors tried to throw some light on the relation between race and incidence of contrast reactions. They showed that the incidence of mild reactions in the Indian patients (19%) was significantly higher than reported in white patients (5-15%) but that there was no difference in the incidence of moderate or severe reactions between the two populations (2c). A previous study has shown that the incidence of contrast reactions amongst patients of Indian origin in the UK was significantly higher than in the endogenous white population with an 8-fold increase in severe reactions (3c). There was also a significant increase in the incidence of reactions amongst patients of Mediterranean origin, but to a lesser degree. There is no clear explanation for racial differences in the incidences of contrast reactions. Hypotension has been reported after the administration of an iodinated contrast medium (4c). Cardiovascular

A 44-year-old man had a CT scan of the head with intravenous contrast enhancement (35 ml of ioversol 350). He developed severe back pain 90 minutes later and then became acutely unwell with R1Q

520 nausea, vomiting, chills, tremor, and faintness. He rapidly became shocked (systolic blood pressure 80 mmHg, pulse 140 beats per minute) and had a petechial rash over the trunk and upper limbs. He was given intravenous fluids (polygeline 2 1 and crystalloid 2 1) and adrenaline. Blood cultures were negative, and echocardiography, CT scan of the chest and abdomen, and abdominal ultrasound were normal. He continued to deteriorate, developed acute renal insufficiency with disseminated intravascular coagulation, and was given dopamine, aggressive fluid resuscitation, and antibiotics (gentamicin, ceftriaxone, and erythromycin). His general condition gradually improved and he recovered fully. The authors attributed these events to a severe delayed reaction to the contrast medium, manifesting as prolonged hypotension. Iodixanol (a non-ionic dimer, 320 mg of iodine per ml) and ioxaglate 320 (a low-osmolar ionic dimer, 320 mg of iodine per ml) have been compared in a randomized study in 110 consecutive patients referred for coronary angiography and ventriculography (5c). The incidence of adverse reactions was significantly higher with ioxaglate (28% vs 3%) but there was no difference in angiographic quality between the two agents. The increase in left ventricular enddiastolic pressure was significantly less with iodixanol than ioxaglate. The QT interval was significantly prolonged by both agents, but the changes were less marked after iodixanol. The authors concluded that iodixanol and ioxaglate are of comparable diagnostic efficacy in coronary angiography and ventriculography but that iodixanol is better tolerated and has less marked hemodynamic and electrophysiological effects. The hemodynamic effect of direct intraarterial injection of contrast agents on capillary perfusion in man has been investigated (6c). This was achieved through continuous recording of peffusion in the nail-fold capillaries of the fight hand before and after a bolus injection of 20 ml of iodixanol 270 (a non-ionic dimer) or iopentol 150 (a non-ionic monomer) into the fight axillary artery. The high-viscosity contrast agent iodixanol (5.8 mPa/sec) caused a significant reduction in erythrocyte velocity, while iopentol, which has a much lower viscosity (1.7 mPa/sec), had no effect. The authors concluded that high-viscosity contrast media can cause reduced organ perfusion. This effect could be significant in patients with atherosclerotic disease, as it might lead to reduced perfusion of the myocardium during coronary angiography.

Chapter 46

Sameh K. Morcos and Peter Brown

Although it is now widely acknowledged that low-osmolar non-ionic contrast media are better tolerated than high-osmolar ionic media, the choice of contrast agent does not affect the early results of percutaneous transluminal coronary angioplasty (7c). However, the authors acknowledged that high-osmolar ionic agents carry higher risks of acute left ventricular failure. They retrospectively reviewed 401 patients who underwent percutaneous transluminal coronary angioplasty, 220 of whom received high-osmolar ionic media and 181 low-osmolar non-ionic contrast media. Acute left ventricular failure occurred more often in the high-osmolar group (1.4% vs 0%). There were no differences in the incidences of acute myocardial infarction (3.3% in each group) or urgent surgical intervention (0.5% with the high-osmolar agents and 0.6% with the lowosmolar non-ionic media). There were two cases of mild and transient central nervous system complications (loss o f orientation and transient hemiparesis) with the high-osmolar contrast media. The authors concluded that in the majority of cases the type of contrast medium used does not influence the early results of percutaneous transluminal coronary angioplasty in relation to its efficacy, the degree of revascularization, and residual narrowing. However, they acknowledged that the use of high-osmolar ionic media increases the risk of acute left ventricular failure after angioplasty. They attributed the finding that non-ionic contrast media increased the risk of abrupt vessel closure (4.5% vs 1.5%) to intravascular clotting. The suggestion that non-ionic agents are procoagulant is contentious, and there is no conclusive evidence to support this view (SEDA-22, 501). R e s p i r a t o r y Life-threatening adult respiratory distress syndrome after intravascular radiographic contrast injection is a rare complication, only five cases having been previously described. It has been successfully managed by extracorporeal membrane oxygenation (8A). A 62-year-old man developed adult respiratory distress syndrome 5 minutes after receiving a lowosmolar ionic contrast medium (140 ml of ioxaglate 200) during coronary angiography. His respiratory rate was 35 per minute, blood pressure 60/40 mmHg, pulse rate 125 beats/minute, Pat2 49 mmHg, main pulmonary artery pressure 21 mmHg, central venous pressure 9 mmHg, and pulmonary capillary pressure 10 mmHg. A chest X-ray showed pulmonary ed-

Radiological contrast agents

Chapter 46

ema. Laboratory investigations, electrocardiography, echocardiography, and coronary angiography were normal. In view of life-threatening hypoxia, extracorporeal membrane oxygenation was given for 50 hours and 2 weeks later he was discharged without pulmonary symptoms.

Nervous system Tolerance of non-ionic contrast media in myelography has been well documented (SEDA-22, 500). A report from India has documented the safety and diagnostic efficacy of the non-ionic monomer iohexol 7-10 ml (300 mg of iodine per ml) injected into the subarachnoid space in 25 patients (9c). Only three patients developed minor adverse effects--headache and paresthesia in the legs. The risk of neurological complications after cerebral angiography is 0.55-3.2% but increases to 10% in patients with symptomatic carotid stenosis; the incidence of clinically silent cerebral embolism is unknown. Diffusionweighted magnetic resonance imaging before and after cerebral angiography has been carded out to assess the prevalence of embolic events in 100 consecutive angiographies in 91 patients (10C). The patients underwent neurological assessment before, immediately after, and 1 day after angiography. There were 42 bright lesions in 23 patients after 23 procedures in a pattern consistent with embolic events. There were no new neurological deficits after any angiographic procedure. The frequency of lesions correlated significantly with a history of atherosclerotic arterial disease, the complexity of the angiographic procedure, and the amount of contrast medium used. The authors concluded that after diagnostic and interventional cerebral angiography embolic events are more frequent than the neurological complication rate. The incidence of embolism is closely related to the vascular risk profile.

Psychiatric Visual hallucinations are very rare adverse effects of contrast media, with isolated reports after vertebral angiography or myelography. The mechanism of this adverse reaction could be similar to that reported in transient cortical blindness after infusion of contrast media. However, other possibilities include a toxic effect of contrast media on the optic nerve, transient impairment of cerebral blood flow, which could be mediated through the release of the potent vastconstrictor endothelin, or the formation of microclots. Two cases of visual hallucinations

521 after coronary angiography have been reported (llA). A 70-year-old woman with a history of mastectomy developed syncope which lasted a few seconds. She had taken tamoxifen 10 mg bd for 10 years and had no history of allergic reactions. Doppler ultrasound showed aortic stenosis and coronary angiography was performed using 150 ml of iopromide (a non-ionic contrast medium, 370 mg of iodine per ml). She had visual hallucinations (spiders on the wall, moving curtains) 30 minutes after the injection of iopromide. The symptoms resolved 72 hours later without any specific treatment. Neurological and psychiatric examinations were normal, as were brain MRI and Doppler ultrasound of the carotid and vertebral arteries. A 64-year-old man with a history of ischemic heart disease underwent coronary angiography with 150 ml of iopromide (370 mg of iodine per ml). One hour later he had visual hallucinations (moving objects, pictures of familiar persons), which resolved about 40 hours later without any treatment. He had taken the following drugs for a year: nifedipine 10 mg tds, metoprolol 50 mg bd, and aspirin 325 mg/day. His serum creatinine concentration was in the reference range and there was no history of allergies or previous exposure to contrast media.

Sensory systems Transient cortical blindness due to non-ionic low-osmolar media is rare (SEDA-23, 497), but it has been reported again (12A). A 29-year-old man had a subarachnoid hemorrhage due to an arteriovenous malformation, which was embolized. During the procedure he suddenly lost consciousness, regained it 15 minutes later, but complained of total blindness. Cerebral angiography showed no arteriovenous malformation and no abnormality in the vertebrobasilar system. CT scan of the head showed considerable contrast enhancement of the occipital lobes and 2 hours later the contrast had cleared. An MR/scan 12 hours later showed no evidence of infarction in the occipital lobes. Two days later his sight gradually returned and 7 days later he had completely recovered. The authors thought that these adverse effects were probably due to the contrast medium. Disruption of the blood-brain barrier is a factor in the pathophysiology of this complication. U r i n a r y tract In patients who have received iodinated contrast media urinary fl2microglobulin, albumin, epidermal growth factor, y-glutamyltranspeptidase, and N-acetylfl-D-glucosaminidase, and serum angiotensinconverting enzyme (ACE) activity are sensitive

522 markers for the early detection of subclinical contrast medium-induced neph rotoxicity (13 C). At 24 hours after injection of contrast media in 16 patients (aged 18-62 years, nine men), serum ACE and urinary fl2-microglobulin, albumin, and enzymes were significantly raised. At 48 hours, serum creatinine concentrations increased significantly and urinary excretion of albumin remained significantly increased, but urinary enzyme excretion began to recover. Urinary excretion of epidermal growth factor was significantly reduced, due to tubular injury; healthy tubular cells release this factor into the urine and it is not filtered at the glomeruli. The observation that urinary albumin excretion continued to increase after the urinary enzymes started to recover suggests that the albuminuria induced by contrast media is probably due to glomerular and not tubular dysfunction. The mechanism of the rise in serum ACE activity is not known, but it may be due to damage to the vascular endothelial cells of glomeruli, ACE release from the brush borders of the epithelial cells of the proximal tubules, or an increase in vascular permeability and leakage of the enzyme into the blood. The renal effects of iodixanol 40-100 ml and iohexol 42-I02 ml have been compared in 116 patients undergoing renal and/or peripheral angiography (14c). The two groups had the same baseline renal function and prevalence of diabetes. The serum creatinine rose by more than 10% in 15% of the patients given iodixanol and in 31% of the patients given iohexol, and by more than 25% in 3.7% of the patients given iodixanol and in 10% of the patients given iohexol during the week after angiography. There was a correlation between the dose of contrast medium and the change in serum creatinine in both groups. These results suggest that iodixanol may be slightly less nephrotoxic than iohexol. However, previous reports have failed to show a significant difference between the non-ionic dimers and non-ionic monomers in relation to renal tolerance. The authors suggested that factors other than contrast media may have contributed to the rise in serum creatinine in some of their patients. Skin The incidence of skin reactions to drugs has been analyzed from spontaneous reports in Italy (15CR). Antibiotics most commonly caused skin reactions, followed by nonsteroidal anti-inflammatory drugs, analgesics,

Chapter 46

Sameh K. Morcos and Peter Brown

and radiocontrast media, which were responsible for 2.7% of the reactions (71 cases); these included nine cases of exanthems and 36 cases of urticaria. Fixed drug eruption caused by non-ionic contrast media is rare (SEDA-22, 502), but has been attributed to the non-ionic contrast medium iomeprol (Iomerone, Bracco) (16AR). A 67-year-old Japanese woman developed multiple pea-sized erythematous plaques on the trunk and extremities 4 days after receiving 100 ml of iomeprol intravenously for a CT scan. It was treated with oral fl-methasone 1.5 mg/day and ghitathione 300 mg/day for 3 days. She then used topical /~methasone valerate ointment for a month until the erythematous plaques completely disappeared, leaving pigmentation. Six months later she was erroneously given 100 ml of iomeprol intravenously during a CT scan and the next morning developed erythematous plaques mixed with vesicles at the same sites as before. Biopsy showed histological changes compatible with a fixed drug eruption. In addition, both patch testing and intradermal testing were positive to iomeprol. This report shows that non-ionic contrast media can cause multiple fixed eruptions and that repeated administration of the causative agent can be associated with a more severe eruption. Iododerma can occur after the administration of iodinated contrast media and causes a papulopustular eruption. Vegetating iododerma, in which pustules and vesicles coalesce to form large vegetating masses that later ulcerate, is very rare and its pathogenesis is unclear. A cell-mediated immune reaction, an inflammatory mechanism, and an idiosyncratic reaction in patients with other underlying diseases have been suggested. Iododerma occurs more often in patients with renal insufficiency, because of impaired clearance of contrast media. Oral or topical corticosteroids have been of some benefit in treating this condition~ A case of vegetating iododerma with a fatal outcome has been reported (17c). A 65-year-old woman with a history of allergy to penicillin and abnormal renal function had cardiac angiography and a week later became breathless and slightly febrile and developed pustulovesicular lesions on the face, elbows, and legs. The lesions on the face coalesced into vegetating masses. Cultures from the skin lesions did not yield bacteria, fungi, or mycobacteria. Histological examination of the vegetating mass showed an inflammatory exophytic

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lesion with an ulcerated surface and an inflammatory infiltrate consisting mainly of neutrophils and eosinophils in the dermis. The lesions responded to 1:1000 copper sulfate solution. However, she continued to deteriorate despite hemodialysis and died 6 days later. In this patient renal insufficiency contributed to the development of iododerma and her death was due to poor cardiorespiratory function. Delayed reactions to intravascular contrast media have received interest over the last decade, particularly the allergic-like skin reactions that develop 24-96 hours after administration (18A). A 73-year-old woman underwent CT scanning with contrast enhancement (250 ml of intravenous iopentol, a non-ionic contrast medium, 300 mg of iodine per ml) for staging a malignant melanoma. Four days later she developed progressive pruritus beginning on the back and neck. On the sixth day she had a disseminated pruriginous papular partially confluent rash involving the trunk, neck, and proximal extremities. The eruption became generalized while she was receiving local corticosteroids and oral clemastine. Remission of the eruption was achieved with intravenous prednisolone 64 mg and dimethindene maleate 12 mg. Patch and intracutaneous tests to iopentol, but not to other contrast media, evoked a red indurated skin reaction after 48 and 72 hours. Histology and immunocytochemistry of the skin test site to iopentol showed an infiltrate consisting mainly of CD45RO+ and CD4+ lymphocytes together with eosinophils. This reaction shared the features of a delayed hypersensitivity reaction (exanthematous rash, positive patch test) and of a late phase reaction (CD4+ lymphocytic infiltrate together with eosinophils). The authors emphasized the importance of skin testing in the diagnosis of delayed skin reactions to contrast media. Three further cases of delayed skin reactions have been reported. A 64-year-old woman with a history of an exanthematous skin eruption to an antibiotic and allopurinol had had a previous adverse reaction after angiography with radiographic contrast media. Her symptoms had included shivering and a generalized pruritic exanthema. Then, 30 minutes after intravenous angiography with iopromide (a non-ionic contrast medium), she developed shivering and dyspnea immediately followed by loss of consciousness; 3 hours later a generalized pruritic maculopapular rash developed.

523 A 63-year-old woman with glomerulonephritis underwent angiography. She had a history of an immediate adverse reaction to lidocaine and of dyspnea, wheeze, and paresthesia of the fingers to repeated infusion of contrast media. Several hours after the last procedure she developed a generalized prufiginous maculopapular rash. A 60-year-old man underwent coronary angiography with iopamidol 200 ml. One day later he developed infiltrated erythema of the face with a generalized maculopapular rash. The skin symptoms receded within 1 week after treatment with a corticosteroid ointment. Coronary angiography with iopamidol was repeated 3 years later and again within 1 day a maculopapular rash developed and regressed within a few days with intravenous dimethindene and prednisolone-21-hydrogen succinate. Intracutaneous and patch tests were performed in the first two patients (19 A) with a series of ionic and non-ionic contrast media in concentrations of 1% according to international guidelines. In the first patient there were late positive intracutaneous and patch tests after 2 4 48 hours only to some of the tested contrast agents. In the second patient intracutaneous and patch tests showed late reactions to nearly the same contrast media. More than 20 patients with only immediate anaphylactoid reactions to contrast media gave negative results to these tests. The authors concluded that positive skin tests suggest an immunological basis for late reactions to contrast media. In the third case (20 A) patch and prick skin tests were performed using several iodinated contrast media. Intravenous provocation tests were also performed with several water-soluble contrast media using 5 ml in each case at strengths of 1:1000, 1:100, 1:10, and undiluted. Positive skin tests were observed with iopamidol, and the intravenous provocation test caused infiltrated erythema of the face and generalized maculopapular rashes. Skin biopsies showed heavy lymphohistiocytic infiltration at the site of positive skin tests. The authors concluded that the rashes represented delayed allergy to iopamidol. I m m u n o l o g i c A life-threatening anaphylactoid reaction occurred in a child after intravenous administration of a non-ionic contrast medium (ioversol) (21A). A 3-year-old girl was investigated for hypertension and a renal arteriogram was performed. Her blood pressure before the study was 125/60 mmHg. She received 30 ml of ioversol (320 mg of iodine per ml). Within 30 seconds she developed tachycar-

524 dia (200 beats per minute) and hypotension (60/20 mmHg). She developed diffuse urticaria over her entire body and there was wheezing on auscultation. Cardiopulmonary resuscitation was begun and she received a saline infusion and adrenaline 1:1000 subcutaneously, 0.01 ml/kg, intravenous diphenhydramine 1 mg/kg, and intravenous hydrocortisone 5 mg/kg. She responded rapidly. Surprisingly, the authors thought that the contrast medium had not caused this response, and the patient was subsequently given a second injection of ioversol 320 in a dose of 1 ml/kg. Within 60 seconds she again became tachycardic and hypotensive and urticaria reappeared over the whole body with wheezing. Similar treatment was offered and she responded rapidly. The authors claimed that this was the first case report of anaphylactoid shock after the administration of ioversol in a child. A fatal anaphylactoid reaction to an intravenous non-ionic contrast medium occurred during a CT scan (22A). The authors highlighted the value of measuring serum tryptase in the diagnosis of anaphylactoid reactions. An 81-year-old man underwent CT scanning of the head with intravenous contrast enhancement (100 ml of the non-ionic contrast medium iopamidol). After the injection he complained of sweating and nausea and had a cardiorespiratory arrest. Immediate resuscitation and intravenous dexamethasone and adrenaline was not successful. Mast cell tryptase activity in a sample taken 4 hours after death was high. At autopsy, the coronary and pulmonary arteries were patent. The right heart chambers were moderately enlarged. The lungs were hyperemic and edematous and there was obstructive edema of the larynx. This patient showed all the features of anaphylactoid reactions, which include pulmonary and laryngeal edema and a massive rise in serum tryptase. The half-life of tryptase is about 2 hours. Moderately raised post-mortem tryptase activity in the absence of anaphylaxis has been described. Therefore, only very high serum tryptase activity, as seen in this case, should be regarded as specific for fatal anaphylactoid reactions. Risk factors A high incidence of histamine release and anaphylactoid reactions to contrast media has recently been reported in 130 patients with malignant tumors (23c). Patients with malignant tumors were randomized into two groups. One group (n = 66) received non-ionic low-osmolar contrast media (iopamidol) and the other (n = 64) received high-osmolar ionic

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contrast media (ioxithalamate). An average of 100 ml of contrast medium (range 60-140 ml) was given before CT scanning in both groups. The incidence of reactions (tachycardia, bradycardia, hypertension and hypotension, a fall in oxygen saturation, nausea, vomiting, headache, and skin reactions) was similarly high in both groups (58% with iopamidol and 42% with ioxithalamate). The increases in plasma histamine concentrations were also similar: median 0.43 (range 0-13) ng/ml with iopamidol and 0.15 (0-12) ng/ml.with ioxithalamate. The authors concluded that patients with malignancies are at risk of histamine-associated contrast reactions and suggested that antihistamine prophylaxis with histamine H1 and H2 receptor antagonists should be considered in these patients. However, there is no conclusive evidence that antihistamines offer effective prophylaxis against contrast reactions.

ENTERAL RADIOCONTRAST MEDIA Barium formulations Respiratory Aspiration of barium sulfate into the lungs during barium meal examination can cause significant respiratory embarrassment, particularly in patients with poor respiratory function. It is now recommended that watersoluble low-osmolar contrast media, which are less harmful, should be used instead of barium if there is a possibility of aspiration during examination of the upper gastrointestinal tract. Aspiration of barium sulfate can cause obstruction of the small air passages, compromising respiratory function, and can cause inflammation in the bronchial tree and lung parenchyma (24A). A 68-year-old woman with a history of alcohol abuse and a leiomyoma of the stomach aspirated barium sulfate and became dyspneic and developed hypoxia (PaO2 46 mmHg). At bronchoscopy the bronchial mucosa was coated with barium and a chest X-ray showed heavy alveolar deposition of barium sulfate distributed over the entire lung, with some predominance in the lower zones. The patient developed a fever (39~ C) and a leukocytosis (12 x 109/1) the day after aspiration. She was given cefotiam 2000 mg and metronidazole 500 mg intravenously every 8 hours. The fever resolved within 2 days and Staphylococcus aureus was cultured from

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the bronchial fluid. She was discharged 2 days later but the chest X-ray continued to show persistent alveolar deposition of the barium sulfate with only a slight improvement compared with the initial X-ray. A 60-year-old man with carcinoma of the hypopharynx aspirated barium into both lower lobes. He became hypoxic (Pat2 64 mmHg) and barium was extracted at bronchoscopy. He was given prophylactic antibiotics (cefotiam 2000 mg and metronidazole 500 mg intravenously every 8 hours for 4 days). A chest X-ray 6 days later showed residual barium deposition in the lower lobes. No further respiratory complications occurred. The authors recommended that bronchoscopy should be performed early after aspiration to extract barium from the bronchial tree, and that prophylactic antibiotic therapy is important to prevent lung infection. Gastrointestinal Baroliths are rare complications of barium contrast examinations and usually seen in colonic diverticula. They are often asymptomatic but may be associated with abdominal pain, appendicitis, and bowel obstruction or perforation. A case of ileal obstruction by a barolith has been reported (25AR). An 83-year-old woman developed postprandial abdominal pain. Physical examination and laboratory tests were normal. She underwent gastroscopy, abdominal ultrasound, small bowel barium meal, and a double-contrast barium enema, all of which were normal, although a moderate amount of barium refluxed into the small bowel during the double-contrast examination. She continued to have postprandial abdominal pain and weight loss. A repeat abdominal X-ray 6 months after the barium enema showed an unremarkable bowel gas pattern without evidence of obstruction. However, there was a 4.5-cm triangular radio-opaque structure in the right lower quadrant, consistent with retained barium possibly in a diverticulum. A small bowel barium meal showed that the retained barium was intralluminal within a loop of ileum. At laparotomy a hardened short segment of ileum was resected and histology showed an intraluminal barolith adjacent to a carcinoid tumor. In this case narrowing of a loop of ileum secondary to a carcinoid tumor caused interference with the flow of barium and caused the development of a barolith.

525

Systemic adverse effects of enteral contrast media Oral radiographic contrast media can intravasate during gastrointestinal examination. Septicemia has been reported (26A). A 46-year-old patient developed ischemic necrosis of the small bowel complicating mesenteric volvulus. Small bowel resection was carried out and ileal and jejunal stomas were established. Six weeks after the operation Gastrografin was given through the jejunal stoma. A mesenteric vein fiUed with Gastrografin and this was followed by rapid washout of the intravascular contrast medium. The examination was stopped immediately and 60 minutes later the patient developed chills and a high fever. Hemodynamic instability required the use of vasoactive drugs and infusion of isotonic solutions. Blood cultures grew Escherichia coli, Pseudomonas aeruginosa, and Enterobacter spp. Treatment included imipenem and after 48 hours the patient was stable and the vastactive agents were stopped. Endoscopy through the jejunal stoma showed multiple stenoses, which required surgical treatment, and the jejunum in the area of intravasation was resected. Gram negative septicemia possibly related to oral Gastrografin has also been reported in a premature neonate with necrotizing enterocolitis (27 a ). A baby born after 26 weeks of gestation received oral Gastrografin (0.5 ml 8 hourly)for gut stimulation. Three days after the last dose of Gastrografin there was sudden clinical deterioration leading to shock. Blood cultures grew Enterobacter. Progressive deterioration continued to occur, with multisystem failure, leading to death. Autopsy was not performed. The authors suggested that the high osmolality o f Gastrografin may have aggravated the pre-existing mucosal injury in the gastrointestinal tract, leading to complete loss o f mucosal integrity and an increase in gut permeability to micro-organisms and toxins. Oral Gastrografin and other hyperosmolar contrast media should not be used in patients, particularly neonates, with compromised bowel integrity, since the high osmolarity may aggravate the bowel injury. Low-osmolar contrast media should always be used in such patients. Disseminated intravascular coagulation and severe hypotension have been documented after intravenous administration o f Gastrografin (a high-osmolar water-soluble contrast medium used f o r imaging the gastrointest-

526 inal tract and suitable only f o r oral or rectal administration) (26A). Barium intravasation after enema examination has also been reported and can be associated with a 55% mortality. The amount and speed o f intravasation o f the contrast medium as well as the site o f the intravasation and the general health o f the patient determine the outcome o f this complication. Low-osmolar water soluble contrast media should be used in preference to Gastrografin or barium formulations in patients with suspected compromise of bowel wall integrity.

ALTERNATIVES TO IODINATED CONTRAST AGENTS Carbon dioxide Carbon dioxide (CO2), a highly soluble gas, has been used in a number of centers around the world as an alternative to iodinated contrast agents for angiographic examination and acts as a negative contrast agent (SEDA-20, 423). In a UK study the safety and diagnostic efficacy of carbon dioxide as an arterial contrast agent have been investigated in 63 patients (36 men and 27 women, aged 46-86 years) who underwent angiographic examinations with CO2 via an automated injector and iodinated contrast medium (28CR). There were adverse effects in 15 patients, including nausea (four patients), abdominal pain (eight patients), and leg and groin pain (eight patients). All the symptoms were directly related to the injection of CO2 and resolved within a minute or two of injection. No arteriogram had to be abandoned because of adverse effects, and the incidence of adverse reactions was less with selective studies. Although it has been reported that CO2 is well tolerated with minimal discomfort, in this study there was a variety of mild to severe unpleasant symptoms, but no serious complications. The abdominal symptoms were related to the passage of a large volume of CO2 into the mesenteric vessels. The catheter was above the mesenteric vessels in most of the patients with abdominal symptoms. These symptoms can be reduced by placing the tip of the catheter in non-selective studies at the aortic bifurcation to reduce the amount of CO2 that passes into the superior or inferior mesenteric arteries. The

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symptoms are also reduced by injecting smaller volumes. The authors concluded that when iodinated contrast media are contraindicated CO2 provides a diagnostic alternative.

Xenon Xenon-enhanced CT scanning is becoming a valuable diagnostic tool in functional neuroimaging (29CR). It is based on the use of stable xenon gas, which is radiodense and lipidsoluble, as an inhaled, contrast agent. The patient inhales a mixture of xenon, usually 2633%, and oxygen for several minutes via a face mask. The inhaled xenon dissolves in the blood and passes into the brain parenchyma. CT scans can be acquired before, during, and after inhalation. The new fast spiral CT system has improved the capability of this technique. However, xenon can cause adverse reactions. Overall, about 10% of patients have unpleasant but usually transient adverse reactions. Xenon is a narcotic gas, more potent than nitrous oxide, and inhalation of 71% xenon is sufficient for anesthesia in 50% of patients. Lower concentrations of xenon are currently used, but some euphoric or dysphoric effects are still observed and may cause temporary exacerbation of neuropsychiatric symptoms. Mild nausea can also occur, and patients should have an empty stomach before the scan to reduce the risk of vomiting and possible aspiration. Very rarely apnea can occur and can be reversed by instructing the patient to breathe. Like other narcotic gases, xenon causes mild cerebral vasodilatation.

MRI CONTRAST AGENTS (SED-14, 1624; SEDA-21, 476; SEDA-22, 498; SEDA-23, 500)

Extracellular contrast agents The variety of gadolinium chelates available for contrast-enhanced MRI continues to increase. They have an excellent safety record and generally have similar MR relaxivities, pharmacokinetics, and biodistribution, behaving as non-specific extracellular fluid space agents analogous to iodinated contrast media. Although identical efficacy is presumed, there

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have been few direct comparisons to assess equivalence and safety. In a multicenter, randomized, double-blind comparison of the safety, tolerability, and efficacy of gadoversetamide ( a n e w non-ionic gadolinium chelate) and gadolinium DTPA (diethylenelriaminepenta-acetic acid) in 99 patients during contrast enhanced hepatic imaging, both agents were well tolerated and there were no serious or unexpected adverse events (30c). A total of 154 adverse events were recorded in 82 patients, of which 33 (21%) were thought to be related to either agent. Headache and taste disturbances were the most common adverse effects; they occurred in about equal frequency in the two groups. There were no clinically relevant changes in electrocardiography or any laboratory parameter in either group. The safety of intravenous gadoversetamide 0.1, 0.3, and 0.5 mmol/kg has also been confirmed in a study of its pharmacokinetics, safety, and tolerability in 163 patients with CNS or liver pathology and varying degrees of renal function (31c). All the adverse events that were thought to be related to gadoversetamide were mild or moderate, and there was no difference between doses. There were no changes in laboratory parameters. Gadoversetamide was well tolerated, even in patients with prolonged elimination due to renal impairment. The similar safety and efficacy of ionic and non-ionic gadolinium-based extracellular contrast agents suggests that the choice of contrast medium will in future be determined by economic rather than clinical considerations (30c).

on T1 images, which persists for up to 2 hours. Liver tumors generally do not contain functioning hepatocytes and therefore do not take up gadobenate dimeglumine; they therefore appear as unenhanced hypointense lesions. The safety and efficacy of gadobenate dimeglumine in phase 1, 2, and 3 studies have recently been reviewed in 732 patients, of whom 168 received 0.05 mmol/kg and 564 received 0.1 mmol/kg (32c). The overall incidence of adverse events was 14% with the lower dose and 9.9% with the higher dose. The vast majority of events were mild, transient, and selflimiting. There were no sex-, age-, or doserelated differences and no clinically important effects on vital signs or laboratory parameters. The most common adverse events were hypertension (1.37%), nausea (1.09%), tachycardia (0.96%), and albuminuria (0.75%). The authors concluded that gadobenate dimeglumine is safe and efficacious as a contrast agent for use in hepatic MRI. The safety of gadobenate dimeglumine has also been confirmed in phase 2 and phase 3 studies in Japan (33 C, 34c). The overall adverse reaction rate was 3.5-5% and all the reactions were mild or moderate. There were no differences in the rates of adverse reactions with different dosage regimens (0.05-2.0 mmol/kg). A safety evaluation of gadobenate dimeglumine in patients with renal impairment has also been reported (35c). In a placebo-controlled double-blind study there were no changes in laboratory parameters or vital signs and no clinically important adverse events.

Gadobenate dimeglumine (Gd BOTA)

Pancreas Acute pancreatitis has been attributed to gadodiamide, a gadolinium-based contrast medium (36A).

Gadobenate dimeglumine is a novel paramagnetic contrast agent that combines the properties of a conventional extracellular contrast agent with those of a liver-specific contrast agent. It has potential for both hepatic and non-hepatic targeted imaging. Unlike standard gadolinium chelates, which are excreted by the kidneys, 3-5% of gadobenate dimeglumine is taken up by functioning hepatocytes and is excreted unchanged in the bile. It also has an inherently higher TI relaxivity than conventional gadolinium chelates, and so causes very marked enhancement of the liver parenchyma

Gadodiamide

A 58-year-old man was given intravenous gadodiamide (non-ionic gadolinium chelate) 16 ml (0.2 mmol/kg) for hepatic MRI and immediately after the injection developed fatigue, nausea, vomiting, sweating, and later intense upper abdominal pain. His serum amylase was 4262 iu/l and abdominal MRI showed a diffusely enlarged pancreas, confirming the diagnosis of acute pancreatitis. A full history and biliary tract ultrasound excluded other causes. The attack was mild and the clinical course uneventful.

528

MRI blood-pool contrast agents Interest is growing in the use of blood-pool contrast agents for cardiovascular MRI. These agents have the following advantages: 9 higher dose efficiency; 9 prolonged blood-pool enhancement; 9 the ability to measure tissue blood volume and perfusion using indicator dilution principles; 9 the ability to evaluate changes in capillary membrane integrity, which is advantageous for tissue characterization. Several types of agent are being developed with different molecular sizes. There have been relatively few human studies. MS -325 This is a new gadolinium-based small molecular weight chelate, which binds strongly and reversibly to human serum albumin after injection. Its relative MR relaxivity in human plasma is very high (RI = 48 mM -1 sec -1 at 0.47 T and 37 ~ C, which is 10 times higher than gadolinium DTPA), and MS-325 can be given as a bolus, allowing dynamic arterial imaging. Prolonged blood-pool retention also allows steadystate imaging. There are promising results from early studies of carotid and coronary arteries. No serious adverse effects have been reported after the injection of MS-325, although transient nausea andparesthesia were reported in two of seven volunteers (37RE).

Ultrasmall superparamagnetic particles of iron oxide Ultrasmall superparamagnetic particles of iron oxide (USPIOs) have also been studied as blood-pool agents in humans. A new USPIO, NC100150 (Nycomed, Oslo, Norway), has been given to 18 healthy men in doses of 2, 3, and 4 mg/kg (38c). There were no significant adverse effects during or after the scans. However, NC100150 interferes with iron metabolism, since iron is incorporated into the body after biodegradation. NC100150 shows promise for myocardial perfusion analysis. Studies in animals have also suggested a role for NC100150 in the detection and localization of intra-abdominal bleeding (37RE).

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Ferumoxtran-10 (Advanced Magnetics, Cambridge, MA) is an ultrasmall superparamagnetic iron oxide agent. It targets the reticuloendothelial system but also functions as a blood-pool agent. In a phase 2 study in 104 patients with focal liver or spleen pathology who underwent MRI with ferumoxtran-10 (0.8, 1.1, and 1.7 mg of iron per kg), 15% reported a total of 33 adverse events, most commonly dyspnea (3.8%), chest pain (2.9%), and rashes (2.9%) (39c). There were no serious adverse events during the 48-hour observation period and no changes in vital signs, physical examination, or laboratory parameters. The authors concluded that ferumoxtran-10 is safe and well tolerated.

Intermediate-sized contrast agents Intermediate-sized contrast agents are based on gadolinium and act like blood-pool contrast agents during the first pass (37RE). However, because they diffuse into the interstitium, they later act like extracellular agents. Examples are P760 (Guerbet, Aulnay sous Bois, France) and Gadomer-17 (Schering, Berlin, Germany). These intermediate-sized agents may be useful for the following purposes: 9

the detection of small, slow-flowing, tortuous vessels; 9 the detection of increased capillary permeability in sufficiently injured tissues; 9 improved and prolonged demonstration of zones of myocardial ischemia; 9 estimating myocardial blood flow 9 tumor characterization. There are no reports as yet about their safety.

Macromolecular contrast agents The classical macromolecular blood-pool contrast agents are based on gadolinium DTPA or gadobenate dimeglumine, which are linked to albumin, dextran, or polylysine (37RE). Albumin-based agents are not considered optimal for clinical development, as it is difficult to obtain highly consistent synthetic products. There are also problems with cardiovascular toxicity and retention of gadolinium in bones and liver. Dextran-based agents appear to be safer, and there is a new agent, CMD-

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A2-gadobenate dimeglumine (Guerbet, Aulnay sous Bois, France), which has a favorable toxicity profile.

Oral MRI contrast agents A major limitation of abdominal and pelvic MRI has been poor visualization of the bowel, because of a lack of a suitable oral MRI contrast agent. Various agents have previously been evaluated for MRI but have been limited in their application because of their palatability, adverse effects, image artefacts, and enhancement effects predominantly seen only in T1 or T2 sequences but not both. A phase 3 multicenter study of a new gastrointestinal contrast agent based on manganese chloride, LumenHance (Bracco Diagnostics Inc, Princeton, N J), has been reported (40c). At a concentration of 40 Ixg/mi of Mn 2+ the agent causes the lumen to have high-signal intensity on T1 weighted images and low signal intensity on T2 weighted images. The contrast agent was reconstituted with water and given in three 300 ml doses, 45 minutes, 30 minutes, and immediately before imaging in 226 patients, of whom 48 complained of one or more adverse effects, mainly related to the gastrointestinal tract (nausea was the most common). There were no serious adverse effects and no changes in vital signs or laboratory parameters. Reported adverse effects were not statistically different from placebo, and the authors concluded that LumenHance is a safe and efficacious oral gastrointestinal MRI contrast agent.

ULTRASOUND CONTRAST AGENTS (SED-14, 1625; SEDA-21, 476; SEDA-22, 498; SEDA-23, 501) Echo-enhancing contrast agents are extremely safe, and their use in opacifying the left ventricle and assessing ventricular function continues to be investigated. In a recent assessment of the safety of the ultrasound contrast agent AIbunex (air-filled human albumin microspheres, Molecular Biosystem Inc USA, Nycomed, Oslo Norway) in imaging the left ventricle in 52 patients, there were no major or minor adverse events and no changes in vital signs (41c).

529 A new cardiac application for ultrasound contrast agents is the assessment of myocardial perfusion. This is only possible with secondgeneration agents, which are relatively stable and cross the pulmonary circulation. NC100100 (Nycomed, Oslo Norway), which is composed of stabilized perfluorocarbon microbubbles, is one agent that is being evaluated. In a randomized comparison of 99mtechnetium sestamibi single-photon emission-computed tomography (SPECT) and NC100100 in the assessment of myocardial perfusion in 203 patients with myocardial infarction, NC100100 was well tolerated with no serious adverse events or deaths (42c). Similarly there were no clinically important changes in vital signs, laboratory parameters, or electrocardiography. NC100100 correctly identified the vast majority of normallyperfused segments assessed by SPECT. There has been a further confirmation of the safety of Levovist (Schering, Berlin, Germany), an agent that contains galactose microparticles and palmitic acid, in a phase 3b clinical trial in 38 patients with hepatocellnlar carcinoma (43c). There were only two minor reactions of nausea and vomiting.

Oral ultrasound contrast agents Artefacts that arise from gas in the stomach and adjacent bowel often limit the diagnostic accuracy of abdominal ultrasound. Recent research to overcome this problem has focussed on cellulose-based suspensions. A new agent has been developed based on simethicone-coated cellulose--SonoRx (Bracco Diagnostics, Princeton, NJ), which displaces and disperses gas bubbles. In a phase 2 clinical study 93 patients underwent upper abdominal sonography before and after a randomized dose of the contrast agent (200, 400, 600, 800, or 1000 ml) (44c). Anatomic visualization was improved as follows: the stomach in 82% of patients, the duodenum in 63%, the pancreatic head and body in 61%, and the pancreatic tail in 67%. There were 14 adverse events in 11 patients and only five were considered to be related to the contrast agent. The main adverse effects were mild diarrhea and nausea.

530

Thorotrast (SED-14, 1634; SEDA-21, 476; SEDA-22, 498; SEDA-23, 500) Thorotrast was widely used as an X-ray contrast medium between 1928 and 1955. It contains thorium dioxide, which has a radioactive halflife of about 400 years. After intravascular injection Thorotrast is retained mainly in the reticuloendothelial system, especially in the liver, spleen, and bone-marrow. Thorotrast recipients often develop malignant liver tumors (hepato-

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SamehK. Morcos and PeterBrown

cellular carcinoma, cholangiocarcinoma, and angiosarcoma) about 20 years after injection. Several studies have documented that mutations of the TP53 gene (formerly known as p53) are important in the genesis of Thorotrast-induced tumors (45CR-47CR). The retention of Thorotrast in the bone-marrow leads to the development of leukemia. Chromosome aberrations in bone-marrow cells occurred at a high frequency in Japanese patients who had been given Thorotrast (48CR).

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11. Iliopoulou A, Giannakopoulos G, Goutou P, Pagou H. Visual hallucinations due to mdiocontrast media. Report of two cases and review of literature. Br J Clin Pharmacol 1999; 47: 226-7. 12. Nakai Y, Hyodo A, Okazaki M, Shibata Y, Matsumaru Y, Nose T. Transient cortical blindness and convulsion mimicking a hemorrhagic complication during embolization of the cerebellar AVM. Neurol Surg 1999; 27: 249-53. 13. Duan SB, Wu H. W, Luo JA, Liu FY. Assessment of renal function in the early stages of nephrotoxicity induced by iodinated contrast media. Nephron 1999; 83: 122-5. 14. Chalmers N, Jackson RW. Comparison of iodixanol and iohexol in renal impairment. Br J Radiol 1999; 72: 701-3. 15. Naldi L, Conforti A, Venegoni M, Troncon MG, Caputi A, Ghiotto E, Cocci A, Moretti U, Velo G, Leone R. Cutaneous reactions to drugs. An analysis of spontaneous reports in four Italian regions. Br J Clin Pharmacol 1999; 48: 839-46. 16. Watanabe H, Sueki H, Nakada T, Akiyama M, Iijima M. Multiple fixed drug eruption caused by iomeprol (Iomeron), a nonionic contrast medium. Dermatology 1999; 198: 291-4. 17. Mirand-Romero A, Sanchez-Sambucety P, Esquivias Gomez JI. Vegetating iododerma with fatal outcome. Dermatology 1999; 198: 295-7. 18. Brockow K, Becker EW, Worret WI, Ring J. Late skin test reactions to radiocontrast medium. J Allergy Clin Immunol 1999; 104:1107-8. 19. Brockow K, Kiehn M, Kleinheinz A, VielufD, Ring J. Positive skin tests in late reactions to radiographic contrast media. Allerg Immunol 1999: 31: 49-51. 20. Gall H, Pillekamp H, Peter RU. Late-type allergy to the x-ray contrast medium Solutrast (iopamidol). Contact Dermatitis 1999; 40: 248-50. 21. Zuckerman GB, Riess PL, Patel L, Constantinescu AR. Development of a life-threatening anaphylactoid reaction following administration of ioversol in a child. Pediatr Radiol 1999; 29: 295-7. 22. Brockow K, Vieluf D, Puschel K, Grosch J, Ring J. Increased postmortem serum mast cell

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tryptase in a fatal anaphylactoid reaction to nonionic radiocontrast medium. J Allergy Clin Immunol 1999; 104: 237-8. 23. Celik I, Hoppe M, Lorenz W, Sitter H, Ishaque N, Jungraithmayr W, Kapp B, Schmiedel E, Klose KJ. Randomised study comparing a non-ionic with an ionic contrast medium in patients with malignancies: first answer with a new diagnostic approach. Inflamm Res 1999; 48 Suppl 1: $47-8. 24. Tamm I, Kortsik C. Severe barium sulfate aspiration into the lung: clinical presentation, prognosis and therapy. Respiration 1999; 66: 81-4. 25. Regan JK, O'Neil HK, Aizenstein RI. Small bowel carcinoid presenting as a barolith. Clin Imaging 1999; 23: 22-5. 26. Glauser T, Savioz D, Grossholz M, LopezLiuchi J, Robert J, Huber O, Morel P. Venous intravasation of Gastrografin: a serious but underestimated complication. Eur J Surg 1999; 165: 274-7. 27. Tuladhar R, Daftary A, Patole SK, Whitehall JS. Oral Gastrografin in neonates: a note of caution. Int J Clin Pract 1999; 53: 565. 28. Bees NR, Beese RC, Belli AM, Buckenham TM. Carbon dioxide angiography of the lower limbs: initial experience with an automated carbon dioxide injector. Clin Radiol 1999; 54: 833-8. 29. Taber KH, Zimmerman JG, Yonas H, Hart W, Hurley RA. Applications of xenon CT in clinical practice: detection of hidden lesions. J Neurophsychiatry Clin Neurosci 1999; 11: 423-5. 30. Rubin DL, Desser TS, Semelka R, Brown J, Nghiem HV, Steven WR, Bluemke D, Nelson R, Fultz P, Reimer P, Ho V, Kristy RM, Pierro JA. A multicenter, randomised, double-blind study to evaluate the safety, tolerability, and efficacy of Optimark (gadoversetamide) injection compared with Magnevist (gadopentetate dimeglumine) in patients with liver pathology: results of a phase HI clinical trial. J Magn Reson Imaging 1999; 9: 240-50. 31. Swan SK, Baker JE Free R, Tucker RM, Barron B, Barr R, Seltzer S, Gazelle GS, Maravilla KR, Barr W, Stevens GR, Lambrecht LJ, Pierro JA. Pharmacokinetics, safety, tolerability of gadoversetamide injection (OptiMARK) in subjects with central nervous system or liver pathology and varying degrees of renal function. J Magn Reson Imaging 1999; 9: 317-21. 32. Hamm B, Kirchin M, Pirovano G, Spinazzi A. Clinical utility and safety of MultiHance in magnetic resonance imaging of liver cancer; results of multicenter studies in Europe and the USA. J Comput Assisted Tomogr 1999; 23 Suppl 1: $53-60. 33. Tanimoto A, Kuwatsuru R, Kadoya M, Ohtomo K, Hirohashi S, Murakami T, Hiramatsu K, Yoshikawa K, Katayama H. Evaluation of gadobenate dimeglumine in hepatocellular carcinoma: results from phase III clinical trials in Japan. J Magn Reson Imaging 1999; 9: 450450. 34. Kuwatsuru R, Kadoya M, Ohtomo K, Tanimoto A, Hirohashi S, Murakami T, Tanaka Y, Yoshi-

531 kawa K, Katayama H. Clinical late phase II trials of MultiHance (Gd-BOPTA) for the magnetic resonance imaging of liver tumours in Japan. J Comput Assisted Tomogr 1999; 23 Suppl 1: $65-74. 35. Swan SK, Lambrecht LJ, Townsend R, Davies BE, McCloud S, Parker JR, Bensel K, LaFrance ND. Safety and pharmacokinetic profile of gadobenate dimeglumine in subjects with renal impairment. Invest Radiol 1999; 34: 443-8. 36. Terzi C, Sokmen S. Acute pancreatitis induced by magnetic resonance imaging contrast agent. Lancet 1999; 354: 1789-90. 37. Kroft LIM, De Roos A. Blood pool contrast agents for cardiovascular MR imaging. J Magn Reson Imaging 1999; 10: 395-403. 38. Panting JR, Taylor AM, Gatehouse PD, Keegan J, Yang GZ, NcgiU S, Francis JM, Burman ED, Firmin DN, Pennell DJ. First-pass myocardial perfusion imaging and equilibrium signal changes using the intravascular contrast agent NC100150 injection. J Magn Reson Imaging 1999; 10: 40410. 39. Sharma R, Saini S, Ros PR, Hahn PF, Small WC, De Lange E, Stillman A, Edelman RR, Runge VM, Outwater EK, Morris M, Lucas M. Safety profile of ultrasmall superparamagnetic iron oxide ferumoxtran-10; phase II clinical trial data. J Magn Reson Imaging 1999; 9: 291-4. 40. Small WC, Desimone-Macchi D, Parker JR, Sukerkar A, Hahn P, Rubin DL, Zelch JV, Kulman JE, Outwater EK, Weinreb JC, et al. A multisite phase l]I study of the safety and efficacy of a new manganese chloride-based gastrointestinal contrast agent for MRI of the abdomen and pelvis. J Magn Reson Imaging 1999; 10: 15-24. 41. Castini D, Gentile E Ornaghi M, Mangiarotti E, Garbin M, Ravaglia R, Gioventu M, Mantero A, Corno R, Limido A, et al. Left ventricular opacification by intravenous contrast echocardiography. G Ital Cardiol 1999; 29: 620-9. 42. Binder T, Assayag P, Baer F, Flachskampf F, Kamp O, Nienaber C, Nihoyannopoulos P, Pieraard L, Steg G, Vanoverschelde JL, et al. NC100100, a new echo contrast agent for the assessment of myocardial perfusion--safety and comparison with technetium-99m sestamibi single-photon emission computed tomography in a randomised multicenter study. Clin Cardiol 1999; 22: 273-82. 43. Khong PL, Chan MT, Fan ST, Leong LLY. Ultrasound contrast agent Levovist in colour Doppler sonography of hepatocellular carcinoma in Chinese patients. Australas Radiol 1999; 43: 156-9. 44. Lev-Toaff AS, Langer JE, Rubin DL, Zelch JV, Chong WK, Barone AE, Goldberg BB. Safety and efficacy of a new oral contrast agent for sonography: a phase [I trial. Am J Roentgenol 1999; 173: 431-6. 45. Wada I, Horiuchi H, Moil M, Ishikawa Y, Fukumoto M, Moil T, Kato Y, Kitagawa T, Machinami R. High rate small TP53 mutation and infrequent loss of heterozygosity in malignant liver tumors associated with Thorotrast: implications for alpha-

532 particle carcinogenesis. Radiat Res 1999; 152 Suppl: S125-7. 46. Kamikawa T, Amenomori M, Itoh T, Momoi H, Hiai H, Machinami R, Ishikawa Y, Mori T, Shimahara Y,Yamaoka Y, Fukumoto M. Analysis of genetic changes in intrahepatic cholangiocarcinoma induced by Thorotrast. Radiat Res 1999; 152 Suppl: S118-24. 47. Iwamoto KS, Fujii S, Kurata A, Suzuki M, Hayashi T, Ohtsuki Y, Okada Y, Narita M, Taka-

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Sameh K. Morcos and Peter Brown

hashi M, Hosobe S, et al. P53 mutations in tumor and non-tumor tissues of Thorotrast receipients: a model for cellular selection during radiation carcinogenesis in the liver. Carcinogenesis 1999; 20: 1283-91. 48. Tanosaki S, Minamihisamatsu M, Ishihara T, Hachiya M, Kumatori T, Akashi M. Chromosome aberrations in bone marrow cells from Japanese patients with Thorotrastosis. Radiat Res 1999; 152 Suppl: $128-32.

B.C.R Polak

47

Drugs used in ocular treatment

Drugs used in ocular treatment are widely prescribed by opticians, optometrists, nurses, and other professionals without medical training. It is therefore of increasing importance to improve awareness, recognition, and treatment of potentially fatal reactions due to the use of topical eye medications, which may also occur inside or outside hospital (SEDA-23, 503).

successfully treated with topical timolol and dorzolamide. He was atopic and wheezed when exposed to cats. Immunological investigations revealed a mildly raised total IgE of 590 ku/1 (reference range less than 120 ku/l) with specific IgE against cat (grade III), house dust mite (grade IV), and grass pollen (grade II), confirming his atopic tendency. RAST tests to local anesthetics are not commercially available. Skin prick and intradermal tests to a variety of local anesthetics, including oxybuprocaine eye drops at various dilutions, showed no local or systemic reactions.

DIAGNOSTIC OPHTHALMIC DRUGS

This reaction to oxybuprocaine was assumed to be idiosyncratic and not a classic type I hypersensitivity reaction.

Local anaesthetics Local anaesthetics can provoke adverse idiosyncratic, cardiovascular, and allergic reactions, which can be life threatening.

Oxybuprocaine (Benoxinate, Novesine) Cardiovascular Two cases of severe bradycardia following exposure to oxybuprocaine eye drops have been reported (1 A, 2 A), of which the following is the second. A 29-year-old male physician attended an optician for routine tonometry. Within 1 minute after the instillation of oxybuprocaine he had a subjective sensation of throat swelling, followed by collapse and loss of consciousness. His wife, a medical doctor, noted no respiration and a pulse of 12 beats/rain. Cardiopulmonary resuscitation was performed and adrenaline was given intramuscularly. There was a rapid return of cardiac output and he made a full recovery, with no abnormalities. Intraocular pressures were 56 mmHg bilaterally, caused by open-angle glaucoma due to pigment dispersion syndrome. He was 9 2001 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

Nervous system Another patient developed seizures after the application of oxubuprocain/fluorescein solution (Fluress) (3A). In a series of 12 493 drug applications in ophthalmic clinics in the USA there were eight cases (0.21%) of adverse reactions. Five of these were to oxybuprocaine, but all as a component of oxybuprocaine/fluorescein solution (Fluress), including increased intraocular pressure (1), stinging (1), dull ache with redness and swelling (2), and one case of dizziness and coldness with collapse (4A).

Cycloplegics and mydriatics Adverse reactions to mydriatic eyedrops are not uncommon (SEDA-23, 504). Tropicamide and phenylephrine are often used in the same patient, since they act synergetically and give maximal pupillary dilatation.

Tropicamide An solution containing tropicamide 1% and benzalkonium chloride 0.01% (Mydriaticum) was introduced in 1979 to obtain mydriasis and cycloplegia for diagnostic purposes. Con533

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534

tact dermatitis from ophthalmic formulations is common, ~preservatives being the most frequent causes (5~). Recently a case of allergic contact dermatitis has been reported, implicating tropicamide as a sensitizer (6A).

Sympathomimetie drugs Phenylephrine Phenylephrine hydrochloride eye drops are used in concentrations of 2.5-10% and two drops of phenylephrine 5% are similar to 5 mg of active ingredient. In young patients not more than 1.5 mg will be used intravenously, whereas subcutaneously a maximum 10 mg will be used. Hypertensive crises and serious cardiovascular adverse reactions can occur, especially in older patients, after the application of several eye drops of phenylephrine. It is always wise to advocate nasolacrimal occlusion by digital compression of the lacrimal drainage system when using phenylephrine eye drops in patients at risk or in patients in whom higher concentrations are necessary. In normotonic or medically treated patients with hypertension preoperative mydriasis using 5% phenylephrine eye drops is safe when patients block the systemic resorption themselves by nasolacrimal occlusion (7R).

B.C.P.Polak

Pregnancy A critical review of the medical literature on drug therapy for allergic rhinitis during pregnancy has been published (8R). Mast cell stabilizers (e.g. sodium cromoglycate) are not teratogenic and can be considered as excellent first-line choices to treat allergic conjunctivitis and rhinitis. However, any recommendation should be accompanied by informed consent.

New anti-allergic drugs Ophthalmic formulations of ketotifen fumarate (Zaditor), nedocromil sodium (Alocril) , and pemirolast potassium (Alamast) have recently been approved by the FDA for use in adults and children with itching eyes due to allergic conjunctivitis. Pemirolast and nedocromil are mast-cell stabilizers and ketotifen has both mast-cell stabilizing and H1 receptor antagonist activity. Ocular irritation, burning, or stinging can occur with all these drugs (9R).

Ketotifen The antihistaminic effect of ketotifen occurs within minutes after administration and has a duration of up to 12 hours. Conjunctival injection, headache, and rhinitis are common. Allergic reactions, stinging, discharge, eye pain, and photophobia occurred in less than 5% of patients.

THERAPEUTIC OPHTHALMIC

DRUGS

Nedocromil

Anti-allergic agents

Headache was the most common adverse effect, but unpleasant taste and nasal congestion also occurred commonly.

Antihistamine + decongestant combinations available in several countries over the counter for ophthalmic use have a short duration of action and can cause rebound vasodilatation with continued use. Ophthalmic mast cell stabilizers, such as cromolyn and iodoxamide, are effective in vernal conjunctivitis, and the histamine H1 receptor antagonists levocabastine and emedastine are effective in seasonal allergic conjunctivitis. An ophthalmic formulation of ketorolac, a non-steroidal anti-inflammatory drug, is also marketed for the treatment of itching due to seasonal allergic conjunctivitis, but can be irritating on instillation and may be less effective than mast cell stabilizers or H1 receptor antagonists.

Pemirolast The most common adverse effects were headache, rhinitis, and mild cold- or flu-like symptoms. After ocular administration for 2 weeks, plasma concentrations were detectable, but with no significant accumulation.

Corticosteroids Long-term use of ophthalmic corticosteroids can cause cataracts and increased intraocular pressure and infections may be precipitated or prolonged. Corticosteroids are not indicated for

Drugs used in ocular treatment

535

Chapter 47

mild seasonal allergies and are reserved for severe allergic reactions, such as limbic vernal conjunctivitis. Despite these potential risks the use of these drugs is c o m m o n in the absence of clear indications. Recently three visionthreatening complications have been described due to the indiscriminate use of corticosteroidcontaining ointments (10c). A 31-year-old man noted a blind spot in his right eye. He had worn contact lenses for 10 years to correct his myopia. He had applied Tobradex ointment (tobramycin 0.3% and dexamethasone 0.1%) to each eye every evening for the past 4 years because of irritation due to contact lenses, and continuous refills of this prescription were obtained through an acquaintance who was employed in a pharmacy. With spectacle correction his visual acuity was 20/25 in each eye. The intraocular pressure was 52 mmHg in his right eye and 37 mmHg in his left eye. The optic discs showed glaucomatous cupping in each eye. Automated visual field testing showed superior and inferior arcuate defects typical of glaucoma in both eyes. Slit-lamp biomicroscopy showed mild papillary conjunctivitis bilaterally due to contact lenses. Use of the antibiotic + corticosteroid ointment was discontinued and his bilateral corticosteroid-induced openangle glaucoma was treated with antiglaucomatous drugs. A 15-year-old boy felt a foreign body sensation in his right eye after he had been raking hay. His local physician prescribed a suspension of tobramycin 0.3% + dexamethasone 0.1% tds, but 6 days later referred him for evaluation of a suspected fungal keratitis. He had a corneal epithelial defect with an underlying dense inflammatory infiltrate. Corneal scrapings contained fungal hyphae and Fusarium species was identified. Natamycin 5% was administered topically every hour, the infection resolved, and his visual acuity returned to 20120 despite a dense corneal scar. A 56-year-old woman had bilateral primary open-angle glaucoma without visual field loss, which was well controlled with a long-term topical /% blocker in each eye. She underwent a left dacryocystorhinostomy for nasolacrimal duct obstruction, but developed persistent tearing and irritation of the left eye several months postoperatively. A suspension of tobramycin 0.3% + dexamethasone 0.1% was prescribed, which she continued to use as needed for 6 months. Pain and reduced vision persisted in her left eye. Corrected visual acuity was 20/20 in her right eye and 20/60 in her left eye. The intraocular pressures were 18 mmHg in her right eye and 68 mmHg in her left eye. Automated visual field testing showed a normal field in her right eye, but only a central island and a crescent of temporal visual field in her left eye. External examination showed persistent nasolacrimal duct obstruction on the left side with mild conjunctival injection. The diagnosis was primary open-angle glaucoma in both eyes, which

was exacerbated by topically applied corticosteroids in her left eye. The antibiotic + corticosteroid suspension was withdrawn, and a topical ocular hypotensive therapeutic regimen was initiated in her left eye.

New eortieosteroids used in the eye Loteprednol etabonate 0.5% has been shown to increase intraocular pressure less than dexamethasone. Studies on animal models of uveitis and two randomized double-masked trials showed that loteprednol etabonate 0.5% was less potent than dexamethasone, prednisolone acetate 1%, or fluorometholone, which may partly explain the improved toxicity profile of loteprednol etabonate (11E). Clinicians should not prescribe corticosteroid-containing eye drops unless they have performed a slit-lamp examination with tonometry, have assurance of appropriate follow-up, and understand the differential diagnosis, evaluation, and treatment. Unless clearly indicated, prescribing volumes larger than 5 ml or providing refillable prescriptions should be avoided. When long-term use is necessary, even with oral or inhalation therapy, eye examination should be performed every 6 months. For eyes with milder inflammation and a history of a corticosteroid-induced increase in intraocular pressure, new drugs such as loteprednol etabonate may be an important addition to the armamentarium of the practising ophthalmologist.

Antiglaueomatous drugs ~-adrenoeeptor agonists Apraclonidine (Iopidine) is a relatively nonspecific c~l and ct2 adrenoceptor agonist, which is less likely to cross the blood-brain barrier than clonidine. Apraclonidine suppresses aqueous humor flow by 39 4A.% and lowers intraocular pressure by 20-23%. Over longer periods of follow-up, efficacy may be lost in up to 31% of patients, with a similar rate of development of allergy. Brimonidine tartrate 0.2% (ugan) is a highly selective ct2 adrenoceptor agonist. Unlike apraclonidine, brimonidine appears to both reduce aqueous humor production and increase aqueous outflow through the uveoscleral pathway. Brimonidine is less polar than apraclonidine and is therefore more likely to cross

536 the blood-brain barrier. Brimonidine should be avoided in children, because apnea and hypotension occur. Symptoms of fatigue can occur. Brimonidine causes fewer adverse effects than apraclonidine, and because it is a highly selective or2 adrenoceptor agonist it does not cause mydriasis, lid retraction, or conjunctival blanching/rebound hyperemia (12R).

Chapter 47

B.C.P.Polak

Topical carbonic anhydrase inhibitors Brinzolamide (Azopt) is a sulfonamide, chemically similar to dorzolamide. It is more comfortable than dorzolamide. Because it comes as a suspension, it can cause transient blurred vision (12 R ). Dorzolamide (Trusopt) has so far a minimal adverse effects profile. Some patients report a bitter taste. RecentlY it has been reported that dorzolamide can cause irreversible corneal edema in glaucoma patients with endothelial compromise (13c).

REFERENCES 1. Christensen C. Bradycardia as a side-effect to oxybuprocaine. Acta Anaesthesiol Scand 1990; 34: 16545. 2. Sewell WAC, Croucher JJ, Bird AG. Immunological investigations following an adverse reaction to oxybuprocaine eye drops. Br J Ophthalmol 1999; 83: 632. 3. Cohn H, Jocson V. A unique case of grand mal seizures after Fluress. Ann Ophthalmol 1981; 13: 1379-80. 4. Applebaum M, Jaanus S. Use of diagnostic pharmaceutical agents and incidence of adverse effects. Am J Optom Physiol Optics 1983; 60: 384-8. 5. Herbst RA, Maibach HI. Allergic contact dermatitis from ophthalmics: update 1997. Contact Dermatitis 1997; 37: 252-3. 6. Boukhman MP, Maibach HI. Allergic contact dermatitis from tropicamide ophthalmic solution. Contact Dermatitis 1999; 41: 47-8. 7. Hempel S, Senn P, Pakdaman F, Schmid MK, Suppiger M, Schipper I. Einfluss der Pupillener-

weiterung mit Phenylephrin 5% auf das perioperative Kreislaufverhalten. Klin Monatsbl Augenheilkd 1999; 215: 298-304. 8. Mazzotta P, Loebstein R, Koren G. Treating allergic rhinitis in pregnancy. Safety considerations. Drug Saf 1999; 20: 361-75. 9. Anonymous. New drugs for allergic conjunctivitis. Med Lett Drugs Ther 2000; 42: 39-40. 10. Baratz KH, Hattenhauer MG. Indiscriminate use of corticosteroid-containing eyedrops. Mayo Clin Proc 1999; 74: 36245. 11. Whitcup SM, Ferris FL. New corticosteroids for the treatment of ocular inflammation. Am J Ophthalmol 1999; 127: 597-9. 12. Doyle JW, Smith ME New aqueous inflow inhibitors. Semin Ophthalmol 1999; 14: 159453. 13. Konowal A, Morrison JC, Brown SVL, Cooke DL, Maguire LJ, Verdier DV, Fraunfelder FT, Dennis RF, Epstein RJ. Irreversible corneal decompensation in patients treated with topical dorzolamide. Am J Ophthalmol 1999; 127: 40345.

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48

Treatments used in complementary medicine

Various interested parties are keen to promote the idea that complementary/alternative medicines carry no risks. Even though the risks may be less than those in some areas of mainstream medicine, this notion is clearly incorrect. Like any other interventions, complementary/alternative therapies are associated with adverse effects, and as with all other treatments they have to be viewed in relation to their potential benefits (1R). Adverse effects continue to be reported with depressing regularity. In the vast majority of such reports a cause-and-effect relation has not been established beyond reasonable doubt. Proper benefit:harm assessments are further impeded by the incompleteness of the evidence that these therapies are effective.

HERBAL MEDICINAL PRODUCTS Several overviews have addressed the safety of herbal medicinal products, in general terms (2R-4R), related to specific countries, e.g. the USA (5 R) or Malaysia (6R), or related to specific organs (7R). Realising that, vis h vis the current high prevalence of the use of complementary/alternative medicine, these issues have gained considerable importance for public health, the UK Government recently decided to extend its "yellow card" scheme of pharmacovigilance to herbal medicinal products, which are marketed mostly as food supplements in the UK

(8r).

9 2001 Elsevier Science B.V. All fights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

Asian herbal mixtures Liver A Japanese herbal mixture ("Tsumura") has been associated with hepatotoxicity (9A). A 49-year-old Japanese woman had taken oral Tsumura for about 6 weeks to treat internal hemorrhoids when she felt unwell. Her liver enzymes were raised and a diagnosis of drug-induced hepatic damage caused by Angelicae radix and Bupleuri rad/x contained in the mixture was made. The liver function tests normalized 4 months after withdrawal. Important results, which allow us to estimate incidence figures, have come from a German hospital of Traditional Chinese Medicine (10 c , 11t~). About 1% of 1507 consecutive patients treated with Chinese herbal mixtures had clinically relevant rises in liver enzymes. Glycyrrhizae radix and Atractylodis macrocephalae rhizoma were most consistently associated with such problems. In most of these cases there were no associated clinical signs and the abnormalities tended to normalize without specific therapy and in spite of continued treatment with Chinese herbal mixtures. U r i n a r y tract Chinese herbal mixtures often contain a multitude of herbs. Some of these are from the Aristolochia species, which contains highly nephrotoxic aristolochic acids. The use of such mixtures in Belgium has resulted in an epidemic of subacute intestinal nephropathy, also termed Chinese-herb nephropathy. Many of the affected patients required kidney transplantation. When 19 kidneys and urethras removed from ten such patients were examined histologically, there were conclusive signs of neoplasms in 40% (12c). In the UK, the long-term (2 and 6 years) use of Aristolochia species in Chinese herbal mixtures (taken as an oral medication or herbal 537

Chapter 48

538 tea) has resulted in Chinese-herb nephropathy with end-stage renal insufficiency (13A). Similar cases have also been reported from mainland China (14 A) and Taiwan (15A). In reaction to these reports, the Medicines Control Agency has banned all Aristolochia species for medicinal use in the UK.

Bee pollen Hepatic veno-occlusive disease has been attributed to bee pollen (16 A). A 33-year-old woman took two tablespoons of pure bee pollen daily for several months and had sharp midepigastric pain associated with meals. She also took aspirin, caffeine, and erythromycin for chronic acne. Most relevant findings were normal except for rises in liver enzyme. A liver biopsy showed hepatic veno-occlusive disease. The product was withdrawn while the other medications continued, and this resulted in complete resolution of symptoms and laboratory tests within 6 weeks. The authors concluded that the bee pollen was responsible in this case.

Angelica sinensis (Dong quai) Dong quai is recommended in traditional Chinese medicine for dysmenorrhea, irregular menstruation, anemia, post-partum weakness, and other problems. It can cause hypertension (17A). A 32-year-old woman, 3 weeks post-partum, developed acute headache, weakness, light-headedness, and vomiting. Her blood pressure was 195/85 mmHg. She had taken Dong quai for post-partum weakness and said that she had not been taking any other medicines. Her 3-week-old son's blood pressure was raised at 115/69. Dong quai medication of the mother and breast-feeding of the child were discontinued and the blood pressure normalized in both patients within 48 hours.

Chelidonium majus (greater

celandine) Ten cases of acute hepatitis induced by formulations of greater celandine were observed over 2 years in a German University hospital (18R). Perhaps ironically, this product is popular in Germany for gastric and gall-bladder problems. In five cases there was marked cholestasis but no liver failure. After withdrawal of the product,

E. Ernst

the symptoms subsided and the liver enzymes normalized within 2-6 months. Unintentional rechallenge led to a further episode of acute hepatitis in one patient.

Echinacea Echinacea has become increasingly popular in recent years, particularly for the prophylaxis and treatment and prevention of cold and flu symptoms. Between July 1996 and November 1998, the Australian Adverse Drug Reactions Advisory Committee received 37 reports of suspected adverse drug reactions in association with Echinacea (19R). Over half of these (21) described allergic reactions, including bronchospasm (9 reports), dyspnea (8), urticaria (5), chest pain (4), and angio-edema (3). The 21 patients were aged 3-58 (median 31) years and 12 had a history of asthma (7) and/or allergic rhinitis/conjuctivitis/hayfever (5). Echinacea was the only suspected cause in 19 of the 21 cases. The symptoms began at variable times, within 10 minutes of the first dose to a few months, and all but two cases occurred within 3 days of starting treatment. At the time of reporting 17 of the patients had recovered, two had not yet recovered, and the outcome was unknown in the other two cases.

Ephedra (Ma huang) Ma huang is the predominant constituent of "herbal ecstasy", a herbal product and a fashionable drug of abuse. A 21-year-old man presented with hypertension (blood pressure 220/110 mmHg) and ventricular dysrhythmias after taking four capsules of herbal ecstasy (20A). He was treated with lidocaine and sodium nitroprusside and his symptoms resolved within 9 hours.

Glycyrrhizae radix (licorice) Licorice is a common constituent of Chinese herbal mixtures, but it is also often taken as a single product. Its aldosterone-like effects are well established and it can cause hypokalemia (21 A, 22A). A 44-year-old woman developed an irregular heart rhythm and repeated episodes of lifethreatening torsade de pointes. Her serum potassium was 2.3 mmol/l. Treatment with an infusion of po-

Treatments used in complementary medicine

Chapter48

tassium and magnesium promptly restored normal rhythm. The cause of the problem was identified as the patient's habit of consuming large (but not more closely defined) quantities of licorice daily. One year after this episode she was still abstaining from licorice and showed no signs of cardiac disease. A 39-year-old woman had a potassium concentration of 2.9 mmol/1 at a routine checkup. She denied taking any medications except a "cleansing tea" purchased from a health food company. The tea was analyzed and found to contain significant amounts of licorice. Her potassium concentration normalized after withdrawal of the product and potassium supplementation.

Hypericum perforatum

(St John's wort) Psychiatric

Two cases of mania have been associated with the use of St John's wort (23A). The authors pointed out that St John's wort, like all antidepressants, can precipitate hypomania, mania, or increased cycling of mood states, particularly in patients with occult bipolar disorder. Alternatively, the mania experienced by these patients could simply be the expression of the natural cause of their psychiatric illness. D r u g interactions St John's wort is also a hepatic enzyme inducer (24 R) and can lower the plasma concentrations of various prescribed drugs, including oral anticoagulants

539

A 44-year-old woman chewed a castor bean seed and within minutes developed uticaria, drowsiness, Quincke's edema, and extreme hypotension. Her anaphylactic shock was treated with adrenaline, intravenous steroids, antihistamines, and intravenous fluids. She quickly recovered and a subsequent blood test demonstrated CAP-RAST to castor beans.

Scutellaria (skullcap) Skullcap has repeatedly been associated with hepatotoxicity and a case of veno-occlusive disease has been reported (27A). A 28-year-old man presented with jaundice after taking six tablets of skullcap (together with zinc and pau d'arco) daily for the previous 6 months to help his multiple sclerosis. His liver enzymes were raised and hepatitis A, B, and C serologies were negative. He developed progressive liver failure and received a transplant but died shortly after. His explant liver showed fibrous stenosis and obliteration of most of the terminal venules with extensive perivenular fibrosis, indicative of veno-occlusive disease. Skullcap contains pyrrolizidine alkaloids, which have repeatedly been implicated in venoocclusive disease of the liver.

Silybum marianum (milk thistle) Milk thistle is recommended for liver problems, e.g. hepatitis.

and ciclosporin.

Lupinus (lupin) A 72-year-old Portuguese woman presented to an emergency department with classic anticholinergic signs: sudden onset of nausea and vomiting, blurred vision, generalized weakness, and tachycardia (25A). She had taken a herbal product containing lupin seeds in the belief that it would cure her recently diagnosed diabetes mellitus. Analysis of the product identified the preponderant compound as oxosparteine, which has powerful anticholinergic effects. Lupin seeds are commonly taken as an appetizer in Southern Europe and the Middle East.

Ricinus communis (castor beans) Castor oil is a commonly used laxative, which is expressed from castor beans. However, the whole beans contain other substances, one adverse effect of which is anaphylaxis (26A).

A 57-year-old Australian woman presented with a 2-month history of intermittent episodes of sweating, nausea, colicky abdominal pain, fluid diarrhea, vomiting, weakness, and collapse (28A). She was taking ethinylestradiol and amitriptyline and had taken milk thistle for 2 months. A thorough check-up showed no abnormalities. On reflection she realized that all her attacks had invariably occurred after taking the milk thistle. She stopped taking it and had no symptoms until a few weeks later, when she tried another capsule and had the same symptoms. This idiosyncratic reaction to milk thistle seems to be a rarity. The Australian authorities knew of only two other adverse drug reactions associated with milk thistle.

Taxus cuspidata (Jui) Thrombocytopenia has been attributed to the Chinese herbal mixture Jui (29A). A 51-year-old Japanese woman developed gingival bleeding and petechiae. The only medication

Chapter 48

540 she had taken was Jui. She had thrombocytopenia and the causal relation was demonstrated through rechallenge with Jui. She recovered on withdrawal of the product and has since had a normal platelet count.

PHYSICAL METHODS Acupuncture On a global basis, acupuncture is one of the most commonly used forms of complementary/alternative medicine. Contrary to prevailing public opinion it is not entirely risk free. Several review articles have addressed this issue, and it has been pointed out that tissue trauma (e.g. pneumothorax) and infections (e.g. hepatitis B) are the most common complications of acupuncture (30R). Both are rare and both could be avoidable with adequate training and experience of acupuncturists.

Infection risk In a recent review of serious complications three cases of infection have been described, one of auricular perichondritis that resulted in permanent disfigurement, one of bacterial meningitis with full recovery, and one of pyarthrosis also with full recovery (31r). A retrospective cohort serological study identified five confirmed cases of acute hepatitis B virus infection within 3.5 years related to one London acupuncture clinic (32c). The acupuncturist was hepatitis B-positive and the strain of his virus was identical to that from the patient. Nine further patients of his had antibodies to the hepatitis B core antigen but had other risk factors for hepatitis B infection. A nationwide community-based survey in Taiwan has been carried out in seven locations in a total of 11 904 men tested for antibodies against hepatitis C virus. Exposure to acupuncture was a risk factor for hepatitis C positivity (33c). T r a u m a Traumatic complications of acupuncture have been reviewed (34R). They have been described in relation to the thoracic and abdominal viscera, in the peripheral and central nervous systems, and in blood vessels. Several deaths have been reported from pneumothorax and cardiac tamponade. The anatomical tissues at several acupuncture points are such that needles can injure vulnerable structures. Thus,

E. Ernst

good knowledge of anatomy is an essential precondition for acupuncturists. A recent review of serious complications included one case of cardiac tamponade (with full recovery of the patient after surgery), one case of peripheral nerve damage (foot drop with residual weakness after 6 years), and three cases ofpneumothorax (all with full recovery) (3 lr). A further case of pneumothorax has been reported elsewhere (35A). A 60-year-old woman was treated by a nonmedically qualified acupunctufist for chronic fib pain. About 15 needles were inserted along either side of her back, and one (in the fight lower thoracic region) caused immediate discomfort. After removal of the needle she noted pain and breathlessness. A chest X-ray 2 days later confirmed a small fight pneumothorax, which resolved spontaneously within one week.

Massage There are many different forms of massage therapy, which are not normally associated with serious adverse effects. However, trauma can occur (36A). A 39-year-old woman with an unremarkable medical history underwent deep body massage, including the abdomen. Within 24 hours she experienced discomfort and nausea and after 72 hours she had a CT scan, which showed a large hematoma in the fight hepatic lobe. There was no evidence of a plausible cause for this. In spite of adequate medical treatment, her recovery was slow and she had nausea and low-grade fever for about 6 months.

Spinal manipulation Spinal manipulation is an important therapeutic element in chiropractic and osteopathic management, and is mostly (but not exclusively) used for back and neck pain. Spinal manipulation, particularly when performed on the cervical spine, has repeatedly been associated with adverse effects, some of which are serious (37R). An authoritative summary of all cases of complications of spinal manipulation of the cervical spine published since 1925 has appeared (38R). In all, 177 cases of severe injury were found. The most frequently reported injuries involved arterial dissection or spasm and brain stem lesions. In 32 instances (18%) they were fatal. The author concludes that high velocity

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thrusts of the cervical spine are not demonstrably associated with more benefit than harm and should therefore be avoided. A Ukrainian doctor has reported a series of 49 additional cases with neurological complications after spinal manipulation (39c). Swedish authors have summarized all such cases reported to three Swedish insurance companies within 2 years (40c). They found 21 cases associated with the cervical spine, six associated with the thoracic spine, 13 with the lumbar spine, and 14 with the sacro-iliac joints. Cervical spinal manipulation had caused damage to the vertebral artery with subsequent paralysis in three cases and disk herniation in three cases. Lumbar spinal manipulation had caused disk herniation in six cases, three of whom suffered severe and persistent problems. German neurologists have reported 10 cases of ischemic stroke due to either vertebral arterial dissection (n = 8) or internal carotid artery dissection (n = 2) after chiropractic spinal manipulation (41A). There were no identifiable predisposing factors. In three cases the dissections were bilateral. The onset of symptoms was

541

immediate (n = 5) or delayed by up to 2 days. Neurological deficits developed during up to 3 weeks. In five patients the eventual clinical outcome was good while marked deficits persisted in three patients. One patient continued to suffer from a locked-in syndrome and another was in a persistent vegetative state. A 34-year-old woman had pain, dizziness, vomiting, and diplopia immediately after cervical spinal manipulation (42A). An MRI scan showed a left cerebellar infarction, and duplex sonography showed dissection of both vertebral arteries leading to 50% occlusion on the right side and total occlusion on the left side. A highly unusual case of thoracic epidural hematoma after spinal manipulation of the lumbar spine has been reported (43A). A 64-year-old woman experienced acute severe pain and progressive neurological defects for the first time during spinal manipulation. Swift surgical intervention was initiated and a thoracic epidural hematoma was evacuated. This resulted in complete recovery.

REFERENCES 1. Jonas WB, Ernst E. Evaluating the safety of complementary and alternative products and practices. In: Jonas WB, Levin JS, editors. Essentials of complementary and alternative medicine. Philadelphia: Lippincott Williams Wilkins, 1999: 89-107. 2. Marrone CM. Safety issues with herbal products. Ann Pharmacother 1999; 33: 1359-62. 3. Ko RJ. Causes, epidemiology, and clinical evaluation of suspected herbal poisoning. J Toxicol Clin Toxicol 1999; 37: 697-708. 4. Ernst E. Phytotherapeutika: Wie harmlos sind sie wirklich? Dtsch fitrzteblatt 1999; 48: 3107-8. 5. Matthews HB, Lucier GW, Fisher KD. Medicinal herbs in the United States: research needs. Environ Health Perspect 1999; 107: 773-8. 6. Hussain SH. Potential risks of health supplements--self-medication practices and the need for public health education. Int J Risk Saf Med 1999; 12: 167-71. 7. Fontana RJ. Acute liver failure. Curr Opin Gastroenterol 1999; 15: 270-7. 8. Yamey G. Government launches green paper on mental health. Br Med J 1999; 319: 1322. 9. Nagai K, Hosaka H, Ishii K, Shinohara M, Sumino Y, Nonaka H, Akima M, Yamamuro W. A case report: acute hepatic injury induced by Formula secundarius-haemorrhoica. J Med Soc Toho Univ 1999; 46:311-17.

10. Melchart D, Linde K, Weidenhammer W, Hager S, Shaw D, Bauer R. Liver enzyme elevations in patients treated with traditional Chinese medicine. J Am Med Assoc 1999; 282: 28-9. 11. Melchart D, Linde K, Hager S, Kaesmayr J, Shaw D, Bauer R, Weidenhammer W. Monitoring of liver enzymes in patients treated with traditional Chinese drugs. Complement Ther Med 1999; 7: 208-16. 12. Cosyns J-P, Jadoul M, Squiffiet J-P, Wese F-X, Van Ypersele de Strihou C. Urothelial lesions in Chinese-herb nephropathy. Am J Kidney Dis 1999; 33: 1011-17. 13. Lord GM, Tagore R, Cook T, Gower P, Pusey CD. Nephropathy caused by Chinese herbs in the UK. Lancet 1999; 354: 481-2. 14. But PP-H, Ma S-Ch. Chinese-herb nephropathy. Lancet 1999; 354: 1731-2. 15. Lee C-T, Wu M-S, Lu K, Hsu K-T. Renal tubular acidosis, hypokalemic paralysis, rhabdomyolysis, and acute renal failure--a rare presentation of Chinese herbal nephropathy. Renal Fail 1999; 21: 227-30. 16. Shad JA, Chinn CG, Brann OS. Acute hepatitis after ingestion of herbs. South Med J 1999; 92: 1095-7. 17. Nambiar S, Schwartz RH, Constantino A. Hypertension in mother and baby linked to ingestion

542 of Chinese herbal medicine. West J Med 1999; 171: 152. 18. Benninger J, Schneider HT, Schuppan D, Kirchner T, Hahn EG. Acute hepatitis induced by greater celandine (Chelidonium majus). Gastroenterology 1999; 117: 1234-7. 19. Anonymous. Echinacea--allergic reactions. WHO Pharm Newslett 1999; 5/6 (May-Jun): 7. 20. Zahn KA, Li RL, Purssell RA. Cardiovascular toxicity after ingestion of "herbal ecstacy". J Emerg Med 1999; 17: 289-91. 21. Eriksson JW, Carlberg B, Hili6rn V. Lifethreatening ventricular tachycardia due to liquorice-induced hypokalaemia. J Intern Med 1999; 245: 307-10. 22. Feingold RM. Should we fear "health foods"? Arch Intern Med 1999; 159: 1502. 23. Nierenberg AA, Burt T, Matthews J, Weiss AP. Mania associated with St John's wort. Biol Psychiatry 1999; 46: 1707-8. 24. Ernst E. Second thoughts about safety of St John's wort. Lancet 1999; 345: 2014-16. 25. Tsiodras S, Shin RK, Christian M, Shaw LM, Sass DA. Anticholinergic toxicity associated with lupine seeds as a home remedy for diabetes mellitus. Ann Emerg Med 1999; 33: 715-17. 26. Navarro-Rouimi R, Charpin D. Anaphylactic reaction to castor bean seeds. Allergy Eur J Allergy Clin Immunol 1999; 54:1117. 27. HuUar TE, Sapers BL, Ridker PM, Jenkins RL, Huth TS, Farraye FA. Herbal toxicity and fatal hepatic failure. Am J Med 1999; 106: 267-8. 28. ADRAC. An adverse reaction to the herbal medication milk thistle (Silybum marianum). Med J Aust 1999; 170: 218-19. 29. Azuno Y, Yaga K, Sasayama T, Kimoto K. Thrombocytopenia induced by Jui, a traditional Chinese herbal medicine. Lancet 1999; 354: 3045. 30. Jonas WB, Ernst E. Adverse effects of acupuncture. In: Jonas WB, Levin JS, editors. Essentials of complementary and alternative medicine. Philadelphia: Lippincott Williams Wilkins, 1999: 172-5.

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31. Ernst E, White AR. Indwelling needles carry greater risks than acupuncture techniques. Br Med J 1999; 318~ 536. 32. Walsh B, Maguire H, Carrington D. Outbreak of hepatitis B in an acupuncture clinic. Commun Dis Public Health 1999; 2: 137-40. 33. Sun C-A, Chen H-C, Lu C-F, You S-L, Man YC, Ho M-S, Lin S-H, Chen C-J. Transmission of hepatitis C virus in Taiwan: prevalence and risk factors based on a nationwide survey. J Med Virol 1999; 59: 290-6. 34. Peuker ET, White A, Ernst E, Pera F, Filler TJ. Traumatic complications of acupuncture. Arch Faro Med 1999; 8: 553-7. 35. Halvorsen R. Another acupuncture pneumothorax. Acupunct Med 1999; 17: 71. 36. Trotter JF. Hepatic hematoma after deep tissue massage. New Engl J Med 1999; 341: 2019-20. 37. Jonas WB, Ernst E. Adverse effects of spinal manipulation. In: Jonas WB, Levin JS, editors. Essentials of complementary and alternative medicine. Philadelphia: Lippincott Williams Wilkins, 1999: 176-9. 38. Di Fabio RP. Manipulation of the cervical spine: risks and benefits. Phys Ther 1999; 79: 50--65. 39. Ole I. The neurological complications caused by manual therapy in spinal osteochondrosis [in Ukrainian]. Likarska Sprava 1999; 6: 79-82. 40. Rydell N, Raf L. Spinal manipulation-treatment associated with a high risk of complications [in Swedish]. Lakartidningen 1999; 96: 3536-40. 41. Hufnagel A, Hammers A, SchSnle P-W, Btihm K-D, Leonhardt G. Stroke following chiropractic manipulation of the cervical spine. J Neurol 1999; 246: 683-8. 42. Leweke F, Teschendorf U, Stolz E, Kern A, Hahn M, Dorndorf W. Doppelsietige Dissektionen der Vertebralarterien nach chiropraktischer Behandiung der Halswirbelsaule. Aktuel Neurol 1999; 26: 35-9. 43. RueUe A, Datti R, Pisani R. Thoracic epidural hematoma after spinal manipulation therapy. J Spinal Disord 1999; 12: 534--6.

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49

Miscellaneous drugs, materials, and medical devices

BISPHOSPHONATES (SED-14, 1695; SEDA-22, 520; SEDA-23, 515)

Clodronate Clodronate is a bisphosphonate that has demonstrated efficacy in patients with a variety of disorders of enhanced bone resorption, including Paget's disease, osteolytic bone metastases, and hypercalcemia of malignancy (1 R, 2R). Long-term administration of low doses of oral bisphosphonates is considered to be valuable in patients with postmenopausal osteoporosis (3C, 4c). In preclinical studies, it prevented bone loss during immobilization (5c). Reasons for premature withdrawal of clodronate in one study included refusal to continue treatment (five patients) and progressive disease of the bone (four patients) (6c). One patient refused to take clodronate from the start; seven discontinued clodronate after a median of 13 (range 0.2-23) months because of adverse events. In five patients the cause was nausea, combined with vomiting in four and diarrhea in one. After 0.9, 1.0, and 1.3 months the dosage of clodronate was reduced to 800 mg/day in three patients (one had nausea, another dyspepsia, and a third had uncharacteristic sensations in the skeleton).

Liver Although adverse events associated with bisphosphonates are usually gastrointestinal, raised aminotransferases (AsT and AIT) have also been described in many cases. However, the frequency of such changes has been poorly investigated. The Probone study is a continuing phase II trial in 610 osteopenic women 9 2001 Elsevier Science B.V. All fights reserved. Side Effects of Drugs, Annual 24 J.K. Aronson, ed.

randomized for 3 years to receive placebo or clodronate 65, 400, 800 mg/day, or 400 mg/day for 15 days out of 90 (intermittent group) (7c). During the first study year, gastrointestinal adverse events were reported by 20-26% of the patients in the five study groups, but there were no differences between groups. The highdose clodronate groups (400 and 800 mg/day) had no more hepatic adverse effects than the low-dose groups, and there were no serious adverse effects on the liver. However, these higher doses of clodronade caused a significant mean increase in A1T of 5.4-5.8 iu compared with placebo. In volunteers with initially normal aminotransferase activity the risk ratio for an increase to above normal was 1.8 with clodronate 400 mg/day and 2.5 with clodronate 800 mg/day. In these groups AsT and A1T respectively rose above the top of the reference ranges in 12% and 18% of the volunteers. The respective percentages in the placebo group were 6.2% and 7.2%. All bilirubin concentrations were normal. The authors concluded that oral clodronate may increase the activity of serum aminotransferases, and that these enzymes most likely come from the liver. Skin A case of necrobiotic palisading granuloma has been attributed to intravenous disodium clodronate (8A).

Drug administration route Intermittent intravenous clodronate is effective in preventing and treating postmenopausal bone loss (gr). In Italy, it is also available for intramuscular administration, which might be an acceptable alternative for some patients. However, intramuscular injection caused substantial pain at the site of injection, which led to withdrawal in almost 50% of the patients who received a weekly dose (10r). These results suggest that intermittent intramuscular clodronate can improve 543

544 skeletal bone density in osteoporotic postmenopausal women, but in situ pain may limit its extensive use.

Etidronate Olfactory hallucinations have been attributed to etidronate (11A).

Pamidronate Pamidronate in the disodium form, a secondgeneration bisphosphonate, has an intermediate antiresorptive activity; its continuous administration produces rapid suppression of bone resorption. In patients with osteoporosis, pamidronate increased bone mineral density by 6.8% over 2.2 years (12c). The frequently observed adverse effects with pamidronate therapy were gastrointestinal: gastritis due to either a local reaction when a high concentration of the drug stays in the mucus or by chelation with calcium ions (13c). Endocrine A patient who was receiving disodium pamidronate developed gynecomastia and of another 13 patients two more men had gynecomastia and one woman had tender swollen breasts (14A).

Mineral balance In another study of the use of pamidronate to treat immobilization hypercalcemia after acute spinal cord injury in nine patients, one patient had transient drug-related fever and four had asymptomatic hypocalcemia

(15c). Risk factors Caution should be exercised when using pamidronate in children, since there may be an immediate calcium-lowering effect and persistence of hypocalcemia, hypomagnesemia, and hypophosphatemia, particularly when high doses (e.g. 30 mg) are given intravenously (16c). The authors recommended that children be given doses of 15-20 mg.

Residronate Residronate is a pyridinyl bisphosphonate with potent antiresorptive properties. In animal studies it was about 1000 times more potent than etidronate and 3-5 times more potent than alendronate (17E), which enables the use of a lower dose and a shorter treatment regimen, with

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consequent potential minimization of adverse effects. In a randomized, double-blind, multicenter study of the efficacy, safety, and tolerability of residronate in 62 patients taking oral residronate for Paget's disease of bone, adverse effects were recorded in 29 patients (18c). Twelve had upper gastrointestinal adverse events, of which three were moderate to severe. Four other patients withdrew because of adverse events, but one only was considered to be possibly drugrelated (mild colitis). There was a transient reduction in serum calcium and phosphorus concentrations, greatest at 1 month after the start of treatment, and followed by a gradual return toward baseline concentrations.

Ethylenediamine Systemic contact dermatitis is a delayed hypersensitivity skin reaction that results from systemic exposure. Exanthematous systemic contact dermatitis from ethylenediamine has been reported with aminophylline (theophylline ethylenediamine). Disodium edetate (ethylenediamine tetra-acetic acid) has caused contact dermatitis after local application (SEDA-23, 242), and ethylenediamine cross-reacted in a patch test in a patient who had had contact dermatitis with hydroxyzine, an ethylenediamine derivative (SEDA-22, 178). Prior sensitization can occur when ethylenediamine is used as a stabilizer in creams and ointments (SED- 14, 485). Originally described in 1984, baboon syndrome is a form of systemic contact dermatitis involving the buttocks and adjacent skin in a distribution reminiscent of the erythematous buttocks seen in baboons (19A). Areas under the underwear, the inner thighs, and the axillae can also be affected. Most cases are caused by oral agents, suggesting that excretion of the antigen may be a factor. There has been a recent report in which systemic administration caused a reaction at a site that may have been previously exposed to topical ethylenediamine (2oh). A 64-year-old man developed a pruritic erythematous eruption in the perineal area a few hours after a stress test, during which he received dipyridamole and intravenous aminophylline. He had a morbilliform erythema of the perineal area under his under-

Miscellaneous drugs, materials, and medical devices clothing anteriorly, with still more prominent erythema posteriorly. The measles-like exanthem lacked epidermal changes of exudation of scaling. A series of 20 standard patch tests were negative, except for a +++ response to ethylenediamine. On being questioned, he remembered using a topical medicament prescribed for his wife on this area in the distant past. He improved uneventfully with time and avoidance. The authors proposed that the topical medicament had contained ethylenediamine. A 30-year-old woman developed a generalized urticarial reaction immediately after the intravenous administration of aminophylline (21A). Skin intradermal testing was positive to ethylenediamine. Rechallenge was positive with intravenous aminophylline but negative with diprophylline, which does not contain ethylenediamine. Most reports of aminophylline hypersensitivity reactions in the English language literature were delayed reactions. However, most of the Japanese cases were immediate reactions. Acetylation is the main metabolic pathway of ethylenediamine. Most Japanese are rapid or intermediate acetylators, while 50% of Caucasians are slow acetylators. This difference suggests an explanation for the different incidences of immediate and delayed reactions to ethylenediamine in Japanese and Caucasians.

Melatonin Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that is commonly used for sleep induction (22R). Acute exogenous administration of melatonin has produced sedation,

fatigue, self-reported vigor, confusion, and a reduction in body temperature in healthy subjects. Nervous system No serious long-term adverse effects have hitherto been reported during long-term use of melatonin, and it is therefore considered to be safe. However, dyskinesia and akathisia has been reported after withdrawal of long-term melatonin (23A). A 22-year-old woman of Ashkenazi origin, with spastic diplegia resulting from cerebral palsy and severe mental retardation, had insomnia for 6 years. She had taken melatonin 5 mg each night at 8 p.m. for the past year with a good response. However, 1 week after melatonin was stopped because of repeated vomiting she gradually developed involuntary lip-smacking movements and tongue protrusion, with extreme restlessness, moaning, and shouting. These

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symptoms continued for 2 weeks, accompanied by marked worsening of insomnia. She was restless, could not sit still, and was shouting, moaning, and grunting. Melatonin was reintroduced in gradually increasing doses, and 2 days after a dose of 5 mg was reached, the involuntary movements disappeared and her agitated state and insomnia improved. A month later, another episode of abdominal pain and vomiting made her discontinue melatonin again. Within 2 days she developed identical involuntary lip and tongue movements and akathisia. Melatonin 5 mg was readministered and all her symptoms disappeared by the next day. No antiemetic drugs were given during these episodes. This case raises an important question regarding the dopamine-blocking effect of melatonin. Like dopamine receptor blockers drugs, melatonin should be used with care because of the risk of tardive dyskinesia, which has serious morbidity and a low remission rate. Melatonin should be used with special caution in patients with organic brain damage. E n d o c r i n e Gynecomastia has been attributed to melatonin (24A). A 56-year-old man complained of painful asymmetrical gynecomastia that had gradually developed over 3 months. He had had amyotrophic lateral sclerosis with spinal onset for 3 years and had taken riluzole 50 mg bd for 2 years and melatonin for 1.5 years (1 mg/day during the first year then gradually increasing 2 mg/day). He had bilateral painful gynecomastia and homogeneously enlarged breasts. There was no galactorrhea. Sexual function had been poor since his diagnosis of amyotrophic lateral sclerosis. There were no signs or symptoms of other endocrine dysfunction. Withdrawal of melatonin resulted in complete regression of the gynecomastia within a few weeks. This report is the first of symptomatic gynecomastia attributed to melatonin, and is a warning against the uncontrolled use of apparently innocuous substances. The absence of adverse effects in healthy people taking melatonin for various reasons does not mean safety in certain diseased populations.

Nicotine (SED-14, 472, 1701; SEDA-21, 498; SEDA-22, 521; SEDA-23, 517) Nicotine is the drug of choice to assist smoking cessation. In a recent meta-analysis of 42 nicotine chewing gum studies and nine patch studies, comprising 17 000 subjects, the odds ratios

546 of long-term success were 1.61 for gum and 2.07 for patch compared with placebo (25M). However, effective use of nicotine gum requires careful instructions. Transdermal uptake of nicotine from patches is about 1 mg/hour (26r). Large multicenter studies of 16-hour and 24-hour nicotine patches in primary care have shown twice the success rate of placebo (27c). The main objectives of the Collaborative European Anti-Smoking Evaluation (CEASE) were to examine whether long-term success rates (i.e. complete abstinence sustained for 1 year) could be increased by using higher than standard doses of transdermal nicotine, and/or by prolonging the patch treatment period (28c). There were four cases of myocardial infarction during the study period, which comprised 950 treatment years and 1700 study years. One 59-year-old man had a myocardial infarct during treatment with the 25 mg nicotine patch, and one 48-year-old man and one 50-year-old man had myocardial infarcts after discontinuing treatment with 15 mg; one 66-year-old man had a myocardial infarct in the placebo ann. This compared with the 10.2 cases expected during the study period, based on calculations using data from the Framingham study (29c). The overall incidence of adverse events was low, and they were generally transient. In order to examine possible dose-related adverse events, the occurrence of events during the first 8 weeks of treatment in each of the three groups (25 mg, 15 mg, and placebo) was analysed, and nausea and vomiting were the only reported symptoms, with a higher frequency in the 25 mg group (7.3%) than the 15 mg group (5.4%). Skin tolerability in patients with a history of eczema, psoriasis, or other skin disorders has been studied in 1481 participants (30c). The adverse effects reported were erythema,

rash, pruritus, irritation, edema at the site of application, musculoskeletal pain related to the application site, dreaming, and other sleep disturbances. In a pilot study of oral nicotine in the treatment of primary sclerosing cholangitis in eight patients, only five completed 1 year of treatment; two had no adverse effects, but three had to temporarily reduce the dose of nicotine because of nausea, dizziness, insomnia, or lightheadedness, but later resumed the full dose (31c). One patient completed only 4 months of treatment because of dizziness and bouts of palpitation, even at the lowest dose, requiring per-

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manent discontinuation of nicotine. One patient with ulcerative colitis, who was completely asymptomatic at the time of entry, had insomnia and watery diarrhea shortly after starting oral nicotine; however, his ulcerative colitis later responded to transdermal nicotine. One patient had moderately active Crohn's colitis and bloody diarrhea treated with corticosteroid enemas and mesalazine; his bloody diarrhea increased shortly after starting oral nicotine, requiring drug withdrawal and an increased frequency of corticosteroid enemas; nicotine was not restarted.

Miscellaneous compounds Reported adverse effects of other substances are listed in Table 1.

MEDICAL DEVICES

Catheters (SED-14, 1692; SEDA-21, 501) Venous access for long-term parenteral nutrition requires centrally-placed catheters. Tunnelling of catheters under the skin from the entry point to the appropriate vein minimizes the risk of infection, and the inclusion of an internal cuff on the catheter provides a more reliable subcutaneous anchor point. The purpose of the cuff is to fibrose to the wall of subcutaneous tissue, helping to prevent dislodgement of the catheter and reduce the risk that infection will migrate from the entrance site in the skin. Cuffed catheters can be composed of polyurethane or silicone. It has been suggested that the former is better, because they are theoretically less thrombogenic. However in a recent prospective study there was no difference between the two types (46c). Mean catheter life-spans were similar, as were complication rates (including sepsis, obstruction, dislodgement, and thrombosis). However, fractures were entirely associated with the detachable flowcontrol device. The authors therefore concluded that there was little evidence to support the hypothesis that polyurethane catheters offer more security in long-term parenteral nutrition. Cardiovascular A major complication of intravenous infusion is thrombophlebitis, which is a principle limitation of peripheral parenteral

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Table 1. Miscellaneousreports Compound

Adverse effect(s)

References

Calcium Cyanamide Fluorescein Lactose Lecithin Monofluorophosphate Parathion Phosphate infusion Polidocanol 1% solution Polyethyleneglycol Polyvinylpyrrolidone Sodiummetabisulfate

Hypercalciuria Lichenoid skin eruptions,eczematous erythroderma Non-convulsivestatus epilepticus,anaphylaxis Skin eruptions Atopic dermatitis Leg pain Death Calcified right atrial thrombus Emboliacutis medicamentosa Contact dermatitis Contact allergy (facial eczema) Allergic contact dermatitis

(32r) (33A, 34A) (35A, 36A) (37A) (38A) (39A) (40A) (41A) (42A) (43A) (44A) (45A)

nutrition. Its precise pathogenesis is unclear, but venospasm has been proposed as the most likely cause. However, in a recent study with ultrasound techniques to monitor vein caliber, there was no evidence to support this hypothesis, although thrombophlebitis was observed (47c). The author suggested that the initiating event may be venous endothelial trauma, caused by the venepuncture itself, abrasion at the catheter tip, or the delivery of the feeding solution. Venous reactions could also theoretically be influenced by the composition of the fat emulsion, because long-chain triglycerides in particular generate prostaglandin synthesis which can in turn effect vein tolerance. This potentially important issue has been assessed in a randomized comparative trial of peripheral parenteral nutrition regimens with fat emulsions containing either long-chain triglycerides alone or in equal proportions with mediumchain triglycerides (48c). All other factors were standardized. Long-chain triglyceride-based fat emulsions significantly prolonged the fife of the peripheral vein, compared with mixtures of medium and long-chain triglycerides. The authors hypothesized that this effect was due to a reduced reaction of the venous epithelium to the irritating nutritional mixture. Cardiac tamponade is a serious complication of central venous catheterization. A classical case history has recently been described with detailed discussion of prevention and management (49at). Most serious complications,

including air embolism, pneumothorax, hemothorax, chylothorax, chylopericardium, rupture of the right atrium, ventricular dysrhythmias, and cardiac tamponade, are essentially mechanical injuries relating to catheter insertion. Cardiac tamponade can be caused by acute perforation of the superior vena cava during insertion. Alternatively, a delayed event may be due to catheter-related erosion of the vascular wall, either in the vena cava or ventricular wall. The consequences are impairment of diastolic filling and a dramatic decrease in cardiac output, with a very high death rate (about 70%). A 63-year-old man with cancer of the esophagus developed severe dysphagia. A central venous catheter was introduced for presurgical parenteral nutrition and 3 hours later he reported severe epigastric and retrosternal pain. His condition deteriorated rapidly, with loss of consciousness, a weak pulse, hypotension, distant heart sounds, and jugular venous distension. A chest X-ray showed an enlarged mediastinal shadow and an electrocardiogram showed reduced voltage. The catheter was promptly removed. An emergency laparotomy showed only hepatic engorgement and about 100 ml of ascites, but at thoracotomy the pericardial sac was distended by about 500 ml of clear fluid. There was no apparent injury to the right subclavian artery or evidence of pleural hemorrhage. The authors concluded that the right ventricle had been perforated by the catheter and they pointed out that these events can be insidious, and can take several months before symptoms suddenly start, requiring quick diagnosis

Chapter 49

548 and immediate intervention. This includes immediate removal of the catheter and often also emergency surgical intervention. Infection risk Infective endocarditis is a serious complication of centrally-placed venous access devices. The successful treatment in situ of a large thrombus associated with the tip of the catheter has been described (50A). The antibiotic regimen was gentamicin and vancomycin, both delivered via the venous access device; vancomycin was allowed to remain in situ between each 8 hourly dosing. This regimen successfully eradicated the thrombus within 3 weeks, without removal of the line.

Blood glucose meters Sports like hiking and skiing at moderate high altitude make glucose estimation mandatory for people with diabetes. Changes in temperature, PO2, and humidity can result in errors in blood glucose determination. When tested at 3000 meters (10000 feet) the glucose meter Elite (Bayer Diagnostics) had a tendency to overestimate glucose concentrations, while the Life Scan One Touch II had a tendency to underestimate them (51r). The bias was not clinically meaningful, although some care may be necessary when low or intermediate blood glucose concentrations are measured with the Glucometer Elite.

SURGICAL DEVICES

MATERIALS

AND

Silicone (SED-14, 1686) Silicone gel breast prostheses are associated with a mild foreign body response resulting in the formation of a collagenous capsule around the prosthesis (52 c, 53c). Although many such patients may have evidence of a microscopic granulomatous foreign body reaction on examination of the capsular material at explantation of a prosthesis, it is unusual to have large palpable granulomas, even in the presence of rupture or leakage (54r). Nevertheless, rare patients have had severe local inflammation and complications resulting from silicone migration to the axilla, arm, or abdominal wall (55 A,

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56A). Three patients had significant problems with deforming granulomas after implant rupture (57A). More importantly, they suffered the consequences of silicone gel migrating down the arm. Once silicone gel leaves the implant it is not biologically inert and in some people it can elicit profound pathological responses. The FDA has issued a ruling requiring the filing of a premarket approval application or a notice of completion of a product development protocol for silicone inflatable breast prostheses, a generic type of medical device intended to enlarge or reconstruct the female breast. This device is made of a silicone shell that is inflated with sterile isotonic saline (58R). The agency has taken this action because the requirement of premarket approval will provide an opportunity to assess more fully the risks and benefits of these devices, in order to determine whether there is reasonable assurance of their safety and effectiveness, or what regulatory course should be taken in the absence of such assurance. Silicone gel-filled breast prostheses have already been subjected to this requirement. Local complications have been associated with both types of breast prostheses, including

rupture, pain, capsular contracture, disfigurement, and serious infection, which may lead to medical interventions and repeated surgery.

Talc (SED-14, 1687) Talc is a three-layered magnesium sheet with lubricant properties; it is rarely found as a pure entity in nature. Its mechanism of action in pleurodesis has not been fully elucidated, although talc is thought to stimulate a typical local inflammatory response, with reduced fibrinolytic activity, mesothelial cell injury, and fibroblast proliferation. Pneumonitis or respiratory failure may be secondary to downstream inflammatory mediators from more proximal talc injury (59c). This acute phase inflammatory response is dose-related (60c, 61 c) and is inhibited by corticosteroids (62c). Talc may also have an adhesion stimulating quality, since empyema alone stimulates a typical inflammatory response but does not lead to pleurodesis (63c). In fact, talc stimulates intercellular adhesion molecule-1 in mesothelial cells (64r). The mechanism of chronic fibrosis may involve continuous fibroblast activation by foreign body giant cell released mediators or macrophages.

Miscellaneous drugs, materials, and medical devices Sterile talc is therefore currently the agent of choice for pleurodesis. Its success rate is excellent and it is generally well tolerated. However, a recent case offulminant pneumonitis following talc pleurodesis has prompted a review of the existing experience (65~-). Of 78 patients with recurrent pleural effusions or pneumothorax treated by pleurodesis five had bilateral pleural effusions, resulting in a total of 89 procedures. Talc was administered via poudrage in 19 procedures and in a slurry in 70. The dose was 5 g in 85 procedures, and 2.5 and 10 g each in two procedures. Talc was administered in a slurry with 50-500 ml of isotonic saline and 20-30 ml of 1% lidocaine. Of the patients who presented with malignant effusions, 18 had a primary carcinoma in the lung, 12 in the ovary, and 10 in the breast; there were six cases of lymphoma; 13 patients had less common primaries. Nine patients had benign or undiagnosed effusions and nine had spontaneous pneumothorax.

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Of the procedures evaluated 19 involved only minor complications, includingfever over 38.1~ within 12 hours of pleurodesis in 13, asymptomatic hypoxemia in 19, dyspnea relieved by oxygen in six, and increased need for narcotics in five. Subcutaneous emphysema, local infection, and asymptomatic hypotension each occurred after one procedure. There were major complications in 11 patients, including one patient with pulmonary embolism, three with unilateral pulmonary edema, eight who developed bilateral pulmonary edema, and one who died within 24 hours after bilateral talc administration. Patients developed respiratory complications after 24 of 28 talc pleurodesis procedures. The most significant respiratory complication was adult respiratory distress syndrome, defined by bilateral diffuse infiltrates on chest roentgenography and hypoxemia requiting mechanical ventilation, which occurred after eight procedures in seven patients. This figure includes one patient who died after simultaneous bilateral talc poudrage.

REFERENCES 1. Kanis JA. Clodronate: a new perspective in the treatment of neoplastic bone disease. Bone 1987; 8 Suppl: 1-86. 2. Kanis JA. McCloskey EV, Paterson AHG. Use of diphosphonates in hypercalcaemia due to malignancy. Lancet 1990; 335: 170-1. 3. Storm T, Thamsborg G, Genant HK, Steiniche T, Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. New Engl J Med 1990: 322: 1265-71. 4. Walkema R, Vismans FJFE, Papapoulos SE, Pauwels EKJ, Bijvoet OLM. Maintained improvement in calcium balance and bone mineral content in patients with osteoporosis treated with the bisphosphonate APD. Bone Miner 1989; 5: 183-92. 5. Minaire P, Berard E, Meunier PJ, Edouard C, Goedert G. Effects of disodium dichloromethylene diphosphonate on bone loss in paraplegic patients. J Clin Invest 1981; 68: 1086-92. 6. Kristensen B, Ejlertsen B, Groenvold M, Hein S, Loft H, Mouridsen HT. Oral clodronate in breast cancer patients with bone metastases: a randomized study. J Int Med 1999; 246: 67-74. 7. Laitinen K, Taube T. Clodronate as a cause of aminotransferase elevation. Osteoporosis Int 1999; 10: 120-2. 8. Lalinga AV, PeUegrino M, Laurini L, Miracco C. Necrobiotic palisading granuloma at injection site of disodium clodronate: a case report. Dermatology 1999; 198: 394-5.

9. Kaastad TS, Reikeras O, Madsen JE, Narum S, Stromme JH, Obrant KJ, Nordsletten L. Effects of clodronate on cortical and trabecular bone in ovariectomized rats on a low calcium diet. Calcif Tissue Int 1997; 61: 158-64. 10. Rossini M, Braga V, Gatti D, Gerardi D, Zamberlan N, Adami S. Intramuscular clodronate therapy in postmenopausal osteoporosis. Bone 1999; 24: 125-9. 11. Burnet SP, Petrie JP. "Wake up and smell the roses" a drug reaction to etidronate. Aust NZ J Med 1999; 92: 93. 12. PapapoulosSE. The role of biphosphonates in the prevention and treatment of osteoporosis. Am J Med 1993; 95: 48S-52S. 13. HerreraJA, Sarabia MO, Gonzalez MM. Effects of treatment with biphosphonates on gastrointestinal and esophageal mucosa in patients with osteoporosis: pamidronate versus alendronate. Curr Ther Res 1996; 60: 307-13. 14. Russell L. Disodium pamidronate. Aust Prescr 1999; 22: 30. 15. MassagliTL, Cardenas DD. Immobilization hypercalcemia treatment with pamidronate disodium after spinal cord injury. Arch Phys Med Rehabil 1999; 80: 998-1000. 16. De Schepper J, De Pont S, Smitz J, De Coster D, Schots R, Otten J. Metabolic disturbances after a single dose of 30 mg pamidronate for leukemiaassociated hyperealcaemia in a 11-year-old boy. Eur J Pediatr 1999; 158: 765-6.

550 17. Geddes AD, D'Souza SM, Ebetino FH, Ibbotson KJ. Bisphosphonates: structure-activity relationship and therapeutic implications. In: Heersche JNM, Kanis JA, editors. Bone and Mineral Research. Amsterdam: Elsevier, 1994: 265-74. 18. Miller PD, Brown JP, Sifts ES, Hoseyui MS, Axelrod DW, Bekker PJ. A randomized, doubleblind comparison of residronate and etidronate in the treatment of Paget's disease of bone. Am J Med 1999; 106: 513-20. 19. Andersen KE, Hjorth N, Menne T. The baboon syndrome: systematically-induced allergic contact dermatitis. Contact Dermatitis 1984; 10: 97-100. 20. Guin JD, Fieldes P, Thomas KL, Baboon syndrome from iv aminophylline in a patient allergic to ethylenediamine. Contact Dermatitis 1999; 40: 170-1. 21. Yoshizawa A, Araki Y, Kobayashi N, Kudo K. A case of aminophylline hypersensitivity reaction due to ethylenediamine. Jpn J Allergol 1999; 48: 1206-11. 22. Brzezinski A. Melatonin in humans. New Engl J Med 1997; 336: 186-93. 23. Giladi N, Shabtai H. Melatonin induced withdrawal emergent dyskinesia and akathisia. Mov Disord 1999; 14: 381-2. 24. De Bleecker JL. Lamont BH, Verstraete AG, Schelfhout VJ. Melatonin and painful gynecomastia. Neurology 1999; 53: 435-6. 25. Silagy C, Mant D, Fowler G, Lancaster T. The effect of nicotine replacement on smoking cessation. In: Lancaster T, Silagy C, Fullerton D, editors. Tobacco Addiction Module of the Cochrane Database of Systematic Reviews. Oxford, The Cochrane Collaboration, 1997: 1-18. 26. Palmer KJ, Buckley MM, Faulds D. Transdermal nicotine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an aid to smoking cessation. Drugs 1992; 44: 498-529. 27. Imperial Cancer Research Fund General Practice Research Group. Randomized trial of nicotine patches in general practice: results at one year. Br Med J 1994; 308: 1476-7. 28. Tonnesen P, Paoletti P, Gustarsson G, Russell MA, Saracci R, Gulsvik A, Rijcken B, Sawe U. Higher dosage nicotine patches increase one-year smoking cessation rates: results from the European CEASE trial. Eur Resp J 1999; 13: 238-46. 29. The Framingham Study. An epidemiological investigation of cardiovascular disease. US Department of Health Education and Welfare. Public Health Service. NIH. National Heart and Lung Institute. DHEW publication No (NIH) 76-1083. April 1976. 30. Gourlay SG, Forbes A, Marftner T, McNeil JJ. Predictors and timing of adverse experiences during transdermal nicotine therapy. Drug Saf 1999; 20: 455-555. 31. Angulo P, Bharucha AE, Jorgensen A, DeSotel CK, Sandborn WJ, Laruss NF, Lindor KD. Oral nicotine in treatment of primary sclerosing

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cholangitis. A pilot study. Dig Dis Sci 1999; 44: 602-7. 32. Adachi JD, Ioannidis G. Calcium and vitamin D therapy in corticosteroid-induced bone loss: what is the evidence? Calcif Tissue Int 1999; 65: 332-6. 33. Aguilar A, Gallego MA, Pique E. Lichenoid drug eruption due to cyanamide. Int J Dermatol 1999; 38: 950-1. 34. Abajo P, Feal C, Sanz-Sanchez T, SanchezPerez J. Garcia-Diez A. Eczematous erythroderma induced by cyanamide. Contact Dermatitis 1999; 40: 160-1. 35. Coeytaux A, Reverdin A, Jallon P, Nahory A. Non convulsive status epilepticus following intrathecal fluorescein injection. Acta Neurol Scand 1999; 100: 278-80. 36. Butrus SI, Negvesky GJ, Rivera-Valazques PM, Schwartz LB. Serum tryptase: an indicator of anaphylaxis following fluorescein angiography. Graefe's Arch Clin Exp Ophthalmol 1999; 237: 433-4. 37. Cox NH, Duffey P, Royle J. Fixed drug eruption caused by lactose in an injected botulinum toxin preparation. J Am Acad Dermatol 1999; 40: 263-4. 38. Palm M, Moneret-Vautrin DA, Kanny G, Denery-Papini S, Fremont S. Food allergy to egg and soy lecithins. Allergy 1999; 54: 111617. 39. Ringe JD, Kipshoven C, Coster A, Umback R. Therapy of established postmenopansal osteoporosis with monofluorophosphate plus calcium: dose-related effects on bone density and fracture rate. Osteoporosis Int 1999; 9: 171-8. 40. Hamen J, Wennig R. Diagnostic d'une intoxicaiton aigu8 au Parathion et consequences medicolegales. Acta Clin Belg 1999; 54: 54-8. 41. Spencer K, Weinert L, Pentz WH. Calcified right atrial mass in a woman receiving long-term intravenous phosphate therapy. J Am Soc Echocardiogr 1999; 12: 215-17. 42. Geukens J, Rabe E, Bieber T. Embolia curls medicamentosa in the foot after sclerotherapy. Eur J Dermatol 1999; 9: 132-3. 43. Guijarro SC, Sanchez-Perez J, Garcia-Diez A. Allergic contact dermatitis to polyethylene glycol and nitrofurazone. Am J Contact Dermatitis 1999; 10: 223-7. 44. Smith HR, Armstrong K, Wakelin SH, White IR. Contact allergy to PVP/eicosene copolymer. Contact Dermatitis 1999; 40: 283. 45. Tucker SC, Yell JA, Beck MH. Allergic contact dermatitis from sodium metabisulfite in Tftmovate cream. Contact Dermatitis 1999; 40: 164. 46. Beau P, Matrat S. A comparative study of polymethane and silicone cuffed-catheters in long-term home parenteral nutrition patients. Clin Nutr 1999; 18: 175-7. 47. Everitt NJ. Effect of prolonged infusion on vein calibre: a prospective study. Ann R Coll Surg Engl 1999; 81: 109-12. 48. Smirtniotis V, Kotsis TE, Antoniou S, Kostopanagiotou G, Labrou A, Kourias E. Incidence of

Miscellaneous drugs, materials, and medical devices vein thrombosis in peripheral intravenous nutrition: effect of fat emulsions. Clin Nutr 1999; 18: 79-81. 49. Gluszek S, Kot M, Matykiewicz J. Cardiac tamponade as a complication of catheterization of the subclavian vein--prevention and principles of management. Nutrition 1999; 15: 580-2. 50. Venugopalan P, Louon A, Akinbami FO, Elnour IB. Endocarditis with a large thrombus complicating a central venous access device. Ann Trop Paediatr 1999; 19: 101-3. 51. Pecchio O, Maule S, Migliardi M, Trento M, Veglio M. Effects of exposure at an altitude of 3000 m on performance of glucose meters. Diabetes Care 2000; 23: 129-31. 52. Barker DE, Retsky MI, Schultz S. "Bleeding" of silicone from bag-gel breast implants, and its clinical relation to fibrous capsule reaction. Plast Reconstr Surg 1978; 61: 836-41. 53. Van Diest PJ, Beekman WH, Hage JJ, Pathology of silicone leakage from breast implants. J Clin Pathol 1998; 51: 493-7. 54. Brown SL, Silverman BG, Berg WA. Rupture of silicon-gel breast implants: cause, sequelae, and diagnosis. Lancet 1997; 350: 1531-6. 55. Teuber SS, Ito LK, Anderson M, Gershwin ME. Silicone breast implant-associated scarring of the arm. Arch Dermatol 1995; 131: 54--6. 56. Sanger JR, Matloub HS, Yousif NJ, Komorawski R. Silicone gel infiltration of a peripheral nerve and constrictive neuropathy following rapture of a breast prosthesis. Plast Reconstr Surg 1992; 89: 949-52.

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57. Teuber SS, Reilly DA, Howell L Oide C, Gershwin ME. Severe migratory granulomatous reactions to silicone gel in three patients. J Rheumatol 1999; 23: 699-704. 58. Anonymous. Silicone inflatable breast prosthesis--requirement for premarket approval. WHO Pharm Newslett 1999; 9/12 (Sep--Dec): 22. 59. Kennedy L, Harley RA, Sahn SA, Strange C. Talc slurry pleurodesis: pleural fluid and histological analysis. Chest 1995; 107: 1707-12. 60. Rinaldo JE, Owens GR, Rogers RM. Adult respiratory distress syndrome following intrapleural instillation of talc. J Thorac Cardiovasc Surg 1983; 85: 52345. 61. Todd TR, Delarue NC, Ilves R. Talc poudrage for malignant pleural effusion. Chest 1980; 78: 542-3. 62. Xie C, Teixeira LR, Mc Govern JP, Light RW. Systemic corticosteroids decrease the effectiveness of talc pleurodesis. Am J Respir Crit Care Med 1998; 157: 1441-4. 63. Kennedy L, Sahn SA. Talc pleurodesis for the treatment of pneumothorax and pleural effusion. Chest 1994; 106: 1215-22. 64. Nasreen H, Hartman DL, Mohammed KA, Antony VB. Talc-induced expression of C-C and C-X-C chemokines and intercellular adhesion molecule-1 in mesothelial cells. Am J Respir Crit Care Med 1998; 158: 971-8. 65. Rehse DH, Aye RW, Florence MG. Respiratory failure following talc pleurodesis. Am J Surg 1999; 177: 437-40.

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5O

The WHO international drug monitoring programme

History The WHO International Drug Monitoring Programme was established in 1968 as a pilot project, with the participation of ten countries that had organized national pharmacovigilance systems at that time. The intent was to develop international collaboration in order to make it easier to detect rare adverse drug reactions not revealed during clinical trials. The Centre for International Drug Monitoring was moved from WHO headquarters in Geneva, Switzerland to a WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden in 1978. This was the result of an agreement between WHO and the Swedish Government, by which Sweden assumed the operational responsibility for the Programme. WHO headquarters in Geneva retained responsibility for policy matters. The Collaborating Centre is often referred to as the Uppsala Monitoring Centre (UMC).

Current programme structure At present 60 countries are active members of the WHO Programme. Another six countries have formally applied for membership; they are considered associated members while the issue of the technical compatibility of their reports with the requirements of WHO is established. Member countries and associated member countries are listed in Table 1. In each country a national centre, designated by the competent health authority, is responsible for collecting, processing, and evaluating adverse reaction case reports submitted by health professionals. Information obtained from these reports is passed back to the profes9 2001 Elsevier Science B.V. All rights reserved. Side Effects of Drugs, Annual 24

J.K. Aronson, ed.

sionals on a national basis, but is also submitted to the WHO Centre for inclusion in the international database. Collectively the centres annually provide over 200 000 individual reports to WHO of reactions suspected of being drug-induced. The cumulative database of the WHO Programme now comprises over two and a half million case reports. Case reports submitted to the WHO Centre according to an agreed format, are checked for technical correctness and then incorporated into the international data base in a weekly routine. The material is screened at least four times a year for new and serious reactions, as well as the reporting frequencies of associations of particular interest. Many additional examinations of the data are made on an ad hoc basis. The WHO Centre in Uppsala currently has 20 staff members. Its Director is Professor I. Ralph Edwards, a clinical toxicologist. This staff is supported by people from various national centres, about 50 consultants of various kinds, as well as companies that provide particular specialist services. The Centre's strategy is to create a global network to tackle drug safety issues optimally.

Signal generation A combination of automatic signalling devices and scanning by experienced medical personnel is considered most advantageous to successfully fulfil the original aim of the programme, i.e. the early identification of new adverse drug reactions. In 1998 a new set of methods (1), developed at the Uppsala Monitoring Centre, using a Bayesian Confidence Propagation Neural Network (BCPNN) in analysing the database, was put into routine use. This method provides a quantitative measure of the strength of association of a drug/reaction combination in the database. Combinations that occur more frequently

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Table 1. Membersof the WHO lnternational Drug Monitoring Programmeand their year of entry Country

Year of entry

Country

Year of entry

Country

Year of entry

Argentina Australia Austria Belgium Bulgaria Canada Chile China, PR Costa Rica Croatia Cuba Cyprus Czech Republic Denmark Estonia Fiji Islands Finland France Germany Greece

1994 1968 1991 1977 1975 1968 1996 1998 1991 1992 1994 2000 1992 1968 1998 1999 1974 1986 1968 1990

Hungary Iceland India Indonesia Iran Ireland Israel Italy Japan Korea, Republic of Macedonia Malaysia Mexico Morocco Netherlands New Zealand Norway Oman Philippines Poland

1990 1990 1998 1990 1998 1968 1973 1975 1972 1992 2000 1990 1998 1992 1968 1968 1971 1995 1995 1972

Portugal Romania Russia Singapore Slavak Republic South Africa Spain Sri Lanka Sweden Switzerland Tanzania Thailand Tunisia Turkey United Kingdon USA Venezuela Vietnam Yugoslavia FR Zimbabwe

1993 1976 1998 1993 1993 1992 1984 2000 1968 1991 1993 1984 1993 1987 1968 1968 1995 1999 2000 1998

Associated member countries Armenia Egypt Ghana

than expected compared with the generality of the database are highlighted. When the new data have been processed and entered into the A D R database, a B C P N N scan is run to generate statistical measurements for each d r u g - A D R combination. The resulting Combinations Database (Combination: Adverse drug reaction (ADR) data elements occurring together in ADR reports) is made available to national centres and to pharmaceutical companies, in the latter case including only information on the company's own patented products. The database is presented in a computerized form which facilitates searching and sorting of the information. An Associations Database (Association: Combinations selected from a database on a quantitative basis) is generated by selecting those combinations that pass a pre-set threshold. Based on the results of the test runs of the B C P N N the threshold for associations is that of the lower 95% confidence limit of the IC

Netherlands Antilles Pakistan Peru

value crossing zero when a new batch of reports is added. All associations are followed automatically for 2 years, the data being checked at 6-monthly intervals. After the final listing, an association may be reintroduced for another 2-year followup. The associations are also copied to a cumulative log file (history file), which will serve as a filter to exclude combinations that have in previous quarters passed the threshold. This will prevent d r u g - A D R combinations with a confidence limit fluctuating around zero from being fed into the review process repetitiously. A panel of experts has been established to analyse reactions pertaining to particular body systems. The associations database is sent to the expert review panel for evaluation. Before distributing the database, associations are checked against standard reference sources (e.g. the Physician's Desk Reference, Martindale's Extra Pharmacopoeia), and the published literature (using, for example, Medline and Reac-

554 tions Weekly). This facilitates the review and identifies those associations that have been, if not generally known, at least identified previously. Searching and sorting of the associations data can be done, not only on drug, ADR, and the various statistical measurements, but also on System/Organ/Class (SOC) and on therapeutic drug groups using the AnatomicalTherapeutic-Chemical (ATC) classification. To ensure that there are at least two reviewers per SOC, we intend to extend the panel of reviewers beyond the 35 experts involved today. To the Associations stage, the process is purely quantitative, but clinical knowledge and judgement is necessary for the evaluation of associations, and is provided by the national centres and expert reviewers. Short summaries of their findings are circulated to participating national centres in a memorandum called Signal | . An investigation has demonstrated that the WHO Programme is successful in finding new drug-ADR associations at an early stage and in providing useful information about them to national centres (2). Individualized sections of the Signal document will be provided to companies on a subscription basis (only on their patented products). To aid the expert reviewers, and also to facilitate interpretation of the information presented in the Signal document, a set of guidelines is being established. As with the associations, all signals will be automatically reassessed on a 6-monthly basis for 2 years, with a possibility of re-introduction for followup, and also copied to a history file for easy tracking. With the new follow-up procedures we have introduced a mechanism by which signals can be re-evaluated following the acquisition of new information. This enables, for example, renewed consideration of associations for which there initially was not enough information to merit signalling. Signals that are later supported by new evidence can also be highlighted. The nature of the signal will determine what measures need be taken in terms of follow-up. A larger number of variables than the routine drug-ADR combinations can also be considered using the Bayesian approach, as described above. For example, a specific pair of adverse reactions can be highly associated with a specific drug, or the effects can be determined of any other report variable or combination of

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variables on the "information component" values. Also the effects of including drugs reported as "concomitant medications" can be studied using the BCPNN. One of the outcomes of these analyses may be to identify patient subgroups that may be at particularly high risk of getting a specific adverse reaction when they have taken a specific drug. Another possibility is to establish that a drug safety problem is related to a particular country or region, or a certain time period. However, it should be pointed out that in order for these data to be useful there needs to be a substantial number of cases reported.

A reference source The database of the WHO Programme is a unique reference source used in many different circumstances. When a national centre receives the first report of an unfamiliar drug-reaction association the WHO database is often consulted to find out whether a similar observation has been made elsewhere in the world. If so, the initial signal may be strengthened. National centres are provided with an annual reference document that provides summary figures of suspected drug-reaction associations reported to the WHO. On-line search facilities are also at the disposal of national centres, for up-to-date checking of the current status of reports. From the database, cohorts of patients affected by similar kinds of drug associated reactions may be retrieved. By looking for common features in these reports, risk factors and hypotheses for underlying mechanisms may be revealed.

Quantification There is a general need to quantify adverse drug reaction information. Under-reporting of adverse reactions in routine monitoring is the norm. However, the degree of under-reporting differs from time to time, from place to place, and between drugs. The WHO Centre is working jointly with IMS International to analyse adverse reaction reports together with drug use data from different countries. This allows national differences in reporting rates to be further analysed for reasons that may be due to differences in indications for use, medical practice, demographic differences, etc. (3, 4). It is hoped that this type of analysis of international data

The WHO international drug monitoring programme

will serve as a guide to the need for more precise pharmacoepidemiologicai investigations.

A clearing house for information The Uppsala Monitoring Centre has an important role to play as a communication centre--a clearing house for information on drug safety at the service of drug regulatory agencies, the pharmaceutical industry, researchers, and other groups in need of drug safety information. Each year about 325 requests for special database searches and investigations are received from these parties. In addition, flexible on-line retrieval programmes are made available, by which the database users can perform a variety of standardized searches by themselves. Access for non-member parties is subjected to confidentiality restrictions agreed by Programme members. Some countries maintain the right to refuse the release of their own information if they so wish. Use of the information released is subject to a caveat document as to its proper use. Detailed manuals for the on-line service and the customized retrievals on request are available from the Uppsala Centre. National centres were provided with a threemonthly Adverse Reactions Newsletter from 1982 to 1999. The Newsletter contained reviews of national adverse drug reactions bulletins and news of drug problems being investigated in various countries, supplemented by figures from the WHO register. It was recently decided to incorporate this information into the WHO Pharmaceuticals Newsletter, distributed by the Health Technology & Pharmaceuticals Department of WHO headquarters, leading to a wider distribution of the information to all member countries of WHO. Through an agreement with the publishing company Adis International, the Uppsala Monitoring Centre offers national centres subscriptions for the review journal Reactions Weekly| at heavily reduced rates. This service provides participating countries with good coverage of the world adverse reactions literature. Uppsala Reports | is the name of a bulletin that is made freely available to all interested parties by the UMC. It provides an easy-toread account of news about pharmacovigilance, the WHO Programme, its members, and its services. Communications within the WHO Programme has improved with the increasing

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use of electronic communications media. The Uppsala Monitoring Centre is maintaining an email discussion group called "Vigimed", which allows rapid exchange of information around the world on drug safety matters. Membership is restricted to persons connected to national pharmacovigilance centres. The Internet home page of the WHO Programme (http://www.who-umc.org) was introduced in 1996. It is intended to be developed into a dynamic tool for communicating with all clients of the Uppsala Monitoring Centre. Recently intemet-based seminars and training courses have been introduced on the UMC web site. The Uppsala Monitoring Centre publishes a book "National Pharmacovigilance Systems-Country Profiles and Overview" (2nd edition, 1999), in which the operating procedures of the national centres participating in the WHO Programme are described.

Terminologies and standards The WHO Programme has assumed responsibility for developing a standardized adverse reactions terminology (WHO--ART) and a comprehensive index of reported drugs (WHODD), both of which have a utility beyond their importance to the monitoring system. These tools are used in the pre-marketing safety area, as well as for post-marketing studies by many pharmaceutical companies. W H O ART has also been adopted by the International Programme on Chemical Safety as the medical terminology to describe poisoning incidents. The WHO Drug Dictionary is unique in its coverage of drugs marketed throughout the world. It is available in paper print or as computer files. The Uppsala Centre is developing it further to incorporate more detailed information and make it compatible with the prestandard proposed by the European Committee for Standardization (CEN). The Centre is also working with XML standards for its terminologies and dictionaries, as well as supporting such work with ICD10. The use of XML versions of terminologies will greatly enhance their combined utility and availability, for example by internet. Within the WHO Programme definitions of commonly used terms like adverse reaction, side effect, adverse event, and signal, have been

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worked out (5). These definitions contribute to a harmonized way of communicating both inside and outside the Programme.

Education In order to foster education and communication in pharmacovigilance, every other year the WHO Centre offers a 2-week training course in Adverse Reactions and Adverse Reactions Monitoring in Uppsala, to which 25 health-care professionals are accepted. The course is focused on methods used in pharmacovigilance and the practicalities of managing a drug monitoring centre. It also offers hands-on experience in using the database of the WHO Programme. A separate module provides an introduction to wider issues in pharmacoepidemiology. There is an increasing trend towards local and regional meetings and courses in pharmacovigilance. The WHO Programme often takes part in such meetings, particularly those organized in developing countries, to provide support and technical advise.

Annual meetings Every year representatives of national centres are invited to a meeting arranged jointly by WHO and one of the participating countries. At these meetings technical issues are discussed, both in relation to how to improve global drug monitoring in general and concerning individual drug safety problems. Since the meetings have very high attendance rates, they are important for the establishment and maintenance of personal relationships, subsequently contributing to good communications.

Programme development The Uppsala Monitoring Centre is currently exploring a number of leads to improve further the use of the information collected and to develop the services of the Programme. By furtJaer developing the method of Bayesian artificial neural networks (see above) for the analysis of the large amount of data in the WHO database it is expected that it will be possible to detect hitherto unrevealed risk factors for the development of drug-related ailments.

S. Olsson and LR. Edwards

9

In response to the challenge to safety monitoring offered by traditional herbal remedies, the WHO Centre has taken initiatives to improve the classification systems for such medicines. In a joint project with institutions in the UK and the Netherlands a system compatible with the ATC system used for modem synthetic medicines is being developed. Input from experts from all parts of the world, representing different therapeutic traditions, will be indispensable for this project. 9 A new, extended adverse reactions database is being developed, based on the recommendations of the CIOMS 1A and the ICH E2B working parties. In this data model much more detailed information on each case may be stored and case reports can also, in principle, be received directly from drug companies. Other software to support the functions of national centres is also being developed. 9 With the aim of improving communications in pharmacovigilance, initiatives have been taken to call together representatives of all major groups involved in the provision of drug safety information. The so-called Erice declaration on communicating drug safety information sets out the basis for further development in this area (6). The Uppsala Monitoring Centre is collaborating with the Council for International Organizations of Medical Sciences (CIOMS) to work out detailed recommendations on good communication practices in pharmacovigilance.

Collaboration with other organizations Co-operation with organizations interested in developing early signals of significance is of importance to achieve a safer drug therapy. The International Society for Pharmacoepidemiology (ISPE) is specifically interested in the science of pharmacovigilance, and the Council for International Organizations of Medical Sciences (CIOMS) is pivotal in bringing interested parties together to mount various collaborative projects. Much support has been given to the International Society of Pharmacovigilance (ISOP), which is gaining increasing international status. The Centre also supports the European Pharmacovigilance Research Group

The WHO international drug monitoring programme

which has allowed regulators and drug safety specialists from a variety of European countries to come together to plan co-ordinated drug safety exercises. Initiatives like these may pave the way for a much more logical development and investigation of drug safety signals world wide.

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9

Joining the WHO Programme Considering the sensitive nature of the data being collected within the Programme, countries that contribute data to the scheme have agreed on certain requirements that should be complied with by countries who wish to join. Collaborating with the WHO, an organization for co-operation between member states, also requires a certain administrative structure for drug monitoring activity. The basic requirements are:

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There must be a general acquaintance with the methods of spontaneous monitoring; a country that joins the WHO Programme must have in place a programme for collecting spontaneous adverse reactions reports. A national centre for pharmacovigilance must be designated and recognized by the country's Ministry of Health (or equivalent). There must be technical competence to fulfil reporting requirements to the WHO; case reports collected in the national drug monitoring programme must be submitted to the WHO Programme in a defined format=

The Uppsala Monitoring Centre has published "Guidelines for Setting-up and Running a Pharmacovigilance Centre".

Contact addresses For further information please contact: World Health Organization Health Technology and Pharmaceuticals CH-1211 Geneva 27 Switzerland telephone: +41-22 7912111 telefax: +41-22 7910746 e-mail: [email protected]

WHO Collaborating Centre for International Drug Monitoring (the Uppsala Monitoring Centre) Stora Torget 3 S-753 20 Uppsala, Sweden telephone: +46-18 656060 telefax: +46-18 656080 e-mail: [email protected]

REFERENCES 1. Bate A, Lindquist M, Edwards IR, Olsson S, Orre R, Lansner A, De Freitas RM. A Bayesian neural network method for adverse drug reaction signal detection. Eur J Clin Pharmacol 1998; 54: 315-21. 2. Fucik H, Edwards IR. Impact and credibility of the WHO adverse reaction signals. Drug Inf J 1996; 30: 461-4. 3. Lindquist M, Sanderson J, Claesson C, Imbs J-L, Rohan A, Edwards IR. New pharmacovigilance information on an old drug; an international study of spontaneous reports on digoxin. Drug Invest 1994; 8: 73-80.

4. Stahl MMS, Lindquist M, Pettersson M, Edwards IR, Sanderson JH, Taylor NFA, Fletcher AP, Schou J. Withdrawal reactions with selective serotonin re-uptake inhibitors as reported to the WHO system, Eur J Clin Pharmacol 1997; 53: 163-9. 5. Biriell C, Edwards IR. Harmonisation in pharmacovigilance. Drug Saf 1994; 10: 93-102. 6. Olsson S. The Role of the WHO Programme on International Drug Monitoring in Coordinating Worldwide Drug Safety Efforts. Drug Saf 1998; 19: 1-10.

Address list of national centres that participate in the WHO drug monitoring programme

Argentina (ARG) Dr Mabel Teresa Foppiano Tel: +54-1-340 0866 Fax: +54-1-340 0866 E-mall: snfvg@ anrnat.gov.ar Australia (AUS) Dr John McEwen Tel: +61-2-6289 8671 Fax: +61-2-6232 8392 E-mall: john.mcewen @health.gov.au Austria (AUT) Ms Renate Jentzsch Tel: +43-1-711 00, Ext 4638 Fax: +43-1-712 0823 E-mail: viiia3 @bmsg.gv.at Belgium (BEL) Mr Andr6 Pauwels Tel: +32-2-227 5567 Fax: +32-2-227 5528 E-mail: andre.pauwels @afigp.fgov.be Bulgaria (BUL) Ms Daniela Encheva Tel: +359-2-445 990 04 4347 356 Fax: +359-2-9434 487 E-mail: [email protected] Canada (CAN) Ms Heather Sutcliffe Tel: +1-613-946 1138 Fax: +1-613-957 0335 E-mall: heather-sutcliffe @hc-sc.gc.ca

Administraci6n Nacional de Medicamento, Alimentos y Tecnologia Medica (ANMAT) Sistema Nacional de Farmacovigilancia Avenida de Mayo 869, piso 1 lo (1084) Buenos Aires, Argentina Therapeutic Goods Administration Dept of Community Services and Health PO Box 100 Woden, ACT 2606, Australia Federal Ministry for Social Security and Generations Pharmacovigilance Unit VIII/A/3 Radetzkystrasse 2 A-1031 Vienna, Austria Ministry of Health, Pharmacy General Inspectorate Centre National de Pharmacovigilance Vesale Building 20 rue Montagne de l'Oratoire, 3rd Floor B-1010 Brussels, Belgium Bulgarian Drug Agency Pharmacovigilance Centre 26, Yanko Sakazov Boulevard BG-1504 Sofia, Bulgaria Adverse Reaction Review and Information Unit Bureau of Licensed Product Assessment Therapeutic Products Programme, Health Canada Finance Bldg, 1st Floor, Tunney's Pasture A/L 0201C2 Ottawa, Ontario K1A 1B9, Canada

559

Address list of national centres Canada (VAR) Dr Wikke Walop Tel: +1-613-954 5590 Fax: +1-613-957 1340 or 998 6413 E-mail: Wikke.Walop @hc-sc.gc.ca

Chile (CHL) Dr Q F Cecilia Morgado-Cadiz Tel: +56-2-239 8769 Fax: +56-2-239 8760 E-mail: [email protected]

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

Instituto de Salud Publica de Chile Centro Nacional de Informaci6n de Medicamentos y Farmacovigilancia - CENIMEF Avenida Marathon 1000 3 piso, Nufioa-Casilla 48, Santiago, Chile

China, People's Republic of (CHN) Prof Li Shaoli Tel: +86-10-6716 4982 Fax: +86-10-6716 4984 E-mail: lshaoli@ sina.com

Center for Drug Re-evaluation (CDR) National Center for ADR Monitoring Building 11, Fa-Hua-Na-Li Chongwen District Beijing 100061, People's Republic of China

Costa Rica (COR) Dr Albin Chaves Matamoros Tel: +506-222 1878 Fax: +506-257 7004 E-mail: farmaco @info.ccss.sa.cr

Caja Costarricense de Seguro Social Centro Nacional de Fannacovigilancia Apartado 10-105 San Jos~ 1000, Costa Rica

Croatia (CRO) Prof Bozidar Vrhovac Tel: +385-1-2421 875 Fax: +385-1-2388 284 E-mall: vrhovac@ rebro.mef.hr

Cuba (CUB) Francisco Debesa Tel: +53-7-24 09 24 Fax: +53-7-24 72 27 E-mall: [email protected] Cyprus ( CYP) Dr Athos Tsinontides Tel: +357-230 96 17 Fax: +357-234 9758 E-mail: [email protected] Czech Republic (CZE) MUDr Ivana Koblikova Tel: +42-02-7218 5848, 7218 5111 Fax: +42-02-7143 2377, 7218 5816 E-mail: klinhodn@ sukl.cz

National Adverse Drug Reactions Monitoring Centre Section of Clinical Pharmacology Department of Medicine University Hospital Centre 12 Kispaticeva, 41000 Zagreb, Croatia

Pharmacoepidemiology Development Center 44 No 502 esq 5a Ave Miramar, Playa Havana CP 11300, Cuba

Pharmaceutical Services Ministry of Health 1475 Lefkosia, Cyprus

Branch of Clinical Trials and Pharrnacovigilance State Institute for Drug Control Srobarova 48 10041 Prague 10, Czech Republic

560 Denmark (DEN) Dr J~rgen Thode Tel: +45-44-91 73 73 E-mail: [email protected]

Address list of national centres Danish Medicines Agency Department of Medicines Evaluation 378, Frederikssundsvej DK-2700 BrOnshcj, Denmark

Estonia (EST) Dr Maia Uuskifla Tel: +372-7-374 140 Fax: +372-7-374 142 E-mail: maia.uuskula@ sam.ee

Riigi Ravimiamet State Agency of Medicines 19 Ravila Street 50411 Tartu, Estonia

Fiji (FJI) Mr Peter Zinck E-mail: pzinck@ govnet.gov.fj

Government Pharmacy Box 106, Suva, Fiji

Finland (FIN) Prof Erkki Palva Tel: +358-9-4733 4288 Fax: +358-9-4733 4297 E-mail: [email protected]

National Agency for Medicines--Laakelaitos Drug Information Centre P.O. Box 55, Mannerheimintie 166 SF-00301 Helsinki, Finland

France (FRA) Dr Carmen Kreft Jais Tel: +33-1-5587 3000 Fax: +33-1-5587 3532 E-mail: fr-h.eudrawatch @fr-h.eudra.org

Agence de M6dicament Unit6 de Pharmacovigilance 143-145, Boulevard Anatole France F-93285 Saint-Denis, Cedex, France

Germany (GFR) Dr Jiirgen Beckmann Tel: +49-30-4548 3000, 4548 3311 Fax: +49-30-4548 3515 E-mail: j.beckmann @bfarm.de

Federal Institute for Drugs and Medical Devices Bundesinstitut fur Arzneimittel und Medizinprodukte Seestrasse 10, D-13353 Berlin, Germany

Germany (GFR) Monika Schutte Tel: +49 221 4004 527 Fax: +40 221 4004 539

Arzneimittelkommission der Deutschen ,~rzgeschaft PO Box 41 01 25, Aachener Strasse 233-237 D-50931 K61n, Germany

Greece (GRC) Dr Georgia Athanassiou Tel: +30-1-6507 337 Fax: +30-1-654 9585 E-mail: [email protected]

National Organization for Medicines Adverse Drug Reactions Section 284 Messogion Avenue GR-155 62 Holargos, Greece

Hungary (HUN) Dr S~ndor Elek Tel: +36-1-215 4462 Fax: +36-1-215 8977 E-mail: sandor.elek@ elender.hu

National Institute of Pharmacy Adverse Drug Reactions Monitoring Centre Zrinyi u 3-1051, PO Box 450 H-1372 Budapest, Hungary

Iceland (ICE) Dr Sigurdur Gudmundsson Tel: +354-5-10 1900 Fax: +354-5-10 19 19 E-mail: sigurdur @landlaeknir.is

Director General of Health Landlaeknir Laugavegi 116 IS-150 Reykjavik, Iceland

561

Address list of national centres India (IND ) Prof Suresh K Gupta Tel: +91-11-686 4930 Fax: +91-11-686 2663 or 652 10 41 E-mall: [email protected]

Chief National Pharmacovigilance Centre Department of Pharmacology All India Institute of Medical Sciences Ansari Nagar New Delhi 110029, India

Indonesia (INO ) Dr Lucky S Slamet Tel: +62-21-424 5459 Fax: +62-21-424 3605 E-mail: [email protected]

Ministry of Health Directorate General of Drug and Food Control National Centre for Monitoring of Adverse Drug Reactions Jalan Percetakan Negara 23 Jakarta 10560, Indonesia

Iran, Islamic Republic of (IRN) Dr Mohammed Sharifzadeh Tel: +98-21-641 7252 Fax: +98-21-675 868 E-mail: iadrmc @damavand.mohem.gov.ir

Ministry of Health and Medical Education Iranian ADR Centre Building no. 3, Fakhre Razi Enghlab Avenue Tehran 13145, Islamic Republic of Iran

Ireland (IRE) Ms Niamh Arthur Tel: +353-1-676 4971 Fax: +353-1-676 7836 E-mall: [email protected]

Irish Medicines Board Pharmacovigilance Unit Earlsfort Centre, Earlsfort Terrace Dublin 2, Ireland

Israel (ISR) Dr Dina Hemo Tel: +972-2-568 1219 Fax: +972-2-672 58 20 E-mail: dina.hemo @moh.health.gov.il

Ministry of Health Department of Clinical Pharmacology Drug Monitoring Center 29 Rivka Street, PO Box 1176 Jerusalem 91010, Israel

Italy (ITA) Dr Nello Martini Tel: +39-6-5994 3212 Fax: +39-6-5994 3365 E-mail: dvf-uosi.sanita@ interbusiness.it

Ministry of Health Dipartimento per la valutazione dei medicinale e la farmacovigilanza Via Civilth Romana 7 1-00144 Roma, Italy

Japan (JPN) Dr Tatsuo Kurokawa Tel: +81-3-3595 2435 Fax: +81-3-3508 4364

Ministry of Health and Welfare Pharmaceutical and Medical Safety Bureau Safety Division 1-2-2, Kasumigaseki, Chiyoda-Ku Tokyo 100-8005, Japan

Korea, Republic of(KOR) Dr Soo-Young Choi Tel: +82-2-382 0185 Fax: +82-2-383 2870 E-mail: syc [email protected]

Korea Food and Drug Administration Pharmaceutical Safety Bureau 5 Nokbun-dong, Eunpyong-ku Seoul 122-700, Republic of Korea

Macedonia (MKD) Ms Vesna Nasteska-Nedanovska Tel: +389-91-237 669 Fax: +389-91-230 857

Ministry of Health 50 Divizija BB 91 000 Skopje, Macedonia

562 Macedonia (MKD) Prof Stojmir Petrov Tel: +389-91-111 828, 235 966 Fax: +389-91-111 828 E-mail: pharma @lotus.mpt.com.mk

Address list of national centres

Institute of Preclinical and Clinical Pharmacology and Toxicology National Center for Adverse Drug Reaction Monitoring 50 Divizija br 6, 91 000 Skopje, Macedonia

Malaysia (MAL) Mr Mohd Zin Che Awang Tel: +60-3-7573 611 Fax: +60-3-7562 924 E-mail: [email protected]

Ministry of Health National Pharmaceutical Control Bureau Jolan University, PO Box 319 MA-46730 Petaling Jaya, Malaysia

Mexico (MEX) Dr Carmen Becerril Martinez Tel: +52-5-203 4378 Fax: +52-5-203 4378 E-mail: [email protected]

Ministry of Health Gauss No 4, 7 piso Col Casa Blanca Mexico City, DF CP 11590, Mexico

Morocco (MOR) Dr Rachida Soulaymani-Bencheikh Tel: +212-7-68 64 64 Fax: +212-7-772 067 E-mail: [email protected]

Institut National d'Hygi~ne Centre Anti Poisons et de Pharmacovigilance Avenue Ibn Batouta 27 BP 769, Agdal, M-11400 Rabat, Morocco

Netherlands (NET) Dr Arthur P Meiners Tel: +31-70-356 7400 Fax: +31-70-356 7515 E-mail: ap.meiners @cbg-meb.nl

Medicines Evaluation Board PO Box 16229 Kalvermarkt 53 NL-2500 BE, The Hague, The Netherlands

Netherlands (NET) Dr A C van Grootheest Tel: +31-73-646 9700 Fax: +31-73-642 6136 E-mall: ac.vangrootheest @lareb.nl

Netherlands Pharmacovigilance Foundation LAREB Goudsbloemvallei 7 NL-5237 MH s'Hertogenbosch, The Netherlands

New Zealand (NEZ) Dr David Coulter Tel: +64-3-479 7249 Fax: +64-3-477 0509 E-mail: david.coulter@ stonebow.otago.ac.nz

Centre for Adverse Reactions Monitoring Dunedin School of Medicine PO Box 913 9001 Dunedin 9000, New Zealand

Norway (NOR) Ms Ingebjorg Buajordet Tel: +47-22-897 700 Fax: +47-22-897 799 E-mail: ingebjorg.buajordet @sik.no

Oman (OMN) Dr Sawsan Ahmad Jaffar Tel: +968-600 016 Fax: +968-602 287 E-mail: mohphar @omantel.net.om

Norwegian Medicines Control Authority Statens Legemiddelskontroll (SLK) Adverse Drug Reaction Section Sven Oftedals vei 6 N-0950 Oslo 9, Norway Ministry of Health Directorate General of Pharmaceutical Affairs and Drug Control PO Box 393, 113 Muscat, Sultanate of Oman

Address list of national centres Philippines (PHL) Dr Kenneth Hartigan-Go Tel: +63-2-807 85 17 Fax: +63-2-781 2516 or 807 82 85 E-mail: hartigan@ doh.gov.ph Poland (POL) Dr Agata Maciejczyk Tel: +48-22-8416 742 Fax: +48-22-851 4366 E-mail: [email protected]

Portugal (POR) Dr Ant6nio M N Faria Vaz Tel: +351-21-798 7140 Fax: +351-21-798 7155, 795 9069 E-mail: faria.vaz @infarmed.pt

563 Bureau of Food and Drugs Department of Health, Filinvest Corporate City Muntinlupa, Metro Manila 1770, Philippines

Drug Institute Pharmacoepidemiology Centre Centre for Adverse Drug Reactions Monitoring 30/34 Chelmska Street PL-00725 Warsaw, Poland

Centro Nacional de Farmacovigilancia Instituto Nacional da Farm~icia e do Medicamento (INFARMED) Parque de Satlde de Lisboa Avenida do Brasil, no. 53 1749-048 Lisboa, Portugal

Romania (ROM) Dr Juliana Daniela Stanciu Tel: +40-1-224 1102, 224 1710 Fax: +40-1-230 5083 E-mail: anca.dragan @anm.kappa.ro

National Medicines Agency Str Aviator Sanatescu no 48, Sector 1 R-71 324 Bucuresti, Romania

Russia (RUS) Prof Victor Cheltsov Tel: +7-95-434 52 44 Fax: +7-95-434 02 92 E-mail: rfcadr @med.pfu.edu.ru

Department of Clinical Pharmacology Miklukho-Maklay Street, 8 117198 Moscow, Russia

Singapore (SIN) Ms Lim Peck Seah Tel: +65-325 5604, 325 5610 Fax: +65-325 5448 E-mail: [email protected]

Slovakia (SVK) Dr Pavol Gibala Tel: +421-7-5293 17 35, 5493 17 32 Fax: +421-7-5293 17 34 E-mail: [email protected] South Africa (SOA) Ms Ushma Mehta Tel: +27-21-447 1618 Fax: +27-21-448 6181 E-mail: umehta@ uctgshl.uct.ac.za

Ministry of Health Adverse Drug Reaction Monitoring Unit National Pharmaceutical Administration No. 2 Jalan Bukit Merah Singapore 169547

National Centre for Monitoring Adverse Reactions to Drugs State Institute for Drug Control Kvetnfi 11,825 08 Bratislava 2, Slovakia

National Adverse Drug Event Monitoring Centre c/o Department of Pharmacology Faculty of Medicine University of Cape Town, K45 Old Main Building Observatory 7925, South Africa

564 Spain (SPA) Dr Fransisco Jos6 de Abajo Tel: +34-91-596 7711 Fax: +34-91-596 7891 E-mail: fabajo@ agemed.es

Address list of national centres

Agencia Espafiola del Medicamento Divisi6n de Farmacoepidemiologia y Farmacovigilancia Carretera a Pozuelo, Km 2 E-28220 Majadahonda (Madrid), Spain

Sri Lanka (LKA) Dr Rohini Fernandopulle Tel: +94-1-695 230 Fax: +94-1-695 230 E-mail: phrm_cmb @slt.lk

Faculty of Medicine University of Colombo Kynsey Road, PO Box 271 Colombo 8, Sri Lanka

Sweden (SWE) Dr Ingemar Persson Tel: +46-18-17 46 00 Fax: +46-18-54 85 66 E-mail: Ingemar.Persson @mpa.se

Medical Product Agency PO Box 26 Husargatan 8 S-751 03 Uppsala, Sweden

Switzerland (SCH) Dr Ruedi Stoller Tel: +41-31-322 0348 Fax: +41-31-322 0418 E-mail: rudolf.stoller @iks.admin.ch

Interkantonale Kontrollstelle fiir Heilmittel Pharmacovigilance Centre Erlachstrasse 8 CH-3000 Bern 9, Switzerland

Tanzania (TAN) Mr Henry Irunde Tel: +255-22-2450 512 / 2450 929 Fax: +255-22-2450 793 E-mail: [email protected]

Tanzania Drug and Toxicology Information Service (TADATIS) PO Box 77150 Dar Es Salaam, Tanzania

Thailand (THA) Mrs Suboonya Hutangkabodee Tel: +66-2-590 7281 Fax: +66-2-591 8497, 590 7253 E-mail: suboonya@ health.moph.go.th

Drug Information Center and NADRM Technical Division National Adverse Drug Reaction Monitoring Centre Ministry of Public Health Food and Drug Administration Ti-wa-nondh Rd Nonthaburee 11000, Thailand

Tunisia (TUN) Prof Chalbi Belkahia Tel: +216-1-562 098 Fax: +216-1-571 390 or 57 81 96 E-mail: chalbi.belkahia @rns.tn

Centre National de Pharmacovigilance Sis H6pital Ch Nicolle Bd du 9 Avril Tunis 1006, Tunisia

Turkey (TUR) Ms Eda Cindoglu Tel: +90-312-230 1674, 230 2769 Fax: +90-312-230 1610 E-mail: [email protected]

Ministry of Health General Directorate of Drugs and Pharmacy Ilkiz Sokak No 4 Sihhiye, Ankara 06430, Turkey

United Kingdom (LINK) Dr June Raine Tel: +44-207-273 0400 Fax: +44-207-273 0282, 273 0675

Medicines Control Agency Pharmacovigilance, Department of Health Market Towers, 1 Nine Elms Lane Vauxhall, London SW8 5NQ, UK

565

Address list of national centres United States of America (USA) Dr M Miles Braun Tel: +1-301-827 6079 Fax: +1-301-827 3529 E-mail: [email protected] United States of America (USA) Dr Peter Honig Tel: +1-301-827 3219 Fax: +1-301-443 5161 E-mail: [email protected]

Food and Drug Administration Center for Biologics Evaluation and Research Division of Biostatistics and Epidemiology 1401 Rockville Pike, HFM-225 Rockville 20852-1448, USA Office of Post-Marketing Drug Risk Assessment Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane (HFD-400) Rockville, MD 20857, USA

Venezuela (VEN) Dr Jestls Querales Castillo Tel: +58-2-6624 797 Fax: +58-2-6624 797, 693 1455

Instituto Nactional de Higiene "Rafael Rangel" Apartado Postal 60.412-Ofic del Este Ciudad Universitaria, Caracas, Venezuela

Vietnam (VNM) Prof Hoang Tich Huy~n Tel: +84-4-245 292 Fax: +84-4-823 1253 E-mail: [email protected]

Adverse Drug Reaction Centre Institute for Drug Quality Control Ministry of Health 48 Hai Ba Trung Street, Hanoi, Vietnam

Yugoslavia, Federal Republic of(YUG) Prof Vaso Antunovic Tel: +381-11-361 5531 Fax: +381-11-361 56 30 Zimbabwe (ZWE) Mr M N Dauramanzi Tel: +263-4-736 981/5 Fax: +263-4-736 980 E-mail: mcaz @africaonline.co.zw

Clinical Centre of Serbia National Centre for Adverse Drug Reactions Visegradska 26 YU-11000 Belgrade, Fed Rep of Yugoslavia Medicines Control Authority PO Box UA 559 Union Avenue Harare, Zimbabwe

Associate Member Countries Armenia (ARM) Dr Samvel Azatyan Tel: +374-1-584 020, 584 120 Fax: +374-1-151 697 E-mail: [email protected] Egypt (EGY) Prof Abdulla Molokhia Tel: +20-2-3484 989 Fax: +20-2-3379 445 E-mail: molokhia @pharmaco, sti.sci.eg Ghana (GHA) Dr Alex Dodoo Tel: +233-21-675 885 Fax: +233-21-666 8219 E-mail: [email protected]

Department of Pharmacovigilance and Rational Use of Drugs Armenian Drug and Medical Technology Agency 15, Moskowian Street Yerevan 375001, Armenia Ministry of Health National Organization for Drug Control and Research PO Box 29, Cairo, Egypt Centre for Tropical Clinical Pharmacology & Therapeutics University of Ghana Medical School Korle-Bu Teaching Hospital Accra, Ghana

566

Address list of national centres

Netherlands Antilles (ANT)

Msc Zjumira G M Wout Tel: +599-9-7374877 Fax: +599-9-737 4844 E-mail: zgwout@ attglobal.net

Bureau of Pharmaceutical Affairs Groot Davelaar K-139-140 Fokkerweg #26 PO Box 3824 Curacao, Netherlands Antilles

Pakistan (PAK)

Prof Akhlaque Un-Nabi Khan Tel: +92-21-588 2997, 589 2801 Fax: +92-21-588 1444, 589 3062 E-mail: cpsp@ super.net.pk

College of Physicians & Surgeons Pakistan (CPSP) Department of Clinical Pharmacology 7th Central Street Phase II, Defence Housing Authority Karachi 75 500, Pakistan

Peru (PER)

Ms Susana Vasques Tel: +51-14-724 419, 751 090 Fax: +51-14-725 028 E-mall: SVASQUEZ @digemid.gob.pe

Ministerio de Salud Centro Nacional de Informacion de Medicamentos Proyecto de Farmacovigilancia Direccion General de Medicamentos, Insumos y Drogas (DGMID) Avenue Arenales # 1302-Of 318 Lima 11, Peru

Institutions EMEA

Ms Priya Bahri Tel: +44-207-418 8454 Fax: +44-207-418 8551 E-mail: priya.bahri@ emea.eudra.org

EMEA-The European Agency for the Evaluation of Medicinal Products Pharmacovigilance Section 7 Wesfferry Circus, Canary Wharf London El4 4HB, UK

EC

Emer Cooke Tel: +32-2-296 7072 Fax: +32-2-296 1520 E-mail: Emer.Cooke @cec.eu.int

European Commission Directorate General III-Industry Rue de la Loi 200 B-1049 Brussels, Belgium

FDA

Dr Peter Honig Tel: +1-301-827 1050 Fax: +1-301-827 1271 E-mall: honigp @cder.fda.gov

Food and Drug Administration Office of Post-Marketing Drug Risk Assessment Center for Drug Evaluation and Research 5600 Fishers Lane (HFD-400) Rockville, MD 20857, USA

WHO

Dr Mary Couper Tel: +41-22-791 3643 Fax: +41-22-791 4730 E-mail: [email protected]

World Health Organization Policy, Access and Rational Use, EDM-HTP CH-1211 Geneva 27, Switzerland

Index of drugs Page numbers in bold indicate where the given drug is discussed in detail. abacavir, 342 interaction, 342 acarbose, 495, 496 interaction, 202 acebutolol, 221 acecainide, 214 ACE inhibitor s e e dipeptidyl carboxypeptidase inhibitor Acel immune s e e diphtheria acellular pettussis tetanus vaccine acenocoumarol, 240 interaction, 122, 123, 299, 318, 398, 402, 424 acetaminophen s e e paracetamol acetazolamide, 249, 452 interaction, 249 n acetyl 5 methoxytryptamine s e e melatonin acetyldigitoxin, 200 acetylsalicylicacid, 7, 118-120, 121-123, 257, 314, 334, 398, 399, 456, 497, 521 interaction, 121,236, 237, 249, 493 acetylsalicylicacid derivative, 121 interaction, 121 aciclovir, 176 ACTH s e e corticotropin ActHIB s e e haemophilus influenzae type b vaccine Actidose aqua s e e activated carbon activated carbon, 4, 220, 223, 243, 287, 405 interaction, 201 activated charcoal s e e activated carbon activated prothrombin complex, 386, 387 acupuncture, 540 Acutane s e e isotretinoin ACV s e e aciclovir acycloguanosine

s e e aciclovir acyclovir s e e aciclovir adenosine, 205, 394 adrenalin, 103, 141, 142, 147, 149, 151,152, 163, 241,394, 448, 456, 520, 524, 533 adrenergic receptor blocking agent, 242 a adrenergic receptor blocking agent, 233 /3 adrenergic receptor blocking agent, 142, 205,220, 233, 246, 247, 251,271,493, 535 interaction, 197, 209, 493 adrenergic receptor stimulating agent, 163, 226, 534 a adrenergic receptor stimulating agent, 164, 535 c~2 adrenergic receptor stimulating agent, 70 fl 1 adrenergic receptor stimulating agent, 165 132 adrenergic receptor stimulating agent, 187, 189, 225 c~adrenoceptor agonist s e e ct adrenergic receptor stimulating agent fl adrenoceptor agonist s e e / 3 adrenergic receptor stimulating agent adrenoceptor antagonist s e e adrenergic receptor blocking agent c~adrenoceptor antagonist s e e ot adrenergic receptor blocking agent cl adrenoceptor blocker s e e ct adrenergic receptor blocking agent /3 adrenoceptor blocker s e e / 3 adrenergic receptor blocking agent adriamycin s e e doxorubicin AIK C vaccine s e e measles vaccine ajmaline, 206 ajmaline derivative, 206 Alamast

s e e pemirolast albendazole, 356, 357, 360, 361 albumin, 383 albumin derivative, 528 Albunex, 529 albuterol s e e salbutamol alclometasone dipropionate, 175 alcohol, 3, 14, 19, 35, 36, 46, 47, 243, 442, 488, 495, 497, 524 interaction, 3, 36, 43, 71, 122, 172, 335, 442, 443, 493 aldophosphamide interaction, 458 aldosterone antagonist, 246, 251 alemtuzumab, 419 alendronic acid, 296, 544 alfacalcidol, 446 alfentanil, 101, 102, 104, 108, 128, 159 interaction, 104, 135, 318 allopurinol, 240, 241, 512, 523 allylamine derivative, 314 Alocril s e e nedocromil alosetron, 401,402 alprazolam, 46, 48 interaction, 60, 299, 318 alprostadil s e e prostaglandin E1 alteplase, 399, 400 alum s e e aluminium potassium sulfate alumininm, 253, 258, 370, 388 aluminium hydroxide, 253 interaction, 484 aluminium magnesium hydroxide, 253 aluminium potassium sulfate, 254 aluminium salt, 253 amalgam, 260 amantadine, 15, 167 AmBisome s e e amphotericin B lipid complex ambucaine s e e oxybuprocaine amethocaine s e e tetracaine

567

568 amfebutamone, 16 interaction, 24 amikacin, 285, 289 amiloride, 234 interaction, 251 amiloride plus hydrochlorothiazide interaction, 251 amineptine, 61 aminocaproic acid, 399 aminoglycoside antibiotic agent, 283 interaction, 285 aminophylline, 394, 544, 545 interaction, 71 5 aminosalicylic acid s e e mesalazine aminosalicylic acid derivative, 406

amiodarone, 197, 204, 206, 221, 298, 336 interaction, 209, 210, 354 amisulpride, 53, 54, 60 interaction, 27 amitriptyline, 6, 61, 70, 143 amlodipine, 222, 223, 242, 324, 334, 455 interaction, 223, 226, 231 amoxicillin, 276, 294, 404, 405 amoxicillin plus clavulanic acid, 250, 276 amphetamine derivative, 2, 32 interaction, 342 Amphocil s e e amphotericin B amphotericin B, 315, 317, 324 amphotericin B aerosol, 315 amphotericin B colloid, 316 amphotericin B deoxycholate, 315 interaction, 315 amphotericin B lipid complex, 316 ampicillin, 277, 280, 287, 294, 470 interaction, 274 amprenavir interaction, 321 amtolmetin guacil, 122 anabolic agent, 476 analeptic agent s e e central stimulant agent analgesic agent, 120, 347, 522 Androderm s e e testosterone androgenic agent, 275,476 Andropatch s e e testosterone anesthetic gas, 132 anesthetic vapor, 128 Angelicae radix, 537 Angelicae sinensis, 538 angiopeptin, 505, 506

Index of drugs

angiotensin II antagonist, 239, 248, 388 interaction, 26, 251 angiotensin converting enzyme inhibitor s e e dipeptidyl carboxypeptidase inhibitor aniline derivative, 121,122 anorectic agent s e e anorexigenic agent anorexigenic agent, 4 antacid agent interaction, 484 anthelminthic agent, 356 anthracycline derivative, 421, 515 antiallergic agent, 157, 534 antiandrogen, 479 antiandrogenic agent s e e antiandrogen antiarrhythmic agent, 54, 197, 2O4

antibacterial agent s e e antiinfective agent antibiotic agent, 130, 150, 193, 194, 237, 273, 522, 523, 525 interaction, 274, 275 inhalation, 193, 285 anticholinergic agent s e e cholinergic receptor blocking agent anticholinesterase s e e cholinesterase inhibitor anticoagulant agent s e e a l s o coumarin derivative and oral anticoagulant agent interaction, 318 anticonvulsant agent s e e anticonvulsive agent anticonvulsive agent, 82 interaction, 83, 87, 89, 91 anticytomegalovirus agent, 340 antidepressant agent, 12, 539 interaction, 12, 23, 27, 60 antidiabetic agent, 496 s e e a l s o oral antidiabetic agent interaction, 424 antiemetic agent, 4111 antiepileptic agent s e e anticonvulsive agent antiestrogen, 475 antifibrinolytic agent, 387, 399 antifungal agent, 314 interaction, 318 antiglaucoma agent, 535 antihepatitis agent, 341 antihistaminic agent, 17, 179, 192, 242, 317, 347, 456, 534 s e e a l s o histamine HI receptor antagonist interaction, 180, 318 antiH1V agent

antihuman immunodeficiency virus agent antihuman immunodeficiency virus agent, 342 interaction, 342 antihypertensive agent, 233, 247 interaction, 231 antiinfective agent, 283 antiinflammatory agent, 115 s e e a l s o nonsteroid antiinflammatory agent antiinfluenza agent, 348 antileishmanial agent, 336 antileprosy agent s e e leprostatic agent antilipemic agent, 346, 510 antimalarial agent, 330 antimicrobial agent s e e antiinfective agent antimigraine agent, 229 antimony, 254 antimony derivative, 254, 336 antimony trioxide, 254 antineoplastic agent, 298, 343, 388, 418, 476, 515 interaction, 295,344, 423 antioxidant, 122, 175 antiplatelet agent s e e antithrombocytic agent antiprotozoal agent, 330, 335 antipsychotic agent s e e neuroleptic agent antipyretic analgesic agent, 115 antipyrine s e e phenazone antiretrovirus agent, 342 interaction, 231,342 antiseptic agent, 270, 343 antithrombocytic agent, 389 antithrombotic agent s e e anticoagulant agent antithyroid agent, 484 antitrypanosomal agent, 335 antituberculosis agent s e e tuberculostatic agent antivirus agent, 340 anxiolytic agent, 45 apomorphine, 166, 167 appetite suppressant s e e anorexigenic agent apraclonidine, 535 aprindine, 210 aprotinin, 399 ara C s e e cytarabine arginine, 399 Aristolochia, 537 aristolochic acid, 537 arsenic, 254 arsenic trioxide, 254 artelinic acid interaction, 299 see

569

Index of drugs

artemether plus benflumetol, 331,332 artemisia derivative, 331 artemisinin, 331 artemisinin derivative, 331 artesunate interaction, 331 arylalkanoic acid derivative, 122 ascorbic acid, 297 Aspirin s e e acetylsalicylic acid aspoxicillin, 277 astemizole, 179, 180 atenolol, 197, 220, 234, 324, 496 atorvastatin, 510, 511 interaction, 91,299, 321,322, 426, 511 atorvastatin lactone interaction, 321 atovaquone, 333, 334 interaction, 323, 334, 344 Atractylodis macrocephalae, 537 atropine, 7, 157, 226, 237, 243 aurothioglucose, 257 aurothiomalate, 257 Autoplex s e e activated prothrombin complex azapropazone, 123 azaspirone derivative, 45 azathioprine, 225, 422, 424, 432, 452 interaction, 424 azelastine, 192 intranasai, 192 azidothymidine s e e zidovudine azithromycin, 294, 295, 299, 334 interaction, 184, 202, 296, 334 azlocillin, 276 azo dye, 174 azole derivative, 318 interaction, 318, 321, 511 AZT s e e zidovudine aztreonam, 276, 296 Bacille Calmette Guerin vaccine s e e BCG vaccine bacitracin, 301 baclofen, 159 bacterial vaccine, 365 balsalazide, 407 bambuterol, 188 barbiturate interaction, 172 barium, 524, 526 barium sulfate, 519, 524 basiliximab, 419 BCG vaccine, 352, 433 beclometasone dipropionate, 183, 186, 297, 455 bee pollen, 538

benazepril, 237, 496 bendroflumethiazide, 18, 237 benflumetol, 331 benoxinate s e e oxybuprocaine benperidol, 70 benserazide plus levodopa, 165, 166 benzaikonium chloride, 173, 533 benzatropine, 14 benzethonium chloride, 135 benzimidazole derivative, 356 benzocaine, 151 benzodiazepine, 46, 48, 84, 102, 128, 133 interaction, 17, 65,318, 348 benzoic acid derivative, 494 benzoxonium chloride, 172 benzoyl peroxide, 173 benztropine s e e benzatropine benzyl alcohol, 173 bergapten, 276 Betadine s e e povidone iodine betamethasone, 450, 45 l, 454, 457, 458, 522 betamethasone dipropionate intra-articular, 459 betamethasone valerate, 522 Betaseron s e e interferon fl serine bezafibrate, 510 bicalutamide, 479 bicarbonate, 221 biguanide deriviative, 495, 497 bile acid, 408 biperiden interaction, 71 biphenylacetic acid s e e felbinac bisacodyl, 406 bisbiguanide derivative, 270 bismuth, 255 bismuth gallate, 255 bismuth salicylate, 255 bismuth salt, 404, 405 bismuth subgaUate s e e bismuth gallate bismuth subsalicylate s e e bismuth salicylate bisphosphonic acid derivative, 256, 543 bleomycin, 516 blood, xxviii, 383 blood clotting factor, 386 interaction, 388 blood dotting factor 2, 386 blood clotting factor 7, 386, 387 blood clotting factor 7a, 386, 387 blood clotting factor 8, 386-388 blood clotting factor 9, 386-388 blood clotting factor 10, 386, 387

blood component, 383 blood substitute, 383 blood transfusion, 385, 389 BMI 60, 300 bosentan interaction, 202 botulinum toxin A, 160 brachial plexus anesthesia, 141 brachial plexus block s e e brachial plexus anesthesia brain derived neurotrophic factor, 284 brimonidine, 535 brinzolamide, 536 bromazepam, 455 bromocriptine, 166, 167, 180 bromperidol, 2 interaction, 321 brompton mixture, 151 bropirimine, 433 budesonide, 185-188, 192, 193, 455, 456, 458 bufexamac, 174 buflomedil, 229 buformin, 492 bupivacaine, 101, 103, 135, 140-142, 151 interaction, 322 epidural, 142, 143 intraocular, 148, 149 intrathecal, 144, 147 paravertebral block, 149 spinal, 145, 146 Bupleuri radix, 537 buprenorphine, 110 bupropion s e e amfebutamone buspirone, 15, 45 interaction, 45, 60, 181,299, 319 p a r a t e r t i a r y butylphenol s e e 4 t e r t butylphenol 4 t e r t b u t y l p h e n o l , 174 butyrophenone derivative, 179 BY 841 s e e pumaprazole cabergoline, 166, 167 cadmium, 255 caffeine, 1, 45, 50, 163 interaction, 19, 66, 83 calamine, 448 calciferol derivative s e e ergocalciferol derivative s e e a l s o vitamin D calcipotriol, 173 calcitonin, 503 caicitriol, 447 calcium, 226, 547 calcium antagonist, 197, 222, 225,233, 234, 247 interaction, 223, 319, 493, 512 calcium chloride, 136

570 calcium gluconate s e e gluconate calcium CAMPATH 1H s e e alemtuzumab candesartan, 239, 240 Canesten s e e clotrimazole cannabinoid, 36 cannabis, 36, 37, 67 canrenoate potassium, 203 canrenone, 203 captopril, 201,223, 225,234, 237, 239, 240, 297 interaction, 237 carbamazepine, 23, 24, 50, 56, 82-84, 86-88, 90, 92 interaction, 3, 17, 18, 47, 60, 71, 83, 85, 87, 319 carbenicillin, 277. carbetocin, 506 carbidopa plus levodopa, 50, 168 carbimazole, 485 carbomer, 174 Carbomix s e e activated carbon carbonate dehydratase inhibitor, 249, 536

carbon dioxide, 526 carbonic anhydrase inhibitor s e e carbonate dehydratase inhibitor carboplatin, 515, 516 carboxymethylcellulose, 140 cardiac glycoside s e e digitalis glycoside carmustine, 173 /~ carotene, 442 interaction, 442, 443 carotenoid interaction, 442, 443 13carotin s e e ~ carotene carteolol, 221 carvedilol, 221 castor bean s e e Ricinus communis castor oil, 174, 539 catechol methyltransferase inhibitor, 165, 167 catheter, 270, 546 caudal anesthesia, 142 CDDP s e e cisplatin cefalexin, 448 cefazolin, 285,289, 290, 301 cefotaxime, 292 cefotetan, 277 cefotiam, 524, 525 cefradine, 289 ceftazidime, 276, 287, 289 ceftizoxime, 277 ceflriaxone, 277, 334, 450, 470, 520

Index of drugs

cefuroxime, 276 celandine s e e Chelidonium majus celecoxib, 116-119 interaction, 27 central depressant agent, 46, 49 central stimulant agent, 1, 2 cephalosporin, 295 cephalosporin derivative, 277 cerivastatin, 511 interaction, 202, 321,426, 511,512 cerivastatin lactone interaction, 321 Certiva s e e diphtheria acellular pertussis tetanus vaccine cetacaine, 151 cetirizine, 179, 180 cetrorelix, 504 Chelidonium majus, 538 chickenpox vaccine, 380 chinese herb, 458, 537 chiropraxis s e e manipulative medicine chloral hydrate, 49 chloramphenicol, 276, 287 interaction, 287, 426 chlorhexidine, 270 chlormethiazole s e e clomethiazole chloroprocaine, 140 intravenous, 148 chloroquine, 331, 333 interaction, 181 chloroquine derivative, 331 chloroquine plus proguanil, 332 chlorpheniramine, 180, 448 interaction, 181,331 chlorpromazine, 13, 58, 59, 61 interaction, 23, 27, 172 chlorpropamide, 492, 493 chlortalidone, 242, 248 chlorzoxazone interaction, 511 cholelitholytic agent, 408 cholestyramine s e e colestyramine cholinergic receptor blocking agent, 157, 168, 189 cholinesterase inhibitor, 6, 157 chorionic gonadotropin, 473, 474, 477, 503 chromium, 255, 256, 454 interaction, 255 chromium picolinate, 255 interaction, 255 cibenzoline, 210 ciclosporin s e e cyclosporin a cidofovir, 340 cigarette s e e tobacco

ciglitazone, 496 cilastatin plus imipenem interaction, 292, 426 cilazapril, 220 cilostazol, 229 interaction, 299 cimetidine, 291,402 interaction, 60, 333, 402, 493 cinnarizine, 179, 180 ciprofloxacin, 285, 296 interaction, 71 cisapride, 401 interaction, 297, 299, 401 cisplatin, 260, 416, 444, 515, 516 citalopram, 14 interaction, 14, 15 cladribine, 517 clarithromycin, 295, 296, 404 interaction, 60, 184, 202, 211, 295-297, 320, 344, 432, 458 clebopride, 401 clemastine, 523 clindamycin, 293 interaction, 294, 425 clindamycin phosphate, 294 clobazam, 84 interaction, 91 clobetasol propionate, 175 topical, 459 clodronic acid, 543 clomethiazole, 49 clomiphene, 474, 475, 477 clomipramine, 13 clonazepam, 13, 47 interaction, 47, 83 clonidine, 103, 135, 142, 144, 225, 242 interaction, 3 clopidogrel, 399 interaction, 202 clotiapine, 58 clotrimazole, 174 cloxacillin, 274 clozapine, 24, 53, 58, 61, 67, 69, 70, 166 interaction, 15, 17, 27, 48, 65, 66, 279, 320 Clozaril s e e clozapine CMD A2 gadobenate dimeglumine, 528 coamilozide s e e amiloride plus hydrochlorothiazide coamoxiclav s e e amoxicillin plus clavulanic acid cobalt, 255 cocaethylene interaction, 3 cocaine, 2, 37, 41,151 interaction, 3, 225

571

Index of drugs

topical, 150 co-careldopa s e e carbidopa plus levodopa cocodamol s e e codeine plus paracetamol codeine, 39, 41,109, 239 codeine plus paracetamol, 41, 109 coffee, 1 s e e a l s o caffeine colchicine, 241,425 colestyramine interaction, 484 colistin, 276 colony stimulating factor, 417 complementary therapy, 537 compound A, 130, 131 concanavalin A, 284 conjugated estrogen, 456, 468, 470, 472 contact lens interaction, 287 continuous ambulatory peritoneal dialysis, 395 contrast medium, 346, 519, 522 copper, 256, 396 copper intrauterine device, 256, 473 copper sulfate, 523 coproxamol s e e dextropropoxyphene plus paracetamol corticosteroid, 17, 68, 123, 173-175, 183-185, 188, 194, 225,229, 242, 314, 317, 330, 340, 342, 345, 347, 424, 425, 444, 445, 459, 478, 493, 497, 522, 523, 534, 535 s e e a l s o glucocorticoid interaction, 345,458 epidural, 459 inhalation, 185 intra-articular, 459 intranasal, 459 intrathecal, 459 topical, 459 corticotropin, 450 s e e a l s o corticosteroid cortisol s e e hydrocortisone cosmetic, 171 cotrimoxazole, 280, 296, 331, 334, 352, 450 interaction, 274, 493 coumarin derivative, 398 s e e a l s o o r a l anticoagulant agent interaction, 398 crack s e e cocaine Cremophor EL s e e ricinomacrogol croconazole, 174

cromoglycate disodium, 534 cromolyn sodium s e e cromoglycate disodium cromone derivative, 192 crystalloid, 383, 520 cyamemazine interaction, 60 cyanamide, 547 cyanocobalamin, 446 cyclodextrin, 325 cycloguanil, 333 interaction, 333 cyclooxygenase inhibitor s e e prostaglandin synthase inhibitor cyclooxygenase 2 inhibitor, 116 interaction, 251 cyclophosphamide, 417, 421, 427, 444, 516, 517 interaction, 91,320, 415,427, 458 cycloplegic agent, 533 cyclosporin a, 326, 424, 430--432 interaction, 17, 184, 223, 225, 226, 287, 294, 319, 335, 424--427, 430, 479, 511, 512, 539 cyproheptadine, 14 cyproterone acetate plus flutamide, 504 cytarabine, 254, 411,444, 445 cytosine arabinoside s e e cytarabine cytostatic agent s e e antineoplastic agent Cytoxan s e e cyclophosphamide dacarbazine, 416 danazol, 478, 479 interaction, 479 dapsone, 291,334, 352 daunorubicin, 444, 445 DDAVP s e e desmopressin ddI s e e didanosine DDS s e e dapsone n deamino 8 d arginine vasopressin s e e desmopressin Decloban s e e clobetasol propionate decongestive agent, 192, 534 deferiprone, 265 deferoxamine, 258, 265, 330 interaction, 265 dehydrocilostazol interaction, 299 delavirdine, 344 dental anesthesia, 147 dental material, 173

2' deoxycoformycin s e e pentostatin depolarizing neuromuscular blocking agent, 158 dermatological agent, 171 DES s e e diethylstilbestrol desbutylhalofantrine interaction, 320 Desferal s e e deferoxamine desferrioxamine s e e deferoxamine desflurane, 108, 130, 131,293 desmethylclomipramine s e e norclomipramine desmethylclozapine s e e norclozapine desmethyldiazepam s e e nordazepam desmopressin, 506 desogestrel, 471,476 interaction, 322 detajmium bitartrate, 206 dexamethasone, 444, 445, 451-454, 456, 458, 524, 535 interaction, 292, 397, 456, 457 dexamethasone plus tobramycin, 535 dexamphetamine, 2 dexfenfluramine, 4, 5 dexmedetomidine interaction, 132 dextran, 393 dextran 1,393 dextran 40, 393 dextran derivative, 528 dextromethorphan, 104 interaction, 6, 15 dextromethorphan plus pseudoephedrine, 104, 164 interaction, 104 dextropropoxyphene, 104 dextropropoxyphene plus paracetamol, 105 dextrorphan, 104 DFO s e e deferoxamine diagnostic agent, 533 2,5 diaminotoluene, 175 diamorphine, 40, 42, 43, 103, 105

interaction, 43 diatrizoate, 519, 525, 526 diazepam, 47, 48, 84, 133, 180, 330, 456 interaction, 47, 65, 71 dibromopropamidine, 173 dichromate potassium, 286 diclofenac, 116, 117, 122, 257, 462 interaction, 214, 426 dicloxacillin, 274

572 didanosine, 343, 346 dietary preparation interaction, 60 diethylcarbamazine, 357 diethylene glycol, xxv diethyl sebacate, 173 diethylstilbestrol,xxviii-xxx, 467 dittuuisal, 122 digitalis s e e digitalis glycoside digitalis glycoside, 197, 199, 200, 205, 206 interaction, 197, 202, 203 digitoxin, 201,202 interaction, 201,203 digoxin, 197, 199-203, 226, 238, 240, 246, 251 interaction, 201-203, 297, 320, 354 digoxin antibody, 203 dihydrostreptomycin, 286 1,25 dihydroxycholecalciferol s e e calcitriol diltiazem, 197, 205, 222, 223, 296 interaction, 223, 225,432, 493, 511 dimetindene, 523 dinoprostone s e e prostaglandin E2 dipeptidyl carboxypeptidase inhibitor, 222, 233, 240, 246--248, 251,388 interaction, 236, 237, 239, 241,251,493 diphenhydramine, 180, 237, 291, 296, 316, 524 diphenylpyraline, 180 diphtheria acellular pertussis tetanus vaccine, 370, 371, 372, 374 diphtheria pertussis tetanus haemophilus influenzae type b vaccine, 371 diphtheria pertussis tetanus vaccine, 366, 369, 371 diphtheria whole cell pertussis tetanus vaccine, 371, 372 diprophyUine, 180 dipyridamole, 398 disinfectant agent, 176, 270 disodium edetate s e e edetate disodium disodium cromoglycate s e e cromoglycate disodium disopyramide, 211 interaction, 211,297 disulfiram interaction, 130, 214 diuretic agent, 51,233, 246, 386 s e e a l s o loop- and thiazide diuretic agent

Index of drugs

interaction, 424 Divalproex s e e valproate semisodium dizocilpine, 283 dobutamine, 165 domiphen bromide, 173 domperidone, 401 donepezil, 6 interaction, 7, 320 Dong quai s e e Angelicae sinensis dopamine, 243, 520 dopamine antagonist s e e dopamine receptor blocking agent dopamine receptor blocking agent interaction, 19 dopamine receptor stimulating agent, 165 dopaminergic agonist s e e dopamine receptor stimulating agent dornase or, 193 Dorsacaine s e e oxybuprocaine dorzolamide, 533, 536 doxapram, 3 doxazosin, 242 doxepin, 23 interaction, 27 doxercalciferol, 447 doxorubicin, 417, 444, 515 doxycycline, 278-280, 331 interaction, 279 droperidol, 55, 66, 100 drug of abuse, 32 DTP vaccine s e e diphtheria pertussis tetanus vaccine Duramorph s e e morphine EACA s e e aminocaproic acid ebastine, 179 interaction, 179, 298, 318 ecabapide interaction, 299 Echinacea, 538 ecstasy s e e 3,4 methylenedioxymethamphetamine edetate disodium, 544 edrophouium, 157 efavirenz, 344 Efudix s e e fluorouracil egg protein, 373 electrolyte, 396 Elemenmic, 259 Elohes s e e hetastarch

emedastine, 534 EMLA s e e prilocaine plus lidocaine enalapril, 222, 223, 234-236, 237-240, 247, 297, 394 interaction, 236, 493 enalaprilat, 235 endoperoxide derivative, 331 enflurane, 128, 129, 132 entacapone, 168 enzyme inhibitor interaction, 180, 458 Ephedra, 538 ephedrine, 6, 143, 146, 147, 149, 163 interaction, 6, 136 epidural analgesia s e e epidural anesthesia epidural anesthesia, 142 epinephrine s e e adrenalin epirubicin, 173, 362, 517 eplerenone, 251 Epoetin s e e recombinant erythropoietin Epoetin c~ s e e recombinant erythropoietin epoprostenol s e e prostacyclin eprosartan, 239, 240 equine estrogen s e e conjugated estrogen ergocalciferol derivative, 446 ergometrine interaction, 230 ergonovine s e e ergometrine ergot alkaloid, 166, 168, 348 interaction, 230 ergotamine, xxiii, 168, 230 interaction, 168, 230, 348 erythrocyte transfusion, 388, 461 erythromycin, 293-295, 297, 298, 300, 431,520 interaction, 16, 66, 179, 181, 184, 202, 214, 298, 318, 432 erythromycin ethylsuccinate, 298 interaction, 299 erythromycin stearate, 298 erythropoietin s e e recombinant erythropoietin estradiol, 467, 468, 470, 472 17/~ estradiol s e e estradiol estradiol plus dienogest, 473 estrogen, xxiv, 238, 275,456, 467, 472, 476 s e e a l s o oral contraceptive agent interaction, 275 transdermal, 469

573

Index of drugs

estrogen progestogen replacement, 469 etanercept, 420 ethambutol, 296 ethanol s e e alcohol ethinylestradiol, 472 interaction, 322 ethinylestradiol plus desogestrel, 472 ethinylestradiol plus gestodene, 472 ethinylestradiol plus norethisterone interaction, 354 ethinylestradiol plus norethisterone acetate, 472 ethyl alcohol s e e alcohol ethylenediamine, 108, 180, 286, 544

ethylene oxide, 271 n ethyl 3,4 methylenedioxyamphetamine, 32, 33 ethylphenidate interaction, 3 etidronic acid, 544 etiracetam, 90 etodolac, 116 etoposide, 260, 516, 517 Eudragit 1 30 d 55, 408 eve s e e n ethyl 3,4 methylenedioxyamphetamine excipient, 469 Exoderm s e e phenol Exoderm Lift s e e phenol eye anesthesia, 148 famotidine, 241 interaction, 320 fat emulsion s e e lipid emulsion felbamate, 85 interaction, 85 felbinac, 174 felodipine, 208, 234 interaction, 223 fenfluramine, 4 fenofibrate, 510 fentanyl, 100-103, 105, 108, 128, 136, 137, 293 interaction, 106, 132, 152, 291,320, 348 epidural, 143, 144 intrathecal, 147 ferrous fumarate interaction, 484 ferrous sulfate interaction, 484 fertility promoting agent, 474

Ferumoxtran 10 s e e ultrasmall superparamagnetic iron oxide fibric acid derivative, 510 fibrinolytic agent interaction, 122 fllgrastim s e e recombinant granulocyte colony stimulating factor finasteride, 479, 480 fish oil, 331 fk 506 s e e tsukubaenolide flecainide, 198, 204, 210, 211 flosulide, 123 flu vaccine s e e influenza vaccine flucloxacillin, 274, 276 fluconazole, 290, 296, 317, 324, 326, 343 interaction, 85, 134, 225, 318-324, 427 fludarabine, 517 fluindostatin, 512 interaction, 321, 511 flumethasone, 459 FluMist s e e influenza vaccine fluocinonide, 174 fluocortin, 459 fluorescein, 547 fluorocarbon, 383, 384, 529 s e e a l s o perfluoro compound fluorometholone, 535 fluorophosphate, 547 ttuoroquinolone derivative, 285, 287, 302 fluorouracil, 173, 358, 359, 413, 417, 515,516 interaction, 359 ltuosol da, 383 fluoxetine, 6, 14, 15, 49 interaction, 15, 17-19, 60, 71 flupentixol, 57, 60 fluphenazine, 53, 59 fluphenazine decanoate, 58 flurbiprofen, 122 Fluress s e e oxybuprocaine plus fluorescein flutamide, 479, 503 fluticasone propionate, 185, 186 interaction, 459 intranasal, 459 fluticasone propionate plus salmeterol, 189 fluvastatin s e e fluindostatin fluvoxamine, 14, 15 interaction, 15, 16, 18, 19, 55, 60, 65, 71 folic acid, 296 folinic acid, 359

follitropin, 503 fomivirsen, 340 food interaction, 341 food additive, 300, 330 formoterol, 187 interaction, 188 foscarnet, 340 fosfestrol, 469 fosfomycin, 302 interaction, 292 fosfomycin trometamol, 302 fosinopril interaction, 250 fresh frozen plasma, 384 frusemide s e e furosemide FSH s e e follitropin 5FU s e e fluorouracil furaltadone, 174 furosemide, 223, 238, 240, 248-250, 297, 334, 447, 463 interaction, 250, 292 fusidic acid, 288 interaction, 288 G CSF s e e granulocyte colony stimulating factor gabapentin, 86 gadobenate dimeglumine, 527, 528 gadodiamide, 527 gadolinium compound, 519, 526, 528 gadolinium DTPA s e e gadolinium pentetate gadolinium pentetate, 527, 528 gadomer 17, 528 gadoversetamide, 527 galactose microparticle, 529 gallium, 256 gallium 67, 256 gallopamil interaction, 299 Galloy s e e gallium ganciclovir, 296, 341, 347 interaction, 341 ganirelix, 504 Gastrografin s e e diatrizoate gastrointestinal agent, 401 gelatin, 374, 389 gemcitabine, 290, 516 gemfibrozil, 314 interaction, 295, 512 gemifloxacin interaction, 203 general anesthetic agent, 127, 146, 147

574 interaction, 237 gentamicin, 276, 283, 285,286, 287, 290, 520 interaction, 286 germanium, 256 germanium derivative, 256 germanium lactate citrate, 257 gestagen, 275,456, 467, 469, 470-472 s e e a l s o oral contraceptive agent interaction, 275 gestodene, 471 ginseng interaction, 12 glibenclamide, 13, 185, 239, 314, 487, 488, 492-496 interaction, 325,493 gliclazide, 492, 495, 496 interaction, 325 glimepiride, 491,493, 497 glipizide, 492 interaction, 325 glucagon, 220, 226 glucocorticoid, 450 s e e a l s o corticosteroid interaction, 134, 397, 458 ghicocorticosteroid s e e ghicocorticoid gluconate calcium, 223 glucose, 226, 238, 393, 487, 492, 493 glucose blood level meter, 548 ct glucosidase inhibitor, 495 interaction, 202 ghitamic acid, 395 glutathione, 522 glyburide s e e glibenclamide glycerol stearate, 173 glyceryl stearate s e e glycerol stearate glyceryt trinitrate, 149, 222, 238, 297 interaction, 222, 231 glycopeptide, 288, 291,292 glycopyrrolate s e e glycopyrronium bromide glycopyrronium bromide, 294 Glycyrthiza, 537, 538 GM CSF s e e granulocyte macrophage colony stimulating factor GnRH s e e gonadorelin gold, 257 gold salt, 266, 452 gonadorelin, 503, 506 gonadorelin agonist, 503, 504 gonadorelin antagonist, 504 gonadotropin, 473, 503 gonadotropin releasing hormone s e e gonadorelin

Index of drugs

gonadotropin releasing hormone antagonist s e e gonadorelin antagonist goserelin, 503 granulocyte macrophage colony stimulating factor, 417-419 granulocyte colony stimulating factor, 237, 314, 417, 419, 484, 485 grapefruit juice interaction, 60, 214, 320, 401, 511 griseofulvin, 326 growth hormone, xxviii, 504 growth hormone release inhibiting hormone s e e somatostatin guaifenesin, 164, 180 Gynefix s e e copper intrauterine device haemaccel s e e polygeline haemophilus influenzae type b vaccine, 365, 368, 369, 371, 372 haemophihis influenzae vaccine, 368 interaction, 457 hair dye, 175 Halcion s e e triazolam halofantrine, 331 interaction, 299, 320, 331 haloperidol, 2, 16, 53, 56, 57, 59-61, 65-69, 71, 72 interaction, 60, 135, 320 halothane, 127-130, 132 harringtonine, 444 hashish s e e cannabis HbOC vaccine s e e haemophilus influenzae type b vaccine HCG s e e chorionic gonadotropin Hectorol s e e doxercalciferol Helicobacter pylori eradication therapy, 404 hemoglobin derivative, 384 heparin interaction, 388 hepatitis A vaccine, 273 hepatitis B vaccine, 372, 374 herb s e e phytomedicine herbal ecstasy, 163 heroin s e e diamorphine hetastarch, 394 hexachlorophene, 41 1,2,6 hexanetriol, 174

2 hexyldecanoic acid, 174 hGH s e e human growth hormone Hib vaccine s e e haemophilus influenzae type b vaccine HibTITER s e e haemophilus influenzae type b vaccine high osmolar contrast medium, 519, 520 histamine interaction, 172 histamine H1 receptor antagonist, 157, 524, 534 histamine H2 receptor antagonist, 157, 402, 404, 524 HIV protease inhibitor s e e proteinase inhibitor HMG Coenzyme A reductase inhibitor s e e hydroxymethylglutaryl coenzyme A reductase inhibitor HMR 3004, 295 HMR 3647 s e e telithromycin Hoe 901 s e e insulin glargine hormonal contraceptive agent, 467, 471

contraceptive agent hormonal replacement therapy, s e e a l s o oral

t 86, 468

human growth hormone, 504 human insulin, 488-490 s e e a l s o insulin human serum albumin, 389 hyaluronidase, 140 intraocular, 148, 149 hydrochlorothiazide, 234, 237, 241 interaction, 250 hydrocortisone, 149, 394, 448, 453,455-457, 459, 524 hydrocortisone acetate, 286 hydromorphone, 106 hydroxocobalamin, 446 2 hydroxyatorvastatin acid interaction, 321 2 hydroxyatorvastatin lactone interaction, 321 2 hydroxybenzoic acid s e e salicylic acid y hydroxybutyrate s e e 4 hydroxybutyric acid 4 hydroxybutyric acid interaction, 342 hydroxychloroqnine, 174, 452 lot hydroxycholecalciferol s e e alfacalcidol hydroxyclarithromycin

575

Index of drugs

interaction, 297 4 hydroxycyclophosphamide interaction, 320, 458 40 o (2 hydroxyethyl)rapamycin, 430 interaction, 430 hydroxyethyl starch s e e hetastarch hydroxyitraconazole interaction, 320 hydroxymethylglutaryl coenzyme A reductase inhibitor, 510 interaction, 18, 295, 321,426, 511 hydroxymidazolam interaction, 318 17u hydroxyprogesterone, 456 hydroxyprogesterone acetate, 456, 470 3 hydroxyquinidine interaction, 322 hydroxyquinine, 333 9 hydroxyrisperidone interaction, 19 5 hydroxytryptamine s e e serotonin hydroxyurea, 516 hydroxyzine, 45, 544 hyoscine s e e scopolamine Hypericum perforatum s e e Saint Johns wort hypnosedative, 45 hypnotic agent, 45, 149 hypoglycemic agent s e e antidiabetic agent s e e a l s o oral antidiabetic agent hypolipidemic agent s e e antilipemic agent ibuprofen, 116, 117, 122, 144 interaction, 47, 250 icodextrin, 393 idarubicin, 254, 444, 517 interaction, 426 ifetroban interaction, 236 IL2 s e e interleukin 2 IL3 s e e interleukin 3 imidapril, 238 imidazole derivative, 174 imidazoline receptor agonist s e e imidazoline receptor stimulating agent imidazoline receptor stimulating agent, 242 imipenem, 276, 525 imipenem plus cilastatin s e e cilastatin plus imipenem imipramine, 13

interaction, 71 imiquimod, 433 immunoenhancing agent s e e immunostimulating agent immunoglobulin, 385 immunomodulating agent, 411 immunostimulating agent, 433 immunosuppressive agent, 394, 422 interaction, 420 implanted hormonal contraceptive agent, 473 indapamide, 247 indinavir, 296, 343-346 interaction, 164, 209, 231, 321,342, 347 indometacin, 118, 119, 122, 175 interaction, 241,426 Infanrix s e e diphtheria acellular pertussis tetanus vaccine infiltration anesthesia, 147 infliximab, 420 interaction, 420 influenza vaccine, xxiv, 373, 375 INH s e e isoniazid injectable hormonal contraceptive agent, 473 inotropic agent, 197 insulin, 226, 236, 238, 284, 334, 487, 492, 493,495-497 interaction, 325 insulin aspart, 490 insulin derivative, 489 insulin detemir, 490 insulin glargine, 490, 491 insulin like growth factor s e e somatomedin insulin pen, 489 insulin pump, 488, 489 insulin zinc suspension, 488, 489 interferon, 411 interferon/3 serine, 415, 416, 456 interferon, 341,411, 416, 419 interaction, 415 u2b interferon, 413 /3 interferon, 415 /3la interferon, 415,416 fl lb interferon s e e interferon fl serine y interferon, 416 interleukin, 416 interleukin 2, 413, 416 interaction, 417 intedeukin 3, 417 intrathecal anesthesia, 144 intrauterine device, xxvi, 473 intravenous anesthetic agent, 133 intravenous emulsion, 393 intravenous infusion, 393 intravenous regional anesthesia, 148

intravenous solution, 393 iodide, 485 iodinated contrast medium, 519, 521-523, 526 iodine, 271,485 iodine 131, 24 iodixanol, 520, 522 iodized salt, 485 iodophor, 271 iodoxamic acid, 534 iohexol, 521,522 iomeprol, 522 Iomerone s e e iomeprol iopamidol, 523, 524 iopentol, 520, 523 Iopidine s e e apraclonidine iopromide, 521,523 ioversol, 519, 523, 524 ioxaglic acid, 520 ioxitalamic acid, 524 ioxoprofen, 238 ipratropium bromide, 169, 192, 296, 456 intranasal, 192 irbesartan, 239, 240 iron, 257, 330, 389 iron chelating agent, 330 isepamicin, 285 ISIS 2922 s e e fomivirsen isoflurane, 128, 129, 130-132, 159 interaction, 130 isoniazid, 286, 296, 352 isonicotinic acid hydrazide s e e isoniazid isopalmitate s e e 2 hexyldecanoic acid isopalmityl diglyceryl sebacate, 174 isophane insulin, 490, 491 isoprenaline, 220 isopropanolamine, 174 isoproterenol s e e isoprenaline isosorbide dinitrate, 142, 224 isotretinoin, 444 ispagula, 506 isradipine, 234 interaction, 223 itraconazole, 174, 296, 314, 325, 326 interaction, 60, 203, 214, 297, 315,318-323, 325, 432, 458, 511 ivermectin, 357 Japanese encephalitis vaccine, 373,376 interaction, 6 josamycin, 299

576

Index

Jui see

Taxus cuspidata

kanamycin, 285,287 karaya gum, 406 ketamine, 134 interaction, 104, 135 ketoconazole, 326 interaction, 18, 179, 181, 318-323, 432, 511 ketolide antibiotic agent, 294 ketorolac, 534 ketotifen, 534 kininogen, 386 Konakion s e e phytomenadione Koo Sar, 259 L1 s e e deferiprone labetalol, 225 /~ lactam antibiotic agent, 285 lactated ringer solution s e e ringer lactate solution lactoferrin interaction, 292, 302 lactose, 547 lactulose, 406 lamivudine, 296, 343, 459 lamotrigine, 82, 87, 453 interaction, 82, 83, 87-90, 92 lanolin, 174 lanreotide s e e angiopeptin lansoprazole, 296, 402-404 Lariam s e e mefloquine latanoprost, 460, 462 latex, 301,394 laxative, 406 interaction, 484 lead, 258 lecithin, 547 lenercept, 420 Lente insulin s e e insulin zinc suspension leprostatic agent, 352 leukotriene modifier, 183 leukolriene receptor blocking agent, 183 leuprolide acetate s e e leuprorelin leuprorelin, 479, 503 levamisole, 358 interaction, 359 levetiracetam s e e etiracetam levobupivacaine epidural, 143, 144 levocabastine, 534 interaction, 181, 318 levodopa, 165 levodopa plus benserazide

s e e benserazide plus levodopa levodopa plus carbidopa s e e carbidopa plus levodopa levomepromazine, 2, 58, 459 interaction, 60 levonorgestrel, 471,473 levorphanol interaction, 74 Levovist s e e galactose microparticle licorice s e e Glycyrrhiza lidocaine, 107, 140-142, 152, 159, 212, 270, 523 interaction, 152, 299 epidural, 142-144 infiltration, 147 intraarterial, 147 intraocular, 148, 149 intrathecal, 145, 146 intravenous, 148 spinal, 145, 146 subcutaneous, 147 topical, 150 lidocaine plus benzalkonium bromide, 448 lignocaine s e e lidocaine lincomycin, 293, 294 lincosamide derivative, 293 lindane, 358 linoleic acid, 395 liothyronine interaction, 484 lipid, 454 lipid emulsion, 135, 136, 317, 395,547 interaction, 397 Lipofundin, 135 a lipoic acid s e e thioctic acid liposomal amphotericin B, 317, 336 liposome, 384 LiquiVent s e e perfluorooctyl bromide lisinopril, 13, 222, 234-236, 238, 240-242, 324, 334 lisinopril plus hydrochlorothiazide, 314 lispro insulin, 488--491 lithium, 22, 59, 68, 453 interaction, 23, 24, 26, 27, 71, 74 lithium carbonate s e e lithium lithium citrate s e e lithium local anesthetic agent, 140, 533 interaction, 322 loop diuretic agent, 246 loratadine, 179, 192 lorazepam, 48, 59, 453

of drugs

interaction, 60 lomoxicam, 122 interaction, 122 losartan, 239, 240 interaction, 241,251 loteprednol ebonate, 535 lovastatin s e e mevinolin lovastatin acid interaction, 321 low molecular weight heparin interaction, 388 low osmolar contrast medium, 51.9-521,526 loxapine, 24, 49 interaction, 46 lumefantrine s e e benflumetol LumenHance s e e manganese chloride lupin s e e Lupinus Lupinus, 539 lyme disease vaccine, 366 LYMErix s e e lyme disease vaccine lysine, 399 M9 interaction, 319 Ma Huan s e e Ephedra macrogol, 223, 547 interaction, 203 macrolide derivative, 293, 295 interaction, 184, 211,275,295 macromolecule, 528 magnesium carbonate, 484 magnesium hydroxide interaction, 484 magnesium oxide interaction, 484 magnesium sulfate, 56, 224, 406 magnetic particle, 519 magnetic resonance imaging s e e nuclear magnetic resonance imaging Malarone s e e proguanil plus atovaquone maltodextrin glucose polymer, 393 manganese, 259, 396 manganese chloride, 529 manipulative medicine, 540 MAO inhibitor s e e monoamine oxidase inhibitor marijuana s e e cannabis massage, 540 MDE s e e n ethyl 3,4 methylenedioxyamphetamine

577

Index of drugs

MDMA s e e 3,4 methylenedioxymethamphetamine measles mumps rubella vaccine, 374, 377 measles mumps vaccine, 377 measles rubella vaccine, 377 measles vaccine, 149, 377 mebendazole, 356 medical device, xxvi, 270, 497, 546 medroxyprogesterone acetate, 473 mefebutamone s e e amfebutamone mefloquine, 331,332, 333 interaction, 331,332 megestrol acetate, 296, 470 meglitinide derivative, 494 meglumine antimonate, 336 interaction, 210 melarsoprol, 335 melatonin, 545 Melleril s e e thioridazine meloxicam, 116, 123 meningococcus vaccine, 368, 372 meperidine s e e pethidine mepivacaine, 140-142 spinal, 146 mequitazine, 180 mercaptopropionylglycine s e e tiopronin mercaptopurine, 422, 517 interaction, 423, 424 mercury, 260 meropenem, 276 mesalamine s e e mesalazine mesalazine, 406, 407 metabisulfite, 547 metal antagonist, 265 metandienone, 477 metformin, 185, 239, 314, 487, 491495, 497 interaction, 325 methacholine, 187 methadone, 40, 106, 296 interaction, 74, 322, 323, 345 methamphetamine, 2 methimazole s e e thiamazole methotrexate, 420, 427, 454, 516 interaction, 279 methoxamine, 237 methoxyflurane, 131 methoxy isobutyl isonitrile technetium tc 99m, 529 5 methoxypsoralen s e e bergapten 4 methylcatechol, 284

methylene blue, 148, 151,352 3,4 methylenedioxymethamphetamine, 32 interaction, 36, 342 methylphenidate, 3, 220 interaction, 3 methylprednisolone, 47, 241, 293, 323, 407, 450, 452, 455, 456 interaction, 297, 322, 458 methylprostaglandin E1 s e e misoprostol methylxanthine derivative, 1 methysergide interaction, 168, 230 meticillin, 288, 290, 291 metildigoxin, 336 metoclopramide, 401,452 metoprolol, 234, 238, 521 interaction, 512 metrifonate, 7 metronidazole, 289, 335, 404, 405,524, 525 interaction, 286, 335 mevinolin, 425, 511 interaction, 295,299, 321, 322, 426, 511 mexiletine, 212 interaction, 213 MF 59, 375 mibefradil interaction, 203 miconazole, 325 interaction, 318, 398 midazolam, 4, 66, 84, 127, 134, 137, 142, 293 interaction, 134, 318, 348 mifepristone, 461 miglitol, 491,495 milk thistle s e e Silybum marianum milodistim, 417 milrinone, 204 Mineralin, 259 minocycline, 278, 280 interaction, 275 minoxidil, 243 misoprostol, 461 mitomycin, 516 MM vaccine s e e measles mumps vaccine MMR vaccine s e e measles mumps rubella vaccine moclobemide, 12 interaction, 12 modified hemoglobin, 384 molgramostim s e e recombinant granulocyte macrophage colony stimulating factor monoamine oxidase inhibitor, 12, 104, 165

interaction, 12, 18 monoclonal antibody, 419 monoclonal antibody cd3, 421 monoethylglycinexylidide, 212 monofluorophosphate s e e fluorophosphate montelukast, 183, 184 interaction, 184 morphine, 40, 100, 101, 103, 106, 107, 110, 135, 157, 296, 316 interaction, 43, 152 epidural, 142 intrathecal, 147 spinal, 145 moxonidine, 242 MR vaccine s e e measles rubella vaccine MS 325, 528 muscle relaxant, 157, 159 interaction, 291 mycophenolate mofetil s e e mycophenolic acid 2 morpholinoethyl ester mycophenolic acid 2 morpholinoethyl ester, 296, 429

interaction, 427, 430 Mydriacil s e e tropicamide mydriatic agent, 340, 533 Mydriaticum s e e tropicamide Myocrisin s e e aurothiomalate nabumetone,'116, 117 interaction, 250 nafarelin, 503 nalbuphine, 101, 103, 109, 110 nalidixic acid, 287 nalmefene, 110 naloxone, 101, 110, 142, 152 naltrexone, 111 nandrolone, 477 nandrolone decanoate, 477, 478 nandrolone phenpropionate, 477 naproxen, 116, 118, 122, 239, 257 interaction, 27 narcotic analgesic agent s e e opiate natamycin, 535 nateglinide, 494 NC 100100, 529 NC 100150 s e e ultrasmall superparamagnetic iron oxide nedocromil, 534 nefazodone, 17 interaction, 12, 17, 18, 27, 65, 299

578 nelfinavir, 345-347 interaction, 91,347, 433 neomycin, 283, 285,286 neomycin sulfate, 286 Neoral s e e cyclosporin a neostigmine, 157, 294 netilmicin, 285 neuroleptic agent, xxviii, 13, 24, 25, 53, 130, 179, 200 interaction, 12, 26, 27, 60 neuromuscular blocking agent, 157

neurotrophin 3, 284 nevirapine, 345, 346, 459 interaction, 345 niacin s e e nicotinic acid nicardipine, 222, 224, 238, 457 interaction, 223 nickel, 260 nicotinamide, 446 nicotine, 545 s e e a l s o tobacco nicotinic acid, 446 nifedipine, 222-224, 521 interaction, 223-225, 319 nilutamide, 479 nimesulide, 116, 123 nimodipine, 225 interaction, 225 nisoldipine interaction, 319 nitrate derivative, 222 nitrazepam, 48 nitrendipine, 225 interaction, 225,226 nitric oxide, 190 nitrofurantoin, 302 nitroglycerin s e e glyceryl trinitrate nitrous oxide, 127-130, 132, 147, 293, 526 interaction, 134 NN 304 s e e insulin detemir nondepolarizing muscle relaxant agent, 159 nonionic contrast medium, 519-521 nonsteroid antiinflammatory agent, 15, 115, 120-122, 130, 174, 176, 200, 461,522 interaction, 27, 241, 250, 251, 426 noradrenalin, 143 norclomipramine, 13 norclozapine interaction, 320 nordazepam, 47 norephedrine, xxviii, 164 interaction, 164, 342 norepinephrine

Index of drugs s e e noradrenalin norfluoxetine interaction, 18 norgestimate, 471 Normacol s e e karaya gum norpethidine, 108 Norplant s e e levonorgestrel norpropoxyphene, 105 nortriptyline, 13 Novesin s e e oxybuprocaine novobiocin, 302 interaction, 302 Novolet s e e insulin pen Novopen s e e insulin pen NPH insulin s e e isophane insulin NSAID s e e nonsteroid antiinflammatory agent nuclear magnetic resonance imaging, 519, 526, 529 nucleoside analog, 342, 344 nystatin, 175, 296

octadecanol, 173 octreotide, 505 ocular agent, 533 ocular anesthesia s e e eye anesthesia OKT 3, 421 olanzapine, 24, 53, 54, 66, 73 interaction, 71 olsalazine, 406 omeprazole, 238, 402, 403--405, 455 interaction, 298, 322 OmniH1B s e e haemophilus influenzae type b vaccine ondansetron, 101 OPC 13015 s e e dehydrocilostazol opiate, 39, 70, 100, 102, 134 interaction, 291 opiate antagonist, 110 opioid s e e opiate opioid agonist antagonist s e e partial opiate agonist opioid antagonist, 100 s e e opiate antagonist oral contraceptive agent, xxviii, 200, 275, 398,468, 470--473, 479, 504 interaction, 274, 275, 322, 345, 354 oral anticoagulant agent, 398 s e e a l s o coumarin derivative

interaction, 122, 239, 539 oral antidiabetic agent, 454, 491 interaction, 325 oral hypoglycemic agent s e e oral antidiabetic agent organic nitrate interaction, 231 orlistat interaction, 425 ornipressin, 507 Orthoclone s e e OKT 3 ovulation inductor, 473 oxacillin, 301,431 oxaliplatin, 515 oxazepam interaction, 344 oxcarbazepine, 90 oxicam derivative, 122 oxybuprocaine, 140, 533 oxybuprocaine plus fluorescein, 533 oxybutynin, 168 oxycodone, 107 Oxygen(tm) s e e perfluorooctyl bromide oxymetazoline, 164 oxymetholone, 477 oxytocin, 460, 461,506 oxytocin derivative, 506 P 760, 528 palmitic acid, 529 pamidronate s e e pamidronic acid pamidronic acid, 544 pancreas enzyme, 408 Pancreatin s e e pancreas enzyme paracetamol, 120-122, 222, 239, 316, 334 interaction, 122, 344 paramethasone intra-articular, 459 parasympathicolytic agent s e e cholinergic receptor blocking agent parasympatholytic agent s e e cholinergic receptor blocking agent parathion, 547 paratoluenediamine s e e 2,5 diaminotoluene paravertebral block, 149 paraxanthine, 1 parenteral nutrition, 395 interaction, 397 paroxetine, 14, 15 interaction, 7, 15, 16, 19, 27, 60, 226 partial opiate agonist, 110 Paxyl

579

Index of drugs

lidocaine plus benzalkonium bromide PedvaxHIB s e e haemophilus influenzae type b vaccine pefloxacin, 285 pemirolast, 534 penicillamine, 266, 267 penicillin derivative, 276, 277, 295, 399, 522 interaction, 275 pentamidine interaction, 251 pentastarch, 394 pentavalent antimony derivative, 336 pentazocine, 110 pentostatin, 516, 517 peptide, 300 Perdiem s e e senna extract Perflubron s e e perfluorooctyl bromide perfluorocarbon s e e fluorocarbon perfluoro compound, 383, 384 s e e a l s o fluorocarbon perfluorodecalin, 384 perfluorodichlorooctane, 383 perfluorooctyl bromide, 383, 384 perfluorooctylethane, 383 perfluorotripropylamine, 384 pergolide, 166, 167 perindopril, 240 perphenazine, 14, 24, 58, 59, 325 interaction, 66 pertussis acellular vaccine, 369, 370 pertussis vaccine, 369 pethidine, 41, 101, 103, 107, 109, 237, 316 phenacetin, 120, 121 phenazone interaction, 288 phenelzine, 220 pheniramine maleate, 180 phenobarbital, 4, 82, 83, 330, 447 interaction, 60, 83 phenol, 271,272 phenol derivative, 271 phenothiazine derivative, 58, 176, 179 phenprocoumon, 398 interaction, 122, 123 phentermine, 4, 6 phenylalanine derivative, 494 phenylbutazone derivative, 123 phenylephrine, 243, 534 phenylpropanolamine s e e norephedrine phenytoin, 82-90 see

interaction, 47, 60, 83, 85, 89, 91,324, 347 phosphate derivative, 396, 547 phosphodiesterase inhibitor, 192, 204 phospholipid, 387 photochemotherapy s e e PUVA phytomedicine, 258, 537 interaction, 12 phytomenadione, 448 Picolax s e e picosulfate sodium picosulfate sodium, 406 pimozide, 54 interaction, 60, 298 pindolol, 220, 234 pioglitazone, 496 piperacillin, 276, 277 piperacillin plus tazobactam, 277, 288 PIXY 321 s e e milodistim Plantago ovata, 406 plasma, 383 plasma product, 383 plasma substitute, 393 platinum, 260 platinum compound s e e platinum derivative platinum derivative, 260 pneumococcus vaccine, 371 Pneumovax 23 s e e pneumococcus vaccine polidocanol, 547 poliomyelitis vaccine, 378 poliomyelitis vaccine, inactivated, 366, 371 poliomyelitisvaccine, oral, 372, 373, 375, 378 polyclonal antibody, 421 polyene derivative, 324 polyethoxylated castor oil s e e ricinomacrogol polyethylene glycol s e e macrogol polyethyleneglycolelectrolyte lavage solution, 406 polygeline, 393, 520 polymyxin B, 300, 301 polymyxin derivative, 300 polysorbate 80, 208 polyurethan, 546 polyvinylpyrrolidone s e e povidone polyvinylpyrrolidoneeicosene copolymer, 175 Ponderal s e e fenfluramine Ponderax s e e fenfluramine potassium dichromate s e e dichromate potassium

potassium salt, 248 potassium sparing diuretic agent, 248, 251 interaction, 251 povidone, 175, 547 s e e a l s o povidone iodine povidone iodine, 175, 271 s e e a l s o povidone pramipexole, 166 pranlukast, 183, 184 pravastatin, 496, 497, 510, 512 interaction, 18, 321,426, 511, 512 praziquantel, 360 prazosin, 225 prednisolone, 183,394, 445, 447, 448, 454, 455, 459, 523, 535 interaction, 298, 427 prednisone, 225, 287, 291,296, 430, 432, 452-457 interaction, 458 preservative, 146, 534 Prevnar s e e pneumococcus vaccine prilocaine, 140, 147 dental, 147 infiltration, 147, 148 topical, 142 prilocaine plus lidocaine caudal, 142 topical, 149, 150 primaquine, 332 primaquine derivative, 332 primidone, 83, 84 pristinamycin, 300 interaction, 432 probenecid, 340 procainamide, 198, 213 prochlorperazine, 56 progesterone, 470, 474 progestogen s e e gestagen proguanil, 333 interaction, 333 proguanil plus atovaquone, 333 ProHIBit s e e haemophilus influenzae type b vaccine promethazine, 47, 179, 180, 394, 462 propafenone, 198, 199, 204, 214 proparacaine s e e proxymetacaine propofol, 129, 132, 135, 141, 149, 159, 293 interaction, 6, 134, 136 propranolol, 49, 220, 221,316 interaction, 60 propylthiouracil, 485 prostacyclin, 463 prostacyclin derivative, 463 prostaglandin derivative, 459 interaction, 172

580 prostaglandin El, 459 prostaglandin E2, 460 prostaglandin synthase inhibitor, 115 prosthesis, 255, 261,548 protamine, 488 protease inhibitor s e e proteinase inhibitor proteinase inhibitor, 345, 346 interaction, 321,345, 426, 433 prothrombin complex, 384, 386, 387 protirelin, 506 proton pump inhibitor, 402, 404 proxymetacaine, 152 PRP D Hib vaccine s e e haemophilus influenzae type b vaccine pseudoephedrine, 6, 163, 296 interaction, 6 Psorcutan Salbe s e e calcipotriol psychotropic agent s e e neuroleptic agent psyllium s e e ispagula Pulmozyme s e e dornase ot pumaprazole, 403 PUVA, 176 pyrazinamide, 425 pyridoxine, 446, 447 pyrrolizidine alkaloid, 539 quetiapine, 58, 71 quinapril, 238 quinidine, 199, 204, 214 interaction, 19, 60, 104, 214, 299, 322 quinine, 331,333 interaction, 299 quinine sulfate, 333 quinupristin plus dalfopristin, 301

rabeprazole, 403,404 rabies vaccine, 373 interaction, 332 radiocontrast medium s e e contrast medium radiological contrast medium s e e contrast medium raloxifene, 476 ramipril, 233-235, 239 interaction, 493 ranitidine, 239, 402-404 interaction, 493 rapacuronium bromide, 159 rapamycin, 430 Rebif s e e / 3 1 a interferon reboxetine, 18 interaction, 18, 323

Index of drugs

recombinant blood clotting factor 7a, 387 interaction, 388 recombinant blood clotting factor 8, 387 recombinant erythropoietin, 388 interaction, 265 recombinant granulocyte colony stimulating factor, 343,419 recombinant granulocyte macrophage colony stimulating factor, 419 recombinant a interferon, 412 recombinant interleukin 3, 417 s e e a l s o interleukin 3 recombinant somatomedin c, 491 Regibloc s e e bupivacaine remifentanil, 108, 135,205 remoxipride, 54 repaglinide, 491,494 reserpine interaction, 172 respiratory tract agent, 183 retinoic acid, 254, 284, 444 interaction, 442 all trans retinoic acid s e e retinoic acid 13 cis retinoic acid s e e isotretinoin retinoid, 347, 444 interaction, 442, 443 retinol, 331,442, 443 interaction, 442 reverse transcriptase inhibitor s e e RNA directed DNA polymerase inhibitor ribavirin, 341, 411 interaction, 415 ribonucleic acid, 433 ricinomacrogol, 448 Ricinus communis, 539 rifabutin, 296, 354 interaction, 354 rifampicin, 176, 286, 353 interaction, 60, 203, 210, 274, 275, 319, 323, 344, 354, 432, 484 rifamycin, 175 rimantadine, 296 ringer lactate solution, 271 risedronic acid, 544 Risperdal s e e risperidone risperidone, 2, 6, 50, 53, 54, 58, 60, 69-71, 453 interaction, 19, 27, 74, 94, 279, 299 ritalinic acid, 3 ritodrine, 222, 225 ritonavir, 345-347 interaction, 106, 168, 209, 342, 348, 426, 433, 459

rituximab, 421 rivastigmine, 8 rizatriptan, 230 interaction, 12, 16 RNA directed DNA polymerase inhibitor, 342, 344, 346 rofecoxib, 116-119 ropinirole, 166, 167 interaction, 203 ropivacaine, 105, 140, 141 interaction, 322 epidural, 143, 144 infiltration, 147 intraocular, 148 intrathecal, 144 intravenous, 148 nerve block, 149 rosiglitazone, 496, 497 Rotashield s e e rotavirus vaccine rotavirus vaccine, 379 roxithromycin, 295, 299, 405 rubella vaccine, 379 Saint Johns wort, 539 interaction, 12, 203, 425, 539 salazosulfapyddine, 407, 408, 452, 454 interaction, 426 salbutamol, 187, 296, 297, 456, 457 interaction, 188 saicatouin, 503 salicylic acid, 284 salicylic acid derivative, 408 interaction, 249, 288, 493 saline s e e sodium chloride Saline Pens s e e insulin pen salmeterol, 187, 189 interaction, 188 salmeterol plus fluticasone s e e fluticasone propionate plus salmeterol salmon calcitonin s e e salcatonin sameridine intrathecal, 145 saquinavir, 345, 346, 348 interaction, 134, 342, 348, 433 sargramostim s e e granulocyte macrophage colony stimulating factor Schwarz FFB vaccine s e e measles vaccine sciatic nerve block, 149 scopolamine, 169 scorpion venom, 2 Scutellaria, 539 sdz rad s e e 40 o (2 hydroxyethyl) rapamycin

Index of drugs

selective estrogen receptor modulator, 476 selective serotonin re-uptake inhibitor s e e serotonin uptake inhibitor selenium, 260, 396 senna extract, 406 Seroquel s e e quetiapine serotonin interaction, 172 serotonin agonist, 230 interaction, 17 serotonin 3 antagonist, 401 serotonin reuptake inhibitor s e e serotonin uptake inhibitor serotonin uptake inhibitor, 14, 16, 17, 19, 104, 220 interaction, 7, 12, 15, 17, 18, 27, 65, 74 sertindole, 54 sertraline, 14, 15, 325 interaction, 15, 16, 45, 50, 94, 255, 279, 299 sestamibi Tc 99m s e e methoxy isobutyl isonitrile technetium tc 99m sevoflurane, 108, 127-130 interaction, 60, 132, 213 sex hormone, 467 sildenafil, xxiii, 191,192, 231 interaction, 222, 223, 231,347 silicone, 546, 548 silver, 261 silver nitrate, 261 silver salt, 261 Silybum marianum, 539 simethicone coated cellulose, 529 simvastatin, 238, 394, 407, 425, 510-512 interaction, 18, 91,224, 321, 322, 426, 497, 511,512 simvastatin acid interaction, 321,322 sirolimus s e e rapamycin skeletal muscle relaxant agent s e e muscle relaxant skullcap s e e Scutellaria smoking s e e tobacco sodium aurothiomalate s e e aurothiomalate sodium bicarbonate s e e bicarbonate sodium chloride, 301,388, 524 sodium metabisulfite, 175 sodium polyphosphate s e e tripolyphosphate sodium stibogluconate s e e stibogluconate sodium

5 81

sodium valproate s e e valproic acid Solian s e e amisulpride somatomedin, 491 somatostatin, 505 somatostatin analog, 505 somatotrophin s e e human growth hormone sorbitol, 243, 296 sotalol, 199, 200, 204, 206 sparfloxacin, 296 interaction, 181,203 spectinomycin, 286, 287, 302 spinal manipulation s e e manipulative medicine spinal anesthesia, 144 interaction, 237 spironolactone, 203, 238, 240, 241,246, 248, 251 interaction, 251 stavudine, 296, 342, 345 stearic acid, 173 stearyl alcohol s e e octadecanol stem cell factor, 419 sterculia s e e karaya gum stibogluconate sodium, 336 stiripentol, 91 interaction, 91 St. Johns wort s e e Saint Johns wort streptogramin A, 300 streptogramin B, 300 streptogramin derivative, 293, 300

streptokinase interaction, 121 streptomycin, 283, 286, 287, 302 strychnine, 4 succinic acid, 158 succinylcholine s e e suxamethonium sucralfate, 404 sucrose, 386 sufentanil, 102, 103, 109, 222 epidural, 143 sulbenicillin,277 sulfadiazine, 270 sulfadiazine silver, 271 sulfanilamide, xxv sulfasalazine s e e salazosulfapyridine sulfonamide, 119, 287, 295 sulfonylurea derivative, 236, 492, 495,497 s e e a l s o oral antidiabetic agent interaction, 493 sulindac, 122 interaction, 250 sulpiride, 2, 22, 58, 180 sulprostone, 462

sultiame, 91 sumatriptan, 230 interaction, 16, 168, 230 sunscreen, 174 suramin, 361 surfactant, 451 surgical material, 548 suxamethonium, 158, 159, 293 sympathicolyfic agent s e e adrenergic receptor blocking agent sympathicomimetic agent s e e adrenergic receptor stimulating agent T4 s e e thyroxine tacrolimus s e e tsukubaenolide tafenoquine, 332 talc, 548 tamoxifen, 416, 475, 517, 521 tasosartan, 239 taxane derivative, 515 Taxus cuspidata, 539 tazobactam, 276 3TC s e e lamivudine teicoplanin, 288, 289, 292 telithromycin, 295 telmisartan, 239, 241 temazepam, 48 temocapril, 239 interaction, 239 temocillin, 276 terazosin, 239 terbinafine, 314, 326 terbutaline, 188 terfenadine, 179, 180 interaction, 180, 511 terlipressin, 507 testosterone, 476--478 transdermal, 478 testosterone enantate, 476 testosterone propionate, 477 tetanus toxoid, 369 tetrabenazine, 57 tetracaine, 140, 148, 151 topical, 150 tetracosactide, 457 tetracycline, 279, 287, 295, 399 interaction, 74, 279 tetracycline derivative, 278, 295 interaction, 275,279 thalidomide, xxv, xxvi, 171 interaction, 172 theophylline, 189, 456 interaction, 184, 185, 250, 292, 298 thiamazole, 485 thiamine, 331,395 thiamphenicol, 287 interaction, 287

582 thiazide diuretic agent, 239, 246-250, 455 interaction, 250 thiazolidinedione derivative, 491, 496 thioctic acid, 284 thiomersal, 374 thionamide derivative, 484, 485 thiopental, 128, 133, 136, 141, 144, 159 thiopentone s e e thiopental thioridazine, 47, 54, 55, 59, 133 interaction, 16, 55, 60 thorium dioxide, 530 Thorotrast s e e thorium dioxide thrombocyte concentrate, 290 thrombolytic agent s e e fibrinolytic agent thyroid hormone, 484 interaction, 484 thyrotropin releasing hormone s e e protirelin thyroxine interaction, 354, 484 tiagabine, 91 interaction, 91 tibolone, 480 ticarcillin, 276 ticarcillin plus clavulanic acid, 296 TiceBCG s e e BCG vaccine tick borne meningoencephalitis vaccine, 380 ticlopidine, 399 interaction, 91,426 Ticovac s e e tick borne meningoencephalitis vaccine timolol, 221,533 tinidazole, 404 tiopronin, 267 tiotropium bromide, 189 titanium, 261 tixocortol pivalate, 456, 459 tobacco, 16, 443 interaction, 60, 66, 71,442, 443 Tobradex s e e dexamethasone plus tobramycin tobramycin, 285,287, 334 interaction, 287 inhalation, 193 tocopherol s e e ct tocopherol a tocopherol, 331 interaction, 443 tolbutamide interaction, 325, 493

Index of drugs

tolcapone, 167, 168 tolmetin, 122 tolterodine, 168 interaction, 323 topical agent, 171 topical anesthesia, 149 topiramate, 92 tramadol, 46, 100, 103, 106, 109 trandolapril, 239 transforming growth factor a, 284 trastuzumab, 421 trazodone, 15, 17, 18, 59, 296 interaction, 12, 18, 27, 85 trecovirsen, 345 TRH s e e protirelin triacetyloleandomycin s e e troleandomycin triamcinolone, 185, 453, 456 triazolam, xxviii, 48, 165 interaction, 318 tribenoside, 175 trichlormethiazide, 223 trichloroethylene, 132 tricyclic antidepressant agent, 12, 19, 55, 102, 143, 221 interaction, 12, 27 triethyltin, 41 trifluoperazine, 58, 59 interaction, 19 trifluperidol, 23 triglycyl lysine vasopressin s e e terlipressin triiodothyronine s e e liothyronine trimethoprim, 286 interaction, 251,341 Trimovate, 175 Tripedia s e e diphtheria acellular pertussis tetanus vaccine tripolyphosphate interaction, 302 triptan derivative, 229 triptorelin, 503, 504 troglitazone, 492, 494--497 interaction, 497 troleandomycin, 299 interaction, 299 tropicamide, 533 tropisetron, 402 Trusopt s e e dorzolamide tsukubaenolide, 296, 425, 430 interaction, 224, 298, 323, 335, 430, 432, 433 Tsumura, 537 tuberculostatic agent, 352 Tween 80 s e e polysorbate 80 tylosin, 299 typhoid vaccine, 372

typhoid vaccine, inactivated, 373 interaction, 6 ultrasmall superparamagnetic iron oxide, 528 ultrasound contrast medium, 519, 529 unoprostone, 460, 462 ursodeoxycholic acid, 395,408 usnic acid, 261 vaccine, 364 valaciclovir, 461 valproate semisodium, 22, 24, 25, 94 s e e a l s o valproic acid valproic acid, 13, 34, 82, 83, 85, 87-89, 93, 325,453 s e e a l s o valproate semisodium interaction, 27, 47, 60, 66, 82, 83, 87-92, 94, 323 valsartan, 239, 241 interaction, 26 vancomycin, 284, 288-290, 296, 301,302, 334 interaction, 250, 291,292 varicella vaccine s e e chickenpox vaccine vasoconstrictor agent, 143 vasodilator agent, 229, 243 vasopressin, 506 vasopressin derivative,506 vecuronium, 4 venlafaxine, 18 interaction, 19, 27, 74 venom antiserum, 2 verapamil, 205,226, 453 interaction, 223, 226, 319 Viagra s e e sildenafil vigabatrin, 85, 92, 94 vincristine interaction, 323 vinorelbine, 515 virginiamycin, 302 virus vaccine, 373 vitamin, 334, 442 vitamin A s e e retinol vitamin B, 331,446 vitamin B 1 s e e thiamine vitamin B6 s e e pyridoxine vitamin B12 s e e cyanocobalamin vitamin C s e e ascorbic acid vitamin D, 331,446 vitamin E s e e et tocopherol vitamin K s e e vitamin K group

583

Index o f drugs

vitamin K group, 448 voglibose, 492 interaction, 202 VP 16 213 s e e etoposide warfarin, 296, 384, 448 interaction, 71,122, 123, 184, 185, 210, 239, 288, 296, 297, 348, 424, 512 xenon, 526 yohimbine interaction, 12 Zaditor

see ketotifen zafirlukast, 183, 184 interaction, 184, 296 zaleplon, 49 zanamavir, 348 interaction, 348 Zestoric see lisinopril plus hydrochlorothiazide zidovudine, 296, 342, 343, 388, 459 interaction, 323, 344 zileuton, 183, 184 interaction, 184 zinc, 261, 331 zinc derivative, 261

zinc sulfate, 261 ziprasidone, 74 interaction, 27, 85 zolmitriptan, 230 zolpidem, 49, 50 interaction, 50, 323 zonisamide, 93 interaction, 47 zopiclone, 50 zotepine, 58 Zovirax s e e aciclovir zuclopenthixol, 59 Zyprexa see olanzapine

Index of adverse effects

abdominal bloating

abdominal distension abdominal cramp acarbose, 496 acetazolamide, 249 2,5 diaminotoluene, 175 Helicobacter pylori eradication therapy, 405 misoprostol, 462 see

abdominal discomfort

acarbose, 495 lidocaine, 140 miglitol, 495 modified hemoglobin, 384 picosulfate sodium, 406 praziquantel, 361 abdominal distension acarbose, 495, 496 albendazole, 356 mebendazole, 356 miglitol, 495 abdominal pain albendazole, 356 barium sulfate, 525 carbon dioxide, 526 clarithromycin, 297 cyclooxygenase 2 inhibitor, 116 gadodiamide, 527 Helicobacter pylori eradication therapy, 405 itraconazole, 325 ivermectin, 358 mebendazole, 356 meglumine antimonate, 336 milodistim, 417 misoprostol, 461 nicotinic acid, 446 nonsteroid antiinflammatory agent, 116 oral contraceptive agent, 472 oxytocin derivative, 506 prednisone, 455 retinoic acid, 445 rivastigmine, 8 stibogluconate sodium, 336 trecovirsen, 345 zolpidem, 50 abortion

caffeine, 1 losartan, 241 584

paraxanthine, 1 absence see

epilepsy

abuse see

alprazolam, 46 agranulocytosis

drug abuse

acantholysis

enalapril, 237, 238 acanthosis nigrans

growth hormone, 505 accidentai injury see

zaleplon, 49 agoraphobia

injury

acidosis

cocaine, 37 acne

anabolic agent, 477 betamethasone, 457 desogestrel, 476 lithium, 25 testosterone enantate, 476 tibolone, 480 adrenal insufficiency

fosfestrol, 469 adrenal suppression corticosteroid, 185 fluticasone propionate, 185 triamcinolone, 185 ageusia s e e dysgeusia aggression clarithromycin, 296 donepezil, 7 prednisone, 453, 454 propofol, 136 topiramate, 92 aggressive behavior s e e aggression agitation amfebutamone, 16 bupivacaine, 147 dexamethasone, 453 donepezil, 7 fentanyl, 147 fluvoxamine, 14 Helicobacter pylori eradication therapy, 405 mepivacaine, 142 morphine, 147 risperidone, 71, 73 ropivacaine, 141 scorpion venom, 2 sevoflurane, 127

abacavir, 343 captopril, 237 clozapine, 61, 62, 65, 69, 70 deferiprone, 265 olanzapine, 69, 70 omeprazole, 403 thionamide derivative, 484, 485 airway obstruction hydroxychloroquine, 174 midazolam, 134 opiate, 134 akathisia

cinnarizine, 179 domperidone, 401 droperidol, 66 interferon, 412 melatonin, 545 metoclopramide, 401 neuroleptic agent, 56 olanzapine, 67 risperidone, 53, 72 ziprasidone, 74 akinesia

diphenhydramine, 180 akinetic mutism baclofen, 159, 160 albuminuria s e e proteinuria alertness

antihistaminic agent, 179 alkaline phosphatase blood level

granulocyte colony stimulating factor, 418 allergic contact dermatitis s e e skin hypersensivity allergic reaction s e e hypersensitivity allergic skin reaction s e e skin hypersensitivity allergy s e e hypersensitivy alopecia

anticonvulsive agent, 82 epirubicin, 362 ganciclovir, 347

585

I n d e x o f adverse effects

immunoglobulin, 386 indinavir, 347 ot interferon, 414 retinoid, 347 Alzheimer disease aluminium, 253 amenorrhea clozapine, 65 implanted hormonal contraceptive agent, 473 risperidone, 71, 72 ritonavir, 347 thalidomide, 172 aminotransferase blood level acarbose, 496 albendazole, 356 amphotericin B deoxycholate, 315 atorvastatin, 510 clarithromycin, 297 clodronic acid, 122 fluconazole, 324 human insulin, 488 isoniazid, 353 levamisole, 358, 359 mebendazole, 356 methotrexate, 428 repaglinide, 494 troglitazone, 494 zileuton, 184 amnesia cannabis, 36 diazeparn, 47, 133 glucocorticoid, 453 insulin, 487 zaleplon, 49 amylase blood level bezafibrate, 510 clarithromycin, 297 prednisone, 454, 455 amyloidosis aurothiomalate, 257 amyotrophy see muscle atrophy analgesic nephropathy analgesic agent, 120 nonsteroid antiinflammatory agent, 120 paracetamol, 120 phenacetin, 120 anaphylactic reaction abacavir, 343 adenosine, 205 alteplase, 399 amoxicillin, 405 bacitracin, 301 blood clotting factor 8, 388 blood clotting factor 9, 387, 388 buflomedil, 229 chlorhexidine, 270 cocaine, 38 contrast medium, 523, 524

Cremophor EL, 448 delavirdine, 344 gelatin, 389 glyceryl trinitrate, 222 immunoglobulin, 386 iopamidol, 524 ioversol, 523 ioxitalamic acid, 524 methylprednisolone, 456 neuromuscular blocking agent, 157, 158 OK 432, 421 omeprazole, 403 pentastarch, 394 phytomenadione, 448 polygeline, 393, 394 recombinant erythropoietin, 389 recombinant intedeukin 3, 417 ricinomacrogol, 448 Ricinus communis, 539 rifampicin, 354 rifamycin, 175 vancomycin, 291 anaphylacfie shock ceftizoxime, 277 chlorhexidine, 270 fentanyl, 291 iopamidol, 524 ioversol, 524 vancomycin, 291 anaphylactoid purpura clarithromycin, 297 anaphylaetoid reaction s e e anaphylactic reaction anaphylaxis s e e anaphylactic reaction anemia amiodarone, 209 flutamide, 480 lamivudine, 343 mycophenolic acid 2 morpholinoethyl ester, 430 penicillarnine, 266 repaglinide, 495 suramin, 362 trastuzumab, 421 troglitazone, 495 zidovudine, 388 anesthesia bupivacaine, 148, 149 lidocaine, 148, 149 ropivacaine, 148 angiitis s e e vasculitis angina pectoris fluorouracil, 515 nifedipine, 224 angioedema see angioneurotic edema angioneurotie edema angiotensin II antagonist, 241

captopril, 241 cocaine, 39 dipeptidyl carboxypeptidase inhibitor, 235,236 Echinacea, 538 erythromycin, 298 lisinopril, 236 losartan, 241 methotrexate, 428 omeprazole, 403 polygeline, 394 ankle edema s e e edema anorexia deferiprone, 265 donepezil, 6 glibenclamide, 492 measles vaccine, 377 quinapril, 238 rivastigmine, 8 topiramate, 92 anorgasmia see sexual dysfunction antibody formation blood clotting factor 8, 387 blood product, 385 blood transfusion, 385 dexamethasone, 456 etanereept, 420 infliximab, 420 insulin, 488 levamisole, 360 penicillamine, 267 recombinant blood clotting factor 7a, 387 recombinant blood clotting factor 8, 387 recombinant erythropoietin, 389 antichoHnergie symptom diphenhydramine, 180 Lupinus, 539 tiotropium bromide, 189 anticonvulsant hypersensitivity syndrome carbamazepine, 85 antisocial behavior paroxetine, 14 anuria teicoplanin, 289 vancomycin, 289 ai~ety codeine, 41 domperidone, 401 insulin, 487 t~ interferon, 412 metoclopramide, 401 nefazodone, 17 olanzapine, 68 prednisone, 453 risperidone, 72 ropivacaine, 141 aorta valve regurgitation

586 dexfenfluramine, 4 apgar score diamorphine, 43 pethidine, 43 aphasia lidocalne, 147 aplastic anemia etanercept, 420 felbamate, 85 perphenazine, 58 apnea benzocaine, 151 brimonidine, 536 cetacalne, 151 xenon, 526 appendicitis barium sulfate, 524 appetite increase nateglinide, 494 olanzapine, 67 appetite loss see anorexia apra~a benserazide plus levodopa, 166 argyria silver salt, 261 arousal cocaine, 39 arteriopathy manipulative medicine, 540, 541 prostacyclin, 463 arteritis cannabis, 36 ephedrine, 163 artery occlusion bromocriptine, 166 ergotamine, 168 artery thrombosis granulocyte colony stimulating factor, 418 arthralgia amfebutamone, 17 azathioprine, 422 chlorhexidine, 270 deferiprone, 265 infliximab, 420 isoniazid, 353 ivermectin, 358 levamisole, 358 lyme disease vaccine, 367 meglumine antimonate, 336 milodistim, 417 nystatin, 175 rapamycin, 430 retinoic acid, 445 stibogluconate sodium, 336 thionamide derivative, 485 arthritis hepatitis B vaccine, 375 lyme disease vaccine, 366-368

I n d e x o f adverse effects

quinupristin plus dalfopristin, 301 arthropathy thionamide derivative, 485 aseptic meningitis OKT 3, 421 asterixis lithium, 23 asthma acetylsalicylic acid, 119 hydroxychloroquine, 174 leukotriene receptor blocking agent, 183 lithium, 22 paracetamol, 122 asystole see heart arrest ataxia amiodarone, 206 carbamazepine, 84, 87 dextromethorphan, 104 lamotrigine, 87 levamisole, 358, 359 phenytoin, 87 thalidomide, 171 atheroselerosis ritonavir, 346 atrial flutter see heart atrium flutter atrioventricular block see heart atrioventricular block attention impairment cocaine, 39 auditory hallucination amfebutamone, 16 dexamphetamine, 2 methamphetamine, 2 testosterone, 477 topiramate, 93 triptorelin, 503 autism measles mumps rubella vaccine, 377, 378 autoimmune disease hepatitis B vaccine, 374 levamisole, 359 lyme disease vaccine, 366-368 autonomic symptom oxybutynin, 168 tolterodine, 168 backache bupivacalne, 144, 146 contrast medium, 519 general anesthetic agent, 146 granulocyte colony stimulating factor, 419 phytomenadione, 448 prednisone, 452 ropivacaine, 144 spinal anesthesia, 146

teicoplanin, 290 trecovirsen, 345 back pain see backache bacteremia s e e bacterial infection bacterial endocarditis see endocarditis bacterial infection catheter, 546 diatrizoate, 525 interleukin 2, 416 barolith barium sulfate, 525 behavior disorder clobazam, 84 cocaine, 39 olanzapine, 69 prednisone, 453, 454 propofol, 136 tiagabine, 92 topiramate, 92 Bell palsy chickenpox vaccine, 380 benign intracranial hypertension see brain pseudotumor benign liver tumor danazol, 479 bezoar sucralfate, 404 bicarbonate blood level topiramate, 93 biliary tract disease fluconazole, 324 bilirubin blood level nefazodone, 17 birth weight diazcpam, 47, 180 fexofenadinc, 180 terfenadine, 180 bleeding acetylsalicylic acid, 121 ipratropium bromide, 193 misoprostol, 461 nitric oxide, 190 proteinase inhibitor, 346 quinupristin plus dalfopristin, 301 ritonavir, 346 serotonin uptake inhibitor, 14 valproic acid, 94 blepharospasm lamotriginc, 88 blindness cisplatin, 260 cocaine, 150 contrast medium, 521 blister captopril, 237 hydroxocobalamin, 446 isoniazid, 353 lidocaine, 150

587

I n d e x o f adverse effects

blood clotting albumin, 383 contrast medium, 520 corticosteroid, 453 propofol, 137 trecovirsen, 345 tsukubaenolide, 431 blood dotting factor deficiency tsukubaenolide, 431 blood dyscrasia clozapine, 61 neuroleptic agent, 58 blood pressure bacitracin, 301 bupivacaine, 145 cocaine, 225 fiuoxetine, 14 lidocaine, 146 modified hemoglobin, 384 morphine, 145 nimodipine, 225 octreotide, 505 oxytocin derivative, 506 rosiglitazone, 497 sildenafil, 231 somatostatin, 505 spinal anesthesia, 146 blood toxicity dapsone, 335, 352 blood urea nitrogen see urea nitrogen blood level blood viscosity recombinant erythropoietin, 388 blurred vision brinzolamide, 536 cocaine, 150 glucocorticoid, 452 ipratropium bromide, 169 ivermectin, 358 lamotrigine, 87 oxymetazoline, 164 prilocaine plus lidocaine, 150 body equilibrium disorder alprazolam, 46 anabolic agent, 477 zolpidem, 50 body weight dexamethasone, 454 bone atrophy corticosteroid, 186 glucocorticoid, 455 hydrocortisone, 455 bone density s e e bone mineral density bone disease aluminium hydroxide, 253 bone fracture amisulpride, 61 corticosteroid, 186 glucocorticosteroid, 455,456 bone injury anabolic agent, 477

bone loss s e e bone atrophy bone marrow suppression ot interferon, 413 mercaptopurine, 422 thionamide derivative, 484 bone marrow toxicity stibogluconate sodium, 336 bone mass methotrexate, 428 bone metabolism corticosteroid, 186 methotrexate, 428 bone mineral density beclometasone dipropionate, 186 budesonide, 186 corticosteroid, 186 ghicocorticosteroid, 455 medroxyprogesterone acetate, 473 bone necrosis betamethasone, 457 glucocorticosteroid, 455 bone pain granulocyte colony stimulating factor, 417, 418 ivermectin, 358 recombinant erythropoietin, 388 tsukubaenolide, 432 bone toxicity cadmium, 255 bovine spongiform encephaiopathy see brain spongiosis bradycardia adenosine, 203 amiodarone, 197, 198 antiarrhythmic agent, 200 bupivacaine, 143 captopril, 237 carvedilol, 221 citalopram, 14 flecainide, 198 fluoxetine, 14 imidapril, 238 iopamidol, 524 ioxitalamic acid, 524 lidocaine, 145, 152 lithium, 22 methylprednisolone, 450 metrifonate, 8 minoxidil, 243 oxybuprocaine, 533 povidone iodine, 271 propofol, 135, 136 remifentanil, 108 ropivacaine, 143, 149 spinal anesthesia, 145 verapamil, 226 brain abscess

mycophenolic acid 2 morpholinoethyl ester, 429 brain atrophy valproic acid, 93 brain damage s e e brain injury brain edema desmopressin, 507 n ethyl 3,4 methylenedioxyamphetamine, 33 glutamic acid, 395 3,4 methylenedioxymethamphetamine, 33, 35 brain embolism contrast medium, 521 brain hemorrhage nitric oxide, 190 oral contraceptive agent, 471 retinoic acid, 444 warfarin, 384 brain hypoxia opiate, 40 brain injury dexamethasone, 451 manipulative medicine, 540 3,4 methylenedioxymethamphetamine, 34 brain pseudotumor chorionic gonadotropin, 503 follitropin, 503 goserelin, 503 growth hormone, 504 prednisone, 452 brain spongiosis diamorphine, 40, 41,105 hemoglobin derivative, 384 virus vaccine, 373 brain thrombosis glucocorticosteroid, 452 breast cancer fertility promoting agent, 474 hormonal replacement therapy, 469 raloxifene, 476 breathlessness see dyspnea bronchospasm adenosine, 205 basiliximab, 420 cocaine, 39 cyclooxygenase 2 inhibitor, 119 Echinacea, 538 lidocaine, 140 propafenone, 198 rifamycin, 176 scorpion venom, 2 bronchus obstruction s e e airway obstruction bronchus secretion

588 cholinesterase inhibitor, 157 brugada syndrome antiarrhythmic agent, 204 bruising corticosteroid, 186 bullous dermatitis prednisone, 455 bullous pemphigoid s e e pemphigoid bullous skin disease anticonvulsive agent, 82 diazepam, 47 nifedipine, 225 bundle branch block antiarrhythmic agent, 204 digitalis glycoside, 199 quinidine, 199 calcification alfacalcidol, 446 continuous ambulatory peritoneal dialysis, 395 cancer s e e carcinogenesis candidlasis fluticasone propionate, 189 fluticasone propionate plus salmeterol, 189 salmeterol, 189 capillary leak syndrome basiliximab, 420 /~ interferon, 415 interleukin 2, 416 carcinogenesis alcohol, 442 antineoplastic agent, 517 /~ carotene, 442, 443 carotenoid, 443 cocaine, 39 cyclophosphamide, 427 dantron, 406 ethylene oxide, 271 fertility promoting agent, 474 granulocyte colony stimulating factor, 418 hormonal replacement therapy, 469 iron, 258 mercaptopurine, 423 methotrexate, 428 monoclonal antibody, 421 mycophenolic acid 2 morpholinoethyl ester, 429 phenolphthalein, 406 poliomyelitis vaccine, 378, 379 repaglinide, 494 retinoid, 443 retinol, 442 somatomedin, 491 tamoxifen, 476 tobacco, 442 trichloroethylene, 132

I n d e x o f a d v e r s e effects

troglitazone, 494 cardiac s e e also heart cardiac valvulopathy see heart valve disease cardiogenic shock amiodarone, 206 dextropropoxyphene, 104 cardiomyopathy anthracycline derivative, 515 betamethasone, 450, 451 clozapine, 62 doxorubicin, 515 glucocorticoid, 450 ot interferon, 411 lithium, 22 zidovudine, 344 cardiopulmonary arrest cocaine, 37 iopamidol, 524 cardiotoxicity bupivacaine, 143 propranolol, 220 risperidone, 71, 73 ropivacaine, 143 trazodone, 18 tricyclic antidepressant agent, 18, 221 verapamil, 226 cardiovascular collapse see collapse cardiovascular depression /3 adrenergic receptor blocking agent, 221 bupivacaine, 149 carvedilol, 221 propranolol, 221 ropivacaine, 149 cardiovascular disease /~ carotene, 442, 443 doxazosin, 242 tobacco, 443 cardiovascular malformation lithium, 26 cardiovascular symptom antihistaminic agent, 179 bupivacaine, 143 calcium antagonist, 225 cocaine, 151 gadolinium compound, 528 iodixanol, 520 ioxaglic acid, 520 local anesthetic agent, 533 nifedipine, 224, 225 nonsteroid antiinflammatory agent, 120 phenylephrine, 534 ritodrine, 222 ropivacaine, 141, 143 sumatriptan, 230 carpal tunnel syndrome thalidomide, 171 cataract

corticosteroid, 534 ethylene oxide, 271 neuroleptic agent, 57 catatonia gabapentin, 86 risperidone, 72 catecholamine release . neomycin, 286 cauda equiua syndrome lidocaine, 146 spinal anesthesia, 146 celiac disease ot interferon, 413 central nervous system depression baclofen, 159 propranolol, 220 central nervous system malformation methotrexate, 429 central nervous system symptom aprindine, 210 chloroprocaine, 148 clarithromycin, 296 efavirenz, 344 lidocaine, 148 quinidine, 199 tiagabine, 91 central nervous system toxicity s e e neurotoxicity eerebellar ataxia s e e ataxia cerebellum disease lithium, 23, 26 cerebral palsy dexamethasone, 451 eerebrospinal fluid pressure prednisone, 452 cerebrovascular disease repaglinide, 494 troglitazone, 494 eheilitis aciclovir, 176 retinoic acid, 444, 445 chemical burn phenol, 271 chest pain s e e thorax pain chest tightness s e e thorax pressure chickenpox chickenpox vaccine, 380 children (risk) ampbotericin B deoxycholate, 315 amphotericin B lipid complex, 317 cetirizine, 180 digoxin, 201 fluconazole, 324 ot interferon, 414 itraconazole, 325

589

I n d e x o f adverse effects

mycophenolic acid 2 morpholinoethyl ester, 429 neuroleptic agent, 59 pamidronic acid, 544 propranolol, 220 terbinafine, 314 chill amphotericin B colloid, 316 amphotericin B deoxycholate, 315 amphotericin B lipid complex, 316 diatrizoate, 525 infliximab, 420 ioversol, 520 liposomal amphotericin B, 317 misoprostol, 461,462 quinupristin plus dalfopristin, 301 recombinant erythropoietin, 388 teicoplanin, 289 cholelithiasis octreotide, 505 cholestasis anabolic agent, 477 aprindine, 210 chlorzoxazone, 511 cinnarizine, 180 enalapril, 237 erythromycin stearate, 298 gold salt, 257 parenteral nutrition, 395, 396 progesterone, 470 cholestatic hepatitis azathioprine, 422 flucloxacillin, 274 fluindostatin, 512 josamycin, 299 pravastatin, 512 thiamazole, 485 cholestatic jaundice amiodarone, 208 quinine, 333 cholesterol blood level atorvastatin, 510 hydroxymethylglutaryl coenzyme A reductase inhibitor, 510 proteinase inhibitor, 345 ritonavir, 345, 346 simvastatin, 510 cholinergic symptom methamphetamine, 2 metrifonate, 8 scorpion venom, 2 chondrolysis chlorhexidine, 270 chondropathy chlorhexidine, 270 chorea digoxin, 200

choreoathetosis lamotrigine, 83 phenytoin, 83 Churg-Strauss syndrome leukotriene receptor blocking agent, 183 montelukast, 183 pranlukast, 183 zafirlukast, 183 clitoris priapism antidepressant agent, 17 nefazodone, 17 serotonin uptake inhibitor, 17 trazodone, 17 coagulation disorder see blood clotting cognition disorder see cognitive defect cognitive defect amisulpride, 61 atenolol, 220 carbamazepine, 84, 86 clobazam, 84 cocaine, 38 corticosteroid, 453 fentanyl, 106 gabapentin, 86 hydrocortisone, 453 ct interferon, 412 lamotrigine, 87 levamisole, 358 lithium, 23 morphine, 106 opiate, 102 topiramate, 92 triazolam, 48 valproic acid, 93 cold limb adrenergic receptor blocking agent, 233 adrcnergic receptor blocking agent, 233 dipeptidyl carboxypeptidase inhibitor, 233 cold sensation oxybuprocaine plus fluorescein, 533 prilocaine plus lidocaine, 149 colitis carbamazepine, 85 cyclooxygenase 2 inhibitor, 118 itraconazole, 325 neuroleptic agent, 58 nonsteroid antiinflammatory agent, 118 ornipressin, 507 pseudoephedrine, 6, 163 risedronic acid, 544 collapse glucocorticoid, 450 methylprednisolone, 450 oxybuprocaine, 533

oxybuprocaine plus fluorescein, 533 Silybum marianum, 539 sumatriptan, 230 colon perforation carbamazepine, 84 colon ulcer neuroleptic agent, 58 coma clonidine, 142 cyclosporin a, 223 diltiazem, 223 glibenclamide, 487 insulin, 487 metformin, 487 sumatriptan, 230 common cold etiracetam, 90 influenza vaccine, 376 concentration loss efavirenz, 344 confusion clomipramine, 13 diphenhydramine, 180 donepezil, 6 fentanyl, 106 Helicobacter pylori eradication therapy, 405 lidocaine, 150 manganese, 259 melatonin, 545 morphine, 106 tiagabine, 92 zolpidem, 50 zopiclone, 51 congenital anomaly see congenital malformation congenital disorder amiodarone, 209 congenital malformation anticonvulsive agent, 83 antihistaminic agent, 180 budesonide, 458 caffeine, 83 chlorpheniramine, 180 cyclophosphamide, 427 estrogen, 467 fexofenadine, 180 gestagen, 467 haloperidol, 59 mercaptopurine, 423 methotrexate, 429 misoprostol, 462 retinol, 443 terfenadine, 180 congestive heart failure see heart failure conjunctiva disease azithromycin, 296 lidocaine, 140 conjunctiva hyperemia unoprostone, 462 conjunctivitis

590

I n d e x o f a d v e r s e effects

dexamethasone, 535 hydroxychloroquine, 174 recombinant erythropoietin, 388 consciousness disorder

baclofen, 159 consciousness loss see

unconsciousness

constipation

acetazolamide, 249 alosetron, 402 clozapine, 53 fentanyl, 106 itraconazole, 325 methadone, 106 oxycodone, 107 povidone iodine, 271 risperidone, 53 thalidomide, 172 contact allergy s e e contact hypersensitivity contact dermatitis aminophylline, 545 estrogen, 469 ethylenediamine, 544, 545 preservative, 534 proparacaine, 152 tropicamide, 534 contact hypersensitivity alclometasone dipropionate, 175 azo dye, 174 bendazac, 174 benzoxonium chloride, 172 benzoyl peroxide, 173 benzyl alcohol, 173 budesonide, 455, 456 bufexamac, 174 4 tert butylphenol, 174 calcipotriol, 173 carmustine, 173 castor oil, 174 clotrimazole, 174 corticosteroid, 173 croconazole, 174 dibromopropamidine, 173 diethyl sebacate, 173 epimbicin, 173 fluorouracil, 173 furaltadone, 174 glucocorticoid, 455 glycerol stearate, 173 1,2,6 hexanetriol, 174 2 hexyldecanoic acid, 174 hydroxychloroquine, 174 imidazole derivative, 174 indometacin, 175 isopalmityl diglyceryl sebacate, 174 isopropanolamine, 174 itraconazole, 174 lanolin, 174

nonsteroid antiinflammatory agent, 174 nystatin, 175 polyvinylpyrrolidone eicosene copolymer, 175 povidone iodine, 175 Psorcutan Salbe, 173 sodium metabisulfite, 175 stearic acid, 173 stearyl alcohol, 173 sunscreen, 174 tribenoside, 175 contact urticaria see urticaria convulsion

chickenpox vaccine, 380 desmopressin, 504 donepezil, 7 itraconazole, 325 lithium, 23 midazolam, 134 norpethidine, 108 pethidine, 108 prilocaine, 147 propofol, 136 ropivacaine, 141 coordination loss

alprazolam, 48 lorazepam, 48 copper deficiency

parenteral nutrition, 396

enalapril, 235,238, 240 enalaprilat, 235 eprosartan, 240 imidapril, 238 infliximab, 420 influenza vaccine, 376 ot interferon, 411 interleukin 2, 416 lidocaine, 149 lisinopril, 238, 240 losartan, 240 measles vaccine, 377 perindopril, 240 ramipril, 235 sevoflurane, 127 telmisartan, 241 timolol, 221 tobramycin, 193 trandolapril, 239 trastnzumab, 421 creatine kinase blood level

clarithromycin, 297 methamphetamine, 2 modified hemoglobin, 384 nifedipine, 225 nortriptyline, 13 suxamethonium, 158 valproic acid, 13 ereatine phosphokinase see creatine kinase blood level creatinine blood level

buprenorphine, 110 sulprostone, 462 cortical blindness see blindness

aminoglycoside antibiotic agent, 284 amphotericin B lipid complex, 316 clarithromycin, 297 contrast medium, 522 enalapril, 235 enalaprilat, 235 indinavir, 346 iodixanol, 522 iohexol, 522 isotretinoin, 444 liposomal amphotericin B, 317 lithium, 25 losartan, 240 rapamycin, 430 teicoplanin, 289 vancomycin, 291 creatinine clearance see creatinine blood level

coryza

Creutzfeldt Jacob disease

common cold coughing /~ adrenergic receptor blocking agent, 233, 235 amphotericin B aerosol, 315 angiotensin II antagonist, 240 captopril, 201 corticotropin, 450 dipeptidyl carboxypeptidase inhibitor, 233-236, 240

virus vaccine, 373, 374 Creutzfeldt-Jacob-fike

cornea deposit

fluorouracil, 515 cornea disease clarithromycin, 296 cornea edema

brinzolamide, 536 eye anesthesia, 148 cornea injury

perfluorodecalin, 384 cornea toxicity

latanoprost, 461 coronary artery constriction

acetyldigoxin, 200 coronary artery disease

/~ carotene, 443 tobacco, 443 coronary artery spasm

see

syndrome see

Creutzfeldt Jacob disease

Crohn disease

measles mumps rubella vaccine, 377, 378 cross hypersensitivity

azathioprine, 421 benzalkonium chloride, 173

591

Index of adverse effects

benzoxonium chloride, 173 bupivacaine, 140 celecoxib, 119 clotrimazole, 174 domiphen bromide, 173 doxycycline, 280 gestagen, 456 glucocorticoid, 456, 459 hydroxyprogesterone acetate, 456 imidazole derivative, 174 lidocaine, 140 mepivacaine, 140 mercaptopurine, 421 minocycline, 280 neuromuscular blocking agent, 157 ropivacaine, 140 sulfonamide, 119 crying diphtheria whole cell pertussis tetanus vaccine, 371 meningococcus vaccine, 369 poliomyelitis vaccine, inactivated, 371

deafness s e e hearing impairment

death s e e mortality deearboxyprothrombin blood

level anticonvulsive agent, 85 carbamazepine, 85 deep vein thrombosis s e e vein thrombosis

defecation lidocaine, 146 spinal anesthesia, 146

dehydration captopril, 237

delayed hypersensitivity s e e hypersensitivity ddifium amantadine, 167 amfebutamone, 16 amiodarone, 206 opiate, 102 sevoflurane, 131

delusion

s e e cushing syndrome cushing syndrome fluticasone propionate, 452 prednisone, 452

dexamphetamine, 2 methamphetamine, 2 naltrexone, 111 testosterone, 477 triptorelin, 503 demyelinaling disease chickenpox vaccine, 380 etanercept, 420 hepatitis B vaccine, 375 levamisole, 358

cyanosis

demyelinating neuropathy

cryoglobulinemia c~ interferon, 413 crystalluria indinavir, 346

cnshingoid syndrome

alteplase, 400 benzocaine, 151 cetacaine, 151 lithium, 26 prilocaine, 142 prilocaine plus lidocaine, 142, 149 silver nitrate, 261

cystoid macular edema see

retina edema

cytokine blood level antimony trioxide, 254 azithromycin, 295 clarithromycin, 295 fusidic acid, 288 lithium, 24 macrolide derivative, 295 roxithromycin, 295 tsukubaenolide, 432 cytokine release syndrome basiliximab, 420 eytolysis meloxicam, 123

dapsone syndrome dapsone, 334, 335 Darier disease lithium, 25

s e e neuropathy depersonalization s e e personality disorder

depression alprazolam, 48 amiodarone, 207 calcium antagonist, 222 cibenzoline, 210 cinnarizine, 179 codeine, 41 diltiazem, 222 dipeptidyl carboxypeptidase inhibitor, 239 domperidone, 401 enalapril, 222 insulin, 487 ct interferon, 412 fl interferon, 415 levamisole, 358 levonorgestrel, 473 lisinopril, 222 lorazepam, 48 medroxyprogesterone acetate, 473 metoclopramide, 401 mexiletine, 213 nicardipine, 222 prednisone, 453

quinapril, 238 risperidone, 72 tiagabine, 91 vigabatrin, 95 zaleplon, 49 zopiclone, 51

dermatitis benzoyl peroxide, 173 gestagen, 456 glipizide, 492 hydroxychloroquine, 174 hydroxyprogesterone acetate, 470 neomycin, 286 phytomenadione, 448 thionamide derivative, 485 dermatamyasitis quinidine, 214 developmental disorder amiodarone, 209 anticonvulsive agent, 83 methotrexate, 429 diabetes insipidns lithium, 25 diabetes mellitns glucocorticoid, 454 o~interferon, 413 itraconazole, 325, 326 olanzapine, 69 tsukubaenolide, 431 diabetic ketoacidosis clozapine, 64 olanzapine, 69 diaphragm paralysis bupivacaine, 141 local anesthetic agent, 141 mepivacaine, 141

diarrhea abacavir, 343 acarbose, 496 aminosalicylic acid derivative, 406 ampicillin, 294 azathioprine, 422 azithromycin, 294 cilostazol, 229 cisapride, 401 clindamycin, 294 cyclooxygenase 2 inhibitor, 116 2,5 diaminotoluene, 175 donepezil, 6 fluconazole, 324 fosfomycin, 302 fusidic acid, 288 Helicobacter pylori eradication therapy, 404, 405 influenza vaccine, 376 itraconazole, 325 lincomycin, 294 losartan, 240 measles vaccine, 376

592 metformin, 495 misoprostol, 461 nicotine, 546 nonsteroid antiinflammatory agent, 116 nystatin, 175 octreotide, 505 olanzapine, 67 polyene derivative, 324 rapamycin, 430 recombinant erythropoietin, 388 simethicone coated cellulose, 529 teicoplanin, 289 trastuzumab, 421 trecovirsen, 345 tropisetron, 402 ursodeoxycholic acid, 408 vancomycin, 289 zidovudine, 343 digestive system see gastrointestinal

diplopia botulinum toxin A, 160 bupivacalne, 148 carbamazepine, 84 eye anesthesia, 148 hydroxymethylglutaryl coenzyme A reductase inhibitor, 511 lamotrigine, 87 levamisole, 358, 359 lidocaine, 148 retinoic acid, 445 ropivacaine, 148 zaleplon, 49 disease aggravation (pre-existing) lamotrigine, 87 tiagabine, 92 disorientation amfebutamone, 16 dexamethasone, 453 levamisole, 359 levobupivacaine, 144 disseminated intravascular coagulation activated prothrombin complex, 387 clomipramine, 13 diatrizoate, 525 n ethyl 3,4 methylenedioxyamphetamine, 33 ioversol, 520 lamotrigine, 89 3,4 methylenedioxymethamphetamine, 33 nortriptyline, 13 quinine, 333

Index of adverse effects

recombinant blood clotting factor 7a, 387 valproic acid, 13 disulfirum like reaction metronidazole, 335 dizziness alprazolam, 48 amfebutamone, 16 bupivacaine, 148 buspirone, 45 calcitonin, 503 candesartan, 240 carbamazepine, 84, 87 carvedilol, 221 cilostazol, 229 dipeptidyl carboxypeptidase inhibitor, 234, 235 donepezil, 6 efavirenz, 344 etiracetam, 90 Helicobacter pylori eradication therapy, 405 lamotrigine, 87, 90 lidocaine, 141,148, 150, 212 lisinopril, 235 lorazepam, 48 losartan, 240 mepivacaine, 142 metrifonate, 8 misoprostol, 461 nateglinide, 494 nefazodone, 17 nicotine, 546 olanzapine, 68 opiate, 102 oxybuprocaine plus fluorescein, 533 oxycodone, 107 prilocaine plus lidocaine, 149 progesterone, 470 pyridoxine, 447 quinine, 333 rizatriptan, 230 ropivacaine, 141,148 serotonin uptake inhibitor, 14 zaleplon, 49 zolmitriptan, 230 zolpidem, 49 dreaming efavirenz, 344 ketamine, 135 driving ability insulin, 488 drowsiness alprazolam, 48 antihistaminic agent, 179 benzocaine, 151 cetacaine, 151 droperidol, 66 ivermectin, 358 levobupivacaine, 144 lidocaine, 212 lorazepam, 48

methadone, 106 progesterone, 470 thalidomide, 171 zolpidem, 50 drug abstinence see drug withdrawal drug abuse alcohol, 2, 442 analgesic agent, 120 caffeine, 1 cocaine, 2 codeine, 41, 42 ephedrine, 163 methamphetamine, 2 methylphenidate, 3 nonsteroid antiinflammatory agent, 120 paracetamol, 120 phenacetin, 120 tramadol, 109 drug accumulation gallium 67, 256 iron, 258 drug allergy see hypersensitivity drug antibody amiodarone, 209 aprotinin, 399 ceftizoxime, 277 rifampicin, 354 drug contamination albumin, 383 blood clotting factor 8, 388 dexamethasone, 458 glucocorticosteroid, 458 hemoglobin derivative, 384 immunoglobulin, 386 poliomyelitis vaccine, 378, 379 poliomyelitis vaccine, oral, 373 virus vaccine, 373 drug dependence buprenorphine, 110 codeine, 41, 42 hormonal replacement therapy, 468 opiate, 110 zaleplon, 49 drug eruption activated prothrombin complex, 387 anticonvulsive agent, 82 clindamyein, 294 contrast medium, 522 diazepam, 47 hydroxyprogesterone acetate, 456 iomeprol, 522 minocycline, 280 pristinamycin, 300 vancomycin, 291 drug fever

593

Index o f adverse effects see fever

drug hypersensitivity see hypersensitivity

drug intoxication caffeine, 1 calcitriol, 447 diamorphine, 42 n ethyl 3,4 methylenedioxyamphetamine, 33 germanium derivative, 256 manganese, 259, 260 methamphetamine, 2 3,4 methylenedioxymethamphetamine, 33 strychnine, 4 vancomycin, 289 vitamin D, 447 drug misuse anabolic agent, 477 androgenic agent, 477

drug overdosage acebutolol, 221 adrenalin, 163 ajmaline, 206 alprazolam, 46 astemizole, 180 buflomedil, 229 buprenorphine, 110 caffeine, 1 calcitriol, 447 carbamazepine, 85 chloral hydrate, 49 chlorpheniramine, 180 chlorpropamide, 493 cibenzoline, 211 citalopram, 14 clozapine, 65 detajmium bitartrate, 206 digoxin, 200, 201 diltiazem, 223 diphenhydramine, 180 donepezil, 7 flecainide, 211 gabapentin, 86 lamotrigine, 90 lithium, 26 losartan, 240 metformin, 495 methylphenidate, 3 minoxidil, 243 nitric oxide, 190 olanzapine, 70 propafenone, 214 propranolol, 220 risperidone, 73 temazepam, 48 tobramycin, 287 trazodone, 18 vancomycin, 292 veniafaxine, 19 verapamil, 226

vitamin D, 447 zaleplon, 49 zolpidem, 50 zopiclone, 51

drug resistance amikacin, 285,286 aminoglycoside antibiotic agent, 285 ampicillin, 287 antibiotic agent, 273 antimony derivative, 254 azithromycin, 296 bacitracin, 302 chloramphenicol, 287 ciprofloxacin, 285 clarithromycin, 297 clindamycin, 293, 294 erythromycin, 293, 294 fluoroquinolone derivative, 285, 287 fusidic acid, 288 gentamicin, 285 isepamicin, 285 isoniazid, 286 kanamycin, 285, 287 lincomycin, 293 lincosamide derivative, 293 macrolide derivative, 293, 295 nalidixic acid, 287 neomycin, 285 netilmicin, 285 pefloxacin, 285 penicillin derivative, 294 polymyxin derivative, 300 pristinamycin, 300 rifampicin, 286 spectinomycin, 286, 287, 302 streptogramin B, 293 streptomycin, 286, 287 sulfonamide, 287 tetracycline, 287 tobramycin, 285, 287 tylosin, 299 vancomycin, 291 virginiamycin, 302

drug safety ot adrenergic receptor blocking agent, 233 /3 adrenergic receptor blocking agent, 233 Albunex, 529 amlodipine, 225 amphotericin B, 318 amphotericin B colloid, 316 amphotericin B deoxycholate, 315 amphotericin B lipid complex, 316, 317 antihypertensive agent, 233 botulinum toxin A, 160 buspirone, 45 calcium antagonist, 233 candesartan, 239

carvedilol, 221 cetirizine, 180 citalopram, 14 contrast medium, 519 cyclooxygenase 2 inhibitor, 116, 117 dipeptidyl carboxypeptidase inhibitor, 233, 234 diuretic agent, 233 donepezil, 7 enalapril, 239 eye anesthesia, 148 fluconazole, 324 gadopentetate dimeglumine, 527 gadoversetamide, 527 galactose microparticle, 529 immunoglobulin, 385 itraconazole, 314, 325 lidocaine, 148 neuromuscular blocking agent, 157 nitrendipine, 225 nonsteroid antiinflammatory agent, 117 phenol, 272 stibogluconate sodium, 336 sumatriptan, 229 suxamethonium, 158 tafenoquine, 332 terbinafine, 314 tetracaine, 148 triptan derivative, 229 vaccine, 364

drug tolerability acetylsalicylicacid, 123 alosetron, 402 azapropazone, 123 bupivacaine, 143 candesartan, 239 captopril, 240 carvedilol, 221 cyclooxygenase 2 inhibitor, 116 donepezil, 7 enalapril, 239 gadoversetamide, 527 losartan, 240 metrifonate, 8 nonsteroid antiinflammatory agent, 116 rivastigmine, 8 ropivacaine, 143 ursodeoxycholic acid, 408 valsartan, 241 zaleplon, 49

drug tolerance caffeine, 1 formoterol, 187 salmeterol, 187

drug toxicity aluminium, 388 cocaine, 37

594 cyclooxygenase 2 inhibitor, 115 ethylene oxide, 271 lidocaine, 152 lithium, 22, 23, 26 nitric oxide, 190 nonsteroid antiinflammatory agent, 115

drug withdrawal amantadine, 167 caffeine, 1 diamorphine, 42 lithium, 22, 25 melatonin, 545 nefazodone, 17 neuroleptic agent, 59 nitric oxide, 191 opiate, 42 paroxetine, 14 serotonin uptake inhibitor, 14, 15, 17 zaleplon, 49 zolpidem, 50 dry mouth s e e xerostomia dry skin lidocaine, 150 retinoic acid, 445 duodenum disease thalidomide, 172

dysarthria bupivacaine, 149 levamisole, 358 lidocaine, 149 manganese, 259 ropivacaine, 141

dysesthesia carboxymethylcellulose, 140 retinoic acid, 445

dysgeusia acetazolamide, 249 amphotericin B aerosol, 315 brinzolamide, 536 bupivacaine, 142 chloroprocaine, 148 clarithromycin, 296 deferiprone, 265 gadolinium pentetate, 527 gadoversetamide, 527 Helicobacter pylori eradication therapy, 404, 405 ketamine, 135 lidocaine, 147, 152 metronidazole, 335 nedocromil, 534 oxytocin derivative, 506 sparfloxacin, 296 sumatriptan, 230

dyskinesia baclofen, 159 clebopride, 401 levodopa, 165

I n d e x o f a d v e r s e effects

melatonin, 545 neuroleptic agent, 56

dyslipidemia rapamycin, 430

dysmenorrhea see

menstruation disorder

dyspareunia tamoxifen, 475

dyspepsia albendazole, 356 amlodipine, 223 cyclooxygenase 2 inhibitor, 116 losartan, 240 mebendazole, 356 mesalazine, 407 nonsteroid antiinflammatory agent, 116 ranitidine, 402

dysphagia bupivacaine, 147, 149 fentanyl, 147 lidocalne, 149, 150 morphine, 147 neuroleptic agent, 57 spinal anesthesia, 147

dysphonia see

speech disorder

dysphoria a interferon, 412 lidocalne, 141 xenon, 526

dyspnea adenosine, 205 fl adrenergic receptor blocking agent, 233 amiodarone, 206 arsenic trioxide, 254 barium sulfate, 524 calcitonin, 503 contrast medium, 523 dextran 1,393 dextran 40, 393 dipeptidyl carboxypeptidase inhibitor, 233, 234 dipyridamole, 399 glyceryl trinitrate, 222 granulocyte colony stimulating factor, 418 infliximab, 420 iodinated contrast medium, 522 iopromide, 523 ivermectin, 358 lidocaine, 149, 152 losartan, 240, 241 mesalazine, 407 methylprednisolone, 456 prostacyclin, 463 talc, 549 timolol, 221 tobramycin, 193 trastuzumab, 421

ultrasmall superparamagnetic iron oxide, 528 vinorelbine, 515 zidovudine, 343

dystonia clozapine, 63 diamorphine, 105 neuroleptic agent, 57 olanzapine, 68 risperidone, 73

dysuria indinavir, 346

ear disease thalidomide, 172

ecchymosis tiagabine, 92 ECG change see electrocardiogram change

eczema amisulpride, 61 benzoxonium chloride, 173 budesonide, 456 clobetasol propionate, 459 gestagen, 456 mycophenolic acid 2 morpholinoethyl ester, 429

edema aciclovir, 176 amfebutamone, 17 bacitracin, 301 cilostazol, 229 clindamycin, 294 cyclooxygenase 2 inhibitor, 118 dipeptidyl carboxypeptidase inhibitor, 234 doxercalciferol, 447 1,2,6 hexanetriol, 174 iopamidol, 524 losartan, 240 nonsteroid antiinflammatory agent, 118, 120 praziquantel, 360 quinupristin plus dalfopristin, 301 retinoic acid, 445 thalidomide, 172 thiazolidinedione derivative, 497 valproic acid, 94

EEG change electroencephalogram change

see

ejaculation disorder clozapine, 65 dextromethorphan, 104

elastosis perforans serpiginosa penicillamine, 267

elderly (risk) fl adrenergic receptor blocking agent, 220 amfebutamone, 16

595

Index of adverse effects

dipeptidyl carboxypeptidase inhibitor, 236 glucocorticosteroid, 455 hypnosedative, 45 risperidone, 73 venlafaxine, 19 electrocardiogram change amisulpride, 61 antiarrhythmic agent, 204 bupivacaine, 143 cibenzoline, 210 cisapride, 401 citalopram, 14 clindamycin, 293 clozapine, 62 cocaine, 37, 151 digitalis glycoside, 199 ebastine, 179 erythromycin, 298 fluconazole, 324 formoterol, 187 halofantrine, 331,332 halothane, 129 imidapril, 238 iodixanol, 520 ioxaglic acid, 520 isoflurane, 129 levobupivacaine, 143 loratadine, 179 meglumine diatrizoate, 336 minoxidil, 243 neuroleptic agent, 54-56 nifedipine, 224, 225 quinidine, 199 repaglinide, 494 risperidone, 71 ropivacaine, 149 salmeterol, 187 sotalol, 200 stibogluconate sodium, 336 terfenadine, 181 thioridazine, 55 trazedone, 18 troglitazone, 494 zolmitriptan, 230 electroencephalogram change anesthetic vapor, 129 anticonvulsive agent, 83 baclofen, 159 insulin, 487, 488 a interferon, 411 sevoflurane, 129, 131 tiagabine, 92 triazolam, 48 embryotoxicity carotenoid, 443 cyclophospharnide, 427 fluconazole, 324, 325 phenytoin, 324, 325 retinoid, 443 emesis see vomiting emotional disorder

clarithromycin, 297 desogestrel, 476 nefazodone, 17 testosterone enantate, 476 emphysema talc, 549 encephalitis hepatitis B vaccine, 375 encephalomyelitis Japanese encephalitis vaccine, 376 encephaiopathy aluminium potassium sulfate, 254 cisplatin, 260 cyclosporin a, 223 diltiazem, 223 immunoglobulin, 385 a interferon, 411 Japanese encephalitis vaccine, 376, 377 measles vaccine, 377 melarsoprol, 335 3,4 methylenedioxymethamphetamine, 34 parenteral nutrition, 396 recombinant erythropoietin, 389 tiagabine, 92 zolpidem, 50 endocarditis catheter, 548 endocrine disease amisulpride, 60, 61 haloperidol, 60 risperidone, 60 endometriosis estrogen, 469 endometrium cancer tamoxifen, 476, 517 endometrium hyperplasia tibolone, 480 endometrium polyp tamoxifen, 476 end stage renal disease see kidney failure enteritis copper intrauterine device, 256 enuresis clozapine, 64 eosinophilia acarbose, 496 leukotriene receptor blocking agent, 183 mebendazole, 356 montelukast, 184 thalidomide, 172 tsukubaenolide, 432 eosinophilic fasciitis penicillamine, 267 epididymitis

amiodarone, 209 epidural hematoma manipulative medicine, 541 epigastralgia see epigastric pain epigastrie pain benazepril, 237 cyclooxygenase 2 inhibitor, 116 lisinopril, 238 nonsteroid antiinflammatory agent, 116 zolpidem, 50 epilepsy baclofen, 159 benzodiazepine, 84 bupivacaine, 141 chickenpox vaccine, 380 clomipramine, 13 clonidine, 142 clozapine, 53, 6 1 ~ 3 cocaine, 37 diazepam, 47 diphtheria whole cell pertussis tetanus vaccine, 371 infiltration anesthesia, 147 ct interferon, 412 lamotrigine, 87 levamisole, 358 lidocaine, 147, 212 measles vaccine, 377 melarsoprol, 335 midazolam, 84, 134 olanzapine, 67 opiate, 40 oxybuprocaine plus fluorescein, 533 poliomyelitis vaccine, inactivated, 371 praziquantel, 361 recombinant erythropoietin, 389 ropivacaine, 141, 149 sevoflurane, 131 epileptic state olanzapine, 67 tiagabine, 92 epistaxis budesonide, 193 ipratropium bromide, 193 erectile dysfunction apomorphine, 167 clozapine, 65 risperidone, 71 ropinirole, 167 erythema activated prothrombin complex, 387 alprazolam, 46 captopril, 237 clindamycin, 294 clonidine, 242 diazepam, 47

596 erythromycin, 298 fentanyl, 106 gabapentin, 86 1,2,6 hexanetriol, 174 hydroxychloroqnine, 174 imiquimod, 433 iomeprol, 522 iopamidol, 523 lidocaine, 140 paramethasone, 459 phenol, 271 phytomenadione, 448 prilocaine plus lidocaine, 150 retinoic acid, 445,446 ribonucleic acid, 433 teicoplanin, 289 terbinafine, 314 vancomycin, 290, 291 erythema multiforme acarbose, 496 anticonvulsive agent, 82 gentamicin, 286 glibenclamide, 492 lisinopril, 238 meloxicam, 123 prednisone, 455 terbinafine, 314 tribenoside, 175 erythema nodosum thalidomide, 172 erythrocyte aplasia zidovudine, 343 erythrocyte count metrifonate, 8 erythrocytosis anabolic agent, 477 erythroderma captopril, 237 icodextrin, 393 thalidomide, 172 tramadol, 109 erythromelaigia hepatitis B vaccine, 375 esophagitis doxycycline, 279 esophagus cancer retinol, 442 esophagus fistula thalidomide, 172 esophagus obstruction karaya gum, 406 senna extract, 406 estradioi blood level finasteride, 479 euphoria clarithromycin, 296 mepivacaine, 142 xenon, 526 exanthema see rash excitability levobupivacaine, 144 exfoliative dermatitis

I n d e x o f adverse effects

methotrexate, 428 thalidomide, 172 vancomycin, 290 exophthalmos carboplatin, 516 etoposide, 516 extrapyramidal symptom amisulpride, 60 cinnarizine, 179 clebopride, 401 clozapine, 61 droperidol, 100 haloperidol, 60, 66, 67, 71, 72 neuroleptic agent, 53, 56 olanzapine, 66 quetiapine, 71 risperidone, 54, 60, 71-73 extrasystole fluconazole, 324 procainamide, 198 propafenone, 198 sildenafil, 231 eye see also intraocular eye discharge olanzapine, 69 eye inflammation anti human immunodeficiency virus agent, 342 fomivirsen, 340 eye injury aluminium oxide, 253 eye irritation ketorolac, 534 ketotifen, 534 nedocromil sodium, 534 oxybuprocaine plus fluorescein, 533 pemirolast, 534 prilocaine plus lidocaine, 150 eyelid edema lidocaine, 140 losartan, 241 eye movement lidocaine, 140 zolpidem, 50 eye myasthenia penicillamine, 267 eye pain dexarnethasone, 535 ketotifen, 534 nedocromil sodium, 534 pemirolast, 534 prilocaine plus lidocaine, 150 ropivacaine, 148 eye toxicity botulinum toxin A, 160 carboplatin, 516 etoposide, 516 scorpion venom, 2 face edema lamotrigine, 88, 89

face malformation anticonvulsive agent, 85 carbamazepine, 85 methotrexate, 429 facial dyskinesia see dyskinesia fainting see syncope faintness ioversol, 520 falling hypnosedative, 45 fasciculation fluvoxamine, 14 suxamethonium, 158 fatality see mortality fatigue abacavir, 343 acetazolamide, 249 ct adrenergic receptor blocking agent, 233 13 adrenergic receptor blocking agent, 233 brimonidine, 536 cytarabine, 411 desogestrel, 476 diazepam, 133 dipeptidyl carboxypeptidase inhibitor, 233 gadodiamide, 527 influenza vaccine, 376 interferon, 411 ketamine, 135 lidocaine, 147 losartan, 240 nefazodone, 17 rizatriptan, 230 sultiame, 91 testosterone enantate, 476 triazolam, 48 fatty liver interferon, 414 nicotinic acid, 446 prednisolone, 454 tamoxifen, 475 feces incontinence lidocaine, 146 picosulfate sodium, 406 spinal anesthesia, 146 feeding intolerance see nutritional intolerance femoral head necrosis see bone necrosis fetal methotrexate syndrome methotrexate, 429 fetotoxicity amiodarone, 209 anticonvulsive agent, 83 betamethasone, 458 cocaine, 39 diamorphine, 42 diazepam, 47

597

I n d e x o f a d v e r s e effects

fluoxetine, 15 lithium, 26 nimesulide, 123 serntonin uptake inhibitor, 15 tricyclic antidepressant agent, 13 fetus bradycardia misoprostol, 461,462 fetus heart rate misoprostol, 461 fetus vitreous persistence clomiphene, 475 fever amphotericin B colloid, 316 amphotericin B deoxycholate, 315 amphotericin B lipid complex, 316 barium sulfate, 524 bezafibrate, 510 bropirimine, 433 captopril, 237 clarithromycin, 297 clomipramine, 13 corticotropin, 450 dextran 1,393 dextran 40, 393 diatrizoate, 525 diazepam, 47 diethylcarbamazine, 357 diphtheria acellular pertussis tetanus vaccine, 370 enalapril, 238 fluorocarbon, 384 fluvoxamine, 14 glibenclamide, 492 granulocyte colony stimulating factor, 417 haemophilus influenzae type b vaccine, 366 hydrocortisone, 456 hydroxychioroquine, 174 immunoglobulin, 385 infliximab, 420 iodinated contrast medium, 522 leukotriene receptor blocking agent, 183 lyme disease vaccine, 367 measles vaccine, 377 meningococcus vaccine, 368, 369 methylphenidate, 3 milodistim, 417 misoprostol, 461 neuroleptic agent, 13 nicotinic acid, 446 nystafin, 175 prednisone, 455 procainamide, 214 quinupristin plus dalfopristin, 301

recombinant erythropoietin, 388 retinoic acid, 444, 445 rotavirus vaccine, 379 teicoplanin, 289, 290 tick borne meningoencephalitis vaccine, 380 typhoid vaccine, 373 vancomycin, 289, 290 fibrinolysis estrogen, 473 propofol, 137 fibrosing colonopathy pancreas enzyme, 408 finger gangrene diazepam, 133 fixed drug eruption see drug eruption flatulence acarbose, 495,496 miglitol, 495 proton pump inhibitor, 403 fluid overload lidocaine, 152 fluid retention desmopressin, 507 fosfestrol, 469 flu like syndrome bropirimine, 433 fluorocarbon, 384 hydroxyprogesterone acetate, 456 lyme disease vaccine, 367 pemirolast, 534 penicillamine, 266 proton pump inhibitor, 403 rifampicin, 353, 354 fluoride blood level isoflurane, 131 metboxyflurane, 131 sevoflurane, 131 flushing adenosine, 205 amiodarone, 206 bambuterol, 188 calcitonin, 503 magnesium sulfate, 56 methylprednisolone, 456 misoprostol, 461 oxytocin derivative, 506 propafenone, 198 raloxifene, 476 vancomycin, 291 fontanelle bulging retinol, 443 food allergy tsukubaenolide, 432 foreign body silicone, 548 fracture see bone fracture frozen shoulder

indinavir, 347

gait disorder alprazolam, 46 diphenhydramine, 180 granulocyte macrophage colony stimulating factor, 419 manganese, 259 galaetorrhea amisulpride, 61 risperidone, 71, 72 gallbladder motility somatostatin analog, 505 gallstone see cholelithiasis gangrene diazepam, 47 gastrin blood level proton pump inhibitor, 403 gastritis interferon, 413 pamidronic acid, 544 proton pump inhibitor, 403 gastroduodenal ulcer see gastrointestinal ulcer gastroenteritis proton pump inhibitor, 403 gastrointestinal bleeding see gastrointestinal hemorrhage gastrointestinal erosion cyclooxygenase 2 inhibitor, 117 nonsteroid antiinflammatory agent, 117 gastrointestinal hemorrhage acetylsalicylic acid, 118 amtolmetin guacil, 122 antidepressant agent, 15 celecoxib, 117 cyclooxygenase 2 inhibitor, 116, 117, 119 diclofenac, 117 ibuprofen, 117 interferon, 413 nabumetone, 117 nonsteroid antiinflammatory agent, 15, 116, 117, 121 rofecoxib, 117 serotonin uptake inhibitor, 15 trazodone, 15 gastrointestinal injury cyclooxygenase 2 inhibitor, 116 diatrizoate, 525 iron, 257, 258 nonsteroid antiinflammatory agent, 116 gastrointestinal perforation amtolmetin guacil, 122 celecoxib, 117

598 cyclooxygenase 2 inhibitor, 117, 119 diclofenac, 117 ibuprofen, 117 nabumetone, 117 nonsteroid antiinflammatory agent, 117, 121 rofecoxib, 117 gastrointestinal symptom acarbose, 496 alprazolam, 48 amtolmetin guacil, 122 aurothiomalate, 257 azithromycin, 296 bropirimine, 432 celecoxib, 116 cibenzoline, 210 clodronic acid, 543 codeine, 41 cyclooxygenase 2 inhibitor, 116 digoxin, 197 domperidone, 401 doxapram, 3 epirubicin, 362 fluconazole, 324 fluvoxamine, 14 fusidic acid, 288 halofantrine, 332 Helicobacter pylori eradication therapy, 404, 405 40 o (2 hydroxyethyl)rapamycin, 430 itraconazole, 325 lactulose, 406 lorazepam, 48 manganese chloride, 529 mesalazine, 406, 407 metformin, 495 metoclopramide, 401 nonsteroid antiinflammatory agent, 116, 122 paroxetine, 14 Plantago ovata, 406 polyethyleneglycolelectrolyte lavage solution, 406 pranilukast, 184 praziquantel, 360, 361 primaquine, 332 proguanil, 333 proton pump inhibitor, 402, 403 pyridoxine, 447 quinidine, 199 ranitidine, 402 risedronic acid, 544 ritonavir, 347 rizatriptan, 230 Silybum marianum, 539 suramin, 362 topiramate, 92 trastuzumab, 421

I n d e x o f a d v e r s e effects

valproate semisodium, 94 valproic acid, 94 zolpidem, 50 gastrointestinal toxicity cyclooxygenase 2 inhibitor, 117, 118 nonsteroid antiintlammatory agent, 117, 118 gastrointestinal ulcer celecoxib, 117, 118 cyclooxygenase 2 inhibitor, 115-117, 119 diclofenac, 117 ibuprofen, 117 nabumetone, 117 nonsteroid antiinflammatory agent, 115-117 rofecoxib, 117, 118 gastrotoxicity see stomach toxicity genital tract cancer monoclonal antibody, 421 genotoxieity ethylene oxide, 271 isoflurane, 129 nitrous oxide, 129 geographic tongue lithium, 25 Gerstmann syndrome acetazolamide, 249 giddiness see vertigo glnglva hyperplasia amlodipine, 222, 223 calcium antagonist, 222 diltiazem, 222, 223 nifedipine, 222 glnglva hypertrophy see gingiva hyperplasia glaucoma carboplatin, 516 cocaine, 150 dexamethasone, 535 etoposide, 516 glomerulonephritis /~ interferon, 416 penicillamine, 266, 267 thionamide derivative, 485 glomeralopathy /~ interferon, 416 glomerulus filtration rate carboplatin, 516 indometacin, 118 naproxen, 118 rofecoxib, 118 glossitis Helicobacter pylori eradication therapy, 404, 405 lithium, 25 glucose blood level proteinase inhibitor, 345 glucose intolerance

digoxin, 200 glucose metabolism dexamethasone, 454 somatostatin analog, 505 y glutamyitransferase blood level fluindostatin, 512 glyeosuria fluticasone propionate, 185 glycosylated hemoglobin blood level fluticasone propionate, 185 goiter lithim, 23, 26 gonadotropin blood level thalidomide, 172 Goodpasture syndrome penicillamine, 267 graft rejection infuenza vaccine, 376 granulocytopenia clozapine, 24, 27 fusidic acid, 288 levamisole, 358 terbinafine, 314 granuloma silicone, 548 granulomatous hepatitis see hepatitis granulomatous vasculitis see vasculitis Graves disease alemtuzumab, 419 growth dexamethasone, 454 growth disorder dexamethasone, 452 growth failure s e e growth disorder growth retardation budesonide, 186, 187 corticosteroid, 186, 187 gynecomastia melatonin, 545 pamidronic acid, 544 pravastatin, 512 saquinavir, 348 spironolactone, 246, 512 hair loss ot interferon, 411 somatostatin analog, 505 hallucination dextromethorphan, 104 etidronic acid, 544 lamotrigine, 90 naltrexone, 111 opiate, 102 scopolamine, 169 topiramate, 92, 93 halogenoderma lithium, 25 HDL cholesterol blood level

599

I n d e x o f a d v e r s e effects see cholesterol blood level headache abacavir, 343 adenosine, 205 albendazole, 356 amiodarone, 206 amlodipine, 223 azelastine, 192 bambuterol, 188 bropirimine, 433 budesonide, 192 bupivacaine, 148 buspirone, 45 calcitonin, 503 candesartan, 240 cilostazol, 229 cocaine, 150 corticosteroid, 453 deferiprone, 265 diethylcarbamazine, 357 dipeptidyl carboxypeptidase inhibitor, 234 dipyridamole, 398 domperidone, 401 doxercalciferol, 447 ergotamine, 230 formoterol, 188 gadolinium pentetate, 527 gadoversetamide, 527 glucocorticoid, 452 glyceryl trinitrate, 222 granulocyte colony stimulating factor, 417, 418 growth hormone, 504 Helicobacter pylori eradication therapy, 404, 405 hydroxyzine, 45 immunoglobulin, 385 infliximab, 421 influenza vaccine, 376 interleukin 3, 417 iohexol, 521 isotretinoin, 444 itraconazole, 325 ivermectin, 358 ketamine, 135 ketotifen, 534 lamotrigine, 87, 90 lidocaine, 148, 150 loratadine, 192 losartan, 240 mebendazole, 356 meglumine antimonate, 336 meningococcus vaccine, 369 mesalazine, 407 metoclopramide, 401 misoprostol, 461 nateglinide, 494 nedocromil, 534 nefazodone, 17 OKT 3, 421 oxytocin derivative, 506

pemirolast, 534 praziquantel, 361 protirelin, 506 proton pump inhibitor, 402, 403 ranitidine, 402 recombinant erythropoietin, 388 retinoic acid, 444, 445 risperidone, 71 ropivacaine, 148 rosiglitazone, 497 salmeterol, 188 serotonin agonist, 230 serotonin uptake inhibitor, 14 stibogluconate sodium, 336 sumatriptan, 230 teicoplanin, 290 thalidomide, 171 trastuzumab, 421 trecovirsen, 345 triptan derivative, 230 zolpidem, 50 hearing impairment aminoglycoside antibiotic agent, 283 lidocaine, 148 ropivacaine, 148 hearing loss aminoglycoside antibiotic agent, 283 azithromycin, 295,296 clarithromycin, 296 tsukubaenolide, 432 heart s e e a l s o cardio heart arrest

acebutolol, 221 lidocaine, 152 meglumine diatrizoate, 336 methylprednisolone, 450, 456 nitric oxide, 192 remifentanil, 108 suxamethonium, 158 verapamil, 226 heart arrhythmia adenosine, 205 antiarrhythmic agent, 204 antihistaminic agent, 179 astemizole, 179 bupivacaine, 151 cetirizine, 179 chloral hydrate, 49 cibenzoline, 210 cisapride, 401 cocaine, 37 digitalis glycoside, 199 dobutamine, 165 ebastine, 179 halothane, 128, 129 lithium, 22 loratadine, 179 neuroleptic agent, 54, 55

phenol, 272 propafenone, 199 quinidine, 199 quinine, 333 repaglinide, 494 sertindole, 54 sevoflurane, 128, 129 sildenafil, 231 stibogluconate sodium, 336 sumatriptan, 230 terfenadine, 179 thiopental, 128 troglitazone, 494 tsukubaenolide, 431 venlafaxine, 19 heart atrioventricular block adenosine, 205 arsenic trioxide, 254 bacitracin, 301 propofol, 135 verapamil, 226 heart atrium arrhythraia loratadine, 179 heart atrium fibrillation clozapine, 62 meglumine diatrizoate, 336 mepivacaine, 142 heart atrium flutter amiodarone, 198 antiarrhytlmaic agent, 200 digitalis glycoside, 199 flecainide, 198 propafenone, 198 quinidine, 199 heart attack see heart infarction heart block dipyridamole, 398 propafenone, 214 heart conduction disturbance see heart muscle conduction disturbance heart dysrhythmia see heart arrhythmia heart extrasystole see extrasystole heart failure amiodarone, 197 anthracycline derivative, 515 basiliximab, 420 carvedilol, 221 cyclooxygenase 2 inhibitor, 120 donepezil, 7 doxazosin, 242 doxorubicin, 515 fresh frozen plasma, 384 milrinone, 204 nonsteroid antiinflammatory agent, 120 trastuzumab, 421 heart hypertrophy

600

thiazolidinedione derivative, 497 heart infarction bromocriptine, 166 buprenorphine, 110 cocaine, 37 contrast medium, 520 desmopressin, 506 dipeptidyl carboxypeptidase inhibitor, 235 fosfestrol, 469 fresh frozen plasma, 384 glimepiride, 493 nicotine, 546 nifedipine, 224, 225 oral contraceptive agent, 472 recombinant blood clotting factor 7a, 387 repaglinide, 494 sulprostone, 462 tamoxifen, 475 tricyclic antidepressant agent, 12 troglitazone, 494 heart left ventricle failure see heart ventricle failure heart muscle conduction disturbance citalopram, 14 cocaine, 37 dextropropoxyphene, 105 neuroleptic agent, 55, 56 verapamil, 226 heart muscle ischemia adenosine, 205 digoxin, 200 fluorouracil, 515 glibenclamide, 492 nifedipine, 224, 225 ritodrine, 225 venlafaxine, 19 vinorelbine, 515 heart muscle necrosis activated prothrombin complex, 386 blood clotting factor, 386 n ethyl 3,4 methylenedioxyamphetamine, 33 kininogen, 386 3,4 methylenedioxymethamphetamine, 33 ritodrine, 225 heart palpitation ot adrenergic receptor blocking agent, 233 bambuterol, 188 buspirone, 45 cilostazol, 229 dipeptidyl carboxypeptidase inhibitor, 234 fluconazole, 324

I n d e x o f adverse effects

fluticasone propionate, 189 fluticasone propionate plus salmeterol, 189 nicotine, 546 povidone iodine, 271 quinidine, 199 ritodrine, 222 salmeterol, 188, 189 heart rate nifedipine, 224 prilocaine plus lidocaine, 149 rapacuronium bromide, 159 heart tamponade acupuncture, 540 catheter, 547 heart valve disease anorexigenic agent, 4, 5 dexfenfluramine, 4, 5 fenfluramine, 4, 5 phentermine, 4, 5 heart valve regurgitation anorexigenic agent, 4 dexfenfluramine, 4, 5 heart valvulopathy see heart valve disease heart ventriele arrhytiamia adrenalin, 163 antihistaminic agent, 179 astemizole, 179 cetirizine, 179 cibenzoline, 210 Ephedra, 538 growth hormone, 504 halofantrine, 331 meglumine diatrizoate, 336 terfenadine, 179, 181 heart ventricle extrasystole ephedrine, 163 neuroleptic agent, 55 heart ventricle failure contrast medium, 520 digoxin, 200 iodixanol, 520 ioxaglic acid, 520 nitric oxide, 192 heart ventricle fibrillation clindamycin, 293 clozapine, 62 digoxin, 200 sulprostone, 462 sumatriptan, 230 heart ventricle hypertrophy dexamethasone, 452 heart ventricle tachycardia acebutolol, 221 amiodarone, 197, 198 clomipramine, 13 cocaine, 152 erythromycin, 298 halothane, 128 lidocaine, 147 milrinone, 204 ornipressin, 507

quinidine, 199 sildenafil, 231 sumatriptan, 230 trazodone, 18 heat sensation zolmitriptan, 230 hemangioma thalidomide, 172 hematocrit metrifonate, 8 rosiglitazone, 497 thiazolidinedione derivative, 497 hematoma botulinum toxin A, 160 hetastarch, 394 meningococcus vaccine, 369 prostaglandin El, 460 retinoic acid, 445 hematuria foscarnet, 340 indinavir, 346 isotretinoin, 444 hemiparesis contrast medium, 520 hemiplegia glibenclamide, 492 hemoglobin blood level metrifonate, 8 praziquantel, 361 rosiglitazone, 497 thiazolidinedione derivative, 497 hemolysis glibenclamide, 492 immunoglobulin, 385, 386 primaquine, 332 rifampicin, 353, 354 hemolytic anemia cefotetan, 277 ceftizoxime, 277 ceftriaxone, 277 indinavir, 346 u interferon, 413 levamisole, 360 mercaptopurine, 422 pipemcillin, 276 hemolytic uremic syndrome gemcitabine, 516 pentostatin, 516 hemorrhage see bleeding hemorrhagic stroke norephedrine, 164 Henoch Schoenlein purpura see anaphylactoid purpura hepatic see also liver hepatic encephalopathy cimetidine, 402 valproic acid, 94 hepatitis acarbose, 496

601

I n d e x o f adverse effects

albumin, 383 amiodarone, 208 atorvastatin, 511 bergapten, 276 blood clotting factor 8 concentrate, 388 buprenorphine, 110 Chelidonium majus, 538 cotrimoxazole, 334 desflurane, 130 enalapril, 237 flucloxacillin, 274, 276 fluoxetine, 15 immunoglobulin, 386 a interferon, 414 mebendazole, 356 meloxicam, 123 mesalazine, 407 nefazodone, 17 nicotinic acid, 446 omeprazole, 403 paroxetine, 15 rifampicin, 354 venlafaxine, 19 hepatomegaly zidovudine, 343 hepatosplenomegaly levamisole, 360 hepatotoxicity see liver toxicity hernia desmopressin, 507 manipulative medicine, 541 herpes simplex latanoprost, 461 herpes zoster chickenpox vaccine, 380 virus vaccine, 373 hiccup betamethasone dipropionate, 459 dexamethasone, 452 midazolam, 134 sevoflurane, 127 hip fracture see bone fracture hirsutism betamethasone, 457 valproic acid, 94 histamine release iopamidol, 524 ioxitalamic acid, 524 rapacuronium bromide, 159 vancomycin, 291 hoarseness fluticasone propionate, 189 fluticasone propionate plus salmeterol, 189 salmeterol, 189 homocysteine blood level oral antidiabetic agent, 491 hormone blood level alprazolam, 46

lithium, 23 Homer syndrome bupivacaine, 141, 143, 149 ropivacaine, 141 hot flushes see flushing hyperactivity clarithromycin, 297 paroxetine, 14 hyperadrenocortidsm betamethasone, 454, 457 hyperalgesia morphine, 107 opiate, 102 hyperandrogenism valproic acid, 93 hyperbilirubinemia gold salt, 257 hypercalcemia lithium, 24 hypercholesterolemia 40 o (2 hydroxyethyl)rapamycin, 430 rapamycin, 430 hypereoagulability granulocyte colony stimulating factor, 418 hyperglycemia amisulpride, 61 cisplatin, 516 clozapine, 64 dexamethasone, 452 growth hormone, 505 itraconazole, 325 olanzapine, 69 somatostatin analog, 505 hyperhidrosis diphenhydramine, 180 hyperinsulinemia lipid, 454 hyperkalemia aminocaproic acid, 399 eplerenone, 251 imidapril, 238 potassium sparing diuretic agent, 248 spironolactone, 246, 248, 251 suxamethonium, 158 hyperlipidemia propofol, 135 proteinase inhibitor, 346 ritonavir, 346 hypermanganesemia parenteral nutrition, 396 hypermenorrhea implanted hormonal contraceptive agent, 473 ritonavir, 347 hyperosmolar coma cisplatin, 516 hyperparathyroidism lithium, 25 hyperpigmentation

chlorpromazine, 13 imipramine, 13 methotrexate, 428 unoprostone, 462 hyperprolactinemia haloperidol, 72 fisperidone, 71, 72 hyperpyrexia see fever hypersalivation clozapine, 53, 61 domase a, 193 olanzapine, 70 scorpion venom, 2 hypersensitivity abacavir, 343 amphotericin B lipid complex, 317 apraclonidine, 535 azathioprine, 422 bacitracin, 301 basiliximab, 419 carboplatin, 516 c arboxymethylcellulose, 140 catheter, 270 celecoxib, 119 cephalosporin, 295 chlorhexidine, 270 clonidine, 242 cocaine, 38 contrast medium, 523 cotrimoxazole, 334 cyclooxygenase 2 inhibitor, 119 dapsone, 335 delavirdine, 344 dextropropoxyphene plus paracetamol, 105 2,5 diaminotoluene, 175 diazepam, 133 dipyridamole, 398 Echinacea, 538 estrogen, 469 gold salt, 257 granulocyte macrophage colony stimulating factor, 419 haemophilus influenzae type b vaccine, 366 human insulin, 488 hyaluronidase, 140 hydrocortisone, 456 immunoglobulin, 385 infliximab, 420 insulin, 488 iopentol, 523 Japanese encephalitis vaccine, 376, 377 ketotifen, 534 lamotrigine, 88, 89 leukotriene receptor blocking agent, 183, 184 lidocalne, 140, 270

602 local anesthetic agent, 533 lyme disease vaccine, 367 macrolide derivative, 295 measles mumps rubella vaccine, 374 medical device, 270 mercaptopurine, 422 neomycin, 286 oxybuprocaine, 140, 533 penicillamine, 267 penicillin derivative, 295 prednisone, 455 procainamide, 214 propylthiouracil, 485 protamine, 488 quinidine, 199 quinine, 333 quinupristin plus dalfopristin, 301 rofecoxib, 119 somatomedin, 491 sulfadiazine, 270 sulfonamide, 119, 295 teicoplanin, 289 tetracycline derivative, 295 thalidomide, 172 hypertension amphotericin B colloid, 316 amphotericin B deoxycholate, 316 amphotericin B lipid complex, 316, 317 Angelicae sinensis, 538 bupivacalne, 149 cocaine, 152 dexamethasone, 452 Ephedra, 538 ephedrine, 163 gadopentetate dimeglumine, 527 immunoglobulin, 385 iopamidol, 524 ioxitalamic acid, 524 isotretinoin, 444 lidocaine, 147, 149 liposomal amphotericin B, 317 losartan, 241 mepivacalne, 142 moclobemide, 12 monoamine oxidase inhibitor, 12 nifedipine, 224 phenylephrine, 534 proton pump inhibitor, 403 recombinant erythropoietin, 388, 389 ropivacaine, 141 tibolone, 480 vancomycin, 291 venlafaxine, 18 hyperthermia diphenhydramine, 180

Index o f adverse effects

n ethyl 3,4 methylenedioxyamphetamine, 33 3,4 methylenedioxymethamphetamine, 33 misoprostol, 462 promethazine, 180 pseudoephedrine, 164 hyperthyroidism amiodarone, 207 gabapentin, 84 granulocyte colony stimulating factor, 418 a interferon, 413 iodinated contrast medium, 486 iodine, 485 iodized salt, 485 lithium, 24 povidone iodine, 271 hypertrichosis unoprostone, 462 hypertriglyceridemia 40 o (2 hydroxyethyl)rapamycin, 430 lipid, 454 propofol, 135, 136 rapamycin, 430

hyperuricemia diuretic agent, 247

hypervolemia albumin, 383

hypesthesia

carboxymethylcellulose, 140 local anesthetic agent, 146

hypocalcemia insulin, 487 pamidronic acid, 544

hypofibrinogenemia activated prothrombin complex, 387

hypogammaglobulinemia see immunoglobulin

deficiency

hypoglycemia acetylsalicylicacid, 493 fl adrenergic receptor blocking agent, 493 cibenzoline, 210 cimetidine, 493 cotrimoxazole, 493 dipeptidyl carboxypeptidase inhibitor, 236 disopyramide, 211 enalapril, 236 glibenclamide, 487, 492-495 glimepiride, 493 insulin, 325, 487, 488, 490, 491,493, 495 insulin glargine, 490, 491 insulin pen, 489 insulin pump, 488, 489

isophane insulin, 490, 491 itraconazole, 325 lispro insulin, 489-491 metformin, 487, 493-495 methylphenidate, 220 nateglinide, 494 oral antidiabetic agent, 325 propranolol, 220 quinine, 333 ramipril, 239 repaglinide, 494, 495 rosiglitazone, 497 serotonin uptake inhibitor, 15 somatostatin analog, 505 thiazolidinedione derivative, 496 troglitazone, 494, 495

hypogonadism gonadorelin agonist, 503

hypokalemia

amphotericin B, 317 cMortalidone, 248 diuretic agent, 248 Glycyrrhiza, 538 insulin, 487

hypokinesia

manganese, 259

hypomagnesemia aminoglycoside antibiotic agent, 284 cyclosporin a, 424 platinum derivative, 260 hypomania see mania

hyponatremia

amiodarone, 207 carbamazepine, 84 desmopressin, 506 dipeptidyl carboxypeptidase inhibitor, 236 3,4 methylenedioxymethamphetamine, 35 oxcarbazepine, 90 zopiclone, 51

hypophosphatemia parenteral nutrition, 396

hypophysis apoplexy protirelin, 506

hypotension adenosine, 205 adrenergic receptor blocking agent, 221 alprazolam, 46 amiodarone, 197, 198 amitriptyline, 143 amphotericin B colloid, 316 brimonidine, 536 buflomedil, 229 bupivacaine, 142, 143, 145, 147, 149 captopril, 237 clozapine, 61, 62

603

I n d e x o f a d v e r s e effects

dipeptidyl carboxypeptidase inhibitor, 235 dobutamine, 165 fentanyl, 105, 143, 147 flecalnide, 198 fluorocarbon, 384 glyceryl trinitrate, 222 infliximab, 420 interleukin 2, 416 iopamidol, 524 ioversol, 519, 524 ioxitalamic acid, 524 ivermectin, 358 levobupivacaine, 143 lidocaine, 142, 145, 152 liposomal amphotericin B, 317 methylprednisolone, 450 metrifonate, 8 milrinone, 204 minoxidil, 243 moclobemide, 12 morphine, 142, 145, 147 neuroleptic agent, 54 nicotinic acid, 446 nifedipine, 224, 225 nitric oxide, 190, 192 opiate, 102, 103 pneumococcus vaccine, 372 povidone iodine, 271 procainamide, 198 propafenone, 198 propofol, 127, 136 remifentanil, 108 rifamycin, 176 risperidone, 73 ropivacalne, 141 sameridine, 145 spinal anesthesia, 144 spironolactone, 246 sufentanil, 143 talc, 549 teicoplanin, 289 valproic acid, 93 vancomycin, 289 venlafaxine, 18 verapamil, 226 hypothermia melatonin, 545 serotonin uptake inhibitor, 15 hypothyroidism amiodarone, 207 anticonvulsive agent, 82 lithium, 23 povidone iodine, 271 hypoventilation granulocyte macrophage colony stimulating factor, 419 hypoxemia lidocaine, 152 talc, 549 hypoxia

amphotericin B colloid, 316 barium sulfate, 524 dextran 1,393 dextran 40, 393 lidocaine, 149 liposomal amphotericin B, 317 midazolam, 134 opiate, 40, 134

idiosyncrasy acarbose, 496 oxybuprocaine, 533 quinine, 333 ileum disease barium sulfate, 525 retinoic acid, 445 immediate type hypersensitivity s e e hypersensitivity immune complex disease immunoglobulin, 386 immune deficiency corticotropin, 450 fluorocarbon, 384 immune hemolytic anemia s e e hemolytic anemia immune response alcohol, 35, 36 antimony trioxide, 254 aprotinin, 399 mercury, 260 3,4 methylenedioxymethamphetamine, 35, 36 penicillamine, 265 immunoglobulin A deficiency bulious skin disease furosemide, 250 vancomycin, 291 immunoglobulin antibody procainamide, 213 immunoglobulin deficiency azathioprine, 424 immunomodulafion fosfomycin, 302 fusidic acid, 288 lithium, 24 macrolide derivative, 295 impaired glucose tolerance s e e glucose intolerance impotence lidocaine, 146 risperidone, 53 spinal anesthesia, 146 inappropriate ADH secretion see inappropriate vasopressin secretion inappropriate vasopressin secretion amiodarone, 207 zopiclone, 50 indigestion

pyridoxine, 447 infection acupuncture, 540 betamethasone, 457 corticosteroid, 534 glucocorticosteroid, 457 40 o (2 hydroxyethyl)rapamycin, 430 infliximab, 420 mycophenolic acid 2 morpholinoethyl ester, 429 prednisone, 457 proton pump inhibitor, 403 silicone, 548 suramin, 362 trastuzumab, 421 tsukubaenolide, 431,432 inflammation quinupristin plus dalfopristin, 301 silicone, 548 injection complication amphoteficin B, 317 amphotericin B deoxycholate, 315 amphotericin B lipid complex, 316, 317 chickenpox vaccine, 380 diphtheria acellular pertussis tetanus vaccine, 370 etanercept, 420 ganirelix, 504 granulocyte colony stimulating factor, 418 haemophilus influenzae type b vaccine, 366, 372 imiquimod, 433 influenza vaccine, 375,376 /~ interferon, 416 lyme disease vaccine, 367 meningococcus vaccine, 368, 369 milodisfim, 417 pneumococcus vaccine, 371, 372 ribonucleic acid, 433 stem cell factor, 419 injection pain chickenpox vaccine, 380 clodronic acid, 122 diphtheria acellular pertussis tetanus vaccine, 370 influenza vaccine, 376 meningococcus vaccine, 368 propofol, 135, 136 quinupristin plus dalfopristin, 301 injection site reaction see injection complication injury acupuncture, 540 manipulative medicine, 540 massage, 540

604 metrifonate, 8 insomnia ct adrenergic receptor blocking agent, 233 fl adrenergic receptor blocking agent, 233 amfebutamone, 16 amiodarone, 206 bambuterol, 188 cibenzoline, 210 clarithromycin, 296 dipeptidyl carboxypeptidase inhibitor, 233 domperidone, 401 granulocyte colony stimulating factor, 417 Helicobacter pylori eradication therapy, 405 ketamine, 134 lamotrigine, 87, 90 levamisole, 358, 359 metoclopramide, 401 povidone iodine, 271 quinapril, 238 risperidone, 53, 73 trastuzumab, 421 zolpidem, 50 insulin blood level cetrorelix, 504 insulin resistance growth hormone, 504 intellectual impairment alprazolam, 48 lorazepam, 48 intelligence anticonvulsive agent, 83 clobazam, 84 intermittent clandication cannabis, 36 ergotamine, 168 interstitial nephritis clarithromycin, 297 clozapine, 65 nimesulide, 123 propylthiouracil, 485 interstitial pneumonia cabergoline, 166 dextropropoxyphene plus paracetamol, 105 flutamide, 479, 503 leuprorelin, 503 rapamycin, 430 timolol, 221 intervertebrai disk hernia s e e hernia intestine ischemia cocaine, 38 diatrizoate, 525 intestine motility cholinesterase inhibitor, 157 intestine necrosis oral contraceptive agent, 472 retinoic acid, 445

Index of adverse effects

intestine obstruction amtolmetin guacil, 122 barium sulfate, 525 celecoxib, 117 copper intrauterine device, 256 cyclooxygenase 2 inhibitor, 117 nonsteroid antiinflammatory agent, 117 intestine perforation barium sulfate, 525 copper intrauterine device, 256 dexamethasone, 451 intestine permeability indometacin, 118 rofecoxib, 118 intraeranial pressure opiate, 102 praziquantel, 361 intrahepatic cholestasis s e e cholestasis intraocular pressure corticosteroid, 534 dexamethasone, 535 fomivirsen, 340 loteprednol ebonate, 535 oxybuprocaine plus fluorescein, 533 triamcinolone, 453 intrauterine growth retardation losartan, 241 intravasation barium, 526 diatrizoate, 525 intussusception rotavirus vaccine, 379 iododerma iodinated contrast medium, 522 iris color latanoprost, 460 unoprostone, 462 iris disease latanoprost, 460 iris pigmentation s e e iris color iritis cidofovir, 340 iron deficiency recombinant erythropoietin, 389 iron metabolism ultrasmall superparamagnetic iron oxide, 528 irritability dextromethorphan, 104 haemophilus influenzae type b vaccine, 366 lamotrigine, 90 measles vaccine, 377

paroxetine, 14 propofol, 136 retinol, 443 topiramate, 92 ischemie colitis s e e colitis ischemic heart disease metformin, 495 sulfonylurca derivative, 495 jaundice albendazole, 356 cloxacillin, 274 dicloxacillin, 274 erythromycin ethylsuccinate, 298 erythromycin stearate, 298 flucloxacillin, 274 glibenclamide, 492 mebendazole, 356 metformin, 492 jitteriness s e e nervousness joint pain s e e arthralgia Kaposi sarcoma mycophenolic acid 2 morpholinoethyl ester, 429 keratitis latanoprost, 461 keratopathy amiodarone, 207 suramin, 362 keratosis follicularis s e e Darier disease ketoaddosis insulin pump, 488 kidney atrophy indinavir, 346 kidney calcification furosemide, 248 kidney cancer analgesic agent, 120, 121 nonsteroid antiinflammatory agent, 120 phenacetin, 120 kidney carcinoma acetylsalicylic acid, 121 analgesic agent, 121 nonsteroid antiinflammatory agent, 121 paracetamol, 121 phenacetin, 121 kidney colic indinavir, 346 kidney concentrating capacity lithium, 25 kidney damage s e e kidney injury kidney disease chinese herb, 537 isotretinoin, 444

605

Index of adverse effects

kidney dysfunction amphotericin B, 324 cyclooxygenase 2 inhibitor, 118, 119 immunoglobulin, 386 interferon, 416 intefleukin 2, 416 isoflurane, 129 methoxyflurane, 131 naproxen, 118 nonsteroid antiinflammatory agent, 118, 119 rofecoxib, 118 sevoflurane, 129, 131 sucrose, 386 teicoplanin, 289 vancomycin, 289 kidney failure aminoglycoside antibiotic agent, 284 amiodarone, 208 amphotericin B deoxycholate, 315 anabolic agent, 477 ceftriaxone, 278 chinese herb, 538 clarithromycin, 297 clomipramine, 13 cocaine, 38 cyclooxygenase 2 inhibitor, 118 foscarnet, 341 fresh frozen plasma, 384 germanium derivative, 256 immunoglobulin, 386 indinavir, 346 ioversol, 520 irbesartan, 240 lisinopril, 235 lithium, 25 losartan, 240 mesalazine, 407 3,4 methylenedioxymethamphetamine, 34 nimesulide, 123 nitric oxide, 191 nonsteroid antiinflammatory agent, 118 povidone iodine, 271 propylthiouracil, 485 rifampicin, 354 ritonavir, 347 spironolactone, 240 sucrose, 386 suramin, 362 kidney function ivermectin, 357 kidney injury foscarnet, 340 kidney insufficiency s e e kidney failure kidney pelvis cancer

analgesic agent, 121 aniline derivative, 121 nonsteroid antiinflammatory agent, 121 paracetamol, 121 phenacetin, 121 kidney stone s e e nephrolithiasis kidney toxicity s e e nephrotoxicity kidney tubule injury cidofovir, 340 contrast medium, 522 isofltwane, 129 sevoflurane, 129 sucrose, 386 kidney tubule necrosis n ethyl 3,4 methylenedioxyamphetamine, 33 3,4 methylenedioxymethamphetamine, 33 knee disease chlorhexidine, 270 knee pain s e e arthralgia laboratory test influence bacitracin, 302 chloramphenicol, 288 digoxin, 203 immunoglobulin, 386 lithium, 27 macrolide derivative, 295 vancomycin, 292 lactate dehydrogenase blood level clarithromycin, 297 granulocyte colony stimulating factor, 418 lactation lithium, 26 zidovudine, 344 lactic acidosis didanosine, 343 metformin, 495 zidovudine, 343 language disability amiodarone, 209 topiramate, 92 zonisamide, 93 larynx edema iopamidol, 524 lassitude s e e fatigue lead poisoning Koo Sar, 259 leg cramp s e e muscle cramp leg ischemia cannabis, 36 leg ulcer

hydroxyurea, 516 leg weakness s e e muscle weakness lens color amiodarone, 207 lens opacity s e e cataract leptin blood level cetrorelix, 504 lethargy alprazolam, 48 corticotropin, 450 Helicobacter pylori eradication therapy, 405 lorazepam, 48 zopiclone, 51 leukemia antineoplastic agent, 517 ethylene oxide, 271 mercaptopurine, 423 retinoic acid, 445 leukocyte count fluorocarbon, 384 leukocytoclastic vaseulitis s e e vasculitis leukocytosis amiodarone, 208 arsenic trioxide, 254 barium sulfate, 524 retinoic acid, 444 leukocncephalopathy cocaine, 41 diamorphine, 40, 41, 105 levamisole, 358 recombinant erythropoietin, 389 leukopenia antineoplastic agent, 516 clozapine, 63, 69 40 o (2 hydroxyethyl)rapamycin, 430 lamotrigine, 89, 90 olanzapine, 69 prostacyclin, 463 rapamycin, 430 suramin, 362 trastuzumab, 421 libido anabolic agent, 477 tamoxifen, 475 lichenoid anticonvulsive agent, 82 granulocyte colony stimulating factor, 418 lithium, 25 lightheadedness s e e vertigo limb edema diphtheria acellular pertussis tetanus vaccine, 370 phenytoin, 90 ritonavir, 347 limb ischemia

606 buprenorphine, 110 linear IgA disease see immunoglobulinA deficiency bullous skin disease fipase blood level lisinopril, 238 valproic acid, 94 lipid blood level cetrorelix, 504 oral coneraceptive agent, 503 ritonavir, 346 triptorelin, 503 lipid metabolism atorvastatin, 510 desogestrel, 477 estrogen, 473 hydroxymethylglutaryl coenzyme A reductase inhibitor, 510 insulin, 488 proteinase inhibitor, 345 raloxifene, 476 simvastatin, 510 stavudine, 342 zidovudine, 342 fipoatrophy insulin, 488 fipodystrophy nevirapine, 345 proteinase inhibitor, 345 stavudine, 342 zidovudine, 342 fipomatosis corticosteroid, 459 glucocorticoid, 452 prednisone, 452 fisflessness sultiame, 91 fivedo reticularis amantadine, 167 fiver adenoma see benign liver tumor fiver cancer danazol, 479 fiver cardnoma iron, 258 liver cirrhosis interferon, 414 retinol, 442 tamoxifen, 475 fiver damage see liver injury fiver disease alcohol, 442 copper, 256 nicardipine, 224 oral antidiabetic agent, 492 parenteral nutrition, 395 retinol, 442 fiver dysfunction gonadotropin, 474 itraconazole, 325

I n d e x o f adverse effects

lamotrigine, 89 metformin, 492 nefazodone, 17 parenteral nutrition, 395 repaglinide, 495 teicoplanin, 289 troglitazone, 495, 497 venlafaxine, 19 liver enzyme fluoxetine, 15 human insulin, 488 lamotrigine, 88-90 metronidazole, 404 nateglinide, 494 nefazodone, 17 nicotinic acid, 446 proguanil plus atovaquone, 333 proton pump inhibitor, 403 ranitidine, 402 risperidone, 72 venlafaxine, 19 zafirlukast, 184 fiver failure didanosine, 343 fluconazole, 324 nefazodone, 17 nevirapine, 345 phenprocoumon, 398 prednisolone, 454 Scutellaria, 539 troglitazone, 497 valproic acid, 94 zidovudine, 343 fiver fibrosis carotenoid, 443 mesalazine, 407 retinoid, 443 liver granuloma mebendazole, 356 liver hematoma anaholic agent, 477 chorionic gonadotropin, 477 clomiphene, 477 fiver injury alcohol, 443 amiodarone, 208 amoxicillin plus clavulanic acid, 276 amphotericin B deoxycholate, 315 benzimidazole derivative, 356 /~ carotene, 443 fluconazole, 324, 326 histamine H1 receptor antagonist, 180 human insulin, 488 itraconazole, 326 ketoconazole, 326 mequitazine, 180 prednisolone, 454 terbinafine, 326 troglitazone, 497

zolpidem, 50 liver necrosis acarbose, 496 alcohol, 442 enalapril, 237 isoflurane, 130 nefazodone, 17 retinol, 442 troglitazone, 497 venlafaxine, 19 liver steatosis see fatty liver liver tosidty acarbose, 496 alcohol, 442 amoxicillin plus clavulanic acid, 276 amphotericin B deoxycholate, 315 azathioprine, 422 fl carotene, 442, 443 cerivastatin, 512 desflurane, 130 dicloxacillin, 274 n ethyl 3,4 methylenedioxyamphetamine, 33 flucloxacillin, 274, 276 fluconazole, 324 fluindostatin, 512 fluorocarbon, 384 flutamide, 480 gold salt, 257 halothane, 130 isoniazid, 353 lamotrigine, 88 3,4 methylenedioxymethamphetamine, 33 nefazodone, 17 nicotinic acid, 446 oral antidiabetic agent, 492 paracetamol, 122 retinol, 442 Scutellaria, 539 serotonin uptake inhibitor, 15 teicoplanin, 289 tolcapone, 168 troglitazone, 492, 497 Tsumura, 537 vancomycin, 289 liver venoocelusive disease azathioprine, 422 bee pollen, 538 Scutellaria, 539 local toxicity silicone, 548 long QT syndrome fluconazole, 324 loose stool see diarrhea lung alveolitis rituximab, 421

607

Index of adverse effects

lung aspiration barium sulfate, 524 lung cancer antineoplastic agent, 517 fl carotene, 442 lung edema dextran 1,393 dextran 40, 393 n ethyl 3,4 methylenedioxyamphetamine, 33 fresh frozen plasma, 384 insulin, 488 iopamidol, 524 lidocaine, 147, 149 3,4 methylenedioxymethamphetamine, 33-35 nitric oxide, 190 octreotide, 505 prostacyclin, 463 talc, 549 vinorelbine, 515 lung embolism activated prothrombin complex, 387 conjugated estrogen, 472 hormonal replacement therapy, 468 lidocaine, 152 talc, 549 lung fibrosis amiodarone, 206 talc, 548 lung hemorrhage n ethyl 3,4 methylenedioxyamphetamine, 33 3,4 methylenedioxymethamphetamine, 33 thionamide derivative, 485 lung infiltrate amiodarone, 206 intedeukin 2, 416 mesalazine, 407 lung injury blood product, 385 blood transfusion, 385 fresh frozen plasma, 385 nitric oxide, 190 lung insufficiency bupivacalne, 141 lung toxicity amiodarone, 206 lupus anticoagulant lamotrigine, 82 valproic acid, 82 lupus erythematosus amiodarone, 208 infliximab, 420 penicillamine, 266 procainamide, 213

terbinaline, 314 zafirlukast, 184 lupus like syndrome s e e lupus erythematosus Lyell syndrome s e e toxic epidermal necmlysis lymphadenopathy lamotrigine, 88, 89 rifampicin, 354 lymphocele rapamycin, 430 lymphocytopenia amiodarone, 209 azathioprine, 424 recombinant erythropoietin, 389 lymphocytosis OKT 3, 421 lymphoma antineoplastic agent, 517 infliximab, 420 mercaptopurine, 423 methotrexate, 428 lymphopenia s e e lymphocytopenia lymphoproliferative disease antineoplastic agent, 516 rituximab, 421

maeulopapular rash s e e rash malaise abacavir, 343 captopril, 237 doxercalciferol, 447 erythromycin stearate, 298 ganirelix, 504 glibenclamide, 492 isoniazid, 353 losartan, 240 metrifonate, 8 nystatin, 175 typhoid vaccine, 373 malignant neoplastic disease s e e carcinogenesis mallory body amiodarone, 208 felodipine, 208 mania corticosteroid, 453 dextromethorphan, 104 dipeptidyl carboxypeptidase inhibitor, 239 gabapentin, 86 olanzapine, 68 paroxetine, 14 pindolol, 220 risperidone, 72 Saint Johns wort, 539 serotonin uptake inhibitor, 14 testosterone, 477 memory disorder cannabis, 36

carbamazepine, 84 diazepam, 48 ephedrine, 163 levamisole, 359 lorazepam, 48 3,4 methylenedioxymethamphetamine, 34 memory loss s e e amnesia meningism immunoglobulin, 385 meningitis immunoglobulin, 385 menstruation disorder amisulpride, 61 copper intrauterine device, 473 implanted hormonal contraceptive agent, 473 valproic acid, 94 mental deficiency methotrexate, 429 mental disease valproic acid, 93 mental symptom s e e neuropsychiatric symptom metabolic acidosis acetazolamide, 249 povidone iodine, 271 topiramate, 93 metallic taste s e e dysgeusia methemoglobinemia benzocaine, 151 bupivacaine, 142 cetacaine, 151 dapsone, 334, 352 isosorbide dinitrate, 142 lidocaine, 142 local anesthetic agent, 142 nitric oxide, 190, 191 prilocaine, 142, 147 prilocaine plus lidocaine, 142 silver nitrate, 261 mieroangiopathy tsukubaenolide, 431 mieturifion disorder calcitonin, 503 tramadol, 109 migraine buspirone, 45 codeine, 41 hydroxyzine, 45 losartan, 240 oxycodone, 107 mitral valve regurgitation dexfenfluramine, 4 fenfluramine, 4 phentermine, 4 Moebius syndrome misoprostol, 462 mood disorder

608 alprazolam, 46 insulin, 487 ketamine, 135 sultiame, 91 thalidomide, 172 mortality /3 adrenergic receptor blocking agent, 221 albumin, 383 amiodarone, 206 amphotericin B deoxycholate, 315 buflomedil, 229 carvedilol, 221 clomipramine, 13 clozapine, 61, 62 contrast medium, 519 Cremophor EL, 448 deferoxamine, 330 desmopressin, 506 dexamethasone, 454 diazepam, 330 didanosine, 343 digoxin, 201 dornase or, 194 n ethyl 3,4 methylenedioxyamphetamine, 32, 33 glibenclamide, 492 growth hormone, 504 insulin, 487 ot interferon, 415 iopamidol, 524 lamotrigine, 88 lidocaine, 152 melarsoprol, 335 metformin, 492, 495 methamphetamine, 2 3,4 methylenedioxymethamphetamine, 32, 33, 35 methylphenidate, 3 methylprednisolone, 450 milrinone, 204 moxonidine, 242 nefazodone, 17 neuroleptic agent, 54 nifedipine, 224 nitrazepam, 48 phenobarbital, 330 phenol, 272 prednisolone, 454 promethazine, 180 prostacyclin, 463 recombinant erythropoietin, 389 retinoic acid, 444 ricinomacrogol, 448 sulfonylurea derivative, 495 sumatriptan, 230 terfenadine, 179 thalidomide, 172 troglitazone, 497

I n d e x o f a d v e r s e effects

valproic acid, 13 venlafaxine, 19 zolpidem, 50 motor dysfunction

levodopa, 165 olanzapine, 67 praziquantel, 361 propofol, 127 risperidone, 73 sevoflurane, 127 motor nerve block

hupivacaine, 143, 144 fentanyl, 144 levobupivacaine, 143, 144 lidocaine, 144 ropivacaine, 143, 144 sufentanil, 143 mouth ulcer

cytarabine, 411 deferiprone, 265 erythromycin, 298 ct interferon, 411 movement disorder see

motor dysfunction

mucormycosis

iron, 258 mucosa inflammation

antineoplastie agent, 516 intefleukin 3, 417 mueositis see mucosa inflammation multlfoeai leukoeneephalopathy see leukoencephalopathy multiple organ failure fl interferon, 415 suramin, 362 multiple sclerosis etanercept, 420 hepatitis B vaccine, 374, 375

muscle atrophy

betamethasone, 457 botulinum toxin A, 160 muscle cramp

bambuterol, 188 calcitonin, 503 cyclosporin a, 425 granulocyte colony stimulating factor, 419 hydroxymethylglutaryl coenzyme A reductase inhibitor, 511 raloxifene, 476 thalidomide, 171 muscle damage see

muscle injury

muscle disease

cyclosporin a, 425 muscle faseieulation see fasciculation muscle fibrosis pentazocine, 110 muscle hyperexeitability

suxamethonium, 158 muscle hypertonia

n ethyl 3,4 methylenedioxyamphetamine, 33 3,4 methylenedioxymethamphetamine, 33 nortriptyline, 13 valproic acid, 13 muscle injury botulinum toxin A, 160 muscle pain s e e myalgia muscle rigidity diphenhydramine, 180 fluvoxamine, 14 olanzapine, 68 remifentanil, 108 muscle stiffness deferiprone, 265

muscle twitch

lidocaine, 141 muscle weakness

botulinum toxin A, 160 bupivacaine, 143 cyclosporin a, 425 intrathecal anesthesia, 146 lidocaine, 146, 212 metrifonate, 8 mexiletine, 212 prednisone, 452 thalidomide, 171 troglitazone, 497 musculoskeletal symptom

lidocaine, 146 spinal anesthesia, 145, 146 suxamethonium, 158 mutagenesis ethylene oxide, 271 isoflurane, 129 nitrous oxide, 129 myalgia acarbose, 496 albendazole, 357 amphotericin B lipid complex, 316 cerivastatin, 512 cyclosporin a, 425 diethylcarbamazine, 357 hydroxymethylglutaryl coenzyme A reductase inhibitor, 511 immunoglobulin, 385 infliximab, 420 ivermectin, 357 lyme disease vaccine, 367 meglumine antimonate, 336 nefazodone, 17 nicotine, 546 proton pump inhibitor, 403 recombinant erythropoietin, 388

609

I n d e x o f a d v e r s e effects

simvastatin, 512 stibogluconate sodium, 336 suxamethonium, 158 troglitazone, 497

myasthenia gravis penicillamine, 266, 267 mydriasis apraclonidine, 536 bupivacaine, 151 cocaine, 150

myelitis etanercept, 420

myelodysplasia mercaptopurine, 421

myelodysplastic syndrome antineoplastic agent, 517

myelosuppression see

bone marrow suppression

myocardial infarction see

heart infarction

myocardiopathy see

cardiomyopathy

myocarditis clozapine, 62

myoelonus cisplatin, 260 clomipramine, 13 gabapentin, 86 lamotrigine, 87 lithium, 23 3,4 methylenedioxymethamphetamine, 34 opiate, 102

myopathy bezatibrate, 510 bupivacaine, 148 eye anesthesia, 148 lidocaine, 148 pravastatin, 512 simvastatin, 512

myopia diethylstilbestrol, 467

myositis bczafibrate, 5 i0

myotonia pravastatin, 512 nail disease cyclosporin a, 425 indinavir, 343, 347 retinoid, 347 zidovudine, 343

nausea abacavir, 343 alprazolam, 48 amfebutamone, 16 amlodipine, 223 amphotericin B aerosol, 315 anesthetic agent, 128 benazepril, 237 bupivacaine, 141,143, 148, 149

buspirone, 45 calcitonin, 503 captopril, 237 carbamazepine, 84 carbon dioxide, 526 cholinesterase inhibitor, 157 citalopram, 14 cocaine, 150 contrast medium, 520 cyclooxygenase 2 inhibitor, 116 deferiprone, 265 donepezil, 6 fentanyl, 105, 106, 143 fluoxetine, 14 fluvoxamine, 14 fosfomycin, 302 gadodiamide, 527 gadopentetate dimeglumine, 527 galactose microparticle, 529 gallium nitrate, 256 ganirelix, 504 granulocyte colony stimulating factor, 417, 418 hydromorphone, 106 immunoglobulin, 385 iopamidol, 524 ioxitalamic acid, 524 isoniazid, 353 itraconazole, 325 lamotrigine, 87 levobupivacaine, 143 lidocaine, 147, 148 lorazepam, 48 losartan, 240 magnesium sulfate, 224 manganese chloride, 529 metformin, 495 methadone, 106 mexiletine, 213 misoprostol, 461 morphine, 107 MS 325,528 nefazodone, 17 nicotinic acid, 446 nonsteroid antiinflarnmatory agent, 116 opiate, 100, 101, 103 oxycodone, 107 paroxetine, 14 pethidine, 107, 108 propofol, 127 pyridoxine, 447 quinine, 333 quinupristin plus dalfopristin, 301 recombinant erythropoietin, 388 remifentanil, 108 rivastigmine, 8 ropivacaine, 141,143, 148 serotonin uptake inhibitor, 14

sevoflurane, 127 simethicone coated cellulose, 529 sufentanil, 143 teicoplanin, 289 thalidomide, 172 tramadol, 109 typhoid vaccine, 373 vancomycin, 291 xenon, 526 zidovudine, 343 zolmitriptan, 230 necrotizing arteritis etanercept, 420 minocycline, 280

necrotizing vasculitis see

necrotizing arteritis

nephritis isotretinoin, 444

nephro see also kidney nephroealeinosis see kidney calcification

nephrolithiasis indinavir, 346

nephropathy see

kidney disease

nephrotic syndrome foscarnet, 340 lithium, 25 penicillamine, 266 nephrotoxicity aminoglycoside antibiotic agent, 283-285 aminosalicylic acid derivative, 406 amphotericin B colloid, 316 amphotericin B deoxycholate, 315 analgesic agent, 120 anesthetic vapor, 129 cadmium, 255 cerivastatin, 512 contrast medium, 522 cyclooxygenase 2 inhibitor, 119 cyclosporin a, 223, 424 dexfenfluramine, 5 flosulide, 123 gallium nitrate, 256 hemoglobin derivative, 384 iodixanol, 522 iohexol, 522 liposomal amphotericin B, 317 nimesulide, 123 nitric oxide, 191 nonsteroid antiinflammatory agent, 119, 121 paracetamol, 120 phenacetin, 120 platinum derivative, 260 polymyxin derivative, 300

610

sevotturane, 131 teicoplanin, 289 tsukubaenolide, 431,432 vancomycin, 289, 302 nerve block

bupivacaine, 143 ropivacaine, 148 sufentanil, 143 nerve cell vacuolization

vigabatrin, 94 nerve compression

oral contraceptive agent, 472 nerve conduction

retinoic acid, 445 nerve injury

acupuncture, 540 botulinum toxin A, 160 nervousness

serotonin uptake inhibitor, 15 tricyclic antidepressant agent, 13 neuralgia amisulpride, 61 bupivacaine, 151 neural tube defect

thalidomide, 172 neurobehavior see behavior disorder

neuroleptie syndrome

butyrophenone derivative, 179 clozapine, 63 diphenhydramine, 180 neuroleptic agent, 13, 57, 63 nortriptyline, 13 olanzapine, 68 phenothiazine derivative, 179 promethazine, 179 valproic acid, 13 neurological symptom anticonvulsive agent, 83 artemether, 331 artemisinin derivative, 331 bromocriptine, 166 cytarabine, 411 dexamethasone, 451 ethylene oxide, 271 granulocyte macrophage colony stimulating factor, 419 ot interferon, 411 Japanese encephalitis vaccine, 377 levamisole, 358 manipulative medicine, 541 mefloquine, 332 ritonavir, 347 neuromuscular blocking

aminoglycoside antibiotic agent, 283 clindamycin, 293 lincosamide derivative, 293 neomycin, 283 streptomycin, 283

Index of adverse effects

neuromuscular symptom

botulinum toxin A, 160 neuropathy

antilipemic agent, 510 cyclosporin a, 424 hydroxymethylglutaryl coenzyme A reductase inhibitor, 510 metronidazole, 335 nitrous oxide, 132 pyridoxine, 446 retinoic acid, 444 rubella vaccine, 379 sevoflurane, 130 thalidomide, 171, 172 neuropsychiatric symptom

amphetamine derivative, 2 baclofen, 160 bambuterol, 188 clarithromycin, 296 ganciclovir, 341 insulin, 487 levodopa, 166 mefloqnine, 332 3,4 methylenedioxymethamphetamine, 35 opiate, 102 xenon, 526 neurotoxicity

aluminium, 253 buflomedil, 229 bupivacaine, 141 cyclosporin a, 424 epirubicin, 362 germanium derivative, 256 infiltration anesthesia, 147 ot interferon, 412 ketamine, 135 lidocaine, 146 lithium, 23 manganese, 259 mefloquine, 332 methamphetamine, 2 3,4 methylenedioxymethamphetamine, 33-35 opiate, 102 parenteral nutrition, 396 platinum derivative, 260 polymyxin derivative, 300 ropivacaine, 141 scorpion venom, 2 spinal anesthesia, 146 suramin, 362 neurotransmision

diphenhydramine, 180 neomycin, 286 promethazine, 180 neutropenia aprindine, 210 atovaquone, 334 azathioprine, 422, 424

captopril, 237 clozapine, 61, 64, 70 epirubicin, 362 fluoxetine, 14 ganciclovir, 341 immunoglobulin, 385 levamisole, 359 olanzapine, 24, 69, 70 omeprazole, 403 paroxetine, 14 recombinant erythropoietin, 389 suramin, 362 terbinaflne, 314 thalidomide, 172 thionamide derivative, 485 vancomycin, 290 zidovudine, 343 neutrophil cytoplasmic

antibody carbimazole, 485 propylthiouracil, 485 thionamide derivative, 485 neutrophilia

granulocyte colony stimulating factor, 418 retinoic acid, 445 newborn development

amiodarone, 209 newborn hemorrhagic disease

anticonvulsive agent, 85 carbamazepine, 85 nightmare amiodarone, 197 nefazodone, 17 nonhodgkin lymphoma monoclonal antibody, 421 somatomedin, 491 nose congestion

budesonide, 193 carboxymethylcellulose, 140 ipratropium bromide, 193 nedocromil, 534 nose dryness

budesonide, 193 ipratropium bromide, 193 nose irritation budesonide, 193 desmopressin, 506 ipratropium bromide, 193 numbness see paresthesia nutritional intolerance doxapram, 3

nystagmus

amiodarone, 209 anabolic agent, 477 carbamazepine, 84 obesity neuroleptic agent, 58 valproic acid, 93, 94 obsessive compulsive disorder

I n d e x o f adverse effects

clozapine, 64 lamotrigine, 88 olanzapine, 68 risperidone, 71, 72 ocular see also eye ocular explosion eye anesthesia, 148 oculogyric crisis diamorphine, 105 oxcarbazepine, 90 oculotoxicity see eye toxicity oligomenorrhea thalidomide, 172 ophthalmoplegia carboplatin, 516 etoposide, 516 opportunistic infection see infection optic disk edema latanoprost, 461 optic neuritis see optic neuropathy optic neuropathy amiodarone, 207 carboplatin, 516 etanercept, 420 etoposide, 516 hepatitis B vaccine, 374, 375 orgasm disturbance see sexual dysfunction orthostatic hypotension captopril, 237 clozapine, 63 metrifonate, 8 monoamine oxidase inhibitor, 12 neuroleptic agent, 54 risperidone, 71 osteo see also bone osteocaicin blood level glucocorticoid, 455 hydrocortisone, 455 osteomalacia aluminium salt, 253 osteoporosis antineoplastic agent, 516 corticosteroid, 186 glucocorticoid, 455 ototoxicity aminoglycoside antibiotic agent, 283, 284 azithromycin, 296 carboplatin, 516 cisplatin, 516 gentamicin, 286 neomycin, 286 teicoplanin, 289 vancomycin, 289 ovary cancer estrogen, 469

611

fertility promoting agent, 474 hormonal replacement therapy, 469 raloxifene, 476 ovary cyst tamoxifen, 475 ovary disease thalidomide, 172 ovary failure see ovary insufficiency ovary follicle development lithium, 25 ovary hyperstimulation chorionic gonadotropin, 473 gonadorelin agonist, 503 gonadotropin, 473, 503 tamoxifen, 475 ovary insufficiency thalidomide, 172

pain albendazole, 357 carbon dioxide, 526 indinavir, 346 quinupristin plus dalfopristin, 301 retinoic acid, 445 rizatriptan, 230 teicoplanin, 290 trastuzumab, 421 palpitation s e e heart palpitation pancreas cancer caffeine, 1 cocaine, 39 pancreatitis azathioprine, 422 benazepril, 237 bezafibrate, 510 celecoxib, 119 clotiapine, 58 clozapine, 64 cotrimoxazole, 334 didanosine, 343 gadodiamide, 527 ot interferon, 414 lisinopril, 238 mesalazine, 407 nelfinavir, 347 prednisone, 454 propofol, 136 qninapril, 239 ritonavir, 346 sulfonamide, 119 thiamazole, 485 valproic acid, 94 pancytopenia etanercept, 420 methotrexate, 428 perphenazine, 58 panic alprazolam, 46 codeine, 41

olanzapine, 68 papilledema amlodipine, 223 prednisone, 452 papular skin disease methotrexate, 428 paralysis botulinum toxin A, 160 bupivacaine, 146 fluvoxamine, 14 nondepolarizing muscle relaxant agent, 157 retinoic acid, 445 spinal anesthesia, 146 paralytic ileus chlorpromazine, 62 paranoia amiodarone, 206 dextromethorphan, 104 sevoflurane, 131 paranoid psychosis amfebutamone, 16 topiramate, 93 paraplegia bupivacaine, 149 paresthesia acetazolamide, 249 contrast medium, 523 gold salt, 257 granulocyte colony stimulating factor, 418 intrathecal anesthesia, 146 lidocaine, 146, 147, 212 mepivacaine, 142 MS 325, 528 nitrous oxide, 133 propafenone, 199 pyridoxine, 447 sameridine, 145 spinal anesthesia, 146 zolmitriptan, 230 parkinson disease aluminium salt, 253 parkinsonism cinnarizine, 179 clebopride, 401 clozapine, 63 manganese, 259, 260 3,4 methylenedioxymethamphetamine, 33 neuroleptic agent, 53, 56, 57, 179 valproic acid, 34 paronychia see nail disease parotid gland swelling lidocaine, 150 parotitis thiamazole, 485 pellagra isoniazid, 353 pemphigoid

612

I n d e x o f a d v e r s e effects

PUVA, 176

pemphigus gestagen, 470 nifedipine, 225 penicillamine, 267 PUVA, 176

pemphigus foliaceus see pemphigus pemphigus vulgaris see pemphigus penis disease prostaglandin El, 460

penis erection dysfunction see

erectile dysfunction

perception deafness azithromycin, 295, 296 mefloquine, 332 metronidazole, 335 pericardial disease pergolide, 166 pericarditis bromocriptine, 167 cabergoline, 167 mesalazine, 407 periorbital edema dipyridamole, 399

peripheral edema see

edema

peripheral neuropathy neuropathy peritonitis continuous ambulatory peritoneal dialysis, 395 recombinant erythropoietin, 389 personality disorder zolpidem, 49 see

petechia immunoglobulin, 386

pharmacogenetics amoxicillin plus clavulanic acid, 276 azathioprine, 422 clozapine, 70 dextromethorphan, 104 ethylenediamine, 545 felbamate, 85 haloperidol, 60 penicillamine, 267 phenytoin, 91 procainamide, 214 thioridazine, 55

pharmaeoldnetics abacavir, 342 amikacin, 285 aminoglycoside antibiotic agent, 283, 285 amprenavir, 321 atorvastatin, 321 azole derivative, 318 benzodiazepine, 318 budesonide, 185 bupivacaine, 322

buspirone, 319 caffeine, 1 carbamazepine, 84, 319 cerivastatin, 321 cidofovir, 340 clindamycin, 294 clomipramine, 13 clonazepam, 47 clozapine, 320 corticosteroid, 185 cyclophosphamide, 320 cyclosporin a, 223, 319, 424 diamorphine, 42 diazepam, 47 digoxin, 320 diltiazem, 223 enalaprilat, 235 ethinylestradiol, 322 fluconazole, 324 fluindostatin, 321 fluticasone propionate, 185 fusidic acid, 288 gadolinium compound, 528 gadoversetamide, 527 ganciclovir, 341 glimepiride, 493 halofantrine, 320 haloperidol, 320 hydroxymethylglutaryl coenzyme A reductase inhibitor, 321 hypnosedative, 45 ibuprofen, 47 insulin, 490 insulin detemir, 490 insulin glargine, 490 isoflurane, 130 itraconazole, 320, 323 ketoconazole, 320, 321 lidocaine, 212 local anesthetic agent, 322 lorazepam, 48 mesalazine, 406 methadone, 322 methylprednisolone, 322 metrifonate, 7 mevinolin, 321 midazolam, 318 montelukast, 184 nifedipine, 225, 319 nisoldipine, 319 nordazepam, 47 norfluoxetine, 14 nuclear magnetic resonance imaging, 526 olsalazine, 406 omeprazole, 322 pravastatin, 321 quinidine, 214, 322 quinine, 333 rapacuronium bromide, 159 reboxetine, 18, 323

recombinant erythropoietin, 389 repaglinide, 494 ropivacaine, 148, 322 sevoflurane, 130 sildenafil, 231 simvastatin, 321 teicoplanin, 289 thyroxine, 484 tobramycin, 287 tolterodine, 323 triazolam, 48 tsukubaenolide, 224, 323 .verapamil, 319 zafirlukast, 184 zaleplon, 49 zidovudine, 323 zolpidem, 323

phlebitis quinupristin plus dalfopristin, 301 teicoplanin, 289 vancomycin, 289

phocomefia neuroleptic agent, 59 thalidomide, 172 photoallergy see photodermatosis

photodermatosis aciclovir, 176 disinfectant agent, 176 interferon, 341 nonsteroid antiinflammatory agent, 176 phenothiazine derivative, 176 ribavirin, 341

photophobia immunoglobulin, 385 ketotifen, 534

photosensitivity alprazolam, 46 anticonvulsive agent, 82

pigment disorder anticonvulsive agent, 82 stem cell factor, 419

Pisa syndrome neuroleptic agent, 57

pivka 2 blood level decarboxyprothrombin blood level

see

placental transfer diamorphine, 42 nondepolarizing muscle relaxant agent, 159 rapacuronium bromide, 159

pleura effusion clozapine, 65 granulocyte colony stimulating factor, 418 imrnunoglobulin,385 procainamide, 213 vinorelbine, 515

pleura fibrosis

I n d e x o f adverse effects

pergolide, 166

pneumocystis carinii pneumonia tsukubaenolide, 432

pneumonia aprindine, 210 corticotropin, 450 glibenclamide, 492 glucocorticoid, 457 methotrexate, 427 rapamycin, 430 talc, 548, 549

613

losartan, 241 magnesium sulfate, 224 meltoquine, 332 nicardipine, 224 nifedipine, 225 promethazine, 180 rapacuronium bromide, 159 somatostatin analog, 505 terfenadine, 180 zidovudine, 343

premature labor losartan, 241

pneumothorax

priapism

acupuncture, 540 fluorocarbon, 384 polyarthritis procainamide, 213 polydipsia acetazolamide, 249 polymyositis immunoglobulin, 386 interferon, 414 penicillaminc, 267 tiopronin, 268

cocaine, 38 nefazodone, 17 neuroleptic agent, 59 olanzapine, 70 prostaglandin El, 460 trazodone, 17 tsukubaenolide, 432 progressive spongiform

polyneuropathy germanium lactate citrate, 257 gold salt, 257 hepatitis B vaccine, 375 tsukubaenolide, 431 polyuria acetazolamide, 249 sevoflurane, 132

pompholyx see polymyositis porphyria hydroxychloroquine, 174 porphyria cutanea tarda hydroxymethylghitaryl coenzyme A reductase inhibitor, 511 portal hypertension hetastarch, 394 posturai hypotension see orthostatic hypotension

potassium blood level enalapril, 235 enalaprilat, 235 formoterol, 187 salmeterol, 187 suxamethonium, 158

pregnancy antihistaminic agent, 180 betamethasone, 457 caffeine, 1 chlorpheniramine, 180 cromoglycate disodium, 534 cyclophosphamide, 517 diazepam, 180 disopyramide, 211 fexofenadine, 180 fluconazole, 324 insulin, 491 lispro insulin, 491

leukoencephalopathy see

brain spongiosis

prolactin blood level domperidone, 401 metoclopramide, 401 neuroleptic agent, 53

proptosis see

exophthalmos

prostate cancer antineoplastic agent, 517

prosthesis failure cobalt, 255

protein metabolism dexamethasone, 454

proteinuria contrast medium, 522 epirubicin, 362 foscarnet, 341 gadopentetate dimeglumine, 527 /3 interferon, 416 isotretinoin, 444 ivermectin, 357 penicillamine, 266 prednisolone, 455 suramin, 362 pruritus activated prothrombin complex, 387 alprazolam, 46 benzoxonium chloride, 173 buflomedil, 229 bupivacaine, 143 captopril, 237 clonidine, 242 fentanyl, 105, 143 glyceryl trinitrate, 222 granulocyte colony stimulating factor, 418 hetastarch, 394 1,2,6 hexanetriol, 174 hydromorphone, 106

hydroxyprogesterone acetate, 456 icodextrin, 393 immunoglobulin, 386 indinavir, 347 lidocaine, 145 liposomal amphotericin B, 317 morphine, 107 opiate, 101-103 oxycodone, 107 pethidine, 107 phytomenadione, 448 prednisone, 455 prilocaine plus lidocaine, 150 quinupristin plus dalfopristin, 301 retinoic acid, 445 ropivacaine, 143 sameridine, 145 sufentanil, 109, 143 teicoplanin, 289 vancomycin, 290

pseudomembranous colitis itraconazole, 325

pseudoporphyria flutamide, 480

psoriasis lithium, 25 terbinafine, 314

psychiatric symptom see

neuropsychiatric symptom

psychomotor activity amisulpride, 61

psychomotor disorder hypnosedative, 45 topiramate, 92 triazolam, 48

psychosis amfebutamone, 16 cannabis, 67 corticosteroid, 453 dexamethasone, 453 dexamphetamine, 2 dextromethorphan, 104, 164 dextromethorphan plus pseudoephedrine, 164 dipeptidyl carboxypeptidase inhibitor, 239 levodopa, 166 methamphetamine, 2 naltrexone, 111 pindolol, 220 procainamide, 213 topiramate, 93 vigabatrin, 95

ptosis botulinum toxin A, 160 clindamycin, 294

pulmonary hypertension nitric oxide, 191, 192

purple limb syndrome phenytoin, 90

614

purpura corticosteroid, 186 thionamide derivative, 485 pustuloderma thalidomide, 172 pustulosis chromium picolinate, 255 pylorus stenosis erythromycin, 298 pyoderma gangrenosum thionamide derivative, 485 pyramidal tract disorder thalidomide, 171 QT interval see electrocardiogram change rabbit syndrome risperidone, 72 radicular irritation bupivacaine, 145 general anesthetic agent, 146 lidocaine, 143, 145 mepivacaine, 146 spinal anesthesia, 145, 146 radiculoneuropathy rubella vaccine, 379 rash abacavir, 343 allopurinol, 523 alprazolam, 48 amiodarone, 197, 206 antibiotic agent, 523 anticonvulsive agent, 82, 88 budesonide, 456 buflomedil, 229 captopril, 237 carbamazepine, 88 cibenzoline, 210 clonidine, 242 clozapine, 65 contrast medium, 522 delavirdine, 344 efavirenz, 344 erythromycin, 298 glipizide, 493 haemophilus influenzae type b vaccine, 366 Helicobacter pylori eradication therapy, 404, 405 hydrocortisone, 456 hydroxychloroquine, 174 hydroxyprogesterone acetate, 456 icodextrin, 393 indinavir, 347 infliximab, 420 interleukin 3, 417 iodinated contrast medium, 522, 523 iopamidol, 523 iopentol, 523

Index o f adverse effects

iopromide, 523 ioversol, 520 lamotrigine, 87-90 levamisole, 359 lidocaine, 150 liposomal amphotericin B, 317 lorazepam, 48 losartan, 240 measles vaccine, 377 mycophenolic acid 2 morpholinoethyl ester, 429 nystatin, 175 penicillamine, 266 phenytoin, 88 praziquantel, 360 procainamide, 213 proton pump inhibitor, 403 quinupristin plus dalfopristin, 301 somatomedin, 491 teicoplanin, 289 terbinafine, 314 tixocortol pivalate, 456 tramadol, 109 ultrasmall superparamagnetic iron oxide, 528 valproic acid, 88 vancomycin, 290 reactive oxygen species aminoglycoside antibiotic agent, 284 red man syndrome teicoplanin, 290 vancomycin, 289-291 renal see kidney respiration depression alfentanil, 104 alprazolam, 48 diazepam, 47, 84 fentanyl, 103, 106, 143 lorazepam, 48 opiate, 40, 102, 103 pethidine, 107 sufentanil, 103, 143 respiratory arrest desmopressin, 507 diazepam, 330 3,4 methylenedioxymethamphetamine, 35 oxybuprocaine, 533 phenobarbital, 330 respiratory distress alprazolam, 48 corticotropin, 450 hydrocortisone, 456 ot interferon, 411 lorazepam, 48 mesalazine, 407 methylprednisolone, 456 retinoic acid, 444

serotonin uptake inhibitor, 15 vancomycin, 291 respiratory distress syndrome dextran 1,393 dextran 40, 393 ioxaglic acid, 520 talc, 549 respiratory failure amiodarone, 206 basiliximab, 420 interleukin 2, 416 talc, 548 zidovudine, 343 respiratory tract disease dornase a, 194 ethylene oxide, 271 repaglinide, 494 respiratory tract infection etiracetam, 90 infliximab, 420 rosiglitazone, 497 sdz rad, 430 respiratory tract irritation fluticasone propionate, 189 fluticasone propionate plus salmeterol, 189 salmeterol, 189 respiratory tract symptom latanoprost, 460 restless legs syndrome neuroleptic agent, 56 olanzapine, 67 restlessness nefazodone, 17 zaleplon, 49 retina blood vessel occlusion hormonal replacement therapy, 468 retina edema cidofovir, 340 latanoprost, 461 vancomycin, 290 retina hemorrhage amikacin, 285 suramin, 362 retinoic acid syndrome arsenic trioxide, 254 retinoic acid, 254, 444, 445 retinopathy deferoxamine, 265 oxymetazoline, 164 somatomedin, 491 retrobulbar optic neuropathy see optic neuropathy retroperitoneal aneurysm rupture phentermine, 6 retroperitoneal fibrosis pergolide, 166, 167 rhabdomyolysis atorvastatin, 511 azole derivative, 511 chlorzoxazone, 511

I n d e x o f a d v e r s e effects

clomipramine, 13 cocaine, 38 fenofibrate, 510 hydroxymethylglutaryl coenzyme A reductase inhibitor, 295, 511 itraconazole, 511 ketoconazole, 511 methamphetamine, 2 3,4 methylenedioxymethamphetamine, 34 mevinolin, 511 naltrexone, 111 pravastatin, 512 sevoflurane, 132 simvastatin, 511,512 terlipressin, 7 troglitazone, 497 rhinhis azelastine, 192 budesonide, 192, 193 desmopressin, 506 ipratropium bromide, 193 ketotifen, 534 lamotrigine, 87 loratadine, 192 paracetamol, 122 pemirolast, 534 rhinorrhea

lithium, 22 measles vaccine, 377 risk situation (for side effect)

alfentanil, 104 aluminium, 254 candesartan, 240 clozapine, 65 digoxin, 201 fusidic acid, 288 granulocyte colony stimulating factor, 418 tz interferon, 414 macrolide derivative, 295 metformin, 495 oral antidiabetic agent, 492 quinupristin plus dalfopristin, 301 rapacuronium bromide, 159 risperidone, 73 suxamethonium, 158 thalidomide, 172 tobramycin, 287 tricyclic antidepressant agent, 12 zolpidem, 50 saecadie eye movement see

eye movement

sagittal sinus thrombosis

lithium, 23 sderoderma

dexfenfluramine, 5 fenfluramine, 5

615

screaming ropivacaine, 141 sedation benserazide plus levodopa, 165 bupivacaine, 143 clomethiazole, 49 clonidine, 144 clozapine, 53, 61, 63 diazepam, 47 fentanyl, 105 melatonin, 545 olanzapine, 54, 67, 68 opiate, 100, 102, 103 pethidine, 107 risperidone, 54, 73 ropivacaine, 143 sufentanil, 143 tetrabenazine, 57 thalidomide, 171, 172 tramadol, 109 triazolam, 165 seizure see

epilepsy

selenium deficiency

parenteral nutrition, 396 sensorimotor neuropathy

amantadine, 167 suramin, 362 sensorineural deafness s e e perception deafness sensory neuropathy

oxaliplatin, 515 sepsis see

bacterial infection

septic shock

hemoglobin derivative, 384 serotonin syndrome

clomipramine, 12, 13 fluvoxamine, 14 lithium, 23 perphenazine, 14 serotonin uptake inhibitor, 14 sertraline, 14 serum sickness

amfebutamone, 16 sexual behavior a adrenergic receptor blocking agent, 233 /~ adrenergic receptor blocking agent, 233 dipeptidyl carboxypeptidase inhibitor, 233 serotonin uptake inhibitor, 15 sexual dysfunction amfebutamone, 16 clozapine, 65 desogestrel, 476 fluoxetine, 15 gabapentin, 86 olanzapine, 66 risperidone, 71, 72

serotonin uptake inhibitor, 15, 16 testosterone enantate, 476 shivering

contrast medium, 523 iopromide, 523 misoprostol, 461 prilocaine plus lidocaine, 149 shock

diphtheria whole cell pertussis tetanus vaccine, 371 ioversol, 520 lidocaine, 147 poliomyelitis vaccine, inactivated, 371 sulprostone, 462 shortness of breath see

dyspnea

sialorrhea see

hypersalivation

sinoatrial block

digitalis glycoside, 199 propafenone, 199 quinidine, 199 sinus arrest

phenytoin, 91 sinus arrhythmia

sumatriptarl, 230 sinus bradycardia

amiodarone, 197, 209 dipyridamole, 398 donepezil, 7 methylprcdnisolone, 456 ropivacaine, 149 suxamethonium, 158 sinus node dysfunction lithium, 22, 23 sinus tachycardia

alteplase, 400 cocaine, 151 ephedrine, 163 lidocalne, 149 ropivacaine, 141 sinusitis

ranitidine, 402 sister ehromatid exchange

isoflurane, 129 nitrous oxide, 129 skeleton malformation

methotrexate, 429 skin allergy see

skin hypersensitivity

skin color

amiodarone, 208 levamisole, 358 zidovudine, 343 skin eruption see

rash

skin fibrosis

pentazocine, 110 skin granuloma

clodronic acid, 543 skin hypersensitivity

616

carteolol, 221 gold, 257 icodextrin, 393 lamotrigine, 88 liposomal amphotericin B, 317 local anesthetic agent, 140 nickel, 260 prilocaine plus lidocaine, 150 suramin, 362 tetracaine, 150 tropicamide, 534 zidovudine, 343 skin inflammation alprazolam, 48 lorazepam, 48 skin injury mevinolin, 511 skin irritation fluorouracil, 173 glyceryl trinitrate, 222 lidocaine, 150 skin lupus erythematosns etanercept, 420 lithium, 25 skin necrosis bupivacaine, 151 fl la interferon, 416 skin papule see papular skin disease skin pigmentation see skin color skin reaction analgesic agent, 522 androgenic agent, 478 antibiotic agent, 522 anticonvulsive agent, 82, 88 calcitonin, 503 cetirizine, 180 chickenpox vaccine, 380 clonidine, 242 contrast medium, 522, 523 diazepam, 47 diphenylpyraline, 180 diphtheria acellular pertussis tetanus vaccine, 370 ethylenediamine, 180 fluconazole, 324 fusidic acid, 288 gabapentin, 86 haemophilus influenzae type b vaccine, 366, 372 hydroxychloroquine, 174 influenza vaccine, 375, 376 iopamidol, 524 ioxitalamic acid, 524 itraconazole, 325 meloxicam, 123 meningococcus vaccine, 368, 369 nevirapine, 345 nicotine, 546

Index of adverse effects

nonsteroid antiintlammatory agent, 121,522 oxycodone, 107 pheniramine maleate, 180 pneumococcus vaccine, 372 prilocaine plus lidocaine, 150 stem cell factor, 419 sulfonamide, 119 tetracaine, 150, 151 thalidomide, 172 usnic acid, 261 zinc sulfate, 261 zolpidem, 50 skin stria indinavir, 345 skin thickness corticosteroid, 186 skin ulcer diazepam, 47 methotrexate, 428 sleep disorder alprazolam, 48 efavirenz, 344 lamotrigine, 87 lorazepam, 48 nicotine, 546 sleepiness see somnolence sneezing estradiol, 467 hypnotic agent, 149 ipratropium bromide, 193 local anesthetic agent, 149 thiopental, 149 sodium metabolism progesterone, 470 sodium retention cyclooxygenase 2 inhibitor, 118 nonsteroid antiinflanunatory agent, 118 somnolence azelastine, 192 budesonide, 192 buspirone, 45 carbamazepine, 87 clozapine, 63, 166 diazepam, 47 domperidone, 401 etiracetam, 90 hydroxyzine, 45 ketamine, 134 lamotrigine, 87 lomtadine, 192 metoclopramide, 401 olanzapine, 66, 68 oxycodone, 107 phenytoin, 87 pramipexole, 166 proton pump inhibitor, 403 risperidone, 73 rizatriptan, 230 ropinirole, 166

zaleplon, 49 ziprasidone, 74 zolmitriptan, 230 zolpidem, 49, 50 sore throat deferiprone, 265 influenza vaccine, 376 spastic diplegia ot interferon, 415 spastidty 3,4 methylene~lioxymethamphetamine, 34 speech disorder androgenic agent, 478 bupivacaine, 149 clindamycin, 294 2,5 diaminotoluene, 175 fluticasone propionate, 189 fluticasone propionate plus salmeterol, 189 glibenclamide, 492 levobupivacaine, 144 lidocaine, 147, 149 salmeterol, 189 tiagabine, 91 topiramate, 92 splenomegaly prostacyclin, 463 spotting implanted hormonal contraceptive agent, 473 Stevens Johnson syndrome anticonvulsive agent, 82, 86, 88 carbamazepine, 82, 86 erythromycin, 298 fluoxetine, 15 fluvoxamine, 15 lamotrigine, 87-89 nevirapine, 345 phenytoin, 82, 86 sertraline, 15 terbinafine, 314 stillbirth mefloquine, 332 stomach toxicity amtolmetin guacil, 122 diclofenac, 122 diflunisal, 122 flurbiprofen, 122 ibuprofen, 122 indometacin, 122 naproxen, 122 stomach ulcer cyclooxygenase 2 inhibitor, 118 stomatitis levamisole, 359 penicillamine, 266 proton pump inhibitor, 403 stroke amfebutamone, 16

617

I n d e x o f a d v e r s e effects

cocaine, 37 doxazosin, 242 manipulative medicine, 541 metformin, 495 nifedipine, 224 sulfonylurea derivative, 495 stupor digoxin, 200 stuttering clozapine, 64 lidocalne, 147 sudden deafness s e e hearing impairment sudden death amiodarone, 204, 206 amisulpride, 61 antiarrhythmic agent, 204 neuroleptic agent, 54-56 sertindole, 54 terfenadine, 179 suiddal behavior anabolic agent, 477 calcium antagonist, 222 quinapril, 238 supraventricular arrhythmia adenosine, 205 loratadine, 179 supraventricular extrasystole sevoflurane, 128 supraventricular tachyeardia amiodarone, 198 fresh frozen plasma, 384 ropivacaine, 149 swallowing disorder see dysphagia sweating fluvoxamine, 14 gadodiamide, 527 iopamidol, 524 lidocaine, 149 nateglinide, 494 Sweet syndrome retinoic acid, 445 swelling see edema syncope antiarrhythmic agent, 200 donepezil, 7 fluconazole, 324 hydroxocobalamin, 446 metrifonate, 8 synovitis chlorhexidine, 270 systemic lupus erythematosus c~ interferon, 414 systemic reaction /~ adrenergic receptor blocking agent, 220 cocaine, 152 lidocaine, 150 meningococcus vaccine, 369 mepivacaine, 142

nonsteroid antiinflammatory agent, 121 phenol, 271

tachycardia albendazole, 356 alprazolam, 46 bambuterol, 189 clozapine, 53 fluorocarbon, 384 gadopentetate dimeglumine, 527 iopamidol, 524 ioversol, 523, 524 ioxitalamic acid, 524 methylphenidate, 3 nifedipine, 225 propafenone, 199 risperidone, 53, 71 ritodrine, 222 tachyphylaxis formoterol, 187 salmeterol, 187 tachypnea clindamycin, 294 corticotropin, 450 dextran 1,393 dextran 40, 393 vinorelbine, 515 zidovudine, 343 tardive akathisia s e e akathisia tardive dyskinesia haloperidol, 68 neuroleptic agent, 54, 57 olanzapine, 68 risperidone, 72, 73 tardive dystonia s e e dystonia taste azelastine, 192 budesonide, 192 loratadine, 192 taste disorder s e e dysgeusia telangieetusia amlodipine, 223 telogen effluvium ot interferon, 414 teratogenesis anticonvulsive agent, 83 antihistaminic agent, 180 azathioprine, 423 budesonide, 458 chlorpheniramine, 180 clomiphene, 475 cyclophosphamide, 427, 517 diazepam, 180 erythromycin, 298 estrogen, 467 fertility promoting agent, 475 fexofenadine, 180 fluconazole, 324

fluoxetine, 15 gestagen, 467 lamotrigine, 89 lithium, 26 mercaptopurine, 423 methotrexate, 428 metronidazole, 335 misoprostol, 462 phenytoin, 324 promethazine, 180 retinol, 443 serotonin uptake inhibitor, 15 terfenadine, 180 thalidomide, 171,172 testis carcinoma mercaptopurine, 423 testosterone blood level eplerenone, 251 spironolactone, 251 thiamine deficiency parenteral nutrition, 395 thorax pain adenosine, 205 buprenorphine, 110 doxycycline, 279 fluorouracil, 515 granulocyte colony stimulating factor, 417 immunoglobulin,385 infliximab, 420 nifedipine, 225 quinupristin plus dalfopristin, 301 repaglinide, 494 ritodrine, 225 tobramycin, 193 troglitazone, 494 ultrasmall superparamagnetic iron oxide, 528 zolmitriptan, 230 thorax pressure adenosine, 205 losartan, 241 meglumine diatrizoate, 336 rizatriptan, 230 zolmitriptan, 231 throat irritation s e e respiratory tract irritation throat soreness see sore throat thrombocyte aggregation albumin, 383 cyclooxygenase 2 inhibitor, 118 nitric oxide, 190 thrombocytopenia albendazole, 356 atovaquone, 334 blood clotting factor 8, 387 clarithromycin, 297 desmopressin, 507 fluorocarbon, 384 fusidic acid, 288

618

granulocyte colony stimulating factor, 418 40 o (2 hydroxyethyl)rapamycin, 430 indinavir, 346 lamotrigine, 89 penicillamine, 265 prostacyclin, 463 rapamycin, 430 rifampicin, 353, 354 stibogluconate sodium, 336 suramin, 362 Taxus cuspidata, 539 tiagabine, 92 vancomycin, 290 thromboembolism activated prothrombin complex, 387 cyclooxygenase 2 inhibitor, 118 estrogen, 468 fosfestrol, 469 gestagen, 468, 470-472 hormonal replacement therapy, 468 oral contraceptive agent, 471--473 raioxifene, 467 recombinant blood clotting factor 7a, 387 thrombophlebitis amiodarone, 197, 198 blood clotting factor 7a, 387 catheter, 546 quinupristin plus dalfopristin, 301 thalidomide, 171 thrombosis catheter, 546 immunoglobulin, 385 proteinase inhibitor, 346 recombinant erythropoietin, 389 thalidomide, 171 thrombotic mieroangiopathy see thrombotic thrombocytopenic purpura thrombotic thrombocytopeulc purpura clopidogrel, 399 cyclosporin a, 425 c~ interferon, 414 pentostatin, 516 ticlopidine, 399 tsukubaenolide, 431 thyroid crisis see hyperthyroidism thyroid dysfunction arniodarone, 207, 209 thyroid hormone blood level anticonvulsive agent, 82 thyroiditis gahapentin, 86

I n d e x o f adverse effects

ot interferon, 413, 414 thyrotropin blood level lithium, 23 tia s e e transient ischemic attack tic lamotrigine, 88 methylphenidate, 3 tingling amfebutamone, 16 lidocaine, 147 pyridoxine, 447 tinnitus azithromycin, 296 lidocaine, 212 mefloquine, 332 mepivacaine, 142 metronidazole, 335 quinine, 333 tsukubaenolide, 431 tiredness s e e fatigue tissue injury aluminium, 253 pentazocine, 110 tongue disease erythromycin, 298 scorpion venom, 2 tongue ischemia ornipressin, 507 tonic clonic seizure see epilepsy tooth fracture gallium, 256 torsade des pointes arniodarone, 206, 336 dobutamine, 165 fluconazole, 324 halofantrine, 331 haloperidol, 56 meglumine diatrizoate, 336 neuroleptic agent, 54-56 sotalol, 204 thioridazine, 55 Tourette syndrome lamotrigine, 88 methylphenidate, 3 toxic epidermal necrolysis anticonvulsive agent, 82 captopril, 237 hydroxymethylglutaryl coenzyme A reductase inhibitor, 511 lamoUigine, 88, 89 nevirapine, 345 terbinafine, 314 thalidomide, 172 zidovudine, 343 transaminase increase s e e aminotransferase blood level transient isehemic attack amfebutamone, 16

cocaine, 37 transitional blindness see blindness tremor amfebutamone, 16 bambuterol, 188, 189 citaiopram, 14 clomipramine, 13 fluoxetine, 14 fluticasone propionate, 189 fluticasone propionate plus salmeterol, 189 fluvoxamine, 14 formoterol, 187 ioversol, 520 lamotrigine, 90 mexiletine, 213 nateglinide, 494 paroxetine, 14 dsperidone, 54, 72 salmeterol, 187-189 serotonin uptake inhibitor, 14 sertraline, 14 tiagabine, 91 valproic acid, 90 tremulousness see tremor triglyceride blood level olanzapine, 69 retinoic acid, 444 ritonavir, 345, 346 stavudine, 342 zidovudine, 342 tumor lysis syndrome see lymphoproliferative disease ulcerative colitis zafirlukast, 184 unconsciousness clonidine, 142 contrast medium, 521 2,5 diaminotoluene, 175 donepezil, 7 insulin, 487 iopromide, 523 mepivacaine, 142 minoxidil, 243 neuroleptic agent, 13 oxybuprocaine, 533 prilocaine, 147 ropivacaine, 141 urea nitrogen blood level clarithromycin, 297 uremia spironolactone, 246 urinary tract cancer analgesic agent, 121 urinary tract disease cyclophosphamide, 427 urinary tract stone s e e urolithiasis urine incontinence

I n d e x o f a d v e r s e effects

clozapine, 64 donepezil, 7 lidocaine, 146 spinal anesthesia, 146 urine retention mepivacaine, 146 morphine, 107 spinal anesthesia, 145 urolithiasis ephedrine, 164 guaifenesin, 164 indinavir, 346, 347 urothelium carcinoma see urinary tract cancer urticaria albendazole, 356 amfebutamone, 17 anticonvulsive agent, 82 basiliximab, 420 buflomedil, 229 chloroprocaine, 148 cocaine, 38, 39 contrast medium, 522 Echinacea, 538 erythromycin, 298 hair dye, 175 hydroxychloroquine, 174 immunoglobulin, 386 infliximab, 420 ioversol, 524 lidocaine, 140, 148 losartan, 241 mebendazole, 356 methylprednisolone, 456 polygeline, 394 rifampicin, 176 rifamycin, 176 stem cell factor, 419 vancomycin, 291 uterine cervix ectropion diethylstilbestrol, 467 uterus bleeding misoprostol, 461 uterus cancer tamoxifen, 476 uterus contractility propofol, 127 sevoflurane, 127 uterus contraction disopyramide, 211 uterus hyperstimulation misoprostol, 461 uterus rupture misoprostol, 461,462 oxytocin, 506 prostaglandin E2, 460 uveitis cidofovir, 340 influenza vaccine, 376 vagina bleeding tibolone, 480 vagina discharge

619

diethylstilbestrol, 467 vaginitis fosfomycin, 302 vascular disease cyclooxygenase 2 inhibitor, 119 vascular leak syndrome see capillary leak syndrome vasculitis antihuman immunodeficiency virus agent, 342 carbimazole, 485 cocaine, 38 diazepam, 47, 133 hepatitis B vaccine, 421 ketamine, 135 leukotriene receptor blocking agent, 183 levamisole, 360 propylthiouracil, 485 retinoic acid, 445 thionamide derivative, 485 vasoconstriction cocaine, 37, 38 triptan derivative, 229 vasodilatation antihistaminic agent, 534 decongestive agent, 534 xenon, 526 vasospasm catheter, 547 ergometrine, 230 fusidic acid, 288 immunoglobulin, 385 sumatriptan, 230 vein thrombosis activated prothrombin complex, 387 gestagen, 470, 471 glucocorticosteroid, 452 hormonal replacement therapy, 468 methylprednisolone, 452 oral contraceptive agent, 471, 472 vertigo adenosine, 205 albendazole, 356 alprazolam, 48 anabolic agent, 477 ketamine, 135 lidocaine, 147, t48, 150 lorazepam, 48 mebendazole, 356 mepivacaine, 142 misoprostol, 461 praziquantel, 361 risperidone, 71 ropivacaine, 148 zolpidem, 50 vestibular disorder aminoglycoside antibiotic agent, 284

gentamicin, 286 streptomycin, 283 vibroacoustic startle reflex betamethasone, 457 vigilance see alertness violence anabolic agent, 477 virilization androgenic agent, 478 virus infection acupuncture, 540 albumin, 383 immunoglobulin, 386 virus transmission albumin, 383 blood clotting factor 8, 388 blood transfusion, 330 immunoglobulin, 386 poliomyelitis vaccine, 378, 379 vision disturbance see visual disorder vision loss see visual impairment visual acuity carboplatin, 516 deferoxamine, 265 dexamethasone, 535 etoposide, 516 lidocaine, 140 visual disorder clomiphene, 475 corticosteroid, 535 deferoxamine, 265 dexamethasone, 535 ephedrine, 163 ethylene oxide, 271 protirelin, 506 retinoic acid, 445 zaleplon, 49 visual field defect vigabatrin, 95 visual hallucination contrast medium, 521 dexamethasone, 453 iopromide, 521 procainamide, 213 recombinant erythropoietin, 389 visual impairment corticosteroid, 535 prednisone, 452 vitamin blood level nitrous oxide, 132 vitamin metabolism anticonvulsive agent, 85 carbamazepine, 85 vitiligo tolcapone, 168 vivid dreams see dreaming vocal cord paralysis

620 cisplatin, 260 etoposide, 260 voice disorder

androgenic agent, 478 vomiting

abacavir, 343 activated carbon, 405 alprazolam, 48 anesthetic agent, 128 benazepril, 237 hupivacaine, 141, 143, 148, 149 captopril, 237 cholinesterase inhibitor, 157 cocaine, 150 2,5 diaminotohiene, 175 donepezil, 6 doxapram, 3 fluconazole, 324 gadodiamide, 527 galactose microparticle, 529 gallium nitrate, 256 granulocyte colony stimulating factor, 417, 418 hydromorphone, 106 immunoglobulin, 385 iopamidol, 524 ioversol, 520 ioxitalamic acid, 524 itraconazole, 325 lamotrigine, 87 levobupivacaine, 143 lidocaine, 148 lisinopril, 238 lorazepam, 48 losartan, 240 magnesium sulfate, 224 methadone, 106 midazolam, 134 misoprostol, 461 morphine, 107 mycophenolic acid 2 morpholinoethyl ester, 429 nefazodone, 17 nicotinic acid, 446 opiate, 100, 101, 103, 134 oxycodone, 107 pethidine, 107, 109

Index of adverse effects

picosulfate sodium, 406 polyene derivative, 324 prednisone, 455 quinupristin plus dalfopristin, 301 recombinant erythropoietin, 388 retinoic acid, 444 retinol, 443, 444 rivastigmine, 8 ropivacaine, 141,143, 148 spinal anesthesia, 144 sufentanil, 143 tramadol, 109 xenon, 526 zidovudine, 343 von Willebrand disease

hetastarch, 394 warmth feeling see heat sensation water intoxication

3,4 methylenedioxymethamphetamine, 35 water retention

cyclooxygenase 2 inhibitor, 118 nonsteroid antiinflammatory agent, 118 weakness

abacavir, 343 acarbose, 496 alprazolam, 46 cibenzoline, 210 clindamycin, 293 clomipramine, 13 prilocaine plus lidocaine, 149 retinoic acid, 445 rizatriptan, 230 tiagabine, 91 trecovirsen, 345 venlafaxine, 19 zaleplon, 49 zolmitriptan, 230 zolpidem, 49 weight gain

amisulpride, 54, 61

clozapine, 53, 58, 61 haloperidol, 69 implanted hormonal contraceptive agent, 473 lithium, 24 medroxyprogesterone acetate, 473 neuroleptic agent, 58 olanzapine, 66-69 perphenazine, 24 pioglitazone, 496 repaglinide, 494 retinoic acid, 444 .risperidone, 53, 54, 69, 71, 73 rosiglitazone, 496, 497 thalidomide, 172 thiazolidinedione derivative, 496 troglitazone, 494, 496 valproate semisodium, 24 valproic acid, 93, 94 weight reduction

barium sulfate, 525 cytarabine, 411 ot interferon, 411 wheezing

contrast medium, 523 ioversol, 524 prilocaine plus lidocaine, 149 tobramycin, 193 withdrawal syndrome

buprenorphine, 110 opiate, 110 xerostomia

clozapine, 61 olanzapine, 68 oxybutynin, 168 retinoic acid, 445 risperidone, 53 thalidomide, 172 tiotropium bromide, 189 tolterodine, 168 tramadol, 109 tropisetron, 402 zolmitriptan, 230

Side Effects of Drugs Annual 24, Volume 24: A world-wide survey of new data and trends in adverse drug reactions

Side Effects of Drugs Annual, Volume 31: A worldwide yearly survey of new data and trends in adverse drug reactions

Side Effects of Drugs Annual, Volume 32: A worldwide yearly survey of new data and trends in adverse drug reactions

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 30, Volume 30: A worldwide yearly survey of new data and trends in adverse drug reactions (Side Effects of Drugs Annual)

Side Effects of Drugs Annual, Volume 33: A worldwide yearly survey of new data in adverse drug reactions

Side Effects of Drugs Annual 29, Volume 29: A worldwide yearly survey of new data and trends in adverse drug reactions

Side Effects of Drugs Annual 25, Volume 25: A world-wide survey of new data and trends in adverse drug reactions

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

Side Effects Of Drugs Annual 27 (Side Effects of Drugs Annual)

Side Effects of Drugs Annual 23

Stephens' Detection of New Adverse Drug Reactions

Adverse Drug Reactions

Annual Review of Immunology Volume 24 2006

ADVANCES IN GENETICS VOLUME 24, Volume 24

ADVANCES IN IMMUNOLOGY VOLUME 24, Volume 24 (v. 24)

Meyler's Side Effects of Cardiovascular Drugs (Meylers Side Effects)

Adverse Drug Effects: A Nursing Concern

Handbook of Statistics, Volume 24: Data Mining and Data Visualization

Meyler's Side Effects of Endocrine and Metabolic Drugs (Meyler's Side Effects of Drugs)

Meyler s Side Effects of Psychiatric Drugs

Analytical Profiles of Drug Substances and Excipients Volume 24

Anaphora and Type Logical Grammar (Trends in Logic, Volume 24)

Adverse Drug Reactions (Handbook of Experimental Pharmacology Vol 196)

A Guide to the Extrapyramidal Side Effects of Antipsychotic Drugs

A Guide to the Extrapyramidal Side Effects of Antipsychotic Drugs

A Guide to the Extrapyramidal Side Effects of Antipsychotic Drugs

A Guide to the Extrapyramidal Side Effects of Antipsychotic Drugs

Advances in Agronomy, Volume 24

Handbook of Statistics 24: Data Mining and Data Visualization

24

Side Effects of Drugs Annual 24, Volume 24: A world-wide survey of new data and trends in adverse drug reactions

Side Effects of Drugs Annual, Volume 31: A worldwide yearly survey of new data and trends in adverse drug reactions

Side Effects of Drugs Annual, Volume 32: A worldwide yearly survey of new data and trends in adverse drug reactions

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 30, Volume 30: A worldwide yearly survey of new data and trends in adverse drug reactions (Side Effects of Drugs Annual)

Side Effects of Drugs Annual, Volume 33: A worldwide yearly survey of new data in adverse drug reactions

Side Effects of Drugs Annual 29, Volume 29: A worldwide yearly survey of new data and trends in adverse drug reactions

Side Effects of Drugs Annual 25, Volume 25: A world-wide survey of new data and trends in adverse drug reactions

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

Side Effects Of Drugs Annual 27 (Side Effects of Drugs Annual)

Side Effects of Drugs Annual 23

Stephens' Detection of New Adverse Drug Reactions

Adverse Drug Reactions

Annual Review of Immunology Volume 24 2006

ADVANCES IN GENETICS VOLUME 24, Volume 24

ADVANCES IN IMMUNOLOGY VOLUME 24, Volume 24 (v. 24)

Meyler's Side Effects of Cardiovascular Drugs (Meylers Side Effects)

Adverse Drug Effects: A Nursing Concern

Handbook of Statistics, Volume 24: Data Mining and Data Visualization

Meyler's Side Effects of Endocrine and Metabolic Drugs (Meyler's Side Effects of Drugs)

Meyler s Side Effects of Psychiatric Drugs

Analytical Profiles of Drug Substances and Excipients Volume 24

Anaphora and Type Logical Grammar (Trends in Logic, Volume 24)

Adverse Drug Reactions (Handbook of Experimental Pharmacology Vol 196)

A Guide to the Extrapyramidal Side Effects of Antipsychotic Drugs

A Guide to the Extrapyramidal Side Effects of Antipsychotic Drugs

A Guide to the Extrapyramidal Side Effects of Antipsychotic Drugs

A Guide to the Extrapyramidal Side Effects of Antipsychotic Drugs

Advances in Agronomy, Volume 24

Handbook of Statistics 24: Data Mining and Data Visualization

24

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