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 31 A worldwide yearly survey of new data and trends in adverse drug reactions and interactions EDITOR

J. K. ARONSON MA, DPhil, MBChB, FRCP, FBPharmacolS, FFPM (Hon) Reader in Clinical Pharmacology University Department of Primary Health Care Rosemary Rue Building, Old Road Campus, Headington, Oxford OX3 7LF, UK

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Contributors R.J. ALI, BMEDSCI (HONS), BMBS, MRCP Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall, TR1 3LJ, UK. E-mail: [email protected] M.C. ALLWOOD, BPHARM, PHD Pharmacy Academic Practice Unit, School of Biological, Forensic and Pharmaceutical Sciences, University of Derby, Mickleover, Derby, UK. E-mail: [email protected] BRIAN J. ANGUS, MD Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. E-mail: [email protected] J.K. ARONSON, MA, DPHIL, MBCHB, FRCP, FBPHARMACOLS, FFPM(HON) University Department of Primary Health Care, Rosemary Rue Building, Old Road Campus, Headington, Oxford OX3 7LF, UK. E-mail: [email protected] I. AURSNES, MD University of Oslo, Department of Pharmacotherapeutics, PO Box 1065 Blindern, N­ 0316 Oslo, Norway. E-mail: [email protected] PATRICK A. BALL, PHD Charles Sturt University, Correspondence Locked Bag 588, Wagga Wagga, New South Wales 2678, Australia. E-mail: [email protected] V.V. BANU REKHA, MBBS Tuberculosis Research Centre, Mayor VR Ramanathan Road, Chetpet, Chennai 600031, India. E-mail: [email protected] M. BEHREND, MD, PHD Klinik für Viszeral-, GefäX-, Thorax- und Kinderchirurgie, Klinikum Deggendorf, Perlasberger Str. 41, D-94469 Deggendorf, Germany. E-mail: matthias.behrend@klini­ kum-deggendorf.de STEFAN BEYENBURG, MD Service de Neurologie, Centre Hospitalier de Luxembourg, 4 rue Barblé, L-1210 Luxembourg. E-mail: [email protected] KRISTIEN BOELAERT, MRCP, PHD Division of Medical Sciences, IBR Building 2nd floor, The Medical School, University of Birmingham, Birmingham B15 2TT, UK. E-mail: [email protected]

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Contributors

FELIX BRAUN, MD Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Zentrum Chirurgie, Universität Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 7, 24105 Kiel, Germany. E-mail: [email protected] DIETER C. BROERING, MD Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Zentrum Chirurgie, Universität Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 7, 24105 Kiel, Germany. E-mail: [email protected] T.F. BUTT, MBCHB, MRCP(UK) Department of Clinical Pharmacology, Division of Medical Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail: [email protected] ANDREW BYRNE, BA, MB, BCH, BAO, MRCPSYCH, DIPMEDSC Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe Lane, Wakefield WF1 3SP, UK. E-mail: [email protected] ALFONSO CARVAJAL, MD, PHD Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. Email: [email protected] J.A. CENTENO, PHD, FRSC Division of Biophysical Toxicology, Department of Environmental & Infectious Disease Sciences, Armed Forces Institute of Pathology, Building 54, 14th Street & Alaska Avenue NW, Washington, DC 20306-6000, USA. E-mail: Centeno@afip.osd.mil K. CHAN, PHD, DSC, FIBIOL, FCP, FRPHARMS, FRSM Research Institute in Healthcare Sciences, School of Applied Sciences, Universities of Wolverhampton, Wulfruna Street, Wolverhampton WV1 1LY, UK. E-mail: prof. [email protected] N.H. CHOULIS, MD, PHD LAVIPHARM Research Laboratories, Agias Marinas Street, 19002 Peania, Attika, Greece. E-mail: [email protected] J.J. COLEMAN, MBCHB, MRCP(UK) Department of Clinical Pharmacology, Division of Medical Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail: [email protected] NATASCIA CORTI, MD University Hospital Zurich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: [email protected] J. COSTA, MD Clinical Pharmacology Department, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Ctra. de Canyet s/n, 08916 Badalona, Spain. E-mail: [email protected] P.J. COWEN, MD University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK. E-mail: [email protected]

Contributors

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STEPHEN CURRAN, BSC, MBCHB, MMEDSC, MRCPSYCH, PHD Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe Lane, Wakefield WF1 3SP, UK. E-mail: [email protected] H.R. DALTON, BSC, DPHIL, FRCP, DIPMEDED Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall TR1 3LJ, UK. E-mail: [email protected] S. DITTMANN, MD, DSCMED 19 Hatzenporter Weg, 12681 Berlin, Germany. E-mail: sd.internat.immun.consult@t­ online.de IDA DUARTE Santa Casa de São Paulo Medical School, Sao Paulo, Brazil. E-mail: idaduarte@terra. com.br M.N.G. DUKES, MD, MA, LLM Trosterudveien 19, 0778 Oslo, Norway. E-mail: [email protected] RIF S. EL-MALLAKH, MD Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, MedCenter One, 501E Broadway, Suite 340, Louisville, Kentucky 40202, USA. E-mail: [email protected] M. FARRÉ, MD Unitat de Farmacologia, Institut Municipal d’Investigació Mèdica (IMIM)-Hospital del Mar, Universitat Autònoma de Barcelona, Doctor Aiguader 88, 08003 Barcelona, Spain. E-mail: [email protected] M.G. FRANZOSI, PHD Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche “Mario Negri”, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] CATHERINE FULLER, MBBS(HONS) Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, WA 6847, Australia. E-mail: [email protected] SUE GALEA, MD, MRCPSYCH, MSC (ADDICTIVE BEHAVIOUR), DIP (FORENSIC MENTAL HEALTH) Centre for Addiction Studies, St George’s Hospital Medical School, 6th Floor, Hunter Wing, Cranmer Terrace, London SW17 0RE, UK. E-mail: [email protected] A.H. GHODSE, MD, PHD, FRCP, FRCPSYCH Centre for Addiction Studies, St George’s Hospital Medical School, 6th Floor, Hunter Wing, Cranmer Terrace, London SW17 0RE, UK. E-mail: [email protected] FREYA A. GOUMAS, MD Department of Hepatobiliary Surgery and Solid Organ Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany SARAH GUZOFSKI, MD University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation Street, Worcester, MA 01605, USA. E-mail: [email protected]

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Contributors

JOB HARENBERG, MD Vascular Therapeutics, Institute of Experimental and Clinical Pharmacology, Faculty of Medicine, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany. E-mail: [email protected] J.T. HARTMANN, PHD, MD Department of Hematology/Oncology/Immunology/Rheumatology/Pneumology, Eberhard Karls University Tübingen, UKT-Medical Center II, Department of Hematology, Oncology, Immunology, Rheumatology, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany. E-mail: [email protected] KATHARINA HARTMANN, MSCPHARM Berna Biotech Ltd, 3000 Berne, Switzerland. E-mail: [email protected] ALEXANDER IMHOF, MD University Hospital Zurich, Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail: [email protected] NATALIA JIMENO, MD, PHD Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. E-mail: [email protected] MARKUS JOERGER, MD Department of Oncology and Hematology, Kantonsspital, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland. E-mail: [email protected] CLARISSE KOBATA, MD Clinic of Dermatology, Santa Casa de São Paulo, São Paulo, Brazil. OLIVER KOCH Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. E-mail: [email protected] MAX KUHN, MD Department of Internal Medicine, Division of Pneumology, Kantonsspital, Loestrasse 170, 7000 Chur, Switzerland. E-mail: [email protected] R. LATINI, MD Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche “Mario Negri”, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] JOSHUA H.P. LAU, BMEDSCI (HONS I), MBBS Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, WA 6847, Australia. E-mail: [email protected] ROSANA LAZZARINI, MD Santa Casa de São Paulo Medical School, São Paulo, Brazil. E-mail: lazzarini@fototerapia. com.br MARTIN LEUWER, MD School of Clinical Science, University of Liverpool, The Duncan Building, Daulby Street, Liverpool L69 3GA, UK. E-mail: [email protected]

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T.X. LIN, MB, MSC Division of Basic Medical Institute, 103#, Beijing University of Traditional Chinese Medicine & Pharmacology, Beisanhuandonglu, No.11, Chaoyang District, Beijing 100029, PR China. E-mail: [email protected] H.-P. LIPP, PHD Eberhard-Karls-University Tübingen, Department of Clinical Pharmacy, Röntgenweg 9, 72076 Tübingen, Germany. E-mail: [email protected] P. MAGEE, BSC, MSC, MRPHARMS University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UK. E-mail: [email protected] A.P. MAGGIONI, MD Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche “Mario Negri”, Via Eritrea 62, 20157 Milan, Italy. E-mail: [email protected] LUIS H. MARTÍN ARIAS, MD, PHD Instituto de Farmacoepidemiología, Facultad de Medicina, 47005 Valladolid, Spain. Email: [email protected] R.H.B. MEYBOOM, MD, PHD Department of Pharmacoepidemiology and Pharmacotherapy, Faculty of Pharmacy, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands. E-mail: [email protected] T. MIDTVEDT, MD, PHD Laboratory of Medical Microbial Ecology, Von Eulers v. 5, Karolinska Institutet, Box 60 400, S-171 77 Stockholm, Sweden. E-mail: [email protected] SAMEH K. MORCOS, FRCS, FFRRCSI, FRCR Department of Diagnostic Imaging, Northern General Hospital, Sheffield Teaching Hospitals (NHS) Trust, Sheffield S5 7AU, UK. E-mail: [email protected] SHABIR MUSA, MBCHB, MRCPSYCH Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe Lane, Wakefield WF1 3SP, UK. E-mail: [email protected] R.C.L. PAGE, MD, FRCP, MA(ED) Endocrine Unit, Dundee House, City Hospital, Hucknall Road, Nottingham NG5 1PB. E-mail: [email protected] JAYENDRA K. PATEL, MD University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation Street, Worcester, MA 01605, USA. E-mail: [email protected] ANITA ROTTER, MD Clinic of Dermatology, Santa Casa de São Paulo, São Paulo, Brazil DIETER SCHMIDT, MD Epilepsy Research Group Berlin, Goethestrasse 5, D-14163 Berlin, Germany. E-mail: [email protected]

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Contributors

J.S.A.G. SCHOUTEN, MD Department of Ophthalmology, Maastricht University Hospital, PO Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail: [email protected] STEPHAN A. SCHUG, MD, FANZCA, FFPMANZCA Level 2, MRF Building G Block, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. E-mail: [email protected] R.P. SEQUEIRA, PHD, FCP Department of Pharmacology & Therapeutics, College of Medicine & Medical Sciences, Arabian Gulf University, PO Box 22979, Manama, Bahrain. E-mail: [email protected] ROBERT SERAFINO Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. E-mail: robert.serafi[email protected] SUSANNE SHEEHY Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. E-mail: [email protected] OSCAR OZMUND SIMOOYA, BSC, MBCHB, MSC The Copper Belt University, Health Services Division, PO Box 21692, Kitwe, Zambia, Central Africa. E-mail: [email protected] P.F.W. STRENGERS, MD Sanquin CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: p. [email protected] SOUMYA SWAMINATHAN, MD Tuberculosis Research Centre, Mayor VR Ramanathan Road, Chetpet, Chennai 600031, India. E-mail: [email protected] GIJSBERT B. VAN DER VOET, PHD, ERT Toxicology Laboratory, Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Building 1, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail: Gijsbert.VanderVoet@afip.osd.mil P.J.J. VAN GENDEREN, MD, PHD Havenziekenhuis and Institute of Tropical Diseases, Department of Internal Medicine, Harbour Hospital, Haringvliet 2, 3011 TD Rotterdam, The Netherlands. E-mail: p.van. [email protected] E. VAN TWUIJVER, PHD Sanquin CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected] R. VERHAEGHE, MD Center for Vascular Diseases, University of Leuven, Herestraat, 49, 3000 Leuven, Belgium. E-mail: [email protected] P. VERHAMME, MD Center for Vascular Diseases, University of Leuven, Herestraat, 49, 3000 Leuven, Belgium. E-mail: [email protected]

Contributors

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G.M. WALSH, MSC, PHD School of Medicine, Institute of Medical Sciences Building, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. E-mail: [email protected] INGEBORG WELTERS, MD, PHD School of Clinical Science, University of Liverpool, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. E-mail: [email protected] EILEEN J. WONG, MD Harvard Medical School, Massachusetts Mental Health Center, Department of Psychiatry, Jamaica Plain, MA 02130, USA. E-mail: [email protected] OLIVER ZUZAN, MD Department of Anaesthesia, 12th Floor, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK. E-mail: [email protected]

Special reviews Effects of stimulant treatment on growth in children and adolescents with ADHD Adverse effects of methylphenidate at different ages SSRIs and sucide Psilocybin Aripiprazole Safety of codeine during breast-feeding Aspirin-exacerbated respiratory disease Rasburicase Lipid rescue for local anesthetic toxicity Rocuronium hypersensitivity reactions—the link to pholcodine Myocardial infarction and other vasospastic effects of adrenaline The relation between Parkinson’s disease, levodopa therapy, and malignant melanoma Rasagiline Anticholinergic adverse effects of newer anticholinergic drugs Drug overdose with doxylamine and rhabdomyolysis The effects of inhaled glucocorticoids on hypothalamic–pituitary–adrenal axis function Inhaled glucocorticoids and the risk of fracture Respiratory adverse effects of long-acting beta2-adrenoceptor agonists Genetic susceptibility factors with the therapeutic use of long-acting beta2-adrenoceptor agonists Management of amiodarone-induced thyrotoxicosis Angioedema due to ACE inhibitors Non-cardiogenic pulmonary edema due to hydrochlorothiazide Tumorigenicity of aluminium Combining iron chelators Resistance to antibacterial drugs Tetracyclines, chemically-modified tetracyclines, and their non-antimicrobial properties Drug–drug interactions with antifungal azoles Hepatotoxicity of antituberculosis drugs Newer drugs for tuberculosis The Mazzotti reaction Vaccines and Guillain–Barré syndrome Vaccines and autism Rotavirus vaccine and Kawasaki disease Infection risk from antagonists of TNF-a Genetic susceptibility factors for thiopurine toxicity Phytoestrogens in foodstuffs Possible transgenerational effects of diethylstilbestrol Cardiovascular adverse effects of hormone replacement therapy Risk of adverse cardiovascular effects in patients taking thiazolidinediones DNA alkylating N-Lost derivatives Contrast medium-induced nephrotoxicity Gadolinium-based contrast agents and nephrogenic systemic fibrosis Alcohol Latex allergy

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4 6 18 49 70 154 193 203 231 249 259 267 270 273 298 305 307 309 310 327 352 373 383 399 413 419 459 495 500 507 515 516 522 594 634 655 657 659 697 721 731 735 757 761

Cumulative indexes of special reviews, Annuals 12–30 Index of drugs Note: the format 29.460 refers to SEDA-29, p. 460. Abetimus, drug development, 29.460 ACE inhibitors acetylsalicylic acid, interaction, 28.124 angioedema, 22.225, 29.207 cough, 19.211 indications, 24.233 Acetaminophen, see Paracetamol Acetylsalicylic acid, 21.100 ACE inhibitors, interaction, 28.124 antithrombotic effectiveness, 12.74 benefit to harm balance in preventing strokes and heart attacks, 27.109 co-medication, 26.423 gastrointestinal effects, 17.95, 18.90 Reye's syndrome, 15.85 rhinosinusitis/asthma, 17.94 sensitivity, 12.75 Acupuncture incidence of adverse effects, 29.589 traumatic effects, 29.590 Aerosols, delivery, 27.172 Albumin, human, anaphylaxis, 14.296 Alcohol, vitamin A, beta-carotene, interaction, 24.442 Aldosterone antagonists, in heart failure, 24.246 Aluminium in albumin solutions, 23.359 toxicity in children, 12.185 Aminoglycoside antibiotics, 17.304 contact dermatitis, 13.225 dosage regimens, 20.234, 21.265, 23.264 nephrotoxicity, 15.268, 17.305 ototoxicity, 14.222, 18.268 and ribostamycin, 15.270 Amiodarone, dysrhythmias, 25.211 respiratory toxicity, 15.168 thyroid disease, 27.192 Amphetamines, 29.3 Amphotericin, liposomal, 17.319 nephrotoxicity, 13. 231, 14.229, 27.276 Anabolic steroids, abuse in sport, 29.508

Analgesics choice of drug and dose, 12.63 headache, 21.95 headaches in children, 23.114 nephropathy, 21.98 Androgens, in women, 24.477 Anesthesia, dental, safety of, 16.122 Anesthetics halogenated, renal damage, 20.106 local, combinations, 20.121 local, neurotoxicity, 21.129, 25.152 ocular, 17.542 Angiotensin II receptor antagonists, angioedema 31.238 Anisoylated plasminogen-streptokinase activator complex (APSAC), 12.313 Anorectic drugs cardiac valvulopathy 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Anthracyclines, 25.533 Anticancer antimetabolites, 29.531 Anticholinergic drugs, 22.507 Anticoagulants, oral, skin necrosis, 29.358 Anticonvulsants, see Antiepileptic drugs Anti-D prophylaxis, hemolytic disease of the newborn, 31.293 Antidepressants, see also individual agents during and after pregnancy, 21.17 mania, 29.18 overdose, 28.14 Antidysrhythmic drugs in atrial fibrillation, 24.197 prodysrhythmic effects, 17.218, 23.196 Antiepileptic drugs bone loss, 27.74 comparison, 25.78 death, 23.83 overdosage, 22.84 psychiatric effects, 22.82, 27.72 Antiestrogens, genotoxicity and tumorigenicity, 27.429

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Cumulative indexes of special reviews, Annuals 12–30

Antifungal drugs drug interactions (azoles), 24.318, 28.299, 29.282, 31.320 Pneumocystis jiroveci (carinii) pneumonia, 18.289 Antihistamines cardiovascular adverse effects, 17.196, 22.176, 25.183, 26.180 drowsiness/sedation, 21.170, 23.171, 26.182 Antihypertensive drugs, 19.209 in diabetes mellitus, 28.226 fixed-dose combinations, 22.224 individualizing therapy, 17.246 Antimalarial drugs, 14.237, 17.325, 20.257 adjunctive treatments, 24.330 prophylaxis, 13.239, 23.304 Antimicrobial drugs allergic reactions, 23.251 coagulation disorders, 18.258 colitis, 12.216, 17.303 intestinal motility, 13.220 male fertility, 16.262 new, 13.210 new, with adjuvants, 17.296 the pill and pregnancy, 24, 274 policies and politics, 16.273 prescribing, 15.254 preterm infants, 21.258 prudent use, 25.279 , 27.242, 28. 265 resistance, 12.206, 13.210, 19.237, 20.228, 21.257, 22.265, 23.250, 24.273, 29.244 seizures, 18.261 side chains, 16.264 Antioxidant vitamins, 20.363 Antiprotozoal drugs African trypanosomiasis, 18.293 toxoplasmosis, 20.262 Antipsychotic drugs comparisons of different types 25.53, 27.50 diabetes mellitus, 28.60 use in conditions other than schizophrenia, 27.49 use in elderly patients, 31.59 weight gain, 26.56 Antiretroviral drugs, metabolic complications, 28.329 Antischistosomal drugs, 12.261 Antithyroid drugs, pregnancy, 13.377 Antituberculosis drugs, 16.341 genetic susceptibility, 28.342 liver damage, 25.363, 26.339 Mycobacterium avium–complex infection, 20.278 Appetite suppressants cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Aspirin, see Acetylsalicylic acid Asthmamedications,exacerbationofasthma,20.165 Atovaquone, 19.266

Avoparcin lessons from, 27.242 resistance, 29.244 Azoles, see Antifungal drugs Baclofen, withdrawal syndrome, 26.152 Bambuterol, cardiac failure, 23.181 Benzodiazepines brain damage, 14.36 dependence, 12.41 depression, 17.43 medicolegal aspects, 13.33 Beta2-adrenoceptor agonists, 18.159 asthma, 19.178, 21.179 asthma deaths, 17.164 long-acting, respiratory adverse effects, 31.198 long-acting, genetic susceptibility factors, 31.199 Beta-adrenoceptor antagonists, sexual function, 15.188 Beta-carotene, see also Vitamin A alcohol, vitamin A, interaction, 24.442 tumorigenicity, 25.454 Beta-lactam antibiotics effects on eukaryotic cells, 13.212 immediate hypersensitivity reactions, 14.211 pregnancy, 25.280 Blood, see Transfusions Botulinum toxin A, use in primary axillary hyperhidrosis, 27.161 Budesonide, children, susceptibility factors, 31.194 Calcium antagonists, long-term safety, 20.185, 21.208, 22.214 Carnitine, 13.269 Carotenoids, tumorigenicity, 25.454 Ceftriaxone, 15.258 nephrolithiasis, 29.246 Cephalosporins immunological reactions, 28.267 hypersensitivity reactions, cross-reactivity with penicillins, 31.280 and vitamin K, 12.210 Charcoal, activated, in digitalis overdose, 24.201 Chloramphenicol, children, 15.267 Chloroquine, 15.286 Chondroprotective agents, 14.439 Chymopapain, 14.264 Ciclesonide, 31.196 Ciclosporin, urinary system, 19.348 Clozapine, 15.50 agranulocytosis, 22.1359 Cocaine cardiovascular effects, 18.5 fetotoxicity, 29.41, 31.35 prenatal exposure and perinatal effects, 27.1 second-generation effects, 20.24 Cocamidopropylbetaine, allergy, 19.151

Cumulative indexes of special reviews, Annuals 12–30 Complementary and alternative therapies, indirect risks, 27.521 esophagus, adverse effects on, 14.442 Contrast media adverse effects, 13.431, 24.525 anaphylactoid and allergic reactions, 20.422 delayed reactions, 26.513 in magnetic resonance imaging, 20.419 nephrotoxicity, 27.500, 28.556, 29.575 Corticosteroids, see Glucocorticoids Cosmetics adverse effects, 13/117 contact allergy, 16.150, 19.151 ingredient labeling 22.159 Co-trimoxazole, hypersensitivity reactions, 20.264 COX-2 inhibitors, 24.115, 25.126, 26.116 vascular disease, 29.116 Daptomycin, muscle damage, 31.309 Deferiprone, cardiac siderosis, 29.235 Deferoxamine, 16.247 bone dysplasia, 23.241 cardiac siderosis, 29.235 bone dysplasia, 23.241 cardiac siderosis, 29.235 Diamorphine, progressive spongiform leukoencephalopathy, 24.40 Diclofenac, liver damage, 20.91 Digitalis, in atrial fibrillation, 24.197 Digoxin, compared with other drugs in heart failure in sinus rhythm, 14.141 compared with other drugs in chronic uncomplicated atrial fibrillation, 14.144 in heart failure in sinus rhythm, 18.196 Dipeptidyl peptidase IV inhibitors, 31.498 Diuretics diabetes mellitus, electrolyte abnormalities, and the ALLHAT trial, 27.219 hyponatremia, 29.219 interactions with NSAIDs, 12.80 renal cell carcinoma, 23.225 renal insufficiency, 25.250 Dofetilide, 26.208 Dopamine receptor agonists pathological gambling, 31.174 sleep disorders, 26.160, 27.149 Ecstasy, see MDMA EDTA, pseudothrombocytopenia, 21.250 Endothelin receptor antagonists, in hypertension, 26.233 Enzyme inhibitors, 15.337 Erythromycin, versus the new macrolides, 21.269 Erythropoietin, pure red cell aplasia, 27.348 status and safety, 16.400 Ethambutol, optic neuropathy, 31.358 Etoposide, 27.477 Etretinate, ossification, 12.127

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Euxyl K 400, contact allergy, 16.150 Felbamate aplastic anemia, 19.68, 22.86 risk/benefit ratio, 23.86 Fenfluramine cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 primary pulmonary hypertension, 18.7, 21.2, 23.2, 25.5 Fenoterol, safety in severe asthma, 23.182 Fentanyl, buccal and transdermal administration, 20.77 Fertility drugs malignant melanoma, 26.434 ovarian cancer, 24.474 Finasteride, 31.480 Fish oil, 13.460 Flecainide,insupraventriculardysrhythmias,21.200 Fluoroquinolones, 12.250, 18.271 Fluorouracil, adverse effects, 23.476 Folic acid, dietary supplementation, 19.369 safety aspects, 27.407 Formoterol, tolerance, 24.187 Fragrances, contact allergy, 20.149 Gadolinium salts, nephrotoxicity, 28.561 General anesthetics, see Anesthetics Germanium, 16.545 Glucocorticoids bone, 16.447, 22.182, 25.195 contact allergy, 15.139, 21.158 effective dose and therapeutic ratio, 23.175 and eyes, 29.481 and growth, 14.335 inhaled, effects on mouth and throat, 29.168 inhaled, effects on skin, 29.169 inhaled, growth inhibition, 26.186 inhaled, risks in children, 27.174 inhaled, systemic availability, 24.185, 26.187 musculoskeletal adverse effects, 21.417 osteoporosis and osteonecrosis, 16.447, 19.377, 20.374, 21.417, 22.182, 28.473 preterm infants, 17.445 Grapefruit juice, drug interactions 23.519 Growth hormone adults, 16.501 insulin resistance, 24.504 malignancy, 23.468 Heparin low-molecular-weight, 12.311 thrombocytopenia, 31.404 Hepatitis B vaccine, demyelinating diseases, 21.331, 22.346, 24.374 Herbal medicines, warfarin, interactions, 31.400 Heroin, see Diamorphine

xx

Cumulative indexes of special reviews, Annuals 12–30

Histamine (H2) receptor antagonists, 13.330, 15.393 HIV-protease inhibitors insulin resistance, 22.317 lipodystrophy, 22.317 HMG Co-A reductase inhibitors, interactions, 25.530, 31.517 Hormones, sex, tumors, 22.465 5-HT, see Serotonin Hypnotics, 20.30 avoiding adverse effects, 21.37 Hypoglycemic drugs, combinations of, 27.458, 28.521 Immunization adverse effects, 24.364 and autoimmune disease, 27.336 bioterrorism, 25.378, 26.354 multiple, 27.334 surveillance after, 15.340, 22.333, 23.335, 24.364, 25.376, 26.353, 27.334 Immunotherapy, in leishmaniasis, 15.299 Incretin mimetics, 29.528 Indometacin, fetal and neonatal complications, 18.102 Influenza vaccine, 29.332 Insulin human, and hypoglycemia, 15.452 inhalation, 31.495 modes of administration, 26.464 resistance, and growth hormone, 24.504 synthetic analogues, 24.489 Interferon + ribavirin, 31.344 Interferons, psychological and psychiatric effects, 29.384 Interleukin-2, 14.325 Irinotecan, 27.477 Isoniazid genetic susceptibility factors, 12.257 prophylactic, toxicity, 24.352 Kava kava liver damage, 27.518 adverse effects, 28.579 Ketoconazole, hepatotoxicity, 12.229 Ketorolac, risk of adverse effects, 17.110 Khat, 31.43 Lamotrigine, skin rashes, 20.62, 24.88 Laxatives, abuse, 13.336 Leflunomide, 29.435 Leukotriene receptor antagonists, Churg–Strauss syndrome, 24.183, 27.177, 29.174 Lipid-lowering drugs, 13.402, 15.479 Lithium adverse effects, prevention and treatment, 13.17, 17.28 beneficial uses other than in bipolar disorder, 27.19 efficacy, comparisons with other agents, 30.23

interactions, 16.13, 18.30 intoxication, prevention and treatment, 17.29 monitoring therapy, 18.25 mortality, 19.14 urinary system, 14.18, 19.16 thyroid, 12.26 Local anesthetics, see Anesthetics Loop diuretics, see Diuretics Lorenzo's oil, 27.475 Lyme disease vaccine, autoimmune disease, 24.366 Macrolides, drug interactions, 14.220 intestinal motility, 18.269 Malaria vaccines, 22.306 Mannitol, 28.236 MAO inhibitors, see Monoamine oxidase inhibitors MDMA cognitive effects, 26.32 deaths, 24.32 epidemiology of use, 30.37 Measles immunization autism, 23.350 Crohn's disease, 23.350 neurological adverse effects, 23.348 subacute sclerosing panencephalitis, 29.335 Mebendazole, hypersensitivity reactions, 12.263 Melatonin, 25.523 Metamfetamine, 29.3 Metformin contraindications, 28.515 lactic acidosis, 23.459, 29.526 Methyldibromoglutaronitrile, contact allergy, 16.150, 19.151 Mibefradil, drug interactions, 23.210 Midazolam, 15.112 Midodrine, 26.159 Milrinone, intravenous, acute heart failure, 21.196 MMR immunization autism, 23.350, 25.387, 28.363 Crohn's disease, 23.350, 25.387 Mometasone furoate, 30.197 Monoamine oxidase inhibitors, 12.8, 13.6, 17.361 Morphine, managing adverse effects, 26.98 Muscle relaxants emergency medicine, 20.133 eyes, 21.145 hypersensitivity reactions, 27.138 intensive care, 19.140 Niacin, extended-release, 16.440 Neuromuscular blocking agents, anaphylaxis, 29.145 non-depolarizing neuromuscular blockers, 15.127 recovery in intensive care, 12.114 residual paralysis, 27.139 NSAIDs, see also COX-2 inhibitors acute renal insufficiency, 28.122

Cumulative indexes of special reviews, Annuals 12–30 blood pressure, 19.92, 27.102 children, 19.96 current controversies, 17.102 COX-2 inhibitors, 24.115, 25.126, 26.116 dyspepsia, 28.120 gastrointestinal adverse effects, 14.79, 17.95, 18.90, 18.99, 20.86, 21.96, 22.108, 23.114 gastrointestinal damage, role of Helicobacter pylori, 27.105 gastrointestinal damage, reducing, 30.125 gastrointestinal toxicity, prevention, 19.93 inflammatory bowel disease, 25.131 inhibiting cardioprotective effects of acetylsalicylic acid, 28.118 interactions with diuretics, 12.80 intracerebral hemorrhage, 28.119 necrotizing fasciitis, 28.121 nephrotoxicity, 18.100, 20.89, 24.120, 26.111 skin reactions, 13.72 topical, 18.163 Ocular drugs allergic reactions, 21.486 geriatric patients, 16.542 risk factors for adverse effects, 22.507 Omeprazole, tumors, 16.423 Opioids abuse, 29. 44 adverse effects, prevention, 24.100 death, 25.37 obstetric use, 24.102 routes of administration, 30.106 tolerance in neonates, 23.97 Oral contraceptives antimicrobial drugs, and pregnancy, 24.274 and breast cancer, 15.426 formulations, 24.472 third-generation, 25.484, 26.442 venous thromboembolism, 23.442 Orlistat, 30.429 Paclitaxel, adverse effects, 21.463 Pancreatic enzyme supplements, fibrosing colonopathy, 20.322 Paracetamol asthma, 30.129 hepatotoxicity in alcoholism, 12.76 liver damage, 17.98, 18.94 overdose, 13.68, 23.117 Parenteral nutrition bone effects, 22.378 cholestasis, 22.376 infections, 22.379 Penicillins acute desensitization, 23.252 hypersensitivity reactions, cross-reactivity with cephalosporins, 30.280 immunological reactions, 28.267

xxi

Peritoneal dialysis fluids, effects on peritoneum, 22.381 Phentermine, cardiac valvulopathies, 24.4 Piroxicam, gastric effects, 12.91 Pivalic acid, and carnitine, 12.209 Platinum compounds, 26.490 Polio vaccine, AIDS, 23.352 Polyaspartic acid, protective against nephrotoxicity, 17.305 Polyethylene glycol, electrolyte, mineral, metal, and fluid balance, 29.376 Polystyrene sulfonates, 25.271 Polyvinylpyrrolidone, storage disease, 22.522 Pregabalin, 30.86 Propofol infusion syndrome, 26.135 prevention of pain, 30.143 Propolis, allergy, 17.181 Proton pump inhibitors, tumors, 23.383 PUVA, malignant melanoma, 22.166 Pyrazinamide, in latent pulmonary tuberculosis, 27.323 Quinidine, versus quinine, 15.295 Quinine, versus quinidine, 15.295 Renin inhibitors, 30.242 Rhesus anti-D, prophylaxis, 13.297 Ribavirin + interferon, 30.344 Ribostamycin, and aminoglycosides, 15.270 Rocuronium, allergic reactions, 26.150 Rotashield, intussusception, 23.354 Salbutamol, adrenoceptor genotypes, 29.173 Salmeterol, tolerance, 24.187 Sedatives, 29.128 Sex hormones, tumors, 22.465 Serotonin receptor antagonists, 15.391 selective serotonin reuptake inhibitors, drug interactions, 22.13 selective serotonin reuptake inhibitors, suicidal behavior, 29.19 Smallpox vaccination, 27.339 Somatostatin, 15.468 Spinal manipulation, adverse effects, 29.591 Statins, see HMG Co-A reductase inhibitors Steroids, see Glucocorticoids Sulfonamide derivatives, hypersensitivity reactions, 30.252 Sumatriptan, 17.171 Suprofen, nephrotoxicity, 12.88 Suramin, patients with prostate cancer, 20.283 Surgam, gastric effects, 12.89 Suxamethonium, postoperative myalgia, 28.155

xxii

Cumulative indexes of special reviews, Annuals 12–30

Tamoxifen, versus aromatase inhibitors, 30.475 Teniposide, 27.477 Tetracyclines adverse effects, 12.212, 26.268 comparative toxicity, 22.268 and metalloproteinases, 26.266 non-antimicrobial properties, 30.288 in pregnancy, 25.280 in rheumatology, 23.255 therapeutic effects, 24.278 Theophylline, asthma, 17.2, 18.1, 18.2 Thiazides, see Diuretics Thiazolidinediones, peripheral edema, 29.531 Thiomersal, in vaccines, 28.357 Thyroid hormones, 29.464 Thyroxine, drug interactions, 24.484 Tiaprofenic acid, cystitis, 18.106 Toiletries, see Cosmetics Topiramate, cognitive effects, 26.81 Topoisomerase inhibitors, 27.477 Topotecan, 27.477 Transfusions AIDS, 12.298 complications, 12.300 Tretinoin, topical, teratogenicity, 18.164 Triazolam, 16.33 Tricyclic antidepressants, mania, 13.8 L-tryptophan, eosinophilia-myalgia syndrome, 15.514 Tumor necrosis factor antagonists, infection risk, 29.395

Tyrosine kinase inhibitors, 30.520 Vaccines, see also individual agents combinations, 29.327, 30.369 HIV-infected individuals, 12.269 national compensation systems, 12.271 poliomyelitis, 22.352 thiomersal in, 28.357 Valproate, polycystic ovary syndrome, 26.81 Vancomycin lessons from, 27.242 resistance, 29.244 Vigabatrin psychosis and abnormal behavior, 18.71 visual field defects, 21.78, 24.95, 25.98, 26.82 Vinca alkaloids, 28.538 Vitamin A, 17.436 alcohol, beta-carotene, interaction, 24.442 hypervitaminosis, 15.411 in pregnancy, 21.405 and prostate cancer, 13.346 Vitamin B6, debate, 23.420 Vitamin E, co-medication, 26.423 Vitamin K cancer, 23.424 skin reactions, 25.461 Vitamins, in old age, 22.431 Warfarin, herbal medicines, interactions, 30.400 Ximelagatran, hepatotoxicity, 30.411 Zidovudine, 13.246

Index of adverse effects Cardiovascular atrial fibrillation, antidysrhythmic drugs, 24.197 atrial fibrillation, digitalis, 24.197 cardiac failure, aldosterone antagonists, 24.246 cardiac failure, bambuterol, 23.181 cardiac siderosis, deferoxamine/deferiprone, 29.235 cardiotoxicity, antihistamines, 17.196, 25.183, 26.180 cardiotoxicity, calcium antagonists, 20.185 cardiotoxicity, cocaine, 18.5 cardiotoxicity, coxibs, 29.116 cardiotoxicity, propofol, 26.135 dysrhythmias, antihistamines, 22.176 dysrhythmias, amiodarone, 25.211 heart attacks, acetylsalicylic acid, 27.109 hypertension, NSAIDs, 19.92, 27.102 prodysrhythmic effects, antidysrhythmic drugs, 17.218, 23.196 QT interval prolongation, 24.54 valvulopathies, fenfluramine, 22.3, 23.2, 24.4, 25.5 valvulopathies, phentermine, 24.4, 25.5

venous thromboembolism, oral contraceptives, 23.442 Respiratory amiodarone, 15.168 asthma, acetylsalicylic acid, 17.94 asthma, fenoterol, 23.182 asthma, paracetamol, 30.129 asthma, in pregnancy, 28.186 asthma deaths, beta2-adrenoceptor agonists, 17.164 asthma exacerbation, asthma medications, 20.165 beta2-adrenoceptor agonists, long-acting, 30.198 bronchoconstriction, paradoxical, nebulizer solutions, 13.134 Churg–Strauss syndrome, leukotriene receptor antagonists, 24.183, 27.177, 29.174 cough, ACE inhibitors, 19.211 primary pulmonary hypertension, appetite suppressants, 18.7, 21.2, 23.2, 25.5 rhinosinusitis, acetylsalicylic acid, 17.94 Ear, nose, throat glucocorticoids, inhaled, 29.168

Cumulative indexes of special reviews, Annuals 12–30 Nervous system brain damage, benzodiazepines, 14.36 demyelinating diseases, hepatitis B vaccine, 21.331, 22.346, 24.374 drowsiness/sedation, antihistamines, 21.170, 23.171, 26.182 headache, analgesics, 21.95, 23.114 intracerebral hemorrhage, NSAIDs, 28.119 neuroleptic malignant syndrome, 20.41 neurotoxicity, anesthetics, local, 21.129 neurotoxicity, measles immunization, 23.348 overdosage, antiepileptic drugs, 22.84 pain, propofol, 30.143 poliomyelitis, vaccines, 22.352 progressive spongiform leukoencephalopathy, diamorphine, 24.40 seizures, antimicrobial drugs, 18.261 sleep disorders, dopamine receptor agonists, 26.160, 27.149 strokes, acetylsalicylic acid, 27.109 strokes, risperidone, 28.76 subacute sclerosing panencephalitis, measles vaccine, 29.335 tardive dyskinesia, 14.47, 20.38 tardive syndromes, 17.54 transient symptoms, intrathecal anesthetics, 25.152 Neuromuscular residual paralysis, neuromuscular blocking drugs, 27.139 Sensory systems eye effects, drug abuse, 12.33 eye effects, glucocorticoids, 29. 481 eye effects, muscle relaxants, 21.145 optic neuropathy, ethambutol, 30.358 ototoxicity, aminoglycosides, 14.222, 18.268 visual field defects, vigabatrin, 21.78, 24.95, 25.98, 26.82 Psychological cognitive effects, MDMA, 26.32 cognitive effects, metamfetamine, 29.3 cognitive effects, topiramate, 26.78 gambling, dopamine receptor agonists, 30.174 interferons, 29.384 Psychiatric antiepileptic drugs, 22.82, 27.72 autism, MMR/measles immunization, 23.350, 25.387, 28.363 depression, benzodiazepines, 17.43 mania, antidepressants, 13.8, 29.18 interferons, 29.384 psychosis and abnormal behavior, vigabatrin, 18.71 suicidal behavior, SSRIs, 29.19 Endocrine diabetes mellitus, antihypertensive drugs, 28.226 diabetes mellitus, antipsychotic drugs, 28.60

xxiii

diabetes mellitus, diuretics, 27.219 insulin resistance, growth hormone, 24.504 insulin resistance, HIV-protease inhibitors, 22.317 ovarian hyperstimulation syndrome, valproate, 26.477 polycystic ovary syndrome, valproate, 26.81 thyroid disease, amiodarone, 27.192 thyroid disease, lithium, 12.26 Metabolism antiretroviral drugs, 28.329 hyperlactatemia, 29.302 hypoglycemia, insulin, 15.452 lactic acidosis, metformin, 23.459, 29.526 lipoatrophy, 29.302 lipodystrophy, HIV-protease inhibitors, 22.317 metabolic acidosis, propofol, 26.135 mitochondrial toxicity, 29.302 polyvinylpyrrolidone storage disease, 22.522 weight gain, antipsychotic drugs, 26.56 Electroyte balance electrolyte abnormalities, diuretics, 27.219, 29.219 polyethylene glycol, 29.376 Mineral balance polyethylene glycol, 29.376 Metal balance polyethylene glycol, 29.376 Fluid balance peripheral edema, thiazolidinediones, 29.531 polyethylene glycol, 29.376 Hematologic agranulocytosis, clozapine, 22.59 aplastic anemia, felbamate, 19.68, 22.86 coagulation disorders, beta-lactam antibiotics, 18.258 eosinophilia-myalgia syndrome, tryptophan, 15.514 hemolytic disease of the newborn, anti-D prophylaxis, 12.293 hemostasis, cephalosporins, 12.210 pseudothrombocytopenia, EDTA, 21.250 pure red cell aplasia, erythropoietin, 27.348 thrombocytopenia, heparin, 30.404 Mouth Glucocoricoids, inhaled, 29.168 Gastrointestinal bleeding, acetylsalicylic acid, 17.95, 18.90 cholestasis, total parenteral nutrition, 22.376 colitis, antimicrobial drugs, 12.216, 17.303 Crohn's disease, MMR/measles immunization, 23.350, 25.387 dyspepsia, NSAIDs, 28.120 fibrosing colonopathy, pancreatic enzyme supplements, 20.322 inflammatory bowel disease, NSAIDs, 25.131 intestinal motility, antimicrobial drugs, 13.220 intestinal motility, macrolides, 18.269

xxiv

Cumulative indexes of special reviews, Annuals 12–30

intussusception, Rotashield, 23.354 piroxicam, 12.91 Surgam, 12.89 ulceration, bleeding and perforation, NSAIDs , 14.79, 16.103, 17.95, 18.90, 18.99, 19.93, 20.86, 21.96, 22.108, 23.114, 27.105, 30.125 Liver hepatotoxicity, alcohol/vitamin A/betacarotene, 24.442 hepatotoxicity, antituberculosis drugs, 25.363, 26.339 hepatotoxicity, diclofenac, 20.91 hepatotoxicity, kava kava, 27.518 hepatotoxicity, ketoconazole, 12.229 hepatotoxicity, paracetamol, 12.76, 17.98, 18.94 hepatotoxicity, ximelagatran, 30.411 Reye's syndrome, acetylsalicylic acid, 15.85 Urinary tract acute renal insufficiency, NSAIDs, 28.122 cystitis, tiaprofenic acid, 18.106 nephrolithiasis, ceftriaxone, 29.246 nephrotoxicity, aminoglycosides, 15.268, 17.305 nephrotoxicity, amphotericin, 13.231, 14.229, 27.276 nephrotoxicity, analgesics, 21.98 nephrotoxicity, anesthetics, halogenated, 20.106 nephrotoxicity, ciclosporin, 19.348 nephrotoxicity, contrast media, 27.500, 28.556, 29.575 nephrotoxicity, gadolinium salts, 28.561 nephrotoxicity, lithium, 14.18, 19.16 nephrotoxicity, NSAIDs, 18.100, 20.89, 24.120, 26.111 nephrotoxicity, suprofen, 12.88 renal cell carcinoma, diuretics, 23.225 renal insufficiency, diuretics, 25.250 Skin contact allergy, 23.160 contact allergy, glucocorticoids, 15.139 contact dermatitis, aminoglycosides, 13.225 cutaneous reactions, NSAIDs, 13.72 glucocorticoids, inhaled, 29.169 necrosis, oral anticoagulation, 29.358 rashes, lamotrigine, 20.62, 24.88 vitamin K1, 25.461 Serosae peritoneum, peritoneal dialysis, 22.381 pleurodesis, 25.189 Musculoskeletal bone, total parenteral nutrition, 22.378 bone dysplasia, deferoxamine, 23.241 bone loss, antiepileptic drugs, 27.74 bone mineral density, glucocorticoids, 25.195 eosinophilia-myalgia syndrome, tryptophan, 15.514

growth in children, inhaled glucocorticoids, 26.186 growth in children, oral glucocorticoids, 14.335 muscle damage, daptomycin, 30.309 ossification, etretinate, 12.127 osteoporosis and osteonecrosis, glucocorticoids, 16.447, 19.377, 20.374, 21.417, 22.182, 28.473 rhabdomyolysis, propofol, 26.135 postoperative myalgia, suxamethonium, 28.155 Sexual function and beta-adrenoceptor antagonists, 15.188 Immunologic allergic reactions, antimicrobial drugs, 23.251 allergic reactions, rocuronium, 26.150 anaphylaxis, human albumin, 14.296 anaphylaxis, neuromuscular blocking agents, 29.145 angioedema, ACE inhibitors, 22.225, 29.207 aspirin sensitivity, 12.75 autoimmune disease, immunizations, 27.336 autoimmune disease, Lyme disease vaccine, 24.366 cocamidopropylbetaine, 19.151 contrast agents, 20.422 cosmetics, 16.150, 19.151 co-trimoxazole, 20.264 desensitization, penicillin, 23.252 Euxyl K 400, 16.150 fragrances, 20.149 glucocorticoids, 21.158 hypersensitivity reactions, beta-lactam antibiotics, 14.211, 30.280 hypersensitivity reactions, muscle relaxants, 27.138 hypersensitivity reactions, mebendazole, 12.263 hypersensitivity reactions, sulfonamide derivatives, 30.252 immune reconstitution disease, 29.315 methyldibromoglutaronitrile, 16.150, 19.151 ocular drugs, 21.486 propolis, 17.181 red man syndrome, 17.312 Autacoids angioedema, angiotensin II receptor agonists, 30.238 Infection risk AIDS, polio vaccine, 23.352 AIDS, transfusions, 12.298 necrotizing fasciitis, NSAIDs, 28.121 total parenteral nutrition, 22.379 tumor necrosis factor antagonists, 29.395 Body temperature malignant hyperthermia, 18.112 Trauma acupuncture, 29.590

Cumulative indexes of special reviews, Annuals 12–30 Death antiepileptic drugs, 23.83 calcium antagonists, 22.214 ecstasy, 24.32 lithium, 19.14 opiates, 25.37, 29.44 Drug abuse anabolic steroids in sport, 29.508 Drug tolerance antimicrobial drug resistance, 12.208, 19.237, 20.228, 21.257, 22.265, 23.250, 24.273, 25.279, 29.244 opioids in neonates, 23.97 Drug dependence benzodiazepines, 12.41 Drug withdrawal baclofen, 26.152 Genotoxicity antiestrogens, 27.429 Tumorigenicity alcohol/vitamin A/beta-carotene, 24.442 antiestrogens, 27.429 beta-carotene, 25.454 carotenoids, 25.454 fertility drugs, 24.474, 26.434 growth hormone, 23.468 omeprazole, 16.423 oral contraceptives, 15.426 proton pump inhibitors, 23.383 PUVA, malignant melanoma, 22.166 sex hormones, 22.465 vitamin K, 23.424 Fertility fertility, male, antimicrobial drugs, 16.262 Pregnancy affective disorders in, 21.17 antimicrobial drugs and the pill, 24.274 antithyroid drugs, 13.377 asthma, 28.186 beta-lactams, 25.280 cocaine, 27.1 opioids, 24.102 tetracyclines, 25.280 vitamin A, 21.405 Teratogenicity tretinoin, topical, 18.164 Fetotoxicity cocaine, 20.24, 27.1, 29.41, 30.35 indometacin, 18.102 Susceptibility factors children, aluminum, 12.185 children, budesonide, 30.194 children, inhaled glucocorticoids 27.174 children, NSAIDs, 19.96 elderly patients, antipsychotic drugs, 30.59 genetic susceptibility, antituberculosis drugs, 28.342

xxv

genetic susceptibility, beta-adrenoceptor agonists, 29.173, 30.199 genetic susceptibility, isoniazid, 12.257 HIV infection, immunization, 12.269 intensive care, muscle relaxants, 19.140 neonatal complications, indometacin, 18.102 ocular drugs, 22.507 old age, vitamins, 22.431 preterm infants, beta-lactam antibiotics, 21.258 Drug administration delivery of aerosols, 27.172 dosage regimens, aminoglycosides, 23.264 errors, 28.587, 29.596 formulations, oral contraceptives, 24.472 inhaled glucocorticoids, systemic availability, 24.185 inhaled insulin, 30.495 intravitreal and parabulbar injection, 29.581 labeling problems, cosmetics, 22.159 opioids, 30.106 Drug overdose antidepressants, 28.14 digitalis, charcoal, 24.201 paracetamol, 23.117 Drug formulations enantiomers and racemates, 13.442 Drug–drug interactions acetylsalicylic acid/ACE inhibitor, 28.124 acetylsalicylic acid/NSAIDs, 28.118 alcohol/vitamin A/beta-carotene, 24.442 antimicrobial drugs/the pill, 24.274 antifungal azoles, 24.318, 28.299, 29.282, 30.320 diuretics/NSAIDs, 12.80 grapefruit juice, 23.519 herbal medicines/warfarin, 30.400 HMG Co-A reductase inhibitors, 25.530, 30.517 lithium, 16.13 lithium/selective serotonin reuptake inhibitors, 18.30 macrolides, 14.220 mibefradil, 23.210 monoamine oxidase inhibitors/foods, 13.6 NSAIDs/ACE inhibitors, 28.122 paracetamol, 13.68 selective serotonin reuptake inhibitors, 22.13 thyroxine, 24.484 Methods ethnopharmacology, 14.429 eukaryotic cells, effects of beta-lactams, 13.212 hemolytic disease of the newborn, prophylaxis, 13.297 onchocerciasis, treatment, 14.261 post-marketing surveillance, 14.210, 15.266, 24.274

Table of Essays, Annuals 1–30 SEDA

Author

Country

Title

1 2 3

M.N.G. Dukes K.H. Kimbel L. Lasagna

The Netherlands Germany USA

4 5

The Netherlands UK Hungary Canada Denmark UK Denmark Denmark Switzerland UK Denmark

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

15

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

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

UK

16 17 18

M.N.G. Dukes M.N.G. Dukes R.D. Mann

Denmark Denmark UK

19

A. Herxheimer

UK

20

E. Ernst

UK

21

H. Jick

USA

22

UK

24

J.K. Aronson, R.E. Ferner K.Y. Hartigan-Go, J.Q. Wong I. Palmlund

25 26

L. Marks D.J. Finney

UK UK

26 27 27 28

L.L. Iversen J.K. Aronson H. Jick J.K. Aronson

UK UK USA UK

29

M. Hauben, A. Bate J.K. Aronson

USA/Sweden

The nocebo effect—poorly known but getting stronger Good enough for Iganga? The mists of tomorrow Databases, privacy, and confidentiality — the effect of proposed legislation on pharmacoepidemiology and drug safety monitoring Side effects: freedom of information and the communication of doubt Complementary/alternative medicine: what should we do about it? Thirty years of the Boston Collaborative Drug Surveillance Program in relation to principles and methods of drug safety research Errors in prescribing, preparing, and giving medicines: definition, classification, and prevention Inclusion of therapeutic failures as adverse drug reactions Secrecy hiding harm: case histories from the past that inform the future The pill: untangling the adverse effects of a drug From thalidomide to pharmacovigilance: a personal account How safe is cannabis? Louis Lewin—Meyler’s predecessor The General Practice Research Database Classifying adverse drug reactions in the 21st century Data mining in drug safety

UK

Drug withdrawals because of adverse effects

6 7 8 9 10 11 12 13 14

23

30

xxvi

Philippines UK

Classifications of adverse drug reactions

Adverse drug reactions are classified in SEDA using two complementary systems, EIDOS and DoTS. These two systems are illustrated in Figures 1 and 2.

1. EIDOS The EIDOS mechanistic classification of adverse drug effects (Ferner & Aronson, Drug Safety 2010; in press) has five elements: � � � � �

the the the the the

Extrinsic species that initiates the effect; Intrinsic species that it affects; Distribution of these species in the body; (physiological or pathological) Outcome; Sequela, which is the adverse effect.

Extrinsic species This can be the parent compound, an excipient, a contaminant or adulterant, a degradation product, or a derivative of any of these (e.g. a metabolite).

Figure 1. Classifying adverse drug reactions—two complementary systems. Note that the triad of drug– patient–adverse reaction appears outside the triangle in EIDOS and inside the triangle in DoTS.

xxvii

xxviii

Classifications of adverse drug reactions

Figure 2. Classifying adverse drug reactions—two complementary systms. Here the two triangles in Figure 1 are superimposed, to show the relation between the two classification systems. An adverse reaction occurs when a drug is given to a patient (Gothic letters). Adverse reactions can be classified mechanistically (EIDOS; sans-serif letters) by noting that the extrinsic (drug) species, when co-distributed with an intrinsic (patient) species, has a pharmacological or other effect (the outcome), producing the adverse effect (the sequela). The sequela can be further classified (DoTS; serif letters) by considering the three main features of the adverse reaction—its dose-relatedness, its time-course, and individual susceptibility.

Intrinsic species This is usually the endogenous molecule with which the extrinsic species interacts; this can be a nucleic acid, an enzyme, a receptor, an ion channel or transporter, or some other protein. Distribution A drug will not produce an adverse effect if it is not distributed to the same site as the target protein that mediates the adverse effect. Thus, the pharmacokinetics of the extrinsic species can affect the occurrence of adverse effects. Outcome Interactions between extrinsic and intrinsic species in the production of an adverse effect can result in physiological or pathological changes. Physiological changes can involve either increased actions (e.g. clotting due to tranexamic acid) or decreased actions (e.g. bradycardia due to beta-adrenoceptor antagonists). Pathological changes can involve cellular adaptations (atrophy, hypertrophy, hyperplasia, metaplasia, and neoplasia), altered cell function (e.g. mast cell degranulation in IgE-mediated anaphylactic reactions), or cell damage (e.g. cell lysis, necrosis, or apoptosis). Sequela The sequela of the changes induced by a drug describes the clinically recognizable adverse drug reaction, of which there may be more than one. Sequelae can be classified using the DoTS system.

2. DoTS In the DoTS system (SEDA-28, xxvii-xxxiii; BMJ 2003; 327: 1222-5) adverse reactions are classified according to the Dose at which they usually occur, the

Classifications of adverse drug reactions

xxix

Time-course over which they occur, and the Susceptibility factors that make them more likely, as follows: � Relation to dose – Toxic reactions (reactions that occur at supratherapeutic doses) – Collateral reactions (reactions that occur at standard therapeutic doses) – Hypersusceptibility reactions (reactions that occur at subtherapeutic doses in susceptible individuals) � Time course – Time-independent reactions (reactions that occur at any time during a course of therapy) – Time-dependent reactions 3 Immediate or rapid reactions (reactions that occur only when a drug is administered too rapidly) 3 First-dose reactions (reactions that occur after the first dose of a course of treatment and not necessarily thereafter) 3 Early reactions (reactions that occur early in treatment then either abate with continuing treatment, owing to tolerance, or persist) 3 Intermediate reactions (reactions that occur after some delay but with less risk during longer term therapy, owing to the “healthy survivor” effect) 3 Late reactions (reactions the risk of which increases with continued or repeated exposure) 3 Withdrawal reactions (reactions that occur when, after prolonged treatment, a drug is withdrawn or its effective dose is reduced) 3 Delayed reactions (reactions that occur some time after exposure, even if the drug is withdrawn before the reaction appears) � Susceptibility factors – Genetic – Age – Sex – Physiological variation – Exogenous factors (e.g. drug–drug or drug–food interactions, smoking) – Diseases The following reactions have been classified in previous issues of SEDA using the DoTS system: ACE inhibitors: angioedema Adrenaline: hypertension Angiotensin II receptor antagonists: angioedema Anticoagulants, oral: skin necrosis Antipsychotic drugs: diabetes mellitus Bisphosphonates: osteonecrosis of the jaw Cocaine: myocardial infarction Contrast media: nephrotoxicity Diuretics, loop and thiazide: hyponatremia Dopamine receptor agonists: pathological gambling Dopamine receptor agonists: sleep attacks Ephedrine: vasospasm Ergot-derived dopamine receptor agonists: fibrotic reactions Ethambutol: optic neuropathy Exenatide: nausea

29.207 30.170 30.238 29.358 28.60 30.562 29.38 29.575, 30.535 29.219 30.174 28.162 30.171 30.176 30.358 30.499

xxx Gadolinium salts: nephrotoxicity Glucocorticoids: osteoporosis Heparin: type II thrombocytopenia Nitrofurantoin: lung disease Pseudoephedrine: toxic epidermal necrolysis SSRIs: suicidal behavior Statins: myopathy and rhabdomyolysis Thionamides: agranulocytosis Vigabatrin: visual field loss Ximelagatran: liver damage

Classifications of adverse drug reactions

28.561 28.185 30.404 30.303 30.172 29.19 30.516 29.520, 30.490 28. 101, 29.99, 30.98 30.411

How to use this book

THE SCOPE OF THE ANNUAL Volumes in the Side Effects of Drugs Annual (SEDA) series have been published since 1977. The series is designed to provide a critical 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 International Encyclopedia of Adverse Drug Reactions and Interactions, the 15th edition of which was published in 2006.

PERIOD COVERED The present Annual reviews all reports that presented significant new information on adverse reactions to drugs during 2006. During the production of this Annual, some more recent papers have also been included; older literature has also been cited when it is relevant. Special reviews (see below) often cover a much wider range of literature.

SELECTION OF MATERIAL In compiling the Side Effects of Drugs Annual particular attention is devoted to publications that provide essentially new information or throw a new light on problems already recognized. Some confirmatory reports are also described. In addition, some authoritative new reviews are listed. Publications that do not meet these criteria are omitted. Readers anxious to trace all references on a particular topic, including those that duplicate earlier work, or to cross-check an electronic search, are advised to consult Adverse Reactions Titles, a monthly bibliography of titles from about 3400 biomedical journals published throughout the world, compiled by the Excerpta Medica International Abstracting Service.

Special reviews The special reviews deal in more detail with selected topics, often interpreting conflicting evidence, providing the reader with clear guidance. They are identified by the traditional prescription symbol and are printed in italics. This volume includes a Cumulative Index of the Special Reviews that were published in SEDA-12 to SEDA-30 and a list of the Special Reviews that appear in the current Annual.

xxxi

xxxii

How to use this book

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 (e.g. lidocaine is mentioned in Chapter 11 as a local anesthetic and in Chapter 17 as an antidysrhythmic drug). Fixed combinations of drugs are dealt with according to their most characteristic component or as a combination product.

DRUG NAMES Drugs are usually called by their recommended or proposed International Non-proprietary Names (rINN or pINN); when these are not available, chemical names have been used. If a fixed combination has a generic combination name (e.g. co-trimoxazole for trimethoprim + sulfamethoxazole) that name has been used; in some cases brand names have been used instead.

SYSTEM OF TAGGING REFERENCES References in the text are tagged using the following system, which was introduced in SEDA-24: M A R r C c H E S

A meta-analysis or other form of systematic review; 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; A hypothesis article; An experimental study (animal or in vitro); Official (e.g. Governmental, WHO) statements.

The various editions of Meyler’s Side Effects of Drugs are cited in the text as SED-l4, SED-15, etc; the Side Effects of Drugs Annuals 1–30 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. For indexing purposes American spelling has been used, for example anemia, estrogen rather than anaemia, oestrogen.

J. Harrison and P. Mozzicato1 SIDE EFFECTS OF DRUGS ESSAY

MedDRAs: The tale of a terminology The history of MedDra The Medical Dictionary for Regulatory Activities terminology (MedDRAs) is a clinically validated international med­ ical terminology used by regulatory authorities and biopharmaceutical com­ panies in both pre-marketing and postmarketing regulatory reporting. MedDRA is used for data entry, retrieval, evaluation, and presentation. It is one of the most successful of all the initiatives established by the International Con­ ference on Harmonisation of Technical Requirements for Registration of Phar­ maceuticals for Human Use (ICH). As late as the early 1990s, there was no single international standard for reporting adverse events. In the USA, the Coding

1 The authors of this year’s Side Effects of Drugs Essay are Judy Harrison, MA (Cantab) BMBCh (Oxon), and Patricia Mozzicato, MD (Tufts). Dr. Harrison is Principal, Harrison Clinical Con­ sulting, LLC, and Medical Officer, MedDRA Maintenance and Support Services Organization. Dr. Mozzicato is Chief Medical Officer, MedDRA Maintenance and Support Services Organization. MedDRAs is a registered trademark of the International Federation of Pharmaceutical Manu­ facturers and Associations (IFPMA).

Symbols for Thesaurus of Adverse Reac­ tion Terms (COSTART) had been widely used. In Europe and other places in the world, the World Health Organization’s Adverse Reaction Terminology (WHO­ ART) was frequently used. The Japanese Ministry of Health, Labour, and Welfare (MHLW) had developed the Japanese Adverse Reaction Terminology (J-ART). Added to this mix were entire custom dictionaries developed by some pharma­ ceutical companies to suit their particular needs (1). Before MedDRA, there was a general lack of specificity in most of these older terminologies, which limited their usage for other purposes besides encoding adverse events. In additional, it was not uncommon for adverse events data to be coded and summarized using one termi­ nology in pre-marketing clinical trials, while the counterpart adverse events data for marketed products were coded using a different terminology. This presented a considerable challenge in trying to inte­ grate adverse events data across the premarketing/post-marketing divide, and it forced organizations to invest resources in maintaining multiple terminologies for reporting and evaluating adverse events. In the mid-1990s, an ICH Expert Working Group was formed (M1 EWG) to address the need for a standard terminology for regulatory purposes (2,3). The EWG worked on an existing terminology used by the British regulatory xxxiii

xxxiv agency, refining and testing its capabilities in representing reported adverse events (4,5). By near the end of the 20th century, they achieved their goal, and MedDRA was ready for release.

MedDRAs: The tale of a terminology

reported verbatim information is assigned in the process of coding (2).

Sustaining MedDra: the MSSO and Management Board The scope and structure of MedDra MedDRA was designed to classify a wide range of types of adverse events, such as signs, symptoms, diseases and diagnoses, therapeutic indications, qualitative results of investigations (e.g. laboratory tests), surgical and medical procedures, health effects, malfunction of devices, and med­ ical, social, and family history. For the most part, it excludes demographic qua­ lifiers (age, sex) unless relevant to the concept (e.g. neonatal hyperbilirubin­ emia), severity descriptors, and descrip­ tors of clinical trial design. MedDRA terms are arranged in a fivetiered multi-axial hierarchy (Figure 1), which provides increasing specificity as one descends it. At the top are 26 System Organ Classes (SOCs) containing terms for dis­ orders by body system (e.g. SOC Eye disorders), or relating to etiology (e.g. SOC Infections and infestations), or serving a classification purpose (e.g. SOC Surgical and medical procedures). Linked to the SOCs are more specific groupings called High Level Group Terms (HLGTs), 332 of them. Below the High Level Group Terms are High Level Terms (HLTs), which are more specific; there are 1688 of these. The single medical concept level of MedDRA is the Preferred Term (PT), of which there are 18 209; High Level Terms group related Preferred Terms. Finally, the “synonym” level of MedDRA is the Lowest Level Terms (LLTs), which are linked to their “parent” Preferred Terms. The Lowest Level Terms—66 587 in all—constitute the entry level of the terminology to which

In November 1998, the ICH awarded a maintenance contract for MedDRA to a US information technology firm called BDM Technologies. BDM was later acquired by the system integration com­ pany called TRW, and TRW was subse­ quently acquired by Northrop Grumman Corporation. This contract established the Maintenance and Support Services Organization (MSSO), which today is still part of the Northrop Grumman Informa­ tion Technology sector. The MSSO has two essential missions: to establish a mechanism for international support and development of the MedDRA; and to foster the use of MedDRA world wide through communication, edu­ cation, and services. The MSSO consists of experts in information technology and medicine to support these missions. MedDRA is distributed by subscription (licence) on a sliding scale fee based on company revenues (it is provided to regulators at no cost). The MSSO has a sister organization, the Japanese Mainte­ nance Organization (JMO), which pro­ vides MedDRA services in Japan and maintains the Japanese language version of the terminology. Besides English and Japanese, MedDRA is also translated into Spanish, French, German, Portuguese, Dutch, Italian, and Czech; other language versions—including Mandarin Chinese— will probably be available in the future. The MSSO and JMO, together with the MedDRA user community, are responsible for the development and maintenance of MedDRA through a controlled change request process. MedDRA subscribers may submit requests to

MedDRAs: The tale of a terminology

xxxv System Organ Class

High Level Group Term

High Level Term

Preferred Term

Lowest Level Term

Fig. 1. The MedDRA hierarchy.

add terms, make terms inactive, or change the hierarchical position of terms. Aggregate change requests are provided in biannual updated versions of the terminology, which are provided to MedDRA subscribers on 1 March and 1 September of each year. The MedDRA Management Board acts as a board of directors for the MSSO. Board membership includes representa­ tives of the regulatory authorities from the three ICH regions (EU, Japan, and USA); representatives of the ICH regions industry groups (EFPIA, JPMA, and PhRMA); representatives of the Medicines and Healthcare products Reg­ ulatory Agency (MHRA, the UK reg­ ulatory authority) and Health Canada; an observer from WHO; and representation from the International Federation of Pharmaceutical Manufacturers & Asso­ ciations (IFPMA). The Board provides financial oversight and approval of

subscription prices and directs the MSSO on how best to support users’ needs.

MedDra and regulatory agencies ICH regulatory authorities have a keen interest in the use of MedDRA, particu­ larly as a standard terminology that sup­ ports electronic exchange of safety data. In particular, the European Medicines Agency (EMEA) and the MHLW in Japan have steadily moved MedDRA into their regulatory frameworks. Since autumn 2003, the MHLW has required adverse events coded in MedDRA to be reported to them electronically, and since April 2004, periodic infection and safety reports must also be MedDRA-coded. For the EMEA, the use of MedDRA has been mandatory for single case reports received

xxxvi electronically since January 2002 and for all reporting of adverse drug reactions since January 2003. Both Suspected Unexpected Serious Adverse Reactions (SUSARs) in clinical trials and post-authorization Indi­ vidual Case Safety Reports (ICSRs) reported to the EudraVigilance database must be submitted electronically and coded using MedDRA. MedDRA is required to be used in the interface between EudraVi­ gilance and the EU Risk Management Plan. The latest revision of the Summary of Product Characteristics (December 2007) calls for MedDRA terms to be used in several sections (e.g. “Undesirable Effects”) and it gives further guidance in Annex 2 on how to aggregate MedDRA­ coded data to estimate the frequency of events. In the USA there is to date no regulation that requires MedDRA coding for reports of adverse events from either spontaneous sources or clinical trials. However, the lack of a US mandate to require coding with MedDRA does not seem to have impeded its use by the FDA. The FDA incorporated MedDRA into its new safety database before the “official” version (release 2.1) was made available to all other users. The current Adverse Event Reporting System (AERS)—the FDA’s database for spon­ taneous reports—is MedDRA-coded. The FDA’s vaccine safety database— VAERS—has recently been converted from COSTART to MedDRA. Also the reviewing division of the FDA is gaining experience with the terminology.

Applications of MedDra: coding In biopharmaceutical companies, “cod­ ing” is a commonly used expression that describes the process of assigning raw data to a concept from a standard list. To code using MedDRA means that a term

MedDRAs: The tale of a terminology

is selected to correspond to verbatim information reported from either a spon­ taneous source or a clinical trial investi­ gator. The LLTs represent the “entry” or coding level in MedDRA. The LLT that most accurately matches the reported term is selected by the coder and then the links to its associated PT up through the hierarchy to the primary SOC loca­ tion, as well as any secondary SOC locations, are automatically assigned by means of the relational tables in MedDRA. The fixed hierarchy ensures that MedDRA is kept intact as a standard. The high degree of specificity or “gran­ ularity” of MedDRA, with over 66 000 LLTs, makes it easier to find a match for a verbatim term; however, if a direct or lexical match cannot be found among the existing LLTs, it can be a challenge to identify the best match from the large number of LLTs available. Organizations have found that even experienced coders need some degree of training to code accurately with MedDRA. In a study of MedDRA coding for HIV clinical trials, Toneatti et al. found that one of the most significant determinants of their ability to successfully code using MedDRA was the quality of the initial verbatim information provided by the investigator (6). Continu­ ing instruction of their clinical investiga­ tors was one of the significant “lessons learned” from their coding experience. The overall quality of the data can be improved and the number of queries necessary for coding reduced by training investigators and clinical research associ­ ates to avoid vague terms, “combination” terms (e.g. a single verbatim term “nausea and vomiting”), and other problematic MedDRA coding pitfalls (7). Despite the fact that MedDRA is a well-maintained standard terminology, it was recognized that diverse coding practices could undermine its use as a standard. To address this, the ICH established a Working Group, which

MedDRAs: The tale of a terminology

developed a coding guideline—the “MedDRA Term Selection: Points to Consider” document (8)—aimed at pro­ viding recommended coding approaches for medically appropriate analysis. The “Term Selection” document is considered a “companion” to MedDRA, and many organizations have found it useful to structure their own coding conventions with this document as a guide. The document is updated with each release of MedDRA, and it provides conventions for coding information related to adverse events as well as addressing how to code therapeutic indications, medication errors, transmission of infectious agents, and other topics of regulatory interest. Organizations also use other methods— such as autoencoders and implementing process improvements (9)—for optimal matching of the verbatim term without getting lost in a sea of synonyms.

Applications of MedDra: data retrieval and presentation While MedDRA’s granularity is helpful for accurate representation of individual events and relative easy matching of verbatim information, there is a flip-side to its specificity. With over 18 000 PTs— the “concept” or analysis level of the terminology—it can be challenging to identify and aggregate related terms. For example, MedDRA has four separate PTs relating to myocardial infarction: PT Acute myocardial infarction, PT Myocardial infarction, PT Post procedural myocardial infarction, and PT Silent myocardial infarction. Another characteristic of MedDRA that can present challenges in data retrieval is the multi-axial nature of the terminology. Multi-axiality means that a PT may be assigned to more than one SOC, and its purpose is to allow terms to

xxxvii be grouped by different classifications (e.g. by etiology or site of effect), allow­ ing retrieval and presentation by differ­ ent data sets. For example, PT Pneumonia is linked to two different SOCs; its primary linkage is to SOC Infections and infestations and its second­ ary linkage is to SOC Respiratory, thoracic and mediastinal disorders. The standard method to present data is according to the primary SOC, but secondary SOC allocations can be used for alternative views of the data and for more focussed searches. The primary SOC allocation rules are described in the MedDRA Introductory Guide (1), and a detailed discussion of these rules is beyond the scope of this article. How­ ever, reviewers need to be aware that the rules allow medically related terms to reside in different SOCs; thus, in a primary search, all relevant SOCs should be examined when reviewing data sets to avoid overlooking relevant events. The particular way that MedDRA relegates a medical condition term—for example, PT Thrombocytopenia—to a “disorder” SOC—in this case, SOC Blood and lymphatic system disorders—while a simi­ lar term representing an investigation result—PT Platelet count decreased—is in a separate and non-multi-axial SOC, namely SOC Investigations, can be parti­ cularly challenging from an analytical standpoint, as described by Tremmel and Scarpone (10). Awareness of this MedDRA characteristic—particularly as it relates to the statistical analysis plan— and training of investigators in how MedDRA codes such data were recom­ mended approaches to deal with this. Just as it provided a useful guideline for MedDRA coding, the same ICH Working Group that provided the “MedDRA Term Selection: Points to Consider” has drafted a second guideline, this time to assist MedDRA users with data retrieval and presentation (11). The

MedDRAs: The tale of a terminology

xxxviii purpose of this document is to promote user understanding of the way that options for data retrieval affect the accuracy and consistency of MedDRA­ coded output. The topics discussed include the impact of MedDRA’s granu­ larity, grouping terms (HLTs and HLGTs), and multi-axiality on data retrieval. The document also provides practical examples of data displays, including line listings, tables, and graphs, and considers when it might be appro­ priate to display terms according to their secondary SOC allocations. Recognizing the need for a standar­ dized approach to data retrieval, a joint venture of CIOMS and ICH in 2003 resulted in the formation of a Working Group that set out to create Standar­ dized MedDRA Queries (SMQs). These are groups of MedDRA terms, typically PTs, related to a defined medical condi­ tion or area of interest; their purpose is to act as a starting point for analysis by helping to identify cases of interest for further medical analysis. SMQs begin with a definition of the condition or area of interest, from which is built a candi­ date list of MedDRA terms. Subse­ quently, the CIOMS Working Group tests the retrieval capabilities of the aggregated terms on test databases of products known to be associated with that condition. Once the Working Group is satisfied that the testing has provided a reasonable list of terms to aid in case identification, the SMQ is released to the subscribers by the MSSO. Once in this “production” phase, MedDRA subscri­ bers are free to recommend changes to SMQs in a similar change request process as used for the main MedDRA terminol­ ogy (12). As of MedDRA Version 11.1, there are 67 SMQs in production, and about a dozen additional ones in the develop­ ment and testing phases. The available queries cover a wide variety of important

areas in clinical safety and post-market­ ing pharmacovigilance. Topics include: � � � � � � �

anaphylactic reactions; cerebrovascular disorders; depression and suicide/self-injury; hepatic disorders; lack of efficacy/effect; rhabdomyolysis/myopathy; torsade de pointes/QT interval prolongation.

SMQs are being enthusiastically adopted by the MedDRA community. As noted previously, the EU regulators have recommended their use for signal detection in Volume 9 A of “The Rules Governing Medicinal Products in the European Union—Guidelines on Phar­ macovigilance for Medicinal Products for Human Use”. EMEA has implemented SMQs within its EudraVigilance database and is conducting studies evaluating their ability to identify safety signals. A case study of an antipsychotic drug with a known association with hyperglycemia and diabetes showed that the SMQ Hyperglycaemia/new onset diabetes mellitus (narrow search) detected a safety signal several weeks earlier than tradi­ tional methods based on the single terms PT Hyperglycaemia and PT Diabetes mellitus, or on the relevant HLT and HLGT (13). Further studies are needed on larger data sets and to develop statistical criteria for term selection in SMQs to improve the specificity. The FDA and regulators in Japan are also in the process of implementing and evaluat­ ing SMQs. Biopharmaceutical companies are applying SMQs to identify and report safety concerns in Periodic Safety Update Reports, clinical trials reports, and annual reports, and to respond to regulatory queries. However, their imple­ mentation in some organizations has been hindered somewhat by the lack of integration with data management and

MedDRAs: The tale of a terminology

xxxix

analytical tools, although data system vendors are now working towards inte­ gration, so that SMQs can be used with minimal IT and programming support. VigiBase is the global individual case safety report (ICSR) database of the WHO International Drug Monitoring Programme, and it holds more than 3.8 million ICSRs submitted by the more than 80 participating member countries. The Uppsala Monitoring Center (UMC) is responsible for the maintenance and development of VigiBase on behalf of WHO. In 2007, an initiative was under­ taken by IFPMA (on behalf of the MedDRA Management Board), the MSSO, and the UMC for the integration of MedDRA into VigiBase. The com­ pleted project enhances the VigiBase system to be compatible with both WHO-ART and MedDRA (14). Data can now be entered directly into VigiBase using either MedDRA or WHO-ART, whereas previously, all MedDRA-coded reports were converted by UMC into WHO-ART before entry into the data­ base. Individual report data fields now store both terminologies, and users can obtain VigiBase outputs, such as single case reports, statistical reports, and line listings in WHO-ART, MedDRA, or both. In addition, SMQs are being incor­ porated into the search functionality, in order to aid in the identification and retrieval of potentially relevant case safety reports. The integration of MedDRA in VigiBase, with its pool of almost 4 million

cases, provides a worldwide repository of adverse events data that is an important resource in pharmacovigilance.

The future of MedDra As medicine evolves, so does MedDRA, and the fact that it can grow is a major benefit. The main driver of MedDRA’s growth and development continues to be the MedDRA user community. The MSSO coordinates, facilitates, and pro­ motes the development of MedDRA in a variety of ways, based on feedback from subscribers. The day-to-day maintenance of MedDRA is via the MSSO’s change request process, by which MedDRA core sub­ scribers request additions or changes to the existing version. MedDRA’s growth has slowed in recent years; that is, the total number of new terms added to MedDRA is considerably smaller now than in the early years of its use (Table 1). There is no reason to believe that this slow, steady growth rate will change drastically in the near future, although small spikes may occur if there is a need to augment MedDRA with “specialty” terms, for example, to support the devel­ opment of gene therapy. A recent area of growth in MedDRA has been terms relating to medical devices. Although terms related to complications of devices have been a part of MedDRA since the beginning, the number of such

Table 1. The growth of MedDRA—numbers of items in different versions Term

System Organ Class High Level Group Terms High Level Terms Preferred Terms Lowest Level Terms

Version 1.5

2.1

4.1

8.1

9.1

10.1

11.1

26 88 653 8658 35 335

26 334 1663 11 193 46 258

26 333 1685 14 287 51 083

26 332 1683 16 976 62 950

26 332 1682 17 505 64 620

26 332 1682 17 867 65 605

26 332 1688 18 209 66 587

MedDRAs: The tale of a terminology

xl terms was small, and it was only in around 2004, when the use of drug–device combi­ nation products became widespread, that the need for additional terms and a supporting hierarchy became apparent. About 60 device-related terms were added to MedDRA in versions 11.0 and 11.1. The MSSO is continuing to work with the FDA’s Center for Devices and Radiologi­ cal Health (CDRH) and other interested parties to review device-related terms and to incorporate them into MedDRA as appropriate. Vaccine pharmacovigilance is another area in which MedDRA is evolving. The very high level of safety required for vaccines presents unique challenges in benefit:harm assessment in clinical trials and in post-authorization pharmaco­ vigilance. To aid in the identification of specific vaccine-related events—as dis­ tinct from drug, device, or biological events—two new HLTs are being added to MedDRA in version 12.0, and new

vaccine-specific LLTs and PTs are being added to populate these groupings.

Conclusions MedDRA was developed to fulfil a need for a well-maintained standard terminol­ ogy to classify a wide range of safety data and support electronic submissions. The terminology is used today by a worldwide subscriber community engaged in all aspects of clinical safety and pharmaco­ vigilance. In the future, MedDRA will continue to evolve and adapt to serve the needs of its expanding user base.

Acknowledgements The authors wish to thank Mr Patrick Revelle, MSSO Director, for helpful editorial comments.

References 1. Introductory Guide, MedDRA Version 11.1, September 2008. (Provided as part of a subscription to MedDRA). 2. Cone M. Regulatory update: the longawaited MedDRA has arrived! Good Clin Pract J 1999;6(1):42–3. 3. Wood KL. The Medical Dictionary for Drug Regulatory Affairs (MEDDRA) project. Pharmacoepidemiol Drug Saf 1994;3: 7–13. 4. Huntley K, Veverka MJ, Golden M. The FDA’s Medical Dictionary for Drug Regula­ tory Affairs alpha test. Drug Inf J 1995;29 (4):1133–43. 5. Brown EG, Clark E. Evaluation of MedDRA in representing medicinal product data

6.

7.

8.

9.

sheet information. Pharmac Med 1996;10:111–8. Tonéatti C, Saïdi Y, Meiffrédy V, Tangre P, Harel M, Eliette V, Dormont J, Pierre Aboulker J. Experience using MedDRA for global events coding in HIV clinical trials. Contemp Clin Trials 2006;27:13–22. Harrison J, Zhao-Wong A. Working with MedDRA to improve data standards. Good Clin Pract J 2006;13(9):25–8. MedDRA Term Selection: Points to Con­ sider, Release 3.10, 1 April 2008. Available at: http://www.meddramsso.com/MSSOWeb/ document_library/TermSelPTC_R3.10.pdf. Tucker MD. Data Normalization Techniques and autoencoding algorithms for the Medical

MedDRAs: The tale of a terminology Dictionary for Regulatory Activities (MedDRA). Drug Inf J 2002;36:927–33. 10. Tremmel LT, Scarpone L. Using MedDRA for adverse events in cancer trials: experience, caveats, and advice. Drug Inf J 2001;35:845–52. 11. Data Retrieval and Presentation: Points to Consider, Release 1.5, 1 April 2008. Available at: http://www.meddramsso. com/MSSOWeb/Document_Library/ DatRetPTC_R1.5.pdf.

xli 12. Development and Rational Use of Stan­ dardised MedDRA Queries (SMQs). Report of the CIOMS Working Group, 2004. 13. Slattery J. Standardised MedDRA Queries: a case study of the potential for signal detection. Presentation at DIA Annual Meeting, Atlanta, 2007. 14. Lindquist M. VigiBase, the WHO Global ICSR Database System: basic facts. Drug Inf J 2008;42:409–19.

Reginald P. Sequeira

1

Central nervous system stimulants and drugs that suppress appetite

(SED-15, 180; SEDA-28, 4, 28; SEDA-29, 1; SEDA-30, 1)

AMPHETAMINES

Note on spelling: In International Nonproprietary Names (INNs) the digraph -phis usually replaced by -f-, although usage is not consistent, and -ph- is used at the beginnings of some drug names (e.g. compare fenfluramine and phentermine) or when a name that begins with a phis modified by a prefix (e.g. chlorphentermine). For the amphetamines the spellings that are used in SEDA are as follows: amfetamine, benzfetamine, dexamfetamine, metamfetamine (methylamphetamine), and methylenedioxymetamfetamine (ecstasy); however, for the general term for the group of drugs the more common spelling “amphetamines” is used. Nervous system Two young women had strokes from carotid artery dissection following chronic metamfetamine use; extensive workup failed to reveal any other risk factors (1A). In a case–control study using a telephone survey in California, prolonged exposure to amphetamines (amfetamine, metamfeta­ mine, or dexamfetamine) was associated with an increased rate of Parkinson’s disease (2c). “Prolonged exposure” was Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03101-8 r 2009 Elsevier B.V. All rights reserved.

defined as twice per week for at least 3 months, or once a week for at least 1 year. In most cases, prior amphetamine exposure was unknown to the treating physician. The study did not distinguish between prescribed and non-prescribed use of amphetamines. A previous study had suggested amphetamine exposure as a possible risk factor for Parkinson’s disease (3c).

Ecstasy (3,4-methylenedioxymetamfetamine, MDMA) See Chapter 4.

Metamfetamine

(SEDA-29, 3;

SEDA-30, 2) Cardiovascular Patients with idiopathic pulmonary arterial hypertension (PAH) are significantly more likely to have used stimulants than patients with other forms of pulmonary hypertension. In a retrospective study, rates of stimulant use were determined in 340 patients with idiopathic PAH, PAH with known susceptibility factors, or chronic thromboembolic pulmonary hypertension. “Stimulant” use was defined as any self-reported use of amfetamine, metamfetamine, or cocaine (4C). There was a history of stimulant use in 29% of patients with a diagnosis of idiopathic PAH, compared with 3.8% of patients with PAH and a known risk factor (such as portopulmonary hypertension,

1

2

Chapter 1

Reginald P. Sequeira

HIV-related pulmonary hypertension, col­ lagen vascular diseases, congenital sys­ temic-to-pulmonary shunts, persistent pulmonary hypertension of the newborn, and drug-related pulmonary hyperten­ sion), and 4.3% of patients with chronic thromboembolic pulmonary hypertension. The central finding was that metamfeta­ mine exposure appears to be strongly associated with idiopathic PAH. Patients with idiopathic PAH were about 10 times more likely to have a history of stimulant use than patients with PAH and known susceptibility factors and almost 8 times more likely to have a history of stimulant use than patients with chronic throm­ boembolic pulmonary hypertension, after adjustment for age. These ratios are similar to those found in studies with fenfluramine (5C,6C). Despite methodolo­ gical limitations inherent in a retrospective chart review study, these preliminary results are important, because of the widespread and increasing use of both prescription and illicit stimulants.

benzodiazepines (midazolam, lorazepam, or diazepam) and haloperidol were used to control agitation. A median dose of haloperidol (0.05 mg/kg) was given intra­ venously. There were no reports of respiratory depression, intubation, prolon­ gation of the QT interval, dystonic reac­ tions, or aspiration associated with the use of benzodiazepines and haloperidol (8c). However, the role of haloperidol as an adjunct to benzodiazepines in the man­ agement of metamfetamine-poisoned chil­ dren needs further evaluation. Some clinicians may have reservations about using haloperidol to sedate ampheta­ mine-poisoned patients, because of con­ cerns about its ability to impair heat dissipation and the risk of worsening hyperthermia associated with metamfeta­ mine toxicity. Furthermore, patients with different severities of illness may already have received haloperidol from another physician in the emergency department or ICU.

Susceptibility factors Genetic An Ala/ Val polymorphism of the superoxide dismutase 2 (SOD2) gene could be associated with a risk of metamfetamine psychosis (7C). Metamfetamine psychosis has been studied in 116 patients and 189 controls in Japan, and in 135 patients and 204 controls in Taiwan. Those who had taken metamfe­ tamine were divided into two clinical subtypes: a transient type of psychosis (i.e., a good prognosis) and a prolonged type of psychosis (i.e., a poor prognosis). There was a significant difference between individuals with prolonged metam-fetamine psychosis and controls from both Japan and Taiwan, in the genotypic and allelic frequen­ cies of an Ala/Val functional polymorphism in exon 2. These results suggest that an Ala/ Val polymorphism of the SOD2 gene could be associated with the risk of metamfetamine psychosis.

Atomoxetine

Management of adverse drug reactions In a case series of 18 children with metamfetamine poisoning, parenteral

Atomoxetine is a non-stimulant noradre­ naline reuptake inhibitor that is efficacious in the treatment of ADHD (9R). Sudden deaths of children and adolescents taking Adderall XRs have led to the need to screen children for risks of heart defect before beginning this stimulant medication. The label for atomoxetine has been altered to include a boxed warning and additional warning statements regarding an increased risk of suicidal thinking in children and adolescents treated with this medication. An association of ADHD and completed suicide, particularly in adolescent males, has been reported (10R). However, there is little evidence to suggest a direct link. Rather, co-morbidities (such as mood dis­ orders, conduct disorder, and substance abuse) that are commonly associated with ADHD may lead to an increased risk of completed suicide, and may be related to increased suicidal ideation in patients taking atomoxetine.

Central nervous system stimulants and drugs that suppress appetite

Methylphenidate

(SED-15, 2307; SEDA-29, 10; SEDA-30, 4)

The complexities and controversies of ADHD, including new treatment options, have been reviewed (9R). Transdermal methylphenidate produces blood concen­ trations and behavioral improvements simi­ lar to oral methylphenidate. Observational studies In a preliminary study in 32 women with breast cancerrelated fatigue, methylphenidate reduced the Brief Fatigue Inventory score (11c). Six patients (19%) withdrew owing to adverse events such as restlessness/anxiety (16%), dizziness (8%), headache (8%), palpitation (2%), and back spasm (2%). While evalua­ tion of fatigue, a subjective symptom whose presence or severity is difficult to prove, the quality of life of cancer patients is an important component of management. The promising results of this study need to be replicated in a randomized controlled trial. Cardiovascular Hypertension has been attributed to methylphenidate in a child with ADHD and ultrarapid metabolizer status of CYP2D6 (12A).
A 6-year-old Caucasian boy with ADHD took

methylphenidate 10 mg/day for 2 months and developed arterial hypertension; his blood pressure rose from 100/60 to 140/110 mmHg. A dosage reduction to 5 mg/day did not normalize the blood pressure; methylpheni­ date was withdrawn and the hypertension abated. He was subsequently given amitripty­ line, but the plasma concentrations were low and clomipramine was used instead.

Since the plasma concentration of amitriptyline was very low, genotyping and phenotyping of CYP2D6 was performed. He had three functional alleles and was therefore considered to be an ultrarapid metabolizer, confirmed by phenotyping with dextromethorphan. He was homozygous for a functional allele of the CYP2C9 gene and heterozygous for a nonfunctional allele of the CYP2C19 gene; these genotypes are compatible with normal enzyme activities. The metabolism of methylphenidate does not involve CYP2D6 (13c). Therefore, the

Chapter 1

3

CYP2D6 status of the child does not explain the arterial hypertension observed during treatment with methylphenidate. The formation of a toxic metabolite in ultrarapid metabolizers is speculative. Nervous system In a double-blind, pla­ cebo-controlled study there was no increased risk of first-onset tics in children with ADHD taking methylphenidate (14cr). Although there may be a close temporal relation in a few patients, the roles of treatment duration, dose of stimulant, genetic vulnerability, and developmental aspects need to be further explored to clarify possible pathophysiological mechan­ isms of the occurrence of tics in those taking stimulants. Earlier equivocal views about tics during methylphenidate treatment might be explained by the shortcomings of the few studies on first-onset tics during stimulant treatment, such as small sample sizes and unclear disentangling of first-onset tics from exacerbation of pre-existing tics. Important confounders include waxing and waning of tics and a high frequency of transient tics at an age when stimulant medication is usually started (15R). Methylphenidate-associated rabbit syndrome (a movement disorder characterized by involuntary, rapid, fine, rhythmic, vertical movements of the perioral muscles resem­ bling the chewing movements of a rabbit) has been described in an 8-year-old boy (16A). There were no associated tongue move­ ments or any other signs of extrapyramidal symptoms. He scored 5 (most severe) on the Abnormal Involuntary Movement Scale. There was complete resolution within 2 days after methylphenidate withdrawal. Psychological In a double-blind, placebocontrolled, crossover study in eight patients with a frontal variant of frontotemporal dementia, methylphenidate attenuated risk-taking on a laboratory measure of decision-making (the Cambridge Gamble Task) (17c). This was a relatively selective effect, since there were no measurable effects of drug treatment on recognition memory, planning, extradimensional shift­ ing, or working memory.

Chapter 1

4 Psychiatric An association between stimu­ lants and mania or psychosis, in therapeutic doses, has been described anecdotally (18r). It is estimated that toxicosis occurs in about 1 in 400 children taking stimulants, a proportion that suggests an infrequent but not rare adverse effect of therapeutic dosing.
After taking a modified-release formulation

of methylphenidate 40 mg/day for 8 months, a 7-year-old boy developed a flu-like illness and new symptoms, which included “complaints of hearing voices and seeing adults” when no one was present, a desire to “throw himself down the stairs,” high anxiety, tearfulness at school, irritability, and an unwillingness to leave his mother’s side (19A). The dose of methylphe­ nidate was reduced to 20 mg/day, and over the following 3 weeks the psychotic-like symptoms gradually resolved. Several months later, again after a flu-like illness, he developed a milder version of the same symptoms. During this episode, methylphenidate was withdrawn, and all his symptoms resolved within 36 hours. Methylphenidate was reintroduced a week later and the symptoms did not recur. His attention dysfunction markedly improved.

This case raises questions about the diagnosis and treatment of psychotic-like and manic-like symptoms that arise during stimulant use in children with ADHD. Susceptibility factors Genetic There was no association between the dopamine trans­ porter gene DAT1 and a variable number of tandem repeats (VNTR) and the therapeutic response to methylphenidate or cardiovas­ cular adverse effects in a double-blind, 6­ week, randomized, placebo-controlled, paral­ lel-design study of methylphenidate in 285 adults with ADHD (20C). Subjects homozy­ gous for the 10-repeat DAT1 allele were not distinguishable from heterozygous 9/10 or homozygous 9-repeat allele subjects in level of symptom reduction, dose required for response, cardiac adverse effects, or sponta­ neously reported adverse effects. In a previous study there was no difference in response based on DAT1 (21C). A lack of consistency in the literature could be due to etiological heterogeneity or, more likely, small sample sizes that lead to reduced power or falsepositive findings (22R). It is important to note

Reginald P. Sequeira

a limitation of this study: examining a single marker does not provide adequate informa­ tion about other variants across this large gene. A previous study examined three additional single nucleotide polymorphisms (SNPs) in the promoter region of the gene and failed to find any association with response to methylphenidate (21C). In methylphenidate-treated preschool children with ADHD there was an associa­ tion between symptom response and variants at the dopamine receptor DRD4 promoter and the synaptosomal membraneassociated protein 25 (SNAP 25) alleles T1065G and T1069C (23C). SNAP 25 variants were associated with tics, buccolin­ gual movements, and irritability. DRD4 variants were associated with picking. Increasing dose predicted irritability and social withdrawal with DRD4 variants. There were no significant effects of the dopamine transporter DRD1. These results require replication with more specific hypotheses, larger samples, and conserva­ tive levels of significance. Other candidate genes, additional variants, or haplotypes may better predict methylphenidate response. Effects may also be caused by unidentified polymorphisms in linkage dis­ equilibrium with the selected candidates. Genome-wide investigations that make no prior assumptions about likely candidates are better suited to assess genetic contribu­ tion to response, but are more expensive and require much larger sample sizes.

Effects of stimulant treatment on growth in children and adolescents with ADHD Stimulant medications are the most commonly used agents for the management of ADHD, and methylphenidate is the most widely prescribed. Its safety and efficacy have been established in more than 50 randomized controlled trials (24M) and after decades of clinical experience (25R). Because ADHD is a chronic condition that often persists into adolescence and adulthood, patients generally take stimulant drugs for many years.

Central nervous system stimulants and drugs that suppress appetite

There has been controversy as to whether stimulant treatment reduces growth in children with ADHD. Effects on growth in children with ADHD were first reported in the 1970s (26C, 27C, 28c), and were supported by several later studies (29c, 30C, 31C). However, other studies have contradicted these results (32C, 33C, 34c, 35c). Some have suggested that growth suppression is associated with ADHD rather than the medication (36C) and that the effect is limited to childhood and early adolescence (37C), and in females (38C). It is also possible that the risk of growth suppression is limited to a small subset of children with ADHD (39C). The use of Z scores (height data standardized according to age) is considered to be an accurate method for measuring growth deficits, especially when assessing growth across different ages (40H). Similar standardization can be applied to body weight data, although standardized body mass index is regarded as more useful measure of effects on weight. Recent studies that have evaluated effect of stimulants on growth parameters have used Z scores (36C, 38C). Other methodological issues are important: for example, dose and drug holidays can affect the effect size of stimulants on growth (41cr). Considerable variation in physiological growth velocity among children should also be considered when interpreting the effect size. The dose and formulation type change over time in response to the child’s clinical situation, and addition of medications may also be necessary for controlling symptoms. Most of the earlier studies on growth in children with ADHD taking stimulant medications rarely extended beyond 1 year. Differential effects of methylphenidate and mixed amfetamine salts on height in children with ADHD have been evaluated by retrospective analysis of data. Neither the type of stimulant used to treat ADHD nor the duration of treatment was related to changes in height Z scores. No effects of sex were evident. Linear regression showed a small but statistically significant negative relation between the cumulative dose of stimulant and change in height. Stimulant treatment appears to have an impact on weight, patients

Chapter 1

5

becoming thinner over time, and this effect was more pronounced in patients taking mixed amfetamine salts (42C). There remain many unanswered questions about growth in children with ADHD. To resolve the question of stimulant effects on growth, it may be necessary to study a sample of children with ADHD and matched controls, longitudinally, from the onset of treatment in childhood through adolescence and into young adulthood. Growth rates have been studied in 79 children with ADHD aged 6–12 years followed annually for up to 5 years after the start of stimulant treatment (43C). Annual height and weight, reported as Z scores, were standardized for age and sex. Methylphenidate dose was standardized in mg/kg and hierarchical linear modeling was used to determine the influence of dose and duration of stimulant treatment on the rate of growth in height and weight. Adherence to stimulant medication was defined as “the child taking methylphenidate (regular or slow-release), dextro-amfetamine (regular or slow-release), or pemoline for Z5 days/week, with the exception of drug holidays when not in school.” Drug holidays totaled not more than 14 weeks per year. There was a small but distinct risk of reduced rate of growth in children with ADHD who used stimulants for prolonged periods of time at doses equivalent to at least 42.5 mg/day methylphenidate for at least 4 years. The estimates for impaired growth after prolonged use revealed a dose-dependent pattern, with earlier effects at lower doses on the rate of weight gain than on the rate of height gain. Most probably, the appetite suppressant effect of stimulants is the cause of the reduced weight gain. In turn, compromised weight gain over several years may slow the rate of growth in height. There were several limitations to this study, such as the lack of an untreated control group and the use of standardized growth charts that do not provide specific information about the growth trajectories of children with ADHD, which presumably differ (44C). Pubertal staging was not considered in the growth model. Also, collapsing the data for dexamfetamine and methylphenidate into one dosepotency variable complicates the interpretation.

6 Because the study occurred in the 1990s in Canada, the results may not reflect patterns of growth that might occur with currently available modified-release formulations. A modified-release formulation of methylphenidate (OROS methylphenidate) has gradually replaced immediate-release methylphenidate as a stimulant for use in ADHD. The effect of OROS methylphenidate on growth has been evaluated for 21 months in 178 subjects in an open study (44C). The effect of prolonged OROS methylphenidate on growth was clinically insignificant and limited to a slight reduction in weight during the first months of therapy. Drug holidays did not reduce any impact on growth. The authors concluded that drug holidays are of unproven value for limiting potential effects of treatment on growth. Several assumptions have been made in the design and data analysis of this study. First, for ethical reasons, the study did not include an untreated control group. The putative effect on growth was determined by calculating Z scores. This assumes that the subjects in this study were representative of the general US population, which was not necessarily so. The assumptions that changes in Z scores reflect effects of stimulant therapy rather than other factors, such as diet, may not be appropriate. Second, most of the children in this study (86%) had previously received stimulant therapy. Because the impact on growth tends to be greater in stimulant-naive children, the study would have underestimated the initial effect on growth. Third, the study involved children aged 6–13 years old, so the data may not necessarily be applicable to younger children or to adolescents. In conclusion, there is now reasonable evidence to believe that typical doses of stimulants, equivalent to methylphenidate 1.5 mg/kg/day, are unlikely to produce clinically significant growth suppression in children with ADHD. Even so, regular monitoring of growth is necessary in all children exposed to stimulant treatment for several years. Whether any minimal changes in growth are of concern would depend on the individual child’s stature. The clinical management of a slowed rate of growth may include dosage adjustment, medication

Chapter 1

Reginald P. Sequeira

withdrawal, or consideration of alternative therapeutic agents. There seems to be no rationale for routine use of drug holidays in an attempt to maintain a normal pattern of growth in otherwise healthy children with ADHD. There is a need to study a cohort of children with ADHD and matched controls longitudinally from the onset of treatment in childhood through adolescence and into young adulthood. This is particularly true in an era when many children with ADHD continue taking stimulant treatment into late adolescence and adulthood.

Adverse effects of methylphenidate at different ages The adverse effects of methylphenidate in patients of different age groups with ADHD have been evaluated. Preschool children In 183 preschool children with ADHD, aged 3–5 years, there was a higher rate of methylphenidate withdrawal because of spontaneously reported adverse events than in school-age children. Also, the pattern of adverse events such as irritability, emotional outbursts, difficulty in falling asleep, repetitive behaviors and thoughts, and reduced appetite was more common, and resulted in treatment withdrawal in 11% of children (45C). These results are in agreement with a previous observation that preschool children with ADHD may experience more stimulant-related adverse events than older children (46c). Adolescents In a multisite, double-blind, placebo-controlled, four-phase study, OROS methylphenidate produced clinically and statistically significant improvements in ADHD in 220 adolescents aged 13–18 years (47C). Individualized dosages of OROS methylphenidate (a modified-release formulation) were titrated (18, 36, 54, or 72 mg/ day). Efficacy was measured using investigator, parent, and patient assessments. The most frequently reported adverse events considered by investigators to be treatmentrelated during the open dose-titration phase

Central nervous system stimulants and drugs that suppress appetite

of the study included headache (25%), reduced appetite (21%), insomnia (15%), and abdominal pain (9%). During the double-blind phase, 16 subjects (16%) taking placebo reported at least one adverse event deemed by the investigators to be probably or possibly related to the medication. Serious adverse events were reported in only one subject during the open dosetitrating phase: a 16-year-old woman with a history of depression and suicidal ideation threatened suicide on the third day; her symptoms resolved after withdrawal of methylphenidate. These findings should be interpreted in light of the methodological limitations of the study. Adolescents with unstable psychiatric and medical disorders and clinically important concurrent psychiatric co-morbidity requiring treatment were excluded. Moreover, the study design may have biased the results, favoring improved efficacy and tolerability in the double-blind phase. Accordingly, these findings may not be generalizable to routine clinical practice. Adults Treatment with OROS methylphenidate (a modified-release formulation) in daily doses of up to 1.3 mg/kg was effective in the treatment of 141 adults with ADHD (48C). These results were based on a randomized, 6-week, placebo-controlled, parallel-design study. Although methylphenidate was associated with a higher drop-out rate because of adverse effects (14% versus 4%), there were no serious adverse effects. Methylphenidate was associated with higher incidences of anorexia, dry mouth, moodiness and anxiety, insomnia, subjective cardiovascular complaints, and dizziness. In addition to subjective complaints of reduced appetite, those taking methylphenidate were statistically more likely to lose weight over the course of the 6-week study. There was an increase in heart rate and blood pressure in addition to the subjective reports of cardiovascular symptoms: a minority of those who took methylphenidate had systolic blood pressures over 140 mmHg (8%) and heart rates over 100 per minute (9%). Hence, adults with ADHD, particularly those with borderline hypertension or those who are underweight, should be monitored for

Chapter 1

7

changes in blood pressure or weight loss when they take methylphenidate.

Drug–drug interactions Cocaine Methyl­ phenidate did not significantly alter the pharmacokinetics of cocaine in seven non­ treatment-seeking cocaine-dependent indi­ viduals in a placebo-controlled, crossover study (49c). Two doses of oral methylphe­ nidate (60 and 90 mg) and two doses of cocaine (20 and 40 mg) were administered by infusion. Methylphenidate was well tolerated and did not alter the effects of cocaine on blood pressure and heart rate, and reduced some of its positive subjective effects. A similar finding that methylpheni­ date attenuates some of the subjective effects of cocaine has also been reported (50c). Although these studies provide evidence for the safe use of methylphenidate in a cocaine-abusing population, there were several deficiencies in the study design, conclusions, and generalizability of the results. The safety of methylphenidate among cocaine abusers with cardiovascular disease, including hypertension, is yet to be established.

Modafinil

(SED-15, 2369; SEDA-29, 10;

SEDA-30, 6) Placebo-controlled studies In a rando­ mized, double-blind, placebo-controlled crossover study that followed CONSORT guidelines, modafinil increased certain aspects of cognitive function and improved participants’ ability to attend post-nightshift didactic classroom sessions, but made it more difficult for them to fall asleep whenever there was an opportunity (51C). The participants were emergency depart­ ment residents and attending physicians (n ¼ 25). The symptoms that they recorded after taking modafinil 200 mg included headache (n ¼ 2), anxiety (n ¼ 2), nervousness (n ¼ 2), nausea (n ¼ 1), euphoria (n ¼ 1), abnormal vision (n ¼ 1), and

Chapter 1

8 diuresis (n ¼ 1). The only symptom reported by participants taking placebo was diarrhea (n ¼ 1). Susceptibility factors Old age Elderly people may have an increased risk of drug-induced hyperkinetic movement disorders (52A).

Reginald P. Sequeira

average 35% increase in plasma concentra­ tions of caffeine in healthy men, probably because of a proportional reduction in its metabolic clearance mediated by CYP1A2 (54c). Concomitant administration of caf­ feine with propafenone should probably be avoided in patients with atrial fibrillation or atrial flutter and especially in those with reduced CYP2D6 activity.


A 76-year-old woman with a history of major

depressive disorder (DSM-IV) was given venlafaxine and zopiclone. Modafinil (200 mg/day) was added and there was rapid improvement and full remission from depres­ sion after 2 weeks. She was discharged taking venlafaxine 150 mg/day and modafinil 200 mg/ day. After 4 months of continuous treatment she developed bothersome, non-dystonic, hyperkinetic, involuntary movements affecting the orofacial region and legs. After modafinil withdrawal her movements improved and resolved within 4 days.

METHYLXANTHINES

(SEDA-

28, 1; SEDA-29, 1; SEDA-30, 5)

Caffeine (SED-15, 588; SEDA-29, 1; SEDA-30, 5) Drug–drug interactions Fluvoxamine Caffeine significantly reduced the plasma concentrations and total AUC of fluvoxamine in 12 healthy men (53c). Genotyping confirmed that none of the subjects was a poor metabolizer of CYP2D6. Caffeine did not change the tmax or terminal half-life of fluvoxamine and did not change its pharmacodynamic effects. There were two drawbacks in this study. First, caffeine treatment for 11 days might have been too short to produce full induction of CYP1A2. Second, caffeine concentrations were not measured when fluvoxamine was administered. Never­ theless, since patients taking antide­ pressants probably often consume caffeinated beverages, this study has important implications. Propafenone Concomitant administration of propafenone and caffeine leads to an

Theophylline (SED-15, 3361; SEDA-29, 1; SEDA-30, 5) Nervous system Encephalopathy has been reported in a patient taking theophylline (55c).
A 12-year-old girl who had been taking

theophylline for bronchial asthma developed an acute encephalopathy with refractory status epilepticus, and had bilateral mesial temporal and claustral lesions. A marker of oxidative stress, 8-hydroxydeoxyguanosine, was increased in the cerebrospinal fluid, plasma, and urine. The theophylline plasma concentration was in the target range.

The authors speculated that oxidative stress was associated with refractory status epilepticus, accompanied by neuronal damage, due to theophylline, despite the fact that the plasma concentration was not raised, which is often so in such cases (56cr). Serial measurements of oxidative stress markers, including 8-hydroxydeoxyguanosine, could clarify the relation between acute brain damage and free radicals. Susceptibility factors Liver disease Flu­ voxamine-induced inhi-bition of theophyl­ line clearance fell from 62% in healthy subjects (n ¼ 10) to 52% in patients with mild cirrhosis (Child class A; n ¼ 10) and 12% in those with severe cirrhosis (Child class C; n ¼ 10). CYP1A2-mediated forma­ tion of 3-methylxanthine and 1-methyluric acid was almost completely inhibited in control subjects, whereas they were only reduced by one-third in patients with severe cirrhosis. Inhibition of the formation of

Central nervous system stimulants and drugs that suppress appetite

1,3-dimethyluric acid, which is catalyzed by CYP1A2 and CYP2E1, progressively fell from 58% in healthy subjects to 43 and 7% in patients with mild and severe cirrhosis, respectively (57c). The effect of liver dysfunction on the inhibition of CYP1A2-mediated drug elim­ ination is a general phenomenon, indepen­ dent of the pharmacokinetic characteristics of the CYP1A2 substrate. Therefore, for any drug metabolized by CYP1A2, the clinical consequences of enzyme inhibition are expected to become less important as liver function deteriorates. The two impor­ tant mechanisms are: (a) reduced sensitivity to fluvoxamine of CYP1A2-mediated bio­ transformation in the cirrhotic liver, prob­ ably resulting from reduced uptake of the inhibitory drug, and (b) reduced hepatic expression of CYP1A2, which makes its contribution to overall drug elimination less important.

DRUGS THAT SUPPRESS APPETITE (SEDA-28, 6; SEDA-29, 11; SEDA-30, 7)

Cardiovascular The adverse effects of drugs used for weight loss and the treatment of obesity have been reviewed (58R). The Surveillance of Pulmonary Hypertension in America (SOPHIA) Group has been monitoring both primary and secondary pulmonary hypertension. The data on newly diagnosed cases (n ¼ 1335) from 13 tertiary pulmonary hypertension centers showed no epidemic of anorexigen-related PAH. The SOPHIA registry was established 3 months after fenfluramines were withdrawn from the market. The use of fenfluramine derivatives and associated pulmonary hypertension in many cases is consistent with prior studies. The associations of PAH with St John’s wort and over-the­ counter diet pills that contain phenylpropanolamine were new and unexpected findings (59Cr).

Chapter 1

9

Phentermine (SED-15, 2804; SEDA-27, 4) Drug contamination Despite the with­ drawal of many appetite suppressants from the market, illegally imported “weight­ reducing products” may still contain these unsafe drugs. They are promoted to the general public through the electronic media, print advertisements, and health food stores. A case of cardiac arrhythmia caused by an illicit “weight-reducing pill” containing phentermine and chlorphena­ mine has been reported (60A).
A 23-year-old woman developed marked

lethargy and syncope. Her initial heart rate was 100 per minute and blood pressure 96/ 42 mmHg. There was prolongation of the QT interval and polymorphic ventricular tachycar­ dia. Her family stated that 3 days before admission she had started taking 1 capsule/day of an illegally imported weight-lowering pill. She was given intravenous magnesium sulfate and recovered uneventfully in 36 hours. A urine drug screen was positive for phenter­ mine and chlorphenamine. Serum drug con­ centrations were not measured.

Sibutramine

(SED-15, 3131; SEDA-28, 8; SEDA-29, 11; SEDA-30, 7)

Cardiovascular Post-marketing surveil­ lance using prescription event monitoring in the New Zealand Intensive Medicines Monitoring Program (IMMP) identified a case of QT interval prolongation and asso­ ciated cardiac arrest in a patient who had taken sibutramine for 25 days (61A). There was a novel mutation in a cardiac potassium subunit gene, KCNQ1, which is likely to prolong cardiac membrane depolarization and increase the susceptibility to long QT intervals. Assessment of further IMMP reports identified five other patients who had palpitation associated with syncope or presyncopal symptoms, one of whom had a QTc interval at the upper limit of the reference range. Assessment of reports from the WHO database identified three reports of QT interval prolongation and one fatal case of torsade de pointes in a patient who was also taking cisapride. Sibutramine may cause potentially fatal dysrhythmias in

Chapter 1

10 patients with long QT syndrome or in those taking other medications known to prolong the QT interval. Hematological Evidence from postmarketing surveillance suggests that there is a causal association between sibutramine and bruising/ecchymosis. In an IMMP cohort of 9532 patients who took sibutra­ mine between February 2001 and Novem­ ber 2002, there were five reports of ecchymosis (62A). Search of the WHO– UMC database identified a further 89 reports, of which 39 were classified as ecchymosis. Of these 39 reports, 31 had sufficient information for causality assess­ ment. In 11 of these 31 cases there was a positive dechallenge; of these, 1 patient had recurrence of ecchymosis on rechallenge. In the remaining 10 cases with a positive dechallenge, either the outcome of rechal­ lenge was unknown or rechallenge was not performed. In two of these cases either aspirin or co-trimoxazole had also been used. The time to onset for these events was 1–86 days. Four patients developed bruising within 2 days of starting sibutramine. The case with a positive rechallenge developed ecchymosis 86 days after starting sibutra­ mine. The incidence of ecchymosis in premarketing trials of sibutramine was under 1%. Although it appears that bruis­ ing/ecchymosis is not a common adverse reaction to sibutramine, a potential concern is that it may be associated with more serious hemorrhagic events. Drug contamination A metabolite of sibu­ tramine was identified in a urine sample of a 16-year-old girl by gas chromatography and mass spectrometry. Her parents had noticed a conspicuous mood change and her mother found a package labelled “LiDa Dai Dai Hua Jiao Nang,” a Chinese “pure herbal” weight loss product (63A). In another case a 20-year-old woman devel­ oped severe headache, vertigo, and numb­ ness within 2 days after starting LiDa Dai Dai Hua Jiao Nang capsule. Sibutramine was identified in the urine, as well as in the capsule. Each capsule contained sibutra­ mine base 27.4 mg (64A).

Reginald P. Sequeira

DRUGS USED IN ALZHEIMER’S DISEASE (SEDA-28, 9; SEDA-29, 12; SEDA-30, 8)

Donepezil

(SED-15, 1179; SEDA-28, 9; SEDA-29, 12; SEDA-30, 8)

Observational studies In the symptomatic treatment of Alzheimer’s disease over several years, early treatment with donepezil produces a slight benefit (65C). The longterm efficacy and safety of donepezil has been established. Nevertheless, one should define what will be a clinically important outcome for an individual patient in Alzheimer’s disease (66r), and explore the use of outcome measures such as goal-attainment scaling (67c). Comparative studies The duration and the dose of donepezil or galantamine were not related to an increase in mortality in patients with Alzheimer’s disease. The related variables were advanced age, the severity of the dementia, being male, heart failure, and treatment with atypical anti­ psychotic drugs (68c). Placebo-controlled studies Donepezil improves cognition and preserves function in individuals with severe Alzheimer’s disease who live in nursing homes (69C). In a 6-month, double-blind, parallel group, placebo-controlled study in 248 patients with severe Alzheimer’s disease (mini mental state examination score 1–10) who were living in assisted care nursing homes in Sweden, patients were given donepezil (5 mg/day for 30 days and up to 10 mg/day thereafter; n ¼ 128) or matched placebo (n ¼ 120). The primary end-points were change from baseline to month 6 in the Severe Impairment Battery (SIB) and mod­ ified Alzheimer’s disease Cooperative Study Activities of Daily Living Inventory for severe Alzheimer’s disease (ADCS-ADL-severe). Patients who took donepezil improved more in SIB scores and declined less in ADCDADL-severe scores at 6 months after starting treatment compared with baseline than controls (mean difference 5.7, 95% CI ¼ 1.5, 9.8, P ¼ 0.008; and mean difference 1.7,

Central nervous system stimulants and drugs that suppress appetite

CI ¼ 0.2, 3.2, P ¼ 0.03, respectively). The incidences of adverse events were comparable (donepezil 82% versus placebo 76%). Most of the adverse events were transient and were mild to moderate severity. More patients discontinued treatment because of adverse events in the donepezil group (n ¼ 20) than in the placebo group (n ¼ 8). Cardiovascular Donepezil-induced reductions in heart rate and increases in PR interval were observed only in patients with Alzheimer’s disease who were not treated with negatively chronotropic or dromotropic drugs; these changes were not associated with bradycardia-induced syn­ cope (70c). These findings provide reassur­ ance about the safety of donepezil in patients taking concomitant cardioactive medications.
An 82-year-old patient with Alzheimer’s dis­

ease developed complete atrioventricular block and a ventricular tachyarrhythmia with dizziness and syncope 1 month after starting donepezil. A temporary ventricular pacing catheter placed in the right ventricle restored sinus rhythm on the fourth day (71A).

Nervous system Leg pain has been attrib­ uted to donepezil (72A).
An 85-year-old woman with a 4-year history of

Alzheimer’s dementia and glaucoma and hypertension controlled with timolol eyedrops and candesartan, respectively, was given donepezil 5 mg/day, gradually increasing to 10 mg/day; within 10 days of the increase in dose she developed bilateral leg pain, which was continuous, severe in the morning, and reducing in severity by evening, resulting in severe distress.

The authors argued that donepezil had contributed to leg pain, in view of the temporal association, dechallenge, and lack of recurrence of the symptoms after switchover to galantamine. It is important to exclude any interaction between candesar­ tan and donepezil. Psychiatric Behavioral effects have been attributed to donepezil (73A).
An 80-year-old White woman developed

alcohol abuse and other behavioral changes, such as outbursts and irritations after starting

Chapter 1

11

to take donepezil; the compulsive behavior ceased after dechallenge and recurred on rechallenge.

Gastrointestinal Two episodes of upper gastrointestinal bleeding occurred in an 86-year-old woman with Alzheimer’s dis­ ease treated with donepezil 5 mg/day; she required blood transfusion and intravenous omeprazole (74A). In the absence of other risk factors, bleeding was possibly attribu­ table to donepezil. Monitoring therapy Preliminary data in 42 Italian patients with Alzheimer’s disease compared with 48 matched elderly Italian healthy volunteers from the same geogra­ phical region suggest that CYP2D6 poly­ morphism influences both donepezil metabolism and the therapeutic outcome (75c). Knowledge of a patient’s CYP2D6 genotype together with donepezil plasma concentration measurement might be useful in improving clinical efficacy.

Rivastigmine (SED-15,3072;SEDA-30,10) Monitoring therapy Treatment with rivastigmine produced modest neuronal functional recovery in the frontal cortex only, measured as reversal of a diseaserelated reduction in N-acetylaspartate/ creatine ratio but did not alter the diseaserelated myoinositol/creatine ratio in any cortical regions (76c). Since the modest clinical changes correlated with small changes in metabolite ratios, magnetic resonance spectroscopy could be useful in monitoring the response to drug treatments in Alzheimer’s disease. Butyryl cholinesterase wild-type carriers younger than 75 years had a significantly greater treatment response to rivastigmine over 2 years than patients taking donepezil. In contrast, butyrylcholinesterase K-variant carriers experienced similar long-term treatment effects with both agents, although adverse events were more frequent in those taking rivastigmine (77c). These differences may reflect an ability of rivastigmine to inhibit both butyrylcholinesterase and acet­ ylcholinesterase enzymes.

12

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Reginald P. Sequeira

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11. Hanna A, Sledge G, Mayer ML, Hanna N, Einhorn L, Monahan P, Daggy J, Bhatia S. A phase II study of methylphenidate for the treatment of fatigue. Support Care Cancer 2006;14:210–5. 12. Bonnet-Brilhault F, Broly F, Blanc R, Furet Y, Barthelemy C, Paintaud G. An ADHD 6 yearold child ultra-rapid metabolizer for CYP2D6. J Clin Psychopharmacol 2006;26:442–4. 13. De Vane CL, Markowitz JS, Carson SW, Boulton DW, Gill HS, Nahas Z, Risch SC. Single-dose pharmacokinetics of methylphe­ nidate in CYP2D6 extensive and poor metabolizers. J Clin Psychopharmacol 2000;20:347–9. 14. Roessner V, Robatzek M, Knapp G, Banaschewski T, Rothenberger A. Firstonset tics in patients with attention-deficit­ hyperactivity disorder: impact of stimulants. Dev Med Child Neurol 2006;48:616–21. 15. Varley CK, Vincent J, Varley P, Calderon R. Emergence of tics in children with attention deficit hyperactivity disorder trea­ ted with stimulant medications. Compr Psychiatry 2006;42:228–33. 16. Mendhekar DN, Duggal HS. Methylpheni­ date-induced rabbit syndrome. Ann Phar­ macother 2006;40:2076. 17. Rahman S, Robbins TW, Hodges JR, Mehta MA, Nestor PJ, Clark L, Sahakian BJ. Methylphenidate (‘Ritalin’) can ameliorate abnormal risk-taking behavior in the frontal variant of frontotemporal dementia. Neu­ ropsychopharmacology 2006;31:651–8. 18. Hellander M. Medication-induced mania: ethical issues and the need for more research. J Child Adolesc Psychopharmacol 2003;13:199. 19. Ross RG. Psychotic and manic like symp­ toms during stimulant treatment of attention deficit-hyperactivity disorder. Am J Psychia­ try 2006;163:1149–52. 20. Mick E, Biederman J, Spencer T, Faraone SV, Sklar P. Absence of association with DAT1 polymorphism and response to methylphenidate in a sample of adults with ADHD. Am J Med Genet (Part B) 2006;141B:890–4. 21. Langley K, Turic D, Pierce TR, Mills S, Van den Bree MB, Owen MJ, O’Donnovan MC,

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14 43. Charach A, Figueroa M, Chen S, Ickowicz A, Schachar R. Stimulant treatment over 5 years: effects on growth. J Am Acad Child Adolesc Psychiatry 2006;45:415–21. 44. Spencer TJ, Faraone SV, Biederman J, Lerner M, Cooper KM, Zimmerman Bon behalf of the Concerta Study Group. Does prolonged therapy with a long-acting stimu­ lant suppress growth in children with ADHD? J Am Acad Child Adolesc Psy­ chiatry 2006;45:527–35. 45. Wigal T, Greenhill L, Chuang S, McCough J, Vitiello B, Skrobala A, Swanson J, Wigal S, Abikoff H, Kollins S, McCracken J, Riddle M, Posner K, Ghuman J, Davies M, Thorp B, Stehl A. Safety and tolerability of methylphenidate in preschool children with ADHD. J Am Acad Child Adolesc Psychiatry 2006;45:1294–303. 46. Greenhill LL, Pliszka S, Dulcan MK. Summary of the practice parameter for the use of stimulant medications in the treat­ ment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry 2002;40:1352–5. 47. Wilens TE, McBurnett K, Bukstein O, McCough J, Greenhill L, Lerner M, Stein MA, Conners K, Duby J, Newcorn J, Bailey CE, Kratochvil CJ, Coury D, Casat C, Denisco MJC, Halstead P, Bloom L, Zim­ merman BA, Gu J, Cooper KM, Lynch JM. Multisite controlled study of OROS methyl­ phenidate in the treatment of adolescents with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 2006;160:82–90. 48. Biederman J, Mick E, Surman C, Doyle R, Hammerness P, Harpold T, Dunkel S, Dougherty M, Aleardi M, Spencer T. A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 2006;59:829–35. 49. Winhusen T, Somoza E, Singal BM, Harrer J, Apparaju S, Mezinskis J, Desai P, Elkashef A, Chiang CN, Horn P. Methyl­ phenidate and cocaine: a placebo-controlled drug interaction study. Pharmacol Biochem Behav 2006;85:29–38. 50. Collins S, Levin F, Foltin R, Kleber H, Evans S. Response to cocaine, alone and in combination with methylphenidate, in cocaine abusers with ADHD. Drug Alcohol Depend 2006;82:158–67.

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51. Gill M, Haerich P, Westcott K, Godenick KL, Tucker JA. Cognitive performance following modafinil versus placebo in sleep-deprived emergency physicians: a double-blind randomized crossover study. Acad Emerg Med 2006;13:158–65. 52. Luborzewski A, Regen F, Schindler F, Anghelescu I. Modafinil-induced reversible hyperkinetic nondystonic movement disor­ der in a patient with major depressive disorder. J Neuropsychiatry Clin Neurosci 2006;18:248–9. 53. Fukasawa T, Yasui-Furukori N, Suzuki A, Ishii G, Inoue Y, Tateishi T, Otani K. Effects of caffeine on the kinetics of fluvoxamine and its major metabolite in plasma after a single oral dose of the drug. Ther Drug Monit 2006;28:308–11. 54. Michaud V, Moukassi MS, Labbe L, Bèlanger P-M, Ferron LA, Gilbert M, Grech-Bèlanger O, Turgeon J. Inhibitory effects of propafe­ none on the pharmacokinetics of caffeine in humans. Ther Drug Monit 2006;28:779–83. 55. Shihara T, Kato M, Ichiyama T, Takahashi Y, Tanuma N, Miyata R, Hayasaka K. Acute encephalopathy with refractory status epilepticus: bilateral mesial temporal and claustral lesions, associated with a periph­ eral marker of oxidative DNA damage. J Neurol Sci 2006;250:159–61. 56. Delanty N, French JA, Labar DR, Pedley TA, Rowan AJ. Status epilepticus arising de novo in hospitalized patients: an analysis of 41 patients. Seizure 2001;10:116–9. 57. Orlando R, Padrini R, Perazzi M, De Martin S, Piccoli P, Palatini P. Liver dysfunction markedly decreases the inhibition of cyto­ chrome P-450 1A2-mediated theophylline metabolism by fluvoxamine. Clin Pharmacol Ther 2006;79:489–99. 58. Ionnides-Demos LL, Proietto J, Tonkin AM, McNeil JJ. Safety of drug therapies used for weight loss and treatment of obesity. Drug Saf 2006;29:277–302. 59. Walker AM, Langleben D, Korelitz JJ, Rich S, Rubin LJ, Strom BL, Gonin R, Keast S, Badesch D, Barst RJ, Bourge RC, Channick R, Frost A, Gaine S, McGoon M, McLaugh­ lin V, Murali S, Oudiz RJ, Robbins IM, Tapson V, Abenhaim L, Constantine G. Temporal trends and drug exposures in pulmonary hypertension: an American experience. Am Heart J 2006;152:521–6.

Central nervous system stimulants and drugs that suppress appetite 60. Hung Y-M, Chang J-C. Weight-reducing regimen associated with polymorphic ven­ tricular tachycardia. Am J Emerg Med 2006;24:714–6. 61. Harrison-Woolrych M, Hill GR, Clark DWJ. Bruising associated with sibutramine: results from post-marketing surveillance in New Zealand. Int J Obesity 2006;30:1315–7. 62. Conway CR, Ziaee L, Langenfeld SJ. Ephedrine-induced emergence of bipolar symptoms. Bipolar Disord 2006;8:204–5. 63. Vidal C, Quandte S. Identification of a sibutramine-metabolite in patient urine after intake of a “pure herbal” Chinese slimming product. Ther Drug Monit 2006;28:690–2. 64. Jung J, Hermanns-Clausen M, Weinmann W. Anorectic sibutramine detected in a Chinese herbal drug for weight loss. Foren­ sic Sci Int 2006;161:221–2. 65. Winblad B, Wimo A, Engedal K, Soininen H, Verhey F, Waldemar G, Wetterholm A-L, Haglund A, Zhang R, Schindler Rfor the Donepezil Nordic Study Group. 3-Year study of donepezil therapy in Alzheimer’s disease: effects of early and continuous therapy. Dementia 2006;21:353–63. 66. Hogan DB. Donepezil for severe Alzhei­ mer’s disease. Lancet 2006;367:1031–2. 67. Rockwood K, Graham JE, Fay S, ACADIE Investigators. Goal setting and attainment in Alzheimer’s disease patients treated with donepezil. J Neurol Neurosurg Psychiatry 2002;73:500–7. 68. Lopez-Pousa S, Olmo JG, Franch V, Estrada AT, Cors OS, Nierga IP, GeladaBatlle E. Comparative analysis of mortality in patients with Alzheimer’s disease treated with donepezil or galantamine. Age Ageing 2006;35:365–71. 69. Winblad B, Kilander L, Eriksson S, Min­ thon L, Batsman S, Wetterholm A-L, Jansson Blixt C, Haglund Afor the Severe

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Alzheimer’s Disease Study Group. Donepe­ zil in patients with severe Alzheimer’s disease: double-blind, parallel-group, place­ bo-controlled study. Lancet 2006;367: 1057–65. Bordier P, Garrigue S, Lanusse S, Margaine J, Robert F, Gencel L, Lafitte A. Cardio­ vascular effects and risk of syncope related to donepezil in patients with Alzheimer’s disease. CNS Drugs 2006;20:411–7. Suleyman T, Tevfik P, Abdulkadir G, Ozlem S. Complete atrioventricular block and ventricular tachyarrhythmia associated with donepezil. Emerg Med J 2006;23:641–2. Kuloor CB, Puranik A. Pain with donepezil. Age Ageing 2006;35:639–40. Marinho V, Laks J, Engelhardt E, Conn D. Alcohol abuse in an elderly woman taking donepezil. J Clin Psychopharmacol 2006;26: 683–5. Cholongitas E, Pipili C, Dasenaki M. Recurrence of upper gastrointestinal bleed­ ing after donepezil administration. Alzhei­ mer’s Dis Assoc Disord 2006;20:326. Blesa R, Bullock R, He Y, Bergman H, Gambina G, Meyer J, Rapatz G, Nagel J, Lane R. Effect of butyryl-cholinesterase genotype on the response to rivastigmine or donepezil in younger patients with Alzheimer’s disease. Pharmacogenomics 2006;16:771–4. Modrego PJ, Pina MA, Fayed N, Diaz M. Changes in metabolite ratios after treatment with rivastigmine in Alzheimer’s disease. A nonrandomized controlled trial with mag­ netic resonance spectroscopy. CNS Drugs 2006;20:867–77. Versaldi F, Miglio G, Scordo MG, Dahl M­ L, Villa LM, Biolcati A, Lombardi G. Impact of the CYP2D6 polymorphism on steady-state plasma concentrations and clin­ ical outcome of donepezil in Alzheimer’s disease patients. Eur J Pharmacol 2006;62:721–6.

P.J. Cowen

2

Antidepressant drugs

GENERAL Psychological Antidepressant drugs are usually taken by people who are trying to maintain their usual occupational and social activities. Thus, possible adverse effects on cognitive and psychomotor performance assume significant clinical importance. Most reported studies on this topic involve shortterm treatment of healthy participants. As expected, such studies generally show that acute treatment with sedating antidepressants (e.g., tertiary tricyclic antidepressants) impair psychomotor performance more than nonsedating agents, such as selective serotonin re-uptake inhibitors (SSRIs). However, depression itself is associated with significant cognitive and psychomotor impairment, and there are few data on whether courses of antidepressant treatment improve performance as depression remits, leave it unchanged, or even cause further impairment (SEDA-30, 15). There has been a cross-sectional study of memory and cognitive performance in 56 patients who had taken tricyclic antidepres­ sants and fluoxetine for at least 6 months and had responded to treatment to some extent, although mild-to-moderate depres­ sive symptoms persisted in most subjects (1C). In general, the patients performed worse on the psychological tasks than the controls, but the degree of impairment was mild and not thought to be clinically significant. There were few differences between the drugs, but imipramine seemed to impair psychomotor performance more than clomipramine and fluoxetine. Patients’ Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03102-X r 2009 Elsevier B.V. All rights reserved.

perceptions of their cognitive performance were significantly worse than the impair­ ment shown by the objective tests. This could be explained if persisting depressive symptoms led to negative self-assessment. Alternatively, it is possible that the psycho­ logical tests used were not sufficiently sensitive to detect differences that might be important in real-world activities. In a study of both computerized tasks of cognition and real-life driving performance in 24 patients who had taken SSRIs or venlafaxine for depression for 6–52 weeks, the mean score on the Hamilton Depres­ sion Rating Scale was modest (8.8) but the range was wide (0–26), suggesting that some patients at least were still significantly depressed (2C). While depressed patients showed normal performance on the labora­ tory tasks of memory and attention, their driving performance was significantly impaired. The authors suggested that impairment in driving performance in depressed patients was due to residual depressive symptoms, but there was no correlation between scores on the Hamilton Scale and driving performance. However, because repeated administration of SSRIs and venlafaxine to healthy volunteers does not impair driving (3R), an effect of depression seems the most likely explana­ tion. It is not clear whether the driving impairment seen in depressed patients might be associated with an increased risk of road accidents. The depressed patients in the study rated their own driving ability significantly less than controls, although the instructor travelling with them did not. The effects of depression and its treat­ ment on cognitive performance are likely to be more striking in elderly people. In 48 patients with major depression (mean age 68 years), who were given either fluoxetine or the selective noradrenaline re-uptake

17

18 inhibitor reboxetine and assessed again 6 months later, the 33 patients who achieved clinical remission (judged by scores on the Hamilton Scale) showed improvements in memory, having been significantly worse than controls before treatment on a variety of tests of memory, without impaired attention; however, relative to controls they were still somewhat impaired in more complex memory tasks that required sus­ tained cognitive effort (4R). There were no clear differences in the effects of the two antidepressants on memory. These data confirm prospectively that improvement in depression is associated with better mem­ ory performance, but it remains unclear whether antidepressant treatment may have effects separate from its ability to improve mood. In fact, cognitive impairment can persist in unmedicated recovered depressed patients (5R), suggesting that such deficits may be related more to depression, either as a vulnerability factor or as a consequence of repeated episodes of illness. Pregnancy Whether to prescribe antide­ pressant drugs in pregnancy has always been a difficult decision, requiring careful analysis of the potential benefits and harms to mother and baby. Such decisions often have to be taken with limited information about the possible adverse effects of anti­ depressants in these special circumstances. As well as the adverse effects of anti­ depressants, clinicians need to weigh the deleterious consequences of depression itself on mother and baby and also how far antidepressant withdrawal may increase the risk of depressive recurrence. The tradi­ tional view that pregnancy may be protec­ tive against depression is probably fallacious. In a prospective study of women who had become pregnant while taking antidepressants, 82 maintained their medi­ cation throughout pregnancy, of whom 26% relapsed compared with 68% of the 65 women who discontinued medication (OR ¼ 5.0; 95% CI ¼ 2.8, 9.1) (6C). This study suggests that stopping antidepressant treatment during pregnancy (or presumably before conception) causes a significantly increased risk of depression in the mother. Depression in the mother itself is associated

Chapter 2

P.J. Cowen

with poorer birth outcomes and adverse effects on infant development. This complex state of affairs has prompted the production of several guide­ lines and opinion pieces. Those produced by the National Institute for Health and Clinical Excellence (NICE) are likely to be influential because of their explicit evidence base (7M). While recognizing that the decision to introduce or continue with an antidepressant during pregnancy must be based on individual circumstances, the NICE guidelines suggest that tricyclic anti­ depressants, such as amitriptyline and nortriptyline, have lower risks in pregnancy than other antidepressants, while fluoxetine has the lowest risk of the SSRIs. Tricyclic antidepressants and sertraline are suggested to be the most appropriate antidepressants for breast-feeding mothers. It has also been suggested that tricyclic antidepressants should be preferred to SSRIs in pregnant and breast-feeding women (8r). While this is reasonable advice, it is worth remember­ ing that tricyclic antidepressants (with the exception of the less well-studied lofepra­ mine) are dangerous in overdose and generally not as well tolerated as tricyclics. Therefore, a degree of continued SSRI prescribing during pregnancy seems inevi­ table (9r). In these circumstances careful monitoring of infants for neonatal with­ drawal symptoms is advisable.

SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs) (SED-15, 3109; SEDA-28, 15; SEDA-29, 19; SEDA-30, 16)

SSRIs and suicide The relation between SSRIs and suicidal behavior continues to be widely discussed. Most of the current focus is on the use of antidepressants in children and adolescents following a warning by the US Food and Drug Administration (FDA) in 2005 that all

Antidepressant drugs

Chapter 2

antidepressants increase the risk of suicidal thinking and behavior in children and adolescents (10S). The FDA warning was based on a review of 24 randomized trials involving over 4000 young people. The risk of adverse events involving suicidal thinking and behavior was twice as great in the drug-treated group as in the placebo group (4% versus 2%). However, no completed suicides occurred in either group. Further analysis of the whole FDA database showed striking age-related differences in the effect of SSRI treatment on suicidality (defined as all increases in suicidal thinking and suicidal behavior). In those aged 65 years and over, SSRIs significantly protected against the risk of suicidality relative to placebo (OR ¼ 0.39; 95% CI ¼ 0.18, 0.78). However, with decreasing age this protective effect steadily diminished in a linear fashion, until in those aged 18–24 years, SSRIs non-significantly increased the risk of suicidality (OR ¼ 1.55; 95% CI ¼ 0.91, 2.70) (11M). As noted above, in patients under 18 years the risk of suicidality was significantly greater with SSRIs (OR ¼ 2.2; 95% CI ¼ 1.4, 3.6). These intriguing results add plausibility to suggestions that younger people, particularly those under 18 years, have a specific vulnerability to suicidality when they take SSRIs. However, reviewers have pointed out that the trials were not designed to measure druginduced changes in suicidal thinking or behavior and the definition of suicidality is therefore post-hoc and unsatisfactory (12R). Across all randomized studies of new antidepressants in adolescents and children, the mean number to treat to obtain a therapeutic response (NNTB ¼ 17) is substantially less than the number needed to harm in terms of suicidality (NNTH ¼ 402). Therefore, the benefit to harm balance appears favorable, particularly when one remembers that there were no completed suicides in any of the studies (13R). However, the high NNTB emphasizes the limited efficacy of antidepressants in the treatment of depression in young people, and at present fluoxetine is the only agent whose efficacy has satisfied the regulatory authorities in this respect. It is uncertain if this is because of some pharmacological idiosyncrasy of

19 fluoxetine or the effects of differing trial designs and participant recruitment. The latter seem more plausible.

Gastrointestinal There is a reported asso­ ciation between SSRIs and upper gastrointestinal bleeding (SEDA-28, 16), which is greater if patients are taking concomitant non-steroidal anti-inflammatory drugs (NSAIDs). In a review of this topic it was concluded that epidemiological studies have confirmed the association between gastrointestinal bleeding and the prescrip­ tion of drugs with potent serotonin reuptake inhibiting properties (14R). There is less evidence that drugs such as SSRIs are associated with serious bleeding in other body areas. For example, while there are case reports of intracranial bleeding in patients taking SSRIs, epidemiological sur­ veys have not confirmed the presence of a significant association. However, it would be prudent to avoid the use of SSRIs and other potent serotonin re-uptake inhibitors in patients who, for example, have suffered a hemorrhagic stroke. The question of whether SSRIs might increase postopera­ tive bleeding is clearly important, and one study has suggested that SSRI treatment at the time of operation leads to an increased need for perioperative blood transfusion (15C). From this it seems necessary that anesthetists and surgeons be aware if patients under their care are taking SSRIs or related drugs. Teratogenicity Selective serotonin reuptake inhibitors (SSRIs) are now the most widely prescribed antidepressant agents, and studies of their adverse effects on birth outcomes have generally been reassuring (SEDA-30, 16). However, in March 2006, the manufacturer of paroxetine, Glaxo SmithKline, issued additional safety infor­ mation reporting data from two observa­ tional studies, both of which showed a small absolute increase in the risk of cardiovascular abnormalities in the babies of women who took paroxetine during the first trime­ ster of pregnancy (population risk about 1 per 100 births, paroxetine-treated infants

20 1–2 per 100 births). The majority of abnormalities consisted of atrial or ventricular septal defects (16r). Fetotoxicity There is an increased risk of persistent pulmonary hypertension of the newborn (PPHN) in babies of mothers exposed to SSRIs after the 20th week of pregnancy. In babies with PPHN, pulmon­ ary arterial pressure remains high after birth, which results in shunting of poorly oxygenated blood to the systemic circula­ tion. PPNH is a serious condition associated with a significant mortality (5–10%), and survivors can have serious neurological sequelae. The infants of women who took SSRIs during the second half of pregnancy had a significantly increased risk of PPHN (adjusted OR ¼ 6.1; 95% CI ¼ 2.2, 17) (17r). PPHN is uncommon (incidence about 2 per 1000 live births), so even an increase in the risk by a factor of six would not result in a large number of cases, which might have made this particular adverse effect harder to detect. There was no apparent increase in the risk of PPNH in infants whose mothers had taken SSRIs in the first half of pregnancy or in mothers who had taken other kinds of antidepres­ sants at any time during the pregnancy. In a retrospective cohort study of 972 pregnant women in Saskatchewan who had taken an SSRI at some stage during preg­ nancy and 3878 pregnant women free of antidepressant treatment, matched for year of infant birth, type of institution where the birth occurred, and mother’s postal code, the infants of SSRI-treated mothers had sig­ nificantly higher rates of low birth weight, preterm birth, and seizures (18C). However, the women exposed to SSRIs were older, more likely to receive social assistance, more likely to have a diagnosis of drug depen­ dence, and more likely to be taking several medications. Adjusting for such important confounders in adverse birth outcomes is difficult, which suggests that the findings from the study should be treated with caution. It now seems clear that when mothers take SSRIs during the later stages of pregnancy, their newborn infants are at risk of serotonin-related symptoms,

Chapter 2

P.J. Cowen

including jitteriness, hypoglycemia, hypothermia, and convulsions (SEDA-28, 17; SEDA-30, 16). In a prospective cohort study of 120 infants, half of whom were born to mothers taking SSRIs for pro­ longed periods (mean duration of treat­ ment 35 weeks), 18 of the latter showed evidence of neonatal SSRI symptoms while none of the controls was affected (19C). Peak symptoms were usually present on the second day of birth, and there was some evidence of a dose–response relation between the severity of the neonatal symptoms and the dose of SSRI that the mother had been taking. All the infants recovered without specific treatment. It has been unclear whether the syn­ drome described in neonates is due to SSRI withdrawal or a form of serotonin toxicity because the clinical symptoms in both these conditions are similar. Six infants born to mothers who had been taking SSRIs up to delivery had restlessness, feeding problems, jitteriness, and myoclonic activity (20A). In three of the cases, the symptoms occurred on the first day after delivery, while the other babies had difficulties at 3–7 days. In the latter SSRIs were not detectable in the serum. The authors suggested that the late onset of the withdrawal syndrome in some of the babies in the absence of measurable SSRI concentrations implied that the neonatal syndrome is due to SSRI withdrawal. Presumably, however, it is possible that the symptoms associated with SSRI use in mothers might be due to withdrawal in some infants but toxicity in others, particularly when SSRI-related symptoms occur very soon after delivery. Lactation SSRIs are all excreted in breast milk, but the extent to which this occurs varies with individual drugs. Sertraline and paroxetine are found in very low concen­ trations, while fluoxetine and citalopram concentrations in breast milk are relatively greater and can be associated with adverse effects. Tricyclic antidepressants, particu­ larly amitriptyline and nortriptyline, are present in breast milk in relatively low amounts, as is the selective noradrenaline re-uptake inhibitor, reboxetine (7M,21A).

Antidepressant drugs

Chapter 2

Drug–drug interactions SSRIs SSRIs, particularly fluoxetine, paroxetine, and flu­ voxamine, are potent inhibitors of cyto­ chrome P450 enzymes (SEDA-22, 13) and numerous drug–drug interactions of this type have been described in case reports. Interactions have also been demonstrated in healthy volunteers. However, in a review, it has been argued that postmarketing surveillance data suggest that, in practice, clinically significant drug–drug interactions due to this mechanism are infrequent (22R). For example, fluvoxamine reduces caffeine clearance by 80% and extends its half-life in humans from 5 to 30 hours. The magni­ tude of this increase would lead one to predict that caffeine intoxication should be widespread among patients taking fluvox­ amine; however, this does not seem to be the case. There are several possible explanations for this apparent absence of serious drug– drug interactions in clinical practice. For example, SSRI-induced increases in blood concentrations of other drugs might not lead to detectable clinical consequences. In addition, real-world adherence to antide­ pressant medication is often erratic, and so patients may often have low SSRI blood concentrations. A further factor is that pharmacokinetic modelling studies suggest that where alternative pathways of drug metabolism exist (which is usually the case) the effect of inhibition of particular P450 enzyme is much reduced. While this view is reassuring, some SSRI interactions are clearly clinically significant and can occa­ sionally have devastating consequences. Digoxin SSRIs can increase serum digoxin concentrations. Inhibition of P450 enzymes is an unlikely mechanism because digoxin is not metabolized extensively by the liver. The possibility that they might inhibit the renal clearance of digoxin has been assessed in a case–control study of 3144 patients aged 65 years and over, admitted to hospital with digitalis toxicity after SSRI treatment (23C). While there was a significantly increased risk of digoxin toxicity in those taking paroxetine (OR ¼ 2.8; 95% CI ¼ 1.6, 4.7), similar

21 increases were seen in patients taking fluoxetine and fluvoxamine, SSRIs that do not inhibit P glycoprotein. The mechanism of this interaction remains in doubt.  A 68-year-old woman, with no previous

history of psychiatric illness, developed a major depressive disorder (24A). She had atrial fibrillation, for which she had taken digoxin 0.25 mg/day and warfarin 1 mg/day for 2 years. She was given paroxetine 20 mg/day and 2 days later developed nausea, vomiting, and dizziness; after 4 days she became delirious, with visual hallucinations and disorientation. Digitalis intoxication was suspected and con­ firmed by a raised serum concentration (5.2 ng/ ml, target concentration 0.8–2.0 ng/ml). An electrocardiogram showed many ventricular extra beats and complete atrioventricular block. All medications were withdrawn, but it took over 2 weeks for the delirium to resolve fully. During this time she became bedridden, developed an aspiration pneumonia, and even­ tually died.

This report shows that serious drug interactions involving SSRIs are most likely with coadministered drugs that have a narrow therapeutic index and in people who are physically frail. A particular problem here was that the early symptoms of digoxin toxicity (nausea and dizziness) are not dissimilar to the early adverse effects of paroxetine. Macrolide antibiotics Serotonin toxicity can reportedly be precipitated by the addition of erythromycin to sertraline (SEDA-24, 16). A similar case has now been reported with clarithromycin.  A 36-year-old woman, who had been taking a

low dose of paroxetine (10 mg/day) for anxiety for 3 months, developed an upper respiratory tract infection and was given clarithromycin 500 mg bd (25A). After the fourth dose, she developed acute ocular clonus, akathisia, and fever. She was given intravenous fluids and lorazepam. Clarithromycin was withdrawn and the syndrome resolved within 24 hours.

The description of the serotonin syndrome in this case was convincing, but the mechanism was unclear. Possibly inhibition of CYP3A4 may have been involved, as was suggested in the interaction between erythromycin and sertraline.

Chapter 2

22

SEROTONIN AND NORADRENALINE RE­ UPTAKE INHIBITORS (SNRIs) Venlafaxine

(SED-15, 3614; SEDA-28, 19; SEDA-29, 24; SEDA-30, 19)

Fetotoxicity Venlafaxine is a potent serotonin re-uptake inhibitor, so it is not surprising that it has been associated with serotonin-related symptoms in neonates.  A boy was born by forceps delivery at 39

weeks gestation to a 29-year-old woman who had been taking venlafaxine 225 mg/day (26A). He failed to feed properly, had vomiting, and after 24 hours developed multifocal myoclonic seizures. These were treated successfully with intravenous phenobarbital 20 mg/kg. He had showed normal electrolytes and glucose con­ centrations and an EEG and head ultrasound showed no significant abnormality. He made a full recovery and was well 1 year later.

The authors described a second case of seizures in a neonate whose mother had been taking long-term venlafaxine. In this case the seizures started soon after delivery. Infants of mothers taking venlafaxine therefore also require close monitoring after delivery.

OTHER ANTIDEPRESSANTS Bupropion (amfebutamone)

(SED15, 108; SEDA-28, 18; SEDA-29, 24; SEDA-30, 20) Sexual function Bupropion is less likely than SSRIs to cause sexual dysfunction and may be an appropriate choice for patients experiencing sexual difficulties thought to be induced by SSRIs. In 18 minority women (5 Hispanic, 10 African–American, 2

P.J. Cowen

Asian–American, and 1 Native American), who were experiencing low sexual desire after at least 8 weeks of treatment with an SSRI, bupropion 150–300 mg/day was crosstapered (27C). In the group as a whole there were significant improvements in desire, arousal, and orgasm; depression scores also improved. The latter observation raises the possibility that the improvement in sexual function seen after bupropion might be a consequence of reduced depression. However, there was no correlation between change in sexual function and improvement in depression. Whether the improvement in sexual function is entirely due to the removal of SSRI treatment or whether bupropion may have an independent beneficial effect is unclear.

Reboxetine

(SED-15, 3028; SEDA-30,

21) Urinary tract The adverse effect of reboxetine to cause urinary hesitancy has been put to beneficial use in children with enuresis. Reboxetine 4–8 mg at bedtime has been used in an open study on 22 young people (aged 8–26 years) with severely socially handicapping enuresis resistant to an enuresis alarm, desmopressin, and anticholinergic drugs (28C). Complete dryness was achieved with reboxetine, either as monotherapy or combined with desmopressin, in 13. The authors reported adverse effects as mild and transient, but two of the subjects reported aggression and two dysphoria, showing that the use of antidepressants in young people should be accompanied by careful monitoring of mental state. The findings suggest that reboxetine may be a useful alternative to imipramine in refractory enuresis, but placebo-controlled trials will be needed to support this conclusion.

References 1. Gorenstein C, de Carvalho SC, Artes R, Moreno RA, Marcourakis T. Cognitive performance in

depressed patients after chronic use of antide­ pressants. Psychopharmacology 2006;185:84–92.

Antidepressant drugs

Chapter 2

2. Wingen M, Ramaekers G, Schmitt JA. Driving impairment in depressed patients receiving long-term antidepressant treat­ ment. Psychopharmacology 2006;188: 84–91. 3. Ramaekers JG. Antidepressants and driver impairment: empirical evidence from a standard on-the-road test. J Clin Psychiatry 2003;64:20–9. 4. Gallassi R, Di Sarro R, Morreale A, Amore M. Memory impairment in patients with late-onset major depression: the effect of antidepressant therapy. J Affect Disord 2006;91:243–50. 5. Chamberlain SR, Sahakian BJ. The neu­ ropsychology of mood disorders. Curr Psych Ther Rep 2006;3:117–22. 6. Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonixs AF, Stowe ZN. Relapse of major depression during preg­ nancy in women who maintain or discon­ tinue antidepressant treatment. JAMA 2006;295:499–507. 7. National Institute for Health and Clinical Excellence. Antenatal and postnatal mental health: clinical management and service guidance—NICE Guidance. February 2007; http://guidance.nice.org.uk/CG45. 8. Wieck A, Gregoire A. Drugs, hormones and ECT in childbearing women with psychiatric disorders. Psychiatry 2006;5: 25–8. 9. Austin M-P. To treat or not to treat: maternal depression, SSRI use in pregnancy and adverse neonatal effects. Psychol Med 2006;36:1663–70. 10. US Food & Drug Administration. Tem­ plates for antidepressant black box warning and medication guide posted on FDA website, February 3, 2005. 11. Leon AC. The revised warning for anti­ depressants and suicidality: unveiling the black box of statistical analysis. Am J Psychiatry 2007;164:1786–9. 12. Klein DF. The flawed basis for FDA postmarketing safety decisions: the example of anti-depressants and children. Neuropsy­ chopharmacology 2006;31:689–99. 13. Mann JJ, Emslie G, Baldessarini J, Beard­ slee W, Fawcett JA, Goodwin FK, Leon

23

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20.

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23.

AC, Meltzer HY, Ryan ND, Shaffer D, Wagner D. ACNP task force report on SSRIs and suicidal behavior in youth. Neuropsychopharmacology 2006;31:473–92. de Abajo FJ, Montero D, Garcia Rodriguez LA, Madurga M. Antidepressants and risk of upper gastrointestinal bleeding. Pharma­ col Toxicol 2006;98:304–10. Movig LK, Janssen MW, Malefijt JW, Kabel PJ, Leufkens HG, Egberts AC. Relationship of serotoninergic antidepres­ sants and need for blood transfusion in orthopedic surgical patients. Arch Intern Med 2003;163:2354–8. Anonymous. Use of Paxil CR or Paxil during pregnancy. http://us.gsk.com/docs­ pdf/media-news/mi_letter_paroxetine_preg­ nancy.pdf. Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA. Selective serotonin-reup­ take inhibitors and risk of persistent pul­ monary hypertension of the newborn. N Engl J Med 2006;6:579–87. Wen SW, Yang Q, Garner P, Fraser W, Olatunbosun O, Nimrod C, Walker M. Selective serotonin reuptake inhibitors and adverse pregnancy outcomes. Am J Obst Gynecol 2006;194:961–6. Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med 2006;160:173–6. Bot P, Semmekrot BA, van der Stappen J. Neonatal effects of exposure to selective serotonin reuptake inhibitors during preg­ nancy. Arch Dis Child Fetal Neonatal Ed 2006;91:F153. Hackett LP, Ilett KF, Rampono J, Kristen­ sen JH, Kohan R. Transfer of reboxetine into breastmilk, its plasma concentrations and lack of adverse effects in the breastfed infant. Eur J Clin Pharmacol 2006;62:633–8. DeVane CL. Antidepressant–drug interac­ tions are potentially but rarely clinically significant. Neuropsychopharmacology 2006;31:1594–604. Juurlink DN, Mamdani MM, Kopp A, Herrmann N, Laupacis A. A populationbased assessment of the potential interac­ tion between serotonin-specific reuptake

24 inhibitors and digoxin. Br J Clin Pharmacol 2004;59:102–7. 24. Yasui-Farukori N, Kaneko S. Digitalis intoxication induced by paroxetine co­ administration. Lancet 2006;367:788. 25. Jaber BL, Lobon LF, Madias NE. The serotoin syndrome complicating prescrip­ tion of paroxetine and clarithromycin. Am J Med 2006;119(4):e3. 26. Pakalapati RK, Bolisetty S, Austin M-P, Oei J. Neonatal seizures from in utero

Chapter 2

P.J. Cowen

venlafaxine exposure. J Paediatr Child Health 2006;42:737–8. 27. Dobkin RD, Menza M, Marin H, Allen LA, Rousso R, Leiblum SR. Bupropion improves sexual functioning in depressed minority women. J Clin Psychopharmacol 2006;26:21–6. 28. Nevéus TT. Reboxetine in therapy-resistant enuresis: results and pathogenetic implica­ tions. Scand J Urol Nephrol 2006;40(1): 31–4.

Rif S. El-Mallakh

3 Lithium in neuroprotection Several ani­ mal and in vitro studies have demonstrated a neuroprotective effect of lithium against a wide array of toxic insults (1E,2E,3E). In humans, grey matter density was greater in 20 lithium-treated patients compared with 8 patients not taking lithium and 29 matched healthy controls, particularly in the right anterior cingulate (4c). Furthermore, there was a bilateral increase in the volume of the hippocampus and hippocampal head in patients with bipolar disorder who took lithium for 1–8 weeks compared with unmedicated patients and healthy controls (5c). While these studies suggest a neuror­ estorative effect of lithium, it has not been clearly demonstrated that the observed increases in the sizes of brain structures are not merely related to increases in water content secondary to lithium accumulation. Observational studies In a prescription study of the use of lithium in Spain between 1985 and 2003, the use of lithium increased from 0.21 to 0.79 defined daily doses per 1000 inhabitants (6C). However, prescriptions do not mean that the patients are actually taking the lithium. In a study of 44 637 patients attending Veteran’s Administration Hospi­ tals and Clinics throughout the United States, adherence to lithium or mood stabi­ lizing anticonvulsants was less than optimal (7C). Only 54% of the patients were fully adherent (defined as a medication posses­ sion ratio of over 0.8). An additional 25% were partially adherent (defined as a medi­ cation possession ratio of 0.5–0.8), while the Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03103-1 r 2009 Elsevier B.V. All rights reserved.

Lithium remaining 21% were non-adherent. Nonadherent subjects were more likely to be non-White, unmarried, and younger, and to have a substance abuse disorder. Subjects for whom more than one agent had been prescribed had better adherence than those taking monotherapy. Unlike other reports, these authors found that poorer adherence to a treatment regimen was associated with reduced rates of hospitalization (once con­ founding factors were adjusted for, such as substance abuse, prior hospitalizations, and number of out-patient visits). Adherence, lithium concentrations, and relapse are intimately linked. A prospective study of 86 patients on lithium followed for 2.5 years to determine if polarity of recur­ rence is related to lithium concentrations showed that the concentration before relapse was significantly lower before a manic episode (0.5370.13 mmol/l) than before a depressive episode (0.6670.21 mmol/l) (8C). The authors suggested that higher lithium concentrations may be required to prevent a manic episode as opposed to the prevention of a depressive episode. However, the data can also be interpreted in the opposite manner, that even higher concentrations are required to prevent a depressive episode, since depression occurred despite higher concentrations. Regardless of the interpreta­ tion of these results, this valuable observation needs to be studied further. In an effectiveness retrospective chart review study of 120 subjects with type I or type II bipolar disorder, 30% had a full response (9C). While this number is some­ what low, it is much higher than with olanzapine (25%), valproate (13%), lamo­ trigine (11%), or carbamazepine (0%). In an augmentation study of 34 patients with unipolar depression, lithium or lamo­ trigine was added to existing treatments in a

25

26 randomized, open fashion. There was at least a 50% improvement (response) in 41% and 18% went into remission; this was equivalent to the effect seen with lamotrigine (10C). Placebo-controlled studies and systematic reviews Mania Documentation of the efficacy of lithium in the treatment of mania and in the prevention of future episodes has been recently presented in several rando­ mized placebo-controlled studies. Lithium was also reported to be effective in the treatment of acute manic episodes when added to quetiapine (11C). The combina­ tion was more effective than lithium alone, but not significantly so. Bipolar disorder Two large studies intended to study the efficacy of lamotrigine in the maintenance of euthymia in patients with type I bipolar disorder with recent episodes of mania or depression, previously reported (12C), were reanalysed to deter­ mine if the treatment agents (lithium and lamotrigine) were effective when relapses in the first 90 or 180 days were excluded (13C). The analysis was intended to deter­ mine if these agents actually prevent recurrence (of a new episode) or simply delay relapse (of the same episode). The reanalysis confirmed the original finding: both lithium and lamotrigine are effective in delaying (and preventing) relapse into either mania or depression in type I bipolar disorder. Cardiovascular Several individual case reports of lithium toxicity have highlighted the ability of lithium to induce sinoatrial block and bradycardia (14A,15A,16A,17A, 18A). Lithium was also associated with a cardiomyopathy discovered after 16 years of lithium treatment, although causality was not established (19A). These cases highlight the effects of lithium on the sodium channel and intracellular sodium concentrations; lithium reduces abnormally raised intracellular sodium concentrations in cell culture (20E). Respiratory Pulmonary hypertension (21A) during lithium therapy was unlikely to repre­ sent a true effect of lithium.

Chapter 3

Rif S. El-Mallakh

Nervous system The predilection of lithium toxicity for the central nervous system is supported by several individual case reports of lithium-associated neuro­ toxicity. Initial signs of lithium toxicity usually manifest in dyscoordination (22R). Cases of cerebellar syndrome with thera­ peutic lithium concentrations (23A) and long-lived cerebellar signs after lithium toxicity (24A) support the likelihood that lithium toxicity will affect the cerebellum. Lithium can cause confusional states as well as myoclonic jerks (25R). Conse­ quently, confusing lithium with Creutz­ feld–Jakob disease is understandable (26A). Since lithium interferes with intracellular calcium mobilization and can weaken mus­ cular activity, it can unmask myasthenia gravis (27A). Long-lived sequelae of lithium toxicity have previously been reported with severe toxicity, and are highlighted in cases of persistent signs of neurotoxicity after lithium poisoning (24A, 28A). Abnormal electroencephalographic changes, which have long been associated with lithium treatment (29R), have been reported in a case of non-convulsive status epilepticus that recurred with lithium rechallenge (30A). Neuroleptic malignant syndrome occurred in a 47-year-old man taking lithium and valproate who had ziprasidone added (31A). Psychological All mood stabilizers can cause cognitive dysfunction. In a compara­ tive study of commonly used mood stabi­ lizers lithium caused cognitive problems that were greater than lamotrigine and olanzapine, but less than topiramate, valproate, and carbamazepine (32A). Psychiatric Dementia Patients with bipolar disorder are at greater risk of dementia as they age. In 114 elderly euthymic bipolar patients, of whom 66 were taking lithium and 48 were not, the pre­ valence of dementia was 19% compared with 7% in a comparable non-bipolar population (33C). However, only 3 of those taking lithium developed dementia, com­ pared with 16 of those who were not. This

Lithium

Chapter 3

may be related to the ability of lithium to inhibit glycogen synthase kinase 3 beta (GSK 3beta), which results in reduced phosphorylation of the tau protein in a mouse model of Alzheimer’s disease (34E). Suicide risk Additional data have emerged that suggest that lithium reduces suicide risk. A meta-analysis of 31 available studies comprising some 85 229 person years showed that the risk of completed suicide was nearly five times lower in lithium-treated patients (RR ¼ 4.91; 95% CI ¼ 3.82, 6.31) (35M). Additionally, an analysis of suicides in eight studies compris­ ing 2434 person years in 329 patients with major depression showed a significant reduction with lithium (RR ¼ 6.77; 95% CI ¼ 2.10, 77) (36M). Sensory systems Optic neuritis associated with lithium toxicity (37A) may not have been caused by lithium. Endocrine Thyroid Both lithium and mood disorders are associated with a wide range of thyroid abnormalities (38M). How­ ever, thyroid disease itself is not particularly common. In an epidemiological study of thyroid disease in over half a million people in Denmark for 4 years (2 027 208 person years) there were only 685 cases of newonset hypothyroidism; lithium was asso­ ciated with only a small fraction of those cases (1.6%) (39C). In a more targeted study of 46 psychiatric out-patients taking lithium, 17% developed overt hypothyroid­ ism and 35% with subclinical hypothyroid­ ism (raised thyroid stimulating hormone) (40C). These high rates of increases in TSH increase the risk of thyroid cancer, and thyroid papillary carcinoma has been reported in a patient taking long-term lithium (41C). Parathyroid Because lithium reduces the intracellular calcium signal, it is occasion­ ally associated with increases in parathyroid hormone (PTH).  A 56-year-old man with bipolar illness who

had taken lithium for 5 years developed an incidental increase in PTH with a concomitant

27 increase in serum calcium; lithium was with­ drawn and all the values normalized (42A).

Of 12 patients who underwent parathyr­ oid gland resection while maintaining their lithium intake, only 8 remained normocal­ cemic (43c). Subclinical increases in PTH probably underlie the observation that lithium was associated with a reduced likelihood of bone fracture in a study of 231 778 bone fractures (OR ¼ 0.75), despite the observation that bipolar illness itself may be related to an increase in bone fractures in subjects not taking lithium (OR ¼ 1.35) (44C). Diabetes insipidus Glomerular dysfunc­ tion with lithium is rare, but polyuria and diabetes insipidus are more common (45R,46R). This appears to be related to a reduction in cyclic adenosine monopho­ sphate (cAMP) in response to vasopressin (47C). Generally, diabetes insipidus is more of a nuisance than a significant problem. However, if these patients are fluid deprived they can experience complica­ tions. Nearly all cases of lithium-related diabetes insipidus occur while people are taking lithium, and they frequently resolve after withdrawal. However, in one case diabetes insipidus occurred after lithium withdrawal (48A). Acute hypernatremia occurred in a 55­ year-old woman taking lithium, who was made to fast in preparation for surgery for a hip fracture and was loaded with large volumes of fluid during the operation; the authors attributed this to decompensation of undiagnosed nephrogenic diabetes insipidus due to chronic lithium treatment (49Ar). Metabolism The general perception among clinicians is that lithium causes minimal to moderate weight gain in a similar fashion to quetiapine, risperidone, and valproate (50R). This is in line with actual observations of long-term changes in weight in subjects randomly assigned to receive lithium (n ¼ 166), lamotrigine (n ¼ 227), or placebo (n ¼ 190) (51C). After 1 year of lithium treatment, there was an average gain of 2.2 kg, compared with 0.2 kg in placebo-treated subjects, and

28 a loss of 1.2 kg in patients taking lamotri­ gine. Weight gain was greatest in obese subjects. Non-obese lithium-treated patients gained 1.1 kg after 12 months, which was minimally greater than placebo-treated patients (0.7 kg over 1 year) and lamotrigine­ treated subjects (0.5 kg over 1 year). However, obese lithium-treated patients gained 6.1 kg. Lamotrigine-treated obese patients lost 4.2 kg, while placebo-treated obese subjects lost 0.6 kg over 1 year of study follow-up (52C). Combination treatments in bipolar illness cause more weight gain than monotherapy over 3 months. Monotherapy with lithium or other mood stabilizing anticonvulsants in children caused an average weight gain of 1.2 kg; combining two mood stabilizers resulted in a gain of 2.1 kg; combining a mood stabilizer with a second-generation antipsychotic drug resulted in a gain of 5.5 kg (53C). Lithium has an insulin-like effect (54E). Sudden lithium withdrawal was associated with transient diabetes in a young man with bipolar disorder (55A). Skin Although lithium can cause rashes (56RH), typical drug rashes (57A) are rare, since lithium is an ion that cannot activate the immune system. Reproductive system Menometrorrhagia during lithium therapy (58A) was unlikely to have represented a true effect of lithium. Teratogenicity Lithium has been classified as a weak teratogen (59R). Malformations attributable to lithium are limited to the heart, with a focus on Ebstein’s anomaly. Babies born to mothers taking lithium also tend to have higher birth weights. Lithium given to animals at doses that are thera­ peutic in bipolar disorder in humans does not show animal teratogenicity. Drug overdose In Scotland, there were 172 inquiries about lithium overdoses to the Scottish Poisons Information Bureau from 2000 to 2005 (29 calls per year) (60C). In the Czech Republic there were 70 calls to the Czech Toxicological Infor­ mation Centre between 2000 and 2003

Chapter 3

Rif S. El-Mallakh

(18 calls per year) (61C). The severity of the episode of poisoning was greater if it occurred slowly. Thus, if a patient became toxic while taking lithium over a long period of time without an overdose, there was a greater likelihood of moderate to severe toxicity (55% of such cases). If a patient took an overdose of lithium with­ out previously taking lithium, the like­ lihood of a moderate to severe episode was low (9.9%). If the presentation occurred after an overdose superimposed on routine clinical use of lithium, the likelihood of moderate to severe poison­ ing was intermediate between the two previous conditions (26%). Drug–drug interactions Risperidone Toxic encephalopathy due to the combina­ tion of lithium and risperidone (62A) is likely to be rare, given that such cases were not seen in formal studies of the combination of lithium with risperidone (63A). Valsartan The observation that lithium combined with the angiotensin II receptor antagonist valsartan led to toxicity (64A) may represent a rare event. Venlafaxine Lithium given with venlafax­ ine can cause the serotonin syndrome. This has been reported in an elderly woman taking a high dose of venlafaxine, but would have probably occurred with venlafaxine alone (65A). Monitoring therapy Lithium concentration monitoring is believed to help reduce the likelihood of toxicity. A study of drug concentration monitoring in a population of 17 174 members of the Kaiser Permanente insurance group showed that lithium concen­ trations were checked more often than other potentially toxic drugs (over 50% of lithiumtreated patients) (66C). Lithium concentra­ tion monitoring was performed less often at the Veteran’s Administration Hospitals. In 435 patients taking a mood stabilizer, a concentration was checked only 40% of the time (67C). Similarly, in a large urban hospital in Thailand, monitoring of lithium concentra­ tions in 60 patients followed published local guidelines only 36% of the time (68C).

Lithium

Chapter 3

A report of a 64-year-old woman devel­ oped moderately severe lithium toxicity with a concentration of 2.42 mmol/l, having taken a static dose of lithium for 33 years (69A). This highlights the importance of regular monitoring, particularly at the time of an intercurrent illness or when another drug is added. Management of toxicity The gold standard for severe lithium toxicity remains

29 haemodialysis (70R). However, since lithium is distributed widely throughout the body, the serum lithium concentration commonly rebounds after the first rounds of dialysis. Continuous venous or arteriovenous hae­ mofiltration is slower but avoids this rebound effect. Alternatively, haemodialysis with a bicarbonate dialysate and a high-flux mem­ brane may also reduce the rebound effect while still allowing for rapid reduction in serum lithium concentration (71c).

References 1. De Vasconcellos AP, Nieto FB, Crema LM, Diehl LA, de Almeida LM, Prediger ME, da Rocha ER, Daimaz C. Chronic lithium treatment has antioxidant properties but does not prevent oxidative damage induced by chronic variate stress. Neurochem Res 2006;31:1141–51. 2. Yazlovitskaya EM, Edwards E, Thotala D, Fu A, Osusky KL, Whetsell WO, Boone B, Shinohara ET, Hallahan DE. Lithium treat­ ment prevents neurocognitive deficit result­ ing from cranial irradiation. Cancer Res 2006;66:11179–86. 3. Zhong J, Yang X, Yao W, Lee W. Lithium protects ethanol-induced neuronal apopto­ sis. Biochem Biophys Res Commun 2006; 350:905–10. 4. Bearden CE, Thompson PM, Dalwani M, Hayashi KM, Lee AD, Nicoletti M, Trakh­ tenbroit M, Glahn DC, Brambilla P, Sassi RB, Mallinger AG, Frank E, Kupfer DJ, Soares JC. Greater cortical gray matter density in lithium-treated patients with bipo­ lar disorder. Biol Psychiatry 2007;62(1):7–16. 5. Yucel K, Taylor VH, McKinnon MC, MacDonald K, Alda M, Young LT, MacQueen GM. Bilateral hippocampal volume increase in patients with bipolar disorder and short-term lithium treatment. Neuropsychopharmacology 2007;195(3): 357–67. 6. Castells X, Vallano A, Rigau D, Pérez J, Casas M, Capellá D. Trends in lithium prescription in Spain from 1985 to 2003. J Affect Disord 2006;91:273–6. 7. Sajatovic M, Valenstein M, Blow F, Ganoczy D, Ignacio R. Treatment adherence

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with lithium and anticonvulsant medications among patients with bipolar disorder. Psychiatr Serv 2007;58:855–63. Kleindienst N, Severus WE, Greil W. Are serum lithium levels related to the polarity of recurrence in bipolar disorders? Evi­ dence from a multicenter trial. Int Clin Psychopharmacol 2007;22:125–31. Garnham J, Munro A, Slaney C, MacDou­ gall M, Passmore M, Duffy A, O’Donovan C, Teehan A, Alda M. Prophylactic treat­ ment response in bipolar disorder: results of a naturalistic observation study. J Affect Disord 2007;104(1–3):185–90. Schindler F, Anghelescu IG. Lithium versus lamotrigine augmentation in treatment resistant unipolar depression: a rando­ mized, open-label study. Int Clin Psycho­ pharmacol 2007;22:179–82. Yatham LN, Vieta E, Young AH, Möller HJ, Paulsson B, Vågerö M. A double blind, randomized, placebo-controlled trial of quetiapine as an add-on therapy to lithium or divalproex for the treatment of bipolar mania. Int Clin Psychopharmacol 2007;22: 212–20. Goodwin GM, Bowden CL, Calabrese JR, Grunze H, Kasper S, White R, Greene P, Leadbetter R. A pooled analysis of 2 placebo-controlled 18-month trials of lamo­ trigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry 2004;65(3): 432–41. Calabrese JR, Goldberg JF, Ketter TA, Suppes T, Frye M, White R, DeVeaughGeiss A, Thompson TR. Recurrence in bipolar I disorder: a post hoc analysis

Chapter 3

30

14.

15. 16.

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22. 23.

24.

25.

excluding relapses in two double-blind maintenance studies. Biol Psychiatry 2006; 59:1061–4. Fragakis N, Iliadis I, Papanastasiou S, Lambrou A, Katsaris G. Brugada type electrocardiographic changes induced by concomitant use of lithium and propafe­ none in patient with Wolff–Parkinson– White syndrome. Pacing Clin Electrophy­ siol 2007;30:823–5. Goldberger ZD. Sinoatrial block in lithium toxicity. Am J Psychiatry 2007;164:831–2. Oudit GY, Korley V, Backx PH, Dorian P. Lithium-induced sinus node disease at therapeutic concentrations: linking lithiuminduced blockade of sodium channels to impaired pacemaker activity. Can J Cardiol 2007;23:229–32. Waring WS. Delayed cardiotoxicity in chronic lithium poisoning: discrepancy between serum lithium concentrations and clinical status. Basic Clin Pharmacol Toxicol 2007;100:353–5. White B, Larry J, Kantharia BK. Protracted presyncope and profound bradycardia due to lithium toxicity. Int J Cardiol 2008;125 (3):e48–50. Aichhorn W, Huber R, Stuppaeck C, Whitworth AB. Cardiomyopathy after long-term treatment with lithium—more than a coin­ cidence? J Psychopharmacol 2006;20:589–91. Huang X, Lei Z, El-Mallakh RS. Lithium normalizes elevated intracellular sodium. Bipolar Disord 2007;9(3):298–300. Ceylan ME, Alpsan MH. Pulmonary hyper­ tension during lithium therapy: clinical case study. Psychopharmacol Bull 2007;40:110–2. El-Mallakh RS. Acute lithium neurotoxi­ city. Psychiatr Dev 1986;4:311–28. Ozsoy S, Basturk M, Esel E. Cerebellar syndrome in a patient with pneumonia under lithium treatment: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:1532–4. Niethammer M, Ford B. Permanent lithium-induced cerebellar toxicity: three cases and review of literature. Mov Disord 2007;22:570–3. Kaplan PW, Birbeck G. Lithium-induced confusional states: nonconvulsive status epilepticus or triphasic encephalopathy? Epilepsia 2006;47:2071–4.

Rif S. El-Mallakh

26. Mouldi S, Le Rhun E, Gautier S, Devemy M, Destée A, Defebvre L. Encéphalopathie induite par le lithium mimant un tableau de maladie de Creutzfeldt-Jakob. [Lithium-in­ duced encephalopathy mimicking Creutzfeldt–Jakob disease.] Rev Neurol (Paris) 2006;162:1118–21. 27. Alevizos B, Gatzonis S, Anagnostara Ch. Myasthenia gravis disclosed by lithium carbonate. J Neuropsychiatry Clin Neurosci 2006;18:427–9. 28. Araújo LC, Nery-Fernandes F, Quarantini LC, Miranda-Scippa A. Neurotoxicidade persistente secundária ao uso de lítio: relato de caso. [Persistent neurotoxicity secondary to lithium use: case report.] Rev Brax Psiquiatr 2006;28:163. 29. Mucci A, Volpe U, Merlotti E, Bucci P, Galderisi S. Pharmaco-EEG in psychiatry. Clin EEG Neurosci 2006;37:81–98. 30. Bellesi M, Passamonti L, Silverstrini M, Bartolini M, Provinciali L. Non-convulsive status epilepticus during lithium treatment at therapeutic doses. Neurol Sci 2006;26: 444–6. 31. Borovicka MC, Bond LC, Gaughan KM. Ziprasidone- and lithium-induced neurolep­ tic malignant syndrome. Ann Pharmacother 2006;40:139–42. 32. Gualtieri CT, Johnson LG. Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium. Medscape Gen Med 2006;8(3):46. 33. Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer’s disease in elderly patients with bipolar disorder. Br J Psychiatry 2007;190:359–60. 34. Caccamo A, Oddo S, Tran LX, LaFerla FM. Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. Am J Pathol 2007; 170:1669–75. 35. Baldessarini RJ, Tondo L, Davis P, Pompill M, Goodwin FK, Hennen J. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord 2006;8:625–39. 36. Guzzetta F, Tondo L, Centorrino F, Bal­ dessarini RJ. Lithium treatment reduces suicide risk in recurrent major depressive disorder. J Clin Psychiatry 2007;68:380–3.

Lithium

Chapter 3

37. Fujii S, Oku H, Takahashi R, Kanbara Y, Sugasawa J, Ikeda T. Optic nerve dysfunc­ tion secondary to long-term use of lithium carbonate. Jpn J Ophthalmol 2007;51:79–81. 38. Bocchetta A, Loviselli A. Lithium treat­ ment and thyroid abnormalities. Clin Pract Epidemiol Ment Health 2006;2:23. 39. Carlé A, Laurberg P, Pedersen IB, Knud­ sen N, Perrild H, Ovensen L, Rasmussen LB, Jorgensen T. Epidemiology of subtypes of hypothyroidism in Denmark. Eur J Endocrinol 2006;154:21–8. 40. Aliasgharpour M, Abbassi M, Shafaroodi H, Razi F. Subclinical hypothyroidism in lithium-treated psychiatric patients in Teh­ ran, Islamic Republic of Iran. East Mediterr Health J 2005;11:329–33. 41. Aksoy S, Kilickap S, Erman M. Lithiumassociated hypothyroidism and thyroid papillary carcinoma: a case report. South Med J 2006;99:279–81. 42. Khandwala HM, Van Uum S. Reversible hypercalcemia and hyperparathyroidism associated with lithium therapy: case report and review of literature. Endocr Pract 2006; 12:54–8. 43. Hundley JC, Woodrum DT, Saunders BD, Doherty GM, Gauger PG. Revisiting lithium-associated hyperparathyroidism in the era of intraoperative parathyroid hor­ mone monitoring. Surgery 2005;138:1027–31. 44. Wilting I, de Vries F, Thio BM, Cooper C, Heerdink ER, Leufkens HG, Nolen WA, Egberts AC, van Staa TP. Lithium use and the risk of fractures. Bone 2007;40:1252–8. 45. Raedler TJ, Wiedemann K. Lithiuminduced nephropathies. Psychopharmacol Bull 2007;40:134–49. 46. Khanna A. Acquired nephrogenic diabetes insipidus. Semin Nephrol 2006;26:244–8. 47. Wilting I, Baumgarten R, Movig KL, Laarhoven JV, Apperloo AJ, Nolen WA, Heerdink ER, Knoers NV, Egberts AC. Urine osmolality, cyclic AMP and aqua­ porin-2 in urine of patients under lithium treatment in response to water loading followed by vasopressin administration. Eur J Pharmacol 2007;566:50–7. 48. Paw H, Slingo ME, Tinker M. Late onset nephrogenic diabetes insipidus following cessation of lithium therapy. Anaesth Inten­ sive Care 2007;35:278–80.

31 49. Vergnaud E, Baudin O, Desachy A, Groupe ARCO. Une prise en charge périopératoire “usuelle” peut conduire à un coma hyper­ osmolaire chez les patients traités par lithium. [Standard perioperative manage­ ment of patients treated with lithium can lead to hyperosmolar coma.] Ann Fr Anesth Reanim 2007;26(2):168–70. 50. Ketter TA, Haupt DW. Perceptions of weight gain and bipolar pharmacotherapy: results of a 2005 survey of physicians in clinical practice. Curr Med Res Opin 2006; 22:2345–53. 51. Sachs G, Bowden C, Calabrese JR, Ketter T, Thompson T, White R, Bentley B. Effects of lamotrigine and lithium on body weight during maintenance treatment of bipolar I disorder. Bipolar Disord 2006;8:175–81. 52. Bowden CL, Calabrese JR, Ketter TA, Sachs GS, White RL, Thompson TR. Impact of lamotrigine and lithium on weight in obese and nonobese patients with bipolar I disorder. Am J Psychiatry 2006;163:1199–201. 53. Correll CU. Weight gain and metabolic effects of mood stabilizers and antipsycho­ tics in pediatric bipolar disorder: a systema­ tic review and pooled analysis of short-term trials. J Am Acad Child Adolesc Psychiatry 2007;46:687–700. 54. Rodriguez-Gil JE, Fernandez-Novell JM, Barbera A, Guinovart JJ. Lithium’s effects on rat liver glucose metabolism in vivo. Arch Biochem Biophys 2000;375:377–84. 55. Okosieme OE, Campbell A, Patton K, Evans ML. Transient diabetes associated with withdrawal of lithium therapy. Dia­ betes Care 2006;29:1181. 56. O’Brien M, Koo J. The mechanism of lithium and beta-blocking agents in indu­ cing and exacerbating psoriasis. J Drugs Dermatol 2006;5:426–32. 57. Sharma A, Padala PR. Lithium-induced rash. Prim Care Companion J Clin Psychia­ try 2006;8:377. 58. Even C, Thuile J, Rouillon F. Lithiuminduced menometrorrhagia. Psychiatry Clin Neurosci 2007;61:203. 59. Giles JJ, Bannigan JG. Teratogenic and developmental effects of lithium. Curr Pharm Des 2006;12:1531–41. 60. Waring WS, Laing WJ, Good AM, Bateman DN. Pattern of lithium exposure

Chapter 3

32

61.

62.

63.

64.

65.

predicts poisoning severity: evaluation of referrals to a regional poisons unit. Q J Med 2007;100:271–6. Krenová M, Pelclová D. A 4-year study of lithium intoxication reported to the Czech Toxicological Information Centre. Pharm World Sci 2006;28:274–7. Böker H, Brandenberger M, Schopper C. Neurotoxische Enzephalopathie unter Kombinationsbehandlung mit Lithium und Risperidon bei einer Patientin mit schizoaf­ fektiver Störung: [Neurotoxicity related to lithium–risperidone combination treatment in a patient with schizoaffective disorder]. Psychiatr Prax 2007;34:38–41. Sachs GS, Grossman F, Ghaemi SN, Oka­ moto A, Bowden CL. Combination of a mood stabilizer with risperidone or halo­ peridol for treatment of acute mania: a double-blind, placebo-controlled compari­ son of efficacy and safety. Am J Psychiatry 2002;159:1146–54. Su YP, Chang CJ, Hwang TJ. Lithium intoxication after valsartan treatment. Psy­ chiatry Clin Neurosci 2007;61:204. Adan-Manes J, Novalbos J, López-Rodri­ guez R, Ayuso-Mateos JL, Abad-Satos F. Lithium and venlafaxine interaction: a case of serotonin syndrome. J Clin Pharm Ther 2006;31:397–400.

Rif S. El-Mallakh

66. Raebel MA, Carroll NM, Andrade SE, Chester EA, Lafata JE, Feldstein A, Gun­ ter MJ, Nelson WW, Simon SR, Chan KA, Davis RL, Platt R. Monitoring of drugs with a narrow therapeutic range in ambu­ latory care. Am J Manag Care 2006;12: 268–74. 67. Kilbourne AM, Post EP, Bauer MS, Zeber JE, Copeland LA, Good CB, Pincus HA. Therapeutic drug and cardiovascular dis­ ease risk monitoring in patients with bipolar disorder. J Affect Disord 2007;102(1–3): 145–51. 68. Ratanajamit C, Soorapan S, Doangngern T, Waenwaisart W, Suwanchavalit L, Suwan­ siri S, jantasaro S, Yanate I. Appropriate­ ness of therapeutic drug monitoring for lithium. J Med Assoc Thai 2006;89:1954–60. 69. Nielsen JB, Vestergaard P. Forgiftning med lithium: vurdering, behandling og forebyg­ gelse. [Lithium intoxication: assessment, treatment and prevention.] Ugeskr Laeger 2007;169:522. 70. Waring WS. Management of lithium toxi­ city. Toxicol Rev 2006;25:221–30. 71. Peces R, Fernández EJ, Regidor D, Peces C, Sánchez R, Montero A, Selgas R. Treatment of acute lithium intoxication with high-flux haemodialysis membranes. Nefrologia 2006;26:372–8.

Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

4 CANNABINOIDS (SED-15, 614; SEDA-28, 36; SEDA-29, 35; SEDA-30, 31; for dronabinol see Chapter 36)

In research on the effects of cannabinoids the routes of administration include smoking a plant-derived cigarette, oral dronabinol (synthetic delta-9-tetrahydro­ cannabinol, THC), or intravenous THC. Each method has specific characteristics: cigarettes deliver a wide range of dosages, dronabinol has a slower onset of action and lower potency, and intravenous THC offers precise dose and timing (1r). Careful screening of subjects’ medical backgrounds and status and close monitoring during research participation are essential. Cardiovascular Cannabis smoking is associated with an increased risk of cardiovascular events (SEDA-30, 31). In one case acute myocardial infarction was an outcome of inherited thrombophilia and cannabis smoking (2A).
A 24-year-old man developed severe chest

pain, which radiated to the arms and back for 4 hours. He had a 16 cigarette pack-year habit. There was ST segment elevation in leads V2–6, with reciprocal ST segment depression in II, III, and aVF. Troponin-T (18.0 ng/ml) and creatine kinase activity (7266 IU/l) were both raised. An anterolateral myocardial infarction was diagnosed. He was given clopidogrel, aspirin, heparin, and streptoki­ nase. A stent was inserted at coronary angiography. Drug screening was positive for THC. Genetic testing revealed a hypercoagul­ able state with a combination of factor V

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03104-3 r 2009 Elsevier B.V. All rights reserved.

Drugs of abuse Leiden mutation and the methylenetetrahy­ drofolate reductase (MTHFR) C677T and A1298C polymorphism.

In this case, the increased risk of coronary artery thrombosis was inherited and smok­ ing may have predisposed to coronary spasm and subsequent thrombosis. Activation of cannabinoid CB1 receptors by cannabis or THC is associated with reduced blood pressure. The effects of rimo­ nabant, a CB1 receptor antagonist, on blood pressure have been reported in 63 male cannabis smokers (3C). The smokers were assigned to eight groups and were pretreated with oral rimonabant (1, 3, 10, 30, 90 mg) or placebo. They smoked active (2.64% THC) or placebo marijuana cigarettes 2 and 6 hours after rimonabant. Cannabis alone had no consistent effect on blood pressure but 22% reported hypotensive symptoms (dizziness, lightheadedness) as did 20–33% of rimona­ bant recipients (1, 3, or 10 mg). Subjects who had symptomatic hypotension had higher mean peak plasma THC concentrations than those who did not. Rimonabant had a dosedependent effect on the hypotensive response to cannabis. Subjects receiving the two highest doses, 30 and 90 mg, did not have symptomatic hypotension. Respiratory Cannabis smoking can cause serious injury to the lungs (SEDA-30, 33). “Bong lung” involves histological changes characteristic of irregular emphysema (4A).
A 39-year-old man developed weight loss,

fever, dry cough, and pleuritic chest pain. His cannabis and cigarette smoking history had started at age 12 and his current habit was 3 g of cannabis daily and 50 cigarette packs per year. A CT scan of the lung showed a pattern of large peripheral paraseptal bullae.

The authors compared this patient’s CT scan with one from a cigarette smoker. The

33

34

Chapter 4

Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

second scan illustrated a strikingly different pattern of emphysema, with smaller pana­ cinar bullae in a uniformly distributed centrilobular pattern. An explanation of the differences in lung findings due to cannabis and cigarettes would take into account a number of variables. Cannabis smoking requires longer inhalation and breath-holding time. Inhaled cannabis through a bong is at a higher temperature. A cannabis joint, which lacks a filter, also has a greater delivery of the drug. Psychological Memory Cannabis has acute effects on memory, specifically tran­ sient deficits in immediate and delayed free recall of information presented after expo­ sure. Recognition recall is not affected and neither is recall of information learned before exposure. These findings emerged from a literature review of 35 studies of varied populations (occasional to heavy cannabis users) and varied doses of cannabis (5M). The authors concluded that cannabi­ noids have significant acute effects on processes of encoding, retrieval, and con­ solidation of memory, but they pointed to several limitations of the studies they reviewed, including small sample sizes, sample selection, and the effects of tolerance and dependence. Driving skills In a double-blind, placebocontrolled study to define the concentrations of THC needed to cause significantly impaired driving, 20 recreational cannabis users were given a series of performance tests at between 15 minutes and 6 hours after smoking 0, 250, or 500 mg/kg of THC (6c). The tests included measures of perceptualmotor control, motor impulsivity, and cog­ nitive function. THC concentrations in saliva and blood were monitored throughout. At higher THC concentrations, there was impairment in an increasing proportion of trials, becoming significant at concentrations of 2–5 ng/ml, and for the perceptual-motor control task, at 5–10 ng/ml. The authors suggested that concentrations of THC, rather than positive versus negative drug screens, should be used to set legal standards for driving under the influence.

Motor control To assess how highpotency (13%) THC affects motor control, 20 recreational marijuana users were given single doses of placebo, low-dose THC (250 mg/kg), or high-dose THC (500 mg/kg) in a double-blind crossover study (7c). Participants were aged 19–29 years, had no medical or psychiatric problems, and used marijuana on average 3.4 times per month. Impairments in object tracking, executive function and planning, and response inhibition were greatest at 15– 75 minutes after smoking and persisted for up to 6 hours. The authors suggested that high-potency cannabis, rather than the less commonly used low potency THC, should be assessed in future studies. Psychiatric Cannabis has been implicated as having a neurodevelopmental role in conditions such as schizophrenia, substance abuse, mood and anxiety disorders, and impaired cognitive function. Exposure of the developing brain to cannabis can occur at several key periods: in utero, by crossing the placenta from mother to fetus; after birth through breast milk; and in adoles­ cence by smoking. This topic has been reviewed, along with relevant animal stu­ dies (8R). Co-morbid substance use, beyond canna­ bis, may account for the increased positive symptoms observed in chronic schizophre­ nic cannabis users. When lifetime positive and negative symptoms were compared for those with (n ¼ 66) or without (n ¼ 139) cannabis abuse and dependence, there was no difference in positive symptoms between the two groups, after controlling for use of other substances; cannabis users also had fewer negative symptoms than non-canna­ bis users (9C). The reduction in avolition and apathy was more pronounced when the analysis was restricted to those chronic schizophrenics who used cannabis and no other substances. The authors offered several hypotheses for these findings: can­ nabis use may be a susceptibility factor for schizophrenia in those who have a genetic predisposition for a lower severity of negative symptoms; alternatively, cannabis itself may reduce negative symptoms; lastly, those who have fewer negative symptoms

Drugs of abuse

Chapter 4

may have a greater social ability to acquire the drug. Research suggests that a functional poly­ morphism of the catechol-O-methyltransfer­ ase gene (COMT Val158Met) may mediate an increased risk of psychosis in response to cannabis exposure. In a double-blind, pla­ cebo-controlled, crossover study, individuals with a psychotic disorder (n ¼ 30), healthy controls (n ¼ 32), and relatives of indivi­ duals with a psychotic disorder (n ¼ 12) were exposed to either cannabis or placebo (10C). All underwent assessments of psycho­ tic symptoms (Positive and Negative Syn­ drome Scale (PANSS)) and susceptibility to psychosis (Community Assessment of Psy­ chic Experiences (CAPE)), a cognitive battery (including measures of attention and memory, and genotyping). Cannabis expo­ sure most significantly increased psychotic symptoms, memory, and attention deficits among those with the Val allele compared with those with the Met allele. Susceptibility to psychosis among the Val carriers was increased most among those with CAPE scores suggesting susceptibility. The authors suggested that the increased risk of psychosis associated with the Val allele may be mediated through an additional pre-existing susceptibility. Sensory systems Eyes There has been a pilot evaluation of the effect of sublingual cannabinoids (THC and cannabidiol) on intraocular pressure in a randomized, dou­ ble-masked four-way, crossover study in six patients with ocular hypertension or early primary open-angle glaucoma (11c). A single dose of THC 5 mg was well tolerated but temporarily reduced intraocular pres­ sure. Intraocular pressure was unaffected by cannabidiol 20 mg, but 40 mg resulted in a transient increase. Gastrointestinal Cannabinoids stimulate appetite and relieve nausea in patients with cancer. These effects are mediated by cannabinoid receptors in the gut, nervous system, and immune system (CB1 receptors in the colon and ileum, inhibiting smooth muscle, and CB2 receptors in the colon, where they are involved in hypermotility, inflammation, and pain (12R)).

35 The effects of stimulating cannabinoid receptors with dronabinol on gastrointest­ inal transit and postprandial satiation have been studied in 30 healthy volunteers who were given either dronabinol 5 mg bd or placebo (13c). Each subject received three doses of medication and underwent non­ invasive physiological tests 1 hour after the first and third doses. Dronabinol delayed gastric emptying, with a more pronounced effect in women. Men who received drona­ binol had higher fasting gastric volumes, a finding that is associated with reduced postprandial symptoms and satiation after a meal and possibly greater appetite. Skin An unusual case of cannabis-related contact dermatitis has been reported (14A).
A

29-year-old otherwise healthy female worker for the Forensic Science Service in the UK developed urticarial wheals, headaches, and rhinitis within minutes after contact with cannabis plants. For 6 years she had grown, stripped, and ground cannabis plants; her symptoms started after 2 years and were gradually worsening, with a quicker onset after exposure. Patch tests to dried and fresh cannabis leaf, flower, and resin were positive.

This was a type I hypersensitivity reaction to cannabis, with a wheal-and-flare reaction due to urticaria. Reproductive system Cannabis is the most widely used illegal recreational drug among men and women of reproductive age. The effects of cannabis on in vitro fertilization (IVF) and gamete intrafallo­ pian transfer (GIFT) outcomes have been reported in 221 couples undergoing IVF or GIFT at fertility centers in California (15C). Outcomes for a single cycle per couple were included. Data collection included three questionnaires for women and two for men and the medical records were accessed for information on sperm characteristics (num­ bers, motility, and morphology). Both the amount of cannabis use and the timing had negative effects. Women who had lifetime heavy cannabis use had 27% fewer oocytes retrieved and fewer embryos transferred. Moderate cannabis use in men and women was associated with 15% and 17%

36

Chapter 4

Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

falls in infant birth weight respectively. As to timing, women who used cannabis for 1 year before IVF/GIFT had 25% fewer oocytes retrieved and couples had 28% fewer oocytes fertilized. Teratogenicity Findings from two long­ itudinal studies of children exposed to cannabis in utero have been included in a review of neurodevelopmental effects (8R). Cannabis exposure resulted in small reduc­ tions in length, head circumference, and birth weight (about 100 g), but did not increase rates of prematurity or miscar­ riage. The children in these studies also had deficits in visuospatial reasoning and memory at ages 9–12 and 13–16 respectively. Fetotoxicity Exposure to cannabis during pregnancy and its adverse effects on the fetus are difficult to assess, for several reasons. Concentrations of the psychoactive agents in cannabis sold on the street vary widely, from a trace of THC to as much as 20%. The amount of drug use by expectant mothers and duration of use are also difficult to determine. A study of altered neurobehavior in term neonates with prenatal cannabis exposure within 24–72 hours of life has been reported (16C). Between July 2001 and November 2002, 928 (25%) of 3685 infants at a hospital in Brazil were born to adolescent mothers; 26 infants (4.6%) of 561 infants who met the study criteria had marijuana exposure detected by maternal hair and neonatal meconium analysis for marijuana and cocaine metabolites. Neo­ nates who had prenatal exposure to tobacco, alcohol, or cocaine were excluded. The infants were assessed with the Neona­ tal Intensive Care Unit Network Neurobe­ havioral Scale (NNNS). Infants exposed to marijuana scored significantly higher in variables of arousal, regulation, and excit­ ability than non-exposed infants. Only one of 26 mothers who used cannabis during pregnancy revealed this during the inter­ view. Research on cannabis use in adolescent pregnancy is complicated by a number of variables (17r). Adolescent mothers

frequently have poor nutrition, use other substances, and have poor mental health. The parenting environment of an infant born to an adolescent mother is likely to have a number of psychosocial stressors. A systematic review of studies on neuro­ behavioral and cognitive outcomes asso­ ciated with cannabis in utero exposure has been published (18M). To date, there have been only two longitudinal studies, the Ottawa Prenatal Prospective study (2002) and the Maternal Health Practices and Child Development Study (1998). The consequences of heavy prenatal exposure to cannabis appear to be subtle, with the prefrontal brain region negatively affected by prenatal cannabis use. There have been no studies focused on moderate or low cannabis use during pregnancy. A small fMRI study has suggested that prenatal cannabis exposure may have effects on neural activity during tasks involving visuospatial working memory in young adults (19c). In this study, 16 prenatally exposed and 15 unexposed indi­ viduals (aged 18–22) performed a task involving visuospatial working memory while being imaged by fMRI. While there was no difference in performance between the two groups, there were differences in the neural networks that were activated during the task. Those exposed to cannabis had more activity in the left inferior and left middle frontal gyri, the left parahippocam­ pal gyrus, the left middle occipital gyrus, and the left cerebellum, whereas they had less activity in the right inferior and right middle frontal gyri. Tumorigenicity Cannabis smoking is asso­ ciated with an increased risk of some of the traditional tobacco-related cancers. Cannabis smoke contains tar, which has many of the same carcinogens as tobacco tar, such as vinyl chlorides, nitrosamines, phenols, and reactive oxygen species. The smokingassociated cancers affect organs such as the lungs, upper airways, and bladder, which have long-term exposure to these carcinogens. Transitional cell carcinoma of the blad­ der has been reported in a smoker of marijuana (20A).

Drugs of abuse

Chapter 4


A 45-year-old man who had a 30+ year habit

of smoking of up to five marijuana cigarettes a day developed macroscopic painless hema­ turia. He had no history of tobacco use, chemical exposure, or family history of transi­ tional cell carcinoma. There was a 7-cm bladder mass on CT scan and cystoscopy showed papillary lesions along the right lateral wall. The bladder tumor was resected and was a high-grade stage T1 transitional cell carci­ noma. He received intravesical BCG for 6 weeks. After 3 months cytology was normal. He stopped using cannabis.

The association between cannabis and transitional cell carcinoma has been investi­ gated in 156 men aged less than 60 years in a US Veterans Association Hospital, 52 with a transitional cell carcinoma and 104 agematched controls, who completed selfadministered questionnaires (21C). Detailed questions on tobacco and cannabis use and duration and exposure to other potential carcinogens, including radiation, Agent Orange, smoked or processed meats and dyes, were included. There was significantly higher habitual cannabis use by 46 of the 52 patients with transitional cell carcinomas compared with 72 of the 104 age-matched controls. The former had engaged in greater cannabis use as measured in joint-years (the product of joints per day and years smoked), with a mean of 48 joint-years compared with 29 joint-years in controls. In both groups, there was high tobacco use, with rates greater than 90%. The association between cannabis smoking and the development of lung cancer has been the subject of a systematic review of research studies written in English on adult subjects for the period 1966 to 1995; 19 articles out of 186 abstracts were identified and categorized (22M). There was an association between marijuana smoking and increased tar expo­ sure, alveolar macrophage tumoricidal dys­ function, increased oxidative stress, and bronchial mucosal histopathological abnorm­ alities compared with tobacco smokers and non-smoking controls. However, there were no significant associations between marijuana smoking and lung cancer after adjusting for use of tobacco, although the age of the participants was too young to allow conclu­ sions based on long-term exposure.

37

COCAINE (SED-15, 848; SEDA-28, 38; SEDA-30, 31; see also Chapter 11) Cardiovascular The prevalence of coronary atherosclerosis (SEDA-29, 38) has been described in 51 patients (49 men) aged under 50 years with an acute persistent STsegment elevation myocardial infarction with and without cocaine exposure who were admitted to a US hospital; 17 patients (16 men) self-reported cocaine use more than 10 times in a lifetime and 35 were noncocaine controls (23c). Coronary angio­ graphy showed that cocaine users had a higher prevalence of atherosclerosis (65%) and a higher number of coronary artery lesions (2.3 per patient) compared with controls (32% and 1.6 per patient). Cocaine users had a lower mean age and a lower mean number of cardiac risk factors. The authors challenged a popular explanation that spasm in otherwise normal coronary arteries is the main cause of myocardial infarction in young cocaine users. Their findings strongly support a proatherosclerotic effect of cocaine. The effect of cocaine on the QT interval (SEDA-29, 39) has been further studied. The effect of cocaine on QT variability (a measure of cardiac repolarization), has been assessed in 29 healthy volunteers with past cocaine exposure, who received ran­ domized sequential intravenous infusions of cocaine 20 mg and 40 mg or placebo; 17 repeated the course 1 week later (24c). Cocaine significantly and dose-dependently increased QT variability; the results were reproducible 1 week later. In 14 habitual cocaine users, who smoked cocaine 25 mg during closely monitored 12­ minute sessions with electrocardiographic recording, the heart rate increased by a mean of 22/minute; there was significant QTc prolongation, reduced T wave ampli­ tude, and increased U wave amplitude (25c). One patient developed an accelerated junc­ tional rhythm and five had non-specific ST­ T wave abnormalities. The authors of these papers discussed how cocaine has a destabilizing effect on cardiac repolarization, which contributes to cardiac dysrhythmias. Like other sympatho­ mimetic agents, cocaine is an alpha1, beta1,

Chapter 4

38

Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

and beta2 adrenoceptor agonist with sodium channel blocking properties. Fatal vasoconstriction of the aorta has been attributed to cocaine (26A).
After a 5-day crack cocaine binge, a 32-year­

old woman developed severe bilateral leg pain and inability to walk. She drank several cans of beer to try to relieve the pain. She had a history of “speed balling”, or injecting a mix of heroin and cocaine. She was lethargic, with a systolic blood pressure of 70 mmHg, a heart rate of 172/minute, and a respiratory rate of 22/ minute. Her truncal skin was mottled below the umbilicus. The abdomen was diffusely tender and no bowel sounds were detectable. Her limbs were mottled, pale, and cold to the touch. The femoral pulses were faintly audible with Doppler. There were no pulses distally. Sensation was markedly reduced in the legs. She was given oxygen, intravenous isotonic saline, and glyceryl trinitrate infusion. Her systolic blood pressure rose to 110 mmHg and her pulse rate to 110/minute. Abdominal ultrasound showed severe vasoconstriction of the abdominal aorta above the renal arteries. She had a raised creatinine kinase activity (56 mg/l), blood urea nitrogen of 156 mg/dl, creatinine of 6.2 mg/dl, and potassium of 4.0 mmol/l. On day 3, she had fever, acute septic shock, and disseminated intravascular coagulopathy and died.

Myocarditis has cocaine (27A).

been

attributed

to


A 42-year-old healthy occasional user of

cocaine developed fatigue, fever, cough, mus­ cle aches, and abdominal pain after using cocaine 3 days before, and collapsed and died. Autopsy showed a mottled enlarged heart weighing 585 g and 50 ml of serous pericardial fluid. Histology of the myocardium showed a mononuclear inflammatory cell infiltrate with lymphocytes in and around the sinoatrial node and the bundle of His and the left bundle branch. Prominent contraction band necrosis, some coagulative necrosis, and myocyte loss were also present, and there was evidence of myocyte apoptosis. There were cocaine meta­ bolites in the blood.

Before this report, cocaine-induced myo­ carditis has been associated solely with chronic use. The authors also pointed out that this is a first report of involvement of the bundle of His and left bundle branch. The mechanism of damage may include myocardial adrenergic stress and cardiac myocyte apoptosis.

Nervous system Neuroimaging research has significantly improved our understand­ ing of the neurobiological effects of acute cocaine on the brain. Brain regions such as the basal forebrain, caudate, nucleus accumbens, thalamus, ventral tegmentum, cingulate, and prefrontal cortex are acti­ vated during cocaine use. Electroencepha­ lographic measurements have elucidated the acute effects of cocaine on brain neurophysiology. Quantitative electroen­ cephalographic profiles were obtained from 13 crack cocaine-dependent users who self-administered single-blinded doses of smoked cocaine base 50 mg versus placebo in monitored sessions (28c). Cocaine rapidly increased the absolute theta, alpha, and beta power of the prefrontal cortex for up to 25 minutes. Increased theta power was associated with reported “good drug effect” and increased alpha power with reported “nervousness”. Increased delta power was positively associated with plasma cortisol concentra­ tion and negatively with reported nervous­ ness. Placebo increased alpha power in the prefrontal cortex. The authors propose that slow wave delta and theta activity are involved in the rewarding properties of cocaine. Cocaine also affects cerebral blood flow. Hypoperfusion of the orbitofrontal cortex and possible differences among male and female cocaine users has been reported in 35 abstinent cocaine-dependent subjects and 37 healthy controls, using single photon emission computed tomography for regio­ nal cerebral blood flow after infusion of cocaine or saline (29c). There were sexspecific anatomical differences: regional blood flow was reduced bilaterally in the orbitofrontal cortex in male cocaine users and in the medial orbitofrontal cortex in female cocaine users compared with con­ trols. The authors explained that the orbitofrontal cortex is involved in assessing prospective rewards and making decisions. When it is injured, a person tends to make impulsive impaired decisions. They sug­ gested that these sex differences may be important in developing methods for treat­ ing relapses.

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Fatal cocaine-related encephalopathy has been reported (30c).
A 21-year-old man with a history of depres­

sion and no prior cocaine use was found comatose in a hotel room with injection marks in the left cubital fossa. A syringe, empty packets with traces of white powder, later identified as cocaine, and a farewell letter were also found. He was unresponsive, with intact brain stem reflexes, bilateral hyper-reflexia, and moderately increased muscle tone. There was a mild metabolic acidosis (pH 7.30), raised liver enzymes, rhabdomyolysis, leukocytosis, and increased creatinine and hyperkalemia. There was cocaine in the urine. Electroence­ phalography after 3 and 12 days showed diffuse 2–4 Hz activity, with 2–30 seconds episodes of flattening and lack of response to visual or tactile stimulation. An MRI scan of the brain on day 21 showed diffuse symme­ trical white matter lesions in the cerebrum, with preservation of U fibers. Proton nuclear magnetic resonance spectroscopy (1H-MRS) on day 21 in the occipitoparietal white matter and mid-occipital gray matter showed signifi­ cant reductions in N-acetylaspartate, myoino­ sitol, and creatine, with increased lactate, lipids, and macromolecules, consistent with major neuroaxonal injury and white matter demyelination. He died at 24th day. Autopsy showed severe leukoencephalopathy, with demyelination and liquefaction of the central cerebral white matter. The cortex, subcortical white matter and U fibers, brain stem, cerebellum, and hippocampus appeared rela­ tively intact.

The authors pointed out that the clinical presentation may vary, whereas the radi­ ological and histological findings in toxic leukoencephalopathy due to cocaine or other drugs of abuse are fairly characteristic. Sleep There has been a longitudinal study of maternal substance use and child sleep behavior in 65 cocaine-exposed and 53 non-exposed infants and their primary care-givers, recruited at the time of deliv­ ery (31c). By 7 months 18 of the cocaineexposed infants had been removed from parental care, compared with only one of the non-cocaine group. At 7 months the care-givers’ psychopathology was assessed with the Brief Symptom Inventory (BSI) and the Maternal Cognitions about Infant Sleep questionnaire, a measure of mothers’ awareness about their infants sleep

39 pattern, was administered. Infant physio­ logical assessment during rest was done at both 4–8 weeks and 7 months. The severity of sleep difficulties significantly related to the severity of prenatal cocaine exposure, and maternal anxiety had a key role in this association. Altered sleep regulation in 7-month-old infants was strongly influ­ enced by the care-givers’ environment. Non-maternal care-givers had fewer mental health problems than cocaine-using mothers. Infants who were in non-parental care had milder sleep problems than those who remained in parental care. Dysregulation of sleep with impairment of cognition and learning associated with cocaine has been studied (32c). In a 23-day in-patient study, 12 abstinent chronic cocaine users self-administered blinded dosages of either intravenous cocaine (8, 16, and 32 mg per 70 kg at 30-minute intervals) or placebo on each of study days 4, 5, 6, 18, 19, and 20 in 2-hour sessions. Six took cocaine on days 4–6 (early bingers) and the other six on days 18–20 (late bingers). There was a marked discrepancy between recorded sleep and self-reports. Over the period of controlled abstinence (up to 17 days), sleep deterioration as measured objectively (total sleep time, sleep latency, and times awake after sleep onset) was timed to the sleep that chronic cocaine users reported as “at its best”. Spectral activity showed increased slow wave sleep, suggestive of chronic insomnia. Vigilance and procedural learning were also impaired. The authors suggested that chronic cocaine users are unaware of “occult insomnia”, which relates to dysre­ gulation of homeostatic sleep drive. In this proposed mechanism, increased time awake is not recognized and translated into a drive to sleep. Sensory systems Eye Corneal distur­ bances have been reported with crack cocaine, including ulcerative keratitis (33A).
A

42-year-old African–American woman developed blurred vision and a mucopurulent discharge and progressive pain in her left eye. She had a history of polysubstance

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Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

abuse, but no history of contact lens use, trauma, or surgery. She had injected heroin the evening before and again several hours later. The left cornea had a deep paracentral stromal ulcer with an overlying epithelial defect. Toxicology screen was positive for cocaine and heroin. Corneal cultures grew Candida albicans. With topical therapy the lesion regressed in size and her symptoms abated.

Ulcerative keratitis is a sight-threatening condition. Crack-cocaine vapors can have a direct toxic effect, which impairs the pro­ tective capacity of the corneal epithelium and predisposes the corneal tissue to blemishes and infection. They also have anesthetic properties, which may increase the risk of mechanical trauma from exces­ sive eye rubbing. Psychiatric One of the common psy­ chiatric manifestations of cocaine use is paranoia, an intense, irrational suspicion of others or a fear of being harmed. Cocaine-induced paranoia is usually brief and reversible, as it is associated with acute intoxication. However, some cases are protracted or even chronic. Of 420 cocaine-dependent full-sibling pairs (n ¼ 840) who participated in a SemiStructured Assessment for Drug Depen­ dence and Alcoholism (SSADDA) interview, 273 (65%) reported cocaineinduced paranoia (34C). Factors associated with sibling cocaine-induced paranoia were analysed by logistic regression, with alcohol dependence as a positive control. No familial component was identified as a possible susceptibility factor. However, members of the subject’s family had more severe cocaine dependence (as measured by Diagnostic Manual IV symptom count) and an earlier age of onset. They were more likely to smoke cocaine and also to have reduced their amount of cocaine use in the preceding year. Whereas probands with cocaine-induced paranoia had a higher proportion of siblings with the trait, the difference was not statistically significant (66% versus 59%). Endocrine Stress, drug cues, and drug craving are the principal influences on

substance users’ behaviors of use and relapse. The combined neuroendocrine and cardiovascular responses to stress has been studied in relation to sex differences in 25 abstinent female cocaine users and 25 abstinent male cocaine users (35c). Subjects were instructed to imagine a recent personal stressful experience, a personal drug-related one, and a neutral-relaxing one. Subjective craving and anxiety, cardi­ ovascular measures, and plasma ACTH, cortisol, and prolactin were measured. Both men and women reported increased cocaine craving and anxiety in response to the stress and drug-cue exercises, but there were significant sex differences. Men had higher ACTH and cortisol concentrations at base­ line and more robust response measures after all three exercises. Women had lower ACTH and cortisol with higher heart rates and prolactin at baseline and less marked responses to the exercises. The authors proposed that clarification of sex differ­ ences in sensitivity and responses in the hypothalamus–pituitary–adrenal axis and in cardiovascular responses may be useful in developing treatments. Pregnancy Cocaine body packing during pregnancy has been reported (36A).
A 26-year-old woman at 32 weeks gestation

was detained in customs at the Miami Inter­ national Airport for possessing cocaine pack­ ets. She confessed to swallowing packets for concealment. She was admitted to hospital and Golytely was administered to facilitate passage of the packets. A few hours later she had generalized seizures and became apneic and unresponsive. Ventricular tachycardia ensued. Ultrasound showed a singleton fetus with a bradycardia of 80/minute. A 2800 g boy was delivered by cesarean section, with Apgar scores of 2, 4, and 5 at 1, 5, and 10 minutes respectively. The mother died. Autopsy showed an ischemic uterus and 157 latex packets containing about 830 g of cocaine in the stomach and small and large intestines. One condom had ruptured. The maternal serum cocaine concentration was 4.6 mg/l and serum benzoylecgonine 12 mg/l. At 1 year the child had neurodevelopmental delay.

The authors reported that in pregnancy the activity of plasma esterase, which degrades cocaine, is reduced and that progesterone,

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which may slow the metabolism of cocaine, is increased. Fetotoxicity (SEDA-29, 41; SEDA-30, 35) Adverse morphological and craniofacial outcomes in 154 children aged 6 years with in utero cocaine exposure and 131 high-risk controls (matched for race and social class) have been described (37C). Prenatal cocaine exposure was associated with lower standardized height and weight for height at age 6 years. No pattern of craniofacial or structural abnormalities was found. Drug–drug interactions Methylphenidate Attention-deficit/hyperactivity disorder (ADHD) is diagnosed in up to 30% of cocaine users. Methylphenidate, used to treat ADHD, is, like cocaine, a stimulant with potential cardiovascular and central nervous system toxicity. The concomitant use of cocaine and methylphenidate has been described (38c). Seven subjects who were cocaine users completed a placebocontrolled, crossover study with methyl­ phenidate 60 and 90 mg and cocaine 20 and 40 mg. Methylphenidate and cocaine were well tolerated in combination. Methylphe­ nidate had no significant effects on vital signs, electrocardiography, or the phar­ macokinetics of cocaine. However, this conclusion cannot be generalized; the maximum dose of cocaine was 40 mg, and cocaine users on the street are likely to use more than that.

Ecstasy (3,4-methylenedioxymetamfetamine, MDMA) (SED-15, 180; SEDA-28, 4, 28; SEDA-29, 1; SEDA-30, 37; for other amphetamines see Chapter 1) Drugs that are often used in dance clubs or at rave parties, also known as “club drugs”, are commonly used by populations at high risk of HIV infection. According to the 2004 National Survey on Drug Abuse and Health, 1.9 million persons aged 12 years and over used MDMA in the USA (39R). Use of club drugs is more prevalent among

41 men who have sex with men than in the general population. Its use is also more common among populations with and at high risk of HIV infection. Most epidemio­ logical data show that club drugs increase sexual risk behavior. Their use may interact with certain antiretroviral medications and has been associated with reduced adher­ ence. The authors suggested that clinicians should ask all patients about patterns of club drug use, counsel patients about the risks associated with club drugs, and refer patients to appropriate behavioral treat­ ment programs for substance use when clinically indicated. Nervous system Acute myelopathy after intranasal insufflation of amphetamines and heroin has been reported (40A).
A 17-year-old woman became drowsy and

unable to walk after an overdose of intranasal insufflated heroin and amphetamines. Within a few hours she became stuporose, with weakness in all four limbs, especially the legs. She had massive rhabdomyolysis (creatine kinase 368 mg/l), acute renal failure, and hepatic failure. She had habitually used ecstasy and cannabinoids since age 12, and in the previous week had insufflated heroin about once a day; the previous night she had used twice the dose of heroin along with 1 g of amfetamine. The next day she was alert and cooperative, but complained of diffuse muscle pain and tenderness, especially in the legs, where weakness rapidly worsened to flaccid areflexic paralysis. Urinary MDMA was 7.68 mg/l, 3,4-methylenedioxyamfetamine 2.0 mg/l, and opiates over 2.0 mg/l. The acute renal failure resolved by day 10. Muscle weakness resolved in the arms but flaccid paralysis persisted in the legs. There were no sensory symptoms or signs and no sphincter abnormalities. Electromyography showed complete non-excitability of the leg motor nerves innervated by L3–S1. MRI after 1 month showed selective T2 hyperintensity of the anterior horns and signal alteration in the lumbar nerve roots associated with volume increase and intense gadolinium enhancement. Intravenous high-dose steroid therapy had no effect, and 4 months later she was still paraplegic.

According to the authors, the neurophysio­ logical and neuroradiological evidence in this case suggested selective lumbar motor neuron involvement. The pathological pro­ cess primarily affected spinal anterior horn

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cells conditioning motor neuron cell death, and then nerve roots and the lumbar plexus as a consequence of Wallerian degenera­ tion. They suggested that this presentation was probably due to the combined effect of heroin and ecstasy. Ecstasy use has spread from the clubs to urban and rural areas, and young whites are not the only group using club drugs (41A). This is illustrated by a case report of an African–American who had a stroke after using ecstasy.
A 20-year-old African–American man was

seen to drink beer, smoke marijuana, and take ecstasy before performing at a rap concert, during which he suddenly stopped rapping, started vomiting, and became aphasic. An hour later he was awake, non-verbal, and was able to follow verbal instructions. He did not have any signs of trauma and the strength in his limbs was 5+/5 bilaterally. It was difficult to complete the examination as he was comba­ tive. His cardiac examination was normal. His white blood cell count was raised without a shift or bands. His creatine kinase activity was 692 U/l. His ethanol concentration was 1130 mg/l and his urine drugs screen was positive only for cannabinoids. His head CT scan was negative. After about 18 hours he developed new right-sided weakness, a leftsided facial droop, and bilateral hyper-reflexia in the legs. An MRI scan showed complete infarction of the left middle cerebral artery and mild-to-moderate stenosis of the distal left internal carotid artery.

The authors speculated that ecstasy causes massive synaptic release of serotonin, resulting in down-regulation of 5HT recep­ tors, which can lead to low cerebral blood vessel volume, thereby increasing the risk of stroke through vasoconstriction. How­ ever, this report was criticized for assigning causality to the event in absence of a positive drug screen; other forms of amphe­ tamines could have been used or passed as ecstasy and there was no past history of drug abuse (42r). One of the authors of the original report expressed frustration at not being able to confirm the toxin, but explained that owing to the devastation caused by hurricane Katrina they had been unable to review or obtain any additional information about this case, and concurred with the criticism that ecstasy ingestion by the patient was purely speculative, despite a

reliable witness (43r). However, there had been no doubt about the stroke and the temporal connection to the abuse of street drugs. Other drugs are sold as ecstasy and could have been used, but they were not picked up by the toxicology screen, which was done at least 12 hours after ingestion, by which time drugs could have cleared the system. Psychological Behavior The acute effects of ecstasy on driving performance or drivingrelated psychomotor performance have been assessed in 18 recreational ecstasy users aged 21–39 years in a double-blind, pla­ cebo-controlled, three-way, crossover study (44A). Ecstasy 75 mg, methylphenidate 20 mg, and placebo were administered on day 1 and driving tests were conducted 3 and 5 hours later. The test was repeated at 27– 29 hours during withdrawal. On-the-road driving tests consisted of a road-tracking test and a car-following test in a specially instrumented vehicle over a 100-km primary highway circuit. Standard Deviation of Lateral Position (SDLP) is a composite index of allowed weaving, swerving, and overcorrecting during the test duration of 1 hour. In the second test, time to speed adaptation, brake reaction time, and gain were assessed. Gain is the amplification factor between the speed signals collected from both the leading and following cars and indicates the magnitude of overshoot in reaction. Ecstasy and methylphenidate both reduced SDLP relative to placebo but not during withdrawal. Mean gain differed sig­ nificantly between treatments during intox­ ication but not withdrawal. Ecstasy and not methylphenidate significantly increased the modulus or gain of the subjects’ response to speed decelerations of the leading vehicle. Time to speed adaptation and brake reac­ tion time were not significantly affected. Thus, ecstasy not only improved road-track­ ing performance but also reduced carfollowing performance. The authors reported that these and other data suggest that ecstasy has activating or stimulating properties that may improve performance in certain aspects of the driving tasks but impair others.

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Chapter 4

In another study, the acute effects of ecstasy and alcohol, alone and in combina­ tion, on behavioral measures of impulsivity and risk-taking behavior were measured in 18 recreational users in a double-blind, placebo-controlled, six-way, crossover study (45C). The treatments consisted of ecstasy 0, 75, and 100 mg with and without alcohol (0.6 g/l peak blood concentration). The tests were conducted 1.5–2 hours after the dose of ecstasy and included a stopsignal task, a go/no-go task, and a gambling task. Ecstasy impaired stop reaction time, suggesting increased impulse control. Alcohol increased the proportion of com­ mission errors in the stop-signal task and the go/no-go task. The gambling task performance was not affected by either. None of the behavioral measures of impulsivity showed an interaction with ecstasy or alcohol. The authors speculated that the possible mechanism underlying the effect of ecstasy in improving impulse control may be related to acute serotoner­ gic or dopaminergic mechanisms after a single dose. However, ecstasy did not affect measures of impulsivity in every behavioral task. Decision-making pro­ cesses in the gambling task were not affected, which seems to indicate that the effects of ecstasy on stop reaction time in the stop-signal task were selective. The authors further distinguished between cog­ nitive impulsivity and motor impulsivity and suggested that they are probably controlled by different centers in the brain. Ecstasy selectively improved control over motor impulsivity while leaving cognitive impulsivity intact. Thus, pharmacological manipulations may affect these controls independently and selectively. With alco­ hol, on the other hand, the commission errors may reflect impairment of percep­ tual or attentive processing, rather than increased motor impulsivity. The gambling task performance tended to improve after alcohol, with more cautious decision-mak­ ing. This suggests that alcohol does not increase cognitive impulsivity in this type of decision-making task. According to the authors, absence of an alcohol effect on decision-making tasks versus the presence of a detrimental effect of alcohol on motor

43 inhibition tasks demonstrates that impul­ sivity is not a unitary concept, but com­ prises several independent psychological domains or brain regions that can respond very selectively to a pharmacological manipulation. They further observed that the CNS stimulant effects of ecstasy were never sufficient to overcome alcohol­ induced impairment on measures of impul­ sivity or risk taking and may be of particular importance in terms of road safety, especially crashes. Subjective effects Acute subjective effects following use of ecstasy have been studied. The authors of a meta-analyses searched for published articles that provided data on self-reported acute effects associated with use of ecstasy while intoxicated or within 24 hours after consumption (46M). The study criteria were met by 24 studies in 3074 ecstasy users. There was a slight preponderance of men; ages were 14–74, the largest proportion being 21–36 years.
Somatic effects were more frequent than any other effects, and 80% or more participants in one or more studies had bruxism/teeth problems, body tempera­ ture changes, fatigue or mental fatigue, accelerated heart rate or heart beat, sweaty palms, dry mouth/thirst, and increased energy. A few subjects com­ plained of stomach and/or intestinal pain, inability to urinate, shortness of breath, motor tics/shakiness, nausea and/or vomiting, headache, dizziness and/or ver­ tigo, and muscle aches or tightness.
For emotional effects, 80% or more participants in three or more studies reported feeling tenderness/affection, peaceful/calm, euphoria or improved mood, and reduced defensiveness. A few subjects reported anxiety or nervous­ ness, fear/paranoia, omnipotence, greater self-confidence or self-acceptance, and insecurity.
Cognitive effects reported in three or more investigations were confused thoughts (3–50%), loss of memory/ forgetfulness (3–28%) and increased alertness/attention focused on the hereand-now (7–100%).

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Sexual effects, especially arousal/ increased sensual awareness (7–100% in 8 studies) and decreased sexual desire (3– 45% in 4 studies) were also reported.
Sensory perceptions reported in three or more studies were visual effects/changes in visual perception (14–85%), sound hallucinations/altered sound perception (13–100%), enhanced sense of touch/ tactile illusions (3–95%), and hallucina­ tions not otherwise specified (2–60%).
Sleepiness was the only sleep effect recorded by more than one investigator (9–85%).
Decreased appetite was reported by 14– 100% subjects in 9 studies. Factors that affected ecstasy experience as reported in some studies were women having more negative physical and psycho­ logical effects than men. Larger doses were reported to be associated with more hallu­ cinatory experiences, disorientation, loss of control, and increased adverse effects. Acute subjective experiences usually peaked at 45–90 minutes and lasted 4.5– 9 hours. Desirable acute subjective experi­ ences were experienced more often than non-desirable ones. The authors suggested that acute subjective experiences may motivate or restrain ecstasy use, and that educators and researchers could use these data to develop credible prevention messages. The subjective experiences of ecstasy use have been explored in 305 unpaid volun­ teers (268 ecstasy users and 37 abstainers; mean age 26. range 18–72, years; 63% men) (47C). Lifetime use of ecstasy significantly correlated with estimated consumption of other drugs, including alcohol, cannabis, cocaine, and LSD; heavy use of ecstasy was associated with heavy use of all substances. Of the 262 individuals who specified their usual location of ecstasy use, 110 (41%) reported usually taking it at entertainment venues, 52% reported usually taking it in private houses, and 5% reported usually taking it outside. A heterogeneous sample of polysubstance misusers revealed six main components of acute ecstasy effects. These components were perceptual alterations, entactogenesis, pro-social effects, esthetic

and mood effects, negative intoxication effects, and sexual effects. More experienced ecstasy users reported fewer negative, perceptual, and esthetic effects. Naïve individuals expected greater perceptual alterations, esthetic and mood effects, negative intoxication, and sexual effects than those who reported frequent use of ecstasy. Respondents reported using ecstasy for a variety of reasons, most often for raves, dancing, enjoyment of music, to be sociable, to produce altered states of consciousness, and for self-defined psy­ chotherapy. There were no sex differences, in contrast to previous studies. The authors suggested that expectations may be primed by media reference to the negative effects of ecstasy and that those using the drug for other purposes, for example for spirituality, may adopt strategies to counteract negative effects or withdraw from social interactions as part of their drug use practice. They suggested that drug intervention strategies would be more effective if targeted to the particular user groups defined by the reasons given for substance use. Thus, people using ecstasy while dancing or to be social may be more interested in hearing harm reduction information focusing on ways to reduce negative effects. However, people who are not as attentive to negative effects, as those using ecstasy in self-defined therapeutic or spiritual context may be less interested in this information. A drawback of this study was that as many of the respondents were frequent polysubstance users, it would be difficult to differentiate the effects of ecstasy from those of other drugs. It has been suggested that lowering of serotonin for a period after ecstasy use could account for increases in both selfrated and objective measures of aggression previously found in ecstasy users several days after taking the drug (48c). A total of 46 participants were tested, 19 were ecstasy users and 27 controls. They were compared on the night of drug use and 4 days later. On day 4, a task designed to tap cognitive bias toward material with aggressive con­ tent was administered. To investigate sex differences, another data set from a pre­ vious study with similar study design was

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combined, resulting in 107 participants. Ecstasy users recognized more aggressive sentences than controls. They rated them­ selves as being more aggressive and depressed than controls on day 4, but there were no sex differences on any measure of aggression in the combined data set. Neurocognition Chronic ecstasy use has been associated with memory deficits in abstinent users. Memory deficits were evaluated in 19 ecstasy-abstinent men, 19 cannabis-abstinent men, and 19 drug-naïve male controls (49C). The aim of this study was to investigate whether memory deficits in ecstasy users arose from temporal lobe dysfunction or whether the frontal lobes were also involved. Ecstasy users had widespread marked verbal memory deficits compared with drug-naïve controls and cannabis users. Cannabis users did not differ from the control subjects in memory performance. Ecstasy users had impair­ ments in learning, consolidation, recall, and recognition. There was a significant correla­ tion between memory performance and the amount of ecstasy taken, supporting the authors’ view that the memory deficits were caused by a selective neurotoxic effect of ecstasy, possibly on the serotonergic sys­ tem, as seen in animal studies. Moreover, these patients had worse recall consistency and strong retroactive interference. The authors suggested that these measures have been previously associated with frontal lobe function, implying that memory deficits in ecstasy users are related not only to temporal or hippocampal dysfunction but also to the frontal lobes. The postulated negative effects of ecstasy on brain serotonin neurons, which may underlie cognitive dysfunction (especially memory), may be associated with serotonin transporters. Some have suggested that the serotonin transporter promoter gene region may be involved in ecstasy dose and cognition. The effects of moderate and heavy ecstasy use on cognitive function and the effects of long-term abstention from ecstasy have been related to the serotonin transporter promoter gene region genotype (5-HTTLPR) (50C). There were 15 moder­ ate ecstasy users (under 55 lifetime tablets),

45 22 heavy MDMA users (over 55 lifetime tablets), 16 ex-ecstasy users (last tablet over 1 year ago), and 13 controls. There was a significant group effect only on memory function tasks, not on reaction times or attention/executive functioning. Heavy and ex-ecstasy users performed significantly poorly on memory tasks compared with controls. In contrast, there was no evidence of memory impairment in moderate ecstasy users. There were no significant effects of 5-HTTLPR or sex on memory impairment and ecstasy use. The persistent effect of memory problems in the ex-ecstasy users may suggest irreversibility of ecstasyinduced serotonin neurotoxic changes in the brain. Thus, there was a dose-dependent increase in memory dysfunction in ecstasy users, which may not be reversible. Transient persistent sequelae associated with an unusual amount of ecstasy con­ sumption have been reported (51Ar).
A 37-year-old man estimated that he had

used more than 40000 ecstasy tablets between the ages of 21 and 30. He concurrently consumed cannabis and had previously used other drugs. After three episodes of collapse at parties, he stopped using ecstasy. For a few months he felt as if he was still under the influence of ecstasy and had several episodes of tunnel vision. He eventually developed severe panic attacks, recurrent anxiety, depression, muscle rigidity (particularly in the neck and jaw), hallucinations, and para­ noid ideation. He was disoriented in time and had poor concentration and short-term mem­ ory difficulties. He reduced his cannabis intake, and his paranoid ideas and hallucina­ tions disappeared and his panic attacks reduced but his other symptoms remained. The Wechsler Memory Scale showed global memory impairment. There were major behavioral consequences of his memory loss (i.e., repeating activities several times). He fully understood instructions, but his concen­ tration and attention were so impaired that he was unable to follow the sequence of tasks required. A brain MRI scan was normal. He was given olanzapine 10 mg/day and his memory skills improved through the use of compensatory strategies.

The authors thought that this was the largest amount of ecstasy lifetime consump­ tion ever described. The “tunnel vision” effect observed in the first few months after withdrawal has never been reported before.

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The neurocognitive profile was very similar to that shown by current heavy ecstasy users, suggesting that the extent of memory impairment correlates positively with the intensity or frequency of ecstasy consump­ tion. Furthermore, selective impairment of neuropsychological performance associated with regular ecstasy use is not reversed by prolonged abstinence. Cognitive performance and extrapyrami­ dal function have been evaluated in 13 ecstasy users 10–15 hours after exposure and in controls (52c). Ecstasy subjects had impairment of executive functions and pro­ blems with short-delay free recall but they did not have any extrapyramidal motor effects. Contrary to expectations, the authors found minimal memory impairment and no frontal lobe dysfunction. The deficits in executive functions (probably transient) were thought to represent more global than frontal lobe dysfunction. The authors specu­ lated that these effects were more probably related to noradrenergic function. Cognitive function has been evaluated in 11 users of ecstasy and cannabis (THC), 15 THC users, and 15 non-drug controls matched for age and intellect, in order to test the hypothesis that feelings of depres­ sion and anxiety and cognitive impairment are more severe in combined ecstasy/THC users than in THC users alone (53c). Memory function was impaired in both groups of drug users. Ecstasy/THC users had slower psychomotor speed and less mental flexibility than non-drug users. THC users had less mental flexibility and per­ formed worse on the decision-making task than non-drug users, but these functions were similar to those in ecstasy/THC users. Ecstasy users had more feelings of depres­ sion and anxiety than THC users and controls. THC users had impairment of some cognitive abilities to the same degree as ecstasy/THC users, suggesting that some cognitive impairment attributed to ecstasy is more probably due to concurrent THC use. “Stereotype threat” has been the subject of studies of cognitive function in ecstasy users (54CR). According to the authors, “stereotype threat occurs when individuals, believed to be intellectually inferior, perform

badly on cognitive tests they perceive to confirm stereotypes about them.” They suggested that stereotype threat creates an additional burden that interferes with cog­ nitive ability, resulting in a higher mental workload, and that stereotype threats may be created by wide discussion of the negative cognitive effects of ecstasy in the media, by government sponsored drug education campaigns, by websites supported by NIDA, etc. They studied 68 unpaid volunteers (aged 18–36 years) recruited by traditional means. Polysubstance users who reported lifetime use of ecstasy were classi­ fied as ecstasy users. The controls were subjects who used alcohol and other illicit drugs but did not report lifetime use of ecstasy. People were excluded if they were currently using heroin or crack cocaine, had a lifetime diagnosis of a psychological disorder, or had an immediate family mem­ ber with a lifetime diagnosis of a psycholo­ gical disorder. Half of the subjects in both groups received a study information sheet that stated that there was strong evidence linking ecstasy use to mnemonic dysfunction (primed group). The other half did not receive the sheet, were told that there was no conclusive evidence supporting the link, and were verbally reinforced by the investi­ gators (non-primed group). Of all the participants, 84% believed that drug use caused memory loss and 77% believed that drug use caused psychiatric problems. Ecstasy users who were primed recalled fewer items in the delay component of the prose recall task compared with the nonprimed group. To the authors, this suggested that individuals using ecstasy may experi­ ence stereotype threat, raising the concern that stereotype threat may be an important variable in these types of studies. The nonprimed ecstasy users had better memory performance than the other three groups. A higher proportion of ecstasy users reported lifetime use of amfetamine, cannabis, cocaine, ecstasy, and LSD than controls, but there were no differences between the primed and unprimed subjects. Clearly there are limitations to such studies: for instance, controlled drug use was not quantified and it was possible that some subjects may have been recently intoxicated. Cognitive

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Chapter 4

functioning in ecstasy users was comparable to that of their non-ecstasy using peer group. None of them self-reported that they had memory loss. The authors interpreted this to mean that ecstasy users believe what they are told about the negative effects of ecstasy use on memory but do not experience these problems themselves. They further sug­ gested that these users may believe that the probability of negative things happening to them is very low, despite the fact that these problems exist. Thus, they suggested that media reports about the short- and longterm effects of ecstasy may actually be counterproductive. They suggested that researchers should take extra precautions to guard against inducing or amplifying stereotype threat in their studies. Liver Acute hepatitis after ecstasy expo­ sure has again been reported (55A).
A 19-year-old man developed jaundice. There

was no history of surgical procedures, blood transfusion, or ingestion of paracetamol or other medications. He had taken two tablets of ecstasy 2 weeks before, and biochemical confirmation of exposure was not possible. His mother had a history of chronic viral hepatitis B. He was afebrile with an enlarged liver and spleen and no signs of chronic liver disease. Histopathology showed macrovesicu­ lar fatty changes, foci of cell necrosis, and portal tracts expanded by edema and inflam­ matory cells. All other investigations were negative. His serum alanine transaminase and aspartate transaminase activities and bilirubin were markedly raised, with evidence of intrahepatic cholestasis.

Liver damage from ecstasy ranges from being asymptomatic to acute hepatic fail­ ure, and the occurrence and severity of hepatocellular toxicity are unpredictable. Moreover, the severity of symptoms is not related to the magnitude of use or the length of exposure to ecstasy. Although the exact mechanism of liver damage is unclear, the clinical course is the most reliable prognostic factor in ecstasy-induced hepati­ tis. The authors performed HLA typing to rule out a trait of idiosyncrasy and found that the patient had A11 molecules. HLA­ A11 has been reported in 50% of patients with hepatitis caused by tricyclic antide­ pressants and 75% of patients with

47 diclofenac, compared with 12% of controls. The authors suggested that the possibility of an association of specific HLA phenotypes with ecstasy-induced hepatotoxicity should be further investigated. If established, it would offer strong evidence for an immune pathogenetic mechanism. Drug overdose Accidental ecstasy poison­ ing has been reported in a toddler (56A).
While playing, a 17-month-old girl had picked

up a cigarette packet that contained a single ecstasy tablet; an older child had seen her place the tablet in her mouth and immediately alerted her mother, who saw the tablet under the tongue and removed it. About 5 minutes later she developed generalized tonic–clonic seizures. Her rectal temperature was 38.51C. When rectal diazepam 5 mg and paracetamol 180 mg failed, she was given lorazepam 1 mg intravenously, repeated 10 minutes later. She was than sedated with a midazolam infusion and given a single bolus dose of atracurium 10 mg. Her brain CT scan was normal. The serum MDMA concentration was 0.30 mg/l; no other toxins were detected. Her temperature rapidly normalized with tepid sponging and a fan. She was discharged within 48 hours and made a full recovery without sequelae.

The authors cautioned that with widespread use of ecstasy there is increased risk of accidental poisoning in children. This may be exacerbated by a false perception that ecstasy is safe, which may lead to lax supervision. Ecstasy tablets are often very colorful and therefore particularly attrac­ tive to young children. The authors were surprised that there were very few case reports of such poisoning. It appeared that children present with symptoms sooner (within 20 minutes) than adults and that convulsions are the initial manifestation. Other common features are hypertension, tachycardia, and moderate hyperthermia. However, in this case, the symptoms started within 5 minutes, suggesting that sublingual absorption is rapid. MDMA serum concen­ trations were higher than reported for recreational use (below 0.25 mg/l). Hyperthermia in infants is likely to be due to seizures. The authors suggested that termination of seizures combined with cool­ ing measures may be sufficient to restore core temperature. This suggests that

Chapter 4

48

Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

hyperthermia in children may be from a different etiology than in adults and may not warrant the use of dantrolene. As the contents of ecstasy tablets tend to be variable, the authors suggested performing a full toxicological screen, even with a clear history of ecstasy use.

Khat

(SEDA-30, 43)

Khat is a stimulant commonly used in East Africa, Yemen, and southern Saudi Arabia. Because the major active component, cath­ inone, degrades to norpseudoephedrine and norephedrine within days of leaf picking, its use was initially limited to this region. However, with air travel and more sophisti­ cated distribution, khat is now also used in North America and Western Europe. Tra­ ditionally, it is ingested as a part of khat “sessions”, which may begin in the late afternoon and last for many hours. The social and economic impact of khat is significant and has been investigated in a small interview study. Among 50 subjects in Northeast Kenya, 88% of whom had a history of khat use, more than half reported spending over 50% of their household income on khat and 40% felt that it contributed to low productivity in the work­ place (57c). Cardiovascular Khat can cause cardiovas­ cular complications and has been associated with myocardial infarction (58A).
A 33-year-old man had an acute anterior

myocardial infarction after using khat con­ tinuously over the course of 2–3 days. After recovery, he used khat daily and 27 months later presented with shortness of breath and chest pain. He had biventricular heart failure (ejection fraction 15%).

The authors commented that while myo­ cardial infarction is a known complication of khat, guidelines specific to khat-induced cardiac events have not been established. Stroke has been attributed to khat (59A).
A 41-year-old Somali man had an acute left

hemiplegia 2 hours after chewing khat. He was hypertensive (190/95 mmHg) and a CT scan

showed a right middle cerebral artery infarct. He had used khat regularly, but used no other drugs and had no known medical problems. His carotid arteries were normal and there was no hypercoagulability. He was given aspirin and amlodipine and recovered over the course of several months. He resumed using khat and 18 months after the initial event had a left hemiplegia with a larger right middle cerebral artery infarction and white matter changes. After another full recovery, he stopped using khat and 3 years later had had no further ischemic events.

Psychiatric Two further cases of khatinduced psychosis have been described (60A).
Two young Somali men, aged 25 and 35, with

no known psychiatric co-morbidities, had brief self-limiting episodes of psychosis in the context of khat use. The episodes were characterized by paranoia and aggression, necessitating hospitalization; in both cases the episodes resolved over the course of weeks without specific treatment. The 35-year-old man was also given venlafaxine 75 mg/day for a depressed, dysphoric, anxious mood.

The authors pointed out the severe func­ tional impairments associated with khat use; both patients were withdrawn and unemployed. Liver Hepatitis has been attributed to khat (61A).
A 35-year-old East African with no known

medical problems developed hepatitis, with jaundice, dark urine, and pruritus, soon after he began chewing khat daily. He had no recent travel history, no history of transfusions, no infectious contacts, no medications, no family history of hepatitis, and no heavy alcohol or other recreational drug use. Hepatitis virology and autoimmune tests were negative. The symptoms resolved and liver function tests normalized with supportive care alone.

OPIOID ANALGESICS See Chapter 8, in which both therapeutic and abuse aspects of the opioids are covered.

Drugs of abuse

Chapter 4

Psilocybin Psilocybin-containing mushrooms, also called “magic mushrooms”, are used recrea­ tionally, with an expanding worldwide dis­ tribution. They are sold in “smart shops” and over the internet. Psilocybin is showing up in the nightclub scene, although its use is not as popular as “club drugs” such as ecstasy or amphetamines. In 1957, psilocy­ bin was isolated from the Psilocybe mex­ icana mushroom and it has since been identified as a component of over 75 distinct mushroom species (62R). Psilocybin and psilocin are listed as Schedule I drugs under the United Nations 1971 Convention on Psychotropic Sub­ stances. Spore prints, which are distributed in home-growing kits, are currently legal in several states of the USA and can be purchased over the internet (63r). Psilocybin content varies based on such factors as species and preparation. The most commonly used mushroom is Psilocybe cubensis, which contains 10–12 mg of psilo­ cybin per gram of dried mushrooms; effec­ tive oral doses range from 6 to 20 mg and about 40 mg/kg is considered the threshold level for intoxication (64R). Structure Psilocybin (N-phosphoryloxy-N, N-dimethyltryptamine), a simple tryptamine, is dephosphorylated to psilocin (4-hydroxy­ N,N-dimethyltryptamine) by alkaline phos­ phatase in the gastrointestinal tract and kidneys during first-pass metabolism. Psilo­ cin, the pharmacologically active compound, is an indole derivative with structural simila­ rities to serotonin. Psilocybin is detectable by high performance liquid chromatography, but this is not available in most clinical settings. Action Psilocin is a high-affinity agonist at serotonin 5-HT2A receptors, which are espe­ cially prominent in the prefrontal cortex. The net result of 5-HT2A agonism is increased cortical activity secondary to down-stream postsynaptic glutamate effects. Psilocin is also active at 5-HT1A, 5-HT1D, and 5-HT2C receptors, although these are thought to play a lesser role in its effects.

49 Additional evidence about the mechanism of action comes from studies of receptor antagonists. In the presence of the 5-HT2A antagonist ketanserin, the mental status changes typical of psilocybin do not occur, supporting the notion that primary effects are due to action at presynaptic 5-HT2A receptors (65R). Although psilocybin has no affinity for dopamine D2 receptors, a PET study using the D2 receptor ligand raclopride showed that psilocybin increases dopamine transmission in the striatum, probably through secondary increases in dopamine (66c, 67R). Some psilocybin-containing mushrooms contain phenylethylamine, which may contribute to sympathomimetic effects. Psilocybin like other serotonergic hallu­ cinogens, such as lysergic acid diethyla­ mide (LSD) and N,N-dimethyltryptamine (DMT), alters mood, perception, and cognition. In healthy volunteers, changes in emotion, consciousness, perception, and thought begin within 20–30 minutes of ingestion and peak in 30–50 minutes. Peak effects persist for 2 hours, with resolution of effect within 6 hours. Lower doses may produce shorter lasting effects of 1–2 hours. Moderate oral doses (12–30 mg) alter consciousness, increase introspection, and induce derealiza­ tion, dream-like states, illusions, complex hallucinations, synesthesia, and altered per­ ceptions of time and space. Muscle relaxation is also experienced with intoxication. Disrup­ tions in attention, such as difficulty in disen­ gaging from prior stimuli and impairment in monitoring several simultaneous visual sti­ muli, have been described (68c). Euphoria, grandiosity, and other amplifications of affec­ tive experience are common. The majority of psilocybin users experience a pleasant altera­ tion in mood, but some experience panic or dysphoria. A user’s expectations and envir­ onment very strongly influence the hallucino­ genic effects. Settings with more interpersonal support reduce panic and paranoia and increase positive experiences (69c). Psilocybin and psilocin are renally excreted, and about two-thirds of excretion occurs in the first 3 hours. The half-life is about 50 minutes (67R). After 24 hours, the compound is undetectable in the urine (70c).

50

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Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

Uses Psilocybin has been used in obsessivecompulsive disorder (OCD) and some studies support its efficacy in this disorder. In a double-blind study, nine subjects received four doses, low (100 mg/kg), medium (200 mg/kg), and high (300 mg/kg), in a series of 8-hour sessions with a very low dose (25 mg/kg) inserted randomly in a doubleblind manner. All the subjects had a reduc­ tion in their symptoms (measured by the Yale-Brown Obsessive Compulsive Scale) during at least one of the sessions, and improvement lasted at least 24 hours. No dose effect was noted. With the exception of one subject who had transient hypertension, psilocybin was well tolerated and without adverse effects (71c, 72R). Synthetic psilocybin (Indocybin) was used for investigational and psychotherapeutic purposes in the 1960s. The serotonin hypoth­ esis of schizophrenia grew in part from the psychotomimetic effects of psilocybin seen in these investigations, as well as similar obser­ vations in studies of LSD. Psilocybin impairs thalamic sensory gating, resulting in an inability to screen out extraneous stimuli and difficulties attending to appropriate stimuli, which overwhelms frontal organizational capacities and is thought to result in the observed psychotomimetic effects (67R, 73R).

Adverse effects Cardiovascular An 18-year-old man devel­ oped Wolff–Parkinson–White syndrome and had a myocardial infarction during psilocy­ bin intoxication (74A). The mechanism for myocardial infarction is not known, although it is theorized that serotonin-induced changes in platelet aggregation and sympatheticallyinduced vasospasm may play a role (75R). In a study of the dose-dependent effects of psilocybin 45–315 mg/kg in eight subjects, there was no effect on the electrocardiogram or heart rate (76c). At the highest doses, mean arterial blood pressure rose signifi­ cantly in the 60 minutes after psilocybin ingestion, leading the authors to recommend that those with untreated hypertension should abstain from psilocybin. Nervous system In an interview study of 53 subjects with cluster headaches who were

using psilocybin or LSD to treat their symptoms, 32 had episodic cluster headache and 21 had chronic cluster headaches; 17 of 19 who tried sublingual psilocybin reported that it terminated the headache within 20 min­ utes (77c). Of the 29 who used psilocybin as prophylaxis, 15 described it as completely effective in avoiding headaches and 12 (42%) reported that it reduced the frequency or intensity of headaches. Of the 21 subjects with chronic cluster headaches, seven tried psilo­ cybin to abort a headache and five felt that it was effective; 20 tried psilocybin as prophy­ laxis and 10 reported a complete response, while eight reported partial efficacy. This small study used a retrospective design and may have been affected by recall bias, selection bias, and by its unblinded and uncontrolled design. Psychiatric Two cases of exacerbation of pre-existing psychosis have been reported (60A).
A 35-year-old man with a history of schizo­

phrenia developed anxiety, irritability, agitation, and aggression while using “a handful” of psilocybin-containing mushrooms plus cannabis twice daily. He also reported delusions of external control and persecution as well as auditory, olfactory, and gustatory hallucinations. He was given risperidone 3 mg/day and his symptoms gradually improved over 2 weeks.
A 35-year-old man with a 10-year history of paranoid schizophrenia experienced mood ele­ vation, anxiety, and psychomotor agitation as well as illusions, hallucinations, “sensory dys­ perceptions”, paranoia, compulsive thinking, and poor attention after taking psilocybin (amount and duration of exposure not speci­ fied). The symptoms resolved within days without pharmacologic treatment.

While these case studies suggest a possible role for psilocybin in exacerbating psychosis, the small number of cases and factors such as the simultaneous use of cannabis in the first case make it difficult to draw a more definitive conclusion. Hallucinogen persisting perceptual disor­ der (HPDD) has been reported after psilocybin (78A).
An 18-year-old man with no prior psychiatric

history who smoked cannabis weekly and took a single dose of 40 psilocybin-containing mushrooms, after which he experienced visual

Drugs of abuse

Chapter 4

distortions, temporal and spatial distortions, depersonalization, and derealization. These symptoms remitted, but recurred the next day in conjunction with cannabis use and continued daily thereafter. His symptoms, including hal­ lucinations, depersonalization, derealization, and dysphoric mood, remitted 8 months later, after discontinuation of cannabis and treatment with sertraline 150 mg/day and risperidone 2 mg/day.

The authors commented that both canna­ bis and psilocybin may play a role in triggering HPDD. Previous anecdotal reports that hallucino­ gens induce religious experiences and heigh­ tened spirituality have been investigated in a double-blind study in 36 healthy hallucinogennaïve volunteers, who were assigned to either psilocybin (30 mg per 70 kg) or methylphe­ nidate (40 mg per 70 kg) in an 8-hour drug session, returning at a later date for a session with the other drug (69c). Monitors were assigned to provide support throughout the sessions and a comfortable environment was maintained. Based on criteria from the Mysticism Scale and the States of Conscious­ ness Questionnaire, 22 of 36 volunteers had a “complete” mystical experience with psilo­ cybin, compared with four of 36 in response to methylphenidate. The authors noted that 33% of participants described the psilocybin experience as their most significant spiritual experience in life and another 38% rated the experience within their top 10 most signifi­ cant experiences. Dysphoria or anxiety in the 6 hours after psilocybin was reported by eight of the 36 participants; these reactions responded to reassurance and did not persist beyond the duration of the session. Of these healthy volunteers without a history of psychosis, 17% reported transient ideas of reference or paranoia in response to psilocybin; there were no lasting adverse effects. Endocrine In a double-blind, placebocontrolled study of psilocybin in 32 healthy volunteers, drug exposure did not affect prolactin, cortisol, or growth hormone concentrations (79c). In a study of the dose-dependent effects of psilocybin 45–315 mg/kg in eight subjects, there were transient rises in thyroid stimulat­ ing hormone, prolactin, ACTH, and cortisol

51 (76c). These effects were unlikely to be clinically relevant, since all values returned to baseline by 300 minutes after ingestion. The authors noted that only the prolactin concen­ trations fell outside the reference range. Electrolyte balance Psilocybin has no effect on electrolyte balance (measured at 105 and 300 minutes after exposure to 45–315 mg/kg) (76c). Liver Psilocybin has no clinically relevant effects on liver function (76c). Brief, statis­ tically significant increases in gamma-gluta­ myltransferase and aspartate transaminase activity resolved within 300 minutes of exposure. Body temperature Psilocybin has no effect on axillary body temperature (76c). Trauma Hallucinogen intoxication can result in traumatic injury if people believe that they have superhuman powers (80R). Death Psilocybin mushrooms are not known to cause major organ toxicity or death, but mis-identification can lead to the ingestion of toxic species with potentially fatal outcomes. For example, there have been reports of renal failure after ingestion of Cortinarius mushrooms that were mis­ taken for Psilocybe species (81A, 82A). Drug abuse and tolerance Psilocybin and other hallucinogens are not considered classic drugs of abuse because they do not have reinforcing properties and do not produce drug-seeking behaviors (69c). Use tends to be episodic and is generally shortterm and experimental (80R). Tolerance occurs with repeated dosing and is thought to be due to down-regulation of 5HT2A receptors (80R). There may also be crosstolerance between LSD and psilocybin (67R, 64R). Psilocybin, like other hallucinogens, is not known to cause dependence, craving, or withdrawal. Interference with diagnostic tests Urine toxicology may be falsely positive for amphe­ tamines because of the phenylethylamine in psilocybin-containing mushrooms (62R).

52

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Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

Management of adverse drug reactions Treatment should begin with reassurance and observation in a low-stimulation envir­ onment. Benzodiazepines are considered first line for agitation. Most symptoms of

intoxication resolve within 6 hours of inges­ tion (64R, 83c). If it is suspected that another, potentially toxic, type of mushroom was ingested, activated charcoal should be admi­ nistered (62R).

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cognitive performance and extrapyramidal signs in human subjects. Cogn Behav Neurol 2006;19(3):157–64. Lamers CTJ, Bechara A, Rizzo M, Ramae­ kers JG. Cognitive function and mood in MDMA/THC users, THC users and nondrug using controls. J Psychopharmacol 2006;20:302–11. Cole JC, Michailidou K, Jerome L, Sumnall HR. The effects of stereotype threat on cognitive function in ecstasy users. J Psycho­ pharmacol 2006;20:518–25. Brncic N, Kraus I, Viskovic I, MijandrusicSincic B, Vlahovic-Palcevski V. 3,4-methyle­ nedioxymethamphetamine (MDMA): an important cause of acute hepatitis. Med Sci Monit 2006;12:CS107–9. Duffy MR, Swart M. Severe ecstasy poison­ ing in a toddler. Anaesthesia 2006;61 (5):498–501. Aden A, Dimba EAO, Ndolo UM, Chindia ML. Socio-economic effects of khat chewing in North Eastern Kenya. East Afr Med J 2006;83(3):69–73. Saha S, Dollery C. Severe ischemic cardio­ myopathy associated with khat chewing. J R Soc Med 2006;99:316–8. Vanwalleghem IE, Vanwalleghem PW, De Bleecker JL. Khat chewing can cause stroke. Cerebrovasc Dis 2006;22(2-3):198–200. Nielen RJ, van der Heijden FMMA, Tuinier S, Verhoeven WMA. Khat and mushrooms associated with psychosis. World J Biol Psychiatry 2004;5:49–53. Brostoff JM, Plymen C, Birns J. Khat—a novel cause of drug-induced hepatitis. Eur J Intern Med 2006;17:383. Berger KJ, Guss DA. Mycotoxins revisited: Part II. J Emerg Med 2005;28(2):175–83. Halpern JH. Hallucinogens and dissociative agents naturally growing in the United States. Pharmacol Ther 2004;102:131–8. Halpern JH, Sewell RA. Hallucinogenic botanicals of America: a growing need for focused drug education and research. Life Sciences 2005;78:519–26. Vollenweider FX, Leenders KL, Scharfetter C, Maguire P, Stadelmann O, Angst J. Positron emission tomography and fluoro­ deoxyglucose studies of metabolic hyper­ frontality and psychopathology in the psilocybin model of psychosis. Neuropsycho­ pharmacology 1997;16(5):357–72.

Drugs of abuse

Chapter 4

66. Vollenweider FX, Vontobel P, Hell D, Leenders KL. 5-HT modulation of dopamine release in basal ganglia with psilocybininduced psychosis in man—a PET study with (11C) raclopride. Neuropsychopharmacol­ ogy 1999;20:424–33. 67. Passie T, Seifert J, Schneider U, Emrich HM. The pharmacology of psilocybin. Addict Biol 2002;7:357–64. 68. Carter OL, Burr DC, Pettigrew JD, Wallis GM, Hassler F, Vollenweider FX. Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors. J Cogn Neurosci 2005;17:1497–508. 69. Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mysticaltype experiences having substantial and sustained personal meaning and significance. Psychopharmacology 2006;187:268–83. 70. Hasler F, Bourquin D, Brenneisen R, Vollenweider FX. Renal excretion profiles of psilocin following oral administration of psilocybin: a controlled study in man. J Pharm Biomed Anal 2002;30(2):331–9. 71. Moreno FA, Wiegand CB, Taitano EK, Delgado PL. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessivecompulsive disorder. J Clin Psychiatry 2006;67(11):1735–40. 72. El Mansari M, Blier P. Mechanisms of action of current and potential pharmacotherapies of obsessive-compulsive disorder. Progr Neuro-Psychopharmacol Biol Psychiatry 2006;30:362–73. 73. Vollenweider FX, Geyer MA. A systems model of altered consciousness: integrating natural and drug-induced psychosis. Brain Res Bull 2001;56(5):495–507. 74. Borowiak KS, Ciechanowski K, Walsoszczyk P. Psilocybin mushroom (Psilocybe semilan­ ceata) intoxication with myocardial

55

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infarction. J Toxicol Clin Toxicol 1998; 36(1-2):47–9. Ghuran A, Nolan J. Recreational drug misuse: issues for the cardiologist. Heart 2000;83:627–33. Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX. Acute physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled doseeffect study. Psychopharmacology 2004; 172:145–56. Sewell RA, Halpern JH, Pope HG. Response of cluster headaches to psilocybin and LSD. Neurology 2006;66:1920–2. Espiard M, Lecardeur L, Abadie P, Halbecq I, Dollfus S. Hallucinogen persisting perception disorder after psilocybin con­ sumption: a case study. Eur Psychiatry 2005;20:458–60. Gouzoulis-Mayfrank E, Thelen B, Haber­ meyer E, Kunert HJ, Kovar KA, Lindenblatt H, Hermle L, Spitzer M, Sass H. Psychopathological, neuroendocrine and autonomic effects of 3,4-methylenedioxyethy­ lamphetamine (MDE), psilocybin, and dmethamphetamine in healthy volunteers: results of an experimental double-blind pla­ cebo-controlled study. Psychopharmacology 1999;142:41–50. Nichols DE. Hallucinogens. Pharmacol Ther 2004;101:131–81. Franz M, Regele H, Kirchmair M, .Kletzmayr J, Sunder-Plassmann G, Horl WH, Pohanka E. Magic mushrooms: hope for a “cheap high” resulting in end-stage renal failure. Nephrol Dial Transplant 1996;11:2324–7. Raff E, Halloran PF, Kjellstrand CM. Renal failure after eating “magic” mushrooms. Can Med Assoc J 1992;147(9):1339–41. Persson H. Mushrooms. Medicine 2007;35 (12):635–7.

Andrew Byrne, Shabir Musa, and Stephen Curran

5

Hypnosedatives and anxiolytics

(SED-15, 429; SEDA-28, 52; SEDA-29, 51; SEDA30, 49)

BENZODIAZEPINES

Alprazolam

(SED-15, 91; SEDA-28, 52; SEDA-29, 51; SEDA-30, 49)

Psychiatric In a double-blind, placebocontrolled, crossover study 18 healthy male volunteers took a single dose of alprazolam 0.75 or 1.75 mg or placebo in randomized order (1C). Performance on cognitive tests included immediate and delayed recall, digit symbol substitution, critical flicker fusion, and choice reaction time as well as subjective ratings. Alprazolam impaired cognitive performance and subjective sedation in a dose-dependent manner. Drug withdrawal Abrupt withdrawal of alprazolam in 26 patients with panic dis­ order resulted in dysphoric mood, fatigue, low energy, confusion, and raised systolic blood pressure, which were notable as the fall in plasma concentrations approached 50% (2c). In addition, there was a psycho­ motor deficit, which persisted beyond dose stabilization. An anxiety-prone cognitive affect, measurable before undertaking treatment, may be a risk factor for more severe anxiety on withdrawal. These obser­ vations provide a rationale for applying cognitive behavioral therapy when tapering doses of benzodiazepines. Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03105-5 r 2009 Elsevier B.V. All rights reserved.

Formulations A modified-release formu­ lation of alprazolam (Xanax XR) has been studied in a randomized, open, single-dose, two-period crossover study in healthy volunteers, 12 adolescents (13–17 years) and 12 adults (20–45 years), who took single doses of 1 or 3 mg (3C). At both doses, mean plasma concentration–time profiles of alprazolam, a-hydroxyalprazolam, and 4-hydroxyalprazolam were similar in adolescents and adults. Parent–metabolite ratios were similar in the two age groups and were consistent with those previously reported. The most common adverse event was somnolence, which was dose-related. Based on the similar pharmacokinetic pro­ files, the doses of Xanax XR should be similar in adolescents and adults.

Diazepam

(SED-15, 1103; SEDA-29, 54; SEDA-30, 50)

Comparative studies Baclofen can reduce the symptoms of the alcohol withdrawal syndrome and has been compared with diazepam in 37 patients, who were randomized into two groups (4C). Baclofen 30 mg/day was given orally to 18 patients and diazepam 0.5–0.75 kg/kg/day to 19 patients. The Clinical Institute Withdrawal Assessment was used to evaluate physical symptoms of alcohol withdrawal syndrome. Both baclofen and diazepam significantly reduced the score, and there were no significant differences between the two. When subscales for sweating, tremors, anxiety, and agitation were evaluated singly, baclofen and diazepam both significantly and equally reduced sweating, tremors, and anxiety. Both reduced the

57

58

Chapter 5

agitation score, although diazepam acted slightly more rapidly than baclofen. Psychological The effects of diazepam on word list recall, prospective memory, sus­ tained attention, and subjective ratings of arousal have been studied in 48 healthy participants, aged 19–35 years, who took oral diazepam mean dose 0.19 mg/kg or placebo in a double-blind study (5C). Retro­ spective memory and prospective memory were assessed by free recall of unrelated word lists and by instructing participants to ask for a hidden belonging at the end of the session. Sustained attention was measured by multiple trials of a digit cancellation task and subjective arousal was assessed by selfratings of drowsiness. Diazepam impaired performance on all measures. Diazepam reduced prospective memory performance associated with reduced subjective arousal, but unrelated to sustained attention. This is the first report of the effects of benzodiaze­ pines on prospective remembering and further supports the view that the arousal/ attentional system is composed of partially independent subsystems that have differen­ tial relationships to memory.

Flunitrazepam

(SED-15, 1394)

Psychological The acute effects of flunitrazepam (1.0 and 1.3 mg) and placebo in healthy volunteers on immediate and delayed free recall of word lists have been evaluated, with a focus on serial positions and semantic relations between words (6C). Flunitrazepam promoted a global amnesic effect, impairing recall in all serial positions except the last words (recency effect). Primacy and recency effects were preserved by larger recall of the first and last words in relation to adjacent items. Facilitation in recall of semantically related words was not impaired compared with recall in adjacent positions, in spite of a dose-dependent diminution in the number of words recalled in mid-list positions. Flunitrazepam-induced deficits were interpreted as impairment in the formation of new associations between items, or groups of items in the case of related words, and context.

Andrew Byrne, Shabir Musa, and Stephen Curran

Monitoring therapy The relation between behavior and blood flunitrazepam concen­ tration has been studied in 415 drivers suspected of driving under the influence and 7 suspects of violent crime (7C). These selected cases had flunitrazepam as the only drug in blood samples and had been evaluated by a clinical test for impairment performed by a police physician at the time of blood sampling. The impaired drivers had higher blood flunitrazepam concentra­ tions than the non-impaired drivers. Multi­ variate analysis showed that blood flunitrazepam concentration and age had independent effects on impairment, sug­ gesting tolerance with age. Most of the effects measured were sedative and were related to flunitrazepam concentration. There were possible paradoxical reactions in a subgroup of 23 individuals (6%), but these reactions were not related to blood flunitrazepam concentration. The suspects of violent crimes had similar impairment but did not have more paradoxical reactions than the suspected drugged drivers. The findings are in agreement with other research that suggests that paradoxical reactions should be viewed as a reaction in certain individuals, and do not support the idea that flunitrazepam in high concen­ trations produces aggression in all indivi­ duals taking it.

Lorazepam

(SED-15, 2163; SEDA-29, 55; SEDA-30, 51)

Psychiatric Delirium is a predictor of death, increased cost, and longer duration of stay in ventilated patients. Markov regression modeling (adjusting for 11 covariates) has been used in the evaluation of 198 mechanically ventilated patients to determine the probability of daily transition to delirium as a function of sedative and analgesic dose administration during the previous 24 hours (8C). Lorazepam was an independent susceptibility factor for daily transition to delirium, whereas fentanyl, morphine, and propofol were associated with higher but not statistically significant odds radios. Increasing age and Acute Physiology and Chronic Health Evaluation

Hypnosedatives and anxiolytics

Chapter 5

II scores were also independent predictors of the transition to delirium. Etifoxine, a non-benzodiazepine anxiolytic drug, 50 mg tds and lorazepam 0.5–1 mg/day have been compared in a double-blind, randomized, parallel group study for 28 days in 191 out-patients with adjustment disorders with anxiety (9C). The main efficacy assess­ ment criterion was the Hamilton Rating Scale for Anxiety score. There was clinical improve­ ment in both treatment arms, but etifoxine had a more marked therapeutic effect without adverse effects. Moreover, 1 week after stopping treatment, more patients taking lorazepam had rebound anxiety. Dosage regimens In a randomized open study of the duration of mechanical ventila­ tion in patients randomized to lorazepam by intermittent bolus administration (n ¼ 64) versus continuous infusions of propofol (n ¼ 68) using protocols that include scheduled daily interruption of sedation (10c). The primary outcome was median ventilator days; secondary out­ comes included 28-day ventilator-free sur­ vival, intensive care unit and hospital length of stay, and hospital mortality. Median ventilator days were significantly lower in the daily interruption propofol group com­ pared with the intermittent bolus lorazepam group. The difference was largest for hospital survivors. There was a trend toward greater ventilator-free survival for patients in the daily interruption propofol group. Hospital mortality was not different.

Midazolam

(SED-15, 2337; SEDA-29, 56; SEDA-30, 51)

Observational studies The records of 227 children, aged 4 months to 18 years, who had received intravenous ketamine+midazolam for 356 painful procedures in the pediatric sedation unit of a university hospital over 3 years have been retrospectively reviewed to determine indications, dosing, assessment of the degree of sedation, adverse events, and recovery time for each procedural sedation and analgesia (11c). There were 46 adverse events (12.9%) in all, including oxygen saturations below 85% without apnea

59 (n ¼ 14), apnea (n ¼ 3), transient stridor (n ¼ 2), hypertension and tachycardia (n ¼ 8), hypersalivation (n ¼ 6), vomiting (n ¼ 5), hallucinatory emergence reactions (n ¼ 4), and rash (n ¼ 4). No adverse outcomes were attributable to the combination of ketamine with midazolam. Comparative studies The efficacy and adverse effects of midazolam and propofol have been compared in 70 patients of two age groups, under 65 years and 65 years and over, who underwent cardioversion for atrial fibrillation (12C). The participants were randomized to four groups: those under 65 years who received midazolam (n ¼ 12) or propofol (n ¼ 11) and those of 65 years and over who received midazolam (n ¼ 25) or propofol (n ¼ 22). During cardioversion, induction time, recovery time, and adverse effects, including desaturation, apnea, and hemodynamic changes, were recorded blind. Mean induction times were similar in the four groups. Mean recovery time was shorter after propofol compared with midazolam. Older participants needed less medication than younger patients. There were no hemodynamic differences across the groups. Desaturation was greater after midazolam compared with propofol. Sensory systems The effects of midazolam on stapedius reflex thresholds and transi­ ent-evoked otoacoustic emissions have been studied in 10 patients who were scheduled for operation and who had normal hearing (13c). Midazolam signifi­ cantly increased ipsilateral and contralateral stapedius reflex thresholds and reduced the wave reproducibility of the otoacoustic emissions. The authors concluded that midazolam premedication may affect audio­ logical evaluation. Drug formulations The pharmacokinetics and pharmacodynamics of single 5 mg doses of midazolam have been studied after the administration of a novel intranasal formulation of midazolam compared with intramuscular and intravenous administra­ tion in an open, randomized, three-way, crossover study in 12 healthy volunteers (14c). Intranasal doses were delivered as

Chapter 5

60

0.1 ml unit-dose sprays. Blood samples were taken serially from 0 to 12 hours after each dose. Mean midazolam bioavailability was 73 and 93% after the intranasal and intra­ muscular doses, respectively. Median tmax was 10 minutes for intranasal doses. Adverse events were minimal with all routes of administration, but nasopharyngeal irrita­ tion, watering of the eyes, and a bad taste were reported after intranasal doses. Intranasal midazolam 0.2 mg/kg and rec­ tal diazepam 0.3 mg/kg have been compared in the treatment of 188 seizure episodes in 46 children (15c). Mean time from drug admin­ istration to cessation of the seizure was significantly less with midazolam. Mean heart rate and blood pressure were not different between the two drugs. However, mean respiratory rate and oxygen saturation were significantly reduced at 5, 10, and 30 minutes after administration by rectal but not intranasal midazolam. The authors suggested that intranasal midazolam is pre­ ferable to rectal diazepam in the treatment of acute seizures in children. It is easy to administer, has a rapid onset of action, has no significant effect on respiration and oxygen saturation, and is socially acceptable. This route of administration may also have potential in children requiring sedation.

Quazepam

(SED-15, 2295)

Drug–food interactions Grapefruit juice The effects of grapefruit juice on quazepam 15 mg have been studied in nine healthy subjects (16c). Pharmacodynamic effects were determined by the digit symbol substitution test (DSST) and using a visual analog scale. Grapefruit juice increased the plasma concentrations of quazepam and of the active metabolite of quazepam, 2­ oxoquazepam, but not its sedative effects.

Temazepam

(SED-15, 3312; SEDA-28, 52; SEDA-29, 51; SEDA-30, 52)

The effects of temazepam 10 mg on noctur­ nal oxygenation and next-day performance at altitude after a 17-day trek from 410 m have been assessed in a randomized, pla­ cebo-controlled, crossover study in 33

Andrew Byrne, Shabir Musa, and Stephen Curran

healthy volunteers (17C). Temazepam reduced periodic breathing from a median of 16% of the night to 9.4%, associated with a small but significant reduction in mean nocturnal oxygen saturation from 78 to 76%. There was no change in sleep latency or restlessness. Temazepam had no adverse effects on next-day reaction time, sedation, maintenance of wakefulness, cognition, or acute mountain sickness. At high altitude, temazepam reduces periodic breathing dur­ ing sleep without an adverse effect on nextday reaction time, maintenance of wakeful­ ness, or cognition. The 2% reduction in mean oxygen saturation is likely to have been predominantly because of acclimatiza­ tion. At high altitude temazepam reduces periodic breathing and is safe to use, without any adverse effects on next-day perfor­ mance. These findings may also have impli­ cations for patients on intensive care wards and in older people with reduced oxygen saturation.

Triazolam

(SED-15, 3486)

Drug–food interactions Grapefruit juice The effects of grapefruit juice on triazolam 0.25 mg have been studied in nine healthy subjects (15c). Pharmacodynamic effects were determined by the DSST and using a visual analog scale. Grapefruit juice increased the plasma concentrations of triazolam, but not its sedative effects.

OTHER HYPNOSEDATIVES Chloral hydrate (SED-15, 705; SEDA-27, 46; SEDA-30, 52) Observational studies In a retrospective analysis of 1095 children who were sedated for echocardiography with chloral hydrate, vital signs and oxygen saturations were recorded every 5 minutes and adverse events were noted (18c). There was significant co-morbidity as assessed by the fact that 38% of the subjects were classified as American Society of Anesthesiologists class 3

Hypnosedatives and anxiolytics

Chapter 5

or 4. Hemodynamic responses to chloral hydrate sedation included at least a 20% fall in heart rate (24% of the patients) and blood pressure (59%). There were no deaths or permanent morbidities. There were adverse events in 11% of patients, including apnea, airway obstruction, hypoxia, hypotension with poor perfusion, vomiting, and prolonged sedation. No intervention was required in 93%, minor interventions were necessary in 7%, and major interventions were required in 0.5%. Multivariate analysis identified only age under 6 months as a predictor for adverse events, whereas cyanosis, hospitalization, American Society of Anesthesiologists class, fasting time, oxygen requirement, and the use of additional sedation were not predictors. Moderate falls in heart rate and blood pressure, in the absence of clinical deterioration, are expected responses to chloral hydrate sedation in this pediatric population. Tumorigenicity Chloral hydrate has been shown to be carcinogenic in some animal studies. The potential causal association between chloral hydrate exposure and cancer risk in humans has therefore been investigated (19C). Cancer incidence was previously determined by biennial screen­ ing analyses of the 215 drugs that were most commonly used by 143 574 out-patients between 1976 and 1998. Among users of chloral hydrate, there were statistically significant increases in standardized mor­ bidity ratios during various years for can­ cers at five anatomical sites, including the lung, stomach, prostate, skin (melanoma), and floor of the mouth. These associations were investigated using a dose–response analysis among exposed subjects and a twostage design in exposed and non-exposed persons. There was an increasing risk of prostate cancer with increasing numbers of prescriptions for chloral hydrate, which persisted after controlling for benign pro­ static hyperplasia, vasectomy, and obesity; however, the trend was not statistically significant. There was no evidence of a dose–response relation between chloral hydrate and the risk of any of the other four cancers. In the two-stage design, analyses comparing exposed and

61 unexposed subjects showed no increased risk of cancer after controlling for con­ founding variables; however, the data were suggestive for prostate cancer, for which the increased risk associated with chloral hydrate exposure after adjustment for con­ founding variables persisted. There was no dose–response relation for any of the other four cancer sites. These results suggest that chloral hydrate is probably not carcinogenic in humans during short-term use.

Zolpidem

(SED-15, 3723; SEDA-28, 56; SEDA-29, 57; SEDA-30, 53)

Psychological Residual psychomotor and cognitive effects of zolpidem have been assessed with a psychometric test battery in 24 healthy elderly volunteers, who took four treatments (zolpidem-MR 6.25 and 12.5 mg, flurazepam 30 mg, and placebo) using a randomized, crossover, doubleblind design (20C). Quality of sleep and residual effects were evaluated subjectively with the Leeds Sleep Evaluation Questionnaire. Psychometric performance was significantly impaired by flurazepam but not by either dose of zolpidem-MR. Ease of falling asleep and sleep quality were significantly improved by both doses of zolpidem-MR and flurazepam. Neither drug modified perception of well-being on awakening. Drug dependence There is evidence that zolpidem produces spatial working memory deficits and dependence; however, the underlying mechanisms are unknown. The auditory N400 component of event-related potentials (ERPs), which is considered to be an index of memory use of contact processing, has been used to study a patient with zolpidem dependence (21A). A com­ parison of the patient’s N400 waveform with the patterns obtained from healthy controls showed that zolpidem dependence is accompanied by reduced amplitudes located at posterior brain areas and diffuse prolongation of N400. These findings sug­ gest that zolpidem dependence may alter memory associated with context processing,

62

Chapter 5

involving or affecting a wide network of the brain’s structures. Drug formulations A modified-release formulation of zolpidem has been devel­ oped to maintain effective plasma concen­ trations for 3–6 hours after the dose. Modified-release zolpidem 12.5 mg, stan­ dard zolpidem 10 mg, and placebo have been compared in a double-blind, singledose, crossover study in 70 healthy volun­ teers (22C). Scores on the DSST and measures of sedation were not significantly different at 8 hours after the dose. The tmax was significantly longer after the modifiedrelease formulation. Tolerability was not specifically reported, but the authors con­ cluded that modified-release zolpidem pro­ duced enhanced pharmacodynamic effects 3–6 hours after the dose.

Zopiclone

(SED-15, 3710; SEDA-28, 56; SEDA-29, 57) The prescription of zopiclone and other “Z” drugs is rising in the UK and use of

Andrew Byrne, Shabir Musa, and Stephen Curran

benzodiazepines as hypnotics is falling. A cross-sectional survey of 84 general practitioners showed that they believed that these drugs were more effective than benzodiazepines and had fewer adverse effects (23c). In particular, zopiclone and the other “Z” drugs were thought to be associated with significantly fewer accidents and better day-time functioning, total sleep, quality of sleep, and tolerability in older people. However, the authors concluded that these perceptions are not based on current evidence or national guidance. Drug–drug interactions Gemfibrozil In a randomized crossover study, 10 healthy volunteers took gemfibrozil 600 mg or placebo orally twice daily for 3 days (24C). On day 3, each took zopiclone 7.5 mg. Gemfibrozil increased the mean plasma concentration of N-desmethylzopiclone 1.2-fold and reduced renal clearance by 48%. The pharmacodynamic effects of zopiclone were not affected by gemfibrozil. The authors concluded that gemfibrozil may slightly enhance the effect of zopi­ clone.

References 1. Drabant S, Tömlo J, Tóth M, Péterfai E, Klebovich I. The cognitive effect of alprazo­ lam in healthy volunteers. Acta Pharmacol Hung 2006;76(1):25–31. 2. Uhlenhuth EH, Starcevic V, Qualls C, Antal EJ, Matuzas W, Javaid JI, Barnhill J. Abrupt discontinuation of alprazolam and cognitive style in patients with panic disorder: early effects on mood, performance, and vital signs. J Clin Psychopharmacol 2006;26(5):519–23. 3. Glue P, Fang A, Gandelman K, Klee B. Pharmacokinetics of an extended release formulation of alprazolam (Xanax XR) in healthy normal adolescent and adult volun­ teers. Am J Ther 2006;13:418–22. 4. Addolorato G, Leggio L, Abenavoli L, Agabio R, Caputo F, Capristo E, Colombo G, Gessa GL, Gasbarrini G. Baclofen in the treatment of alcohol withdrawal syndrome: a comparative study vs diazepam. Am J Med 2006;119(3):e13–8.

5. Rich JB, Svoboda E, Brown GG. Diazepaminduced prospective memory impairment and its relation to retrospective memory, atten­ tion, and arousal. Hum Psychopharmacol 2006;21:101–8. 6. Nogueira AML, Pompéia S, Galduróz JCF, Bueno OFA. Effects of a benzodiazepine on free recall of semantically related words. Hum Psychopharmacol 2006;21:327–36. 7. Bramness JG, Skurtveit S, Mørland J. Fluni­ trazepam: psychomotor impairment, agitation and paradoxical reactions. Forensic Sci Int 2006;159:83–91. 8. Pandharipande P, Shintani A, Peterson J, Pun BT, Wilkinson GR, Dittus RS, Bernard GR, Ely EW. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 2006;104 (1):21–6. 9. Nguyen N, Fakra E, Pradel V, Jouve E, Alquier C, Le Guern M-E, Micallef J, Blin O.

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16.

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Efficacy of etifoxine compared to loraze­ pam monotherapy in the treatment of patients with adjustment disorders with anxiety: a double-blind controlled study in general practice. Hum Psychopharmacol 2006;21:139–49. Carson SS, Kress JP, Rodgers JE, Vinayak A, Campbell-Bright S, Levitt J, Bourdet S, Ivanova A, Henderson AG, Pohlman A, Chang L, Rich PB, Hall J. A randomized trial of intermittent lorazepam versus pro­ pofol with daily interruption in mechani­ cally ventilated patients. Crit Care Med 2006;34(5):1326–32. Karapinar B, Yilmaz D, Demirag˘ K, Kantar M. Sedation with intravenous ketamine and midazolam for painful procedures in chil­ dren. Pediatr Int 2006;48:146–51. Parlak M, Parlak I, Bulent E, Ergin A, Sagiroglu E. Age effect on efficacy and side effects of two sedation and analgesia pro­ tocols on patients going through cardiover­ sion: a randomized clinical trial. Acad Emerg Med 2006;13:493–9. Guven S, Tas A, Adali MK, Yagiz R, Alagol A, Uzun C, Koten M, Karasalihoglu AR. Influence of anaesthetic agents on transient evoked otoacoustic emissions and stapedius reflex thresholds. J Laryngol Otol 2006;120(1):10–5. Wermeling DP, Record KA, Kelly TH, Archer SM, Clinch T, Rudy AC. Pharma­ cokinetics and pharmacodynamics of a new intranasal midazolam formulation in healthy volunteers. Anesth Analg 2006;103:344–9. Bhattacharyya M, Kalra V, Gulati S. Intra­ nasal midazolam vs rectal diazepam in acute childhood seizures. Pediatr Neurol 2006;34:355–9. Sugimoto K, Araki N, Ohmori M, Harada K, Cui Y, Tsuruoka S, Kawaguchi A, Fujimura A. Interaction between grapefruit juice and hypnotic drugs: comparison of triaolam and quazepam. Eur J Clin Phar­ macol 2006;62:209–15.

63 17. Nickol AH, Leverment J, Richards P, Seal P, Harris GA, Cleland J, Dubowitz G, Collier DJ, Milledge J, Stradling JR, Mor­ rell MJ. Temazepam at high altitude reduces periodic breathing without impair­ ing next-day performance: a randomized cross-over double-blind study. J Sleep Res 2006;15:445–54. 18. Heistein LC, Ramaciotti C, Scott WA, Coursey M, Sheeran PW, Lemler MS. Chloral hydrate sedation for pediatric echocardiography: physiologic responses, adverse events, and risk factors. Pediatrics 2006;117(3):e434–41. 19. Haselkorn T, Whittemore AS, Udaltsova N, Friedman GD. Short-term chloral hydrate administration and cancer in humans. Drug Saf 2006;29:67–77. 20. Hindmarch I, Legangneux E, Stanley N, Emegbo S, Dawson J. A double-blind, placebo-controlled investigation of the resi­ dual psychomotor and cognitive effects of zolpidem-MR in healthy elderly volunteers. Br J Clin Pharmacol 2006;62:538–45. 21. Liappas IA, Papageorgiou CC, Rabavilas AD. Abnormal auditory N400 in a case of zolpidem dependence, during a working memory test. Eur Psychiatry 2006;21:135–7. 22. Greenblatt DJ, Legangneux E, Harmatz JS, Weinling E, Freeman J, Rice K, Zammit GK. Dynamics and kinetics of a modifiedrelease formulation of zolpidem; compar­ ison with immediate-release standard zolpi­ dem and placebo. J Clin Pharmacol 2006;46 (12):1469–80. 23. Siriwardena AN, Qureshi Z, Gibson S, Collier S, Latham M. GPs’ attitudes to benzodiazepines and Z-drug prescribing; a barrier to implementation of evidence and guidance on hypnotics. Br J Gen Pract 2006;56:964–7. 24. Tornio A, Neuvonen PJ, Backman JT. The CYP2C8 inhibitor gemfibrozil does not increase the plasma concentrations of zopi­ clone. Eur J Clin Pharmacol 2006;62(8): 645–51.

A. Carvajal, L.H.M. Arias, and N. Jimeno

6 GENERAL

Antipsychotic drugs (SED-15, 2438)

Off-label use Off-label prescription of antipsychotic drugs for psychiatric patients of all ages is very common. A recent review concluded that off-label prescription of antipsychotic drugs often lacks the support of robust clinical trials (1R). When prescribing off-label, prescribers must carry out a careful assessment of the benefit to harm balance in the individual patient; they should also inform the patient that the prescription is off label. For example, there is a disproportionate use of off-label antipsychotic medications in elderly patients for conditions such as dementia and affective disorders (2c), which accounts for billions of dollars in annual spending by public health insurers (3r). The US Food and Drug Administration (FDA) issued a public health advisory notice containing new safety information concerning unapproved (i.e., “off-label”) use of Abilify (aripiprazole), Zyprexa (olanzapine), Seroquel (quetiapine), Ris­ perdal (risperidone), Clozaril (clozapine), Geodon (ziprasidone), and Symbyax (fluox­ etine/olanzapine) (4S). Clinical studies of these drugs to treat behavioral disorders in elderly patients with dementia have shown a rate of death among elderly patients with dementia of about 1.6 to 1.7 times that of placebo; although the causes of death were varied, most seemed to be either heartrelated (such as heart failure or sudden death) or infections (pneumonia) (see SEDA-30, 59 for a review in depth of the Side Effects of Drugs, Annual 31 J.K. Aronson (Editor)

ISSN: 0378-6080

DOI: 10.1016/S0378-6080(09)03106-7

r 2009 Elsevier B.V. All rights reserved.

use of antipsychotic drugs in elderly patients). Comparative studies Quality of life across 1 year has been evaluated in a multisite, randomized, controlled trial of antipsycho­ tic drug classes (5C). People aged 18–65 years with schizophrenia and related dis­ orders assessed for medication review because of inadequate response or adverse effects were assigned to typical antipsycho­ tic drugs (n ¼ 118) or atypical antipsychotic drugs other than clozapine (n ¼ 109). The choice of individual drug was made by the managing psychiatrist. With blind assess­ ments, participants in the typical antipsy­ chotic drug arm showed a trend toward greater improvements in quality of life; however, they reported no clear preference for either drug group. There were three deaths in each arm. The trial was funded by the Health Technology Assessment Pro­ gramme of the UK National Health Service and received no financial support from a pharmaceutical company. Violent behavior by patients with schizo­ phrenia prolongs hospital stay and inter­ feres with their integration into the community. Two atypical antipsychotic agents, clozapine and olanzapine, have been compared with one another and with haloperidol in the treatment of physical assaults and other aggressive behaviors in physically assaultive patients with schizo­ phrenia and schizoaffective disorder in a randomized, double-blind, parallel-group, 12-week trial (6C). Physically assaultive subjects with schizophrenia or schizoaffec­ tive disorder (age range 18–60 years) who were inpatients in state psychiatric facilities were randomly assigned to clozapine (n ¼ 37), olanzapine (n ¼ 37), or haloper­ idol (n ¼ 36). Clozapine was superior to both olanzapine and haloperidol in

65

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reducing the number and severity of physi­ cal assaults; olanzapine was superior to haloperidol in reducing the number and severity of aggressive incidents. There were no significant differences among the three groups in the use of treated-as-needed medication or in sedation or extrapyramidal symptoms (probably because of the pro­ phylactic use of anticholinergic medication in the haloperidol group). A randomized controlled trial with blinded assessment of outcome has been conducted in 12 specialist nursing homes for people with dementia in London, Newcastle, and Oxford to evaluate the effectiveness of a training and support intervention for nursing home staff in reducing the proportion of residents with dementia who are given neuroleptic drugs (7C). At 12 months, the proportion of residents taking neuroleptic drugs in the intervention homes (23%) was significantly lower than that in the control homes (42%): average reduction in neuroleptic use 19% (95% CI ¼ 0.5, 38). There were no signifi­ cant differences in agitated or disruptive behaviors between intervention and control homes. Systematic reviews Children and adolescents Prescription of antipsychotic medications for children and adolescents is widely practiced, despite the fact that the potential adverse impact that pharmacolo­ gical interventions have on child develop­ ment is unclear. In a meta-analysis of the efficacy of antipsychotic drugs in patients with early-onset schizophrenia aged 5–18 years, the average response rate among eight studies of atypical antipsychotic drugs (n ¼ 85) was 56% compared with 72% among 13 studies of typical antipsychotic drugs (n ¼ 209) (8M). The effect size on a continuous measure was 0.36 in favor of the typical drugs; the effect of medication type was unchanged when study quality was considered. Average weight gain in patients treated with typical drugs was 1.4 kg com­ pared with 4.5 kg for those treated with atypical drugs. Sedation was more common among those taking atypical drugs. The rate of extrapyramidal adverse effects was simi­ lar between the two groups. Although the

A. Carvajal, L.H.M. Arias, and N. Jimeno

overall results were in accordance with the results obtained in the meta-regression by Geddes (9M) (SEDA-25, 53), heterogeneity and small sample sizes precluded clear conclusions. Delirium has been defined as an altera­ tion in mental status characterized by disturbance of consciousness, attention, cognition, and perception for a brief period of time. The efficacy and safety of anti­ psychotic drugs in this condition have been previously addressed (SEDA-29, 60). Now, there has been a systematic review of randomized, controlled trials to determine which antipsychotic drug is associated with the greatest efficacy and safety in the management of delirium (four studies in 158 patients) (10M). Antipsychotic agents, either atypical or typical, were effective compared with baseline for treatment of delirium in medically or surgically ill patients without underlying cognitive dis­ orders. Oral haloperidol was associated with more frequent extrapyramidal adverse effects. According to some figures, nearly 50% of people with intellectual disability have been using psychotropic medications for the treatment of psychiatric disorders and/or behavioral problems during the last 20 years (11R). There has been a systematic review of all the evidence resulting from interna­ tional trials searched for in Medline, com­ paring the efficacy and adverse effects of different antipsychotic drugs in people with both intellectual disability and psychotic disorders and/or behavioral disorders (12M). Of 195 studies that were identified, a small number were randomized con­ trolled trials or systematic reviews. The main conclusion was that methodological integrity of scientific studies that support the use of antipsychotic drugs in people with intellectual disability is often lacking. Severe adverse effects can occur in these patients. Aggression, agitation, or psychosis occurs in most people with dementia at some point in the illness. A systematic review has been conducted to determine whether the evidence supports the use of atypical antipsychotic drugs for the treat­ ment of aggression, agitation, and

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67

psychosis in people with Alzheimer’s dis­ ease (13M). Sixteen placebo-controlled trials have been completed with atypical antipsychotic drugs, although only nine had sufficient data to contribute to a meta-analysis and only five have been published in full in peer-reviewed journals. The main conclusions were: significant improvement in aggression with risperi­ done and olanzapine compared with pla­ cebo; significant improvement in psychosis with risperidone; risperidone and olanza­ pine were associated with significantly higher incidences of serious adverse cere­ brovascular events (including stroke), extrapyramidal adverse effects, and other important adverse outcomes; a significant increase in drop-outs in patients taking risperidone (2 mg) and olanzapine (5– 10 mg). The data were insufficient to examine the impact of treatment on cognitive function. The authors concluded that despite modest efficacy, neither ris­ peridone nor olanzapine should be used routinely to treat dementia patients with aggression or psychosis unless there is a marked risk or severe distress, because there is a significant increase in adverse events.

who received 51 individual trials of differ­ ent atypical neuroleptic drugs in daily clinical practice (15c). Of the trials 63% resulted in moderate-to-severe extrapyra­ midal symptoms. Four of 51 trials led to mild de novo tardive dyskinesia; younger age was associated with more akathisia. Children and adolescents are supposed to be more sensitive than adults to the development of movement disorders when they take antipsychotic drugs. A study supported by Novartis has investigated the prevalence of antipsychotic drug-induced movement disorders in 93 patients with schizophrenia (average age 20 years) with onset in childhood or adolescence in a cross-sectional/retrospective study; 76 patients (82%) received atypical antipsy­ chotic drugs, 10 (11%) typical antipsychotic drugs, and 7 (7.5%) combinations (16c). There were movement disorders in 37 patients (40%), fulfilling strict/subthreshold criteria for tardive dyskinesia (5.4/12%), parkinsonism (2.2/26%), or akathisia (1.1/ 12%). Patients taking typical antipsychotic drugs had a significantly higher proportion of extrapyramidal symptoms than patients taking atypical antipsychotic drugs.

Nervous system Antipsychotic druginduced extrapyramidal symptoms are often treated with antiparkinsonian drugs, the most common being anticholinergic agents; the adverse effects of these medica­ tions include urinary retention, worsened cognition, sedation, constipation, and xer­ ostomia, which are of particular concern in the elderly. Whether the reduced risk of motor adverse effects with atypical anti­ psychotic drugs translates into less use of antiparkinsonian drugs has been analyzed by using the Medicare Current Beneficiary Survey database (14c). Among residents of nursing homes and assisted-living facilities without Parkinson’s disease, concomitant use of antiparkinsonian drugs and antipsy­ chotic drugs fell from 21% in 1997 to 9% in 2000. Over a half of patients with bipolar disorder treated with atypical neuroleptic drugs have extrapyramidal symptoms. This has been observed in 37 bipolar patients

developed symptoms consistent with neurolep­ tic malignant syndrome after abrupt withdrawal of a variety of psychotropic medications (venlafaxine 75 mg every morning and 37.5 mg qhs; quetiapine 100 mg tds; oxcarbaze­ pine 300 mg tds; clonazepam 1 mg tds; diphen­ hydramine 25 mg od; ibuprofen 800 mg tds) (17A). She was admitted to a state psychiatric hospital, all medications were withdrawn except ibuprofen, and 4 days later a dystonic reaction was diagnosed and treated with benzatropine 2 mg bd. She was given loraze­ pam 2 mg intramuscularly for possible catato­ nia followed by lorazepam 1 mg tds. After 4 hours she was verbalizing without difficulty, eating independently, and walking with assis­ tance.


A 31-year-old woman with mental retardation

Endocrine New-onset diabetes mellitus (SEDA-28, 60) Information from the UK General Practice Research Database (GPRD) has been used to determine hazard ratios of new-onset diabetes mellitus in patients who took an antipsychotic drug between January 1, 1994 and December 31, 2001 (18c). Compared with the general

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GPRD patient population (n ¼ 1491548), patients who were exposed to conventional (n ¼ 59089), or atypical antipsychotic drugs (n ¼ 9053), had a higher risk of diabetes (atypical antipsychotic cohort: HR ¼ 2.9; 95% CI ¼ 2.0, 4.4; conventional antipsy­ chotic cohort: HR ¼ 1.9; 95% CI ¼ 1.6, 2.3). Similarly, the incidence of new-onset type-2 diabetes mellitus in patients with a variety of psychiatric diagnoses maintained for 1 year on olanzapine (n ¼ 112), risper­ idone (n ¼ 100), or quetiapine (n ¼ 100), compared to a reference group receiving haloperidol (n ¼ 100) has been studied by means of a chart review (19c). Using a multivariate model, there was a significant association between olanzapine (but not other atypical agents) and the development of diabetes compared with haloperidol (OR ¼ 8.4; 95% CI ¼ 1.8, 38.7). In addition, a case–control study included schizophrenic patients who had received monotherapy with clozapine (n ¼ 251), olanzapine (n ¼ 745), or risperidone (n ¼ 836) for 1–3 years to estimate the risk of new-onset diabetes (20c). Patients with schizophrenia in whom diabetes was diag­ nosed during psychiatric treatment and those who had fasting glycemia of at least 7.0 mmol/l (126 mg/dl) at two consecutive measurements were considered as cases (n ¼ 51); the other patients who were receiving treatment and did not have these alterations were considered as controls. In the adjusted analysis, the risk of new-onset diabetes for olanzapine relative to risper­ idone was 2.2 (95% CI ¼ 1.1, 4.2), and that for clozapine relative to risperidone was 2.9 (95% CI ¼ 1.2, 6.9). Metabolic Excessive weight gain has been reported in a large proportion of patients receiving long-term antipsychotic drugs (SEDA-29, 64; SEDA-30, 58; SEDA-26, 56). The effect of atypical antipsychotic drugs on weight gain has been evaluated in a study using a national electronic medical records database (21c). Weight gain was defined as at least a 7% increase in BMI from baseline within 1 year of antipsychotic drug prescription and a post-increase BMI of at least 25 kg/m2. In all, 9394 patients (aged at least 18 years)

A. Carvajal, L.H.M. Arias, and N. Jimeno

who had received a prescription for an antipsychotic drug between January 1995 and March 2004 were identified; there were 1514 cases of increased BMI after initial prescription (16%). Risperidone (OR ¼ 1.4; 95% CI ¼ 1.2, 1.7), quetiapine (OR ¼ 1.4; 95% CI ¼ 1.1, 1.7), and olanzapine (OR ¼ 1.8; 95% CI ¼ 1.5, 2.1) were signifi­ cantly more likely to cause weight gain than typical antipsychotic drugs; aripiprazole (OR ¼ 0.7; 95% CI ¼ 0.4, 1.5), ziprasidone (OR ¼ 0.7; 95% CI ¼ 0.4, 1.2), and cloza­ pine (OR ¼ 1.0; 95% CI ¼ 0.6, 1.8) were less likely to induce weight gain than typical antipsychotic drugs. Moreover, a review has further emphasized the association between metabolic effects of antipsychotic drug treatment and the risk of cardiovascular disease (22R). Sexual function Sexual dysfunction in patients with schizophrenia is common but often not reported to doctors nor explored; it can reduce quality of life and adherence to treatment (SEDA-29, 64). A comparison of the effects of selected atypical and typical antipsychotic drugs on sexual function in a large population of outpatients with schizophrenia treated over 1 year has been carried out in the course of an observational study (23c). Based on patient perceptions, the odds of experien­ cing sexual dysfunction during 1 year of therapy was significantly lower among patients taking olanzapine (n ¼ 2638) and quetiapine (n ¼ 142) compared with patients taking risperidone (n ¼ 860) or haloperidol (n ¼ 188). Women taking olan­ zapine (14%) or quetiapine (8%) had a lower rate of menstrual irregularities than those taking risperidone (23%) or haloper­ idol (29%). There was significant discor­ dance between patients’ reports and psychiatrists’ perceptions of sexual dysfunc­ tion, which they underestimated. Sexual functioning in 238 outpatients (age at least 18 years) with diagnoses of schizo­ phrenia or schizoaffective disorder who took quetiapine (n ¼ 57), olanzapine (n ¼ 94), or risperidone (n ¼ 87) has been evaluated using a one-time rating (24c). The antipsy­ chotic drug group designation was based on medication treatment at study entry

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(i.e., non-random assignment). There was a significant treatment effect on severity of sexual dysfunction; quetiapine was asso­ ciated with less severe sexual dysfunction. The efficacy and safety of sildenafil in 31 married men with schizophrenia or delu­ sional disorders and antipsychotic druginduced erectile dysfunction has been assessed in a randomized, double-blind, placebo-controlled, flexible-dose, two-way, crossover trial (25C). Sexual function was assessed from patients’ logs of sexual activity. There was no significant period effect or treatment–period interaction. Patients reported that sildenafil produced significant improvement in the number of adequate erections, satisfaction with sexual intercourse, and the duration of erections over 2 weeks. The odds ratios for adequate erections and for satisfactory sexual inter­ course with sildenafil were 4.07 and 3.77 respectively. The most common adverse effects were nasal stuffiness (n ¼ 4, 12.5%) and headache (n ¼ 3, 9.4%). Death Mortality among people with schi­ zophrenia has been studied in a represen­ tative population sample of 7217 Finns aged at least 30 years (26c). During 17 years of follow-up, 39 of 99 people with schizophre­ nia died. Adjusted for age and sex, the relative mortality risk between those with schizophrenia and others was 2.8 (95% CI ¼ 2.1, 3.9); it was 2.2 (95% CI ¼ 1.6, 3.1) after further adjustment for somatic diseases, blood pressure, cholesterol, body mass index, smoking, exercise, alcohol intake, and education. Among people with schizophrenia taking at baseline one, two, or more neuroleptic drugs, 11 (35%), 15 (44%), and 8 (57%) respectively died during follow-up, whereas the correspond­ ing rate was 5 (20%) among those without neuroleptic medication; adjusted for age, sex, somatic diseases, and other potential risk factors for premature death; the rela­ tive risk was 2.5 (95% CI ¼ 1.5, 4.3) per increment of one neuroleptic drug. It was pointed out in an editorial that dose escalations or additional treatments are not the best for patients and sometimes “all that is needed is a small amount of good and that the social network on a ward or in a

69 community may then capitalize on such changes over a longer period to produce greater benefits” (27r). Tumorigenicity Information from the US Food and Drug Administration’s Adverse Event Reporting System (AERS) database has been used to analyze disproportional reporting of hyperprolactinemia, galactor­ rhea, and pituitary tumors in patients taking seven widely used antipsychotic drugs (28c). Risperidone had the highest adjusted reporting ratios for hyperprolactinemia (Empiric Bayes Geometric Mean [EBGM] value ¼ 35; 90% CI ¼ 33, 37), galactorrhea (EBGM ¼ 20; 90% CI ¼ 19, 21), and pitui­ tary tumors (EBGM ¼ 19; 90% CI ¼ 15, 23) among the seven antipsychotic drugs studied, and one of the highest scores for all drugs in the AERS database. Some tumors were associated with visual field defects, hemorrhage, convulsions, surgery, and severe (over 10-fold) rises in prolactin. The EBGM values for risperidone for these adverse events were higher in women, but there were also high-EBGM values for these events in men and children. More­ over, the rank order of the EBGM values for pituitary tumors corresponded to the affinities of these seven drugs for D2 receptors.

INDIVIDUAL DRUGS Amisulpride

(SED-15, 173; SEDA-29,

65) Comparative studies Similarly to other antipsychotic drugs, amisulpride has been used in psychiatric diseases other than schizophrenia. Amisulpride 50 mg/day (n ¼ 94, mean age 50 years, 33% men) and acetyl-L-carnitine 1000 mg/day (n ¼ 99, mean age 45 years, 30% men) have been compared in a 12-week double-blind study in 193 patients with pure dysthymia (29c). There was improvement in both treatment groups throughout the study with no statistically significant differences. There were 21 dropouts related to adverse

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events in patients taking amisulpride and three in patients taking acetyl-L-carnitine; 15 patients had an increase in prolactin; four events (three in patients taking amisulpride and one in a patient taking acetyl-L-carnitine) were judged severe. Nervous system Tardive dyskinesia occurred in a 34-year-old man with schizo­ phrenia after 20 months of taking amisul­ pride 400 mg/day; it resolved when he switched to quetiapine 1200 mg (30A). Tics may be related to amisulpride (31A).
A 15-year-old girl with schizophrenia was

given amisulpride 1000 mg/day; 5 months later she developed frequent involuntary eye-blink­ ing movement, which resolved completely with dosage reduction to 800 mg/day; when the psychosis recurred, she was given an additional 100 mg/day of quetiapine and had no more tic-like eye movements.

Aripiprazole Aripiprazole (Abilifys) is a relatively new antipsychotic drug, said to be the prototype of a new third generation, the so-called “dopamine–serotonin system stabilizers” (32R). Aripiprazole’s mechanism of action differs from currently marketed typical and atypical antipsychotic drugs; it is a partial agonist at D2 receptors, with properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity respectively, and this is believed to contribute to stabilization rather than blockade of dopaminergic tone; it is also a partial agonist at 5-HT1A receptors and an antagonist at 5­ HT2A receptors (33E). Nevertheless, as stated in the Summary of Product Characteristics, “ ythe mechanism of action of aripiprazole, as with other drugs having efficacy in schizophrenia, is unknown” (34S). Aripiprazole was first approved by the US FDA for the treatment of schizophrenia in 2002, and then by the European Medicines Agency in 2004; finally, it was approved in Japan in 2006. It has been included in recent guidelines on schizophrenia treatment (35R); thereafter, it was approved for other

A. Carvajal, L.H.M. Arias, and N. Jimeno

conditions, such as bipolar disorder, and it is anticipated that many physicians will use it off-label for a similar range of indications to other atypical antipsychotic drugs (36R). Aripiprazole is currently presented as being similar in efficacy to other antipsycho­ tic drugs but devoid of their most trouble­ some adverse reactions; independent reviews, at best, considered aripiprazole as one more to add to the list (37R,38R). All in all, it is difficult to know the therapeutic role for aripiprazole, since most of the trials have been conducted to fulfill regulatory require­ ments and most of the published studies have been supported by the Marketing Author­ ization Holders, Otsaka Pharmaceuticals and Bristol Myers Squibb; some reanalyses do not add anything new and are in fact redundant publications (39C,40R). Most trials have included participants with few comorbidities. Most of the studies were not designed to provide results relevant to daily clinical practice. Adverse effects are reported when they occurring in at least 5–10%, which means that rare serious adverse effects have not [yet] been described. Pivotal clinical trials, the regulatory review process, and further information can be accessed on line (41S,42S). Observational studies Resistant schizo­ phrenia Since a certain proportion of treatment-resistant schizophrenia fails to respond to clozapine, a 6-week open study of the effects of adjunctive aripiprazole has been conducted (43c). Ten clozapine-treated subjects (mean age 39 years) received aripiprazole augmentation; eight completed the 6-week trial and two ended at week 4. There was no significant change in total PANSS score. There was a significant fall in weight and fasting total serum cholesterol comparing baseline to study end-point. In addition, a retrospective review of case notes of treatment-resistant patients with this con­ dition who took the combination clozapine +aripiprazole for an average of 34 weeks has been carried out (44c). There was overall improvement in hallucinations and delu­ sions. Clozapine+aripiprazole was asso­ ciated with a 22% reduction in clozapine dose; 18 of 24 patients lost a mean weight of 5.05 kg. Two patients taking aripiprazole

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alone were not included in the study as one developed severe dyskinesia affecting the trunk and limbs and the other atypical neuroleptic malignant syndrome. Three patients with psychotic symptoms despite clozapine and with significant adverse effects received aripiprazole 15 mg/ day in combination (45c). There was general improvement, loss of weight, and reduced obsessive-compulsive symptoms. One patient complained of mild transient nausea. Case series, although of some importance on occasions, can not be controlled for bias (the most frequent fallacy in these instances being the “post hoc ergo propter hoc” error). Psychosis associated with Parkinsonus disease Treatment-induced psychosis affects a significant proportion of patients with idiopathic Parkinson’s disease; treat­ ment options include reducing medications or introducing an atypical antipsychotic drug. Only clozapine has been shown to be efficacious and well tolerated in clinical trials. Now 14 patients (median age 74, range 51–90, years) meeting the entry criteria (Parkinsonus disease and psychosis deemed to be medica­ tion-induced for at least 1 month) were given aripiprazole 1 mg/day and titrated up to a maximum dose of 5 mg/day as needed for 6 weeks (46c) in a study supported by the manufacturers. Eight subjects withdrew owing to worse parkinsonism (n ¼ 3), worse psychosis (n ¼ 2), worsening of both (n ¼ 2), and lack of efficacy (n ¼ 1); these findings are similar to those of three other published reports on the use of aripiprazole for psycho­ sis in Parkinson’s disease (47A–49A). The authors concluded that aripiprazole did not seem to be a promising agent. Children with developmental disabilities A retrospective chart review of the first 32 children (age range 5–19 years) treated with aripiprazole at an urban clinic for children with developmental disabilities has been conducted (50c). Efficacy differed depend­ ing on the disorder. There was improve­ ment in aggression in 15 of 28 children, in hyperactivity in 10 of 21, and in impulsivity in 5 of 13. Adverse effects that resulted in withdrawal included sleepiness (n ¼ 4), tics (n ¼ 1), increased aggression (n ¼ 2),

71 stiffness (n ¼ 1), myalgias (n ¼ 1), facial dyskinesia (n ¼ 1), and diarrhea (n ¼ 1). The average daily maintenance dose was 10.5 mg/day (range 1.2–30 mg); the average length of treatment and follow-up was 6.1 months (range 0.2–15 months). Children with bipolar disorder A retro­ spective chart review of 30 children (age range 5–19 years) taking aripiprazole for bipolar disorders has been conducted (51c). The mean overall psychiatric illness Clinical Global Impression-Severity score signifi­ cantly improved from baseline to end-point. The most common adverse effect was seda­ tion (n ¼ 10) and the second most common was akathisia (n ¼ 7); most of the patients were taking other medications. The average daily maintenance dose was 9 mg/day (range 5–15 mg); the average length of treatment and follow-up was 4.4 months (range 1–9 months). Most of the patients lost weight (12 of 14 patients for whom there was informa­ tion on weight gain; mean weight loss, 3 kg). Comparative studies Schizophrenia A comparison of aripiprazole with haloperidol involved two 52-week double-blind trials that were pooled for analysis (40R). Halo­ peridol was given in a moderate dose (10 mg/ day). These trials were designed to demon­ strate the superiority of high-dose aripipra­ zole (30 mg/day), but failed to do so. The proportion of patients who “responded” during an acute episode, based on an analysis of trial completers (495, 39%, of 1283 patients) were not statistically different (aripiprazole 77%, haloperidol 74%). There was a statistically significant lower rate of discontinuation due to adverse effects with aripiprazole (8.0%) compared with haloper­ idol (18.4%). Fewer aripiprazole-treated patients (23%) required concomitant medica­ tion for extrapyramidal symptoms compared with haloperidol-treated patients (57%). Several open comparative studies have been carried out. In an 8-week, multicenter, open study, 1599 outpatients with schizo­ phrenia or schizoaffective disorder were randomly assigned to receive either aripi­ prazole (n ¼ 1295) or another antipsychotic medication (safety control group; n ¼ 304) (52c); aripiprazole was begun at 15 mg/day

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with the option to adjust between 10 and 30 mg/day. The control medication and dosage was specifically selected for each patient by the clinician. The mean aripipra­ zole dose at the end was 20 mg/day and 65% of the patients completed the study. At the end, the mean Clinical Global Impression– Improvement score of 2.8 showed that aripiprazole was minimally to moderately effective; the mean score for the control group was 3.6, indicating minimal effective­ ness to no change. Treatment-related adverse effects were reported in 72% (901/1255) of patients taking aripiprazole and in 64% (170/265) of controls; the most frequent adverse effect in those taking aripiprazole was insomnia (24%). Extrapyramidal symp­ toms were reported in 10% of patients taking aripiprazole and in 8% of controls. Five patients died during treatment with aripipra­ zole group or within 30 days after the 8-week phase of the study; three deaths (cardiac death, death of unknown cause 16 days after completing therapy, and homicide) were considered unrelated to the study medica­ tion, and the other two deaths (both of unknown cause) were judged by the inves­ tigator unlikely to be related to the study medication. In a 26-week, open, multicenter study, 555 patients were randomized to receive aripi­ prazole (n ¼ 284) or a control drug (quetia­ pine, n ¼ 110; olanzapine, n ¼ 75; risperidone, n ¼ 81) (53c). Aripiprazole was significantly better than control treatment. The incidence of treatment-related adverse effects was similar in the two treatment groups; the most common adverse effects in those taking aripiprazole were insomnia, anxiety, headache, and nausea. One patient taking aripiprazole committed suicide; the two deaths in controls were attributed to lung cancer and to aspiration and cardiac failure. An open comparative study has been conducted in patients with either acute relapsing or chronic stable schizophrenia (54c). The patients were randomized to aripiprazole (15–30 mg/day; n ¼ 104) or olanzapine (10–20 mg/day; n ¼ 110). Effi­ cacy improvements were similar between groups at the end. Olanzapine caused more extrapyramidal symptoms (18%) than aripi­ prazole (10%); mean weight gain with

A. Carvajal, L.H.M. Arias, and N. Jimeno

olanzapine was 2.54 versus 0.04 kg with aripiprazole. The increase in prolactin was significantly greater with olanzapine than with aripiprazole (9.3 versus 0.8 ng/ml). One death occurred in the olanzapine group due to heart failure. Finally, in an independent study, 327 patients were randomized to open treatment with aripiprazole, haloperidol, olanzapine, quetiapine, risperidone, or ziprasidone for a minimum of 3 weeks (55C). The measure of effectiveness was improvement in mental status so that the patient no longer required acute inpatient care. Haloperidol (89%), olanzapine (92%), and risperidone (88%) were significantly more effective than aripi­ prazole (64%), quetiapine (64%), and zipra­ sidone (64%). The difference among the six treatments in rates of withdrawals because of adverse effects was not statistically signifi­ cant. Treatment-resistant schizophrenia In a multicenter, double-blind, randomized study aripiprazole (15–30 mg/day; n ¼ 154) and perphenazine (8–64 mg/day; n ¼ 146) were compared in 300 treatment-resistant patients with schizophrenia (56C). After 6 weeks both aripiprazole and perphenazine were asso­ ciated with clinically relevant improvements in PANSS total scores from baseline. More patients needed concomitant medication for extrapyramidal symptoms in the perphena­ zine group (28%) than in the aripiprazole group (18%). There was abnormal total creatine kinase activity in 7 patients taking perphenazine and 12 taking aripiprazole (two of whom withdrew as a result). Mania In a double-blind trial, patients with bipolar I disorder were randomized to aripiprazole (n ¼ 175) or haloperidol (n ¼ 172) for an acute manic or mixed episode (57C). At week 12, significantly more patients taking aripiprazole (50%; average daily dose, 22 mg) were in remission compared with those taking haloperidol (28%; average daily dose, 11 mg). Overall, 208 patients (60%) withdrew during the study period (aripiprazole, 49%; haloper­ idol, 71%). There were extrapyramidal adverse effects in the two groups (aripipra­ zole, 24%; haloperidol, 63%); mean change

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in weight from baseline at week 12 was not significantly different in the two groups (aripiprazole +0.3 kg, haloperidol 0.1 kg); serum prolactin concentrations fell from baseline with aripiprazole (13 ng/ml) and rose with haloperidol (+7.7 ng/ml). Insomnia was more frequent with aripiprazole (14%) than with haloperidol (7.1%). The nonavailability of anticholinergic medication specified in the study protocol and the limited dosage range permitted for haloper­ idol could have affected the results. Placebo-controlled studies Schizophrenia In a 4-week, double-blind, randomized study in 36 US centers 414 patients with schizo­ phrenia or schizoaffective disorder were randomized to aripiprazole (15–30 mg/day), haloperidol (10 mg/day), or placebo (58c). Haloperidol and both doses of aripiprazole produced statistically significant improve­ ments from baseline compared with placebo. Unlike haloperidol, aripiprazole was not associated with significant extrapyramidal symptoms or raised prolactin at the end­ point. A higher percentage of patients taking haloperidol required benzatropine for extra­ pyramidal symptoms (30%) compared with other groups (12% for the placebo group, 8% for aripiprazole 15 mg and 15% for aripiprazole 30 mg). There were no statisti­ cally significant differences in mean changes in body weight. The percentages of clinically significant weight gain (at least a 7% increase from baseline) were 7, 4, and 10% for aripiprazole 15 mg, aripiprazole 30 mg, and haloperidol 10 mg respectively (1% for pla­ cebo). Prolactin concentrations fell slightly in the aripiprazole and placebo groups but not with haloperidol. No patients who took aripiprazole had clinically significant increases in the QTc interval. Aripiprazole has been compared with risperidone in a 4-week double-blind study (59C). The patients were randomized to aripiprazole 20 mg/day (n ¼ 101) or 30 mg/day (n ¼ 101), placebo (n ¼ 103), or risperidone 6 mg/day (n ¼ 99). Aripiprazole (20 and 30 mg/day) and risperidone (6 mg/ day) were significantly better than placebo on all efficacy measures. There were no significant differences between aripiprazole and placebo in mean change from baseline

73 in the extrapyramidal symptom rating scales. Mean prolactin concentrations fell with aripiprazole but significantly increased five­ fold with risperidone. The mean change in QTc interval did not differ significantly from placebo with any active treatment group. The overall incidence of extrapyramidal symptoms was not lower with aripiprazole than with risperidone (aripiprazole 20 mg 32%, aripiprazole 30 mg 31%, risperidone 31%); in the placebo group the incidence of these symptoms was 20%. The use of benzatropine was comparable across the three active treatment groups. Measurements of body weight showed similar increases in the three groups (aripiprazole 20 mg 1.2 kg, aripiprazole 30 mg 0.8 kg, risperidone 1.5 kg); the incidence of clinically significant weight gain (at least a 7% increase from baseline) was statistically significant com­ pared with placebo for all active treatments. In a randomized, double-blind, placebocontrolled study, 420 patients requiring inpatient hospitalization for an acute exacer­ bation of schizophrenia were randomized to a daily dose of aripiprazole 10 (n ¼ 106), 15 (n ¼ 106), or 20 (n ¼ 100) mg/day or pla­ cebo (n ¼ 108) for 6 weeks (60C). Aripipra­ zole 10, 15, and 20 mg/day each produced significantly greater improvements from baseline than placebo for all efficacy mea­ sures. Aripiprazole was not associated with changes in prolactin or weight versus pla­ cebo. Akathisia was reported by 12 patients taking aripiprazole 10 mg/day (11%; two patients withdrew), six patients taking aripi­ prazole 15 mg/day (6%), five patients taking 20 mg/day (5%), and four patients taking placebo (4%). The incidence of increased standing heart rate (over 120/minute and an increase from baseline of at least 15/minute) was higher in all aripiprazole groups com­ pared with placebo (placebo, 3%; aripipra­ zole 10 mg/day, 7%; aripiprazole 15 mg/day, 10%; aripiprazole 20 mg/day, 6%). Acute agitation in schizophrenia Intra­ muscular aripiprazole 9.75 mg, intramuscu­ lar haloperidol 6.5 mg, and intramuscular placebo have been compared in a doubleblind study supported by the manufacturers in the treatment of acute agitation in 448 patients with schizophrenia or

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schizoaffective disorder (61C). The patients could receive up to three injections over 24 hours. Aripiprazole and haloperidol were similar in efficacy and better than placebo. The most frequently reported adverse effects were headache, dizziness, nausea, and insomnia with aripiprazole, and insomnia, headache, and extrapyramidal disorders with haloperidol; most of the reported adverse effects were mild or moderate. Of the 183 patients who received a second injection, 58 (32%) had a more severe adverse event, and the incidence was highest with haloperidol (haloperidol 44%, aripi­ prazole 33%, placebo 14%). The incidence of injection site reactions was highest with aripiprazole (aripiprazole 3.4%, haloperidol 1.1%, placebo 2.3%). The incidence of extrapyramidal symptoms was similar with aripiprazole (1.7%) and placebo (2.3%) and lower than with haloperidol (13%). There were no clinical concerns regarding electrocardiographic measurements of rate, rhythm, conduction, infarction, or altered ST/T morphology; there were no treatment differences versus placebo in QTc interval. No patient died. It is not clear from the published data whether the assessments were blind in most of the 60 participant centers. Acute agitation in patients with bipolar disorder Intramuscular aripiprazole 9.75 mg (n ¼ 78), aripiprazole 15 mg (n ¼ 78), lora­ zepam 2 mg (n ¼ 70), and placebo (n ¼ 75) have been compared in a double-blind study supported by the manufacturers in 301 patients with bipolar I disorder (62C). The active treatments were better than placebo. Most of the reported adverse effects were mild or moderate. Three patients (aripiprazole 9.75 mg, n ¼ 1; aripiprazole 15 mg, n ¼ 2) received concomitant benzatropine for extra­ pyramidal symptoms. One patient died 2 days after the study: a 41-year-old man with a history of psoriasis, chronic obstructive pul­ monary disease, tobacco use (one pack per day), and polysubstance drug abuse (no current use); he received two injections of aripiprazole 9.75 mg. Bipolar disorder Aripiprazole 30 mg has been compared with placebo in 272

A. Carvajal, L.H.M. Arias, and N. Jimeno

hospitalized patients with bipolar I disorder in a 3-week, randomized, double-blind trial (63C). Aripiprazole produced significantly greater improvement from baseline to end­ point in mean Young Mania Rating Scale total score than placebo. Somnolence occurred more often with aripiprazole (20%) than placebo (11%); nausea, dyspep­ sia, and constipation were also more com­ mon. Limb pain occurred in 10% of patients taking aripiprazole and in 5.3% of those taking placebo. Akathisia occurred in 18% of those taking aripiprazole and 4.5% of those taking placebo. Aripiprazole 30 mg/day has been com­ pared to placebo in patients with an acute or mixed episode of bipolar disorder in a 3-week, randomized, multicenter, doubleblind study (64C). Aripiprazole (n ¼ 130) did better than placebo (n ¼ 132) and more patients completed the study (42% versus 21%). Extrapyramidal symptoms were more frequent with aripiprazole (17%) than with placebo (3%). Somnolence, insomnia, and accidental injury were by far more frequent with aripiprazole (20, 15, and 12% respec­ tively) than with placebo (5, 9, and 2%). Alzheimer’s disease A randomized, dou­ ble-blind, placebo-controlled study supported by the manufacturers has addressed the efficacy, safety and tolerability of aripiprazole in 208 outpatients (mean age 82 years) with psychosis associated with Alzheimer’s disease (65C). A total of 172 patients completed the 10-week study period, 84 in the placebo group and 88 in the aripiprazole group, with no differences between groups in the primary efficacy parameter (a caregiver-assessed scale score—delusions; hallucinations). Serious adverse effects were reported by 25 patients (placebo, n ¼ 9; aripiprazole, n ¼ 16); the most common was accidental injury (placebo, n ¼ 2; aripiprazole, n ¼ 5). There were four deaths, all in the aripiprazole group: one during treatment and three after withdrawal of medication (all due to adverse effects). Three patients (aripiprazole, n ¼ 2; placebo, n ¼ 1) had potentially clinically significant increases in QTc interval using the FDA Neuropharmacological Division correction factor.

Antipsychotic drugs

Chapter 6

Borderline personality In 52 patients (43 women and 9 men) meeting the criteria for personality disorders who were randomly assigned to aripiprazole 15 mg/day (mean age 22 years; n ¼ 26) or placebo (mean age 21 years; n ¼ 26) for 8 weeks, there were significant changes in scores on currently used scales with the exception of somatiza­ tion (66C). Detailed data on adverse effects were not given; it was merely stated that neither serious adverse effects, including weight gain, nor suicidal acts were observed during the study. Systematic reviews Information from 10 different randomized comparisons of aripi­ prazole with placebo and with other anti­ psychotic drugs for schizophrenia and involving a total of 4125 patients has been summarized (67M). None of the studies made the method of randomization explicit or tested masking; accordingly, they all carry a moderate risk of bias and may therefore overestimate the positive effects of aripipra­ zole. The time span for the different studies was 4–12 months and the patients were mostly in their 30s and 40s with few comorbidities. In an intention-to-treat ana­ lysis more patients allocated to aripiprazole completed the studies compared with those allocated to placebo (RR ¼ 0.7; 95% CI ¼ 0.5, 0.9; n ¼ 1658) but not when compared with typical antipsychotic drugs (RR ¼ 0.9; 95% CI ¼ 0.9, 1.2; n ¼ 2213) or atypical antipsychotic drugs (RR ¼ 1.0; 95% CI ¼ 0.9, 1.2; n ¼ 618). Similarly, there were fewer relapses with aripiprazole than pla­ cebo (relapse by 12 weeks: RR ¼ 0.6; 95% CI ¼ 0.4, 0.8; n ¼ 310) but there was no comparison with other antipsychotic drugs in this regard—only one study provided data. When combined, two trials that com­ pared aripiprazole with other atypical anti­ psychotic drugs failed to show any significant difference for the outcome of weight gain of 7% or more above baseline (RR ¼ 0.5; 95% CI ¼ 0.1, 1.9; n ¼ 556); aripiprazole 20 mg/day resulted in signifi­ cantly less change in QTc interval than risperidone in the short term (weighted mean difference ¼ 6.0; 95% CI ¼ 13, 1.1; n ¼ 200). Aripiprazole was associated with

75 significantly less risk of an increase in prolactin concentrations above 23 ng/ml than risperidone 6 mg/day (RR ¼ 0.04; 95% CI ¼ 0.02, 0.08; n ¼ 301). Eight people who were allocated to aripiprazole died, some from suicide, in open extension arms of two of the studies (201c,202S). Since most of the studies reported only adverse effects that occurred in at least 5–10% of participants, some uncommon and potentially serious adverse effects were not recorded; however, insomnia appears to be more frequently associated with aripiprazole. Aripiprazole does not differ significantly from some typical or other atypical antipsychotic drugs in terms of several global outcomes and adverse effects; however, it does not appear to cause hyperprolactinemia. A review for the Cochrane Collaboration has been previously carried out by some of the same authors, with similar results (68M). Nervous system Data from the first clinical trials did not find any significant difference between aripiprazole and placebo on extra­ pyramidal adverse effects; moreover, haloper­ idol-induced dyskinesia was reported to improve after switching to aripiprazole (69A). However, extrapyramidal adverse effects have been described in several cases.
A 56-year-old woman developed extreme stiff­

ness of her trunk and limbs along with parkinsonian gait, mask-like facial expression, and hypersalivation after 5 weeks of treatment with aripiprazole 10–30 mg/day and 3 weeks at 50 mg/day (70A). Seven days after the onset of these symptoms and after reducing the dosage, aripiprazole was finally withdrawn and she was given olanzapine 5 mg/day; the residual hyper­ salivation improved.

Another case of parkinsonism during treatment with aripiprazole (71A) and two cases of rabbit syndrome have been reported (72A,73A). Pisa syndrome (or pleurothoto­ nus) is an axial dystonia, characterized by tonic lateral flexion and slight rotation of the trunk. This condition has been reported in a patient taking aripiprazole (74A).
Off-label aripiprazole (15 mg/day) was adminis­

tered to a 77-year-old woman with dementia because of poor control of behavioral and

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psychological symptoms and poor compliance with quetiapine, which was tapered and with­ drawn; she continued taking aspirin, 160 mg/day and clonazepam 0.5 mg/day. Six days later she had an acute dystonic reaction (tonic flexion of trunk and head toward right). Aripiprazole was withdrawn and the Pisa syndrome completely disappeared within 3 days, without any adjunc­ tive treatment.

The authors stated that withdrawn of quetiapine could not be ruled out as the cause of this dystonia; in fact, some cases have been described after withdrawal of an atypical antipsychotic drug (75A). All these reported cases, along with a few cases of motor worsening in parkinsonian patients treated with this drug for druginduced psychosis (47A), suggest that these reactions can occur with aripiprazole. Three cases of neuroleptic malignant syndrome have been associated with aripiprazole (76A,77A,78A), although a new evaluation by standardized criteria (79r,80cr) has raised doubts on the validity of the diagnosis in these patients. Postmarketing pharmacovigilance schemes in Australia have collected a higher proportion of cases of neuroleptic malignant syndrome with aripiprazole compared with the total number of reports received for other drugs (cloza­ pine 85 reports, 2.3%; olanzapine 49 reports, 4.1%; quetiapine 16 reports, 5.2%; risper­ idone 45 reports, 5.7%; amisulpride 15 reports, 6.7%; aripiprazole 15 reports, 10%) (81c).

Endocrine Aripiprazole is believed to sta­ bilize the dopaminergic system and amelio­ rate schizophrenic symptoms without increasing serum prolactin. There has been an 8-week open pilot study of aripiprazole as a replacement for other antipsychotic agents in women with schizophrenia suffering from symptomatic hyperprolactinemia (82c). Seven women with symptomatic hyperpro­ lactinemia (mean 168, reference range 5–25 ng/ml) taking risperidone or amisulpride were given aripiprazole (10–20 mg/day); at the end of week 4, serum prolactin concen­ trations had normalized (mean 8.8 ng/ml) and symptoms had resolved in all patients. Nevertheless, aripiprazole was withdrawn

A. Carvajal, L.H.M. Arias, and N. Jimeno

within 6 weeks in two patients because of aggravated auditory hallucinations. In con­ trast to the results of this and other studies, galactorrhea has been described (83A).
A 29-year-old woman with a schizoaffective

disorder took haloperidol 5 mg/day and then 9 mg/day because of acute psychotic episodes. She had no adverse effects such as amenorrhea or galactorrhea. Haloperidol was then replaced by aripiprazole 15 mg/day and on the evening of the second day she developed breast tender­ ness and marked galactorrhea. The serum prolactin concentration was 32 ng/ml (reference range 5–25 ng/ml). Aripiprazole was withdrawn and haloperidol restarted. The galactorrhea resolved in 1 week.

Metabolic A patient tolerated and responded to high-dose aripiprazole and lost weight after having taken olanzapine for several years (84A).
A 57-year-old man with schizophrenia, who

had taken olanzapine 20 mg/day for 4 years, and whose initial average weight was 82 kg, gained a significant amount of weight (the maximum being 103 kg); his treatment was switched to aripiprazole 60 mg/day. He achieved control of his psychiatric symptoms and his weight returned to 86 kg within 7 months; no adverse effects were observed.

Musculoskeletal Bone pain with positive re-challenge has been reported (85A).
A 37-year-old single white woman, who was

taking sertraline 50 mg/day, was given aripi­ prazole 7.5 mg at night. Ten days later she reported significantly improved affective symptoms but noted severe bone pain radiat­ ing down both legs. Aripiprazole was with­ drawn. One week later, the bone pain completely resolved and did not recur. She then decided to take aripiprazole again, but at a much lower dose and at a slower rate of titration. Aripiprazole was restarted at a dose of 2.5 mg at night for the next 2 weeks. She was no longer taking sertraline. Two weeks later the dose of aripiprazole was increased to 5 mg/day. One week later she began complaining of bone pain not only in her legs, but also in her arms. Aripiprazole was withdrawn and within 7 days the bone pain again resolved.

According to the package insert for aripi­ prazole, bone pain is listed as “unlikely to be drug related” and “infrequent”

Antipsychotic drugs

Chapter 6

(i.e., occurring in under 1% but in over 0.1% of all patients). Drug overdose In premarketing studies, of 5500 patients taking aripiprazole, there were seven cases of overdose (86R). Two of these patients reportedly took 180 mg; these patients were given supportive care only. One of these two patients reportedly had somnolence, nausea, and vomiting. During 2003, eight cases of overdose due to aripiprazole were identified in a poison control center in Arizona (mean age 24, range 3–43 years) (87c). The most com­ mon formulation of aripiprazole taken was the 15 mg tablet commonly prescribed as initial therapy. There were four acci­ dental cases and four intentional. The average amount of aripiprazole was 82 mg (data from six cases). All cases had favorable outcomes.
A 27-year old woman intentionally took

aripiprazole 330 mg in a suicide attempt and developed mild sedation (88A). Her serum concentrations were six times the upper limit of the accepted target range. She was observed for 8 hours, during which there were no further adverse effects; the drowsiness completely resolved and she did not develop any symptoms of orthostatic hypotension.

In addition, a series of cases of overdose in five children has been published (89c). Two adolescents remained asymptomatic despite doses of 120 mg and 300 mg while a third who took an unknown dose had lethargy. This symptom was also experienced by a 2­ year-old and a 6-year-old child; the former also had vomiting and the latter drooling and flaccid facial muscles, which improved with diphenhydramine. Drug formulations In January 2005, an oral solution of aripiprazole was approved by the FDA, providing an option for adults with difficulty in swallowing (90S,91R). Drug–drug interactions Lithium In an open study, patients took aripiprazole 30 mg/day on days 1–14 and aripiprazole with lithium on days 15–36 (92c); lithium was titrated from 900 mg until serum con­ centrations reached 1.0–1.4 mmol/l for at

77 least 5 days (n ¼ 12). Co-administration with lithium increased mean Cmax and AUC of aripiprazole by about 19% and 15% respectively; the apparent oral clearance fell by 15%. There was no effect on the steadystate pharmacokinetics of the active metabo­ lite of aripiprazole. Thus, therapeutic doses of lithium had no clinically significant effects on the pharmacokinetics of aripiprazole in patients with schizophrenia or schizoaffec­ tive disorder. Carbamazepine In an open study, nine men with schizophrenia or schizoaffective disorder took aripiprazole monotherapy (30 mg/day) for 14 days, after which aripi­ prazole steady-state pharmacokinetics were assessed (93c); they then took carbamaze­ pine together with aripiprazole for 4–6 weeks. The dose of carbamazepine was titrated to produce a trough serum concen­ tration within the range 8–12 mg/l. Co­ administration with carbamazepine reduced the mean peak Cmax and AUC of aripi­ prazole by 66% and 71% respectively. Similarly, co-administration with carbama­ zepine reduced the mean peak Cmax and AUC over the 24-hour dosing interval of the major active metabolite of aripiprazole, dehydroaripiprazole, by 68% and 69% respectively. Both aripiprazole and dehy­ droaripiprazole are substrates for CYP3A4, which is induced by carbamazepine. When carbamazepine is added to aripipra­ zole, the dose of aripiprazole should be doubled (to 20–30 mg/day). Additional dose increases should be based on clinical evalua­ tion. When carbamazepine is withdrawn, the dose of aripiprazole should be reduced. Valproate In an open study, patients took aripiprazole 30 mg/day on days 1–14 and aripiprazole with valproate on days 15–36 (92c); valproate was titrated to 50–125 mg/l (n ¼ 10). Co-administration with valproate reduced the AUC and Cmax of aripiprazole by 24% and 26% respec­ tively, with minimal effects on the active metabolite. Thus, therapeutic doses of valproate had no clinically significant effects on the pharmacokinetics of aripiprazole in

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patients with schizophrenia or schizoaffec­ tive disorder.

Clozapine

(SED-15, 823; SEDA-28, 65; SEDA-29, 66; SEDA-30, 61)

Comparative studies Switching to clozapine has been compared with switching to another atypical antipsychotic drug in 99 patients who had discontinued treatment with a newer atypical antipsychotic drug (94C). Patients who had stopped taking olanzapine, risperidone, or ziprasidone in the first phase of the trials, primarily because of lack of efficacy, were randomly assigned to open treatment with clozapine (n ¼ 49) or blinded treatment with another newer atypical antipsychotic drug not previously received in the trial: olanzapine (n ¼ 19), quetiapine (n ¼ 15), or risperidone (n ¼ 16). Time until treatment discontinuation for any reason was significantly longer for clozapine than for quetiapine or risperidone, but not for olanzapine; similarly, at 3-month assessments, PANSS total score had fallen more in patients taking clozapine than in patients taking quetiapine or risperidone but not olanzapine. Insomnia was the most common adverse effect with risperidone (31%) and was less common with clozapine (4%). Anticholinergic symptoms (urinary hesitancy, dry mouth, constipation) were most common with quetiapine (47%) and quite common with clozapine (20%). Sialorrhea was most common with clozapine (33%). There were no noteworthy differences in metabolic measures or the rate of use of hypoglycemic or lipid-lowering treatments. Prolactin concentrations rose in patients taking risperidone and fell in patients in the other three treatment groups. In the clozapine group, one patient had a serious adverse event of eosinophilia and one patient developed agranulocytosis: both events led to discontinuation of treatment. The aim of another randomized con­ trolled trial was to compare the effect of clozapine therapy in patients with resistant

A. Carvajal, L.H.M. Arias, and N. Jimeno

schizophrenia with those of other atypical antipsychotic drugs (clozapine, n ¼ 67; ris­ peridone, n ¼ 7; olanzapine, n ¼ 31; que­ tiapine, n ¼ 21; amisulpride, n ¼ 10) (95C). After 1 year, the intention-to-treat compar­ ison showed no statistically significant advantage for using clozapine in quality of life scores versus the rest of the atypical drugs considered as a group (n ¼ 69); there were no significant differences in rates of adverse effects, including weight. Doubtful designs and small sample sizes precluded firm conclusions. Cardiovascular It has previously been estimated that clozapine is associated with a risk of potentially fatal myocarditis (0.01– 0.19%) (SEDA-30, 62); the FDA and the drug’s manufacturer have since strength­ ened warnings to include potentially fatal myocarditis. Reports of myocarditis have emerged.
An 18-year-old man who had recently started

to take clozapine (dose not specified) devel­ oped cardiac sounding chest pain, shortness of breath, and tachycardia of a few hours’ duration (96A). Cardiac markers were raised and an electrocardiogram showed ST eleva­ tion in the inferior and lateral leads; echocar­ diography showed a dilated left ventricle and apical akinesia. Viral serology, rheumatoid antibody, thyroid function, autoimmune screen, and immunoglobulins were normal. When clozapine was withdrawn, he made a good recovery, with normalization of his cardiac markers and electrocardiogram.
A 27-year-old man complained of flu-like symptoms, including generalized body aches, nasal congestion, and a scratchy throat 3 days after starting to take clozapine (97A). He then developed slight dysarthria, fever, tachycardia, and an acute change in mental status. His serum troponin concentration was raised. An electrocardiogram showed sinus tachycardia with T wave inversion in lead III. Cardiac catheterization showed a markedly reduced left ventricular ejection fraction. Clozapine was withdrawn and he improved.

Metabolic syndrome is a collection of risk factors that are associated with increased morbidity and mortality due to cardiovas­ cular disease. Since clozapine has been associated with a substantial effect on metabolic parameters, such as weight gain, hypertriglyceridemia, increased total

Antipsychotic drugs

Chapter 6

cholesterol concentrations, and hyperten­ sion, the aim of a recent controlled open study was to compare the prevalence of the metabolic syndrome among 93 outpatients and a matched group of 2701 subjects drawn from a database (98c). The metabolic syndrome was defined as three or more of the following: a waist circumference over 102 cm for men and over 88 cm for women; a fasting blood triglyceride concentration higher than 1.7 mmol/l (150 mg/dl); a highdensity lipoprotein cholesterol concentra­ tion below 1.0 mmol/l (40 mg/dl) for men and 1.3 mmol/l (50 mg/dl) for women; a blood pressure of over 130 mmHg systolic or 85 mmHg diastolic; and a fasting blood glucose concentration over 5.6 mmol/l (100 mg/dl). The prevalence of the meta­ bolic syndrome was significantly higher among patients taking clozapine (54%) than in the comparison group (21%); a logistic regression analysis showed signifi­ cant associations with age and body mass index in both groups, and treatment dura­ tion for clozapine. Nervous system It is currently thought that clozapine causes less tardive dyskinesia than haloperidol and that it can even improve pre-existing dyskinesia (SEDA­ 27, 56). Clozapine-associated tardive dyski­ nesia and hypothyroidism has been reported (99A).
A

47-year-old woman currently taking levothyroxine for hypothyroidism took cloza­ pine for schizophrenia and after 7 months developed horizontal grinding movements of the lower jaw and dyskinetic movements of the tongue. She scored 9 on the Abnormal Involuntary Movements Scale (AIMS). Levothyroxine was withdrawn for 8 weeks without any effect on the abnormal move­ ments or the AIMS score; neither a reduction nor an increase in the dose of clozapine produced any improvement in the dyskinetic movements.

Metabolism Weight gain has been com­ monly associated with clozapine (SEDA-27, 56; SEDA-28, 66; SEDA-29, 66; SEDA-30, 62). An 8-year retrospective chart review of 96 hospitalized patients with schizophrenia has analyzed data on monthly weight change, initial response, age, sex, clozapine dose, and

79 concomitant use of mood stabilizers and other antipsychotic drugs (100c). There was an average weight gain of 11.7 kg in 55 patients who took clozapine over the entire 8-year period; of these, 17 who had a significant initial clinical response gained significantly more weight (13.8 kg) than the 38 patients without a significant initial response (4.5 kg). Lower baseline body mass index was also associated with significantly more weight gain. Hematologic Agranulocytosis and neutro­ penia associated with clozapine have been extensively studied and discussed (SED-15, 829). Now, data from the Clozaril Patient Monitoring System for 6782 patients who took clozapine for 11 years in Korea have been analyzed (101c). The cumulative incidence of agranulocytosis was 1.64% between 6 and 11 years and the crude incidence was 0.8%; 29 of 54 cases of agranulocytosis occurred within the first 18 weeks. The cumulative incidence of neu­ tropenia was 20% between 8 and 11 years, and the crude incidence was 10%; 365 of 697 cases of neutropenia also occurred within the first 18 weeks. There were no cases of agranulocytosis or neutropenia after the ninth year of clozapine treatment.
A 49-year-old mentally retarded man took

clozapine for 7 years and after suffering from severe recurrent infections developed fatal agranulocytosis more than 4 years after discontinuing clozapine (102A).

It is known that agranulocytosis can occur several months or even years after withdrawal of clozapine. Patients with severe neutropenia second­ ary to clozapine are at high risk of recurrent neutropenia and, more importantly, agra­ nulocytosis, if they are re-exposed to clozapine (SEDA-28, 67). Of 53 patients who were rechallenged with clozapine following leukopenia or neutropenia during previous clozapine therapy 20 had a further blood dyscrasia; in 17 of these 20 patients the second event was more severe, in 12 it lasted longer, and in 17 it occurred more quickly on rechallenge (103c). Of the original 53 patients, 29 are still taking clozapine.

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A case of prolongation of clozapine­ induced leukopenia by olanzapine has been reported (104A). Salivary glands Sialorrhea is a common and well-known adverse effect of clozapine, and the use of antimuscarinic agents, adrenoceptor antagonists, and adrenocep­ tor agonists has been proposed (SED-15, 831; SEDA-29, 68; SEDA-30, 63). A comprehensive review of all relevant stu­ dies available on clozapine-induced sialor­ rhea through a PubMed search supplemented by manual searching has been published (105M). Most of the studies evaluating the drug treatment of clozapine­ induced sialorrhea were limited by small sample sizes, lack of controls, poor objec­ tive measures, and short follow-up. Although no drug has been found to be superior, the authors of this review pointed out that drugs such as pirenzepine, trans­ dermal hyoscine, intranasal ipratropium, and sublingual atropine solution are rela­ tively free of adverse effects when used with clozapine. Other drugs, such as benzatro­ pine+terazosin and clonidine-like drugs, may be useful alternatives; botulinum toxin could be an option for treatment-resistant or persistent troublesome sialorrhea. Gastrointestinal Constipation has often been associated with clozapine and may be even fatal (SEDA-27, 57). In previous reported deaths due to clozapine-induced constipation, patients have had prior abdominal symptoms over weeks or months. A new case has appeared of sudden death due to constipation with rapid bowel ischemia in a healthy 20-year-old man without any history of prior abdominal symptoms (106A). Susceptibility factors Genetic Changes in Brief Psychiatric Rating Scale (BPRS) scores and weight changes in association with a G-308A polymorphism of the TNFalpha gene have been examined in, respec­ tively, 153 and 247 patients taking clozapine (107c). Patients with allele A had significant improvements in BPRS after 3 and 6 months of clozapine treatment compared with patients without the allele. Moreover, there

A. Carvajal, L.H.M. Arias, and N. Jimeno

were trends for genotype A/A with clinical improvement in BPRS after 6 months, and for allele G with weight gain. Other authors did not find an association between TNFalpha and the response to clozapine (108c). Drug–drug interactions Valproic acid Valproic acid can increase the sedative effect of clozapine; this interaction has only a small effect on plasma clozapine concen­ trations (SEDA-25, 64). In 51 Chinese patients with treatment-resistant schizo­ phrenia a fixed dose of clozapine 300 mg/ day was given for 6 weeks and nonresponders were then given 500 mg/day for another 6 weeks (109c). Clozapine plasma concentrations were checked at weeks 6 and 12. Sodium valproate raised clozapine plasma concentrations; however, at 6 and 12 weeks, there was no association between clozapine plasma concentration, response, and adverse effects. Smoking Plasma concentrations of cloza­ pine are lower in smokers than in non­ smokers (SEDA-27, 58). Cigarette smoking induces CYP1A2, of which clozapine and olanzapine are substrates. The effects of cigarette smoking on serum concentrations of these drugs have been studied in 33 patients taking clozapine and 40 taking olanzapine (110c). Smokers (n ¼ 59) were stratified into the following groups accord­ ing to the number of cigarettes smoked daily: 1–6 (n ¼ 0), 7–12 (n ¼ 13), 13–19 (n ¼ 18), and 20 or more (n ¼ 28). The mean ratio of plasma concentrations was twice as high in non-smokers than in smokers for both drugs; daily consumption of 7–12 cigarettes was sufficient for max­ imum induction of clozapine and olanza­ pine metabolism.

Haloperidol

(SED-15, 1576; SEDA-28, 69; SEDA-29, 70)

Placebo-controlled studies Patients with acute migraine were randomized to two groups and received either haloperidol 5 mg intravenously in 500 ml of isotonic saline or

Antipsychotic drugs

Chapter 6

saline alone (111C). There was significant pain relief in 80% of the patients treated with haloperidol (n ¼ 20), whereas only three patients (15%) responded to placebo (n ¼ 20). The most common adverse effects of haloperidol were sedation and akathisia, the latter being more troublesome and occurring in 53% of the patients; 16% of the patients considered the adverse effects intolerable and would not like their migraine attacks to be treated with haloperidol again.

Olanzapine (SED-15, 2598; SEDA-28, 70; SEDA-29, 70; SEDA-30, 64) Observational studies New uses for olanzapine treatment have been tried, including severe conduct disorder, major depressive disorder, and even fibromyalgia and subacute prurigo. A mean olanzapine dose of 8 mg/day was given for a mean duration of 9 months to 23 adolescents (mean age 14, range 11–17 years) with conduct disorder, of whom 70% had acutely aggressive behavior; other psychiatric medications included antiepilep­ tic mood stabilizers and lithium (112c). Aggression significantly improved; appetite increased in 15 patients (mean weight gain 4.6, range 2–12 kg). In an open 6-week study, 14 patients with non-psychotic major depressive disorder were given olanzapine as monotherapy and improved (113c). The most frequent adverse effects were reduced concentration, dry mouth, agitation, light-headedness, somnolence, and pharyngitis. In a retrospective study of 51 patients with fibromyalgia (mean age 44 years, 96% women) taking olanzapine, weight gain (n ¼ 12) and somnolence/sedation (n ¼ 11) were the most frequent adverse events (114c). Weight gain and insomnia (n ¼ 1) occurred in four patients taking olanzapine for subacute prurigo (115c). In a retrospective study, the medical records of 463 inpatients with bipolar I disorder were examined to select those taking either olanzapine (n ¼ 51; mean

81 dose 11 mg/day), risperidone (n ¼ 61; mean dose 3.3 mg/day), or quetiapine (n ¼ 46; mean dose 421 mg/day) as a sole antipsy­ chotic adjunct to mood stabilizers for more than 1 month (n ¼ 158) (116c). Similar clinical improvements were found in the three groups. Body weight increased sig­ nificantly more in patients on olanzapine than on risperidone or quetiapine. Akathi­ sia occurred in 13 patients taking risper­ idone and in six taking olanzapine; dystonia occurred in seven and three respectively; mean equivalent doses of prescribed benza­ tropine were significantly higher in patients taking risperidone. Mean ages ranged from 35 years in the quetiapine group to 38 in the olanzapine group; lithium and valproate were the most frequently used mood stabilizers. Comparative studies Heroin-dependent patients receiving substitution treatment were given olanzapine (n ¼ 32) or fluox­ etine/paroxetine+clonazepam (n ¼ 35) to reduce aggressiveness in a 12-week obser­ vational study (117c). The numbers of patients who remained in treatment at week 12 were not significantly different. Mea­ sures of aggressiveness showed a signifi­ cantly more consistent reduction from baseline with olanzapine. Both groups gained weight (4.6% and 3.1% respectively; the difference was not significant). In phase 2 of the CATIE study (for phase 1 see SEDA-30, 56), subjects with schizo­ phrenia who had discontinued atypical antipsychotic treatment (n ¼ 444; mean age 41 years) were randomly reassigned double-blind to a different antipsychotic drug: olanzapine (n ¼ 108), risperidone (n ¼ 104), quetiapine (n ¼ 95), or ziprasi­ done (n ¼ 137) (118C). Time to withdrawal was longer in patients taking risperidone and olanzapine (median 7.0 and 6.3 months respectively) than quetiapine and ziprasi­ done (4.0 and 2.8 months). Patients taking olanzapine gained more body weight than patients in any other group, with a mean increase of 0.6 kg per month; on the other hand, patients taking ziprasidone had a mean loss of 0.7 kg monthly; the proportion of patients who gained 7% or more of their baseline body weight was greater in the

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olanzapine group than in the other groups. Weight gain or metabolic adverse effects accounted for dropouts in 10% of patients taking quetiapine, 8% taking olanzapine, 5% taking risperidone, and none taking ziprasidone. Patients taking risperidone had higher rates of sexual dysfunction com­ pared to the other drugs. Finally, there were no differences in the incidence of extrapyramidal adverse effects or electro­ cardiographic QTc interval prolongation between drugs. Olanzapine and haloperidol In a doubleblind, multicenter, 2-year study sponsored by Eli Lilly, 263 first-episode psychotic patients (mean age 24 years; 82% men) were randomized to olanzapine or haloper­ idol (mean modal doses 10 and 4.8 mg/day respectively) (119C). Patients in both groups showed significant clinical improve­ ment as assessed by PANSS scale and CGI score. Treatment withdrawals were more common with haloperidol (mean time in the study 230 versus 322 days); adverse effects were the cause in 16% of those taking haloperidol and in 7% of patients taking olanzapine. However, mean weight gain was estimated at 10.2 kg for olanzapine and 4.0 kg for haloperidol; 72% and 42% of patients respectively had a greater than 7% weight gain. Patients taking olanzapine had a higher cholesterol concentration; non-fasting glucose concentration was greater in patients taking olanzapine at weeks 12 and 24. Olanzapine and risperidone Elderly patients with schizophrenia taking typical antipsychotic drugs (mean age 70 years) were randomized to olanzapine (n ¼ 34; mean dose 12 mg/day) or risperidone (n ¼ 32; mean dose 1.9 mg/day) (120c). From baseline to end-point at 6 months, there were nine dropouts in patients taking olanzapine and five in those taking risper­ idone; reasons for dropout included adverse events (n ¼ 2 and n ¼ 6 respectively), death (n ¼ 2 with risperidone), and non­ compliance (n ¼ 2 and n ¼ 1 respectively). There were no significant differences in extrapyramidal symptom scales or in the clinical scale for akathisia. Mean weight

A. Carvajal, L.H.M. Arias, and N. Jimeno

gain was 4.3 kg with olanzapine and 1.7 kg with risperidone. Olanzapine and risperidone have been compared in a multicenter, randomized, open, 1-year study supported by Eli Lilly (121C). A total of 235 patients were assigned either to olanzapine (n ¼ 120; mean dose 12 mg/day) or risperidone (n ¼ 115; mean dose 4.9 mg/day). There were significant improvements from baseline to end-point in both groups in different scale scores; patients taking risperidone had significantly more tremor (14% versus 5.6%), akathisia (8.9% versus 1.6%), and sexual dysfunction (5.7% versus 0.8%); subjects taking olanza­ pine had greater weight gain (3.8 versus 2.1 kg; 41% had a 7% or higher weight increase versus 17% with risperidone); weight gain occurred up to week 16 in patients taking olanzapine and throughout the 48 weeks in patients taking risperidone. Olanzapine and antidepressants Patients with unipolar, non-psychotic, treatment-resis­ tant depression, who took venlafaxine for 7 weeks, took part in a 12-week double-blind study supported by Eli Lilly (122c). They were randomized to olanzapine monother­ apy (n ¼ 62), olanzapine+fluoxetine (n ¼ 59), fluoxetine (n ¼ 62), or venlafaxine (n ¼ 59); mean modal doses were olanzapine 7.9 mg/day, fluoxetine 38 mg/day, and venla­ faxine 275 mg/day. Patients on the combina­ tion improved more than those in the other groups. There was similar weight gain (mean increases 4.3 and 3.5 kg respectively) in patients taking olanzapine+fluoxetine and olanzapine; there was a small increase in QTc interval in patients taking the combina­ tion and those taking fluoxetine; mean cholesterol changes were 0.24 mmol/l in patients taking olanzapine+fluoxetine and 0.05 mmol/l in those taking venlafaxine. Placebo-controlled studies In a multicen­ ter, randomized, double-blind study sup­ ported by Eli Lilly, 60 young subjects with prodromal symptoms of psychosis (median age 16, range 12–36 years; 65% men) were treated for 1 year with olanzapine (n ¼ 31) or placebo (n ¼ 29) and followed for 1 year after treatment (123C). There was conversion to psychosis in five patients taking olanzapine

Antipsychotic drugs

Chapter 6

and in 11 taking placebo. There was one dropout for adverse events in each group; mean change in weight was 8.8 kg in patients taking olanzapine and 0.3 kg in those taking placebo; there were no significant changes in extrapyramidal symptoms, blood glucose, or cholesterol. Olanzapine has also been used for pre­ venting relapse in bipolar I disorder (124C). Of 961 patients with manic or mixed episodes who entered screening, 731 received open olanzapine (mean dose 12 mg/day) as acute therapy for 6–12 weeks. As 361 met symptomatic criteria, they were assigned, in a double-blind maintenance phase, to olanzapine (n ¼ 225, mean dose 13 mg/day) or placebo (n ¼ 136) for up to 48 weeks. Time to relapse to manic, depressive, or mixed episodes was significantly longer in patients taking olanzapine (174 days versus 22 days). Weight gain was again the main adverse effect of olanzapine. In the open acute phase the mean change was 3.0 kg and weight gain 7% or higher from baseline occurred in 29% (n ¼ 731). In the main­ tenance phase, the mean change with olanzapine was 1.0 kg and in the placebo group –2.0 kg. There were electrocardio­ graphic abnormalities in eight of 179 patients (4.5%) who took olanzapine and in one of 117 (0.9%) who took placebo. During the open phase, prolactin abnormalities occurred in 64 (29%) of 218 patients who were ultimately randomly assigned to treat­ ment groups in the double-blind phase. Among these 64 patients, prolactin abnorm­ alities occurred in the double-blind phase in 19 of 43 patients randomly assigned to receive olanzapine and in two of 21 patients randomly assigned to receive placebo. Three patients taking olanzapine and two taking placebo had treatment-related rises in glu­ cose concentration during the double-blind phase; the maximum glucose values were 13.9, 15.2, and 16.3 mmol/l respectively in the three patients who took olanzapine, and 11.8 in both of the patients who received placebo. Two patients taking olanzapine had treatment-related rises in cholesterol concentration; maximum cholesterol values for those patients were 7.3 and 6.4 mmol/l respectively. No patient taking placebo had a rise in cholesterol concentration.

83 Nervous system Patients with schizophre­ nia taking olanzapine monotherapy (n ¼ 54) or polytherapy (n ¼ 38) had increased rates of slow and sharp waves in the electroencephalogram compared with patients taking no pharmacological treat­ ment (n ¼ 54), but did not have spike- or sharp-slow-wave complexes (125c). A possible case of olanzapine-induced dyskinesia has been described, being iden­ tified as paradoxical dyskinesia because of its early onset, younger age, and moderate drug dose (126A).
A 40-year-old woman with bipolar disorder

previously treated with haloperidol for 4 months was given olanzapine 30 mg/day. On day 20 she developed orofacial dyskinesias, particularly lip-licking, which disappeared when olanzapine was withdrawn.

Dystonia (SED-15, 2602; SEDA-28, 72; SEDA-29; 73) has been related to olanza­ pine combined with fluoxetine; possible mechanisms include reduced clearance of the antipsychotic drug by inhibition of CYP2D6 or a synergistic increase in the release of noradrenaline and dopamine (127A).
A 21-year-old man, who had taken fluoxetine

1 week before, took abruptly olanzapine 70 mg; 1 hour later he developed abnormal movements in the trunk and limbs, which extended to neck and face, and also had akathisia; the symptoms did not resolve with diphenhydramine 50 mg or benzatropine 2 mg but responded to lorazepam 4 mg.

Oculogyric crisis has been described (128A).
A 22-year-old woman taking lithium 900 mg/

day and paroxetine 40 mg/day took olanzapine for the first time and soon afterwards developed a dystonic upward deviation of her eyes, which responded to biperiden 5 mg intravenously.

Psychiatric Obsessiveness described (129A).

has

been


A 19-year-old-man taking olanzapine 10 mg/

day developed highly distressing vivid visual images of sexual content after 1 month; they disappeared on withdrawal of olanzapine and recurred 1 day after it was reintroduced; they

84

Chapter 6

disappeared again when olanzapine was replaced by risperidone.

Endocrine Hyperprolactinemia (SED-15, 2604; SEDA-29, 73), defined as over 18.8 ng/ml in men and over 24.4 ng/ml in women, has been studied in patients with schizophrenia taking conventional antipsy­ chotic drugs or risperidone (n ¼ 54), who were randomized to receive olanzapine (n ¼ 27, mean dose 13 mg/day) or to remain on current therapy (mean risperidone dose 4.8 mg/day, n ¼ 18; mean chlorpromazine equivalents for conventional antipsychotic drugs 453 mg/day, n ¼ 9) (130c). Baseline prolactin concentrations in women rando­ mized to olanzapine were 66 ng/ml (n ¼ 14) and 82 ng/ml in those who remained on the same therapy (n ¼ 14); in men baseline prolactin concentrations were 34 ng/ml (n ¼ 13) and 34 ng/ml (n ¼ 13) respectively. At month 4, mean prolactin changes were 32 ng/ml in women switched to olanzapine and +7.3 ng/ml in those who continued therapy; in men mean changes were 20 ng/ml and 1.6 ng/ml. Galactorrhea was present in nine women at study entry and continued in two of the four patients who were switched to olanzapine. Breast enlar­ gement (six women) and gynecomastia (one man) resolved in three (two females and one male) when four of them switched to olanzapine. There was a moderate increase in pro­ lactin concentrations in a double-blind, randomized, crossover study in 11 healthy men who received one dose of olanzapine 5 mg, quetiapine 50 mg, haloperidol 3 mg, or placebo (131c). Blood samples were taken hourly from 1 to 8 hours. For ACTH, cortisol, and prolactin there was a signifi­ cant effect of treatment on AUC. Com­ pared with placebo, quetiapine and olanzapine, but not haloperidol, signifi­ cantly reduced ACTH. Compared with placebo, haloperidol and olanzapine increased the AUC of prolactin plasma concentrations, but there was no significant effect for quetiapine. In relation to prolactin, some studies point to a possible sex difference. This has been observed in a sample of 20 Japanese drug-naive patients with schizophrenia

A. Carvajal, L.H.M. Arias, and N. Jimeno

(aged 12–46 years) who took olanzapine 5–10 mg/day (132c). Prolactin concentra­ tions remained higher, at weeks 3 and 8, in 10 women compared with 10 men. Metabolic Diabetes is associated with olanzapine (SED-15, 2604; SEDA-29, 74; SEDA-28, 60). The risk of new-onset diabetes has been evaluated in 15767 non­ diabetic patients with schizophrenia who started monotherapy with olanzapine (n ¼ 5981), risperidone (n ¼ 5901), quetia­ pine (n ¼ 877), or haloperidol (n ¼ 3008) from 1999 to 2001; the mean age was 50–52 years and the male percentage 92–95% (133C). Patients were considered to have new-onset diabetes if they were given diabetes diagnostic codes on at least two separate days, or if they filled a prescription for an antidiabetic drug. During the first year of patient follow-up, except for a shorter time for quetiapine, whose use was approved during the study, the numbers of newly diagnosed cases of diabetes were 200 for patients taking olanzapine (3.3%), 193 taking risperidone (3.3%), 21 taking que­ tiapine (2.4%), and 60 taking haloperidol (2.0%). The risks were greater for patients under 50 years. Mean time to event ranged from 214 days with quetiapine to 304 days with haloperidol. After adjusting for poten­ tial confounders, with patients taking halo­ peridol as the reference group, hazard ratios (HR) were: olanzapine 1.64 (95% CI ¼ 1.2, 2.2); risperidone 1.6 (1.2, 2.1); and quetiapine 1.7 (1.0, 2.8). A post hoc analysis of data pooled from seven clinical trials in elderly patients with dementia taking olanzapine showed that treatment-emergent diabetes (n ¼ 29, 2.1%) was significantly associated with a high glucose at baseline (blood concentra­ tion over 7.9 mmol/l; HR ¼ 11) but not with other clinical factors, such as body mass index over 25 (HR ¼ 0.9), weight gain of 7% or more (HR ¼ 2.3), or antipsychotic drug treatment (HR ¼ 1.4) (134M). Olanzapine has been consistently asso­ ciated with weight gain (SED-15, 2605; SEDA-28, 72; SEDA-29, 74; SEDA-30, 66). Predictors of substantial weight gain (gaining over 5 kg or over 7% of initial

Antipsychotic drugs

Chapter 6

weight in a mean of 30 weeks) have been analyzed using data from four long-term, randomized, multicenter studies in patients with bipolar or mixed mania taking olanza­ pine (n ¼ 948, 41% men, mean age 40 years) (135c). Baseline characteristics significantly associated with substantial weight gain included younger age, non-white ethnicity, lower body mass index, non-rapid cycling, and psychotic features; weight gain of 2 kg or more in the first 3 weeks of therapy predicted substantial weight gain by 30 weeks. Some genetic factors might influence olanzapine-associated weight gain (SEDA­ 29, 64). The a2a–adrenergic receptor –1291 C/G polymorphism was studied in 62 Korean patients with schizophrenia taking olanzapine as the sole antipsychotic for at least 3 months (mean dose 14.3 mg/day) (136C). A total of 28 patients had severe weight gain, defined as more than 10% of weight gain from baseline; the frequency of the G allele (GG, n ¼ 14; CG, n ¼ 13; CC, n ¼ 1) was significantly higher in these subjects than in those with weight gain below 10% (OR ¼ 2.58; 95% CI ¼ 1.21, 5.51). The potential role of adiponectin, an insulin-sensitizing anti-inflammatory plasma protein produced by mature adi­ pocytes, for olanzapine-induced insulin resistance has been examined in patients with schizophrenia treated for a minimum of 6 months with olanzapine (n ¼ 9, median dose 10 mg/day) or typical anti­ psychotic drugs (n ¼ 9; four of them with haloperidol as monotherapy) compared with healthy volunteers (n ¼ 16) (137cE). Patients who took olanzapine had signifi­ cantly lower total serum adiponectin com­ pared with those taking conventional antipsychotic drugs and controls (5.2 ng/ ml versus 8.2 and 8.8 ng/ml); conversely, in the same study, in vitro treatment of human adipocytes had no direct effect on adiponectin expression or secretion. This is consistent with what was observed in another study, in which adiponectin concentration did not significantly change in 13 patients with schizophrenia after 4 weeks on olanzapine (mean dose 15 mg/day) (138c). The patients had significant increases in weight, body

85 mass index, and leptin serum concentration, and reduced ghrelin concentrations, sub­ stances that may also be involved in anti­ psychotic drug-induced weight gain. Hematologic Neutropenia has previously been described with olanzapine (SED-15, 2606; SEDA-28, 72; SEDA-29, 75), and a new case has been reported (139A).
A 31-year-old man taking olanzapine 20 mg/day

had a total white blood cell count of 8.3  109/l, which fell to 2.1  109/l when he switched to clozapine. When clozapine was withdrawn the count normalized to 7.9  109/l, and after 3 weeks with olanzapine the count fell again to 3.6  109/l; it normalized after olanzapine with­ drawal.

Teratogenicity A possible relation between olanzapine treatment during preg­ nancy and hip dysplasia has been reported (140A).
A 33-year-old woman with a 17-year history of

psychosis, previously treated with haloperidol and currently with olanzapine, was referred for consultation at the third month of her pregnancy; olanzapine was reduced to 2.5– 5 mg/day. Pregnancy was uneventful and at term she delivered a healthy female by cesarean section. Clinical and ultrasound hip screening at birth were normal, but at 3 months of age developmental dysplasia was diagnosed and successfully treated with a harness for 3 months.

Drug–drug interactions Fluoxetine Two FDA alerts concern the combination of olanzapine with fluoxetine (Symbyax), which may cause the serotonin syndrome and infant persistent pulmonary hyperten­ sion (141S). Fluvoxamine (SED-15, 2609; SEDA-28, 73; SEDA-29, 75; SEDA-30, 66) Some speci­ fic adverse events have been described when olanzapine and fluvoxamine are co-adminis­ tered, including hypersalivation (142A).
A

34-year-old Japanese man developed somatic hallucinations and was given fluvox­ amine up to 200 mg/day; 3 weeks later olanzapine was also prescribed at an initial dose of 2.5 mg/day; at a dose of 7.5 mg/day he developed increased salivation without swal­ lowing difficulties; no other causes for

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Chapter 6

hypersalivation were found; his symptoms resolved after withdrawal of olanzapine.

Lamotrigine Some studies have shown that co-administration of olanzapine with lamotrigine does not modify olanzapine pharmacokinetics nor cause adverse events in healthy volunteers (143c, 144c).

Quetiapine

(SED-15, 2995; SEDA-29, 75; SEDA-30, 67)

Observational studies In an open pilot study, 20 adults with acute bipolar mania took quetiapine 200 mg on day 1, increased by 200 mg/day on days 2, 3, and 4 up to 800 mg/day taken in two divided doses on day 4 (145c). From day 5 onward, patients took a flexible total dose of 400–800 mg/day until completion of 3 weeks’ treatment. There was significant improvement. Overall, 20% of patients withdrew because of adverse events: agitation was the most common cause. Dosage adjustment was required in 35% of patients because of adverse effects after rapid dose administration was complete; the most common adverse effect was tremor (30%). Tolerability to rapid introduction of highdose quetiapine in 8 patients with acute schizophrenia (n ¼ 5) or mania (n ¼ 3) has been evaluated (146c). For most of these patients, rapid dose escalation (quetiapine 200–300 mg on day 1 to a maximum dose of 600–1200 mg over 4 weeks) was well tolerated; there were no serious adverse effects and vital clinical parameters were unchanged; one patient had transient somnolence. The efficacy of quetiapine in patients with bipolar I or II disorder with a major depressive episode has previously been reviewed (SEDA-30, 67). Now the results of a prospective, open, non-comparative, flexible-dose, 20-week study of quetiapine (mean dose 315 mg/day) in 14 patients with treatment-resistant depression has been published (147c). Augmentation with

A. Carvajal, L.H.M. Arias, and N. Jimeno

quetiapine significantly reduced total scores and scores listed in the anxiety subscale of the Hamilton scale. Quetiapine add-on treatment significantly reduced the scores listed in the insomnia subscale after the second week of treatment. Of the 18 patients who entered this study, four patients dropped out because of persistent hypoten­ sion and lack of response to quetiapine. Two adolescent girls with major depres­ sive disorder, sleep disturbances, and cut­ ting behaviors were successfully treated with quetiapine augmentation (148A). In recent years, as with other antipsycho­ tic drugs, there has been enormous interest in finding new indications for quetiapine other than schizophrenia or bipolar dis­ order. Thus, 35 consecutive patients with Parkinson’s disease with drug-induced psy­ chosis, 19 with dementia, were included in a 6-month open study (149c). The intentionto-treat analysis did not show a significant effect of quetiapine; in those who com­ pleted the study (n ¼ 24), quetiapine was more effective in those without dementia. Treatment was stopped in 11 patients (5 demented and 6 non-demented) because of lack of response (n ¼ 8), or lack of response and adverse effects (two with somnolence and one with orthostatic hypotension). A 6-week open flexible-dose pilot study of quetiapine (at doses of 25–300 mg/day) for aggression secondary to traumatic brain injury has been conducted in seven patients (150c). Quetiapine reduced irritability and aggression with associated improvement in cognitive function. Sedation was reported in three patients; in two cases it resolved by week 3 and in the remaining case it did not resolve until week 6. There were mild extrapyramidal adverse effects and akathisia in one subject. Quetiapine has been assessed in nine alcoholics with persistent craving, sleep disorder, excitement, depressive symptoms, or anxiety symptoms after withdrawal (151c). Eight patients were abstinent with quetiapine over 2–7 months; one of these relapsed after he stopped taking quetiapine on his own initiative after 10 weeks. The ninth stopped taking it immediately because of swollen nasal mucosa.

Antipsychotic drugs

Chapter 6

Comparative studies The efficacy of que­ tiapine in the treatment of mania or bipolar disorder has been assessed in several studies. In a double-blind study, 50 adoles­ cents (aged 12–18 years) with bipolar I disorder with manic or mixed episodes were randomized to quetiapine (400–600 mg/day) or sodium valproate (serum concentration 80–120 mg/l) for 28 days (152C). The treat­ ments were similar in efficacy. One serious adverse event occurred during the study; a patient taking sodium valproate was rehos­ pitalized because of symptom exacerbation and treatment was withdrawn; no other patients withdrew because of treatmentrelated adverse effects. The most common adverse effects in both groups were sedation (quetiapine 60%, sodium valproate 36%), dizziness (quetiapine 36%, sodium valpro­ ate 36%), and gastrointestinal upset (que­ tiapine 24%, sodium valproate 28%). Nervous system Although quetiapine seems to cause fewer extrapyramidal adverse effects than other antipsychotic drugs (SEDA-30, 68), quetiapine-induced neuroleptic malignant syndrome has been reported (SED-15, 2995; SEDA-30, 68). Now another case has been published, supposedly for the first time, in a patient with Lewy-body dementia (153A).
A 68-year-old man with Parkinson’s disease,

visual hallucinations, and delusions of perse­ cution was treated with amantadine 200 mg/ day and quetiapine 50 mg/day, increased to 75 mg/day; 7 days later his temperature was 38.61C and he had a tachycardia, tachypnea, and sweating. His extrapyramidal symptoms had worsened, including “lead pipe” rigidity and dysphagia, with a raised serum creatine kinase activity. He met the diagnostic criteria for neuroleptic malignant syndrome and was also thought to have Lewy-body dementia.

The authors concluded that patients with Lewy­ body dementia are particularly vulnerable to the adverse effects of antipsychotic drugs. However, antiparkinsonian drug-induced psychosis and dementia are off-label indications for quetiapine. Replacement of antipsychotic drugs with quetiapine has been evaluated in 22 patients who still had moderate psychiatric symptoms as well as extrapyramidal

87 adverse effects (154c). There were improve­ ments in clinical symptoms, objective and subjective quality of life, and extrapyrami­ dal symptoms. The extrapyramidal adverse effects were measured before and 6 months after the addition of quetiapine in 21 cases, and the ad hoc scores improved signifi­ cantly; likewise, the doses of antiparkinso­ nian drugs as biperiden equivalent doses were significantly reduced. However, there was no correlation between scores and quality of life. Because quetiapine has little D2 antago­ nist properties and low intrinsic anticholi­ nergic activity, it has been proposed quetiapine as the treatment of choice when there are persistent symptoms of extrapyr­ amidal adverse effects with other atypical antipsychotic drugs (155R).
A 44-year-old man with neurosyphilis pre­

sented with agitation, auditory hallucinations, and delusions of persecution (156A). He was given penicillin G, memantine, and risperi­ done, with partial response of his psychotic symptoms but with significant extrapyramidal adverse effects. Risperidone was withdrawn and replaced by quetiapine 1200 mg/day; he improved immediately without extrapyramidal adverse effects.

Psychiatric Surprisingly, quetiapine can cause psychiatric symptoms, such as audi­ tory hallucinations, in some patients (SEDA-30, 68). An association has been reported between the de novo appearance of obsessive-compulsive symptoms and que­ tiapine treatment in a patient with schizo­ phrenia (157A).
A 33-year-old woman with previous auditory

and visual hallucinations developed aggressive obsessions without hallucinations after having taken quetiapine 1000 mg/day for 2 weeks. The symptoms abated when fluoxetine was added to her treatment regimen while keeping the quetiapine dosage unchanged.

Endocrine Dose-dependent reductions in total T3 and T4 and free T4, without an increase in TSH, have been reported; these changes have not been observed with other antipsychotic drugs (SED-15, 2295). Now a case of hypothyroidism has been reported (158A).

88

Chapter 6


A 49-year-old woman with depression took

quetiapine 800 mg/day for 6 months and developed hypothyroidism, with modest weight gain, reduced appetite, a hoarse voice, an expressionless face, slowing of intellectual and motor activity, and constipation. Thyroid laboratory measurements were: total serum T3: 0.77 ng/ml (reference range 0.76–1.78), total serum T4: 42 mg/l (61–122), free T4: 5.3 ng/l (5.8–16), and TSH: 6.78 mIU/l (0.34– 5.60).

TSH concentrations have been reported to be unaffected by quetiapine, which is in disagree­ ment with this case. The authors suggested an autoimmune mechanism. Quetiapine was with­ drawn and the thyroid tests rapidly normalized. Musculoskeletal Rhabdomyolysis been attributed to quetiapine (159A).

has


A 33-year-old man with bipolar disorder

developed chest and muscle pain while taking a very low dose of quetiapine (50 mg/day) and mirtazapine 30 mg/day. Creatine kinase was 9135 U/l (40 times the upper limit of the reference range). There was no evidence of neuroleptic malignant syndrome.

Sexual function Sexual dysfunction occurred in four of 25 patients taking quetiapine (SEDA-29, 79). Increased libido associated with quetiapine has now been reported, supposedly for the first time (160A). The authors proposed that relative blockade of 5-HT7, 5-HT2A, D2, and a2 adrenoceptors determine the sexual adverse effects of this drug.

A. Carvajal, L.H.M. Arias, and N. Jimeno

and psychotic symptoms can occur imme­ diately after the stroke or months to years later. This patient showed hypersexuality and delusional jealousy 2 years after a right cerebral infarction. Quetiapine was effec­ tive although the patient developed some adverse effects, including a worsening of motor functions. Drug overdose Quetiapine overdose has been reported (162A).
A 41-year-old man with bipolar disorder took

4500 mg of quetiapine in a suicide attempt. He had mental status changes, a prolonged QTc interval, and myoclonus. Within 24 hours he developed respiratory failure, requiring intu­ bation and mechanical ventilation. Chest radiograph showed bilateral infiltrates consis­ tent with acute respiratory distress syndrome.

Drug–drug interactions The effects on steady-state quetiapine concentrations of CYP3A4 inhibition has been evaluated in 12 healthy volunteers who took quetiapine 25 mg before and after 4 days of treatment with ketoconazole 200 mg/day(163c). Keto­ conazole increased quetiapine plasma con­ centrations and reduced its clearance. The effects on steady-state quetiapine concentrations of CYP3A4 induction has been evaluated in 18 patients with psychia­ tric disorders who were given carbamaze­ pine for 2 weeks (163c). Carbamazepine reduced quetiapine plasma concentrations and increased its clearance.


A 44-year-old man, with schizophrenia since a

teenager, previously taking multiple antipsy­ chotic drugs (trifluoperazine, chlorpromazine, haloperidol, risperidone, flupentixol, and flu­ phenazine), started to take quetiapine 200 mg/ day, which was increased to 600 mg on day 4 and to 750 mg 1 month later. When taking 600 mg/day he reported that quetiapine had “changed his sexuality”. When taking 750 mg/ day, he reported an increased drive to masturbate and spontaneous ejaculation at night time.

Despite this, quetiapine has been pro­ posed for the treatment of hypersexuality and delusional jealousy following a stroke in a 66-year-old man (161A). Hypersexuality and psychotic behavior are rare after strokes, but when such behavior does occur, the lesion is usually in the right hemisphere,

Risperidone

(SED-15, 3052; SEDA-28, 74; SEDA-29, 76; SEDA-30, 69)

Observational studies In 51 patients with first-episode schizophrenia who had not responded to olanzapine (mean age 21 years, 47% men) risperidone was used instead (3.1 mg/day at the 12-week study end-point) (164c). The responder rate in these patients, defined as a minimum of a 20% reduction in BPRS total score plus final Clinical Global Impression score of 3 or less, was 35%. Parkinsonism occurred in four patients and akathisia in three; other

Antipsychotic drugs

Chapter 6

reported adverse events included headache (n ¼ 11), somnolence (n ¼ 10), dry mouth (n ¼ 10), and fatigue (n ¼ 9). Aggressiveness in patients of different age groups with mental retardation has been treated with risperidone in 40 patients (aged 8–56 years; 21 children and adoles­ cents and 19 adults) with this condition and a history of at least 6 months’ aggression, property destruction. or self-injury, 36 of whom also had autism spectrum disorder (165c). A first 22-week crossover doubleblind study was followed by a 24-week open maintenance phase, mean doses being 2.0 mg/day for children and adolescents and 3.6 mg/day for adults. There were 13 cases of drug reduction because of adverse events (sedation and gastrointestinal complaints) and two patients withdrew because of severe akathisia (one of them also with 12.3 kg weight loss); other events were oculogyric crisis (n ¼ 1) and weight gain greater than 3 kg (n ¼ 28). Mean weight gain over the 46 weeks was 7.9 kg for children, 8.3 for adolescents, and 6.0 for adults. Comparative studies Risperidone (n ¼ 37, mean dose 3 mg/day) has been compared to clozapine (n ¼ 57, mean dose 254 mg/day) in patients with schizophrenia who had been clinically stable for at least 4 weeks before study entry (166c). Scores obtained from the Drug Attitude Inventory (DAI­ 10) showed a positive subjective view of both treatments. There were no significant differences between the groups in extrapyr­ amidal symptoms, or anticholinergic, auto­ nomic, psychic, allergic, hormonal, and miscellaneous adverse effects; however, there was a significant positive correlation between risperidone dose and hormonal adverse effects subscale score. Placebo-controlled studies Risperidone has been assessed in treatment-resistant depression in a three-phase study: (i) 4–6 weeks of open citalopram monotherapy; (ii) 4–6 weeks of open risperidone augmenta­ tion; (iii) a 24-week randomized doubleblind phase (risperidone, n ¼ 122; placebo, n ¼ 119) (167c). A total of 489 patients with

89 major depressive disorder and 1–3 docu­ mented treatment failures entered the citalopram monotherapy phase (20–60 mg/ day). In phase 2, the most frequent adverse events were dry mouth, headache, and dizziness; there were no significant changes in different extrapyramidal symptom scales. At end-point, the mean prolactin concen­ tration was 35 ng/ml with risperidone versus 6.6 ng/ml with placebo; galactorrhea was reported in 2.5% of patients taking risper­ idone and none of those taking placebo. The proportion of patients who gained 7% or more of body weight from baseline to end-point in phase 2 was 3.1% (all of them taking risperidone) and 8.3% and 2.6% in those taking risperidone or placebo respec­ tively during phase 3; mean weight changes in this third phase were 1.3 kg and –0.5 kg respectively. Mean risperidone modal doses were 1.1 mg/day in phase 2 and 1.2 mg/day in phase 3. There has been some focus on children and adolescents with disruptive behavior disorder. In a study supported by Johnson & Johnson patients aged 5–17 years, with­ out moderate or severe intellectual impair­ ment, and with conduct disorder (n ¼ 390), oppositional defiant disorder (n ¼ 318), or other diagnoses (n ¼ 19) were studied; 349 children also had attention deficit disorder with hyperactivity (168C). Patients who had responded to risperidone over 12 weeks (acute and continuation phases) were ran­ domly assigned to 6 months of double-blind maintenance treatment with either risper­ idone (n ¼ 172) or placebo (n ¼ 163). Risperidone was associated with a signifi­ cantly lower rate of symptom recurrence than placebo (27% versus 42%). Treat­ ment-related adverse events were reported more often during acute treatment (55%) than during the continuation phase (35%) and the maintenance phase (48% for risperidone and 36% for placebo); the most frequent adverse events were headache, somnolence, fatigue, and increased appe­ tite, all of them with n ¼ 54 (10%) to n ¼ 61 (12%) in the acute phase. Prolactin increased during acute and continuation therapy in 10 patients (six men had gynecomastia, one woman had amenorrhea and three had lactation) as well as in the

90

Chapter 6

maintenance phase (three men had gyne­ comastia, one woman had amenorrhea and lactation, and one had breast discharge). Mean prolactin plasma concentrations increased during the acute and continuation phases from 8.3 to 27 ng/ml and fell during the maintenance phase, both in patients taking risperidone (29–20 ng/ml) and pla­ cebo (30–9.6 ng/ml). Mean weight increased from baseline to the end of the continuation phase by 3.2 kg, and during the mainte­ nance phase by an additional 2.1 kg in patients taking risperidone, while in those taking placebo there was a mean fall of 0.2 kg. These are difficult to extrapolate to daily clinical practice. The fact that only those patients who responded to initial treatment were randomized potentially introduced selection bias; heterogeneity of patients studied was another important flaw. The risperidone SPC clearly states that “There is no clinical experience of risperidone treat­ ment in children less than 15 years old”. In a randomized, double-blind study, 68 patients with schizophrenia and a poor response to clozapine were randomly assigned to augmentation with risperidone 3 mg/day (n ¼ 34) or placebo (n ¼ 34) for 8 weeks (169c). There was no statistically significant difference in symptomatic bene­ fit between risperidone and placebo. The increase in fasting blood glucose concentra­ tions was slightly greater with risperidone group than placebo. Systematic reviews In a review of 15 studies in 86 patients treated with clozapine in which risperidone was added at a mean dosage of 4.6 mg/day for a mean of 8 weeks, there was overall significant improvement in 37 patients (170M). A lower dosage of risperidone and a longer duration of study seemed to be associated with a better outcome. The main adverse effects reported in these studies were: extrapyr­ amidal symptoms or akathisia (9.3%), sedation (7%), and hypersalivation (5.8%). Clinical evidence regarding the efficacy and safety of risperidone in bipolar mania has been reviewed by selecting six rando­ mized trials and six observational studies comprising data from 838 patients taking risperidone monotherapy and 1717 taking

A. Carvajal, L.H.M. Arias, and N. Jimeno

risperidone polytherapy, in combination with haloperidol, carbamazepine, lithium, topiramate, divalproex, or valproate (171M). Risperidone monotherapy reduced manic symptoms in patients with moderate mania and both in moderately and severely ill patients when combined. Adverse events caused 3–8% of dropouts in patients taking monotherapy, the most frequent being somnolence (up to 28%), weight gain, and extrapyramidal symptoms (similar to the haloperidol group in one of two comparison studies). Endocrine Risperidone can cause hyper­ prolactinemia (SED-15, 3058; SEDA-28, 77; SEDA-29, 98; SEDA-30, 70). In a 12­ week study in 27 psychotic patients, mean prolactin concentrations at baseline were 18 ng/ml in men and 24 ng/ml in women (172c). At end-point, mean prolactin concen­ trations were 54 and 107 ng/ml respectively; hyperprolactinemia occurred in nine patients (two men and seven women); related symp­ toms were menstrual abnormalities (n ¼ 7), galactorrhea (n ¼ 2), and erectile dysfunction (n ¼ 2). Increases in prolactin in women were higher than in men. The changes in serum prolactin concentrations did not cor­ relate with the improvements in total BPRS scores. Metabolism Risperidone can cause dra­ matic weight gain new-onset diabetes (173A).
A Caucasian 33-year-old woman with schizo­

phrenia taking risperidone 6 mg/day took fluox­ etine 40 mg/day for depression. After 9 months the fluoxetine was withdrawn. She experienced an increase in appetite, binge eating, and weight gain of 52 kg. She also developed diabetes mellitus, which was controlled with metformin 1700 mg/day. The addition of orlistat 360 mg/ day and topiramate 200 mg/day contributed to weight loss of 30 kg.

Hematologic Leukopenia has been reported in patients taking risperidone (SED-15, 3059; SEDA-29, 79) and a new case has been identified (174A).
A 69-year-old man with somatic pluripathol­

ogy and polypharmacy (antihypertensive, anti­ diuretic, beta-blocker, and anticoagulant) was

Antipsychotic drugs

Chapter 6

given risperidone 0.5 mg bd for a confusional state; 4 weeks later he developed fever and his leukocyte count fell to 700  106/l. He recovered when risperidone was with­ drawn.

Pancytopenia has been reported in a patient taking risperidone and with valpro­ ate (175A).
A 36-year-old man with an acute confusional

state and a 12-year history of psychiatric disease and substance abuse, who had taken valproate 1500 mg/day for several years, took risperidone for 10 days and developed a mild pancytopenia (hemoglobin 11.2 g/dl, white cell count 3.2  109/l, platelets 75  109/l). The serum valproate concentration was 166 mg/l. Valproate and risperidone were withdrawn, and after 3 weeks the blood count returned to normal.

Urinary Risperidone may be associated with urinary incontinence in adults and three cases have been described in women aged 46, 47, and 50 years while taking risperidone (176A). This may be an underreported adverse effect. Skin Risperidone-induced erythema mul­ tiforme minor has been reported (177A).
A 21-year-old man with epilepsy, controlled

with oxcarbazepine 900 mg/day, and an acute psychosis was given risperidone (initially 2 mg/ day, final dose 4 mg/day). Five days later he gradually developed multiple rashes all over the body with edematous papules acrally distributed and no involvement of mucous membranes; risperidone was withdrawn and at 1-month follow-up he had become completely asymptomatic.

Susceptibility factors Genetic (SEDA-29, 64) Perhaps the most promising research has focused on the serotonin 2C receptor gene polymorphism HTR2C –759 C/T. An association has been identified between the T allele and less weight gain from antipsychotic drug use, although the results have not been consistent across all studies. With the pur­ pose of identifying some genetic and envir­ onmental factors associated with risperidone­ induced weight gain, 123 Han Chinese inpatients (mean age 34 years, 55% men) with acute schizophrenia taking monother­ apy were studied for up to 42 days (178C).

91 The risperidone target dose of 6 mg/day could not be reached in 31 patients. No patient withdrew because of adverse events. Mean body weight increased from 61 kg at baseline to 64 kg at end-point. A multiple regression analysis showed that from 15 genetic variants across 10 candidate genes considered, 5-HT2A 102-T/C 102-T/T, 5­ HT2C -759-C/T in men, C/T or T/T in women, BDNF 66-Met/Met and CYP2D6 188-C/C were significantly associated with lower weight gain, and 5-HT6 267-T/C 267-C/ C with higher weight gain. Non-genetic factors In the same study, other factors associated with risperidone­ induced weight gain were baseline body weight (1 kg increment at baseline was associated with a 1 kg increase in post­ treatment body weight), age (1 year of age increment reduced body weight by a mean of 0.05 kg), sex (men gained more weight, mean 0.65 kg), schizophrenia subtype (paranoid subtype was predictive of lower weight by 0.95 kg), treatment duration (every 1-week increase significantly raised body weight by 0.44 kg), and treatment efficacy (a 1-point increase in the PANSS total score significantly reduced body weight by 0.02 kg) (178C). Drug formulations The constant and slow release of risperidone from a long-acting injectable formulation leads to less fluctua­ tion in drug plasma concentrations (SEDA­ 29, 79; SEDA-30, 70). Oral dosing with 2, 4, or 6 mg/day produces mean peak active concentrations of 33, 74, and 107 ng/ml respectively, compared with 23, 57, and 81 ng/ml for risperidone long-acting injec­ tions of 25, 50, and 75 mg every 2 weeks (179r). Long-acting injectable risperidone was also associated with D2-like receptor occupancy of less than 80% (considered as the threshold for extrapyramidal symp­ toms). PET has been used to evaluate dopamine D2 occupancy profile in nine patients receiving long-acting injectable risperidone 25–75 mg every 2 weeks (180c). Mean D2 occupancy levels for 25, 50, and 75 mg were 71%, 54%, and 74% respectively, at post-injection and 66%, 82%, and 75.0% respectively at pre-injection. Prolactin

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Chapter 6

concentrations were not correlated with drug concentrations or D2 occupancy. This drug formulation was effective as measured with the PANSS scale in 40 patients with schizophrenia (mean age 37 years, 63% men) in a 48-week open study (181c). The following adverse events were associated with drug administration: extra­ pyramidal symptoms (n ¼ 6), insomnia (n ¼ 2), headache (n ¼ 1), dizziness (n ¼ 1), irregular menstruation (n ¼ 1), and momentary blurred vision (n ¼ 1); the following adverse events led to drug with­ drawal: extrapyramidal symptoms and irre­ gular menstruation (each n ¼ 1). Two cases of lingual lesions in patients taking orally disintegrating risperidone (Ris­ perdal M-tab) have been described (182A).
A 44-year-old woman was given orally disin­

tegrating risperidone (1 mg in the morning and 2 mg at bedtime) for psychosis. After 3 days she developed tongue paresthesia and multiple erythematous sloughing lesions at the tip and bilateral anterior edges; the lesions resolved within 3 days after risperidone withdrawal.

Drug dosage regimens In order to estab­ lish the dose–response relation for oral risperidone in relapsed schizophrenia, a medical literature search for fixed-dose studies of oral risperidone in these patients was performed and 18 reports evaluating the efficacy of oral risperidone were retrieved (183r). The data strongly suggested that doses of around 4 mg/day are optimal; a dose of 2 mg/day consistently produced a lower degree of efficacy, doses of 6 mg/day or greater produced no additional benefit, and doses of 10 mg/day and above tended to be less efficacious. The frequency of extrapyr­ amidal adverse effects increased with dose. Drug–drug interactions Melperone A probable effect of melperone on the metabo­ lism of risperidone via CYP2D6 has been described in three cases (184A). For example, a 19-year-old man with schizophrenia took risperidone 6 mg/day and melperone 50 mg/ day to improve sleep; the initial risperidone plasma concentration of 2.1 mg/l fell 8 days after melperone was introduced to 1 mg/l, and 9-hydroxyrisperidone rose from 21 to 40 mg/l.

A. Carvajal, L.H.M. Arias, and N. Jimeno

Selective serotonin re-uptake inhibitors Adverse events due to interactions between risperidone and selective serotonin re-uptake inhibitors have been reported (SEDA-28, 78). Hypothermia occurred in a patient taking risperidone and paroxetine (185A).
A

79-year-old woman with hypertension, depression, dementia, and hallucinations taking risperidone 0.5 mg/day, amlodipine 5 mg/day, galantamine 12 mg/day, docusate sodium 100 mg/day, celecoxib 200 mg/day, calcium citrate 1200 mg/day, and paroxetine 4 weeks before consultation, developed lethargy and a deteriorated mental state. The only major findings were dehydration and a rectal body temperature of 33.41C; she recovered when paroxetine and galantamine were withdrawn and after warming and rehydration.

Sarcosine Sarcosine, called also N-methylglycine, is an inhibitor of the glycine transporter-1; it has been proposed as adjuvant therapy for patients with schizophrenia taking clozapine. In a 6-week double-blind, placebo-controlled trial in 20 patients, sarcosine had no effects on the symptom domains of patients with schizophrenia who were taking clozapine (186c). There were no changes in adverse effects profiles. Treatment-related adverse events in the placebo group included constipation (n ¼ 1) and salivation (n ¼ 1) and in the sarcosine group insomnia (n ¼ 2).

Ziprasidone

(SED-15, 3721; SEDA-28, 79; SEDA-29, 81; SEDA-30, 72)

Observational studies Ziprasidone has been used as an augmentation agent in two clozapine-resistant women with schizophrenia (aged 29 and 51 years; clozapine 600 and 750 mg/day) (187A). Both complained of adverse effects (sedation, hypersalivation, weight gain) and ziprasidone 40 mg/day was added and increased to 80 mg/day within 1 week. After 24 weeks, the daily clozapine dose was

Antipsychotic drugs

Chapter 6

reduced to 400 and 625 mg, and the adverse effects abated in both cases, which in turn led to better compliance. By the end of week 24, the BPRS score improved by more than 20% (from 40 to 28 points in the 29-year-old woman and 36 to 22 points in the 51-year-old woman). Ziprasidone has been used to treat beha­ vioral and psychological symptoms of demen­ tia in a 7-week open trial in 25 patients (188c). The main reason for withdrawal (n ¼ 10) was adverse events. The most frequent adverse events were somnolence, gastrointestinal symptoms, and parkinsonism. It should be remembered that behavioral and psychologi­ cal symptoms of dementia is an unproven and unlicensed indication for antipsychotic drugs (SEDA-30, 59). Psychosis during the course of Parkin­ son’s disease is an unlicensed indication for all antipsychotic drugs except clozapine. Four patients with Parkinson’s disease and drug-induced psychosis received ziprasi­ done after clozapine and quetiapine had failed (189A). Three had significant improvement without deteriorating motor function. In one case, ziprasidone consider­ ably improved off-periods. Two patients developed pathological laughing as a possi­ ble adverse effect. A 63-year-old Taiwanese patient with Parkinson’s disease had an improvement in his psychotic symptoms with no adverse effects after taking ziprasidone 40 mg/day increased to 120 mg/day; treatment with high dose of quetiapine had previously failed (190A). Cardiovascular Particular attention has been devoted to QT prolongation and sudden death in relation to ziprasidone (SEDA-27; SEDA-28, 79). The SPC warns that ziprasidone should be avoided in combination with other drugs that prolong the QTc interval. Clinicians should also be alert to identify other drugs that have been consistently observed to prolong the QTc interval. Such drugs should not be pre­ scribed with ziprasidone. Ziprasidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac dysrhythmias.

93 A complex case in which torsade de pointes developed in an individual taking ziprasidone has been published (191A).
A 28-year-old Hispanic woman with systemic

lupus erythematosus and hypothyroidism and a complicated psychiatric history of mood disorder, not otherwise specified, with psycho­ tic features, post-traumatic stress disorder, and borderline personality disorder, developed severe lithium toxicity. The QT interval was prolonged to 600 ms at a heart rate of 68/ minute. All medications, including ziprasi­ done, were withheld on admission, except the patient’s regular thyroid replacement and steroid therapy. She was readmitted about 2 weeks later, with complaints of chest pain and a prolonged QT interval (540 ms at 58/min­ ute). Olanzapine, which had been introduced to replace ziprasidone, had been withdrawn because of ineffectiveness, and ziprasidone had been restarted and titrated to a dose of 80 mg bd; trazodone, levetiracetam, flucona­ zole, and ciprofloxacin had also been started. Potassium concentration was 3.3 mmol/l and supplementation was given. Ciprofloxacin was withdrawn. On day 3 telemetry showed an asymptomatic non-sustained polymorphous ventricular tachycardia preceded by a pro­ longed QT interval. Ziprasidone was with­ drawn. Her magnesium concentration was 0.78 mmol/l and potassium 3.8 mmol/l the morning before the run of torsade de pointes. The QT interval remained between 455 and 480 ms for the remainder of her stay, but the dysrhythmia and hypotension did not return. She remained psychotic throughout and was given aripiprazole 15 mg/day.

The electrocardiographic safety profile of ziprasidone has been evaluated in a nonrandomized, single-arm trial in 20 children with Touretteus syndrome, obsessive-com­ pulsive disorder, or pervasive developmen­ tal disorder (192c). Ziprasidone prolonged the QTc interval from a single baseline measurement by 28 ms, with a maximum increase of 114 ms. However, effects on the QT interval were not determined in a manner that is consistent with current standards and it is believed that the results of that study are questionable and poten­ tially misleading (193r). Nervous system Ziprasidone is said to cause extrapyramidal adverse effects at a rate similar to that of placebo (194R); nevertheless, some cases of extrapyramidal

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adverse effects have been previously described (SEDA-29, 81). Acute dystonia has also been reported (195A).
A 18-year-old man with obsessive-compulsive

disorder who had taken fluoxetine 40 mg/day for 2 months, received ziprasidone 40 mg bd. Four hours after the evening dose, he devel­ oped torticollis and a dystonic posture, which resolved with intramuscular biperiden 5 mg.

Five cases of sudden akathisia after ziprasidone dosage reduction have been reported (196A).
Intramuscular ziprasidone, which was intro­

duced for use in the emergency management of acute psychosis, has been associated with parkinsonism in a 63-year-old man with a history of chronic paranoid schizophrenia (197A). He had uncontrollable violent behavior and assaulted staff members twice, necessitat­ ing the use of restraints and intramuscular haloperidol 10 mg/day for 3 consecutive days. A day after the last haloperidol injection, he was given intramuscular ziprasidone 20 mg bd. On day 3 he developed drooling, a flat expression, bradykinesia, a shuffling gait, and a pill-rolling tremor. The dosage was restricted to 40 mg/day, and the symptoms of parkinsonism resolved. However, at that dose, his aggression continued and ziprasidone was therefore withdrawn and intramuscular olanzapine was started, which reduced the agitation and allowed resumption of oral administration.
Neuroleptic malignant syndrome occurred in a

47-year-old white man with a history of schizoaffective disorder who had an exacerba­ tion of severe mania (198A). He had been taking lithium 450 mg bd and sodium valproate

A. Carvajal, L.H.M. Arias, and N. Jimeno

750 mg/day. On day 2, ziprasidone 80 mg bd was added, plus intramuscular ziprasidone 20 mg and lorazepam 2 mg as needed for agitation. On day 6, he developed hyperthermia (39.41C), a raised creatine kinase activity (26 units/l) and white blood cell count (21  109/l), myoglobi­ nuria, hypotension (68/40 mmHg), altered men­ tal state, and tachypnea (28/minute).

Musculoskeletal Rhabdomyolysis related to hyponatremia and/or its correction occurred in a 32-year-old man with schizo­ phrenia who had taken ziprasidone 60 mg bd for 3 weeks before having a generalized tonic-clonic seizure (199A). He had primary polydipsia and secondarily developed hypo­ natremia and rhabdomyolysis was diagnosed. The authors stated that, although the role of antipsychotic drugs in this case was speculative, rhabdomyolysis related to hypo­ natremia and/or its correction should not be underestimated and should be assessed thoroughly. Immunologic Some cases of pedal edema have been associated with immunoglobulin E (IgE)-related allergic reactions, although the exact mechanism is unclear. Severe bilateral pedal edema, which extended to the lower trunk within 2 days, developed in a 51-year-old Chinese woman after she had taken ziprasidone 80 mg/day for 6 weeks (200A). The serum IgE concentration was significantly raised (1124 IU/ml (reference range 62–99). The pedal edema subsided after withdrawal of ziprasidone and the administration of diuretics.

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unsuccessful treatment of olanzapine in the first-episode schizophrenia: an open trial. Prog Neuropsychopharmacol Biol Psychia­ try 2006;30:1067–72. Hellings JA, Zarcone JR, Reese RM, Valdovinos MG, Marquis JG, Fleming KK, Schroeder SR. A crossover study of risperidone in children, adolescents and adults with mental retardation. J Autism Dev Disord 2006;36:401–11. Kim JH, Kim SY, Ahn YM, Kim YS. Subjective response to clozapine and ris­ peridone treatment in outpatients with schizophrenia. Prog Neuropsychopharma­ col Biol Psychiatry 2006;30:301–5. Rapaport MH, Gharabawi GM, Canuso CM, Mahmoud RA, Keller MB, Bossie CA, Turkoz I, Lasser RA, Loescher A, Bouhours P, Dunbar F, Nemeroff CB. Effects of risperidone augmentation in patients with treatment-resistant depres­ sion: results of open-label treatment fol­ lowed by double-blind continuation. Neuropsychopharmacology 2006;31:2505–13. Reyes M, Buitelaar J, Toren P, Augustyns I, Eerdekens M. A randomized, doubleblind, placebo-controlled study of risper­ idone maintenance treatment in children and adolescents with disruptive behavior disorders. Am J Psychiatry 2006;163: 402–10. Honer WG, Thornton AE, Chen EYH, Chan RCK, Wong JOY, Bergmann A, Falkai P, Pomarol-Clotet E, McKenna PJ, Stip E, Williams R, MacEwan GW, Wasan K, Procyshyn Rfor the Clozapine and Risperidone Enhancement (CARE) Study Group. Clozapine alone versus clozapine and risperidone with refractory schizophre­ nia. N Engl J Med 2006;354:472–82. Kontaxakis VP, Ferentinos PP, HavakiKontaxaki BJ, Paplos KG, Pappa DA, Christodoulou GN. Risperidone augmen­ tation of clozapine: a critical review. Eur Arch Psychiatry Clin Neurosci 2006;256:350–5. Nguyen LN, Guthrie SK. Risperidone treatment of bipolar mania. Ann Pharmac­ other 2006;40:674–82. Lee BH, Kim YK. The relationship between prolactin response and clinical

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efficacy of risperidone in acute psychotic inpatients. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:658–62. Theleritis CG, Papadimitriou GN, Papa­ georgiou CC, Dikeos DG, Masdrakis V, Kostoulas C, Psarros C, Soldatos CR. Excessive weight gain after remission of depression in a schizophrenic patient trea­ ted with risperidone: case report. BMC Psychiatry 2006;6:37–40.
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e S. Leucope­ Lopez FX, Munoz nia asociada al uso de risperidona: pre­
de un caso y revision
de la sentacion literatura. [Leukopenia associated with risperidone a case report and lilterature review.] Rev Clin Esp 2006;206:161–6. Keown P, McAllister-Williams H, Young A. A case of pancytopenia. J Psychophar­ macol 2006;20(5):690–2. Kantrowitz JT, Srihari VH, Tek C. Three cases of risperidone-induced enuresis. Schi­ zophr Res 2006;84:174–5. Desarkar P, Nizamie SH. Risperidone­ induced erythema multiforme minor. Br J Clin Pharmacol 2006;62:504–5. Lane HY, Liu YC, Huang CL, Chang YC, Wu PL, Lu CT, Chang WH. Risperidone­ related weight gain: genetic and nongenetic predictors. J Clin Psychopharmacol 2006; 26:128–34. € Medori R, Mannaert E, Grunder G. Plasma antipsychotic concentration and receptor occupancy, with special focus on risperidone long-acting injectable. Eur Neuropsychopharmacol 2006;16: 233–40. Remington G, Mamo D, Labelle A, Reiss J, Shammi C, Mannaert E, Mann S, Kapur S. A PET study evaluating dopamine D2 receptor occupancy for long-acting inject­ able risperidone. Am J Psychiatry 2006; 163:396–401. Lee MS, Ko YH, Lee SH, Seo YJ, Kim SH, Joe SH, Han CS, Lee JH, Jung IK. Long-term treatment with long-acting ris­ peridone in Korean patients with schizo­ phrenia. Hum Psychopharmacol 2006;21:399–407. Dowling NM, Megna JL, Burgdorf A, Yashaswi V. Lingual lesions with orally disintegrating risperidone. Am J Psychiatry 2006;163:1841–2.

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183. Ezewuzie N, Taylor D. Establishing a dose–response relationship for oral risper­ idone in relapsed schizophrenia. J Psycho­ pharmacol 2006;20:86–90. € 184. Kohnke MD, Lutz U, Wiatr G, Schw€arzler F, Weller B, Schott K, Buchkremer G. Cytochrome P450 2D6 dependent metabo­ lization of risperidone is inhibited by melperone. Eur J Clin Pharmacol 2006;62:333–4. 185. Al Chekakie MO, Ketz JM, Whinney CM. Hypothermia in a patient receiving risper­ idone and paroxetine. J Clin Psychophar­ macol 2006;26:332–3. 186. Lane HY, Huang CL, Wu PL, Liu YC, Chang YC, Lin PY, Chen PW, Tsai G. Glycine transporter I inhibitor, N-methyl­ glycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psy­ chiatry 2006;60:645–9. 187. Ziegenbein M, Calliess IT. Clozapine and ziprasidone: a useful combination in patients with treatment-resistant schizo­ phrenia. J Neuropsychiatry Clin Neurosci 2006;18:246–7. 188. Rocha FL, Hara C, Ramos MG, Kascher GG, Santos MA, de Oliveira Lanc- a G, Magalh~aes Scoralick F. An exploratory open-label trial of ziprasidone for the treatment of behavioural and psychological symptoms of dementia. Dement Geriatr Cogn Disord 2006;22:445–8. € 189. Schindehutte J, Trenkwalder C. Treatment of drug-induced psychosis in Parkinson’s disease with ziprasidone can induce severe dose-dependent off-periods and pathologi­ cal laughing. Clin Neurol Neurosurg 2007;109:188–91. 190. Shiah IS, Lin CL, Mao WC, Luu SU. Ziprasidone in the treatment of Parkin­ son’s disease psychosis. Eur Psychiatry 2006;21:578–9. 191. Heinrich TW, Biblo LA, Schneider J. Torsades de pointes associated with zipra­ sidone. Psychosomatics 2006;47:264–8. 192. Blair J, Scahill L, State M, Martin A. Electrocardiographic changes in children

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A. Carvajal, L.H.M. Arias, and N. Jimeno and adolescents treated with ziprasidone: a prospective study. J Am Acad Child Adolesc Psychiatry 2005;44:73–9. Loebel A, Miceli J, Chappell P, Siu C. Electrocardiographic changes with ziprasi­ done. J Am Acad Child Adolesc Psychiatry 2006;45:636–7. Weiden PJ, Iqbal N, Mendelowitz AJ, Tandon R, Zimbroff DL, Ross R. Best clinical practice with ziprasidone: update after one year of experience. J Psychiatr Pract 2002;8:81–97. Yumru M, Savas HA, Selek S, Savas E. Acute dystonia after initial doses of zipra­ sidone: a case report. Prog Neuropsycho­ pharmacol Biol Psychiatry 2006;30:745–7. Oral ET, Altinbas K, Demirkiran S. Sudden akathisia after a ziprasidone dose reduction. Am J Psychiatry 2006;163:546. Bilal L, Tsai C, Gasper JJ, Ndlela JC. Parkinsonism with intramuscular ziprasi­ done. Am J Psychiatry 2005;162:2392–3. Borovicka MC, Bond LC, Gaughan KM. Ziprasidone- and lithium-induced neuro­ leptic malignant syndrome. Ann Pharmac­ other 2006;40:139–42. Akkaya C, Sarandol A, Sivrioglu EY, Kotan Z, Kirli S. A patient using ziprasi­ done with polydipsia, seizure, hyponatremia and rhabdomyolysis. Prog Neuropsycho­ pharmacol Biol Psychiatry 2006;30:1535–8. Ku HL, Su TP, Chou YH. Ziprasidone­ associated pedal edema in the treatment of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:963–4. Carson WH, Ali M, Saha AR et al. A double-blind placebo-controlled trial of aripiprazole and haloperidol in patients with schizophrenia or schizoaffective disorder. 39th Anual Meeting of the American College of Neuropsychopharmacology. San Juan, Puerto Rico 10–14 Dec 2000. Adson D, Basi B, Bona J, et al. Abilify (aripiprazole) tablets. Medical Review Part I. Rockville, MD: US Food and Drug Adminisration, 2002. http://www.fda.gov/ cder/foi/nda/2002/21-436-Abilify.htm.

Dieter Schmidt and Stefan Beyenburg

7

Antiepileptic drugs

GENERAL Although many believe that some modern antiepileptic drugs are better tolerated than older ones, the authors of the ILAE Treatment Guidelines have suggested that statistically this has been very hard to show, except in a few studies (1S). Many of these studies were designed to support marketing strategies, and some of the methods used in these trials can skew the results in favor of the sponsor’s product (2R). For example, choice of inclusion and exclusion criteria, choice of comparator drug and formulation (modified-release or not), dosing intervals, titration rates, and end-points can influence outcome (1S). Endocrine The effect of vitamin B supple­ ments on thyroid function has been studied in 32 patients taking antiepileptic drugs who had hyperhomocysteinemia and low folate, B6, and B2 concentrations, of whom 22 were taking monotherapy (carbamazepine, n ¼ 14; phenytoin, n ¼ 5; phenobarbital, n ¼ 1; primidone, n ¼ 1; valproate, n ¼ 1) (3c). They were all given pyridoxine, ribo­ flavin, and folic acid for 30 days. At baseline, they had low serum concentrations of free thyroxine and slightly raised TSH. On day 30 homocysteine had fallen, but thyroid function was unchanged. The authors con­ cluded that patients with hyperhomocystei­ nemia taking antiepileptic drugs have evidence of hypothyroidism, and that sup­ plementation with B vitamins did not alter thyroid function. Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03107-9 r 2009 Elsevier B.V. All rights reserved.

Metabolism In 75 patients with epilepsy taking carbamazepine (n ¼ 19), phenytoin (n ¼ 16), valproate (n ¼ 22), or no antiepi­ leptic drug (n ¼ 18) and 11 controls, the patients taking antiepileptic drugs had higher blood homocysteine concentrations (4c). There were no differences according to the antiepileptic drug used. Patients taking phenytoin had significantly lower folic acid concentrations and those taking carbamaze­ pine had marginally lower pyridoxal-5u­ phosphate concentrations compared with those using other antiepileptic drugs. There was a negative correlation between homo­ cysteine and folic acid concentrations in those taking antiepileptic drugs. The dura­ tion of drug use correlated with the reduction in folic acid concentrations, but not with changes in homocysteine, vitamin B12, or pyridoxal-5u-phosphate concentrations. There was no relation between seizure frequency and homocysteine concentrations. Musculoskeletal A major concern with the use of antiepileptic drugs is the risk of associated fractures. In a case–control study using data from the General Practitioners Research Database (GPRD) patients with a first fracture (n ¼ 1018) were matched with up to four controls (n ¼ 1842) by practice, sex, year of birth, timing of first epilepsy diagnosis, index date, and duration of GPRD history (5C). Cumulative exposure to antiepileptic drugs was assessed by summing the duration of all antiepileptic drug prescriptions. Medical conditions and drugs known to be associated with bone metabolism or falls were evaluated as potential confounders. The risk of fractures increased with cumulative dura­ tion of exposure, being greatest at over 12 years of use (adjusted OR ¼ 4.15; 95% CI ¼ 2.71, 6.34). Risk estimates were higher in women than in men. There was no

105

106 difference between users of antiepileptic drugs that do or do not induce CYP isoenzymes. The authors concluded that long-term use of antiepileptic drugs was associated with an increased risk of frac­ tures, especially in women. Osteopenia has been studied in 30 insti­ tutionalized children taking chronic antiepileptic drug monotherapy; 15 were taking valproic acid, 11 carbamazepine, and 4 phenobarbital (6C). Age- and sex-specific Z-scores of bone mineral density were measured at anterior–posterior L2–L4 by dual-energy X-ray absorptiometry. Druginduced osteopenia was defined in only two patients (one taking carbamazepine and the other taking phenobarbital), with Z-scores of bone mineral density worse than –1.5. Serum concentrations of active vitamin D and biochemical markers did not correlate significantly with the Z-scores of bone mineral density. The frequency of antiepi­ leptic drug-induced osteopenia after 2 years of monotherapy was 6.7%. However, osteo­ penia was not attributed to a defect in serum active vitamin D production owing to hyperparathyroidism. The effects of carbamazepine and sodium valproate on vitamin D status have been evaluated prospectively in 51 ambulatory children with epilepsy who were followed during the first year of the study and in 25 and 6 children during the second and third years, respectively (7C). The control group con­ sisted of 80 healthy children. There were no significant differences between the two groups before treatment. There was a fall in serum 25-hydroxycolecalciferol and a rise in serum parathyroid hormone in all seasons between patients before treatment and at 3 years. Hypovitaminosis D developed during the study in 25 patients. The authors suggested that their study provided evidence that carbamazepine and sodium valproate can cause hypovitaminosis D in children. Pregnancy The use of antiepileptic drugs in pregnancy has been reviewed (8R). In pregnant women with epilepsy who are taking antiepileptic drugs careful clinical management is vital, because seizure fre­ quency can change during pregnancy and both seizure activity and antiepileptic drug

Chapter 7

Dieter Schmidt and Stefan Beyenburg

treatment can have effects on the develop­ ing fetus. Complications of epilepsy and antiepileptic drug treatment include still­ births, prematurity, low birth weight, major and minor malformations, and cognitive delay later in life. Certain antiepileptic drugs probably have more adverse effects than others; data from prospective studies suggest that phenobarbital and valproate are associated with significant increases in major malformations and retrospective stu­ dies show lower verbal IQs and greater need for extra assistance in school in children whose mothers took valproate during pregnancy. Monitoring antiepileptic drug concentrations and dosage adjustment are warranted throughout pregnancy, and vitamin K1 10 mg/day should be given in the last month, particularly when cytochrome P450 enzyme-inducing antiepileptic drugs are used. In the postpartum period, breast feeding is recommended; however, there is differential transfer of individual antiepi­ leptic drugs in breast milk, and the infant should be observed clinically. For all women of reproductive age, preconceptual counseling is important, and includes opti­ mization of the antiepileptic drug regimen and advising the mother to take supple­ mentary folic acid. Pregnant women with epilepsy have been enrolled in a prospective observational study across 25 epilepsy centers in the USA and UK, to determine if there are differential long-term cognitive and behavioral neuro­ developmental effects on their offspring across the four most commonly used antiepileptic drugs. In a report on the incidence of serious adverse outcomes, including major congenital malformations (which could be attributable to antiepileptic drugs) or fetal death, a total of 333 mother/child pairs were analyzed for monotherapy exposures: carba­ mazepine (n ¼ 110), lamotrigine (n ¼ 98), phenytoin (n ¼ 56), and valproate (n ¼ 69) (9C). The numbers of pregnancies that resulted in serious adverse outcomes were as follows: carbamazepine 8.2%, lamotrigine 1.0%, phenytoin 10.7%, and valproate 20.3%. The estimated relative risks (95% confidence limits) of congenital malforma­ tions for valproate relative to each antiepi­ leptic drug at a standardized antiepileptic

Antiepileptic drugs

Chapter 7

drug dose were as follows: valproate versus carbamazepine ¼ 4.59 (1.58, 15), valproate versus lamotrigine ¼ 23 (4.25, 424), and valproate versus phenytoin ¼ 2.87 (0.91, 11). The distribution of serious adverse outcomes differed significantly across antiepileptic drugs and was not explained by factors other than in utero antiepileptic drug exposure. The effect of valproate was doserelated in the therapeutic range (i.e., it was a collateral effect). There was no difference in fetal deaths across the four drugs. These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus of all antiepileptic drugs. For women who fail other antiepilep­ tic drugs and require valproate, the dose should be limited if possible. Drug–drug interactions Antipsychotic drugs Antiepileptic and antipsychotic drugs are often co-prescribed, and interactions may affect both efficacy and toxicity. The clinical data on important interactions between car­ bamazepine, valproic acid (sodium valpro­ ate), vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine, oxcarbazepine, levetir­ acetam, pregabalin, felbamate, zonisamide, phenobarbital, and phenytoin with the anti­ psychotic drugs risperidone, olanzapine, que­ tiapine, clozapine, amisulpride, sulpiride, ziprasidone, aripiprazole, haloperidol, and chlorpromazine have been reviewed (10R). The limited information on interactions between antiepileptic drugs and zuclo­ penthixol, periciazine, fluphenazine, flupen­ tixol, and pimozide was also presented.

Carbamazepine (SED-15, 627; SEDA28, 88; SEDA-29, 88; SEDA-30, 78) Comparative studies In a meta-analysis of responses to lamotrigine or carbamazepine monotherapy using data on individual patients from five randomized trials in 1384 patients, the time to treatment withdrawal (an outcome reflecting both seizure control and tolerability) was significantly better with lamotrigine than carbamazepine (HR ¼ 0.55; 95% CI ¼ 0.35, 0.84) (11M).

107 Nervous system Inappropriate use of antiepileptic drugs can aggravate idiopathic generalized epilepsy syndromes. In a retro­ spective study in 14 adults with idiopathic generalized epilepsy taking at least one potentially aggravating antiepileptic drug, video-EEG showed typical absence status epilepticus in 5, atypical absence status epilepticus in 5, atypical myoclonic status epilepticus in 3, and typical myoclonic status epilepticus in 1 (12c). Epilepsy had been misclassified as cryptogenic partial in eight cases and cryptogenic generalized in four. The correct diagnosis was juvenile absence epilepsy in six patients, juvenile myoclonic epilepsy in four, epilepsy with grand mal on awakening in two, and child­ hood absence epilepsy in two. All patients had been taking carbamazepine and had had seizure aggravation or new seizure types. Seven were taking polytherapy with pheny­ toin, vigabatrin, or gabapentin. Potential precipitating factors included increases in the dose of carbamazepine or carbamaze­ pine+phenytoin; introduction of carbamaze­ pine, vigabatrin, or gabapentin; and a reduced dose of phenobarbital. Withdrawal of the aggravating agents and adjustment of medication resulted in full seizure control. Psychological The cognitive effects of carbamazepine and tiagabine in adults with newly diagnosed epilepsy have been com­ pared using pooled data from two rando­ mized studies with similar populations, dosing, and cognitive assessments. Tiaga­ bine monotherapy 20–30 mg/day had a cognitive profile similar to that of long-term carbamazepine monotherapy 400–800 mg/ day. There was no deterioration in any cognitive functions between tests per­ formed at baseline and after 52 weeks of treatment (for more information see also below Tiagabine (13C). Metabolism The concentrations of serum lipids and lipoprotein (a) were measured in 20 children taking carbamazepine, 25 taking valproic acid, and 5 taking phenobarbital (14c). In those taking carbamazepine total, HDL, and LDL cholesterol were increased while they were eating a normal diet and

108 normalized with a low-fat diet and 3 months after the end of treatment. Hematologic In a case–control study in 173 patients with aplastic anemia and 497 controls, of the 16 patients who had used antiepileptic drugs during the year before the index date, 8 had used carbamazepine, 6 valproate, and 4 phenytoin (15C). There was a ninefold increased risk of aplastic anemia in patients taking antiepileptic drugs, especially carbamazepine and valproate. Polytherapy with antiepileptic drugs was more strongly associated with aplastic anemia than monotherapy. Skin Drug-induced cutaneous adverse effects with systemic symptoms (DRESS syndrome) related to the use of antiepileptic drugs have been investigated retrospectively in 216 patients, including 63 patients taking carbamazepine, who were compared with 32 cases from the literature (16c). The clinical pattern was variable: fever, various eruptions, hepatic abnormalities, and eosinophilia were the most common findings. Rash, eosinophi­ lia, and at least one systemic symptom occurred in 41 of the 63 patients.  A 39-year-old Korean woman took valproate

600 mg/day for epilepsy for 11 months without any skin reaction (17A). After stopping valproate for more than 5 years she was given carbamazepine because of worsening seizures (dose not stated) and after 1 month developed facial edema and a generalized rash. Carba­ mazepine was withdrawn and valproate given. However, her skin lesions worsened, with diffuse edematous patches on the entire body associated with tense bullae on the arms and legs. There was a high fever but no mucosal involvement, a leukocytosis, eosinophilia, and abnormal liver function tests. Valproate was withdrawn but reintroduced after another epileptic seizure. The skin lesions became worse again and she had signs and symptoms of systemic involvement. A circulating auto­ antibody to a 190-kDa antigen was detected in her serum by indirect immunofluorescence and immunoblotting. Her epilepsy was finally controlled with topiramate.

This case suggests cross-sensitivity between aromatic and non-aromatic antiepileptic drugs. Musculoskeletal In a study of biochemical markers of bone metabolism in children

Chapter 7

Dieter Schmidt and Stefan Beyenburg

taking different antiepileptic drugs (carba­ mazepine, valproate, oxcarbazepine) those who took carbamazepine (n ¼ 23) for more than 1 year had no significant differences in the serum concentrations of calcium, phos­ phorus, or albumin or in transaminase activities; however, serum alkaline phospha­ tase activity was higher in the patients compared with controls (18c). Moreover, bone mineral density was significantly reduced. The authors concluded that longterm treatment with carbamazepine reduces bone mineral density. In a study of bone mineral status in children taking antiepileptic drug monotherapy, 30 were taking a normal diet, 15 were taking valproate, 11 carbamazepine, and 4 phenobarbital (6c). Bone mineral density, serum active vitamin D (1,25­ dihydroxycolecalciferol), and biochemical markers of bone formation (calcium, phos­ phorus, alkaline phosphatase, intact para­ thyroid hormone, osteocalcin, calcitonin, and urinary calcium to serum creatinine and urinary phosphorus to serum creatinine ratios) were studied at the beginning of therapy and after 2 years. There was drugrelated osteopenia in only two patients (one taking carbamazepine and the other phe­ nobarbital), with Z-scores worse than –1.5. Serum concentrations of active vitamin D and biochemical markers did not correlate significantly with the Z-scores. Immunologic Drug-induced hypersensitivity syndrome has been attributed to carba­ mazepine.  A 76-year-old Caucasian man took carbamaze­

pine 600 mg/day for partial seizures for 12 days and developed an erythematous trash in a photodistributed pattern, fever, lymphadeno­ pathy, eosinophilia, abnormal liver function tests, and atypical lymphocytosis fulfilling the criteria for drug-induced hypersensitivity syn­ drome (19A). Withdrawal of carbamazepine and topical application of a glucocorticoid resulted in clearance of the rash within 6 weeks, normalization of liver function tests, and improvement in eosinophilia.

Drug withdrawal The effect of withdraw­ ing antiepileptic drugs in patients taking monotherapy on measures of attention, reaction time, and speed of information

Antiepileptic drugs

Chapter 7

processing has been assessed in a rando­ mized, double-blind, placebo-controlled study in 150 subjects who had been seizurefree for over 2 years (20C). Each patient was studied for 12 months or until seizure relapse. Withdrawal of major antiepileptic drugs significantly improved performance on tests that require complex cognitive proces­ sing under time pressure (such as divided attention, rapid language discrimination, and rapid form discrimination). However, simple tasks of attention and reaction time were not affected. Most of the subjects in the study were taking carbamazepine (62%) or valproate (23%). Withdrawal of carbamaze­ pine had a similar outcome as in the total study population, whereas withdrawal of valproate resulted in only a non-significant trend in the same direction. Pregnancy Of 1350 Swedish women who took antiepileptic drugs during pregnancy and had singleton deliveries most (n ¼ 1207, 89%) used single antiepileptic drugs, of which carbamazepine was the most common (n ¼ 683), followed by val­ proic acid (n ¼ 255) (21C). The rate of cesarean sections was significantly increased (OR ¼ 1.64; 95% CI ¼ 1.43, 1.89), but it was not possible to differentiate between elective and emergency sections. The risk of pre-eclampsia (OR ¼ 1.66; 95% CI ¼ 1.32, 2.08) was increased, and highest with carbamazepine (OR ¼ 1.83; 95% CI ¼ 1.37, 2.44). The risk of hemorrhage after vaginal delivery was also increased (OR ¼ 1.29; 95% CI ¼ 1.02, 1.63), slightly more by carbamazepine and valproate (OR ¼ 1.30; 95% CI ¼ 1.00, 1.70) than other antiepileptic drugs. The neonates had an increased risk of respiratory distress (OR ¼ 2.06; 95% CI ¼ 1.62, 2.63). Teratogenicity Outcomes after in utero exposure to antiepileptic drugs have been analyzed during a prospective observational study across 25 epilepsy centers in the USA and UK (9C). A total of 333 mother/child pairs were included: carbamazepine (n ¼ 110), lamotrigine (n ¼ 98), phenytoin (n ¼ 56), and valproate (n ¼ 69). The frequencies of pregnancies that resulted in

109 serious adverse outcomes were: carbama­ zepine 8.2%, lamotrigine 1.0%, phenytoin 11%, and valproate 20%. There were fetal deaths in 4/110 (3.6%) patients taking carbamazepine and congenital malforma­ tions in 5/110 (4.5%). Congenital malfor­ mations attributed to carbamazepine were: absent kidney, duplicate renal pelvis, hypospadias (n ¼ 2), and inguinal hernia. Obstetric and neonatal outcomes in sin­ gleton pregnancies were analyzed in 179 women with active epilepsy compared with 24 778 pregnancies in the general population (22C). In epilepsy the rate of small-for-dates infants was significantly higher, the head circumference significantly smaller, Apgar scores at 1 minute lower, and the need for care in the neonatal ward and neonatal intensive care higher. Of the 127 children of women with epilepsy, 6 had major congeni­ tal malformations. For carbamazepine expo­ sure during pregnancy these were: cleft palate, polydactyly, and cleft lip. Six children exposed to carbamazepine were admitted to the neonatal intensive care unit or to the neonatal ward. Susceptibility factors The possible invol­ vement of virus infection in the development of anticonvulsant hypersensitivity syndrome has been prospectively analyzed in 23 patients, of whom 12 were taking carbama­ zepine (23A). There was no association with viral infections, including Herpes simplex, Varicella zoster, herpesvirus-8, cytomegalo­ virus, Epstein–Barr virus measles, rubella, or parvovirus B19. Increased serum anti­ herpesvirus-6 IgG and herpesvirus-7 titers and the presence of herpesvirus-6 and herpesvirus-7 DNA in the serum, revealed by PCR, suggested reactivation of herpes­ virus-6. In contrast to controls, DNA for herpesvirus-6 was detected in serum in 5 of the 23 patients and herpesvirus-7 in 2. There was evidence linking reactivation of herpes­ virus-6 or herpesvirus-7 in the development of carbamazepine-induced anticonvulsant hypersensitivity syndrome. Herpesvirus infection may contribute to the severity, prolongation, or relapse of anticonvulsant hypersensitivity syndrome and may have fatal consequences in some susceptible individuals.

110  A 34-year-old man taking citalopram and

trazodone took carbamazepine for 2 months and developed DRESS syndrome (24A). After withdrawal of all three drugs and treatment with methylprednisone 100 mg/day he became afebrile within 18 hours and his white blood cell count and liver function tests became normal within a few weeks. After 2 weeks the skin rash completely disappeared.

Drug overdose During a prospective study over 6 months patients with acute carbama­ zepine poisoning (mean blood carbamaze­ pine concentration 29 mg/l) were randomized to either multiple-dose activated charcoal (n ¼ 6) or a single dose of 1 g/kg (n ¼ 6) (25c). The durations of coma and mechanical ventilation were significantly reduced by multiple-dose activated charcoal (20 hours versus 29 hours for coma and 24 hours versus 36 hours for mechanical ventilation), as was length of stay (30 hours versus 40 hours). Multiple-dose activated charcoal significantly shortened the half-life of carbamazepine (13 hours versus 28 hours). Drug–drug interactions Protease inhibitors Carbamazepine toxicity induced by lopinavir+ritonavir and nelfinavir has been described (26Ar).  A 50-year-old man developed excessive drow­

siness secondary to carbamazepine 1200 mg/ day when he took an antiretroviral regimen containing lopinavir+ritonavir. The carbama­ zepine serum concentration rose from 10 to 15 mg/l. The dose of carbamazepine was reduced to 800 mg/day and later increased to 1200 mg/day. The protease inhibitor was chan­ ged to nelfinavir. Within 3 days he again developed excessive drowsiness and became unsteady on his feet. The carbamazepine dosage was reduced to 800 mg/day, and his symptoms resolved.

The authors reviewed four other cases of carbamazepine toxicity secondary to protease inhibitors. Lopinavir+ritonavir and nelfinavir may inhibit carbamazepine metabolism. Quetiapine CYP3A4 is the main enzyme responsible for the metabolic clearance of quetiapine. Carbamazepine reduced quetia­ pine plasma Cmax from 1042 to 205 ng/ml and increased its clearance from 65 to 483 l/ h (27Ar).

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Dieter Schmidt and Stefan Beyenburg

Warfarin Warfarin dosage is affected by CYP2C9 genotype, age, weight, and co­ treatment with drugs that inhibit its metabo­ lism. In patients with the CYP2C9�1/�1 genotype taking stable maintenance war­ farin therapy (n ¼ 82) those taking carba­ mazepine (n ¼ 5) had significantly higher plasma 10-hydroxywarfarin concentrations than patients not taking any interacting drugs (n ¼ 54) (28C). (S)- and (R)-warfarin clearances were higher in the carbamazepine co-treated group, as were warfarin dosage requirements (median: 9.00 mg/day versus 3.86 mg/day). Patients taking warfarin should be frequently monitored, especially when at the start or end of carbamazepine therapy.

Gabapentin

(SED-15, 1465; SEDA-28, 89; SEDA-29, 89; SEDA-30, 80)

Observational studies The efficacy of gabapentin 600–900 mg/day for 31 days has been evaluated in 16 patients with neurogenic overactive bladder; there were no significant adverse effects (29c). A single preoperative dose of gabapentin 800 mg 2 hours before surgery did not augment postoperative analgesia in 60 patients given interscalene brachial plexus blocks for arthroscopic shoulder surgery in a placebo-controlled study, although head­ aches were less frequent in those who were given gabapentin (n ¼ 27) (30c). The inci­ dence of adverse effects was comparable in the two groups. In 99 patients with cocaine dependence randomized to either gabapentin 3200 mg/ day or placebo for 12 weeks, gabapentin was very well tolerated (31c). The most frequently reported adverse effects were dizziness (10%) and tiredness/sedation (8%). There were five serious adverse events, four with gabapentin; three were transient (chest pain, bloody stools, calf pain) and one patient dropped out because of depression with suicidal tendencies; none of theses adverse event was judged to be related to gabapentin.

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Chapter 7

In a randomized study in 41 patients with postamputation pain, gabapentin up to 2400 mg/day during the first 30 postoperative days was ineffective (32C). Adverse events (nausea, stomachache, fatigue, confusion, nightmares, itching, ataxia) were transient and occurred in nine patients who received gabapentin, and in eight who received placebo. Four patients were withdrawn (two in each group). Medication was reduced or temporarily stopped in seven (gabapentin, n ¼ 5; placebo, n ¼ 2) because of adverse effects. The use of gabapentin 900 mg/day in cardiothoracic surgery has been assessed in 60 consecutive out-patients with refrac­ tory pain persisting at 4 weeks or more after thoracic surgery or trauma (33C). Follow-up data (median 21, range 12–28 months) were available for 45 patients. The mean dura­ tion of gabapentin use was 22 (range 1–68) weeks. There were no deaths or major complications. There were minor adverse effects, mostly somnolence and dizziness, in 18 patients, and had to discontinue gaba­ pentin. Satisfaction with gabapentin was expressed by 40 patients. Adverse effects were not a source of dissatisfaction in any patient. Snellen visual acuity, subjective visual function, and eye movement recordings have been retrospectively analyzed in 23 patients with nystagmus (13 secondary to multiple sclerosis, 3 associated with other neurologi­ cal diseases, 2 idiopathic infantile, and 5 with associated ocular diseases) treated with gabapentin (600–2400 mg/day); 3 had addi­ tional memantine 10–20 mg/day (34c). Adverse effects with gabapentin were mild, and mostly consisted of transient fatigue. Three patients discontinued gabapentin because of adverse events such as fatigue, memory loss, tingling, and numbness. The effects of perioperative gabapentin for the control of acute postoperative pain in six studies have been reviewed (35M). Single preoperative doses of gabapentin 1200 mg were associated with lower risks of vomiting and urinary retention. There was no difference between gabapentin and controls for other adverse events. Five studies used a single preoperative dose of

111 gabapentin under 1200 mg (range 300– 900 mg). The risk of sedation was higher than in controls; for other adverse effects there was no difference. Gabapentin given as multiple doses perioperatively was inves­ tigated in five studies and was associated with lower incidences of pruritus and nausea. In one study there was a lower incidence of constipation with gabapentin and no difference for other adverse events. All 16 studies reported nausea as an adverse outcome, and 1 reported nausea and vomiting as a single adverse event. Gabapentin caused less vomiting than con­ trol treatments. The incidence of sedation was higher with gabapentin. Six studies reported the incidence of pruritus: gaba­ pentin was associated with less pruritus. Four trials reported urinary retention, three trials reported constipation, and two reported respiratory depression as adverse events; there were no significant differences between the groups. Placebo-controlled studies The effect of gabapentin on the perception of pruritus has been tested in a double-blind, rando­ mized, placebo-controlled trial in 16 women (36C). The starting dose of gabapentin was 300 mg/day in divided doses and it was increased to a maximum of 2400 mg/day or until the pruritus was relieved. Gabapentin was associated with an increased perception of pruritus. Gabapentin has been used as adjunctive treatment in postoperative pain to reduce the occurrence of postoperative delirium in a double-blind, randomized, placebo-con­ trolled trial in 21 patients (37C). There was postoperative delirium in 5/12 patients who received placebo versus 0/9 patients who received gabapentin. Two patients (one in each group) had postoperative sedation. None had dizziness, nystagmus, or ataxia. In a randomized, double-blind, placebocontrolled study, 49 patients with tonsillect­ omy received gabapentin 1200 mg preo­ peratively, followed by gabapentin 600 mg bd on the day of operation and gabapentin 600 mg tds for the next 5 days (38C). Both groups were given rofecoxib 50 mg/day. Postoperatively intravenous morphine was

112 administered in doses of 2.5 mg on request and from 4 hours to 5 days postoperatively, ketobemidone was offered as escape ther­ apy. As a result of the global withdrawal of rofecoxib, the study had to be terminated prematurely when 22 patients had been randomized to gabapentin and 27 to pla­ cebo. Gabapentin caused more dizziness, gait disturbance, and vomiting during days 0–5 than placebo. The effects of different doses of gaba­ pentin on muscle and cutaneous pain have been studied in 16 healthy volunteers in a double-blind, three-session, placebo-con­ trolled crossover comparison (39C). Mus­ cle pain was induced by infusing 0.5 ml of hypertonic saline into the anterior tibial muscle. Gabapentin pretreatment reduced the sensitivity to electrical induction of skin pain by 14%. Secondary hyperalgesia was also abated. Mechanical pain thresh­ olds were unaffected. Pain induced by intramuscular infusion of hypertonic saline was not affected by gabapentin. Adverse effects (dizziness, tiredness, weakness, and fatigue) were mild and transient, but more frequent with higher doses of gabapentin: placebo—dizziness (n ¼ 1) and tiredness (n ¼ 1); 1200 mg gabapentin single dose— dizziness (n ¼ 5), tiredness (n ¼ 1), and fatigue (n ¼ 1); 2600 mg gabapentin fourdose regimen—dizziness (n ¼ 9), tiredness (n ¼ 7), weakness (n ¼ 2), and fatigue (n ¼ 1). Gabapentin (titrated to 2400 mg/day) and conjugated estrogens (0.625 mg/day) have been compared in the treatment of hot flushes in a randomized, double-blind, placebo-controlled trial for 12 weeks in 60 postmenopausal women (40C). Headache, dizziness, and disorientation were more common with gabapentin; the NNTH was 4. Other reported adverse effects in the gabapentin group were gastrointestinal symptoms (n ¼ 4); pain (n ¼ 1); cold, flu, and allergy (n ¼ 7); sleep disturbances (n ¼ 4); weight gain and/or edema (n ¼ 2); hormonal problems (n ¼ 2); other (n ¼ 2). In a double-blind, crossover, placebocontrolled study six patients with primary orthostatic tremor were studied while tak­ ing gabapentin 600–2700 mg/day, 7 days

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Dieter Schmidt and Stefan Beyenburg

after drug withdrawal, and again after two 2-week periods of treatment with either gabapentin or placebo, using force platform posturography to quantify postural sway and tremor (41C). Other tremor medica­ tions were continued unchanged. Quality of life improved in all patients. There were no adverse drug-related effects and sympto­ matic benefit was maintained at follow-up (mean 19 months). In a prospective study 40 patients under­ going lower extremity surgery procedures were randomly assigned to either placebo or oral gabapentin 1200 mg/day before and for 2 days as an adjunct to epidural analgesia after surgery (42C). Gabapentin reduced pain and analgesic consumption and increased patient satisfaction. The incidence of dizziness was higher with gabapentin (n ¼ 7 versus 1). The effect of gabapentin in perioperative pain management has been studied in 100 patients undergoing abdominal hysterect­ omy, who were randomly assigned to one of four treatment groups: placebo before and for 2 days after surgery; rofecoxib 50 mg/ day before and after surgery; gabapentin 1200 mg/day before and after surgery; rofecoxib 50 mg/day+gabapentin 1200 mg/ day before and after surgery (43C). The following adverse effects were attributed to gabapentin (n ¼ 25): dizziness (n ¼ 4), nausea (n ¼ 12), vomiting (n ¼ 9), somnolence (n ¼ 5), diarrhea (n ¼ 2), pruritus (n ¼ 1), urinary retention (n ¼ 1), and dry mouth (n ¼ 4). Adverse events observed in the combination group were: dizziness (n ¼ 6), nausea (n ¼ 10), vomiting (n ¼ 7), somnolence (n ¼ 5), diarrhea (n ¼ 2), pruritus (n ¼ 1), urinary retention (n ¼ 1), and dry mouth (n ¼ 3). Systematic reviews In a meta-analysis of 12 randomized controlled trials in 896 patients of the analgesic effects of gaba­ pentin in perioperative and postoperative pain management, preoperative doses were 300–1200 mg and postoperative doses 1200– 1800 mg/day for 2–10 days (44M). Gabapen­ tin was associated with sedation and anxio­ lysis (OR ¼ 3.28; CI ¼ 1.21, 8.87) but no difference in lightheadedness, dizziness, nausea, or vomiting.

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Chapter 7

Nervous system Myoclonus has attributed to gabapentin (45A).

113 been

 A 66-year-old man with impaired renal func­

tion had vasculitis with macroglobulinemia, causing a painful sensorimotor neuropathy. He was given gabapentin 900 mg/day and a fentanyl patch every 3 days for 2 years and developed generalized myoclonus. He was unable to stand and walk, his speech was dysarthric, and he had mental slowing. There were signs and symptoms of a polyneuropathy. The gabapentin serum concentration 4 hours after the last gabapentin intake was very high. After withdrawal of gabapentin for 24 hours the myoclonus, dysarthria, and mental slowing disappeared. The serum gabapentin concen­ tration returned to normal.

Fluid balance Edema has been attributed to gabapentin (46A).  A 76-year-old man developed bilateral pre­

tibial edema for 3 weeks after taking gaba­ pentin 300 mg/day for neuropathic pain for 6 weeks. Gabapentin was withdrawn and after 3 days the edema disappeared.

Drug overdose Cardiac conduction abnormalities occurred after an overdose of nefazodone and gabapentin (47A).  A 44-year-old woman took an overdose of

nefazodone and gabapentin. An electrocardio­ gram showed a QRS duration of 148 milli­ seconds, and a QTc interval of 490 milliseconds about 1 hour later. After appropriate emer­ gency treatment an electrocardiogram 40 min­ utes later was normal, apart from sinus tachycardia (105 per minute). She was lethargic and drowsy, with a low blood pressure, but never lost consciousness. She recovered completely.

Lamotrigine

(SED-15, 1990; SEDA-29, 90; SEDA-30, 80)

Comparative studies During a 12-week, randomized, double-blind pilot trial lamotrigine was compared with citalopram in 20 patients with bipolar affective disorder, of whom 12 completed the study (48C). One patient taking lamotrigine complained of dizziness and did not return for follow-up assessment. One patient

discontinued because of hypomania and one because of worsening of symptoms. The adverse effects profiles of several antiepileptic drugs, including lamotrigine 300 mg/day, and several antipsychotic agents in the treatment of bipolar disorder have been reviewed, drawing data from randomized trials, open studies, and reviews (49C). The adverse effects of lamotrigine were: dizziness (31%), diplopia (24%), nausea (18%), vomiting (11%), blurred vision (11), ataxia (10%), and benign rash (8%). In patients with bipolar disorder adverse effects were less common, with the exception of headache. In an open study of the use of lamotri­ gine (mean dose 132 mg/day for 8 weeks) as adjunctive or monotherapy in 20 adoles­ cents with bipolar disorder during a depres­ sive episode (n ¼ 20) adverse effects reported at any time included headache (84%), fatigue (58%), nausea (53%), sweating (47%), and sleep disturbances (11%) (50C). There were no significant laboratory abnormalities after 8 weeks, and no sig­ nificant weight change, rash, or other significant adverse effects. Nervous system Exacerbation of Tourette’s syndrome has been attributed to lamotrigine (51A).  A 55-year-old woman suffering from bipolar I

disorder took lamotrigine 200 mg/day (plasma concentration 4.6 šg/ml) for mood stabiliza­ tion. After 3 months she developed motor tics of increasing extent and complexity, having had a history of motor tics during childhood, and had vocal tics for the first time in her life. Lamotrigine was withdrawn and the tics completely disappeared within 2 weeks.

Psychological The cognitive effects of lamotrigine compared with topiramate as add-on therapy in adults with epilepsy have been studied in a multicenter, double-blind, randomized trial (52C). Lamotrigine or topiramate was introduced in addition to carbamazepine or phenytoin and titrated over 8 weeks to target doses. During the maintenance phase, the average daily dose of lamotrigine was 494 mg and the average daily dose of topiramate was 299 mg. The

Chapter 7

114 primary end-point was a change from screening to the end of the maintenance phase in a combined analysis of standar­ dized measures of cognition. For the primary end-point, cognitive performance at the end of the maintenance phase was better with lamotrigine than with topira­ mate. The cognitive complaints reported as adverse events in this study are shown in Table 1. The frequencies of cognitive adverse events and of premature with­ drawals related to cognitive decline were higher with topiramate than with lamotri­ gine (6% versus 0%). The effect of lamotrigine on cognition in 61 children with well-controlled or mild epilepsy has been studied in a double-blind, placebo-controlled, crossover study (53C). They were randomly assigned to add-on therapy with either lamotrigine followed by placebo or placebo followed by lamotrigine. Each treatment lasted 9 weeks and the crossover period was 5 weeks. Seizure frequency was similar during the two phases. There were no significant differ­ ences in various neuropsychological tests between placebo and lamotrigine. The following adverse events were reported (lamotrigine, n ¼ 59 versus placebo, n ¼ 52): coryza or other viral illness (lamo­ trigine 9; placebo 9), rash (7 versus 2), nausea (5 versus 2), injury or accident (4 versus 0), pharyngitis (4 versus 1), headache (1 versus 2), dizziness (1 versus 2), and abdominal pain (0 versus 2). Some

Dieter Schmidt and Stefan Beyenburg

patients were withdrawn (6 versus 0); five of the withdrawals were due to a rash and one was due to nausea and dizziness. Treat­ ment-related adverse effects were observed in 39% of the patients with lamotrigine and in 37% with placebo; all were mild and transient. Psychiatric Three patients (two men, one woman) with bipolar or schizoaffective disorders developed signs and symptoms of mania shortly after starting lamotrigine 100–200 mg/day; after reduction of lamotri­ gine the manic symptoms disappeared (54A). The authors concluded that lamotri­ gine may act as a rapid antidepressant and that provocation of mania is related to the dosage and the rate of titration. Metabolism The effect of lamotrigine, lithium, and placebo on weight in obese and non-obese patients with bipolar dis­ order has been investigated in a post hoc analysis of two double-blind, placebo-con­ trolled, 18-month studies (55M). Mean changes in weight among obese patients (n ¼ 155) at week 52 were –4.2, +6.1, and –0.6 kg with lamotrigine, lithium, and pla­ cebo, respectively. Among non-obese patients (n ¼ 399) mean changes in weight at week 52 were –0.5, +1.1, and +0.7 kg, respectively, with no significant differences. The authors concluded that obese patients with bipolar I disorder lose weight while

Table 1 Adverse cognitive effects of lamotrigine and topiramate Effect

Lamotrigine (n ¼ 96) (%)

Topiramate (n ¼ 96) (%)

Memory impairment Disturbed attention Depression Altered mood Confusion Speech disorder Amnesia Aphasia Cognitive disorder Mental impairment Affect liability Flat affect

4 3 3 1 1 1 1 0 0 0 0 0

7 6 4 3 3 1 0 3 2 2 2 1

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Chapter 7

taking lamotrigine and gain weight while taking lithium. The effect of lamotrigine on body weight has been assessed retrospectively using data from two double-blind, placebo-controlled and lithium-controlled, 18-month studies in patients with bipolar I disorder (n ¼ 227 for lamotrigine, 190 for placebo, 166 for lithium) (56C). Lamotrigine was associated with stable body weight during 1 year of treatment and was comparable to placebo in mean weight change, incidence of clini­ cally significant weight change, and inci­ dence of weight changes reported as adverse events in patients with bipolar disorder. Skin The predictors of lamotrigine-asso­ ciated rash and the incidence of serious and benign rash have been investigated in a retrospective chart review of 988 out­ patients, of whom 56 (5.7%) had a rash attributed to lamotrigine, and 39 (3.9%) discontinued lamotrigine because of a rash (57c). Of the 478 patients who took lamo­ trigine as monotherapy at any time, 26 (5.4%) had a rash while taking lamotrigine monotherapy, and 19 (4.0%) discontinued therapy because of a rash. A history of rash after another AED was the strongest pre­ dictor of LTG-rash (13.9% versus 4.6%; OR ¼ 3.62), with children younger than 13 years also experiencing significantly more LTG-rash (10.7% versus 4.3%, OR ¼ 2.77). Of children with a rash attributed to another antiepileptic drug, 18% had a lamotrigine­ associated rash, whereas of adults without a rash from another antiepileptic drug, 3% had a lamotrigine-associated rash. For a patient with a rash from another antiepilep­ tic drug, the chance of developing a rash from lamotrigine was about 14%, compared with about 5% for a subject without a history of rash from another antiepileptic drug. No patient had toxic epidermal necrolysis or required hospitalization because of a lamotrigine-associated rash. There was one case of mild probable Stevens–Johnson syndrome. The authors concluded that severe rash due to lamotri­ gine is rare when the currently recom­ mended titration rate is used.

115 A possible weakness in the current classification of Stevens–Johnson syndrome compared with anticonvulsant hypersensi­ tivity syndrome has been revealed by a case report (58A).  A 43-year-old man developed a rash typical of

Stevens–Johnson syndrome with erosions of the lips and buccal mucosa 2 weeks after starting to take lamotrigine 100 mg/day for epilepsy. His temperature was 39.61C, his liver enzymes were raised, and there were atypical lymphocytosis in the peripheral blood. A skin biopsy showed dermatitis with focal epidermal necrosis and chronic perivascular inflamma­ tion. After treatment with glucocorticoids the symptoms disappeared within 1 week.

The authors suggested that this case illustrated a clinical picture compatible with both Stevens–Johnson syndrome and anticonvulsant hypersensitivity syndrome or rash with eosinophilia and systemic signs (DRESS syndrome). A purpuric rash has been attributed to lamotrigine (59A).  A 10-year-old girl with epilepsy due to a brain

tumor developed localized purpura after tak­ ing lamotrigine 200–250 mg/day for 23 months, having previously taken phenytoin, carbama­ zepine, and levetiracetam. Cytotoxic drugs were withdrawn but the rash persisted. With­ drawal of lamotrigine resulted in disappear­ ance of the rash within 1 week.

The authors considered this to have been an atypical lamotrigine-induced reaction. Pregnancy Pregnancy outcomes after in utero exposure to antiepileptic drugs have been analyzed during a prospective obser­ vational study across 25 epilepsy centers in the USA and UK (9C). The frequency of pregnancies that resulted in serious adverse outcomes with lamotrigine was 1.0%. There were congenital malformations in 1/98 of the patients studied (a ventricular septal defect); there were no fetal deaths. Fetotoxicity Maternal intake of lamotri­ gine can cause raised neonatal gammaglutamyl transpeptidase activity (60C).  A boy born after 39 weeks gestation to a 30­

year-old mother with epilepsy who had taken lamotrigine 400 mg/day throughout pregnancy had a raised gamma-glutamyl transpeptidase

116 activity (527 IU/l). Bilirubin was also raised and there was mild jaundice, which was attributed to low-grade hemolysis due to ABO incompatibility. There was no clinical or biochemical evidence of liver or bile duct dysfunction. The infant’s plasma lamotrigine concentration was within the target range. The abnormalities resolved spontaneously.

The authors recommended routine monitoring of liver enzymes and function in exposed infants. Lactation Six breast-feeding women took lamotrigine 175–800 mg/day for epilepsy (n ¼ 5) or bipolar disorder (61c). The mean absolute infant dose more than 12 days after birth was 0.45 mg/kg/day and the infant/maternal plasma lamotrigine ratio was 0.18. Examination of three of the children showed no abnormalities. None of the infants had adverse reactions. Drug–drug interactions Hormonal contraceptives The variations in lamotri­ gine plasma concentrations with monthly cycles of hormonal contraceptive have been analyzed in eight patients with epilepsy (62c). Lamotrigine plasma concentrations were significantly higher (median increase 27%) during the washout week than during administration, with wide interpatient variability. The authors concluded that standardization of blood sampling in rela­ tion to hormonal contraceptive cycles may be mandatory when planning lamotrigine monitoring. The interaction between lamo­ trigine and hormonal contraceptives may be due to increased glucuronidation by the estrogen component. The pharmacokinetic and pharmacody­ namic effects of co-administration of a combined oral contraceptive (ethinylestra­ diol plus levonorgestrel) and lamotrigine have been evaluated (63c). Healthy women took lamotrigine (titrated up to 300 mg/day) and the combined oral contraceptive, either individually or as co-therapy, over 130 days. In 16 subjects serum lamotrigine concentra­ tions fell by 39% on average during co-administration. Ethinylestradiol pharma­ cokinetics were unchanged by lamotrigine. There was a modest reduction in the plasma concentration of levonorgestrel, but there

Chapter 7

Dieter Schmidt and Stefan Beyenburg

was no corresponding hormonal evidence of ovulation. FSH and LH concentrations rose 4.7 and 3.4 times, respectively, in the presence of lamotrigine, but the low serum progesterone concentrations suggested that suppression of ovulation was maintained. Intermenstrual bleeding was reported by 7/ 22 of subjects during co-administration. Thus, dosage adjustment of lamotrigine may be needed when these agents are co­ administered.

Levetiracetam

(SED-15, 2035; SEDA28, 91; SEDA-29, 91; SEDA-30, 82)

Observational studies In a multicenter, prospective, long-term, open study of levetiracetam (500 mg bd increased to 3000 mg/day according to response) in patients with newly diagnosed juvenile myoclonic epilepsy (n ¼ 10) or resistant/ intolerant to previous antiepileptic drugs (n ¼ 38) for 19 (range 0.3–38) months, the mean monthly seizure frequency was significantly reduced (64C). Five patients dropped out, owing to lack of efficacy and pregnancy. Five patients complained of adverse effects, somnolence in three cases, and nervousness in two. The authors suggested that levetiracetam may become a reasonable alternative to valproate in juvenile myoclonic epilepsy. The effects of levetiracetam have been studied in 218 patients with epilepsy, of whom 199 were treated for at least 6 months (65C). There was a significant reduction in the number of seizures after 6 months. There were adverse effects in 18% and withdrawal was required in 6.4%. The adverse effects leading to withdrawal were not identified. The most frequent adverse effects were somnolence (11%), mood changes (5%), and dizziness (4%). There was aggression in 1%. The effects of levetiracetam 2–3 g/day as either “de novo” (monotherapy; n ¼ 8) or “add-on” therapy (n ¼ 27) have been stu­ died for 12 months in 35 patients (mean age 25 years, 21 women) with different types of generalized epilepsies (juvenile myoclonic

Antiepileptic drugs

Chapter 7

epilepsy, severe myoclonic epilepsy of infancy, Lennox–Gastaut syndrome, myo­ clonic–astatic epilepsy, myoclonic absences, and benign myoclonic epilepsy in infancy) (66C). In all, 29 patients achieved at least a 50% reduction in seizure frequency, of whom 15 were free from seizures. Six discontinued levetiracetam because of inef­ ficacy or seizure worsening, none because of adverse effects, which were not described. In an observational, multicenter study of levetiracetam as add-on treatment in 251 patients with partial-onset epilepsy for 16 weeks, the starting dose was 1 g/day and doses were adjusted at 2-weekly intervals in 1-g steps, to a maximum of 3 g/day, based on seizure control and tolerance (67C). There was a 62% reduction in frequency of partial-onset seizures; 19% of the patients became seizure-free and 57% had a reduction in seizure frequency of at least 50%. Most adverse events were mild to moderate and only 10% of events led to withdrawal from the study. The most frequently reported adverse events were weakness in 25%, somnolence in 18%, dizziness in 16%, headache in 14, and depression in 5%. Levetiracetam by nasogastric tube has been evaluated in six patients with status epilepticus of various types, four of whom were refractory to at least two antiepileptic drugs, including benzodiazepines; all had complete resolution (68c). Effective doses of oral levetiracetam were 500–3000 mg/day and seizure control was achieved within 12–96 hours. Adverse events were not specified, but there were said to have been no significant adverse events. Placebo-controlled trials The adverse effects of an intravenous infusion of ascend­ ing doses of levetiracetam (2, 3, and 4 g over 15 minutes; 1.5, 2, and 2.5 g over 5 minutes) have been evaluated in 48 healthy subjects in a randomized, placebo-controlled study (69C). Adverse events that occurred after the administration of 4 g over 15 minutes or 2.5 g over 5 minutes were primarily related to the CNS—dizziness 53%, somnolence 33%, fatigue 11%, and headache 8.3%— and were consistent with the established profile for the oral formulation.

117 The effects of levetiracetam 60 mg/kg/day have been studied in children (4–16 years) with treatment-resistant partial-onset sei­ zures in a 14-week, multicenter, rando­ mized, placebo-controlled trial preceded by an 8-week baseline (70C). There were one or more adverse events in 88% of those who took levetiracetam and 92% of those who took placebo. The most common treatment-related adverse events, which occurred in at least 10% of patients taking levetiracetam, were somnolence, accidental injury, vomiting, anorexia, hostility, nervousness, rhinitis, cough, pharyngitis, and nervousness. A similar number of patients in each group required a dosage reduction or withdrew from the study as a result of an adverse event. Of 25 patients (aged over 6 years) with resistant focal epilepsies undergoing pre­ surgical evaluation randomized to levetir­ acetam 500–1000 mg bd for 7 days or placebo, 1 complained of tiredness on day 1, which resolved on day 3; there were no other adverse effects (71C). The efficacy and safety of levetiracetam 500–1000 mg bd in controlling partial-onset seizures refractory to other antiepileptic drugs has been assessed in 94 Taiwanese adults aged 16–60 years with refractory partial seizures in a 14-week, placebocontrolled, multicenter study followed by a 12-week maintenance phase and then longterm, open levetiracetam therapy or a 4-week phase of medication withdrawal (72C). Levetiracetam reduced weekly fre­ quency of partial seizures by 24% (95% CI ¼ 10, 35) relative to placebo. Adverse events were reported in 34 of 47 patients taking levetiracetam and 32 of 47 taking placebo. The three most common adverse events in those taking levetiracetam and placebo were somnolence (40 and 15%), dizziness (15 and 9%), and headache (11 and 9%). Four patients withdrew because of adverse events: dizziness, a mouth ulcer, and a rash (levetiracetam) and a rash (placebo). In a 10-week, placebo-controlled, dou­ ble-blind trial of levetiracetam (mean dose 862 mg/kg/day) in 20 patients with autism aged 5–17 years there was no significant therapeutic effect, and agitation and

118

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aggression were reported with levetirace­ tam and placebo (73C).

patients complained of slight dizziness, nervousness, and somnolence.

Nervous system In a study of levetirace­ tam up to 50 mg/kg/day for cerebellar tremor in multiple sclerosis, 3 of 14 patients dropped out because of somnolence, fatigue, and agitation in 1 patient each (74c). In a study of levetiracetam up to 2 g/day for cervical dystonia, 4 of 10 patients dropped out because of vomiting, drowsiness, myalgia, and lack of efficacy (75c). In nine patients with Parkinson’s disease complicated by levodopa-induced dyskine­ sia, levetiracetam was not well tolerated. It worsened the Parkinsonian symptoms, caused intolerable somnolence, and worsened dyskinesia in most patients (76c). In 16 patients with chronic psychosis complicated by tardive dyskinesia, levetir­ acetam 60 mg/kg/day was well tolerated, except in 1 patient with excessive drowsiness (77c). In nine patients with Huntingdon’s disease, levetiracetam up to 3 g/day improved the chorea, but two developed Parkinsonism, one on day 41 at a dose of 500 mg/day, the other after 4 months and a dose of 3 g/day (78c). Symptoms included tremor at rest, increased rigidity, bradykinesia, and imbalance, stooped axial posture, and hypophonia. In both cases the symptoms of Parkinsonism resolved after withdrawal of levetiracetam. Concurrent medications were olanzapine, donepezil, paroxetine, trazodone, furose­ mide, oxybutynin, and gabapentin in one patient and alprazolam, risperidone, and celecoxib in the other. The same authors reported one case of chorea treated with levetiracetam without adverse effects (79c). In a pilot study of 15 patients undergoing alcohol withdrawal treatment, 8 were treated with polytherapy including diazepam and levetiracetam, the latter in a maximum dose of 2 g/day. Mild sedation was reported in three patients and one had mild pruritus (80c). In a small open trial in 16 patients with frequent attacks of migraine with aura levetiracetam 1 g/day for 6 months signifi­ cantly reduced the number of attacks, and in 7 patients, the attacks were completely abolished after 3 months (81c). Levetirace­ tam was generally well tolerated; six

Psychological and psychiatric In 156 patients with temporal lobe epilepsy with (n ¼ 78) and without (n ¼ 78) hippocampal sclerosis levetiracetam was associated with cognitive adverse effects in 8, psychosis in 2, aggressive behavior in 7, and anxiety in 6 (82c). There was no difference in the adverse effects profiles between patients with and without hippocampal sclerosis. Thus, levetir­ acetam seems to be associated with cognitive dysfunction and depression in 5–10% of patients with chronic temporal lobe epilepsy. Metabolism Levetiracetam may be safe in porphyria cutanea tarda (83A).  A 50-year-old man with idiopathic generalized

epilepsy and porphyria cutanea tarda gained control of seizures with valproic acid and phenobarbital monotherapy, but his porphyria worsened; clobazam, clonazepam, and lamo­ trigine monotherapy did not affect the por­ phyria, but did not completely control the seizures. Levetiracetam monotherapy 3 g/day gave complete control of seizures and no porphyrinogenic effects.

Teratogenicity As part of a study to determine the risks of major congenital malformations in infants exposed to antiepileptic drugs in utero, all cases exposed to levetiracetam were identified (84A). Three of 117 exposed pregnancies had major congenital malformations (2.7%; 95% CI ¼ 0.9, 7.7); 2 had spina bifida. However, all three had been exposed to other antiepileptic drugs that have been associated with spina bifida. It is therefore unclear if levetiracetam contributed to the outcome.

Oxcarbazepine

(SED-15, 2646; SEDA-28, 94; SEDA-29, 93; SEDA-30, 83)

Observational studies In a randomized, open trial of oxcarbazepine for prophylaxis of oxaliplatin-induced peripheral neuropathy, 32 patients with colorectal cancers, who received 12 courses of FOLFOX-4 (oxaliplatin, 5-fluorouracil,

Antiepileptic drugs

Chapter 7

and leucovorin), were randomized to oxcarbazepine 600 mg bd or chemotherapy without oxcarbazepine (85c). The incidence of peripheral neuropathy was lower in those who received oxcarbazepine (31% versus 75%). Two patients withdrew early because of oxcarbazepine-related adverse effects, with acute headache and dizziness during titration. Oxcarbazepine has been studied in 36 children (median age 7.75 years) with new diagnoses of partial epilepsy in an open prospective study for up to 24 months (86c). There were adverse effects in 25% of cases. The most common were sedation (n ¼ 4), fatigue (n ¼ 3), headache (n ¼ 2), and rash, muscle pain, hyperphagia, and agitation in one each. Hyponatremia was not reported. Oxcarbazepine as monotherapy and adjunctive therapy has been studied for 1 year in 202 adults, aged 17–83 years, with newly diagnosed or refractory partial epilepsy (87c). In the 160 completers the seizure-free rate was 61% with monotherapy and 28% with adjunctive therapy. There were adverse effects in 16%, mainly sedation (6%), sleepiness (4%), dizziness (3%), and ataxia (2%). There was hyponatremia in three patients. Eight discontinued oxcarbazepine because of unspecified adverse events. Oxcarbazepine has been assessed in a retrospective chart review in 20 children aged 4 years and under (mean 23 months) (88c). Seizure types included partial onset (n ¼ 15), symptomatic generalized (n ¼ 3), and other (n ¼ 2). Oxcarbazepine doses were 4–71 mg/kg/day. Overall, 70% had a significant reduction in seizures, and 50% became seizure-free. Except for transient drowsiness in four patients during dose escalation, no adverse effects were noted. In a retrospective chart review of 60 patients (33 boys) aged 0.5–18 (mean 8.2) years with partial-onset epilepsy taking oxcarbazepine monotherapy 6–71 mg/kg/ day for 3 months to 8 years, 51 achieved at least a 50% reduction in seizure fre­ quency and 25 became seizure-free (89c). Ten reported adverse events, including drowsiness (n ¼ 5), aggressive behavior (n ¼ 2), ataxia, dizziness, diplopia, and leg cramps (n ¼ 1 each). There were no cases of hyponatremia or rash.

119 In an open study of adjunctive oxcarba­ zepine up to 2.4 g/day in 20 patients with bipolar disorder, long-term benefit was noted in 7 (90c). The mean number of adverse effects attributed to oxcarbazepine was 3.2, the most common being nausea (n ¼ 9); drowsiness (n ¼ 8); dizziness, fatigue, blurred vision, and ataxia (n ¼ 7 each); headache (n ¼ 5); gastrointestinal discomfort (n ¼ 4); double vision (n ¼ 3); vomiting and tremor (n ¼ 2 each); and rash, poor coordination, memory loss, and hyponatremia (n ¼ 1 each). Of the 14 patients who with­ drew early, 2 withdrew because of adverse effects attributed to oxcarbazepine: tremor (week 4) and hyponatremia (week 8). Comparative studies In a 24-week, rando­ mized, parallel-group, open comparison of oxcarbazepine and acamprosate in prevent­ ing relapse in 30 recently withdrawn alcoholdependent patients, 5 patients taking oxcar­ bazepine reported adverse events: tiredness (n ¼ 2) and rash (n ¼ 3) (91c). There were no undesired effects when patients taking oxcarbazepine consumed alcohol. Placebo-controlled studies In a multicen­ ter randomized, double-blind, placebo-con­ trolled study of oxcarbazepine, 116 children and adolescents aged 7–18 years with bipolar I disorder, manic or mixed, were given a flexible dose of oxcarbazepine (maximum 900–2400, mean 1515 mg/day) for 7 weeks (92C). Oxcarbazepine did not differ signifi­ cantly from placebo. Dizziness (39%), nausea (18%), somnolence (12%), diplopia (11%), fatigue (10%), and rash (6%) were each reported in at least 5% of the patients taking oxcarbazepine, with an incidence at least twice that with placebo. The incidence of psychiatric adverse effects was similar between the groups (20% versus 18%). Most of the adverse events were mild to moderate and occurred during the titration period. Eleven patients taking oxcarbazepine with­ drew because of unspecified adverse events, compared with two in the placebo group. While the overall adverse events profile was similar to that reported in patients with epilepsy, the incidence of psychiatric adverse events with both oxcarbazepine and placebo was higher.

120 Psychological The effects of oxcarbaze­ pine on cognitive function have been studied in children and adolescents (aged 6–17 years) with newly diagnosed partial seizures in an open comparison with stan­ dard antiepileptic drug therapy (carbama­ zepine and valproate) (93c). There were no differences in cognitive tests between oxcarbazepine and carbamazepine+valpro­ ate over 6 months. The most frequently reported adverse events (10% or more) were fatigue and headache for oxcarbaze­ pine, fatigue and rash for carbamazepine, and headache, increased appetite, and alopecia for valproate. There were no serious adverse events. Endocrine Several antiepileptic drugs are thought to affect thyroid function by increas­ ing the metabolism of thyroid hormones and interfering with the hypothalamic-pituitary axis. Oxcarbazepine was developed to attempt to reduce the adverse effects that have traditionally been observed with antiepileptic drugs that induce hepatic enzymes. Increased metabolism of thyroid hormone was thought to be less likely in patients taking oxcarbazepine, which does not induce hepatic enzymes. However, three patients developed central hypothyroidism associated with oxcarbazepine (94A). Two adolescent girls developed lethargy, weight gain, mild constipation, cold intolerance, dry skin, brittle hair, irregular menses, and a feeling of a swollen face. Both had periorbi­ tal edema and delayed relaxation of tendon reflexes. Neither had thyromegaly. Both had normal serum thyrotropin and low free thyroxine concentrations. An MRI scan showed normal pituitary and thyroid glands. Levothyroxine improved their symptoms. The third patient had marked slowing of growth velocity after starting to take oxcar­ bazepine at age 8.6 years for partial epilepsy. He had normal serum thyrotropin and a low free thyroxine concentration. An MRI scan was normal. Oxcarbazepine was withdrawn and he experienced catch-up growth. This report suggests that oxcarbazepine inter­ feres with the hypothalamic-pituitary axis. Electrolyte balance Hyponatremia occur­ red in 1 patient in an open study of adjunctive

Chapter 7

Dieter Schmidt and Stefan Beyenburg

oxcarbazepine in 20 patients with bipolar disorder (95c). Monitoring therapy The relation between trough and peak serum concentrations of the monohydroxy-derivative of oxcarba­ zepine and adverse effects have been investigated in 44 consecutive patients, aged 18–65 years, with refractory epilepsy taking oxcarbazepine 1500–3300 mg/day (96c). Adverse effects were reported by 5 patients before the morning dose and in 26 patients 2 hours after the dose. The most frequent were nystagmus, sedation, blurred vision, and dizziness. Mean monohydrox­ yoxcarbazepine concentrations associated with adverse effects were 30 mg/l compared with 22 mg/l when no adverse effects were detected. Adverse effects were minimized in most patients by reducing the dose of oxcarbazepine, increasing the number of daily administrations, or both. The authors concluded that patients with serum mono­ hydroxyoxcarbazepine concentrations of 30 mg/l or more are at greater risk of adverse effects. In many patients, adverse effects occur intermittently in relation to fluctuations in serum monohydroxyoxcar­ bazepine concentration. Drug overdose Oxcarbazepine overdose has been reported (97A).  A patient with partial complex seizures and

arterial hypertension took about 42 g of oxcarbazepine and an undefined number of tablets containing a combination of benazepril and hydrochlorothiazide along with several glasses of wine. He became stuporose and gradually lost consciousness. His plasma oxcarbazepine and monohydroxyoxcarbaze­ pine concentrations were 12 and 65 mg/l and he underwent hemodialysis for 4 hours. He recovered fully 3 hours later.

Phenytoin and fosphenytoin (SED-15, 2813; SEDA-28, 95; SEDA-29, 95; SEDA-30, 85) Comparative studies Phenytoin and valproate have been compared in 68 patients with convulsive status epilepticus

Antiepileptic drugs

Chapter 7

121

in a randomized controlled trial (98C). The adverse effects in the two groups did not differ. Phenytoin caused hypotension and respiratory depression in two patients each and a cardiac dysrhythmia in one.

of tongue tremor he was given carbamazepine 20 mg/kg/day, after which he developed symp­ toms suggestive of DRESS. Carbamazepine was withdrawn and he was given a glucocorti­ coid; his symptoms improved again.

Skin Toxic epidermal necrolysis simulta­ neously in a mother and her fetus has been described (99A).

Drug overdose Phenytoin overdose has been described (101A).

 A 17-year-old, 22-week primigravida devel­

nystagmus 1 hour after taking about 175 tablets of phenytoin 100 mg. He was given oral activated charcoal 50 g. After 2 hours the serum phenytoin concentration was 165 mmol/ l. He was given another 25 g of activated charcoal. After another 6 hours the serum phenytoin concentration was 384 mmol/l. He was intubated. His serum phenytoin concen­ tration on day 4 was still of 364 mmol/l. On day 8 (phenytoin concentration 304 mmol/l) hemo­ dialysis was performed. The phenytoin con­ centration fell to 212 mmol/l, and he underwent hemoperfusion on day 10. During the next 2 weeks his phenytoin concentration fell and he was extubated. Follow-up over 1 year showed cognitive and functional impairment.

oped a generalized rash, fever, conjunctivitis, and sore throat after taking phenytoin for 3 weeks. She was not taking any other drugs. Phenytoin was immediately withdrawn and she was given intravenous immunoglobulin (1 g/kg/ day for 4 days). A skin biopsy was consistent with toxic epidermal necrolysis. Ultrasound of the fetus showed skin edema; after 4 days the fetus was stillborn, with generalized erythro­ derma, irregular purpuric macules, and a denuded bulla on the trunk. A skin biopsy was consistent with toxic epidermal necrolysis.

The authors proposed three mechanisms of mother to fetus transmission of toxic epidermal necrolysis: (i) the same inherited defect in detoxification of reactive metabolites of phenytoin; (ii) a genetic predisposition to toxic epidermal necrolysis; (iii) the presence of drugspecific cytotoxic T cells in the mother’s blood circulating in the fetal bloodstream. Drug-induced cutaneous adverse effects with systemic symptoms (DRESS syndrome) related to the use of antiepileptic drugs have been investigated retrospec­ tively in 216 patients, including 7 patients taking phenytoin, who were compared with 33 cases from the literature (16c). Four of the seven patients had drug rash, eosino­ philia, and at least one systemic symptom. Phenytoin-induced DRESS with crossreactivity to carbamazepine has been reported (100A).  A 10-year-old Indian boy with epilepsy took

phenytoin 5 mg/kg/day for 2 weeks and devel­ oped fever, facial puffiness, generalized erythema, generalized lymphadenopathy, and mild hepatomegaly. He had anemia, leukocy­ tosis, eosinophilia, raised erythrocyte sedimen­ tation rate, and raised liver enzymes. A skin biopsy was suggestive of exfoliative dermatitis. After treatment with a glucocorticoid his symptoms improved, but the eosinophilia per­ sisted even after 8 weeks. The authors did not say whether phenytoin was withdrawn. Because

 A 32-year-old man developed ataxia and

Pregabalin (SEDA-28, 56; SEDA-30, 86) Observational studies Pregabalin 75– 300 mg bd has been evaluated in 111 Indian patients with peripheral neuropathic pain in a prospective, multicenter, non-comparative, open study for 3 weeks (102C). Despite the short study duration, there was significant pain reduction. The most common adverse events were somnolence (n ¼ 9), dizziness (n ¼ 9), headache (n ¼ 4), and edema (n ¼ 3). In six patients unspecified adverse events required withdrawal of pregabalin. Comparative studies As optimal pain relief after surgery is difficult to achieve with the use of a single drug, many pain experts advocate the use of two or more classes of medications, in order to reduce the adverse effects from any one drug. The analgesic efficacy of perioperative cele­ coxib, pregabalin, or both has been assessed after spinal fusion surgery in 80 patients scheduled to undergo elective decompres­ sive lumbar laminectomy with posterior

122 spinal fusion (103C). They were randomized to oral placebo 1 hour before and 12 hours after surgery, celecoxib 400 mg 1 hour before and 200 mg 12 hours after surgery, pregabalin 150 mg 1 hour before and 12 hours after surgery, or pregabalin+cele­ coxib 400 mg/150 mg 1 hour before and 200 mg/150 mg 12 hours after surgery. Those who used pregabalin+celecoxib con­ sumed the least patient-controlled mor­ phine. Celecoxib alone or pregabalin alone also reduced opioid use compared with placebo, but not as much as when combined. Pregabalin+celecoxib was the most effective treatment for reducing pain, both at rest and with movement over the 24 hours after surgery. Fewer patients had nausea after pregabalin+celecoxib than after placebo. The most common adverse event was nausea in 6/20 with pregabalin compared with 10/20 in the placebo group. Fewer patients on pregabalin reported excessive sedation than those who received placebo (5 versus 7). However, this work has been retracted since publication because it contained fabricated data. Placebo-controlled trials Pregabalin has been evaluated in patients with chronic postherpetic neuralgia, painful diabetic per­ ipheral neuropathy, generalized anxiety disorder, and fibromyalgia syndrome, and as add-on treatment in refractory partial seizures. In three multicenter randomized, double-blind, placebo-controlled studies in patients with refractory partial epilepsy pregabalin had an antiepileptic effect com­ pared with placebo, as adjunctive therapy, 31–51% of patients having a 50% reduction in seizure frequency (104M). Adverse effects were dose-related, the commonest being dizziness (29%), somnolence (21%), ataxia (13%), weakness (11%), and weight gain of more than 7% (10%). There was weight gain in 14% of patients taking the highest dose, 600 mg/day. About 9000 peo­ ple have been exposed to pregabalin during development. The most frequently reported adverse events in six clinical studies in patients with generalized anxiety disorders were dizziness (30% versus 8% with placebo) and somnolence (29% versus 11%)

Chapter 7

Dieter Schmidt and Stefan Beyenburg

(105M). Withdrawal rates were low: dizzi­ ness (3% with pregabalin and 1% with placebo) and somnolence (4 and 1%, respectively). The dropout rate for prega­ balin was 11% at doses of 150–600 mg/day (n ¼ 1149) compared with 20% for alpra­ zolam 1.5 mg/day (n ¼ 93), 20% for venla­ faxine 75 mg/day (n ¼ 113), 35% for lorazepam 6 mg/day (n ¼ 206), and 9% for placebo (n ¼ 484). Adjunctive pregabalin has been evalu­ ated in central neuropathic pain associated with spinal cord injury in 137 patients, who were randomized to either flexible-dose pregabalin 150–600 mg/day (n ¼ 70) or placebo (n ¼ 67) (106C). The average pregabalin dose after the 3-week stabiliza­ tion phase was 460 mg/day. Pregabalin was significantly better than placebo in pain relief, and was associated with improve­ ment in disturbed sleep and anxiety. The most common adverse events were som­ nolence in 29 of 70 patients (41% com­ pared with 9% in the placebo group), dizziness in 17 patients (24% compared with 9%), and edema in 14 patients (20% compared with 6%). The most common adverse events leading to withdrawal of pregabalin were somnolence and edema, in 6% each. There were serious adverse events attributed to pregabalin in two patients. One day after withdrawal of pregabalin one patient developed spasti­ city and poor coordination; a second patient, who turned out to have a bacterial infection, had edema, hypervolemia, and reduced platelet count, which subsided after antibacterial treatment. Immobility of the legs may have contributed to the development of edema. Psychiatric Psychotic symptoms have been attributed to pregabalin (107A).  A 44-year-old woman took pregabalin for

neuropathic pain and rapidly up-titrated the dose to 600 mg bd. She became somnolent, and developed visual hallucinations, agitation, and paranoid ideation. Electroencephalogra­ phy showed rhythmic slowing and epileptiform discharges in both occipital regions, which disappeared after intravenous lorazepam 4 mg. Pregabalin was withdrawn and lorazepam 2 mg/day was continued for 2 weeks. The symptoms resolved and the EEG normalized.

Antiepileptic drugs

Chapter 7

It was not clear from the report if the patient took amitriptyline; if she did, that may have contributed to the ictal psychosis. Breasts A number of antiepileptic drugs have been associated with gynecomastia, including diazepam, phenytoin, and zonisa­ mide (108A). Two patients with refractory epilepsy developed unilateral painful gyne­ comastia and leg pain (one localized and the other diffuse) soon after taking prega­ balin.  A 15-year-old man with refractory partial

epilepsy continued to have seizures despite taking three antiepileptic drugs (carbamaze­ pine, clobazam, and lamotrigine) and was given pregabalin 150 mg bd. About 5 weeks later he noted painful right gynecomastia and continuous localized pain at the left anterior superior iliac spine. Breast ultrasound con­ firmed glandular hyperplasia. Endocrine investigations were normal and there was no iliac bone damage on MRI. The dose of pregabalin was reduced to 75 mg bd, and 3 months later the gynecomastia and bone pain had resolved.  An 18-year-old man with refractory right temporal lobe epilepsy was given carbamaze­ pine 25 mg/kg/day and pregabalin, the dose of which was gradually increased to 150 mg bd. Four weeks later he developed painful rightsided gynecomastia. Breast ultrasound showed glandular hyperplasia. Endocrine investiga­ tions were normal.

Tiagabine

(SED-15, 3419; SEDA-29, 95; SEDA-30, 89) Observational studies Of nine children with spastic cerebral palsy who took tiagabine 0.4–1.1 mg/kg for a mean of 7.2 months, none had a significant improvement in motor function or a reduced number of limited movements (109c). One child reported fewer nocturnal awakenings due to painful spasms. Eight children had adverse effects during treatment: somnolence (n ¼ 6), anorexia (n ¼ 3), abdominal pain (n ¼ 2), difficulty in concentration/attention (n ¼ 2), hostility (n ¼ 1), moodiness (n ¼ 1), irritability (n ¼ 1), and weakness (n ¼ 1).

123 Nervous system Transient athetosis asso­ ciated with tiagabine has been described (110A).  A 32-year-old woman with drug-resistant focal

epilepsy and hypoplasia of the right cerebral hemisphere with gliotic lesions took lamotri­ gine 200 mg/day, phenobarbital 150 mg/day, and topiramate 200 mg/day. After adding tiagabine 30 mg/day she developed involun­ tary left-hand movements, described as slow and irregular, involving the distal muscles in her left arm. The dose of tiagabine was reduced to 20 mg/day and the abnormal move­ ments resolved within 1 week.

The authors speculated that the presence of a static encephalopathy may have influenced the kind of extrapyramidal adverse effect caused by tiagabine, leading to athetosis. However, the exact mechanism by which tiagabine can induce movement disorders is unclear. Psychological The cognitive effects of carbamazepine and tiagabine in adults with newly diagnosed epilepsy have been com­ pared using pooled data from two rando­ mized studies with similar populations, dosing, and cognitive assessments (111C). The patients (n ¼ 105) took either carba­ mazepine 400–800 mg/day or tiagabine 20– 30 mg/day for 6 weeks. A control group of untreated patients with a single epileptic seizure was included for comparison (n ¼ 19). Cognitive function was assessed at baseline and 52 weeks. During the 52­ week follow-up there was only one statisti­ cally significant difference between the treatment groups and the no-drug group— verbal fluency task, but on further analysis this statistical difference was shown to be based on a worse performance in the patients who had taken carbamazepine. There were statistically significant improve­ ments on 6 of 23 variables with tiagabine and carbamazepine, as well as the no-drug group, although the variables differed between the groups. Significant worsening in the test scores was not seen in any of the study groups. The effect of tiagabine on sleep and nextmorning alertness and performance in adults with primary insomnia has been evaluated in a randomized, double-blind, five-period, Latin square, crossover study

124 (112C). The patients took tiagabine 4, 8, 12, and 16 mg/day, and placebo. Tiagabine increased slow wave sleep and reduced wakefulness after sleep onset in a doserelated manner. Tiagabine 4 and 8 mg/day did not compromise next-morning alertness and psychomotor performance; adverse events were similar to placebo and there were no withdrawals because of adverse effects. In patients taking tiagabine 12 and 16 mg, the most common adverse events (in at least 5% of patients) were dizziness and nausea. In subjects who took higher doses of tiagabine the following adverse effects were observed in 11 patients: dizziness (n ¼ 3, 16 mg), abnormal thinking (n ¼ 2, 16 mg), and confusion (n ¼ 2, 16 mg). Seven patients discontinued tiagabine owing to adverse events, of which one was serious— altered mental status 3 hours after a dose of tiagabine 16 mg; mental status returned to normal overnight.

Topiramate

(SED-15, 3447; SEDA-28, 96; SEDA-29, 96; SEDA-30, 89)

Observational studies Topiramate has been retrospectively evaluated as adjunctive therapy in 36 children with Dravet syndrome, who had not responded to stiripentol, but 25 of whom continued to take stiripentol when topiramate was introduced. Mean follow-up was 13 (4–25) months and the mean optimal dose of topiramate was 3.2 (0.6–9.2) mg/kg/day. Adverse events were reported in 18 patients. The most frequent were gastrointestinal disturbances (n ¼ 12) and behavioral disturbances (n ¼ 5). Others included fatigue (n ¼ 4), insomnia (n ¼ 4), impairment of language (n ¼ 2), and renal calculi (n ¼ 1). Topiramate had to be withdrawn in six patients, because of poor tolerability and/or lack of efficacy (113C). Comparative studies Topiramate and valproate have been compared in the prevention of migraine in a 24-week, randomized, double-blind, crossover, clin­ ical trial in 64 patients. One group received

Chapter 7

Dieter Schmidt and Stefan Beyenburg

topiramate (25 mg/day increasing over 1 week to 50 mg/day) for 2 months. A second group received valproate (200 mg/day increasing over 1 week to 400 mg/day) for 2 months. Adverse events reported in those who took topiramate were: weight loss (18%), paresthesia (9.4%), and paresthesia and weight loss (25%) (114C). Topiramate as first-choice drug has been evaluated in a prospective open study in 54 children with infantile spasms. The average dosage was 5.2 (range 1.6–26) mg/kg/day. There were adverse events in 14 patients. They included anorexia, absence of sweating, and sleeplessness (115C). Topiramate (mean dose 250 mg/day), valproate, and their combination have been compared in a retrospective, case–control, mirror-image study in a maximum-security psychiatric hospital in 45 patients with schizophrenia, schizoaffective disorder, and bipolar disorder, with marked aggression and agitation (116C). Five out of 16 stopped taking topiramate within 1 week owing to increased confusion, agitation, and psychophysical discomfort (n ¼ 3) or worsening of psychotic symptoms, including delusions (n ¼ 2). Placebo-controlled studies Topiramate (target dose, 400 mg/day) has been eval­ uated in a multicenter, double-blind, placebo-controlled, parallel-design trial in 221 patients with moderate to severe essential tremor in the upper limbs for 24 weeks (117C). The most common treatment-limiting adverse events in those taking topiramate were paresthesia (5%), nausea (3%), concentration/attention diffi­ culty (3%), and somnolence (3%). Adverse events were treatment limiting in 32% of those taking topiramate and 9.5% of those taking placebo. Adverse effects reported by two or more of those taking topiramate and requiring withdra­ wal were paresthesia (n ¼ 6), concentration/attention difficulty, nausea, and somnolence (n ¼ 3 each); and fatigue, malaise, dyspepsia, reduced appetite, confusion, psychomotor slowing, and taste disturbance (n ¼ 2 each). Body mass index was reduced by 1.3 kg/m2 from baseline with topiramate and 0.2 kg/m2 with

Antiepileptic drugs

Chapter 7

placebo; body weight was reduced by 3.6 kg with topiramate and 0.6 kg with placebo. Topiramate 100 mg/day has been evalu­ ated in a randomized, double-blind, placebocontrolled study in 50 patients with chronic migraine and medication overuse (118C). The 30 patients who received topiramate were further randomized double-blind to a triptan or placebo. There were 15 dropouts (9 with topiramate and 6 with placebo). The following adverse events occurred in those taking topiramate: paresthesia (n ¼ 18 events, four dropouts), fatigue (n ¼ 8, one dropout), anorexia (n ¼ 9), weight loss (n ¼ 7), altered taste (n ¼ 10, two dropouts), memory impairment (n ¼ 5), difficulty concentration (n ¼ 4), somnolence (n ¼ 2), speech difficulties (n ¼ 6, two dropouts), and insomnia (n ¼ 1). Topiramate titrated from 25 to 200 mg/day has been evaluated in 56 women with borderline personality disorder in a rando­ mized placebo-controlled study for 10 weeks (119C). There were no psychotic symptoms or other serious adverse effects. A few patients had the following adverse effects: memory problems (topiramate 6/28, placebo 3/28), trouble in concentrating (6/28, 3/28), fatigue (4/28, 2/28), headache (2/28, 2/28), menstrual pain (5/28, 3/28), dizziness (3/28, 2/ 28), and paresthesia (3/28, 1/28). Topiramate caused more weight loss than placebo. Topiramate has been assessed in a 10­ week, randomized, double-blind, placebocontrolled study in 96 patients with chronic low back pain. Most tolerated topiramate relatively well, but two dropped out because of adverse effects (severe somno­ lence, vision and memory problems, and psychomotor slowing). These adverse effects occurred when the 200 mg dose was increased to 250 mg. There were no psy­ chotic symptoms or other serious adverse effects. Other patients reported severe somnolence (2/48), psychomotor slowing (2), memory problems (2), dizziness (5), headache (4), and paresthesia and/or tremor (3). There was significantly more weight loss in those who took topiramate (120C). The effect of topiramate on acute phy­ siological and subjective responses to intra­ venous nicotine in overnight abstinent

125 smokers has been studied in 12 smokers in a double-blind, placebo-controlled, cross­ over study, with one adaptation and three experimental sessions (121C). Before each session, participants took either a single dose of topiramate 25 or 50 mg or placebo. Starting 2 hours after medication they received an intravenous injection of saline, followed by intravenous nicotine 0.5 and 1.0 mg/70 kg. Topiramate 50 mg, compared with 25 mg or placebo, attenuated heart rate increases induced by nicotine. Systematic reviews The use of topiramate 50–1400 mg/day in the treatment of bingeeating disorder associated with obesity has been reviewed using MEDLINE and the Cochrane Database (2006, issue 3) (122M). The most common adverse effects in clinical trials included paresthesia, cognitive impairment, somnolence, and gastrointestinal distress. Cardiovascular Severe epistaxis has been associated with topiramate (123A).  A 61-year-old woman with significant cardio­

vascular disease (NYHA class II heart failure, unstable angina, and hypertension), rheuma­ toid arthritis, gastro-esophageal reflux disease, and osteoporosis took topiramate 25 mg/day for a neuropathy in the legs. She was also taking glucocorticoids, clopidogrel (75 mg/ day), and aspirin (325 mg/day). After 7 days she began to have severe intractable epistaxis, which lasted 8 days and disappeared within 1 week of withdrawal of topiramate. When topiramate was restarted 3 months later, she again developed intractable epistaxis, which resolved 1 week after withdrawal.

The authors pointed out that topiramate has been associated with epistaxis in 1–4% of patients in clinical trials in young individuals. It may also be associated with severe, intractable epistaxis in patients at risk (e.g., in those with underlying cardiovascular conditions and co-treatment with antiplatelet drugs). Nervous system Tremor, myoclonus, cramps, and fasciculations have been attrib­ uted to topiramate (124A).  A 46-year-old woman was given topiramate for

migraine prophylaxis and increased the dose

126 gradually by 25 mg/day every week up to 200 mg/ day. Her migraine episodes improved markedly, but 1 month later she started to complain of dizziness, weakness, anorexia, dry mouth, weight loss, muscle cramps, muscle fasciculation, tre­ mor, and paresthesia in the hands and feet. She had a moderate postural tremor in all four limbs, multifocal myoclonic jerks at an estimated frequency of 120–150 per minute, amyotrophy of all four limbs without altered muscle strength, and fasciculation in both quadriceps. Topira­ mate was withdrawn and the effects completely disappeared within 4 weeks.

Psychological Six patients taking topira­ mate for migraine prophylaxis developed cognitive and language dysfunction that improved with donepezil and allowed con­ tinued use of topiramate 75–400 mg/day (125c). The dose of donepezil was 5– 20 mg/day. Cholinesterase inhibition, result­ ing in cholinergic augmentation and enhanced cognition, may have accounted for the improvement. Psychiatric Two men aged 56 and 60 years with essential tremor, but no psychiatric history, developed symptoms of psychosis (daytime visual hallucinations, paranoia, and vivid dreams) 3–4 days after starting to take topiramate 50 mg/day; the symp­ toms resolved several days after topiramate withdrawal (126A).

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Dieter Schmidt and Stefan Beyenburg

migraine prophylaxis (placebo, n ¼ 12; topiramate 50 mg/day, n ¼ 11; topiramate 100 mg/day, n ¼ 15; topiramate 200 mg/day, n ¼ 13) adverse events were most frequent in those who took 200 mg/day (128C). The most common adverse effects in all treat­ ment groups were paresthesia (38% with 100 and 200 mg/day, 9% with 50 mg/day), upper respiratory infection (23% with 100 and 200 mg/day, 45% with 50 mg/day), and weight loss (31% with 200 mg/day, 15% with 100 mg/day, and 18% with 50 mg/day). Cognitive adverse effects occurred in seven patients (five taking topiramate and two placebo). There were two serious adverse events (severe ketoacidosis, acute pharyn­ gotonsillitis with peritonsillar abscess) in two patients (both taking placebo). Drug–drug interactions In 26 patients with different epileptic syndromes, in whom topiramate was used as add-on therapy, co­ medication with enzyme-inducing antiepi­ leptic drugs significantly reduced topira­ mate serum concentrations and the ratio of concentration to dose (129c).

Valproate sodium and semisodium (divalproex) (SED-15, 3579; SEDA-28, 99; SEDA-29, 97; SEDA-30, 92)

Acid–base balance Mixed (type 3) renal tubular acidosis has been associated with topiramate (127A).

The authors suggested that the renal tubular acidosis had been caused by inhibition of carbonic anhydrase by topiramate.

The use of intravenous valproate for the management of refractory status epilepticus has been reviewed (130R). Although intra­ venous valproate has not been objectively assessed in the treatment of status epilepti­ cus, anecdotal reports suggest that it is effective and relatively safe. Valproate is contraindicated in patients with severe liver disease, mitochondrial diseases, and pan­ creatitis, in pregnancy, and in those aged under 2 years; caution should be used in young children. There is also a risk of delaying general anesthesia. Valproate can be infused in a dose of 40–60 mg/kg over 15– 30 minutes. The authors recommended that if it fails general anesthesia should be given.

Drug dosage regimens In 51 patients in three studies of the use of topiramate for

Comparative studies Sodium valproate and phenytoin have been compared in 68

 A

47-year-old woman took topiramate 150 mg/day for 12 months for migraine prevention and developed metabolic acidosis, associated with both proximal and distal tubular dysfunction, which was discovered in a routine blood sample. She had lost weight (6 kg in 4 months) and had muscle weakness, bone pain, and joint sensitivity. Before treatment her plasma bicarbonate concentration had been normal.

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Chapter 7

patients with convulsive status epilepticus in a randomized study; seizures were aborted by valproate in 66% and by phenytoin in 42% (131A). As a second choice in refractory patients, valproate was effective in 79% and phenytoin in 25%. Phenytoin resulted in hypotension, respiratory depression, and abnormal liver function tests in two patients each. In contrast, valproate did not cause hypotension, but there was respiratory depression in one patient, and three had abnormal liver function tests. Topiramate and sodium valproate have been compared in the prevention of migraine in a 24-week, randomized, dou­ ble-blind, crossover, comparison in 64 patients aged 14–57 years (114C). The first group received topiramate 25 mg/day increasing over 1 week to 50 mg/day for 2 months. The second group received sodium valproate 200 mg/day increasing over 1 week to 400 mg/day for 2 months. The two drugs had equivalent efficacy and safety. The most common adverse events asso­ ciated with valproate were dose-related weight gain in 11 patients and somnolence and hair loss in 1 each. Topiramate was associated with dose-related weight loss in six, paresthesia in three, and paresthesia and weight loss in eight. Somnolence, hair loss, and paresthesia disappeared after 1 month of treatment. Systematic reviews The clinical evidence related to the use of valproic acid in the management of alcohol withdrawal syn­ drome has been reviewed, including all controlled clinical trials (132M). Compar­ isons of efficacy were made among various regimens of valproic acid and traditional therapy with benzodiazepines or non-ben­ zodiazepines. Only two of six trials reported a statistically significant differ­ ence in favor of valproic acid and these differences were of marginal clinical sig­ nificance. The number of patients included in these studies did not allow adequate evaluation of safety. The use of anticonvulsants (including valproate) in the continuation and main­ tenance phases of bipolar disorder, when there has been an episode of mania

127 (bipolar I disorder), has been reviewed (133M). Placebo-controlled studies were preferred, but there have been relatively few of these and clinical practice must therefore be guided by evidence carrying a lower level of conviction, and valproate monotherapy lacks a convincing evidence base. The view that valproate is more effective than lithium in rapid cycling has not been borne out. Lamotrigine is effec­ tive in preventing depression after an episode of mania. As monotherapy, lithium appears superior to carbamazepine in bipolar patients not previously treated with either drug. The combination of lithium and carbamazepine may be super­ ior to either drug alone, in certain treat­ ment-resistant patients, but is associated with increased adverse effects. Other anticonvulsants lack evidence supporting their use in bipolar disorder, except in treating co-morbid alcohol dependence, anxiety, and bulimic symptoms. Valproate continues to be recommended in most current guidelines, despite the lack of evidence. Cardiovascular Antiepileptic drugs alter serum lipids and the fatty acid composition of membranes. Homocysteine, which can cause vascular endothelial damage, is raised in patients taking valproate and carbama­ zepine. In this context, microcirculatory changes related to commonly prescribed antiepileptic drugs, such as valproate and carbamazepine, have been examined using capillary microscopy in 14 children taking carbamazepine and 24 taking valproate (134C). The results were compared to reference values determined in former analyses of 207 healthy children. There were significant differences in capillary density, tortuous index of the capillaries, capillary diameter, and flow rate of erythrocytes with both antiepileptic drugs. There were also changes in plasma viscosity and erythrocyte aggregation. Although the clin­ ical relevance of such changes is uncertain, the authors suggested that the microrheo­ logical effects of antiepileptic drugs should be considered in further studies on cardio­ vascular changes in patients taking longterm antiepileptic drugs.

128 Nervous system Valproate-associated cerebral pseudoatrophy has been reported (135A).  A 4-year-old boy took valproate 18 mg/kg/

day) after an unclassified epileptic seizure. He became increasingly irritable and developed learning difficulties. Valproate was further increased to 27 mg/kg/day, after an EEG showed continuous spike-and-wave activity during slow wave sleep. His school perfor­ mance worsened and an MRI scan showed enlarged ventricles and cerebral and cerebel­ lar sulci. Serum ammonia concentrations and an awake EEG were normal. Valproate was withdrawn and there was a dramatic improve­ ment in behavior and school performance.

This boy had a mitochondrial DNA mutation, as had his mother, grandmother, and a maternal uncle, who were all neurologically normal. The authors suggested that valproate may trigger a hitherto phenotypically silent mitochondrial disease. Encephalopathy Valproate-associated en­ cephalopathy has been reviewed in 19 cases based on a questionnaire sent to German epilepsy specialists (136c). The typical signs are impaired consciousness, sometimes marked EEG background slowing, and increased seizure frequency, with or without hyperammonemia. Ten patients had psychomotor retardation; the ages were up to 5 years in six patients, 5–20 years in two, 21–50 years in three, 51–70 years in four, and above 70 years in four. The symptoms resolve after with­ drawal of valproate, usually within days, but it can take as long as 4 months in elderly patients. Encephalopathy with memory impair­ ment has been attributed to hyperammo­ nemia secondary to valproate (137A).  A 45-year-old woman had three tonic–clonic

seizures despite high serum concentrations of phenytoin and phenobarbital. Phenytoin was withdrawn and she was given intravenous valproate 1600 mg over 24 hours. She became somnolent and then comatose. A CT scan was unremarkable. She had a raised serum ammonia concentration (8.17 mg/l; reference range 0.2–0.9) and a low valproate concen­ tration (44 mg/l; target 50–100). Valproate was withdrawn and she recovered quickly. An EEG was normal, bur an MRI scan 10

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Dieter Schmidt and Stefan Beyenburg

days after the onset of coma showed bilateral symmetrical high signal densities in the insular cortex and the hippocampus on diffusion-weighed imaging. Her poor verbal recall and spatial memory persisted for 1 month. She remained seizure-free with phe­ nytoin. Follow-up MRI scan and ammonia concentration were normal.

The authors suggested that hyperammonemia may have impaired long-term potentiation, resulting in memory impairment, and that the high-density signals on the MRI scan may have reflected hyperosmolarity of astrocytic cytoplasm, which the authors also attributed to hyperammonemia. Parkinsonism The frequency of Parkin­ sonism and cognitive decline has been studied in 364 patients with various epilep­ tic syndromes and seizure types taking valproate after 1 year of treatment and at least 1 year of follow-up (138c). There were five cases of Parkinsonism and cognitive decline. Among 140 patients with different adverse effects of valproate, Parkinsonism and cognitive decline were rare but sig­ nificant in terms of drug withdrawal (5 of 17). Early identification and withdrawal of the drug led to complete recovery. Ten cases of reversible Parkinsonism have been associated with valproate (six women and four men), associated with marked cognitive impairment in six cases (139c). These adverse effects can emerge after several years of well-tolerated treat­ ment with valproate. All patients had serum concentrations within the usual target range (50–100 mg/l). The Parkinso­ nian symptoms were insidious and pro­ gressive but they improved several weeks or months after withdrawal of valproate. The mechanism of these disorders is currently unknown. Metabolism Homocysteine Plasma total homocysteine, serum folate, serum vitamin B12, and plasma pyridoxal-5u-phosphate concentrations have been measured in children with epilepsy before and after treatment for 20 weeks with sodium valpro­ ate (n ¼ 32) or carbamazepine (n ¼ 20) monotherapy (140c). Plasma total homo­ cysteine increased significantly in both

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Chapter 7

groups, and serum folate and serum vitamin B12 increased significantly in those taking valproate, while serum folate and plasma pyridoxal-5u-phosphate fell significantly in those taking carbamazepine. Hyperglycinemia Non-ketotic hyperglyci­ nemia is a disorder of amino acid metabo­ lism in which a defect in the glycine cleavage system leads to accumulation of glycine in the brain and other tissues. In the classical form it presents as neonatal apnea, intractable seizures, and hypotonia, fol­ lowed by significant psychomotor retarda­ tion. In some children atypical variants present heterogeneously.  An 11-year-old girl with mild language delay

and mental retardation developed an acute encephalopathy and chorea 2 months after starting to take valproate and was found to have non-ketotic hyperglycinemia (141A). All medications were withdrawn and she was given benzoate. Over 5 days she improved, with reduced choreiform movements and a return to her premorbid state. She was free of chorea 1 month later.

Lipoproteins The effects of carbamaze­ pine and sodium valproate monotherapy on serum lipoprotein (a) concentrations have been studied in 18 children with epilepsy before and at 6, 12, and 24 months of treatment with carbamazepine monother­ apy and in 30 before and at 6, 12, and 24 months of treatment with valproate monotherapy (142C). Serum lipoprotein (a) con­ centrations were significantly raised at 6, 12, and 24 months in both cases. There were no significant correlations between serum lipo­ protein (a) and serum lipids, lipoproteins, apolipoproteins, biochemical markers of liver and renal function, or serum concen­ trations of antiepileptic drugs. It may there­ fore be useful to measure serum lipoprotein (a) concentrations routinely in children with epilepsy taking these antiepileptic drugs, especially in those who already have a higher atherosclerotic risk. The effects of phenobarbital, carbamaze­ pine, and valproate on serum lipid profiles and lipoprotein (a) have been assessed in 64 children with epilepsy (aged 1–15 years); 18 were taking phenobarbital 5 mg/kg/day, 22

129 were taking carbamazepine 10–15 mg/kg/ day, and 24 were taking sodium valproate 20 mg/kg/day (143c). Plasma lipoprotein (a), total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipo­ protein cholesterol, apolipoprotein A and apolipoprotein B concentrations, and liver enzymes alanine aminotransferase, aspar­ tate aminotransferase, alkaline phospha­ tase, and gamma-glutamyl transferase activities were determined before the start of treatment and after 3, 6, and 12 months. The mean age of the children taking phenobarbital was significantly lower than those taking carbamazepine or valproate. The mean lipoprotein (a) concentrations were significantly increased in all groups at 3, 6, and 12 months. The increases in alanine transaminase, aspartate transami­ nase, alkaline phosphatase, total choles­ terol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol at 3, 6, and 12 months were statistically significant in those taking phenobarbital. The higher concentrations in lipoprotein (a) (mean over 300 mg/l) were observed only in those taking carbamazepine at 6 and 12 months. The percentages of children with lipoprotein (a) concentrations over 300 mg/l were 44, 63, and 33% in those taking phenobarbital, carbamazepine, and valpro­ ate, respectively. The authors suggested that lipoprotein (a) concentrations should be closely monitored in patients taking antiepileptic drugs. The serum concentrations of lipids and lipoprotein (a) have been measured in 20 children taking carbamazepine, 25 taking valproic acid, and 5 taking phenobarbital at the following times: (a) during long-term treatment with a normal diet, (b) during long-term treatment with a low-fat diet (children taking carbamazepine and pheno­ barbital with high concentrations of total, high-density lipoprotein, and low-density lipoprotein cholesterol), and (c) 3 months after the end of treatment with antiepileptic drugs (14c). In contrast to higher serum lipids seen during treatment with pheno­ barbital or carbamazepine, children taking valproate had lower total cholesterol, and lower HDL, LDL, and VLDL. In addition, lipoproteins were lower compared than in

130 controls. When patients were switched to a low-fat diet, serum lipids in patients taking carbamazepine and phenobarbital returned to normal. These data show that the changes induced by carbamazepine and phenobarbital are transient, reversible, and influenced by a low-fat diet. The author offered no explanation for the remarkable ability of valproate to lower cholesterol and lipoproteins. Uric acid The data on the effect of sodium valproate monotherapy on serum uric acid concentrations are controversial. The effect of valproate on serum uric acid concentrations and liver function tests in 28 ambulatory children with epilepsy has been investigated in a long-term, prospective study before and at 6, 12, and 24 months of valproate monotherapy (144c). There were no statistically significant changes in serum uric acid concentrations at any time. Serum alanine and aspartate transaminase activities were significantly increased at 6 and 12 months and lactate dehydrogenase activity at 12 months. Hematologic To assess the association between exposure to antiepileptic drugs and aplastic anemia has been the subject of a retrospective case–control study (173 cases and 497 controls) using data from the UK General Practitioners Research Data­ base (GPRD) (145C). Antiepileptic drug use was more prevalent among cases (9.2%) than controls (0.8%). After adjust­ ment for confounders, the use of antiepi­ leptic drugs was significantly associated with aplastic anemia (adjusted OR ¼ 9.5; 95% CI ¼ 3.0, 40). The most frequently used antiepileptic drugs were carbamaze­ pine (OR ¼ 10.3; CI ¼ 2.0, 101), valproic acid (OR ¼ 18.2; CI ¼ 2.5, N), and pheny­ toin (OR ¼ 3.5; CI ¼ 0.4, 44). The 16 exposed cases were heterogeneous with respect to patient and exposure character­ istics: their ages varied from 1 to 92 years and the duration of antiepileptic drug use from 17 days to 6.8 years. This study suggests that antiepileptic drugs, in particu­ lar carbamazepine and valproate, are asso­ ciated with a ninefold increased risk of aplastic anemia.

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Dieter Schmidt and Stefan Beyenburg

Pancytopenia has been reported in a patient taking valproate and risperidone (146A).  A 36-year-old man with an acute confusional

state and a 12-year history of psychiatric disease and substance abuse, who had taken valproate 1500 mg/day for several years, took risperidone for 10 days and developed a mild pancytopenia (hemoglobin 11.2 g/dl, white cell count 3.2  109 per liter, platelets 75  109 per liter). The serum valproate concentration was 166 mg/l. Valproate and risperidone were withdrawn, and after 3 weeks the blood count returned to normal.

However, the time-course in this case suggested that the pancytopenia was more probably related to risperidone than to valproate. There was a high incidence of coagula­ tion problems within 1 year of valproate therapy in eight children, and a further seven children with significant coagulopa­ thies were identified (147A). The disorders included cases of platelet dysfunction (n ¼ 8), von Willebrand disease (n ¼ 6), factor XIII deficiency (n ¼ 6), hypofibrinogenemia (n ¼ 5), deficiency of vitamin Kdependent factors (n ¼ 3), and thrombocytopenia (n ¼ 1). The authors estimated the incidence of coagulation disorders related to valproate in children at nearly 4%. They did not recommended routinely monitoring hemostatic parameters in every patient, but suggested that whenever an increased bleeding tendency is observed, or before surgical procedures, a platelet count, thrombelastography, prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, von Willebrand factor, and factor XIII should be examined. A relatively long-lasting platelet response was achieved in a woman with acute myelogenous leukemia with a 9-day regi­ men of valproate, all-trans retinoic acid, and theophyllamine (148A). Liver Oxidative stress occurs when the body’s production of reactive oxygen spe­ cies exceeds the removal capacity and results in excessive concentrations of free radical intermediates. Oxidative stress has been implicated as one potential mechan­ ism of valproate-induced hepatotoxicity. To determine whether valproic acid alters

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Chapter 7

urinary concentrations of 15-F2t-isopros­ tane, a marker of oxidative stress, morning urine samples were collected from children with epilepsy taking valproate (n ¼ 25), carbamazepine (n ¼ 16), or clobazam (n ¼ 12) for at least 4 weeks and from age-matched control subjects (n ¼ 39) (149c). The mean urinary concentrations (nmol/mmol of creatinine) were: valproic acid 0.36, carbamazepine 0.24, clobazam 0.23, and control group 0.20. Patients treated with valproate had significantly raised concentrations of 15-F2t-isoprostane compared with the controls and those taking carbamazepine and clobazam. Multi­ ple linear regression analysis showed that younger age and exposure to second-hand smoke were significant predictors of raised urinary concentrations in the control group. Pancreas The effects of early treatment with sodium valproate monotherapy on serum total amylase activity, and particu­ larly on its pancreatic isoenzyme and lipase activity, have been evaluated in 23 children with epilepsy before and at 6 and 12 months of valproate monotherapy (150c). None of the children had symptoms of pancreatitis during the study. Serum pancreatic amylase activity fell significantly at 6 and 12 months, whereas serum total amylase and lipase activities did not change. Non-pancreatic isoenzyme amylase activity, which is prob­ ably derived from salivary glands, was significantly increased at 6 and 12 months. Three patients had slightly raised serum total amylase activities at 6 and 12 months. There was no significant correlation of serum pancreatic non-pancreatic amylase activities with serum valproate concentra­ tions at any time. Measurement of serum pancreatic amylase and/or serum lipase activities is indicated in patients with increased serum total amylase activities but without clinical symptoms of pancreatitis and in patients with symptoms that suggest pancreatic dysfunction, in order to avoid unnecessary withdrawal of valproate. Valproic acid-associated pancreatitis in children has been the subject of a chart review, in which 22 cases were identified (151c). The symptoms were similar to those of patients with pancreatitis from other

131 causes, and included abdominal pain/tender­ ness (83%), vomiting/retching (74%), abdominal distention (30%), and fever/chills (26%). Valproic acid concentrations were in the target range in all but one patient and the mean duration of therapy before the onset of pancreatitis was 32 months (i.e., this is a delayed collateral adverse effect; see p. xxvii). The serum lipase activity was more than three times the upper limit of the reference value in all patients; it should be measured when pancreatitis is suspected in such cases. In contrast, serum amylase activity was not significantly raised in 31% of the patients tested and is less useful. The length of stay was generally brief (mean 8 days). Two patients died. Of five patients who were rechallenged, four had relapses. Rechallenge with valproic acid is dangerous and should be avoided. Skin Drug rash with eosinophilia and systemic symptoms (DRESS syndrome) is characterized by fever, rash, and internal organ involvement after exposure to certain drugs. Most of the aromatic anticonvul­ sants, such as phenytoin, phenobarbital, and carbamazepine, can cause DRESS, and there can be cross-sensitivity with non­ aromatic anticonvulsants (17A).  A Korean woman who had previously toler­

ated valproate developed DRESS after taking carbamazepine and then after switching to valproate, suggesting cross-sensitivity. She had diffuse edematous patches on her entire body associated with tense bullae on her arms and legs. There was a circulating autoantibody to 190-kDa antigen in her serum by indirect immunofluorescence and immunoblotting.

Reproductive system There is preliminary evidence that valproate is associated with isolated features of polycystic ovarian syndrome (PCOS), while contradictory data support an association between epilepsy and PCOS. The development of the fea­ tures of PCOS after valproate therapy was therefore examined in 300 women aged 18–45 years with bipolar disorder using a standardized definition of PCOS (152C). A comparison was made between the incidence of hyperandrogenism (hirsutism, acne, male-pattern alopecia, raised

132 androgens) with oligomenorrhea that developed while the patients were taking valproate versus other anticonvulsants (lamotrigine, topiramate, gabapentin, car­ bamazepine, oxcarbazepine) and lithium. Medication and menstrual cycle histories were obtained and hyperandrogenism was assessed. Among 230 women who could be evaluated, oligomenorrhea with hyperan­ drogenism developed in 9 of 86 women taking valproate and in 2 of 144 women taking another antiepileptic drug or lithium (RR ¼ 7.5, 95% CI ¼ 1.7, 34). Oligomenor­ rhea always began within 12 months of valproate use. Monitoring for reproductive endocrine abnormalities is important when starting and using valproate in reproduc­ tive-aged women. Prospective studies are needed to elucidate the susceptibility fac­ tors for PCOS with valproate. The same authors then determined whether the features of PCOS reverse on withdrawal (153c). Women with valproate­ associated PCOS and those at risk of PCOS, who had used valproate for at least 6 months, were re-evaluated. Follow-up (mean 17 months) assessments were com­ pleted in 14 women (5 with treatmentrelated PCOS and none who had taken valproate for at least 6 months). Of seven women who developed valproate-asso­ ciated PCOS, the abnormal reproductive features remitted in three of four who stopped taking it and the menstrual cycle irregularities improved; the features per­ sisted in all three who continued to take it. There was a trend toward lower serum testosterone. Body weight and polycystic ovarian morphology did not change. The authors reported that in the first long­ itudinal study of valproate-associated PCOS, most of those who stopped taking valproate had improved reproductive fea­ tures despite static body weight. Fertility Antiepileptic drugs affect repro­ ductive endocrine function, but their impact on fertility is not well known. All patients with epilepsy, who were approved as being eligible for reimbursement for antiepileptic drug costs from the Social Insurance Insti­ tution (SII) of Finland for the first time in 1985–1994, were identified from the SII

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Dieter Schmidt and Stefan Beyenburg

database; a reference cohort without epi­ lepsy was identified from the Finnish Population Register Centre (154C). Infor­ mation on antiepileptic drug purchases in 1996–2000 was obtained from the SII database through computerized record link­ age with the unique personal identification number assigned to all residents of Finland. The three antiepileptic drugs included were carbamazepine, oxcarbazepine, and valpro­ ate. Birth rates were lower for both men and women with epilepsy taking antiepilep­ tic drugs than the reference cohort without epilepsy. However, compared with patients who did not use antiepileptic drugs, the birth rate was lowered only among men taking oxcarbazepine (rate ratio, RR ¼ 0.52; 95% CI ¼ 0.32, 0.84). It is unclear to what extent the differences found in this study were due to social or biological factors. Pregnancy The authors of a review of pregnancy-related problems noted that, as with many antiepileptic drugs, there are several consequences associated with the use of valproic acid in women of child­ bearing potential (155R). Most pregnancies have a favorable outcome in women with epilepsy, and these women should not be discouraged from becoming pregnant. Unlike many other antiepileptic drugs, valproic acid has no significant pharmaco­ kinetic interactions with the steroid hor­ mones used in oral contraceptives. During pregnancy, the major risks to mother and child result from loss of seizure control on the one hand, and an increased risk of major congenital malformations due to antiepilep­ tic drug treatment on the other. For these reasons, pregnancies in women being trea­ ted with valproic acid need to be planned, and the benefit–harm balance associated with continuing valproic acid or changing treatment need to be discussed with the patient. When treatment with valproic acid is the most appropriate treatment to achieve optimal seizure control, measures can be implemented to minimize the risk to the fetus. These include the use of the lowest possible effective dose of valproic acid in monotherapy (ideally under 1 g/day), appro­ priate folic acid supplementation, and close

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antenatal monitoring. Regular counseling is a prerequisite for informed planning of pregnancies and optimization of the prob­ ability of a healthy outcome. Teratogenicity An increased risk of major congenital malformations associated with valproic acid has been a consistent finding in studies of patient registries and in several large case series (155R). In addition, developmental delay, character­ ized by low verbal IQ, has also been reported in children exposed to valproic acid in utero, although the relative risk is not precisely known. The risks of major congenital malforma­ tions from in utero exposure to antiepileptic drugs have been studied prospectively by the UK Epilepsy and Pregnancy Register, with full outcome data on 3607 cases (156C). The overall rate of major congenital malformations for all patients exposed to antiepileptic drugs was 4.2% (95% CI ¼ 3.6, 5.0). The rate was higher for polytherapy (6.0%) (n ¼ 770) than for monotherapy (3.7%) (n ¼ 2598) (crude OR ¼ 1.63; adjusted OR ¼ 1.83). The rate for women with epilepsy who had not taken antiepileptic drugs during pregnancy (n ¼ 239) was 3.5% (1.8–6.8%). The rate was greater for pregnancies exposed only to valproate (6.2%; 95% CI ¼ 4.6, 8.2%) than only carbamazepine (2.2%; 1.4, 3.4) (OR ¼ 2.78; adjusted OR ¼ 2.97; CI ¼ 1.65, 5.35). There were fewer major congenital malformations for pregnancies exposed only to lamotrigine than only to valproate. There was a dose relation for lamotrigine. Polytherapy combinations con­ taining valproate carried a higher risk of major congenital malformations than com­ binations not containing valproate (OR ¼ 2.49; CI ¼ 1.31, 4.70). Pregnant women with epilepsy have been enrolled in a prospective observational study across 25 epilepsy centers in the USA and UK, to determine if there are differ­ ential long-term cognitive and behavioral neurodevelopmental effects on their off­ spring across the four most commonly used antiepileptic drugs. In a report on the incidence of serious adverse outcomes, including major congenital malformations

133 (which could be attributable to antiepileptic drugs) or fetal death, a total of 333 mother/ child pairs were analyzed for monotherapy exposures: carbamazepine (n ¼ 110), lamo­ trigine (n ¼ 98), phenytoin (n ¼ 56), and valproate (n ¼ 69) (9C). The numbers of pregnancies that resulted in serious adverse outcomes were as follows: carbamazepine 8.2%, lamotrigine 1.0%, phenytoin 10.7%, and valproate 20.3%. The estimated rela­ tive risks (95% confidence limits) of con­ genital malformations for valproate relative to each antiepileptic drug at a standardized antiepileptic drug dose were as follows: valproate versus carbamazepine ¼ 4.59 (1.58, 15), valproate versus lamotrigine ¼ 23 (4.25, 424), and valproate versus phenytoin ¼ 2.87 (0.91, 11). The distribution of serious adverse outcomes differed significantly across antiepileptic drugs and was not explained by factors other than in utero antiepileptic drug exposure. The effect of valproate was dose-related in the therapeutic range (i.e., it was a collateral effect). There was no difference in fetal deaths across the four drugs. These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus of all antiepileptic drugs. For women who fail other antiepileptic drugs and require valproate, the dose should be limited if possible. Susceptibility factors Age The effects of aging on the pharmacokinetics of valproic acid at steady state and on the susceptibility of valproate metabolism to enzyme induc­ tion by antiepileptic co-medications have been studied by searching the database of a large neurological hospital to identify patients aged at least 65 years taking stable valproate therapy (157C). In all, 71 patients, mean age 70 years, including 20 taking enzyme-inducing antiepileptic drugs were included. In the absence of enzyme-indu­ cing co-medications, the apparent oral clearance of valproate was similar to that found in non-elderly controls (9.7 ml/h/kg versus 10.2 ml/h/kg). Elderly patients taking enzyme-inducing co-medications, on the other hand, had lower apparent valproate

134 oral clearances than enzyme-induced younger controls (11.7 ml/h/kg versus 16.0 ml/h/kg). Since apparent valproate oral clearance increases with increasing dosage, lower dosages in elderly patients may have contributed to this difference. Since the measurements of clearance were based on total serum valproate concentrations, and since valproate binding to plasma proteins is reduced in old age, it is likely that the clearance of unbound, pharmacologically active, valproate was significantly reduced in the elderly, presumably as a result of reduced drug metabolizing capacity. Drug formulations It has been suggested that modified-release valproate formula­ tions may be more effective and better tolerated than conventional valproate, because of better compliance and lower fluctuations in valproate serum concentra­ tions; however, comparative trials with conventional valproate in children are scarce. There has been a randomized cross­ over comparison of conventional valproate twice daily with modified-release valproate twice daily or once daily in the morning or once daily in the evening in 48 children (29 girls) aged 5–14 years with newly diagnosed partial epilepsy (n ¼ 26), or idiopathic generalized epilepsy (n ¼ 22) (158C). The study lasted 16 months and consisted of four phases of 4 months each. Mean valproate dosage was 870 mg/day (22 mg/ kg/day) and the mean valproate concentra­ tion was 89 mg/l at 12 hours after the dose and 54 mg/l at 24 hours. There were no significant differences in efficacy (73, 83, 77, and 75%, respectively) or the frequency of adverse reactions (56, 58, 67, and 46%). However, there were significant differences in patients’ (or parents’) preferences (17, 8, 25, and 31%). Drug administration route Rapid intrave­ nous valproate has previously been studied in the treatment of epilepsy and status epilepticus, but rapid oral loading has not been evaluated in children. The standard oral titration scheme takes 10–14 days, but some physicians prefer slower titration up to 4 weeks. A new oral loading scheme to achieve a therapeutic serum concentration

Chapter 7

Dieter Schmidt and Stefan Beyenburg

on the third day of treatment has been proposed (159C). Treatment is started with a single dose of 30 mg/kg, followed by 45 mg/kg on day 2 in two divided doses, and 30 mg/kg on day 3. Two patients, both adolescents, who developed nausea and fatigue, had a mild reversible increase in ammonia concentrations; there were no adverse effects in other patients. Drug overdose Acute intoxication with valproic acid is increasingly being observed. Polish authors have reported that such intoxication often occurs as a result of mixing different drugs or alcohol. They studied the pharmacokinetics of valproic acid in five intoxicated patients who wanted to commit suicide (160A). Three were comatose (Glasgow coma scale 3); the other two patients were less severely affected. All recovered. Two had taken valproic acid alone and the other three patients had also taken other substances, including barbitu­ rates, chlorprotixene, tricyclic antidepres­ sants, cannabis, and alcohol. Valproate was absorbed rapidly, with maximum concen­ trations of 110–724 mg/ml after 3.5– 5.6 hours. The fall in valproic acid concen­ trations in plasma was biphasic, with a terminal half-life of 8.8–31 hours. The cal­ culated apparent volume of distribution was 0.17–0.72 l/kg. Drug–drug interactions Antipsychotic drugs Antiepileptic and antipsychotic drugs are often co-prescribed, and interac­ tions may affect both efficacy and toxicity. The clinical data on important interactions between carbamazepine, valproic acid (sodium valproate), vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine, oxcarba­ zepine, levetiracetam, pregabalin, felba­ mate, zonisamide, phenobarbital, and phenytoin with the antipsychotic drugs risperidone, olanzapine, quetiapine, cloza­ pine, amisulpride, sulpiride, ziprasidone, aripiprazole, haloperidol, and chlorproma­ zine have been reviewed (10R). The limited information on interactions between antiepileptic drugs and zuclopenthixol, pericia­ zine, fluphenazine, flupentixol, and pimozide was also presented. Given the wide diurnal fluctuations in valproate serum

Antiepileptic drugs

Chapter 7

concentrations, it is difficult to be certain that antipsychotic drugs affect its pharma­ cokinetics. No clinically relevant interac­ tions have been reported between valproate and the following antipsychotic drugs: amisulpride, aripiprazole, chlorpro­ mazine, quetiapine, sulpiride, and ziprasi­ done. Risperidone does not consistently affect valproate serum concentrations and vice versa. The published data on an interaction between valproate and cloza­ pine are inconsistent; some have reported an increase and others a decrease in clozapine serum concentrations when valproate is added. In many cases there are no published clinical data on interactions that would be predicted on theoretical grounds. Although olanzapine and valproate are metabolized partly by glucuronidation, interactions were not discussed in the above review; an interaction has been described in four patients, in whom co-administration of valproate lowered the plasma concentration of olanzapine by 50%; in three patients this led to deterioration of psychopathology and relapse of psychosis (161c). Furthermore, both drugs can cause weight gain, and adverse effects may therefore be additive when the combination is used. Hormonal contraceptives Total and unbound serum valproic acid trough con­ centrations at steady state have been mea­ sured during a cycle of combined hormonal contraceptive steroids in nine women on two separate randomized occasions: (a) at the end of the 4–7-day steroid-free interval and (b) on the last day of the cycle (162c). In all the women, total and unbound valproate concentrations were significantly higher during the steroid-free interval (425 mmol/l versus 350 mmol/l for total valproate and 55 mmol/l versus 39 mmol/l for unbound valproate). During steroid administration there was a mean 22% increase in valproate total apparent oral clearance (from 8.0 to 9.7 ml/hour/kg) and a 45% increase in valproate unbound apparent oral clearance (from 79 to 115 ml/hour/kg). The authors concluded that these effects were probably due to induction of glucuronosyl transferase by ethinylestradiol. The magnitude of the

135 effect varied across individuals, and was potentially clinically relevant in some cases. They suggested that serum valproate con­ centrations should be monitored when add­ ing or discontinuing contraceptive steroids and possibly during the on–off intervals of a cycle. In a patient taking divalproex (2500 mg/ day) and aspirin 325 mg/day, aspirin increased the unbound concentration of valproate manyfold, while the total valpro­ ate concentration did not change appreci­ ably (163c). The patient had developed dizziness and coordination difficulties in the presence of aspirin, which resolved when the total dose of divalproex was reduced from 2500 to 1250 mg/day. The authors suggested that the aspirin–valproate inter­ action is an example of displacement accompanied by metabolic inhibition. Both valproate and aspirin are highly bound to plasma proteins, such as albumin. When they are co-administered in sufficient doses, there is mutual displacement and a rise in the unbound fraction of each drug. Addi­ tionally, aspirin is an inhibitor of betaoxidation, which is responsible for about 40% of the metabolism of valproate. Lamotrigine An interaction of valproic acid with lamotrigine has been described. In eight women the lamotrigine dose/ plasma concentration ratio increased by 295% from baseline outside pregnancy to mid-gestation, whereas in six women who took lamotrigine in combination with valproate, the increase was only 60% (164c). There was no difference in lamo­ trigine dose/plasma concentration ratio between users and non-users of oral contra­ ceptives co-medicated with valproate. Thus, valproate seems to inhibit the induction of lamotrigine metabolism associated with pregnancy. Although the sample was small, the authors speculated on the relevance of the findings for potential adverse effects of lamotrigine on the fetus. Women using lamotrigine in combination with valproate have little change in lamotrigine plasma concentrations during pregnancy, in con­ trast to those using lamotrigine monother­ apy, in whom lamotrigine concentrations fall markedly during the first trimester. This

136 interaction might contribute to a higher rate of malformations when valproate and lamotrigine are given in combination com­ pared with lamotrigine alone (see the section “Teratogenicity”). Protease inhibitors A pharmacokinetic interaction has been described between valproic acid and lopinavir+ritonavir (165A).  A 30-year-old man with bipolar disorder and

HIV taking valproate 250 mg tds started to take lopinavir+ritonavir, zidovudine, and lami­ vudine. His most recent valproate concentra­ tion was 495 mmol/l. He became increasingly manic 21 days later, and his valproate con­ centration was 238 mmol/l. The dose of valproate was increased to 1500 mg/day and olanzapine was introduced. The valproate concentration rose to 392 mmol/l, and he improved clinically.

Ritonavir induces the glucuronidation of several medications, including ethinylestradiol, levothyroxine, and lamotrigine. Glucuronidation accounts for 50% of the metabolism of valproate, 40% undergoes mitochondrial betaoxidation, and less than 10% is eliminated by the cytochrome P450 isoenzymes. The authors suggested that ritonavir-mediated induction of valproate glucuronidation had reduced valproate concentration and efficacy. Monitoring therapy Several studies have shown that achieving adequate serum valproate concentrations is critical to rapid stabilization of acute mania, but estimates of the target therapeutic concentration have been imprecise. A post hoc analysis of pooled intention-to-treat data from three randomized, placebo-controlled studies of divalproex in acute mania has therefore been performed to test a hypothesized linear relation between serum concentra­ tion and response and to determine optimal blood concentrations for the management of acute mania in 374 subjects stratified into seven groups (six valproate serum concen­ tration ranges and placebo) (166M). There was a good fit of blood concentrations and response to a linear model. Efficacy was significantly greater than placebo beginning at the 71–85 mg/ml range and for all higher valproate concentrations; concentrations of

Chapter 7

Dieter Schmidt and Stefan Beyenburg

94–107 and W107 mg/ml were superior. The effect size associated with highest serum concentrations (W94 mg/ml) was 1.06 (0.59 after placebo correction). Subjects who obtaining this effect or greater (n ¼ 84) had a mean serum concentration of 88 mg/ ml. Blood concentrations in the lowest effective range were 60% more effective than placebo and in the higher ranges 120% more effective. The mean withdrawal rate because of adverse events across all groups was 3%.

Vigabatrin

(SED-15, 3623; SEDA-28, 101; SEDA-29, 99; SEDA-30, 98)

Nervous system Angelman syndrome is a neurogenetic disorder characterized by severe mental retardation, speech disorder, stereotyped jerky movements, and a peculiar behavioral profile, with a happy disposition and outbursts of laughter. Most patients present with epilepsy and suggestive electroencephalographic patterns, which may be used as diagnostic criteria. Of 19 patients with Angelman syndrome, determined by deletion of chromosome 15q11-13, all had generalized epilepsy, and 10 also had partial epilepsy (167c). The main seizure types were atypical absences and myoclonic and tonic–clonic seizures. The best therapeutic response was obtained with valproic acid, either alone or in combination with phenobarbital or clonazepam. Epilepsy was aggravated by carbamazepine, oxcarbazepine, and vigabatrin. In one patient the introduction of vigabatrin-induced myoclonic status epilepticus. Aggravation of idiopathic generalized epilepsy syndromes by inappropriate antiepileptic drugs is increasingly recognized as a serious and common problem, but pre­ cipitation of status epilepticus by inap­ propriate medication has rarely been reported. In 14 patients (seven men) aged 15–46 years with a mean duration of epilepsy of 16.4 years, video-EEG showed typical absence status epilepticus in 5, atypical absence status epilepticus in 5,

Antiepileptic drugs

Chapter 7

atypical myoclonic status epilepticus in 3, and typical myoclonic status epilepticus in 1 (168c). Epilepsy had been misclassified as cryptogenic partial in eight cases and cryptogenic generalized in four. The correct diagnosis proved to be juvenile absence epilepsy in six patients, juvenile myoclonic epilepsy in four, epilepsy with grand mal on awakening in two, and childhood absence epilepsy in two. All had taken carbamaze­ pine and had had seizure aggravation or new seizure types before referral. Seven patients had polytherapy with phenytoin, vigabatrin, or gabapentin. Potential preci­ pitating factors included an increase in the dose of carbamazepine or of carbamazepine and phenytoin; initiation of carbamazepine, vigabatrin or gabapentin; and a reduction in the dose of phenobarbital. Withdrawal of the aggravating agents and adjustment of medication resulted in full seizure control. Sensory systems DoTS classification: Reaction: Visual field loss from vigabatrin Dose relation: Collateral reaction Time-course: Late Susceptibility factors: More common in adults Vigabatrin causes irreversible visual field constriction in 19–92% of patients. It is unclear whether this correlates with dose, and the natural history of the retinopathy is obscure. The relation of toxicity to daily dose, duration of therapy, and cumulative dose has been studied in a retrospective analysis of 93 patients taking long-term vigabatrin; visual field constriction devel­ oped in 49 and men and women were affected equally (169c). The shortest expo­ sure time to the onset of the effect was 1.1 years. All patients with normal fields on initial assessment continued to have normal fields on follow-up. Most of those who had evidence of constriction on initial assess­ ment and continue to take vigabatrin did not progress on follow-up. One patient had substantial recovery of vision after

137 withdrawal of vigabatrin. There was no correlation between the average mean radial degrees and either the maximum dose of vigabatrin, the duration of expo­ sure, or the cumulative dose. Other con­ tributory factors were not identified. The extent of vigabatrin-induced visual field constriction and genetic variation across six candidate genes (SLC6A1, SLC6A13, SCL6A11, ABAT, GABRR1, and GABRR2) has been studied using HapMap data and a tagging SNP technique in an effort to efficiently capture all common variation within these genes (170c). The degree of visual field constric­ tion correlated with three SNPs and one haplotype in 73 patients. However, this could not be replicated in a second inde­ pendent group of 58 patients, suggesting that the initial results were false positives or variants with weak effects. The authors concluded that the candidate genes studied here were not involved. However, this does not rule out the presence of genetic variants with weak effects in these genes, nor of variants with strong effects in other genes. The ocular safety of short-term vigabatrin in treating cocaine and/or metamfetamine addiction has been studied by testing visual fields at baseline, 1 week, 4 weeks, 8 weeks, and 1 month or more after withdrawal of vigabatrin (171c). Of 18 subjects, 16 had negative test results for cocaine and metam­ fetamine use during the last 6 weeks of the trial. There were no ocular adverse events. Subjective evaluation did not reveal visual field constriction in any of the subjects. Objective group and individual analyses for quadrant mean sensitivity did not show any change from baseline in any quadrant. There were no changes in visual acuity.

Zonisamide

(SED-15, 3728; SEDA-28, 101; SEDA-29, 100; SEDA-30, 99)

Zonisamide has been used extensively world­ wide (over 2 million patient-years experi­ ence) in the treatment of a broad range of types of epilepsy. It was recently approved in Europe as adjunctive therapy for refractory

138 partial seizures in adults, and has been used extensively in Japan and the USA. Its adverse events profile is well defined. The most common adverse events, reported by more than 10% of patients, are usually nervous system-related and include agitation, irritability, confusion, depression, ataxia, dizziness, memory impairment, and diplopia; loss of appetite, weight loss, and kidney stones have also been reported (172R). Observational studies A pooled safety analysis of 1207 patients who took at least one dose of zonisamide in clinical observa­ tions of up to 9 years showed that the most common adverse effects, reported by more than 10% of patients, were: somnolence (22%), dizziness (21%), anorexia (17%), tiredness (15%), nausea (13%), headache (12%), confusion (12%), mental slowing (12%), agitation/irritability (11%), diplopia (11%), and difficulty with memory (10%) (173R). Zonisamide has been studied in an open, prospective, non-randomized, 8-week study in 20 out-patients with bipolar disorder (17 type I, 2 type II, 1 not otherwise specified), aged 38 years, with depressive symptoms (174c). No patient was manic or mixed at study entry. Previous treatments were continued unchanged, and the mean dose of zonisamide was 223 mg/day. Mean Mon­ tgomery Asberg Depression Rating Scale scores improved significantly from baseline to end-point. Ten patients withdrew early because of adverse effects, including nausea/vomiting in six, cognitive impairment in four, and sedation in nine. Other adverse effects included difficulty in coordination, blurred vision, dry mouth, constipation, and tremor (three each), reduced appetite and weight gain (two each), and acne, migraine, akathisia, ataxia, and insomnia (one each). One patient had increased suicidal ideation and one patient had hypomania. In a retrospective chart review of 12 patients, mean age 13.5 years, with refrac­ tory headaches who took zonisamide, 8 had a positive response to zonisamide, with greater than 50% reduction in headaches (175c). Two withdrew early because of adverse effects, one with weight loss and one with behavioral changes.

Chapter 7

Dieter Schmidt and Stefan Beyenburg

In a retrospective chart review of the longterm outcomes of zonisamide monotherapy for 6–180 months in 77 patients, 49 (64%) had a 50% or more reduction in seizure fre­ quency; of those patients 38 (49%) had a 75% or more reduction, and 18 (24%) became seizure-free after 6–180 (median 81) months of follow-up (176c). The following adverse effects were noted: two patients discontinued zonisamide because of mental sluggishness in one and an unspecified behavioral aberration in the other. The mental sluggishness resolved within 1 week of withdrawal. Two other patients developed (unspecified) behavioral disorders, one after 32 months and the other after 40 months; zonisamide was withdrawn in one and the other received unspecified psychiatric medication. Renal stones were discovered after 155 and 164 months in two patients; the stones discharged spontaneously and were not analyzed chemically; the patients continued to take zonisamide. In a retrospective chart review in 69 children and adolescents (19 boys and 50 girls, mean age 13 years) with various types of epilepsy, zonisamide, mean duration of follow-up on treatment 22 (range 3–48) months, 18 patients developed adverse effects: weight loss (n ¼ 9), cognitive impairment (3), sleepiness (3), dizziness (2), and reduced appetite (1) (177c). In seven patients, zonisamide had to be with­ drawn: four because of adverse effects (weight loss and cognitive impairment) and three because of poor seizure control. Placebo-controlled studies Four rando­ mized, placebo-controlled trials (duration more than 6 months) in the USA and Europe (848 patients in total) have shown that zonisamide 300 mg/day or more is effective in refractory partial seizures in adults (178R). Adverse events are generally mild to mod­ erate and few lead to withdrawal; the incidence of serious adverse events is com­ parable to placebo. The most common adverse effects, reported by more than 5% of patients in placebo-controlled trials, were: somnolence (15% for zonisamide versus 8% for placebo), dizziness (14% versus 8%), anorexia (10% versus 8%), nausea (9% versus 6%), tiredness (8% versus 6%), agitation/irritability (7% versus 4%),

Antiepileptic drugs

Chapter 7

headache (6% versus 6%), fatigue (6% versus 6%), and diplopia (6% versus 3%). Psychiatric Acute mania has been attrib­ uted to zonisamide (179A).  A 42-year-old woman took a number of

anticonvulsants for a benign essential tremor, but could not tolerate them because of

139 somnolence. She was given oral zonisamide 100 mg/day and after about 36 hours devel­ oped hyperactivity, racing thoughts, distract­ ibility, insomnia, and talkativeness. On day 4 her husband reported that she had not slept in the previous 48 hours. Zonisamide was dis­ continued and all her symptoms resolved within 24 hours.

The mechanism of action of zonisamide on mood is not known.

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A.H. Ghodse and S. Galea

8

Opioid analgesics and narcotic antagonists

Note on receptor nomenclature: Opioid receptors, originally called d, k, and m receptors, then OP1, OP2, and OP3 recep­ tors, are now called DOR, KOR, and MOR receptors respectively.

GENERAL Observational studies Drug-related emer­ gency department visits have been studied in a district hospital in Finland (1C). Adverse drug reactions were responsible for 2.3% (n ¼ 167) of all visits over a 6-month period; 102 visits were related to adverse drug reactions without intentional overdoses, and 65 were related to overdose. Opioids were responsible for only four adverse drug reactions; three patients complained of nausea and one of constipation. The opioids involved were fentanyl, oxycodone, and tramadol. Two of these patients required admission to hospital. Systematic reviews The administration of opioids has been compared with continuous peripheral nerve block for pain control (2M). Peripheral nerve catheter analgesia resulted in superior pain control and was associated with fewer adverse effects. Per­ ipheral nerve block was associated with motor block, whereas nausea, vomiting, pruritus, and sedation were associated with opioid administration. Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03108-0 r 2009 Elsevier B.V. All rights reserved.

Nervous system Patients using chronic opioids tend to have more pain when attempts are made at managing pain by giving larger doses, and pain is probably best managed by withdrawing the opioid medication. In one study higher degrees of pain were experienced with high potency bolus release medications, such as oxyco­ done modified-release, than with less potent immediate-release medications, such as hydrocodone (3c). On the other hand, a study of opiate addicts undergoing detox­ ification with methadone and/or heroin provided evidence of hyperalgesia (4c). Patients and controls were subjected to a cold pressor test and reactions were mon­ itored. Reactions were suggestive of hyper­ algesia; however, they also indicated increased pain latency and reduced pain intensity. These phenomena are contra­ dictory and require further research. Psychological Delirium and cognitive impairment are common postoperative adverse events, especially in elderly patients. Susceptibility factors and intrao­ perative and postoperative factors influence the development of postoperative delirium and/or cognitive impairment and are asso­ ciated with poor functional recovery and increased morbidity. A systematic review including clinical trials and observational studies explored the use of opioids post­ operatively in elderly patients and the risk of development of postoperative cognitive impairment and/or delirium (5M). Opioids more commonly used postoperatively include morphine, fentanyl, and hydromor­ phone. When comparing the postoperative use of these opioids with postoperative pethidine, the latter was significantly

149

150 associated with an increased risk of delir­ ium or cognitive impairment. These studies did not provide sufficient evidence to establish whether there were any differ­ ences in the risks of morphine, fentanyl, or hydromorphone. The authors also explored whether the route of administration of opioids made a contribution to the risk of cognitive impairment; there was no signifi­ cant difference between epidural and par­ enteral analgesia. They recognized that delirium and/or cognitive impairment are common adverse events that affect morbid­ ity and postoperative recovery and the limitations of the papers reviewed (e.g. small sample sizes and non-standardized measurement of cognitive impairment), and they recommended future studies of post­ operative cognitive impairment in patients given postoperative opioids. In another study postoperative cognitive function was assessed after patient-con­ trolled analgesia in 30 patients undergoing lower abdominal surgery, who received either fentanyl (n ¼ 17) or tramadol (n ¼ 13) intraoperatively and postopera­ tively (6c). Cognitive function was assessed on days 1 and 2 using the Mini Mental State Examination and the Benton Visual Reten­ tion Test. Although the patients in the two groups had similar cognitive abilities, those who received tramadol were motivated to accomplish cognitively demanding tasks. Dependent drug users, current and for­ mer, have impairment of executive and memory function. Executive and memory function has been explored in 25 chronic amphetamine users and 42 chronic opiate users (7C). Compared with controls, drug users had impairment of spatial planning, paired associate learning, and visual pattern recognition. Amphetamine users had greater impairment of spatial planning, pattern recognition memory, and atten­ tional set-shifting. Gastrointestinal Opioid-induced gastroin­ testinal dysfunction contributes to patient dissatisfaction and affects quality of life. The pathophysiological mechanisms under­ lying gastrointestinal dysfunction following opioid use have been reviewed (8R). Nausea and vomiting, experienced by a large

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A.H. Ghodse and S. Galea

number of patients who take opioids, are believed to be triggered by both peripheral and central mechanisms. Constipation, experienced by 40–50% of patients, is induced by doses of opioids lower than the doses required for analgesia. Tolerance to constipation does not tend to develop. The authors suggested several options to reduce the incidence of constipation: e.g., adminis­ tering newer opioid compounds (such as dihydroetorphine hydrochloride); using the transdermal route; opioid-sparing through adjunctive treatment. Another gastrointestinal effect is ileus,+ with several potential underlying pathophy­ siological mechanisms (9A).  A woman on chronic narcotics (oxycodone

5 mg, 2–3 times per week) underwent colono­ scopy, during which she was given midazolam 7 mg, pethidine 100 mg, and fentanyl 125 mg. She later developed acute colonic pseudoobstruction necessitating hospital admission.

Ileus is postulated to result from motor inhibition of the gastrointestinal tract by narcotics. Musculoskeletal The risk of fractures associated in patients using opioids has not been extensively documented. A nation­ wide case–control study in Denmark estab­ lished that opiates were associated with an increased risk of fractures (10C). The study included all individuals who had sustained a fracture in the year 2000 (n ¼ 124 655). For each case, three controls matched for age and sex were randomly drawn from the general population. A number of opioids (morphine, methadone, fentanyl, ketobemi­ done, nicomorphine, oxycodone, codeine, and tramadol) were associated with an increased risk of fractures. However, dex­ tropropoxyphene, pethidine, acetylsalicylic acid+codeine combination, and buprenor­ phine were not associated with an increased risk. With most of the opioids mentioned, there was an increased risk at all doses. Fentanyl increased the risk at higher doses, while nicomorphine and ketobemidone increased the risk at lower doses. The increased fracture risk, even at lower doses and even when the opioids had only been taken for a short time, suggested that the

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Chapter 8

most probable underlying primary reason for fractures was falls due to the central nervous system effects of the opioids, as opposed to weakening of the bone struc­ ture. The use of alcohol was a significant risk factor in all cases. Although the study had significant limitations and potential confounding factors, the large numbers made the results more reliable. Immunologic The immunosuppressive effects of morphine, tramadol, and the combination of tramadol+lornoxicam for pain management after elective gastric cancer surgery (n ¼ 45) have been com­ pared (11c). Immunosuppression was mea­ sured by observing expressions of T lymphocyte subsets, natural-killer cells, and activated T lymphocytes. The combination of tramadol+lornoxicam provided equiva­ lent analgesia but caused less immunosup­ pression than morphine or tramadol alone. Infection risk The immunomodulatory effects of opioids contribute to altered immune responses to injury. In a case– control study patients with burns who developed infections were more likely to be taking high doses of opioids (12C). Both burns and opioids induce immunosuppres­ sion, and the authors suggested that they act synergistically, increasing the risk of infection, especially in mild-to-moderate injuries. In those with large burns, opioids had no effect, possibly because of maximal immunosuppression by the burns. Death Opioid-related deaths due to poi­ soning by both licit and illicit opioids continue to increase in frequency. Uninten­ tional fatal poisoning in the USA increased by 18% per year from 1990 to 2002, and the majority were attributed to “narcotics” and “unspecified drugs” (13C). From 1999 to 2002 opioid analgesic poisoning increased by 91% and heroin poisoning increased by 12%, making licit drugs the most common cause of fatal drug poisoning in the USA, replacing illicit drugs. Of the opioid analge­ sic fatalities 54% were from semisynthetic opioids (e.g., oxycodone and hydrocodone), 32% from methadone, and 13% from other synthetic opioids (e.g., fentanyl). This

151

increase in fatalities has coincided with a change in prescribing practices amongst physicians. Since 1990, they have increased prescribing of opioids for pain manage­ ment. This epidemiological study has sug­ gested that the increase in prescribing may have contributed to the increase in opioidrelated deaths. In an epidemiological study in the USA the trends in opioid-related deaths in 1990– 2003 were analyzed (14C). Fatalities increased by 529%, from 1.4 per 100 000 in 1990 to 8.8 per 100 000 in 2003, among both sexes, all age groups, and all racial/ ethnic groups. These trends in Massachu­ setts are consistent with trends of opioidrelated deaths elsewhere in the USA. Epidemiological data from the UK from 1993 to 2004 give the number of heroin/ methadone deaths as 7072 and methadone deaths as 3298 (15C). Age-standardized mortality rates increased from 5 to 15 per million from 1993 to 1997. Methadone deaths fell from 1997 to 2004. During this period there was an increase in the use of methadone, but the data suggest that this was not associated with an increased number of deaths. Opiate overdose deaths in England fell by 21% from 2002 to 2003; Brighton had the highest drug-related death rate (16r). In 75% of the deaths that involved methadone there was also polydrug use, and in 30% there were toxic concentrations of other substances. The authors highlighted the fact that buprenorphine also carries a significant risk of respiratory depression, is easier to inject, and carries a risk of pulmonary edema. This finding was confirmed in study in Germany (17C). One buprenorphine death was reported in 2002–2003, resulting from injection of crushed buprenorphine. Of note is the higher numbers of incidents reported with methadone (35%) and heroin (62%). Buprenorphine appears to be asso­ ciated with a lower risk of fatal overdoses. Benzodiazepines, identified through tox­ icology screening at autopsy, were found in a significant number of buprenorphine-related deaths in Singapore (18C). Between Sep­ tember 2003 and 2004 there were 21 cases of buprenorphine-related deaths, in 19 of which benzodiazepines had also been used.

152 The risk of accidental overdose in those found to be positive for methadone is increased by the concomitant use of tricyc­ lic antidepressants, benzodiazepines, and both (19C). In a retrospective epidemiolo­ gical study in New York City in 2003, there were 500 (8.6%) methadone positive deaths, of which 493 were analyzed; tricyclic antidepressants were also found in 19% and benzodiazepine in 32%. The authors advised increased awareness of the risk of such combinations. In a review of the literature the three main factors that predicted fatal opioid overdoses were injecting heroin, chronic alcohol misuse, and having been arrested more than three times (20r). Drug abuse The abuse potential and importance of identifying and managing the risks of opioids has been reviewed (21R). Abuse of opioids is highly prevalent globally, and the authors discussed strate­ gies for reducing it, such as making tablets “tamper resistant”, providing controlledrelease dosage forms, partial agonists, and drug combinations that precipitate with­ drawal if misused. Such strategies are linked to a risk of overdose. They suggested a standard procedure for evaluating the abuse potential of substances at various stages of drug development. Drug administration route The usefulness and adverse effects related to different routes of administration was reviewed in SEDA-30 (p. 106). There is now further evidence of adverse effects specific to administration routes. Epidural and intrathecal Intravascular, intrathecal, or subdural epidural needle or catheter misplacement are complications justifying the need for an epidural test dose. The reliability of the epidural test dose has been reviewed (22R). The authors recom­ mended that more studies are required to establish reliable evidence to detect epi­ dural needle or catheter misplacements. The use of an epidural catheter for liver resection can be associated with adverse events resulting from impaired coagulation related to impaired liver function. In one

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study continuous naropine epidural analge­ sia was compared to single-shot intrathecal morphine in 50 patients undergoing liver resection (23c). Both techniques provided adequate pain control. Morphine caused more pruritus (16% versus 0%) and nausea (16% versus 4%), but both groups had the same incidence of vomiting. There were no headaches or hematomas. The authors suggested that the epidural technique was not superior and that the potential asso­ ciated risks of coagulopathies are worth considering. Postoperative epidural analgesia has been compared with postoperative patientcontrolled intravenous analgesia following radical retropubic prostatectomy in 60 patients (24c). The epidural techniques gave better pain management. Significantly more patients who received epidural morphine required antiemetics and maximum expira­ tory pressure was significantly lower at 4 and 24 hours in those whose received it by PCA. Patient-controlled epidural analgesia in labor did not result in increased maternal satisfaction or control compared with con­ ventional epidural blockage in 90 mothers who were randomized to three groups: patient-controlled epidural analgesia with bupivacaine and fentanyl; patient-controlled epidural analgesia with bupivacaine; and intermittent bolus epidural analgesia with bupivacaine and fentanyl (25c). The two groups who took fentanyl had significantly more adverse effects, such as vomiting and pruritus. Several studies have highlighted the benefits of giving adequate postoperative analgesia in cardiac patients, and the use of intrathecal and epidural anesthesia and analgesia for cardiac surgery has been reviewed (26R). Effective postoperative analgesia reduces the risk of postoperative stress and morbidity, hospital stay, and cost, and increases patient satisfaction. There is a role for intravenous opioids in such patients, but those are associated with significant adverse effects. On the other hand, several studies of intrathecal techni­ ques have shown that these provide ade­ quate analgesia although they do not significantly attenuate the stress response

Opioid analgesics and narcotic antagonists

Chapter 8

associated with cardiac surgery. Despite potentially inducing cardiac sympathect­ omy, total spinal anesthesia remains unac­ ceptable. Epidural techniques provide adequate analgesia and can attenuate the stress response associated with cardiac surgery, as well as induce thoracic cardiac sympathectomy. There are significant adverse effects associated with the admin­ istration of opioids by intrathecal or epi­ dural techniques. The most common is pruritus; nausea and vomiting occur in about 30% of cases and urinary retention occurs mostly in young men. Respiratory depression requiring intervention occurs in about 1% of cases, similar to the incidence after intramuscular or intravenous use. Intrathecal or epidural fentanyl or sufenta­ nil is associated with early respiratory depression (within minutes), whereas mor­ phine is associated with delayed depression (hours). Intrathecal use increases the risk of respiratory depression. Hematoma forma­ tion is another complication associated with both intrathecal and epidural techniques. These techniques are therefore associated with significant risks, which make their clinical implementation controversial. The preoperative use of intrathecal morphine 0.5 mg and fentanyl 15 mg has been evaluated in 40 patients undergoing major liver resection in a randomized, double-blind, placebo-controlled study (27c). Preoperative intrathecal analgesia significantly reduced the need for post­ operative morphine for pain management threefold and was not associated with a significant difference in adverse effects. Inhalation The pharmacokinetics, phar­ macodynamics, safety, and efficacy of ther­ apeutic inhalational opioids have been reviewed (28R). Pulmonary delivery of opioids facilitates rapid and increased absorption, making this route suitable for management of acute pain. However, there are very few published data on their safety and efficacy. The literature suggests that this technique is well tolerated and is associated with adverse effects similar to those associated with other routes. The authors highlighted the importance of increased regulatory control of the

153

technique, because of the associated poten­ tial for abuse. Intranasal Intranasal diamorphine spray has been compared it with injectable diamor­ phine for maintenance treatment (29c). Intra­ nasal diamorphine was easier of use associated with reduced stigma and a reduced risk of adverse effects due to injection. Drug–drug interactions Alcohol The use and abuse of alcohol by individuals taking opioid substitution therapy is com­ mon. The effect of opioid substitution therapy on blood alcohol concentration has been studied in compared non-drug-using controls (n ¼ 22) and individuals taking methadone (n ¼ 14), levo-a-acetylmethadol (LAAM) (n ¼ 14), or buprenorphine (n ¼ 12) (30c). Participants were given alcohol 14.7 g/kg 2–3 hours before opioid therapy and 1–2 hours after. In those taking opioid substitution therapy there was a reduced blood alcohol concentration, espe­ cially at peak opiate plasma concentrations. Although the difference was significant the clinical implication is likely to be minimal.

OPIOID RECEPTOR AGONISTS Alfentanil

(SED-15, 72; SEDA-27, 88)

Comparative studies Alfentanil has been compared with morphine in the attenuation of experimental muscle pain in 28 healthy volunteers (31c). The two opioids had similar analgesic effects, with limited effects in attenuating central hypersensitivity, showing that other drugs (in combination or alone) would be required for adequate muscle pain with a central component. The two drugs had similar adverse effects profiles, the main effects being dizziness, tiredness, itching, and flushing. Nausea was more common after morphine. No volunteers withdrew because of adverse effects. Alfentanil has been compared with fenta­ nyl and remifentanil in 135 patients

Chapter 8

154 undergoing stereotactic brain biopsy (32c). All regimens (intravenous alfentanil 7.5 mg/ kg followed by 0.25 mg/kg/minute; intrave­ nous fentanyl bolus 1 mg/kg; and remifentanil 0.05 mg/kg/minute) provided similar hemo­ dynamic and respiratory effects; however, fentanyl produced a lower mean heart rate, providing less hemodynamic stability. Drug dosage regimens The combination of alfentanil+propofol is indicated for classic laryngeal mask airway insertion. In 75 adult Chinese patients undergoing minor surgery there was apnea in all subjects, increasing with increasing doses of alfentanil (5, 10, 15, and 20 mg/kg) (33c). The optimal combina­ tion for effective insertion of a laryngeal mask was propofol 2.5 mg/kg+alfentanil 10 mg/kg. Drug administration route Administra­ tion of intranasal alfentanil to 36 children with acute moderate-to-severe pain pro­ vided adequate analgesia with no adverse events (34r).

Codeine

(SED-15, 880; SEDA-26, 89)

Safety of codeine during breastfeeding There has been a report of opioid toxicity in a breast-fed baby of a mother taking codeine, and a subsequent meta-analysis and a case–control study have supported the view that in a few mothers who are ultraextensive metabolizers of codeine, breast-feeding while taking codeine may not be safe. Codeine is mainly eliminated by glucuronidation, but 10% is O-demethylated by CYP2D6 to morphine and 10% is Ndemethylated to norcodeine; morphine is further metabolized to two glucuronides, morphine-6-glucuronide (via uridine diphosphate-dependent glucuronosyltransferase 2B7), which is active, and morphine-3glucuronide, which is not. CYP2D6-mediated O-demethylation of codeine is necessary for

A.H. Ghodse and S. Galea

its pharmacodynamic effects (35cr), and its adverse effects are mainly due to O-demethylation to morphine or its active metabolite (36cr). The ability to O-demethylate codeine is polymorphically distributed in the population. There are two major phenotypes, called extensive and poor metabolizers. Most people are extensive metabolizers. Poor metabolizers are unable to metabolize codeine to morphine. However, a few individuals are very extensive (so-called “ultrarapid”, better “ultraextensive”) metabolizers, who form larger amounts of morphine and its metabolites than extensive metabolizers (37A). This results from CYP2D6 gene duplication, which occurs with variable frequencies in different populations (Table 1) (38c,39C,40C,41R,42R,43R). In ultraextensive metabolizers even small doses of codeine can cause severe toxicity (44A). An early study of the pharmacokinetics of codeine in 17 samples of breast milk from seven mothers and 24 samples of plasma from 11 healthy full-term neonates showed that milk codeine concentrations were 34–314 ng/ml 20–240 minutes after codeine and morphine concentrations were 1.9–21 ng/ml; infant plasma samples 1–4 hours after feeding had concentrations of codeineo0.8–4.5 ng/ml and morphineo0.5–2.2 ng/ml (45c). The authors

Table 1 Population frequencies of ultraextensive metabolizers Population

Frequency (%)

Korean Scandinavian Chinese Nicaraguan German White British Spanish French Black American White American Croatian Turkish Greek, Portuguese Saudi Arabian Ethiopian

0.3 1 1 1 1–2 1–3 1–10 2 2 2–4 4 6–9 10 21 29

Opioid analgesics and narcotic antagonists

Chapter 8

suggested that moderate codeine use during breast-feeding (no more than four doses of 60 mg) is probably safe, and this has been subsequently taken to be so (46R). However, there have been occasionaly anecdotal reports of adverse events in breast-fed neonates (47C,48c,49c,50c), and a neonate died after being breast-fed by his mother, who had taken codeine (51A).  A neonate developed increasing lethargy and

difficulty in breast-feeding at 7 days of age. On day 13 he was cyanotic and lacked vital signs. Resuscitation was unsuccessful. Full postmortem analysis failed to identify an anatomical cause of death. Postmortem toxicology showed a blood morphine concentration of 70 ng/ml and paracetamol 5.9 mg/ml. Immediately after birth the mother had taken Tylenols 3 (codeine 30 mg+paracetamol 500 mg), initially two tablets twice daily then half that dose on postpartum day 2 because of somnolence and constipation. After the neonate started to feed badly, the mother expressed her milk and stored it in a freezer. Analysis of the milk showed a morphine concentration of 87 ng/ml.

Neonates receiving morphine for analgesia have been reported to have serum concentrations of morphine of 10–12 ng/ml (52C), and the maximum plasma morphine concentration in breast-fed infants of mothers who had taken codeine 60 mg for postnatal pain was 2.2 ng/ml (44A). However, in this case the mother was compound heterozygous for a CYP2D6�2 A allele and a CYP2D6�2  2 gene duplication, possibly originating from a homologous, unequal crossover event involving two 29 kb XbaI wild-type alleles (53E). She had three functional CYP2D6 genes and was an ultraextensive metabolizer. Both the father and the infant had only two functional CYP2D6 alleles (CYP 2D6�1/�2 genotypes). Both the mother and the infant were homozygous for the UGT2B7�2 (–161TT, 802TT) allele, which has been associated with increased formation of morphine-6-glucuronide compared with the UGT2B7�1 allele (–161C, 802C). In a systematic review, three abstracts and two full-length studies werre found that had reported adverse drug reactions (unexplained episodes of drowsiness, apnea, bradycardia, and cyanosis) in 35 infants

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exposed to codeine in breast milk (54M). In a subsequent case–control study, based mainly on telephone interviews, there were 17 cases in which mothers reported nervous system depression in their breast-fed infants, one of whom died; two mothers each had two rare genotypes: CYP2D6 UM, leading to ultraextensive metabolism of codeine to morphine, and UGT2B7�2/�2, leading to extensive formation of morphine6-glucuronide (55c). The mothers of the 17 symptomatic infants had taken a mean 59% higher codeine dose than the mothers of 55 asymptomatic infants (1.62 versus 1.02 mg/ kg/day). There was 71% concordance between maternal and neonatal nervous system depression. Despite the problems in measuring fluid and tissue concentrations of drugs postmortem (56A), this case and the subsequent studies suggest that women with these rare polymorphisms should not breast-feed their babies while taking codeine. Various strategies have therefore been proposed to deal with the use of codeine in breast-feeding mothers (57Ar):  avoid prescribing codeine and use nonsteroidal anti-inflammatory drugs instead; this approach might not be possible in cases of severe pain, although other analgesics may be available;  prescribe codeine-containing products for no more than 2–3 days, so that neonatal accumulation of morphine does not occur; this strategy would not work if the baby also was an ultraextensive metabolizer;  genotype all postpartum women about to receive codeine; this is probably not a costeffective strategy, and in any case the relevant tests are not generally available;  carefully monitor all breast-feeding women taking codeine;  carefully monitor all breast-fed infants of codeine-using mothers; measure morphine concentrations whenever there are adverse events consistent with opioid toxicity; give naloxone if you suspect opioid toxicity. None of these strategies is ideal.

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Dextromethorphan (SED-15, 1088; SEDA-28, 106; SEDA-29, 105; SEDA-30, 109) Comparative studies Dextromethorphan and pholcodine were equally effective in 129 patients with acute, non-productive cough in a double-blind, randomized, parallel-group, multicenter trial (58C). Systematic reviews A systematic review of the postoperative effects of perioperative dextromethorphan in 28 randomized, dou­ ble-blind studies in 1629 patients showed that there was no dosage regimen that could be recommended, but identified its safety as an adjunctive treatment with other opioid analgesics, with potential opioid-sparing effects and reduced opioid-related adverse effects (59M). However, the authors reported that constancy of adverse effects was ques­ tionable and highlighted the fact that effective dextromethorphan analgesia is route specific, the parenteral route being more effective. Nervous system Dextromethorphan-induced nervous system impairment has been described in a man with a history of drug abuse (60A).  A 28-year-old man had episodes of tiredness,

light-headiness, headaches, and disorientation, on one occasion associated with psychomotor retardation, apparent intoxication, and pro­ found sleepiness; 9 hours later he developed mild stupor, had reduced attention, and was slow in responding. He had prominent gaze-evoked nystagmus and gait ataxia. Comprehensive urine toxicology was positive for dextromethorphan.

Susceptibility factors Neurological disease The combination of dextromethor­ phan and quinidine was beneficial in treating pseudobulbar palsy in 150 patients with multiple sclerosis (61c). Dizziness was the only significant adverse effect.

Dextropropoxyphene

(SED-15, 1092;

SEDA-30, 109) Musculoskeletal In a prospective cohort study of 362503 patients during a mean

A.H. Ghodse and S. Galea

follow-up of 464 days, about 10% (37569) had at least one prescription for propox­ yphene and about l% (5065) had a hip fracture (62C).

Diamorphine (heroin) (SED-15, 1096; SEDA-28, 106; SEDA-29, 106; SEDA-30, 110) Nervous system Substance-induced polyradiculopathy has been described in a 23­ year-old Caucasian man after administra­ tion of high doses of heroin and cocaine into the left internal carotid artery (63A). Six patients developed some form of neuropathy following heroin use (64A). Four developed a plexopathy and two a symmetric distal axonal sensorimotor neuropathy. Five also had rhabdomyolysis with high creatinine kinase activities. Spongiform leukoencephalopathy has been described in a 26-year-old after inhalation of heroin (65A). The diagnosis was confirmed by MRI scan. Immunologic Intrathecal diamorphine 0.5 mg for total hip arthroplasty in a 42­ year-old with a history of anaphylaxis resulted in an anaphylactic reaction (66A). The reaction was controlled and diamor­ phine was avoided. Drug overdose Various initiatives have addressed prevention of heroin overdose. Educational programs that aim at harm reduction activities for heroin users are widely accepted. In such programs, heroin users are taught about overdose suscept­ ibility factors and appropriate responses to overdose, such as resuscitation techniques. In a cross-sectional study, 257 heroin overdose survivors recruited by ambu­ lance paramedics in Melbourne between 1999 and 2001 participated in structured interviews within 10 days of the overdose (67c). The questionnaire addressed knowl­ edge of overdose risk reduction strategies, behavior in the 12 hours before the over­ dose, and overdose causality. Most (75%) of the subjects had taken an additional

Opioid analgesics and narcotic antagonists

Chapter 8

overdose, half of them in the preceding 6 months; 20% had engaged in risky over­ dose behaviors before the overdose; and 90% had knowledge of overdose preven­ tion messages. Most overdoses occurred within 5 minutes of purchasing the drug. The heroin user was usually alone at the time of the overdose. Heroin was com­ monly mixed with other drugs. Paradoxi­ cally, subjects who reported awareness of the “don’t mix drugs” message were 2.8 times as likely to have mixed alcohol and or benzodiazepines with heroin than those who did not report such awareness. The authors noted that this last finding is contrary to a popular assumption that increased knowledge may reduce risky behavior. In a retrospective study of outcomes after cardiac arrest caused by heroin overdose the Helsinki Emergency Medical Service in Finland recorded 94 cases of cardiac arrest due to acute drug poisoning (25 heroinrelated and 69 overdoses by other agents) during 1997–2000 (68c). Resuscitation was attempted in 19 of the heroin-related cases and in 53 of the others. Survival after heroin overdose was poor: only three heroin users and six of the others survived, which is not a statistically significant difference. The sur­ vivors had acute renal failure, hypoglyce­ mia, and hypothermia. Susceptibility factors Genetic In 420 Chinese heroin addicts cravings were sig­ nificantly higher in carriers of the dopamine D4 receptor gene with a variable number tandem repeat long type allele than noncarriers (69C).

Fentanyl (SED-15, 1346; SEDA-28, 108; SEDA-29, 106; SEDA-30, 110) Observational studies The incidence of adverse events in 14386 patients receiving fentanyl has been studied after implementa­ tion of the Joint Commission on Accredita­ tion of Healthcare Organization guidelines for procedural sedation and analgesia in an urban tertiary-care children’s hospital (70C). The combination of fentanyl+midazolam

157

was the regimen with the highest incidence (9.7%) of adverse events compared with other regimens involving opioids. The most common adverse event was hypoxemia (7.1%), followed by hypotension (1.0%), prolonged sedation (0.7%), vomiting (0.4%), airway obstruction (0.4%), bradycardia (0.1%), pain-related agitation (0.1%), and agitation (not pain-related) (0.04%). Comparative studies Bupivacaine+cloni­ dine as an alternative to bupivacaine+fen­ tanyl has similar analgesic efficacy and is associated with fewer adverse effects, as reported in a study of 47 children under­ going the Nuss procedure (71C). The children were randomized to bupivacaine +clonidine, bupivacaine+fentanyl, or bupi­ vacaine+fentanyl+clonidine. Vomiting and pruritus were significantly more common in those who received fentanyl. Vomiting occurred in 27% of those who received bupivacaine+clonidine, compared with 69% of those who received bupivacaine+fenta­ nyl and 55% of those who received bupivacaine+fentanyl+clonidine. Pruritus occurred in 85% of those who received bupivacaine+fentanyl and 54% of those who received bupivacaine+fentanyl+cloni­ dine, but in none of those who received bupivacaine+clonidine. Placebo-controlled studies In a placebocontrolled study in 399 patients with mod­ erate-to-severe osteoarthritis transdermal fentanyl produced better pain management (72C). The most common adverse effects were nausea, vomiting, and somnolence. Cardiovascular Bolus intravenous fenta­ nyl 1 mg/kg in stereotactic brain biopsy for intracranial mass lesions in 135 patients was well tolerated but provided less hemodynamic stability than alfentanil and remifen­ tanil (32c). Fentanyl failed to produce adequate protection of the myocardium from ischemic injury following cardiopulmonary bypass in a comparative study with mor­ phine in 46 patients (73c). Global cardiac function was assessed by the myocardial performance index. Fentanyl significantly improved left ventricular function, but

158 morphine improved global ventricular function. Midazolam+fentanyl has been compared with dexmedetomidine during carotid endarterectomy in 56 patients (74c). Those who received fentanyl required more inter­ ventions to control hypertension and/or tachycardia (72% versus 40%), and in the post-anesthesia care unit fewer interven­ tions were required for hypotension (11% versus 28%). Many more of the patients who were given dexmedetomidine required additional pain relief (72% versus 38%). Heart rate variability during anesthesia has been studied in patients who received sevoflurane+fentanyl; in two cases there was reduced heart rate variability associated with junctional rhythm (75A). In a 9-year­ old girl with hereditary sensory autonomic neuropathy type 2 there was altered heart rate variability with improved hemody­ namic stability after the administration of propofol+fentanyl (76A). A 68-year-old man with Brugada syn­ drome developed ventricular tachycardia during general anesthesia and thoracic paravertebral block using anesthetic agents+fentanyl (77A). It is not clear how fentanyl contributed to the cardiac rhythm changes in this case.

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A.H. Ghodse and S. Galea

co-sedation with midazolam+fentanyl (two episodes) than in those who received midazolam alone (no episodes) (80c). How­ ever, the combination provided more reli­ able sedation. Autacoids Surgical procedures generally cause perioperative stress, with release of cortisol, cytokines (interleukin-6 and tumor necrosis factor alfa) and acute phase proteins (C-reactive protein and leptin). Opioids are believed to have an inhibitory effect on cortisol release, reducing the neuroendocrine perioperative response. This has been studied in 14 patients under­ going hemorrhoidectomy, who were given either general anesthesia with thiopental 5– 7 mg/kg (n ¼ 7) or fentanyl 0.5 mg/kg (n ¼ 7) (81c). There were higher leptin concentrations in the general anesthesia group, but this was not clinically significant. There were no other differences between the two groups.

Respiratory The addition of intrathecal fentanyl 20 mg to hyperbaric bupivacaine in 40 women undergoing cesarean section improved the quality of subarachnoid blockade but did not result in worsening of respiratory function (78c).

Susceptibility factors Genetic A study (82C) explored whether beta 2-adrenoceptor genotype affects vasopressor requirements to manage opioid-induced hypotension. Spinal anesthesia with 12 mg hyperbaric bupivacaine, 25 mg fentanyl, and 200 mg morphine was administered to 170 women undergoing elective cesarean section. Vaso­ pressor treatment was required in 90%, but those with glycine at position 16 and/or glutamate at position 27 of the beta 2­ adrenoceptor required lower vasopressor doses for opioid-induced hypotension.

Gastrointestinal Constipation is a com­ mon adverse effect of opioids. In a 13­ month, open, parallel-group comparison of a fentanyl transdermal reservoir and oral modified-release morphine in 677 patients with chronic low back pain who were given transdermal fentanyl or oral modifiedrelease morphine there was less severe constipation with fentanyl (79C). The Patient Assessment of Constipation Symp­ toms 12-item questionnaire was a reliable measure of the severity of opioid-induced constipation. Ileus occurred more commonly in 30 mechanically ventilated patients receiving

Drug formulations The bioequivalence of four 100-mg fentanyl buccal tablets given simultaneously has been compared with that of one 400-mg tablet. Fentanyl Cmax was higher in those receiving four tablets possibly because of an increased surface area expo­ sure; however, there was no significant difference in adverse events (83c). The fentanyl HCl patient-controlled ion­ tophoretic transdermal system (IONSYS) uses low-level electrical energy to transport fentanyl across the skin, providing adequate analgesia with minimal drug-related adverse effects (84M).

Opioid analgesics and narcotic antagonists

Chapter 8

The fentanyl HCL iontophoretic trans­ dermal system has been compared with patient-controlled intravenous morphine after total hip replacement in a multicenter study in 799 patients (85C). Patient global assessment of the route of administration, pain intensity, and adverse events were recorded for the first 24 hours. There were no significant differences, suggesting that transdermal fentanyl was suitable for acute pain after total hip replacement. Drug dosage regimens Continuous epi­ dural infusion during labor in 40 women has been compared with regular intermittent bolus administration of ropivacaine and fentanyl (86c). Intermittent administration resulted in the use of less ropivacaine and fentanyl, less requirement for rescue analge­ sia, equivalent pain relief, and less potential compromise of cardiovascular stability. Co-administration of propofol 3 mg/kg +fentanyl 3 mg/kg was the optimal regimen for tracheal intubation in 60 children aged 3–10 years (87c). This regimen facilitated tracheal intubation with effective blunting of pressor response, but without triggering a fall in cardiac output (as observed in high dose regimens, e.g., propofol 3.5 mg/kg +fentanyl 3 mg/kg). Drug administration route Transdermal administration of fentanyl has been evalu­ ated in a placebo-controlled study in 484 adults admitted to the post-anesthesia care unit after major surgery (88C). They were given supplementary intravenous fentanyl as required. Pain was better controlled by transdermal fentanyl and fewer of these patients withdrew because of dissatisfaction. There were no differences in treatmentrelated adverse effects. Cervical epidural and intravenous patient-controlled analgesia with fentanyl have been compared in 42 patients under­ going pharyngolaryngeal surgery (89c). The cervical epidural route provided better analgesia at rest in the first 6 hours post­ operatively, but this was not accompanied by a reduction in fentanyl dosage require­ ments. There were no differences in adverse effects and there were no episodes of clinical respiratory depression or severe

159

sedation. Although the results were favor­ able, there were no clinical benefits from the cervical epidural technique. Epidural anesthesia in 43 patients under­ going lumbar microdiscectomy has been compared with general anesthesia (90c). Fentanyl 5 mg/kg+propofol+vecuronium was used for induction of general anesthe­ sia, followed by 1.2 mg/kg/hour+N2O/ O2+isoflurane as maintenance anesthesia. The epidural group received fentanyl 100 mg +lidocaine+adrenaline. Nausea, vomiting, and headaches were more common in those who received general anesthesia. Patient-controlled analgesia with intrave­ nous fentanyl was as effective as subacromial ropivacaine with minimal adverse effects and high patient satisfaction in 48 patients under­ going open acromioplasty surgery (91c). In contrast, those who received subacromial fentanyl did not have adequate analgesia and required rescue doses of tramadol. In all cases, nausea and vomiting were the most common adverse effects. Drug–drug interactions Fluconazole Death from respiratory depression and circulatory failure due to fentanyl intoxica­ tion after the addition of fluconazole has been reported (92A).  A

64-year-old man received transdermal fentanyl 150 mg/hour for pain in the mouth following radiation therapy for tonsillar can­ cer. He developed an oral fungal infection and was given fluconazole 50 mg/day. Three days later he died in his sleep. Postmortem blood concentrations of fentanyl were high.

Although the blood concentration of fentanyl before fluconazole was given was not known, the authors believed that fluconazole had increased the concentration of fentanyl by inhibition of CYP3A4, which metabolizes fentanyl. Management of adverse drug reactions Pruritus is a common cause of patient dissatisfaction after opioid administration for postoperative pain control. In 98 parturients undergoing elective cesarean section who were given morphine 160 mg and fentanyl 15 mg postoperatively, ondansetron or tropi­ setron did not prevent itching caused by

160 intrathecal morphine and fentanyl (93c). The incidences of pruritus were 87% with ondan­ setron, 79% with tropisetron, and 76% with placebo. Medication for pruritus was required in all three groups (in 23%, 39%, and 31% respectively). In five prospective randomizedcontrolled studies in 483 outpatients who were given fentanyl for selective spinal anesthesia, pruritus occurred in 75% and was not prevented by ondansetron (94r). The management of pseudoallergic reactions to opioids using continuous intrave­ nous infusion is well exemplified in a case report (95A).  A 22-year-old woman, with a history of

repeated neurosurgical procedures for menin­ gomyelocele and hydrocephalus, developed opioid intolerance. General measures such as substitution with non-opioid medications, a well-tolerated opioid, or antihistamines were not effective. She was then given escalating doses of intravenous fentanyl, and tolerated 0.5 mg/kg, with a cumulative dose of 50 mg. Postoperatively she was given and of infusion fentanyl 0.25 mg/kg/hour. A continuous infusion was chosen, given that the total dose of opioid required for pain control was significantly less than the amount required through inter­ mittent administration. This regimen was better tolerated. A similar regimen was used at a later operation, this time by gradually escalating the dose of hydromorphone. A starting infusion rate of 0.2 mg/hour was inadequate and she required 1 mg bolus doses for pain control, which produced severe dys­ pnea. Increasing the infusion rate by 0.05 mg/ hour as required, up to a maximum of 0.35 mg/ hour, provided adequate pain control, with no need for further bolus doses and no further allergic reactions.

This case shows that continuous opioid infusion is better tolerated than bolus doses, because the total dose requirements with continuous infusions are significantly less.

Frakefamide Frakefamide is a new peripherally acting opioid MOR receptor agonist. It has restricted penetration of the blood–brain barrier into the central nervous system and has selective MOR receptor agonist activ­ ity. It is a large molecule (molar mass 600 Da), a fluorinated tetrapeptide, H-Tyr­ (D)Ala-(pF)Phe-Phe-NH2 hydrochloride,

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A.H. Ghodse and S. Galea

with potent analgesic activity in both rats and humans. Placebo-controlled studies In a rando­ mized placebo-controlled comparison with morphine in 12 healthy volunteers, frake­ famide (like placebo) did not impair responses to hypercarbic or hypoxic chal­ lenges, demonstrating its peripheral activity with no effects on central breathing mechanisms (96c). On the other hand, morphine impaired responses to both hypercarbic and hypoxic challenges. All those who were given frakefamide had transient myalgia (mild to severe) which started within 15 minutes after administra­ tion and disappeared after 15–20 minutes. Six of the subjects also had rhinitis.

Hydrocodone

(SED-15, 1702; SEDA

-29, 106) Comparative studies Hydrocodone is effective in the management of pain after augmentation mammoplasty but is associated with opioid-related adverse effects. In a study of the potential opioid-sparing effect of a combination of hydrocodone+celecoxib one group of 50 patients had postoperative pain managed by hydrocodone and another 50 received celecoxib+hydrocodone (97C). The hydrocodone group required hydrocodone 110 mg (mean dose) in the 7-day postoperative period. The combination group required celecoxib 400 mg/day +hydrocodone 34 mg. The latter also achieved superior pain relief and caused 53% less nausea.

Hydromorphone

(SED-15, 1703; SEDA-28, 47; SEDA-29, 107) Comparative studies Hydromorphone 0.015 mg/kg intravenously has been compared with intravenous morphine 0.1 mg/kg in 198 patients attending the emergency department for acute severe pain (98C). There was adequate pain relief in the two groups and the adverse effects were similar, except for pruritus, which was not experienced in those who received hydromorphone.

Opioid analgesics and narcotic antagonists

Chapter 8

Neuromuscular function Long-term and high-dose opioid administration can cause myoclonus. However, there have been two reports of myoclonus after low doses of short-term hydromorphone.  A 75-year-old man with multiple system

atrophy fractured a hip and was given intra­ venous hydromorphone 1 mg over 20 minutes (99A). He developed severe generalized myo­ clonus and rigidity and reduced consciousness. His symptoms were relieved by naloxone.  A 55-year-old man with non-obstructive hypertrophic cardiomyopathy was given intra­ venous hydromorphone+ondansetron for pain and vomiting (100A). On day 1 he was given a total of 4 mg hydromorphone, which was increased on day 2. He developed myoclonus involving the head, neck, and limbs. The contractions continued even when ondanse­ tron was withdrawn, but the symptoms abated within hours of hydromorphone withdrawal.

These cases suggest that opioid-induced myoclonus can occur after low doses of opioids given for short periods and that neuroexcitotoxicity can be caused by opioids themselves rather than by accumu­ lation of metabolites. Multiple system atro­ phy in the first case is likely to have increased the individual’s susceptibility to opioid-induced myoclonus.

Methadone

(SED-15, 2270; SEDA-28, 47; SEDA, 107; SEDA-30, 112)

Observational studies Methadone is effective in the treatment of chronic non­ malignant pain in patients with problematic opioid use. In 60 patients who enrolled in a methadone program tailored to meet the needs of the patient with pain, the most common causes of pain were: low back pain (n ¼ 12), neuralgia (n ¼ 8), idiopathic (n ¼ 8), and musculoskeletal (n ¼ 7) (101c). The oral opioids most commonly misused were ketobemidone and codeine. Patients took methadone 100 (range 10–350) mg/day for a mean duration of 34 months. Meticulous dose titration was required to achieve optimal dosages for adequate pain control. Most of the patients (75%) achieved good pain relief, and 50% reported a good quality of life. The incidence of adverse effects was

161

significant: 40–60% had sedation, anergia, increased weight, sweating, and sexual dysfunction. There was dyspnea in 30% and edema in 19%. Other serious events include: pulmonary embolism (n ¼ 4), cerebral thromboembolic events (n ¼ 2), and torsade de pointes (n ¼ 1). Although methadone can provide effective pain control in such patients, careful monitoring for adverse effects is necessary. Inpatient treatment with a multiprofessional approach is recommended. Cardiovascular Methadone has been asso­ ciated with cardiac dysrhythmias (102A).  A 6-month-old infant who received metha­

done 0.1 mg/kg on three occasions to counter­ act opiate withdrawal symptoms following treatment with fentanyl for sedation during mechanical ventilation developed a sinus bradycardia, which responded to tactile stimu­ lation. Methadone was withdrawn and 10 hours later sinus rhythm returned.

QT interval prolongation has been studied retrospectively in 167 patients taking metha­ done maintenance and 80 controls (103c). There was QTc prolongation in 16% of the methadone group compared to none of the controls. Torsade de pointes also occurred in six patients in the methadone group. The risk of QTc prolongation correlated positively with methadone dosage, hepatic impairment, potassium depletion, and the use of inhibitors of CYP3A4. However, it was also found at low doses of methadone, even as low as 30 mg/day, raising the question of cardiac monitoring, even for patients not believed to be at risk. In 78 patients taking methadone QTc prolongation was associated with higher doses of methadone (104c). The (R)-enan­ tiomer was found to be responsible. Nervous system Toxic encephalopathy has been reported after accidental ingestion of methadone in a 3-year-old boy, who devel­ oped coma and acute obstructive hydro­ cephalus due to massive cerebellar edema and supratentorial lesions (105A). Endocrine Accidental use of methadone caused acute non-ketotic hyperglycemia in

162 three young children, all of whom devel­ oped central nervous system depression or coma (106A). The first child had a metha­ done blood concentration of 0.36 mg/l and the second had taken 20 mg of methadone. Musculoskeletal In 92 patients taking methadone maintenance treatment there was low bone mineral density in about 83%; the risk was positively correlated with lower weight and heavy alcohol use and was more common in men (107c). Infection risk Anterior uveitis and lens abscess due to infection with Candida albicans has been attributed to methadone by injection (108A).  A 31-year-old woman who injected methadone

mixed with orange juice, developed a painful red eye and impaired vision. Candida albicans was isolated from the anterior chamber and lens.

This patient probably developed the infection from spread of blood-borne fungal spores from the mixture of orange juice and methadone. Drug tolerance Tolerance to opioids is well recognized. In 37 children who had been given a continuous intravenous opioid infusion for at least 120 hours, tolerance was managed by weaning off oral metha­ done (109c). The children were randomized to two groups. One group was weaned off over 5 days (n ¼ 16) and the other over 10 days (n ¼ 21). There were minimal differ­ ences between the groups. Fetotoxicity The effect of chronic maternal methadone use on intrapartum fetal heart rate has been investigated in 56 mothers using methadone, median dose 70 mg/day, and 51 controls (pregnant women attending the general obstetric clinic) (110c). Fetuses who were exposed to methadone had lower fetal heart rate scores, with less marked variability, a lower proportion of accelerations, and a lower baseline. More troublesome fetal heart rate decelerations were also observed in exposed fetuses during the second stage of labor. These findings were not thought to be compatible with hypoxia or acidosis and did not affect outcomes in the neonates.

Chapter 8

A.H. Ghodse and S. Galea

Lactation  A 3.8-kg infant girl had irritability recurrent

episodes of apnea requiring endotracheal intubation (111A). The mother had taken methadone and Vicodins (hydrocodone +paracetamol) before breast-feeding. The infant’s urine drug screen was positive for opioids and she improved with naloxone.

Drug–drug interactions Diazepam The concomitant use of diazepam with metha­ done in individuals with substance misuse problems is common. The effects of single doses of diazepam 10 and 20 mg in patients stable on either methadone or buprenor­ phine did not result in changes in physio­ logical parameters, but the interaction produced changes in subjective effects and psychomotor performance (112c). More methadone-treated patients given diazepam than those given placebo experienced euphoria, drug liking, and strength of drug effects. Similarly, more patients had worse psychomotor performance, reflected in measures of reaction time, cancellation time, and digit symbol substitution task. The effects peaked at 1–2 hours after dosing. The extent of impairment in reac­ tion time (324 milliseconds versus 274 milli­ seconds) suggests risks in the performance of tasks such as driving or operating machinery.

Morphine

(SED-15, 2386; SEDA-28, 109; SEDA-29, 107; SEDA-30, 113)

Observational studies In 20 individuals with heroin dependency attending an addiction outpatient center a mean dose of modified-release morphine 760 mg/day was reached over 2 weeks (113c). There were no serious adverse events, including deaths or withdrawal from study. Mild-to­ moderate events included constipation (5 episodes) and sweating (1 episode). The incidence of adverse events asso­ ciated with sedation and analgesia in 14386 children attending a tertiary care children’s hospital has been described after imple­ mentation of procedural guidelines (68C). A regimen of morphine+midazolam was

Opioid analgesics and narcotic antagonists

Chapter 8

associated with hypoxia (5.5%), prolonged sedation (0.5%), and hypotension (0.5%). No vomiting, bradycardia, airway obstruc­ tion, or agitation was reported. In a prospective study in 186 patients, 75% achieved adequate pain control with morphine, 20% responded to a switch to oxycodone, and 2% responded after switch­ ing to more than one alternative opioid (114c). The main reasons for switching included inadequate pain control, confusion and drowsiness, nausea, and nightmares. Comparative studies Morphine via a patient-controlled device for analgesia after cesarean section was associated with more adverse effects than oral oxycodone+para­ cetamol (115c). Morphine caused more nausea and drowsiness 6 hours after deliv­ ery, but slightly less nausea 24 hours after delivery. In a prospective study (116c) 130 patients with acute renal colic were randomized to intravenous. morphine 5 mg followed by 5 mg at 20 minutes, intravenous ketorolac 15 mg followed by 15 mg at 20 minutes) or both. The combination regimen gave super­ ior analgesia. Morphine was associated with more adverse effects than ketorolac alone or the combination: nausea in 16% (versus 2% and 4% respectively); vomiting 5% (0% and 2%); itching 2% (0% and 0%); and dizziness 9% (0% and 2%). The combination of morphine 0.1 mg/kg +ketamine 0.15 mg/kg has been compared with morphine 0.1 mg/kg alone and keta­ mine 0.15 mg/kg alone in the management of pain after lumbar disk surgery in 68 patients (117c). Postoperative analgesia was more effective with the combination regi­ men and the incidence of nausea and vomiting was less. Morphine and tramadol have been com­ pared in 40 children undergoing cardiac surgery (118c). Morphine was given as an initial dose of 0.2 mg/kg followed by 0.02 mg/kg boluses as nurse-controlled analgesia on a background infusion of 0.015 mg/kg/hour. Tramadol was given as an initial dose of 2 mg/kg followed by 0.2 mg/kg boluses as nurse-controlled analgesia on a background infusion of 0.15 mg/kg/hour. Those who received

163

tramadol recovered earlier, had earlier tracheal extubation, and were less sedated. Epidural morphine and sufentanil have been compared in 60 patients undergoing major abdominal surgery (119c). They were randomized to sufentanil 250 mg or mor­ phine 10 mg, both with ropivacaine 0.2%. Those who received morphine had more adverse effects: hypotension (2 versus 1), pruritus (11 versus 3), nausea and vomiting (11 versus 1), and problems with micturition (12 versus none). Cardiovascular The hemodynamic effects of morphine have been studied in 144 ventilated neonates, who were randomly allocated to morphine or saline (120C). A loading dose of morphine 100 mg/kg was followed by a continuous infusion at a rate of 10 mg/kg/hour. There were no significant differences in blood pressure or the use of volume expanders and vasopressor drugs, suggesting that recommended morphine dosages in neonates were not associated with major adverse effects. On the other hand, in 11 ventilated premature infants morphine reduced cerebral blood oxygena­ tion and increased cerebral blood volume (121c). Furthermore, it has been suggested that morphine may contribute to intraventricular hemorrhage in ventilated preterm infants (122r). Respiratory Intravenous morphine 0.1 mg/ kg caused mild respiratory depression in 38 neonates undergoing central line placement (123c). Hypotension developed in 5% and there was a slight increase in ventilator requirements. In another study in 22 preterm ventilated neonates, those who received morphine by infusion had poor respiratory drive and hypotension (124c). Intrathecal morphine can cause longterm respiratory depression (125A).  A 41-year-old man with chronic pain after a

motorcycle accident 6 years before used regular morphine via an intrathecal drug delivery system. The dose was altered accord­ ing to needs, and was receiving 4 mg/day. He complained of severe tiredness, low mood, and reduced respiratory function. He was weaned

164 off morphine and was eventually switched to oral hydromorphone 12 mg/day. This was followed by considerable improvement in his symptoms, suggesting chronic morphine intoxication.

In 91 preterm neonates low-dose morphine was not associated with apnea, the incidence of which increased at doses above 0.03 mg/kg; increased apnea was only evident after 3 hours (126c). The authors suggested that further evidence is required before morphine can be recommended preterm infants.  A 26-year-old woman with postoperative pain

after anterior cruciate ligament reconstruction and bilateral meniscal repair received four consecutive intravenous doses (total 35 mg) (127A). This produced adequate pain relief, but she developed fatal respiratory depression.

Nervous system Reversible delayed posthypoxic leukoencephalopathy has been reported after morphine overdose(128A).  A 40-year-old woman took an accidental

overdose of morphine 360 mg, from which she had been resuscitated for 15 minutes followed by intubation and ventilation. On day 17 she developed a non-specific headache and visual disturbance, echolalia, persevera­ tion, and severe global cognitive impairment, especially in memory and verbal fluency. Electroencephalography showed a significant encephalopathy, with excess delta activity. T2-weighted MR images on day 22 showed diffuse subcortical and supraventricular white matter changes with sparing of the gray matter. She improved with conservative management, but at day 34 still had deficits in orientation and memory. Repeat MR imaging at 6 months showed improvement in the white matter. At 9 months she had recovered cognitive function.

Pruritus was common among 98 parturi­ ents undergoing elective cesarean section who received postoperative morphine 160 mg and fentanyl 15 mg; neither ondanse­ tron nor tropisetron was effective in pre­ venting pruritus (91c). Neuromuscular function A 7-year-old girl with L5/S1 spondylolisthesis was given a caudal injection of morphine 2.5 mg in 10 ml of saline during surgery for repeat posterior spinal fusion (129A). This technique was used instead of intrathecal morphine, since

Chapter 8

A.H. Ghodse and S. Galea

the usual site of intrathecal administration was close to her spondylolisthesis. After 20 minutes she developed reduced com­ pound muscle action potentials and vigor­ ous electromyographic spontaneous firing. The authors suggested that the temporary loss of motor function and nerve root irritation had been caused by the caudal injection into a narrowed caudal epidural space, causing persistent pressure on the cauda equine from the volume of injectate. Psychological The impact of adverse effects on mood and quality of life were secondary outcome measures in a clinical trial in 41 patients who received morphine or gabapentin, alone or in combination (130c). The most common adverse events were sedation, constipation, and dry mouth. The severity of the adverse effects did not correlate significantly with mood or quality of life, but the study sample size may have been a limiting factor. Gastrointestinal In an epidemiological study of pain management in 1540 patients in a University Hospital in Thailand, the majority (80%) were satisfied with their treatment; severe nausea and vomiting were two of the main reasons for dissatisfaction (131C). Skin Acute generalized exanthematous pustulosis has been attributed to morphine (132A).  A 27-year-old man was given postoperative

analgesia, including intravenous morphine 10 mg. He developed itching, burning erythema, and a widespread rash with nonfollicular pustules, associated with fever. A few months later patch testing and a lymphocyte transformation test identified morphine as the cause of the eruption. He was generally healthy and had no family history of skin conditions.

Susceptibility factors Genetic The role of single nucleotide polymorphisms at nucleotide position 118 at exon 1 of the MOR gene in the effects of morphine has been explored in two studies. In one study patients undergoing total knee arthroplasty were divided into three groups: A118 homozygotes (n ¼ 74), A118 heterozygotes (n ¼ 33), and G118 homozygotes (n ¼ 13)

Opioid analgesics and narcotic antagonists

Chapter 8

(133C). The G118 homozygotes required significantly more morphine for analgesic control, suggesting that this genotype con­ fers a reduced response to morphine. There were no differences in adverse reactions in the three groups. In a second study G118 homozygotes required more morphine for adequate analgesia after total hysterectomy (134c). Drug dosage regimens Low-dose and high-dose regimens of intrathecal morphine and bupivacaine have been compared after selective dorsal rhizotomy in 26 children; 11 received a continuous infusion of morphine 0.4 mg/kg/hour+bupivacaine 40 mg/kg/hour, and 15 received morphine 0.6 mg/kg/hour +bupivacaine 40 mg/kg/hour (135c). Both groups received ketobemidone for break­ through pain. The high-dose regimen was association with better pain control and seven times less ketobemidone. There were no significant differences in the adverse effects profiles of the two regimens. Drug administration route Epidural mor­ phine gave better postoperative pain control than intravenous morphine after pectoralis major myocutaneous flap reconstruction in 60 patients (136c). There were no differences between the two groups in terms of drugspecific adverse effects. The epidural tech­ nique is associated with procedural risk and its benefits do not outweigh the risks. Intrathecal morphine 0.3 mg preopera­ tively+intravenous patient-controlled mor­ phine postoperatively has been compared with intravenous patient-controlled mor­ phine in 78 elderly patients undergoing major colorectal surgery (137c). Intrathecal morphine caused more sedation, delaying recovery, but immediate postoperative pain was better controlled. All other adverse events (mental function, delirium/confu­ sion, timing of ileus, and ambulation) were similar in the two groups.

165

analgesic effect. However, it produces adequate and long-lasting analgesia. Its activity and adverse effects profile have been reviewed (138R). It is better tolerated than morphine, causing significantly less nausea and vomiting and less depression of the hypoxic ventilator response.

Oxycodone

(SED-15, 2651; SEDA-28, 110; SEDA-29, 108; SEDA-30, 115)

Susceptibility factors Genetic A 60-year­ old man, who was taking rifampicin, had negative urine drug screens for oxycodone, despite using a combination of immediateand modified-release oxycodone for chronic pain (139A). He had an intermediate CYP2D6 genotype, and the authors suggested that rifampicin induced CYP3A4 and CYP2D6, causing increased metabolism of oxycodone, inadequate pain control, and negative drug urine screening. This falsely increased the physician’s confidence that the patient was not diverting his medication.

Drug overdose  A 47-year-old man with a history of drug

abuse and suicide attempts was found dead at home, with evidence of cocaine abuse and multiple drug ingestion (140A). The concen­ tration of citalopram in the femoral blood was 0.88 mg/l and the heart blood concentration 1.16 mg/l. Femoral blood concentrations of the other drugs were as follows: cocaine 30 mg/l; oxycodone 60 mg/l; promethazine 20 mg/l; propoxyphene 20 mg/l; and norpro­ poxyphene 70 mg/l.

Drug–drug interactions Selective serotonin reuptake inhibitors Serotonin syndrome has been reported in a few patients taking oxycodone and an SSRI.  A 70-year-old woman developed the serotonin

Morphine-6-glucuronide Morphine-6-glucuronide is less potent than morphine and is slower in exerting its

syndrome after taking oxycodone 40 mg bd in addition to fluvoxamine 200 mg/day (141A).  A 34-year-old man had visual hallucinations and severe tremor after dramatically increasing his dosage of oxycodone while taking stable doses of sertraline and ciclosporin. Withdrawal

Chapter 8

166 of ciclosporin did not resolve his symptoms, but withdrawal of sertraline did (142A).

Oxycodone in a substrate for CYP2D6 (143A) and might inhibit the metabolism of SSRIs that are also metabolized by this isoenzyme.

Oxymorphone

(SEDA-29, 108)

General information Oxymorphone is a pyridine-ring unsubstituted pyridomor­ phinan, with greater analgesic potency than morphine, whose antinociceptive effects are mediated predominantly through DOR and MOR opioid receptors Formulations include oral (144R). immediate-release tablets and modifiedrelease tablets, parenteral solutions, and suppositories. Oxymorphone has a similar adverse effects profile to other potent MOR receptor agonists, although in some studies it caused more nausea and vomiting than morphine when given by patient-controlled devices. There were no differences in nausea and vomiting with the oral modified-release forms of oxymorphone and morphine, but oxymorphone caused more flatulence. Oxymorphone was also reported to provide a better quality of life. Susceptibility factors Oxymorphone should be used with caution in people with renal insufficiency, since it is renally excreted. Drug administration route The intrathecal route of administration has been associated with edema of the legs and feet, owing to vasodilatation.

Papaverine

(SEDA- 30, 115)

Sensory systems Pupillary dilatation has been attributed to papaverine (145A).  A 50-year-old woman with a subarachnoid

hemorrhage had the aneurysm clipped. She was given papaverine 60 mg in isotonic saline 10 ml intracisternally before dural closure. She developed bilateral pupillary dilatation, which was non-reactive to light and resolved after 3–4 hours.

A.H. Ghodse and S. Galea

The authors postulated that papaverine may have traveled to the opposite oculo­ motor nerve causing the bilateral dilatation. In a prospective observational study five patients receiving intra-arterial papaverine for cerebral vasospasm after subarachnoid hemorrhage (146c). Papaverine caused increased intracranial pressure but reduced brain oxygen concentrations, possibly explaining why it is not beneficial, despite the fact that it reverses arterial narrowing.

Pethidine (meperidine)

(SED-15, 2791; SEDA-28, 111; SEDA-29, 108; SEDA-30, 115)

Observational studies Hypotension, hypoxemia, and pain-related agitation were adverse events reported after co­ administration of pethidine and midazolam for sedation and analgesia in children; no other events were reported (68C). Musculoskeletal Muscle rigidity after spinal anesthesia occurred in a 17-year-old man admitted for emergency appendicect­ omy (147A). During the operation, he developed shivering and was given intrave­ nous diazepam 5 mg and pethidine 50 mg. Minutes later he developed severe rigidity in the neck, masseters, arms, thoracoab­ dominal region, and thighs. Pregnancy The use of pethidine during labor is not uncommon. In 383 singleton pregnancies with dystocia pethidine caused a higher incidence of acidosis than placebo (148C).

Remifentanil

(SED-15, 3030; SEDA-28, 111; SEDA-29, 109; SEDA-30, 116)

Comparative studies Remifentanil+propofol and fentanyl+desflurane have been compared in 49 patients undergoing prolonged surgery (elective abdominal prostatectomy lasting more than 150 minutes) (149c). The fentanyl +desflurane combination was associated with faster recovery and extubation, at a significantly lower cost. Significantly more

Opioid analgesics and narcotic antagonists

Chapter 8

patients had postoperative nausea and vomiting with desflurane. Placebo-controlled studies Remifentanil 0.25 mg/kg by continuous infusion has been compared with placebo in 62 women under­ going hysterosalpingography (150c). Remi­ fentanil afforded better analgesia with minimal opioid adverse effects. Cardiovascular and respiratory Remifen­ tanil 0.05 mg/kg/minute by infusion has been compared with alfentanil and fentanyl during stereotactic brain biopsy in 135 subjects (32c). Remifentanil (together with alfentanil) had less hemodynamic effect than fentanyl. Similarly, the combination of remifenta­ nil+propofol in reduction of anterior gleno­ humoral dislocation in 22 subjects provided adequate sedation and analgesia, without hemodynamic and/or respiratory complica­ tions (151c). In contrast to the studies above, three case reports have highlighted the potential for remifentanil 2–5 mg to cause serious respiratory depression, even at moderate doses, possibly due to rapid onset of effect (152A). All recovered without incident. Nervous system Pain sensitization induced by remifentanil 3 and 8 ng/ml has been the subject of a randomized-con­ trolled study (153c). Those who were given the larger dose needed earlier and more postoperative morphine. Nefopam given intraoperatively reversed this effect. Sexual function Remifentanil by infusion caused penile erection in 5.5% of children undergoing cystoscopy (154c). The authors reported this as an unusual adverse effect, which could be alleviated by reduction or complete withdrawal of remifentanil infusion and/or deepening the level of anesthesia. Susceptibility factors Physiological factors When remifentanil 5.7 mg/kg/hour was given to a 66-year-old woman during treatment for self-poisoning with tranylcy­ promine, trifluoperazine, lorazepam, and

167

fluoxetine, she developed agitation, sweating, oxygen desaturation, facial myoclonus, generalized hypertension, hyper-reflexia, conjugate ocular movements, and poorly reactive pupils; she did not respond to painful stimuli (155A). Withdrawal of remi­ fentanil resulted in improved level of consciousness, reduced rigidity, and disap­ pearance of the abnormal ocular move­ ments. The authors suggested that muscle rigidity due to remifentanil had been caused by an interaction with serotonergic hyper­ activity. Drug–drug interactions Magnesium The added analgesic effect of magnesium after on-pump cardiac surgery has been studied in a placebo-controlled study in 40 patients (156C). The dose of either magnesium gluconate was 0.21 mmol/kg by intravenous bolus followed by a continuous infusion of 0.03 mmol/kg/hour for 12 hours after extubation. After surgery, remifentanil was reduced to 0.05 mg/kg/minute and titrated according to needs. Magnesium reduced the dosage requirements of remi­ fentanil without serious adverse effects. The results suggested that the opioid-sparing effect of magnesium may be greater at higher pain intensities and with increased dosages. Propofol Co-administration of propofol with remifentanil in 45 subjects caused loss of consciousness and affected middle latency auditory provoked potentials, although the contribution of remifentanil to the latter was questionable (157c).

Sufentanil

(SED-15, 3210; SEDA-29,

110) Susceptibility factors Genetic A 7-year­ old boy with laminin a2 (merosin) deficiency and severe congenital muscular dystrophy developed suspected malignant hyper­ thermia after total intravenous general anesthesia with sufentanil 0.004 mg/kg/min­ ute and propofol 100 mg/kg/minute (158A). He developed total body rigidity, increased body temperature, low blood pressure, and an increased heart rate. It is not clear

168 whether sufentanil served as a trigger for malignant hyperthermia, but the authors suggested that laminin a2 (merosin) defi­ ciency may increase susceptibility.

Tramadol

(SED-15, 3469; SEDA-28, 112; SEDA-29, 110; SEDA-30, 117)

Comparative studies Tramadol+midazolam has been compared with fentanyl+midazolam in 150 patients undergoing colonoscopy Colonoscopy was performed (159c). smoothly, although the procedure took significantly longer in those who received tramadol. Pain scores were higher with tramadol, requiring additional doses of fentanyl for effective management. Those who received tramadol had significantly more adverse effects, nausea and vomiting being the most common. The incidence was also higher in those who received more tramadol (24% compared with 12%), suggesting that these effects were doserelated. These results suggest that tramadol, even in combination with midazolam, is not as well tolerated as fentanyl and is not the optimal analgesic for colonoscopy. Tramadol+ketamine 0.25 mg/kg has been compared with lidocaine+ketamine in 62 children undergoing surgery for hypospadias (160c). Lidocaine provided better analgesia and sedation than trama­ dol, but both were effective and the incidences of nausea and vomiting were similar. In another study, intravenous tramadol 1.5 mg/kg was compared with ilioinguinal and iliohypogastric nerve blocks in 60 children undergoing herniorrhaphy (161c). Tramadol provided adequate analgesia but was associated with nausea and vomiting. None of the patients had respiratory depression. Valdecoxib 20 mg daily or bd has been compared with tramadol 50 mg qds in 829 patients with acute first- or second-degree ankle sprain (162C). The number of with­ drawals due to adverse events in the tramadol group was higher (12% versus 3.4%). Observational studies The combination of paracetamol+tramadol is synergistic and

Chapter 8

A.H. Ghodse and S. Galea

combines the rapid onset of analgesia of paracetamol with prolonged analgesia from tramadol. When this combination is used for acute, subacute, or chronic pain it is associated with a marked reduction in adverse events compared with either drug alone (163R). Tramadol 75 mg+paracetamol 650 mg +lidocaine 1% provided adequate pain control in 60 men for biopsy of the prostate but was associated with light-headedness, dizziness, and itching (164c). Placebo-controlled studies In a placebocontrolled study in the treatment of idio­ pathic detrusor overactivity (165c) more patients had adverse events while taking tramadol (34% versus 16%). Nausea was the most common (18% of all patients) and was responsible for two withdrawals. Nau­ sea was also reported by 5.3% of patients taking placebo. Other adverse events include vomiting (7.9%), constipation (2.6%), and dizziness (5.3%). Tramadol 50 mg was beneficial in treating premature ejaculation in a placebocontrolled study in 64 men when given about 2 hours before planned sexual activity (166C). There were more adverse events with trama­ dol group but no drug withdrawals. Psychiatric Two elderly patients taking long-term tramadol for chronic back pain experienced fluctuating confusional states over 2 years, alleviated when tramadol was withdrawn (167A). Gastrointestinal Tramadol 2.0 mg/kg was associated with nausea and vomiting in six children undergoing tonsillectomy but not very different from that experienced by those who were given either saline (n ¼ 8) or ketoprofen (n ¼ 7), suggesting other causes (168c). This dosage of tramadol did not provide sufficient analgesia control. Skin Dermatological adverse effects of tramadol are rare, the majority being itching and rash. Tramadol-induced subcutaneous nodules have been described (169A).  A 46-year-old woman with infiltrative ductal

carcinoma of the breast with bone metastases was given tramadol for bone pain. She

Opioid analgesics and narcotic antagonists

Chapter 8

developed skin nodules 1 day later; they disappeared when tramadol was withdrawn but there was residual pigmentation.

Susceptibility factors Genetic The CYP2D6�10 allele commonly found in Chinese is associated with reduced meta­ bolic activity. This affects the dose of tramadol needed to achieve adequate analgesia. In homozygotes for the CYP2D6�10 allele (n ¼ 17) more tramadol was needed than in heterozygotes (n ¼ 26) and those who did not have the allele at all (n ¼ 20) (170C). Diseases: Multiple sclerosis A woman with multiple sclerosis had a generalized seizure during a febrile urinary tract infec­ tion while taking baclofen 45 mg/day and tramadol 100 mg/day (171A). The authors suggested that the multiple sclerosis had increased her susceptibility to a tramadol­ induced seizure.

PARTIAL OPIOID RECEPTOR AGONISTS Buprenorphine

(SED-15, 571; SEDA28, 112; SEDA-29, 111; SEDA-30, 118) International experience with buprenor­ phine has been reviewed, highlighting the role of buprenorphine in reducing drugrelated harm and curtailing the spread of infection (172R). Its effect in reducing drugrelated deaths, premature births, and drug abuse by injection is also described. The adverse effects profile of buprenor­ phine has been reviewed and suggested to be favorable compared with other opioid ago­ nists (173R). The common adverse effects are headache, pain, insomnia, sweating, gastrointestinal discomfort, and the opioid withdrawal syndrome. Although it is rare, respiratory depression has occurred, espe­ cially with parenteral use and with concomi­ tant use of benzodiazepines. This risk has also been highlighted elsewhere (174R).

169

Musculoskeletal Two cases of rhabdomyolysis and compressive neuropathy have been described (175A). In both cases there was a history of drug abuse by injection and intravenous administration of crushed buprenorphine. It is not clear whether the adverse effects were due to buprenorphine or impurities. Pregnancy High-dose buprenorphine and methadone have been compared in 259 pregnant women (176C). There were no major variations in perinatal outcomes between those taking buprenorphine (n ¼ 159) and those taking methadone (n ¼ 100). Delivery was premature in 10% of those who used buprenorphine and 16% of those who used methadone. Neonatal abstinence syndrome occurred in 75% beginning at a mean age of 40 hours; there were no deaths. Lactation A milder neonatal abstinence syndrome and secretion of buprenorphine into breast milk, potentially resulting in exposure to the infant, have been reviewed (172R). Susceptibility factors Age Respiratory depression after the use of buprenorphine in adults tends to be associated with parenteral administration. Respiratory depression and central nervous system depression after oral buprenorphine (2 mg in one case and 8 mg in four cases) has been described in five toddlers (177c). Drug–drug interactions Antiretroviral drugs The interaction of buprenorphine with antiretroviral drugs has been reviewed (178R,179R). Adverse effects due to this interaction have been reported; the interaction of buprenorphine with atazanavir and ritonavir resulted in reduced mental functioning and central nervous system depression (180A). An interaction of buprenorphine+nalox­ one (Suboxone) with delavirdine or ritonavir, which inhibit CYP3A4, can prolong the QT interval. In 50 HIV-positive patients taking antiretroviral drugs, bupre­ norphine+naloxone caused QT interval prolongation which was statistically but

170 not clinically significant; there was no prolongation in opioid-dependent subjects who were taking only buprenorphine +naloxone (181c). Diazepam An interaction of therapeutic doses of diazepam (10 and 20 mg) with buprenorphine in 16 subjects resulted in increased subjective measures of sedation and some impairment of psychomotor performance (deterioration in cancellation time) (110c). This interaction was compared with that of methadone and diazepam. The former caused less psychomotor impairment. Ifosfamide An interaction has been reported between buprenorphine and the chemotherapeutic agent ifosfamide (182A).  A 34-year-old man was given transdermal

buprenorphine for pain, initially 35 mg/hour, later increased to 52.5 mg/hour. He developed respiratory depression, which resolved on withdrawal of the patch.

The authors suggested that respiratory depression had been triggered by the dual action of buprenorphine and ifosfamide on CYP3A4.

Butorphanol Observational studies Butorphanol is a partial agonist at MOR opioid receptors and an agonist at KOR receptors. Intranasal butorphanol has been used to treat five patients with intractable pruritus due to inflammatory skin disease or systemic disease (183A). All had marked improvement, but one had severe nausea and withdrew. No other adverse effects were reported.

OPIOID RECEPTOR ANTAGONISTS Naloxone (SED-15, 2421; SEDA-28, 113; SEDA-30, 119) The adverse effects of naloxone have been reviewed (184R). Its potential long-term

Chapter 8

A.H. Ghodse and S. Galea

effects include increased neuronal damage in asphyxia, altered pain responsiveness, and seizures. It also potentially increases sym­ pathetic nervous system activity, resulting in dysrhythmias, hypertension, and pulmonary edema, in those given high doses of naloxone, whether licit or illicit. Drug administration route Intranasal naloxone in opioid overdose is generally safe and effective. However, lack of effec­ tiveness has been reported in patients with nasal abnormalities, impairing administra­ tion (185M).

Naltrexone

(SED-15, 2423; SEDA-28, 113; SEDA-29, 112; SEDA-30, 120)

The use of naltrexone in alcoholism has been reviewed, highlighting its favorable safety profile (186R). It is associated with nausea, vomiting, headaches, anergia, reduced alertness, anxiety, depression, and rashes. Of these, nausea and vomiting are the most common. Comparative studies The effects of Com­ munity Reinforcement Approach and nal­ trexone have been compared for smoking cessation in 25 subjects (187c). Naltrexone was well tolerated, but 18 complained of an unpleasant taste sensation. Those taking 50 mg/day (compared with 25 mg/day) had more headaches, nausea, dizziness, insomnia, sleepiness, and impaired taste perception. Placebo-controlled studies The effective­ ness of naltrexone (25 mg increased to 50 mg) in smoking cessation has been studied in a placebo-controlled study in 110 subjects (188C). In the first week, naltrexone was associated with nausea, light-headedness, sedation, and flushing. After 4 weeks only light-headedness was significantly more common with naltrexone. One patient withdrew because of gastro­ intestinal distress. Systematic reviews The effectiveness of naltrexone in maintenance treatment of opioid and alcohol dependence has been

Opioid analgesics and narcotic antagonists

Chapter 8

systematically reviewed (189M). There is no evidence to support the suggestion that naltrexone causes or exacerbates hepato­ cellular injury. There are reports of serious adverse events and even deaths after rapid detoxification procedures, and the authors suggested that naltrexone should not be used in this way. The risk of overdose and death from naltrexone withdrawal or receptor hypersensitivity has also been reported. Nervous system The literature on the efficacy and safety of naltrexone in children with autistic disorders has been critically reviewed (190M). The most common reported adverse effect was transient sedation.

171

Naltrexone 15 mg was given to eight frequent tanners with the aim of establish­ ing whether opioid blockade induces with­ drawal symptoms (191c). Nausea and jitteriness occurred in 50%, and in half of those the severity was such that they withdrew. These effects were considered to be consistent with symptoms of opiate withdrawal. Drug formulations In 42 healthy subjects a long-acting intramuscular naltrexone for­ mulation was well tolerated and there were no serious adverse events (192c). Naltrexone implants were well tolerated in an open study in 13 opioid-dependent patients, with minimal adverse effects (193c).

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J.K. Aronson

9

Anti-inflammatory and antipyretic analgesics and drugs used in gout

ANILINE DERIVATIVES Paracetamol (acetaminophen) and combinations (SED-15, 2679; SEDA-28, 125; SEDA-30, 129) Respiratory Further evidence of an association between paracetamol and asthma (SEDA-30, 129) has appeared. In 3000 children aged 6–7 years and 3000 teenagers aged 13–14 years the prevalence of ever wheezing in the younger children who had taken paracetamol in the first year of life was 11% (OR ¼ 1.54; 95% CI ¼ 1.00, 2.38) and the prevalence of ever wheezing in older children who had taken paracetamol at least once a month was 25% (OR ¼ 1.7; 95% CI ¼ 1.43, 2.04) (1c). Taking more paracetamol during the previous 12 months led to a higher prevalence of dry cough at night and symptoms of rhinitis in the younger children and eczema and rhinitis symptoms in the teenagers. In a cross-sectional questionnaire study in 3493 children aged 6–7 years old children were classified as cases if they had had wheezing, rhinitis, or eczema either at any time since their neonatal period or in the 12 months before the study (2c). Para­ cetamol exposure was considered positive if it had occurred often during the first year of life (first analysis) or in the previous 12 Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03101-8 r 2009 Elsevier B.V. All rights reserved.

months (second analysis). Paracetamol intake in the first year of life was significantly associated with an increased risk of wheez­ ing (adjusted OR ¼ 1.69; 95% CI ¼ 1.23, 2.34) and rhinitis (adjusted OR ¼ 1.37; 95% CI ¼ 1.20, 1.59) but not eczema (adjusted OR ¼ 1.45; 95% CI ¼ 0.91, 2.32). Frequent paracetamol intake in the previous year increased the risk of wheezing (OR ¼ 3.3; 95% CI ¼ 1.54, 7.18), rhinitis (OR ¼ 1.61; 95% CI ¼ 1.33, 1.95), or eczema (OR ¼ 1.82; 95% CI ¼ 1.24, 2.66). Gastrointestinal The association between paracetamol and upper gastrointestinal com­ plications has been investigated in a nested case–control study using the UK General Practice Research Database and a systema­ tic review of 12 studies (3CM). Paracetamol was associated with a small increased risk of upper gastrointestinal complications (RR ¼ 1.3; 95% CI ¼ 1.1, 1.5). The relative risk was 3.6 (95% CI ¼ 2.6, 5.1) among paracetamol users of more than 2 g/day, whereas smaller doses did not increase the risk. Among the 12 studies identified in the systematic review, estimates were 0.2–2.0, with a summary estimate of 1.3 (95% CI ¼ 1.2, 1.5). These findings suggest that paracetamol does not greatly increase the risk of upper gastrointestinal complications. Liver Liver damage due to paracetamol is usually associated with suicidal overdosage. However, it has been suggested that the use of paracetamol in children with acute febrile illnesses can cause fulminant hepatic failure (4c). In a case–control study 25 children with fulminant hepatic failure were compared

181

182 with 33 age-matched controls. All of the former and none of the latter had taken supratherapeutic doses of paracetamol (mean 145 mg/kg/day). The mean paraceta­ mol concentration was 1.78 mmol/l. There was no serological evidence of hepatitis A, hepatitis B, or dengue. Three children died. In an analysis of alanine transaminase activity in seven controlled clinical trials involving the use of paracetamol alone 1950–4000 mg/day for 4 weeks up to 12 months, there were no reports of hepato­ toxicity or hepatic failure in 1530 patients (5M). While they were taking long-term paracetamol, 181 of 1039 patients (17%) had an alanine transaminase activity that exceeded the upper limit of the reference range, but none was more than three times the upper limit of the reference range in conjunc­ tion with a serum bilirubin over the upper limit of the reference range, and no patient had an alanine transaminase activity more than 10 times the upper limit of the reference range. All the changes were transient. Acid–base balance Acidosis without liver damage, a rare presentation, has been reported in a case of paracetamol poisoning in a child (6A).  A previously healthy 27-month-old girl started

vomiting and became somnolent without a history of drug exposure. She was intubated and given activated charcoal. The serum paracetamol concentration was 5.3 mmol/l (804 mg/ml) 2.5 hours after the onset of symp­ toms. The pH was 7.32, PaCO2 4.6 kPa, PaO2 46 kPa, and bicarbonate 17 mmol/l. The lactate was 4.6 mmol/l. The serum transaminases were not raised. A urine toxicology screen was negative, and the aspirin concentration was less than 20 mg/l. Four hours after the devel­ opment of symptoms, she was given intra­ venous N-acetylcysteine, which was continued for 36 hours, until the paracetamol concentra­ tion was undetectable. Her liver function tests remained normal, the acidosis resolved, and her mental status returned to normal.

Skin Henoch–Schönlein purpura has been attributed to paracetamol + codeine (co-codamol) (7A).  A 69-year-old man took Co-efferalgan (co­

codamol) for 1 week and developed a fever, hematuria, acute renal failure, palpable

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J.K. Aronson

purpura on the legs, feet, and arms, arthral­ gias, and abdominal discomfort. His serum creatinine and C-reactive protein were raised but there was no thrombocytopenia or hypo­ complementemia. Co-codamol was with­ drawn. The hematuria resolved in 2 days, the purpura disappeared in 10 days, renal function returned to normal after 2 weeks, and the abdominal pain and arthralgias improved during the following 2–3 weeks.

This appears to be the only case of Henoch–Schönlein purpura that has been attributed to co-codamol. Tumorigenicity In a questionnaire study of the effects of paracetamol on the risk of acute leukemia in 169 adults with leukemia and 676 age- and sex-matched hospital controls with non-neoplastic conditions ever use of paracetamol was associated with a slightly increased risk of leukemia (adjusted OR ¼ 1.53; 95% CI ¼ 1.03, 2.26) (8c). There was no difference between men and women. Drug overdose In a retrospective review of all cases of exposure to paracetamol that occurred over 3 years in children under 18 years of age who were managed in a regional poison control center, there were 473 exposures; 76% were in those under 6 years, 3% in those aged 6–12 years, and 21% in those aged 13–17 years (9c). Unintentional ingestion was the most com­ mon type of exposure in the first two age groups (100 and 94%, respectively), but in the older children intentional ingestion was more common (91%); girls represented far more of these exposures than boys (87% versus 14%). In 8 patients aged 16–32 years old who for suicidal purposes took paracetamol, average 17.8 g, there were changes in renal function compared with 21 healthy indivi­ duals (10c). There were transient increases in the activities of N-acetyl-b-D-glucosami­ nidase, a-glutathione transferase, b-glucur­ onidase, g-glutamyltransferase, and the efficiency of nephron resorption through b2-microglobulin enzymes. However, there were no cases of acute renal failure. Oral and intravenous N-acetylcysteine in the management of paracetamol overdose

Anti-inflammatory and antipyretic analgesics and drugs used in gout

have been compared (11R). The advantages and disadvantages are listed in Table 1. The authors concluded that acetylcysteine can be given orally to patients who present within 8–10 hours of paracetamol overdose and intravenously to those who present after 10 hours or have underlying conditions that prevent oral administration. The use of activated charcoal in addition to standard N-acetylcysteine therapy after paracetamol overdose has been assessed in a 1-year non-randomized, prospective, multicenter, observational case series of 145 patients, of whom 58 received N-acetyl­ cysteine only and 87 received N-acetyl­ cysteine + activated charcoal (12c). Activated charcoal was associated with a reduced incidence of liver injury, as assessed by serum transaminases and prothrombin time. Drug–drug interactions Drugs that induce hepatic drug-metabolizing enzymes increase the toxicity of paracetamol after overdose, and another case has been reported in which liver transplantation was necessary (13A).  A 22-year-old man taking steady-state pheny­

toin took 25 ibuprofen tablets 400 mg plus paracetamol 25 g. He was given oral N­ acetylcysteine. The serum phenytoin concen­ tration was 128 mmol/l (32 mg/ml) and the paracetamol concentration at 6 hours after the overdose was 0.87 mmol/l (131 mg/ml) which was judged to be below the treatment thresh­ old of about 1.06 mmol/l (160 mg/ml). On day 3

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he developed hepatic encephalopathy and acute renal failure requiring hemodialysis. His arterial pH was 7.19, alanine transaminase over 3500 U/l, total bilirubin 205 mmol/l, and prothrombin time over 50 seconds (INR over 30). He underwent successful liver transplan­ tation on day 4. The liver explant showed massive hepatic necrosis.

The usual criterion for acetylcysteine therapy when a patient is taking an enzyme-inducing drug is to double the serum paracetamol concentration before using the nomogram. There were many deficiencies in this report (14r), and it is not clear whether this patient was given appro­ priate therapy.

NON-STEROIDAL ANTI­ INFLAMMATORY DRUGS (SED-15, 2555; SEDA-28, 118; SEDA-29, 116; SEDA-30, 125)

Cardiovascular The effects of non­ steroidal anti-inflammatory drugs (NSAIDs) and paracetamol on the risk of major cardiovascular events (non-fatal myocardial infarction, fatal coronary heart disease, non-fatal and fatal stroke) have been studied prospectively in 70 971 women, aged 44–69 years, free of known cardiovascular

Table 1 The advantages and disadvantages of oral and intravenous N-acetylcysteine in the management of paracetamol overdose Formulation Advantages

Disadvantages

Oral

Putrid odor; taste very difficult to mask Nausea and vomiting common Delayed action, depending on rate of absorption (delayed by anticholinergic drugs) Reduces the binding of activated charcoal to paracetamol High concentrations in the liver during first-pass— potential for hepatotoxicity

Cheap Easy to prepare and administer Non-IgE-mediated anaphylactic (anaphylactoid) reactions rare

Intravenous Rapidly effective Difficult to prepare and administer reliably—errors can Reliable access to the systemic occur circulation, not affected by vomiting Adverse effects include non-IgE-mediated anaphylactic (anaphylactoid) reactions, asthma, and epilepsy; severe adverse effects are rare

184 disease or cancer, who provided medication data biennially for 12 years, during which there were 2041 major cardiovascular events (15C). Women who reported occasional use of NSAIDs or paracetamol (1–21 days/ month) did not have a significant increase in the risk of cardiovascular events. However, after adjustment for cardiovascular risk factors, women who frequently used NSAIDs (on at least 22 days/month) had a relative risk for a cardiovascular event of 1.44 (95% CI ¼ 1.27, 1.65) compared with non-users, and those who frequently consumed paracetamol had a relative risk of 1.35 (95% CI ¼ 1.14, 1.59). The increased risk associated with frequent NSAID use was most marked among current smokers (RR ¼ 1.82; 95% CI ¼ 1.38, 2.42) and was absent among never smokers. Risk was also related to dose. The authors concluded that NSAIDs and paracetamol, if taken in high enough dosages, are associated with a significantly increased risk of major cardiovascular events. In an analysis of data from the Taiwa­ nese Bureau of National Health Insurance database of 16 326 patients aged 18 years or over who had taken etodolac (n ¼ 2014), nabumetone (n ¼ 2262), ibu­ profen (n ¼ 5239), naproxen (n ¼ 3049), or celecoxib (n ¼ 3762) for at least 180 days, there were higher prevalences of acute myocardial infarction (4.76% versus 0.99%), angina (4.11% versus 0.43%), strokes (7.74% versus 1.51%), and transi­ ent ischemic attacks (4.03% versus 0.52%) in long-term users with a history of cardiovascular disease than in those with­ out (16C). There were no differences between the non-selective NSAIDs and celecoxib. A history of cardiovascular disease increased the risks, with hazard ratios of 2.29 (1.22, 4.32), 6.19 (3.56, 10.78), 3.56 (2.80, 4.52), and 6.60 (3.72, 11.73) for the four complications respec­ tively. Pre-existing hypertension, dyslipid­ emia, diabetes mellitus, congestive heart failure, and chronic renal disease also significantly affected the risks. In a prespecified pooled analysis of data from three trials in which patients with

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J.K. Aronson

osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib 60 or 90 mg/day or diclofenac 150 mg/day for an average of 18 months, there were equal numbers of thrombotic cardiovascular events with etoricoxib (n ¼ 320) and diclo­ fenac (n ¼ 323), giving event rates of 1.24 and 1.30 per 100 patient-years and a hazard ratio of 0.95 (95% CI ¼ 0.81, 1.11) for etoricoxib compared with diclofenac (17C). Rates of upper gastrointestinal events (perforation, bleeding, obstruction, ulcer) were lower with etoricoxib (0.67 versus 0.97 per 100 patient-years; HR ¼ 0.69; 95% CI ¼ 0.57, 0.83), but the rates of compli­ cated upper gastrointestinal events were similar (0.30 versus 0.32). The time-course of the effects of NSAIDs in increasing the risk of cardio­ vascular events has been assessed in a cohort study in 74 838 users of non-selective NSAIDs or coxibs and 23 532 comparable users of other drugs (18C). There was a significant increase in the event rate for rofecoxib (RR ¼ 1.15; 95% CI ¼ 1.06, 1.25) and a significant reduction in the rate for naproxen (RR ¼ 0.75; 95% CI ¼ 0.62, 0.92). No other coxib or NSAID had an effect. The increased rate associated with rofecoxib was seen in the first 60 days of use and persisted thereafter. The effects of NSAIDs on blood pressure have been studied in a systematic review of 2 meta-analyses, 11 randomized controlled trials, 4 prospective studies, 2 retrospective observational trials, and 1 case–control study (19RM). The results were highly variable, but a few general conclusions can be drawn. In normotensive adults NSAIDs caused a small but non-significant average increase in mean arterial pressure of 1–2 mmHg. In hypertensive adults there was a small but statistically significant increase in mean arterial pressure of about 3–5 mmHg; before and after adjustment for salt intake, naproxen, indometacin, and piroxicam were associated with an increase in mean arterial pressure, whereas ibupro­ fen and placebo were associated with a reduction. When NSAIDs were used in combination with different antihypertensive drugs, beta-blockers + NSAIDs produced a

Anti-inflammatory and antipyretic analgesics and drugs used in gout

statistically significant increase in mean arterial pressure of about 6 mmHg; enala­ pril + NSAIDs increased blood pressure by a similar amount; no other combinations changed the blood pressure. In a meta-analysis of studies in (a) 7462 patients exposed to celecoxib 200–800 mg/ day for 1268 patient-years compared with 4057 patients treated with placebo for 585 patient-years and (b) 19 773 patients treated with celecoxib 200–800 mg/day for 5651 patient-years compared with 13 990 patients treated with non-selective NSAIDs (diclo­ fenac, ibuprofen, naproxen, ketoprofen, and loxoprofen) for 4386 patient-years, the incidence rates of the combined cardiovas­ cular events were not significantly different between patients treated with celecoxib and placebo or between those treated with celecoxib and non-selective NSAIDs (20M). The dose of celecoxib, the use of aspirin, or the presence of cardiovascular risk factors did not alter these results. The authors concluded that there was no evi­ dence of an increased cardiovascular risk with celecoxib relative to placebo and a comparable rate of cardiovascular events with celecoxib compared with non-selective NSAIDs. Liver The hepatotoxicity of celecoxib and rofecoxib compared with non-selective NSAIDs (other than bromfenac, nimesu­ lide, and sulindac) has been studied using the US Food and Drug Administration Freedom of Information (FDA/FOI) data­ base and the Uppsala Monitoring Centre (UMC) database (21C). There were 158 539 and 185 253 reports relating to NSAIDs in the FDA/FOI and UMC databases respec­ tively; 25 and 16% involved other hepato­ toxic drugs. The proportions of reports of hepatic disorders for all COX-2 selective inhibitors and non-selective NSAIDs were 3.0% in the FDA/FOI database and 2.7% in the UMC database. Nimesulide (17 and 14%), bromfenac (12 and 21%), diclofenac (8.1 and 4.7%), and sulindac (6.1 and 9.9%) were associated with higher rates of hepatic disorders than other NSAIDs. Crude and adjusted reported odds ratios for the pre­ valences of overall hepatic disorders and

Chapter 9

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hepatic failure with celecoxib and rofecoxib versus the other NSAIDs were all less than 1.0 in both databases. Thus, bromfenac, nimesulide, sulindac, and diclofenac had higher proportions of reports of hepatic disorders compared with other NSAIDs. The analysis did not raise concerns about celecoxib or rofecoxib compared with non­ selective NSAIDs. Gastrointestinal The adverse effects of NSAIDs on the lower gastrointestinal tract have been studied in a systematic review of 18 randomized studies, 14 case–control studies, 8 cohort studies, and 7 before­ and-after studies (22M). Non-selective NSAIDs had significantly more adverse effects than no NSAIDs in 20 of 22 studies of lower gastrointestinal integrity, 5 of 7 visualization studies, 7 of 11 bleeding studies (OR ¼ 1.9–18 in case–control stu­ dies), 2 of 2 perforation studies (OR ¼ 2.5– 8.1), and 5 of 7 diverticular disease studies (OR ¼ 1.5–11). Coxibs had significantly less effect than non-selective NSAIDs in three of four integrity studies, one endoscopic study (RR for mucosal breaks ¼ 0.3), and two randomized studies (RR for lower gastrointestinal clinical events ¼ 0.5; RR for hematochezia ¼ 0.4). Pancreas Case reports have suggested that the use of newer COX-2 selective inhibitors can cause acute pancreatitis. This has been assessed in a case–control study in 3083 patients with acute pancreatitis and 30 830 controls (23C). For current use the relative risk estimate for celecoxib was 1.4 (95% CI ¼ 0.8, 2.3) and for rofecoxib 1.3 (95% CI ¼ 0.7, 2.3). The overall relative risk for other NSAIDs was 2.7 (95% CI ¼ 2.4, 3.0) with substantial variation in risk between individual drugs. The highest relative risk was for diclofenac (OR ¼ 5.0; 95% CI ¼ 4.2, 5.9) and the lowest for naproxen (OR ¼ 1.1; 95% CI ¼ 0.7, 1.7). Autacoids The risks of angioedema among users of the newer cyclo-oxygenase, COX-2 selective inhibitors celecoxib and rofecoxib, and other non-aspirin NSAIDs have been studied in a case–control study of

Chapter 9

186 377 patients and 10 matched population controls per case (n ¼ 3747) selected from the Civil Registration System (24C). After adjustment for confounding, the relative risk for current use of the COX-2 selective inhibitors was 0.96 (95% CI ¼ 0.46, 2.03), whereas the risk for other NSAIDs was 1.77 (95% CI ¼ 1.23, 2.58). Teratogenicity The teratogenic risk of NSAIDs has been investigated using a population-based pregnancy registry in 36 387 mothers of live singleton infants who took an NSAID or other medications during pregnancy (25c). For each infant with any congenital anomaly diagnosed in the first year of life, up to 10 controls, infants with no congenital anomalies were selected. There were 93 births with con­ genital anomalies in 1056 women (8.8%) who filled prescriptions for NSAIDs in the first trimester of pregnancy, compared with 2478 in 35 331 (7%) who did not. The adjusted OR for any congenital anomalies for the former was 2.21 (95% CI ¼ 1.72, 2.85) and for anomalies related to cardiac septal closure 3.34 (95% CI ¼ 1.87, 5.98). There were no significant associations with anomalies in other major organ systems. Drug–drug interactions Selective serotonin reuptake inhibitors (SSRIs) The interaction between SSRIs and NSAIDs has been reviewed in the light of four retrospective studies of gastrointestinal adverse outcomes (26M). The risk ratio for an upper gastrointestinal bleed from this drug combination (compared with not receiving either agent) was 3.3–16, and the risk ratio for gastrointestinal adverse effects was 12. In two studies the risk for an upper gastrointestinal bleed from the drug combi­ nation exceeded the additive risk of the agents alone. The risk ratio for an upper gastrointestinal bleed from an SSRI–aspirin interaction was 1.9–7.2. The number needed to harm (NNTH) in terms of an upper gastrointestinal bleed from an SSRI– NSAID combination was 62–75 patientyears, and the NNTH for gastrointestinal adverse effects was 2 patient-years.

J.K. Aronson

ARYLALKANOIC ACID DERIVATIVES (SED-15, 2555; SEDA-28, 126)

Aceclofenac Skin Allergic contact dermatitis has been attributed to aceclofenac (27A), as has generalized pustular psoriasis (28A).

Dexketoprofen Skin Photoallergic contact dermatitis in patients taking dexketoprofen has been discussed in the context of six cases (29c).

Diclofenac Sensory systems Keratolysis (corneal melting) occurred after 5 days during the use of topical preservative-free diclofenac qds after laser-assisted subepithelial keratectomy in a 25-year-old man (30A). There was corneal edema with Descemet’s membrane striae and epithelial microcysts and a vertical epithelial defect (1.0 mm  2.0 mm), with 30% tissue loss in the affected area. After withdrawal of diclofenac topical dexamethasone produced improvement but not complete healing. Hematologic Bone marrow necrosis has been attributed to diclofenac (31A).  A 26-year-old man who received 12 doses of

intramuscular diclofenac 75 mg at 30-minute intervals for renal colic developed fever and bone pain 5 days later. His hemoglobin was 7.7 g/dl and there was leukopenia (1.6  109 per liter) and neutropenia (0.5  109 per liter) but no thrombocytopenia (179  109 per liter). Bone marrow aspiration smears showed strik­ ing necrosis and nearly absent intact hemo­ poietic cells; bone marrow biopsy showed bone marrow necrosis. He recovered after blood transfusion.

Anti-inflammatory and antipyretic analgesics and drugs used in gout

The authors attributed the bone marrow necrosis to cytokine release because of the large dose of diclofenac. Gastrointestinal Non-specific colitis has been reported in a 69-year-old man who took modified-release diclofenac 200 mg/ day (32A). Liver Susceptibility to hepatotoxicity due to diclofenac in 24 patients has been associated with polymorphisms in the genes encoding the enzymes UGT2B7 and CYP2C8, which determine the formation of reactive diclofenac metabolites, and in ABCC2, which encodes the transporter MRP2, which contributes to the biliary excretion of the reactive metabolite (33c). The UGT2B7�2 allele was eight times more common in patients with diclofenac hepa­ totoxicity than in controls and the ABCC2 C-24T variant was five to six times more common. Haplotype distributions for CYP2C8 were different in patients com­ pared with hospital controls. Skin Photoallergic contact dermatitis has been attributed to topical diclofenac (34A). Drug administration route NSAIDs should not be injected into the gluteal muscles because of the risk of adverse effects; the lateral thigh should be preferred (35R). During 1997–2002 the Iran pharma­ covigilance center received reports of adverse reactions after intramuscular injec­ tion of diclofenac (36c). An estimated 326 million injections were given; there were 73 reports of foot drop, 40 of leg paralysis, and 63 of difficulty in walking. The sites of injection were not specified. Nicolau syndrome (livedoid dermatitis) is a rare adverse reaction that occurs at the site of intramuscular injection (37H). It typically causes pain around the injection site soon after injection, followed by erythema, a livedoid patch, a hemorrhagic patch, and finally necrosis of skin, subcuta­ neous fat, and muscle. It has commonly been reported in association with NSAIDs, corticosteroids, and penicillins. In a case of Nicolau syndrome after injection of

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diclofenac, a large ulcer over the right buttock became infected with Pseudomonas aeruginosa, and there was subcutaneous fat necrosis and non-specific inflammation without evidence of malignancy or vasculi­ tis; the lesion required repeated debride­ ment and a partial-thickness skin graft (38A). Subcutaneous injection, rather than intramuscular injection, was found to be a determining factor in this case. Many injections into the buttocks that are intended to be intramuscular are actually subcutaneous, because the needle is too short to reach the muscle through a large thickness of subcutaneous fat; intramuscu­ lar NSAIDs should be given into the lateral thigh, if at all (35R).

Ibuprofen

(SED-15, 1709)

Cardiovascular Pulmonary hypertension occurred in 1 of 169 preterm infants who were given lysine ibuprofen (10 mg/kg followed by 5 mg/kg after 24 and 48 hours) for closure of a patent ductus arteriosus; symptoms started within 1 hour of the second dose (39A). Nervous system Ibuprofen can cause asep­ tic meningitis (40A), the incidence of which is increasing, mainly among patients with underlying autoimmune disorders. Recurrent meningitis mimicking bacterial meningitis occurred in two women taking ibuprofen, one with dermatomyositis and one with autoimmune thyroiditis (41Ar). In the authors’ review of 71 reported episodes of ibuprofen-related meningitis in 36 patients, 22 had an autoimmune disorder, mainly systemic lupus erythematosus, and 22 had recurrent episodes. Most of the episodes consisted of an acute meningeal syndrome with a predomi­ nance of neutrophils and raised protein in the cerebrospinal fluid in 26 patients. Sensory systems Optic neuritis with a visual field defect has been associated with ibuprofen (42A).  A 41-year-old man took ibuprofen 400 mg tds

for 3 weeks and developed blurred vision in

188 his right eye and pain during eye and head movements that lasted 2 days. There was a marked reduction in visual acuity to 20/200 in the right eye, with quadrantanopia and absent visual-evoked potentials. After withdrawal of the drug and treatment with high-dose intra­ venous methylprednisolone and subcutaneous low-molecular-weight heparin, his vision improved to 20/70, the visual field defect vanished, and the visual-evoked potentials returned to almost normal values.

Although the authors could not rule out idiopathic optic neuritis, they thought that the absence of other susceptibility factors plus improvement after drug withdrawal suggested a toxic effect. Pancreas An 18-year-old man developed acute pancreatitis immediately after an over­ dose of ibuprofen 51 mg/kg (43A). Other causes of acute pancreatitis were excluded. Urinary tract Acute papillary necrosis causing bilateral ureteric obstruction has been attributed to ibuprofen in an 8-year­ old boy (44A). Skin A fixed drug eruption has been attributed to ibuprofen (45A).  After taking ibuprofen for 2 days a 61-year-old

woman developed erythema and pain affect­ ing the tongue and oral mucosa; 2 months later she started taking ibuprofen and erythro­ mycin, and the same lesions reappeared in the oral mucosa 24 hours later, with two new erythematosus violaceous macular lesions. Topical challenge through an occluded patch with ibuprofen 5% on the residual cutaneous lesion was positive.

Musculoskeletal In a case–control study in 124 655 subjects matched three to one for age and sex with 373 962 controls, there was an increased overall risk of fractures with ibuprofen (OR ¼ 2.09; 95% CI ¼ 2.00, 2.18), but not with celecoxib (OR ¼ 0.76; 95% CI ¼ 0.51, 1.13) (46C). The effects in most cases were small. The authors sug­ gested that falls may be one reason for the increase in fracture risk with some NSAIDs. Immunologic A severe systemic hypersen­ sitivity reaction (fever, rash, altered mental

Chapter 9

J.K. Aronson

status, and hypotension) to oral ibuprofen in an 11-year-old boy was the first evidence of systemic lupus erythematosus; re-chal­ lenge with ibuprofen resulted in a recur­ rence of the previous symptoms (47A). Body temperature Fever accompanied by nausea, vomiting, and hypotension occurred in a 68-year-old woman with Sjögren’s syndrome and a leukocytoclastic vasculitis 15 minutes after a dose of ibupro­ fen; 3 months later she had a similar episode without hypotension and oral chal­ lenge with ibuprofen produced the same symptoms 3 hours after the last dose (48A). Drug overdose A fatal overdose has been reported in a 26-year-old woman who took up to 105 g of modified-release ibuprofen (49A). She presented with a reduced level of consciousness, a severe metabolic acido­ sis, and hemodynamic compromise, and died despite intensive supportive manage­ ment, gut decontamination with multidose activated charcoal, and correction of the metabolic acidosis with sodium bicarbonate and hemofiltration. The ante-mortem blood ibuprofen concentration was 760 mg/l and the post-mortem concentrations were 518 mg/l in blood, 74 mg/kg in liver, and 116 mg/l in the gastric contents. Drug–drug interactions Antifungal azoles The effects of voriconazole and fluconazole on the pharmacokinetics of S( + )-ibuprofen and R(–)-ibuprofen have been studied in 12 healthy men, who took a single oral dose of racemic ibuprofen 400 mg in a randomized order alone or 1 hour after voriconazole or fluconazole 400 mg bd on day 1 and 200 mg bd on day 2 (50C). Voriconazole increased the AUC of S-ibuprofen to 205% and the Cmax to 122%; the half-life was prolonged from 2.4 to 3.2 hours. Fluconazole increased the AUC of S-ibuprofen to 183% and the Cmax to 116%; the half-life was prolonged from 2.4 to 3.1 hours. These effects were attributed to inhibition of CYP2C9­ mediated metabolism of S-ibuprofen. Vor­ iconazole and fluconazole had minor effects on the pharmacokinetics of R-ibuprofen. The authors recommended that the dosage of ibuprofen should be reduced when it is

Anti-inflammatory and antipyretic analgesics and drugs used in gout

co-administered with voriconazole or fluco­ nazole, especially when the initial dose of ibuprofen is high. Pemetrexed In a randomized, crossover study in 27 patients with cancer with a creatinine clearance below 80 ml/minute, ibuprofen 400 mg was given orally every 6 hours, starting 2 days before intravenous administration of pemetrexed 500 mg/m2 and continuing until 1 hour before the infusion (51c). Ibuprofen caused a 16% reduction in the clearance of pemetrexed, a 15% increase in Cmax, and a 20% increase in AUC, but no significant change in Vss.

Indometacin

(SED-15, 1739)

Respiratory The risk of broncho­ pulmonary dysplasia has been determined in 999 infants of extremely low birth weight with and without patent ductus arteriosus who survived to a postmenstrual age of 36 weeks and who were randomized to indometacin prophylaxis or placebo (52C). The incidence of bronchopulmonary dysplasia in infants with patent ductus arteriosus was 52% (55/105) after indometacin and 56% (137/246) after placebo. In contrast, rates of bronchopulmonary dysplasia in those without a patent ductus arteriosus were 43% (170/391) after indometacin prophylaxis and 30% (78/257) after placebo. There was evidence that this difference was related to poor oxygenation and edema formation in those who developed bronchopulmonary dysplasia.

Hematologic Neutropenia has been reported in a preterm male infant with a patent ductus arteriosus during treatment with indometacin; this could have been coincidence, but his mother had also pre­ viously had indometacin-associated neutro­ penia I (53A). Gastrointestinal Both dexamethasone and indometacin can cause spontaneous intest­ inal perforation in very low birth weight

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neonates. In a retrospective case–control study in 16 such neonates and 32 controls matched by birth weight, those who received three or more doses of indometacin for ductal closure or intraventricular hemor­ rhage prophylaxis and three or more doses of dexamethasone (0.3 mg/kg cumulative dose over 3 days) for refractory hypotension during the first postnatal week were 10 times more likely to develop intestinal perforation (95% CI ¼ 1.22, 76) (54c). Pancreas Two cases of acute pancreatitis have been attributed to indometacin.  A 56-year-old man developed acute pancrea­

titis after taking indometacin 150 mg/day orally for 3 weeks (55A). Other causes were ruled out. He made a complete recovery after indometacin was withdrawn.  A 71-year-old woman developed acute pan­ creatitis after taking indometacin for 1 month. Other causes were ruled out (56A). The duct of Wirsung was dilated and the pancreas hyper­ trophied. An abdominal CT scan showed diffuse pancreatic necrosis with fluid collec­ tions in the anterior lateral spaces of both kidneys and in the lower omental sac. She improved spontaneously after withdrawal of indometacin.

Fetotoxicity The risk of premature closure of the ductus arteriosus due to indometacin used during the third trimester of preg­ nancy has been studied in a systematic review of studies in 217 patients exposed to indometacin and 221 to placebo; the risk of ductal closure was 15-fold higher in the group of women exposed to indometacin than in those who took either placebo or other NSAIDs (eight studies; OR ¼ 15; 95% CI ¼ 3.29, 69) (57C). There was no significant increased risk of ductal closure in the infants of women treated with indo­ metacin compared with those who took other NSAIDs (four studies; OR ¼ 2.12; 95% CI ¼ 0.48, 9.25). Fetal hypoxia may be important in increasing the risk of this complication (58A).

Ketoprofen Skin Photoallergic reactions to topical NSAIDs are relatively common. The

Chapter 9

190 allergenic potential of different topical NSAIDs has been determined in a retrospective observational study (59c). There were 139 contact reactions, and ketoprofen was responsible for 28% of cases of allergy and 82% of cases of contact photoallergy, although it was only the third most commonly used topical NSAID, diclofenac being the first. The reporting odds ratio for ketoprofen was 3.9 (2.4, 6.4) and the proportional reporting ratio was 3.4 (2.1, 5.5), confirming the possibility of a signal.

Naproxen Pancreas Acute pancreatitis attributed to naproxen (60A).

has

been

 A 20-year-old man took 10 tablets of naproxen

sodium 550 mg. He developed mild upper abdominal pain and had raised activities of serum amylase 1050 IU/l (25–125 IU/l) and lipase 151 IU/l (8–78 IU/l). There was no evidence of hypercalcemia or hyperlipidemia and a viral screen was negative. He denied alcohol consumption and there was no family history of pancreatitis. Abdominal ultrasound and a CT scan showed a homogeneous pancreas and a normal gall-bladder and biliary tree. The symptoms resolved within a day, but the laboratory findings persisted for 3 days.

Skin Lichen planus has been described in 55 patients taking naproxen; in 42 it was of the eruptive type (61A). In 25 patients no other drugs had been used; 12 had taken naproxen with other drugs that have been associated with lichen planus; 18 had taken naproxen with drugs that had not been previously associated with lichen planus. New lesions did not occur after withdrawal of naproxen. Teratogenicity Renal tubular dysgenesis, a rare, lethal, autosomal recessive disorder characterized by short poorly differentiated proximal convoluted tubules associated with oligohydramnios, Potter sequence, and neonatal death from respiratory failure, has been reported after in utero exposure to naproxen sodium; the glomeruli were not as

J.K. Aronson

crowded as is usually seen in this condition (62A). However, a cause-and-effect associa­ tion in this case cannot be assumed.

COX-2 SELECTIVE INHIBITORS (SEDA-28, 128; SEDA­ 29, 116; SEDA-30, 130)

Celecoxib Cardiovascular The risk of cardiovascular events with celecoxib has been studied in a systematic review and meta-analysis of randomized double-blind trials of at least 6 weeks’ duration with data on serious thromboembolic events (63M). Four placebo-controlled trials in 4422 patients were analysed. The odds ratio for myocardial infarction with celecoxib was 2.26 (95% CI ¼ 1.0, 5.1). There was no significant increase in risk with celecoxib for composite cardiovascular events, cardiovascular deaths, or stroke. A secondary meta-analysis of six studies with placebo, diclofenac, ibuprofen, and paracetamol as comparators in 12 780 patients showed similar findings: there was a significantly increased risk of myocardial infarction with celecoxib (OR ¼ 1.88; 95% CI ¼ 1.15, 3.08) but not other outcome measures. Lactation In six lactating women in the final stage of weaning, celecoxib concentra­ tions in breast milk were low relative to concentrations in the maternal plasma, with a median milk/plasma AUC ratio of 0.18, after single dose of celecoxib 200 mg (64c). Drug overdose In cases of overdose with celecoxib reported to Texas poison control centers from 1999 to 2004 the mean dose was 701 mg, and the patient age distribution was: 5 years or under—48%; 6–19 years—8%; and 20 years or over—44% (65c). In 78% of cases exposure was unintentional. The final medical outcome was classified as no effect in 82% of the cases, and minor effects in 12% of

Anti-inflammatory and antipyretic analgesics and drugs used in gout

the cases. Adverse effects were listed in 5% of the patients, the most common being rash (3%), drowsiness (3%), pruritus (2%), and vomiting (2%). The most frequently listed treatment was decontamination by dilution (43%) or food (32%).

Etoricoxib Skin A fixed drug eruption has been attributed to etoricoxib (66A).  A 38-year-old woman developed a 1.5 cm,

round, well-circumscribed, erythematous patch on the right forearm 3 days after taking etoricoxib for bursitis. Over the next few days, the center of the patch blistered and necrosed and later healed with residual hyperpigmenta­ tion. She had taken various NSAIDs many times in the past, rofecoxib on more than two occasions, celecoxib for at least 1 week 2 years before, and etoricoxib once for 1 week 5 months before. She took a single tablet of etoricoxib again 2 months later, and within 2 hours noticed erythema, itching, and burning at the site of the old lesion. Over the next 3– 4 hours she developed generalized itching and burning followed by intense erythema all over the body. Nikolsky’s sign was negative. There was no mucosal involvement. She had neither a fever nor other constitutional symptoms. There were no systemic abnormalities on physical and routine laboratory examination. She was given systemic steroids, and although most of the symptoms and signs gradually subsided in 10 days, mild acral dusky erythema persisted for 4 weeks. The lesion over the right forearm developed a small blister and healed with a larger area of residual pigmentation. The erythema over the rest of the body resolved without residual pigmentation. A patch test with etoricoxib 10% in petrolatum 6 months later resulted in erythema and edema, double the size of the previous patch but in the same place, within 8 hours. The control area did not react.

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86, whereas there were no effects in groups who were given placebo or paracetamol.

Rofecoxib Psychiatric Acute psychotic syndromes have been reported in two patients taking rofecoxib, one with visual hallucinations and one with auditory hallucinations (68Ar). Liver Two cases of severe hepatotoxicity have been reported in patients, a man and woman, both aged 44 years, soon after exposure to rofecoxib (69A). There was cholestasis and abnormal liver biochemistry and in both cases, liver histology was compatible with drug-induced hepatotoxi­ city. There was rapid clinical and biochemical improvement after withdrawal of rofecoxib. Drug–drug interactions Tizanidine In a randomized, double-blind, two-phase cross­ over study, nine healthy subjects took placebo or rofecoxib 25 mg/day for 4 days and then took tizanidine 4 mg (70c). Rofe­ coxib increased the AUC of tizanidine 14­ fold (95% CI ¼ 8, 16), the Cmax 6-fold (4.8, 7.3), and the half-life from 1.6 to 3.0 hours. Rofecoxib increased severalfold the tizani­ dine/M3 and tizanidine/M4 ratios in plasma and urine and the tizanidine/M5, tizanidine/ M9, and tizanidine/M10 ratios in urine (the Mi being different metabolites of tizani­ dine). Rofecoxib markedly increased the blood pressure-lowering and sedative effects of tizanidine. It also increased the plasma caffeine/paraxanthine ratio 2.4-fold (95% CI ¼ 1.4, 3.4) and this ratio corre­ lated with the tizanidine/metabolite ratios. The authors attributed these effects to inhibition of CYP1A2 by rofecoxib.

Parecoxib

Valdecoxib

Urinary tract The effects of intravenous parecoxib 40 mg on renal function have been studied in 75 elderly patients undergoing orthopedic surgery in a randomized placebo-controlled study (67C). During the first 2 hours after the dose, creatinine clearance fell from 125 to

Drug overdose In a survey of 328 cases of overdose with valdecoxib reported to six Texas poison centers, comparisons were made between isolated and non-isolated cases with respect to various demographic and clinical factors (71c). The results are shown in Table 2.

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J.K. Aronson

withdrawal. The clinical relevance of these findings is not clear. (SEDA-15, 2555; SEDA-28, 128; SEDA-29, 125; SEDA-30, 132)

OXICAMS Meloxicam

Respiratory In 21 subjects with asthma and/or nasal polyps and intolerance of oral aspirin (rhinitis + bronchospasm in 13, isolated rhinitis in three, and extrabronchial reactions in five), meloxicam, cumulative dose 7.5 mg, caused a reaction in only one in a single-blind, placebo-controlled challenge (72c). Skin In oral challenges with two doses of meloxicam 7.5 and 15 mg in 114 patients, mean age 46 years, five developed urticaria (73c). A 49-year-old man developed psoriasis on two different occasions after taking meloxicam 15 mg/day for 16 days on the first occasion and 8 days after two doses on the second (74A). Reproductive system The effects of meloxicam on ovulation have been studied in 20 fertile women, who were monitored during a baseline cycle, two treatment cycles, and a washout cycle between treat­ ment cycles (75c). Compared with placebo, meloxicam caused a 5-day delay in follicle rupture, a 56% increase in mean maximum follicle diameter, and a 34% reduction in plasma progesterone concentrations. The effects reversed during meloxicam

Table 2 Demographic data (%) in a series of 328 episodes of overdose with valdecoxib Feature

Isolated cases

Non-isolated cases

Women Aged under 6 years Aged over 20 years Intentional overdose Management outside health-care facilities Outcome no effect

58 53 71 84 84

69 47 29 67 26

92

35

Immunologic Two cases of meloxicam­ induced anaphylactic reactions have been reported (76A).

Piroxicam Pancreas Acute pancreatitis has been reported in a patient taking piroxicam (77A).

PYRAZOLONE DERIVATIVES Metamizole (dipyrone) (SEDA-30, 132) Hematologic Granulocytopenia and fever have again been reported after exposure to metamizole (78A). Pregnancy Oligohydramnios has attributed to metamizole (79A).

been

 A 26-year-old woman in the 35th week of her

first pregnancy took metamizole 6 g/day for 3 days and papaverine hydrochloride to relieve urinary symptoms. Ultrasonography showed oligohydramnios with an amniotic fluid index of 40 mm (reference range 50–240 mm) and a restricted ductus arteriosus. Metamizole was replaced by paracetamol. Serial fetal ultra­ sonography showed an improvement in the width of the ductus arteriosus and in amniotic fluid volume 2 days after metamizole with­ drawal, and gradual return to normal within 1 week. A normal healthy baby was born vaginally at 40 weeks.

Drug overdose The pattern of episodes of overdose with metamizole reported to six Texas poison centers from 1998 to 2004 has been identified (80c). Of 81 cases 52 were isolated and 29 non-isolated. Most of the episodes occurred at the patient’s own residence (72/76) and the patients were more likely to be women (54/81). Children under 6 years of age accounted for a higher proportion of isolated exposures (33% versus 10%), while a higher proportion of non-isolated exposures involved older chil­ dren (28% versus 8%); 22% (11/51) of

Anti-inflammatory and antipyretic analgesics and drugs used in gout

isolated cases were intentional, compared with 59% (17/29) of non-isolated cases. When the medical outcome was known, there was no adverse clinical effect in 76% (16/21) of isolated exposures and 42% (8/ 19) of non-isolated exposures. The specific adverse effects in isolated exposures were primarily neurological (n ¼ 6), gastrointest­ inal (n ¼ 4), and dermal (n ¼ 3).

SALICYLATES Acetylsalicylic acid (aspirin) and related compounds (SED-15, 15; SEDA-28, 123; SEDA-29, 124; SEDA-30, 128)

Aspirin-exacerbated respiratory disease Aspirin-exacerbated respiratory disease has been reviewed (81R,82R,83R). It consists of chronic hyperplastic eosinophilic sinusitis, nasal polyps, asthma, and aspirin hypersensi­ tivity; respiratory complaints can be precipi­ tated by other factors, such as exercise and inhalation of irritants. The term “aspirin triad disease” has been used since 1980 to describe the combination of asthma, nasal polyps, and aspirin intolerance (84R). The main mechan­ isms appear to be related to reduced produc­ tion of prostaglandin E2, due to deficient COX-2 regulation, increased expression of leukotriene-C4 synthase, and reduced pro­ duction of metabolites (lipoxins) (85R). Prevalence In large questionnaire surveys the prevalence was 1.2% but the incidence of aspirin sensitivity was much higher in patients whose physicians made a diagnosis of asthma (8.8%) (86c). In a survey of 12 971 adults in Poland, 4.3% of asthmatic subjects said that aspirin precipitated attacks of asthma (87c). In 516 asthmatic patients and 1298 randomly selected individuals in Australia, the prevalence was 11% in sub­ jects with asthma and 2.5% in the general population (88c). In a meta-analysis of 15

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studies in which oral aspirin challenge was used to detect aspirin hypersensitivity in patients with asthma, the prevalence was 21% (CI ¼ 14, 29%) and in 5 studies in children it was 5% (CI ¼ 0, 14%) (89M). Features The average age of onset is around 30 years, and women outnumber men about three to five times (90c, 91c). There is initially nasal congestion and rhinitis, which progress to chronic hyper­ plastic eosinophilic sinusitis and nasal polyps. Acute respiratory reactions to aspirin include rhinitis, conjunctivitis, laryngeal spasm, and attacks of asthma. The reactions usually occur within 30–60 minutes after a full therapeutic dose of aspirin, but can occur up to 3 hours later, particularly when the dose is low (30–100 mg). There is cross-reactivity with non-selective NSAIDs, but not generally with highly selective COX-2 inhibitors, including cele­ coxib (92c–94c), etoricoxib (95c), parecoxib (96c), rofecoxib (97c–100c), and valdecoxib (101c). However, reactions to celecoxib (102A–105A), etoricoxib (41A,106A,107A), and rofecoxib (108A) have been reported. High doses of paracetamol can also cause reactions (109c). The natural history of asthma after endo­ scopic sinus surgery in patients with aspirin triad disease has been studied in a retro­ spective review of 65 patients, of whom 31 reported asthma symptoms preoperatively (110c). Of those, 29 had long-term post­ operative improvement and 21 reported further improvement of their asthma beyond the first postoperative year. Attacks of asthma were overall fewer and peak flow rates improved from an average of 60% of the predicted value preoperatively to 86% at the time of follow-up. The numbers of hospital visits and admissions for exacerba­ tions of asthma were reduced. Pathophysiology Circulating and tissue concentrations of proinflammatory cyto­ kines synthesized by epithelial cells, includ­ ing IL-2, IL-3, IL-4, IL-5, IL-13, GM-CSF, and eotaxin, and numbers of activated TH2 lymphocytes are increased in patients with aspirin-exacerbated respiratory disease (111c–113c). As a result, eosinophils and

194 degranulated mast cells are found in nasal biopsies, although their pathophysio­ logical role is not understood. There is also increased secretion of leukotrienes (114c–117c) and prostaglandin PGD2 (118c). The number of cysteinyl leukotriene receptors is also up-regulated in nasal inflammatory cells (119c). In contrast, there is reduced production of anti-inflammatory lipoxins (120c) and of PGE2 (121c). In 26 patients with nasal polyps (11 aspirin-sensitive and 15 aspirin-tolerant) and four controls without a history of nasal polyps or rhinosinusitis, cyclo-oxygenase activity was significantly higher in the nasal columnar epithelium and submucosal glands in those with polyps, irrespective of aspirin sensitivity; lipoxygenase activity was increased in the submucosal glands in the aspirin-sensitive subjects only (122c). In a study of the immunohistochemical expression of 5-lipoxygenase and cyclo-oxy­ genase pathway proteins in nasal polyps from 12 patients with asthma and aspirin intolerance and 13 with asthma and aspirin tolerance, cells that were immunopositive for LTC4 synthase were four times more numerous in those with aspirin intolerance and cells that expressed 5­ lipoxygenase were three times more numerous (123c). LTC4 synthase-positive cell counts correlated with mucosal eosinophils. There were no differences in 5-lipoxygenase activat­ ing protein (FLAP), COX-1, or COX-2. In 34 healthy subjects aged 19–57 years, 39 subjects with mild persistent atopic asthma aged 18–66 years, 24 subjects with aspirin-induced asthma with rhinitis aged 18–56 years, and 10 subjects with aspirininduced asthma and nasal polyps aged 22– 49 years, those with polyps had the highest concentrations of urinary LTE4: asthma + polyps 432 pg/mg, asthma + rhinitis 331 pg/mg, atopic asthma 129 pg/mg, and con­ trols 67 pg/mg (124c). Basal LTE4 concen­ trations were inversely related to basal FEV1. The expression of the G-protein-coupled E-prostanoid receptors EP1, EP2, EP3, and EP4 has been studied in nasal biopsies from patients with aspirin-sensitive (n ¼ 12) and non-aspirin-sensitive (n ¼ 10) polypoid rhinosinusitis and in healthy controls (n ¼ 9) (125c). Global mucosal expression of EP1 and EP2 receptors, but not EP3 or EP4

Chapter 9

J.K. Aronson

receptors, was significantly increased in both groups with rhinosinusitis, which was princi­ pally attributable to increased expression on tubulin( + ) epithelial cells and mucin 5 goblet cells subtypes A and B. In contrast, the percentages of neutrophils, mast cells, eosi­ nophils, and T cells expressing EP2 receptors, but not EP1, EP3, or EP4 receptors, were significantly reduced in the aspirin-sensitive compared with non-aspirin-sensitive patients. The authors concluded that PGE2 might be involved in the increased inflammatory infil­ trate and production of cysteinyl leukotrienes that characterize aspirin-sensitive disease and in mediating epithelial repair in rhinitis and asthma. IgE antibodies specific for staphylococcal superantigens have been implicated in the pathology of several allergic diseases, such as rhinosinusitis, nasal polyps, asthma, and aspirin sensitivity. In 80 patients with asthma and aspirin intolerance, 62 with asthma and aspirin tolerance, and 52 healthy controls, the prevalence of staphylococcal enterotoxin B-specific IgE and toxic shock syndrome toxin-1-specific IgE was significantly higher in the patients with asthma than in the controls, but there was no significant differ­ ence between the aspirin-tolerant and the aspirin-intolerant patients (126c). Expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule I (ICAM-1) and their ligands, the integrins lymphocyte functionassociated antigen 1 and very late activation antigen 4 (VLA-4), has been studied in nasal polyps from 21 patients with aspirin hyper­ sensitivity and 23 aspirin-tolerant individuals (127c). ICAM-1, VCAM-1, and VLA-4 were significantly increased in the patients with aspirin hypersensitivity, but the expression of lymphocyte function-associated antigen 1 did not differ. There was a correlation between the immunoexpression of VCAM-1 and its ligand VLA-4. The authors con­ cluded that up-regulation of the adhesion molecules ICAM-1 and VCAM-1 and the integrin VLA-4 may play an important role in the development of chronic eosinophilic inflammation in nasal polyps in aspirinhypersensitive patients. Plasma concentrations of complement C3a and C4a were higher in 30 patients with

Anti-inflammatory and antipyretic analgesics and drugs used in gout

aspirin-induced asthma than in 24 patients without (128c). After an aspirin challenge, C3 fell in both groups, but the C3a concentration increased only in those with aspirin-induced asthma. C3a and C4a concentrations and the ratios C3a/C3 and C4a/C4 correlated with changes in FEV1 after aspirin challenge. Genetic factors An increased prevalence of a genetic polymorphism in the LTC4S promoter region has been identified in Polish patients with aspirin-induced asthma (129c), although no polymorphisms in the flanking region of the LTC4S gene were discovered (130c,131c). Two single-nucleo­ tide polymorphisms in the LTC4S promoter region, –1702GWA and –444AWC, were not associated with aspirin hypersensitivity in a study in 110 Korean patients with aspirininduced asthma, 125 aspirin-tolerant patients with asthma, and 125 controls (132c). Single-nucleotide polymorphisms in the promoter region of the gene encoding an E­ prostanoid receptor, EP2, were significantly associated with aspirin-exacerbated respira­ tory disease (133c). Reduced transcription of the EP2 receptor for PGE2 might prevent such patients from inhibiting 5-lipoxygenase and 5­ lipoxygenase-activating protein activity. The HLA DPB1�0301 polymorphism is over-represented in aspirin-hypersensitive subjects with asthma (134c). A disintegrin and metalloprotease 33 (ADAM33) is an asthma susceptibility gene, and multiple single-nucleotide polymorph­ isms in ADAM33 have been reported to be associated with asthma and bronchial hyperresponsiveness in Caucasians. Ten such polymorphisms (ST + 4, ST + 7, T1, T2, T + 1, V-3, V-2, V-1, V4, V5) have been genotyped in a study of 102 Japanese patients with asthma and aspirin intolerance, 282 with asthma and aspirin tolerance, and 120 controls (135c). Haplotypes at three sites, ST + 7, V-1, and V5, were significantly different in the intolerant subjects compared with the tolerant subjects and the controls. The authors concluded that sequence varia­ tions in ADAM33 may correlate with susceptibility to aspirin intolerance in the Japanese population. Polymorphisms of the MS4A2 gene (FceR1b –109TWC and FceR1b E237G)

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were determined in 164 Korean patients with aspirin-induced asthma, 144 with asthma and aspirin tolerance, and 264 healthy controls (136c). The genotype frequencies of the FceR1b –109TWC and E237G poly­ morphisms were not significantly associated with the pathogenesis of aspirin-induced asthma. However, the FceR1b –109TWC polymorphism was significantly associated with the presence of specific IgE to staphy­ lococcal enterotoxin B; the number of subjects carrying both homozygous TT genotype of FceR1b –109TWC and specific IgE to staphylococcal enterotoxin B was significantly higher in those with aspirininduced asthma. The authors concluded that the FceR1b –109TWC polymorphism may increase the expression of MS4A2 in mast cells, leading to enhanced release of inflam­ matory mediators, contributing to increased susceptibility to aspirin intolerance. Diagnosis Challenge with aspirin, oral, nasal, inhalational, or intravenous, is the only reliable method of diagnosis. Lysine aspirin can also be used (137c). Antihista­ mines, short-acting beta-adrenoceptor ago­ nists, and anticholinergic drugs should be withdrawn 24 hours before the challenge, since antihistamines can block reactions to aspirin and beta-adrenoceptor agonists and anticholinergic drugs can give false-positive reactions. Nasal challenge using a dilute solution of ketorolac 8 mg/ml in increasing doses every 30 minutes has also been used (138c), as has oral ketoprofen (139c). In vitro tests may be helpful, including a leukotriene release test and a basophil activa­ tion test; these tests, alone or in combination, are positive in 70–75% of cases, with a specificity of over 85% (140R, 141R). Functional eicosanoid typing has been proposed as a method of diagnosing suscept­ ibility to pseudoallergic reactions to aspirin (142c). In one patient there were different patterns of eicosanoid secretion in response to aspirin and celecoxib (143A).  A 30-year-old woman with sinusitis and hyper­

sensitivity reactions to naproxen and ibuprofen was challenged on separate occasions with aspirin and celecoxib. Oral challenge with celecoxib 400 mg caused flushing, dyspnea, a 21% fall in FEV1, and urticaria. Urinary

196 excretion of LTE4 and PGE2-M was unchanged (3132 pg/mg creatinine and 7.4 ng/ mg creatinine, respectively), and 9a11bPGF2 rose from 1.3 to 2.6 pg/mg creatinine at 2 hours. Oral challenge with a cumulative dose of aspirin of 188 mg caused flushing, nasal block­ age, throat irritation, dyspnea, and a 27% fall in FEV1, followed 20 minutes later by hypoten­ sion. Urinary eicosanoid concentrations all rose and peaked at the height of clinical symptoms after 2–4 hours: LTE4 rose from 3448 to 14 310 pg/mg creatinine, 9a11bPGF2 from 1.9 to 2.7 pg/mg creatinine, PGE2-M from 15 to 56 ng/mg creatinine, and 11-dehydro-TXB2 from 2.0 to 4.6 ng/mg creatinine.

The authors suggested that the changes in 9a11bPGF2 (a urinary metabolite of PGD2) after both challenges, without changes in the cysteinyl leukotrienes after celecoxib, implicated mast cell degranula­ tion in the etiology of the sensitivity reactions in this patient. Management Avoidance of aspirin and cross-reacting NSAIDs is desirable, although not always possible. If a reaction occurs, topical corticosteroids, leukotriene receptor antagonists (such as montelukast and zafirlu­ kast), and 5-lipoxygenase inhibitors are stan­ dard treatments; combined treatment may be necessary in those with severe disease. Anti­ bacterial and antifungal drugs are also often required when infection has been demon­ strated. In a study of the medical records of 676 patients who had undergone oral aspirin challenges followed by aspirin desensitiza­ tion, leukotriene modifying drugs protected the lower airways from severe reactions, even in those who were already taking systemic corticosteroids (144c). Aspirin desensitization is often helpful. Various methods have been described, including administration orally (145c,146c, 147c,148c), nasally (149c,150c), and bronchi­ ally (151c). In 172 patients oral desensitization pro­ duced significant reductions in episodes of infectious sinusitis, olfactory scores, the need for hospital visits, and the need for systemic and nasal corticosteroids; however, there were no changes in the doses of the inhaled corticosteroids or leukotriene receptor antagonists (152c). Most of the 16 patients who did not respond to aspirin desensitiza­ tion had concomitant IgE-mediated rhinitis

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J.K. Aronson

and asthma, with reactions to dust mites (n ¼ 14), animals (n ¼ 13), and molds (n ¼ 7). Other cases of failed desensitization have been described (153A). Patients with aspirin-exacerbated respira­ tory disease who are the best candidates for desensitization have been described (154R): 1. those with no concomitant respiratory diseases but who have moderate or severe asthma, intractable nasal congestion, or both, which have failed to respond to drug treatment; 2. those with concomitant respiratory dis­ eases that have not responded to drug treatment; 3. those with multiple nasal polyps; 4. those who require systemic corticoster­ oids for control of their symptoms; 5. those who require aspirin for other diseases. A suggested protocol for aspirin desensi­ tization is given in Table 3. After desensiti­ zation, give aspirin 650 mg bd for 1 month and then reduce to 325 mg bd if the symptoms do not return. If the patient is taking systemic corticosteroids daily or every other day, reduce and withdraw the corti­ costeroids before reducing the dosage of aspirin. After reducing the dose, if symptoms return, increase the dosage of aspirin. Successful rapid desensitization has been performed in four pregnant women with antiphospholipid syndrome and aspirin sen­ sitivity, using increasing doses of aspirin (0.1–125 mg) over 24 hours (155c).

Nervous system Hematoma volume and impaired consciousness are the best pre­ dictors of outcome after spontaneous intracerebral hemorrhage. The effect of preceding aspirin use on outcome after intracerebral hemorrhage has been poorly investigated. In 208 subjects with intracer­ ebral hemorrhage the 3-month mortality was 33% (156c). The independent risk factors for death were regular aspirin use at the onset of intracerebral hemorrhage (RR ¼ 2.5; 95% CI ¼ 1.3, 4.6), warfarin

Anti-inflammatory and antipyretic analgesics and drugs used in gout

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Table 3 A suggested protocol for out-patient aspirin desensitization (153R)

Before desensitization At 1–7 days before, determine airway stability 1. 2. 3. 4. 5. 6.

Measure FEV1—must be over 60% of predicted value and 1.5 l absolute. Measure FEV1 every hour for 3 hours—must be less than 10% variability. Start or continue montelukast 10 mg/day. Start or continue an inhaled corticosteroid and/or a long-acting bronchodilator. Start systemic corticosteroids for a low FEV1 or any bronchial instability. Discontinue antihistamines 48 hours before the challenge.

Oral aspirin challenge 1. Day 1: insert an intravenous line (keep in throughout the period of challenge). 2. Examples of doses of aspirin that can be used are 20 or 40 mg (first dose), followed by 60, 80, 100, 162.5, 325, and 650 mg, increasing the dose every 3 hours; doses at the lower end of this range can be modified according to the type of formulation available. 3. Measure FEV1 and assess clinically every hour or when symptoms occur. 4. A reaction will probably occur at doses between 20 and 100 mg; this is called the provoking dose. 5. Treat reactions as described below until the patient is completely stable. 6. Start again with the provoking dose and increase the dose every 3 hours (on day 1 if there is time, otherwise on day 2). 7. If nasal, gastrointestinal, or cutaneous reactions occur on day 1, pretreat with H1 and H2 receptor antagonists for the rest of the challenge sequence. 8. The chance of a reaction to a repeated threshold dose is small; if it occurs, repeat that dose until reactions stop and then proceed to the next dose. 9. If a reaction occurs, continue as in 5.

Treatment of aspirin-induced reactions 1. 2. 3. 4. 5. 6. 7.

Ocular: topical antihistamine. Nasal: antihistamine (oral) or diphenhydramine 50 mg intravenously; topical decongestant. Laryngeal: nebulized adrenaline 2.5 mg/2 ml, five inhalations and pause. Bronchial: five inhalations of a b-adrenoceptor agonist every 5 minutes until comfortable. Gastrointestinal cramping: intravenous ranitidine, 50 mg. Urticaria/angioedema: intravenous diphenhydramine 50 mg. Hypotension: adrenaline 0.3 ml of a 1:1000 solution intramuscularly.

use at the onset of intracerebral hemor­ rhage (RR ¼ 3.2; 95% CI ¼ 1.6, 6.1), and an intracerebral hemorrhage score over 2 on admission (RR ¼ 14; 95% CI ¼ 6.0, 31). Regular aspirin use (median dose 250 mg/day) preceding the onset of intra­ cerebral hemorrhage was significantly asso­ ciated with hematoma enlargement during the first week after intracerebral hemor­ rhage. Hematologic In 107 consecutive patients who underwent coronary stenting and were given aspirin, clopidogrel, and warfarin and 107 who were given aspirin and clopidogrel, the former had significantly more major

bleeding (6.6% versus 0%) and minor bleed­ ing (15% versus 3.8%) than the latter (157c). In 711 patients, of whom 320 were taking aspirin at the time of surgical resection for cutaneous head and neck lesions, the incidence of significant post­ operative hemorrhage was 1.6% (five cases) versus none in the control group; the use of aspirin was the only suscept­ ibility factor for significant postoperative hemorrhage (158c). However, in other studies there was no effect of aspirin on blood loss in patients with hip fractures (159c), after coronary artery bypass surgery (160c), or after tooth extraction (161c).

198 Gastrointestinal The risks of adverse gas­ trointestinal effects of aspirin have been studied in relation to susceptibility factors using two major databases: the General Practice Research Database in the UK and the Base de Datos para la Investigación Farmacoepidemiológica en Atención Pri­ maria in Spain (162c). The rates of upper gastrointestinal adverse effects varied depending on age, sex, the use of NSAIDs, and the presence of upper gastrointestinal pain or peptic ulceration. The highest rate was in men aged 80 years and over with compli­ cated ulcers taking NSAIDs (300/1000 per­ son-years); the lowest rate was in women not taking NSAIDs and with no other suscept­ ibility factors (0.8/1000 person-years). Urinary tract In 106 elderly in-patients aspirin 100 mg/day for 2 weeks reduced creatinine clearance and uric acid clearance significantly in 70 and 62% of the patients, respectively, with mean reductions of 19 and 17% (163c). After withdrawal of aspirin renal function improved, but 67% of the patients were left with some impairment in creatinine clearance. Those who reacted adversely to aspirin had significantly better prestudy renal function, and lower hemo­ globin and serum albumin concentrations. Drug resistance Aspirin resistance can be defined in two ways—clinical resistance (failure to respond to aspirin) and in vitro resistance (a reduced effect of aspirin on platelet function in vitro). These two are not necessarily related to each other. Resistance has been attributed to two mechanisms: the capability of platelets to produce thromboxane A2, even at very low concentrations, despite aspirin treatment, because of pharmacokinetic or pharmaco­ dynamic problems; and platelet activation independently of TxA2 formation, possibly linked to polymorphisms in platelet recep­ tors or pro-aggregating molecule. The production by other circulating cells of thromboxane or its precursors, bypassing COX-1, may also play a role. Thromboxane biosynthesis and platelet aggregation have been studied in 50 patients taking aspirin 81 mg/day and 38 controls and have been related to clinical

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J.K. Aronson

outcomes (164c). Platelet COX-1 activity only accounted for 6–20% of the individual aggregatory responses. A common factor (other than platelet COX-1) explained 48% of the variation in platelet aggregation induced by collagen, adenosine diphos­ phate (ADP), and collagen-related peptide. In a prospective study of 136 patients taking aspirin, independent susceptibility factors for cardiovascular events were being in the upper quartile of light transmission or having large aggregate formation induced by collagen (i.e., having poor aggregation). The authors concluded that aspirin resis­ tance, expressed as unsuppressed platelet COX-1 activity, is rare in out-patients and that other factors that affect collageninduced platelet aggregation may affect outcomes in patients taking aspirin. The contribution of poor systemic avail­ ability to apparent clinical resistance to aspirin has been studied in 71 healthy volunteers who took modified-release dipyridamole 200 mg bd plus different formulations of aspirin: three different enteric-coated formulations, dispersible aspirin, and a standard-release formula­ tion, each containing 75 mg (165c). Dis­ persible aspirin had a significantly larger effect on serum TXB2 concentrations than all the other formulations, and there was treatment failure (less than 95% inhibition of serum TXB2 formation) in 14 subjects, none of whom was taking dispersible aspirin. The authors concluded that poor systemic availability of aspirin from some formulations could result in inadequate platelet inhibition. The role of aspirin resistance in the risk of major adverse coronary events has been studied prospectively after percutaneous coronary intervention in 146 patients with acute myocardial infarction (166c). Aspirin resistance was characterized in vitro using the collagen–adrenaline closure time. After 1 year there were major adverse coronary events in 44 patients (30%). A significantly higher percentage of patients with major adverse coronary events had aspirin resis­ tance (39% versus 23%); the difference persisted after adjustment for age, sex, cardiovascular risk factors, systolic left ventricular function, number of stenosed

Anti-inflammatory and antipyretic analgesics and drugs used in gout

coronary arteries, and previous myocardial infarction, percutaneous coronary interven­ tion, or coronary artery bypass grafting. The hazard ratio for aspirin resistance as a significant and independent risk factor for major adverse coronary events was 2.9 (95% CI ¼ 1.1, 9.2). Aspirin resistance has been described in a patient with a myocardial infarction in whom two stents occluded 2 days after insertion, despite standard antiplatelet drug therapy (167A). Plasma thromboxane B2 concentrations were raised and there was no thrombophilia. A procedure for evaluating aspirin resis­ tance in vitro using platelets from a single blood sample has been described (168S) and is summarized Figure 1. Pregnancy The association between aspirin and miscarriage has been investi­ gated in a prospective case–control study using data from the Collaborative Perinatal Project in 54 000 pregnant women at 12 sites in the USA from 1959 to 1965 (169C). Women who had miscarriages (n ¼ 542) were matched by clinic and time in preg­ nancy when they came under observation

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with 2587 women who had live births. During pregnancy 29% of cases and 34% of controls used aspirin, which was not associated with an increased risk of mis­ carriage (adjusted OR ¼ 0.64–0.92; 95% CI ¼ 0.48, 1.38) for individual lunar months and combinations of lunar months. Susceptibility factors Genetic Genetic polymorphisms in patients with aspirininduced chronic urticaria have been reviewed (170R, 171R). HLA The role of HLA class I phenotypes and the HLA-DRB1� genotype in patients with chronic idiopathic urticaria associated with aspirin and NSAIDs has been studied in 69 patients and 200 healthy subjects (172c). There were more subjects with HLA-B44 and HLA-Cw5 antigens among patients with chronic idiopathic urticaria than among the controls; conversely, there were more subjects with HLA-A11, HLA­ B13, HLACw4, and HLA-Cw7 among the controls. HLA-Cw4 and HLA-Cw7 were associated with a lower risk of chronic idiopathic urticaria and the HLA-B44 phenotype with a higher risk. There was

Measure platelet aggregation (PA) and thromboxane A2(TxA2) production in response to agonists (ADP, collagen, and arachidonic acid) PA normal; TxA2reduced

PA and TxA2 normal Aspirin challenge

PA and TxA2 reduced

Investigate polymorphisms of glycoproteins and proaggregatory molecules

Aspirin hypersensitivity

Measure platelet aggregation (PA) and thromboxane A2 (TxA2) production in response to agonists (collagen and arachidonic acid) + COX-1 and COX-2 inhibitors

+ COX-1 inhibitor

PA and TxA2 reduced COX-1 polymorphisms

PA and TxA 2 reduced Poor aspirin systemic availability

PA and TxA2 reduced Investigate platelet COX-2

Figure 1. A procedure for evaluating aspirin resistance in vitro using platelets from a single blood sample.

200 no association with the HLA-DRB1� geno­ type. An association between HLA DRB1�1302 and HLA DQB1�0609 alleles and aspirin-induced urticaria has been demonstrated (173c). Patients with these alleles developed urticaria at an earlier age. Leukotriene C4 synthase (LCT4S) In patients with chronic urticaria, the frequency of those carrying the C allele of LTC4S –444AWC was significantly higher among those with aspirin sensitivity than among those who did not react to aspirin; aspirininduced urticaria aggregated in families with the LTC4S –444C allele (174c); the frequency of the –444C allele was significantly higher in patients who were sensitive to aspirin than in those who were not sensitive. However, there was no association between the LTC4S –444AWC polymorphism and the pheno­ type of NSAID-induced isolated periorbital angioedema in Spain (175c) or Korea (176c). Polymorphisms of the LTC4S gene (AA, AC, CC) and the glutathione S-transferase M1 and P1 genes (GSTM1 and GSTP1) have been studied in 74 patients with chronic idiopathic urticaria and a history of aspirin hypersensitivity, 2 of whom had a family history of aspirin intolerance (177c). In both families, the variant genotypes of LTC4S (AC or CC) were present in the parents, but only one of them had urticaria. In one family both parents were healthy but the three children had urticaria, and in two of them it was associated with a variant LTC4S genotype. In the other family, urticaria after aspirin ingestion was present only in those with a variant LTC4S geno­ type. In the patients of both families with positive aspirin challenge tests, there was deletion of the GSTM1 gene. In a study of nine single-nucleotide polymorphisms of four leukotriene­ related genes, 5-lipoxygenase (ALOX5 –1708GWA, 270GWA, and 1728GWA), 5-lipoxygenase-activating protein (ALOX5AP 218AWG), cyclo-oxygenase 2 (PTGS2 –162CWG, 10TWG, and 228GWA), LTC4S (–444AWC), and CYSLTR1 (–634CWT), there were signifi­ cant differences in the frequencies of polymorphisms of ALOX5 (–1708GWA)

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J.K. Aronson

and CYSLTR1 (–634CWT) between patients with aspirin-induced urticaria or angioedema and controls (175c). In another study there were no significant differences in single-nucleotide polymorph­ isms of the genes that encode high-affinity IgE receptor Ib (FceRIb), histamine N­ methyltransferase (HNMT), histamine receptors type 1 (H1), histamine receptors type 2 (H2), or their haplotypes between patients with aspirin-induced urticaria, patients with other drug allergies, and healthy controls (178c). However, there was a sig­ nificant association between two promoter polymorphisms of the FceRIb receptor (–344CWT and –95 TWC) and aspirininduced chronic urticaria. The rare –344CWT polymorphism was significantly more com­ mon in the patients with chronic idiopathic urticaria than in controls and was significantly associated with total serum IgE concentra­ tions and a higher rate of atopy (179c).

Drug overdose Salicylate poisoning, including poisoning by excessive applica­ tion of topical agents, ingestion of salicy­ late-containing ointments, and use of keratolytic agents or agents containing methylsalicylate (e.g. oil of wintergreen), has been reviewed (180R). Liquid formula­ tions are highly concentrated and lipid soluble and can therefore cause severe, rapid salicylate poisoning.  A 34-year-old woman took a large amount of

aspirin for ear pain and developed a metabolic acidosis with a serum salicylate concentration of 668 mg/l (4.84 mmol/l; toxic range above 200 mg/l, 1.45 mmol/l) (181A). Autopsy showed venous congestion of the brain, cardiac dilata­ tion, and pulmonary edema. Brain histology showed myelin disintegration and caspase-3 activation in glial cells, but sparse gray matter changes.

The authors suggested that acute white matter damage underlies cerebral dysfunc­ tion in salicylate intoxication. Drug–drug interactions Anticoagulants In the SPORTIF III and IV randomized trials of anticoagulation with warfarin (INR 2–3) or fixed-dose ximelagatran, 14% of the

Anti-inflammatory and antipyretic analgesics and drugs used in gout

patients took aspirin, the addition of which did not reduce strokes or episodes of systemic embolism (182C). However, major bleeding occurred significantly more often with aspirin plus warfarin (3.9% per year) than with warfarin alone (2.3% per year), aspirin + ximelagatran (2.0% per year), or ximelagatran alone (1.9% per year). The authors concluded that the harms asso­ ciated with the addition of aspirin to antic­ oagulation in patients with atrial fibrillation outweigh the benefits. Pemetrexed In a randomized, crossover study in patients with cancer with a creatinine clearance below 60 ml/minute, oral aspirin 325 mg every 6 hours, starting 2 days before intravenous administration of pemetrexed 500 mg/m2 and continuing until 1 hour before the infusion, had no effect on the pharmacokinetics of pemetrexed (51c). Valproate Aspirin can displace other drugs from protein-binding sites on serum albumin, thus increasing the unbound frac­ tion, producing a toxic unbound concentra­ tion. This can affect the actions of drugs that are highly protein bound and have low volumes of distribution, such as warfarin and phenytoin. However, the clearance of these low-clearance drugs increases in response to the increase in the unbound fraction, the total concentration falls, and the unbound concentration once again becomes non-toxic. Thus, the effects of such interactions are generally transient. If the physician then increases the dose in order to increase the total concentration, toxicity can occur, since the unbound concentration will then be increased to toxic values. This has been reported in a patient taking aspirin and valproate (183A).  A 76-year-old man with bipolar I disorder was

given divalproex sodium 750 mg/day and the total serum valproate concentration was 14 ng/ ml. Aspirin 325 mg/day was added, and during a subsequent admission to hospital his total serum valproate concentration was 19 ng/ml. A psychiatrist suggested titrating the dose of divalproex to produce a total serum trough concentration of 50–70 ng/ml, and the dose was gradually titrated from 750 to 2500 mg/ day. After 2 weeks he started to have increasing difficulty in transferring from bed

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to a wheelchair, and 3 weeks later he became dizzy and had a painful fall. His difficulties with transfers steadily increased. His trough total valproate concentration was 64 ng/ml and the trough unbound concentration was 25 ng/ ml. Throughout this time he had hypoalbumi­ nemia below 30 g/l. The dose of divalproex was reduced to 1250 mg/day.

Displacement of valproate by aspirin and hypoalbuminemia probably both contribu­ ted to the high unbound concentration of valproate in this case. Aspirin may also have inhibited the metabolism of valproate, contributing to an increase in total valpro­ ate concentration.

DUGS USED IN THE TREATMENT OF GOUT Allopurinol

(SEDA-15, 80;

SEDA-28, 133) Urinary tract Another case of chronic granulomatous interstitial nephritis has been attributed to allopurinol, this time in a 79-year-old man without a history of allergies; it occurred after he had taken allopurinol for 10 years (184A). There have been very few previous reports of this supposed adverse reaction, and a true cause-and-effect association is hard to substantiate. Skin An unusual case of rash attributed to allopurinol has been reported (185A).  A 59-year-old man, who had taken Zylorics

tablets 100 mg (allopurinol, lactose, povidone, magnesium stearate, corn starch; Laboratoires Glaxo Wellcome, Marly-le-Roy, France) for 15 years developed a maculopapular rash 3 days after switching to a generic substitute, Allopur­ inol Ges (allopurinol, yellow beeswax, hydro­ genated soy, vegetable oils, peanut oil, soy lecithin, polysorbate 80, ethylparahydroxy­ benzoate, gelatine, glycerol, sorbitol, sorbitan, yellow iron oxide, titanium dioxide; Labora­ toires Eurogenerics, Boulogne Billancourt, France). This was withdrawn, and 4 days later the rash resolved spontaneously. Histology showed perivascular lymphohistiocytic infiltra­ tion with polymorphonuclear eosinophils. Two months later he took Zyloric again and 3 days

202

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J.K. Aronson

later developed generalized itchy eczematous plaques, with more severe involvement in flexures. Three months later Zyloric was with­ drawn and the rash resolved in 3 days. Patch tests with the standard series of excipients and preservatives, allopurinol 10% in petrolatum, water, and alcohol, Allopurinol Ge 30% in petrolatum, water, and alcohol, Zyloric 30% in petrolatum, water, and alcohol, and the exci­ pients of two commercial formulations (gly­ cerol, sorbitol 10% in water, titanium dioxide 10% in water, hydrogenated soy, peanut oil, soy lecithin, gelatine, methylparahydroxybenzoate, ethylparahydroxybenzoate, and propylpara­ hydroxybenzoate), and pricks tests with allo­ purinol, Zyloric, Allopurinol Ge, and their excipients were all negative.

colchicine may adversely affect cognitive function, in 55 patients, mean age 74 years, with familial Mediterranean fever colchi­ cine for an average of 25 years had no adverse effects on cognitive function (188c).

The authors suggested that something about the generic allopurinol formulation may have sensitized this patient to allopur­ inol. Generalized eosinophilic pustular follicu­ litis has been reported in a 71-year-old Cambodian man who took allopurinol for 8 weeks; the rash resolved over 8 weeks after withdrawal of allopurinol and treatment with oral and topical corticosteroids (186A).

Drug–drug interactions The pharmaco­ kinetics and drug interactions of colchicine have been reviewed (190R). Three proteins are important:

Colchicine (SEDA-15, 883; SEDA-28, 133; SEDA-29, 125; SEDA-30, 133) Nervous system Colchicine-induced neuromyopathy generally causes painless subacute muscle weakness but can cause pain (187A).  A 76-year-old man with chronic renal failure

and gout who was taking colchicine 0.5 mg tds for 3 days each month developed bilateral lower leg weakness and severe myalgia. His serum creatinine concentration was 681 mmol/l and creatinine kinase 959 IU/l. There were reduced amplitudes of motor and sensory nerve conduction velocities and electromyo­ graphy showed small-amplitude, short-dura­ tion, polyphasic waves over the right biceps. A muscle biopsy showed vacuolar changes in the cytoplasm, all consistent with colchicine neu­ romyopathy. After withdrawal of colchicine, the creatinine kinase activity fell by about 50% in 6 days, the myalgia abated, and the muscle weakness improved gradually over the next 2 weeks.

Psychological Despite that fact that stu­ dies in animals have suggested that

Skin Colchicine toxicity in a patient pre­ senting with altered mental function caused a diffuse, blanchable, violaceous, morbilli­ form rash on the trunk and proximal limbs; metaphase-arrested keratinocytes with underlying basal vacuolization were typical of colchicine toxicity (189A).

 tubulin, the pharmacological receptor (target) for colchicine; colchicine binds to tubulin, preventing polymerization and thereby disrupting microtubule function; the dissociation half-life of the tubulin–colchicine complex is 20–30 hours and this determines the half-life of colchicine;  intestinal and hepatic CYP3A4, by which colchicine is metabolized; drug inter­ actions can occur when colchicine is combined with other drugs that are CYP3A4 substrates;  P-glycoprotein, which affects its tissue distribution and excretion via the biliary tract and kidneys; drug interactions can occur when colchicine is combined with other drugs that are P-glycoprotein sub­ strates. Clarithromycin An interaction of colchi­ cine with clarithromycin (SEDA-30, 133) has again been reported (191A). Statins Interactions of colchicine with statins (SEDA-30, 134) have again been reported, resulting in rhabdomyolysis.  A 74-year-old Asian man who was taking

prophylactic colchicine for gout developed proximal muscle weakness 2 weeks after starting to take lovastatin (192A). The deep tendon reflexes were symmetrical and reduced in both arms and legs. Serum creatine kinase

Anti-inflammatory and antipyretic analgesics and drugs used in gout was 8370 U/l (0–130 U/l), and electromyogra­ phy showed a myopathic pattern. Lovastatin and colchicine were withdrawn and after several weeks the creatine kinase activity gradually returned to normal, with normal muscle strength.  A 45-year-old man with nephrotic syndrome took colchicine 1.5 mg/day for amyloidosis for 3 years without adverse effects (193A). He then took atorvastatin 10 mg/day for hyper­ cholesterolemia and after 2 weeks developed dyspnea, altered thinking, severe fatigue, myalgia, and reduced muscle strength. The creatinine concentration was 714 mmol/l, the creatine kinase activity 9035 U/l, and there was myoglobinuria and acute renal failure. His muscle strength improved after withdrawal of atorvastatin and colchicine.

Effects on CYP3A4 and P glycoprotein were presumably at least partly responsible for these interactions.

Probenecid

(SEDA-15, 2921)

Lactation Probenecid can enter breast milk (194A).  A breast-fed infant of a 30-year-old woman

taking oral probenecid and cefalexin for a breast infection developed severe diarrhea. The average concentrations of probenecid and cefalexin in the milk were 964 and 745 mg/l, respectively, corresponding to infant doses of 145 mg/kg/day of probenecid and 112 mg/kg/day of cefalexin.

The infant’s adverse effects were rated as possible for probenecid and probable for cefalexin based on the Naranjo probability scale.

Rasburicase Rasburicase is recombinant urate oxidase, which causes the breakdown of uric acid to 5-hydroxyisourate, which is further broken down to allantoin. Although there is a gene for urate oxidase in human, it is non­ functional, and purine catabolism therefore ends with uric acid. This may be advanta­ geous, because uric acid is an antioxidant. In the root nodules of legumes urate oxidase is necessary for nitrogen fixation. Rasburicase is used in the prevention and treatment of chemotherapy-induced hyper­ uricemia in patients with hematologic

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malignancies (195R–203R). In early clinical trials in patients who had received cancer chemotherapy rasburicase significantly reduced plasma uric acid concentrations from baseline by two to four times more than oral allopurinol 10 mg/kg/day. In these trials there was no evidence of renal impair­ ment; rashes occurred in about 2% of patients, and bronchospasm, nausea and vomiting, and hemolysis less often. Rasburicase has also been used to treat acute gout in a patient who developed severe urticaria/angioedema after receiving allopur­ inol, did not tolerate colchicine, and responded poorly to other treatments (204A). Observational studies In 173 children and 72 adults with malignancy who were treated with intravenous rasburicase 0.20 mg/kg/day for 1–7 days there was a dramatic reduction in uric acid concentrations in all patients whether they received it for prophylaxis (n ¼ 79) or treatment (n ¼ 166) (205c). The median post-treatment concentrations were 30–42 mmol/l. Repeated administrations were also effective in 11 patients. Four children and five adults had mild adverse reactions that were drug-related or of unknown cause; in two children, the adverse events occurred during the second course. In eight patients who received rasburicase, a single dose produced rapid sustained reduction of plasma uric acid concentra­ tions, and the effect was sustained for up to 96 hours; no adverse events were reported (206c). In a prospective study in 37 Korean children with hematologic malignancies intra­ venous rasburicase 0.2 mg/kg/day was given for 3–5 days (207c). Drug-related adverse effects were mild and reversible and there were no grade 4 or serious adverse events. Rasburicase was ineffective in controlling tumor lysis syndrome in a 4-day-old neonate with congenital precursor B cell acute lymphoblastic leukemia, despite several intravenous doses (two doses of 0.1 mg/kg and four doses of 0.2 mg/kg) and aggressive supportive therapy (208A). The authors suggested that in the presence of immature renal function other interventions and alter­ native antitumor strategies may be needed.

204 Comparative studies In a multicenter ran­ domized comparison of allopurinol and rasburicase in 52 children with leukemia or lymphoma at high risk of tumor lysis syndrome, the drugs were given for 5–7 days during induction chemotherapy (209C). The mean uric acid AUC0-96 was 7.6 hours mmol/l with rasburicase and 19.7 hours mmol/l with allopurinol. In this study, an 11-year-old boy with pre-B precursor acute lymphoblastic leukemia receiving rasburi­ case developed hemolysis and disseminated intravascular coagulopathy, which resolved after withdrawal; he did not have glucose-6­ phosphate dehydrogenase (G6PD) defi­ ciency and the relation of this event to the treatment was not clear. No patients had anaphylactic reactions and there was no evidence of antibodies to rasburicase. Respiratory Two cases of fatal respiratory arrest have been reported in patients who received rasburicase (210A).  A 51-year-old woman with a history of allergy to

codeine developed acute myelogenous leukemia and was given allopurinol and hydroxycarba­ mide, followed 12 hours later by intravenous rasburicase 0.20 mg/kg/day infusion; during the infusion she developed progressive dyspnea and cardiopulmonary arrest and died, despite cardiopulmonary resuscitation.  A 51-year-old man developed leukemia and was given allopurinol, prednisone, and hydroxycarbamide; he was given rasburicase 18 hours later and a second dose on the next morning; during the infusion his dyspnea increased and he had a cardiopulmonary arrest resulting in anoxic brain damage.

The authors attributed these reactions to acute severe bronchospasm, secondary to an ana­ phylactic reaction to rasburicase, probably associated with tobacco-induced bronchial damage, since both patients were smokers. Nervous system An acute myoclonic reac­ tion has been attributed to rasburicase (211A).

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J.K. Aronson

 A 35-year-old woman with non-Hodgkin’s

lymphoma was given rasburicase 0.20 mg/kg in advance of chemotherapy and within 2 hours became confused, agitated, and mute, with generalized myoclonus and muscular spasticity, with neck extension and protracted deviation of the mouth to the left followed by decorticate positioning of the arms and legs. She was given intravenous diphenhydramine 25 mg, which produced immediate relaxation of the myoclo­ nus and muscle spasticity but did not affect the mutism. Over the next 24 hours she had several episodes of myoclonus and muscle spasticity, which responded to intravenous diphenhydramine. She recovered completely after 36 hours.

Mineral metabolism Of 25 patients trea­ ted with rasburicase and urine alkaliniza­ tion, eight had hypocalcemia and hyperphosphatemia and 10 had hypo­ phosphatemia; the last of these was more common in children with B-cell lymphomas (212A). The authors suggested that alkali­ nization should be avoided during treat­ ment with rasburicase. Hematologic Hemolytic anemia and methemoglobinemia has been attributed to rasburicase in a patient with G6PD defi­ ciency (213A).  A 50-year-old African-American man was

given a single dose of intravenous rasburicase 22.5 mg for acute renal failure secondary to hyperuricemia. He developed methemo­ globinemia of 15% and a hemolytic anemia; the hemoglobin fell from 14.8 to 5.3 g/dl. He made a full recovery after aggressive fluid therapy, blood transfusions, and respiratory support. G6PD deficiency was subsequently confirmed.

Rasburicase is contraindicated in patients with G6PD deficiency, in whom it can cause hemolytic anemia and methemoglobinemia. Other cases of methemoglobinemia have been reported (214A).

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loss after coronary artery bypass surgery. Perfusion 2006;21(1):61–6. Hemelik M, Wahl G, Kessler B. Zahnex­ traktionen unter Medikation mit Acetylsa­ licylsäure (ASS). [Tooth extraction under medication with acetylsalicylic acid.] Mund Kiefer Gesichtschir 2006;10(1):3–6. Hernández-Díaz S, García Rodríguez LA. Cardioprotective aspirin users and their excess risk of upper gastrointestinal com­ plications. BMC Med 2006;4:22. Segal R, Lubart E, Leibovitz A, Iaina A, Caspi D. Renal effects of low dose aspirin in elderly patients. Isr Med Assoc J 2006;8 (10):679–82. Ohmori T, Yatomi Y, Nonaka T, Kobaya­ shi Y, Madoiwa S, Mimuro J, Ozaki Y, Sakata Y. Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity: involvement of other signaling pathway(s) in cardiovascu­ lar events of aspirin-treated patients. J Thromb Haemost 2006;4(6):1271–8. Cox D, Maree AO, Dooley M, Conroy R, Byrne MF, Fitzgerald DJ. Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers. Stroke 2006;37(8):2153–8. Marcucci R, Paniccia R, Antonucci E, Gori AM, Fedi S, Giglioli C, Valente S, Prisco D, Abbate R, Gensini GF. Usefulness of aspirin resistance after percutaneous cor­ onary intervention for acute myocardial infarction in predicting one-year major adverse coronary events. Am J Cardiol 2006;98(9):1156–9. Ruef J, Kranzhöfer R. Coronary stent thrombosis related to aspirin resistance: what are the underlying mechanisms? J Interv Cardiol 2006;19(6):507–9. Pulcinelli FM, Riondino S. More on aspirin resistance: position paper of the Working Group on Aspirin Resistance. Proposal for a laboratory test guiding algorithm. J Thromb Haemost 2006;4(2):485–7. Keim SA, Klebanoff MA. Aspirin use and miscarriage risk. Epidemiology 2006;17 (4):435–9. Kim SH, Ye YM, Lee SK, Park HS. Genetic mechanism of aspirin-induced urticaria/angioedema. Curr Opin Allergy Clin Immunol 2006;6(4):266–70.

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171. Kim SH, Park HS. Genetic markers for differentiating aspirin-hypersensitivity. Yonsei Med J 2006;47(1):15–21. 172. Pacor ML, Di Lorenzo G, Mansueto P, Martinelli N, Esposito-Pellitteri M, Pra­ della P, Uxa L, Di Fede G, Rini G, Corrocher R. Relationship between human leucocyte antigen class I and class II and chronic idiopathic urticaria asso­ ciated with aspirin and/or NSAIDs hyper­ sensitivity. Mediators Inflamm 2006;2006 (5):62489. 173. Kim SH, Choi JH, Lee KW, Kim SH, Shin ES, Oh HB, Suh CH, Nahm DH, Park HS. The human leucocyte anti­ gen–DRB1�1302-DQB1�0609-DPB1�0201 haplotype may be a strong genetic marker for aspirin-induced urticaria. Clin Exp Allergy 2005;35(3):339–44. 174. Mastalerz L, Setkowicz M, Sanak M, Rybarczyk H, Szczeklik A. Familial aggre­ gation of aspirin-induced urticaria and leukotriene C synthase allelic variant. Br J Dermatol 2006;154(2):256–60. 175. Torres-Galván MJ, Ortega N, SánchezGarcía F, Blanco C, Carrillo T, Quiralte J. LTC4-synthase A-444C polymorphism: lack of association with NSAID-induced isolated periorbital angioedema in a Span­ ish population. Ann Allergy Asthma Immunol 2001;87(6):506–10. 176. Kim SH, Choi JH, Holloway JW, Suh CH, Nahm DH, Ha EH, Park CS, Park HS. Leukotriene-related gene polymorphisms in patients with ASA-induced urticaria and ASA-intolerant asthma: differing contribu­ tions of ALOX5 polymorphism in Korean population. J Korean Med Sci 2005;20 (6):926–31. 177. Mastalerz L, Setkowicz M, Sanak M, Rybarczyk H, Szczeklik A. Familial aggre­ gation of aspirin-induced urticaria and leukotriene C synthase allelic variant. Br J Dermatol 2006;154(2):256–60. 178. Choi JH, Kim SH, Suh CH, Nahm DH, Park HS. Polymorphisms of high-affinity IgE receptor and histamine-related genes in patients with ASA-induced urticaria/ angioedema. J Korean Med Sci 2005;20 (3):367–72. 179. Bae JS, Kim SH, Ye YM, Yoon HJ, Suh CH, Nahm DH, Park HS. Significant

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I.D. Welters and M. Leuwer

10

General anesthetics and therapeutic gases

ANESTHETIC VAPORS (SEDA-27, 119; SEDA-28, 139; SEDA-29, 129; SEDA-30, 137)

HALOGENATED VAPORS Desflurane

(SED-15, 1072; SEDA-30, 137)

Respiratory The effect of intravenous fentanyl given before thiopental induction on airway irritation caused by a stepwise increase in desflurane has been studied in 80 children aged 2–8 years in a doubleblind, randomized, placebo-controlled study (1C). Fentanyl reduced the incidence of airway irritation (cough 2.5% versus 43%; secretions 28% versus 83%; excitation 10% versus 83%; apnea 20% versus 65%). The mean expired desflurane concentration at which the first airway irritation symptom occurred was greater with fentanyl. Cytotoxicity Free radicals can trigger oxidative stress, leading to the production of malondialdehyde and protein carbonyl content, and the extent of oxidative status can be increased by volatile agents. The effects of sevoflurane+fentanyl, sevoflurane +nitrous oxide, desflurane+fentanyl, and desflurane+nitrous oxide together with pneumoperitoneum have been reported in Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03110-9 r 2009 Elsevier B.V. All rights reserved.

40 patients (2C). Malondialdehyde concen­ trations and protein carbonyl content were significantly higher and sulfhydryl groups significantly lower in those who received desflurane. Susceptibility factors Genetic In a case of malignant hyperthermia there was a negative gradient between arterial and endtidal CO2 during anesthesia, which was used as a diagnostic and monitoring tool (3A). Smoking Cigarette smokers have a greater risk of respiratory complications during anesthesia than non-smokers, but it is not known to what extent the pungency of inhaled anesthetics contributes. Desflur­ ane and sevoflurane, the latter being more pungent, have been compared in 55 patients each (4C). There were no differences in the incidences of cough (five versus nine patients respectively), breath holding, lar­ yngospasm, or desaturation. Management of adverse drug reactions In two studies the value of combining antie­ metic agents in treating postoperative nau­ sea and vomiting has been demonstrated. Intravenous dexamethasone and tropise­ tron reduced the incidence of postoperative nausea and vomiting by about 35% in a double-blind, randomized, placebo-controlled study in 320 patients after anesthesia with benzodiazepine premedication, propofol, rocuronium, desflurane in air/O2, and fen­ tanyl or sufentanil, followed by a contin­ uous infusion of remifentanil (5C). The two drugs had additive effects, although even in the combination group the incidence of nausea and vomiting was still unacceptably high.

217

218 In another randomized, double-blind study in 105 adults undergoing thyroidect­ omy the addition of propofol 0.5 mg/kg to tropisetron 5 mg improved its antiemetic effects after anesthesia with desflurane (6C) (17% versus 43% with tropisetron alone and 77% with placebo).

Isoflurane (SED-15, 1921; SEDA-30, 138) A Polish Expert Group for Chemical Hazards has suggested that the maximum admissible concentrations for isoflurane in places where it is used should be 32 mg/m3 (4 ppm), and that this limits should protect surgical staff from the adverse neurological, cardiovascular, respiratory, and irritant effects of isoflurane (7RS). Liver Isoflurane-associated hepatotoxicity has been reported (8A).
A 68-year-old man developed fulminant fatal

hepatic necrosis 2 days after open cholecys­ tectomy under isoflurane anesthesia. He had greatly raised transaminases and bilirubin and a prolonged prothrombin time. Serological studies were negative for viral hepatitis. Postmortem examination showed centrilobu­ lar necrosis of the liver.

Sevoflurane

(SED-15, 3123; SEDA-28, 139; SEDA-29, 129; SEDA-30, 138)

Chapter 10

I.D. Welters and M. Leuwer

cardiovascular, respiratory, and irritant effects of sevoflurane (7RS). Cardiovascular The dysrhythmogenic properties of anesthetics are of major concern and there is as yet no safe anesthetic regimen for patients with a prolonged QT interval or those suspected to be at risk. However, electrophysiology experiments have shown that volatile anes­ thetics, such as sevoflurane, prolong the QT interval by inhibiting the repolarization phase of the action potential. The human ether-a-go-go related gene (HERG) chan­ nel appears to be involved in this process. A comparison of the effects of sevoflurane and propofol on the QT interval in guinea pigs has confirmed that sevoflurane pro­ longs the QT interval, and that propofol does not. Furthermore, sevoflurane inhib­ ited the outward tail currents in HERG channels expressed in Xenopus oocytes, whereas propofol had no effect (10E). In a blinded study in 20 women aged 38–51 years of ASA stages I and II, who were given sevoflurane for total abdominal hysterectomy, there were no significant changes between baseline and final QTc dispersion and between the low- and highfrequency components of heart rate varia­ bility, despite a significant increase was seen in the variability in RR interval, which was used as a measure of cardiac autonomic tone (11c).
An 8-year-old boy with congenital long QT

Occupational exposure to anesthetic gases, such as sevoflurane, can be mitigated by the use of anesthetic gas extractors (9c). In the breathing areas around anesthesiologists mean exposure to sevoflurane without an extractor was 12 ppm. In those who worked with an extractor, exposure was 91% lower (1.1 ppm). There were also higher rates of general discomfort (62% versus 11%), nau­ sea (62% versus 0%), and headache (62% versus 0%) in the absence of an extractor. A Polish Expert Group for Chemical Hazards has suggested that the maximum admissible concentrations for sevoflurane in places where it is used should be 55 mg/m3 (7 ppm), and that this limits should protect surgical staff from the adverse neurological,

syndrome (LQT2) continued to have attacks of syncope despite nadolol 80 mg/day (12A). He was anesthetized with 2.8–3% sevoflurane for implantation of an internal cardioverter– defibrillator. After 20 minutes he had a run of multifocal ventricular extra beats followed by a spontaneously resolving episode of torsade de pointes lasting 5 seconds. A second episode caused hemodynamic compromise. The sevo­ flurane was withdrawn and propofol 5 mg/kg/ hour was given intravenously. The dysrhyth­ mias immediately resolved.

Despite the suggestive time course in this case the association of sevoflurane with torsade de pointes has been challenged (13r). Care is perhaps nevertheless indi­ cated when using sevoflurane in patients with congenital long QT syndrome (14r).

General anesthetics and therapeutic gases

Chapter 10

Nervous system A 2-year-old child, ASA grade 1, developed myoclonic jerks during anesthesia with sevoflurane (15A).
A 23-year-old Taiwanese man with no history

of epilepsy had a generalized convulsion with a mild fever after 11 hours of anesthesia with sevoflurane anesthesia (16A). The episode resolved after aggressive management. Another 3 hours were required to complete the operation and the patient recovered uneventfully.

Sensory systems The effects of anesthetic agents on stapedius reflex thresholds and transient evoked otoacoustic emissions have been studied in 50 patients who were scheduled for operation and who had normal hearing (17c). Anesthesia was main­ tained with 70% nitrous oxide +30% oxygen, sevoflurane, desflurane, halothane, or intravenous propofol+sufentanil. Mida­ zolam significantly increased ipsilateral and contralateral stapedius reflex thresholds and reduced the wave reproducibility of the otoacoustic emissions. Propofol signifi­ cantly increased the stapedius reflex thresholds. The other anesthetic agents significantly increased only the contralat­ eral reflex thresholds, the largest effect being with sevoflurane and the smallest with halothane. The authors concluded that sevoflurane should not be used when it is necessary to measure stapedius reflex thresholds under general anesthesia. Psychological The effects of brief sevo­ flurane–nitrous oxide anesthesia on post­ operative cognition and behavior have been studied in 48 children aged 5–10 years undergoing anesthesia without premedica­ tion for multiple dental extractions and 48 control children (18c). Mean choice reaction time and psychomotor co-ordination were significantly impaired postoperatively but had recovered by 48 hours, although mea­ sures of variability suggested residual impairment. There was profound retrograde amnesia postoperatively and at 48 hours, but recognition memory was not impaired. Attention-seeking, tantrums, crying, and nightmares were more frequent in 8–20% of the children 1 week after the procedure.

219

Musculoskeletal A patient had two epi­ sodes of severe muscle rigidity, increased end-tidal CO2, and increased creatine phos­ phate kinase activity after sevoflurane anesthesia (19A). Genetic testing for the 17 known mutations associated with malignant hyperthermia was negative. Although the authors could not rule out malignant hyperthermia or other neuromuscular dis­ eases they suggested that this rare event may have been directly due to sevoflurane.

Trichloroethylene (SED-15, 3488; SEDA-28, 140; SEDA-29, 130; SEDA-30, 140) The health risks of trichloroethylene have been reviewed (20R). Respiratory Acute lung damage has been reported in a man who inhaled trichloro­ ethylene (21A).
A 28-year-old man who cleaned tubes that had

been washed with trichloroethylene became unconscious with acute lung injury. ACT scan showed a ground-glass opacity in the left upper lobe. Bronchoalveolar lavage fluid contained alveolar macrophages, lymphocytes, and neutrophils. There were erythrocytes in the alveolar spaces in a lung biopsy and vacuolation of the cytoplasm of type 2 alveolar pneumocytes.

Nervous system Neurotoxicity from tri­ chloroethylene has again been reported (22A).
A 32-year-old male drug addict had temporal

lobe seizures after “huffing” (i.e., voluntarily inhaling) trichloroethylene. He also developed cognitive dysfunction (with memory disorders in particular) and personality changes. These disorders had not been noticed by the patient’s wife before the last episode of inhalation. Four months later, the cognitive disorders had stabilized and he had had no further seizures.

The authors suggested that trichloro­ ethylene had had a selective effect on the temporal lobe. Skin Workers exposed to trichloro­ ethylene rarely have severe generalized skin disorders and accompanying hepatitis, which resemble drug hypersensitivity reactions. The

220 effects are distinct from solvent-induced irritating contact dermatitis. In a systematic review of the published literature (239 cases) 124 (52%) cases were classified as hyper­ sensitivity syndrome and 115 (48%) as erythema multiforme/Stevens–Johnson syn­ drome/toxic epidermal necrolysis (23M). The reports from Western industrialized coun­ tries were mostly published up to 1990, whereas cases from Asian industrializing countries appeared thereafter. The association between genetic poly­ morphisms of human leukocyte antigenDQ (HLA-DQ) and susceptibility to tri­ chloroethylene-induced severe generalized dermatitis has been investigated in a case– control study in 112 patients with severe generalized dermatitis and 142 healthy con­ trols exposed to trichloroethylene in the same workshop (24C). The frequencies of DQA1�0201 and 060101/0602 were 7.6% (17/224) and 16% (36/224) in cases, signifi­ cantly higher than in the exposed controls: 3.5% (10/284) and 7.0% (20/284). The frequencies of DQA1�0103 and 050101/ 0503/0505 were 5.8% (13/224) and 8.9% (20/224) in cases, significantly lower than in exposed controls: 11% (31/284) and 17% (49/284). Five codons of DQA1 (25, 41, 52, 54, and 69) showed significant differences between cases and controls. There were no significant differences in the frequencies of allelic genotypes of HLA-DQB1. In a similar study, the frequencies of HLA-DMA and HLA-DMB have been studied in 61 patients with trichloroethy­ lene-induced dermatitis and in 60 healthy controls (25C). The frequency of the HLA­ DMA�0101 allele was significantly higher in the patients than in the controls (71% versus 55%), as was the allele frequency of HLA­ DMA�0103 (12% versus 3.3%) and the ratio of �0102 homozygotes of HLA­ DMA�0102 (25% versus 8.2%). The ratio of �0102 heterozygotes of HLA-DMB�0101 was lower in the patients than in the controls. Tumorigenicity Different committees have reported that trichloroethylene is either “probably” (26S) or “reasonably anticipated to be” (27S) carcinogenic in humans. According to the National Toxicology Program “trichloroethylene is reasonably

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I.D. Welters and M. Leuwer

anticipated to be a human carcinogen based on limited evidence of carcinogenicity from studies in humans, sufficient evidence of carcinogenicity from studies in experimental animals, which indicates there is an increased incidence of malignant and/or a combination of malignant and benign tumors at multiple tissue sites in multiple species of experimen­ tal animals, and information suggesting [that it] acts through mechanisms that indicate it would [probably] cause cancer in humans.” The relative risks, standardized incidence ratios, and standardized mortality ratios from cohort studies and the odds ratios from case–control studies for four types of cancers—liver, liver and biliary tract, and kidney tumors, and non-Hodgkin’s lym­ phoma—have been reviewed (28RM). The main problems that beset a proper inter­ pretation of the data are (a) the relative sensitivity of cancer incidence and mortality data; (b) different classifications of lympho­ mas, including non-Hodgkin lymphoma; (c) differences in data and methods for assign­ ing trichloroethylene exposure status; and (d) different methods used for making causal inferences, including statistical approaches and meta-analyses. However, the overall data suggest that there are increased risks of cancers of the kidney, liver, and lymphatic systems in those who are occupationally exposed to trichloroethy­ lene, with typical relative risks of 1.5–2.0. In a meta-analysis of 14 occupational cohort and four case–control studies of workers exposed to trichloroethylene the summary relative risk estimates for non­ Hodgkin’s lymphoma from the cohort studies was 1.29 (95% CI ¼ 1.00, 1.66) for the total cohort and 1.59 (95% CI ¼ 1.21, 2.08) for the seven studies that identified a specific sub-cohort that had been exposed to trichloroethylene (29M). However, com­ parison of the relative risk estimates by trichloroethylene exposure did not indicate a dose–response effect. Case–control stu­ dies had a summary relative risk estimate of 1.39 (95% CI ¼ 0.62, 3.10). The interpreta­ tion of the results of this analysis was hampered by variability in results across the studies, limited assessments of expo­ sure, lack of supportive information from toxicological and mechanistic data, and the

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absence of consistent findings. Although there was a modest positive association in the sub-cohort analysis, there was insuffi­ cient evidence to suggest a causal link between exposure to trichloroethylene and non-Hodgkin’s lymphoma. The carcinogenic effects of trichloroethy­ lene may be at least partly medicated by its metabolites dichloroacetic acid and trichlor­ oacetic acid (30E). A meta-analysis of epidemiological stu­ dies of occupational exposure to trichlor­ oethylene has shown no association with either multiple myeloma or leukemia (31M). Teratogenicity The risks of congenital heart defects after exposure to trichloroethy­ lene have been analyzed by a systematic review of the epidemiological data and animal studies (32M). No single process was clearly affected by trichloroethylene, provid­ ing support that gestational exposure does not increase the prevalence of congenital heart defects. Application of Bradford Hill’s causality guidelines showed no causal link.

OTHER VAPORS

221

by arm weakness, leg paraplegia, and neuro­ genic bladder (33A). He had hyperhomo­ cysteinemia and a low serum vitamin B12 concentration. There was a polymorphism in the MTHFR gene associated with the thermolabile isoform of the 5,10-methylene tetrahydrofolate reductase enzyme, which explained the myelopathy after exposure to nitrous oxide. Therapy with folic acid and vitamin B12 resolved the neurological symptoms. Drug abuse In a 33-year-old man nitrous oxide abuse caused vitamin B12 deficiency, which resulted in bizarre behavior and delusions, which responded to treatment with intramuscular cobalamin (34A). Management of adverse drug reactions Occupational exposure to anesthetic gases, such as nitrous oxide, can be mitigated by the use of anesthetic gas extractors (9c). In the breathing areas around anesthesiologists mean exposure to nitrous oxide without an extractor was 423 ppm. In those who worked with an extractor, exposure was 94% lower (25 ppm). There were also higher rates of general discomfort (62% versus 11%), nausea (62% versus 0%), and headache (62% versus 0%) in the absence of an extractor.

Nitrous oxide

(SED-15, 2550; SEDA28, 140; SEDA-29, 131; SEDA-30, 140)

Observational studies The adverse effects of a 50% nitrous oxide/oxygen mixture have been studied in a 4-year prospective survey of 35942 data sheets received from 191 French hospital pediatric units (82%) and adult units (18%), of which 35828 were sufficiently complete to be used. There were 1581 (4.4%) adverse events reported on 1384 data sheets, mostly gastrointestinal and neuropsychiatric disorders (86%). The main factors associated with adverse events were age, concomitant drugs, and longer duration of inhalation. Of 27 (0.08%) serious adverse events, only 9 (0.03%) were possibly attributable to the mixture. Nervous system A patient who received nitrous oxide on two occasions in 8 weeks developed a diffuse myelopathy, characterized

INTRAVENOUS AGENTS: NON-BARBITURATE ANESTHETICS Etomidate (SED-15, 1302; SEDA-30, 140) Nervous system Myoclonic movements and pain on injection are common during induction of anesthesia with etomidate. The bispectral index is commonly used to judge the level of anesthesia and provides a single dimensionless number derived from a Fourier transform of the electroencephalogram. A value of 0 indicates electroencephalographic silence, 100 is the expected value in a fully awake individual, and values between 40 and 60 are considered appropriate during general anesthesia. Electromyographic activity of the

222 facial muscles is one of the signals used by the bispectral index algorithm. Changes in the bispectral index have been documented in a patient with involuntary movements of the facial muscles during a severe episode of etomidate-induced myoclonus (35A).
A 51-year-old man with no personal or family

history of epilepsy underwent general anesthe­ sia for excision of an anal polyp. Premedica­ tion consisted of oral midazolam. Anesthesia was induced with intravenous fentanyl fol­ lowed by an infusion of etomidate 5 mg/minute to a total of 20 mg. Shortly after losing his response to verbal commands, he started to have twitching of the muscles around the mouth, followed by tonic-clonic movements of the arms and legs. The bispectral index, which had fallen to a minimum of 40, increased rapidly to above 70. The involuntary movements ceased after an intravenous bolus of propofol 70 mg. Anesthesia was then main­ tained with nitrous oxide and sevoflurane. Recovery was uneventful and he had no recall of any of the events.

Myoclonus induced by etomidate appears to be different from epilepsy, as it is not associated with seizure-like electro­ encephalographic activity (36c). In this case, when the movements were terminated with a bolus injection of propofol, the bispectral index rapidly fell to a value consistent with anesthesia. In contrast to previous studies in which changes in bispectral index were investigated after induction with etomidate, this patient was not paralysed and devel­ oped myoclonic movements soon after losing consciousness. The analgesic properties and in particular the inhibitory effects of etomidate on spinal cord neuronal responses to noxious stimuli have been investigated in rats, which were anesthetized with isoflurane (37E). Lami­ nectomy was performed to record single unit activity. Lumbar neuronal responses to noxious thermal stimulation of the hindpaw were recorded before and every 2 minutes after administration of etomidate. The responses at peak effect of etomidate were reduced to 36% of the control response, depending on the dose (0.125, 0.25, 0.5, 1, and 2 mg/kg). The responses usually recovered within 10 minutes after injection. There were similar effects in decerebrate isoflurane-free rats. The authors concluded

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that etomidate depresses spinal cord neu­ ronal responses to noxious stimulation and that this might be a possible mechanism by which etomidate produces analgesia.

Ketamine (SED-15, 1964; SEDA-28, 141; SEDA-29, 131; SEDA-30, 141) Nervous system Ketamine potentiates intravenous or epidural morphine analgesia. The effect of an infusion of a very low dose of ketamine on acute and long-term postthoracotomy pain has been studied in 49 patients who were randomly assigned to one of two regimens: continuous epidural infusion of ropivacaine+morphine for 2 days, along with an intravenous infusion of ketamine 0.05 mg/kg/hour or placebo for 3 days (38c). Postoperative visual analog scale scores and numerical rating scale scores 1 and 3 months after surgery were lower after ketamine. Three months after surgery, more control patients were taking pain medications.

Propofol

(SED-15, 2945; SEDA-28, 142; SEDA-29, 132; SEDA-30, 142) Cardiovascular Because of its fast onset and offset of hypnotic action and its short, context-sensitive half-life, propofol is an attractive intravenous anesthetic for induction and maintenance of anesthesia. Several aspects of its interactions with the cardiovascular system in patients with left ventricular dysfunction have been reviewed (39R). Propofol reduces arterial blood pressure, mainly by reducing sympathetic tone, vascular resistance, and preload, and not by impairing myocardial contractility. Although it has negative inotropic effects, partly mediated by reduced uptake of calcium into the sarcoplasmic reticulum, they do not appear to be clinically important. It is not clear, however, how propofol affects cardiovascular function in patients with severe left ventricular dysfunction. Experiments in rodents have not shown any effects in compensated or congenital hypertrophic cardiomyopathy, and a study on left ventricular trabeculae from pigs with pacing-induced congestive heart failure suggested that the myocardial

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depressive effects of propofol might be more pronounced in the presence of left ventricular dysfunction than in healthy hearts (40E). In dogs with dilated cardiomyopathy induced by continuous pacing at 240 Hz for up to 3 weeks, propofol reduced left ventricular preload, afterload, and regional chamber stiffness, caused a dose-related direct negative inotropic effect, and impaired early diastolic left ventricular filling (41E). The protective effects of propofol in ischemia/reperfusion injury have been reviewed. Propofol inhibits specific subu­ nits of KATP channels, but only in con­ centrations 5–15 times higher than those encountered during clinical anesthesia (42R). Protection may also be provided by scavenging of free oxygen radicals, reduced disulfide bonding in proteins, and inhibition of lipid peroxidation. Additional protective effects may be related to inhibi­ tion of the mitochondrial permeability transition pore, which represents opening of non-specific pores in the inner mito­ chondrial membrane under conditions of increased oxidative stress. The authors concluded that propofol causes only mini­ mal myocardial depression in the healthy heart at clinically relevant concentrations, but that the risk of cardiac depression may be increased in the failing heart. It should therefore be administered slowly, in order to allow the cardiovascular system to compensate for the associated hemody­ namic changes. For intravenous anesthesia, propofol should be combined with opioids, which have relatively few cardiovascular adverse effects and also protect against ischemia/reperfusion injury. Respiratory General anesthesia can cause airway compromise. In a prospective study in nine infants undergoing elective MRI scanning of the brain, spin echo magnetic resonance images of the airways were acquired during different stages of propofol anesthesia (80 and 240 mg/kg/minute) with and without 10 mmHg continuous positive airway pressure (43c). At each anatomical level, airway caliber fell as the depth of propofol anesthesia increase, an effect that was completely reversed by continuous

223

positive airway pressure. This study has highlighted the need for appropriate airway support as the depth of anesthesia increases, even if spontaneous ventilation is maintained. Nervous system There is a debate about whether propofol has proconvulsant or anticonvulsant effects and whether it should be used in patients with epilepsy. The effects of intravenous propofol on the electroencephalogram have been assessed prospectively in children with epilepsy (44c). There were no seizure-like phenom­ ena during and after propofol sedation. Immediately after withdrawal of propofol, the characteristic electroencephalographic patterns in children with epilepsy consisted of transient increased beta wave activity (23/25 children) and suppression of pre­ existing theta rhythms (11/16 children). In addition, spike-wave patterns were sup­ pressed after propofol sedation (16/18 children with epilepsy). In 25 children with learning difficulties there was a transient increase in beta wave activity and there was suppression of theta rhythms in 11 of 12 children. The results of this study have supported the concept that propofol has anticonvulsant properties. In neuroanesthesia propofol has advan­ tages over volatile anesthetics (45R). The authors regard propofol as first-choice anesthetic, because it is associated with lower intracranial pressure and cerebral swelling than volatile anesthetics in patients with brain tumors undergoing craniotomy, hardly interferes with somatosensory, audi­ tory and motor evoked potentials, and provides excellent and predictable recovery conditions as well as minimal postoperative adverse effects. Similar to cardiovascular protection, the potential neuroprotective effect of propofol may be mediated by antioxidant effects. Metabolism The propofol infusion syndrome is the commonest cause of death directly related to the use of propofol, and deaths associated with the use of propofol for sedation have been reviewed (46M). All reports of deaths after sedation with pro­ pofol in children and adults submitted to

224 the Food and Drug Administration (FDA) and entered into its post-marketing drug safety database were considered, as were published reports and studies. The propofol infusion syndrome was defined as metabolic acidosis and/or rhabdomyolysis with pro­ gressive myocardial failure. Between 1989 and April 2005, the Adverse Event Report­ ing System of the FDA received reports of 21 patients aged 16 years or under and 68 patients aged over 16 years who died after administration of propofol for non-proce­ dural sedation. The most frequent symp­ toms were progressive cardiac dysfunction/ failure (bradycardia, cardiac failure, “cardio­ vascular collapse”, dysrhythmias, and cardiac arrest), metabolic acidosis, hypoten­ sion, and rhabdomyolysis. Additional symp­ toms described in the adults were renal failure, respiratory failure/adult respiratory distress syndrome, persistent sedation, hyperthermia/fever, hypertriglyceridemia, multiorgan failure, liver dysfunction, tre­ mors/weakness/polyneuropathy/movement disorders in five, sepsis in five, hepatic failure in four, and hyperkalemia. However, the specificity of the latter symptoms for propofol infusion syndrome is questionable. The authors concluded that some adult deaths and a large number of children’s deaths reported in the post-marketing drug safety database of the FDA have a striking similarity in clinical characteristics, course of illness, and propofol dose and duration to published reports and studies of the propofol infusion syndrome. This review and the many published case reports must lead to the recommendation that propofol in higher doses, in higher concentrations, and for longer durations must be avoided in both children and adults. Doses of propofol should be kept as low as effectively possible, and regular hemodynamic and blood gas monitoring is necessary in patients who are sedated with propofol, in order to detect early signs of cardiovascular failure and lactic acidosis. As previously recommended by the American College of Critical Care Medicine (47S), alternative sedative agents should be con­ sidered for patients who develop increasing requirements for vasopressors or inotropes

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I.D. Welters and M. Leuwer

or cardiac failure during high-dose propofol infusion. The propofol infusion syndrome has been reported in a young patient with traumatic brain injury, which is a suscept­ ibility factor, as high doses are often required to achieve a satisfactory degree of sedation and/or to control raised intra­ cerebral pressure (48A).
A 21-year-old man with traumatic brain injury

was given high doses of propofol for sedation and control of intracranial pressure, combined with vasopressor therapy to maintain a cere­ bral perfusion pressure above 60 mmHg. He developed a significant metabolic acidosis with a lactic acid concentration of 11 mmol/l. Exploratory abdominal laparotomy showed no traumatic injury. During the procedure, the propofol infusion was discontinued and the lactic acidosis improved. An echocardiogram showed severe left ventricular dysfunction and cardiomyopathy, which resolved within 19 days.

The authors thought that a combination of high-dose propofol and catecholamines had been responsible for the lactic acidosis in this case. In addition, the use of intravenous inotropes may aggravate lactic acidosis or even trigger the propofol infu­ sion syndrome. In this case, early diagnosis and immediate withdrawal of propofol may have contributed to the complete reversal of symptoms and the favorable outcome. Liver Postoperative serum aspartate transaminase, alanine transaminase, and lactate dehydrogenase activities increased transiently after the use of propofol in 160 patients undergoing elective coronary artery surgery, more so than in 160 patients who were given sevoflurane (49c). Lactation The transfer of propofol into breast milk has been studied in five women (50c). They were premedicated with mid­ azolam before induction of anesthesia with propofol and fentanyl. Anesthesia was main­ tained with volatile anesthetics. During 24 hours of milk collection, 0.004–0.082% of the dose of propofol was excreted into the milk. Although evidence is scarce, lactating women are frequently advised to pump and discard their milk for 24 hours after the

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operations requiring general anesthesia. However, based on these results, the authors concluded that interrupting breast-feeding in this way is not justified. Susceptibility factors Age The effects of age on sedation induced by propofol and midazolam have been studied in patients under and over 65 years undergoing cardi­ oversion in a randomized study (51C). Mean induction times were similar. However, mean recovery time was shorter in those who received propofol and in patients under 65 years. Older participants needed less medication. There were no hemodynamic differences between the groups, but desa­ turation was higher in the patients who received midazolam. Hemorrhage Four patients with advanced cirrhosis became hemodynamically unstable as a result of massive blood loss during surgery; this was associated with increases in total propofol (twofold) and unbound pro­ pofol (fourfold) (52c). All were resuscitated within 60 minutes. Propofol is highly bound to plasma albumin, erythrocytes, and lipo­ proteins, and the unbound fraction is usually under 3%. Changes in protein binding and reduced renal and hepatic blood flow during shock can alter the clearance of propofol. Drug formulations There has been a report of complications associated with propofol, owing to malfunction of a com­ mon drug infusion pump (53A). The syringe saddle was missing and allowed the syringe barrel to contact the pump case, which reduced outward displacement of the syr­ inge clamp. The infusion pump then falsely detected a smaller syringe size and conse­ quently delivered an increased infusion rate, resulting in propofol overdose. More commonly, an incorrectly mounted syringe may increase outward displacement of the syringe clamp, so that the infusion pump falsely detects a larger syringe size; this results in a reduced infusion rate. Generic propofol (with a sulfite additive) and Diprivan have been compared in a randomized, double-blind study in 60

225

women undergoing abdominal hysterectomy (54c). The mean drug doses adjusted for weight and time were similar, and similar blood propofol concentrations were needed to adjust the depth of anesthesia to a bispectral index of 50–65. Propofol is lipid-soluble and is formu­ lated as a water-in-oil emulsion, which has drawbacks, such as injection pain and micro-organism contamination. A lipid-free formulation of propofol became available in India in 2006 (Cleofol 1%, Themis Pharmaceuticals, Mumbai). However, sev­ eral adverse effects of this formulation, which contained thiomersal as a preserva­ tive, were reported, including extravasation (55A) and acute venous thrombosis (56A).
A 48-year-old woman was given Cleofol 10 ml

premixed with lidocaine via a cannula in the most prominent vein on the dorsum of the left hand. In the postanesthesia care unit, extra­ vasation was observed. She complained of severe pain in her left hand. The skin was erythematous and swollen. The radial pulse was easily palpable. Her left arm was raised and subcutaneous hyaluronidase was injected. Over the next 4 hours the edema increased and the hand was swollen, tense, and cyanotic, with delayed capillary refill. The skin of the dorsum of the left hand was incised, the tissues were flushed out with 500 ml of isotonic saline, and drains were inserted for 24 hours. A layer of betadine soaked gauge was applied to the wound. Four weeks later, the site of extra­ vasation had healed without any undue sequelae.
A 55-year-old woman with well-controlled hypertension was given Cleofol 1.5 mg/kg through an intravenous cannula in the left forearm. At the time of injection she com­ plained of severe pain in the forearm and arm, which subsided after flushing the cannula with isotonic saline. Two subsequent injections of propofol also caused severe pain. Following the fourth bolus of propofol the patient awoke with excruciating pain in the limb. The super­ ficial veins of the left forearm became promi­ nent, tender, and cord-like and the peripheral blood oxygen saturation monitored in the left index finger fell to 78–80%. The left forearm and hand were swollen, dusky blue, and cold. There was retrograde flow of blood into the intravenous giving set. The intravenous infu­ sion in the left forearm was discontinued and a new line started in the right hand. Efforts to flush the cannula in the left forearm were unsuccessful, but a 5-cm blood clot was aspi­ rated. Doppler examination showed blockage of

226 the brachial vein in the left antecubital fossa and compression of the brachial artery by grossly engorged brachial veins.

In the second case the reduction in peripheral blood oxygen saturation in the affected limb was probably related to compression of brachial artery by engorged brachial veins and by edema due to deep vein obstruction. Drug administration route Accidental injection of propofol and remifentanil into the cerebroventricular compartment has been reported (57A).
A 51-year-old patient was accidentally given

remifentanil 150 mg and 10 ml of propofol 1% through an intracerebroventricular totally implantable access port placed in the right infraclavicular region, which was mistakenly thought to be an intravenous line. Severe pain in the head and neck caused the mistake to be discovered rapidly, and 20 ml of a mixture of cerebrospinal fluid and the anesthetic drugs were aspirated from the implantable access port. There were no apparent adverse neuro­ logical sequelae.

Management of adverse drug reactions Pain on injection with propofol occurs in about 70% of patients (SEDA-30, 143), and there have been many studies, with varying success, of ways of minimizing the pain. Low-dose ketamine seems promising in reducing injection pain and in mitigating the respiratory depression and hypotension associated with propofol (58c). Low doses

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I.D. Welters and M. Leuwer

of ketamine have been compared with saline and lidocaine in 240 patients in order to establish the optimal dose for prevention of pain after propofol injection (59C). Ketamine 100 mg/kg immediately before propofol injection was the optimal dose and timing to reduce propofol-induced pain on injection.

INTRAVENOUS AGENTS: BARBITURATE ANESTHETICS Thiopental sodium

(SED-15, 3395;

SEDA-30, 146) Monitoring therapy There has been a survey of how thiopental was used in UK neurosurgery critical care units (60A). It was used in 23 out of 26 participating units, and 14 had a protocol or guidelines of its use. Cerebral monitoring was used to guide dosage in 17 units. Twenty units delayed brain stem testing when patients had had thiopental, two would not perform tests at all, and one incorporated cerebral angiography into their protocol. This survey demonstrates a lack of uniform management regimens for brain stem testing after the administration of thiopental. There is clearly a need to clarify when brain stem testing should be performed in such cases, if at all.

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24.

25.

26.

27.

28.

29.

30.

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32.

hepatitis similar to drug hypersensitivities. Int Arch Occup Environ Health 2007;80(5): 357–70. Li HS, Dai YF, Huang HL, Feng XL, Sun YF, Niu Y, Cheng J, Zhang LY, Li LY, Chen B, Zheng YX. [Possible association between polymorphisms of human leuko­ cyte antigen-DQ genes and susceptibility to trichloroethylene-induced severe general­ ized dermatitis.] Zhonghua Yu Fang Yi Xue Za Zhi 2006;40(3):173–6. Yue F, Huang HL, Huang ZL, Li LY, Liang LY, Chen XM. [Relationship of trichlor­ oethylene-induced medicamentosa like der­ matitis to HLA-DMA and HLA-DMB.] Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2006;24(5):263–5. International Agency for Research on Cancer. Dry cleaning, some chlorinated solvents and other industrial chemicals. IARC Monogra Eval Carcinog Risks Hum 1995;63:74–158. National Toxicology Program. Report on Carcinogens. 11th ed. Research Triangle Park, NC. http://ntp.niehs.nih.gov/ntp/roc/ eleventh/profiles/s180tce.pdf. Scott CS, Chiu WA. Trichloroethylene cancer epidemiology: a consideration of select issues. Environ Health Perspect 2006;114(9):1471–8. Mandel JH, Kelsh MA, Mink PJ, Alexander DD, Kalmes RM, Weingart M, Yost L, Goodman M. Occupational trichloroethy­ lene exposure and non-Hodgkin's lym­ phoma: a meta-analysis and review. Occup Environ Med 2006;63(9):597–607. Caldwell JC, Keshava N. Key issues in the modes of action and effects of trichloroethylene metabolites for liver and kidney tumorigenesis. Environ Health Perspect 2006;114(9):1457–63. Alexander DD, Mink PJ, Mandel JH, Kelsh MA. A meta-analysis of occupational tri­ chloroethylene exposure and multiple myeloma or leukaemia. Occup Med (Lond) 2006;56(7):485–93. Watson RE, Jacobson CF, Williams AL, Howard WB, DeSesso JM. Trichloroethy­ lene-contaminated drinking water and con­ genital heart defects: a critical analysis of the literature. Reprod Toxicol 2006;21(2): 117–47.

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33. Lacassie HJ, Nazar C, Yonish B, Sandoval P, Muir HA, Mellado P. Reversible nitrous oxide myelopathy and a polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase. Br J Anaesth 2006; 96(2):222–5. 34. Sethi NK, Mullin P, Torgovnick J, Capasso G. Nitrous oxide “whippit” abuse present­ ing with cobalamin responsive psychosis. J Med Toxicol 2006;2(2):71–4. 35. Lim TA, Lim KY. BIS during etomidate­ induced myoclonus. Anaesthesia 2006;61(4): 410–1. 36. Doenicke AW, Roizen MF, Kugler J, Kroll H, Foss J, Ostwald P. Reducing myoclonus after etomidate. Anesthesiology 1999;90(1): 113–9. 37. Mitsuyo T, Antognini JF, Carstens E. Etomidate depresses lumbar dorsal horn neuro­ nal responses to noxious thermal stimulation in rats. Anesth Analg 2006;102(4):1169–73. 38. Suzuki M, Haraguti S, Sugimoto K, Kiku­ tani T, Shimada Y, Sakamoto A. Low-dose intravenous ketamine potentiates epidural analgesia after thoracotomy. Anesthesio­ logy 2006;105(1):111–9. 39. Bovill JG. Intravenous anesthesia for the patient with left ventricular dysfunction. Semin Cardiothorac Vasc Anesth 2006;10(1): 43–8. 40. Hebbar L, Dorman BH, Clair MJ, Roy RC, Spinale FG. Negative and selective effects of propofol on isolated swine myocyte contractile function in pacing-induced con­ gestive heart failure. Anesthesiology 1997; 86(3):649–59. 41. Pagel PS, Hettrick DA, Kersten JR, Lowe D, Warltier DC. Cardiovascular effects of propofol in dogs with dilated cardiomyopathy. Anesthesiology 1998;88(1): 180–9. 42. Kawano T, Oshita S, Takahashi A, Tsutsumi Y, Tomiyama Y, Kitahata H, Kuroda Y, Nakaya Y. Molecular mechanisms of the inhibitory effects of propofol and thiamylal on sarcolemmal adenosine triphosphate­ sensitive potassium channels. Anesthesiology 2004;100(2):338–46. 43. Crawford MW, Rohan D, Macgowan CK, Yoo SJ, Macpherson BA. Effect of propofol anesthesia and continuous positive airway pressure on upper airway size and

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configuration in infants. Anesthesiology 2006;105(1):45–50. Meyer S, Shamdeen MG, Kegel B, Mencke T, Gottschling S, Gortner L, Grundmann U. l Effect of propofol on seizure-like phenom­ ena and electroencephalographic activity in children with epilepsy vs children with learning difficulties. Anaesthesia 2006;61(11): 1040–7. Hans P, Bonhomme V. Why we still use intravenous drugs as the basic regimen for neurosurgical anaesthesia. Curr Opin Anaesthesiol 2006;19(5):498–503. Wysowski DK, Pollock ML. Reports of death with use of propofol (Diprivan) for nonprocedural (long-term) sedation and lit­ erature review. Anesthesiology 2006;105(5): 1047–51. Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM, Crippen DW, Fuchs BD, Kelleher RM, Marik PE, Nasraway Jr. SA, Murray MJ, Peruzzi WT, Lumb PD. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002;30(1):119–41. Corbett SM, Moore J, Rebuck JA, Rogers FB, Greene CM. Survival of propofol infusion syndrome in a head-injured patient. Crit Care Med 2006;34(9):2479–83. Lorsomradee S, Cromheecke S, Lorsomra­ dee S, De Hert SG. Effects of sevoflurane on biomechanical markers of hepatic and renal dysfunction after coronary artery surgery. J Cardiothorac Vasc Anesth 2006; 20(5):684–90. Nitsun M, Szokol JW, Saleh HJ, Murphy GS, Vender JS, Luong L, Raikoff K, Avram MJ. Pharmacokinetics of midazolam, propofol, and fentanyl transfer to human breast milk. Clin Pharmacol Ther 2006;79(6):549–57. Parlak M, Parlak I, Erdur B, Ergin A, Sagiroglu E. Age effect on efficacy and side

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229 effects of two sedation and analgesia pro­ tocols on patients going through cardiover­ sion: a randomized clinical trial. Acad Emerg Med 2006;13(5):493–9. Takizawa D, Takizawa E, Miyoshi S, Kawahara F, Hiraoka H. The increase in total and unbound propofol concentrations during accidental hemorrhagic shock in patients undergoing liver transplantation. Anesth Analg 2006;103(5):1339–40. Koch C, Hollister C, Breen PH. Infusion pump delivers over-dosage of propofol as a result of missing syringe support. Anesth Analg 2006;102(4):1154–6. Olufolabi AJ, Gan TJ, Lacassie HJ, White WD, Habib AS. A randomized, prospective double-blind comparison of the efficacy of generic propofol (sulphite additive) with diprivan. Eur J Anaesthesiol 2006;23(4): 341–5. Mahajan R, Gupta R, Sharma A. Extra­ vasation injury caused by propofol. Anesth Analg 2006;102(2):648. Reddy KR, Chandramouli BA, Rao GS. Acute venous thrombosis caused by lipid­ free propofol. Anaesthesia 2006;61(3):300–1. Tiefenthaler W, Tschupik K, Hohlrieder M, Eisner W, Benzer A. Accidental intracerebroventricular injection of anaesthetic drugs during induction of general anaes­ thesia. Anaesthesia 2006;61(12):1208–10. Tomatir E, Atalay H, Gurses E, Erbay H, Bozkurt P. Effects of low dose ketamine before induction on propofol anesthesia for pediatric magnetic resonance imaging. Pae­ diatr Anaesth 2004;14(10):845–50. Koo SW, Cho SJ, Kim YK, Ham KD, Hwang JH. Small-dose ketamine reduces the pain of propofol injection. Anesth Analg 2006;103(6):1444–7. Pratt OW, Bowles B, Protheroe RT. Brain stem death testing after thiopental use: a survey of UK neuro critical care practice. Anaesthesia 2006;61(11):1075–8.

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11

Local anesthetics

Lipid rescue for local anesthetic toxicity An overdose of a local anesthetic systemically administered can cause nervous system toxicity and cardiovascular collapse, highly resistant to conventional treatment and resuscitation. Although such events are rare, the outcomes are often poor, particularly with bupivacaine, and management has been largely supportive. However, evidence from animal studies, and more recently case reports, has demonstrated remarkable effectiveness of lipid emulsions in reversing the adverse effects. Animal studies Despite expectations that lipid emulsions would worsen bupivacaineinduced dysrhythmias, the converse was found in rats. Subsequently, Weinberg’s group, who have pioneered this research, showed that pretreatment with lipid emulsions of increasing concentrations required a correspondingly greater dose of bupivacaine to induce asystole in rats (1E). This suggested that lipid emulsion leads to resistance to toxic effects and that the use of 30% Intralipidt during resuscitation after bupivacaineinduced arrest leads to increased survival. Further experiments in 12 anesthetized dogs who were given bupivacaine 10 mg/kg to induce cardiac arrest showed even more impressive results (2E). After 10 minutes of internal cardiac massage, six dogs were given a 4 ml/kg bolus of either saline or 20% Intralipidt with a further 10 minutes of resuscitation. While all the dogs in the saline Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03111-0 r 2009 Elsevier B.V. All rights reserved.

group died, all the dogs who received lipid recovered, having returned to sinus rhythm within 5 minutes and near baseline blood pressure and heart rate at 30 minutes. Mitochondrial tissue oxygen saturation fell markedly and pH modestly 10 minutes after bupivacaine in all the dogs, but returned toward normal only in the lipidtreated dogs. Human reports Since these animal experiments, several case reports have been published describing the successful use of lipid emulsion in cases of presumed local anesthetic overdose. � A 58-year-old man was given an interscalene

brachial plexus block with 0.5% bupivacaine 20 ml and 1.5% mepivacaine 20 ml for arthroscopic repair of a torn shoulder rotator cuff (3A). Within minutes, he became incoherent, developed generalized seizures, and then asystolic arrest. After unsuccessful advanced life support for 20 minutes, he was given 100 ml of 20% Intralipid via a peripheral intravenous line in addition to continued general supportive measures. Sinus rhythm was established within 15 seconds, with a detectable pulse and blood pressure shortly afterwards. An infusion of Intralipid 0.5 ml/kg/min was maintained for 2 hours and no neurological complications were identified. � An 84-year-old woman was accidentally given 1% ropivacaine 40 ml (rather than 0.5%) to achieve axillary brachial plexus block for surgery for Dupuytren’s contracture (4A). After 15 minutes she lost consciousness and had generalized seizures and asystolic arrest. After cardiopulmonary resuscitation for 10 minutes, she was given a bolus of 20% Intralipid 100 ml, followed by an infusion at 10 ml/minute, resulting in restoration of electrical activity and cardiac output and a good recovery. � A 75-year-old woman received a lumbar plexus block for a fractured neck of femur using 0.5% levobupivacaine 20 ml after failed subarachnoid block (5A). She became unresponsive, had a generalized tonic–clonic seizure, progressive electrocardiographic changes (reduced voltage,

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broad QRS complex), and a fall in blood pressure to 60/40 mmHg. After another brief seizure 2 minutes later she was given Intralipid 20% 100 ml. The QRS morphology recovered rapidly. � An 18-year-old primigravida with pre-eclampsia was inadvertently given intravenous bupivacaine via an epidural catheter that migrated into an epidural vein (6A). After an apparently reassuring test dose of 2% lidocaine 4 ml and good analgesia with 0.25% bupivacaine 6 ml, she was given 0.5% bupivacaine 10 ml in anticipation of an emergency cesarean section. She became twitchy, restless, and uncooperative within 90 seconds, prompting the early use of two 50 ml boluses, and then an infusion, of 20% Intralipid. She regained consciousness within 30 seconds and was given a general anesthetic instead. Both mother and baby were well and discharged on the fourth day.

A further five cases with similar effects have been reported in 2008 and will be summarized in a future annual. Mechanism of action anisms include:

Suggested mech-

(a) the creation of a lipid plasma phase (lipid sink), drawing lipid-soluble local anesthetic from the aqueous plasma, preventing its movement into tissues (1E). (b) movement of lipid from plasma to tissue, followed by a direct interaction with the local anesthetic (2E). (c) prevention of inhibition of fatty acid transport into cardiac mitochondria by local anesthetics (7E). The lipid sink theory is supported by a higher rate of loss of radiolabeled bupivacaine from the cardiac muscle of isolated rat hearts when an infusion of 1% lipid emulsion was delivered, rather than saline (7E). Current strategies In a survey of US academic anesthesia departments, 26% of the 91 respondents said that they would consider using lipid emulsion in cardiac toxicity; departments that performed a high number of peripheral blocks were four times more likely to use it than low-volume centers (8C). However, this survey was conducted before reports of its successful use in humans.

Randomized controlled studies are unlikely to occur in this setting, because of ethical and resource constraints. But even without high-level evidence, the Association of Anaesthetists of Great Britain and Ireland has included lipid emulsion in their 2007 “Guidelines for the Management of Severe Local Anaesthesia Toxicity” (9S). Indeed, the introduction of “lipid rescue” into modern anesthesia practice has been likened to that of dantrolene for malignant hyperthermia, which is now considered the gold standard “antidote” (10r). Despite concerns regarding the generic use of lipid emulsions in all cases of local anesthetic toxicity, lipid appears to be effective in cases of both neurological and cardiovascular compromise, and also when the offending agent is racemic bupivacaine, levobupivacaine, mepivacaine, prilocaine, or ropivacaine. In addition, the potential benefit gained from using it, particularly after a poorly responsive resuscitative effort, seems to outweigh the potential hazards by far. Possible problems include thrombophlebitis, modulation of immune function, allergic reactions, fat emboli, and pulmonary vasoconstriction. However, in the case reports described, all the patients made a full recovery without any significant complications from the lipid infusion (11r). Propofol (which contains 10% lipid) should not be used as an alternative to lipid emulsion, because massive volumes are required and deleterious cardiovascular consequences are likely (12r). Though Intralipid was used in experimental studies and most case reports, the successful use of alternatives, such as Liposyn IIIt and Medialipidt, suggests that the specific brand of lipid emulsion used is unimportant. Initial recommendations advocated the use of lipid only after standard resuscitation proved inadequate (13r,14r). However, with reports of its beneficial effects in prearrest scenarios, its early administration appears justified, and adjustment in local and/or national guidelines to reflect this may follow (15r). Weinberg has established a website (www.lipidrescue.org) that provides summaries of their experimental efforts, a database for case reports, a

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recommended dosage regimen, and links for further reading.

Drug formulations The US FDA has warned five pharmacies to stop compounding and distributing standardized versions of topical anesthetic creams, marketed for general distribution (16S). Such creams contain high doses of local anesthetics, including lidocaine, benzocaine, prilocaine, and tetracaine. The Agency has warned that exposure to high concentrations of these anesthetics can lead to reactions such as cardiac dysrhythmias and seizures. Two deaths have been linked to anesthetic creams compounded by two of the five pharmacies. The Agency says that their warning serves as a general warning to firms that produce standardized versions of anesthetics. The FDA has also issued a Public Health Advisory about life-threatening adverse effects associated with topical anesthetics for cosmetic procedures. These products contain drugs such as benzocaine, lidocaine, prilocaine, and tetracaine (17S). The Agency is aware of two women who developed seizures, became comatose, and subsequently died after applying topical anesthetics before laser hair removal. The Agency has also received reports of serious adverse effects, such as coma, cardiac dysrhythmias, and seizures, associated with these products. Those who are thinking about a cosmetic or medical procedure on the skin are advised to discuss with their doctor whether they need a topical anesthetic and, if so, to use a product approved by the FDA.

EFFECTS RELATED TO MODES OF USE (SED-15, 2121; SEDA-28, 145; SEDA-29, 135; SEDA-30, 152)

Brachial plexus anesthesia Respiratory Phrenic nerve paresis is an extremely common adverse effect of

233 interscalene block, with rates of up to 100%. In contrast to this, a recent study has shown a rate of only 13% (8/60 patients) (18C). In this comparative study of highvolume/low-concentration versus lowvolume/high-concentration local anesthetic for interscalene block, all patients received the same total dose of lidocaine 300 mg, bupivacaine 75 mg and adrenaline 150 mg, in either 60 or 30 ml. There were no complications in the high-volume/lowconcentration group, compared with a 27% rate of phrenic nerve paresis and a 66% rate of bradycardia and hypotension in the lowvolume/high-concentration group. Persistent hemidiaphragmatic paralysis after interscalene brachial plexus block has been described again, this time with a mixture of bupivacaine 0.5% and lidocaine 1% (19A). The patient developed long-term dyspnea with significantly impaired pulmonary function. Nervous system In 133 patients who had interscalene block for elective shoulder surgery (mepivacaine 1.5% alone or combined with bupivacaine 0.5–0.75%, all via paresthesia technique), successful surgical anesthesia was achieved in 98% (20C). There was one major perioperative complication, a seizure within 5 minutes of the block. Two patients developed transient postoperative apraxias and 37 (28%) had neck pain and bruising. Nerve damage after regional anesthesia has many causes, including stretching, compression, ischemia, surgical trauma, and local anesthetic toxicity. Puncture by the block needle and intraneural injection of local anesthetic are thought to be major risk factors that lead to nerve injury. However, the results of a prospective study in 26 patients having ultrasound-guided axillary plexus block have challenged these widely held beliefs (21c). There was ultrasound evidence that 22 of the patients had puncture of at least one nerve, and 21 had intraneural injection into at least one nerve. Despite this, there was no evidence of damage to these nerves, either subjectively or on sensory and motor testing up to 6 months postoperatively. An alternative

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explanation for the nerve was injection into a fascicle rather than into the stroma of the nerve (i.e., piercing the perineurium causes injury while breaching the epineurium does not appear to) (22r). Sharp needles, high injection pressures, and dense fascicles within the nerve all increase the risk.

Epidural anesthesia Systematic reviews An attempt has been made to identify the ideal epidural test dose, which by its adverse effects would allow detection of a misplaced (intravascular instead of epidural) catheter or needle, in order to avoid more serious adverse effects later (23M) The following tests had a sensitivity and positive predictive value of at least 80%: 1. Non-pregnant adults: adrenaline 10 or 15 mg increased systolic blood pressure (SBP) by at least 15 mmHg or either increased SBP by at least 15 mmHg or increased heart rate by at least 10 per minute. 2. Children: adrenaline 0.5 mg/kg increased SBP by at least 15 mmHg. 3. Pregnant women: fentanyl 100 mg caused sedation, drowsiness, or dizziness within 5 minutes. The author stated that the systematic use of adrenaline in non-pregnant adults and children to detect intravascular needle/catheter position is reasonable, considering the absence of serious adverse effects. In contrast, routine use in pregnant women could not be justified, because of the low positive predictive value and potential adverse effects; here an analysis of the benefit to harm balance of each scenario for the parturient is necessary, and its use in testing epidurals for cesarean section appears to be more appropriate than for labor analgesia. There were too few data to determine the best method of detecting intrathecal or subdural catheter misplacement. Cardiovascular Bradycardic arrest developed rapidly secondary to a reflex vagal

response following abdominal wall traction in a patient with a thoracic epidural (24A). � A 53-year-old man with a long smoking

history received a T7/8 thoracic epidural before induction for subtotal gastrectomy. He was given atropine 0.5 mg and midazolam 2 mg intramuscularly 30 minutes before surgery. An epidural test dose of 2% lidocaine 3 ml was given uneventfully, and after induction 0.375% ropivacaine 10 ml. The heart rate fell rapidly 1 minute after the abdominal selfretaining retractor was positioned and bradycardic arrest occurred. Prompt removal of the surgical stimulus, cardiac compression, atropine 0.5 mg, and adrenaline 1 mg resulted in the return of normal hemodynamics.

Sympatholysis from neuraxial blocks results in loss of compensatory mechanisms, thereby potentiating the severity of vagal effects. Awareness and prompt management by removing the vagal stimuli and resuscitation including anticholinergic and/ or sympathomimetic drugs should lead to excellent recovery. Nervous system High neuraxial block occurred after a large volume of local anesthetic was given to expand the epidural space after accidental dural puncture (25A). � A lumbar epidural was attempted in a 50-year-

old woman, ASA grade 1, listed for transabdominal hysterectomy. The first attempt at L4/ 5 resulted in inadvertent dural puncture and another attempt was made at L3/4. After being satisfied that the needle was in the correct location, with a negative aspiration test and no response after a test dose of 0.25% lidocaine 3 ml with adrenaline 0.5 mg/ml, 13 ml of 0.5% plain bupivacaine was given via the needle to expand the epidural space to facilitate insertion of the catheter. Within 7 minutes, the sensory block had spread to T4 and hypotension and respiratory distress subsequently ensued. Intravenous fluids and mephentermine 6 mg were given, general anesthesia was induced, and surgery was performed. The patient was hemodynamically stable with sensory block at T10 at the end of the operation.

The authors suggested that preceding dural puncture is a contraindication to expanding the epidural space before catheter placement. In a retrospective review of 139 patients with pre-existing nervous system disorders

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there was no evidence of new or worsening neurological deficits after neuraxial block (26c). Analysis of patients’ records enabled the characteristics of the disorders to be determined and review of the daily progress notes and follow-up visits identified new or progressive postoperative neurological problems. Previous poliomyelitis, multiple sclerosis, and traumatic spinal cord injury accounted for about 90% of this study population, and 74% of patients described active symptoms. There were technical complications in 15, most commonly paresthesia and traumatic needle placement. There was satisfactory block in 98% and no new neurological deficits in any of the subjects. The authors suggested that the risks of exacerbating pre-existing nervous system disorders with a neuraxial block may have been overestimated, and that neuraxial block should not be considered to be absolutely contraindicated in this population. The limitations of this study included potential selection bias, short (6–8 weeks) postoperative follow-up, and difficulty in detecting minor or subclinical complications. Another patient experienced a high block via unintentional subdural injection of ropivacaine (27A). � Epidural analgesia was planned for a 25-year-

old pregnant woman. The first attempt resulted in dural puncture and another was made one level higher. After a negative aspiration test, 0.2% ropivacaine 12 ml was given in 3 ml increments over 15 minutes. She developed bilateral facial paresthesia toward the tip of her nose, but no other problems. The baby was delivered vaginally without event, and the patient’s numbness disappeared after 6 hours.

The authors suggested that the use of a dilute solution had spared any ventilatory or nervous system symptoms, despite evidence of subdural spread reaching the brainstem. Bilateral foot drop occurred in a 9-year-old boy after removal of his epidural catheter, which had been present for 2 days (28A). He initially underwent a 4-hour urological procedure with a combined general anesthetic and epidural technique, and then had 2 days of epidural analgesia. Electromyography showed focal demyelination of both peroneal

235 nerves at the fibular head, supporting the authors’ belief that the deficit had resulted from direct pressure over a period of hours while local anesthesia persisted. This again highlights the need for careful positioning and pressure area care as long as effects of local anesthetics persist. Reproductive system The effect of continuous epidural bupivacaine 0.075% by infusion for analgesia during labor on uterine artery resistance has been evaluated in 20 pregnant women (29c). There was evidence of increased uterine blood vessel resistance with Doppler-derived velocimetry at 1, 2, and 4 hours. The authors concluded that the clinical significance of this was yet to be determined. Previous studies of the transient effects of bupivacaine 0.25% on uterine blood flow have been inconclusive.

Spinal (intrathecal) anesthesia Systematic reviews Selective spinal anesthesia and general anesthesia for knee arthroscopy have been compared in a systematic review of five prospective randomized control trials in 483 patients (30M). Home readiness was achieved after 3 hours for both procedures with either a combination of bupivacaine 3 mg+fentanyl 10 mg or bupivacaine 4 mg alone. Pain, postoperative nausea and vomiting, and somnolence were more frequent after general anesthesia. Cardiovascular The hemodynamic effects of a single spinal injection and a continuous spinal technique have been compared in 74 elderly patients requiring surgical repair for hip fractures (31C), half of whom were randomized to a single shot of isobaric bupivacaine 7.5 mg and half of whom were given continuous spinal anesthesia with 2.5 mg boluses of isobaric bupivacaine delivered every 15 minutes until a block higher than T12 was achieved. The total dose required (mean 5 mg) was smaller and sensory block lower in those who were given continuous spinal anesthesia.

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Continuous spinal anesthesia caused fewer episodes of hypotension (a greater than 20% fall in systolic pressure) in 31% of patients compared with 68% of those who were given a single injection. Similarly, there were fewer episodes (8% versus 51%) of severe hypotension (a greater than 30% fall in systolic pressure). The authors acknowledged the limitations of their study, including the use of only one dose in single injection group and an inability to use more significant end-points, such as myocardial ischemia. Nervous system Spinal anesthesia leads to sympatholysis, which has more profound effect in adults than children. Measurement of changes in regional temperature may aid in the assessment of adequate spinal block in children. In 15 infants, there was a rise in skin temperature in the foot from 33 to 34.71C at 10 minutes and 35.61C at 20 minutes after spinal anesthesia (32c). This was thought to be a reliable indicator of sympatholysis and thus sensory block. Systolic and diastolic blood pressures also fell, but remained within the normal ranges. Three cases of spinal cord injury following spinal anesthesia have been reported (33A). All three occurred when lumbar spinal anesthesia was attempted at L2/3 in young women. There was pain when the spinal needle was inserted and it increased after the subsequent injection of lidocaine. None of the patients was able to walk postoperatively and they had variable patterns of pain, along with motor and sensory dysfunction. MRI scans 4–6 months later showed myelomalacic changes, with focal syrinx formation in the conus/epiconus of the spinal cord at T12– L1. The muscle weakness and hypesthesia improved over 6 and 12 months, respectively, and all were able to walk unassisted. However, severe pain persisted. Antiepileptic drugs appeared to provide effective analgesia, and after 3 years no analgesic medications were required. These cases stress again the difficulties encountered in determining the correct lumbar space and the importance of avoiding placement at higher lumbar levels.

Transient unilateral Horner’s syndrome (miosis, ptosis, enophthalmos, anhydrosis) has been reported after a combined spinal epidural anesthetic for an elective cesarean section (34A). � A 27-year-old primigravida was given 1%

ropivacaine 2 ml for the spinal component of combined spinal epidural anesthesia. The delivery was uneventful, but 20 minutes after the anesthetic she developed weakness in the left arm and left-sided miosis, ptosis, and conjunctival hyperemia. The sensory level to cold was T3–4 on the left and T4–5 on the right. A CT scan was negative. With removal of the block her symptoms disappeared.

The authors suggested that despite the fact that the sensory block reached only T3– 4, Horner’s syndrome may have occurred because of greater sensitivity of sympathetic fibers to local anesthetics. Sympathetic nervous block after spinal anesthesia is usually higher than the sensory block. Cauda equina syndrome associated with bilateral hearing loss after spinal anesthesia has been described (35A). � A 33-year-old-man received spinal anesthesia

with 0.5% isobaric bupivacaine 2.5 ml for anorectal surgery. He initially reported vertigo, which lasted a few minutes, but 6 hours later had bilateral sensorimotor deficits in the legs, urinary and fecal incontinence, and bilateral hearing loss. Cauda equina syndrome was diagnosed, although the cause could not be ascertained, particularly without magnetic resonance imaging. After 21 months, the paresis, double incontinence, and profound hearing loss were still present.

Pregnancy Parturients undergoing elective cesarean section have previously been found to have higher sensorimotor block with subarachnoid anesthesia via a combined spinal epidural technique compared with single-shot spinal anesthesia. This may be due to loss of negative pressure within the epidural space after the introduction of the anesthetic, creating a smaller dural sac volume. In contrast, there was no difference in 40 patients undergoing labor who were randomized to spinal block by either a single shot or the combined approach (36C). The authors suggested that the lack of

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difference might have been due to the variable epidural pressures encountered during labor. Drug formulations The effect of the temperature of the injectate on the spread of spinal hyperbaric bupivacaine has been studied in 36 patients (37). There was a higher maximal cephalad spread to pinprick sensation with the warmer 371C solution (to T2) compared with 251C (T5). In both groups it took 20 minutes for maximal spread to occur. The authors suggested that warming the solution may lead to increased kinetic energy, causing greater spread. Similar results with isobaric bupivacaine have previously been reported (80E).

237 of transient blurred vision with loss of accommodation in one eye after routine inferior alveolar nerve block have been reported (41A). These were caused by ipsilateral ciliary nerve blockade, possibly due to inadvertent intravascular injection with spread of local anesthetic retrogradely to the orbit. Another case of transient diplopia due to accidental sixth cranial nerve blockade with ipsilateral lateral rectus paresis followed maxillary injection of articaine with adrenaline for dental extraction (42A). In all cases resolution was complete within minutes to hours.

Hematoma blocks Dental anesthesia Nervous system Nerve injury after mandibular nerve block has been previously reported. Articaine, and to a lesser extent prilocaine, has been implicated in an increased incidence of permanent paresthesia after mandibular nerve anesthesia, and lingual nerve injury is most common and most incapacitating. These conclusions have been supported by a recent case series of 54 nerve injuries in 52 patients, in which standardized assessment of neurosensory function showed that toxicity was most likely the central causative factor (38C). Over half of these cases were associated with the use of articaine. The authors concluded that articaine produced a more than 20-fold increase in the incidence of injection injury after mandibular nerve block. Recent reviewers have recommend avoiding articaine and prilocaine for mandibular and lingual nerve block, although they have concluded that it may be the high concentration rather the drug itself that is responsible for nerve damage (39M,40r). Sensory systems Transient cranial nerve palsies have been described after dental nerve block. The exact mechanisms of local anesthetic spread have not been clearly defined, although intra-arterial injection and local spread have been discussed. Two cases

Nervous system A 94-year-old woman developed seizures after hematoma block with 2% lidocaine 10 ml for reduction of a Colles fracture (43A). The authors conclude that the toxicity had been due to injection intravascularly rather than into the hematoma.

Ocular anesthesia Nervous system Seizures and transient hemiparesis have been reported after retrobulbar block (44A). � A 36-year-old man was given a retrobulbar

injection of ropivacaine 50 mg for cryocoagulation and developed localized convulsions of the ipsilateral face and contralateral arm and leg 9 minutes later. The hemiparesis lasted about 1 hour.

The authors proposed that these complications were due to unintentional injection of ropivacaine into the subarachnoid space without involvement of the brainstem. The spread of ropivacaine may have been abnormal in this patient, because of previous intrathecal chemotherapy and possible adhesions. Sensory systems Contralateral amaurosis and extraocular muscle palsies after retrobulbar block have been described again

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(45A). These symptoms are believed to follow injection of local anesthetic into the subdural or subarachnoid space around the optic nerve. Musculoskeletal Inferior oblique muscle injury has again been reported after local anesthesia for cataract surgery (46A). � A 72-year-old man received an injection of 2%

lidocaine and 0.5% bupivacaine and developed inferior oblique damage presenting as a superior oblique palsy. Histological examination showed inferior oblique muscle fibrosis, contracture, and skeletal muscle atrophy.

Peripheral nerve block anesthesia Observational studies In a case survey of 1001 consecutive patients undergoing continuous popliteal nerve block with ropivacaine for ankle or foot surgery, with a high rate of success (97.5%), there was a low rate of complications (47C). The acute complications consisted of paresthesia during nerve localization (0.5%), pain during local anesthesia (0.8%), and blood aspiration (0.4%). The late complications included two cases of inflammation at the puncture site. There were no reports of nerve injury or infection. Nervous system Nerve injury is one of the most serious complications of peripheral nerve block. Patient factors predisposing to nerve injury have been described (48A). � A 72-year-old man developed a femoral

neuropathy after continuous femoral nerve blockade with ropivacaine for total knee replacement. The only susceptibility factor that was found postoperatively was a preexisting subclinical polyneuropathy.

The authors concluded that applying a local anesthetic to an already damaged nerve may predispose to further damage. Transient femoral nerve palsy occurs in up to 10% of cases of percutaneous ilioinguinal–iliohypogastric nerve block (PIINB). Previous reports have implicated excess volume and higher concentrations of local anesthetic as the main contributing

factors. However, a case in an 8-year-old boy undergoing elective hernia repair showed that inadvertent femoral nerve palsy is still possible with the lowest indicated volume (0.25 ml/kg) of low-concentration (0.25%) bupivacaine (49A). The authors recommended using a single rather than double pop technique and a lowpressure injection to minimize the risk.

Tonsillar anesthesia Permanent Horner’s syndrome after tonsillectomy has been previously described. � A 35-year-old woman was given perioperative

local anesthetic (bupivacaine 0.5% 5 ml) for tonsillectomy and developed bradycardia and hypotension postoperatively and then rightsided ptosis and miosis, which resolved within hours (50A).

The authors concluded that transient Horner’s syndrome had been caused by a direct action of bupivacaine on the superior cervical sympathetic ganglion, which is close to the tonsillar bed.

Topical anesthesia Systemic toxicity from topical local anesthetics continues to be a problem. Excessive doses, prolonged application, and a damaged epithelial barrier are common predisposing factors. Nervous system Nervous system toxicity after application of 30% lidocaine gel for dermatological laser resurfacing has been reported (51A). The authors warned that 30% topical lidocaine gel, even if applied to only a limited area in conjunction with photothermolysis, can result in toxic systemic concentrations of the local anesthetic. Systemic toxicity from emla cream has been described in a child (52A). � A 4-year-old girl with atopic dermatitis and

extensive molluscum contagiosum developed a headache, inability to walk, and cyanosis 50 minutes after the application of EMLA cream 30 g. At 90 minutes her methemoglobin

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239

concentration was 19%. The symptoms rapidly resolved after the administration of methylthioninium chloride (methylene blue).

agent is usually not written on the drug chart and is not administered by the physician in charge.

The authors noted that patients with a compromised cutaneous barrier should receive lower doses of topical local anesthetics for a shorter duration.

Immunologic A type 1 immediate hypersensitivity reaction to topical benzocaine has been described (64A).

Skin Topical tetracaine and benzocaine have both reportedly caused irritant contact dermatitis, tetracaine in a premature infant with extremely sensitive skin (53A) and benzocaine as a component of a genital cream (54A). Urticarial reactions to amethocaine gel are more common when it is applied to the cubital fossa compared with the dorsum of the hand and are more frequent in younger children (55c). Sexual function EMLA cream has been used to treat premature ejaculation (56C). Its adverse effects included penile hypesthesia, vaginal numbness, and anorgasmia.

� A 46-year-old woman developed vomiting,

lightheadedness, respiratory distress, and loss of consciousness after the application of topical benzocaine to her lips for oral cosmetic surgery. She was successfully resuscitated without sequelae. Intradermal skin tests confirmed hypersensitivity to benzocaine.

Bupivacaine (SED-15, 568; SEDA-28, 150; SEDA-30, 159) Cardiovascular Cardiac toxicity is a wellrecognized complication of bupivacaine overdose. However, a recent report has shown that bupivacaine can have significant prodysrhythmic effects in patients at risk, even in usual therapeutic doses (65A). � A 56-year-old man with an essentially normal

INDIVIDUAL COMPOUNDS Amethocaine Interference with diagnostic tests Amethocaine gel can interfere with sodium and potassium concentration measurements in capillary blood samples (57c).

Benzocaine

(SED-15, 427; SEDA-28, 150; SEDA-30, 158) Hematologic Methemoglobinemia after topical benzocaine in both adult and children continues to be reported (58A,59A, 60A,61A,62A,63A). Concerns have been raised about the inability to measure doses accurately administered from spray applicators, and significant methemoglobinemia has been seen in adults after as little as two “squirts” of 20% benzocaine. Diagnosis is often delayed, as the causative

preoperative electrocardiogram underwent lung reduction surgery for COPD, with epidural bupivacaine and sufentanil for postoperative analgesia. He developed Brugadalike changes on the first day postoperatively, with new right bundle branch block, downsloping ST elevation in V1–V3, and frequent ventricular extra beats, which quickly evolved into VT, requiring intravenous lidocaine and amiodarone. The electrocardiographic changes and ventricular dysrhythmias persisted until the epidural anesthetic was withdrawn 5 days later. The same pattern of events recurred when a new epidural infusion, again with bupivacaine and sufentanil, was started after surgery to correct an air leak.

This patient was subsequently found to have a genetic mutation consistent with Brugada syndrome, which only became evident on exposure to bupivacaine. The authors concluded that bupivacaine should be added to the list of drugs (including flecainide and procainamide), that can unmask a subclinical form of Brugada syndrome. This is in line with previous similar findings published (66A) and a report with ropivacaine described below.

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Cocaine Cardiovascular Myocardial infarction after the use of topical cocaine has again been reported (67A). � A 68-year-old woman with a history of mitral

valve prolapse developed a myocardial infarction with cardiogenic shock after the application of intranasal cocaine for an ENT procedure.

Lidocaine

(SED-15, 2051; SEDA-28, 152; SEDA-30, 160)

Drug overdose Accidental ingestion of lidocaine/chlorhexidine mouth paint has been described in 28 children because of packaging similarities to children’s paracetamol (68c). The toxic dose of lidocaine in children, although not well defined, is estimated to be 15 mg/kg. In this series there were no serious adverse effects with ingestion up to 6 mg/kg.

Nervous system Accidental overdose of intravenous lidocaine has been described in a patient under general anesthesia (69A). � A 79-year-old woman had general anesthesia

with propofol induction and sevoflurane maintenance for a gynecological operation under bispectral index monitoring for depth of anesthesia. Owing to an inadvertent programming error lidocaine 800 mg was infused over 8 minutes. The bispectral index fell to 0 (flat line EEG) and remained so for about 10 minutes before gradually increasing to 60. The patient developed hypotension, atrial dysrhythmias, and prolonged weakness, despite reversal, the cause of which was not clear.

The effects of local anesthetics on bispectral index monitoring have not been investigated before, but in this case lidocaine suppressed it completely at high doses. Immunologic Allergic reactions to local anesthetics are uncommon. Cross-reactivity between the amide local anesthetics, although very rare, has been reported again (70A). � A 39-year-old man developed urticaria and

facial angioedema after subcutaneous infiltration of mepivacaine. Skin prick testing showed cross-reactivity with lidocaine and ropivacaine.

The authors concluded that in cases of true IgE-mediated allergic reactions to an amide local anesthetic, it is not safe to prescribe other local anesthetics of the same class without prior allergy testing. Lidocaine continues to cause type IV hypersensitivity reactions, and cases of delayed hypersensitivity have been reported after topical (71A), subconjunctival (72A), and intravenous administration (73A).

Prilocaine and Emla

(SED-15, 2916)

Hematologic Prilocaine causes less neurological and cardiac toxicity than other amide local anesthetics, but is associated with methemoglobinemia (74A). � A 30-year-old woman developed weakness,

dizziness, and cyanosis due to methemoglobinemia after subcutaneous infiltration of prilocaine 400 mg for leg epilation.

As these toxic effects occurred at less than the maximum safe dose of 8 mg/kg (or 600 mg for a single injection), the authors postulated that multiple injections and systemic absorption during prilocaine administration may have been contributing factors. In 162 patients who received peripheral nerve blocks with prilocaine the most important predictive factors for methemoglobinemia were higher dose and younger age (75C). Female sex and the use of a highconcentration/low-volume prilocaine solution also increased the risk. Immunologic EMLA cream (lidocaine +prilocaine) caused type IV allergic contact dermatitis in a 67-year-old man undergoing hemodialysis (76A). In this and the few previously reported cases of hypersensitivity to emla it was the prilocaine, rather than the lidocaine, that was implicated.

Ropivacaine (SED-15, 3078; SEDA-28, 152; SEDA-30, 161) Cardiovascular Ropivacaine is less cardiotoxic than bupivacaine, owing to its formulation as the S-isomer only. Previous case reports of successful resuscitation after

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cardiac arrest secondary to ropivacaine toxicity have involved patients with ASA status 1 or 2. Successful resuscitation has now been described in a patient with significant co-morbidities (ASA 3) (77A). � A 54-year-old woman with severe myocardial

disease and chronic renal insufficiency underwent axillary brachial plexus block for formation of an arteriovenous fistula. When 0.75% ropivacaine 23 ml had been injected (3 ml after the last negative aspiration), she became dizzy, lost consciousness, and had a seizure, followed within 1 minute by ventricular fibrillation. She was intubated and ventilated and standard ALS protocols were followed with a series of defibrillating shocks, intravenous adrenaline, and intravenous lidocaine, with reversion to sinus rhythm after 13 minutes. She recovered fully with no neurological deficit.

Ventricular tachycardia complicating Brugada syndrome after the use of ropivacaine has been reported (78A). � A 68-year-old-man received a general anes-

thetic supplemented by a bilateral thoracic paravertebral block for distal gastrectomy. A preoperative electrocardiogram showed ST segment elevation associated with T wave

241 inversion in V1–2, typical of Brugada syndrome. He developed hypotension and bradycardia after 30 minutes and was given a dopamine infusion. After another 20 minutes he suddenly developed a polymorphic ventricular tachycardia which eventually spontaneously reverted to sinus rhythm. There were no neurological complications postoperatively.

Tetracaine

(SED-15, 3327; SEDA-30,

161)

Hematologic Methemoglobinemia associated with tetracaine has been reported (79A). � A previously well 33-year-old man developed

acute respiratory failure associated with hemolysis and a methemoglobin concentration of 11% after self-medicating with tetracaine throat lozenges (about 3.6 mg over 1 week). His symptoms resolved rapidly after treatment with methylthioninium chloride and blood transfusion.

The authors expressed concerns that tetracaine lozenges are available over the counter and primary-care physicians might not be aware of this complication.

References 1. Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology 1998;88(4):1071–5. 2. Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003;28(3):198–202. 3. Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology 2006;105(1):217–8. 4. Litz RJ, Popp M, Stehr SN, Koch T. Successful resuscitation of a patient with ropivacaineinduced asystole after axillary plexus block using lipid infusion. Anaesthesia 2006;61(8): 800–1.

5. Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM. Levobupivacaine-induced seizures and cardiovascular collapse treated with Intralipid. Anaesthesia 2007;62(5):516–8. 6. Spence AG. Lipid reversal of central nervous system symptoms of bupivacaine toxicity. Anesthesiology 2007;107(3):516–7. 7. Weinberg GL, Ripper R, Murphy P, Edelman LB, Hoffman W, Strichartz G, et al. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart. Reg Anesth Pain Med 2006; 31(4):296–303. 8. Corcoran W, Butterworth J, Weller RS, Beck JC, Gerancher JC, Houle TT, et al. Local anesthetic-induced cardiac toxicity: a survey of contemporary practice strategies among academic anesthesiology departments. Anesth Analg 2006;103(5):1322–6.

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9. Association of Anaesthetists of Great Britain and Ireland. Guidelines for the Management of Severe Local Anaesthetic Toxicity. 2007. http://www.aagbi.org/publications/guidelines/ docs/latoxicity07.pdf. Last accessed 5 October 2009. 10. Picard J, Meek T. Lipid emulsion to treat overdose of local anaesthetic: the gift of the glob. Anaesthesia 2006;61(2):107–9. 11. Brull SJ. Lipid emulsion for the treatment of local anesthetic toxicity: patient safety implications. Anesth Analg 2008;106(5):1337–9. 12. Weinberg G, Hertz P, Newman J. Lipid, not propofol, treats bupivacaine overdose. Anesth Analg 2004;99(6):1875–6. 13. Moore N, Kirton C, Bane J. Lipid emulsion to treat overdose of local anaesthetic. Anaesthesia 2006;61(6):607. 14. Weinberg G. Lipid infusion resuscitation for local anesthetic toxicity: proof of clinical efficacy. Anesthesiology 2006;105(1):7–8. 15. Weinberg GL. Lipid infusion therapy: translation to clinical practice. Anesth Analg 2008;106(5):1340–2. 16. Anonymous. Topical anaesthetic creams. Pharmacists warned to cease compounding standardized versions. WHO Pharm Newslett 2007;1:3. 17. Anonymous. Topical anaesthetics. Professional advice needed before use in cosmetic procedures. WHO Pharm Newslett 2007;2:6. 18. Pippa P, Cuomo P, Panchetti A, Scarchini M, Poggi G, D’Arienzo M. High volume and low concentration of anaesthetic solution in the perivascular interscalene sheath determines quality of block and incidence of complications. Eur J Anaesthesiol 2006; 23(10):855–60. 19. Deruddre S, Vidal D, Benhamou D. A case of persistent hemidiaphragmatic paralysis following interscalene brachial plexus block. J Clin Anesth 2006;18(3):238–9. 20. Faryniarz D, Morelli C, Coleman S, Holmes T, Allen A, Altchek D, et al. Interscalene block anesthesia at an ambulatory surgery center performing predominantly regional anesthesia: a prospective study of one hundred thirty-three patients undergoing shoulder surgery. J Shoulder Elbow Surg 2006;15(6):686–90. 21. Bigeleisen PE. Nerve puncture and apparent intraneural injection during ultrasound-

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guided axillary block does not invariably result in neurologic injury. Anesthesiology 2006;105(4):779–83. Borgeat A. Regional anesthesia, intraneural injection, and nerve injury: beyond the epineurium. Anesthesiology 2006;105(4): 647–8. Guay J. The epidural test dose: a review. Anesth Analg 2006;102(3):921–9. Park JY, Park SJ, Kim JY, Shin HW, Lim HJ, Kim J. Cardiac arrest due to a vagal reflex potentiated by thoracic epidural analgesia. J Int Med Res 2006;34(4):433–6. Mahajan R, Sharma A, Gupta R. A contraindication to using local anesthetic solution for expanding the epidural space. Anesth Analg 2006;103(6):1585–6. Hebl JR, Horlocker TT, Schroeder DR. Neuraxial anesthesia and analgesia in patients with preexisting central nervous system disorders. Anesth Analg 2006; 103(1):223–8. Roboubi B, Kodgi SM. Accidental subdural injection of ropivacaine. Anesth Analg 2006;102(5):1595. Yigit NA, Bagbanci B, Celebi H. Drop foot after pediatric urological surgery under general and epidural anesthesia. Anesth Analg 2006;103(6):1616. Chen LK, Lin CJ, Huang CH, Wang MH, Lin PL, Lee CN, et al. The effects of continuous epidural analgesia on Doppler velocimetry of uterine arteries during different periods of labour analgesia. Br J Anaesth 2006;96(2):226–30. Korhonen A-M. Discharge home in 3 h after selective spinal anaesthesia: studies on the quality of anaesthesia with hyperbaric bupivacaine for ambulatory knee arthroscopy. Acta Anaesthesiol Scand 2006;50(5):627. Minville V, Fourcade O, Grousset D, Chassery C, Nguyen L, Asehnoune K, et al. Spinal anesthesia using single injection small-dose bupivacaine versus continuous catheter injection techniques for surgical repair of hip fracture in elderly patients. Anesth Analg 2006;102(5):1559–63. Jetzek-Zader M, Hermanns H, Freynhagen R, Lipfert P, Stevens MF. Increase in skin temperature after spinal anesthesia in infants. Regional Anesthesia and Pain Medicine 2006;31(6):519–22.

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33. Pradhan S, Yadav R, Maurya PK, Mishra VN. Focal myelomalacia and syrinx formation after accidental intramedullary lidocaine injection during lumbar anesthesia: a report of 3 cases. J Neurol Sci 2006;251 (1–2):70–2. 34. Theodosiadis PD, Grosomanidis VO, Gkoutzioulis FV, Tzafettas JM. A case of unilateral Horner’s syndrome after combined spinal epidural anesthesia with ropivacaine 10 mg/mL for cesarean section. Int J Obstet Anesth 2006;15(1):68–70. 35. Moussa T, Abdoulaye D, Youssouf C, Oumar GC, Karim TS, Traore TJ. Cauda equina syndrome and profound hearing loss after spinal anesthesia with isobaric bupivacaine. Anesth Analg 2006;102(6):1863–4. 36. Lim Y, Teoh W, Sia AT. Combined spinal epidural does not cause a higher sensory block than single shot spinal technique for cesarean delivery in laboring women. Anesth Analg 2006;103(6):1540–2. 37. Arai YC, Ueda W, Takimoto E, Manabe M. The influence of hyperbaric bupivacaine temperature on the spread of spinal anesthesia. Anesth Analg 2006;102(1):272–5. 38. Malamed SF. Nerve injury caused by mandibular block analgesia. Int J Oral Maxillofac Surg 2006;35(9):876–7 (author reply 878) 39. Haas DA. Articaine and paresthesia: epidemiological studies. J Am Coll Dentists 2006;73(3):5–10. 40. Peltier B, Dower Jr JS. The ethics of adopting a new drug: articaine as an example. J Am Coll Dentists 2006;73(3):11–20. 41. Ngeow WC, Shim CK, Chai WL. Transient loss of power of accommodation in 1 eye following inferior alveolar nerve block: report of 2 cases. J Can Dent Assoc 2006; 72(10):927–31. 42. Magliocca KR, Kessel NC, Cortright GW. Transient diplopia following maxillary local anesthetic injection. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol 2006; 101(6):730–3. 43. Dorf E, Kuntz AF, Kelsey J, Holstege CP. Lidocaine-induced altered mental status and seizure after hematoma block. J Emerg Med 2006;31(3):251–3. 44. Pragt E, van Zundert AAJ, Kumar CM. Delayed convulsions and brief contralateral

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papulonodular dermatosis associated with topical benzocaine: a report of two cases and evidence that granuloma gluteale, pseudoverrucous papules, and Jacquet’s erosive dermatitis are a disease spectrum. J Am Acad Dermatol 2006;55(5 Suppl): S–80. Proudfoot C, Gamble C. Site-specific skin reactions to amethocaine. Paediatr Nurs 2006;18(5):26–8. Atan A, Basar MM, Tuncel A, Ferhat M, Agras K, Tekdogan U. Comparison of efficacy of sildenafil-only, sildenafil plus topical EMLA cream, and topical EMLAcream-only in treatment of premature ejaculation. Urology 2006;67(2):388–91. Llewellyn N, Liley A, Cropper J, Hutchison L. Does amethocaine gel influence blood results obtained from capillary sampling? Paediatr Nurs 2006;18(6):29–31. Marinella MA. When brown and blue make red: a case of acquired methemoglobinemia. Heart Lung: J Acute Crit Care 2006;35(3): 205–6. Dahshan A, Donovan GK. Severe methemoglobinemia complicating topical benzocaine use during endoscopy in a toddler: a case report and review of the literature. Pediatrics 2006;117(4):e806–9. Jacka MJ, Kruger M, Glick N. Methemoglobinemia after transesophageal echocardiography: a life-threatening complication. J Clin Anesth 2006;18(1):52–4. Khouzam RN. Images in cardiovascular medicine. Methemoglobinemia as a rare complication during a transesophageal echocardiogram. Circulation 2006;113(20):e770. BheemReddy S, Messineo F, Roychoudhury D. Methemoglobinemia following transesophageal echocardiography: a case report and review. Echocardiography 2006;23(4): 319–21. Saha SA, Kordouni MR, Siddiqui M, Arora RR. Methemoglobinemia-induced cardiorespiratory failure secondary to topical anesthesia. Am J Ther 2006;13(6):545–9. Vu AT, Lockey RF. Benzocaine anaphylaxis. J Allergy Clin Immunol 2006;118(2): 534–5. Vernooy K, Sicouri S, Dumaine R, Hong K, Oliva A, Burashnikov E, et al. Genetic and biophysical basis for bupivacaine-induced

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ST segment elevation and VT/VF. Anesthesia unmasked Brugada syndrome. Heart Rhythm 2006;3(9):1074–8. Phillips N, Priestley M, Denniss AR, Uther JB. Brugada-type electrocardiographic pattern induced by epidural bupivacaine. Anesth Analg 2003;97(1):264–7. Makaryus JN, Makaryus AN, Johnson M. Acute myocardial infarction following the use of intranasal anesthetic cocaine. South Med J 2006;99(7):759–61. Balit CR, Lynch A-M, Gilmore SP, Murray L, Isbister GK. Lignocaine and chlorhexidine toxicity in children resulting from mouth paint ingestion: a bottling problem. J Paediatr Child Health 2006;42(6):350–3. Gaughen CM, Durieux M. The effect of too much intravenous lidocaine on bispectral index. Anesth Analg 2006;103(6):1464–5. Gonzalez-Delgado P, Anton R, Soriano V, Zapater P, Niveiro E. Cross-reactivity among amide-type local anesthetics in a case of allergy to mepivacaine. J Investig Allergol Clin Immunol 2006;16(5):311–3. Hall V, Cheng J, Klemawesch P, Guarderas J. Lidocaine sensitivity in a patient with multiple skin cancers. Dermatitis 2006;17 (2):91–2. Levy J, Lifshitz T. Lidocaine hypersensitivity after subconjunctival injection. Can J Ophthalmol 2006;41(2):204–6. Hickey JR, Cook SD, Gutteridge G, Sansom JE. Delayed hypersensitivity following intravenous lidocaine. Contact Dermatitis 2006;54(4):215–6. Aygencel SG, Akinci E, Pamukcu G. Prilocaine induced methemoglobinemia. Saudi Med J 2006;27(1):111–3. Vasters FG, Eberhart LH, Koch T, Kranke P, Wulf H, Morin AM. Risk factors for prilocaine-induced methaemoglobinaemia following peripheral regional anaesthesia. Eur J Anaesthesiol 2006;23(9):760–5. Perez-Perez LC, Fernandez-Redondo V, Ginarte-Val M, Paredes-Suarez C, Toribio J. Allergic contact dermatitis from EMLA cream in a hemodialyzed patient. Dermatitis 2006;17(2):85–7. Khoo LP, Corbett AR. Successful resuscitation of an ASA 3 patient following ropivacaine-induced cardiac arrest. Anaesth Intensive Care 2006;34(6):804–7.

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78. Fujiwara Y, Shibata Y, Kurokawa S, Satou Y, Komatsu T. Ventricular tachycardia in a patient with Brugada syndrome during general anesthesia combined with thoracic paravertebral block. Anesth Analg 2006; 102(5):1590–1. 79. Lavergne S, Darmon M, Levy V, Azoulay E. Methemoglobinemia and acute

245 hemolysis after tetracaine lozenge use. J Crit Care 2006;21(1):112–4. 80. Stienstra R, Gielen M, Kroon JW, Van Poorten F. The influence of temperature and speed of injection on the distribution of a solution containing bupivacaine and methylene blue in a spinal canal model. Reg Anesth 1990;15(1):6–11.

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Neuromuscular blocking agents and skeletal muscle relaxants

DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS

(SED-15,

2489; SEDA-28, 155)

Suxamethonium Electrolyte balance Hyperkalemia after the administration of suxamethonium is usually mild. However, occasionally it can be serious (1R). A patient who underwent emergency surgery for a perforated peptic ulcer after being bedbound for 26 days had a serum potassium concentration before surgery of 4.0 mmol/l and about 3 minutes after injection of suxamethonium 8.8 mmol/l, associated with a ventricular arrhythmia. Immobilization, denervation, and intraabdominal infection were risk factors for hyperkalemia in this patient (2A). Musculoskeletal Because it is a depolariz­ ing muscle blocker, suxamethonium can cause muscle fasciculation. In 55 patients, pretreatment with magnesium sulfate 40 mg/ kg over 5 minutes, 6.5 minutes before induc­ tion reduced suxamethonium-induced fasci­ culation more effectively than vecuronium 0.02 mg/kg 1.5 minutes before induction; however, magnesium did not prevent the rise in serum potassium concentration after induction (3c). Muscle fasciculation Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03112-2 r 2009 Elsevier B.V. All rights reserved.

can also reportedly be reduced by intrave­ nous diazepam 1 mg/kg or lidocaine 1.5 mg/ kg (4c). Postoperative suxamethonium-related myalgia has been studied in 68 patients who were randomized to the selective COX-2 inhibitor, parecoxib, or saline; parecoxib had no significant effect—the incidence of myalgia with parecoxib was 7/34 compared with 11/34 with saline (5c). This study may have been too small to detect a true effect. Immunologic The mechanism of a delayed hypersensitivity reaction to suxamethonium has been studied by harvesting the patient’s T cells from a biopsy at the site of positive intradermal reactions and analyzing the immunophenotype, T cell receptor Vb domain expression, and cytokine profile (6c). The T cells proliferated dose-dependently in response to drug-pulsed autologous antigenpresenting cells. The drug-specific CD4+ T cells were oligoclonal memory CD3+CD4+ T cells and expressed the skin-homing recep­ tors cutaneous lymphocyte antigen (CLA) and CCR4. CD4+ suxamethonium-reactive T cells were interferon gamma-positive and synthesized high concentrations of interferon gamma and TNF-alpha. Susceptibility factors Genetic The tetra­ meric glycoprotein butyrylcholinesterase is one of two enzymes that hydrolyze choline esters. The controlling gene (BCHE) is comprised of four coding exons and is located on chromosome 3q26. Based on butyrylcholinesterase activity in the pre­ sence and absence of dibucaine, two gene

247

248 products have been distinguished—the usual product (designated U) and an atypical product (designated A). Homozy­ gotes for the A gene product are at risk of prolonged apnea after exposure to suxa­ methonium or mivacurium. In a prairie Hutterite kindred there were two BCHE mutations, c.209AWG p. D70 G and c.1615GWA p. A539 T (7c). Homozygotes for the former (i.e., atypical or A) are the only individuals whose butyrylcholinester­ ase activity could lead to adverse reactions to suxamethonium. Age Plasma butyrylcholinesterase activity is higher in young children than in adults and its activity has to be interpreted according to age. There was prolonged neuromuscular blockade in an 18-month­ old girl after administration of a usual dose of suxamethonium, although the cholines­ terase activity was within the adult range but lower than the range in 41 children under 4 years of age (8c). Analysis of dibucaine and fluoride numbers in the family confirmed the hypothesis of an atypical variant (AA phenotype). Sex A retrospective analysis of UK Yellow Card data in which adverse events were reported after the administration of seven neuromuscular blocking drugs over more than 30 years yielded 998 reports, of which 969 mentioned the sex of the patient (9c). Non-allergic and allergic events occurred with similar frequency and most were in women (676; 70%). Men were more likely to have had a reaction to atracurium while women had more reactions to suxametho­ nium. Reactions were fatal in 81 (9%) of the 950 reports for single drugs. Mortality following suxamethonium was significantly higher in men, at 22% compared with 9% for women. More women than men were reported to have allergic reactions—73% (362/499) versus 27% (137/499). The female: male ratio for adverse events was reversed for subjects aged under 10 years compared with peak reports during the fourth decade. The authors commented that the unexpected high frequency of non-allergic events sug­ gests that morbidity and mortality from

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O. Zuzan and M. Leuwer

reactions to established drugs is twice that expected from allergic reactions alone. Drug administration route Accidental epidural administration of suxamethonium resulted in a prolonged onset and a longer duration of neuromuscular blockade than intravenous administration (10c).

NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS (SED-15, 2489; SEDA-28, 155)

Rocuronium

(SED-15, 3073)

Systematic reviews Because of its fast onset of action, rocuronium is a potential alternative to suxamethonium for rapidsequence intubation in patients with an increased risk of aspiration. A meta-analysis has shown that suxamethonium was superior to rocuronium in creating excellent intuba­ ting conditions and avoiding unacceptable intubating conditions (11M). Along the same lines, the Cochrane review of rocuronium versus suxametho­ nium for rapid sequence intubation has recently been updated with the inclusion of 11 additional studies (12M). When rocur­ onium was used the relative risk for excellent intubating conditions was 0.86, with a number-needed-to-harm (NNTH) of 8. The authors concluded that suxametho­ nium creates excellent intubation condi­ tions more reliably than rocuronium and should still be used as a first-line muscle relaxant for rapid-sequence induction intu­ bation. If an alternative agent is required, rocuronium can be used to create accepta­ ble intubation conditions, but it should only be used as a second-line treatment. Neuromuscular Prolonged paralysis has been reported after a single intubating dose of rocuronium, highlighting the clinical impact of interindividual variation in phar­ macokinetics and pharmacodynamics (13A).

Neuromuscular blocking agents and skeletal muscle relaxants
An 84-year-old woman, without any known

co-morbidities, who did not take any regular medication, received rocuronium 0.6 mg/kg at induction of anesthesia to facilitate endotra­ cheal intubation. Two hours later, there was no twitch response to train-of-four stimulation of the ulnar nerve, but the post-tetanic count was 8. After 193 minutes one twitch response to train-of-four stimulation was recorded, and 215 minutes after the injection a second twitch response appeared. At this time, neostigmine 0.05 mg/kg was given for reversal and 8 min­ utes later a train-of-four ratio W 0.9 was observed and the patient was extubated with­ out any clinical signs of residual paralysis.

The authors suggested that the unusually long duration of action of rocuronium in this instance had been caused by a combi­ nation of several factors, including geneti­ cally increased sensitivity to rocuronium, advanced age, decreased liver function, female sex, and the use of sevoflurane.

Rocuronium hypersensitivity reactions—the link to pholcodine There were 29 reports of anaphylaxis among 150000 patients exposed in Norway in 2001, but only eight cases among 800000 patients in Denmark, Sweden, and Finland (14Cr). In several cases of anaphylaxis in Norway, rocuronium was later confirmed as the causative agent (15C). To identify the substance that could have resulted in crosssensitization, several agents were tested using IgE antibody inhibition assays (16C). Pholcodine, an opioid available over the counter in cough syrups, was one of the drugs that inhibited the antibody reaction to suxamethonium and/or morphine and was on the market in Norway but not in Sweden. There was IgE to pholcodine in 6% of blood samples from Norwegian blood donors with no history of anaphylaxis compared with none of the Swedish blood donors. Similarly, 42 of 65 patients (65%) with confirmed anaphylaxis to neuromuscular blocking agents had antibodies to pholcodine. It was therefore hypothesized that exposure to pholcodine could explain the higher number of cases of anaphylaxis in Norway.

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This has recently received further support, when it was shown that exposure to pholcodine could boost IgE concentrations to morphine and suxamethonium (17c). In 17 patients with a history of previous anaphylaxis to neuromuscular blocking agents who were given either pholcodine-containing cough syrup (n ¼ 11) or guaifenesin-containing cough syrup (n ¼ 6) for 7 days, median pre-exposure IgE antibody concentrations to pholcodine, morphine, and suxamethonium were 1.0, 1.1, and 0.1 kUA/l respectively. Four weeks after exposure, the median IgE antibody concentrations had increased to 81, 57, and 9.3 kUA/l. There was no change in the guaifenesin group. Taken together, these publications point in the direction of pholcodine as a potential sensitizing agent for anaphylaxis to rocuronium. However, there are still important unanswered questions. Are patients with antibodies to pholcodine more likely to have anaphylaxis to rocuronium? Is the incidence of anaphylaxis to rocuronium in other countries related to exposure to pholcodine? If pholcodine does sensitize people to rocuronium, does this apply to other neuromuscular blocking agents as well? Owing to the methodological and statistical problems of researching such rare events, we may need to wait a long time for the answers to these questions. On the positive side, there is a new IgE assay that promises to make the diagnosis of anaphylaxis to rocuronium more precise, with a sensitivity of 93% for the detection of IgE (18E).

Sugammadex A new reversal agent called sugammadex has been introduced. It specifically reverses rocuronium and, to a lesser extent, vecur­ onium, without any relevant effect on the duration of action of benzylisoquinolinium neuromuscular blockers. Its pharmacology has been summarized (19r). Among adverse effects in human volunteers were hypotension, coughing, nausea, vomiting, dry mouth, abnormal smell, and a sensation of

250 a changed temperature. No adverse effects have been reported in several clinical studies (20c,21c,22c).

SKELETAL MUSCLE RELAXANTS Baclofen (SED-15, 408; SEDA-27, 141; SEDA-28, 157; SEDA-30, 164) Nervous system Radiculopathy occurred in two patients as complications of intrathecal baclofen therapy early after pump implantation. The first patient had pain at the level of S1 and the second at L5; relief was obtained from analgesic drugs in one and catheter replacement in the other (23A). Psychiatric Psychosis has been attributed to baclofen in therapeutic doses (24A).
A 32-year-old man took oral baclofen 10 mg

bd for muscular spasms secondary to tetanus. After 4 weeks he developed third-person auditory hallucinations and persecutory and referential delusions without underlying mood symptoms. These symptoms resolved within 1 week of withdrawal of baclofen. Rechallenge resulted in re-emergence of the psychotic symptoms, which again disappeared after withdrawal.

Gastrointestinal Paralytic ileus has been reported in a 52-year-old man with tetra­ plegia after he had received baclofen 100 mg/ day intrathecally for 4 days; the dosage of baclofen was reduced to lowest rate of flow and the ileus resolved after 15 days (25A). Musculoskeletal Accelerated progression of scoliosis has been reported in four patients after intrathecal pump insertion, but the association between the two events was not clear (26A). Sexual function Sexual dysfunction has been reported in three patients taking oral baclofen (27A).
A 25-year-old woman with spastic diplegic

cerebral palsy took baclofen 10 mg tds and

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O. Zuzan and M. Leuwer

developed difficulty in attaining orgasm and reduced intensity of orgasm. She reduced the dose of baclofen to minimize sexual dysfunc­ tion.
A 49-year-old man with spastic diplegia took baclofen 20 mg qds and noted reduced sexual drive but could achieve and maintain erections and achieve orgasm without difficulty.
A 47-year-old woman with spasticity took baclofen 10 mg tds and 20 mg at bedtime. She became unable to attain an orgasm although she continued to enjoy sexual activity.

The authors suggested that baclofen produces sexual dysfunction by inhibiting both behavioral and physiologic reflex responses. Infection risk Meningitis due to Escherichia coli has been reported as a delayed complication of an intrathecal baclofen pump (28A). Of 45 infections associated with 571 pump, 21 were due to Gram-negative organisms in 12 patients aged 10–32 years, nine of whom had quadriplegia (29c); two resulted in meningi­ tis. Eleven of the 12 pumps were explanted. Of the 21 Gram-negative infections, Pseudomonas aeruginosa accounted for eight, Escherichia coli for five, Proteus for three, Enterobacter cloacae for two, and Klebsiella, Enterobacter aerogenes, and Enterobacter vulnaris for one each. The two individuals with Gram-negative meningitis were admitted 72–96 hours after hospital discharge following pump replacement. Both rapidly deteriorated and developed coagulopathy and reduced responsiveness, but both recovered. A 37-year-old man developed a baclofen pump pocket infection that did not respond to antimicrobial drugs; the pump was salvaged by wrapped the ipsilateral rectus abdominis muscle around it, allowing con­ tinued administration of baclofen (30A). Drug withdrawal Neuroleptic malignantlike syndrome has been described after abrupt withdrawal of intrathecal baclofen in an 80-year-old man (31A).
A 12-year-old boy received an overdose of

intrathecal baclofen followed by withdrawal symptoms (32A). He initially had a respiratory arrest and then as he recovered from the overdose began to have symptoms of baclofen

Neuromuscular blocking agents and skeletal muscle relaxants withdrawal, including hypertension, hyper­ thermia, and hallucinations.

Susceptibility factors Renal disease Baclofen is mainly excreted by the kidney and is not well removed by dialysis.
A 79-year-old man with end-stage renal

disease on peritoneal dialysis developed altered consciousness and bradypnea (33A). He had mistakenly taken one of his wife’s medications, baclofen, which was detected in a blood sample at a concentration above the usual target range.

Two patients with chronic renal insuffi­ ciency rapidly developed neurotoxicity after taking baclofen 5 mg tds for intractable hiccups (34A). One had mental confusion, incoherent speech, blurred vision, and muscle weakness; the other had confusion, disorientation, muscle weakness, and vomiting. In another case a baclofen-associated encephalopathy developed in a patient with intract­ able hiccups receiving hemodialysis (35A). Drug administration route In a retrospec­ tive review of 314 surgical procedures (226 pediatric and 88 adult) in 195 patients there were 171 new baclofen pump and catheter implants (116 pediatric and 55 adult), 26 elective pump replacements due to end of battery life (15 pediatric and 11 adult), five elective pump repositionings (three pedia­ tric and two adult), 14 elective catheter repositionings (10 pediatric and 4 adult), and two normal pediatric catheter explora­ tions (36C). Surgical procedures for compli­ cation management included seven pump revisions (five pediatric and two adult), 48 catheter revisions (38 pediatric and 10 adult), and 41 wound revisions (37 pedia­ tric and 4 adult). Most of the adult pumps were implanted subdermally, whereas in children they were placed subfascially. There were no significant intraoperative complications, but there was a statistically significantly higher percentage of proce­ dures for overall complication management and wound complication management in children. Coma and generalized seizures occurred in a patient in whom an overdose of

Chapter 12

251

baclofen occurred because of malfunction of an intrathecal pump (37A).
A 33-year-old man with spasticity was given

intrathecal baclofen via an Archimedes Implantable Constant-Flow Pump, 20 ml of Lioresal 500 mg/ml diluted with 40 ml of isotonic water. Within minutes, he developed hypotonicity, hypertension, bradycardia, and respiratory difficulty followed by tonic-clonic seizures. An attempt to withdraw baclofen from the pump failed, suggesting possible pump malfunction and an overdose of about 10 mg of baclofen since the pump was last filled. A spinal catheter was inserted to drain the excessive baclofen. One hour later he had another generalized seizure. Her eventually recovered after about 3 days. The pump was replaced and gave no problems.

A 57-year-old woman was given intrathe­ cal baclofen for leg spasms. After 38 months her dosage requirements increased dramatically because of a granuloma at the tip of the catheter (38A). Drug overdose Baclofen overdose has been reported in 23 patients, of whom eight took baclofen alone (39A). There were seizures in four, a reduced level of con­ sciousness (Glasgow coma scale less than 9) in eight, and delirium in eight. Five had miosis and seven had dilated pupils; 13 patients had absent or depressed reflexes. The only dysrhythmias were sinus bradycar­ dia in six patients and sinus tachycardia in five. There was hypertension in 13 patients and hypotension in one. The reported total ingested dose of baclofen was known in 19 patients (mean 630, range 80–2500 mg). Those who took 200 mg or more were more likely to need intensive care, mechanical ventilation, and a prolonged length of stay. Coma, delirium, and seizures occurred only with doses of 200 mg or more, and hyperten­ sion was more common with higher doses. There have also been individual reports of overdose (40A, 41A).
A 48-year-old man was found at home

unresponsive and having a tonic-clonic sei­ zure. He had been seen awake and responsive about 2 hours before. Numerous investigations in hospital were normal or negative, including a drug screen for amphetamines, cocaine, barbiturates, opioids, and alcohol. His blood pressure was raised (174–207 mmHg systolic

252 and 99–119 mmHg diastolic). It subsequently emerged that he had taking an overdose of an unknown amount of baclofen; the serum baclofen concentration was 1.2 mg/l (usual target range for treatment of spasticity 0.08– 0.4 mg/l). He recovered within 48 hours with­ out specific treatment.

In another case the diagnosis of baclofen overdose was assisted by electroencephalo­ graphy, which showed continuous multi­ focal pseudoperiodic sharp waves, and confirmed by a high plasma baclofen concentration (42A). In a similar case in a 14-year-old girl who presented with coma and seizures, continuous electroencephalo­ graphy showed suppression and semiperio­ dic sharp waves (43A).

Botulinum toxins (SED-15, 551; SEDA28, 168; SEDA-29, 156; SEDA-30, 165)

Systematic reviews The adverse effects of botulinum toxin type A have been reviewed (44R) and subjected to systematic review (45M) in an analysis of data from nine double-blind, placebo-controlled studies in 792 patients with spasticity after stroke (mean age 58 years, 60% men). Most of the patients (69%) received only one injection. After follow-up for a mean of 18 (range 0.1–45) weeks 352 (66%) of the patients who had been given toxin type A group and 163 (63%) of those who had been given placebo reported at least one adverse event. The most frequent adverse events were respiratory infections, seizures, incoordination, and injection site pain, none of which occurred at a significantly higher rate with the toxin. Most of the adverse events were rated as mild or moderate in intensity. Only nausea was reported at a significantly higher rate with botulinum toxin (12/534) than placebo (0/258); in contrast, injection site pain, chest pain, and allergic reactions were reported significantly more frequently with placebo. Nervous system In a double-blind, rando­ mized, placebo-controlled trial of botuli­ num toxin type A injections for 12 weeks in 40 patients with writer’s cramp, the reported adverse effects were hand

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O. Zuzan and M. Leuwer

weakness, which was mostly mild and always transient, and pain at the injection site (46C). Despite weakness in the hand most of the patients preferred to continue treatment. Pain from injection of botulinum toxin can be reduced by the use of a topical local anesthetic (47c). Autonomic adverse effects (constipation and dry mouth) have been reported in four patients after intravesical injection of botulinum toxin type B for detrusor overactivity, suggesting systemic spread of the toxin (48A). Suburothelial injection of small doses of botulinum A toxin may be preferable (49c). A 34-year-old weightlifter with a gait disorder developed generalized muscle weakness 2 weeks after being given botuli­ num toxin 11 units/kg into both gastrocne­ mii and the tibialis posterior in the right leg (50A). Sensory systems Pupillary dilatation has been reported after injection of botulinum toxin into an extraocular muscle (51A).
A 69-year-old man with diplopia after a

stroke was given four doses of botulinum toxin type A into the right lateral rectus muscle over about 7 months, when he was noted to have anisocoria. The right pupil measured 6 mm and was fixed, with no direct or consensual response to light, and it failed to dilate further in scotopic conditions. The left pupil was normal. Botulinum toxin was withheld and 2 months later the right pupil was normal.

The authors speculated that the toxin had reached the ciliary ganglion by diffusion from the lateral rectus muscle. Three cases of diplopia have been reported after cosmetic injection of botuli­ num toxin into the skin close to the eye; it was due to inferior oblique paresis and was bilateral in two cases (52A). Endocrine Left-sided thyroid eye disease developed in a 53-year-old woman with hyperthyroidism 4 days after injection of botulinum toxin on the same side (53A). There was periorbital swelling, proptosis, and eyelid retraction, with extraocular muscle enlargement on CT scan.

Neuromuscular blocking agents and skeletal muscle relaxants

Gastrointestinal Severe dysphagia has been reported as a remote effect of injec­ tion of botulinum toxin (54A).
A 29-year-old woman with cerebral palsy had

injections of botulinum toxin B into her legs and lumbar paraspinal muscles and 4 days later developed difficulty in swallowing, which was more severe with solids than liquids, accompanied by dry mouth, blurred vision, and hoarseness of the voice. She had bilateral vocal cord paresis, delayed oral initiation of swallowing, and no reflex cough.

Infection risk Severe botulism has been reported after the use of unlicensed for­ mulations. Four cases of suspected botulism linked to cosmetic botulinum toxin were reported to the Centers for Disease Control and Prevention in Atlanta in 2004 and were investigated (55c). All had been injected with a highly concentrated unlicensed for­ mulation of botulinum toxin A and may have received doses 2857 times the esti­ mated human lethal dose by injection. Pretreatment serum toxin concentrations in three cases were 21–43 times the estimated human lethal dose. A 100-mg vial of toxin taken from the same manufac­ turer’s lot contained enough toxin to kill about 14286 adults by injection.
A

34-year-old woman developed severe botulism after the cosmetic use of an unapproved formulation of botulinum toxin type A. Electrophysiological studies showed complete denervation with complete electri­ cal silence (56A).

Pregnancy Two patients who received botulinum toxin type A injections once during the first trimester (at 5 and 6 weeks) had healthy babies delivered at term by cesarean section (57A). Drug formulations Preclinical data sug­ gest that the safest formulation is Botoxs, followed by Dysports and Myoblocs (58Er). The dose units of the individual formulations are unique and cannot be interconverted. In a prospective, double-blind placebocontrolled comparison of intradermal Dys­ port (12 units), Botox (3 and 4 units), or

Chapter 12

253

Neurobloc (150 and 300 units) in 10 healthy subjects, Neurobloc injection caused signifi­ cantly more pain than Botox, Dysport, or saline; there was a non-significant trend toward less pain with pure saline (59c). Reconstitution of botulinum toxin A with saline followed by refrigeration reduced efficacy in 32 healthy volunteers and is not recommended (60c). Interference with diagnostic tests Bispectral index, an electroencephalographic vari­ able used in measuring the depth of anesthesia, is altered by neuromuscular blockade with alcuronium and suxametho­ nium (61c). It has been suggested that this might also happen with botulinum toxin if it were injected into the muscle used to measure the index (62r), and preoperative cosmetic use of botulinum toxin has been reported to affect monitoring of neuromus­ cular blockade (63c).

Carisoprodol

(SED-15, 674; SEDA-29,

146) Psychiatric The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) has concluded that there is evidence for a carisoprodol-associated risk of abuse and addiction, intoxication, and psychomotor impairment and found that the risk outweighs the benefits. They have therefore recommended suspension of marketing authorizations of all carisoprodol-containing medicinal products in the EU (64S).

Chlorzoxazone

(SED-15, 735)

Liver Chlorzoxazone has been used as a centrally acting muscle relaxant for several decades but can cause liver damage, as highlighted by a report of severe liver necrosis requiring liver transplant (65A).
A 38-year-old woman developed nausea,

vomiting, scleral icterus, confusion, and lethargy after the administration of chlorzox­ azone 500 mg bd for 6 weeks. Serum alanine

Chapter 12

254 and aspartate transaminases and bilirubin were markedly raised and a transjugular liver biopsy showed acute hepatitis with bridging necrosis, severe hepatocyte ballooning degen­ eration, and a mixed inflammatory cell infil­ trate, suggestive of drug-induced injury. As her condition did not improve, she underwent orthotopic liver transplantation. Extensive exploration revealed no other causes of liver damage.

The authors provided a thorough overview of chlorzoxazone-associated liver damage. So far, few cases have been reported, but some have been severe, including fulminant liver failure and death, with no obvious relation to dose. Surveillance studies did not identify hepatotoxicity as a problem and there were no recommendations for routine monitoring of liver enzymes.

Cyclobenzaprine

(SED-15, 1023)

Drug–drug interactions Two case reports have linked cyclobenzaprine administration with the onset of severe serotonin syndrome in patients already taking serotonergic medication (66A).
A 70-year-old woman received cyclobenzapr­

ine 10 mg tds a few days after hip surgery. She was also taking phenelzine for depression. After the third dose of cyclobenzaprine, she developed confusion, agitation, tremors, tachy­ cardia, fever, and sweating. The cyclobenzapr­ ine was withdrawn. As no other causes were found and the symptoms failed to resolve over the next few days, serotonin syndrome was suspected and phenelzine was also withheld. Over the next 3 days, her symptoms resolved.




O. Zuzan and M. Leuwer

A 53-year-old man developed tachycardia, confusion, agitation, sweating, and tremors 2 days after spinal surgery shortly after cyclo­ benzaprine 10 mg tds was started. He also had hypernatremia (154 mmol/l) and severe lactic acidosis (10.1 mmol/l). His other medications included duloxetine 60 mg/day. Both cycloben­ zaprine and duloxetine were withdrawn and a serotonin antagonist was given for 72 hours (cyproheptadine 8 mg via nasogastric tube every 6 hours). His condition improved and he fully recovered.

The authors suggested that cyclobenzapr­ ine should be added to the list of drugs that can cause serotonin syndrome and that there may be an increased risk of serotonin syndrome when serotonergic drugs are combined.

Diaminopyridine Based on an evaluation of the benefit–risk profile of 3,4-diaminopyridine, AFSSAPS, the Regulatory Agency in France has advised health professionals that there is no evidence of the efficacy of 3,4-diamino­ pyridine in treating fatigue associated with multiple sclerosis (67S). This, combined with the insufficient preclinical data, gives diaminopyridine a poor benefit to harm balance. It should therefore not be used in treating fatigue in patients with multiple sclerosis. However, it does have a favorable profile in treating the symptoms of Lambert–Eaton myasthenic syndrome in patients with no other treat­ ment alternatives.

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3. Sakuraba S, Serita R, Kosugi S, Eriksson LI, Lindahl SG, Takeda J. Pretreatment with magnesium sulphate is associated with less succinylcholine-induced fasciculation and subsequent tracheal intubation-induced hemodynamic changes than precurarization with vecuronium during rapid sequence induc­ tion. Acta Anaesthesiol Belg 2006;57(3): 253–7.

Neuromuscular blocking agents and skeletal muscle relaxants 4. Hassani M, Sahraian MA. Lidocaine or diazepam can decrease fasciculation induced by succinylcholine during induction of anesthesia. Middle East J Anesthesiol 2006;18(5):929–31. 5. Schreiber JU, Mencke T, Pradarutti S, Jeblick S, Fuchs-Buder T. Does preopera­ tively administered parecoxib prevent succinylcholine-associated myalgia? A randomized, placebo-controlled trial. Eur J Anaesthesiol 2006;23(4):332–7. 6. Scala E, Guerra EC, Giani M, Pirrotta L, Locanto M, Mondino C, Mari A. Delayed allergic reaction to suxamethonium driven by oligoclonal Th1-skewed CD4+CCR4 +IFN-gamma+ memory T cells. Int Arch Allergy Immunol 2006;141(1):24–30. 7. Zelinski T, Coghlan G, Mauthe J, TriggsRaine B. Molecular basis of succinylcholine sensitivity in a prairie Hutterite kindred and genetic characterization of the region con­ taining the BCHE gene. Mol Genet Metab 2007;90(2):210–6. 8. Lejus C, Delaroche O, Trille E, Blanloeil Y, Pinaud M. De
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intubating dose of rocuronium. Br J Anaesth 2007;99:514–7. Laake J, Rottingen J. Rocuronium and anaphylaxis—a statistical challenge. Acta Anaesthesiol Scand 2001;45:1196–203. Harboe T, Guttormsen AB, Irgens A, Dybendal T, Florvaag E. Anaphylaxis dur­ ing anesthesia in Norway: a 6-year singlecenter follow-up study. Anesthesiology 2005;102:897–903. Florvaag E, Johansson SG, Oman H, Venemalm L, Degerbeck F, Dybendal T, Lundberg M. Prevalence of IgE antibodies to morphine. Relation to the high and low incidences of NMBA anaphylaxis in Nor­ way and Sweden, respectively. Acta Anaes­ thesiol Scand 2005;49:437–44. Harboe T, Johansson SG, Florvaag E, Oman H. Pholcodine exposure raises serum IgE in patients with previous anaphylaxis to neuromuscular blocking agents. Allergy 2007;62:1445–50. Ebo DG, Venemalm L, Bridts CH, Deger­ beck F, Hagberg H, De Clerck LS, Stevens WJ. Immunoglobulin E antibodies to rocur­ onium: a new diagnostic tool. Anesthesio­ logy 2007;107:253–9. Naguib M. Sugammadex: another milestone in clinical neuromuscular pharmacology. Anesth Analg 2007;104:575–81. de Boer HD, Driessen JJ, Marcus MA, Kerkkamp H, Heeringa M, Klimek M. Reversal of rocuronium-induced (1.2 mg/ kg) profound neuromuscular block by sugammadex: a multicenter, dose-finding and safety study. Anesthesiology 2007;107: 239–44. Sparr HJ, Vermeyen KM, Beaufort AM, Rietbergen H, Proost JH, Saldien V, Velik­ Salchner C, Wierda JM. Early reversal of profound rocuronium-induced neuromuscu­ lar blockade by sugammadex in a randomized multicenter study: efficacy, safety, and pharmacokinetics. Anesthesiology 2007;106:935–43. Sorgenfrei IF, Norrild K, Larsen PB, Stensballe J, Ostergaard D, Prins ME, Viby-Mogensen J. Reversal of rocuro­ nium-induced neuromuscular block by the selective relaxant binding agent sugamma­ dex: a dose-finding and safety study. Anesthesiology 2006;104:667–74.

256 23. Roche N, Schnitzler A, Gene^ t F, Ben Smail D. Radiculalgie apre s implantation de pompe e baclofe ne. [Radiculopathy following intrathecal baclofen pump implantation.] Ann Readapt Med Phys 2006;49(5):248–51. 24. Chawla JM, Sagar R. Baclofen-induced psychosis. Ann Pharmacother 2006;40(11): 2071–3. 25. Morant A, Noe
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MT, Alonso-Navarro H, Marti
n-Prieto M, Jime
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34. Chou CL, Chen CA, Lin SH, Huang HH. Baclofen-induced neurotoxicity in chronic renal failure patients with intractable hic­ cups. South Med J 2006;99(11):1308–9. 35. Quintana LF, Llado
A, Butjosa M, Santamari
a J, Torras A, Poch E. Encefalopati
a asociada a baclofeno como tratamiento del hipo refractario en un paciente en hemodia
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MT, Marti
n-Prieto M, Ruiz-Ezquerro JJ, Jime
nez-Jime
nez FJ. Coma inducido por sobredosis de baclofe
n intratecal. [Coma induced by an overdose of intrathecal baclofen.]. Rev Neurol 2006;43(1):63–4. 41. Wall GC, Wasiak A, Hicklin GA. An initially unsuspected case of baclofen overdose. Am J Crit Care 2006;15(6):611–3. 42. Boutte C, Vercueil L, Durand M, Vincent F, Alvarez JC. Apport de l'EEG dans le diagnostic d’une intoxication au baclofe ne. [EEG contribution to the diagnosis of baclofen overdose.]. Neurophysiol Clin 2006;36(2):85–9. 43. Slaughter AF, Roddy SM, Holshouser BA, Abd-Allah SA. Magnetic resonance spec­ troscopy and electroencephalography in baclofen coma. Pediatr Neurol 2006;34(2): 151–5. 44. Bakheit AM. The possible adverse effects of intramuscular botulinum toxin injections

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55.

and their management. Curr Drug Saf 2006; 1(3):271–9. Turkel CC, Bowen B, Liu J, Brin MF. Pooled analysis of the safety of botulinum toxin type A in the treatment of poststroke spasticity. Arch Phys Med Rehabil 2006; 87(6):786–92. Kruisdijk JJ, Koelman JH, Ongerboer de Visser BW, de Haan RJ, Speelman JD. Botulinum toxin for writer's cramp: a randomised, placebo-controlled trial and 1­ year follow-up. J Neurol Neurosurg Psy­ chiatry 2007;78(3):264–70. O'Riordan JM, Fitzgerald E, Gowing C, O'Grady H, Feeley TM, Tierney S. Topical local anaesthetic (tetracaine) reduces pain from botulinum toxin injections for axillary hyperhidrosis. Br J Surg 2006;93(6):713–4. Ghei M, Maraj BH, Nathan S, Malone-Lee J, Miller R. Autonomic side effects of Botuli­ num toxin Type B intravesical injections: report of 4 cases and review of the literature. Int Urol Nephrol 2006;38(3–4):543–4. Kuo HC. Will suburothelial injection of small dose of botulinum A toxin have similar therapeutic effects and less adverse events for refractory detrusor overactivity? Urology 2006;68(5):993–7. Duffey P, Brown C. Iatrogenic botulism in an amateur weight-lifter. Mov Disord 2006; 21(7):1056. Hemmerdinger C, Srinivasan S, Marsh IB. Reversible pupillary dilation following botulinum toxin injection to the lateral rectus. Eye 2006;20(12):1478–9. Aristodemou P, Watt L, Baldwin C, Hug­ kulstone C. Diplopia associated with the cosmetic use of botulinum toxin A for facial rejuvenation. Ophthal Plastic Reconst Surg 2006;22(2):134–6. Harrison AR, Erickson JP. Thyroid eye disease presenting after cosmetic botulinum toxin injections. Ophthal Plast Reconstr Surg 2006;22(5):397–8. Rossi RP, Strax TE, Di Rocco A. Severe dysphagia after botulinum toxin B injection to the lower limbs and lumbar paraspinal muscles. Am J Phys Med Rehabil 2006;85 (12):1011–3. Chertow DS, Tan ET, Maslanka SE, Schulte J, Bresnitz EA, Weisman RS, Bernstein J, Marcus SM, Kumar S, Malecki

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J, Sobel J, Braden CR. Botulism in 4 adults following cosmetic injections with an unli­ censed, highly concentrated botulinum preparation. JAMA 2006;296(20):2476–9. Souayah N, Karim H, Kamin SS, McArdle J, Marcus S. Severe botulism after focal injec­ tion of botulinum toxin. Neurology 2006; 67(10):1855–6. de Oliveira Monteiro E. Botulinum toxin and pregnancy. Skinmed 2006;5(6):308. Aoki KR, Ranoux D, Wissel J. Using translational medicine to understand clin­ ical differences between botulinum toxin formulations. Eur J Neurol 2006;13 (Suppl 4):10–9. Kranz G, Sycha T, Voller B, Gleiss A, Schnider P, Auff E. Pain sensation during intradermal injections of three different botulinum toxin preparations in different doses and dilutions. Dermatol Surg 2006; 32(7):886–90. Paik NJ, Seo K, Eun HC. Reduced potency after refrigerated storage of botulitum toxin A: human extensor digitorum brevis muscle study. Mov Disord 2006;21(10):1759–63. Messner M, Beese U, Romstöck J, Dinkel M, Tschaikowsky K. The bispectral index declines during neuromuscular block in fully awake persons. Anesth Analg 2003; 97:488–91. Chapman JM. BIS and Botox: a hazardous combination? Anesth Analg 2006;103(5): 1335–6. Miller L, Neustein S. Neuromuscular block­ ade monitoring complicated by the unknown preoperative cosmetic use of botulinum toxin. Anesthesiology 2006;105(4):862. European Medicines Agency. European Medicines Agency recommends suspension of marketing authorisation for carisoprodolcontaining medicinal products. Press Release 16 November 2007. Jackson J, Anania FA. Chlorzoxazone as a cause of acute liver failure requiring liver transplantation. Dig Dis Sci 2007;52:3389–91. Keegan MT, Brown DR, Rabinstein AA. Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs. Anesth Analg 2006;103:1466–8. Anonymous. 3,4 diaminopyridine (DAP). Not for treating fatigue in multiple sclerosis patients. WHO Pharm Newslett; 1: 4.

J.K. Aronson

13 Drugs that affect autonomic functions or the extrapyramidal system DRUGS THAT STIMULATE BOTH ALPHA- AND BETA­ ADRENOCEPTORS (SEDA-27, 145; SEDA-28, 160; SEDA-29, 148; SEDA30, 170)

Adrenaline (epinephrine)

(SED-15, 41; SEDA-29, 148; SEDA-30, 170)

Myocardial infarction and other vasospastic effects of adrenaline EIDOS classification: Extrinsic moiety: Adrenaline Intrinsic moiety: Alpha-adrenoceptors Distribution: Myocardium Outcome: Vasospasm Sequela: Myocardial infarction due to adrenaline DoTS classification: Dose-relation: Toxic Time-course: Time-independent Susceptibility factors: Pre-existing ischemic heart disease The vasoconstrictor action of adrenaline occasionally causes problems, notably when it affects the coronary arteries (1A). Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03115-8 r 2009 Elsevier B.V. All rights reserved.

Myocardial infarction Myocardial infarction has occasionally been reported after administration of therapeutic doses of adrenaline (2A–4A).
A 79-year-old woman developed pituitary

apoplexy in an adenomatous gland and was being prepared for trans-sphenoidal hypophysectomy (5A). Topical adrenaline (1:1000) was applied to both nostrils and then 1.5 ml of 1% lidocaine containing 1:100 000 adrenaline was injected into the nasal mucosa. The blood pressure immediately rose from 100/50 to 230/ 148 mmHg and the pulse rate from 48 to 140 beats/minute. Although she was treated immediately with esmolol and intravenous glyceryl trinitrate, resulting in normalization of her blood pressure, subsequent investigations showed that she had had a painless myocardial infarction. She made a full recovery after pituitary surgery.
A 64-year-old man was given an EpiPen to treat episodes of benign angioedema affecting the face and tongue, although he never considered the reaction to be life-threatening, and on two occasions was treated in an accident and emergency department with intramuscular adrenaline (doses not specified) (6A). On one occasion he developed chest pain and electrocardiographic signs of ischemia, which had not occurred before. The EpiPen was withdrawn and his angioedema was prevented by regular antihistamine administration.
A woman was given intravenous adrenaline for suspected anaphylaxis and immediately developed crushing chest pain with inferior ST segment elevation and a raised serum troponin T (7A).
A 29-year-old woman had an acute severe anaphylactic reaction to penicillin and was given intravenous adrenaline 0.1 mg of a 1:10 000 solution, after which she immediately developed severe chest pain, with ST segment elevation on the electrocardiogram and a raised serum troponin concentration (8A). CT

259

260 angiography showed no evidence of coronary artery disease or abnormal anatomy.

These are probably examples of vasospasminduced myocardial damage and some of these cases illustrate the potential danger of intravenous adrenaline, which may be more hazardous than other routes. Other cases of myocardial infarction have been reported after the administration of large doses of adrenaline.
A 55-year-old man was given 1 mg of adrena-

line because of anaphylaxis and developed angina pectoris, dyspnea, and ST segment elevation. Plasma troponin T and creatine kinase MB were raised. Coronary angiography showed a 66% stenosis in the right coronary artery.

This presentation was attributed to spasm in a diseased coronary artery. A myocardial infarction occurred in a patient who received 30 ml of adrenaline 1:10 000 submucosally for treatment of a bleeding Mallory–Weiss tear; three other patients who received similar treatment had marked rises in blood pressure (9A). However, the balance of benefit to harm may favor the use of a dose of 30 ml, based on a randomized, comparative study in 228 patients with actively bleeding ulcers who were treated with 20, 30, or 40 ml of a 1:10 000 solution of adrenaline by local injection at endoscopy (10C). Good hemostasis was achieved with all three doses, but the rate of peptic ulcer perforation was significantly higher with 40 ml and the rate of recurrent bleeding was significantly higher with 20 ml. Gastrointestinal injection Vasospasm in areas other than the myocardium can occasionally be problematic. Rarely, injection can cause ischemia when injected into a source of bleeding in the gut.
A 77-year-old woman with melena underwent

negative upper endoscopy and colonoscopy, followed by double-balloon enteroscopy (11A). A source of active bleeding was found in the jejunum and injected with 3 ml of adrenaline 1 in 10 000 in hypertonic saline. The bleeding recurred 2 days later and at operation there was segmental ecchymosis of 1.5 cm of intestine,

Chapter 13

J.K. Aronson

280 cm from the ileocecal valve, due to ischemic necrosis.
A 68-year-old woman with diabetes mellitus and a bleeding gastric ulcer had endoscopic sclerotherapy with adrenaline in hypertonic saline 12 ml (12A). On the next day, when the bleeding had not stopped another injection of 27 ml was given. On the next day 3 she developed a high fever and upper abdominal pain. A CT scan showed a large hypodense area in the spleen, characteristic of infarction, and arteriography showed that the splenic artery was obstructed. There was a large splenic abscess and the spleen was necrosed.

The authors of the second report recommended slow injection for endoscopic injection therapy. Penile injection There have been two reports of penile ischemia after injection of adrenaline.
When adrenaline 0.4 ml of a 1 mg/ml solution

was inadvertently injected into the penile skin of a 12-hour-old neonate the skin blanched and the error was immediately realized (13A). After repeated doses of phentolamine (total 0.65 mg) the skin regained its normal color. There were no sequelae.
A 6-year old boy was circumcised with a penile block anesthesia technique including adrenaline (14A). After circumcision, ischemia was immediately evident over the entire penile region and 10 days later there was near total skin necrosis involving the entire glans. The necrotic tissues were excised and the penis was reconstructed with a bipedicular scrotal flap.

Fingers Vasospasm has also been reported after accidental digital injection of adrenaline, reversible by the non-selective alphaadrenoceptor antagonist phentolamine (15A). Other cases have been reported.
A 41-year-old woman accidentally injected

adrenaline 0.3 mg into her own thumb while trying to inject into her son (16A). She experienced severe pain and observed progressive pallor and coldness extending proximally from the end of her thumb to the wrist and forearm over the next 30 minutes. Two rounds of glyceryl trinitrate paste were applied to the area over the next hour, but without improvement, after which hot packs proved beneficial. She did not recover full circulation until the next morning.
A 37-year-old woman, trying to wrestle an Epipen from her 3-year-old son, was

Drugs that affect autonomic functions or the extrapyramidal system accidentally stuck in the palmar aspect of the distal right index finger, presumably injecting all or most of the dose (0.15 mg) (16A). Within a few minutes, she developed pain and pallor throughout the finger, but the symptoms resolved within 2 hours without intervention.
A 5-year-old boy accidentally injected adrenaline 0.15 mg into a finger (17A). He was treated with subcutaneous phentolamine 0.15 mg in 0.5 ml isotonic saline at the site of accidental injection and finger circulation was restored within 20 minutes. He had a headache, nausea, and vomiting after 30 minutes, probably due to the phentolamine. No other complications occurred.

In a review of 26 reports of unintentional injection of adrenaline from an autoinjector in 69 people, 63 sustained injury to a finger or thumb (18c). More than 65% of the 69 individuals were evaluated in an emergency department. Nine were not; in 17 the injured part was warmed; 6 were treated with glyceryl trinitrate paste and 15 with local injections of phentolamine and/or lidocaine. No permanent sequelae were reported. Incidence The incidence of all adverse effects of intravenous adrenaline in adults aged under 55 years with asthma has been studied retrospectively using a structured, medical case record review (19c). During 220 episodes there were 67 adverse events (31%; 95% CI ¼ 25, 37%). Most were minor and self-limiting; there were no deaths. Major adverse events occurred in eight cases (3.6%; CI ¼ 1.7, 7.3%), including one case of chest pain with electrocardiographic changes and one of a raised serum troponin concentration, two cases of supraventricular tachycardia, and four of hypotension requiring intervention. This suggests that the risk of myocardial ischemia in this age group is less than 1%. However, it will presumably be higher in older patients with pre-existing myocardial ischemic damage.

Cardiovascular In a double-blind, rando­ mized, controlled study 84 adults under­ going endoscopic sinus surgery under

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261

general anesthesia were randomly allocated to local nasal 1% lidocaine 4 ml with different doses of adrenaline, 0, 20, or 40 mg (20C). Adrenaline significantly reduced mean arterial pressure and systemic vascular resistance index and increased heart rate, cardiac index, and acceleration index. Overtreatment with adrenaline has been reported to have caused a cardiomyopathy (21A).
A 62-year-old man was given subcutaneous

adrenaline 0.3 mg eight times in 4 hours plus methylprednisolone for acute asthma. His symptoms worsened and an electrocardiogram showed ST segment elevation, loss of R wave progression, negative T waves, and QT inter­ val prolongation, suggesting ischemic heart disease. However, the activities of creatine kinase and its MB isozyme were not raised and myosin light chain I and troponin T were only mildly so. Echocardiography showed apical dyskinesia and basal hypersystole.

The authors suggested that this was a case of Takotsubo cardiomyopathy (stress car­ diomyopathy), probably due to catechola­ mine-mediated myocardial stunning by overuse of adrenaline. Drug administration route Intraperitoneal adrenaline 1–5 mg/l has been combined with intraperitoneal cisplatin 50 mg/l (total dose 100 mg), given in 2 l of saline over 2 hours, in patients with advanced peritoneal carcino­ matosis (17 ovarian cancers, 1 peritoneal mesothelioma) (22c), since there is experi­ mental evidence that intraperitoneal adrena­ line enhances tumor accumulation and antitumor activity of intraperitoneal cisplatin. Abdominal pain limited the dose of intraper­ itoneal adrenaline that could be given. Drug overdose The effects of overdosage of adrenaline have been reviewed (23R). Drug–drug interactions Beta-adrenoceptor antagonists A 47-year-old woman who was taking acebutolol for hypertension failed to respond to two separate intrave­ nous doses of adrenaline 0.1 mg given for an anaphylactic reaction to a penicillin; there was a normal response to a third

262 dose (24A). The authors called this a paradoxical reaction, but it was entirely expected, since the normal response to adrenaline would have been prevented by the acebutolol. As they pointed out, higher doses of adrenaline may be necessary in these circumstances. They also noted that beta-blockers can worsen anaphylactic reactions when they occur; this is presum­ ably because of blockade of endogenous catecholamines and perhaps also by stimu­ lating mediator release through unopposed alpha-adrenoceptor activity.

Ephedra and ephedrine

(SED-15, 1221; SEDA-29, 148; SEDA-30, 171; SEDA-30, 171)

Because they are thermogenic in experi­ mental animals Ephedra alkaloids have been used to aid weight loss (25R). How­ ever, they are associated with too many cardiovascular and nervous system adverse effects to be of use (26R). For example, in one short-term study consumption of two doses 5 hours apart of an Ephedra+caffeine mixture (325+90 mg) in 16 healthy adults, associated with peak plasma ephedrine concentrations of 130–140 ng/ml, caused increased heart rate, blood pressure, and glucose concentrations, and reduced potassium concentrations (27C), and a meta­ analysis showed that ephedrine and Ephedra are associated with increased risks of psychiatric symptoms, autonomic symptoms, upper gastrointestinal symptoms, and palpitation (28M). In 2004 formulations contain­ ing Ephedra alkaloids were banned by the FDA (29r, 30r), although the ban was overturned in Utah by a federal judge in the following year (31r). Cardiovascular Myocardial infarction has been attributed to ephedrine (32A).
A 28-year-old mixed martial arts fighter took

Therma-Prot, a dietary supplement, to lose weight before fights. Besides weight loss, he suffered palpitation, tremors, and insomnia. After taking four tablets a day for 3 days he developed intense tight chest pain at rest,

Chapter 13

J.K. Aronson

which worsened with effort and improved with rest. Simple analgesia was ineffective. Six days later he developed syncope and a right-sided hemiparesis. After 30 days the hemiparesis had resolved but he had congestive heart failure NYHA class II. An electrocardiogram showed an extensive anterior electrical inac­ tivity and echocardiography showed a left ventricle with dimensions at the upper limit of normal and a 45% ejection fraction with anteroseptal, apical, and anterior akinesia and thrombus in the left ventricle. Coronary angiography showed an occluded anterior descending artery.

Therma-Pro contains Ma huang extract 250 mg, equivalent to ephedrine 20 mg. Hypertensive encephalopathy with gener­ alized tonic–clonic seizures has been attrib­ uted to abuse of over-the-counter formulations containing a mixture of ephe­ drine and caffeine alkaloids (33A). Ventricular tachycardia has been attrib­ uted to ephedrine (34A).
A 19-year-old woman took ephedrine to

enhance her sports performance and after 10 days developed hemodynamically unstable ventricular tachycardia resistant to cardiover­ sion and amiodarone. She converted to sinus rhythm 60 hours later, presumably when the plasma ephedrine concentration had fallen sufficiently.

The authors thought that ephedrine had not been the sole cause of tachycardia in this case, but that it had triggered the dysrhyth­ mia in association with an underlying pro­ pensity to idiopathic left ventricular tachycardia, which they reproduced electro­ physiologically during catheterization. In a double-blind, randomized, placebocontrolled, crossover study, 13 healthy volunteers took TrimSpa, which contains more than 30 ingredients, including Ephedra 15 mg and caffeine 60 mg, or matching placebo tds for 7 days with a 7-day washout period between treatments (35C). There were no differences in QTc interval or systolic blood pressure between the two groups. However, in one subject taking TrimSpa the QTc interval increased by 96 milliseconds from baseline, more than double the largest increase in the placebo group.

Drugs that affect autonomic functions or the extrapyramidal system

In an earlier study Metabolife 356, which contains Ephedra and caffeine, prolonged the average QTc interval from 396 to 419 milli­ seconds and increased the mean systolic blood pressure from 119 to 124 mmHg in 15 young healthy volunteers compared with placebo, although the extent to which this was due to Ephedra or other components of Metabolife 356 is not clear (36C). Some individuals may be at particular risk of dysrhythmogenic effects of Ephedra alkaloids, but if so the susceptibility factors, particularly the role of caffeine, are not understood. Sensory systems Transient cortical blindness has been attributed to an Ephedrabased supplement (37A).
A 29-year-old man took the Ephedra-contain­

ing supplements, Stacker 3 and Ripped Fuel Extreme, and had a severe headache and a generalized tonic–clonic seizure. He became stuporose and combative, with a systolic blood pressure of 220 mmHg, a sinus tachycardia, and a temperature of 39.61C. Electrocardio­ graphy and cardiac enzymes confirmed an acute myocardial infarction and he had fulmi­ nant hepatic failure, acute renal failure, and rhabdomyolysis. He recovered, but 1 week later developed complete bilateral visual loss without nystagmus, consistent with cortical blindness. His blood pressure was again markedly raised. He stopped using Ephedra and recovered.

Chapter 13

263

compliance, her manic and depressive symp­ toms re-emerged. Sertraline was added to divalproex and she remained symptom-free for 5 months. She stopped taking her medica­ tions, and in 2 weeks developed severe depression. She was treated with citalopram, divalproex, risperidone, and temazepam and remained stable.

This case is unusual, because most cases of ephedrine-induced mania involve a pre-existing mood disorder, suggesting that ephedrine can exacerbate pre-existing mood disorders. Also, in her first described manic episode the symptoms persisted for several months after ephedrine withdrawal. The authors speculated that ephedrine may “unmask” mood disorders in susceptible individuals. Musculoskeletal Severe rhabdomyolysis has been attributed to a supposedly perfor­ mance-enhancing herbal supplement con­ taining Ephedra (39A).
A healthy 21-year-old Army soldier took two

tablets of a herbal supplement containing Ephedra every day for a month and com­ plained of “complete muscle failure” after collapsing at the end of a physical fitness test. He had tachycardia, hypotension, and myo­ globinuria. His serum creatine kinase activity rose from 426 to 241 418 U/l over 6 days and he developed acute renal failure secondary to acute tubular necrosis.

The authors suggested that Ephedra had caused a reversible posterior leukoencephalopathy.

Pseudoephedrine

Psychiatry Ephedrine-induced mania occurred over a 3-month period in a patient who took the “recommended” dose of a dietary supplement (38A).

Cardiovascular Myocardial infarction has been attributed to pseudoephedrine (40A).


A 40-year-old woman without a prior psy­

chiatric history took the Ephedra-containing weight loss pill Xenadrines, 4 pills/day, for 6 weeks and developed manic symptoms. Within days her family noted confusion, difficulty in falling asleep, and rapid tangential speech. She continued to take the supplement and became more erratic and severely disin­ hibited. She underwent in-patient psychiatric hospitalization and was stabilized over 20 days on risperidone, divalproex, and temazepam. Two months later, despite medication

(SED-15, 1221; SEDA-29, 149, SEDA-31, 171; SEDA-30, 171)


A 16-year-old boy with a sore throat took

cefazolin 2 g/day, paracetamol 1500 mg/day, and three doses of pseudoephedrine 60 mg, and 1 day later developed chest pain lasting 4 hours. An electrocardiogram showed ST segment elevation in the inferolateral leads and his troponin T concentration creatine kinase and creatine kinase-MB activities were raised. Echocardiography showed a low ejection fraction (40%) and hypokinetic anterior, apical, lateral, and inferior wall segments of the left ventricle. Coronary angiography showed normal coronary arteries.

Chapter 13

264 The authors suggested that he had had a myocardial infarction triggered by pseudoe­ phedrine and acute streptococcal infection. Nervous system A stroke has been attrib­ uted to pseudoephedrine (41A).
A 4-year-old girl with a nasopharyngeal

rhabdomyosarcoma had a stroke after taking pseudoephedrine for 3 days, without hemato­ logical abnormalities. She was given intrave­ nous diazepam and phenytoin. An MRI scan showed occlusion of the left middle cerebral artery and a narrowed internal carotid artery. There was significant recovery in 2 months.

Skin Acute generalized exanthematous pustulosis has been attributed to pseudo­ ephedrine (42A).
A 41-year-old man developed acute general­

ized exanthematous pustulosis due to pseu­ doephedrine, confirmed by a positive patch test. He had taken Rinoebastels (ebastine 10 mg, pseudoephedrine 120 mg) 24 hours before for a nasal discharge. There was total resolution within 7 days without specific treatment, followed by desquamation.

Pregnancy Alpha-adrenoceptor agonists slow uterine blood flow. However, among 902 first-trimester exposures to pseudoe­ phedrine there were only nine infants with malformations, suggesting no association with birth defects (43R).

DRUGS THAT PREDOMINANTLY STIMULATE ALPHA1­ ADRENOCEPTORS (SEDA-28, 161; SEDA-29, 150; SEDA-30, 172)

Midodrine

(SED-15, 2343)

Urinary tract Proteinuria has attributed to midodrine (44A).

been


An 82-year-old woman with a serum creati­

nine of 115 mmol/l, creatinine clearance 27 ml/

J.K. Aronson

minute, and 2.3 g of proteinuria was given midodrine for severe hypotension; within 3 months her proteinuria increased to 13 g/ 24 hours and her creatinine clearance fell to 17 ml/minute. After withdrawal of midodrine her proteinuria reduced to 11 g/24 hours at 1 month with a normal blood pressure and 3.7 g/24 hours when her pressure fell to 90/ 38 mmHg.

Midodrine is a prodrug, which is converted to the a1-adrenoceptor agonist desglymidodrine, which is a vasoconstrictor. The authors attributed the worsening proteinuria to renovascular constriction, causing increased intraglomerular pressure.

Phenylephrine

(SED-15, 2808; SEDA27, 147; SEDA-30, 172)

Cardiovascular A severe hypertensive crisis occurred after the topical application of ocular phenylephrine in a healthy 2-year­ old (45A).

Phenylpropanolamine

(SED-15, 2811; SEDA-29, 150; SEDA-30, 173; SEDA-30, 173)

Cardiovascular In November 2000 the FDA asked manufacturers to stop marketing products containing phenylpropanolamine and subsequently banned such products, whether as nasal decongestants or appetite suppressants. This was prompted by the publication by the Hemorrhagic Stroke Project of a 5-year case–control study of 702 patients who had had hemorrhagic strokes and 1376 control subjects aged 18–49 years (46C). The odds ratio for hemorrhagic stroke in those who had taken phenylpropanolamine was 1.49 (95% CI ¼ 0.84, 2.64). In subgroup analyses by type of formulation the OR was 1.23 (0.68, 2.24) for cough/cold remedies and 16 (1.38, 184) for appetite suppressants. In a reappraisal of these results it has been suggested that these results could

Drugs that affect autonomic functions or the extrapyramidal system

have occurred by chance, selection and recall bias, and confounding factors, such as hypertension, cigarette smoking, and heavy alcohol consumption (47R). Among the potential conflicts of interest declared by the authors of this review, one was a defense lawyer for Delaco in the litigation over phenylpropanolamine and the other a member of various data and safety mon­ itoring boards for several drugs companies, among others, and was an expert witness in the litigation over phenylpropanolamine. Subsequently, others criticized this conclu­ sion (48r), claiming that the article “was intended only for litigation advantage to phenylpropanolamine manufacturers in pending court cases,” and pointing to various suggested defects in the reappraisal and to other evidence, at that time pub­ lished in abstract form, but since published in full, showing that phenyl-propanolamine contained in cold remedies increases the risk of hemorrhagic stroke, particularly in women (49C). Both of the authors of this letter had acted on behalf of the plaintiffs in litigation, one as an expert witness, the other as a lawyer. Another letter raised the question of “mercenary epidemiology” (50r). These letters elicited a robust response (51r). It is currently wise to avoid phenylpro­ panolamine. Pregnancy and teratogenicity There was no evidence of teratogenic effects of oral decongestants (mostly that contained phe­ nylpropanolamine) in 2474 Swedish women who had reported the use of oral deconge­ stants during early pregnancy and 1771 women who used oral prescription decon­ gestants later in pregnancy (52C). Paradoxi­ cally, use of decongestants showed favorable neonatal outcomes such as a reduced risk of preterm birth, low birth weight, small-for-date infants, and perinatal deaths. The findings of this study differ from previous reports of congenital mal­ formations, notably gastroschisis and smallbowel atresia, associated with decongestant use (53cr, 54C).

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265

DRUGS THAT STIMULATE BETA1-ADRENOCEPTORS (SEDA-29, 150; SEDA-30, 173)

Dobutamine

(SED-15, 1169; SEDA-29, 150; SEDA-30, 173)

Cardiovascular Coronary artery spasm during stress echocardiography has been attributed to dobutamine (55Ar).
A

45-year-old woman with hypertension underwent dobutamine–atropine stress echocardiography during which she reported sud­ den severe precordial pain. An electrocardiogram showed inferolateral ST segment elevation and echocardiography inferior septal dyskinesia and inferior wall akinesia. The test was stopped immediately. Coronary angiography showed lesions in the left anterior descending, left circumflex, and right coronary arteries.

The authors thought that coronary spasm had been caused by alpha-adrenergic stimulation. This effect can cause false positive results during dobutamine echocardiography. In another case spasm occurred in the right coronary artery during an intravenous dobutamine stress test in a 66-year-old man a few days after a stent had been inserted in the proximal left anterior descending artery (56A). The spasm persisted despite with­ drawal of dobutamine and an intracoronary injection of a nitrate. A stent was implanted in the right coronary artery, with good effect. The mechanism of hypotension during dobutamine stress echocardiography has been studied using multiplane transesopha­ geal echocardiography in 142 adults after infusion of dobutamine 5–40 mg/kg/minute with atropine as needed (57c). Ventricular obstruction was provoked in the left ven­ tricular outflow tract in 13 patients, in the mid-cavity in 10, and at both sites in 4. Compared with the 115 patients in whom dobutamine-induced obstruction did not occur systolic blood pressure at rest was similar but fell more during the stress test. The authors concluded that hypotension is common when dobutamine causes ventri­ cular obstruction.

266 Left ventricular outflow tract obstruction during dobutamine stress echocardiography can also cause myocardial infarction, as happened in a 70-year-old asymptomatic woman who underwent routine pre-opera­ tive cardiac stress evaluation (58A). Coronary artery dissection resulting in myocardial damage has also been reported during dobutamine stress echocardiography in a middle-aged man (59A). The incidence of atrial fibrillation during dobutamine stress echocardiography has been studied prospectively in 3800 conse­ cutive patients in sinus rhythm (60c). There was a 2% incidence of atrial fibrillation, predictors of which included a history of atrial fibrillation, increased left atrial dia­ meter, right bundle branch block, reduced resting heart rate, and hypertension.

DRUGS THAT STIMULATE DOPAMINE RECEPTORS Levodopa

(SED-15, 2039; SEDA-28, 162; SEDA-29, 151; SEDA-30, 174)

Nervous system The prevalence of levodopa motor complications and associated factors has been studied in 154 Thai patients with Parkinson’s disease, average age 68 years (61c). The age of onset was 61 years. Treatment was with levodopa (98%), anticholinergic drugs (30%), dopamine receptor agonists (26%), and COMT inhibitors (9.1%). There were motor complications in 25%: wearing off (79%), on– off fluctuation (45%), freezing (42%), morning dyskinesia (11%), and permanent dyskinesia (24%); 12 developed severe levodopa-induced chorea. Factors that were associated with adverse effects were earlier age of onset, long duration of disease, advanced stage, higher levodopa dosage, and long duration of levodopa therapy. Ropinirole is associated with reduced incidence of dyskinesias. A post hoc analy­ sis of a 5-year study of the use of ropinirole and levodopa in early Parkinson’s disease has shown that those who took levodopa

Chapter 13

J.K. Aronson

had a significantly higher risk of dyskinesias than those who took ropinirole (HR ¼ 6.67; 95% CI ¼ 3.23, 14) (62c). The onset of dyskinesias in those taking ropinirole was delayed by around 3 years compared with those taking levodopa. The authors con­ cluded that the risk of dyskinesias during ropinirole monotherapy is very low but that once levodopa is added the risk changes substantially. In one case, tremor of the arms asso­ ciated with spasmodic dysphonia was exa­ cerbated by co-careldopa (Sinemet CR) and improved when the drug was with­ drawn (63A). Psychological Plasma homocysteine con­ centrations are increased in patients with Alzheimer’s disease (64C) and levodopa causes hyperhomocysteinemia (65C). In 39 patients with Parkinson’s disease plasma homocysteine concentrations were signifi­ cantly higher than in 28 healthy controls (66c). There was a negative correlation between hyperhomocysteinemia and vita­ min B12 and folate concentrations and a positive correlation between hyperhomo­ cysteinemia and the dose of levodopa. There were no effects on cognitive or frontal functions, but those who had a homocysteine concentration over 14 mmol/l had a significantly poorer performance in frontal and memory tests. In 72 consecutive patients with Parkinson’s disease, 62 of whom were taking levodopa the mean plasma homocysteine concentration was 16 mmol/l, and 28 patients had a concen­ tration over 15 mmol/l, the top of the reference range (67c). Homocysteine concentrations were associated with the duration of disease and levodopa treatment, but not with disease severity or dose of levodopa. They were not associated with the thickness of the common carotid intima–media nor with cardiovascular morbidity. There was no association with the neuropsychiatric features of Parkinson’s dis­ ease, such as depression, cognitive perfor­ mance, or psychosis. Levodopa did not adversely affect cogni­ tive function in 22 patients with Parkinson’s disease, 27 with Parkinson’s disease with dementia, and 11 with Parkinson’s disease with Lewy bodies over 3 months (68c).

Drugs that affect autonomic functions or the extrapyramidal system

The relation between Parkinson’s disease, levodopa therapy, and malignant melanoma A tenuous link between levodopa and the development of melanoma has been suggested for many years (69A) and there have been sporadic reports of patients with parkinsonism taking levodopa who developed malignant melanoma (70A–75A, 76Ar, 77A, 78Ar, 79A, 80Ar, 81Ar, 82A, 83A). The hypothesis that levodopa might increase the risk of melanoma was biologically plausible, because of the common metabolic pathways for synthesis of dopamine and melanin. However, in vitro studies have suggested that high concentrations of levodopa might be cytotoxic to melanoma cells (84E). Levodopa/carbidopa had no beneficial effects in 17 patients with metastatic melanoma and there were unacceptable adverse effects in seven (85c). This association has always been dubious. In 1978, in a prospective study of 1099 patients at the time of presentation of their primary melanoma only 1 had been taking levodopa, and it was concluded that levodopa must be playing an inconsequential role in the rapid rise in incidence observed for this tumor over the previous decade (86c). In an analysis of the clinical characteristics of 54 patients with both Parkinson’s disease and melanoma the results suggested that the co-occurrence was coincidental rather than causal (87R). A similar conclusion was reached in an earlier review of 34 published cases (88R). In the DATATOP study there were five cases of malignant melanoma 3.3 (1.1–7.8) times that expected in a standard healthy population; however, there was no association between levodopa therapy and the risk of melanoma (89C). A study of 14 088 patients with Parkinson’s disease showed a twofold higher incidence of malignant melanoma than in the general population and in a nested case– control study of 45 patients with malignant melanoma, 97 patients with non-melanoma skin cancer, and 172 controls, there was a

Chapter 13

267

significant four- to fivefold increase in the risk of malignant melanoma in patients with a probable diagnosis of idiopathic Parkinson’s disease compared with other patients (90C). However, there was no effect of levodopa (OR ¼ 1.0; 95% CI ¼ 0.8, 1.3) per 1000 g cumulative dosage. The authors concluded that the increased rate of malignant melanoma in patients with Parkinson’s disease is restricted to those with idiopathic Parkinson’s disease and is unrelated to levodopa. In a systematic literature search of all published reports using computerized bibliographic databases the authors concluded that (1) there is no epidemiological or experimental evidence of a causal role of levodopa in increasing the risk of melanoma incidence or progression; (2) there is good evidence of an excess risk of melanoma in patients with Parkinson’s disease; (3) there is good evidence of a protective effect of tobacco smoking on the risk of Parkinson’s disease; (4) there is good evidence of a positive correlation between social class and the risk of melanoma; (5) the relation between the risk of Parkinson’s disease and the risk of melanoma may be due to a common genetic profile or confounding by social class, possibly through an inverse relationship with tobacco smoking (91R). Thus, there is an increased risk of melanoma in patients with Parkinson’s disease, the reason being unknown; levodopa therapy is not responsible (92R).

Susceptibility factors Of 220 patients with Parkinson’s disease, weight loss and daily levodopa dose per kilogram body weight were the only significant factors for dyski­ nesia in addition to disease duration in 29 who developed new dyskinesias (93c). They used higher maximum daily doses of levodopa per kilogram body weight (8.4 mg/kg versus 6.0 mg/kg), and lost weight during the course of the disease from 72 to 66 kg. Genetic In 251 patients with Parkinson’s disease the frequency of the homozygote

268 ACE-II genotype of the angiotensin-con­ verting enzyme (ACE) was significantly higher in those with levodopa-induced psychosis (63% versus 43%; OR ¼ 1.44; 95% CI ¼ 1.11, 1.86); logistic regression confirmed that the ACE-II genotype was an independent risk factor for levodopa­ induced psychosis (94c). The ACE-II poly­ morphism was not associated with the risk of dyskinesias or motor fluctuations due to levodopa.

Dopamine receptor agonists (SEDA-28, 162; SEDA-29, 151; SEDA-30, 174) Cardiovascular Ergot-derived dopamine receptor agonists have been associated with fibrotic reactions that affect serosal membranes (SEDA-30, 176) and cardiac valves. EIDOS classification: Extrinsic moiety: Pergolide and cabergoline Intrinsic moiety: ?5HT2B receptors Distribution: Serosae, cardiac valves Outcome: Hyperplasia (fibrosis) Sequela: Fibrotic reactions due to some ergot-derived dopamine receptor agonists DoTS classification: Dose-relation: Collateral Time-course: Late Susceptibility factors: Unknown Pergolide has also been associated with cardiac valvulopathy in patients with Par­ kinson’s disease (95R). Evidence for valvu­ lopathy was found in a review of 22 reports (but no randomized controlled trials) and 246 patients (96R). The susceptibility fac­ tors could not be determined. The valvulo­ pathy associated with pergolide is fibrotic and resembles that described in carcinoid syndrome and in patients taking fenflura­ mine (97R). The mechanism has been suggested to involve agonism at 5HT2B

Chapter 13

J.K. Aronson

receptors (98R). This is consistent with the association with cabergoline, a 5HT2B receptor agonist (99R), although that asso­ ciation has not been uniformly confirmed (100C). It is also consistent with the association with pergolide, a 5HT2B recep­ tor agonist, and with the absence of associations with lisuride, a 5HT2B receptor antagonist (98R) and the non-ergot dopa­ mine receptor agonists pramipexole and ropinirole (99R). Nervous system In a crossover, doubleblind study in 16 healthy men, pramipexole reduced alertness and pupillary light reflex response amplitude, tended to reduce core temperature, reduced prolactin concentrations, and increased growth hormone concentrations (101C). Amisulpride, a dopa­ mine receptor antagonist had the opposite effects, and the authors proposed that the effects of pramipexole were mediated by stimulation of inhibitory D2/D3 autorecep­ tors, for example, on the Edinger–Westphal nucleus (pupillary dilatation) and the locus ceruleus (reduced alertness). Cerebrospinal fluid leakage has been reported occasionally in patients with macroprolactinomas treated with short-act­ ing dopamine receptor agonists. CSF leak­ age occurred in three patients with macroprolactinomas within 10 days after they started to take the long-acting dopa­ mine receptor agonist cabergoline (102A). Cabergoline was not withdrawn. In one patient the leakage stopped spontaneously. The second patient had a surgical repair. The third patient refused surgical repair of the sellar defect and the dosage of cabergo­ line was reduced without effect. Psychiatric Postpartum mania has been attributed to bromocriptine 5 mg/day in a 33-year-old woman after her first pregnancy (103A). However, as the authors pointed out, the postpartum period is a high-risk period for occurrence of mood disorders and the association in this case was doubtful. There have previously been reports of psychoses in non-pregnant patients taking dopamine receptor agonists, and a new report has implicated ropinirole (104A).

Drugs that affect autonomic functions or the extrapyramidal system
A 44-year-old woman with a family history of

schizophrenia and a 1-year history of depres­ sion developed acute psychotic symptoms, including paranoid delusions, disorganized thoughts, and auditory and visual hallucina­ tions; her affect was blunted. She had been taking ropinirole for 1 week before admission for restless legs syndrome. The ropinirole was withdrawn and she was given quetiapine and citalopram. Within 3 days, her paranoia had improved, her thought process had become more organized and logical, and her affect had improved.

The association here was not convincing. Pramipexole, an agonist at D3 receptors, may have antidepressant actions (105C). Psychological Pathological gambling has been associated with dopamine receptor agonists (SEDA-30, 174) and cases con­ tinue to be reported (106A). EIDOS classification: Extrinsic moiety: Dopamine receptor agonists Intrinsic moiety: Dopamine (?D1/D3) receptors Distribution: Brain Outcome: Altered cell function (nature unknown) Sequela: Pathological gambling due to dopamine receptor agonists (particularly pramipexole) DoTS classification: Dose-relation: Collateral Time-course: Intermediate Susceptibility factors: Genetic (dopamine D1 receptor gene allele DRD1-800 T/C); age (younger age of onset of Parkinson’s disease); sex (male); combined therapy with levodopa In a woman taking levodopa and prami­ pexole the effect was rapidly reversible after withdrawal of pramipexole without other interventions (107A). Dopamine receptor agonists can cause changes in sexual behavior.
A 51-year-old man with Parkinson’s disease

took pergolide for a few years and developed a paraphilic disorder, with frotteurism and delusional jealousy (108A). He had mild motor

Chapter 13

269

impairment and little or no cognitive dete­ rioration. The dosage of pergolide was reduced and quetiapine was introduced. His paraphilia and delusional jealousy subse­ quently improved.
Visual and auditory hallucinations and delu­ sional jealousy occurred in a 37-year-old woman within 3–4 weeks of an increase in dosage of pramipexole to 2.8 mg/day (109A). Pramipexole was withdrawn, and in a few weeks the symptoms started to resolve and finally disappeared in 2 months.

Hair Alopecia has been attributed to telo­ gen effluvium occurring over 2 months in a 55-year-old woman taking pramipexole 1 mg tds; hair growth resumed within 4 months after withdrawal (110A). There have also been reports of telogen effluvium in patients taking bromocriptine (111A, 112A), cabergo­ line (113Ar), pergolide (112A), ropinirole (114A), and levodopa (115A). The authors suggested that the effect might be mediated through loss of prolactin.

OTHER DRUGS THAT INCREASE DOPAMINE ACTIVITY Amantadine Nervous system Neurological effects of supposed amantadine toxicity have been reported (116A).
A 70-year-old woman with Parkinson’s disease

took amantadine hydrochloride 150 mg/day and levodopa 200 mg/day and developed poor communication, restlessness, disturbed con­ centration, impaired memory, visual hallucina­ tions, gait disturbance, and general myoclonic jerks in her limbs and trunk; she had marked grasp reflexes. After withdrawal of oral amantadine, all of her symptoms and signs gradually improved; about 3 weeks later she was able to walk without aid.
A 74-year-old woman had a right cerebellar hemorrhage and subsequently developed apathy, depression, and gait disturbance. She was given amantadine hydrochloride 200 mg/ day and droxidopa 200 mg/day. Some time later she began to have visual disturbances

Chapter 13

270 followed about a month later by fever, vomit­ ing, and myoclonic jerks in her limbs, and she became unable to stand independently. She could not speak voluntarily and was bound to her wheelchair. She had myoclonic jerks in the limbs and marked grasp reflexes in both hands. Amantadine was withdrawn and her symptoms and signs gradually improved; after about 3 weeks, she was able to walk without aid.
A 73-year-old woman with Parkinson’s dis­ ease and diabetic nephropathy started to take amantadine 300 mg/day and gradually devel­ oped somnolence and gait disturbance and became bedridden about 1 week later. Amantadine was withdrawn. Generalized myoclonic jerks appeared and she developed an acute high-grade fever, coma, and status epilepticus. She was given dantrolene sodium without major benefit. She developed severe dementia and moderate parkinsonism. She had bilateral grasp reflexes, a mild left hemiparesis due to lacunar infarction in the right corona radiata, multiple cerebral infarc­ tions in the right frontoparietal and occipital lobes, and multiple confluent white matter changes. Oral levodopa 450 mg/day and pra­ mipexole 0.25 mg/day improved her parkin­ sonism, but her daily living skills did not improve.

Renal impairment may have contributed to amantadine toxicity in at least two of these cases. Skin Two patients taking amantadine developed livedo reticularis; however, one had tolerated it for 4 years before without adverse reactions; in the other the livedo developed 1 month after the start of therapy (117A).

Selegiline Psychiatric Hypersexuality and paraphilia have been attributed to selegiline in two cases (118A).
A 29-year-old man with young-onset Parkin­

son’s disease was given selegiline and within 2 months began engaging in cross-dressing behavior that he could not control. Selegiline was withdrawn and replaced by ropinirole but his cross-dressing persisted. He was switched to pramipexole and a few months later noted obsessive–compulsive behavior, an excessive interest in pornography, obsessions, and unwonted gambling.




J.K. Aronson

A 51-year-old man presented with Parkinson’s disease was given selegiline 5 mg bd and 1 year later pramipexole 1.5 mg tds. Shortly after starting to take selegiline, but before starting to take pramipexole, he developed an unhealthy obsession with internet pornogra­ phy, and an increased sex drive. He reported other compulsive behaviors after starting to take pramipexole. After a later switch to ropinirole his obsessions abated somewhat.

Rasagiline The pharmacology, clinical pharmacology, clinical efficacy, and adverse effects of rasagiline have been reviewed (119R–124R). Rasagiline is a propargylamine that irreversibly and selectively inhibits monoamine oxidase type B and is 5–10 times more potent than selegiline. Rasagiline is rapidly absorbed from the gastrointestinal tract and readily enters the brain. Unlike selegiline, which is metabolized to amphetamines, rasagiline is metabolized to the non-amphetamine compound aminoindan. Its clearance is sufficiently slow to allow once-daily dosing. Elderly patients are more likely to have adverse effects (125M). Placebo-controlled studies Rasagiline is associated with improved outcomes in patients with early Parkinson’s disease and reduces “off” time in patients with moderate to advanced disease with motor fluctuations. In a multicenter, double-blind, randomized, placebo-controlled, parallel-group study for 12 weeks in 70 patients with Parkinson’s disease, rasagiline 0.5, 1, and 2 mg/day as adjunctive therapy to levodopa produced a beneficial clinical effect in patients with motor fluctuations; the beneficial effect was still evident 6 weeks after drug withdrawal (126C). In a multicenter, 26-week, parallel-group, randomized, double-blind, placebo-controlled clinical trial in 404 patients with early Parkinson’s disease who did not require dopaminergic therapy rasagiline mesylate 1 or 2 mg/day was compared with placebo (127C). Rasagiline was effective and there

Drugs that affect autonomic functions or the extrapyramidal system

were no differences in the frequencies of adverse events or premature withdrawals. In a double-blind, parallel-group, randomized, clinical trial in 371 subjects with early Parkinson’s disease, who did not require dopaminergic therapy, rasagiline 1 or 2 mg/ day for 1 year was compared with placebo for 6 months followed by rasagiline 2 mg/ day for 6 months (128C). Those who took rasagiline 2 mg/day for 1 year had a 2.29unit smaller increase in mean adjusted total Unified Parkinson’s Disease Rating Scale score than subjects who took placebo for 6 months followed by rasagiline for 6 months. The authors concluded that treatment with rasagiline for 12 months was preferable to delaying treatment for 6 months. In a multicenter, randomized, placebocontrolled, double-blind, parallel-group study in 472 patients with Parkinson disease with at least 2.5 hours of daily “off” time (poor motor function), despite optimized

Chapter 13

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treatment with other medications, rasagiline 0.5 or 1.0 mg/day was compared with placebo (129C). The mean adjusted total daily off-time fell by 1.85 hours with rasagiline 1.0 mg/day, by 1.41 hours with 0.5 mg/ day, and 0.91 hours with placebo. In an 18-week, double-blind, multicenter study in 687 out-patients randomly assigned to oral rasagiline 1 mg/day (n ¼ 231), entacapone 200 mg with every dose of levodopa (n ¼ 227), or placebo (n ¼ 229), 88 did not complete the study (23 rasagiline, 30 entacapone, 35 placebo), mainly because of withdrawal of consent (n ¼ 34) and adverse events (n ¼ 34) (130C). Both rasagiline and entacapone reduced mean daily off-time (by 1.18 hours rasagiline and 1.2 hours entacapone, placebo 0.4 hours) and increased daily on-time without troublesome dyskinesias (0.85 hours for both, placebo 0.03 hours). The frequency of adverse events was similar with all treatments (Table 1). The frequency

Table 1. Frequency of adverse events in a double-blind study of rasagiline in 687 out-patients (130C) Adverse effects

Number of patients (%) Rasagiline (n ¼ 231)

Entacapone (n ¼ 227)

Placebo (n ¼ 229)

All

51 (22%)

62 (27%)

53 (23%)

Cardiovascular system Postural hypotension Syncope

5 (2%) 2 (1%)

4 (2%) 0

0 2 (1%)

Digestive system Constipation Diarrhea Dry mouth Nausea Vomiting

3 3 4 8 3

4 (2%) 10 (4%) 1 13 (6%) 2 (1%)

0 8 (3%) 2 (1%) 10 (4%) 2 (1%)

Metabolic and nutritional disorders Peripheral edema 5 (2%)

4 (2%)

3 (1%)

Nervous system Abnormal dreams Anxiety Confusion Depression Dizziness Dyskinesia Hallucinations Hyperkinesia Sleep disorder Somnolence

2 (1%) 2 (1%) 2 (1%) 6 (3%) 6 (3%) 14 (6%) 8 (4%) 1 9 (4%) 3 (1%)

1 8 2 7 4 9 3 0 5 2

(1%) (1%) (2%) (3%) (1%)

2 (1%) 5 (2%) 1 8 (3%) 6 (3%) 12 (5%) 5 (2%) 1 7 (3%) 3 (1%)

(3%) (1%) (3%) (2%) (4%) (1%) (2%) (1%)

Chapter 13

272 of dopaminergic adverse events with rasagiline was similar to those with placebo and entacapone. The most common cardiovascular-related dopaminergic adverse event in the study, postural hypotension, occurred in nine patients in the rasagiline and entacapone groups. There were serious adverse events in 41 patients (12 rasagiline, 12 entacapone, and 17 placebo). Drug–drug interactions Rasagiline is a substrate for CP1A2 and its elimination is reduced by inhibitors of CYP1A2 (e.g., cimetidine, ciprofloxacin, fluvoxamine). Conversely, inducers of CYP1A2 (e.g., omeprazole) can reduce the effect of rasagiline. However, rasagiline does not inhibit CYP1A2 or a wide range of other CYPs, including 2A6, 2C9, 2C19, 2D6, 2E1, 3A4, and 4A. Tyramine-rich foods At the recommended therapeutic dosage of up to 1 mg/day, tyramine restriction is unnecessary (131C). Serotonin reuptake inhibitors A subanalysis of the PRESTO trial showed no significant differences in the prevalences of adverse events between patients taking rasagiline who were also taking SSRIs (n ¼ 77) and those who were not (n ¼ 395) (132c). An analysis of data from all patients who were given rasagiline in controlled clinical trials (n ¼ 1361) who also took any type of antidepressant (n ¼ 316), most commonly amitriptyline (n ¼ 112), sertraline (n ¼ 75), paroxetine (n ¼ 70), trazodone (n ¼ 60), and citalopram (n ¼ 34), suggested that sleep disorder (RR ¼ 10.1 versus 6.3), dyspnea (2.9 versus 1.6), and confusion (2.9 versus 1.5) occurred significantly more often in patients who took rasagiline plus an antidepressant than in patients who took rasagiline alone (133M). However, these are in any case adverse effects of antidepressants and there were no cases of serotonin syndrome. On the other hand, in a previous survey there were 11 cases of serotonin syndrome (0.24%) among 4568 patients taking both selegiline and an SSRI (134C).

J.K. Aronson

ERGOT DERIVATIVES (SED-15, 1230; SEDA-28, 151; SEDA-30, 176)

Methysergide

(SED-15, 2316; SEDA-

30, 176) Cardiovascular Two cases of mitral valve fibrosis have been described in patients taking methysergide (135A).

DRUGS THAT AFFECT THE CHOLINERGIC SYSTEM (SEDA-28, 165; SEDA-29, 153; SEDA-30, 177)

Acetylcholinesterase inhibitors The history of the toxicology of physostig­ mine has been reviewed (136R). In the middle of the 19th century missionaries to Old Calabar, an eastern province of Nigeria, learnt of the native belief in the power of the seeds of a local plant to determine whether individuals were innocent or guilty of a serious misdemeanor. The seeds, known locally as “chop nut,” were soon referred to as the ordeal beans of Old Calabar, and they were estimated to cause about 120 deaths each year. Samples of the beans found their way to Scotland, and the Edinburgh toxicologist Robert Christison investigated their effects in 1855, eating part of one himself and documenting the consequences. Six years later Balfour described the bean plant botanically and named it Physostigma venenosum. In 1863 an Edinburgh ophthal­ mologist, Argyll Robertson, showed that an extract of Calabar beans constricted the pupil of the eye. The features of physos­ tigmine toxicity were soon documented, but it took many more years before the mechanism was discovered.

Drugs that affect autonomic functions or the extrapyramidal system

Anticholinergic drugs

(SED-15, 264; SEDA-29, 153; SEDA-30, 177)

In 532 patients mean age 74 years, of whom 27% used at least one anticholinergic drug, only two symptoms were statistically more prevalent in those who used anticholinergic drugs: dry mouth (58% versus 46%) and constipation (42% versus 29%) (137c). In a systematic review of 61 trials, 42 with parallel-group designs and 19 crossover trials in 11 956 adults, in which nine drugs were studied (darifenacin, emepronium bromide or carrageenate, oxybutynin, pro­ piverine, propantheline, tolterodine, tros­ pium chloride, and solifenacin) the rate of dry mouth was increased threefold in the medication group (RR ¼ 3.00; 95% CI ¼ 2.70, 3.34), but there was no statisti­ cally significant difference in the rate of withdrawals (RR ¼ 1.11; 95% CI ¼ 0.91, 1.36) (138M). An anticholinergic drug scale has been developed to rank anticholinergic proper­ ties (139R), as follows:
level 0 ¼ no known anticholinergic prop­ erties;
level 1 ¼ potentially anticholinergic as evidenced by receptor binding studies;

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level 2 ¼ anticholinergic adverse events sometimes noted, usually at excessive doses;
level 3 ¼ markedly anticholinergic. All conventional anticholinergic drugs are classed as being at level 3, and the usefulness of this scale therefore lies in comparing the anticholinergic effects of drugs that are not called anticholinergic drugs; the complete list of those in levels 2 and 3 is given in Table 2. It would be helpful if level 3 drugs could be further subdivided according to their affinities for muscarinic receptors.

Anticholinergic adverse effects of newer anticholinergic drugs Various new anticholinergic drugs have been developed in the hope of treating the symptoms of an overactive bladder and other bladder conditions. The hallmark of some of these newer compounds, such as darifenacin, solifenacin, and tolterodine, is that they are supposed to have greater specificity for muscarinic (M3) receptors

Table 2. Level 2 and level 3 drugs in the Anticholinergic Drug Scale (139R) Level 2 Carbamazepine Cimetidine Cyclobenzaprine Cyproheptadine

Disopyramide Loxapine Methotrimeprazine Molindone

Oxcarbazepine Pethidine (meperidine) Pimozide Ranitidine

Level 3 Amitriptyline Atropine Benzatropine Brompheniramine Carbinoxamine Chlorphenamine Chlorpromazine Clemastine Clomipramine Clozapine Darifenacin Desipramine

Dicyclomine Dimenhydrinate Diphenhydramine Doxepin Flavoxate Hydroxyzine Hyoscine Hyoscyamine Imipramine Meclizine Nortriptyline Orphenadrine

Oxybutynin Procyclidine Promethazine Propantheline Protriptyline Pyrilamine Thioridazine Tolterodine Trihexyphenidyl Trimipramine

Chapter 13

274 than more traditional antagonists. They might therefore be expected to reduce the risks of the traditional adverse effects of these drugs, such as dry mouth, constipation, and blurred vision. Contraction of the detrusor muscle is mediated mainly by M3 receptors, even though M2 receptors are more highly represented in the bladder. M3 receptors are also found in salivary glands and are important in salivary secretion. However, the relative affinities of the different drugs for M3 receptors in the bladder and salivary glands may be different. For example, oxybutynin has a higher affinity for mouse salivary M3 receptors than solifenacin (140E). The affinities of some antimuscarinic drugs for human muscarinic receptor subtypes are shown in Table 3 (141R). Observational studies Darifenacin In a 2-year, non-comparative, open extension study of modified-release darifenacin 7.5 or 15 mg/ day in 716 patients with overactive bladder the most commonly reported adverse events were dry mouth and constipation (23 and 21%, respectively), leading to withdrawal in 1.3 and 2.4% of patients (142c). Propiverine In a retrospective study in 74 children and adolescents with neurogenic detrusor overactivity, propiverine caused typical anticholinergic adverse effects (dizziness and visual disturbance) in only one (143c). Solifenacin The effects of solifenacin 5 and 10 mg/day have been studied in a subgroup analysis of four 12-week phase III studies in 3298 patients with an overactive bladder (144c). The most common adverse effects were dry mouth, constipation, and

J.K. Aronson

blurred vision. Dry mouth was reported by 4, 11, and 28% of patients who took placebo and solifenacin 5 and 10 mg/day, respectively. Constipation occurred in 3, 5, and 13% of patients. Blurred vision was reported by 2, 4, and 5%. Most of the adverse effects were mild; the number of patients who discontinued treatment because of adverse effects was low (4.4, 2.8, and 6.8%). In a multicenter, prospective, flexible-dose trial in 2225 adults with overactive bladder, solifenacin succinate 5 or 10 mg for 12 weeks there were treatment-related adverse events in 1321 patients (59%); most were anticholinergic and of mild to moderate intensity: dry mouth, 477 (21%); constipation, 295 (13%); headache, 76 (3.4%); blurred vision, 57 (2.6%); nausea, 39 (1.8%); dyspepsia, 34 (1.5%); and dry eyes, 29 (1.3%); 216 patients (9.7%) discontinued treatment because of adverse effects (145c). Comparative studies Oxybutynin and tolterodine Oxybutynin 5 mg and tolterodine 2 mg orally 1 hour before surgery reduced the incidence and severity of postoperative bladder discomfort in a placebo-controlled study in 234 adults who underwent intraoperative catheterization (146C). The muscarinic antagonists were associated with a significantly increased incidence of dry mouth; although tolterodine has supposedly greater specificity for muscarinic receptors in the bladder than in the salivary glands, there was no difference between the two drugs. There was also a non-significantly increased incidence of facial flushing in those who were given the muscarinic antagonists. In contrast, in 60 children with detrusor instability there were fewer adverse events with

Table 3. Affinities of some antimuscarinic drugs for human muscarinic receptor subtypes (141R) Compound

M1

M2

M3

M4

M5

Trospium Oxybutynin Tolterodine Darifenacin Solifenacin

0.75 1.0 3.0 7.3 25

0.65 6.7 3.8 46.0 125

0.50 0.67 3.4 0.79 10

1.0 2.0 5.0 46.0 NR

2.3 11.0 3.4 9.6 NR

Drugs that affect autonomic functions or the extrapyramidal system

tolterodine (13 events in 13 patients) than oxybutynin (27 events in 20 patients) (147 c). In a comparison of modified-release oxybutynin chloride 10 mg/day and modifiedrelease tolterodine tartrate 4 mg/day in 790 women with overactive bladder, dry mouth occurred significantly more often with oxybutynin (30% versus 22% overall) (148c). Oxybutynin and propiverine In 131 patients with neurogenic detrusor overactivity propiverine 15 mg tds and oxybutynin 5 mg tds for 21 days both improved maximum cystometric capacity and maximum detrusor pressure during the filling phase compared with placebo (149C). Fewer anticholinergic adverse events were attributed to propiverine (63% versus 78%), particularly dryness of the mouth, the most frequent adverse event (47% versus 67%). Placebo-controlled studies Darifenacin The effects of modified-release darifenacin, an M3 selective receptor antagonist, have been studied in 439 adults with an overactive bladder in a multicenter, double-blind, placebo-controlled study (150C). They were randomized to daily doses of 7.5 mg (n ¼ 108), 15 mg (n ¼ 107), or 30 mg (n ¼ 115), or to placebo (n ¼ 109), for 12 weeks. Darifenacin significantly reduced the median number of incontinence episodes per week (–69, –77, and –77% from baseline at the three doses versus –46% with placebo) and improved micturition frequency, frequency and severity of urgency, nocturia, and bladder capacity. Adverse events were mostly mild to moderate dry mouth and constipation. In a multicenter, double-blind, randomized, placebo-controlled study of modified-release darifenacin 15 mg/day for 12 weeks in 445 patients with overactive bladder darifenacin increased warning time, but not significantly compared with placebo. There were significant improvements in the weekly numbers of episodes of urge incontinence, the volume voided, and quality of life. The most common adverse effects were dry mouth and constipation, both infrequently leading to withdrawal (151C).

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Solifenacin In an analysis of 1873 subjects with overactive bladder treated with placebo or solifenacin 5 or 10 mg/day, the main adverse effects were dose-related mild and moderate dry mouth (4.5, 11, and 29%, respectively), constipation (3.6, 6.4, and 14%), and blurred vision (1.8, 4.0, and 4.6%); there were no differences in withdrawal rates between placebo and solifenacin (4.4, 2.8, 6.8%) (152M). In four 12-week, double-blind, phase III, international, multicenter, randomized, parallel-group studies of placebo or solifenacin 5 and 10 mg/day in 1045 elderly subjects with overactive bladder, the main adverse effects were dose-related dry mouth (4.5, 14, and 30%, respectively), constipation (4.3, 8.9, and 17%), and urinary tract infections (3.1, 3.6, and 7.0%) (153M). Most of the adverse events were mild to moderate and did not result in treatment withdrawal. Tolterodine In a placebo-controlled study in 222 men with bladder outlet obstruction and detrusor overactivity tolterodine 2 mg bd caused dry mouth in 24% compared with 1.4% of those who took placebo; there was only one report of severe dry mouth with tolterodine (154C). In a post hoc analysis of data collected from men with overactive bladders in a 12week, double-blind, placebo-controlled trial of modified-release tolterodine 4 mg/day, the most commonly reported adverse events associated with tolterodine versus placebo were dry mouth (16% versus 7%), constipation (4% versus 9%), dyspepsia (4% versus 1%), dizziness (5% versus 1%), and somnolence (3% versus 1%) (155c). In a 12-week, double-blind study of 850 patients randomized to modified-release tolterodine 4 mg/day or placebo, the most common adverse effect was dry mouth (9% versus 2%) (156c). Trospium In a multicenter, parallel, double-blind, placebo-controlled study trospium chloride 20 mg bd for 12 weeks was beneficial in 658 patients with overactive bladder (157C). Dry mouth (trospium 20%, placebo 5.2%) and constipation (trospium 11%, placebo

276 5.8%) were the most frequently reported adverse events; the most common events that led to drug withdrawal were constipation (trospium 1.8%, placebo 0.6%) and dry mouth (trospium 1.5%, placebo 0.0%). Systematic reviews Solifenacin In a study of the pooled data from randomized, placebo-controlled phase III studies of solifenacin 5 or 10 mg/day in 2848 patients with severe symptoms of overactive bladder, more patients who took solifenacin had restoration of continence, resolution of urgency, and normalization of micturition frequency (158M). Conclusions There is evidence that the newer anticholinergic drugs cause fewer anticholinergic adverse effects than the traditional drugs. However, adverse effects of this type still occur and are still relatively common.

Cardiovascular A woman with congenital long QT syndrome had three syncopal episodes shortly after taking a low dose of orphenadrine (159A). The QTc interval was 537 milliseconds. Orphenadrine was with­ drawn, and during the first 12 hours of monitoring there were three short-lived asymptomatic episodes of torsade de pointes. There were no other sustained ventricular dysrhythmias in the Holter monitoring in the ensuing days. Sensory systems In an unusual case spontaneous extrusion of the lens and vitreous has been attributed to atropine in a 2­ month-old boy who underwent penetrating keratoplasty under general anesthesia (160A). Intravenous atropine 0.1 mg was given for bradycardia and caused an increase in heart rate of up to 180–220 per minute for 35 minutes. The eyeball pulsated as a result, leading to extrusion. Similarly unusual is a report of cataract formation after administration of pilocar­ pine (161A).
A 46-year-old man received hyperopic implan­

table collamer lenses bilaterally for correction

Chapter 13

J.K. Aronson

of spherical equivalents of +7 diopters. The left lens developed no complications over 2 years. However, the right natural lens devel­ oped opacification in the anterior pole on the day after intraoperative instillation day of pilocarpine 2% to accelerate recovery from unwanted pupil dilatation. One year after implantation, the right eye had to undergo phacoemulsification and lens implantation, which were uneventful.

The authors concluded that the cataract had developed when pilocarpine caused posterior chamber flattening by shrinking the space between the natural lens and the implant, thus damaging the cells in the natural lens. Transdermal hyoscine (scopolamine), used to reduce drooling in children with disabilities, can cause dilated pupils and a reduction in the near point of accommodation, as has been described in two boys with epilepsy, one with spinal dysraphism and one with cerebral palsy; these effects resolved on removal of the patch (162A). Psychological In 372 people aged over 60 years without dementia the use of antic­ holinergic drugs was associated with impairment of cognitive functions, including poorer performance on reaction time, attention, delayed non-verbal memory, narrative recall, visuospatial construction, and language tasks, but not on tasks of reasoning, immediate and delayed recall of word lists, and implicit memory (163c). There was no difference in the risk of subsequent dementia. Hyoscine also impaired recognition of the facial expressions of disgust and anger in 48 healthy volunteers in a double-blind com­ parison with lorazepam (164C). The effects of modified-release darifena­ cin 7.5–15 mg/day and oxybutynin 10– 20 mg/day on memory have been compared in 150 healthy subjects aged 60 years and over in a multicenter, double-blind, doubledummy, parallel-group, placebo-controlled study for 3 weeks (165C). Darifenacin had no effect on delayed recall but oxybutynin caused memory impairment. Psychiatric Short-lived psychoses been reported in two patients

have after

Drugs that affect autonomic functions or the extrapyramidal system

exposure to oxybutynin, a 7-year-old boy and a 21-year-old man (166A). Skin In addition to the expected systemic anticholinergic adverse effects, a transder­ mal therapeutic system for hyoscine, designed to deliver 0.5 mg over 3 days, caused allergic contact dermatitis in 10% of patients (167c). Musculoskeletal In 364 frail elderly sub­ jects prospectively studied, anticholinergic drugs reduced hand grip strength and impaired functional activities related to daily living scale (168c). Susceptibility factors Liver disease Moderate hepatic impairment increased the AUC and half-life of solifenacin by 60%, without a change in Cmax (169c). Drug dosage regimens Oxybutynin The incidence of dry mouth in 237 patients with urinary incontinence who took a once-daily,

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modified-release formulation of oxybutynin was similar in those who took 10 or 15 mg/day and higher than in those who took 5 mg/day (170c). Drug–drug interactions In an open cross­ over study in 17 healthy subjects aged 18–65 years oral ketoconazole 200 mg/day pro­ longed the half-life of a single oral dose of solifenacin 10 mg from 49 to 78 hours and increased the Cmax 1.43 times and the AUC about twofold (171c). Solifenacin is meta­ bolized by CYP3A4, which is inhibited by ketoconazole. A 53-year-old woman taking warfarin took modified-release tolterodine 4 mg/day, after which her INR rose, although the dosage of warfarin was reduced when the tolterodine was introduced (172A). In a crossover placebo-controlled study in healthy men solifenacin had no effect on the steady-state pharmacokinetics of digoxin or the pharmacokinetics of a single dose of warfarin (173C).

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I. Duarte, R. Lazzarini, C. Kobata, and A. Rotter

14

Dermatological drugs, topical agents, and cosmetics

Editor’s note: The adverse effects of many drugs that are used to treat some skin diseases are covered in other chapters; for example, monoclonal antibodies in Chapter 37 and non-topical corticosteroids in Chapter 39. Vitamin A (carotenoids) is covered in Chapter 34.

COSMETICS

granulomatous reactions at the sites of injection. These reactions develop within a few months to several years after the procedure.
A 48-year-old woman with pulmonary sarcoi­

dosis had cosmetic filler injections of Arte­ colls over both lateral eyebrows, the left zygoma, and the left cheek, and 5 years later developed nodules at the injection sites (2A). A biopsy from a nodule was consistent with both cutaneous sarcoid and a foreign-body granulomatous reaction to the locally injected material.

Of 50 cases of suspected allergy to cos­ metics most of the men were aged 41–50 years whereas most of the women were aged 21–30 years (1A). Contact dermatitis was confirmed in 38 cases by patch testing. Of 2531 patches, 95 had positive reactions (Table 1).

This case emphasizes that the detection of foreign material within cutaneous granulomas does not exclude sarcoidosis and particularly illustrates that the foreign material in Artecolls facial cosmetic filler can act as a stimulus for cutaneous sarcoidal granulomas in susceptible patients.

Artecolls

Eyelash tint

Artecolls is a permanent synthetic cos­ metic filler substance, composed of 80% bovine collagen and 20% polymethylacry­ late. It is used for augmentation of deep wrinkles and is injected subdermally. The collagen is biodegradable with 2–4 months; however, the polymethylacrylate microspheres are non-biodegradable and long-lasting cosmetic effects are achieved. There have been reports of

Ocular argyrosis has been reported after repeated exposure to silver-containing com­ pounds, usually from topical medicinal solutions or occupational exposure. Three women developed ocular argyrosis after long-term self-application of an eyelash tint (Revlon Professional Roux Lash and Brow Tint; Colomber USA Corp, New York, New York, USA) (3A). There were various degrees of silver deposition on the upper eyelids, lid margins, caruncles, and con­ junctivae, and diffuse deposits in Desceme­ tus membrane. In certain circumstances, conjunctival argyrosis can simulate benign and malignant lesions, including conjuncti­ val melanoma.

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03114-6 r 2009 Published by Elsevier B.V.

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Table 1 Positive reactions to various cosmetic ingredients in 50 Indian patients Ingredient

Number with a positive patch test

Gallate mix Cetrimide Thiomersal Paraphenylenediamine Parabens Fragrance mix Quarternium Triethanolamine Tert butylhydroquinone Stearyl alcohol Polyoxyethylene sorbital oleate Benzyl salicylate Jasmine synthetic Imidazolidinyl urea Polyethylene glycol Butylated hydroxyanisole Kathon CG Propylene glycol

20 14 10 7 3 3 2 2 2 2 1 1 1 1 1 1 1 1

I. Duarte, R. Lazzarini, C. Kobata, and A. Rotter

mid-term adverse effects such as exogenous ochronosis and leukoderma en confetti, irritant reactions, and allergic reactions (5R). Long-term adverse effects such as nephrotoxicity and carcinogenicity have only been demonstrated in animals.
A 27-year-old woman used different bleach­

ing creams on her face and developed palpable circumscribed, erythematous, tumid, plaques. Patch testing with the German standard series, preservative series, ointment bases, cosmetic products, and the Pigmanorm series (Louis Widmer GmbH, Rheinfelden, Germany) were performed. There were delayed-type hypersensitivity reactions to nickel, para-phenylenediamine, cobalt chlor­ ide, and Pigmanorm. All the substances in Pigmanorm were tested and there was a positive reaction to hydroquinone.

The authors diagnosed lymphocytic infiltration of Jessner-Kanof as a result of a delayed-type hypersensitivity reaction to hydroquinone (6A).

Talc (See also Chapter 49) Hyaluronic acid Hyaluronic acid-based skin fillers have been used since about 1995 in Europe. These substances are used in the nasolabial lines, for lip augmentation, and for treatment of atrophic scars. Some of the thinner, less viscous hyaluronic acid fillers have been used in the forehead, periorbital areas, and glabelar lines. A product called Restylane SubQ (Q-Med, Uppsala, Sweden) is a larger molecule than Restylane or Perlane (Q-Med) and this difference increases its thickness and viscosity (4A). Its adverse effects are transient bruising and swelling. Extrusion from the subdermal space and mobility of the material, transient hema­ toma are also described. Other complica­ tions described are injury to nerves and vessels, persistent swelling, seroma, and misplacement of the injectable material.

Hydroquinone Hydroquinone has been used in skin-bleach­ ing formulations for the treatment of hyperpigmentation and can cause short- and

Application of talc to wounds (erosions, ulcers) or crusting and/or exudative derma­ tosis can give rise to scab formation, infection, and foreign body granulomas in the dermis (7A).
Over several months a 7-year-old boy devel­

oped multiple papulopustular and erythema­ tous papular scaly lesions with an inflammatory base on his face. A biopsy showed a dense inflammatory granuloma with abundant epithelioid cells mixed with giant multinuclear cells, abundant lymphocytes, and histiocytes. His mother remembered that 6 months before she had applied an antipruritic powder on exudative lesions caused by Varicella to relieve intense itching in the area.

HAIR DYES Tumorigenicity Previous studies have sug­ gested an association between the use of hair dyes and some cancers (SED-15, 1573; SEDA-30, 182). The risk of lymphoid malignancies asso­ ciated with personal use of hair dyes has been studied in a case–control study of 2302

Dermatological drugs, topical agents, and cosmetics

cases of lymphoid neoplasms and 2417 controls from the Czech Republic, France, Germany, Ireland, Italy, and Spain (1998– 2003) (8C). Hair dyes were used by 74% of women and 7% of men. The risk of lymphoma among dye users was signifi­ cantly increased by 19% compared with never use (OR ¼ 1.19; 95% CI ¼ 1.00, 1.41) and by 26% among persons who used hair dyes 12 or more times per year (OR ¼ 1.26; 95% CI ¼ 1.00, 1.60). The risk was significantly higher among those who had started coloring their hair before 1980 (OR ¼ 1.37; 95% CI ¼ 1.09, 1.72) and those who had used hair dyes only before 1980 (OR ¼ 1.62; 95% CI ¼ 1.10, 2.40). The association between the use of synthetic hair dyes and the risk of brain tumors has been evaluated in a case– control study, including adults with gliomas (n ¼ 489), meningiomas (n ¼ 197), or acoustic neuromas (n ¼ 96) between 1994 and 1998 at three urban US hospitals and 799 controls (9C). There was no consistent pattern of increased odds ratios for any of these tumors with use or prolonged use of permanent, semipermanent, temporary, or gradual hair dyes. Although the use of permanent brown hair dye for 20 or more years was associated with glioma among women, the estimate was imprecise (OR ¼ 3.8; 95% CI ¼ 1.2, 13) and was based on just 13 exposed cases; this could be a chance finding, although a previous study has suggested a similar association (SEDA-30, 182). In a case–control study of 712 patients with bladder cancer 712 age-, sex-, and ethnicity-matched control, after adjusting for confounding variables, the use of permanent hair dye was not associated with a risk of bladder cancer in all subjects (OR ¼ 0.81; 95% CI ¼ 0.50, 1.30), in women (OR ¼ 0.90; 95% CI ¼ 0.41, 1.96), or in men (OR ¼ 0.68; 95% CI ¼ 0.36, 1.29) (10C). The lack of association was not modified by duration of use, frequency of use, lifetime use, age at first use, or color of use in subsequent stratified analyses. In a case–control study in 152 women and 166 controls in Spain the use of any hair dye (OR ¼ 0.8; CI ¼ 0.5, 1.4) or of perma­ nent hair dyes (OR ¼ 0.8; CI ¼ 0.5, 1.5)

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was not associated with an increased risk of bladder cancer (11C). There were no differences in women with different drug metabolic genotypes—NAT1, NAT2, CYP1A2, GSTM1, GSTT1, and GSTP1.

Para-phenylenediamine Skin Phenylenediamine is present in black dyes widely used in permanent hair dyes and leather, printer’s ink, fax machine ink, and lithography (12A). It can cause contact dermatitis (13A). The risk is particularly increased in those who also use temporary black tattoos, and as such tattoos have become fashionable among adolescents, the risk of sensitization has increased. Sensitization in eight children under 16 years of age with suspected hair dye allergic reactions and positive patch tests to phenylenediamine has been studied over 2 years in two Danish clinics (14c). They all reacted to several hair dye ingredients. Five were hospitalized, one in the intensive care unit. Six gave a history of a prior reaction to a temporary black tattoo. They had positive patch reactions to N-isopropyl-N­ phenyl-para-phenylenediamine and local anesthetics, and such reactions were not seen in children with hair dye reactions only.
A 16-year-old Moroccan girl developed a

allergic contact dermatitis on her scalp, ears, and neck 36 hours after dyeing her hair for the first time with LuOreal Féria (15A). She had previously used black henna tattoos, common in Moroccan culture.

The authors attributed the initial sensitization for the development of contact to the black henna. In another similar phenylenediamine cross-reacted with azoic dyes used to dye textiles, 5,4-aminophenol, Yellow 3, Orange Red, and Red 1 (16A).
A 65-year-old man with recurrent episodes of

severe hand dermatitis was patch tested with the European standard, cream, facial, per­ fume, and plant series showed a 2+ positive reaction to 0.1% phenylenediamine base in petroleum and a 3+ reaction to 5% benzocaine

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I. Duarte, R. Lazzarini, C. Kobata, and A. Rotter

in petroleum (17A). He had regularly helped his wife color her hair with a paraphenylenediamine-containing permanent dye, without the protection of gloves, which had coincided with exacerbations of his eczema.

The mechanism whereby phenylenediamine causes sensitization has been explored in a study of Bandrowski’s base (a phenylenediamine trimer) and 1,4-benzoquinone (a phenylenediamine hapten) (18c). Patients who had positive patch tests to phenylenediamine were patch tested to Bandrowski’s base and benzoquinone. All tests were negative to 0.01% benzoquinone and 0.01% Bandrowski’s base. Five of 14 tested had true positive reactions to 0.1% benzoquinone. Benzoquinone 1% was irritant. Seven of 43 tested were positive to either 0.1% or 1% Bandrowski’s base. The positive reactions to Bandrowski’s base were weak, even while phenylenediamine reactions were strong, but Bandrowski’s base was about 10 times more potent than phenylenediamine, taking into account molarity. The authors suggested that while phenylenediamine may act as a prohapten, there is probably a spectrum of antigenic determinants in vivo, and that Bandrowski’s base may be bound or metabolized by keratinocytes before it reacts with Langerhans cells.

showed cornoid lamellae on the edges of the specimen and psoriasiform acanthosis and spongiotic pustules in the center.

Immunologic Glucocorticoids can be grouped into four classes, based on chemical structure (Table 2). An allergic reaction to one member of a class usually implies that other members of the same class will produce a reaction. However, cross-reactivity can occur across the class boundaries (21A).
A 60-year-old man developed a bullous con­

tact dermatitis after topical glucocorticoid

Table 2 Classes of glucocorticoids according to structure Group

Examples

A

Cortisone acetate Hydrocortisone Hydrocortisone acetate Methyprednisolone Prednisolone Prednisone Tixocortol pivalate Amcinonide Budesonide Desonide Fluocinolone acetonide Fluocinonide Halcinonide Mometasone Triamcinolone acetonide Triamcinolone alcohol Betamethasone Betamethasone sodium phosphate Desoximetasone Dexamethasone Dexamethasone sodium phosphate Fluocortolone Aclometasone dipropionate Betamethasone dipropionate Betamethasone valerate Clobetasol-17-propionate Clobetasone-17-butyrate Fluocortolone caproate Fluocortolone pivalate Fluprednidene acetate Hydrocortisone-17-butyrate Hydrocortisone-17-valerate Mometasone Prednicarbate

B

Glucocorticoids, topical Skin Earlobe perforation has been reported after long-term application of a topical glucocorticoid cream (19A).

C


A 52-year-old woman used topical hydrocorti­

sone cream 0.1% for contact dermatitis of the earlobe for 24 months. She developed gradual atrophy of the epidermis, dermis, and sub­ cutaneous fat, eventually resulting in incom­ plete clefting of the earlobe. She stopped using the cream and after surgical correction the wound healed well.

Porokeratosis of Mibelli, a chronic disorder that is characterized by slightly atrophic plaques surrounded by keratotic border, has been attributed to a topical glucocorticoid (20A).
A 45-year-old patient used clobetazole pro­

pionate ointment for psoriasis for 15 years and developed characteristic lesions of porokera­ tosis of Mibelli on the elbows. Histopathology

D

Dermatological drugs, topical agents, and cosmetics treatment of dermatitis on his lower leg. Patch testing showed cross-reactions to several glu­ cocorticoids, including desoximetasone and mometasone furoate, but negative results with hydrocortisone and tixocortol pivalate.

Colophony

(SEDA-29, 156)

Immunologic Hypersensitivity reactions to colophony continue to be reported (22A, 23A, 24A).

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total repigmentation in 18%. There were no skin cancers of any kind. Skin Bullous pemphigoid has been described in a 65-year-old woman with psoriasis after several courses of bath psoralen plus UV-A (cumulative dose 467 J/cm2) and UV-B (2.96 J/cm2) plus topical acetonide triamcinolone 0.1% (27A).

SUNSCREENS PHOTOTHERAPY AND PHOTOCHEMOTHERAPY (SED-15, 2823; SEDA-28, 171; SEDA-29, 158)

Immunologic Although sunscreen do not commonly cause allergic contact dermatitis, they are among the most common causes of photoallergic reactions and have been reviewed (28R).

Aminolevulinic acid Genotoxicity The genotoxic potential of 5-aminolevulinic acid and its hexylester have been studied using the 3-(4,5­ dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the alkaline comet assay (25E). Aminolevulinic 750 mmol/l caused marked cytotoxicity and DNA damage in lymphocytes but aminolevulinic hexylester 10 mmol/l did not.

(SED-15, 3653; SEDA-28, 171; SEDA-29, 158; SEDA-30, 185; for vitamin A carotenoids see Chapter 34)

PUVA

Ear, nose, throat Dysphonia occurred in a woman taking acitretin, resolved after withdrawal, and reappeared when acitretin was reintroduced; it was accompanied by bilateral vocal fold edema and congestion (see also isotretinoin below) (29A).

Observational studies The files of 31 patients with vitiligo treated with PUVA between 1982 and 1996 were surveyed and each patient was interviewed by telephone and invited to have a medical examination; 28 completed the questionnaire and 12 were also examined (26c). The average age was 47 (range 25–84) years. The median amount of radiation to which each patient had been exposed was 337 (range 27–1561) J/cm2. The median number of treatments was 77. The average time that elapsed since the start of treatment was 11 (range 7–20) years, and the average time since the end of treatment was 9.4 (range 2–23) years. There was partial or total repigmentation in 60% and total or almost

VITAMIN A (RETINOIDS)

Acitretin

Isotretinoin Ear, nose, throat Hoarseness has been attributed to isotretinoin (30A).
A 45-year-old woman with acne and took

isotretinoin 1 mg/kg/day and became hoarse 5 weeks after the start of therapy. She continued to take isotretinoin; the hoarseness improved with time and disappeared 3 weeks after withdrawal of isotretinoin.

It is thought that granulation tissue or swelling of the vocal cords caused by isotretinoin favors hoarseness (see also acitretin above).

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Psychiatric The use of mental health services in the Israeli Defense Forces during 5 years by 1419 subjects who had been exposed to isotretinoin has been studied in a case–control comparison with 1102 controls with psoriasis (31C). The subjects were aged 18–21 years and were in compulsory military service. The index group had made more use of the mental health services: 245/1419 (17%) compared with 12.5% in the control group. Although the study had several limitations, the find­ ings support a cautious approach to patient with acne who take isotretinoin. There is a clear need to monitor patients during treatment, to educate them about possible psychiatric effects, and to screen subjects to identify those at risk before treatment. Metabolism In 23 patients who had taken oral retinoids between 1979 and 1981 for a mean duration of 5.2 years there were raised cholesterol and/or triglycerides in eight cases, raised serum alkaline phospha­ tase activity in three, and diffuse skeletal hyperostosis in one patient after 2 years of retinoid therapy (32C). In a retrospective cohort study of 13772 patients aged 13–50 years with acne, who took oral isotretinoin between March 1995 and September 2002, there were substantial increases in the cumulative incidence of abnormalities in serum lipid concentrations and transaminase activities, but not in hematology parameters, during isotretinoin treatment compared with baseline (33c). The cumulative incidence of new abnormalities in patients with normal values at baseline was 44% for triglyceride concentration, 31% for total cholesterol concentration, and 11% for transaminase activity. Moderate-to­ severe abnormalities in lipid and transami­ nase activities were generally transient and reversible. New abnormalities in hematolo­ gical test results were uncommon. The clinical significance of these laboratory abnormalities remains to be determined. Gastrointestinal In a study of all the adverse effects reports received by the US Food and Drug Administration (FDA) between 1997 and 2002, 85 cases of inflammatory bowel disease associated with

I. Duarte, R. Lazzarini, C. Kobata, and A. Rotter

isotretinoin were reported (34c). According to the Naranjo probability scale, four cases scored in the highly probable range for isotretinoin as the cause, 58 were probable, 23 were possible, and none was doubtful. The authors concluded that isotretinoin might trigger inflammatory bowel disease. Two adult men developed anal fissures with burning pain and rectal bleeding a few days after starting systemic isotretinoin for acne and rosacea (35A). Musculoskeletal Arthralgia or myalgia develops in about 25% of patients taking isotretinoin and arthritis can occur (36C).
A 19-year-old woman developed acute mono-

arthritis in the right hip after taking isotreti­ noin for 2 months. Synovial fluid cultures were negative. There was prompt improvement after withdrawal of isotretinoin.

Autacoids Angioedema has been attribu­ ted to isotretinoin (37A).
An 18-year-old girl with acne took isotretinoin

1 mg/kg and developed facial swelling a few hours after the first dose. She had edema of the lips and periorbital regions, with promi­ nent swelling and erythema of the eyelids. She improved when the drug was withdrawn. The symptoms reappeared on rechallenge.

Infection risk Vitamin A derivatives have virucidal activity, both in vivo and in vitro, and isotretinoin has been used to treat recurrent herpes simplex infection, with encouraging results. However, frequent attacks of herpes labialis occurred during isotretinoin therapy for acne and were reduced in frequency following strict use of sunscreens (38A).

Tazarotene Tazarotene is a retinoid that is formulated in a gel and used in acne vulgaris and psoriasis. It can cause an irritant contact dermatitis, which is clinically similar to that caused by other topical retinoids, character­ ized by erythema, edema, xerosis/scaling, pruritus, and burning. It is usually mild to

Dermatological drugs, topical agents, and cosmetics

moderate in intensity and concentration related in areas such as the palmoplantar region, where the rash is mild. Skin in an Italian, multicenter, open study of short contact therapy with tazar­ otene gel 0.1% in psoriasis vulgaris, irritant contact dermatitis was less frequent and severe than traditional treatment with the same drug (39C).

VITAMIN D ANALOGS, TOPICAL Calcipotriol

(SED-15, 594; SEDA-28, 169; SEDA-29, 156; for oral vitamin D analogs see Chapter 34)

A combination of calcipotriol+betametha­ sone dipropionate has been marketed for use in the treatment of psoriasis for up to 8 weeks. In a randomized double-blind study

Chapter 14

293

634 patients were divided into three groups: (i) 52 weeks of the two-compound product; (ii) 52 weeks of alternating 4-week periods of the two-compound product and calcipotriol alone; and (iii) 4 weeks of the two-compound product followed by 48 weeks of calcipotriol alone (40C). There were adverse drug reac­ tions in 45 (22%) patients in the twocompound group, 63 (30%) in the alter­ nating group, and 78 (38%) in the calcipo­ triol alone group. The odds ratio for an adverse drug reaction in the two-compound group relative to the calcipotriol alone group was 0.46 (95% CI ¼ 0.30, 0.70). There were adverse drug reactions of concern associated with long-term topical corticosteroid use in ten (4.8%) patients in the two-compound group, six (2.8%) in the alternating group, and six (2.9%) in the calcipotriol alone group; those with the highest incidence were skin atrophy, which occurred in four (1.9%), one (0.5%), and two (1.0%) patients respec­ tively, and folliculitis in three (1.4%), one (0.5%), and no patients.

References 1. Kumar P, Paulose R. Cosmetic dermatitis in an Indian city. Contact Dermatitis 2006;55 (2):114–5. 2. Sidwell RU, Mcl Jonhson N, Francis N, Bunker CB. Cutaneous sarcoidal granulo­ mas developing after Artecolls, facial cosmetic filler in a patient with newly diagnosed systemic sarcoidosis. Clin Exp Dermatol 2006;31:208–11. 3. Gallardo MJ, Randleman JB, Price KM, Johnson DA, Acosta S, Grossniklaus HE, Stulting RD. Ocular argyrosis after longterm self-application of eyelash tint. Am J Ophthalmol 2006;141:198–200. 4. Lowe NJ, Grover R. Injectable hyaluronic acid implant for malar and mental enhance­ ment. Dermatol Surg 2006;32(7):881–5. 5. O’Donoghue JL. Hydroquinone and its analogues in dermatology—a risk-benefit viewpoint. J Cosmet Dermatol 2006;5(3): 196–203. 6. Caroli UM, Berner D, Schlegel C, Metzler G, Rocken M, Biedermann T. Lymphocytic infiltration of skin Jessner–Kanof after

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treatment with a hydroquinone-containing bleaching cream. Arch Dermatol 2006;142: 1655–6. Lázaro C, Reichelt C, Lázaro J, Grasa MP, Carapeto FJ. Foreign body post-varicella granulomas due to talc. J Eur Acad Dermatol Venereol 2006;20(1):75–8. de Sanjosé S, Benavente Y, Nieters A, Foretova L, Maynadié M, Cocco PL, Staines A, Vornanen M, Boffetta P, Becker N, Alvaro T, Brennan P. Association between personal use of hair dyes and lymphoid neoplasms in Europe. Am J Epidemiol 2006;164(1):47–55. Gallardo MJ, Randleman JB, Price KM, Johnson DA, Acosta S, Grossniklaus HE, Stulting RD. Ocular argyrosis after longterm self-application of eyelash tint. Am J Ophthalmol 2006;141:198–200. Lin J, Dinney CP, Grossman HB, Wu X. Personal permanent hair dye use is not associated with bladder cancer risk: evidence from a case–control study. Cancer Epidemiol Biomarkers Prev 2006;15(9):1746–9.

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11. Kogevinas M, Fernandez F, Garcia-Closas M, Tardon A, Garcia-Closas R, Serra C, Carrato A, Castano-Vinyals G, Yeager M, Chanock SJ, Lloreta J, Rothman N, Real FX, Dosemeci M, Malats N, Silverman D. Hair dye use is not associated with risk for bladder cancer: evidence from a case– control study in Spain. Eur J Cancer 2006; 42(10):1448–54. 12. Gawkrodger DJ, English JSC. How safe is patch testing to PPD? Br J Dermatol 2006; 154:1025–7. 13. Ballard MS. Contact dermatitis after henna skin tattooing. J R Army Med Corps 2006; 152(4):242–3. 14. Sosted H, Duus Johansen J, Andersen K E, Menne T. Severe allergic hair dye reactions in 8 children. Contact Dermatitis 2006;54 (2):87. 15. Hink E, Winter JP. Hair-dye allergy: a coloured case. Eur J Pediatr 2006;165:195–6. 16. Di Prisco MC, Puig L, Alomar A. Contact dermatitis due to para-phenylenediamine (PPD) on a temporal tattoo with henna. Cross reaction to azoic dyes. Invest Clin 2006;47(3):295–9. 17. Gass JK, Todd PM. PPD: is this a connubial dermatitis? Contact Dermatitis 2006;55(5): 309. 18. White JM, Kullavanijaya P, Duangdeeden I, Zazzeroni R, Gilmour NJ, Basketter DA, McFadden JP. p-Phenylenediamine allergy: the role of Bandrowski’s base. Clin Exp Allergy 2006;36(10):1289–93. 19. Rogge FJ, Pacifico MD, Grobbelaar AO. Earlobe perforation after prolonged use of a topical corticosteroid. J Plast Reconstr Aesthet Surg 2007;60(1):100–1. 20. Yazkan F, Turk BG, Dereli T, Kazandi AC. Porokeratosis of Mibelli induced by topical corticosteroid. J Cutan Pathol 2006;33(7): 516–8. 21. Donovan JC, Dekoven JG. Cross-reactions to desoximetasone and mometasone furo­ ate in a patient with multiple topical corticosteroid allergies. Dermatitis 2006;17 (3):147–51. 22. Sharma PR. Allergic contact stomatitis from colophony. Dent Update 2006;33(7):440–2. 23. Booken D, Velten FW, Utikal J, Goerdt S, Bayerl C. Allergische Kontaktdermatitis durch Kolophonium und Terpentin in Har­ zen unbehandelter Kiefernholzmobel.

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25.

26.

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31.

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33.

[Allergic contact dermatitis from colophony and turpentine in resins of untreated pine wood.] Hautarzt 2006;57(11):1013–5. Körber A, Kohaus S, Geisheimer M, Grabbe S, Dissemond J. Allergisches Kon­ taktekzem durch einen Hydrokolloidver­ band bei Sensibilisierung auf Kolofonium. [Allergic contact dermatitis from a hydro­ colloid dressing due to colophony sensitiza­ tion.] Hautarzt 2006;57(3):242–5. Chu ES, Wu RW, Yow CM, Wong TK, Chen JY. The cytotoxic and genotoxic potential of 5-aminolevulinic acid on lym­ phocytes: a comet assay study. Cancer Chemother Pharmacol 2006;58(3):408–14. Vussuki E, Ziv M, Rosenman D, David M. [Long-term effects of PUVA therapy on Israeli patients with vitiligo.]. Harefuah 2006;145(7):483–5 552, 551. Barnadas MA, Gilaberte M, Pujol R, Agustí M, Gelpí C, Alomar A. Bullous pemphigoid in a patient with psoriasis during the course of PUVA therapy: study by ELISA test. Int J Dermatol 2006;45(9): 1089–92. Scheuer E, Warshaw E. Sunscreen allergy: a review of epidemiology, clinical char­ acteristics, and responsible allergens. Der­ matitis 2006;17(1):3–11 Erratum 2006; 17 (3):162. Petitpain N, Pouaha J, Cosserat F, Gambier N, Truchetet F, Cuny JF. Recurrent dys­ phonia and acitretin. J Voice 2006;20(4): 642–3. Kim HS, Lee JY, Chow BK. A rare sideeffect of systemic isotretinoin treatment: hoarseness. J Eur Acad Dermatol Venereol 2006;20:1328–9. Friedman T, Wahl Y, Nobler HY, Lubing G, Brenner S, Levi Y, Bark Y. Increased use of mental heath services related to isotretinoin treatment: a 5-year analysis. Eur Neuropsycopharmacol 2006;16:413–6. Katugampola RP, Finlay AY. Oral retinoid therapy for disorders of keratinization: single-centre retrospective 25 years’ experi­ ence on 23 patients. Br J Dermatol 2006; 154:267–76. Gazerani P, Staahl C, Drewes AM, ArendtNielsen L. A population-based analysis of laboratory abnormalities during isotretinoin therapy for acne vulgaris. Arch Dermatol 2006;142:315–25.

Dermatological drugs, topical agents, and cosmetics 34. Reddy D, Sigel CA, Sands BE, Kane S. Possible association between isotretinoin and inflammatory bowel disease. Am J Gastroenterol 2006;101:1569–73. 35. Radmanesh M. Anal fissure, rectal bleeding and proctitis as complication of systemic isotretinoin therapy: report of two cases. J Eur Acad Dermatol Venereol 2006;20:1394. 36. Pedraz T, Martinez A, Pascual E. Acute hip monoarthritis in a patient treated with isotretinoin. J Clin Rheumatol 2006;12(2): 105–6. 37. Saray Y, Sec- kin D. Angioedema and urticaria due to isotretinoin therapy. J Eur Acad Dermatol Venereol 2006;20:118–20. 38. Yazici AC, Baz K, Ikizoglu G. Recurrent herpes labialis during isotretinoin therapy:

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is there a role for photosensitivity? J Eur Acad Dermatol Venereol 2006;20(1):93–5. 39. Veraldi S, Caputo R, Pacifici A, Peris K, Soda R, Chimeti S. Short contact therapy with tazarotene in psoriasis vulgaris. Der­ matology 2006;12:235–7. 40. Kragballe K, Austad J, Barnes L, Bibby A, de la Brassinne M, Cambazard F, Fleming C, Heikkilä H, Jolliffe D, Peyri J, Svensson A, Toole J, Wozel G. A 52-week rando­ mized safety study of a calcipotriol/beta­ methasone dipropionate two-compound product (Dovobet/Daivobet/Taclonex) in the treatment of psoriasis vulgaris. Br J Dermatol 2006;154(6):1155–60.

Garry M. Walsh

15 Antihistamines (H1 receptor antagonists)

Some antihistamines are often used in combination with a nasal decongestant or with a leukotriene receptor antagonist. For example, one randomized, double-blind, placebo-controlled crossover clinical study in patients with persistent allergic rhinitis showed that montelukast combined with either desloratadine or levocetirizine is more effective in reducing symptoms than monotherapy with these agents (1C). All the treatments were well tolerated. Secondgeneration antihistamines may also be beneficial in patients with asthma and concomitant rhinitis (2R).

Cetirizine

(SED-15, 702; SEDA-28, 178; SEDA-29, 161; SEDA-30, 189) Nervous system Drug-induced movement disorders are most commonly associated with neuroleptic drugs. However, there are a few reports of abnormal involuntary movements associated with antihistamines. � A 4-year-old girl weighing 19.5 kg developed

repetitive, stereotyped, involuntary dystonic movements after taking cetirizine syrup 5 mg/ day for 18 days for allergic rhinitis (3A). Her symptoms included a tic of the right eye with frequent shoulder shrugging, followed by intermittent retrocollis and arm abduction movements. These movements did not inter­ fere with voluntary movements and were painless, aggravated by fatigue, and briefly suppressible. One week after the last dose of

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03115-8 r 2009 Elsevier B.V. All rights reserved.

cetirizine, the movements were greatly improved. Similar movements also developed within a few days of exposure to mepyramine 10 mg in an expectorant for congestion. Three weeks later, she had occasional retrocollis and her arms would abduct when she was tired. All involuntary movements resolved 8 weeks after the last dose of cetirizine.

As a piperazine derivative, cetirizine has dopamine receptor blocking properties. The authors therefore postulated that cetir­ izine had caused the dystonic movements although this was not directly tested by rechallenge. Drug–drug interactions Pilsicainide An interaction of cetirizine with pilsicainide has been described (4A). � A 72-year-old woman with renal insufficiency

who was taking oral pilsicainide 150 mg/day complained of feeling faint 3 days after she started to take oral cetirizine 20 mg/day. She had a wide QRS complex and sinus bradycar­ dia. These effects were relieved by withdraw­ ing pilsicainide. Cetirizine was continued and its plasma concentration fell when pilsicainide was withdrawn, which suggested that the fainting symptoms were induced by a pharma­ cokinetic drug–drug interaction.

A pharmacokinetic study in six healthy men after a single dose of cetirizine 20 mg, pilsicainide 50 mg, or both showed that the renal clearance of each was significantly reduced by co-administration. In vitro studies using Xenopus oocytes with micro­ injected human organic cation transporter 2 and renal cells transfected with human multidrug resistance protein 1 showed that the transport of the substrates of these transporters was inhibited by both cetirizine and pilsicainide. The authors concluded

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298 that although cetirizine has less potential for causing dysrhythmias than other anti­ histamines, an interaction should be con­ sidered in patients with renal insufficiency receiving pilsicainide. It is important to note that the 20 mg dose of cetirizine given to the patient and the healthy volunteers is twice the recommended dose.

Cyclizine

Garry M. Walsh

The authors concluded that in both children and adults who are poor metabolizers of desloratadine there is no change in the frequency or profile of adverse events nor any significant changes in electro­ cardiography. However, they also reported that the poor metabolizer phenotype has a higher incidence in Black populations (16–18%), and further studies in such populations may be required.

(SED-15, 1023)

Cardiovascular In a review of 70 papers to establish whether cyclizine adversely affected hemodynamic parameters in patients with cardiac disease, the authors recommended that cyclizine should be avoided in patients with acute coronary events (5R).

Diphenhydramine

(SED-15, 1134; SEDA-28, 179; SEDA-29, 163; SEDA-30, 189)

The authors gave no explanation for the mechanism responsible for this reaction to cyclizine in an otherwise healthy individual undergoing minor surgery.

Drug overdose Diphenhydramine is related to ethanolamine, and has anticho­ linergic, sedative, antivertigo, antiemetic, antidyskinetic, and local anesthetic pro­ perties. It is available over the counter in many countries and is generally regarded as harmless. However, from an analysis of 68 non-fatal and 55 fatal poisonings with diphenhydramine alone or in combination with other drugs between 1992 and 2004 at a single institution (the Institute of Legal Medicine, University Hospital Charité, Berlin, Germany) the authors concluded that overdose leads to a variety of adverse effects, which can often be under-rated on hospital admission (8R). The authors concluded that overdose with diphenhydramine is no less dangerous than that with prescription sedatives. A comprehensive evidence-based guideline for the management of diphenhydramine poisoning has also been made available (9R).

Desloratadine

(SED-15, 1074; SEDA28, 179; SEDA-29, 162; SEDA-30, 189)

Doxylamine

Susceptibility factors Genetic Due to a phenotypic polymorphism, around 6% of individuals have a reduced ability to metabolize desloratadine to its active metabolite 3-hydroxydesloratadine. Pooled data from 41 clinical pharmacology studies have been comprehensively reviewed (7R).

Drug overdose with doxylamine and rhabdomyolysis

Respiratory Respiratory failure has been attributed to cyclizine during anesthesia. � A middle-aged woman was anesthetized with

fentanyl and propofol, oxygen, nitrous oxide, and isoflurane. About 30 minutes later a slow intravenous injection of cyclizine 50 mg was started. Within 5 minutes her respiratory pat­ tern became erratic, with poor tidal volumes. Despite an increase in the depth of anesthesia, her respiration did not improve. She was intubated and manual ventilation initiated. The surgery was successfully completed but at the end of anesthesia she required procyclidine 10 mg intravenously before full consciousness was restored. After 24 hours observation she recovered completely (6A).

(SED-15, 1192)

Anecdotal reports In overdose dosylamine can cause somnolence, coma, seizures, mydriasis, tachycardia, psychosis, and rhabdomyolysis (10A–15A). In one case

Antihistamines (H1 receptor antagonists)

Chapter 15

rhabdomyolysis and acute renal insufficiency was accompanied by acute pancreatitis (16A). A 3-year-old boy took about 100 tablets of Bendectin (doxylamine+pyridoxine) and developed tonic–clonic seizures followed by a fatal cardiac arrest (17A). Surveys Of 442 patients with doxylamine overdose reported to Berlin poison control centers in 1982�1986, 7 had rhabdomyolysis (18c). There was a rise in plasma creatine kinase from 980 to 63 400 U/1 (mean 18 800 U/1) and myoglobinuria in six men and one woman aged 18�31 years (mean 23 years) who had swallowed 500�3000 (mean 1480) mg of doxylamine. There were transient electrocardiographic repolarization disturbances in two patients. Of 109 patients who took doxylamine overdoses, 60% were aged 16�30 years; about 60% took 10�40 times the single therapeutic dose (25 mg) (19c). Doxylamine plasma concentrations exceeded the expected Cmax after a therapeutic dose by a factor of 10�40 in two-thirds of cases. The most frequent symptoms included impaired consciousness, seizures, tachycardia, mydriasis, and a “psychosis” similar to that in catatonic stupor; 39% were asymptomatic. There was no correlation between symptoms and either the amount ingested or doxylamine plasma concentration. Susceptibility factors The susceptibility factors for rhabdomyolysis after doxylamine overdose have been studied in 27 patients who were admitted to a university teaching hospital between July 2000 and September 2005; 16 had rhabdomyolysis and 3 developed acute renal insufficiency (20c). Those who developed rhabdomyolysis differed from those who did not in the amount of doxylamine ingested, the initial serum creatinine concentration, and arterial pH. However, in a multivariate regression analysis, the only reliable predictor of rhabdomyolysis was the amount of doxylamine taken. Rhabdomyolysis occurred in 87% of those who took 20 mg/kg or more and that dose predicted rhabdomyolysis with a sensitivity of 81%, a specificity of 82%, a positive predictive value of 87%, and a negative predictive value of 75%.

299

Mechanism A proposed mechanism for antihistamine-induced rhabdomyolysis is that they damage the sarcolemma, causing influx of sodium; a higher intracellular sodium concentration activates Na/KATPase, depleting cellular ATP and increasing intracellular calcium concentrations, activating proteolytic enzymes (21r). Interference with diagnostic tests Because of structural similarities, overdose with antihistamines can give false positive tests for phencyclidine and methadone in urine samples (10A,22E,23E).

Fexofenadine

(SED-15, 1357; SEDA-28, 179; SEDA-30, 190)

Systematic reviews Fexofenadine can be combined with a decongestant (fexofenadine 60 mg+pseudoephedrine hydrochloride 120 mg) to provide relief from nasal blockade (24R). In a pooled analysis of two randomized, double-blind, placebocontrolled, parallel-group allergen exposure unit studies using subjects with moderate to severe allergic rhinitis, fexofenadine +pseudoephedrine hydrochloride had a rapid onset of action (45 minutes) with a significant positive clinical effect during the 6-hour study period (25M). The main adverse effect was somnolence, which was not considered significant, as this adverse event was comparable in both active and placebo groups. Skin A pustular eruption on pre-existing psoriasis has been attributed to fexofena­ dine (26A). � A 53-year-old man with an 8-year history of

chronic plaque psoriasis involving about 5% of his body surface area suddenly developed pustules all over his body. He reported that the pustules appeared within 24 hours of taking a 180-mg tablet of fexofenadine for itching localized to the psoriasis lesions. The pustules were preceded by a burning sensation localized to the lesions and a feeling of malaise. Before taking the fexofenadine he had used only topical bland emollients and kerato­ lytics. There were multiple pinhead-sized pus­ tules located predominantly over the psoriatic

Chapter 15

300 plaques, with a few isolated pustules scattered elsewhere on the body. There was a narrow zone of perilesional erythema around most of the psoriatic plaques. He was given oral methotrex­ ate 20 mg weekly, which resulted in complete clearing of the pustules within 2 weeks and significant improvement in the psoriatic plaques at 6 weeks. At this point the methotrexate was tapered over the next 6 weeks. Three months after the initial episode, the patient had three to four plaques of psoriasis on his knees. Oral rechallenge with fexofenadine 30 mg provoked increased pruritus on lesions within 3 hours of administration and pustules overlying the psor­ iatic plaques within 24 hours. Oral challenges with cetirizine (2.5 and 5 mg) and pheniramine (12.5 and 25 mg) were negative.

The oral challenge confirmed the role of fexofenadine in pustular aggravation while the effect appeared to be unrelated to H1 receptor blockade, as other antihistamines did not have the same effect. Fexofenadine is a derivative of terfenadine, which reportedly caused exacerbation of psoriasis in two cases before it was withdrawn (27A,28A).

Hydroxyzine

(SED-15, 1705)

Skin Although cutaneous reactions to systemic antihistamines have been described it is often difficult to demonstrate a casual relation. � A 36-year-old man with a 7-year history of mild

psoriasis consisting of small plaques affecting about 20% of the body surface used calcipotriol 50 mg/g+betamethasone dipropionate 0.5 mg/g (Daivobets), and oral hydroxyzine every 8 hours for treatment of a new episode of psoriasis and mild itching (29A). He developed a desquamative erythematous maculopapular rash with severe pruritus 48 hours later. He had previously taken oral hydroxyzine without any complications and had also used Daivobet several times. An epicutaneous test was positive with 2.5% hydroxyzine in petrolatum at 48 and 96 hours, leading to a diagnosis of maculo­ papular drug eruption due to hydroxyzine. He refused an oral provocation test. Patch testing with 2.5% hydroxyzine in 10 control subjects was negative.

The authors emphasized the importance of examining all patients whose skin condition worsens after the introduction of an antihistamine, especially hydroxyzine, and that if such

Garry M. Walsh

reactions do occur a patch test is the first diagnostic step to be considered.

Levocetirizine

(SED-15, 2038; SEDA28, 180; SEDA-29, 163; SEDA-30, 190)

Levocetirizine, the R-enantiomer of cetir­ izine dihydrochloride, has pharmacodyna­ mically and pharmacokinetically favorable characteristics. Clinical trials have shown that it is safe and effective in the treatment of allergic rhinitis and chronic idiopathic urticaria in adults and children, with a minimal number of untoward effects (30R). Skin Fixed drug eruptions are the most frequent types of adverse cutaneous drug reactions, and tetracyclines, sulfonamides, sulfones, penicillins, pyrazolones, barbitu­ rates, and phenolphthalein are among the most frequent causative agents. Cutaneous adverse drug reactions induced by systemic antihistamines are very rare, although some have been previously reported for both cetirizine and levocetirizine (SEDA-27, 166; SEDA-30, 191), and a number of first-generation antihistamines, such as cyclizine lactate, diphenhydramine hydro­ chloride, phenothiazines, dimenhydrinate, and hydroxyzine, can cause fixed drug eruptions. � A 49-year-old woman treated a long-standing

eczematous foot lesion for at least 6 months with topical remedies, including an ointment containing halcinonide+neomycin+amphoteri­ cin B with ethylenediamine as a stabilizer (Anfocort) with little clinical improvement (31A). Her general practitioner prescribed betamethasone and cetirizine for 3 months followed by deflazacort and levocetirizine (doses not stated). After a week she devel­ oped a generalized cutaneous eruption that particularly affected the trunk. The cutaneous eruption resolved within 2 weeks of with­ drawal of levocetirizine. A patch test with ethylenediamine dihydrochloride was positive 2 weeks later, leading to a diagnosis of an ethylenediamine-induced allergic contact der­ matitis of the foot.

The authors also implicated levocetirizine, and by association the parent compound cetirizine, as being responsible for the systemic cutaneous

Antihistamines (H1 receptor antagonists)

Chapter 15

eruptions. However, as the patient refused further skin rests this was not directly tested. Cetirizine and levocetirizine are chemically related to ethylenediamine; cetirizine is a carboxylated metabolite of hydroxyzine, which is structurally derived from a dimer of ethylenediamine. Although cetirizine is well tolerated when taken orally, rare cross-reactions with other piperazine derivatives can cause urticaria or a fixed drug eruption (32A). Due to their rarity fixed drug eruptions to antihistamines can be difficult to detect, as in many cases they mimic the underlying disease for which the drug was prescribed. The ability of second-generation antihis­ tamines to cause daytime drowsiness and sedation remains a cause for concern, particularly in those who operate machin­ ery, including driving (33R). Paradoxically there is also evidence that a number of antihistamines (terfenadine, ebastine, fex­ ofenadine, and desloratadine) have stimu­ latory effects on tasks involving high degrees of attention, for example, divided attention tasks, vigilance tasks, and driving tasks (34R). The underlying mechanisms responsible are as yet unclear.

301

The frequency of drowsiness and seda­ tion with levocetirizine and desloratadine have been studied using prescription-event monitoring (35C). Exposure data were derived from dispensed prescriptions writ­ ten by primary-care physicians in more than 24 000 patients with allergic rhinitis with or without asthma. Outcome data were derived from questionnaires posted to primary-care physicians at least 6 months after the date of the first prescrip­ tion for each patient. The incidences of first reports of drowsiness or sedation for levocetirizine or desloratadine were very low: 46 (0.37%) and 9 (0.08%), respec­ tively, but these values were significantly higher for levocetirizine than deslorata­ dine. The authors acknowledged that these are very low numbers but recommended that primary-care physicians may consider the problem of daytime sedation if it is undesirable. Moreover, they acknowl­ edged that the study did not include assessment of efficacy or patient prefer­ ences for either drug, important considera­ tions when deciding which antihistamine to prescribe (36R).

References 1. Ciebiada M, Górska-Ciebiada M, DuBuske LM, Górski P. Montelukast with deslorata­ dine or levocetirizine for the treatment of persistent allergic rhinitis. Ann Allergy Asthma Immunol 2006;97(5):664–71. 2. Borade PS, Ballary CC, Currie GP, Lee DKC. Modern H1-antihistamines in asthma. Drug Discov Today: Ther Strategies 2006;3:253–9. 3. Rajput A, Baerg K. Cetirizine-induced dystonic movements. Neurology 2006;66: 143–4. 4. Luzza F, Raffa S, Saporito F, Oreto G. Severe arrhythmia as a result of the interaction of cetirizine and pilsicainide in a patient with renal insufficiency: first case presentation showing competition for excretion via renal multidrug resistance protein 1 and organic

5.

6.

7.

8.

cation transporter 2. Clin Pharmacol Ther 2006;79:606–8. May G, Kumar R. Use of intravenous cyclizine in cardiac chest pain. Emerg Med J 2006;23:61–2. Marr R, Orwin A. Transient paralysis after administration of cyclizine. Anaesthesia 2006; 61(12):1226–7. Prenner B, Kim K, Gupta S, Khalilieh S, Kantesaria B, Manitpisitkul P, Lorber R, Wang Z, Lutsky B. Adult and paediatric poor metabolisers of desloratadine: an assessment of pharmacokinetics and safety. Expert Opin Drug Saf 2006;5:211–23. Pragst F, Herre S, Bakdash A. Poisonings with diphenhydramine—a survey of 68 clin­ ical and 55 death cases. Forensic Sci Int 2006; 161:189–97.

302 9. Scharman EJ, Erdman AR, Wax PM, Chyka PA, Caravati EM, Nelson LS, Manoguerra AS, Christianson G, Olson KR, Woolf AD, Keyes DC, Booze LL, Troutman WG. Diphenhydramine and dimenhydrinate poisoning: an evidencebased consensus guideline for out-of-hospi­ tal management. Clin Toxicol 2006;44(3): 205–23. 10. Khosla U, Ruel KS, Hunt DP. Antihistamineinduced rhabdomyolysis. South Med J 2003; 96(10):1023–6. 11. Leybishkis B, Fasseas P, Ryan KF. Doxylamine overdose as a potential cause of rhabdomyolysis. Am J Med Sci 2001;322(1): 48–9. 12. Soto LF, Miller CH, Ognibere AJ. Severe rhabdomyolysis after doxylamine overdose. Postgrad Med 1993;93(8):227–9 232. 13. Siek TJ, Dunn WA. Documentation of a doxylamine overdose death: quantitation by standard addition and use of three instru­ mental techniques. J Forensic Sci 1993;38 (3):713–20. 14. Frankel D, Dolgin J, Murray BM. Non­ traumatic rhabdomyolysis complicating antihistamine overdose. J Toxicol Clin Toxicol 1993;31(3):493–6. 15. Mendoza FS, Atiba JO, Krensky AM, Scannell LM. Rhabdomyolysis complicating doxylamine overdose. Clin Pediatr (Phila) 1987;26(11):595–7. 16. Lee YD, Lee ST. Acute pancreatitis and acute renal failure complicating doxylamine succinate intoxication. Vet Hum Toxicol 2002;44(3):165–6. 17. Bayley M, Walsh FM, Valaske MJ. Fatal overdose from Bendectin. Clin Pediatr (Phila) 1975;14(5):507–9 514. 18. Köppel C, Ibe K, Oberdisse U. Rhabdo­ myolysis in doxylamine overdose. Lancet 1987;1(8530):442–3. 19. Köppel C, Tenczer J, Ibe K. Poisoning with over-the-counter doxylamine preparations: an evaluation of 109 cases. Hum Toxicol 1987;6(5):355–9. 20. Jo YI, Song JO, Park JH, Koh SY, Lee SM, Seo TH, Lee JH. Risk factors for rhabdomyolysis following doxylamine overdose. Hum Exp Toxicol 2007;26(8): 617–21. 21. Larbi EB. Drug induced rhabdomyolysis. Ann Saudi Med 1998;18(6):525–30.

Chapter 15

Garry M. Walsh

22. Levine BS, Smith ML. Effects of diphenhydramine on immunoassays of phencyclidine in urine. Clin Chem 1990;36:1258. 23. Hausmann E, Kohl B, von Boehmer H, Wellhöner HH. False-positive EMIT indi­ cation of opiates and methadone in a doxylamine intoxication. J Clin Chem Clin Biochem 1983;21(10):599–600. 24. Mansfield LE. Once-daily immediate­ release fexofenadine and sustained-release pseudoephedrine combination: a new treat­ ment option for allergic rhinitis. Expert Opin Pharmacother 2006;7(7):941–51. 25. Berkowitz RB, McCafferty F, Lutz C, Bazelmans D, Godfrey P, Meeves S, Liao Y, Georges G. Onset of action of fexofe­ nadine hydrochloride 60 mg/pseudoephe­ drine hydrochloride 120 mg in subjects aged over 12 years with moderate to severe seasonal allergic rhinitis: a pooled analysis of two single-dose, randomized, double-blind, placebo-controlled allergen exposure unit studies. Clin Ther 2006;28: 1658–69. 26. Saraswat A, Saraswat M. Pustular exacer­ bation of psoriasis due to fexofenadine. Clin Exp Dermatol 2006;31:452–82. 27. Navaratnam AE, Gebauer KA. Terfenadine­ induced exacerbation of psoriasis. Clin Exp Dermatol 1990;15:78. 28. Harrison PV, Stones RN. Severe exacerba­ tion of psoriasis due to terfenadine. Clin Exp Dermatol 1988;13:275. 29. Dalmau J, Serra-Baldrich E, Roé E, López-Lozano HE, Alomar A. Skin reaction to hydroxyzine (Ataraxs): patch test utility. Contact Dermatitis 2006;54: 216–7. 30. Hair PI, Scott LJ. Levocetirizine: a review of its use in the management of allergic rhinitis and skin allergies. Drugs 2006;66:973–96. 31. Cusano F, Ferrara G, Crisman G, Sarracco G, Zalaudek I, Argenziano G. Clinico­ pathologic features of systemic contact dermatitis from ethylenediamine in cetiri­ zine and levocetirizine. Dermatology 2006; 213(4):353–5. 32. Schröter S, Damveld B, Marsch WC. Urticarial intolerance reaction to cetirizine. Clin Exp Dermatol 2002;27(3):185–7. 33. Jáuregui I, Mullol J, Bartra J, del Cuvillo A, Dávila I, Montoro J, Sastre J, Valero AL. H1 antihistamines: psychomotor

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performance and driving. J Investig Allergol Clin Immunol 2006;16(Suppl 1):37–44. 34. Theunissen EL, Vermeeren A, Vuurman EF, Ramaekers JG. Stimulating effects of H1antagonists. Curr Pharm Des 2006;12:2501–9. 35. Layton D, Wilton L, Boshier A, Cornelius V, Harris S, Shakir SA. Comparison of the risk of

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drowsiness and sedation between levocetir­ izine and desloratadine: a prescription-event monitoring study in England. Drug Saf 2006; 29(10):897–909. 36. Lehman JM, Blaiss MS. Selecting the optimal oral antihistamine for patients with allergic rhinitis. Drugs 2006;66:2309–19.

M. Joerger, K. Hartmann, and M. Kuhn

16

Drugs acting on the respiratory tract

INHALED GLUCOCORTICOIDS

(SEDA-28, 184; SEDA-29, 168; SEDA-30, 193)

The effects of inhaled glucocorticoids on hypothalamic– pituitary–adrenal axis function Adults Ciclesonide, a non-halogenated glucocorticoid, is a prodrug that is converted locally in the airways to produce the active metabolite, desisobutyrylciclesonide. The effect of inhaled ciclesonide on hypothalamic–pituitary–adrenal axis function in adults has been reviewed (1R); the data from four clinical trials suggest that ciclesonide (320–1280 mg/day) has no clinically relevant effect (2C,3C,4C,5c). These data suggest that the systemic availability of ciclesonide is very low and clinically unimportant over a wide dosage range. The systemic availability of ciclesonide and fluticasone propionate have been compared by studying their effects on hypothalamic–pituitary–adrenal axis function (6C). Ciclesonide is deposited in the lungs to a greater extent than fluticasone propionate (52% versus 12–13%), and with less oropharyngeal deposition. However, the results of studies with low or medium doses of fluticasone propionate are controversial; high doses (over 660 mg/day) clearly result in adrenal suppression (7C,8c). Ciclesonide had no significant effect on adrenal Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03116-X r 2009 Elsevier B.V. All rights reserved.

suppression up to daily doses of 1280 mg (2C,5c,9C,10c). The pharmacokinetics of ciclesonide, with its high pulmonary deposition, high plasma protein binding, and rapid clearance, result in a markedly reduced potential for adrenal suppression (6C). The effects of ciclesonide 80 or 320 mg/day and budesonide 200 mg bd have been studied for 12 weeks in 554 asthmatic patients in a randomized multicenter European study; ciclesonide was not associated with adrenal suppression (11C). Mean urinary cortisol excretion was similar to baseline at week 12 with both doses of ciclesonide, but was significantly reduced from baseline with budesonide. These data suggest that therapeutic doses of ciclesonide do not induce adrenal suppression, whereas budesonide 200 mg bd causes potentially clinically relevant adrenal suppression. A meta-analysis of five placebo-controlled, randomized, dose–response studies of at least 4 weeks duration in 732 adult asthmatic patients was performed to assess the effect of fluticasone propionate on adrenal function (12M,13c,14C,15C,16C). The proportion of subjects on placebo with adrenal function below the lower limit of normal, assessed by a cosyntropin stimulation test, was 3.9%. The odds of impaired adrenal function increased by 1.38 (95% CI ¼ 1.01, 1.59) with fluticasone propionate 500 mg/day compared with placebo. However, in the recommended dosage range of 50–500 mg/day, fluticasone propionate had only minimal effects on adrenal function. As none of the studies assessed adrenal effects after more than 3 months, no conclusions on long-term effects can be drawn. As a note of caution, there are only limited data for daily doses of fluticasone propionate over 500 mg, as only two of the five studies included such information (13c,15C).

305

306

Chapter 16

Children The effect of inhaled budesonide on hypothalamic–pituitary–adrenal axis function and skeletal growth has been evaluated in a cross-sectional comparison of 30 controls and 72 asthmatic children, median age 9.4 years who took inhaled budesonide, median daily dose 363 mg, for a median of 18 months (17c). Although there was a significant negative correlation between height standard deviation score and dose of inhaled budesonide, there was a positive correlation between the height velocity standard deviation score and the duration of treatment. This suggests that the negative effect of inhaled budesonide on skeletal growth abates with longer duration of treatment. In a randomized, double-blind comparison of ciclesonide 160 mg/day and fluticasone propionate 88 mg bd for 12 weeks in 556 asthmatic children aged 6–15 years, creatinine-adjusted 24-hour urine cortisol excretion increased from baseline in both groups, by 10% with ciclesonide and by 6% with fluticasone propionate (18C). These results suggest similar systemic availability of the two compounds. Only two patients who took fluticasone propionate had oral candidiasis and one had voice alteration. In a double-blind, placebo-controlled study in 1310 asthmatic children aged 4–11 years, once-daily inhaled ciclesonide 40, 80, and 160 mg caused no significant adrenal suppression, as measured by 24-hour urine cortisol excretion (19C). The discontinuation rates due to treatment-related adverse events were 6.3–8.6% for ciclesonide and 13% for placebo. There were two cases of subcapsular lens opacities in those who used ciclesonide, possibly treatment related. A new laboratory tool with very high sensitivity and specificity for quantifying adrenal function in children taking inhaled glucocorticoids has been described, involving the use of dehydroepiandrosterone sulfate, the corticotropin-dependent adrenal androgen precursor, as a marker (20E).

Musculoskeletal When selecting an inhaled glucocorticoid for childhood asthma, the benefit to harm balance has to

M. Joerger, K. Hartmann, and M. Kuhn

be assessed carefully, the lowest effective dose should be used, and growth should be monitored regularly (21C). In a double-blind, placebo-controlled study, 229 children aged 4–8 years with perennial moderate-to-severe allergic rhini­ tis were randomized to budesonide aqueous nasal spray 64 mg/day or placebo for 1 year to assess growth velocity (22C). There was no difference between the two groups, and this was supported by determination of the 24-hour urinary cortisol:creatinine ratio at baseline and after 1 year. However, there was a small difference in the 1-year growth velocity of 0.27 cm/year in favor of the placebo group (95% CI ¼ –0.07, 0.62 cm/ year), and the authors suggested that some individuals are more susceptible to growth suppression when exposed to inhaled or nasal corticosteroids. The effects of fluticasone propionate and budesonide on relative growth velocity have been compared in a randomized, double-blind study in children aged 6–9 years with persistent asthma (21C). They were randomized for 12 months to either fluticasone propionate 100 mg bd (n ¼ 114) or budesonide 200 mg bd (n ¼ 119). Adjusted mean growth velocity was sig­ nificantly greater with fluticasone propio­ nate than budesonide (5.5 cm/year versus 4.6 cm/year), although the overnight urin­ ary coritsol:creatinine ratio and bone mineral density were similar. In a double-blind, randomized, placebocontrolled study in 332 asthmatic children aged 24–47 months, fluticasone propionate 44 or 88 mg bd for 12 weeks had no effect on growth velocity or 12-hour overnight urinary cortisol excretion (16C). There were similar results in 359 asthmatic children aged 1–4 years randomized to fluticasone propionate 88 mg bd or placebo for 12 weeks (23C). In 24 asthmatic children randomized to beclomethasone dipropionate 100 mg bd or budesonide 100 or 200 mg bd in a doubleblind crossover study, lower leg growth rate over 3 months did not differ between the groups (24c). This observation was corroborated by comparable adrenal func­ tion, assessed by 24-hour urinary cortisol excretion.

Drugs acting on the respiratory tract

Chapter 16

Linear growth has been evaluated in a double-blind study in 360 asthmatic chil­ dren aged 6.4–9.4 years, randomized in equal ratios to beclomethasone 200 mg bd, montelukast 5 mg/day, or placebo for 56 weeks (25C). Mean growth rate was sig­ nificantly lower with beclomethasone than placebo (–0.78 cm; 95% CI ¼ –1.06, –0.49) or montelukast (–0.81 cm). There was an imbalance in bone markers with beclo­ methasone but not montelukast. This study strongly suggests that linear growth is suppressed by beclomethasone 200 mg bd in prepubertal children.

Inhaled glucocorticoids and the risk of fracture DoTS classification: Reaction: osteoporosis from inhaled glucocorticoids Dose relation: collateral reaction Time course: late Susceptibility factors: elderly patients, female sex (postmenopausal) Until recently, no prospective studies have been large enough or performed for long enough to evaluate adequately the correlation between inhaled glucocorticoids and the risk of fracture (26R). Two large cohort studies have used the UK General Practice Research Database (GPRD) (27c,28c) to address this question, and a third used a Canadian population database (29c). The first UK case–control analysis of 16341 cases (users of inhaled glucocorticoids) and 29889 controls over a mean period of 2.7 years showed an increased risk of hip fractures with the use of inhaled glucocorticoids (OR ¼ 1.19; 95% CI ¼ 1.10, 1.28) after adjusting for the use of oral glucocorticoids (28c). Similarly, in 170818 users of inhaled glucocorticoids compared with 170818 controls there was an increased risk of hip fractures (1.22; 1.04, 1.43), vertebral fractures (1.51; 1.22, 1.85), and non-vertebral fractures (1.15; 1.10, 1.20) (29c). However, the risk of

307 fractures was also increased in 108786 users of bronchodilators compared with controls, suggesting that excess fractures were more likely to be related to the underlying respiratory disease than to the use of inhaled glucocorticoids. In the Canadian study there was no increased risk of upper limb fractures in elderly patients (over 65 years) at daily doses of under 1000 mg of inhaled glucocorticoid in beclomethasone-equivalent units, but there was a dose-related increase in the risk of fractures with daily doses over 1000 mg (29c). The Canadian study compared 133026 elderly patients (65 years and over) using inhaled or nasal glucocorticoids, recruited in 1988–2001, with 191622 controls recruited over at least 4 years. Overall, there were 3326 cases of hip fractures and 6298 cases of upper limb fractures. Although the relative risk was small and the relative risks of the different glucocorticoids remained unclear, these cohort studies provide some evidence that the use of inhaled corticosteroids is associated with a dose-related increase in the risk of fracture. To test the hypothesis of a disease-related increase in the systemic absorption of inhaled glucocorticoids and subsequent bone damage, a large case–control study using data from the GPRD was conducted. Both cases and controls had a history of obstructive airway disease, and each of the 108754 cases was matched with one control patient without a history of a fracture (30C). Higher doses of inhaled glucocorticoids were associated with an increased risk of fracture (OR ¼ 1.95; 95% CI ¼ 1.68, 2.27 in patients exposed to over 1600 mg beclomethasone equivalents per day). However, adjustment for disease severity and bronchodilator use almost completely removed the relationship (OR ¼ 1.19; 95% CI ¼ 1.01, 1.41). In a cohort study of 1671 elderly patients (75 years and over, mean 81; mean time of follow-up 9.4 years) with airflow obstruction, 982 (59%) received a prescription for an inhaled glucocorticoid and 187 patients had a fracture (31C). After adjusting for the effects of age and sex, there was a doserelated increase in fracture risk (OR for a mean daily dose over 601 mg ¼ 2.53; 95%

308

Chapter 16

CI ¼ 1.65, 3.89). The results remained significant after adjusting for oral glucocorticoid exposure, airflow obstruction, historical fracture, and bronchodilator use, and also in the subset of patients with no exposure to oral glucocorticoids (rate ratio ¼ 4.54; 95% CI ¼ 1.23, 17). This large cohort study provides some evidence that inhaled glucocorticoids are an independent susceptibility factor for fractures. However, the fact that most patients used beclomethasone dipropionate (n ¼ 722) and only a few used budesonide (n ¼ 102), might have biased the results, as beclomethasone dipropionate has higher systemic availability than budesonide. The risk of fractures with the use of inhaled glucocorticoids has been assessed in children and adolescents in a cohort study of 3744 patients aged 5–17 years with a fracture and 21757 matched controls using data from the GPRD (32C). Current exposure to inhaled glucocorticoids did not show a substantially altered risk of fracture compared with non-users, even after longterm use (OR ¼ 1.15; 95% CI ¼ 0.89, 1.48). Even current or previous exposure to oral glucocorticoids was not associated with an increased risk of fractures (OR ¼ 1.21; 95% CI ¼ 0.99, 1.49). It can be speculated that in this age group, osteoporosis is of minor etiological importance for bone fractures. Another confounder is increased physical activity in asthmatic children and adults who use inhaled glucocorticoids, which results in increased bone mineral density and a lower risk of fractures.

BETA2-ADRENOCEPTOR AGONISTS (SEDA-28, 188; SEDA-29, 171; SEDA-30, 198)

Comparative studies In the multicenter, double-blind, randomized EXCEL study, salmeterol+fluticasone propionate 50/250 mg bd was compared with formoterol+budeso­ nide 12/400 mg bd in 694 patients with persistent asthma (33C). The incidences and

M. Joerger, K. Hartmann, and M. Kuhn

types of adverse events were similar in the two groups. The most commonly reported treatment-related adverse events were hoarseness/dysphonia (2% in each group), candidiasis of the mouth or throat (2% with salmeterol+fluticasone propionate, 1% with formoterol+budesonide), and headache (1% with salmeterol+fluticasone propionate, 2% with formoterol+budesonide). There were no deaths and only a few patients reported serious adverse events. Cardiovascular Beta1- and beta2-adreno­ ceptors co-exist in the heart in a ratio of 3:1 (34R), and beta2-adrenoceptor agonists have direct effects on the heart. Cardiovas­ cular adverse effects, such as heart failure and dysrhythmias, are more frequent in patients with chronic obstructive pulmonary disease (COPD) than in the general popu­ lation, and such patients have a higher risk of hospitalization and death because of these conditions (35C,36C). In a randomized, placebo-controlled study of the cardiac safety of formoterol 12 mg bd for 8 weeks in 204 patients with COPD, 24-hour continuous electrocardio­ graphy (Holter monitoring) was performed at screening and after 2 and 8 weeks of treatment (37C). Only six patients (four taking formoterol and two taking placebo) had a predefined, prodysrhythmic event. Holter monitoring showed no significant differences between formoterol and pla­ cebo, for variables such as heart rate, number and rate of ventricular extra beats, ventricular tachycardia events, and supra­ ventricular extra beats. Corrected QT intervals were similar. Cardiovascular adverse events were recorded in one patient taking formoterol (atrial flutter) and four taking placebo (atrioventricular block, palpitation, sinus bradycardia, supraventricular tachycardia). Hyperten­ sion was reported in one patient taking placebo. There were no important differ­ ences between the groups in overall adverse events. Although the results of this study are reassuring, larger studies providing more robust statistical power are required to assess the full benefit to harm

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balance of formoterol in this patient population.

Respiratory adverse effects of long-acting beta2-adrenoceptor agonists The overall safety of long-acting beta2adrenoceptor agonists was reviewed in SEDA-30 (p. 198). Recently, several authors have questioned the long-term safety of these agents (38R,39C,40M,41r). In a meta-analysis of 19 trials in 33826 patients with asthma, long-acting beta2adrenoceptor agonists increased exacerbations of asthma that required hospitalization (OR ¼ 2.6; 95% CI ¼ 1.6, 4.3) and life-threatening exacerbations (OR ¼ 1.8; 95% CI ¼ 1.1, 3.9) compared with placebo (40M,42r). The risk of asthma-related death was increased (OR ¼ 3.5; 95% CI ¼ 1.3, 9.3), with a pooled risk difference of 0.07% (95% CI ¼ 0.01, 0.1) over 6 months, using the placebo group of the SMART-study as a reference. Asthma-related hospitalization was more frequent in patients who used salmeterol (OR ¼ 1.7; 95% CI ¼ 1.1, 2.7) or formoterol (OR ¼ 3.2; 95% CI ¼ 1.7, 6.0), and in both adults (OR ¼ 2.0; 95% CI ¼ 1.1, 3.9) and children (OR ¼ 3.9; 95% CI ¼ 1.7, 8.8). Of the 19 studies, 14 contained data on asthma-related deaths. Inhaled glucocorticoids were used in 54% of the patients who used long-acting beta2adrenoceptor agonists and in 53% of those who used placebo. As a note of caution, the SMART study contributed largely to this meta-analysis, and thus introduced potential bias. This meta-analysis had several limitations, owing to the high number of excluded studies, heterogeneity of asthma severity between studies, co-medication, especially with inhaled glucocorticoids, and treatment compliance (42r). In summary, this meta-analysis has provided evidence that regular treatment with long-acting beta2-adrenoceptor agonists is associated with an increased risk of severe asthma exacerbations and of death from asthma in a small but relevant subgroup of patients.

309 The limitations of the studies that have been conducted so far preclude definitive conclusions about the potential of inhaled glucocorticoids to limit or prevent these adverse outcomes. Salmeterol The double-blind, randomized British Salmeterol Nationwide Surveillance study (SNS) compared salmeterol 50 mg bd and salbutamol 200 mg qd over 16 weeks in 25180 patients with asthma in addition to their usual treatment (43C). Life-threatening, asthma-related events were less frequent with salmeterol (9.9%) than with salbutamol (11.6%); however, combined respiratory- and asthma-related mortality was higher with salmeterol (0.07%) than with salbutamol (0.02%), although this difference did not reach statistical significance. Subsequently, the large randomized, double-blind, placebo-controlled Salmeterol Multicenter Asthma Research Trial was (SMART) (38R,39C,44r,45r,46r) designed to clarify the observation of excess asthma-related mortality in patients using salmeterol. This study compared salmeterol 42 mg bd and placebo added to usual asthma care in 26355 patients over 28 weeks (39C). The primary end-point was a comparison of respiratory-related death or life-threatening experiences. In those who used salmeterol there was a small but significant increase in respiratory-related deaths (24 versus 11; RR ¼ 2.16; 95% CI ¼ 1.06, 4.41) and asthma-related deaths (13 versus 3; RR ¼ 4.37; 95% CI ¼ 1.25, 15.34), and in combined asthma-related deaths or life-threatening experiences (37 versus 22; RR ¼ 1.71; 95% CI ¼ 1.01, 2.89). A retrospective subgroup analysis showed no significant differences in respiratory-related deaths or life-threatening experiences in Caucasian patients. AfroAmerican patients had a significantly increased risk of respiratory-related death or life-threatening experiences (RR ¼ 2.8; 95% CI ¼ 1.18, 6.61) and asthma-related death or life-threatening experiences (RR ¼ 4.65; 95% CI ¼ 1.58, 14). Patients who used salmeterol without inhaled glucocorticoids (53% of all patients) had a higher asthma-related mortality than those

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who used concurrent inhaled glucocorticoids (9 versus 0 patients). It is unclear whether the concurrent use of inhaled glucocorticoids together with salmeterol protects patients from harmful effects (47R). Asthma-related life-threatening experiences have also been described after the concurrent use of salmeterol and inhaled glucocorticoids (48r). The inferior outcome in Afro-American patients with asthma receiving salmeterol, as described in the SMART study, may have resulted from interethnic differences in the pharmacogenetic characteristics of the beta2-adrenoceptor (49C). Formoterol There have been three prospective, randomized, placebo-controlled, double-blind pivotal trials of formoterol 12 and 24 mg bd in patients with asthma (50C). Patients who used regular formoterol 24 mg bd had more serious asthma exacerbations than patients who used placebo. In the first study, four (3%) of 135 adults who used formoterol 24 mg bd had serious asthma exacerbations compared with none of the 136 placebo-treated patients (51C). In the second study, five (3.7%) of 136 patients who used formoterol 24 mg bd had serious asthma exacerbations compared with two (1.4%) of 141 placebo-treated patients. In the third study, 11 (6.4%) of 171 children who used formoterol 24 mg bd had serious asthma exacerbations compared with none of the 176 placebo-treated patients (52C). In a post-approval, placebo-controlled, parallel-group, multicenter safety study, 2085 asthma patients were randomized for 16 weeks to formoterol 12 mg bd, formoterol 12 mg bd plus up to 24 mg/day on demand, formoterol 24 mg twice daily, or placebo; there were serious respiratory events in 0.9%, 0.4%, 0.2%, and 0.2% respectively; there were serious asthma exacerbations in 5.9%, 4.4%, 6.3%, and 8.8% (53C). There was no association between high-dose formoterol (24 mg bd) and serious asthma exacerbations. The study had 80% power to detect a 3% difference of serious asthma exacerbations between the groups. In conclusion, to avoid the risk of serious asthma exacerbations, patients with asthma

M. Joerger, K. Hartmann, and M. Kuhn

should not regularly use more than 48 mg of formoterol per day.

Genetic susceptibility factors with the therapeutic use of long-acting beta2-adrenoceptor agonists Data on the relation between beta2-adrenoceptor genotypes and salbutamol treatment were reviewed in SEDA-29 (p. 173) and SEDA-30 (p. 199). New data on the effect of the arginine-16 (Arg16) beta2-adrenoceptor polymorphism on the course of asthma in young patients and on airway hyper-responsiveness in healthy Japanese subjects have since been published. In the first study, a cross-sectional survey, the variants at positions 16 and 27 of the beta2-adrenoceptor gene were determined in 546 children and young asthmatics; the primary outcome measure was asthma exacerbations over the previous 6 months (54C). There was a significantly increased risk of asthma exacerbations when the homozygous genotypes Arg/Arg and Gly/Gly were compared (OR ¼ 2.05; 95% CI ¼ 1.19, 3.53), particularly in patients who had been exposed to salmeterol (OR ¼ 3.40; 95% CI ¼ 1.19, 9.40). Thus, the Arg16 variant of the beta2-adrenoceptor predisposes to exacerbations in asthmatic children and young adults, especially in those exposed to regular salmeterol. This could be explained by genotype-selective down-regulation and impaired receptor coupling by regular salmeterol, and is in agreement with previous studies that showed clinically important increases in asthma exacerbations in homozygous arginine-16 asthmatic patients taking regular salbutamol compared with nonhomozygous patients (55C,56C). This is further in agreement with a more recent retrospective meta-analysis of two randomized, double-blind, placebo-controlled studies that showed no response in salmeterol-treated patients homozygous for Arg16 compared with patients homozygous for Gly16, independent of the additional use of inhaled glucocorticoids (49C).

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However, in another randomized, placebo-controlled study there was no effect of the beta2-adrenoceptor Arg16Gly genotype on treatment response in 183 asthmatic patients who used salmeterol 50 mg bd+fluticasone propionate 100 mg or daily montelukast 10 mg for 12 weeks (57C). Even in the run-out period, all the subjects had similar reductions in measures of asthma control, with no differences between beta2-adrenoceptor genotypes. This might be explained by the fact that this analysis did not evaluate the effect of salmeterol as monotherapy, but concurrently with fluticasone propionate. However, salmeterol as a single agent is not recommended in asthmatic patients. In a study of the association between nonspecific airway hyper-responsiveness and the beta2-adrenoceptor polymorphism at position 16 in 120 asymptomatic healthy Japanese subjects those who carried the Gly16 allele were significantly more responsive to methacholine than those who carried the Arg16 allele (58C). These results are in agreement with a comprehensive meta-analysis of 28 previously published genetic studies that showed a strong association between the Gly16 allele and nocturnal asthma and asthma severity (59M). Overall, the cumulative data suggest that the beta2-adrenoceptor variant at position 16 has a significant impact on airway hyperresponsiveness in individuals who have not been exposed to beta2-adrenoceptor agonists and on beta2-adrenoceptor down-regulation in asthmatic individuals exposed to beta2adrenoceptor agonists. Prospective studies on the safety and activity of beta2-adrenoceptor agonists in patients who carry the Arg16 allele should clarify the latter.

Dosage regimens High-dose formoterol and salbutamol The safety and tolerabil­ ity of high-dose formoterol and salbutamol has been assessed in a two-way, crossover, double-blind study in 17 adults with mild­ to-moderate COPD, randomized to either formoterol 24 mg or salbutamol 600 mg (60c). The treatment was switched after washout for 4–7 days. High-dose formoterol and

311 salbutamol were equally well tolerated, with no reports of serious adverse events. Both were associated with hypokalemia (mean minimum values 3.4 and 3.3 mmol/l respectively), hyperglycemia (mean maxi­ mum values 9.0 and 8.7 mmol/l), and small increases in mean QTc interval (mean maximum 439 ms with both). There were no relevant between-treatment differences in adverse events or laboratory values. However, the study was very small (n ¼ 17), and conclusions should be made with caution. Furthermore, extrapulmonary adverse events were monitored only up to 3 hours after the dose, despite the fact that formoterol has a considerably longer dura­ tion of action than salbutamol. Combined salmeterol and fluticasone propionate In a randomized, double-blind placebo-controlled comparison of salme­ terol 50 mg bd alone, or fluticasone propio­ nate 500 mg bd alone or the combination in a single inhaler, for 3 years in 6112 patients with COPD, the hazard ratio for death with the combination compared with placebo was 0.825 (95% CI ¼ 0.68, 1.0), corre­ sponding to a difference of 2.6% or an 18% reduction in the risk of death. There was no significant difference in the prob­ ability of fractures (6.3% with the combina­ tion, 5.1% with placebo, 5.1% with salmeterol, and 5.4% with fluticasone) (61C). There was no excess of cardiac disorders in patients treated with the combination or salmeterol alone, and there were no significant differences in bone mineral density or cataracts between the groups.

ANTICHOLINERGIC DRUGS (SEDA-28, 190; SEDA-29, 174; SEDA-30, 203)

Tiotropium bromide

(SEDA-28, 190; SEDA-29, 174; SEDA-30, 203) Inhaled ipratropium bromide has gained widespread acceptance in the treatment of

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COPD. Common recognized unwanted effects include urinary retention, dry mouth, constipation, tachycardia, palpitation, and narrow-angle glaucoma. In an analysis of pooled adverse event data from 19 randomized, double-blind, placebo-con­ trolled trials in 4435 patients who used tiotropium bromide and 3384 who used placebo, contributing to 2159 person-years of exposure to tiotropium bromide and 1662 person-years of exposure to placebo, dyspnea, dry mouth, COPD exacerbation, and upper respiratory tract infection were the most commonly reported adverse events (62C). There was a higher relative risk of dry mouth (RR ¼ 3.60; 95% CI ¼ 2.56, 5.05) and a lower relative risk of dyspnea (RR ¼ 0.64; 95% CI ¼ 0.50, 0.81) and COPD exacerbation (RR ¼ 0.72; 95% CI ¼ 0.64, 0.82) with tiotropium. Allcause mortality (RR ¼ 0.76; 95% CI ¼ 0.50, 1.16), cardiovascular mortality including myocardial infarction and cardiac arrest (RR ¼ 0.57; 95% CI ¼ 0.26, 1.26), and respiratory mortality (RR ¼ 0.71; 95% CI ¼ 0.29, 1.74) were not over-represented in those who used tiotropium bromide. However, urinary retention was signifi­ cantly more frequent in the patients who used tiotropium bromide (RR ¼ 11; 95% CI ¼ 1.26, 95). The results of this analysis support the current safety profile of tiotropium, dry mouth and urinary reten­ tion being the most frequent adverse events. A meta-analysis of comparisons of tio­ tropium bromide with placebo, ipratropium bromide, or long-acting beta2-adrenoceptor agonists over at least 12 weeks nine clinical trials in a total of 8002 patients were included (63C). Dry mouth was significantly more common with tiotropium bromide than placebo (OR ¼ 4.6; 95% CI ¼ 3.0, 7.1), ipratropium (OR ¼ 2.1; 95% CI ¼ 1.05, 4.2), and salmeterol (OR ¼ 4.7; 95% CI ¼ 2.4, 9.2); urinary retention was more common with tiotropium bromide than placebo (OR ¼ 2.5; 95% CI ¼ 0.5, 14) and salmeterol (OR ¼ 3.0; 95% CI ¼ 0.1, 75), but not significantly so, and no comparative data were available for ipratropium. There was also a consistent but statistically insignificant increase in

M. Joerger, K. Hartmann, and M. Kuhn

constipation in patients who took tiotro­ pium compared with placebo. The results of this meta-analysis were in agreement with the data from a pooled clinical trial analysis (63C).

LEUKOTRIENE MODIFIERS (SEDA-28, 191; SEDA-29, 174; SEDA-30, 203)

Montelukast Musculoskeletal Linear growth has been evaluated in a double-blind study in 360 asthmatic children aged 6.4–9.4 years, randomized in equal ratios to beclomethasone 200 mg bd, montelukast 5 mg/day, or placebo for 56 weeks (25C). Mean growth rate was significantly lower with beclomethasone than placebo (–0.78 cm; 95% CI ¼ –1.06, –0.49) or montelukast (–0.81 cm). There was an imbalance in bone markers with beclomethasone but not montelukast. Montelukast should be considered for prepubertal asthmatic children, as it is effective in controlling multiple aspects of mild-to-moderate chronic asthma in children and adults (64C). Susceptibility factors Adults Montelu­ kast 10 mg/day was well tolerated in a multicenter phase IV study in 6158 patients with both asthma and allergic rhinitis over 4–6 weeks (65C). There were 21 treatmentrelated adverse events in 14 patients (0.23%), of which headache, gastrointest­ inal infections, and sleepiness were the most common; none was serious. Children The safety of montelukast has been studied in an open, non-comparative, prospective, 12-month trial in 50 children (mean age 5.4 years) with mild persistent asthma (66c). Patients aged 2–4 years received montelukast 4 mg/day and patients over 4 years 5 mg/day for 12 weeks. Of the 50 children, 19 had mild adverse effects, such as loss of appetite (16%), raised liver function tests (18%), and headache (10%).

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None of these mild adverse events required withdrawal. The effect of montelukast 5 mg/day for 4 weeks in exercise-induced bronchocon­ striction has been studied in a double-blind, randomized, placebo-controlled trial in 32 asthmatic children aged 6–12 years (67c). Montelukast was significantly more protective than placebo against exerciseinduced bronchoconstriction after 3, 7, and 28 days, and there was no significant difference in the percentage fall in FEV1 between different days. These data provide reassurance that montelukast does not lead to tolerance to the bronchoprotective effect in children with mild persistent asthma.

PHOSPHODIESTERASE TYPE IV INHIBITORS Phosphodiesterase type IV is a major reg­ ulator of cyclic adenosine monophosphate metabolism in many cell types, including smooth muscle, proinflammatory calls, and immune cells (68R). Inhibitors of phospho­ diesterase type IV inhibit the synthesis of tumor necrosis factor alpha in monocytes, monocyte-derived dendritic cells, and macrophages and inhibit CD4+ T cell pro­ liferation and production of cytokines (e.g., interleukin 2 and interleukin 4), leukotriene B4 synthesis, and the formation of reactive oxygen species (69R). In early preclinical and clinical studies inhibition of phosphodiester­ ase type IV resulted in bronchodilatation, neuromodulation, and reduced numbers and activation of inflammatory cells relevant to obstructive lung disease (70E).

Cilomilast Cilomilast is an orally active, potent, selective inhibitor of phosphodiesterase type IV. Gastrointestinal The safety of cilomilast has been assessed in a randomized,

313 double-blind, placebo-controlled study in 647 patients with COPD, who were rando­ mized to oral cilomilast 15 mg bd or placebo for 24 weeks (71C). The numbers of adverse events that led to withdrawal were similar in the two groups (placebo 16%, cilomilast 22%). Similar proportions of subjects in each group had at least one adverse event (cilomilast 87%, placebo 82%). A higher proportion of those who received cilomilast had gastrointestinal adverse events (e.g., diarrhea, nausea, abdominal pain) com­ pared with placebo (49% versus 25%), but there was a higher proportion of serious gastrointestinal adverse events in patients who took placebo compared with cilomilast (1.9% versus 0.2%). Gastrointestinal events that interfered with daily activities were reported more often after cilomilast than placebo (17% versus 8% respectively). There were no clinically relevant cardio­ vascular adverse events.

Roflumilast Roflumilast, an oral inhibitor of phospho­ diesterase type IV, has anti-inflammatory activity and a pharmacokinetic profile that favors once-daily dosing. A dose of 500 mg/ day reduced exercise-induced asthma and attenuated allergen-induced asthmatic reac­ tions (72c). Dose-ranging studies In a randomized, double-blind phase 2/3 study of roflumilast 100, 250, or 500 mg/day for 12 weeks in 693 patients with mild-to-moderate asthma, 57% of the patients taking 500 mg/day, 48% of those taking 250 mg/day, and 46% of those taking 100 mg/day had adverse events (73C). Most of the adverse events that were considered to be treatmentrelated were mild to moderate and resolved spontaneously with continued treatment. All serious adverse events (18 cases in 693 patients) were considered by the investigator to be unrelated or probably not related to roflumilast. The most fre­ quently reported treatment-related adverse events were headache, diarrhea, and nausea, which were more common in patients who

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took roflumilast 500 mg/day. Most episodes of headache, diarrhea, and nausea occurred within the first week of treatment (53%, 65%, and 75% of events respectively) and lasted for less than 2 weeks in 79%, 83%, and 75% of events respectively. There were no clinically relevant changes in routine laboratory parameters. Comparative studies Roflumilast 500 mg/ day and beclomethasone dipropionate 200 mg bd for 12 weeks have been compared in 499 patients with persistent asthma in a double-blind, randomized, non-inferiority study (74C). The most frequent adverse events were worsening asthma (9%) and nausea (6%) with roflumilast and worsening asthma (4%) and upper respiratory tract infections (4%) with beclomethasone dipro­ pionate. Most of the adverse events were mild to moderate in intensity. All the serious adverse events (1% in each group) were considered to be unrelated to the treatment. Placebo-controlled studies The safety of roflumilast 250 and 500 mg/day for 24 weeks has been assessed in 1411 patients with COPD in a multicenter, double-blind, randomized, placebo-controlled study (75C). Improvement in health-related qual­ ity of life was greater with roflumilast 250 and 500 mg/day than with placebo, although the differences were not signifi­ cant. Adverse events that were thought to be probably treatment related were reported in 12 patients taking placebo (4%), 46 patients taking roflumilast 250 mg/day (8%), and 92 patients taking roflumilast 500 mg/day (17%). Diarrhea was the most common followed by nausea. Headache was least likely to have been treatment related. There were no apparent changes in vital signs, electrocardiography, or clinical laboratory parameters during treatment with roflumilast. The withdrawal rate due to adverse events was higher with roflumilast 500 mg/day (15%) than roflumi­ last 250 mg/day (10%) or placebo (8%). The most frequent serious adverse event was exacerbation of COPD in each group. There was no pattern or trend associating

M. Joerger, K. Hartmann, and M. Kuhn

the incidence or cause of serious adverse events with roflumilast.

Non-prescription cough and cold medicines The US FDA has reviewed the safety and effectiveness of non-prescription cough and cold medicines in children and wants to determine whether the benefits from these products justify the risks of harms, especially in children under 2 years of age (76S). Some of the serious reported adverse events appear to be related to the amounts used. The FDA has issued a Public Health Advisory to warn that an over-the-counter medicine can be harmful if more than the recommended amount is used, if it is given too often, or if more than one cough and cold medicine contain­ ing the same active ingredient is used. Parents are advised to follow the directions for use on the product label carefully. The Advisory lists a set of facts that parents need to know about using cold and cough products in children, including the follow­ ing highlights:  Do not use cough and cold products in children under 2 years of age unless given specific directions to do so by a healthcare provider.  Too much medicine can lead to serious adverse effects, particularly in children aged 2 years and younger.  For liquid products, parents should use the measuring device (dropper, dosing cup, or dosing spoon) that is packaged with each formulation and that is marked to deliver the recommended dose; a kitchen teaspoon is not an appropriate measuring device for giving medicines to children.  If a measuring device is not included with the product, parents should obtain one at the pharmacy.  If a child’s condition worsens or does not improve, stop using the product immedi­ ately and take the child to a health-care provider for evaluation.

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315

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COPD patients. Ann Epidemiol 2006;16(1): 63–70. Campbell SC, Criner GJ, Levine BE, Simon SJ, Smith JS, Orevillo CJ, Ziehmer BA. Cardiac safety of formoterol 12 microg twice daily in patients with chronic obstruc­ tive pulmonary disease. Pulm Pharmacol Ther 2007;20(5):571–9. Martinez FD. Safety of long-acting beta­ agonists—an urgent need to clear the air. N Engl J Med 2005;353(25):2637–9. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multi­ center Asthma Research Trial: a compar­ ison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129(1):15–26. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of longacting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med 2006;144(12):904–12. Ernst P, McIvor A, Ducharme FM, Boulet LP, FitzGerald M, Chapman KR, Bai T. Canadian Asthma Guideline Group. Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroids. Ann Intern Med 2006;145(9):692–4. Glassroth J. The role of long-acting betaagonists in the management of asthma: analysis, meta-analysis, and more analysis. Ann Intern Med 2006;144(12):936–7. Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993;306(6884):1034–7. Vassiliou V, Zipitis CS. Long-acting bronch­ odilators: time for a re-think. J R Soc Med 2006;99(8):382–3. O'Byrne PM, Adelroth E. Beta2 deja vu. Chest 2006;129(1):3–5. Lurie P, Wolfe SM. Misleading data ana­ lyses in salmeterol (SMART) study. Lancet 2005;366(9493):1261–2. Donohue JF, Fromer L. Long-acting betaagonists role in asthma management. J Fam Pract 2006;Suppl:1–6. Weinberger M, Abu-Hasan M. Life-threa­ tening asthma during treatment with salme­ terol. N Engl J Med 2006;355(8):852–3.

317 49. Wechsler ME, Lehman E, Lazarus SC, Lemanske Jr RF, Boushey HA, Deykin A, Fahy JV, Sorkness CA, Chinchilli VM, Craig TJ, DiMango E, Kraft M, Leone F, Martin RJ, Peters SP, Szefler SJ, Liu W, Israel E. National Heart, Lung, and Blood Institute's Asthma Clinical Research Net­ work. Beta-adrenergic receptor polymorph­ isms and response to salmeterol. Am J Respir Crit Care Med 2006;173(5):519–26. 50. Mann M, Chowdhury B, Sullivan E, Nicklas R, Anthracite R, Meyer RJ. Serious asthma exacerbations in asthmatics treated with high-dose formoterol. Chest 2003;124(1): 70–4. 51. Bensch G, Lapidus RJ, Levine BE, Lumry W, Yegen U, Kiselev P, Della Cioppa G. A randomized, 12-week, double-blind, pla­ cebo-controlled study comparing formoterol dry powder inhaler with albuterol metereddose inhaler. Ann Allergy Asthma Immunol 2001;86(1):19–27. 52. Bensch G, Berger WE, Blokhin BM, Soco­ lovsky AL, Thomson MH, Till MD, Castell­ sague J, Della Cioppa G. International Study Group on Foradil Evaluation in Pediatric Asthma. One-year efficacy and safety of inhaled formoterol dry powder in children with persistent asthma. Ann Allergy Asthma Immunol 2002;89(2):180–90. 53. Wolfe J, Laforce C, Friedman B, Sokol W, Till D, Della Cioppa G, van As A. Formoterol, 24 microg bid, and serious asthma exacerbations: similar rates com­ pared with formoterol, 12 microg bid, with and without extra doses taken on demand, and placebo. Chest 2006;129(1):27–38. 54. Palmer CN, Lipworth BJ, Lee S, Ismail T, Macgregor DF, Mukhopadhyay S. Argi­ nine-16 beta2 adrenoceptor genotype pre­ disposes to exacerbations in young asthmatics taking regular salmeterol. Thorax 2006;61(11):940–4. 55. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term beta agonist use: influence of beta(2) adrenoceptor polymorphism. Thorax 2000; 55(9):762–7. 56. Israel E, Drazen JM, Liggett SB, Boushey HA, Cherniack RM, Chinchilli VM, et al. The effect of polymorphisms of the beta(2)­

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Chapter 16 adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000;162(1):75–80. Bleecker ER, Yancey SW, Baitinger LA, Edwards LD, Klotsman M, Anderson WH, Dorinsky PM. Salmeterol response is not affected by beta2-adrenergic receptor geno­ type in subjects with persistent asthma. J Allergy Clin Immunol 2006;118(4):809–16. Fukui Y, Hizawa N, Takahashi D, Maeda Y, Jinushi E, Konno S, Nishimura M. Associa­ tion between nonspecific airway hyperre­ sponsiveness and Arg16Gly beta2­ adrenergic receptor gene polymorphism in asymptomatic healthy Japanese subjects. Chest 2006;130(2):449–54. Contopoulos-Ioannidis DG, Manoli EN, Ioannidis JP. Meta-analysis of the associa­ tion of beta2-adrenergic receptor poly­ morphisms with asthma phenotypes. J Allergy Clin Immunol 2005;115(5):963–72. Rosenkranz B, Rouzier R, Kruse M, Dobson C, Ayre G, Horowitz A, Fitoussi S. Safety and tolerability of high-dose formoterol (via Aerolizer) and salbutamol in patients with chronic obstructive pulmon­ ary disease. Respir Med 2006;100(4):666–72. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J. TORCH investigators. Salme­ terol and fluticasone propionate and survi­ val in chronic obstructive pulmonary disease. N Engl J Med 2007;356(8):775–89. Kesten S, Jara M, Wentworth C, Lanes S. Pooled clinical trial analysis of tiotropium safety. Chest 2006;130(6):1695–703. Barr RG, Bourbeau J, Camargo CA, Ram FS. Tiotropium for stable chronic obstruc­ tive pulmonary disease: a meta-analysis. Thorax 2006;61(10):854–62. Williams B, Noonan G, Reiss TF, Knorr B, Guerra J, White R, Matz J. Long-term asthma control with oral montelukast and inhaled beclomethasone for adults and children 6 years and older. Clin Exp Allergy 2001;31(6):845–54. Virchow JC, Bachert C. Efficacy and safety of montelukast in adults with asthma and allergic rhinitis. Respir Med 2006;100(11): 1952–9.

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66. Ghosh G, Manglik AK, Roy S. Efficacy and safety of montelukast as monotherapy in children with mild persistent asthma. Indian Pediatr 2006;43(9):780–5. 67. de Benedictis FM, del Giudice MM, Fore­ nza N, Decimo F, de Benedictis D, Capristo A. Lack of tolerance to the protective effect of montelukast in exercise-induced bronch­ oconstriction in children. Eur Respir J 2006; 28(2):291–5. 68. Torphy TJ. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 1998; 157(2):351–70. 69. WilliamsBundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, Beume R. In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J Pharmacol Exp Ther 2001; 297(1):280–90. 70. Gamble E, Grootendorst DC, Brightling CE, Troy S, Qiu Y, Zhu J, Parker D, Matin D, Majumdar S, Vignola AM, Kroegel C, Morell F, Hansel TT, Rennard SI, Compton C, Amit O, Tat T, Edelson J, Pavord ID, Rabe KF, Barnes NC, Jeffery PK. Antiinflammatory effects of the phospho­ diesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;168(8): 976–82. 71. Rennard SI, Schachter N, Strek M, Rickard K, Amit O. Cilomilast for COPD: results of a 6-month, placebo-controlled study of a potent, selective inhibitor of phosphodiester­ ase 4. Chest 2006;129(1):56–66. 72. van Schalkwyk E, Strydom K, Williams Z, Venter L, Leichtl S, Schmid-Wirlitsch C, et al. Roflumilast, an oral, once-daily phos­ phodiesterase 4 inhibitor, attenuates aller­ gen-induced asthmatic reactions. J Allergy Clin Immunol 2005;116(2):292–8. 73. Bateman ED, Izquierdo JL, Harnest U, Hofbauer P, Magyar P, Schmid-Wirlitsch C, Leichtl S, Bredenbröker D. Efficacy and safety of roflumilast in the treatment of asthma. Ann Allergy Asthma Immunol 2006;96(5):679–86. 74. Bousquet J, Aubier M, Sastre J, Izquierdo JL, Adler LM, Hofbauer P, Rost KD,

Drugs acting on the respiratory tract

Chapter 16

Harnest U, Kroemer B, Albrecht A, Bre­ denbröker D. Comparison of roflumilast, an oral anti-inflammatory, with beclometha­ sone dipropionate in the treatment of persistent asthma. Allergy 2006;61(1):72–8. 75. Rabe KF, Bateman ED, O'Donnell D, Witte S, Bredenbroker D, Bethke TD.

319 Roflumilast—oral anti-inflammatory treat­ ment for chronic obstructive pulmonary disease: a randomised controlled trial. Lan­ cet 2005;366(9485):563–71. 76. Anonymous. Non-prescription cough and cold medicines. Caution needed with use in. WHO Pharm Newslett 2007;4:5.

J.K. Aronson

17

Positive inotropic drugs and drugs used in dysrhythmias

(SED15, 648; SEDA-28, 196; SEDA-29, 182; SEDA-30, 209)

CARDIAC GLYCOSIDES

Placebo-controlled studies Post-hoc ana­ lyses of the Digoxin Investigation Group (DIG) study continue to appear. In 988 ambulatory patients with chronic heart failure in sinus rhythm and ejection fractions over 45% randomly assigned to digoxin (n ¼ 492) or placebo (n ¼ 496), 102 (21%) in the digoxin group and 119 patients (24%) in the placebo group (HR ¼ 0.82; 95% CI ¼ 0.63, 1.07) experienced the primary combined outcome of heart failure hospitalization or heart failure mortality during a mean follow-up period of 37 months (1c). Digoxin had no effect on all-cause or cause-specific mortality or on all-cause or cardiovascular hospitalization. Digoxin was associated not only with a trend toward a reduction in hospitalizations resulting from worsening heart failure (HR ¼ 0.79; 95% CI ¼ 0.59, 1.04), but also with a trend toward an increase in hospitalizations for unstable angina (HR ¼ 1.37; 95% CI ¼ 0.99, 1.91). The likeliest conclusion from these results is that digoxin does not alter outcomes in this group of patients.

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03117-1 r 2009 Elsevier B.V. All rights reserved.

Cardiovascular Bidirectional ventricular tachycardia has been attributed to digoxin in a 70-year-old man with hypertension, an idiopathic cardiomyopathy, and left bundle branch block (LBBB); there was renal impairment and the serum digoxin concen­ tration was 3.9 ng/ml (2A). Ventricular tachydysrhythmias are often associated with prolongation of the QT interval. However, in a 72-year-old woman syncope, ventricular tachycardia/fibrillation, atrial tachycardia, and atrioventricular block due to digitalis toxicity (plasma concentration 4.3 ng/ml; glycoside not iden­ tified, but presumably digoxin) were asso­ ciated with shortening of the QTc interval to 0.35 seconds, lengthening to 0.41 seconds as the plasma digitalis concentration fell to 0.7 ng/ml (3A). The role of QT interval shortening in the genesis of these effects was not clear. Nervous system Accidental administra­ tion of digoxin intrathecally has been reported in three cases in which ampoules containing digoxin were thought to have been confused with ampoules containing lidocaine, because they looked alike (4A). In one case, paresthesia and paralysis of the lower limbs occurred up to the umbilical level; the patient, a 21-year-old man, was conscious but agitated, tachycardic, and hypertensive, with abdominal distension, urinary retention, and absent leg reflexes. He recovered spontaneously. Sensory systems The adverse visual effects of cardiac glycoside intoxication include chromatopsia, photophobia, and

321

322 photopsia, the perception of flashes of light. Photopsia was the first sign of digitalis intoxication in a 72-year-old woman; the plasma digoxin concentration was only 1.7 ng/ml, but she had renal insufficiency, which may sensitize the tissues to the adverse effects of cardiac glycosides, as well as causing retention of digoxin (5A). The serum potassium was raised, which could have been partly due to digitalis intoxication. Gastrointestinal Digoxin can rarely cause non-occlusive acute mesenteric ischemia, as has been demonstrated in another case, that of a 68-year-old man, in whom ultrasono­ graphy was diagnostic (6A). Drug–drug interactions Josamycin Josa­ mycin has been reported to increase the serum digoxin concentration (7A).  On day 7 a premature infant, born at 32 weeks

with a congenital cardiac defect was given digoxin 5 mg/kg/day, furosemide 2 mg/kg/day, and captopril. On day 62 he developed respiratory failure due to an infection and was given josamycin 50 mg/kg/day. He developed a bradycardia and the electrocardiogram showed sinoatrial block and ventricular extra beats. The serum digoxin concentration was 3.0 ng/ml and digoxin toxicity was exacerbated by hypokalemia of 3.2 mmol/l. Digoxin was withheld and he was given intravenous atro­ pine 15 mg/kg and antidigoxin antibody Fab fragments, with immediate effect.

Josamycin inhibits P glycoprotein (8E), and probably inhibited the renal secretion of digoxin. Paroxetine A similar interaction has been reported with paroxetine (9A).  A 68-year-old woman with atrial fibrillation

taking digoxin 0.25 mg/day and a serum digoxin concentration of 1.5 ng/ml was given paroxetine 20 mg/day for depression. On day 5 she developed nausea, vomiting, and dizziness and on day 7 delirium with visual hallucina­ tions and disorientation. Her serum digoxin concentration was 5.2 ng/ml. The electrocar­ diogram showed many ventricular extra beats and complete atrioventricular block. Paroxe­ tine was withdrawn and her serum digoxin concentration fell.

Chapter 17

J.K. Aronson

Paroxetine inhibits P glycoprotein (10E), and inhibits the renal secretion of digoxin (11r). However, the large increase in digoxin concentration may not have been completely explicable by such an effect. Solifenacin In a crossover placebocontrolled study in healthy men solifenacin had no effect on the steady-state pharma­ cokinetics of digoxin (12C). Telithromycin A similar interaction has been reported with telithromycin (13A).  A 58-year-old woman who had taken digoxin

0.25 mg/day for more than 35 years took a 5-day course of telithromycin. On day 6 she developed general malaise having had three episodes of syncope over the previous 2 days. Her plasma digoxin concentration was raised and electrocardiography showed non-specific repolarization anomalies.

Telithromycin increases digoxin plasma concentrations, probably by inhibiting renal P glycoprotein (14E). Trospium In 40 healthy subjects trospium chloride 20 mg bd for 12 days had negligible effects on the pharmacokinetics of single and repeated doses of digoxin; this was consistent with a lack of effect of trospium in vitro on P glycoprotein activity (15CE). Management of adverse drug reactions Digoxin-specific antibody Fab fragments are effective in the management of digitalis intoxication. However, in patients with severe renal impairment the clearance of antibody–digoxin complexes is reduced, and rebound toxicity can occur if the cardiac glycoside dissociates from the anti­ body. Removal of the complexes by plas­ mapheresis can obviate this (16A).  A 79-year-old patient took digoxin 30 mg and

became comatose, with a junctional rhythm, hemodynamic instability, and acute renal insufficiency. The plasma digoxin concentra­ tion was 16.7 ng/ml. A temporary pacemaker was introduced and Fab fragments 760 mg were given, closely followed by plasmapher­ esis, during which the patient gradually recov­ ered consciousness and sinus rhythm. Plasma digoxin concentrations were 13 and 2.4 ng/ml at 10 and 24 hours after plasmapheresis.

Positive inotropic drugs and drugs used in dysrhythmias

In previous cases treated with late plasmapheresis a second session was required (17A,18A). Repeated doses of activated charcoal reduce mortality in patients who have poisoned themselves with the seeds of the yellow oleander (Thevetia peruviana). The effect of activated charcoal on the pharma­ cokinetics of the cardiac glycosides that are found in T. peruviana has been studied in patients who were given single and multiple doses of activated charcoal (19c). Charcoal shortened the terminal half-life and 24-hour mean residence time of the combined glycosides, measured as digoxin-like immu­ noactivity.

OTHER POSITIVE INOTROPIC DRUGS

(SED-15, 2822; SEDA-28, 199; SEDA-29, 183; SEDA-30, 212)

Milrinone

(SED-15, 2346; SEDA-28, 199; SEDA-29, 183; SEDA-30, 212)

Management of adverse drug reactions Phosphodiesterase inhibitors, such as milri­ none, can cause hypotension due to vasodi­ latation, necessitating the use of vasoconstrictors. Noradrenaline and vaso­ pressin have been compared for this pur­ pose in 50 patients undergoing coronary artery bypass graft surgery who were given a loading dose of milrinone 50 mg/kg infused slowly over 20 minutes, followed by a continuous infusion of 0.5 mg/kg/minute (20Ac). Immediately after the loading dose of milrinone, they were given vasopressin or noradrenaline by infusion. Milrinone reduced both systemic and pulmonary vascular resistances and these effects were reversed by both vasopressin and noradre­ naline. However, only vasopressin reduced the ratio of pulmonary to systemic vascular resistance, which was increased by milri­ none. The authors proposed that vasopres­ sin might be preferable to noradrenaline in reversing the hemodynamic effects of

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323

milrinone during the management of right heart failure.

ADENOSINE RECEPTOR AGONISTS (SED-15, 36; SEDA-28, 203; SEDA-29, 185; SEDA-30, 212)

Adenosine and analogues

Cardiovascular Adenosine is contraindi­ cated in patients with aberrant conduction, because of the risk of cardiac dysrhythmias, such as atrial fibrillation (21A), ventricular tachycardia (22A), or both (23A). However, cases continue to be reported in such patients, as in the case of a 12-year-old boy with Wolff–Parkinson–White syndrome, who developed atrial fibrillation and hypo­ tension after being given two doses of adenosine 6 mg followed by a dose of 12 mg for supraventricular tachycardia (24A). Coronary vasospasm on the background of an unstable coronary plaque has been attributed to adenosine (25A).  A 66-year-old man with recurrent chest pain

underwent radionuclide adenosine (140 mg/kg/ minute) stress myocardial perfusion imaging, 15 seconds after which he developed severe central chest pain associated with profuse sweating; the electrocardiogram showed ST segment elevation in leads V1–6, and subse­ quent coronary angiography showed an unstable plaque in the proximal left anterior descending coronary artery, which was stented.

In previous cases of coronary artery spasm attributed to adenosine coronary angiogra­ phy was normal (26A,27A), and the con­ tribution of adenosine in this case is unclear. Respiratory The effects of placebo and adenosine 10 mg have been compared in six healthy and six asthmatic subjects (28c). Adenosine had no effect on the forced expiratory spirogram, but caused rapidonset dyspnea and tachycardia and increased minute ventilation. The authors suggested that this effect was due to sensitization of vagal C fibers in the lungs.

324

Adenosine receptor agonists (SEDA-30, 213) Placebo-controlled studies Intravenous bolus doses of regadenoson 0.1–30 mg/kg have been studied in 36 healthy men aged 18–50 years in a double-blind, crossover, randomized, placebo-controlled study (29C). Adverse events were dose-related and more common at doses above 3 mg/kg. Most of the adverse events were related to vasodilatation and increased heart rate and were generally mild to moderate. The authors suggested that the maximum tolerated doses of regadenoson were 10 mg/kg standing and 20 mg/kg supine. The half-life of regadenoson was 2 hours, the clearance 38 l/hour, and renal excretion accounted for about 58% of total elimination. The volume of distribution at steady state was 79 l. In a pharmacodynamic model changes in heart rate were related to plasma drug concentrations. The plasma regadenoson concentration that caused a 50% increase in maximum heart rate was 12 ng/ml.

Amiodarone

(SED-15, 148; SEDA-28, 205; SEDA-29, 185; SEDA-30, 213)

Observational studies In a prospective study, the incidence of adverse effects of amiodarone taken for at least 6 months in 98 French patients, mean age 73 years over 38 months, was 14 per 100 person-years: hypothyroidism 4.61 (95% CI ¼ 4.58, 4.63), hyperthyroidism 1.62 (1.60, 1.63), bradycardia and/or conduction problems 3.48 (3.46, 3.50), phototoxicity 2.27 (2.25, 2.28), interstitial pneumonitis 0.97 (0.96, 0.98), peripheral neuropathies 0.65 (0.64, 0.66), tremor 0.32 (0.32, 0.33), storage disease 0.33 (0.32, 0.33), and gastrointestinal disturbances 0.32 (0.32, 0.33) (30c). Thyroid and cardiac effects occurred mainly during the first 6 months. The effects of amiodarone 100 or 200 mg/ day have been studied in 76 patients, mean age 66 years for a mean of 67 months (31c). Actuarial rates of the maintenance of sinus rhythm were similar in the two groups after 5 years of follow-up. There were adverse

Chapter 17

J.K. Aronson

effects in two patients taking 100 mg/day and in 15 patients taking 200 mg/day. Four patients in the lower-dose group had serious adverse effects that necessitated withdrawal of amiodarone. Of the patients taking 200 mg/day, one patient had intoler­ able skin photoallergy; two had pulmonary fibrosis, with improvement in pulmonary function 6 months after discontinuation of amiodarone; one developed hypothyroidism. There were adverse events that did not require the withdrawal of amiodarone in 2 patients taking 100 mg/day and in 11 patients taking 200 mg/day—gastrointestinal discomfort, nausea, liver functional abnormality, and sensitivity to sunlight; these symptoms either disappeared sponta­ neously or were adequately managed. Systematic reviews In a meta-analysis of 18 randomized placebo-controlled trials of amiodarone in 3408 patients amiodarone increased the odds of bradycardia (OR ¼ 1.70; 95% CI ¼ 1.05, 2.74) and hypotension (OR ¼ 1.62; 95% CI ¼ 1.04, 2.54) (32M). Intravenous administration, an average daily dose exceeding 1 g, and post­ operative administration were each asso­ ciated with a greater likelihood of hemodynamic adverse effects. Cardiovascular In a retrospective study in 63 consecutive patients, all of whom received a loading dose of amiodarone for the treatment of atrial fibrillation, the susceptibility factors for polymorphic ventricular tachydysrhythmias, which occurred in 3 patients, were coronary heart disease with a severely reduced left ventricular ejection fraction and therapy with betablockers and digitalis (33c). An association with beta-blocker and digitalis therapy has been reported in three other cases (34A). Two unusual cases of torsade de pointes have been attributed to amiodarone (35A).  A 40-year-old woman with palpitation and

severe dizziness due to atrial fibrillation with poor left ventricular function was successfully cardioverted and given oral amiodarone 200 mg/day with no loading dose. On day 4 she became unconscious and an electrocar­ diogram showed a markedly prolonged QTc interval (533 milliseconds) with T wave

Positive inotropic drugs and drugs used in dysrhythmias alternans. During subsequent monitoring she had frequent ventricular extra beats with a short coupling interval, followed by torsade de pointes. Serum electrolytes were normal. Defibrillation restored sinus rhythm and she was given intravenous isoprenaline and magnesium sulfate; the torsade de pointes did not recur. The QTc interval gradually returned to normal (428 milliseconds) after withdrawal of amiodarone.  An 85-year-old woman with mild coronary artery disease, hypertension, and dilated car­ diomyopathy was given amiodarone 200 mg/ day without a loading dose for paroxysmal atrial fibrillation and 5 days later developed palpitation and presyncope due to non-sus­ tained polymorphic ventricular tachycardia with a markedly prolonged QTc interval (528 milliseconds) and broad T wave inversion. Other medications included aspirin 100 mg/day, amlodipine 5 mg/day, and candesartan 16 mg/day. Amiodarone was withdrawn and the QTc interval gradually normalized over the next 7 days.

The unusual feature in both of these cases was the fact that prolongation of the QT interval occurred within only a few days of treatment with amiodarone without a loading dose, at a time when very little amiodarone or desethylamiodarone, its active metabolite, would have been present in the body. Given an average half-life of 52 days, the amount of amiodarone in the body after 4–5 days would have been about 6% of that predicted to occur at steady state. There was no family history of congenital long QT syndrome or sudden cardiac death in either case and their QTc intervals were normal after withdrawal of amiodarone. However, the authors could not rule out the possibility that these patients had silent mutations in their cardiac ion channels, making them more sensitive to the actions of amiodarone. Amiodarone-associated torsade de pointes in Chinese people has been reviewed (36M). In 100 case reports, amio­ darone-associated torsade de pointes occurred more often in women. The major primary disease in women was rheumatic heart disease while that in men was coronary heart disease. Some cases wor­ sened to ventricular fibrillation and 19 patients died. In many cases there were known predisposing factors, such as heart failure, hypokalemia, drug combinations,

Chapter 17

325

and bradydysrhythmias. Torsade de pointes also occurred in six patients without any predisposing factors except QTc interval prolongation. In 14 observational studies of 2354 patients, 455 had prodysrhythmic events, while only 4 had torsade de pointes or ventricular fibrillation. Thrombophlebitis occurs when amiodar­ one is infused into relatively small veins and can occur when even a very small dose is infused into a very small vein (37A). Respiratory Pleural effusions (38A,39A), organizing pneumonia (40A), interstitial alveolitis or pneumonitis (41A,42A), alveolar hemorrhage (43A), pulmonary fibrosis (44A), and pulmonary infiltrates with acute respiratory distress syndrome (45A) have been attributed to amiodarone, and lung damage can be fatal (46A). One patient, a 44­ year-old man, had interstitial pneumonitis while taking amiodarone, which was with­ drawn (47A). He was given corticosteroids, with good effect, but the pneumonitis recurred whenever the dose of prednisolone was reduced to under 5 mg/day. The authors hypothesized that in this patient, who had a high BMI, amiodarone had been stored in fat and been available long after withdrawal. In four other patients with amiodarone-asso­ ciated pulmonary toxicity there was a corre­ lation between BMI and the time-course of lung shadow disappearance. The radiological pattern of abnormalities in amiodarone-induced lung disease is most commonly subpleural reticular-type inter­ stitial thickening, predominately in the bases of the lungs. Parenchymal nodules have uncommonly been reported (48c). The diagnosis of amiodarone-induced interstitial pneumonitis can be difficult, and there are no pathognomonic tests. In four patients with interstitial lung disease who were taking amiodarone, induced sputum showed lymphocytosis, a high CD4 or CD8 count, eosinophilia, and amiodarone (49c). 99m Tc-hexamethylpropyleneamine oxime (HMPAO) and 99mTc-diethylenetriamine penta-acetic acid (DTPA) scintigraphy have been used in the diagnosis of amio­ darone-induced lung toxicity in a 77-year­ old man (50A). There was rapid alveolar clearance and increased lung uptake of

326 99m

Tc. After 3 weeks of withdrawal of therapy, 99mTc-DTPA alveolar clearance was reduced but there was still uptake of 99m Tc-HMPAO in the lungs, attributed to continuing pulmonary inflammation as a result of the long half-life of amiodarone. Sensory systems Corneal microdeposits occur in virtually all patients who take amiodarone for more than 6 months, secondary to secretion of amiodarone by the lacrimal gland with accumulation in the corneal epithelium. About 10% of patients have symptoms of glare and halos. In some cases cysts can form and can cause pain and occasionally abscesses.  A 69-year-old woman took amiodarone for 6

years but 6 weeks after dosage was increased from 100 to 300 mg she developing halos, glare, and reduced visual acuity in both eyes (51A). Slit lamp examination showed diffuse epithelial edema, with multiple corneal epithe­ lial breaks and punctate keratopathy. High magnification showed multiple small epithelial cysts erupting toward the corneal surface, more concentrated centrally. There was a trace of lenticular nuclear sclerosis. Amiodar­ one was withdrawn and she was given a prophylactic topical antibiotic and supportive preparations (tears/lubricants). However, even after complete resolution of the acute keratitis after 2 weeks, the infiltrative keratopathy persisted, as did the initial complaints of halos and glare. The supportive treatments were maintained for 2 months until full recovery.

Amiodarone-induced keratopathy is usually bilateral, but a contact lens can prevent its development (52A). Optic neuropathy has again been attrib­ uted to amiodarone (53A).  A 54-year-old woman developed bilateral

optic disc edema without substantial visual loss mimicking papilledema after taking amio­ darone 600 mg/day for 6 months. Amiodarone was withdrawn and the optic disc edema gradually resolved over the next 15 months.

Diagnostic criteria for amiodarone­ related optic neuropathy have been devel­ oped from a retrospective case review of 22 patients (54c):  patients are divided into those with bilateral and unilateral disc edema;

Chapter 17

J.K. Aronson

 in those with bilateral disc edema, other causes must be excluded;  those with unilateral disc edema are further subdivided into those with clinical features typical of non-arteritic ischemic optic neuropathy (NAION) and those with atypical features (insidious onset of symptoms, relatively mild optic nerve dysfunction, and a generous cup–disc ratio in the fellow eye, and prolonged duration of disc edema in those who continue to pose a diagnostic challenge some weeks after onset);  the absence of a crowded fellow disc should cast doubt on the diagnosis of NAION;  the presence of systemic symptoms con­ sistent with amiodarone toxicity increases the suspicion that the optic neuropathy is related to amiodarone. Using these criteria three groups of patients were defined:  Group 1: those with bilateral disc edema;  Group 2: those with unilateral disc edema, features considered atypical of NAION, and relative preservation of optic nerve function;  Group 3: those with unilateral disc edema, features considered atypical of NAION, and poor optic nerve function. Endocrine The effects of amiodarone on thyroid function have again been reviewed (55R). In a retrospective comparison of patients with amiodarone-induced thyrotoxicosis (n ¼ 60) with those with Graves’ thyrotox­ icosis (n ¼ 49) and toxic multinodular goiter (n ¼ 40), mean free thyroxine (T4) concen­ trations were significantly higher in the first two (46 and 45 pmol/l) than in toxic multi­ nodular goiter (32 pmol/l) (56c). In contrast, free triiodothyronine (T3) concentrations were only significantly higher in Graves’ disease (15 pmol/l versus 8.6 and 7.4 pmol/l). Six deaths occurred in those with amiodar­ one-induced thyrotoxicosis and none in the other groups. Amiodarone treatment was the most significant predictor of death, whereas free T4, free T3, and age did not affect outcome. Among the amiodarone-treated

Positive inotropic drugs and drugs used in dysrhythmias

group severe left ventricular dysfunction was significantly associated with death. Type 2 amiodarone-induced thyrotoxico­ sis in 60 patients, treated with oral prednisone 30 mg/day, gradually tapered and withdrawn over 3 months, has been compared with De Quervain’s subacute thyroiditis in 60 patients, treated in the same way (57c). Mean serum free T4 and free T3 concentrations at diagnosis were higher in amiodarone­ induced thyrotoxicosis than in subacute thyroiditis. Euthyroidism was restored ear­ lier in subacute thyroiditis. Significantly more patients with amiodarone-induced thyrotox­ icosis became permanently hypothyroid after glucocorticoid withdrawal than those with subacute thyroiditis (10 versus 3). Periodic thyrotoxic hypokalemic paralysis has been attributed to amiodarone (58A).

Management of amiodaroneinduced thyrotoxicosis There are two types of amiodarone-induced thyrotoxicosis: type 1 occurs in those with latent disease and is due to the iodine that amiodarone contains; type 2 is due to a destructive thyroiditis in a previously normal gland; the former is rare. Withdrawal In most cases amiodarone is withdrawn when thyrotoxicosis is diagnosed. However, in one center in which amiodarone is not routinely withdrawn in patients with type 2 thyrotoxicosis, of over 40 such cases there were only 3 cases of recurrence (59A). The first episode occurred 2–4 years after the start of therapy and the second at 5–8 years; the second episode was milder than the first and resolved more rapidly. In 13 consecutive patients who developed type 2 amiodarone-induced thyrotoxicosis amiodarone was continued in 10 with previous ventricular or supraventricular dysrhythmias associated with severe hemodynamic changes and was withdrawn in the others. In eight patients with persistent, severe symptomatic thyrotoxicosis, corticosteroids were added (60c). All recovered, and there was no difference in the duration of thyrotoxicosis between the two groups.

Chapter 17

327

Corticosteroid treatment was associated with a quicker return to euthyroidism (3.7 months versus 6.3 months). Thyrotoxicosis did not recur during long-term follow-up. Thionamides, perchlorate, and corticosteroids The distinction between the two types of amiodarone-induced thyrotoxicosis is important, because type 1 typically responds to thionamides and perchlorate while type 2 often does not respond to conventional therapy with carbimazole or methimazole or with radio-iodine; corticosteroids and the combination of methimazole with potassium perchlorate have been reported to be effective, as have lithium, plasmapheresis, and thyroidectomy. The combination of a corticosteroid with a thionamide has also been reported to be effective, both in patients in whom amiodarone is withdrawn (61C,62C) and in those in whom it is continued (63C). Such combinations have included prednisone with carbimazole and benzylthiouracil, dexamethasone with carbimazole, and dexamethasone with propylthiouracil. Plasmapheresis Plasmapheresis has been used to treat amiodarone-induced thyrotoxicosis (64c,65A). The effect is attributable to extensive removal of thyroxine from the blood. In three cases of severe amiodaroneinduced thyrotoxicosis treated by plasma exchanges and propylthiouracil, there was rapid improvement in two and one died from sepsis; serial assays of T4, free T4, free T3, and rT3 showed rapid but transient reductions after every exchange (66c). Plasmapheresis was reportedly successful in treating amiodarone-induced hyperthyroidism in two of three patients, and was followed by thyroidectomy (67c). It has been suggested that plasmapheresis would be ineffective in type 2 thyrotoxicosis (68r). Lithium In some cases lithium has been effective in refractory cases of amiodaroneinduced thyrotoxicosis (69c). When a 40-yearold patient with severe amiodarone-induced thyrotoxicosis after heart transplantation did not respond to high doses of antithyroid drugs combined with glucocorticoids, a low dose of lithium carbonate resulted in normalization of thyroid function (70A).

328

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J.K. Aronson

Iodine-containing contrast agents Iodinecontaining contrast agents, such as ipodate and iopodate, which are rich in iodine and potent inhibitors of 5u-deiodinase, have been used to treat amiodarone-induced thyrotoxicosis. When five patients with type 2 amiodarone-induced thyrotoxicosis were treated with a combination of sodium ipodate or sodium iopanoate plus a thionamide (propylthiouracil or methimazole) after amiodarone withdrawal, all improved substantially within a few days and became euthyroid or hypothyroid in 15–31 weeks (71c). Four of the five became hypothyroid and required long-term treatment with levothyroxine. Three patients with type 1 disease, two of whom had not responded to methimazole plus perchlorate, were successfully treated with a short course of iopanoic acid 1 g/day, resulting in a marked reduction in the peripheral conversion of T4 to T3 (72A). Euthyroidism was restored in 7–12 days, allowing uneventful thyroidectomy. The patients were then treated with levothyroxine for hypothyroidism and amiodarone was safely restarted. The authors suggested that iopanoic acid is the drug of choice for rapid restoration of normal thyroid function before thyroidectomy in patients with drug-resistant type 1 amiodarone-induced thyrotoxicosis.

Minimally invasive video-assisted thyroidectomy under regional anesthesia has been used to treat amiodarone-induced thyrotoxicosis in eight patients (three with type 1 and five with type 2 thyrotoxicosis), mean age 66 years, after preparation with iopanoic acid (80c). In two elderly patients thyroidectomy was required when the thyroid gland became enlarged and nodular, despite treatment with methimazole or propylthiouracil (81c). The authors discussed the problems of anesthesia in such cases. The use of local anesthesia for total thyroidectomy in patients with amiodarone-induced thyrotoxicosis and cardiac impairment has been reviewed in the context of six patients (82c). Of 14 patients with amiodarone-induced thyrotoxicosis, 11 men and 3 women, aged 26–82 years, 9 were refractory to medical management and in 5 amiodarone needed to be continued (83c). Total thyroidectomy was performed under general anesthesia with no significant intraoperative complications and no deaths. Two patients required short-term calcium supplementation. All had rapid resolution of their symptoms and were euthyroid on thyroxine postoperatively. Thyroidectomy may be the treatment of choice for thyrotoxicosis when amiodarone cannot be withdrawn (84A).

Thyroidectomy In very severe cases subtotal or total thyroidectomy may be needed (73c, 74c, 75C, 76C). Surgical treatment also allows continuation of amiodarone. In a patient taking amiodarone, with repeated episodes of ventricular fibrillation associated with thyrotoxicosis, propylthiouracil plus prednisone was ineffective and subtotal thyroidectomy had to be performed (77A). In one case in which prolonged treatment with methimazole, potassium perchlorate, iopanoic acid, and dexamethasone was unsuccessful in treating thyrotoxicosis, subtotal thyroidectomy was rapidly effective (78c). Two patients with cardiomyopathy and resistant dysrhythmias developed thyrotoxicosis while taking amiodarone (79Ar). Despite medical therapy, they failed to improve. Both underwent total thyroidectomy without difficulty or complications.

Factors that affect response The factors that affect the response of amiodaroneinduced thyrotoxicosis type 2 to prednisone have been studied prospectively in 66 patients (85A). Serum free thyroxine (T4) concentration and thyroid volume, and to a lesser extent serum free triiodothyronine (T3) concentration, at diagnosis were the main determinants. Clinical practice The management of thyrotoxicosis due to amiodarone has been reviewed in the light of the practices of 101 European endocrinologists (86CR). Most (82%) treat type 1 amiodarone-induced thyrotoxicosis with thionamides, either alone (51%) or in combination with potassium perchlorate (31%); the preferred treatment for type 2 thyrotoxicosis is a glucocorticoid (46%). Some initially treat all cases, before the type has been established, with a combination

Positive inotropic drugs and drugs used in dysrhythmias

of thionamides and glucocorticoids. After restoration of normal thyroid function, 34% recommend ablative therapy in type 1 hyperthyroidism and only 8% in type 2. If amiodarone therapy needs to be restarted, 65% recommend prophylactic thyroid ablation in type 1 thyrotoxicosis and 70% recommend a wait-and-see strategy in type 2.

Chapter 17

329

with raised concentrations of the immuno­ suppressants, and attributed to altered meta­ bolism and, in the case of sirolimus, P glycoprotein activity (91A). Statins There have been occasional reports of an interaction of amiodarone with statins (SEDA-29, 187).  A 72-year-old man with diabetes mellitus,

Liver The prevalence of hepatotoxicity after long-term oral amiodarone therapy has been studied in a retrospective crosssectional study in 628 Chinese patients with (n ¼ 90) or without (n ¼ 538) liver dysfunc­ tion at baseline (87c). The prevalence of significant liver dysfunction was 3.7% (CI ¼ 2.1, 5.3%) and 4.4% (CI ¼ 0.2, 8.6%) in patients with normal and abnor­ mal baseline alanine transaminase activ­ ities, respectively. The authors concluded that amiodarone could be safely prescribed in patients with liver dysfunction. Skin Skin necrosis has been attributed to amiodarone (88A). Musculoskeletal In a population-based nationwide pharmacoepidemiological case– control study of 124 655 patients who had a fracture during 2000 and 373 962 age- and sex-matched controls, the risk of any fracture was increased in patients with atrial fibrilla­ tion (OR ¼ 1.14; 95% CI ¼ 1.08, 1.21) and in patients taking amiodarone (OR ¼ 1.47; 95% CI ¼ 1.21, 1.78). In contrast, digoxin reduced the risk of fracture (OR ¼ 0.75; 95% CI ¼ 0.71, 0.79) (89C). The effect was limited to those aged over 65 years. The effect of digoxin was dose-related. Death In a retrospective case–control study in 396 consecutive patients, of whom 25 had taken amiodarone for at least 30 days before transplantation, amiodarone had no effect on mortality or acute graft failure (90c). Drug–drug interactions Calcineurin inhibitors An interaction of amiodarone with sirolimus and tacrolimus has been described in a 2-year-old heart transplant recipient,

hyperlipidemia, hypertension, and mild ure­ mia, who was taking amiodarone 200 mg/day, was given simvastatin 80 mg/day (92A). After 4 weeks he developed thigh weakness, muscle aches, and dark urine. His creatine kinase activity was 19 620 U/l (reference range 60–224), urine myoglobin 71 100 mg/l (o50), serum myoglobin 13 877 mg/l (o110), creatinine 230 mmol/l, aspartate transaminase 912 U/l (30–60), and alanine transaminase 748 U/l (30–60). Simvastatin and amiodarone were withdrawn and he was hydrated with forced alkaline diuresis. He recovered within 13 days.

Simvastatin is metabolized primarily by CYP3A4, which amiodarone inhibits. Monitoring therapy In a retrospective cohort study in 1055 patients who had taken amiodarone for at least 180 days, thyroid function, with or without liver function, was assessed in 62% of patients, and transaminase tests, with or without thyroid function, in 68% (93c). The factor most strongly associated with having both types of laboratory tests was concomitant therapy with a statin (OR ¼ 1.55; 95% CI ¼ 1.05, 2.29).

Bepridil

(SED-15, 445)

Respiratory Pneumonitis attributed to bepridil (94A).

has

been

 A 66-year-old man who had taken bepridil for

atrial fibrillation for about 6 weeks developed exertional dyspnea with hypoxemia. A chest X-ray and CT scan showed diffuse reticulo­ nodular infiltrates in the lower lung fields. Pulmonary function tests showed reduced diffusion capacity for carbon monoxide. Bronchoalveolar lavage fluid contained increased percentages of lymphocytes, neutro­ phils, and eosinophils, and the CD4/8 ratio was low. Transbronchial lung biopsy showed alveolar septal thickening with infiltration of

Chapter 17

330 mononuclear cells and intra-alveolar organiza­ tion. Bepridil was withdrawn, resulting in improvement in the dyspnea and hypoxemia. Corticosteroid treatment then led to complete resolution.

Cibenzoline

(SED-15, 740; SEDA-30,

217) Respiratory Pneumonitis has attributed to cibenzoline (95A).

been

Flecainide

(SED-15, 1370; SEDA-28, 209; SEDA-29, 188; SEDA-30, 217)

Observational studies Intravenous flecain­ ide 2 mg/kg over 10 minutes (maximum 150 mg) has been used to treat paroxysmal atrial fibrillation in 23 patients without congestive heart failure, acute coronary syndrome, electrolyte imbalance, significant hepatic and renal disease, or any previous conduction disturbance (96A). Sinus rhythm was achieved in 10 patients immediately after the intravenous bolus and in 17 patients by 120 minutes. There was hypotension (systolic blood pressure o90 mmHg) in one patient and QRS prolonga­ tion in one. Cardiovascular Typically, flecainide causes ventricular dysrhythmias in patients with structural cardiac abnormalities (97A), but dysrhythmias can occasionally occur in patients with normal cardiac structure.  A 77-year-old woman with hypertension,

J.K. Aronson

was positive in 64 cases and negative in 95. The sensitivity and specificity in SCN5A­ positive probands and their family members were 77 and 80%, respectively. There were no malignant dysrhythmias. Antidysrhythmic drugs can sometimes cause increased capture threshold of a pacemaker, but this is rarely clinically important. However, flecainide was associated with an abrupt rise in the capture threshold in a 72­ year-old man with a VVI pacemaker for sick sinus syndrome, after 15 days of treatment, resulting in ventricular pacing failure; the effect abated 2 days after withdrawal of flecainide acetate (100A).

Lidocaine (lignocaine)

(SED-15, 2051; SEDA-28, 210; SEDA-29, 188; SEDA-30, 218) Placebo-controlled studies In a doubleblind, placebo-controlled, crossover trial of two doses of intravenous lidocaine 5 and 7.5 mg/kg in 15 patients there were no major adverse effects; 1 patient suffered light-headedness (101C). Drug overdose Lidocaine has rarely been used in self-poisoning.  A 31-year-old woman died after taking an

overdose of oral lidocaine. Post-mortem lido­ caine concentrations were as follows: femoral vein blood 31 g/l, gastric contents 2.5 g, liver 10 mg/g, kidney 12 mg/g, brain 9 mg/g, spleen 24 mg/g, lungs 84 mg/g, heart 9 mg/g, urine 9 g/ l, and bile 6 g/l. Histological examination of the myocardium showed segmentation of the myocardial cells and/or widening of interca­ lated discs and associated group of hypercon­ tracted myocardial cells with “square” nuclei in line with hyperdistended ones; there were non-eosinophilic bands of hypercontracted sarcomeres alternating with stretched, often apparently separated sarcomeres, small foci of paradiscal contraction band necrosis, and perivascular fibrosis.

diabetes, and persistent atrial fibrillation was given flecainide 100 mg bd after echocardio­ graphy showed a ventricle of normal size and thicknesses, with normal systolic function and discrete atrial dilatation (98A). She was also taking atenolol 50 mg bd. After a week she developed syncope and general weakness. An electrocardiogram showed a broad complex tachycardia and after electrical cardioversion she had a severe bradydysrhythmia, followed by several episodes of self-limited torsade de pointes and two episodes of sustained syncope requiring defibrillation and flecainide was withdrawn. After 48 hours she had a stable narrow complex sinus rhythm.

The authors concluded that the cause of death was probably cardiac and possibly related to ventricular fibrillation (102A).

Flecainide has been used in 159 subjects at risk of Brugada syndrome (99A). The test

Drug–drug interactions The effects of co­ administration of fluvoxamine 100 mg (an

Positive inotropic drugs and drugs used in dysrhythmias

inhibitor of CYP1A2) with and without erythromycin 1500 mg (an inhibitor of CYP3A4) for 5 days on the pharmacoki­ netics of a single oral dose of lidocaine 1 mg/kg have been studied in a doubleblind, randomized, three-way crossover study in eight healthy volunteers (103A). Fluvoxamine increased the AUC and Cmax of lidocaine 3-fold and 2.2-fold, respec­ tively, and fluvoxamine and erythromycin increased the AUC and Cmax 3.6-fold and 2.5-fold. The half-life of lidocaine was unaffected by fluvoxamine alone but was prolonged from 2.4 to 3.8 hours by fluvox­ amine plus erythromycin. Fluvoxamine alone and in combination with erythromy­ cin also reduced peak concentrations of monoethylglycylxylidine (MEGX), one of the major metabolites of lidocaine, by about 50 and 30%, respectively. The authors concluded that inhibition of CYP1A2 by fluvoxamine considerably reduces the presystemic metabolism of oral lidocaine and that the addition of a CYP3A4 inhibitor could further increase the risk of lidocaine toxicity. Sex hormones The effects of treatment for 3 and 6 months with oral and transdermal 17b-estradiol plus sublingual progesterone on the pharmacokinetics of a single intravenous dose of lidocaine 1 mg/ kg have been studied in 18 postmenopau­ sal women (104c). During oral hormone treatment after 3 months there was a 15% increase in lidocaine AUC, a 15% shorter half-life, and a 14% reduction in clearance. In contrast, transdermal administration did not alter the pharmacokinetics of lido­ caine, and neither route of administration had an effect at 6 months. It seems likely that the small effects seen with oral therapy at 3 months occurred purely by chance.

Mexiletine

(SED-15, 2329; SEDA-30,

218) Immunologic It has been suggested that reactivation of human herpesvirus infection

Chapter 17

331

may be involved in the pathogenesis of drug-induced hypersensitivity syndrome.  A 45-year-old Japanese man developed a

generalized papuloerythematous rash, fever, hepatitis, lymphadenopathy, and lymphocyto­ sis with an increased number of atypical lymphocytes after taking mexiletine hydro­ chloride. Antibody titers against human her­ pesvirus 6 and 7 were increased on days 12–24 and peripheral blood mononuclear cells and skin tissue contained human herpesvirus 7 DNA.

The authors concluded that reactivation of human herpesvirus 7 could be respon­ sible for drug-induced hypersensitivity syn­ drome (105A).

Propafenone

(SED-15, 2939; SEDA-28, 211; SEDA-30, 218)

Cardiovascular In 100 consecutive patients with persistent atrial fibrillation pharmaco­ logical cardioversion was carried out using either intravenous ibutilide (1 mg plus an additional 1 mg, if required; n ¼ 51) or oral propafenone (600 mg) plus the same dose of intravenous ibutilide (n ¼ 49). The QTc interval increased in both groups and there was one case of sustained torsade de pointes, requiring electrical cardioversion, in those who were given propafenone plus ibutilide (106c). LBBB during exercise has been attrib­ uted to propafenone (107A).  A 66-year-old man took propafenone 450 mg/

day for 3 months for paroxysmal atrial fibrillation and underwent maximal symptomlimited exercise testing to rule out the pre­ sence of coronary artery disease. His resting heart rate was 74 per minute and the QRS duration was 124 milliseconds with no repolar­ ization abnormalities. He exercised according to the Bruce protocol for 10 minutes. During exercise his heart rate rose to 144 per minute and his blood pressure rose from 130/80 to 190/90 mmHg. During the test there was gradual prolongation of the QRS duration culminating in LBBB morphology with a QRS duration of 165 milliseconds and left axis deviation at peak exercise. During recovery the LBBB morphology disappeared and the QRS duration gradually returned to the preexercise value.

Chapter 17

332 Immunologic Urticaria and angioedema has been attributed to propafenone (108A). Drug overdose Brugada syndrome and extreme widening of the QRS complex has been reported after propafenone over­ dose (109A).

Procainamide

(SED-15, 2923; SEDA28, 210; SEDA-30, 219)

Hematologic The cause of pure red cell aplasia after treatment with procainamide 750 mg qds in a 63-year-old man was not discovered (110A). Other causes of red cell aplasia were excluded and there was no evidence of lupus-like syndrome. Procaina­ mide and N-acetylprocainamide concentra­ tions were within or below the usual target range, suggesting a hypersusceptibility reac­ tion if procainamide was to blame.

J.K. Aronson

Quinidine and derivatives

(SED-15, 2997; SEDA-28, 212; SEDA-29, 189; SEDA-30, 219)

Susceptibility factors Genetic Quinidineinduced QT interval prolongation has been studied in 13 Caucasian and 24 Korean healthy subjects to investigate interethnic differences in a double-blind, randomized, crossover study (111c). The QTc intervals in the Caucasians were longer than those in the Koreans at the same quinidine concentrations, especially at higher quinidine concentrations and in women. According to an Emax model, E0 (milliseconds) was related to sex, dEmax (milliseconds) was related to ethnicity, and the EC50 was 3.13 mmol/l. The authors concluded that Korean subjects are less sensitive to quinidine-induced QT interval prolongation than Caucasian subjects, and that this trend was particularly true in women.

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including the effect of activated charcoal. Ther Drug Monit 2006;28(6):784–92. Jeon Y, Ryu JH, Lim YJ, Kim CS, Bahk JH, Yoon SZ, Choi JY. Comparative hemody­ namic effects of vasopressin and norepi­ nephrine after milrinone-induced hypotension in off-pump coronary artery bypass surgical patients. Eur J Cardiothorac Surg 2006;29(6):952–6. Cummings M, Raza J, Movahed A. Atrial fibrillation during adenosine pharmacologic stress testing. J Nucl Cardiol 2006;13(4): 576–81. Sandler DA. Adenosine-induced ventricu­ lar tachycardia. J Cardiovasc Electrophysiol 2006;17(11):1251. Bieganowska K, Rekawek J, Szumowski � L, Szymaniak E, Brzezinska-Paszke M, Miszczak-Knecht M, Glinka-Kazimierska E, Kawalec W, Nowak I, Walczak F. Zespol Morgagni–Adams–Stockesa po wstrzyknieciu adenozyny u pacjentki z zespolem WPW. [Morgagni–Adams–­ Stokes after adenosine injection in a patient with WPW syndrome—a case report.] Kardiol Pol 2006;64(12):1453–7. Kaltman JR, Tanel RE, Shah MJ, Vetter VL, Rhodes LA. Induction of atrial fibrilla­ tion after the routine use of adenosine. Pediatr Emerg Care 2006;22(2):113–5. Faganello G, Belham M. Coronary vasos­ pasm during an adenosine stress test. Int J Cardiol 2006;113(3):E84–6. Golzar J, Mustafa SJ, Movahed A. Chest pain and ST-segment elevation 3 minutes after completion of adenosine pharmacolo­ gic stress testing. J Nucl Cardiol 2004;11(6): 744–6. Weissman G, Scandrett RM, Howes CJ, Russell RR 3rd. Coronary vasospasm dur­ ing an adenosine stress test. J Nucl Cardiol 2004;11(6):747–50. Burki NK, Alam M, Lee LY. The pulmon­ ary effects of intravenous adenosine in asthmatic subjects. Respir Res 2006;7:139. Gordi T, Frohna P, Sun HL, Wolff A, Belardinelli L, Lieu H. A population pharmacokinetic/pharmacodynamic analysis of regadenoson, an adenosine A2A­ receptor agonist, in healthy male volun­ teers. Clin Pharmacokinet 2006;45(12): 1201–12.

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334 30. Bongard V, Marc D, Philippe V, Jean-Louis M, Maryse LM. Incidence rate of adverse drug reactions during long-term follow-up of patients newly treated with amiodarone. Am J Ther 2006;13(4):315–9. 31. Jong GP, Chang MH, Chang TC, Chou P, Fu CY, Tien LY, Chen CY, Ma TC. Longterm efficacy and safety of very-low-dose amiodarone treatment for the maintenance of sinus rhythm in patients with chronic atrial fibrillation after successful directcurrent cardioversion. Chin Med J (Engl) 2006;119(24):2030–5. 32. Patel AA, White CM, Gillespie EL, Kluger J, Coleman CI. Safety of amiodarone in the prevention of postoperative atrial fibrilla­ tion: a meta-analysis. Am J Health Syst Pharm 2006;63(9):829–37. 33. Schrickel JW, Schwab JO, Yang A, Bielik H, Bitzen A, Lüderitz B, Lewalter T. Pro­ arrhythmic effects of amiodarone and con­ comitant rate-control medication. Europace 2006;8(6):403–7. 34. Schrickel JW, Schwab JO, Yang A, Bitzen A, Lüderitz B, Lewalter T. “Torsade de pointes” in patients with structural heart disease and atrial fibrillation treated with amiodarone, beta-blockers, and digitalis. Pacing Clin Electrophysiol 2006;29(4): 363–6. 35. Lim HE, Pak HN, Ahn JC, Song WH, Kim YH. Torsade de pointes induced by shortterm oral amiodarone therapy. Europace 2006;8(12):1051–3. 36. Geng DF, Jin DM, Wang JF, Luo YJ, Wu W. Clinical study of amiodarone-associated torsade de pointes in Chinese people. Pacing Clin Electrophysiol 2006;29(7): 712–8. 37. Showkathali R, Earley MJ, Sporton S. Amiodarone induced thrombophlebitis. Emerg Med J 2006;23(8):660. 38. Mittal SR, Maheshwari M. Amiodarone­ induced exudative pleural effusion—a case report and review of literature. Indian Heart J 2006;58(4):352–5. 39. Maheshwari M, Baid JC, Vijayvergia A. Amiodarone related rare toxicity in a burn patient. Burns 2007;33(3):387–92. 40. Sveinsson OA, Isaksson HJ, Guethmunds­ son G. Trefjavefslungnabolga tengd notkun lyfsins amiodaron sjukratilfelli og yfirlit.

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336 68. Topliss DJ, Wong R, Stockigt JR. Plasmapheresis as a potential treatment option for amiodarone-induced thyrotoxicosis. Reply. Intern Med J 2004;34(6):370–1. 69. Dickstein G, Shechner C, Adawi F, Kaplan J, Baron E, Ish-Shalom S. Lithium treat­ ment in amiodarone-induced thyrotoxicosis. Am J Med 1997;102(5):454–8. 70. Boeving A, Cubas ER, Santos CM, Carvalho GA, Graf H. O uso de carbonato de litio no tratamento da tireotoxicose indu­ zida por amiodarone. [Use of lithium carbonate for the treatment of amiodaro­ ne-induced thyrotoxicosis.] Arq Bras Endo­ crinol Metabol 2005;49(6):991–5. 71. Chopra IJ, Baber K. Use of oral cholecystographic agents in the treatment of amiodar­ one-induced hyperthyroidism. J Clin Endocrinol Metab 2001;86(10):4707–10. 72. Bogazzi F, Aghini-Lombardi F, Cosci C, Lupi I, Santini F, Tanda ML, Miccoli P, Basolo F, Pinchera A, Bartalena L, Braverman LE, Martino E. Iopanoic acid rapidly controls type I amiodarone-induced thyrotoxicosis prior to thyroidectomy. J Endocri­ nol Invest 2002;25(2):176–80. 73. Mehra A, Widerhorn J, Lopresti J, Rahim­ toola SH. Amiodarone-induced hyperthyroidism: thyroidectomy under local anesthesia. Am Heart J 1991;122(4 Pt 1):1160–1. 74. Hennen G, Mary-Rabine L, Meurisse M. Hyperthroïdies sévères induites par l’iode: une urgence medico-chirurgicale. Rev Med Liege 1992;47(5):237–44. 75. Meurisse M, Hamoir E, D’Silva M, Joris J, Hennen G. Amiodarone-induced thyrotoxicosis: is there a place for surgery? World J Surg 1993;17(5):622–7. 76. Mulligan DC, McHenry CR, Kinney W, Esselstyn Jr CB. Amiodarone-induced thyr­ otoxicosis: clinical presentation and expanded indications for thyroidectomy. Surgery 1993;114(6):1114–9. 77. Marketou ME, Simantirakis EN, Manios EG, Vardas PE. Electrical storm due to amiodarone induced thyrotoxicosis in a young adult with dilated cardiomyopathy: thyroidectomy as the treatment of choice. PACE Pacing Clin Electrophysiol 2001;24 (12):1827–8. 78. Farwell AP, Abend SL, Huang SKS, Patwardhan NA, Braverman LE.

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Positive inotropic drugs and drugs used in dysrhythmias

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hepatotoxicity in 720 Chinese patients with or without baseline liver dysfunction. Clin Cardiol 2006;29(7):295–9. Russell SJ, Saltissi S. Amiodarone induced skin necrosis. Heart 2006;92(10):1395. Rejnmark L, Vestergaard P, Mosekilde L. Fracture risk in patients treated with amiodarone or digoxin for cardiac arrhyth­ mias: a nation-wide case–control study. Osteoporos Int 2007;18(4):409–17. Sánchez-Lázaro IJ, Almenar L, MartinezDolz L, Chamorro C, Moro J, Agüero J, Rueda J, Zorio E, Arnau MA, Salvador A. Does amiodarone influence early mortality in heart transplantation? Transplant Proc 2006;38(8):2537–8. Nalli N, Stewart-Teixeira L, Dipchand AI. Amiodarone-sirolimus/tacrolimus interac­ tion in a pediatric heart transplant patient. Pediatr Transplant 2006;10(6):736–9. Ricaurte B, Guirguis A, Taylor HC, Zabriskie D. Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother 2006;40(4):753–7. Raebel MA, Carroll NM, Simon SR, Andrade SE, Feldstein AC, Lafata JE, Nelson WW, Chan KA, Gunter MJ, Tolsma D, Platt R. Liver and thyroid monitoring in ambulatory patients pre­ scribed amiodarone in 10 HMOs. J Manag Care Pharm 2006;12(8):656–64. Okubo F, Ando M, Ashihara Y, Okubo T, Nishitake T, Ito T, Matsuno O, Fukami T, Miyazaki E, Kumamoto T. A case of druginduced pneumonitis due to bepridil. Nihon Kokyuki Gakkai Zasshi 2006;44(1): 17–21. Hasegawa M, Nasuhara Y, Maki N, Miura T, Betsuyaku T, Hizawa N, Nishimura M, Onozuka H, Tsutsui H. Cibenzoline succi­ nate induced pneumonitis. Nippon Naika Gakkai Zasshi 2006;95(7):1362–4. Antonelli D, Feldman A, Freedberg NA, Darawsha A, Rosenfeld T. Intravenous flecainide administration for conversion of paroxysmal atrial fibrillation in the emer­ gency room. Harefuah 2006;145(5):342–4 398 Rienstra M, Wiesfeld AC, van Veldhuisen DJ, van Gelder IC. Levensbedreigende ventrikeltachycardie bij

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338 JA. Propafenone added to ibutilide increases conversion rates of persistent atrial fibrillation. Heart 2006;92(5):631–4. 107. Dilaveris P, Synetos A, Giannopoulos G, Massias S, Michaelides A, Stefanadis C. Exercise-induced left bundle branch block and propafenone administration. Int J Cardiol 2006;106(2):279–81. 108. Incorvaia C, Pravettoni C, Riario-Sforza GG. Urticaria–angioedema reaction caused by propafenone. Allergy 2006;61(2):269. 109. Hasdemir C, Olukman M, Ulucan C, Roden DM. Brugada-type ECG pattern

Chapter 17

J.K. Aronson

and extreme QRS complex widening with propafenone overdose. J Cardiovasc Elec­ trophysiol 2006;17(5):565–6. 110. Pasha SF, Pruthi RK. Procainamide­ induced pure red cell aplasia. Int J Cardiol 2006;110(1):125–6. 111. Shin JG, Kang WK, Shon JH, Arefayene M, Yoon YR, Kim KA, Kim DI, Kim DS, Cho KH, Woosley RL, Flockhart DA. Possible interethnic differences in quini­ dine-induced QT prolongation between healthy Caucasian and Korean subjects. Br J Clin Pharmacol 2007;63(2):206–15.

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

18

Beta-adrenoceptor antagonists and antianginal drugs

BETA-ADRENOCEPTOR ANTAGONISTS (SED-15, 452; SEDA-28, 217; SEDA-29, 194; SEDA-30, 223)

Cardiovascular Beta-adrenoceptor antago­ nists are recommended for patients with chronic heart failure to improve outcomes and left ventricular ejection fraction. How­ ever, concerns regarding the tolerability of these drugs by elderly people have contrib­ uted to limited use in this age class. Carvedilol has been assessed in 1030 patients with heart failure aged over 70 years and reasons for drug withdrawal were recorded (1c). The main reasons were worsening of heart failure in less than 10%, symptomatic hypotension in about 13%, and less often bradycardia and wheeze. Skin In an attempt to assess the prevalence of contact allergy after topical use of antiglaucoma agents, data from the Information System of Departments of Dermatology collected in Switzerland, Germany, and Austria from 1993 to 2004 have been analyzed (2c). Of 332 patients who had been tested for allergy with their own antiglaucoma eye drops containing different beta-adrenoceptor anta­ gonists, 43 (13%) were positive for at least one product, without major cross-reactivity. The most frequently used drug was timolol; Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03118-3 r 2009 Elsevier B.V. All rights reserved.

other beta-adrenoceptor antagonists asso­ ciated with similar rates of contact dermatitis were levobunolol and metipranolol.

Atenolol Breasts Breast pain and swelling have been associated with atenolol (3A). � A 54-year-old woman, 6 years postmenopausal

with a history of hyperlipidemia and a new diagnosis of hypertension, was given atenolol 25 mg/day and 6 weeks later, when her blood pressure was controlled, she reported mastitislike pain; prolactin was not measured since there were no signs or symptoms suggesting hyperprolactinemia, which has been reported with beta-blockers. After several interventions had been ineffective, atenolol was withdrawn and the pain resolved. It did not recur when she was given a thiazide diuretic.

Metoprolol Drug–drug interactions Dextropropoxyphene Dextropropoxyphene inhibits cyto­ chrome P450, and a life-threatening interaction with metoprolol has been repor­ ted (4A). � A 48-year-old man with atrial fibrillation took

metoprolol 100 mg/day. After taking a dose of co-proxamol (dextropropoxyphene+paraceta­ mol) he complained of dizziness and sweating for 3 hours. The metoprolol concentrations was raised and related to a profound fall in heart rate to about 30/minute.

The authors attributed this effect to inhibi­ tion of hepatic clearance of metoprolol by dextropropoxyphene.

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Propranolol Skin Many drugs can cause fixed drug eruptions, but propranolol has never been implicated. � A fixed drug eruption occurred in a 61-year-old

hypertensive woman who had taken proprano­ lol 10 mg/day for 2 months (5A). She had a sharply marginated, round, itchy plaque of erythema and edema. Propranolol was with­ drawn and the erythema cleared after treatment for 2 months with topical methylprednisolone.

Timolol Cardiovascular Beta-adrenergic antagonists used in the eyes can cause systemic effects. Syncope triggered by sneezing in a patient using topical timolol has been reported (6A). � An 88-year-old woman with glaucoma well

controlled with timolol eye-drops, developed repeated syncopal episodes 10–20 seconds after sneezing. Holter recording during the episodes showed atrioventricular block, and the syncopal episodes disappeared on with­ drawal of the timolol eye-drops.

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

the preservative benzalkonium chloride cannot be ruled out.

POTASSIUM CHANNEL ACTIVATORS Nicorandil

(SED-15, 2505)

Skin Nicorandil 20–40 mg/day has been implicated in the pathogenesis of parastomal or umbilical ulceration in four patients with an ileostomy or colostomy (8A). The time to development of symptoms was 3–60 months. The ulcers healed after withdrawal of nicorandil and introduction of another antianginal medication. The clinical and histological similarity of these ulcers and the patterns of healing suggest a causative effect of nicorandil, but the pathogenesis is unknown. The authors concluded that nicorandil should be considered as one of the etiological factors of parastomal ulcers and should be actively excluded before any major interventions.

Systemic absorption of the timolol may have precipitated complete atrioventricular block in this case in the presence of pre­ existing conduction delay. Sensory systems Intraocular timolol and its solvent benzalkonium chloride have been reported to enhance disruption of the blood–aqueous barrier, causing uveitis, but benzalkonium has been thought to be the main cause. Now unilateral uveitis has been reported in a patient using travoprost+ timolol (7A). � A

43-year-old man with glaucoma used travoprost in both eyes. Timolol LA was added in the left eye and 3 months later the left eye showed signs of uveitis, which resolved on stopping travoprost. However, the timolol was continued.

The appearance of uveitis only in the left eye suggests that timolol LA may have increased travoprost-related damage to the blood–aqueous barrier, even if an effect of

CALCIUM CHANNEL BLOCKERS (SED-15, 598; SEDA-28, 218; SEDA-29, 195; SEDA-30, 225)

Amlodipine (SED-15, 175; SEDA-28, 219; SEDA-29, 195; SEDA-30, 225) Drug overdose There have been several reports of amlodipine intoxication following attempted suicide, some fatal and a further two cases have been reported. � A 42-year-old man took amlodipine 1000 mg,

chlortalidone 3000 mg, and mefenamic acid 3000 mg (9A). He became deeply hypotension and was treated with fluid replacement, dobutamine and noradrenaline, insulin, and calcium gluconate. Since the hypotension persisted and he developed oliguria, terlipres­ sin was added and the blood pressure and urinary output finally increased.

Beta-adrenoceptor antagonists and antianginal drugs �

A 40-year-old woman took amlodipine 1000 mg (10 mg tablets, not specified as stan­ dard or modified-release) in a suicide attempt and developed severe hypotension (10A). She was treated with fluid replacement therapy, calcium, insulin, adrenoceptor agonists, and whole bowel irrigation and recovered.

Diltiazem (SED-15, 1126; SEDA-28, 219; SEDA-29, 196; SEDA-30, 226) Skin Photosensitivity reactions associated with diltiazem can cause erythema, pruritus, and/or lichenoid eruptions, which mostly develop soon after exposure to the sun. Photodistributed hyperpigmentation associated with diltiazem has also been reported in four patients with a review of eight other reported cases (11Ar). The pigmentary changes developed within 6–24 months. The patient’s ages were 49–77 years; three were men and most were taking diltiazem for hypertension. No other medications causing hyperpigmentation were used. The distribution of hyperpigmentation was on the sun-exposed areas of the face, neck, and forearms, with less pigmentation on the lower chest, back, and shins. To determine the photoabsorption spectrum of diltiazem, photospectrometry analysis was performed. The absorption range of diltiazem was 220–300 nm, within the UV-B spectrum. These results correlated with previous data showing no absorption in the UV-A spectrum. Furthermore, the pattern of photodistributed pigmentation and the history of mild-to-moderate sun exposure during diltiazem therapy in the four patients also supported a photosensitizing effect. Withdrawal of diltiazem is the most effective way to resolve hyperpigmentation.

Nimodipine

(SED-15, 2526; SEDA-29,

199) Placebo-controlled studies Epidural nimo­ dipine reduces pain and opioid require­ ments in patients receiving palliative analgesic therapy. However, a placebocontrolled crossover study in patients with

Chapter 18

341

cancer did not show analgesic benefit of oral nimodipine. A randomized, double-blind, placebo-controlled clinical trial of nimodi­ pine in 40 patients (mean age 70 years, 28 men) with acute postoperative pain after total knee replacement has now been published (12C). They all received three capsules (nimodipine 90 mg or placebo) 1–2 hours before induction of anesthesia, followed by oral nimodipine 30 mg or placebo 6-hourly for 48 hours postopera­ tively. There were no significant differences in pain scores at rest or when moving or in the time to first use of morphine. Morphine consumption was significantly greater in those who were given nimodipine, suggest­ ing that it has no adjunctive analgesic effect and may even inhibit the analgesic effect of morphine.

Nifedipine

(SED-15, 2516; SEDA-28, 220; SEDA-29, 198; SEDA-30, 227)

The use of nifedipine as a tocolytic is becoming more frequent, even if there is no consensus about the appropriate regi­ men. Two cases of serious complications have been reported. � A 37-year-old previously healthy woman went

into preterm labor at 33 weeks and was given two doses of sublingual nifedipine 20 mg 30 minutes apart, followed by maintenance oral nifedipine 40 mg 6-hourly (13A). Her contractions subsided and it was decided to maintain tocolysis until 34 weeks of gestation. On day 3, she complained of dyspnea and orthopnea with tachycardia and tachypnea. Chest radiography showed bilateral interstitial and central alveolar shadowing but no pleural effusions. Nifedipine was withdrawn and she received intravenous furosemide during the first 24 hours and oxygen, with transient improvement. A cesarean delivery was per­ formed. She was extubated 24 hours after delivery and furosemide was maintained for 4 days. She recovered completely. � A 38-year-old woman developed threatened preterm labor at 33 weeks of gestation and was given nifedipine 30 mg followed by three doses of modified-release nifedipine tablets 20 mg 8-hourly (14A). Within 4 hours of the last dose, she had palpitation and left-sided chest pain with an irregular pulse. Electrocardiography confirmed fast atrial fibrillation. Transthoracic echocardiography showed no major structural

342

Chapter 18

cardiac abnormality. The left atrium was not dilated. Cardioversion was undertaken under a short general anesthetic. She reverted to sinus rhythm.

Verapamil

(SED-15, 3618; SEDA-28, 220; SEDA-29, 199; SEDA-30, 228)

Cardiovascular Brugada syndrome and vasospastic angina are separate cardiovas­ cular disorders that can occur together. Although calcium channel blockers are the treatment of choice for vasospastic angina, they can exacerbate the Brugada syndrome. � A 43-year-old man with vasospastic angina

and Brugada syndrome was given intravenous verapamil and had adverse effects on the electrocardiogram and on the termination of

A.P. Maggioni, M.G. Franzosi, and R. Latini ventricular fibrillation (15C). Although base­ line coronary angiography was normal, intracoronary infusion of ergonovine maleate caused complete occlusion of the left anterior descending artery and a 99% occlusion of the proximal right coronary artery, each relieved by intracoronary isosorbide dinitrate. Double extrastimuli delivered at the right ventricular outflow tract induced ventricular fibrillation, which was terminated by a 200 J shock. Verapamil 10 mg intravenously increased ST segment elevation and druginduced ventricular fibrillation was not termi­ nated by 200 J and required an additional 360 J shock.

Verapamil can increase the voltage gradient through the right ventricle and slow intra­ ventricular conduction at very fast heart rates, which may have been responsible for this presentation. Care should be taken when giving a calcium channel blocker to a patient with Brugada syndrome.

References 1. Krum H, Hill J, Fruhwald F, Sharpe C, Abraham G, Zhu JR, Poy C, Kragten JA. Tolerability of beta-blockers in elderly patients with chronic heart failure: the COLA II study. Eur J Heart Fail 2006;8 (3):302–7. 2. Jappe U, Uter W, Menezes de Pádua CA, Herbst RA, Schnuch A. Allergic contact dermatitis due to b-blockers in eye drops: a retrospective analysis of multicentre surveil­ lance data 1993–2004. Acta Derm Venereol 2006;86(6):509–14. 3. Kelleher JA. Atenolol-induced breast pain in a woman with hypertension. Ann Phar­ macother 2006;40(5):990–2. 4. Maraffa JM, Lang L, Ong G, Lehmann DF. Profound metoprolol-induced bradycardia precipitated by acetaminophen–propoxy­ phene. Clin Pharmacol Ther 2006;79 (3):282–6. 5. Zaccaria E, Gualco F, Drago F, Rebora A. Fixed drug eruption due to propranolol. Acta Derm Venereol 2006;86(4):371. 6. Carey BJ. Atishoo! Atishoo! We all fall down! Age Ageing 2006;35(4):446–7.

7. Vishwanath MR, Charles SJ. Does timolol LA enhance the disrupting effect of travo­ prost on the blood-aqueous barrier? Acta Ophthalmol Scand 2006;84(3):441. 8. Abdelrazeq AS, Owen C, Smith L, McAdam J, Pearson HJ, Leveson SH. Nicorandil-associated para-stomal ulcera­ tion: case series. Eur J Gastroenterol Hepatol 2006;18(12):1293–5. 9. Vogt S, Mehling A, Hunziker P, Scholer A, Jung J, González AB, Weinmann W, Marsch S. Survival of severe amlodipine intoxication due to medical intensive care. Forensic Sci Int 2006;161(2):216–20. 10. Harris NS. Case 24-2006: a 40-years-old woman with hypotension after an overdose of amlodipine. N Engl J Med 2006;355 (6):602–11. 11. Saladi RN, Cohen SR, Phelps RG, Persaud AN, Rudikoff D. Diltiazem induces severe photodistributed hyperpigmentation. Arch Dermatol 2006;142(2):206–10. 12. Casey G, Nortcliffe SA, Sharpe P, Buggy DJ. Perioperative nimodipine and postoperative analgesia. Anesth Analg 2006;102(2):504–8.

Beta-adrenoceptor antagonists and antianginal drugs 13. Abbas OM, Nassar AH, Kanj NA, Usta IM. Acute pulmonary edema during tocolytic therapy with nifedipine. Am J Obstet Gynecol 2006;195(4):e3–4. 14. Parasuraman R, Gandhi MM, Liversedge NH. Nifedipine tocolysis associated atrial fibrillation responds to DC cardioversion. BJOG 2006;113(7):844–5.

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15. Chinushi M, Tagawa M, Nakamura Y, Aizawa Y. Shortening of the ventricular fibrillatory intervals after administration of verapamil in a patient with Brugada syn­ drome and vasospastic angina. J Electrocardiol 2006;39(3):331–5.

R. Verhaeghe and P. Verhamme

19 Drugs acting on the cerebral and peripheral circulations DRUGS USED IN THE TREATMENT OF ARTERIAL DISORDERS OF THE BRAIN AND LIMBS

Ginkgo biloba

Cinnarizine and flunarizine (SED-15,

DRUGS USED IN THE TREATMENT OF VENOUS DISORDERS

781; SEDA-27, 209) Drug overdose Overdose of cinnarizine in a child has been reported (1A).
A 30-month-old toddler took 225 mg of

(Ginkgoaceae)

See Chapter 48.

Aescin (Hippocastanaceae) (SED-15, 1629)

cinnarizine (the maximal daily dose for an adult). Four hours later she vomited and became at first jittery and later stuporose. Six hours after ingestion, she had a few short generalized tonic–clonic convulsions. She recovered fully 10 hours after ingestion. Serum cinnarizine concentrations were 25 times higher than the adult target range.

Aescin is the major active principle from the horse chestnut tree (Aesculus hippocastanum) and is claimed to have clinical activity in venous insufficiency. Investigations in animal models suggest that it has anti-oedematous, anti-inflammatory, and venotonic properties. Clinical tolerance is usually excellent.

Convulsions in this case were explained by the antihistaminic activity of cinnarizine, but an antidopaminergic affect may also have contributed.

Respiratory Aescin has been anecdotally implicated as a potential source of occupational asthma (3A).

Sensory systems Apraxia of eyelid open­ ing due to flunarizine has previously been described in the context of extrapyramidal disorders (SEDA-22, 221). Tardive blepharospasm has now been described during prolonged treatment with cinnarizine for vertigo in a 53-year-old woman (2A).


A 51-year-old employee of a pharmaceutical

company developed bronchial asthma while working with plant extracts. Specific inhalation challenge showed that aescin was the culprit.

DRUGS USED IN THE TREATMENT OF MIGRAINE Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03119-5 r 2009 Elsevier B.V. All rights reserved.

Ergot alkaloids (SED-15, 1230; SEDA-28, 224; SEDA-29, 202) Cardiovascular Intermittent, chronic, or excessive use of ergotamine can lead to

345

346 serious ischemic adverse effects in the peripheral, coronary, or cerebral circulations. In a retrospective nested case–control study overuse of ergotamine (defined as more than 90 daily doses over a year) increased the risk of ischemic complications requiring hospitalization (OR: 2.5; 95% CI ¼ 1.22, 5.36) (4C). In patients who simultaneously used other cardiovascular drugs the increase was almost fourfold. Triptans had no such effect. Arterial dissection is mainly associated with vessel wall abnormalities, such as fibromuscular dysplasia, or with arterial trauma. Carotid dissection has been reported in association with ergotamine (SEDA-29, 202), and two new cases have been reported, one in the iliac arteries and one in the coronaries, two sites that are not usually susceptible to spontaneous dissec­ tion (5A,6A).

Triptans

(SED-15, 3525; SEDA-27, 210; SEDA-29, 203)

Cardiovascular The adverse effects of single-dose triptans are generally minor or mild. A meta-analysis of pooled individual patient data from four randomized placebocontrolled studies of almotriptan in over 2000 patients showed no significant difference in the incidence of adverse events (7M). The authors of extensive reviews of sumatriptan, zolmitriptan, and eletriptan also concluded that they are well tolerated (8R,9R,10R). On the other hand, a few new reports of acute ischemic events in various organs (heart, intestine, spleen, kidney) after the use of various triptans are published every year. Nervous system The serotonin syndrome has been reported in conjunction with combined use of triptans+antidepressants, particularly selective serotonin and seroto­ nin–noradrenaline reuptake inhibitors (SEDA-30, 232); the FDA has collected a couple of dozen cases. Prescribers are advised to question patients about medica­ tions that may interact and to be vigilant for

Chapter 19

R. Verhaeghe and P. Verhamme

suggestive symptoms. The syndrome usually has a rapid onset, characterized by changes in mental status and behavior, and by neurological and autonomic symptoms, but a mild reaction is possible (11r).

OTHER PERIPHERAL VASODILATORS Inhibitors of phosphodiesterase type V (SED-15, 3133; SEDA-28, 224; SEDA-29, 203; SEDA-30, 232) Cardiovascular Acute events occurring within a suspected time frame after the use of inhibitors of phosphodiesterase type V (PDE-5) are likely to be ascribed to these drugs, even though there is no obvious pathogenetic mechanism. Vasodilatory drugs would not be expected to cause aortic dissection, but a case has been reported (12A).
A 61-year-old man who had used sildenafil

regularly for 2 years developed vomiting, diarrhea, and abdominal pain 30 minutes after taking sildenafil 50 mg and before he engaged in sexual intercourse. He later developed chest pain, and echocardiography and computerized tomography established the diagnosis of ascending aortic dissection.

The authors advanced some speculative arguments: that the relaxant effect on the aortic wall may differ between layers, favoring intimal tears; and that an antiproliferative effect on the aorta renders the wall more vulnerable. However, in the acute phase of dissection strong vasodilatory drugs are often used to lower blood pressure and to protect patients from progressive dissection. Ear, nose, throat Nasal congestion is com­ mon after the use of oral drugs for erectile dysfunction. Nasal patency has been exam­ ined with anterior rhinomanometry in 16 patients with impotence before and after sildenafil 50 mg (13c). Nasal air flow fell significantly and all but three patients had a sensation of nasal obstruction.

Drugs acting on the cerebral and peripheral circulations

Nervous system Headache is one of the chief complaints with the use of PDE-5 inhibitors. Most commonly, they are described as triggers of migraine headache, but they also can trigger cluster headaches, which are much less common than migraine (14A,15A). A case of typical migraine aura but without headache has been reported in a patient taking tadalafil (16A).
A 64-year-old man developed stereotypical

visual phenomena (a bright ill-defined trian­ gular shape in the visual field) for about 20 minutes. He had used sildenafil for 4 years and began noticing these episodes a few months after switching to tadalafil. After withdrawal of tadalafil and later after restart­ ing sildenafil he kept experiencing the aura, but less often.

Here too, a causal relation with tadalafil intake was difficult to explain. Tadalafil has a much longer half-life than sildenafil, but there was no strict temporal relation between ingestion of a tablet and the onset of the aura. Epileptic seizures have been reported in a few patients after sildenafil (SEDA-27, 211). They have now also been described with vardenafil in two patients, in the first shortly after a high dose (40 mg), in the second after a second normal dose (10 mg) (17A). Sensory systems The possible connection between PDE-5 inhibitors and non-arteritic anterior ischemic optic neuropathy (NAION) remains controversial (18r). Whereas indivi­ dual cases with a temporal relation continue to be published, experts stress in reviews that it is still not possible, on the basis of the available literature, to determine whether NAION is directly related to the use of these drugs, underlying cardiovascular risk factors,

Chapter 19

347

ocular anatomical defects, a combination of these variables, or as yet unidentified factors (19r,20r). Meanwhile, in a retrospective matched case–control study of 38 patients there was a positive association between NAION and PDE-5 inhibitor exposure, but it was significant only in patients with a history of myocardial infarction (21C). Subretinal and choroidal hemorrhage has been reported in a patient with an unsus­ pected uveal melanoma, a few hours after a single dose of tadalafil 20 mg (22A).
A 63-year-old man woke up with a painful red

eye and limited vision after having taken a single tablet the evening before. He was also taking long-term aspirin. His vision did not improve, and further evaluation led to the discovery of a malignant melanoma of the choroid, with recent hemorrhage.

The authors suggested that the vasodilatory effects of tadalafil may have led to conges­ tion of the tumor and rupture of a neovascular membrane beneath the retinal pigment endothelium, causing accumula­ tion of blood. Sensorineural hearing loss has been reported after ingestion of sildenafil (23A).
A 44-year-old man started to take sildenafil

50 mg/day for erectile dysfunction and on the fifth day noticed a ringing sensation, first in one and later in both ears. A week later, while still taking sildenafil, he developed hearing difficulty, which progressed to bilateral unre­ mitting deafness over a few days.

The authors speculated that the hearing loss had resulted from cochlear toxicity of silde­ nafil. However, sudden sensorineural hear­ ing loss is a poorly understood condition, which has been described in conjunction with a variety of diseases, syndromes, and drugs.

References 1. Turner D, Lurie Y, Finkelstein Y, Schmid T, Gopher A, Kleid D, Bentur Y. Pediatric cinnarizine overdose and toxicokinetics. Pediatrics 2006;117:e1067–9.

2. Alonso-Navarro H, Jiménez-Jiménez FJ. Tardive blepharospasm associated with cin­ narizine use. Clin Neuropharmacol 2006;29: 187–9.

348 ~ X, Culebras M, Cruz MJ, Morell Munoz F. Occupational asthma related to aescin inhalation. Ann Allergy Asthma Immu­ nol 2006;96:494–6. 4. Wammes-van der Heijden EA, Rahim­ toola H, Leufkans HG, Tijssen CC, Egberts AC. Risk of ischemic complica­ tions related to the intensity of triptan and ergotamine use. Neurology 2006;67: 1128–34. 5. Molkara AM, Abou-Zamzam Jr AM, Teruya TH, Bianchi C, Killeen JD. Chronic ergot toxicity with bilateral external iliac artery dissection and lower extremity rest pain. Ann Vasc Surg 2006; 20:803–8. 6. Garcia Garcia C, Casanovas N, Recasens L, Miranda F, Bruguera J. Spontaneous coronary artery dissection in ergotamine abuse. Int J Cardiol 2007;118:410–1. 7. Dahlöf CG, Pascual J, Dodick DW, Dowson AJ. Efficacy, speed of action and tolerability of almotriptan in the acute treatment of migraine: pooled individual patient data from four rando­ mized, double-blind, placebo-controlled clinical trials. Cephalalgia 2006;26:400–8. 8. Cady R, Schreiber C. Sumatriptan: update and review. Expert Opin Phar­ macother 2006;7:1503–14. 9. Tuchman M, Hee A, Emeribe U, Siber­ stein S. Efficacy and tolerability of zolmi­ triptan oral tablet in the acute treatment of menstrual migraine. CNS Drugs 2006; 20:1019–26. 10. McCormack PL, Keating GM. Eletriptan: a review of its use in the acute treatment of migraine. Drugs 2006;66:1129–49. 11. Wooltorton E. Triptan migraine treatments and antidepressants: risk of ser­ otonin syndrome. CMAJ 2006;175:874–5. 12. Nachtnebel A, Stöllberger C, Ehrlich M, Finsterer J. Aortic dissection after

Chapter 19

3.

13.

14. 15.

16.

17.

18.

19.

20.

21.

22.

23.

R. Verhaeghe and P. Verhamme

sildenafil-induced erection. South Med J 2006;99:1151–2. Kiroglu AF, Bayrakli H, Yuca K, Can­ kaya H, Kiris M. Nasal obstruction as a common side-effect of sildenafil citrate. Tohoku J Exp Med 2006;208:251. Evans RW. Sildenafil can trigger cluster headaches. Headache 2006;46:173–4. de L Figuerola M, Bruera O, Lestón J, Ferreiro J. Cluster headache attack due to sildenafil intake. Cephalalgia 2006;26:617–9. Dinn RB, Wall M. Tadalafil associated with typical migraine aura without head­ ache. Cephalalgia 2006;26:1344–6. Striano P, Zara F, Minetti C, Striano S. Epileptic seizures can follow high doses of oral vardenafil. BMJ 2006;333:785. Pomeranz HD. Can erectile dysfunction drug use lead to ischaemic optic neuro­ pathy? Br J Ophthalmol 2006;90:127–8. Bella AJ, Brant WO, Lue TF, Brock GB. Non-arteritic anterior optic neuropathy (NAION) and phosphodiesterase type-5 inhibitors. Can J Urol 2006;13:3323–8. Laties A, Sharlip I. Ocular safety in patients using sildenafil citrate therapy for erectile dysfunction. J Sex Med 2006; 3:12–27. McGwin Jr G, Vaphiades MS, Hall TA, Owsley C. Non-arteritic anterior ischae­ mic optic neuropathy and the treatment of erectile dysfunction. Br J Ophthalmol 2006;90:154–7. Abramson DH, Rollins IS, Lin A, Odell P, Folberg R. Tadalafil-induced subret­ inal and choroidal hemorrhage in a patient with an unsuspected uveal (chor­ oidal and ciliary body) melanoma. Arch Ophthalmol 2006;124:1058–60. Mukherjee B, Shivakumar T. A case of sensorineural deafness following inges­ tion of sildenafil. J Laryngol Otol 2007; 121:395–7.

J.J. Coleman and T.F. Butt

20

Antihypertensive drugs

A few reviews and studies have examined several different classes of antihypertensive agent in the same publication. These are included at the beginning of this chapter, followed by information about the adverse effects of specific drug classes and specific agents within those classes. Endocrine Some antihypertensive drugs aggravate glucose tolerance; beta­ adrenoceptor antagonists and thiazide diuretics in combination are most commonly implicated (1M). A prospective study of three large cohorts of patients with hypertension has been conducted to evaluate the incidence of type 2 diabetes mellitus associated with different drug classes in the USA. The Nurses’ Health Survey (NHS) I and II, and the Health Professionals Follow-up Study (HPFS). The authors found 3589 cases of incident diabetes mellitus out of a combined total of 74 816 patients (2C). Both thiazide diuretics and beta-adrenoceptor antagonists were independently associated with a higher risk of incident diabetes, whereas angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers had no such adverse or apparent protective effect. A further review has been published examining the diabetogenic potential of different antihypertensive drug classes (3R). The authors explored whether “older drugs” (beta-adrenoceptor antagonists and thiazide diuretics) are diabetogenic or whether “newer” drugs (calcium channel blockers and ACE inhibitors) protect Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03120-1 r 2009 Elsevier B.V. All rights reserved.

against the development of diabetes. They confirmed previous findings that when combined “older” drugs amplify the natural time-dependent tendency to diabetes in hypertensive patients, and provided evi­ dence that new-onset diabetes mellitus is less common with the “newer” drugs. Sexual function Erectile dysfunction is a significant problem in men with hyperten­ sion, often thought to be related to their antihypertensive treatment. More recent evidence suggests that vascular abnormal­ ities can lead to pathophysiological changes that are causative both in hypertension and erectile dysfunction, therefore leading to controversy about the relative contribution of adverse antihypertensive drug effects. The evidence relating to thiazide diuretics, centrally acting sympatholytic drugs, and beta-adrenoceptor antagonist effects on sexual function has been reviewed, with suggestions about the management of erec­ tile dysfunction in hypertensive men (4R). Drug withdrawal A number of drug with­ drawal states can result in systemic hyper­ tension (5R). Withdrawal of clonidine and beta-adrenoceptor antagonists can both cause rebound hypertension. Patients may also have a state of sympathetic overactivity with tachycardia and anxiety when these and other drugs are withdrawn after longterm treatment. Susceptibility factors Genetic A number of drugs used in cardiovascular medicine have been reported to have differing rates of adverse effects in different ethnic popu­ lations. For example, the rates of angioe­ dema and cough in relation to ACE inhibitors are increased in Afro–Caribbean and Asian populations respectively. Ethnic differences in the risks of adverse drugs

349

350 used in cardiovascular medicine, including some antihypertensive drugs, have been systematically reviewed (6M). Drug–drug interactions Drug interactions of antihypertensive agents have been reviewed, including a brief exploration of drugs that cause or exacerbate systemic hypertension (7R).

ANGIOTENSIN CONVERTING ENZYME INHIBITORS (SED-15, 226; SEDA-

Chapter 20

J.J. Coleman and T.F. Butt

cough (11R). In the summary they con­ cluded that in patients with chronic cough, ACE inhibitors should be considered wholly or partially causative, regardless of the temporal relation between the start of therapy and the onset of the cough. Their advice is that the only uniformly effective treatment for ACE inhibitorinduced cough is withdrawal of therapy and that a switch to an angiotensin II receptor antagonist should be undertaken if conside­ red appropriate. The effects of ACE inhibitors on the respiratory system have been reviewed and the probable pathophysiological mechan­ isms analyzed (12R).

The author of a short editorial on the safety of ACE inhibitors, responding to a review article in the same issue of the journal related to management of ACE inhibitor-induced angioedema, proposed that there are two approaches to the dilemma of bradykininrelated adverse effects: effective patient prescreening or improved ACE inhibitor design (8r). Biomarkers can identify patients at highest risk and structure-guided drug design can contribute in the development of the next generation of ACE inhibitors with a superior safety profile. The pharmacokinetics and pharmacody­ namic effects of the ACE inhibitor class and the impact of various disease states (e.g., renal and hepatic impairment) have been reviewed (9R).

Electrolyte balance Antihypertensive drugs and their effects on potassium homeostasis have been reviewed, in particular the pro­ blem of ACE inhibitor- and angiotensin II receptor antagonist-induced hyperkalemia (13R). The uncertainty about the best way to monitor potassium concentrations is also described and the fact that monitoring guidelines are at best makeshift and drawn from the know-how of the treating physician. Previously published guidelines have been described, together with two case studies that illustrate the role of electrolyte measurement in hypertensive patients tak­ ing ACE inhibitors or potassium-sparing diuretics (14A). Prevention of serious adverse effects with monitoring is impor­ tant, and it is clear that early changes in biochemical parameters may indicate the need for more frequent monitoring or modification of therapy.

Respiratory The adverse respiratory effects of ACE inhibitors are fairly well recognized, especially the association with a dry irritating cough. Several other respira­ tory adverse effects have been described (10r). Medication-related cough may reduce the risk of aspiration pneumonia after stroke and patients with obstructive sleep apnea may be more likely to have rhinopharyngeal inflammation, with a risk of worsening their condition. The American College of Chest Physicians has produced evidence-based clinical prac­ tice guidelines about ACE inhibitor-induced

Pancreas The European case–control study on drug-induced acute pancreatitis has quantified the risk of acute pancreatitis associated with the use of antihypertensive drugs, especially ACE inhibitors (15c). In 724 patients with acute pancreatitis com­ pared with 1791 community control sub­ jects, the adjusted odds ratio of treatment with an ACE inhibitor in the week before the index date was 1.5 (95% CI ¼ 1.1, 2.2). However, there was a similar risk with calcium channel blockers: adjusted odds ratio 1.5 (95% CI ¼ 1.1, 2.1). The risk of acute pancreatitis with ACE inhibitors

28, 227; SEDA-29, 207; SEDA-30, 234)

Antihypertensive drugs

Chapter 20

increased with higher daily doses and was highest in the first 6 months of therapy. The case–control method allowed adjustment for important confounding factors, such as alcohol abuse. Because other potential risk factors could be taken into account and there was an apparent dose relation, this study has substantiated the notion that some cases of acute pancreatitis are attri­ butable to ACE inhibitors, especially when they occur early in therapy. Urinary tract ACE inhibitors are used for several different indications other than hypertension, including cardiac failure and diabetic nephropathy. Their use in patients with impaired renal function poses some difficulties, as their use can be associated with various adverse effects on the kidneys. In a prospective multicenter study of the use of drugs with a supposed risk of renal problems in hospitalized patients with pre­ existing renal impairment, 201 of 808 patients had moderate to severe renal impairment (stage 3 to 5 chronic kidney disease) and the majority of these were taking at least one drug with a possible risk of renal problems (16c). ACE inhibitors were the third most commonly prescribed drug category, after antibacterial and antith­ rombotic drugs, associated with drug-related problems in this study. It is difficult from the reported data to tease out why the ACE inhibitors apparently caused problems, especially when the authors acknowledged that this drug class as well as being classified as “renal risk drugs” (in their coding scheme) is also renoprotective when used appropriately. The renoprotective effect of ACE inhi­ bitors has mainly been examined in shortterm trials, and the long-term risks are less clear. The long-term risk of renal failure in diabetic patients taking ACE inhibitors has been examined in a nested case–control study (17c). Compared with thiazide diure­ tics, the adjusted rate ratio of end-stage renal failure associated with ACE inhibitors was 2.5 (95% CI ¼ 1.3, 4.7). End-stage renal failure rates increased between the first 3 years of follow up and after 3 years, suggesting that ACE inhibitors may con­ tribute to the increasing incidence of

351 end-stage renal disease that is due to diabetes. Although, based on the results of this study, the use of ACE inhibitors by patients with diabetes does not appear to reduce the long-term risk of end-stage renal disease; the results should not dissuade cli­ nicians from using these drugs in patients with diabetic nephropathy based on the clear evidence of efficacy from current ran­ domized evidence. More long-term studies or observational data on the renal effects of ACE inhibitors in diabetes are required. While it is recognized that ACE inhibitors should be used with caution in patients with renal impairment, these drugs are contra­ indicated in patients with confirmed renal artery stenosis. In such cases there is a risk of acute renal deterioration, as ACE inhibitors reduce or abolish glomerular fil­ tration, owing to preferential efferent ar­ teriolar dilatation in the glomerulus. A retrospective evaluation of 25 patients undergoing renal stent revascularization has shown that ACE inhibitors can be safely used in most patients whose renal function is normal after the procedure (18c). Theoreti­ cally, it seems reasonable from a physiolo­ gical basis that the relief of renal artery stenosis should allow the safe use of ACE inhibitors. It is worth noting that in all but 1 of these 25 patients bilateral renal artery revascularization was performed, and it is unclear if the results would be reproducible in unilateral revascularization alone. The investigators also found that despite renal artery stent placement, 5 of 25 patients were unable to reach target doses of ACE inhibitor treatment, because of cough or baseline renal insufficiency. Nevertheless, for patients with renal artery stenosis who have a clear clinical indication for the use of ACE inhibitors the results may help reas­ sure clinicians to treat them appropriately after renovascular intervention. Lastly, in a prospective cohort study of the safety aspects of ACE inhibitors as a risk factor for contrast-induced nephropathy, 230 patients who underwent coronary an­ giography were evaluated for an increase of greater than or equal to 25% in ser­ um creatinine concentration within 48 hours of the procedure—which the authors defi­ ned as contrast-induced nephropathy (19c).

352 The patients received a pre-treatment infu­ sion of saline and angiography was perfor­ med using a low-osmolar non-ionic contrast agent. In a multivariate analysis, chronic use of ACE inhibitors (defined as the use of any type of ACE inhibitor for at least 2 months before admission) was associated with contrast-induced nephropathy with an odds ratio of 3.37 (95% CI ¼ 1.14, 9.94). This re­ sult was contrary to the hypothesized pro­ tective effect of ACE inhibitors and suggests that there is a need to withhold ACE inhibitors before coronary angiography.

Angioedema due to ACE inhibitors Reviews Angioedema due to ACE inhibitors was reviewed in SEDA-29 (p. 207), and further reviews continue to appear. The pathophysiological roles of kinins and metallopeptidases have been reviewed (20R), in addition to published reviews with respect to the clinical particulars (21R), the anesthetic implications (22R), the management options (23R), and the general problems and immunological basis (24R) of ACE inhibitor-induced angioedema. Incidence The incidence and predictors of angioedema in the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) have been analysed (25c). There were 53 participants who developed angioedema during active followup, of whom 70% were taking lisinopril. The overall occurrence and risk factors in the ACE inhibitor treated arm corresponded with previously reported studies. Angioedema is thought to be a class effect of the ACE inhibitors. A patient taking ramipril 2.5 mg/day for hypertension developed angioedema a few days after being switched to trandolapril 2 mg/day because of poor blood pressure control (26A). The authors suggested that the appearance of angioedema with trandolapril in a patient who had previously taken ramipril uneventfully demonstrates that angioedema may not

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J.J. Coleman and T.F. Butt

be a class effect and that safe treatment with one drug does not rule out the occurrence of this adverse effect with another drug in the same class. However, the lack of antihypertensive response to ramipril in this case suggests that the dose may not have been high enough to have caused angioedema in the way that trandolapril did. Cause The cause of angioedema is probably related to ACE inhibitor-induced accumulation of bradykinin, which is likely to cause potentiation of allergic responses in patients taking ACE inhibitors. Several case reports have described severe allergic reactions, including anaphylaxis, in patients taking ACE inhibitors after insect stings or in patients receiving insect venom immunotherapy. A systematic review of the literature surrounding the safety of ACE inhibitors in patients with insect venom allergies has shown that they may exacerbate the response to insect venom, resulting in potentially life-threatening allergic reactions (27R). The exaggerated response may be related to both an underlying defect in the circulating renin–angiotensin–aldosterone (RAA) system in these patients, as well as a reduced ability to counteract allergy-induced hypotension through the RAA and kallikrein– kinin systems in individuals taking ACE inhibitors. Appropriate strategies to reduce the likelihood of insect stings and to ensure the availability of adrenaline for selfadministration are prerequisites in patients with venom allergy taking ACE inhibitors. The kinins (bradykinin and related substances) are also thought to be responsible for adverse hypersensitivity reactions in hemodialysed patients taking ACE inhibitors. In a study of patients who had previously had hypersensitivity reactions during dialysis with the polyacrylonitrile AN69 (negatively charged) dialysis membrane, plasma aminopeptidase P (APP) activity was significantly lower in hypersensitive patients compared with control patients, and there was altered degradation of endogenous des-Arginine9-bradykinin (28E). There were also various genetic differences in the hypersensitive patients, confirming the complex metabolic and genetic components of this adverse effect.

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Chapter 20

Susceptibility factors Patients undergoing hemodialysis are at risk of anaphylactoid (non-IgE-mediated anaphylactic) reactions in association with ACE inhibitors, an association that is usually confounded by the use of polyacrylonitrile (AN69) dialysis membranes (SEDA 29, 209). Two patients undergoing hemodialysis developed predominantly intestinal manifestations attributed to enalapril and ramipril (29A). Both presented with abdominal cramping and diarrhea during hemodialysis using surface-treated AN69 dialysis membranes. Drug–drug interactions Various drugs act synergistically with ACE inhibitors in causing angioedema. Estramustine phosphate, a chemical combination of estradiol and nitrogen mustard, used in the treatment of prostate cancer, caused severe tongue angioedema when it was combined with cilazapril (30A). Case reports of orolingual angioedema Orolingual angioedema has again been attributed to benazepril (31A). This was an unusual case in that the swelling affected one side of the tongue only. Diffuse tongue angioedema has been attributed to captopril (32A). A further case of angioedema has also been reported in association with captopril postoperatively after carotid endarterectomy (33A). The second case proved more difficult diagnostically when the patient, a 71-year-old man, became hoarse and dyspneic 4 hours after surgery. His postoperative symptoms were thought to be related to his surgery, and surgical re-exploration found markedly edematous tissues and a hemostatic operation site. The symptoms resolved after administration of corticosteroids and withdrawal of captopril. Angioedema has been attributed to cilazapril with lisonopril (34A). The patient had been taking cilazapril 5 mg/day and pindolol 15 mg/day for 3 years for hypertension and developed breathing difficulties and speech impairment secondary to tongue swelling; she reported three previous episodes of milder orolingual angioedema over the course of her antihypertensive therapy. Postoperative lingual angioedema has also been described with lisonopril (35A). The

353 patient had taken lisinopril for hypertension and developed upper airway symptoms and tongue swelling immediately after uvulopalatopharyngoplasty and bilateral tonsillectomy for obstructive sleep apnea. It seems from this and other recently reported cases that operative upper airway manipulation should be considered a susceptibility factor for ACE inhibitor-induced angioedema. Case reports of intestinal angioedema Intestinal and gastric angioedema has been attributed to benazepril (36A).  A

45-year-old African–American woman developed diffuse abdominal pain and vomiting 1 day after starting treatment for newly diagnosed hypertension with a combination drug containing amlodipine and benazepril (10/5 mg). She was initially discharged, as no physical abnormalities could be identified, but the next day was readmitted with similar but worse symptoms. She had a distended abdomen, with diffuse tenderness on deep palpation. A plain X-ray showed possible small bowel obstruction and dual contrast CT imaging showed marked thickening of the gastric antrum, duodenum, and proximal jejunum, with free abdominal fluid. ACE inhibitor-induced angioedema of the stomach and small intestine was suspected. She was treated supportively and her antihypertensive medication was stopped. She made a full recovery.

Recurrent ascites secondary to presumed intestinal angioedema has been reported (37A). Extravasation of intravascular fluid into the peritoneal cavity from the edematous bowel wall was thought to be the origin of the ascites.  A

31-year-old woman developed crampy abdominal pain, nausea, vomiting, and diarrhea, with signs of peritoneal irritation. She was taking fosinopril and fenofibrate. Scanning showed evidence of ascites, ileitis, and an inflamed appendix. She underwent appendicectomy. She then had two similar transient episodes, lasting for a few days each, which resolved without specific treatment. On a fourth occasion she developed similar symptoms and imaging again revealed ascites and terminal ileitis. No alternative diagnoses could be made from laboratory or endoscopic investigations. A diagnosis of ACE inhibitor-induced angioedema of the small bowel was made and the fosinopril was withdrawn. The symptoms never recurred and follow-up imaging was normal.

354 Visceral angioedema has been attributed to lisinopril (38Ar). The patient presented with abdominal pain and was found to have small bowel wall thickening and ascites, which resolved quickly on withdrawal of treatment. The authors discussed the radiological features of intestinal angioedema. A patient taking temocapril, valsartan, and spironolactone for membranous nephropathy developed subileus six times in 5 months and was found to have intestinal angioedema when he underwent sigmoid colectomy (39A). The authors attributed this to either the temocapril or the valsartan. Management Angioedema that occurred in a 61-year-old woman while she was taking ramipril was effectively and rapidly reversed by the use of parenteral C1 inhibitor concentrate (40A). This treatment, which is usually very effective in hereditary angioedema, is not routinely recommended for ACE inhibitor-induced angioedema, although in this case it led to resolution of laryngeal edema within the typical 30-minute response time seen in hereditary cases.

Teratogenicity The prescribing informa­ tion for ACE inhibitors highlights the need to withhold treatment in women who become pregnant in order to avoid potential fetotoxic effects in the second and third trimesters. An epidemiological study of 29 507 infants in the Tennessee Medicaid cohort has now reported an association between exposure to ACE inhibitors in the first trimester of preg­ nancy and the risk of congenital malfor­ mations (41c). The group included 209 infants who had been exposed to ACE inhibitors in the first trimester alone and they were compared with the entire cohort and infants who had been exposed to other antihypertensive medications. Mothers with diabetes were excluded since diabetes is a potentially confounding factor for malformations. Infants with only first-trimester exposure to ACE inhibitors had an increased rate of major congenital malformations: risk ratio 2.71 (95%

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J.J. Coleman and T.F. Butt

CI ¼ 1.72, 4.27), and there was no increased risk from other antihypertensive drugs. The increased risk was primarily due to increased risks of malformations of the cardiovascular system and the central nervous system. Post hoc analysis also revealed a significantly increased risk of renal malformations, but the numbers were small. The results are biologically plausible, as angiotensin II is known to have a role in the early embryonic development of the heart, kidneys, and brain. An accompanying editorial pointed out that maternal ACE inhibitor treatment early in pregnancy can cause birth defects and the author therefore suggested that discussion should take place with all women of reproductive age who are taking these drugs (42r). The author acknowledged that babies and their mothers are being harmed because not enough is known about which antihyper­ tensive treatments to use and which to avoid; and that because of this ignorance some pregnant women may not receive beneficial treatments for hypertension in pregnancy. Drug–drug interactions Combination treat­ ments involving ACE inhibitors or angio­ tensin receptor blockers or both, have been scrutinized because of safety con­ cerns mainly related to renal impairment. Dual renin–angiotensin–aldosterone sys­ tem blockade using ACE inhibitors and angiotensin receptor blockers may be more effective than either alone, and this approach has been investigated in several large trials. The use of such combinations means that patients may face the adverse effects of each drug and also some possible additional adverse effects. However, gen­ eral experience has shown that combina­ tion treatment is safe and effective, although there are problems related to more marked increases in serum creatinine and potassium, especially in patients who become dehydrated or develop other acute intercurrent illnesses. The untoward effects of dual RAA system blockade have been examined in 75 patients with nephropathy and proteinuria (43c). The mean serum potassium concentration increased with

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Chapter 20

dual blockade in patients with evidence of chronic renal insufficiency compared with patients with normal renal function. There was also a small drug-induced increase in serum creatinine concentration in patients with pre-existing renal failure. The risks from hyperkalemia or increased creatinine concentration were not considered danger­ ous. Combined treatment did not seem to influence erythropoiesis. Overall the advice is that dual renin–angiotensin–aldosterone system inhibition requires close monitor­ ing, because of adverse effects that cannot be predicted, but similar evaluation of patients with advanced renal failure is required. A review of the effects of dual inhibition has also been published (44R) and dual therapy specifically for the indication of proteinuric renal disease has been reviewed (45M). Diuretics and NSAIDs The concomitant use of ACE inhibitors (or angiotensin II receptor blockers) with a diuretic and a non-steroidal anti-inflammatory drug has been described as a “triple whammy” by the Australian Drug Reactions Advisory Committee (47r), which has again issued a warning about this combination of three drug classes, in view of 21 reports to their spontaneous reporting system about druginduced renal failure (48r). Precipitating causes were similar to the other renal adverse effects of ACE inhibitors, in that acute illness, dehydration, or the recent addition of an NSAID all increased the risk of renal problems. Metformin A combination with recog­ nized adverse effects is the use of metfor­ min with ACE inhibitors, with the consequent risk that lactic acidosis will be potentiated by these agents, especially in the context of intercurrent illness and/or dehydration. Five patients taking ACE inhibitors or angiotensin II receptor antago­ nists developed severe metformin-asso­ ciated lactic acidosis (46A). The authors rightly cautioned against co-prescription of ACE inhibitor or angiotensin II receptor antagonists with metformin, and advised that patients be made aware of the pro­ blems that can occur during acute illnesses,

355 so that dose reduction or temporary with­ drawal of treatment can be considered.

Captopril

(SED-15, 625; SEDA-29, 210)

Respiratory Pulmonary infiltrates with eosinophilia have previously been reported in association with captopril in adults; a pediatric case has now been reported (49A).  An 8-month-old girl with complex congenital

heart disease was given captopril 1 mg tds 4 days after corrective cardiac surgery. Two days later she had a peripheral blood eosinophilia and on postoperative day 17 she returned to the emergency room with clear rhinorrhea, poor feeding, a low-grade fever, and reduced urine output. She was tachypneic with a low oxygen saturation on room air (85%). There was a peripheral eosinophilia and diffuse infiltrates on the chest X-ray. A presumptive diagnosis of captopril-induced pulmonary infiltrates with eosinophilia was made. Captopril was with­ drawn and she was given systemic steroids. Other investigations failed to suggest an alter­ native diagnosis and she improved clinically over 5 days. Serial chest X-rays showed slow resolution of the infiltrates and the full blood count returned to normal.

Enalapril (SED-15, 1210; SEDA-28, 227; SEDA-29, 210; SEDA-30, 235)

Respiratory Obstructive sleep apnea is characterized by upper airway inflammation, and it has been postulated that ACE inhibitors, by inducing cough and rhinopharyngeal inflammation, may contribute (50Ar).  A 64-year-old woman developed likely ACE

inhibitor-induced cough and had evidence of moderate obstructive sleep apnea while taking enalapril 10 mg/day for hypertension. Her symptoms of cough and diurnal sleepiness resolved completely after enalapril withdrawal.

In view of this possible association a small-scale study of patients with obstruc­ tive sleep apnea taking ACE inhibitors was performed, assessing polysomnography and post-sleep exhaled nitric oxide (as a marker of airway inflammation). Withdrawal of ACE inhibitors produced significant poly­ somnographic improvement in four patients

356 who had ACE inhibitor-induced cough, and was associated with recovery of upper airway symptoms and normalization of exhaled nitric oxide concentrations. These results suggest that ACE inhibitors may contribute to obstructive sleep apnea, par­ ticularly in patients who develop cough and upper airway symptoms. Hematologic A randomized study of 40 men to assess whether enalapril slows recovery from anemia following cardiac surgery was based on the hypothesis that ACE inhibitors have an inhibitory effect on erythropoiesis (51c). The results suggested that early enalapril therapy does indeed have an adverse, albeit possibly transient, effect on recovery from anemia after major cardiovascular surgery. The authors con­ cluded that this unfavorable effect on anemia should be considered when pre­ scribing ACE inhibitors for cardiac post­ operative patients. Fetotoxicity The fetotoxic effects of ACE inhibitor exposure during the second and third trimesters of pregnancy are well described. A child who was exposed during gestational weeks 28 to 36 presented at 14 years of age with proteinuria, markedly impaired urinary concentrating ability, and reduced glomerular filtration rate (52A). The patient had had transient acute renal failure in the perinatal period and mild proteinuria at aged 7 years, but had no formally diagnosed chronic renal abnorm­ alities until aged 14 years. The presentation of such a long-term follow-up of a patient exposed in utero to ACE inhibitors is unusual. Drug overdose Mixed overdose with ena­ lapril and verapamil was successfully trea­ ted with low-dose insulin (53A).  A 59-year-old woman who usually took

disothiazide, metoprolol, and enalapril for hypertension took a mixed overdose of enala­ pril and modified-release verapamil. She had severe hypotension, a junctional cardiac rhythm, hyperglycemia, pulmonary conges­ tion, and renal failure. Despite cardiac inten­

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J.J. Coleman and T.F. Butt

sive care unit treatment with calcium gluco­ nate, glucagon, and dopamine, the patient remained oliguric and hypotensive. An intravenous infusion of insulin with dextrose was started on the third day of hospi­ talization, which resulted in restoration of sinus rhythm after 3 hours, as well as an improved blood pressure and adequate urine output. The glucagon and dopamine were stopped; the insulin infusion continued for 38 hours. The patient’s condition improved to normal and she was discharged 8 days after hospitalization.

Drug–drug interactions Glycyrrhizin Pseudoaldosteronism secondary to two Chinese herbal medicines containing glycyr­ rhizin has been reported. The condition became manifest only when the patient devel­ oped symptoms related to hypokalemia when the dosage of enalapril was reduced (54A). Management of adverse drug reactions High-dose chemotherapy, especially with anthracyclines and other combined treat­ ments with cardiotoxic effects, affect out­ comes in patients with cancer. There is great interest in strategies for preventing cardiotoxicity due to chemotherapeutic agents. In a prospective randomized study enalapril had a beneficial effect in prevent­ ing cardiotoxicity in patients undergoing high-dose chemotherapy (55c). Patients with various malignancies, but no evidence of prior cardiac disease, who were receiving different high-dose chemotherapy combina­ tions, were evaluated after treatment for evidence of cardiotoxicity using troponin I assays. There were 114 patients with a positive troponin concentration who were therefore presumed to be at high risk of left ventricular dysfunction and a poor cardiac outcome; they were randomized to escalat­ ing enalapril treatment (up to 20 mg/day, up-titrated as blood pressure allowed) or a control group. Patients in the control group were significantly more likely to have a reduced left ventricular ejection fraction and an increased incidence of cardiac events during 1 year of follow up. The authors concluded that in high-risk patients receiving high-dose chemotherapy, early

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Chapter 20

enalapril both prevents cardiotoxicity and improves cardiological outcome.

Imidapril

(SED-15, 1718; SEDA-30,

236)

Comparative studies The Iberian Mulitcenter Imidapril Study on Hypertension (IMISH) trial has reported the results of a 12-week randomized, double-blind trial of imidapril (n ¼ 55) versus candesartan (n ¼ 57) (56C). There were significant similar reductions from baseline values in mean diastolic and systolic blood pressures, mean 24-hour ambulatory blood pressure monitoring, and mean blood pressure in the two treatment groups. The reduction in blood pressure load was higher with imidapril than with candesartan. The incidences of adverse events were also similar; there were no cases of dry cough.

Lisinopril (SED-15, 2071; SEDA-28, 228; SEDA-29, 210; SEDA-30, 237)

Pancreas Acute pancreatitis has been reported with several of the ACE inhibitors; recurrent pancreatitis attributed to lisinopril has been reported (57A). The case demonstrated that the condition can recur while patients continue to take the medicine. The evidence relating to ACE inhibitor therapy and pancreatitis has also been reviewed (58r). Skin Bullous pemphigoid has been attributed to lisinopril in a 75-year-old man with hypertension (59A). The diag­ nosis of drug-induced pemphigoid was supported by the temporal nature of the reaction, which occurred 2 months after the start of treatment (similar to other cases of bullous pemphigoid, which tends to occur at 1–3 months), and the fact that treat­ ment with corticosteroids was ineffective while the patient was taking lisinopril but remission was achieved quickly after with­ drawal.

357 Drug–drug interactions Losartan The use of low-dose lisinopril in combination with losartan led to acute renal function deterioration associated with hypotension in a 7-year-old boy (60A). The author acknowledged the need for close surveil­ lance of renal function and blood pressure during dual therapy with ACE inhibitors and angiotensin receptor antagonists, and called for further investigation into the utility and safety of such therapy in children.

Quinapril

(SED-15, 2996; SEDA-29, 211; SEDA-30, 237)

Drug overdose A 15-year-old girl took a mixed overdose of flecainide acetate (4 g in a long-acting formulation) and quinapril 560 mg (61A). The clinical presentation was, in the authors’ opinion, mainly dictated by flecainide intoxication, but the patient required intra-aortic balloon pump treatment for sustained hypotension despite inotropic support, to which the quinapril would have contributed.

Ramipril (SED-15, 3022; SEDA-28, 228; SEDA-29, 211; SEDA-30, 237) Mouth and teeth Of six patients with histologically proven lichenoid and granulomatous stomatitis, one, a 54-year-old woman, developed a tender swelling on the upper lip and adjacent gum margin (62A). She was taking ramipril and bendroflumethiazide for hypertension. In view of the fact that ramipril has previously been associated with mucocutaneous lichenoid reactions, the authors proposed that this lesion may have represented an unusual drug eruption. Skin Lichen planus pemphigoides occurred in a 69-year-old woman after she had taken ramipril for hypertension for 3 weeks (63Ar).

358

ANGIOTENSIN II RECEPTOR ANTAGONISTS (SED-15, 223; SEDA-28, 229; SEDA-29, 211; SEDA-30, 238)

Cardiovascular There has been previous debate about the relative safety of angiotensin II receptor antagonists with respect to myocardial infarction. A systematic review and meta-analysis of data on the risk of myocardial infarction and the use of angiotensin II receptor antagonists has shown no increase in risk (64M). In another review of the available evidence for angiotensin II receptor antagonist safety in the context of myo­ cardial infarction in a broad group of highrisk patients there was no evidence of a true association (65R). Drug dosage regimens Hypertension and proteinuria are both predictors of renal and cardiovascular progression in patients with diabetic and non-diabetic renal disease. Reducing proteinuria by using the maximal tolerated dose of angiotensin II receptor antagonists, or an ACE inhibitor, or both, is an important therapeutic strategy to reduce the frequency of cardiovascular and renal events. Experimenters have been using doses above published recommended max­ ima in order to achieve reductions in urinary protein excretion. However, most of the “recommended doses” of these drugs have been based on trials of their efficacy for reducing blood pressure alone, and may not be optimal either for reducing protei­ nuria or for assessing long-term safety if used at higher doses. There has been a retrospective analysis of observational data from a clinical prac­ tice setting of long-term high-dose angio­ tensin II receptor antagonists in the treatment of proteinuria in patients with chronic renal disease (66c). Patients who take 1.5–5 times the recommended max­ imum doses for at least 6 months generally tolerated the treatment well. There was a trend to an increase in serum potassium concentration during the study period, but no patients had sustained hyperkalemia. Similarly, serum creatinine concentrations

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J.J. Coleman and T.F. Butt

increased slightly with increases in dose. There were no cases of serious hyperkale­ mia or episodes of acute renal failure. The authors did however recommend periodic monitoring of potassium and renal function in patients on high-dose therapy but did not explicitly recommend how this should be performed.

Candesartan

(SED-15, 612; SEDA-28, 229; SEDA-29, 211; SEDA-30, 241)

Musculoskeletal An 85-year-old lady taking candesartan for hypertension and donepezil for Alzheimer’s disease reported bilateral severe leg pain when the donepezil was up-titrated (67A). The authors noted that candesartan has been associated with myalgia and hypothesized that a phar­ macokinetic interaction between the two agents may have potentiated this adverse effect. Autacoid Angiotensin II receptor antago­ nists are not always safe alternatives in patients who have previously had angioedema in association with an ACE inhibitor. Candesartan has previously been associated with angioedema. Another case has been described in a 72-year-old German woman who had previously had recurrent captopril­ induced angioedema when she was switched to candesartan (68A). This reaffirms the notion that when switching to an angiotensin II receptor antagonist in patients with ACE inhibitor-induced angioedema the risk of recurrence should be kept in mind. Fetotoxicity The potential fetotoxic effects of angiotensin II receptor antago­ nists are now well recognized. There are several reports for various agents within this class of malformations and physiologi­ cal disturbances in infants with maternal exposure in the second and third trimesters. A boy born to a mother who took candesartan cilexetil 16 mg/day for hyper­ tension developed chronic kidney disease when nearly 3 years of age and had moderate developmental delay (69A).

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Chapter 20

Irbesartan (SED-15, 1908; SEDA-28, 229; SEDA-29, 212; SEDA-30, 241) Skin A skin eruption and fever, thought to be erythema multiforme on skin biopsy, has been attributed to irbesartan (70A).  A 76-year-old man developed malaise, weight

loss, fever, sweats, and a rash on his legs with a targetoid appearance. He had taken bendro­ flumethiazide and propranolol for many years for hypertension, and had taken irbesartan for 2 years. He was apyrexial and had a polycyclic erythematous rash on the calves and ante­ romedial aspects of both legs. A skin biopsy showed occasional epidermal necrotic kerati­ nocytes with minimal associated inflammation, features that were thought likely to represent erythema multiforme.

The authors suggested that this patient’s reaction had probably been due to irbesar­ tan. They went on to demonstrate a positive lymphocyte transformation test when the patient’s peripheral blood monocytes were incubated with irbesartan. Another case of a lichenoid skin eruption has also been attributed to irbesartan (71A). Allergy patch testing was performed and was positive to the formulation of irbesar­ tan combined with hydrochlorothiazide (Karvecides) that the patient had been taking from 1 year before the emergence of the eruption until 3 months before. A patch test to irbesartan alone was negative and the authors therefore attributed the changes to a “compound” allergy or a neoantigenic effect of the substances in combination. Teratogenicity There is relatively little information about the safety of first-trime­ ster exposure to angiotensin II receptor antagonists. A fetus of a 24-year-old diabetic woman developed exencephaly and unilat­ eral renal agenesis after exposure to irbesar­ tan (72A). The authors suggested that angiotensin II receptor antagonists may block the renin–angiotensin system more completely than ACE inhibitors and may therefore produce earlier fetal hypoperfu­ sion. They also stated that hypertensive women of child-bearing age who are not planning to become pregnant should be treated preferentially with ACE inhibitors

359 instead of angiotensin II receptor antagonists in case of inadvertent pregnancy; however, it would be prudent to avoid both drug classes in our opinion, unless there are clear reasons and specific counseling about the risks of teratogenicity.

Losartan

(SED-15, 2168; SEDA-30, 242)

Respiratory Theoretically, adverse effects that are due to the accumulation of bradykinin, substance P, and prostag­ landins, such as cough, should not occur with angiotensin II receptor antagonists, as this class has no effect on angiotensinconverting enzyme. However, cough has previously described with losartan and a further case has been described in a 23-year­ old woman who had an irritating cough for several weeks while taking losartan (73A). The cough resolved when she took enalapril instead. This is an unusual reversal of the expected effects and this type of substitution should not be routinely recommended in similar circumstances. Nervous system Worsening of Parkinson’s disease symptoms has been attributed to losartan (74A).  A 65-year-old man with Parkinson’s disease and

hypertension stabilized on a levodopa/carbi­ dopa combination took losartan 50 mg/day instead of ramipril in order to gain better control of hypertension. His symptoms worsened, with bradykinesia, several falls, and freezing episodes. The symptoms improved after withdrawal for 48 hours but re-emerged after rechallenge with a lower dose (25 mg/day).

This adverse event was considered as a probable effect of losartan using the Nar­ anjo classification. Urinary tract Acute renal failure has been attributed to losartan (75A).  A 14-year-old boy with reflux nephropathy,

who had previously undergone antireflux surgery for bilateral vesicoureteric reflux and had renal impairment at baseline, developed vomiting and diarrhea 8 days after starting losartan 25 mg/day. Six days later he became unwell with hypotension and had acute renal failure. Hemodialysis restored his renal func­ tion to baseline after 3 days.

360 The authors highlighted the fact that patients with pre-existing renal impairment who develop dehydration due to diarrhea and vomiting are at higher risk of renal failure, similar to cases that have been described with ACE inhibitors. Fetotoxicity Fetotoxic effects and transient renal failure in a premature infant have been reported in association with maternal losar­ tan exposure (76Ar). The fetus had anhy­ dramnios and an empty bladder at 29 weeks gestation during an undetected pregnancy and subsequently had a neonatal course complicated by oliguria, hyperkalemia, renal dysfunction, joint contractures, and respira­ tory failure. The authors reviewed other reported pregnancies with maternal expo­ sure to angiotensin II receptor antagonists. In view of the potential fetotoxic effects of losartan, it would be usual to consider with­ drawing treatment if pregnancy is diagnosed in the second or third trimesters. However, fetal inferior vena cava thrombosis, which is an extremely rare in utero complication, has been attributed to withdrawal of losartan at 27 weeks gestation (77A).  A 45-year-old woman with type 2 diabetes and

hypertension was referred at 27 weeks gestation for oligohydramnios. She had been taking losartan for 3 years before the pregnancy. The membranes were intact and fetal monitoring was reassuring. The losartan was withdrawn. Transabdominal amniotic fluid infusion was performed. Ultrasound examination showed fetal vena cava thrombosis at 32 weeks gesta­ tion. An asymptomatic baby was born at 38 weeks by normal delivery. Postnatal ultrasound confirmed occlusive thrombus in the inferior vena cava, with collateral vessels providing flow.

Susceptibility factors Age Age-specific subgroup analysis of the data from the Reduction of Endpoints in Non-insulin dependent diabetes mellitus with the Angio­ tensin II Antagonist Losartan (RENAAL) study has been performed to assess the nephroprotective efficacy and safety of this agent (78C). The analysis specifically assessed the occurrence of hyperkalemia and renal impairment due to susceptibility to these adverse events in elderly patients. The data showed that for aggregate rates of adverse events, none of the tests for interaction

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J.J. Coleman and T.F. Butt

between age and the use of losartan were significant, suggesting that older patients are no more susceptible to adverse reactions to losartan than younger patients.

Telmisartan

(SED-15, 3311; SEDA-28, 229; SEDA-29, 212; SEDA-30, 242)

The use of telmisartan in the treatment of hypertension has been comprehensively reviewed (79R). Skin Vulvar fixed drug eruptions have been attributed to telmisartan in 13 patients (80A).

Valsartan (SED-15, 3593; SEDA-29, 213; SEDA-30, 242) Psychological A further case of nightmares attributed to valsartan has been reported (81A).

DIRECT RENIN INHIBITORS (SEDA-30, 242)

Aliskiren Aliskiren is an orally active, non-peptidic inhibitor of renin, and is the only direct renin inhibitor approved for the treatment of hypertension. It was the topic of a special review in SEDA 30 (p. 242). Its potential adverse effects and a comparison with other renin–angiotensin blockers have been reviewed (82R).

ENDOTHELIN RECEPTOR ANTAGONISTS (SED-15, 1215; SEDA-29, 213; SEDA-30, 245)

Endothelin receptor antagonists have been reviewed (83R). As well as outlining the early phase and clinical trials of selective

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Chapter 20

(ETA receptor) antagonists and mixed (dual) endothelin receptor antagonists, the authors devoted a section of the review to the safety and toxicology of these agents. They pointed out the common adverse effects, such as headaches, flushing, rhinitis, and hypotension, reflecting their vasodila­ tory effects, as well as peripheral edema and worsening of heart failure, early mild anemia (possibly attributable to hemodilu­ tion), and abnormal liver function tests.

Ambrisentan

(SEDA-30, 245)

Ambrisentan is a selective ETA receptor antagonist that has been investigated in the treatment of idiopathic and secondary pulmonary hypertension. Placebo-controlled studies The results of the ARIES 1 and 2 trials, two pivotal Phase 3 clinical trials of ambrisentan in the treatment of pulmonary artery hyperten­ sion, have been reported (84C). Although extension phases of both trials are under way, the initial results of these randomized, double-blind, placebo-controlled studies showed positive efficacy end-points, with improved exercise capacity and reduced symptoms from pulmonary artery hyperten­ sion. No patients taking ambrisentan devel­ oped serum transaminase activities greater than three times the upper limit of normal, compared with two subjects in the placebo group. Extended open studies may show whether ambrisentan has a more beneficial liver safety profile than other agents in this class.

Bosentan (SED-15, 549; SEDA-27, 214; SEDA-29, 213; SEDA-30, 245) Liver In early placebo-controlled trials of bosentan in pulmonary artery hypertension there were cases of raised hepatic transaminases, particularly in association with the highest doses. A 50-year-old woman with pulmonary artery hypertension developed severe hepatotoxicity and consequent cirrhosis while taking bosentan (85S). This report was cited by the

361 manufacturer of bosentan (Actelion) in a letter informing prescribers of changes to the product labeling and reminding them of the importance of monthly liver function testing during treatment. Skin A few cutaneous adverse effects have been attributed to bosentan. A 42-year-old woman developed painful indurated erythema with edematous plaques on the proximal aspects of both legs (86A). A skin biopsy showed thin-walled vascular dilata­ tion and perivascular lymphocytic infiltra­ tion. Skin prick and patch testing with bosentan was negative. Remission occurred over 3 months following drug withdrawal. The authors commented that in view of resolution after dechallenge and in the absence of systemic associated symptoms an adverse effect of the drug was most likely. Susceptibility factors Genetic There are few data on the pharmacokinetics of endothelin receptor antagonists in different ethnic groups. A comparative investigation of the pharmacokinetics of single-dose bosentan in healthy Caucasian and Japanese subjects (10 subjects in each group) has shown similar profiles in both ethnic groups (87E). Of all the pharmacokinetic para­ meters, only one active metabolite showed significantly greater peak plasma concentra­ tions in the Japanese than in the Caucasian subjects. Although extremely limited in scope, this study suggests that no dosage adjustment is needed in Japanese patients. Drug–drug interactions Bosentan is a mild-to-moderate inducer of CYP 2C9 and CYP3A4 and induces its own metabolism, leading to lower plasma concentrations at steady state (88R). As bosentan is used in secondary pulmonary hypertension, for example due to collagen vascular diseases or human immunodeficiency virus (HIV), it is important to be aware of drug–drug interactions with agents used to treat these and other associated diseases. Hormonal contraceptives The effects of bosentan on the pharmacokinetics of a combined oral contraceptive (norethister­ one 1 mg + ethinylestradiol 35 mg) have

Chapter 20

362 been investigated in 20 healthy women (89E). Both constituents of the oral contra­ ceptive showed reduced AUCs. This result is important, as pulmonary artery hyperten­ sion is more common in women, who may suffer from oral contraceptive failure if bosentan is added; other non-hormonal methods of birth control should be con­ sidered in these patients. Indinavir An HIV seropositive patient took bosentan in addition to other antire­ troviral drugs (90A). Trough serum indina­ vir concentrations were below the effective range, whereas the concentrations had been in a stable range before the introduction of bosentan. The authors pointed out that indinavir interacts with other drugs that are inducers or inhibitors of CYP3A4, and hypothesized that induction of CYP iso­ enzymes by bosentan may reduce the effects of indinavir. Methotrexate Two patients who took bosentan for pulmonary artery hypertension secondary to systemic sclerosis had a flare of arthritis (91A). This was attributed to an interaction with oral methotrexate, which the patients were taking weekly. They improved when the bosentan was withdrawn, and their inflammatory markers, which had initially increased, returned to pre-bosentan concen­ trations. No rechallenge was performed.

Sitaxsentan

(SEDA-29, 213; SEDA-30,

245) Placebo-controlled studies The Sitaxsen­ tan To Relieve ImpaireD Exercise part two (STRIDE 2) has now been reported (92C). This was an 18-week double-blind, placebocontrolled trial in 245 patients who took sitaxsentan 100 mg/day with primary or secondary pulmonary artery hypertension, which also included an open bosentan arm (62.5 mg bd, increased to 125 mg bd after 2 weeks). The main aim of the study was to confirm the efficacy of sitaxsentan and determine the optimal dose (safety and tolerability with therapeutic efficacy) in view of an unacceptable safety profile with the higher dose (300 mg/day) used in the

J.J. Coleman and T.F. Butt

STRIDE-1 study. The incidence of liver enzyme abnormalities was similar between the sitaxsentan and placebo groups, and lower than in the open bosentan group; all significant abnormalities (enzyme activities greater than three times normal) reversed on withdrawal. Other treatment-related adverse effects, such as edema, headache, and nasal congestion, were similar in the groups. Although sitaxsentan-treated patients required slightly lower warfarin doses on average than placebo-treated patients, concomitant therapy with warfarin was well tolerated and complications from bleeding were rare. This trial is more reassuring for the future of sitaxsentan therapy. There had been significant safety concerns regarding its hepatotoxic adverse effects as well as a potentially serious interaction with warfarin (by inhibition of CYP2C9). A double-blind trial with bosentan as an active compara­ tor may be required to establish the place of sitaxsentan as a selective ETA antago­ nist in the treatment of pulmonary artery hypertension.

DRUGS THAT ACT ON THE SYMPATHETIC NERVOUS SYSTEM (SEDA-28, 230; SEDA-29, 214; SEDA-30, 245)

PRESYNAPTIC ALPHA­ ADRENOCEPTOR AGONISTS Clonidine

(SED-15, 817; SEDA-28, 230; SEDA-29, 214; SEDA-30, 245)

Psychiatric Clonidine has been associated with a number of psychological and psychiatric adverse effects, ranging from depression to hallucinations and delirium.  Clonidine-induced delirium has been reported

in a 52-year-old man who was admitted to hospital as a hypertensive emergency (93A). He had a history of cerebrovascular and peripheral vascular disease, renal impairment, diabetes mellitus, and hypertension. Having been fully orientated on admission, he became

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agitated and disorientated on the second day of hospitalization, with visual hallucinations and delusional thoughts. No other cause was found for the delirium and the etiology was therefore thought to be clonidine; the symp­ toms resolved on withdrawal.

Drug overdose A 6-year-old boy with autism developed symptoms relating to ingestion of a clonidine transdermal patch (94A). Although the indication was not stated in the report, it was probably for an indication other than hypertension. The symptoms were somnolence, hypotension, and bradycardia. He was treated with activated charcoal and intravenous nalox­ one, and, with the aid of polyethylene glycol whole bowel irrigation, he passed the transdermal patch per rectum after 6 hours. The authors warned of the dangers of toxic exposure from transdermal medica­ tions taken orally, even with “spent” patches, and promoted the benefits from whole bowel irrigation to aid elimination.

Methyldopa

363 intraoperative pupil constriction, billowing of a flaccid iris stroma, and iris prolapse into surgical incisions; it is associated with higher surgical complication rates. Previously it had only been described with tamsulosin. However, an 85-year-old man taking alfu­ zosin for benign prostatic hyperplasia de­ veloped typical features of IFIS (96A). Skin Toxic epidermal necrolysis with a fatal outcome has been reported in a patient taking alfuzosin (97A).  An 80-year-old Chinese man developed fever,

extensive rashes, and oral and genital ulcera­ tion 4 weeks after beginning alfuzosin therapy for symptoms related to benign prostatic hyperplasia. He had confluent red, dusky macules with flaccid bullae and epidermal detachment on over 80% of his body surface area. A presumptive diagnosis of toxic epi­ dermal necrolysis was made and alfuzosin was withdrawn. A skin biopsy confirmed changes consistent with toxic epidermal necrolysis. Despite systemic corticosteroid treatment and intensive care support, he developed sepsis and renal failure and died after 2 weeks.

(SED-15, 2291)

Hematologic Methyldopa was one of the first recognized causes of drug-induced autoimmune hemolytic anemia associated with a positive direct Coombs’ test. A further case of hemolytic anemia requiring transfusion has been reported in a 68-year­ old man who took methyldopa 500 mg tds for hypertension (95A).

POSTSYNAPTIC ALPHA­ ADRENOCEPTOR ANTAGONISTS (SEDA-29, 214; SEDA-30, 246)

Alfuzosin

(SED-15, 74; SEDA-29, 214; SEDA-30, 246)

Sensory systems Intraoperative floppy iris syndrome (IFIS) affects cataract surgery in patients taking alpha-adrenoceptor antagonists. IFIS manifests as poor preoperative pupil dilatation, progressive

Sexual function Priapism is an unusual adverse event that has been described with some alpha-adrenoceptor antagonists. A patient developed priapism 1 week after taking alfuzosin modified-release tablets 10 mg/day for lower urinary tract symp­ toms (98A). Drug formulations An 82-year-old man with esophageal cancer developed dysphagia associated with alfuzosin (99A). He was being treated conservatively for a 3-cm long tumor at 35 cm from the mouth, and had had increasing dysphagia each day after taking a modified-release tablet of alfuzosin (Xatral XLs). Endoscopic examination showed a tablet bolus. Modified-release tablets can increase in size in vivo and often take many hours to dissolve.

Doxazosin

(SED-15, 1188; SEDA-27, 217; SEDA-29, 214; SEDA-30, 246)

The use of doxazosin as add-on therapy in patients with primary hypertension not

Chapter 20

364 adequately controlled with other antihyper­ tensive drugs and co-existent impaired glucose metabolism has been investigated in an open study (100c). Doxazosin was given for 16 weeks in addition to other therapy and led to mean reductions of blood pressure of 15/8 mmHg as well as associated favorable effects on glucose and lipid parameters. Adverse drug reactions were uncommon (2.3% from the total of 264 trial entrants) and consisted of a small number of cases of edema, dizziness, headache, and weakness only.

Phenoxybenzamine

(SED-15, 2803)

Phenoxybenzamine is a non-selective irre­ versible alpha-adrenoceptor antagonist that is given for hypertensive crises associated with pheochromocytoma. It has also been used at low doses to relieve bladder obstructive symptoms. Selective alpha­ adrenoceptor antagonists are usually used for the longer term management of bladder obstruction, and long-term phenoxybenza­ mine is not recommended. Tumorigenicity A 57-year-old man devel­ oped chronic lymphocytic leukemia and a synchronous small cell carcinoma and squamous neoplasia of the urinary bladder after sustaining a spinal cord injury at the age of 28 years and having taken phenoxybenza­ mine for 7 years for neurogenic bladder problems (101A). Phenoxybenzamine is carcinogenic and mutagenic in rodents and may reasonably be suggested to be so in humans. It should either not be recom­ mended for long-term treatment or it should be used with extreme vigilance.

Tamsulosin

(SED-15, 3303; SEDA-29, 214; SEDA-30, 246)

Nervous system Drugs are sometimes implicated in causing seizures, and may do so directly (epileptogenic potential), indirectly by interactions with antiepileptic drugs, as a withdrawal effect, or via

J.J. Coleman and T.F. Butt

secondary metabolic effects. There is experimental evidence that could implicate alpha-adrenoceptor antagonism in causing seizures, but only scant clinical reports of a proconvulsant effect of drugs acting via the adrenergic system.  A 60-year-old man with medial temporal lobe

epilepsy had worsening of his seizure control when tamsulosin was added to his stable treatment of carbamazepine and clobazam (102A).

The authors acknowledged that seizure fluctuation in a single patient may have resulted from many factors, and it is only possible that tamsulosin was the cause of the increased seizure frequency. Sensory systems The intraoperative floppy iris syndrome (IFIS) has been reported in another patient taking tamsulosin (103A). The case was complicated by intraoperative iris tears, with localized separation of the iris from the ciliary body and anterior chamber hemorrhage. Liver Acute hepatitis has previously been described with other alpha-adrenoceptor antagonists. The first observation of a probable drug-induced hepatitis related to tamsulosin has been reported (104A).  A 65-year-old man who had been taking

tamsulosin for 11 days for benign prostatic hyperplasia developed severe right upper quadrant pain and jaundice, raised serum transaminases, a mild leukocytosis, and a raised bilirubin. Imaging showed no evi­ dence of bile duct dilatation or obstruction. Blood cultures, hepatitis serology, and an autoimmune screen were all negative. A liver biopsy showed evidence of centrilobu­ lar cholestasis. Two days after withdrawal of tamsulosin the serum transaminases had improved and his symptoms had resolved. Five weeks later the liver function tests had normalized.

Sexual function The frequency of ejaculatory dysfunction on different alpha-adreno­ ceptor antagonists has been examined in a double-dummy crossover study (105c). The authors wanted to assess the different

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Chapter 20

effects of tamsulosin and alfuzosin on ejaculate volume and sperm concentration in post-ejaculation urine. Each volunteer was given tamsulosin 800 mg/day, alfuzosin 10 mg/day, or placebo for 5 days in a crossover design. Tamsulosin was asso­ ciated with significant reductions in ejacu­ late volume compared with alfuzosin and placebo and was also associated with a nearly 35% rate of complete lack of ejaculation (an effect not seen with alfuzo­ sin or placebo). Post-ejaculation urine sperm concentrations suggested that the dysfunction was not due to retrograde ejaculation. The results may have signifi­ cant effects on the choice of treatment for men treated with alpha-adrenoceptor antagonists for lower urinary tract symp­ toms. Another study has shown that abnor­ mal ejaculatory function may improve following intermittent treatment (106c). Drug–drug interactions Sildenafil Stan­ dard advice is often given to patients who take sildenafil for erectile dysfunction to avoid using it within a few hours of certain antihypertensive drugs, in view of the risk of severe and/or postural hypotension. Drugs that should be avoided include alpha-adrenoceptor antagonists, calcium channel blockers, and nitrates. Pronounced hypotension occurred in one of 16 men with benign prostatic hyperplasia who took tamsulosin and sildenafil during orthostatic testing (107E). The authors concluded that even though tamsulosin and sildenafil are considered hemodynamically safe, they may cause considerable vasodilatation and subsequently harmful hypotension in sus­ ceptible patients.

Hydralazine

(SED-15, 1701)

Respiratory Hydralazine can cause a lupus-like syndrome and a fatal case of hydralazine-associated lupus pneumonitis has been reported (108A).

365  A

36-year-old African–American woman developed fatigue, dyspnea on exertion, weak­ ness, dizziness, and arthralgias. She had taken atenolol, clonidine, nifedipine, fosinopril, and hydralazine 100 mg/day for hypertension. Computed tomographic chest imaging 5 months before for an incidental bony abnorm­ ality had shown ground glass abnormalities in the lower lobes of both lungs. She was hypotensive and hypoxic. Her antihypertensive medications were withdrawn. Blood tests showed an inflammatory response and raised lactate dehydrogenase and serum trans­ aminase activities. Further chest imaging showed bilateral alveolar infiltrates and small pleural effusions. Despite treatment with broad-spectrum antibiotics she required inva­ sive ventilation by the third day of admission. In the absence of evidence of vasculitis or pulmonary hemorrhage, she was given methyl­ prednisolone and underwent one cycle of plasmapheresis for presumed lupus pneumoni­ tis. She died despite full intensive care support on the fourth day. Postmortem laboratory results confirmed the presence of antinuclear, antihistone, and anti-single stranded DNA antibodies. There was organized diffuse alveo­ lar damage and evidence of pericarditis.

The authors acknowledged that a definite diagnosis of drug-induced lupus could not be made, as the patient had died before the effects of drug withdrawal could be known. However, several features of her presenta­ tion supported the presumed diagnosis, including a typical immune profile and no obvious renal involvement.

Sodium nitroprusside

(SED-15, 2529)

Hematologic Sodium nitroprusside is a direct vasodilator used parenterally for hypertensive crises and for controlled hypotension in critically ill patients. Four children aged 6 months to 4 years deve­ loped carboxyhemoglobinemia 5.5–7.7% when nitroprusside was used as a vasodi­ lator after cardiac transplantation (109A). This effect was thought to be due to heme oxygenase induction. The authors did not think that other factors or concomitant treatments had been responsible. One of the children died and three recovered with no sequelae after withdrawal of sodium nitroprusside.

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366

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infarction: systematic review. BMJ 2005; 331:873. Tsuyuki RT, McDonald MA. Angiotensin receptor blockers do not increase risk of myocardial infarction. Circulation 2006; 114:855–60. Weinberg AJ, Zappe DH, Ramadugu R, Weinberg MS. Long-term safety of high-dose angiotensin receptor blocker therapy in hypertensive patients with chronic kidney disease. J Hypertens Suppl 2006;24:S95–9. Kuloor CB, Puranik A. Pain with donepezil. Age Ageing 2006;35:639–40. Hellebrand MC, Kojda G, Hoffmann TK, Bas M. Angioödeme durch ACE-Hemmer und AT1-Rezeptorblocker. Hautarzt 2006;57:808–10. Simonetti GD, Baumann T, Pachlopnik JM, von Vigier RO, Bianchetti MG. Non-lethal fetal toxicity of the angiotensin receptor blocker candesartan. Pediatr Nephrol 2006;21:1329–30. Constable S, Farrell J, Naisbitt D, King C, Leonard N, Pirmohamed M. Systemic ill­ ness with skin eruption, fever and positive lymphocyte transformation test in a patient on irbesartan. Br J Dermatol 2006;155 (2):491–3. Pfab F, Athanasiadis GI, Kollmar A, Ring J, Ollert M. Lichenoid drug eruption due to an antihypertonic drug containing irbesar­ tan and hydrochlorothiazide. Allergy 2006;61:786–7. Boix E, Zapater P, Pico A, Moreno O. Teratogenicity with angiotensin II receptor antagonists in pregnancy. J Endocrinol Invest 2005;28:1029–31. Dashti-Khavidaki S, Faghihi T, Ahmadi F, Khalili H. Cough induced by losartan with resolution after substitution with enalapril. Clin Ther 2008;30:548–51. Gosala S, Vikram K, Ajit RK. A case of parkinsonism worsened by losartan: a prob­ able new adverse effect. Movement Disord 2006;21:S372. Fujinaga S, Kaneko K, Ohtomo Y, Yama­ shiro Y. Acute renal failure induced by an angiotensin II receptor antagonist in a 14-year-old boy with reflux nephropathy. Pediatr Nephrol 2006;21:601–2. Bass JK, Faix RG. Gestational therapy with an angiotensin II receptor antagonist and

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transient renal failure in a premature infant. Am J Perinatol 2006;23:313–7. Bakkum JN, Brost BC, Johansen KL, John­ ston BW, Watson WJ. In utero losartan withdrawal and subsequent development of fetal inferior vena cava thrombosis. Obstet Gynecol 2006;108:739–40. Winkelmayer WC, Zhang Z, Shahinfar S, Cooper ME, Avorn J, Brenner BM. Effi­ cacy and safety of angiotensin II receptor blockade in elderly patients with diabetes. Diabetes Care 2006;29:2210–7. Battershill AJ, Scott LJ. Telmisartan: a review of its use in the management of hypertension. Drugs 2006;66:51–83. Fischer G. Vulvar fixed drug eruption. A report of 13 cases. J Reprod Med 2007; 52:81–6. Kastalli S, El AS, Loueslati MH, Daghfous R, Belkahia C. Nightmares induced by valsartan. Therapie 2006;61:81–2. Cheng H, Harris RC. Potential side effects of renin inhibitors—mechanisms based on comparison with other renin–angiotensin blockers. Expert Opin Drug Saf 2006;5: 631–41. Battistini B, Berthiaume N, Kelland NF, Webb DJ, Kohan DE. Profile of past and current clinical trials involving endothelin receptor antagonists: the novel—"sentan" class of drug. Exp Biol Med (Maywood) 2006;231:653–95. Oudiz RJ, Torres F, Frost AE, Badesch DB, Olschewski H, Galie N, McGoon MD, McLauchlin V, Rubin LJ. ARIES-1: A placebo-controlled efficacy and safety study of ambrisentan in patients with pulmonary artery hypertension. Chest Meeting Abstracts 2006;130:121S–a. Actelion Pharmaceuticals US Inc. Impor­ tant prescribing information: changes to the Tracleer (bosentan) product labeling 2006. http://www.fda.gov. Gallardo F, Gil A, Comin J, Molina L, Iglesias M, Pujol RM. Persistent painful indurated erythema secondary to bosentan. Acta Derm Venereol 2006;86:186–7. van Giersbergen PL, Dingemanse J. Com­ parative investigation of the pharmacoki­ netics of bosentan in Caucasian and Japanese healthy subjects. J Clin Pharmacol 2005;45:42–7.

370 88. Dingemanse J, van Giersbergen PL. Clin­ ical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Phar­ macokinet 2004;43:1089–115. 89. van Giersbergen PL, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006;44:113–8. 90. Cozzi F, Ostuni PA, Marotta H, Sfriso P, Favaro M, Todesco S. Bosentan may induce arthritis flare in patients with scleroderma concomitantly treated with methotrexate. Ann Rheum Dis 2006;65: 692–3. 91. Beau-Salinas F, Garot D, Le Guellec C, Jonville-Béra AP, Ingremeau V, AutretLeca E. Possible reduction in indinavir serum concentrations by bosentan. Ther Drug Monit 2005;27(6):822–3. 92. Barst RJ, Langleben D, Badesch D, Frost A, Lawrence EC, Shapiro S, Naeije R, Galie N. Treatment of pulmonary arterial hypertension with the selective endothe­ lin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 2006;47:2049–56. 93. Delaney J, Spevack D, Doddamani S, Ostfeld R. Clonidine-induced delirium. Int J Cardiol 2006;113:276–8. 94. Horowitz R, Mazor SS, Aks SE, Leikin JB. Accidental clonidine patch ingestion in a child. Am J Ther 2005;12:272–4. 95. Ko N, Averett L, Brown C. An unex­ pected finding. Am J Med 2005;118:477–9. 96. Settas G, Fitt AW. Intraoperative floppy iris syndrome in a patient taking alfuzosin for benign prostatic hypertrophy. Eye 2006;20:1431–2. 97. Wang YS, Tay YK, Kwok C. Toxic epidermal necrolysis caused by alfuzosin, an alpha1-adrenoceptor antagonist. Arch Dermatol 2006;142:938. 98. Qazi HA, Ananthakrishnan K, Manikan­ dan R, Fordham MV. Stuttering priapism after ingestion of alfuzosin. Urology 2006;68:890–6. 99. Selinger CP, Clements DG. Tablet induced dysphagia in oesophageal cancer. Gut 2006;55:587–8.

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100. Pessina AC, Ciccariello L, Perrone F, Stoico V, Gussoni G, Scotti A, Muggeo M. Clinical efficacy and tolerability of alpha-blocker doxazosin as add-on ther­ apy in patients with hypertension and impaired glucose metabolism. Nutr Metab Cardiovasc Dis 2006;16:137–47. 101. Vaidyanathan S, Mansour P, Soni BM, Hughes PL, Singh G. Chronic lymphocytic leukaemia, synchronous small cell carci­ noma and squamous neoplasia of the urinary bladder in a paraplegic man following long-term phenoxybenzamine therapy. Spinal Cord 2006;44:188–91. 102. Ivanez V, Ojeda J. Exacerbation of seizures in medial temporal lobe epilepsy due to an alpha1-adrenergic antagonist. Epilepsia 2006;47:1741–2. 103. Lim LA, Frost A. Iris tears secondary to intraoperative floppy-iris syndrome asso­ ciated with tamsulosin. J Cataract Refract Surg 2006;32:1777. 104. Fremond L, Diebold MD, Thiefin G. Hépatite aiguë pseudo-angiocholitique probablement induite par la tamsulosine. [Acute pseudoangiocholitic hepatitis prob­ ably induced by tamsulosin.] Gastro­ enterol Clin Biol 2006;30:1224–5. 105. Hellstrom WJ, Sikka SC. Effects of acute treatment with tamsulosin versus alfuzosin on ejaculatory function in normal volun­ teers. J Urol 2006;176:1529–33. 106. Naruganahalli KS. Abnormal ejaculation associated with tamsulosin in benign pro­ static hyperplasia patients. Expert Opin Investig Drugs 2006;15(12):1635–8. 107. Nieminen T, Koobi T, Tammela TL, Kahonen M. Hypotensive potential of sildenafil and tamsulosin during orthosta­ sis. Clin Drug Investig 2006;26:667–71. 108. Birnbaum B, Sidhu GS, Smith RL, Pillin­ ger MH, Tagoe CE. Fulminating hydrala­ zine-induced lupus pneumonitis. Arthritis Rheum 2006;55:501–6. 109. Lopez-Herce J, Borrego R, Bustinza A, Carrillo A. Elevated carboxyhemoglobin associated with sodium nitroprusside treatment. Intensive Care Med 2005;31: 1235–8.

J.K. Aronson

21 CARBONIC ANHYDRASE INHIBITORS (SED-15, 643; SEDA28, 233; SEDA-29, 220; SEDA-30, 254)

Comparative studies In 56 patients with glaucoma (28 men and 28 women, 22 with normal-tension glaucoma and 34 with primary open-angle glaucoma) who had used dorzolamide 1% eye drops tds for at least 3 months, an open switch to twicedaily 1% brinzolamide was associated with fewer local adverse effects (1c). The mean ocular comfort scores were 1.1 dorzolamide and 0.2 for brinzolamide. At 1 month after switching, 50 patients said that they preferred brinzolamide. The local adverse effects after switching to brinzolamide were stinging (n ¼ 3), blurred vision (2), superficial punctate keratopathy (2), the sensation of a foreign body (1), dryness (1), and hyperemia (1); the only systemic adverse effect was a disturbance of taste sensation in one patient.

Acetazolamide Placebo-controlled studies The use of acetazolamide 250 mg/day in preventing acute mountain sickness has been studied in a double-blind, randomized, placebocontrolled trial in 400 male Nepali porters in the Mount Everest region of Nepal, trekking from Namche Bazaar (3440 m) to Lobuche (4930 m) (2C). Only 109 of the porters completed the study. Acute mountain sickness occurred in 13, of Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03121-3 r 2009 Published by Elsevier B.V.

Diuretics whom 7 were taking acetazolamide, and 6 placebo, all lowlanders. Adverse effects were more common in those who took acetazolamide, but none was serious. The authors concluded that acetazolamide is not useful in the routine prevention of acute mountain sickness in these individuals. Urinary tract A 58-year-old man devel­ oped renal failure that was attributed to acetazolamide 250 mg 8-hourly (3A).

Brinzolamide Observational studies In an open study in 82 patients with inadequate intraocular pres­ sure control with travoprost monotherapy the addition of brinzolamide 1% bd produced better control (4c). Common adverse events were mild and included ocular hyperemia, dysgeusia, and eye irritation. Comparative studies In a randomized, single-blind study 32 patients (52 eyes) with open-angle glaucoma or ocular hypertension were randomized to timolol maleate 0.5%, brinzolamide 1%, or brimonidine tartrate 0.2% eye drops bd plus daily travoprost for 4 weeks (5A). The fall in intraocular pressure was significantly smaller with brimonidine than with timolol or brinzolamide. There were no adverse events apart from occa­ sional conjunctival hyperemia.

Dorzolamide Sensory systems Eyes Latanoprost, tra­ voprost, and a fixed combination of dorzo­ lamide + timolol have been compared in 42 patients with pseudoexfoliation glaucoma (6c). Dorzolamide + timolol was more effective than latanoprost or travoprost in lowering intraocular pressure. Five (three

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372 travoprost, one latanoprost, one dorzola­ mide + timolol) withdrew because of adverse events. The most common treatment-related adverse event was conjunctival hyperemia. In a comparison of latanoprost and dorzolamide + timolol in patients with primary open-angle glaucoma the most common adverse effect was hyperemia, which occurred in 44% of patients (7c). Taste In a randomized, single-blind com­ parison of travoprost 0.004% and a fixed combination of dorzolamide 2.0%+timolol maleate 0.5% in 56 patients with primary open-angle glaucoma or ocular hyperten­ sion travoprost was more effective (8c). Taste disturbances were more common in those who used dorzolamide + timolol.

THIAZIDE AND THIAZIDE­ LIKE DIURETICS (SED-15, 3375; SEDA-28, 233; SEDA-29, 221; SEDA-30, 256)

Electrolyte balance The frequencies of hyponatremia and hypokalemia in patients taking a thiazide diuretic have been studied in primary care in the UK (9C). Of 32 218 adults 3773 had received at least one prescription for a thiazide between 1990 and 2002 and detailed prescribing data were available for 2942 patients, of whom 951 (32%) had had their electrolytes checked. In 196 (21%) the serum sodium and/or potassium concentration was below the reference range. There was hyponatremia in 130 (14%) patients and hypokalemia in 79 (8.5%) patients. Hyponatremia was significantly associated with increased age, the odds ratio in patients over 70 years being 3.87. Hypokalemia was significantly associated with increased thiazide dose. The effect of climate on the incidence of thiazide-induced hyponatremia has been studied retrospectively in Hong Kong in 201 subjects (10c). There were on average 2.9 cases of thiazide-induced hyponatremia per month (range 0–10, median 3) and there was neither seasonal variation nor any correlation between the monthly number of

J.K. Aronson

cases and average temperature or relative humidity. However, patients who had thia­ zide-induced hyponatremia in July and August had significantly higher serum sodium concentration (118 mmol/l versus 114 mmol/l in other months), and tempera­ ture correlated with serum sodium concen­ tration. Metabolism The extent to which different antihypertensive drugs are associated with diabetes mellitus has been reviewed (11R). Thiazide diuretics worsen glycemic control by reducing insulin secretion rather than by altering peripheral insulin sensitivity (12c, 13c, 14c, 15c, 16r). Hypokalemia is a susceptibility factor, as has been confirmed in a meta-analysis of 59 trials, in which there was a mean increase in blood glucose of 0.6 mmol/l for each 1 mmol/l fall in potassium (17M). This may be because the insulin secretory process in pancreatic beta cells is mediated via ATP-dependent potas­ sium channels. Potassium supplementation reduces the risk of thiazide-induced glucose intolerance (18M).

Chlortalidone Metabolism Despite the increased risk of impaired glucose tolerance and new-onset diabetes mellitus in patients taking thiazide and thiazide-like diuretics (see above), it has been argued that the benefit of lowering the blood pressure with these drugs outweighs the risk of harm. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) the 4-year rate of new-onset diabetes in patients taking chlortalidone (n ¼ 8419) was 12% compared with 9.8% for amlodipine (n ¼ 4958) and 8.1% for lisinopril (n ¼ 5034) (19C). In post hoc subgroup analyses from ALLHAT, mean fasting blood glucose concentrations rose during follow-up with all three treatments, but at year 2 those taking chlortalidone had the largest increase: 0.47 mmol/l versus 0.31 mmol/l with amlodipine and 0.19 mmol/l with lisinopril (20c). The odds ratios for the development of diabetes mellitus at 2 years compared with chlortalidone were 0.55 with

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lisinopril (95% CI ¼ 0.43, 0.70) and 0.73 with amlodipine (0.58, 0.91). There were no significant associations between fasting blood glucose and cardiovascular disease, total mortality, or end-stage renal disease or between the risk of diabetes mellitus at 2 years and clinical outcomes, except for coronary heart disease (RR ¼ 1.64); however, the risk ratio was lower and non­ significant with chlortalidone (RR ¼ 1.46). The authors concluded that there is no conclusive or consistent evidence that the diuretic-induced increase in the risk of diabetes increases the risk of clinical events.

Hydrochlorothiazide Electrolyte balance Potassium depletion due to thiazide diuretics can be accompanied by magnesium depletion. In a double-blind, randomized trial of the effects of potassium magnesium citrate and potassium chloride during long-term treatment with hydro­ chlorothiazide 50 mg/day in 22 healthy subjects, serum potassium concentrations were unchanged but serum magnesium rose significantly by about 10% in those who took the former (21C). However, serum magne­ sium did not change in those who were given potassium chloride. The authors suggested that potassium chloride may be less effective than potassium magnesium citrate in main­ taining normokalemia because of “subtle magnesium wasting.” However, the results of this study do not confirm that that is so, and it is generally thought to be important to use a chloride salt in preventing potassium depletion in patients taking diuretics. Skin A lichenoid drug eruption occurred in a patient taking a combination of irbesartan and hydrochlorothiazide (22A).

Non-cardiogenic pulmonary edema due to hydrochlorothiazide Since diuretics can be used to treat pulmonary edema due to left ventricular failure it is paradoxical that there have been reports of pulmonary edema secondary to

373 hydrochlorothiazide (23R). Since the first report was published (24A), over 50 further reports have appeared (25Ar).  A 56-year-old woman developed severe breath-















lessness due to non-cardiogenic pulmonary edema 20 minutes after taking a single tablet of hydrochlorothiazide 50 mg. She had taken hydrochlorothiazide for hypertension until 3 months before (26A). A 42-year-old White woman developed severe respiratory distress 30 minutes after taking hydrochlorothiazide (27A). She had pulmonary edema without a gallop, jugular venous distention, or a history suggesting cardiac disease. The electrocardiogram and echocardiogram were normal and radionuclide ventriculography showed normal systolic and diastolic functions. A 67-year-old man developed non-cardiogenic pulmonary edema after taking a single tablet of hydrochlorothiazide (28Ar). The symptoms resolved with supportive treatment and recurred after rechallenge. Immunoglobulin E was increased, but a lymphocyte transformation test was negative, and there were normal blood lymphocyte subpopulations and complement concentrations and negative antinuclear antibodies. A 73-year-old woman developed acute pulmonary edema and hypotension less than 1 hour after taking hydrochlorothiazide 50 mg, with a refractory low cardiac output state for more than 24 hours (29A). A 50-year-old woman developed severe respiratory failure due to pulmonary edema after taking hydrochlorothiazide 25 mg (30A). She was intubated and ventilated and given nitric oxide 10–20 parts per million. On day 3 she developed deep central cyanosis due to methemoglobinemia of 67%, which responded to methylthioninium chloride. Two women aged 58 and 69 years took hydrochlorothiazide and developed fever, gastrointestinal symptoms, severe dyspnea, hypotension, and a hemodynamic pattern resembling hypovolemia (31A). Both responded to volume repletion and vasoactive drugs and recovered fully. A 54-year-old woman with mitral valve prolapse and rheumatoid arthritis, for which she took steroids, developed dyspnea and hypotension 30 minutes after taking a single tablet containing hydrochlorothiazide and enalapril (32A). Her pulmonary capillary pressure was 5 mmHg, systemic vascular resistance 887 dyn second/cm5, and cardiac output 10 l/minute. A 66-year-old woman had an acute episode of nausea, vomiting, sweating, shaking, and fever after taking a single tablet of Diuzines (hydrochlorothiazide 50 mg + amiloride 5 mg) (33A). On a subsequent occasion she developed dyspnea, vomiting, and abdominal pain after

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taking an unknown medicine. On a third occasion she developed acute respiratory failure and hypotension after taking a single dose of Amerides(hydrochlorothiazide 50 mg + amiloride 5 mg). On a fourth occasion she took a single tablet of Flebo Stops(hydrochlorothiazide 15 mg + bromelain 50 mg + aesculin 25 mg + etophylline 100 mg) and 40 minutes later developed dyspnea, abdominal pain, nausea, and vomiting. On each occasion she had noncardiogenic pulmonary edema. A 66-year-old Hispanic woman developed acute pulmonary edema 30 minutes after taking a single tablet of hydrochlorothiazide 50 mg + triamterene 75 mg (34A). There was hemoconcentration; leukopenia with a shift to a predominance of polymorphonuclear cells; reduced serum IgG, IgG1, and IgG4; and increased serum IgM and complement 3 concentrations. A 72-year-old woman had repeated episodes of sudden-onset pulmonary edema, each occurring immediately after the ingestion of hydrochlorothiazide 12.5 mg (35A). A 64-year-old man developed non-cardiogenic pulmonary edema on two occasions 1 hour after taking single doses of hydrochlorothiazide 12.5 mg (36A). On the first occasion he had severe dyspnea and on the second severe dyspnea, vomiting, face flushing, and profuse sweating. An in vitro basophil activation test and a late cellular activation study (CD69 and production of interferon gamma), both with chlorothiazide, were negative. Three women, aged 56, 59, and 64 years, developed non-cardiogenic pulmonary edema after taking a single dose of hydrochlorothiazide 25 mg (37Ar). The first developed sudden onset of shortness of breath, nausea, vomiting, and diarrhea. The second had sudden shortness of breath 10 minutes after the dose. The third had dyspnea and hypotension within 60 minutes and developed acute respiratory failure and subsequent multiple-organ dysfunction. All had had a previous similar but minor reaction to a thiazide diuretic. A 49-year-old woman took a single tablet of Amerides(hydrochlorothiazide 50 mg + amiloride 5 mg) for mild ankle edema (38A). She had taken the same product for the same reason 1 year before without any adverse effect. After 40 minutes she felt dizzy and had epigastric pain, chills, nausea, and intense dyspnea, due to noncardiogenic pulmonary edema. There was leukopenia during the acute phase but a subsequent lymphocyte stimulation test with hydrochlorothiazide and measurement of specific IgG and IgE were negative. A 71-year-old woman developed acute respiratory failure due to non-cardiogenic pulmonary edema shortly after taking a single tablet containing hydrochlorothiazide + amiloride (39A). She had had an episode of mild dyspnea and

J.K. Aronson

malaise shortly after taking a single dose of the same combination 2 years before.  In a 60-year-old woman who developed acute pulmonary edema attributed to hydrochlorothiazide, B-type natriuretic peptide, a marker of cardiac dysfunction, increased significantly unrelated to ventricular dysfunction; the concentrations returned to normal as the pulmonary edema resolved (40A).

Other cases have been reported (41A–66A, 67 , 68A–74A). Ar

Features Most cases occur in women. In a review of 30 cases the ratio of women to men was 9:1; the mean age was 56 (range 32–84) years and so most of the women were postmenopausal (75R). Over two-thirds of the patients had one to three positive prechallenges or rechallenges, some lifethreatening and one fatal. The reaction usually occurs after the first or occasionally second exposure to the drug and occurs within 10–60 minutes, with dyspnea, wheezing, cyanosis, nausea, vomiting, chest or abdominal pain, and acute hypoxemia; the chest X-ray shows pulmonary edema. Mechanism The clinical and laboratory features of these cases all suggest that pulmonary edema due to hydrochlorothiazide is an immediate (type I) hypersensitivity reaction, although the exact mechanism is unclear. It has been suggested that it is not necessary to invoke an immunological mechanism, since hydrochlorothiazide inhibits the Na/K/2Cl co-transporter, which could be involved in non-cardiogenic pulmonary edema (76A). However, the speed of onset in many cases is too rapid to accommodate this type of mechanism. Furthermore, the reaction has been almost exclusively reported with other hydrochlorothiazide and not other thiazide diuretics, suggesting that it is not a class effect and therefore not related to the pharmacological target of these drugs. There is a single report of an association with chlorothiazide.  A 66-year-old woman who was taking furose-

mide left her tablets at home when visiting her sister, who suggested that she use one of her Chlotrides(chlorothiazide) tablets instead (77A). She developed severe breathlessness and wheeze, followed by cardiovascular collapse

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Chapter 21

with acute pulmonary edema. Three months later the same thing happened. About 10 minutes after taking a tablet of chlorothiazide she collapsed with acute pulmonary edema.

Management Management of the acute problem is as for other types of noncardiogenic pulmonary edema. Prevention is by avoidance of hydrochlorothiazide. Genotoxicity The genotoxicity of hydro­ chlorothiazide 5 and 40 mg/ml (17 and 134 mmol/l) in cultured human lymphocytes from 32 healthy adults has been studied using the cytokinesis blocked micronucleus assay and by analyzing micronucleus induc­ tion using fluorescence in situ hybridization with an alpha-satellite DNA centromeric probe to distinguish between clastogenic and aneugenic effects (78E). Hydrochlor­ othiazide increased the frequency of micro­ nucleus induction dose-relatedly principally by chromosome delay (aneugenicity) but also by chromosome breakage. The effect was related to age. Drug–drug interactions Aliskiren Aliski­ ren does not inhibit CYP enzymes, is mini­ mally metabolized, and is not extensively protein bound; it therefore has little potential for drug–drug interactions. The pharmacoki­ netic interaction of aliskiren 300 mg/day with hydrochlorothiazide 25 mg has been studied in 22 healthy subjects (79C). The Cmax.ss of aliskiren fell by 22% when hydrochlo­ rothiazide was co-administered and the AUC of hydrochlorothiazide during a dosage inter­ val fell by 10% and the Cmax.ss by 26%. The authors considered that these changes were not clinically important.

375 three children (aged 8, 18, and 24 months) who were given furosemide 1–2 mg/kg/day for 4 weeks after surgery for congenital heart disease (80C). Skin Acute generalized exanthematous pustulosis has been attributed to furose­ mide in a 52-year-old woman with type II diabetes mellitus, dyslipidemia, and osteo­ myelitis who had been taking metformin and simvastatin and was also given vanco­ mycin (81Ar). Bullous pemphigoid has also been reported (82Ar). Drug–drug interactions NXY-059 NXY­ 059 traps free radicals and has been used as a neuroprotectant in animal models of acute ischemic stroke. The interaction of NXY-059 with furosemide has been investigated in a double-blind, randomized, crossover, placebo-controlled study in 24 healthy men and women; there was no significant inter­ action (83C). Drug dosage regimens It has been thought that furosemide is more effective when given by intravenous infusion than by bolus doses. However, in a meta-analysis there was no significant difference in total urine output or changes in serum electro­ lytes between continuous infusion and intermittent bolus doses after cardiac sur­ gery (84M). This result cannot be general­ ized to other conditions, such as cardiac failure.

ALDOSTERONE RECEPTOR ANTAGONISTS Spironolactone

(SED-15, 3176; SEDA28, 235; SEDA-29, 222; SEDA-30, 259)

(SED-15, 567, 1454; SEDA-28, 233; SEDA-29, 222; SEDA-30, 258)

LOOP DIURETICS

Urinary tract Renal calculi without nephrocalcinosis have been reported in

Electrolyte balance In a population-based cohort of 9165 patients with heart failure hospitalized in Canada, 1502 patients were given spironolactone at discharge, although 18% had serum potassium concentrations over 5 mmol/l during hospitalization

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and 23% were discharged on concurrent potassium supplements. Gastrointestinal In a case–control study in 306 645 adults in the Netherlands 10 con­ trols were matched to each case of gastroduodenal ulcer or upper gastrointestinal bleeding by age, sex, and index date (85C). There were 523 patients with upper gastro­ intestinal events (bleeding or ulcers) and 5230 controls. Current use of spironolac­ tone was associated with a 2.7-fold (95% CI ¼ 1.2, 6.0) increased risk of a gastro­ intestinal event. The shortcomings of this study have been highlighted (86r, 87r). The patients who took spironolactone may have been more severely ill; they were also taking other drugs that could have caused ulcers; and a confounding effect of Helicobacter pylori infection could not be ruled out. However, increasing dosages of loop diuretics were not associated with increased risk, while there was a strong dose– response relation with increasing dosages of spironolactone, suggesting that severity of heart failure was not a confounder. These results have been supported by the results of a retrospective study of 762 patients, average age 67 years, taking spironolactone for heart failure (n ¼ 585) or hypertension (n ¼ 155) over 7 years (88c). Of the 762 patients, 81 had adverse effects: 40 had hyperkalemia (5.3%), 14 had gynecomastia (1.8%), and 15 had gastritis (2%). Breasts Painful gynecomastia is a wellknown adverse effect of spironolactone. Bilateral painful gynecomastia that occurred after treatment with spironolactone 100 mg tds for 2 months in a 54-year-old Caucasian man resolved within 1 month after treatment was switched to eplerenone 25 mg tds (89A). Eplerenone is 370-fold less potent than spironolactone in blocking dihydrotestoster­ one activation of androgen receptors (90R), which probably explains this. In the EPHESUS study (91C) the incidence of gynecomastia was 0.5% compared with 9% with spironolactone in the RALES study (92C).

OSMOTIC DIURETICS Mannitol

(SED-15, 2203; SEDA-29, 222; SEDA-30, 260)

Nervous system The use of mannitol to reduce brain edema and raised intracranial pressure in patients with brain tumors is sometimes followed by rebound cell swelling, which has mainly been studied in animal cells in vitro. For example, in rat glioma cells hypertonic mannitol produced initial cell shrinkage followed by rapid volume recovery and rebound swelling, which was inhibited by furosemide (93E). In 21 patients with brain tumors (10 malignant gliomas, 4 meningiomas, and 7 metastatic) an 18% solution of mannitol 1 g/kg was given as a bolus 30 minutes before craniotomy (94c). During resection, a sample of the surroun­ ding edematous white matter was taken at the same time as a 10 ml venous blood sample. In most of the patients with gliomas, mannitol concentrations in white matter were two to six times higher than in the plasma. In the patients with meningiomas and metastases the plasma concentrations of mannitol were higher than those in white matter, except in three patients with infiltra­ tion by neoplastic cells. The authors conclu­ ded that leakage of mannitol through the altered blood–brain barrier near gliomas reversed the initial plasma-to-blood osmotic gradient, aggravating peritumoral edema and promoting a rebound increase in intracranial pressure.

Electrolyte balance Hyperkalemia has been attributed to mannitol in a 15-year­ old boy during removal of an arter­ iovenous malformation under general anesthesia (95A). After an infusion of mannitol, he had a severe metabolic acidosis and an increased serum potassium with electrocardiographic changes. The hyperkalemia quickly resolved by admin­ istration of calcium gluconate and sodium bicarbonate.

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377

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J.K. Aronson

30. Hovenga S, Koenders ME, van der Werf TS, Moshage H, Zijlstra JG. Methaemoglo­ binaemia after inhalation of nitric oxide for treatment of hydrochlorothiazide-induced pulmonary oedema. Lancet 1996;348(9033): 1035–6. 31. Marín P. Edema pulmonar agudo asociado a hidroclorotiazida. [Pulmonary edema associated with the ingestion of hydrochlor­ othiazide.] Rev Med Chil 1996;124(12): 1492–5. ~ A, Jalil J, Gaete P, Fajuri A, Castro 32. Saldana P, Godoy I, Corbalán R. Edema pulmonar no-cardiogenico relacionado con la hidro­ clorotiazida. [Noncardiogenic pulmonary edema associated with hydrochlorothiazide use.] Rev Med Chil 1996;124(6):720–4. 33. Mas A, Jordana R, Valles J, Cervantes M. Recurrent hydrochlorothiazide-induced pulmonary edema. Intensive Care Med 1998;24(4):363–5. 34. Bernal C, Patarca R. Hydrochlorothiazideinduced pulmonary edema and associated immunologic changes. Ann Pharmacother 1999;33(2):172–4. 35. d’Aloia A, Fiorina C, Vizzardi E, Faggiano P, Dei Cas L. Episodi ricorrenti di edema polmonare acuto non cardiogeno indotti dall’as­ sunzione di idroclorotiazide. [Recurrent episodes of acute non-cardiogenic pulmonary edema caused by ingesting hydrochlorothia­ zide.] Ital Heart J Suppl 2001;2(8):904–7. 36. Gamboa PM, Achotegui V, Irigoyen J, Perez-Asenjo J, Merino J, Sanz ML. Hydro­ chlorotiazide-induced acute non-cardiogenic pulmonary edema. J Investig Allergol Clin Immunol 2005;15(4):299–301. 37. Knowles SR, Wong GA, Rahim SA, Binkley K, Phillips EJ, Shear NH. Hydro­ chlorothiazide-induced noncardiogenic pul­ monary edema: an underrecognized yet serious adverse drug reaction. Pharma­ cotherapy 2005;25(9):1258–65. 38. Vereda A, Cárdaba B, Quirce S, de las Heras M, Cuesta J, Sastre J. Immunological studies in a case of hydrochlorothiazide­ induced pulmonary edema. J Investig Aller­ gol Clin Immunol 2005;15(4):297–8. 39. Solar M, Ceral J, Kvasnicka J. Hydrochlor­ othiazide induced pulmonary edema—a rare side effect of common diuretic drug. Int J Cardiol 2006;112(2):251–2.

Diuretics

Chapter 21

40. Andresen M, González A, Espino A, Mercado M, Regueira T, Dougnac A. Edema pulmonar agudo por uso de tiazidas, ¿existe falla cardiaca?: Comunicacion de un caso. [Thiazide-induced acute pulmonary edema: report of a case.] Rev Med Chil 2007;135(4):496–500. 41. Beaudry C, Laplante L. Severe allergic pneumonitis from hydrochlorothiazide. Ann Intern Med 1973;78:251–3. 42. Kaufman A, Montilla E, Helfgott M, Fiorelli R, Mueller H. Pneumonitis and hydrochlorothiazide. Ann Intern Med 1973; 79(2):283. 43. Farrell Jr TC, Schillaci RF. Hydrochlor­ othiazide-induced pulmonary edema mimic­ king metastatic carcinoma of the breast. Cardiopulm Med 1976;15:16–7. 44. Bell RT, Lippmann M. Hydrochlorothiazide­ induced pulmonary edema. Arch Intern Med 1979;139:817–9. 45. Gould L, Reddy CVR, Zen B, Singh BK. Life threatening reactions to thiazides. N Y State J Med 1980;80(13):1975–6. 46. Carlson RW, Schaeffer Jr RC, Puri VK, Brennan AP, Weil MH. Hypovolemia and permeability pulmonary edema associated with anaphylaxis. Crit Care Med 1981;9(12): 883–5. 47. Dorn MR, Walker BK. Noncardiogenic pulmonary edema associated with hydrochlor­ othiazide therapy. Chest 1981;79(4):482–3. 48. Piper C, Wallem D, Wesche D, Brattig N, Diao GJ, Berg PA. Lungenodum nach Eurnahme von Hydrochlorothiazid. [Lung edema after administration of hydrochlorothiazide. A rare and life-threatening side effect.] Dtsch Med Wochenschr 1983;108 (39):1480–3. 49. Prupas HM, Brown D. Acute idiosyncratic reaction to hydrochlorothiazide ingestion. West J Med 1983;138(1):101–2. 50. Wagner AC. Interstitial pulmonary edema due to hydrochlorothiazide: case report. Va Med 1983;110(12):715–6. 51. Levay ID. Hydrochlorothiazide-induced pulmonary edema. Drug Intell Clin Pharm 1984;18(3):238–9. 52. Napke E, Stevens DGH. Excipients and additives: hidden hazards in drug products and in product substitution. Can Med Assoc J 1984;131(12):1449–52.

379 53. Bégaud B, Evreux JC, Jouglard J, Lagier G. Imputabilite des éffets inattendus ou toxiques des médicaments. Actualisation de la méthode utilisée en France. [Imputation of the unexpected or toxic effects of drugs. Actualization of the method used in France.] Therapie 1985;40:111–8. 54. Kounis NG, Nikolaou S, Zavras G, Siablis D. Severe acute interstitial pulmonary edema from Moduretics (amiloride plus hydro­ chlorotiazide). Ann Allergy 1986;57:417–8. 55. Watrigant Y, Wallaert B, Ramon P, Gosse­ lin B, Peng W, Tonnel AB. Pneumopathie à l’hydrochlorothiazide d’évolution subaiguë. [Subacute pneumopathy caused by hydrochlorothiazide. Cytologic study of the broncho-alveolar lavage.] Rev Mal Respir 1986;3(4):227–9. 56. Alted E, Navarro M, Cantalapiedra JA, Alvarez JA, Blasco MA, Nunez A. Non­ cardiogenic pulmonary edema after oral ingestion of hydrochlorothiazide. Intensive Care Med 1987;13(5):364–5. 57. Klein MD. Noncardiogenic pulmonary edema following hydrochlorothiazide inges­ tion. Ann Emerg Med 1987;16(8):901–3. 58. Caduff F, Gloor HJ. Hydrochlorothiazid­ induziertes Lungenodem mit Schock. [Hydrochlorothiazide-induced lung edema with shock.] Schweiz Med Wochenschr 1988;118(4):139–42. 59. Anderson TJ, Berthiaume Y, Matheson D, Boiteau P. Hydrochlorothiazide-associated pulmonary edema. Chest 1989;96(3):695–7. 60. Grace AA, Morgan AD, Strickland NH. Hydrochlorothiazide causing unexplained pulmonary oedema. Br J Clin Pract 1989; 43(2):79–81. 61. Pedrol E, Bosch X, Sajche JC, Font J. Edema pulmonar no cardiogenico inducido por hidroclorotiacide. [Non-cardiogenic pulmonary edema induced by hydrochloro­ thiazide.] Rev Clin Esp 1989;185(6):94–5. 62. Hoegholm A, Rasmussen SW, Kristensen KS. Pulmonary oedema with shock induced by hydrochlorothiazide: a rare side effect mimicking myocardial infarction. Br Heart J 1990;63(3):186. 63. Kavaru MS, Ahmad M, Amirthalingam KN. Hydrochlorothiazide-induced acute pulmonary edema. Cleve Clin J Med 1990; 57(2):181–4.

Chapter 21

380 64. Reed CR, Glauser FL. Drug-induced noncardiogenic pulmonary edema. Chest 1991; 100(4):1120–4. 65. Barroso MS, Solé T, Moitinho E, Pedrol E. Hidroclorotiazida y edema agudo de pulmon no cardiogenico: aporacion de un nuevo caso. [Hydrochlorothiazide and non-cardio­ genic pulmonary acute edema: presentation of a new case.] An Med Int 1993;10(4):207. 66. Leser C, Bolliger CT, Winnewisser J, Burkart F, Perruchoud AP. Pulmonary oedema and hypotension induced by hydrochlorothiazide. Monaldi Arch Chest Dis 1994;49(4):308–10. 67. Fine SR, Lodha A, Zoneraich S, Mollura JL. Hydrochlorothiazide-induced acute pul­ monary edema. Ann Pharmacother 1995; 29(7–8):701–3. 68. Blaauwwiekel EE, Zijlstra JG. Acuut long­ oedeem door hydrochloorthiazide. [Acute pulmonary edema caused by hydrochlorothiazide.] Ned Tijdschr Geneeskd 1996; 140(44):2193–5. 69. Young CC, Kyle JL, Young RT. Acute pulmonary edema caused by ingestion of hydrochlorothiazide. Wis Med J 1997;96(3): 38–9. 70. Daszenies C. Edema pulmonar agudo asociado a hidroclorotiazida. Experiencia en un hospital rural de Chiloé. [Acute pulmonary edema associated with hydrochlorothiazide. Experience in a rural hospital of Chiloé, Chile.] Rev Med Chil 1998;126(2):227–8. 71. Almoosa KF. Hydrochlorothiazide-induced pulmonary edema. South Med J 1999; 92(11):1100–2. 72. Chittivelu S. Comment: hydrochlorothiazideinduced pulmonary edema and associated immunologic changes. Ann Pharmacother 1999;33(9):1010–1. 73. Torné Cachot J, Pe~narrubia María MT, Moner Coromina L. Edema agudo de pulmon no cardiogenico y leucopenia recurrente por hidroclorotiazida. [Non-cardiogenic acute pulmonary edema and recurrent leu­ kopenia caused by hydrochlorothiazide.] Rev Clin Esp 2001;201(2):107–8. 74. Jara Chinarro B, de Miguel Díez J, García Satue JL, Juretschke Moragues MA, Serrano Iglesias JA. Edema agudo de pulmon no cardiogenico secundario a hidroclorotiazida. [Acute non-cardiogenic pulmonary edema

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secondary to hydrochlorothiazide therapy.] Arch Bronconeumol 2003;39(2):91–3. Biron P, Dessureault J, Napke E. Acute allergic interstitial pneumonitis induced by hydrochlorothiazide. Can Med Assoc J 1991;145(1):28–34 erratum 391 Eisenhut M. Hydrochlorothiazide induced pulmonary oedema and alveolar epithelial ion transport. Int J Cardiol 2007;118(1): 118–9. Bowden FJ. Non-cardiogenic pulmonary oedema after ingestion of chlorothiazide. BMJ 1989;298(6673):605. Andrianopoulos C, Stephanou G, Demo­ poulos NA. Genotoxicity of hydrochlorothiazide in cultured human lymphocytes. I. Evaluation of chromosome delay and chro­ mosome breakage. Environ Mol Mutagen 2006;47(3):169–78. Vaidyanathan S, Valencia J, Kemp C, Zhao C, Yeh CM, Bizot MN, Denouel J, Dieter­ ich HA, Dole WP. Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, val­ sartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers. Int J Clin Pract 2006;60(11):1343–56. Ali SK. Renal calculi complicating shortterm furosemide therapy after congenital heart surgery. Congenit Heart Dis 2006; 1(5):251–3. Davidovici BB, Naveh HP, Cagnano E, Halevy SRegiSCAR Study Group. Acute generalized exanthematous pustulosis (AGEP) following intake of furosemide. Harefuah 2006;145(7):477–9 552 Lee JJ, Downham 2nd TF. Furosemideinduced bullous pemphigoid: case report and review of literature. J Drugs Dermatol 2006;5(6):562–4. Strid S, Nilsson D, Borgå O, Wemer J, Grahnén A. NXY-059 does not significantly interact with furosemide in healthy volun­ teers. J Clin Pharmacol 2006;46(12):1417–25. Gulbis BE, Spencer AP. Efficacy and safety of a furosemide continuous infusion follow­ ing cardiac surgery. Ann Pharmacother 2006;40(10):1797–803. Verhamme K, Mosis G, Dieleman J, Stricker B, Sturkenboom M. Spironolactone and risk of upper gastrointestinal events: population

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based case–control study. BMJ 2006; 333(7563):330. Dawwas MF. Spironolactone and risk of upper gastrointestinal events: association is unproved. BMJ 2006;333(7566):501. Campbell E, Shonde A, Foley S. Spirono­ lactone and risk of upper gastrointestinal events: spironolactone may not be guilty. BMJ 2006;333(7566):500. Williams EM, Katholi RE, Karambelas MR. Use and side-effect profile of spirono­ lactone in a private cardiologist’s practice. Clin Cardiol 2006;29(4):149–53. Karagiannis A, Tziomalos K, Kakafika A, Florentin M, Athyros VG. Eplerenone relieves spironolactone-induced painful gynaecomastia in a patient with primary aldosteronism. Nephrol Dial Transplant 2007;22(1):293. Garthwaite SM, McMahon EG. The evolu­ tion of aldosterone antagonists. Mol Cell Endocrinol 2004;217(1–2):27–31. Pitt B, Williams G, Remme W, Martinez F, Lopez-Sendon J, Zannad F, Neaton J, Roniker B, Hurley S, Burns D, Bittman R, Kleiman J. The EPHESUS trial: eplerenone

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in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone Post-AMI Heart Failure Efficacy and Survival Study. Cardi­ ovasc Drugs Ther 2001;15:79–87. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341: 709–17. McManus ML, Soriano SG. Rebound swelling of astroglial cells exposed to hyper­ tonic mannitol. Anesthesiology 1998;88(6): 1586–91. Palma L, Bruni G, Fiaschi AI, Mariottini A. Passage of mannitol into the brain around gliomas: a potential cause of rebound phe­ nomenon. A study on 21 patients. J Neuro­ surg Sci 2006;50(3):63–6. Kimura S, Ogawa H, Katayama Y. Hyperka­ lemia caused by intravenous administration of mannitol in a patient with arteriovenous malformation: case report. No Shinkei Geka 2006;34(1):51–6.

G.B. van der Voet and J.A. Centeno

22 Aluminium (SED-15, 97; SEDA-28, 244; SEDA-29, 225; SEDA-30, 262) In spite of the new developments in phos­ phate binder therapy aluminium-compounds continue to be used (1R,2R). Musculoskeletal Macrophagic myofasciitis is an uncommon inflammatory disorder of muscle, believed to be due to persistence of vaccine-derived aluminium hydroxide at the site of injection. Although the role of aluminium remains ambiguous, cases of macrophagic myofasciitis continue to be diagnosed. The condition is charac­ terized by diffuse myalgia, arthralgia, and fatigue (3A).
A 50-year-old woman developed myalgia in her

back, left scapular region, left anterior chest wall, neck, and side of the face. An open muscle biopsy from the left deltoid showed a striking collection of macrophages, mainly within the perimysium and extending focally into the endomysium. There were no granulomata. Vasculitis was not present. The macrophages were PAS-positive, CD68 positive, and CD1a negative. A small number of admixed lympho­ cytes were present together with occasional plasma cells. The muscle had a mildly myo­ pathic appearance with variations in muscle fiber size and increased internal nuclei. The fluorescent Morin stain for aluminium was positive. The features were of macrophagic myofasciitis. The patient had a history of frequent travel requiring immunization. Steroid therapy led to rapid improvement.

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03122-5 r 2009 Elsevier B.V. All rights reserved.

Metals Tumorigenicity of aluminium Many studies have documented an increased cancer risk—particularly lung and bladder—among workers in the aluminum industry. While workers in the aluminum industry are heavily exposed to fluorides, these studies have assumed that the main chemicals causing the cancer are polycyclic aromatic hydrocarbons, which are also present in the workplace. It is difficult to overstate the importance of this observation, especially considering that lung and bladder cancer are the two main cancers found in the aluminum industry, and that these are consistently blamed on polycyclic aromatic hydrocarbons, not fluoride. Yet, in the aluminum industry there is a cryolite plant, with no exposure polycyclic aromatic hydrocarbons, and the two main cancers observed are lung and bladder cancer. Indeed, the evidence that there is an increased risk of lung and bladder cancer in the aluminum industry has become so strong that even ALCOA—the world’s largest producer of aluminum—has warned its workers about the problem. In December of 1999, ALCOA sent a memo to its workforce across the globe, informing them that they were at increased risk of developing lung and bladder cancers. According to a report from The Associated Press (December 17, 1999): “Aluminum manufacturer ALCOA is warning thousands of the past and present employees that they may face a greater risk than previously believed of developing lung or bladder cancer”. The epidemiologic evidence of the risk of cancer among workers in aluminum reduction plants has been reviewed, with an emphasis on associations with specific work

383

384 areas and exposures (4R). Studies of workers manufacturing carbon products outside the aluminum industry have also been reviewed, since the work environment is similar to that encountered in the carbon area of aluminum plants; 22 reports from references cited in earlier reviews, through a compact disc literature search 1980–1990, and from the Nordic Aluminum Industry’s Secretariat for Health, Environment, and Safety were obtained. In a historical cohort study of 4213 men who worked for 5 or more years at a Soderberg aluminum reduction plant in British Columbia (BC), Canada, the standardized mortality and incidence ratios were used in order to compare the mortality and cancer incidence of the cohort with that of the BC population and to examine risk by cumulative exposure to coal-tar pitch volatiles (CTPV) and electromagnetic fields(5R). There were significantly increased rates for bladder cancer (standardized incidence ratio, SIR, 1.69) and brain cancer mortality (standardized mortality ratio ¼ 2.17). The risk of bladder cancer was strongly related to cumulative exposure to CTPV. The risk of non-Hodgkin’s lymphoma also increased with increasing exposure, although the overall rate was similar to that of the general population (SIR ¼ 1.06). The lung cancer rate was as expected (SIR ¼ 0.97), and showed a weak association with CTPV exposure that was not statistically significant. Finally, a 14-year update to a previously published historical cohort study of aluminum reduction plant workers has been conducted(6M). All men with 3 or more years at an aluminum reduction plant in BC, Canada between the years 1954 and 1997 were included; a total of 6423 workers. Cancers were diagnosed in 662 men, representing a 400% increase from the original study. Standardized mortality and incidence ratios were used to compare cancer mortality and incidence in the cohort to that of the BC population. Poisson regression was used to examine risk by cumulative exposure to CTPV measured as benzene-soluble materials and benzo(a)pyrene. The risk of bladder cancer was related to cumulative exposure to CTPV measured by benzene-soluble materials and benzo(a)pyrene and the risk of

Chapter 22

G.B. Van Der Voet and J.A. Centeno

stomach cancer was related to exposure measured by benzo(a)pyrene. The risks of lung cancer, non-Hodgkin lymphoma, and kidney cancer also increased with increasing exposure, although the overall rates were similar to those of the general population. Analysis of the joint effect of smoking and CTPV exposure on cancer showed the observed dose–response relations to be independent of smoking.

Antimony

(SED-15, 316; SEDA-28, 244; SEDA-29, 226; SEDA-30, 263)

Antimonials remain the cornerstone of the treatment of various forms of helminthic disease. There are economic benefits in choosing one antimonial above another based on price, efficacy, and adverse effects (7C). Observational studies The safety and effi­ cacy of generic sodium stibogluconate (from Albert David Ltd) has been studied in patients with cutaneous leishmaniasis and mucous leishmaniasis in Bolivia, who were treated with 20 mg/kg/day for 20 and 30 days respectively. A questionnaire recording adverse effects was completed by a physician in each treatment center. Efficacy of treat­ ment was assessed at the end of treatment and at follow-up 1, 3, 6, and 12 months later. Overall, 146 patients, previously treated with intramuscular meglumine antimoniate (Glucantime), completed intravenous treat­ ment with generic sodium stibogluconate in 2003–2004 (20 mg/kg/day, for 20 or 30 days for cutaneous leishmaniasis and mucous leishmaniasis respectively). There were no fatalities or severe adverse effects, but there were mild-to-moderate adverse effects in 41 patients (28%). They included arthralgias and/or myalgias (8%), headache (7%), phlebitis (4%), pain at the injection site (3%), malaise (3%), insomnia (3%), bradycardia (2%), fever (2%), vertigo (1%), vomiting (1%), weight loss (1%), pruritus (1%), and anorexia (1%). Ten (6.8%) of the patients given generic sodium stibogluconate

Metals

Chapter 22

were considered to have had moderate adverse effects, but there were no fatalities or other severe adverse effects. The inci­ dence of adverse effects was significantly higher among the patients with mucous leishmaniasis than those with cutaneous leishmaniasis. Of the 86 patients with cutaneous leishmaniasis who completed 6 months of follow-up, 81 were considered to have been clinically cured; a comparable group of 69 patients with cutaneous leish­ maniasis who had been treated with Glu­ cantime in 2001–2002 had a similar frequency of clinical cure (90%). The authors concluded that sodium stibogluconate, being several times cheaper than Glucantime, could contribute to improving access to treatment by patients with cutaneous or mucous leishmaniasis, not only in Bolivia but also in other countries of Latin America.

Arsenic

(SED-15, 339; SEDA-28, 245; SEDA-29, 227; SEDA-30, 263)

Arsenic is used in the treatment of hema­ tologic malignancies (8R,9R). Common adverse effects of arsenic trioxide include acute promyelocytic leukemia differentiation syndrome, leukocytosis, prolongation of the QT interval, and renal or hepatic impairment. Other non-life-threatening adverse events are also common: nausea, vomiting, cough, fatigue, headache, insomnia, diarrhea, tachycardia, hypokalemia, hyperglycemia, and neuropathy. Musculoskeletal A flare-up of rheumatoid arthritis has been described as a new adverse effect of arsenic trioxide (10A).
A 69-year-old man with active rheumatoid

arthritis for 23 years developed acute promye­ locytic anemia. He was given all-trans-retinoic­ acid 45 mg/m2, and arsenic trioxide 0.15 mg/kg/ day was added on day 10. Three days after starting arsenic trioxide he complained of pain and swelling of the ankles, knees, metacarpo­ phalangeal joints, wrists, and elbows. These joints were warm to touch and tender. On day 23 he developed fever, edema, weight gain, and cough, with patches on the chest X-ray. Both

385 all-trans-retinoic-acid and arsenic trioxide were withdrawn on suspicion of acute promyelocytic anemia differentiation syndrome. Later arsenic trioxide was reintroduced and after 3 days the ankles, knees, wrists, elbows, and metacarpo­ phalangeal joints swelled, with warmth and tenderness of the joints.

The authors suggested that arsenic trioxide might have induced cytokines that led to this flare-up of rheumatoid arthritis.

Bismuth

(SED-15, 518; SEDA-28, 245; SEDA-29, 227; SEDA-30, 264) Bismuth compounds continue to play a role in the treatment of a large number of gastrointestinal disorders. Bismuth subsali­ cylate is currently the most common for­ mulation of bismuth marketed in the USA and is indicated for the treatment of mild dyspepsia, diarrhea, and peptic ulcer dis­ ease. Ranitidine bismuth subcitrate is a part of quadruple therapy in eradication of Helicobacter pylori (11R). Bismuth gallate is topically used as an astringent/hemostatic in tonsillectomy (12R). Immunologic Although the literature contains some historical descriptions of cutaneous manifestations of bismuth hyper­ sensitivity, contemporary documentation is limited. A polysquamous eruption reminiscent of pityriasis rosea has been reported following multiple doses of bismuth subsalicylate (13A).
A 67-year-old woman was admitted to a center

for narcotic detoxification and depression and was given bismuth subsalicylate. She developed a pruritic eruption, which started on her abdo­ men and spread to her chest, back, and arms within 24 hours. There were multiple oval patches, papules, and plaques, primarily on the abdomen, chest, back, and buttocks, with some involvement of the arms. The inframammary folds were diffusely erythematous. The face and legs were spared. The lesions ranged in size from 2 to 3 cm, the largest being on the lower abdomen. After withdrawal of bismuth subsalicylate and treatment with fluocinonide ointment twice daily and hydroxyzine the rash began to improve by day 6 and had completely resolved by week 3, with minimal post-inflam­ matory hyperpigmentation.

386

Cesium Cardiovascular Prolongation of the QT interval and life-threatening dysrhythmias have been attrbuted to cesium chloride (14M).
An 8-year-old boy with a history of osteogenic

sarcoma had undergone an uneventful limb salvage procedure 2 years earlier. During a subsequent admission, he had a cardiopul­ monary arrest with complete recovery. Tele­ metry electrocardiogram rhythm recordings obtained during the event showed torsade de pointes, which degenerated into ventricular fibrillation but then terminated spontaneously. On a subsequent ECG, the QTc interval was 694 ms. The prolonged QT interval was attributed to the homeopathic use of cesium chloride supplements; the QT interval normal­ ized after cesium was withdrawn.

Cerium See Lanthanoids.

Chromium

(SED-15, 737; SEDA-28, 246; SEDA-29, 228; SEDA-30, 264) Chromium is an essential metal and forms a normal part of our diet. Chromium picoli­ nate is a widely used nutritional supplement for optimal insulin function (15R). Urinary tract The use of dietary supple­ ments has become increasingly popular in the USA, and these supplements are not subject to thorough regulation. Acute tubular necrosis has been attributed to uncontrolled use of a dietary supplement containing chromium picolinate (16A).
A 24-year-old white man developed weakness,

nausea, vomiting, reducing urine output, and right-sided flank pain. He had been taking 1–2 capsules/day of a dietary supplement (Arsenal X, Nutritional Delivery System, Omaha, NE) before his workout sessions for 2 weeks. The recommended dose was one capsule after meals. Serum creatinine was 362 mmol/l (refer­ ence range 44–124 mmol/l). The urine con­ tained more than 3 g/l of protein. A CT scan and ultrasound of the abdomen showed a 13.5-cm solitary right kidney with diffusely

Chapter 22

G.B. Van Der Voet and J.A. Centeno

increased echogenicity of the cortex and subtle perinephric edema, without evidence of obstruction. An open renal biopsy confirmed acute tubular necrosis. He developed signifi­ cant renal impairment and required hemodia­ lysis. He ultimately recovered normal renal function.

The authors stated that the current information regarding the beneficial effects of trivalent chromium is not very convincing and that uncontrolled use of dietary supplements may lead to adverse effects.

Cobalt

(SED-15, 847; SEDA-30, 264)

Cobalt is an essential metal and a part of our nutrition. It is used in medical implant materials, often combined with chromium. Adverse effects are related to wear and loss of integrity of these implants in the course of time and are often related to the mechanics. On the other hand, specific ions may leak from the implants and concentra­ tions may be increased in the surrounding tissue (17R,18R). Sensory systems Loss of vision and hearing due to cobalt poisoning followed dete­ rioration of a hip implant (19A).
A healthy 53-year-old man received a cemented

total hip arthroplasty including a ceramic-on­ ceramic pairing 6 years before and revision surgery 3 years later because of chronic pain in the operated hip, when the stem and socket were left in place but the head was replaced by a long metal head. Two years later he developed increasing impairment of hearing and sight and eventually could just recognize outlines and colors but could not read. He had numbness in his feet and his head and neck were affected by dermatitis. He also had pain in the hip again, and radiographs showed deterioration of the metal head. Further revision surgery was performed, removing all prosthetic components and insert­ ing a total hip prosthesis. At the time of revision cobalt, chromium, and molybdenum were mea­ sured in the serum. The concentration of cobalt was remarkably high at 398 mg/l postoperatively (reference range o0.45 mg/l). The removed metal head showed debris of cobalt and chro­ mium. Postoperatively, the cobalt concentration in serum fell to 36 mg/l after 8 weeks and o1 mg/l after 6 months. He had toxic atrophy of the

Metals

Chapter 22

optical nerve and a retinopathy with malfunction of the macula, which recovered with time. His hearing returned and the numbness in his feet and the dermatitis disappeared.

Copper

(SED-15, 901; SEDA-28, 246; SEDA-29, 228; SEDA-30, 265) The role of copper in medicine has been reviewed (20R). As one of the most impor­ tant essential transition metals, copper is involved in a great variety of biological processes. Copper complexes have antitu­ mor potential and may have relatively fewer adverse effects than platinum-based drugs. Copper containing intrauterine devices are still used in family planning. Adverse effects include pelvic pain, irregular menses, bleeding, and uterine perforation often due to migration of the device (21R). Liver Copper histidine is the only treat­ ment of choice in Menkes disease, but carries the risks of copper overload and liver cirrhosis. A patient who took copper histidine for about 10 years providing longterm data on copper concentrations in the liver (22A).
A boy with Menkes disease was given parent­

eral copper histidine therapy from the age of 16 months. The initial dose was 124 mg (11 mg/kg) subcutaneously every other day, with plasma copper concentrations in the low reference range; later the dosage was increased to 1150 mg (62 mg/kg) with plasma copper concen­ trations in the upper reference range. He took d-penicillamine 150 mg every other day to bind free plasma copper. Liver needle biopsies were performed under general anesthesia 6 times over 8 years. Copper concentrations were quantified in dry liver samples. The copper concentrations did not exceed the reference range (under 50 mg/g dry weight) during these 10 years. Liver histology showed non-specific findings, such as moderate activation of Kupffer cells, anisocytosis, anisokaryosis, and increased glycogen storage, but no fibrosis or fatty degeneration. These findings had been present before copper histidine treatment and did not regress over time.

Information about copper concentrations and histological evaluation of liver tissue in patients with Menkes disease is sparse. These long-term

387 data illustrate that copper histidine treatment can be safe with respect to potential copper overload of the liver.

Gold and gold salts

(SED-15, 1520; SEDA-28, 246; SEDA-29, 228; SEDA-30, 265)

Gold compounds remain important in the treatment of rheumatic diseases. Gold is still in use as a material in dental restorations and in implant materials. Gold coordination complexes are being developed as anticancer agents (23R). The mechanism of action of auranofin has been reviewed (24R). Skin Laser therapy of lentigines in patients with a history of gold therapy can lead to localized chrysiasis (25A).
A 49-year-old woman developed persistent

multiple 6-mm, well circumscribed, blue-gray circular macules on the backs of her hands, forehead, and thighs 7 months after several of her solar lentigines had been treated with a Qswitched ruby laser. The lesions, which had been stable over the previous 7 months and were otherwise asymptomatic, corresponded exactly to the treated areas. She had rheuma­ toid arthritis, previously controlled with aur­ othioglucose 50 mg intramuscularly every 1–3 weeks for 10 years.

The authors diagnosed chrysiasis related to laser therapy for solar lentigines and recommended that all patients treated with lasers should be routinely screened for previous gold therapy, even gold therapy that may have been withdrawn many years before.

Iron salts

(SED-15, 1911; SEDA-28, 247; SEDA-29, 229; SEDA-30, 265)

The molecular and clinical aspects of iron hemostasis have been reviewed (26R,27R). Hematologic Severe intravascular hemolysis with acute renal failure have been attributed to iron dextran (28A).

388
A 40-year-old Arabic woman with microcytic

anemia and severe iron deficiency was given oral iron supplementation repeatedly but always stopped because of adverse gastroin­ testinal effects. She was given intravenous low­ molecular-weight iron dextran (Cosmofers) at a slow infusion rate, but soon developed anxiety, chest discomfort, and a reduced blood pressure and heart rate. The infusion was stopped and she was given intravenous hydro­ cortisone and quickly recovered. Four weeks later she received two erythrocyte transfu­ sions. The next day, another attempt was made to give her iron dextran. Again, she developed anxiety and chest pain without any change in blood pressure or signs of bronch­ ospasm. She was given intravenous hydrocor­ tisone, clemastine, and sublingual nitro­ glycerine. Within 5 minutes of withholding the infusion, all her symptoms disappeared. After 7 days, she was readmitted to hospital with back pain and almost black urine. Blood tests showed acute renal failure and hemolysis. The platelet count fell from 422 to 212  109/l and then remained within the reference range. Within 24 hours after admission she developed anuria, and hemodialysis was begun. Over the next 18 days she received 9 hemodialysis treatments, 6 plasma exchanges, and 14 eryth­ rocyte transfusions. The hemolysis ceased and she regained kidney function. Two months later she had normal kidney function and no signs of hemolysis.

Infection risk Bacteremia rates have been studied in a retrospective single-center study in patients receiving different types or amounts of intravenous iron formula­ tions (29C) from April 2001 to November 2002, a period during which there was a global switch from ferric gluconate (period I) to iron sucrose (period II). One group (A: n ¼ 63) received hemodialysis during both periods I and II. Another group (B: n ¼ 41) received hemodialysis during either period I or II. The adjusted bacteremia incidence rate ratios (IRRs) associated with the use of iron sucrose versus ferric gluconate were 2.92 (95% CI ¼ 1.01, 8.5) and 2.84 (95% CI ¼ 1.32, 6.09) in groups A and B respec­ tively. The adjusted bacteremia IRRs asso­ ciated with receiving more than 2 g of iron were 2.42 (95% CI ¼ 1.03, 5.6) and 1.54 (95% CI ¼ 0.43, 5.69) in the two groups. The use of catheters as hemodialysis access increased the risk of bacteremia in both groups.

Chapter 22

G.B. Van Der Voet and J.A. Centeno

LANTHANOIDS The lanthanoids form a group of elements with atomic numbers from 57 to 71, from lanthanum to lutetium. Lanthanum, cerium, and gadolinium have gained attention in the use and design of pharmaceutical drugs (30R); lanthanum has been used in the management of hyperphosphatemia and gadolinium as a contrast agent in MRI (see Chapter 45) and in cancer treatment. Ear­ lier attention was given to cerium as an antiemetic and as part of the treatment of burns combined with silver sulfadiazine. The biological properties of the lanthanoids are primarily based on their similarity to calcium. Ln3+ ions have a high affinity for Ca2+ sites on biological molecules and can act as either Ca2+ inhibitors or probes. One of the major actions of Ln3+ is to block voltage-operated calcium channels. Generally lanthanoids salts are non-toxic, primarily because they cannot cross cell membranes and are therefore not absorbed if taken orally. However, they are toxic if given intravenously, since they can gain access to cells that express calcium chan­ nels. Acute toxicity via this route can cause a fall in blood pressure followed by cardiovascular collapse and pulmonary paralysis. Chronic toxicity is generally associated with hepatotoxicity and edema. After intravenous administration of lantha­ noid salts the lanthanoids are rapidly cleared from the blood and redistributed to the tissues, primarily the liver and bone. The lighter lanthanoids initially go to the liver, where they can cause fatty liver. They then rapidly redistribute to the bone with a half-life of 10–20 days. The heavier lantha­ noids accumulate in bones, where they can reside for considerable periods of time, with half-lives of several years. The toxic effects of the lanthanoids depend on the chemical form and the route of exposure.

Cerium nitrate Cerium nitrate has broad-spectrum antibac­ terial activity. Combination studies with Ce(NO3)3 and silver sulfadiazine, another

Metals

Chapter 22

metal-based agent with efficacy in the treat­ ment of burns (SED-15, 3140), have shown synergistic antimicrobial interaction between the two agents, although this is ambiguous (31R,32R). The combination is manufactured commercially as Flammacerium in Europe and as Dermacerium in South America. Topical cerium nitrate leads to a firm impermeable eschar, which is leather-like in appearance with a greenish discoloration and is firmly attached to the wound. This is in contrast to the eschar formed with silver sulfadiazine, which is typically soft, moist, uneven, and macerated. The eschar formed by cerium nitrate contains deposits of cal­ cium and insoluble pyrophosphate and car­ bonate salts. The resulting eschar acts as a biological dressing, forming an impermeable crust over the wound. This covering prevents both ingress and egress of bacteria from the wound, thus preventing bacterial coloniza­ tion. This leaves the wound in a clean healthy state, ready to accept a skin graft. Cerium nitrate has been used with good results in individual burns units across Europe, the UK, and the USA for nearly 30 years, although the rationale for its use has changed over time. Despite extensive clinical use of cerium, there is no unequivocal evidence of improve­ ments in mortality in patients with burns from randomized controlled trials. Simi­ larly, adverse effects are not frequently reported. Hematologic Methemoglobinemia has been attributed to cerium nitrate (33A).
A 16-year-old girl with 95% third-degree burns

had Flammaceriums dressings applied every day. Arterial gases were normal at the start but she had multiple episodes of de-saturation on days 4 and 5 (92% SaO2). On day 6, bluish skin coloring was observed in the healthy areas of the face and hands. SaO2 was now 94%, and was not correlated with the arterial blood gases (measured SaO2 98%, PaO2 12.2 kPa, FiO2 0.3). The methemoglobin concentration was 32% (reference range 0–1.5%). She was treated with oxygen and methylthioninium chloride 1.5 mg/kg (i.e., 100 mg). The Flamma­ cerium dressing was replaced with Flamma­ zine. The anomalies were quickly corrected and there was no recurrence. However, she died on day 33 from multiple organ failure.

389 Skin Granulomatous dermatitis has been attributed to cerium (34A).
A 57-year-old woman developed papulonod­

ular lesions affecting only areas that had been burned before 4 years after treatment with topical cerium nitrate+silver sulfadiazine cream (Flammacerium). Biopsies showed sar­ coidal granulomata associated with exogenous particles. Electron probe X-ray microanalysis showed a high cerium content. Screening for systemic sarcoidosis was negative. She was treated with hydroxychloroquine and after 4 months there was clinical and histological evidence of reduced infiltration.

Lanthanum carbonate Obstacles to the successful management of hyperphosphatemia in chronic kidney dis­ ease include inadequate control of dietary phosphate and non-compliance with phos­ phate-binder therapy. The three major classes of phosphate binders include cal­ cium-based binders, sevelamer HCl, and lanthanum carbonate. Calcium-based bin­ ders are effective, but their potential to contribute to total body calcium overload and vascular calcification is an important long-term clinical concern. Sevelamer HCl reduces serum phosphate, has no systemic absorption, and does not increase total body calcium load. However, it binds bile acids, is not an efficient phosphate binder in an acidic environment, and contributes to metabolic acidosis. However, lanthanum carbonate is a potent and selective phos­ phate binder that retains a high affinity for phosphate over a wide pH range, does not bind bile acids or contribute to metabolic acidosis, and has the potential to reduce tablet burden and increase patient compli­ ance compared with other phosphate bin­ ders (35R,36R). Liver Accumulation of lanthanum in the liver may be a concern. Three studies have investigated lanthanum deposition in the liver in experimental models of chronic renal failure. In nephrectomized and adeninetreated rats, liver lanthanum concentration increased in lanthanum-treated animals compared with uremic untreated rats (37E)

390 and uremic rats treated with lanthanum carbonate had a greater (100-fold increase) accumulation of lanthanum, which increased in a time-dependent manner (38E). In another study, lanthanum was deposited in uremic rat liver, but without rises in plasma transaminase and cholestatic enzyme activ­ ities (39E), as already demonstrated in dialy­ sis patients treated for 3 years with lantha­ num carbonate. Magnetic resonance imaging of the liver did not demonstrate abnormal­ ities; liver weights were similar in each experimental condition and light microscopy did not show any signs of lanthanuminduced hepatic toxicity. As yet the con­ sequences for patients are unresolved (40r). Gastrointestinal Lanthanum is a rare earth, atomic number, 57, and the atomic number of barium is 56; like barium, lanthanum may be visualized on radio­ graphy of the intestine (41A).
An 82-year-old man with hypertension, cor­

onary artery disease, congestive heart failure, chronic constipation, degenerative joint dis­ ease of the hips, and a 5-year history of hemodialysis for end-stage renal disease devel­ oped worsening hip pain. Radiography of the pelvis without contrast medium did not pro­ vide a reason for his increased hip pain but did show diffuse opacifications throughout the colon. Renal failure had induced hyperpho­ sphatemia, which was initially managed with calcium acetate, but this had been changed to lanthanum carbonate 1.5 g orally tds. In this patient, analgesia for his hip discomfort brought relief, lanthanum was discontinued, and calcium acetate was resumed.

Magnesium salts

(SED-15, 2196; SEDA-28, 248; SEDA-30, 266)

Magnesium-containing compounds are in use as mineral supplements, cathartics, and antacids. Magnesium sulfate can be used to regulate blood pressure. Symptomatic hypermagnesemia is a common adverse effect. Cardiovascular Several epidemiological studies have shown an association between

Chapter 22

G.B. Van Der Voet and J.A. Centeno

calcium and magnesium and coronary heart disease mortality and morbidity. Western diets often have a shortage of magnesium, and daily intake of magnesium does not reach the current recommended daily allowance in many subjects. Therefore, magnesium deficiency is common in indus­ trialized countries. The recommended diet­ ary allowance of magnesium is 420 mg/day for men and 320 mg/day for women. Resi­ dents in soft-water areas have lower concen­ trations of magnesium in heart muscle and coronary arteries than do residents in hardwater areas (42M). This suggests that the content of magnesium in the diet is inade­ quately low. The findings of a positive correlation between cardiovascular mortal­ ity and the estimates of the calcium:magne­ sium ratio in the diet of various countries thus suggest that a high calcium:magnesium ratio in the diet may be harmful. The underlying mechanisms explaining the effect of calcium and magnesium on myosin ATPase are different. Magnesium is essential to maintain the enzymatic activity of myosin in cardiac muscle contraction. Calcium has a role conducting signals and regulating functions. Magnesium deficiency may reduce ATPase activity, leading to increases in intracellular calcium and vaso­ constriction. Magnesium is closely involved in maintaining cellular ionic balance through its association with calcium, sodium, and potassium, and may influence the binding of other cations, such as calcium, that may have antagonistic or synergistic effects, depending on their concentrations. Finally, magnesium deficiency can encourage atherosclerosis and platelet aggregation. A high calcium:magnesium ratio in water and thus deficiency of magnesium in the diet and in water significantly increases the risk of acute myocardial infarction. The relation between the risk of acute myocardial infarc­ tion and the content of calcium, magnesium, and chromium in local groundwater in Finnish rural areas has been examined (43M). Data on 14 495 men aged 35–74 years with their first acute myocardial infarction in the years 1983, 1988, or 1993 were pooled. Geochemical data consisted of 4300 mea­ surements of each element in the local groundwater. The median concentrations

Metals

Chapter 22

of calcium, magnesium, and chromium in well water were 12 mg/l, 2.6 mg/l, and 0.27 mg/l respectively; the calcium:magne­ sium ratio was 5.39. Each 1 mg/l increment in magnesium concentration reduced the risk of acute myocardial infarction by 4.9%, whereas a one unit increment in the calcium: magnesium ratio increased the risk by 3.1%. Calcium and chromium did not have any statistically significant effect on the incidence and spatial variation of acute myocardial infarction. This result is compatible with previously reported assumptions about a protective role of hard water against cardi­ ovascular disease (44R). A positive correla­ tion between cardiovascular disease and the estimated calcium:magnesium ratio in the diet has also been suggested in several countries (45C). It can be assumed that residents of areas with soft drinking water but a high calcium: magnesium ratio have an increased risk of cardiovascular disease. Musculoskeletal Magnesium-induced osteomalacia has been attributed to the phosphate binding capacity of a magnesium-containing antacid (46A).
A 42-year-old woman developed widespread

joint pain involving the ankles, knees, hips, and shoulders. She could hardly walk without the help of crutches and had extreme difficulty in sitting down and getting up. Her weight had fallen from 160 to 74 kg in the previous 2 years as a result of a diet that had begun 15 years ago. She had started to use magnesium hydroxide in the last 2 years (2–3 units a day, 10–15 g/day) for its laxative properties. She sometimes consumed up to half a bottle (50 g/day) of magnesium hydroxide in order to lose weight. Her total calcium concentration was 2.04 mmol/l (refer­ ence range 2.10–2.64 mmol/l), phosphorus 0.84 mmol/l (0.81–1.49 mmol/l), and magnesium 1.9 mmol/l (0.7–1.2 mmol/l). Calcium and phos­ phorus concentrations in the 24-hour urine were 0.40 mmol/day (2.50–7.49 mmol/day) and 10 mmol/day (13–42 mmol/day). The 25-hydro­ xycolecalciferol concentration was 25 nmol/l (25–100 nmol/l) and parathormone 11 pmol/l (1–7 pmol/l). There were stress fractures at both femoral necks and at the upper part of the tibia. An MRI scan showed vascular necrosis and stress fractures at both femoral necks. A bone scan showed osteomalacia and magnesium was withdrawn. She was given intramuscular vitamin D 300 000 IU/day and oral calcium (ionized calcium 1 g/day). After 2 months her serum

391 calcium was 2.36 mmol/l, phosphorus 1.35 mmol/ l, magnesium 1.22 mmol/l, and alkaline phos­ phatase 261 U/l. Her calcium concentration in a 24-hour urine sample was 104 mg/day (100– 300 mg/day). Clinical improvement parallelled the improvements in her laboratory results. She finally started to walk without support.

Mercury and mercurial salts

(SED15, 2259; SEDA-28, 248; SEDA-29, 230; SEDA-30, 268) The debate about mercury-containing dental amalgams has continued for about two centuries without any definitive conclusion (47R), although more attention seems to be given to neurodegenerative developments in children. The debate about the use of thiomersal in vaccines and its role in neuro­ developmental outcomes such as autism has also not been concluded, although the number of skeptics seems to increase (48R). Nervous system Mercury is used as a component in traditional Asian medicines and food ingredients, commonly escaping any form of regulation; it regularly causes poisoning (49A).
A 28-year-old man developed nausea, lethargy,

and tremor. He had been defecating an increas­ ingly large quantity of silver droplets, which were identified on laboratory analysis as ele­ mental mercury. An abdominal X-ray showed punctuate opacities along the entire course of the colon. The urine mercury concentration was 26 mg/l (130 nmol/l). He was treated with an antiemetic. For 12 weeks his mother-in-law had been provided him with a traditional Indian medicine containing elemental mercury and meals to which about three tablespoons of elemental mercury had been added. His lethargy, nausea, and tremor resolved within 8 weeks after he stopped taking mercury, and his urine mercury concentration fell to 21 mg/l (102 nmol/l) at 4 weeks, 14 mg/l (69 nmol/l) at 36 weeks, and 3.3 mg/l (17 nmol/l) at 2 years.

Ingestion of elemental mercury is widely regarded as harmless, because it is poorly absorbed. However, prolonged exposure caused by continuous oral intake of large quantities can result

392 in systemic toxicity, because the elemental mercury is volatilized into a highly absorbed vapor or converted to a toxic divalent form.

Nickel

(SED-15, 2502; SEDA-28, 249; SEDA-29, 230; SEDA-30, 268)

Nickel is used in medical implant materials and is often combined with titanium. Nickel is found in many orthodontic appliances. The safety of nickel in dental alloys has been reviewed (50R,51R). The authors concluded that adverse reactions to these appliances in patients with nickel allergy are uncommon. None of these alloys has been associated with an increased risk of cancer. Immunologic Nickel allergy mimicking a basal cell carcinoma has been reported (52A).
A 61-year-old man developed a solitary ulcer­

ated plaque below the right eye, which gradually increased in size over 8 months. There was a 1-cm ulcer with a rolled edge inferiorly, and a diagnosis of basal cell carci­ noma was made. An incision biopsy from the rolled edge showed non-specific inflammation, so a second biopsy was taken from a different area to rule out a sampling error. This showed an acute inflammatory infiltrate within the epidermis, with acanthosis and a more chronic infiltrate within the dermis. He was then referred for patch tests, which showed a strongly positive reaction to nickel. Examina­ tion of the patient’s spectacles showed that the gold plating on the right side had worn off on the rim, which rested on the ulcerated area on his cheek. A dimethylglyoxime spot test from the worn area was strongly positive for nickel but was negative from where the gold plating remained on his spectacles.

It was concluded that the patient’s lesion was in fact due to contact dermatitis to nickel.

Potassium salts

(SED-15, 2905; SEDA28, 249; SEDA-29, 230)

Electrolyte balance Massive hyperkalemia has been reported in a patient with Gitelman’s syndrome taking potassium chlo­ ride supplements and spironolactone (53A).

Chapter 22

G.B. Van Der Voet and J.A. Centeno


A 58-year-old man developed vomiting, diar­

rhea, and profound muscle weakness. At the age of 11 he had begun to have tetany and muscle spasms associated with low potassium concentrations, supposedly due to Bartter’s syndrome, for which he took spironolactone 125 mg/day plus magnesium and potassium chloride 5 g qds. He also had osteoarthritis and hypothyroidism and long-standing bilateral knee pain, which limited walking to 100 yards. Recently he had consumed extra salt and mineral supplements because he had noticed “undigested capsules” in his stool and vomit. His serum potassium concentration was over 10 mmol/l. Because of mutations in his SLC12A3 gene, the diagnosis was revised to Gitelman’s syndrome, with hyperkalemia sec­ ondary to acute renal failure plus exogenous potassium supplementation. He was given intravenous calcium gluconate, insulin, dex­ trose, and temporary continuous venovenous hemodiafiltration.

Gitelman’s syndrome is due to mutations of the SLC12A3 gene, which encodes NCCT, the thiazide-sensitive co-transporter in the distal convoluted tubule. There are more than 100 reported mutations of SLC12A3, which are widely distributed throughout the gene. Gitelman’s syndrome is usually associated with hypomagnesemia and hypocalciuria. In contrast, genetic heterogeneity and phenotypic variability characterize Bartter’s syndrome, the responsible genes affecting function of the epithelial cells that make up the thick ascending limb of Henle’s loop.

Selenium

(SED-15, 3119; SEDA-28, 250; SEDA-29, 231; SEDA-30, 269)

Selenium is an essential trace element and an important constituent of the antioxidant glutathione peroxidase. Selenium has been discussed in many epidemiological investi­ gations into the prevention and treatment of cancer, especially prostate carcinoma (54R). Multiorgan failure Selenium is being used more often in complementary and alter­ native medicine, and fatal selenium poison­ ing is therefore being seen more often (55R). Fatal selenium poisoning has been reported (56A).
A 75-year-old man who was concerned about

prostate cancer researched it on the Internet

Metals

Chapter 22

and discovered that selenium may have a role in its prevention and treatment. He purchased sodium selenite powder and tablets, and developed vomiting and diarrhea 3.5 hours after taking 10 g of sodium selenite (purity 96%). He had severe abdominal pain, poor perfusion, and hypotension, with a pulse rate of 76/minute, a blood pressure of 75/45 mmHg, and a prolonged QT interval. He had a metabolic acidosis and hypokalemia (serum potassium concentration, 3.4 mmol/l). The serum selenium concentration was 68.0 mmol/l (reference range 0.6–2.3 mmol/l). He was transferred to the intensive care unit, where he remained hypotensive (85/50 mmHg) but conscious. He developed ventricular tachycar­ dia, interspersed with normal complexes with ST depression. The acidosis and hypokalemia worsened. He was given intravenous magne­ sium 10 mmol and potassium 25 mmol/l over 40 minutes. The dysrhythmia persisted and worsened. Lidocaine was added without effect. He then had a cardiac arrest and died.

A coroner decided that the cause of death had been acute selenium toxicity.

Silver salts and derivatives (SED-15, 3140; SEDA-28, 250; SEDA-29, 231; SEDA-30, 269) Silver compounds have a long history in medicine, and are used to treat infections encountered in burns, open wounds, and chronic ulcers (57R,58R). Silver sulfadiazine is commonly used to treat burns. However, recent findings suggest that it may delay wound healing and have serious toxic effects. Colloidal silver preparations are often used in alternative medicine. Argyria Cases of argyria, often considered an entity of the past, continue to be reported after the uncontrolled use of colloidal silver preparations (59A). Argyria is characterized by an irreversible, generalized blue-gray discoloration of the subepithelial layer of the skin; later, the entire skin, deep tissues, mucous membranes, nails, conjunctivae, corneae, and lens may be affected. Argyria discoloration may be misdiagnosed as cyanosis, methemoglobinemia, or hemochromatosis.

393 The Australian Agency, ADRAC, has received four reports of silver toxicity (argyria) following ingestion of homemade products containing colloidal silver (tiny particles of metallic silver suspended in liquid) prepared using a “colloidal silver generator” (60A).
A 5-year-old boy who ingested colloidal silver daily for several months developed gray discoloration of the skin and tongue and abnormal hepatic function.
An elderly man who drank colloidal silver daily for 6 months required hospital admission for debilitating fatigue accom­ panied by blue skin discoloration, dilated cardiomyopathy, amnesia, and incoher­ ent speech.
An elderly man who consumed a liquid made using a “colloidal silver generator” over 4 years developed gray skin dis­ coloration.
A man who ingested homemade colloidal silver daily for 3 years and also applied it topically after shaving developed generalized skin discoloration. ADRAC has received no reports of argyria associated with legitimate therapeu­ tic goods, for example, topical silver nitrate for neonatal conjunctivitis or silver sulfa­ diazine for burns. There are no products containing colloidal silver approved for marketing in Australia. ADRAC has cau­ tioned that with the exception of registered topical silver preparations, there is no evidence to support the efficacy or safety of silver, regardless of its form or method of manufacture; that silver has no known nutritional benefit; and that its well-defined toxic effects can occur with all forms of the metal, including silver salts and colloids. A silver-coated wound dressing, Acticoat (Smith & Nephew Inc), has become avail­ able for use in patients with burns. It contains a layer of nanocrystalline silver. This preparation has caused hepatotoxicity and argyria (61A).
After 1 week of local treatment with Acticoat

a young, previously healthy 17-year-old boy with 30% mixed-depth burns developed hepatotoxicity and argyria-like symptoms,

394 including a grayish discoloration of the face. Silver concentrations in the plasma (107 mg/kg) and urine (28 g/kg) were clearly raised and liver enzymes (aspartate transaminase, alanine transaminase, and g-galactosyltransferase) were abnormal. As soon as the local applica­ tion of Acticoat was aborted, the clinical symptoms and liver enzymes returned to normal. After 7 weeks the silver concentra­ tions were still markedly raised, but 10 months later silver was hardly detectable in blood (0.9 mg/kg) or in urine (0.4 mg/kg).

This is the first report of silver toxicity in a patient with 30% burns who received Acticoat for local treatment.

Titanium

(SED-15, 3434; SEDA-28, 250; SEDA-29, 231; SEDA-30, 270)

Titanium is used in medical implant mate­ rial, often in combination with nickel. Immunologic Usually the allergic poten­ tial of nickel is a risk factor in alloys, but titanium itself may incidentally also be the reason for such a reaction. Hypersensitivity to a titanium osteosynthetic device has been reported (62A).
A 35-year-old man was referred for evaluation

of suspected hypersensitivity to implant mate­ rials. He had had hand eczema several months and a hand fracture had failed to heal. The eczema had started within a few weeks after osteosynthesis of a right metacarpal fracture with a pure titanium miniplate and screws. He had gradually developed itching, erythema, and scaling of the skin of the right hand, and a vesiculopapular eruption on several fingers, mainly ventrally. Over the next weeks, the lesions extended to the left hand and the forearms. Patch tests showed no reactions to titanium, nickel, chromium, or cobalt. How­ ever, in a lymphocyte transformation test, his lymphocytes showed markedly enhanced

Chapter 22

G.B. Van Der Voet and J.A. Centeno

proliferation in vitro to titanium. After remo­ val of the titanium material, the fracture healed and the eczema cleared. Parallel to this, in vitro hyper-reactivity to titanium disappeared.

Zinc

(SED-15, 3717; SEDA-28, 251; SEDA-29, 232; SEDA-30, 270)

Zinc is an essential element. Its role in health has been reviewed (63R). Metal metabolism Regular zinc supple­ mentation can cause copper deficiency (64A).
A 61-year-old woman with chronic renal insuffi­

ciency developed a progressive gait ataxia, lower limb weakness, and numbness of her feet. During each hemodialysis zinc 140 mg was added to the hemodialysis solution for trace element substitution. She had a macrocytic hyperchromic anemia. Serum copper was redu­ ced at 8 mmol/l (reference range 10–26 mmol/l) as was ceruloplasmin at 1.3 g/l (2–6 g/l), while serum zinc was markedly raised at 25 mmol/l (13–18 mmol/l). Myelopathy due to zinc-induced copper deficiency associated with anemia was diagnosed. Consequently, zinc substitution dur­ ing hemodialysis was discontinued and she was given copper gluconate 600 mg/day. Two weeks later, her symptoms began to improve.

Acknowledgement This manuscript has been reviewed in accor­ dance with the policy of the Armed Forces Institute of Pathology and the Department of Defense, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Department of the Army or the Depart­ ment of Defense, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

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Metals

Chapter 22

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395 14. Curry TB, Gaver R, White RD. Acquired long QT syndrome and elective anesthesia in children. Paediatr Anaesth 2006; 16(4):471–8. 15. Broadhurst CL, Domenico P. Clinical studies on chromium picolinate supplementation in diabetes mellitus—a review. Diabetes Technol Ther 2006;8(6):677–87. 16. Wani S, Weskamp C, Marple J, Spry L. Acute tubular necrosis associated with chromium picolinate-containing dietary sup­ plement. Ann Pharmacother 2006;40(3): 563–6. 17. Sargeant A, Goswami T, Swank M. Ion concentrations from hip implants. J Surg Orthop Adv 2006;15(2):113–4. 18. Cobb AG, Schmalzreid TP. The clinical significance of metal ion release from cobalt-chromium metal-on-metal hip joint arthroplasty. Proc Inst Mech Eng (H) 2006;220(12):385–98. 19. Steens W, von Foerster G, Katzer A. Severe cobalt poisoning with loss of sight after ceramic-metal pairing in a hip—a case report. Acta Orthop 2006;77(5):830–2. 20. Wang T, Gua Z. Copper in medicine: homeostasis, chelation therapy and antitu­ mor drug design. Curr Med Chem 2006; 13(5):525–7. 21. Tinelli A, Tinelli R, Malvasi A, Cavalotti C, Tinelli FG. The intrauterine device in modern contraception: still an actuality?. Eur J Contracept Reprod Health Care 2006;11(3):197–201. 22. Kroepfl T, Mair E, Deutsch J, BrunnerKrainz M, Paschke E, Plecko B. Copper concentration of liver tissue under long-term copper-histidine therapy in a patient with Menkes disease. J Inherit Metab Dis 2006;29(4):593. 23. Kostova I. Gold coordination complexes as anticancer agents. Anticancer Agents Med Chem 2006;6(1):19–32. 24. Youn HS, Lee JY, Saitoh SI, Miyake K, Hwang DH. Auranofin, as an anti-rheumatic gold compound, suppresses LPS-induced homodimerization of TLR4. Biochem Bio­ phys Res Commun 2006;350(4):866–71. 25. Geist DE, Phillips TJ. Development of chrysiasis after Q-switched ruby laser treat­ ment of solar lentigines. J Am Acad Dermatol 2006;55(2 Suppl):S59–60.

396 26. Nairz M, Weiss G. Molecular and clinical aspects of iron homeostasis: from anemia to hemochromatosis. Wien Klin Wochenschr 2006;118(15–16):442–62. 27. Syed BA, Sargent PJ, Farnaud S, Evans RW. An overview of molecular aspects of iron metabolism. Hemoglobin 2006;30(1):69–80. 28. Buus NH, Jensen JD. Severe intravascular haemolysis and acute renal failure following intravenous administration of iron dextran. Nephrol Dial Transplant 2007;22(2):661–2. 29. Sirken G, Raja R, Rizkala AR. Association of different intravenous iron preparations with risk of bacteremia in maintenance hemodialysis patients. Clin Nephrol 2006; 66(5):348–56. 30. Fricker SP. The therapeutic application of lanthanides. Chem Soc Rev 2006;35(6): 524–33. 31. Monafo WW, Tandon SN, Ayvazian VH, Tuschmidt J, Skinner AM, Deitz F. Cerium nitrate: a new topical antiseptic for extensive burns. Surgery 1976;80(4):465–73. 32. Garner JP, Heppell PS. Cerium nitrate in the management of burns. Burns 2005; 31(5):539–47. 33. Attoff R, Magnin C, Bertin-Maghit M, Olivier L, Tissot S, Petit P. Methemoglobi­ nemia by cerium nitrate poisoning. Burns 2006;32(8):1060–1. 34. Boye T, Terrier JP, Coillot C, Guennoc B, Fournier B, Carsuzaa F. Cerium-induced granulomatous dermatitis. Ann Dermatol Venereol 2006;133(1):50–2. 35. Behets GJ, Verberckmoes SC, D’Haese PC, De Broe ME. Lanthanum carbonate: a new phosphate binder. Curr Opin Nephrol Hypertens 2004;13(4):403–9. 36. Sprague SM. A comparative review of the efficacy and safety of established phosphate binders: calcium, sevelamer, and lanthanum carbonate. Curr Med Res Opin 2007; 23(12):3167–75. 37. Lacour B, Lucas A, Auchere D, Ruellan N, + de Serre Patey NM, Drueke TB. Chronic renal failure is associated with increased tissue deposition of lanthanum after 28-day oral administration. Kidney Int 2005; 67(3):1062–9. 38. Slatopolsky E, Liapis H, Finch J. Progres­ sive accumulation of lanthanum in the liver

Chapter 22

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G.B. Van Der Voet and J.A. Centeno

of normal and uremic rats. Kidney Int 2005;68(6):2809–13. Ben-Dov IZ, Pappo O, Sklair-Levy M, Galitzer H, Ilan Y, Naveh-Many T, Silver J. Lanthanum carbonate decreases PTH gene expression with no hepatotoxicity in uraemic rats. Nephrol Dial Transplant 2007;22(2):362–8. Cozzolino M, Brancaccio D. Lanthanum carbonate—new data on parathyroid hor­ mone control without liver damage. Nephrol Dial Transplant 2007;22(2):316–8. Cerny S, Kunzendorf U. Images in clinical medicine. Radiographic appearance of lanthanum. N Engl J Med 2006;355(11):1160. Anderson TW, Neri LC, Schreiber GB, Talbot FD, Zdrojewski A. Ischemic heart disease, water hardness and myocardial magnesium. Can Med Assoc J 1975;113:199. Kousa A, Havulinna AS, Moltchanova E, Taskinen O, Nikkarinen M, Eriksson J, Karvonen M. Calcium:magnesium ratio in local groundwater and incidence of acute myocardial infarction among males in rural Finland. Env Health Persp 2006;114:730–4. Sauvant MP, Pepin D. Drinking water and cardiovascular disease. Food Chem Toxicol 2002;40:1311–25. Punsar S, Wolf W, Mertz W, Karvonen MJ. Urinary chromium excretion and athero­ sclerotic manifestations in two Finnish male populations. Ann Clin Res 1977;9:79–83. + Sivas F, Gunesen, Ozoran K, Alemdaroglu E. Osteomalacia from Mg-containing anta­ cid: a case report. Rheumatol Int 2007;27:679–81. Martin MD, Woods JS. The safety of dental amalgam in children. Expert Opin Drug Saf 2006;5(6):773–81. Herman LM, Gerbert DA, Larson LW, Léger MM, McNellis R, O’Donoghue DL, Ulshafer C, Van Dyke EM. Vaccines, thimerosal, and neurodevelopmental out­ comes. JAAPA 2006;19(1):16–9. Yoong JK. Images in clinical medicine. Heavy-metal meals of mercury. N Engl J Med 2006;354(3):e3. Setcos JC, Babaei-Mahani A, Silvio LD, + IA, Wilson NH. The safety of nickel Mjor containing dental alloys. Dent Mater 2006;22(12):1163–8.

Metals

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51. Volkman KK, Inda MJ, Reichi PG, Zachar­ isen MC. Adverse reactions to orthodontic appliances in nickel-allergic patients. Allergy Asthma Proc 2007;28(4):480–4. 52. Hague J, Ilchyshyn A. Nickel allergy mimicking basal cell carcinoma. Contact Dermatitis 2006;54(6):244–5. 53. Phillips DR, Ahmad KI, Waller SJ, Meisner P, Karet FE. A serum potassium level above 10 mmol/l in a patient predisposed to hypokalemia. Nat Clin Pract Nephrol 2006; 2(6):340–6. 54. Brinkman M, Reulen RC, Kellen E, Buntinx F, Zeegers MP. Are men with low selenium levels at increased risk of prostate cancer? Eur J Cancer 2006;42(15):2463–71. 55. Nuttall KL. Evaluating selenium poisoning. Ann Clin Lab Sci 2006;36(4):409–20. 56. See KA, Lavercombe PS, Dillon J, Ginsberg R. Accidental death from acute selenium poisoning. Med J Aust 2006;185(7):388–9. 57. Landsdown AB. Silver in health care: antimicrobial effects and safety in use. Curr Probl Dermatol 2006;33:17–34. 58. Atiyeh BS, Costagliola M, Hayek SN, Dibo SA. Effect of silver on burn wound infection control and healing: review of the literature. Burns 2007;33(2):139–48.

397 59. Chang AL, Khosravi V, Egbert B. A case of argyria after colloidal silver ingestion. J Cutan Pathol 2006;33:809–11. 60. Anonymous. Colloidal silver. Health risks associated with chronic ingestion. WHO Pharm Newslett 2007;5:6–7. 61. Trop M, Novak M, Rodi S, Hellbom B, Kroell W, Goessler W. Silver-coated dressing acticoat caused raised liver enzymes and argyria-like symptoms in burn patient. J Trauma 2006;60(3):648–52. 62. Thomas P, Bandl WD, Maier S, Summer B, Przybilla B. Hypersensitivity to titanium osteosynthesis with impaired fracture healing, eczema, and T-cell hyperresponsive­ ness in vitro: case report and review of the literature. Contact Dermatitis 2006;55(4): 199–202. 63 Frassinetti S, Bronzetti G, Caltavuturo L, Cini M, Croce CD. The role of zinc in life: a review. J Environ Pathol Toxicol Oncol 2006;25(3):597–610. 64. Yaldizli O, Johansson U, Gizewski ER, Maschke M. Copper deficiency myelo­ pathy induced by repetitive parenteral zinc supplementation during chronic hemodialysis. J Neurol 2006;253(11): 1507–9.

R.H.B. Meyboom

23

Metal antagonists

IRON CHELATORS Uses Iron mismanagement or iron-derived radicals are known or thought to play a role in many diseases; examples are Alzheimer’s disease, Friedreich’s ataxia, hepatic cirrhosis, macular degeneration, and solid tumors (1R,2R,3R,4R,5R). The therapeutic use of drugs with an affinity for iron is therefore likely to expand in years to come. Metals such as iron and copper have many physiological actions and play fundamental roles in cell growth and angiogenesis. Tumor cells may have increased sensitivity to shortages of metals (iron, copper) or metal toxicity (copper, platinum). Others have discussed the possible future uses of chelators such as deferoxamine, Triapine, trientine, and tetrathiomolybdate in the management of malignant diseases, for example, leukemias, neuroblastoma, cancer of the liver, kidney, and prostate, and other solid tumors. Relatively little is known, however, of the pharmacology and toxicology of iron chelators in patients without iron overload. Table 1 lists iron chelating drugs that are currently in use or in development.

Combining iron chelators Because of pharmacological differences, the combination of, for example, deferoxamine with deferiprone can have additive effects on iron excretion (SEDA 26, 253). Furthermore, the adverse effects profiles of the drugs Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03123-7 r 2009 Elsevier B.V. All rights reserved.

in use so far are remarkably different. The neurosensory toxicity of deferoxamine is seen with neither deferiprone nor deferasirox; arthropathy and agranulocytosis are typical only for deferiprone, while deferasirox fairly often causes skin rashes. These apparent differences may reflect different modes of interfering with the complex metabolism of iron as well as other pharmacological features of the drugs. Future novel oral iron chelators may be envisaged to have different and unexpected adverse effects. Thus, combining drugs makes sense—the beneficial effects can be increased while the adverse effects can be spread out. In a 12-month period the efficacy and safety of the combined use of these drugs was followed in 50 homogeneously treated patients with thalassemia whose ferritin concentrations were above 2000 mg/l and/or with cardiac dysfunction (defined as a left ventricular ejection fraction below 29%) (6CR). Nine patients had had splenectomy and 20 were positive for hepatitis C antibodies. The treatment consisted of a subcutaneous infusion of deferoxamine over 8–10 hours in doses of 30–55 mg/kg/day plus oral deferiprone 25 mg/kg/day taken in two portions, of which the first portion was taken at the start and the second 2 hours before the end of the deferoxamine infusion. Table 1. Examples of iron chelators in current use or being studied for various indications Ciclopirox Deferoxamine Starch-deferoxamine polymers Deferiprone Deferasirox Deferitrin

Desferrithiocin Dexrazoxane HBED L1NAII Triapine Tachpyr (tachypyridine)

399

400 Compliance was excellent in 36 and good (66–84% of the prescribed dose) in 14 patients; 43 patients completed the 12-month course. Of seven withdrawals, two were because of adverse reactions—agranulocytosis in both, occurring after 6 and 11 months. In these two patients bone marrow morphology showed mild myeloid hypoplasia, while in vitro bone marrow cultures showed normal development of myeloid precursors. A third patient had neutropenia (overall incidence 4.2 per 100 patient-years). One of the 50 patients developed fairly severe joint pain, which improved after reducing the dose of deferiprone. Mild gastrointestinal symptoms (nausea, vomiting, abdominal discomfort) occurred in 10 patients. In addition to these typical reactions to deferiprone, one patient developed Yersinia enterocolitica enteritis, which is known to occur in connection with deferoxamine. Nine of the patients had transient rises in alanine transaminase to two to five times the upper limit of normal. In a large retrospective study of 516 patients with thalassemia, the 157 who received deferoxamine plus deferiprone at some time had a stronger cardioprotective effect than the 359 who received deferoxamine alone (7CR). However, since randomization was not possible in this study, the comparability of the two groups may have been limited. In 46 (31%) of the 157 patients deferiprone was discontinued because of clinical or laboratory adverse events, including increases in ferritin concentrations or liver iron content in 21 patients, arthropathy in 10, and neutropenia in 9, one of whom had agranulocytosis. In a further 21 patients deferiprone was withdrawn for other reasons, in particular non-compliance. The combination therapy protocol of the International Committee on Oral Chelators (ICOC) for rapid clearance of excess cardiac iron has been tested in 11 patients with thalassemia (age range 22–44 years) (8cr). In all patients oral deferiprone (80–110 mg/kg/ day) in combination with subcutaneous deferoxamine (40–60 mg/kg on at least 3 days/week) over 9–28 months caused substantial reductions in serum ferritin (one patient had a paradoxical increase, but the final concentration was still below 1000 mg/l) and cardiac iron

Chapter 23

R.H.B. Meyboom

load (measured by MRI T2� or MRI T2 relaxation time). In one patient neutropenia necessitated a dosage reduction of deferiprone while in another the administration of deferoxamine was limited to 2 days/week because of injection site reactions. In a study in Taiwan of 21 children being treated with deferiprone alone and 12 children using it in combination with deferoxamine, a start was made on the important issue of studying the effect of different chelation treatment regimens on the quality of life (9cr). One of the findings was that parents and children may have different views. Such differences need to be taken into account in the design of future studies. In 42 patients with thalassemia receiving long-term subcutaneous deferoxamine (20– 40 mg/kg over 8–12 hours on 2–6 days/week), the addition of deferiprone 75–90 mg/kg/day led to improved glucose intolerance and liver iron deposition (10CR). Serum ferritin concentrations fell markedly (from 2991 to 638 g/l), the responses to oral glucose tolerance tests generally improved, quantitative glucose secretion fell significantly, and insulin secretion increased markedly. In 91 Omani patients with beta-thalassemia in whom deferoxamine by subcutaneous infusion 160–200 mg/kg/week had for various reasons been insufficiently effective, deferiprone 75 mg/kg/day was added. In two patients deferiprone had to be stopped because of agranulocytosis (11cr); two other patients had arthropathy, which responded to lowering the dose. There were severe gastrointestinal upsets in six patients. Susceptibility factors When assessing adverse events in patients, a thorough knowledge is needed of the common and rare complications of their diseases. Thalassemia has occasionally been associated with bleeding or thrombosis. In a study in 54 transfusion-dependent patients with thalassemia their hemostatic parameters were measured and compared with the values in 30 control patients (12CR). One-third of these patients had low platelet counts (under 100
109 per liter in 5.5%) while some increase in clotting time and some reduction in clotting factors or thrombolytic

Metal antagonists

Chapter 23

Table 2. Abnormal clotting parameters in patients with thalassemia Parameter

Patients with abnormal values (%)

Prolonged PT Prolonged aPTT AT III Protein C Protein S

41 46 47 26 29

factors were common (Table 2); none had laboratory evidence of disseminated intravascular coagulation. Serum ferritin concentrations are an important disease parameter of thalassemia. However, as has been emphasized in a report from Cyprus, iron storage cardiomyopathy can occur despite normal serum ferritin concentrations (13CR). Sixteen of the 54 patients had a history of bleeding (i.e., epistaxis); none had had thrombotic events. The authors’ conclusion, that patients with thalassemia are often at the verge of bleeding or thrombosis, is important in the evaluation of safety data of iron chelators.

Deferasirox

(SEDA-29, 236; SEDA-30,

273) Deferasirox is a highly lipophilic tridentate iron chelator and an N-substituted bishydroxyphenyltirazole compound for oral use, available as 125, 250, and 500 mg tablets and administered in a daily dose of 20– 50 mg/kg. It is rapidly absorbed (about 70%), highly bound to albumin, has a plasma half-life of 11–19 hours, and probably undergoes enterohepatic recirculation (14R,15R,16R). Two molecules of deferasirox form a stable complex with one iron Fe3+ atom. Deferoxamine is mainly glucuronidated; about 84% is excreted in the feces and only about 8% in the urine. Excretion of the deferasirox–iron complex and its metabolites is probably mainly by hepatobiliary anion transport. At therapeutic doses induction and inhibition of cytochrome P450 enzymes have not been observed. A daily

401 dose of 20–30 mg/kg successfully controls iron balance in many but not in all patients (17R). In some patients with high transfusion burdens a higher dose may be needed to prevent rising serum ferritin concentrations and hepatic iron concentrations. Comparative studies In a multinational phase III trial in 65 clinical centers in 12 counties, with the primary aim of investigating the hypothesis that deferasirox is not inferior to deferoxamine, 586 patients were randomly allocated to deferasirox (n ¼ 296) or deferoxamine (n ¼ 290) (18CR). Depending on the iron load, deferasirox 5– 10 mg/kg/day was given to patients with low liver iron content, 20 mg/kg/day to patients with moderate liver iron content, and 30 mg/ kg/day to patients with high iron burdens requiring major reduction. For comparison, deferoxamine was given in doses of 20–35, 35– 50, and 50 mg/kg and higher; the doses of deferoxamine were normalized to administration on 5 days a week. Most of the patients (541; 92.3%) completed a 1-year treatment course; 17 stopped using deferasirox and 12 stopped using deferoxamine. Both baseline and 1-year liver iron content were measured in 587 patients. The primary end-point (maintenance or reduction of liver iron content) was not met in the overall population, possibly owing to proportionately lower doses of deferasirox. Dosage adjustment, dosage interruption, and discontinuation combined were similar. A skin rash occurred in 11% of patients, 15% had gastrointestinal upsets (nausea, vomiting, abdominal pain, diarrhea, constipation; median duration 8 days or less), and in 38% there were mild increases in serum creatinine (less than twice the upper limit of normal and generally within the reference range), more frequently with high doses. Deafness (neurosensory deafness or hypoacusis) was reported in eight patents receiving deferasirox, but was considered to be drug-related in only one, and in seven receiving deferoxamine, but considered to be drug-related in five. In the deferasirox group cataracts or lenticular opacities were reported as adverse events in two patients, but considered to be drug-related in only one, compared with seven of the patients on deferoxamine, and considered to be

402 drug-related in four. In neither group was there any case of agranulocytosis. One patient died suddenly of an unknown cause while using deferasirox.

Deferiprone

(SED-15, 1054; SEDA-28, 256; SEDA-29, 237; SEDA-30, 273)

Observational studies Patients with hemoglobin H disease present with anemia of the thalassemia intermedia type. Although transfusions are rarely needed, these patients often acquire iron overload, presumably owing to increased dietary absorption secondary to ineffective erythropoiesis, and diabetes and liver and heart failure can ensue. In 16 patients with hemoglobin H disease whose serum ferritin concentrations were above 900 mg/l deferiprone reduced serum ferritin and cardiac iron content in 12 (19CR). Treatment began with 50 mg/kg/day and was slowly increased to 75 mg/kg/day in most patients. All passed reddish urine, especially during the early phase of treatment. There was mild to significant arthralgia in 10 of the 16 patients, usually affecting the large joints (knees, shoulders, hips). One patient had a persistent gastrointestinal upset, which did not respond to lowering the dose and required permanent withdrawal. Two patients complained of loss of appetite in the initial period, but another had increased appetite and gained 4 kg. In 61 patients deferiprone was more efficacious than deferoxamine in improving asymptomatic cardiac siderosis (20c). Oral deferiprone (n ¼ 29) was started at 75 mg/kg/ day and was subsequently increased to 100 mg, while for deferoxamine (n ¼ 32) the prescribed dose was 35 mg/kg/day. Of those who took deferiprone two withdrew, both because of liver enzymes (unrelated in at least one). The adverse effects pattern of these treatments was different. While gastrointestinal upsets were most common in deferiprone users (n ¼ 19), they did not occur in deferoxamine users, in whom infusion site reactions were frequent (n ¼ 12). Nine patients who used deferiprone reported increased appetite. Mild or moderate arthropathy occurred in 28% of those who used deferiprone and in 19% of those who used deferoxamine.

Chapter 23

R.H.B. Meyboom

Transient mild neutropenia occurred in one patient and did not necessitate withdrawal. In a retrospective study in 45 hepatitis C positive patients with thalassemia deferiprone 75 mg/kg for 23–60 months was not associated with worsening of hepatic fibrosis or injury (21CR). In another study liver biopsies were assessed in 17 patients with thalassemia using deferiprone 75 mg/kg/day for a mean period of 39 months, including 11 with positive hepatitis C serology (22cr). In these patients liver histology was compared with previous samples. There were no changes in fibrotic scores in 15 patients, while 2 had slight worsening. Of 88 patients in Taiwan using deferiprone 75–80 mg/kg/day for beta-thalassemia, 1 had mild and transient neutropenia and 2 had arthropathy; deferiprone was continued in these patients (23cr).

Deferoxamine

(SED-15, 1058; SEDA28, 256; SEDA-29, 237; SEDA-30, 274)

Observational studies In a 39-year-old woman with primary hemochromatosis and poor tolerance of phlebotomy, excellent results were obtained from deferoxamine 1 g intramuscularly five times a week for 3 months (24A). Although deferoxamine is not usually recommended in hereditary hemochromatosis, and the use of chelators is limited, iron chelators can be beneficial in combination with phlebotomy in a subset of these patients. In a retrospective study in 14 children with various hematologic disorders (mean age 11 years, range 4–17), transfusional iron overload was treated with deferoxamine in a “weekend very-high dose” regimen (25cr). A single course was defined as 720 mg/kg in 48 hours (in isotonic saline 960 ml/day) by continuous intravenous infusion. The mean duration of treatment was 18 months. In one patient treatment was stopped because of the occurrence of transient paresthesia during the third infusion; presumably the dose of deferoxamine had been unnecessarily high. Another patient complained of muscle cramps in the legs toward the end of the infusion, which did not prevent continued treatment. Two patients with pre-existent hearing impairment had no worsening of symptoms.

Metal antagonists

Chapter 23

Comparative studies In 61 randomized patients who had previously been treated for a long time with deferoxamine, a comparison was made between deferiprone and deferoxamine in improving asymptomatic cardiac siderosis; deferiprone was more efficacious (20CR). Oral deferiprone (n ¼ 29) was started at 75 mg/kg/day and was then increased to 100 mg/kg/day; the dose of deferoxamine (n ¼ 32) was 35 mg/ kg/day. Two of those given deferiprone withdrew because of raised liver enzymes (unrelated in at least one); three of those given deferoxamine withdrew, because of deterioration of cardiac function in one and personal reasons in two. The adverse effects patterns of these treatments were different. Gastrointestinal upsets were most common with deferiprone and did not happen with deferoxamine. In 12 patients deferoxamine caused infusion site reactions and mild or moderate arthropathy occurred in 19%. Sensory systems A cross-sectional study in Lebanon has confirmed that ophthalmic disorders are common in patients with thalassemia and that it is difficult to distinguish between disease- and treatment-related disturbances (26cr). Severe toxic retinopathy has been described in connection with high-dose continuous infusion of deferoxamine and a sudden fall in serum ferritin concentration (27AR).  A 17-year-old boy with thalassemia stopped

self-administration of subcutaneous deferoxamine after 14 years. He developed a dilated cardiomyopathy and a cardiac dysrhythmia. The serum ferritin concentration was 6370 mg/l (therapeutic index ¼ 0.007, four times above the limit). He was given deferoxamine 44 mg/ kg/day through an indwelling intravenous catheter. After 4 months he developed impaired color vision and his visual acuity was 6/18 in both eyes. Since there were no fundus abnormalities and because of the severe cardiac involvement deferoxamine was continued. Three weeks later his vision had deteriorated to counting fingers, and fundus examination showed diffuse pigmentary changes in the macula and peripheral retina. The serum ferritin had fallen to 430 (therapeutic index ¼ 0.103) and deferoxamine was reduced to 11 mg/kg/day subcutaneously. One year later his visual acuity was 6/60 and the retinal pigmentation was unchanged. An electrooculogram showed a severely reduced response,

403 with an Arden ratio of 1.1; bilaterally full field electroretinography showed reduced scotopic and photopic response amplitudes with normal implicit times in both eyes.

This emphasizes the importance of frequent serum ferritin measurements and maintaining the therapeutic index below 0.025. In a multicenter comparative study in 290 patients using deferoxamine, there was neurosensory deafness or hypoacusis in 7 patients, considered to be drug-related in 5 (1.7%) (16CR). Cataracts or lens opacities were reported as adverse events in seven patients and were considered to be drugrelated in four (1.4%). Infection risk In the past much attention has been paid to the increased risk of infections such as mucormycosis or Yersinia in users of deferoxamine (SED-15, 1064). In a followup study of the combined use of deferoxamine (subcutaneously) and deferiprone Y. enterocolitica enteritis occurred in one patient (6c). In a 1-year follow-up of 290 patients being treated with deferoxamine 1 died suddenly of unspecified septicemia (6CR). Fatal nasal–orbital–cerebral mucormycosis occurred in a patient receiving deferoxamine (28C). Tumorigenicity In the context of a case study of a 37-year-old patient with thalassemia and a primary gastric B cell lymphoma the many uncertainties were discussed regarding possibly increased risks of malignant diseases that might follow from thalassemia-associated immune deficiency, chronic iron storage, or perhaps chelating agents (29AR).

PENICILLAMINE AND RELATED DRUGS (SED-15, 2729; SEDA-28, 257; SEDA-29, 238; SEDA-30, 274)

Bucillamine In Japan bucillamine has long been regarded as a useful disease-modifying antirheumatic drug.

404 Comparative studies In a retrospective 12month review of the medical records of 348 patients with rheumatoid arthritis (ACR classification) bucillamine and methotrexate were compared (30CR). There were 74 adverse events in 71 patients; none was lifethreatening. Skin rashes were the most common (47%) followed by proteinuria (25%). One patient had nephrotic syndrome for about 6 months; bucillamine was withdrawn and the patient made a good recovery. Other adverse events were stomatitis, glossitis, cough, and raised transaminase activities. Rashes mainly occurred in the first 3 months of use, while proteinuria often developed after a longer interval. The authors concluded that the effectiveness of bucillamine can usually be judged within 3 months of use and that it is indicated in the treatment of rheumatoid arthritis of moderate severity, either before or after methotrexate.

Penicillamine Comparative studies Penicillamine 600– 1800 mg/day (n ¼ 23) and zinc sulfate (n ¼ 12) have been compared in Wilson’s disease (31cR). Neuropsychiatric symptoms became worse or remained unchanged in 75% of the patients who received penicillamine, whereas zinc sulfate improved these symptoms in 90% of patients. In six patients penicillamine was withdrawn because of adverse reactions: proteinuria and microhematuria in two, high titers of antinuclear antibodies or a lupus-like syndrome in three, and amenorrhea in one. The drugs were equally effective in improving liver involvement and there were no differences in follow-up hepatic copper contents. Systematic reviews The Cochrane HepatoBiliary Group in Copenhagen have reported a meta-analysis of the benefit to harm balance of penicillamine in primary biliary cirrhosis, encompassing seven clinical trials and 706 patients (32M). In the penicillamine group there was a fourfold increase in adverse events, often serious adverse reactions characteristic of penicillamine, while there was no beneficial effect on hard end-points.

Chapter 23

R.H.B. Meyboom

Sensory systems In a study of the feasibility of giving penicillamine to five neonates with extremely low birth weights, there were no signs of immediate intolerance (33cr). Against an incidence of retinopathy of prematurity of 54% in a historical cohort, only one of the children had mild transient retinopathy. Urinary tract Penicillamine-induced nephrotic syndrome in published reports of 63 patients has been reviewed (34R). The mean duration of penicillamine use before detection of proteinuria was 7.6 months and the mean duration of use until the diagnosis of nephrotic syndrome was 11.9 months. The mean dose at the time of diagnosis was 1 g/day and the peak amount of proteinuria was 11 g/ day. Proteinuria usually improved or recovered within 7 months after withdrawal of penicillamine; treatment with corticosteroids in 12 patients produced a faster response. Five patients died with sepsis; two had received corticosteroids. There was minimal change disease in 27% of the patients and 55% had membranous glomerulonephritis. However, because of the literature search strategy this study may not represent the full picture of penicillamine nephropathy.

OTHER CHELATORS Di-2-pyridylketone-4,4-dimethyl3-thiosemicarbazone (Dp44mT) The antitumor activity and iron chelation efficacy of a new class of iron chelators has been evaluated using human tumors. Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which inhibits the uptake of iron from transferrin and increases cellular iron release, was the most effective chelator identified. After 7 weeks, net growth of a melanoma xenograft in Dp44mT-treated mice was only 8% of that in mice treated with the vehicle. There was no marked systemic iron depletion. Dp44mT up-regulated iron-responsive tumor growth and the metastasis suppressor Ndrg1 in the tumor but not in the liver (35E).

Metal antagonists

Chapter 23

Ethylene diamine tetra-acetic acid (EDTA) (SED-15, 1300; SEDA-30, 276) On the basis of three case observations, the Centers of Disease Control and Prevention have issued a warning that disodium edetate can be inadvertently administrated instead of calcium sodium edetate and can lead to serious hypocalcaemia and fatal cardiac dysrhythmias (36C). In the comprehensive ACC/AHA guidelines for the management of patients with peripheral arterial disease, it has been reiterated that in patients with intermittent claudication chelation treatment with, for example, EDTA is not indicated and can be harmful (37R).

Triapines The iron chelator Triapine, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, is a potent inhibitor of ribonucleotide reductase and is used in combination with cytarabine in the treatment of leukemia and

405 myelodysplastic syndrome. It is about 500 times more potent than hydroxycarbamide (hydroxyurea) (38c). Hematologic Triapine has been associated with the occurrence of mild methemoglobinemia (39c). Oxidants that induce methemoglobinemia can cause severe symptoms in patients with G6PD deficiency and a case report originating from a phase II clinical trial for renal cell carcinoma has emphasized the importance of G6PD screening before starting to give Triapine (40A).  A 59-year-old Filippino man with metastatic

renal cell carcinoma was given intravenous Triapine 96 mg/m2/day for 2 days. On the second and third days he became cyanotic and short of breath. His serum methemoglobin was 35% of total hemoglobin (pretreatment concentration 6%). After treatment with methylthioninium chloride 3 mg/kg in three portions he developed gross intravenous hemolysis with jaundice and hemoglobinuria. He had G6PD deficiency (o0.1 IU/g); methemoglobin reductase was normal and there was no hemoglobinopathy.

References 1. Weinberg ED. Therapeutic potential of iron chelators in diseases associated with iron mismanagement. J Pharm Pharmacol 2006; 58(5):575–84. 2. Yu Y, Wong J, Lovejoy DB, Kalinowski DS, Richardson DR. Chelators at the cancer coalface: desferrioxamine to Triapine and beyond. Clin Cancer Res 2006;12(23):6876–83. 3. Wang T, Guo Z. Copper in medicine: homeostasis, chelation therapy and antitumor drug design. Curr Med Chem 2006;13(5):525–37. 4. Birch N, Wang X, Chong H-S. Iron chelators as therapeutic iron depletion agents. Expert Opin Ther Patents 2006;16(11):1533–56. 5. Kontoghiorghes GJ. Future chelation monotherapy and combination therapy strategies in thalassemia and other conditions. Comparison of deferiprone, deferoxamine, ICL670, GT56-252, L1NAll and starch deferoxamine polymers. Hemoglobin 2006;30(2):329–47. 6. Kattamis A, Ladis V, Berdousi H, Kelekis NL, Alexopoulou E, Papasotiriou I, Drakaki K,

Kaloumenou I, Galani A, Kattamis C. Iron chelation treatment with combined therapy with deferiprone and deferioxamine: a 12-month trial. Blood Cells Mol Dis 2006;36(1):21–5. 7. Borgna-Pignatti C, Cappellini MD, De Stefano P, Del Vecchio GC, Forni GL, Gamberini MR, Ghilardi R, Piga A, Romeo MA, Zhao H, Cnaan A. Cardiac morbidity and mortality in deferoxamine- or deferipronetreated patients with thalassemia major. Blood 2006;107(9):3733–7. 8. Kolnagou A, Kontoghiorghes G. Effective combination therapy of deferiprone and deferoxamine for the rapid clearance of excess cardiac iron and the prevention of heart disease in thalassemia. The protocol of the International Committee on Oral Chelators. Hemoglobin 2006;30(2):239–49. 9. Kuo H-T, Tsai M-Y, Peng C-T, Wu K-H. Pilot study on the “quality of life” as reflected by psychosocial adjustment of children with thalassemia major undergoing iron-chelating

Chapter 23

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10.

11.

12.

13.

14.

15.

16.

17.

18.

treatment in western Taiwan. Hemoglobin 2006;30(2):291–9. Farmaki K, Angelopoulos N, Anagnostopoulos G, Gotsis E, Rombopoulos G, Tolis G. Effect of enhanced iron chelation therapy on glucose metabolism in patients with beta-thalassaemia major. Br J Haematol 2006;134(4):438–44. Daar S, Pathare AV. Combined therapy with desferrioxamine and deferiprone in beta thalassemia major patients with transfusional iron overload. Ann Hematol 2006; 85(5):315–9. Naithani R, Chandra J, Narayan S, Sharma S, Singh V. Thalassemia major—on the verge of bleeding or thrombosis? Hematology 2006;11(1):57–61. Kolnagou A, Economides C, Eracleous E, Kontoghiorghes G. Low serum ferritin levels are misleading for detecting cardiac iron overload and increase the risk of cardiomyopathy in thalassemia patients. The importance of cardiac iron overload monitoring using magnetic resonance imaging T2 and T2�. Hemoglobin 2006;30(2): 219–27. Porter JB. Deferasirox: an effective oncedaily orally active iron chelator. Drugs Today 2006;42(10):623–37. Van Orden HE, Hagemann TM. Deferasirox—an oral agent for chronic iron overload. Ann Pharmacother 2006;40(6):1110–7. Cappellini MD. Deferasirox: a novel, oncedaily oral iron chelator to individual patient needs. Therapy 2006;3(4):453–60. Neufeld EJ. Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions. Blood 2006;107(9):3436–41. Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu L, Aydinok Y, Kattamis A, Kilinc Y, Porter J, Capra M, Galanello R, Fattoum S, Drelichman G, Magnano C, Verissimo M, AthanassiouMetaxa M, Giardina P, Kourakli-Symeonidis A, Janka-Schaub G, Coates T, Vermylen C, Olivieri N, Thuret I, Opitz H, Ressayre-Djaffer C, Marks P, Alberti D. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood 2006;107(9): 3455–62.

R.H.B. Meyboom

19. Chan JCW, Chim C-S, Ooi CGC, Cheung B, Liang R, Chan T-K, Chan V. Use of the oral chelator deferiprone in the treatment of iron overload in patients with Hb H disease. Br J Haematol 2006;133(2): 198–205. 20. Pennell DJ, Berdoukas V, Karagiorga M, Ladis V, Piga A, Aessopos A, Gotsis ED, Tanner MA, Smith GC, Westwood MA, Wonke B, Galanello R. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood 2006;107(9):3738–44. 21. Chen A-C, Peng C-T, Wu S-F, Wu K-H, Chiang I-P, Tsai C-H. Effect of deferiprone on liver iron overload and fibrosis in hepatitis C virus-infected thalassemia. Hemoglobin 2006;30(2):209–14. 22. Wu S-F, Peng C-T, Wu K-H, Tsai C-H. Liver fibrosis and iron levels during long-term deferiprone treatment of thalassemia major patients. Hemoglobin 2006;30(2):215–8. 23. Peng C-T, Wu K-H, Wu S-F, Liang D-C, Yang C-P, Jang R-C, Wang L-Y, Hsiao CC. Deferiprone or deferoxamine vs. combination therapy in patients with beta-thalassemia major: a case study in Taiwan. Hemoglobin 2006;30(1):125–30. 24. Polo-Romero FJ. Intramuscular deferoxamine in hereditary hemochromatosis. Am J Hematol 2006;81(3):225–6. 25. Nelson SC, Hennessy JM, McDonough EA, Guck KL. Weekend very high-dose intravenous deferoxamine in children with transfusional iron overload. J Pediatr Hematol Oncol 2006;28(3):182–5. 26. Taher A, Bashshur Z, Shamseddeen WA, Abdulnour R-EE, Aoun E, Koussa S, Baz P. Ocular findings among thalassemia patients. Am J Ophthalmol 2006;142(4):704–5. 27. Lai TYY, Lee GKY, Chan W-M, Lam DSC. Rapid development of severe toxic retinopathy associated with continuous intravenous deferoxamine infusion. Br J Ophthalmol 2006;90(2):243–4. 28. Wu V-C, Wang R, Lai T-S, Wu K-D. Deferoxamine-related fatal nasal–orbital– cerebral mucormycosis. Kidney Int 2006; 70(11):1888. 29. Vlachaki E, Perifanis V, Haralambidou S, Tsatra I, Koussi A, Paraskeuopoulos P,

Metal antagonists

30.

31.

32.

33.

34.

35.

36.

37.

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Staurogianni N, Athanasiou M. A case of primary gastric lymphoma in a patient with thalassemia major. Leuk Lymphoma 2006; 47(9):1979–81. Sekiguchi N, Kameda H, Amano K, Takeuchi T. Efficacy and safety of bucillamine, a D-penicillamine analogue, in patients with active rheumatoid arthritis. Mod Rheumatol 2006;16(2):85–91. Medici V, Trevisan CP, D’Inca R, Barollo M, Zancan L, Fagiuoli S, Martines D, Irato P, Sturniolo GC. Diagnosis and management of Wilson’s disease: results of a single center experience. J Clin Gastroenterol 2006;40(10): 936–41. Gong Y, Klingenberg SL, Gluud C. Systematic review and meta-analysis: D-penicillamine vs. placebo/no intervention in patients with primary biliary cirrhosis— Cochrane Hepato-Biliary Group. Aliment Pharmacol Ther 2006;24(11):1535–44. Christensen RD, Alder SC, Richards SC, Horn JT, Lambert DK, Baer VL. A pilot trial testing the feasibility of administering D-penicillamine to extremely low birth weight neonates. J Perinatol 2006;26(2): 120–4. Habib GS, Saliba W, Nashashibi M, Armali Z. Penicillamine and nephrotic syndrome. Eur J Intern Med 2006;17(5):343–8. Whitnall M, Howard J, Ponka P, Richardson DR. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Natl Acad Sci USA 2006; 103(40):14901–6. Brown MJ, Willis T, Omalu B, Leiker R. Deaths resulting from hypocalcemia after administration of edetate disodium: 2003–2005. Pediatrics 2006;118(2):e534–6. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WR, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor Jr LM, White CJ, White J, White RA, Antman EM, Smith Jr SC, Adams CD,

407 Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. American Association for Vascular Surgery/Society for Vascular Surgery; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society of Interventional Radiology; ACC/ AHA Task Force on Practice Guidelines. ACC/AHA guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Associations for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (writing committee to develop guidelines for the management of patients with peripheral arterial disease)—summary of recommendations. J Vasc Interv Radiol 2006;17(9):1397. 38. Yee KW, Cortes J, Ferrajoli A, GarciaManero G, Verstovsek S, Wierda W, Thomas D, Faderl S, King I, O’Brien SM, Jeha S, Andreeff M, Cahill A, Sznol M, Giles FJ. Triapine and cytarabine is an active combination in patients with acute leukemia or myelodysplastic syndrome. Leuk Res 2006;30(7):813–22. 39. Yen Y, Margolin K, Doroshow J, Fishman M, Johnson B, Clairmont C, Sullivan D, Sznol M. A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer. Cancer Chemother Pharmacol 2004;54(4):331–42. 40. Foltz LP, Dalal BI, Wadsworth LD, Broady R, Chi K, Eisenhauer E, Kobayashi K, Kollmannsburger C. Recognition and management of methemoglobinemia and hemolysis in a G6PD-deficient patient on experimental anticancer drug Triapine. Am J Hematol 2006;81(3):210–1.

P. Magee

24 ALDEHYDES

Antiseptic drugs and disinfectants (SED-15, 1439, 1513;

SEDA-23, 247)

Respiratory Aldehydes are ideal agents for cold sterilization of medical instruments, although occupational asthma is a welldocumented risk (SEDA-20, 225). This has led to the search for alternative aldehydes that could be used for decontaminating medical instruments and that might not be respiratory sensitizers. However, when four aldehydes were entered into an Asthma Hazard Assessment Program using a quantitative structure–activity relationship model, all four had a common structural basis for increasing the risk of asthma (1r).

Formaldehyde Tumorigenicity In 2004 the International Agency for Research on Cancer reclassified formaldehyde as a proven human carcinogen based on “sufficient evidence” of nasopharyngeal cancer. It also concluded that there was “strong but not sufficient evidence for a causal association between leukemia and occupational exposure to formaldehyde”. This was primarily based on the observation that a mechanism for

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03124-9 r 2009 Elsevier B.V. All rights reserved.

leukemia induction had not been identified. In a subsequent review of the data to assess the biological plausibility of formaldehyde as a potential human carcinogen there was inadequate evidence to conclude that there is a causal relation between formaldehyde and the risk of leukemia (2R).

Glutaral (glutaraldehyde) Gastrointestinal Glutaral is still widely used as a sterilizing agent, despite recognition of its toxicity and potential dangerous effects when strict precautions are not taken. � During uncomplicated right laparoscopic orch-

idopexy in a 3-year-old boy a few milliliters of 2% glutaral was deposited inadvertently into the peritoneal cavity from insufflation tubing that had been sterilized with glutaral. This resulted in multiple small bowel fistulae, poor bowel healing, fibrosis, and impaired gastrointestinal motility caused by segmental necrosis of the muscularis propria (3A).

Tumorigenicity Although glutaral represents a substantial proportion of the human exposure to aldehydes in medicine and industry, the epidemiology of cancer risk in exposed workers has not been extensively studied. Data on 188 male workers from a glutaral production unit have been evaluated to assess the risk of cancer. The rates of respiratory tract cancer or leukemia related to glutaraldehyde exposure were not increased, although the population was small and there was a low prevalence of smoking (4c).

409

410

BISBIGUANIDES Chlorhexidine (SED-15, 714; SEDA-28, 261; SEDA-29, 241; SEDA-30, 278) Observational studies Chlorhexidine has been used extensively for many decades as a broad-spectrum antiseptic in hospitals and elsewhere. It has also been given as a maternal vaginal lavage, full-body newborn skin cleanser, and for umbilical cord cleansing to prevent infection in neonates. Recent evidence has suggested that these chlorhexidine interventions may have a significant effect on the burden of neonatal infection and mortality in developing countries. Of the 4 million annual neonatal deaths that occur globally, more than 99% occur in developing countries, and about 36% are attributed to infections. The potential of chlorhexidine vaginal cleansing to reduce vertical transmission of HIV has been examined in developing countries; the use of a 1% chlorhexidine concentration has been recommended (SEDA-29, 241). A review of the literature on chlorhexidine interventions (vaginal, newborn skin, and umbilical cord cleansing) focused on neonatal outcomes and safety. In summary, tens of thousands of neonates have received these chlorhexidine-based cleansing interventions without reported adverse effects. However, the data on safety are incomplete. Although the chlorhexidine concentrations used and reported thus far appear to be safe, the upper level of chlorhexidine that can be considered safe is not known and further research is required to inform public health safety in developing countries (5R). Mouth Plaque control is often compromised by poor compliance with oral hygiene. Chlorhexidine mouth wash, although reported to cause brown staining of the teeth, an unpleasant taste, desquamation of the oral mucosa, and rarely pain, is easy to use (SEDA-30, 278). Dental flossing is effective in reducing interproximal gingivitis and preventing caries on proximal tooth surfaces. However, representative surveys have shown that dental flossing is used by only a small part of the population.

Chapter 24

P. Magee

The results of a trial designed to assess if chlorhexidine mouth rinse was a suitable alternative to flossing suggested that daily use of the tested mouth rinses may result in greater interproximal plaque reduction than daily flossing. However adverse effects were reported with chlorhexidine mouthwash, mainly staining of the teeth and tongue. Although from a medical viewpoint these were not considered severe, they may be esthetically unacceptable and can lead to reduced compliance (6c). The use of a chlorhexidine oral spray has been proposed as an alternative to reduce the adverse effects associated with chlorhexidine mouthwashes. The plaque inhibitory effects of chlorhexidine, cetypyridinium chloride, and triclosan delivered by sprays and mouth rinses have been investigated in 15 volunteers (7c). Although the effects on plaque regrowth observed with chlorhexidine rinses was superior to that of chlorhexidine sprays, the latter did not cause adverse effects. Urinary tract Following the report of a case series of systemic allergic reactions to urethral chlorhexidine (SEDA-28, 261) the authors instigated a prospective randomized single-blind study of the effect of chlorhexidine in urethral local anesthetic gel in 141 patients undergoing flexile cystoscopy (8c). They were randomized to either 2% lidocaine gel with 0.05% chlorhexidine gluconate or 2% lidocaine aqueous gel. Pain scores were recorded on a numerical visual analog scale form 0 to 10. The pain scores were not significantly different between the groups at the time of insertion of the scope or immediately after cystoscopy; however, there were significant differences in the mean pain scores between groups during the first void (1.8 versus 1.0) and after the first void (2.4 versus 1.2). There was also a significant increase in the levels of urgency after cystoscopy with chlorhexidine. There was no difference in the level of culture-proven symptomatic infection. Thus, chlorhexidine appears to contribute to significant pain and urgency after outpatient flexible cystoscopy and its presence in urethral local anesthetic preparations should be questioned.

Antiseptic drugs and disinfectants

Chapter 24

Immunologic Intraoperative anaphylaxis to the chlorhexidine polymer polyhexanide (9A), used as a wound cleanser, suggests that although chlorhexidine allergy is considered rare (SEDA-15, 714; SEDA 27, 239; SEDA28, 261; SEDA-30, 278), it is well documented in surgical patients and is an important cause of intraoperative anaphylaxis.

IODOPHORS (SEDA-15, 1896; SEDA28, 262; SEDA-29, 242; SEDA-30, 279)

Polyvinylpyrrolidone Observational studies Chemical pleurodesis is well accepted for patients with recurrent pleural effusions and pneumothorax. Until recently, talc was the most widely used agent, but there are now serious concerns about its safety, which has led to the search for alternative agents. Iodopovidone is a topical antiseptic that has been shown to be safe and effective in many studies. In a meta-analysis of observational studies of iodopovidone for chemical pleurodesis, the only significant complication was chest pain of varying degree (10M). Systemic hypotension was reported in three patients in only one study. There were no deaths related to chemical pleurodesis. Overall, the review supported the safety and efficacy of iodopovidone as an agent for chemical pleurodesis. Endocrine Transient hypothyroidism has previously been documented in neonates from the use of iodinated skin products (SEDA-25. 277; SEDA-28, 263; SEDA-30, 279). A further report of hypothyroidism in a neonate in whom povidone iodine was used as an operative and postoperative skin disinfectant has drawn attention to the risk of transient hypothyroidism in neonates through the Wolff–Chaikoff effect, the prevention of iodine organification by iodinecontaining drugs or solutions. It has been suggested that in three neonates with endstage renal insufficiency hypothyroidism

411 developed as a consequence of the Wolff– Chaikoff effect (11A). Iodine is normally cleared from the circulation by the kidneys. Neonates or infants with renal insufficiency are therefore less likely to clear any iodine to which they are exposed and are potentially at increased risk of hypothyroidism. In all three cases the infants received renal replacement therapy using peritoneal dialysis. Iodine concentrations were higher in the peritoneal dialysis fluid than in the plasma, and it was suggested that the source of iodine had been the povidone iodine in the cap used at the end of the peritoneal dialysis catheter, which helps reduce the incidence of local infection and peritonitis (12A). Skin Chemical burns are a rare but potentially serious complication of povidone iodine used as a topical antiseptic (13A). � A 38-year-old woman underwent laparoscopic

right ovarian cystoscopy and endometrial ablation. The antiseptic skin preparation used was 1% povidone-iodine solution. She had no allergies and was not taking any drugs. The morning after the procedure she developed burning, itching, pain, and marked redness on her back and buttocks. On the next day blisters developed. There was superficial skin loss on both sides of her back, some medial tenderness, but no evidence of cellulitis. The partial thickness chemical burns were treated with polymyxin B sulfate+bacitracin zinc ointment, and at 1 week the affected area was healed, with no permanent sequelae. There was some superficial skin loss, but no loss of pigmentation.

ORGANIC MERCURY COMPOUNDS (SED-15, 2259; SEDA-26, 259; SEDA-27, 241)

Thiomersal Thiomersal (ethylmercury thiosalicylic acid) is used to prime immunoadsorption columns between applications, as these columns are reusable for about 20 treatment sessions. Mercury and ethylmercury blood concentrations have been found to exceed the reference range in patients after

412 immunoadsorption treatments, although there were no clinical signs of mercury toxicity. However accidental mercury overdose by thiomersal during protein A immunoadsorption treatment prompted the

Chapter 24

P. Magee

authors to replace thiomersal as a column preservative with a mercury-free disinfectant. Although the patient did not show any signs of mercury toxicity, the potential for ethylmercury poisoning remained (14A).

References 1. Seed MJ, Hussey LJ, Lines SK, Turner S, Agius RM. Prediction of asthma hazard of glutaraldehyde substitutes. Occup Med (Lond) 2006;56:284–5. 2. Golden R, Pyatt D, Shields PG. Formaldehyde as a potential human leukemogen: An assessment of biological plausibility. Clin Rev Toxicol 2006;36:135–53. 3. Karpelowsky JS, Maske CP, Sinclair-Smith C, Rode H. Glutaraldehyde-induced bowel injury after laparoscopy. J Pediatr Surg 2006;41:E23–5. 4. Collins JJ, Burns C, Spencer P, Bodnar CM, Calhoun T. Respiratory cancer risks among workers with glutaraldehyde exposure. J Occup Environ Med 2006;48:199–203. 5. Mullany LC, Darmstadt GL, Tielsch JM. Safety and impact of chlorhexidine antisepsis interventions for improving neonatal health in developing countries. Ped Infect Dis J 2006;25:665–79. 6. Zimmer S, Kolbe C, Kaiser G, Krage T, Ommerborn M, Barthel C. Clinical efficacy of flossing versus use of antimicrobial rinses. J Periodontol 2006;77:1380–5. 7. Pizzo G, Guiglia R, Imburgia M, Pizzo I, D’Angelo M, Giuliana G. The effects of antimicrobial sprays and mouthrinses on supragingival plaque regrowth: A comparative study. J Periodontol 2006;77:248–56.

8. Jayathillake A, Mason DFC, Broome K, Tan G. Chlorhexidine in urethral gel: Does it cause pain at flexible cystoscopy? Urology 2006;67:670–3. 9. Ferrarini A, Baggi M, Fluckiger R, Bianchetti MG. Intraoperative anaphylaxis to a chlorhexidine polymer in childhood. Pediatr Anaesth 2006;16:705. 10. Agarwal R, Aggarwal AN, Gupta D, Jindal SK. Efficacy and safety of iodopovidone in chemical pleurodesis: A meta-analysis of observational studies. Respir Med 2006;100: 2043–7. 11. Aliefendiog�lu D, Sanli C, Cakmak M, Ag�ar A, Albayrak M, Evliyaog�lu O. Wolff– Chaikoff effect in a newborn: Is it an overlooked problem? J Pediatr Surg 2006; 41:e1–3. 12. Brough R, Jones C. Iatrogenic iodine as a cause of hypothyroidism in infants with end stage renal failure. Pediatr Nephrol 2006;21: 400–2. 13. Lowe DO, Knowles SR, Weber EA, Railton CJ, Shear NH. Povidone-iodine-induced burn: Case report and review of the literature. Pharmacotherapy 2006;26: 1641–5. 14. Koch M, Trapp R. Ethyl mercury poisoning during protein A immunoadsorption therapy. Am J Kidnhey Dis 2006;47:e31–4.

Tore Midtvedt

25

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

Resistance to antibacterial drugs Ever since penicillin was introduced into clinical practice in the early 1940s, bacterial resistance has increased and has been addressed almost yearly in this chapter of SEDA, as “the most serious adverse effect of this type of drug” (SEDA-29, 244). In the first four to five decades after the introduction of penicillin, pharmaceutical companies tried to meet the challenge by steadily introducing new classes of antibacterial drugs, or at least by improving the drugs already on the market. However, in the last one to two decades the flood of new antimicrobial drugs has abated, and very few, if any, are currently entering the market. At the same time there has been an increase in the number of officially supported programs for following the development of bacterial resistance and the establishment of programs for more proper use of these drugs in human and veterinary medicine (SEDA30, 280). However, the sad fact is that despite all efforts antibiotic resistance is as widespread as ever. In order to cope with such an obstacle, we have to understand why it has come about. Among the many answers to this simple question, I shall point out just one. Over the years, teachers of microbiology and

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03125-0 r 2009 Published by Elsevier B.V.

infectious diseases have told their students that if you stop using a drug for a certain period of time, resistance will cease and the virgin situation—that is, bacterial sensitivity to the banned drug—will return. This comforting theory was based on the fact that it costs bacteria some effort to become resistant and to retain resistance; consequently, resistant bacteria will lose when competing with sensitive ones if the pressure for selection, that is, exposure to the drug in question, disappears. However, Mother Nature is full of surprises. The development of vancomycinresistant enterococci in chicken farms showed that these resistant bacteria were present even more than a decade after farmers had stopped using glycopeptide antibiotics (SEDA-29, 245). The mechanisms behind this persistence are still not clearly understood. Now there seems to be some light in the tunnel. In a recent impressive article the authors first summarized current knowledge and theories about horizontal gene transfer, that is, the basic mechanisms by which bacteria obtain genes from the entire prokaryotic, archeal, and even eukaryotic DNA “sequence space” (1HE). Bacterial recombination, which includes acquisition and incorporation of DNA by horizontal gene transfer from other organisms, enables bacteria to sample and obtain genes from the entire prokaryotic, archeal, and even eukaryotic DNA “sequence space,” through which they can acquire beneficial genes. Three mechanisms of horizontal gene transfer have been proposed—conjugation, transduction, and transformation. However, the

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414 authors pointed out that the ability to acquire such genes need not have been the main selective force in bacterial evolution and maintenance of the machinery required for that capacity. They proposed a hypothesis, “episodic selection,” based in part on the observation that in Bacillus subtilis, in which transformation is widespread, competence is associated with periods of nongrowth in otherwise growing populations. Central to their hypothesis is a theoretical prediction: when populations of bacteria periodically encounter agents that kill replicating bacteria at a higher rate than non-growing bacteria, the persistent subpopulation would have a selective advantage over faster growing populations without this ability. The short-term fitness cost associated with this phenomenon can be compensated for, and the capacity to produce these competent cells is favored when the population encounters conditions that kill dividing bacteria. They speculated that episodic selection for transiently nongrowing bacteria can maintain competence for the uptake and expression of exogenous DNA transformation. With the aid of a mathematical model and computer simulation of the population dynamics of competence performance, transformation, and antibiotic-mediated selection, they showed that within populations, episodic trauma affecting growing cells will favor bacteria that can generate subpopulations of competent, non-growing cells. Under experimental conditions, they validated their theory in B. subtilis. They also critically reviewed other hypotheses for the maintenance of resistant bacteria, stating that “we cannot reject any of these hypotheses or the possibility that competence and transformation are maintained by more than one mechanisms. Nature, unlike those of us who study this, has no need to favor a single hypothesis.” The bottom line is that once bacterial resistance is established Nature may have several mechanisms by which it may be maintained. We should stop dreaming of getting rid of resistance—it is here to stay. As usual, prevention is better than cure.

Chapter 25

Tore Midtvedt

BETA-LACTAM ANTIBIOTICS (SED-15, 478; SEDA28, 267; SEDA-29, 267; SEDA-30, 280)

Skin Baboon syndrome and beta-lactam antibiotics Historically the condition called “baboon syndrome” was described as a special entity of a mild cutaneous erythema after exposure to so-called type IV allergens, such as nickel, mercury, immunoglobulins, and several drugs, such as aminophylline, heparin, terbinafine, and some antibacterial drugs. It is located on the buttocks and anogenital area, reminiscent of the red buttocks of baboons. It has recently been proposed that this term be replaced by the acronym symmetrical drug-related intertriginous and flexural exanthem (SDRIFE). The condition has been described in a child who received cefadroxil (2A) and in another who received amoxicillin (3A). Immunologic Beta-lactams and druginduced immune hemolytic anemia Drug-induced hemolytic anemia, which is uncommon, is characterized by a sudden fall in hemoglobin concentration. The full range of causative drugs has not been fully evaluated, but beta-lactams are often involved. This view has been verified in a 20-year retrospective analysis of 73 patients with drug-dependent antibodies to 23 different drugs from an immune hematological reference laboratory in the USA (4R). Cephalosporins were at the top of the list (n ¼ 37), followed by penicillins and/or penicillin derivatives (n ¼ 12), non­ steroidal anti-inflammatory drugs (n ¼ 11), and others (n ¼ 13).

(SED-15, 638; SEDA-29, 246; SEDA-30, 246)

CARBAPENEMS

In the era of multidrug resistance, espe­ cially among Gram-negative bacteria, and a lack of new classes of antimicrobial agents,

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

keen interest needs to be taken in already existing groups in developing new deriva­ tives and taking a closer look at previous developed, not yet fully investigated deri­ vatives. Carbapenems are typical examples of this approach. The first carbapenem, imipenem, used in combination with cilas­ tin, came on to the market about three decades ago. Now five more compounds, meropenem, ertapenem, panipenem, biape­ nem, and doripenem, are also on the market, at least in some countries. Taken together, they are among the most potent types of antibacterial agents and are among those used as last resort against serious infections, especially those caused by Gram-negative bacteria.

Doripenem Nervous system The first carbapenems were, although to a varying degree, associated with different types of seizures. When it was first marketed, ertapenem was claimed to have less seizure-causing activity, but seizures can occur, even after a few doses (SEDA-29, 246). It would be wise to assume that all carbapenems can cause seizures. The potential convulsive activity of doripenem was tested in an extensive study in dogs, rats, and mice (5E). Four carbapenems, imipenem, meropenem, panipenem, and doripenem, were investigated. In dogs, intraventricular injection of imipenem, panipenem, and meropenem caused seizures. On the other hand, doripenem had no effect on electroencephalogram and behavior, even at doses of 1 g/dog. A similar discrepancy between doripenem and the other carbapenems investigated was found in mice and rats. In in vitro studies, imipenem, meropenem, panipenem, and cefazolin inhibited the binding of muscimol to GABA receptors in mouse brain homogenates, while doripenem did not cause any inhibition at up to 10 mmol/l. In addition, doripenem had no influence on the anticonvulsive action of valproic acid in the pentylene tetrazole or bicuculine-induced convulsive models. The authors claimed that their results “clearly indicate that

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doripenem has no convulsive activity, suggesting that its neurotoxicity may be negligible in clinical use.” However, seizures can occur rarely in patients taking doripenem (6R,7R) and the manufacturer’s package insert http://www. doribax.com/doribax/interactive_pi.htggml states that seizures have been reported during post-approval use of doripenem outside the USA, although it is stressed that “causality has not been established.”

Tebipenem pivoxil Tebipenem pivoxil is a novel oral carbape­ nem. It is claimed to have remarkable chemical stability, good systemic availabil­ ity in humans, and effects against both Gram-positive and Gram-negative organ­ isms (8R). However, the pivoxil part of the molecule might give rise to predictable adverse effects. Nutrition Pivoxil and carnitine depletion Depletion of carnitine after the use of pivmecillinam, a beta-lactam antibiotic that contains the organic acid pivoxil, was first described two decades ago (9A). Since then, similar depletion has been associated with all beta-lactams associated with pivoxil. Pivoxil also interferes with the pharmacokinetics of valproic acid, causing serious adverse effects (10A). Drug–drug interactions Valproic acid Interactions of carbapenems with valproic acid are so common that the Ministry of Health and Welfare in Japan has banned co-administration (SEDA-30, 283). Several mechanisms have been discussed, and it has been suggested that carbapenems inhibit valproic acid hydrolysis in the liver (11C). It currently seems safest to assume that tebipenem has a similar effect and that consequently it should be avoided to patients who are also taking valproic acid. The additional effect of the pivoxil part of the molecule on carnitine metabolism should also be taken into consideration. If tebipenem and valproic acid are

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416 co-administered, adverse effects can be expected.

(SED-15, 688; SEDA-28, 268; SEDA-29, 246; SEDA-30, 284)

CEPHALOSPORINS

Skin Fixed drug eruptions are unusual and are characterized by recurrent site-specific lesions each time the drug thought to be responsible is given. A ceftriaxone­ associated fixed drug eruption has been reported (12A). Topical provocation with ceftriaxone, both at previously affected sites and in unaffected skin, was negative, whereas re-exposure to ceftriaxone 1 g intravenously confirmed the diagnosis. The patient tolerated cefazolin and amoxicillin, suggesting that the sensitizing portion was not the beta-lactam ring. Immunologic Hypersensitivity reactions to cephalosporins (SEDA-30, 284) have been reported in 148 children who had such reactions, mainly to cefaclor and ceftriax­ one; 105 had non-immediate effects (occur­ ring after 1 hour—mostly urticarial eruptions and maculopapular rashes) and 43 had immediate effects (occurring within 1 hour—anaphylactic shock, urticaria, and/or angioedema, and erythema) (13C). None of the non-immediate reactors had positive results in patch tests and/or delayed skin tests and only one had positive responses to penicillin skin-tests reagents. Of 104 children with negative results, 95 underwent chal­ lenges, which 94 tolerated. The others reacted to cefaclor pediatric suspension, but tolerated a challenge with a cefaclor capsule. In the 43 children with immediate reactions, there was IgE-mediated hypersensitivity in 34 (79%). The authors concluded that “extremely few non-immediate manifesta­ tions with cephalosporin therapy are actually hypersensitivity reactions, whereas most immediate reactions to cephalosporins are IgE-mediated.” Drug reactions with eosinophilia and systemic symptoms (DRESS) can occur

Tore Midtvedt

3–6 weeks after drug administration. Although the clinical and biological mani­ festations of DRESS are characteristic, the diagnosis can be missed because of the time gap between drug consumption and the onset of symptoms and signs. Although the syndrome is rare, many drugs have been implicated, often in connection with a viral infection (14R). Three reports have also implicated cefixime (15A), cefa­ droxil (16A), and ceftriaxone (17A).

Cefdinir Gastrointestinal Cefdinir has been reported to cause red stools in a child (18A).  A 7-month-old girl, with a history of apnea of

prematurity, developed red-colored stools after taking oral cefdinir 100 mg/day for 6 days for recurrent otitis media. The stools were guaiacum negative on two separate tests. Cefdinir was withdrawn and she had had no further episodes of red stools.

The incidence of red stools in children taking cefdinir is not known, although estimates vary from 1% (19R) to 10% (20R). The few reports have so far been limited to children. However, the possibility that it also may occur in adults can by no means be excluded. The mechanism is not known, but it seems to occur most often in children who are also taking iron supple­ ments. Despite the mild nature of this effect, it can create distress and confusion among both parents and physicians.

Cefepime Nervous system Cefepime often causes neurotoxicity and neuropsychiatric adverse effects (SEDA-30, 283), and new reports continue to appear, especially in patients with impaired kidney function (21A–25A). It might be wise to follow a recommendation given in a recent review: “Since reports of neurotoxic effects and of an increased mortality have created some concerns regarding its safety y. caution in the use of cefepime should be adopted until new evidence on [its] safety is available” (26R).

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

Ceftriaxone Drug–drug interactions Calcium salts Biliary sludge and nephrolithiasis are wellknown adverse effects of ceftriaxone (SEDA-30, 285). Animal and in vitro studies of the physiochemical basis for this have suggested that when the solubility product of the ceftriaxone–calcium salt is exceeded, precipitation can occur. In France four deaths occurred in neonates who received ceftriaxone and calcium simultaneously through the same intravenous line (27S). Precipitates were observed in the intravenous line or pulmonary or renal tissue. The mechanism of death was assumed to be that calcium/ ceftriaxone insoluble particles had occluded small arteries and capillaries, in both the lungs and kidneys. In a fatal case in a neonate, ceftriaxone was given at different times and sites. The FDA in the USA subsequently identified four additional cases (three fatal), and crystals were found in the lungs of one patient. The manufacturer and the FDA have now recommended that ceftriaxone should not be given to neonates under 4 weeks of age. In addition, solutions containing cef­ triaxone and calcium should not be co­ administered within 48 hours of each other (based on the half-life of ceftriaxone), regardless of patient age (28R). However, the last statement has given rise to some debate (29r,30r). Ceftriaxone has been on the market for more than 20 years, and it has been suggested that one need not be concerned about adults. As the calcium/ceftriaxone interaction is a physi­ cochemical interaction, occurring in vitro as well as in vivo, it seems reasonable to assume that microcrystals might be found in adults. Neonates, given the anatomical structure of their pulmonary and renal vasculatures, might be most vulnerable to this problem. However, especially in elderly people, who have reduced vascular capa­ city, it might be wise to take a safe approach and not to administer calcium salts within 48 hours after the last dose of ceftriaxone. A panel of experts has provided a summary; ceftriaxone should be avoided or signifi­ cantly minimized in neonates (especially

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those treated concomitantly with intrave­ nous calcium solutions and those with hyperbilirubinemia) and potentially restricted in the geriatric population who are being treated concomitantly with intra­ venous calcium (31R).

Cefprozil Liver A rare case of hepatitis has been attributed to cefprozil (32A).

(SED-15, 2378; SEDA-29, 247; SEDA-30, 286)

MONOBACTAMS Aztreonam

Immunologic Allergic reactions to beta­ lactams are the most frequent immunologic drug reactions. Questions about crossreactivity have been discussed in SEDA (SEDA-29, 245; SEDA-30, 281). However, although it has been claimed that there is little cross-reactivity between aztreonam and other beta-lactams, clinical evidence for this statement has been scanty. In a study from Italy all patients over 14 years of age, with a clinical history of immediate reactions to any beta-lactam, and with positive immediate-type skin tests and/or positive specific IgE antibodies to any beta­ lactam were studied for their ability to tolerate aztreonam (33C). There were 45 patients (27 women and 18 men) with positive skin tests and/or IgE who underwent a skin test with aztreonam. All had negative skin tests and all were asymptomatic after an intramuscular challenge with aztreonam. The authors claimed that their data confirm the general opinion of poor cross-reactivity between beta-lactams and aztreonam. Immediatetype skin tests with aztreonam might represent a simple and rapid diagnostic tool for establishing tolerability in beta­ lactam allergic patients who urgently need this type of drugs.

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PENICILLINS

(SED-15, 2756; SEDA-

30, 286)

Nervous system Acute seizures are wellknown adverse effects of many beta-lactam antibiotics. However, tardive seizures in psychiatric patients undergoing electrocon­ vulsive therapy and receiving a beta-lactam have rarely been reported. Now two cases from the same hospital have been reported (34R).  A 62-year-old man undergoing ECT devel­

oped pneumonia and was given piperacillin 2 g/day+tazobactam. After 5 days, and after his third ECT session, he had generalized tonic– clonic convulsions. Electroencephalography showed no focal abnormalities and other examinations, including MRI scans, laboratory tests, and cerebrospinal fluid examination, were all negative. Piperacillin was withdrawn. He had recurrent seizures during the next 2 days and gradually improved over the next weeks.  A 24-year-old man undergoing ECT devel­ oped a urinary tract infection and was given cefotiam 2 g/day intravenously for 5 days. One day later and after his third ECT session, he had recurrent attacks of generalized tonic– clonic seizure. Electroencephalography showed no focal seizure activity and MRI and labora­ tory findings were normal. ECT was stopped and he gradually improved. Four weeks later he had ECT again without subsequent seizures.

Reviewing the literature, the authors found a case of seizures in a patient receiving ECT who was given ciprofloxacin (35A). The epileptogenic effect of ciprofloxacin is thought to be mediated through suppression of the inhibitory function of GABA, as is that of some beta-lactams. In mice piper­ acillin and cefotiam inhibit GABA receptor function, inducing convulsions (36E). Interference with diagnostic tests Aspergillus and penicillins It is clinically well established that the presence of Aspergillus galactomanan antigen is useful in the early detection of invasive aspergillosis, but it is also well recognized that this test can yield false-positive results. This has been reported in patients taking piperacillin +tazobactam and co-amoxiclav (SEDA-29, 248). An increasing number of reports continue to appear (37A–39A, 40CA).

Tore Midtvedt

In a multicenter prospective Spanish 4-year study 85 patients who had received liver transplants had 414 samples tested for the presence of galactomanan antigens using a commercially available test (41C). The mean number of samples per patient (among those who could be assessed) was 4.8. There were 40 false-positive results (9.6%), corresponding to 28 patients. The frequency of false-positive results in sam­ ples obtained during the first week after transplantation was 36% (27 of 75), falling to zero in the fourth week. Multivariate analysis showed that prophylaxis with ampicillin was the only independent factor associated with a false-positive result. The authors investigated three vials of three different beta-lactams, and obtained a positive galactomanan test in four of six different vials, in three of six vials contain­ ing piperacillin+tazobactam, and in none of six vials containing cefotaxime. They under­ lined the fact that ampicillin is routinely used prophylactically for 2–5 days after transplantation, whereas piperacillin+tazo­ bactam is rarely used. They also mentioned that the epitope detected in their test is not exclusively present in Aspergillus species, but can also be found in Penicillium species. Obviously, some producers have still a way to go until their products are good enough.

Amoxicillin Teeth Effects on the mineralization of teeth in children are usually associated with tetracyclines. The possibility that other antibiotics may also be involved has been investigated (42CE). The authors nvestigated molar incisor hypomineralization in 141 schoolchildren and recorded the use of antibiotics before 4 years of age. There was molar incisor hypomineralization in 16%, most commonly in those who had taken amoxicillin during their first year of life (OR ¼ 2.06; 95% CI ¼ 1.01, 4.17) com­ pared with children who had not used antibiotics. In mouse E18 cells exposed to amoxicillin there was an altered pattern of mineralization.

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

Co-amoxiclav and clavulanic acid Immunologic Allergic reactions to amoxicillin+clavulanic acid (co-amoxiclav) are usually assumed to be caused by the amoxicillin, although there have been reports of allergic reactions to clavulanic acid (SEDA-30, 287). Allergy to clavulanic acid has been reported in 10 children aged 4–12 years (43A). The diagnosis was based on the confirmation of an IgE-mediated etiology by a positive oral challenge test with clavulanic acid and negative tests, including skin tests with amoxicillin, ampicillin, penicillins G and V, and cefaclor. Allergic contact dermatitis has also been attributed to clavulanic acid (44A).

Nafcillin Urinary tract There have been reports of renal dysfunction in patients taking nafcillin (45R). During 1 year four patients developed acute kidney damage, which the authors attributed to nafcillin-induced interstitial nephritis (46A). Similar damage was also described in a patient receiving flucloxacillin (47A). In such cases withdrawal of the antibiotic is a must. Referral should be made to a nephrologist, as renal biopsy and corticosteroids may be necessary. Drug–drug interactions Warfarin Over the years, interactions between warfarin and penicillins have been infrequently reported. Most of them have been related to use of nafcillin, followed by dicloxacillin. In one case a patient first took nafcillin then dicloxacillin (48A).  A 39-year-old man, with a history of deep vein

thrombosis and septic arthritis was stabilized on warfarin (32 g/week) and cefazolin (49AR). When nafcillin 2 g six times a day was given instead of cefazolin, his INR started to fall and his warfarin dosage had to be increased to a maximum of 88 g/week to achieve the target INR. After nafcillin was withdrawn his warfarin requirements slowly fell over several weeks to a maintenance dose of 42–48 mg/week.

The authors thought that enzyme induction by nafcillin was the most likely explanation

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for this interaction. They described the clinical course as follows: the usual onset is within 1 week after starting nafcillin and the offset is usually evident 4 weeks after withdrawal.

TETRACYCLINES AND GLYCYLCYCLINES (SED-15, 3330; SEDA-28, 270; SEDA-29, 248; SEDA-30, 288)

Tetracyclines, chemicallymodified tetracyclines, and their non-antimicrobial properties Reports of the use of the non-antimicrobial properties of these drugs continue to appear. Up to now, minocycline has been the agent most often tested. Because of its assumed neuroprotective, anti-apoptotic, and antiinflammatory properties, it was forecast several years ago that it could be of value in the therapy of several neurological diseases, including amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, Parkinson’s disease, and spinal cord injury (50R). Several trials have been performed, but few have fulfilled the promises or provided hard facts on which to rely. Minocycline and schizophrenia Minocycline inhibits inducible nitric oxide synthase (iNOS) and delays disease onset in mouse models of neuropsychiatric disorders. This was the background for a recent Japanese study, in which minocycline 150 mg/day was given for 4 weeks as an open adjunct to antipsychotic medication to 22 patients with schizophrenia (51C). Using a “Positive and Negative Syndrome Scale” for schizophrenia, there was a statistically significant clinical improvement, which was maintained at follow-up 4 weeks after the end of minocycline treatment. There were no adverse events. The authors claimed enthusiastically that “augmentation with minocycline may prove to be a valuable

Chapter 25

420 strategy for boosting antipsychotic efficacy and for treating schizophrenia.” There are several possible mechanisms for these effects. More than a quarter of a century ago it was shown that even one single dose of doxycycline significantly reduced memory capacity in healthy volunteers (52A). Since then, millions of teenagers have used various tetracyclines, including doxycycline and minocycline, for long-term treatment of acne, at the time of life when memory capacity and creativity are assumed to be needed. Additionally, some millions of individuals take such drugs for long-term prophylaxis and treatment of periodontitis. In both cases the therapeutic effects are most probably due to their effects on matrix metalloproteases (MMPs). Minocycline and the treatment of rabies New therapeutic agents are needed for the treatment of rabies encephalitis in humans. This was the background for experimental studies with minocycline, whose results were expressed declaratively in the title: “Therapy with minocycline aggravates experimental rabies in mice” (53E). There was no beneficial effect of minocycline in primary neuron cultures and in the mouse model, minocycline aggravated the clinical neurological disease and resulted in a higher mortality (54E). The authors ended by stating that “this team recommends that empirical therapy with minocycline be avoided in the management of rabies and viral encephalitis in humans until more information becomes available.” Minocycline and experimental autoimmune encephalitis Experimental autoimmune encephalitis is an antigen-specific T cellmediated autoimmune disease of the central nervous system, which has long served as an animal model for studying multiple sclerosis. Minocycline in high doses attenuated the development of experimental autoimmune encephalitis (55E), supposedly through an effect on MMPs 9 (56). However, clinical trials with minocycline in patients with multiple sclerosis have shown variable results. In a study in mice polyethyleneglycol minocycline liposomes given every 5 days were reportedly as effective in

Tore Midtvedt

ameliorating experimental autoimmune encephalitis as daily intraperitoneal injections of minocycline (57E). Whether it will have the same effect in human multiple sclerosis remains to be seen.

Doxycycline (SEDA-27, 247; SEDA-29, 270; SEDA-30, 289) Placebo-controlled studies Doxycycline is currently used in the treatment of filariasis to deplete Wolbachia endosymbionts, which leads to inhibition of worm development, embryogenesis, fertility, and viability in onchocerciasis. In a double-blind, placebocontrolled trial of doxycycline 200 mg/day for 3 weeks, followed by standard antifilarial treatment (albendazole 400 mg + ivermectin 150 mg/kg) at month 4 in 44 individuals from the western region of Ghana with Wuchereria bancrofti infections adverse reactions to standard antifilarial treatment were similar in frequency between doxycycline and placebo (58C). Moderate adverse reactions (increased body temperature and/or chills, papular rash, itching, and headache) occurred only with placebo followed by standard antifilarial treatment and were recorded in 3 of 17 patients. The severity of the adverse reactions was associated with microfilaremia, Wolbachia bacteria in the plasma, and proinflammatory cytokines in the plasma, in line with previous observations that suggest that adverse events after antifilarial treatment are related to the release of parasite-related antigens into the circulation. Skin Sweet’s syndrome has been attribu­ ted to doxycycline (59A).

Minocycline Immunologic DRESS has most commonly been associated with anticonvulsive drugs,

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

but has been reported with other drugs, including minocycline (60A–62A).  A 15-year-old woman developed a fever and a

diffuse erythematous skin eruption after tak­ ing minocycline 100 mg/day for 4 weeks for acne vulgaris. Minocycline was withdrawn and she was given oral antihistamines for 1 week followed by 4 days of prednisone in escalating doses from 10 mg/day to 40 mg bd. Despite treatment, she developed progressive erythro­ derma associated with pruritus, facial swelling, pharyngitis, and diffuse lymphadenopathy. Her white blood cell count was raised domi­ nated by eosinophils (14%). Her serum transaminase activities rose. Viral studies were all negative, thyroid function tests were normal, and antithyroid antibodies were nega­ tive. She was treated with corticosteroids, and her cutaneous symptoms, hepatitis, eosinophi­ lia, and leukocytosis gradually improved. She was subsequently found to have autoimmune thyroiditis (Graves’ disease) and type 1 diabetes.

According to the authors, this is the first reported case of type 1 diabetes following minocycline-induced DRESS. At the time when diabetes was diagnosed, she had raised antinuclear (ANA), anti-Smith, and anti-Sjögren syndrome-A (SS-A/ro) anti­ body titers. Screening for other organspecific autoantibodies, including those associated with pernicious anemia, celiac disease, and Addison disease, was negative. The mechanisms underlying these auto­ immune manifestations after minocycline therapy are not well understood. Hypoth­ eses include reduced production of free radicals (63E), inhibition of phospholipase A2 (64E), and altered expressing of tumor necrosis factor and interferon-gamma (65E). It seems wise to avoid using minocycline as much as possible, advice that seems to have to be repeated over and over again (66c).

Tetracycline Urinary tract Tetracyclines should be used with caution in patients who have pre-existing kidney disease, since they can precipitate acute renal insufficiency, another case of which has been reported (67A).  A 42-year-old woman with polycystic kidney

disease took tetracycline 250 mg qds after

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undergoing tooth extraction. She developed nausea, vomiting, and diarrhea within days and end-stage renal disease within 2 weeks. Hemodialysis was required.

Tigecycline Drug–drug interactions Ciclosporin Tigecycline does not undergo extensive metabolism. It works independently of the cytochrome P-450 enzyme system and therefore does not affect medications metabolized by these enzymes. Biliary and fecal excretion account for 59% of the administered dose, 32% is excreted renally, and 22% is excreted unchanged in the urine (68R). However, interactions between tigecycline and other drugs that are handled by the liver have been reported (69A).  A 61-year-old woman with a urinary tract

infection 5 years after renal transplantation was given meropenem and then tigecycline 100 mg/day intravenously. She was also taking oral ciclosporin 120 mg/day. On the third day of tigecycline therapy, the whole-blood trough concentration of ciclosporin was about 600 ng/ ml, about double the concentration found before tigecycline was given. Her serum creatinine concentration rose from around 100 ìmol/l to a peak around 170 mmol/l. Ciclos­ porin was omitted for 1 day and the dosage was reduced by 50%. During the entire period of tigecycline therapy no other potentially interacting drugs were administered.

The authors suggested that ciclosporin con­ centrations should be monitored during treatment with tigecycline. It was subse­ quently suggested that both drugs might depend on the P glycoprotein efflux trans­ porter system in the small intestine (70c). This led to the conclusion that intravenous tigecycline could alter the pharmacokinetics of many other drugs. Even though this has not been shown to be so, it would be wise not to give tigecycline to patients who are taking other drugs that might be handled by P glycoprotein. When monitoring ciclosporin in such cases intralymphocytic concentra­ tions, if available, might be helpful, since lymphocytes express P glycoprotein (71c).

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Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines 23. Parotte MC, Krzesinski JM. Le cas clinique du mois. Antibiotiques et patient dialyse: trois cas de toxicite neurologique du cefe­ pime [Clinical case of the month. Antibio­ tics and hemodialysis: three cases of neurotoxicity from cefepime]. Rev Med Liège 2008;63(3):119–21. 24. Bresson J, Paugam-Burtz C, Josserand J, Bardin C, Mantz J, Pease S. Cefepime overdosage with neurotoxicity recovered by high-volume haemofiltration. J Antimicrob Chemother 2008;62:849–50. 25. De Silva DA, Pan ABS, Lim SH. Cefepimeinduced encephalopathy with triphasic waves in three Asian patients. Ann Acad Med 2007;6:450–1. 26. Drago L, De Vecchi E. The safety of cefipime in the treatment of infections. Expert Opin Drug Saf 2007;7:377–87. 27. Agence franc- aise de sécurité sanitaire des produit de santé (2006). Ceftriaxone et incompatibilités physico-chimiques, particu­ lièrement avec les solutions contenant des sels de calcium. Modifications des Résumés des Caractéristiques du Produit, http://www.afssaps.fr/Infos-de-securite/Lettres­ aux-professionnels-de-sante/Ceftriaxone-et­ incompatibilites-physico-chimiques-particulierement-avec-les-solutions-contenant-des­ sels-de-calcium-Modifications-des-Resumes­ des-Caracteristiques-du-Produit/(language)/ fre-FR, 30 November. 28. US Food and Drug Administration. Cef­ triaxone (marketed as Rocephin) Informa­ tion. http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/ucm109103.htm. 2007. 29. Rapp RP, Kuhn R. Clinical pharmaceutics and calcium ceftriaxone. Ann Pharmac­ other 2007;41(12):2072. 30. Gin AS, Wheaton H, Dalton B. Comment. Clinical pharmaceutics and calcium ceftriaxone. Ann Pharmacother 2007;42(3):450–1. 31. Monte SV, Prescott WA, Johnson KK, Kuhman L, Paladino JA. Safety of cefriaxone at extremes of age. Expert Opin Drug Saf 2008;7(5):515–23. 32. Bilici A, Karaduman M, Cankir Z. A rare case of hepatitis associated with cefprozil therapy. Scan J Infect Dis 2007;39:190–2. 33. Patriarca G, Schiavino D, Lombardo C, Altomonte G, De Cinti M, Buonomo A, Nucera E. Tolerability of aztreonam in

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patients with IgE-mediated hypersensitivity to beta-lactams. Int J Immunopathol Phar­ macol 2008;21(2):375–9. Saito T, Nakamura M, Watari M, Isse K. Tardive seizure and antibiotics: case reports and review of the literature. J ECT 2008;24 (4):275–6. Kisa C, Yildirim SG, Aydemir C, Cebeci S, Goka E. Prolonged electroconvulsive ther­ apy seizure in a patient taking ciprofloxacin. J ECT 2005;21(1):43–4. Sugimoto M, Uchida I, Mashimoto T, Yamazaki S, Hatano K, Ikeda P, Mochizuki Y, Terai T, Matsuoka N. Evidence for the involvement of GABA(A) receptor blockade in convulsion induced by cephalos­ porin. Neuropharmacology 2003;43:304–14. Alhambra A, Cuétara MS, Ortiz MC, Moreno JM, del Pelacio A, Pontón J, del Palacio A. False positive galactomannan results in adult hematological patients treated with piperacillin–tazobactam. Rev Iberoam Micol 2007;24(2):106–12. Penack O, Rempf P, Graf B, Thiel E, Blau IW. False-positive Aspergillus antigen test­ ing due to application of piperacillin/tazo­ bactam—is it still an issue? Diagn Microbiol Infect Dis 2008;60(1):117–20. Zandijck E, Mewis A, Magerman K, Car­ tuyveis R. False-positive results by the platelia Aspergillus galactomannan antigen test for patents treated with amoxicillin– clavulanate. Clin Vaccine Immunol 2008; 15(7):1132–3. Orlopp K, von Lilienfeld-Toal M, Marklein G, Reiffert SM, Welter A, Hahn-Ast C, Purr I, Gorschlüter M, Molitor E, Glasma­ cher A. False positivity of the Aspergillus galactomannan platelia ELISA because of piperacillin/tazobactam treatment: does it represent a clinical problem? J Antimicrob Chemother 2008;62(5):1109–12. Fortún J, Martín-Dávila P, Alvarez ME, Norman F, Sánchez-Sousa A, Gajate L, ~o SJ, Moreno S. FalseBárcena R, Nun positive results of Aspergillus galactomannan antigenemia in liver transplant recipients. Transplantation 2009;87(2): 256–60. Laisi S, Ess A, Sahlberg C, Arvio P, Lukinmaa PL, Alaluusua S. Amoxicillin may cause molar incisor hypomineralization. J Dent Res 2009;88(2):132–6.

Chapter 25

424 43. Tortajada GM, Ferrer FA, Gracia AM, Clement PA, Garia ME, Tallion GM. Hypersensitivity to clavulanic aid in children. Allergol Immunopathol 2008;36:308–10. 44. Kim YH, Ko JY, Kim YS, Ro YS. A case of allergic contact dermatitis to clavulanic acid. Contact Dermatitis 2008;59(6):378–9. 45. Lestico MR, Vick KE, Hietsko CM. Hepa­ tic and renal dysfunction following nafcillin administration. Ann Pharmacother 1992;26: 985–90. 46. Hoppes T, Prikis M, Segal A. Four cases of nafcillin-associated acute interstitial nephri­ tis in one institution. Nat Clin Pract Nephrol 2007;3:456–61. 47. Xu B, Murray M. Flucloxacillin-induced acute renal failure. Aust Fam Physician 2008;37:1009–11. 48. Taylor AT, Pritchard DC, Goldstein AO, Fletcher Jr JL. Continuation of warfarin– nafcillin interaction during dicloxacillin therapy. J Fam Pract 1994;39:182–5. 49. Kim KY, Frey RJ, Epplen K, Foruhari F. Interaction between warfarin and nafcillin: case report and review of the literature. Pharmacotherapy 2007;27:1467–70. 50. Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol 2004;3:744–51. 51. Miyakaoka T, Yasukawa R, Yasuda H, Hayashida M, Inagaki T, Horiguchi J. Minocycline as adjunctive therapy for schi­ zophrenia: an open-labeled study. Clin Pharmacol 2008;31:287–92. 52. Idzekowski C, Oswald I. Interference with human memory by an antibiotic. Psycho­ pharmacology 1983;79:108–10. 53. Jackson AC, Scott CA, Owen J, Weli SC, Rossiter JP. Therapy with minocycline aggravates experimental rabies in mice. J Virol 2007;81:6248–53. 54. Jackson AC, Scott CA, Owen J, Weli SC, Rossite JP. Human rabies therapy: lessons learned from experimental studies in mice. Dev Biol 2008;131:377–85. 55. Nessler S, Dodel R, Bittner A, Reuss S, Du Y, Hemmer B, Sommer N. Effect of minocycline in experimental autoimmune encephalomyelitis. Ann Neurol 2002;52(5): 689–90. 56. Brundula V, Rewcastle NB, Metz IM, Bernard CC, Yong V. Targeting leucocyte

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MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 2002;125:1297–308. Hu W, Metselaar J, Ben LH, Cravens PD, Singh MP, Frohman EM, Eagar TN, Racke MK, Kieseier BC, Stüve O. PEG minocy­ cline-liposomes ameliorate CNS autoim­ mune disease. PLoS ONE 2009;4(1):e4151. Turner JD, Mand S, Debrah AY, Muehlfeld J, Pfarr K, McGarry HF, Adjei O, Taylor MJ, Hoerauf A. A randomized, double­ blind clinical trial of a 3-week course of doxycycline plus albendazole and ivermec­ tin for the treatment of Wuchereria bancrofti infection. Clin Infect Dis 2006;42: 1081–9. Jamet A, Lagarce L, Le Clec’h C, Croué A, Hoareau F, Diquet B, Laine-Cessac P. Doxycycline-induced Sweet’s syndrome. Eur J Dermatol 2008;18(5):595–6. Peyrière H, Dereure O, Breton H, Demoly P, Cociglio M, Blayac JP, Hillaire-Buys DNetwork of the French Pharmacovigi­ lance Centers. Variability in the clinical pattern of cutaneous side-effects of drugs with system symptoms: does a DRESS syndrome really exists? Br J Dermatol 2006;155(2):422–8. Maubec E, Wolkenstein P, Loriot MA, Wechler J, Mulot C, Beaune P, Revuz J, Roujeau JC. Minocycline-induced DRESS: evidence for accumulation of the culprit drug. Dermatology 2008;216:200–4. Brown RJ, Rother KI, Artman H, Mercur­ ion MG, Wang R, Looney J, Cowen EW. Minocycline-induced drug hypersensitivity syndrome followed by multiple autoimmune sequelae. Arch Dermatol 2009;145:63–6. Miyachi U, Yoshioka A, Imamura S, Niwa Y. Effect of antibiotics on the generation of reactive oxygen species. J Invest Dermatol 1986;86:449–53. Pruzanski W, Greenwald RA, Street IP, Laliberte F, Stefanski E, Vadas P. Inhibi­ tion of the enzymatic activity of phospholi­ pase A2 by minocycline and doxycycline. Biochem Pharmacol 1992;44:1165–70. Kloppenburg M, Brinkman BM, de Rooij­ Dick HHH, Miltenburg AM, Faha MR, Breedveld FC, Dijkmans BA, Verwilj C. The tetracycline derivative minocycline differentially affects cytokine production by monocytes and T lymphocytes.

Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines

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Antimicrob Agents Chemother 1996;40: 934–40. McManus P, Iheanacho I. Don’t use mino­ cycline as first line oral antibiotic in acne. BMJ 2007;334(7585):154. Miller CS, McGarity GJ. Tetracycline­ induced renal failure after dental treatment. J Am Dent Assoc 2009;140:56–60. Bhattacharya M, Parakh A, Narang M. Tigecycline. Drug Rev 2009;55:65–8. Stumf AN, Schmidt C, Hiddeman W, Gerbitz A. High serum concentration of ciclosporin related to administration of

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tigecycline. Eur J Clin Pharmacol 2009;65: 101–3. 70. Srinivas NR. Tigecycline and cyclosporine interaction—an interesting case of biliaryexcreted drug enhancing the oral bioavail­ ability of cyclosporine. Eur J Clin Pharma­ col 2009;65(5):543–4. 71. Falck P, Asberg A, Gulseth H, Bremer S, Akhlaghi F, Reuset J, Pfeffer P, Hartmann A, Midtvedt K. Declining intra-cellular T-lymphocyte concentration of cyclosporine precedes acute rejection in kidney transplant recipients. Transplantation 2008;85:179–84.

N. Corti and A. Imhof

26

Miscellaneous antibacterial drugs

AMINOGLYCOSIDE ANTIBIOTICS (SED-15, 118; SEDA28, 274; SEDA-29, 253; SEDA-30, 297)

Amikacin (SED-15, 111; SEDA-28, 254; SEDA-29, 253) Cardiovascular Episodes of hypotension have been attributed to amikacin (1A).
A 68-year-old woman on continuous ambula­

tory peritoneal dialysis was given amikacin (250 mg/day) and on the third day fainted and had a blood pressure of 90/60 mmHg. On the next 2 days, she had episodes of postural hypotension of between 90/60 and 80/ 50 mmHg two or three times a day. She was given antibiotics for the next 6 days and felt very bad the entire time, with a blood pressure of 80/50 mmHg. Her condition improved 2 days after withdrawal of amikacin and the episodes of hypotension did not recur.

Gentamicin

(SED-15, 1500; SEDA-29, 253; SEDA-30, 297)

Sensory systems Ears Gentamicin ototo­ xicity presents with gait imbalance and oscillopsia, but only rarely with hearing loss and vertigo. Sinusoidal rotational stimuli with a high rate of acceleration, such as the bedside head-thrust test or rotational step Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03126-2 r 2009 Published by Elsevier B.V.

changes in velocity, are useful in diagnosing bilateral vestibulopathy. In a retrospective review of the quantitative vestibular function testing results in 35 patients with imbalance, 33 of whom had oscillopsia, 3 reported a noticeable change in hearing and 5 reported vertigo; 15 had renal insufficiency at the time of gentamicin administration (2c). Those with pre-existing peripheral neuropathy compensated poorly. In a review of the literature 54 patients with vestibular toxicity attributed to genta­ micin were found, 24 of whom had asso­ ciated auditory toxicity (3R). A mutation in the mitochondrial genome A1555G can result in hypersensitivity to the ototoxic effects of the aminoglycosides compared with non-carriers of the mutation, which suggests that there may be an additional intrinsic sensitivity to ototoxicity in certain individuals. The pathogenesis of Ménière’s disease is associated with a disorder of ionic home­ ostasis, the pathological correlate being endolymphatic hydrops. Despite uncer­ tainty about its mode of action, it is accepted wisdom that intratympanic genta­ micin has a definite therapeutic role in the control of symptoms in patients who fail to respond to other medical therapy. In a retrospective review of 56 patients under­ going intratympanic gentamicin treatment for Ménière’s disease there was a 21% rate of significant hearing loss, defined as greater than 10 dB, with an average loss of 19 dB; however, there was an overall significant improvement in vertigo symptoms of 81% (4c).

427

428 In a retrospective case series from previously published prospective and retro­ spective studies of vestibular function in 25 patients receiving gentamicin, patients with vestibulotoxic reactions to gentamicin therapy had little additional hearing loss than the general population (5c). The authors of a literature review found two cases of hearing loss attributable to gentamicin and 14 patients with tympanic membrane perforations who had ototoxi­ city from Garasone (gentamicin sulfate 0.3%, betamethasone, sodium sulfate) (3R). The effect of aspirin in preventing genta­ micin-induced hearing loss has been studied in a double-blind, randomized, placebocontrolled trial in 195 patients (6C). They received gentamicin 80–160 mg bd by intra­ venous infusion (generally for 5–7 days) and were randomly assigned to aspirin 3 g/day divided into three doses (n ¼ 89) or placebo (n ¼ 106) for 14 days. The incidence of hearing loss in the placebo group was within the anticipated range (13%) but in the aspirin group it was significantly lower (3%). The efficacy of gentamicin was not affected by aspirin. However, gastric symp­ toms were more common in the aspirin group and three patients were removed from the study because of gastric bleeding. Urinary tract Aminoglycoside-induced renal tubular dysfunction can be divided into Fanconi-like syndrome and Bartter-like syn­ drome. Rarely they can occur together.
A 66-year-old Chinese man developed Fanconi­

like syndrome, Bartter-like syndrome, distal renal tubular acidosis, acute renal failure, and deafness after receiving a large dose of genta­ micin, which was considered a major risk factor (7A). The dose of gentamicin was 4.9 mg/kg/day, higher than the calculated dose of 3.75 mg/kg/ day based on estimated creatinine clearance.

Impaired mitochondria and ATP genera­ tion might participate in the mechanism of renal tubular dysfunction due to aminoglycosides.
A 53-year-old man who received intermittent

intravenous gentamicin (320–560 mg/day) for a total of 4 months to a total cumulative dose of 9.4 g developed Fanconi syndrome, with

Chapter 26

N. Corti and A. Imhof

profound hypophosphatemia, hypocalcemia, hyperphosphaturia, and aminoaciduria (8A). The electrolyte disturbances persisted until gentamicin was withdrawn and recurred after rechallenge.

Neomycin

(SEDA-28, 275)

Sensory systems Ears Neomycin/polym­ yxin B ear drops can rarely cause severe inner ear damage, even in low concentration, in patients who are known not to be hypersusceptible to aminoglycosides. A review of the literature revealed 11 patients with cochlear toxicity and two cases of vestibular toxicity in patients who received neomycin-based ear drops (3R).

Tobramycin

(SED-15, 3437; SEDA-29, 254; SEDA-30, 297)

Sensory systems Ears Tobramycin for inhalation is a mainstay of therapy for cystic fibrosis. Routine monitoring of serum concentrations is not performed in patients who use tobramycin by this route.
A 15-year-old young man with cystic fibrosis,

renal failure and a serum concentration of 134 mg/l developed profound sensorineural hearing loss after using inhaled tobramycin 600 mg every 12 hours for 3 weeks (total dose 29 g or 640 mg/kg) (9A).

Urinary tract A new formulation of tobra­ mycin by inhalation improves antibacterial activity and reduces the risk of nephrotoxi­ city. However, a 73-year-old woman with COPD developed nephrotoxicity after using inhaled tobramycin (10A), as did a 62-year-old Caucasian woman (11A), and two lung transplant patients developed renal failure when nebulized tobramycin was started (12A). Cement laden with tobramycin and/or vancomycin can cause systemic toxicity, as in two cases of acute renal failure asso­ ciated with the use of antibioticladen cement incorporated in total hip arthroplasties (13A).

Miscellaneous antibacterial drugs

Chapter 26

429

CHLORAMPHENICOL AND RELATED DRUGS (SED-15, 706;

controlled trials in acute cystitis in 7535 women (17M). Photosensensitivity reactions were more common with sparfloxacin than ofloxacin. Adverse cutaneous events and photosensitivity causing withdrawal were more common with lomefloxacin than ofloxacin. Nervous system adverse events and insomnia were reported more frequently with rufloxacin and enoxacin than with pefloxacin or ciprofloxacin.

SEDA-29, 254; SEDA-30, 298)

Chloramphenicol Hematologic Chloramphenicol eye drops are used to treat bacterial conjunctivitis and infections of the external eye. Among more than 200 million ocular chloramphenicol products dispensed in the UK in the past 10 years, only 11 cases of suspected chloramphenicol-induced blood dyscrasias (none fatal) were reported to the Committee on Safety of Medicines (14r). However, under-reporting in this way, which may be as low as 6% (15C), suggests that the number of incidents could have been as many as 200. Over 40 cases of blood dyscrasias or aplastic anemia after the use of topical ocular chloramphenicol have been reported in the literature or to the National Registry of Drug-Induced Ocular Side Effects (Casey Eye Institute, Portland, Oregon, USA). Although there was no proof of causality, we feel, based on WHO criteria, that the association in these cases was probable. The medical literature contains many papers both for and against the use of chloramphenicol in ophthalmology.

Thiamphenicol Respiratory To date, there have been no reports of rhinitis or asthma caused by thiamphenicol, but three cases of occu­ pational asthma and rhinitis have been attributed to thiamphenicol inhalation; both immunoglobulin E (IgE)-mediated and non­ IgE-mediated responses were involved (16A).

Immunologic The frequency of fluoro­ quinolone-associated anaphylaxis has been estimated at 1.8–23 per 10 million days of treatment, based on spontaneous reports (18C). All fluoroquinolone-associated cases of IgE- and non-IgE-mediated anaphylac­ tic reactions spontaneously reported to the Federal Institute for Drugs and Medical Devices in Germany between January 1, 1993 and December 31, 2004 were identi­ fied and assessed with regard to the correctness of the diagnosis. In 166 of 204 cases, the diagnosis of anaphylaxis and a causal relation with the drug were considered at least possible. Moxifloxacin, levofloxacin, ciprofloxacin, and ofloxacin respectively accounted for 90 (54%), 25 (15%), 21 (13%), and 16 (10%) of the 166 cases; the corresponding reporting rates per 1 million defined daily doses based on crude estimates of exposure were 3.3, 0.6, 0.2, and 0.2. Anaphylaxis after the first dose or within the first 3 days was reported in 71 of 166 (43%) cases, but there was no information about prior exposure with this or any other fluoroquinolone. In 21 (13%) of the 166 cases, the reaction occurred within the first 3 days and it was stated that the particular fluoroquinolone had never been taken before.

Ciprofloxacin

FLUOROQUINOLONES

(SED-15, 783; SEDA-29, 255; SEDA-30, 298)

Comparative studies Quinolones have been compared retrospectively in 11

Cardiovascular The risk of ciprofloxacin­ associated torsade de pointes appears to be low, but caution is still warranted when it is given in the presence of pre-existing QT prolongation.

(SED15, 1396; SEDA-28, 276; SEDA-29, 254; SEDA-30, 298)

430
A

70-year-old woman who was taking azathioprine, olanzapine, and valsartan devel­ oped marked QT interval prolongation after the intravenous administration of ciprofloxacin 800 mg/day. Ciprofloxacin was immediately replaced by a third-generation cephalosporin, and during the next few days the QT interval gradually returned to normal (19A).
Torsade de pointes and QT interval prolonga­ tion occurred when intravenous ciprofloxacin was given to a 22-year-old healthy man with pneumonia (20A).

Psychiatric Acute psychoses have been associated with ciprofloxacin.
A 28-year-old white man with a history of

Chapter 26

N. Corti and A. Imhof

Urinary tract A 77-year-old man devel­ oped interstitial nephritis after taking cipro­ floxacin for an infected knee-prosthesis; withdrawal led to recovery of renal function (24A). Acute renal failure secondary to cipro­ floxacin crystal nephropathy has been reported (25A).
A 90-year-old woman had surgery for a

perforated duodenal ulcer and was given ciprofloxacin 750 mg bd for a respiratory infection. After 8 days her serum creatinine rose to 140 mmol/l (1.6 mg/dl) and she devel­ oped oliguria. The fractional sodium excretion was 2%, the urine pH was 6.5, and the urine sediment showed granular casts, epithelial cells, and needle-shaped birefringent crystals in round conglomerates. There was no eosi­ nophilia and no urinary leukocytes. Intrave­ nous fluids had no effect on urine output. Ciprofloxacin was withdrawn and the oliguria resolved over the next day. The serum creatinine peaked at 336 mmol/l (3.8 mg/dl) and returned to baseline within 10 days.

primary sclerosing cholangitis and controlled ulcerative colitis developed signs of suppura­ tive cholangitis and was treated with intrave­ nous metronidazole 500 mg bd, intravenous cefazolin 1 g 8-hourly, intravenous ciproflox­ acin 400 mg bd, Gravol 25–50 mg 4-hourly, ursodeoxycholic acid 1500 mg bd, and folate 1 mg/day (21A). On day 1, sulfasalazine 300 mg tds was added and increased on the next day to 1000 mg tds. He improved quickly. On day 5, all medications were discontinued, except ciprofloxacin 500 mg bd. The next day, he became agitated and violent. He was highly irritable, expansive, and grandiose, wanting to publish a book and run a religious mission. He was given piperacillin+tazobactam 4.5 g qds, thiamine 100 mg, and aciclovir 600 mg 8-hourly. Ciprofloxacin was withdrawn, and he was given intramuscular haloperidol 5 mg every 4–6 hours as required and sublingual lorazepam 1 mg 8­ hourly. He was then given olanzapine 5 mg bd, the dose of haloperidol was reduced to 2.5 mg 2-hourly (maximum 10 mg/day), and all other medications were withdrawn. On the next day, he had increased delusional thought content and expansive mood. By day 15, he was alert and oriented, with no delusions or persisting hostility, and with insight into his previous mental disturbance.
A 45-year-old man without previous mental disorders developed an acute delusional para­ sitosis after taking ciprofloxacin. He had a complete sustained remission within a few days after withdrawal of ciprofloxacin, without the use of any other medication (22A).

Musculoskeletal Tendinitis and tendon rupture are well recognized but rare com­ plications of treatment with ciprofloxacin. In two cases there was bilateral Achilles tendon rupture (27A,28A).

Hematologic In two patients with cystic fibrosis the INR and activated partial thromboplastin time rose after ciprofloxacin treatment and returned to normal after withdrawal (23A).

Immunologic Ciprofloxacin-induced ANCAnegative cutaneous and renal vasculitis has been described in a 50-year-old man with a history of hypertension who developed gross hematuria after taking ciprofloxacin for 10 days (29A).

Skin Photosensitivity reactions reported with ciprofloxacin mimic those of sunburn, with erythema and edema in the milder forms and painful blistering with subse­ quent peeling when severe. Purpuric eruptions during treatment with ciprofloxacin have been rarely reported.
A 30-year-old man took a 15-day course of

ciprofloxacin 500 mg bd and after exposure to the sun developed an itchy eruption consisting of erythematous, petechial lesions located on the anterior aspect of his thighs and legs, clearly delimited by his bathing suit. The lesions cleared completely after withdrawal of the drug and treatment with topical clobetasol (26A).

Miscellaneous antibacterial drugs

Chapter 26


A 15-year-old girl had an anaphylactoid

reaction, with angioedema, shock, and loss of consciousness, within a few minutes of taking an oral dose of ciprofloxacin. She regained consciousness within a few hours of treatment with fluid resuscitation (60 ml/kg), hydrocortisone, and diphenhydra­ mine (30A).

Drug–drug interactions Phenazopyridine In a double-blind, crossover, randomized trial in 24 healthy men oral co-administration of phenazopyridine increased the sys­ temic availability of a single dose of ciprofloxacin (31c). Tizanidine In a retrospective survey of medical records obtained from 1165 patients there were eight patients who took tizanidine and ciprofloxacin (32Ac). None was taking medications that inhibit CYP1A2, besides ciprofloxacin. There were adverse effects attributed to tizanidine in three patients (low heart rate in two, low body temperature in one, low blood pres­ sure in two, drowsiness in two, and confu­ sion in one). In one patient ciprofloxacin was withdrawn because of confusion.
A 45-year-old Japanese woman taking tizani­

dine 3 mg/day was given ciprofloxacin 400 mg/ day for 7 days. On day 2 she complained of drowsiness and had a low blood pressure (92/ 54 mmHg). She recovered immediately after withdrawal of ciprofloxacin. The doses of her other medications remained unchanged during this period.

Gatifloxacin

(SED-15, 1482; SEDA-29, 256; SEDA-30, 299)

Nervous system Status epilepticus has been attributed to gatifloxacin 400 mg/day in a 79-year-old woman with a non-febrile urinary tract infection with Escherichia coli (33A). Sensory systems In phase III trials of gatifloxacin, the most frequently reported adverse events were conjunctival irritation, increased lacrimation, keratitis, and papillary conjunctivitis, which occurred in 5–10% of patients with bacterial conjunctivitis (34R). Chemosis, conjunctival hemorrhage,

431 dry eyes, discharge, eye irritation, eye pain, eyelid edema, headache, red eye, reduced visual acuity, and taste disturbance were reported by 1–4% of patients. Treatmentrelated adverse events were reported by 3.8% of those who took twice-daily doses and 1.9% of those who took doses four times a day. Psychiatric Gatifloxacin-induced hallucinations have been described (35A).
An otherwise-healthy 19-year-old young mili­

tary recruit developed a community-acquired pneumonia, for which he was given intrave­ nous gatifloxacin 400 mg/day. He denied a past psychiatric history, but did have a brother with bipolar affective disorder. After 2 days he complained of hallucinations and had para­ noia. No changes in his medications were made for 2 days, and he continued to have intermittent hallucinations. The pneumonia did not improve and piperacillin/tazobactam 3.375 g 6-hourly was added. The gatifloxacin was then withdrawn, and his hallucinations resolved with a time-course consistent with the half-life of gatifloxacin, 7–14 hours.

A psychosis attributed to gatifloxacin occurred in an elderly woman with demen­ tia (36A). Metabolism In two population-based nested case–control studies of 788 patients who were treated for hypoglycemia within 30 days of antibiotic therapy, gatifloxacin was associated with an increased risk of hypogly­ cemia (adjusted OR ¼ 4.3; 95% CI ¼ 2.9, 6.3) (37C). Levofloxacin was also associated with a slightly increased risk (adjusted OR ¼ 1.5; 95% CI ¼ 1.2, 2.0), but there was no such risk with moxifloxacin or ciproflox­ acin. In 470 patients treated for hyperglyce­ mia within 30 days of antibiotic therapy, gatifloxacin was associated with a consider­ ably increased risk of hyperglycemia (adjusted OR ¼ 17; 95% CI ¼ 10, 27), but there was no risk with the other antibiotics. In a review of hypoglycemia or hyperglycemia attributed to fluoroquinolones, 93% of all episodes of dysglycemia were due to gatifloxacin; only 11% of reports were asso­ ciated with levofloxacin and only 10% of reports associated with moxifloxacin involved

432 either hypoglycemia or hyperglycemia (38R). Analysis of the data suggested that signifi­ cantly more episodes of hypoglycemia were associated with gatifloxacin than with either levofloxacin or moxifloxacin. Gatifloxacin-induced hypoglycemia is associated with concomitant use of sulfony­ lureas, and usually occurs immediately after drug administration. It stimulates insulin secretion in mouse pancreatic beta-cells and the effect is additive with glibenclamide (39E). On the other hand, long-term gatifloxacin treatment reduces islet cell insulin contents by inhibiting insulin biosynthesis, which may be associated with gatifloxacin-induced hyper­ glycemia, which often takes several days to develop. Withdrawal of gatifloxacin results in improved insulin secretion. The manufacturer of gatifloxacin has changed the labeling to strengthen an existing warning about hypoglycemia and hyperglycemia, adding a contraindication to its use in people with diabetes, and provid­ ing information identifying other suscept­ ibility factors for low or high blood glucose concentrations, including advanced age, kidney malfunction, and taking glucosealtering medications while taking gatiflox­ acin (40r–43r).
Hyperglycemia occurred in an 86-year-old

man who took (44A) gatifloxacin 400 mg/day for suspected pneumonia. After 4 days his mean blood glucose concentration increased from 7.4 mmol/l (133 mg/dl) to 30 mmol/l (537 mg/dl). Although he had glycosuria, he did not complain of symptoms of hyperglyce­ mia, such as polyuria, polyphagia, or poly­ dipsia. The hyperglycemia resolved after gatifloxacin was withdrawn and he had received regular insulin 15 U subcutaneously over 5 hours.

Chapter 26

N. Corti and A. Imhof

when normalized for total body weight or lean body weight. Given the smaller volume of distribution, women may have slightly higher maximum concentrations, but these differences are unlikely to have clinical significance. Drug–drug interactions Warfarin Antico­ agulation has been studied retrospectively in patients taking stable dosages of warfarin who started taking levofloxacin (n ¼ 54) or gatifloxacin (n ¼ 38), by reviewing general patient databases and electronic medical records (49c). The INR was above 4 in one patient taking levofloxacin and in eight patients taking gatifloxacin. The authors concluded that close monitoring of INR is warranted when gatifloxacin is added. Interference with diagnostic tests Gati­ floxacin can interfere with urinary screening for opiates (50A).
A 48-year-old man was given gatifloxacin for a

urinary tract infection. While he was taking the antibiotic, two urine screens were positive for opiates; the results of previous screens had been negative. A test using a different assay method was negative and 2 weeks after completing the course of gatifloxacin the urine screen was again negative for opiates.

The mechanism by which gatifloxacin cross-reacted with the opiate immunoassay was not known.

Levofloxacin

(SED-15, 2047; SEDA-29, 257; SEDA-30, 299) Respiratory Pneumonitis has been attributed to levofloxacin and a kampo medicine (51A).

Another 15 cases of dysglycemia asso­ ciated with gatifloxacin have been described (45A–47A).


A 55-year-old woman developed dyspnea on

Susceptibility factors Sex The effects of sex on the pharmacokinetics of a single oral dose of gatifloxacin 400 mg have been investigated in 12 healthy subjects (6 men, 6 women) (48c). The women had a sig­ nificantly smaller volume of distribution. However, there was no significant difference

exertion. She had hypoxemia and restrictive ventilatory impairment. Chest X-rays showed diffuse patchy infiltration in both lungs. She gradually improved after withdrawal of the drugs. Transbronchial lung biopsy specimens showed lymphocyte dominant infiltration in the alveolar septa and Masson bodies. Lym­ phocyte stimulation tests were positive for levofloxacin and shin-i-seihai-to, a kampo medicine.

Miscellaneous antibacterial drugs

Chapter 26

Nervous system A myasthenic crisis and respiratory depression occurred in a 45­ year-old man 36 hours administration of levofloxacin (52A). Metabolism Hypoglycemia attributed to levofloxacin.

has

been


A 64-year-old woman with type 2 diabetes

treated by diet was given levofloxacin 500 mg/ day for a urinary infection and pneumonia (53A). After 2 days she became lethargic and disoriented. Her blood glucose concentration was 1.8 mmol/l (32 mg/dl) and the simulta­ neous blood insulin concentration was 6.7 (reference range 5–25) IU/ml. A 30% dextrose infusion was started, and she regained con­ sciousness without any neurological deficit. Although she did not take any insulin during the dextrose infusion, her blood glucose concentrations were 3 and 3.4 mmol/l at 1 hour and 4 hours. On day 3 of levofloxacin treat­ ment, she had another episode of hypoglyce­ mia. Levofloxacin was withdrawn and she was given piperacillin+tazobactam instead. There were no further episodes of hypoglycemia.
A 65-year-old woman who took levofloxacin 500 mg/day had episodes of hypoglycemia, which stopped spontaneously 6 days after the end of therapy (54A).
A 78-year-old, non-diabetic man had steroidinduced hyperglycemia, which was treated with glibenclamide; 12 hours after taking levoflox­ acin 500 mg orally he developed severe hypo­ glycemia, resulting in anoxic brain injury (55A).

In two population-based, nested case–con­ trol studies in 788 patients who had been treated for hypoglycemia within 30 days after antibiotic therapy, levofloxacin was asso­ ciated with a slightly increased risk (adjusted OR ¼ 1.5; 95% CI ¼ 1.2 to 2.0) (37C). The effect of levofloxacin on serum glucose concentrations has been investi­ gated in rats (56E). The serum glucose concentration fell after injection of levo­ floxacin 100 mg/kg, and increased after levofloxacin 300 mg/kg. Adrenaline and histamine concentrations rose after levo­ floxacin 300 mg/kg. Diphenhydramine pre­ vented the hyperglycemia induced by levofloxacin 300 mg/kg. Hematologic Pancytopenia occurred 9 days after treatment of pelvic inflammatory disease with levofloxacin 500 mg/day and resolved after withdrawal (57A).

433 Gastrointestinal In a double-blind, rando­ mized, controlled trial in 394 patients who received either intravenous/oral moxiflox­ acin 400 mg/day) or intravenous/oral levo­ floxacin 500 mg/day) for 7–14 days, the rate of treatment-related adverse events due to any cause was significantly higher in those who received moxifloxacin, although the rates of drug-related and serious adverse events were similar in the two treatment arms (58C). There was no difference between treatments with regard to the rate of premature discontinuation because of an adverse event; 17 of 35 of these events were considered to be drug related (10 in the moxifloxacin arm and 7 in the levofloxacin arm). Serious adverse events were reported in 23% of patients in both treatment groups. The most commonly reported adverse event in the levofloxacin arm was diarrhea (5%). Urinary tract Levofloxacin can cause interstitial nephritis and vasculitis (59A). Musculoskeletal Rhabdomyolysis occur­ red in a patient taking levofloxacin (60A).
After receiving a second cadaveric-donor

renal transplant and after 10 days of therapy with levofloxacin 250 mg/day a 68-year-old woman developed worsening myalgia and difficulty in walking. Her proximal leg muscles were tender. Her creatine kinase activity was up to 6200 U/l and there was myoglobinuria. Levofloxacin, simvastatin, and colchicine were withdrawn. Intravenous hydration was main­ tained for 5 days. The serum creatine kinase activity fell and her muscle pain and tender­ ness disappeared after 14 days.

It was not clear in this case what the relative contributions of the three drugs were. Levofloxacin can cause tendon rupture (61A). Drug–drug interactions Concomitant tre­ atment with levofloxacin and ciclosporin or tacrolimus increased the AUC of ciclos­ porin and tacrolimus by 25%, probably by inhibition of hepatic metabolism by levofloxacin (62c).

434 In patients with cystic fibrosis, but not healthy volunteers, calcium carbonate reduced the Cmax of levofloxacin by 19% and increased the tmax by 37% (63c). The AUC was unaffected, but the authors concluded that multivalent cations should be taken at a separate time from oral levofloxacin in patients with cystic fibrosis.

Moxifloxacin

(SED-15, 2392; SEDA-29, 257; SEDA-30, 300)

Cardiovascular In a prospective obser­ vational uncontrolled and monitored study in 13 578 patients with respiratory tract infection moxifloxacin 400 mg/day was associated with 1046 adverse events; there were reports about 678 patients (5%), including 854 drug-related events in 564 patients (4.15%) (64R). Of these 1046 adverse events, 95 in 62 patients (0.46%) were serious. Of 34 cardiac adverse events, 25 in 19 patients (0.14%) were thought to have been drug-related: palpitation (n ¼ 13), tachycardia (n ¼ 4), malaise (n ¼ 4), vertigo (n ¼ 3), and pallor (n ¼ 1). All the adverse events were transient and had favorable outcomes. Sensory systems In in vitro studies in rabbit eyes (65E), monkey eyes, and human eyes (66c) high concentrations of moxiflox­ acin ophthalmic solution 0.5% demon­ strated a favorable margin of safety in ocular and extraocular tissues and in corneal tissue, which has the highest expo­ sure to the commercial formulation. However, in clinical studies of corneal wound healing with the use of moxifloxacin ophthalmic solution 0.5%, the findings were inconsistent (67R). In two cases sterile corneal ulcers persisted after several weeks of therapy with topical moxifloxacin 0.5% and resolved when antibiotic therapy was changed (68A). Gastrointestinal In a double-blind, rando­ mized, controlled trial in 394 patients who received either intravenous/oral moxiflox­ acin 400 mg/day or intravenous/oral levo­ floxacin 500 mg/day for 7–14 days, the rate

Chapter 26

N. Corti and A. Imhof

of adverse events attributed to any cause was significantly higher with moxifloxacin, although the rates of drug-related and serious adverse events were similar in the two treatment arms (58C). There was no difference between treatments with regard to the rate of premature withdrawal owing to an adverse event; 17 of 35 events were considered to be drug related (10 with moxifloxacin and 7 with levofloxacin). There were serious adverse events in 23% of the patients in both treatment groups. The most common adverse event with moxifloxacin was diarrhea (5.6%). In 36 patients treated with moxifloxacin 400 mg/day orally for resistant tuberculosis, the mean duration of treatment was 6.3 months (69c). Twelve patients reported at least one adverse effect due to moxiflox­ acin, mostly gastrointestinal (n ¼ 8), gen­ eral (n ¼ 5), and central nervous system (n ¼ 3). In four patients the drug was withdrawn because of major adverse events; there were no irreversible or fatal events. Susceptibility factors In 10 patients with peritonitis who required surgery and drai­ nage of the abdominal cavity who were given a single intravenous infusion of moxifloxacin 400 mg over 1 hour, plasma moxifloxacin concentrations fell from a geometric mean of 3.61 mg/l at 1 hour to 0.36 mg/l at 24 hours (70c). Concentrations in peritoneal exudate were highest at 2 hours after the start of the infusion, reached a geometric mean of 3.32 mg/l, and fell to a geometric mean of 0.69 mg/l at 24 hours. The exudate/plasma concentra­ tion ratio rose from 1.45 at 2 hours to 1.91 at 24 hours. The AUC tended to be greater in the exudate; the time to peak concentra­ tions was longer in the exudate than in the plasma, as were the half-life and mean residence time.

Ofloxacin (SED-15, 2597; SEDA-29, 258; SEDA-30, 300) Sensory systems Topical ofloxacin in the treatment of bacterial keratitis caused corneal deposits in six cases (71A).

Miscellaneous antibacterial drugs

Chapter 26

Skin Sweet’s syndrome has been asso­ ciated with ofloxacin 400 mg/day in a 40­ year-old woman with Crohn’s disease (72A). Musculoskeletal Achilles tendon rupture has been attributed to ofloxacin and a short course of prednisolone (73A).

Sparfloxacin

(SED-15, 3172; SEDA-29, 259; SEDA-30, 300)

Drug–drug interactions Antacids Con­ current administration of antacids and sparfloxacin reduces the gastrointestinal absorption of sparfloxacin, and therapeutic failure can result. An in vitro study was designed to evaluate the effect of some antacids on the systemic availability of sparfloxacin. The release of sparfloxacin from tablets in the presence of sodium bicarbonate, calcium hydroxide, calcium carbonate, aluminum hydroxide, magnesium hydroxide, magnesium carbonate, magne­ sium trisilicate, and magaldrate was markedly reduced (74E). However, maga­ ldrate and calcium carbonate had relatively higher adsorption capacities in simulated gastric juice and magnesium trisilicate and calcium hydroxide in simulated intestinal juice.

GLYCOPEPTIDES (SEDA-28, 280; SEDA-29, 260; SEDA-30, 300) Dalbavancin

(SEDA-29, 260; SEDA-30,

300) Dalbavancin is a lipoglycopeptide antibacter­ ial with in vitro activity against a variety of Gram-positive pathogens (75R). Compared with other available agents it has favorable minimum inhibitory concentration ranges against meticillin-susceptible and meticillin­ resistant Staphylococcus aureus. It is highly protein bound (> 90%), which contributes to its prolonged half-life of 149–300 hours,

435 because of which once-weekly dosing strate­ gies have been used in clinical trials. Preclinical studies in rats and dogs have shown that dalbavancin is well tolerated, even at dosages several-fold higher than those likely to be used clinically. In Phase I, II, and III clinical trials, dalbavancin was well tolerated, without evidence of dose- or duration-related adverse effects. It is impor­ tant to note that clinical and pharmacoki­ netic studies published to date have excluded patients with a history of glyco­ peptide hypersensitivity, and there is no information about the incidence of cross-reactivity (76R).

Teicoplanin

(SED-15, 3305; SEDA-29, 260; SEDA-30, 301) Immunologic IgE-mediated allergy to teic­ oplanin has been described (77A).


A 41-year-old woman had an episode of

severe generalized urticaria/angioedema and vomiting about 2 minutes after the start of an intravenous infusion of teicoplanin. The infu­ sion was immediately stopped and she was promptly and successfully treated with intra­ venous corticosteroids and antihistamines. She had not had a similar episode in the past, but about 4 months before the last administration of a 10-day course of intramuscular teicoplanin had been followed by local pain, hardening, and inflammation in the buttock that lasted for 3 days. A skin prick test with teicoplanin 75 mg/ml did not elicit any skin reaction, but intradermal injection of 0.02 ml of the same solution induced an immediate wheal-and­ flare reaction (mean diameter 2 cm) followed by a red, pruritic, slightly infiltrated lesion of the same size that lasted for about 3 days.

Drug hypersensitivity syndrome to both vancomycin and teicoplanin has not been previously reported (78A).
A 50-year-old man developed hypersensitivity

syndrome to both vancomycin and teicoplanin. Skin rash, fever, eosinophilia, interstitial pneumonitis, and interstitial nephritis devel­ oped after the administration of each drug, and resolved after withdrawing the drugs and treatment with high-dose corticosteroids. Skin patch tests 2 months after recovery showed a weak positive result for vancomycin (with erythema and vesicles) and a doubtful result for teicoplanin (with macular erythema).

436

Vancomycin

(SED-15, 3593; SEDA-29, 261; SEDA-30, 301)

Hematologic In a retrospective chart review of 114 patients treated with van­ comycin 14 cases of vancomycin-induced neutropenia were identified; four included a reduction in absolute neutrophil count to 500  106/l or less (79c). The mean duration of vancomycin therapy and time to neutropenia were 32 and 26 days respectively. Resolution occurred promptly after withdrawal. The total vancomycin dose and serum concentrations were not related to the neutropenia, suggesting a hyper­ susceptibility reaction. A 2-year-old boy developed severe thrombocytopenia during vancomycin therapy; it resolved promptly after withdrawal (80A). Delayed myeloid engraftment due to vancomycin has been described in a 59­ year-old man who received a non-myeloa­ blative allogeneic hemopoietic stem cell transplant (81A). Liver Raised liver enzymes have been attributed to oral vancomycin (82A).
A 57-year-old man who took oral vancomycin

125–500 mg/day on five separate occasions had significant rises in alanine transaminase to 371 U/l and aspartate transaminase to 203 U/l. The rises resolved on each occasion after withdrawal of vancomycin.

Urinary tract The reported rate of nephrotoxicity of vancomycin is 7–16%, but it can reach 35% with concurrent aminoglycoside therapy and is associated with serum concentrations over 40 mg/ml. In a retrospective study in 19 patients (mean age 51 years; 12 women) who had a 50% increase in their normal baseline serum creatinine during vancomycin therapy, there was no correlation between vanco­ mycin serum concentration and serum creatinine (83c). Antibiotic-laden cement with aminogly­ cosides and/or vancomycin can cause sys­ temic toxicity. In two cases acute renal failure was associated with the use of antibiotic-laden cement incorporated in total hip arthroplasties (13A).

Chapter 26

N. Corti and A. Imhof

Skin Linear IgA bullous dermatosis is a rare autoimmune blistering disorder with clinical features that can overlap with bullous pemphigoid and dermatitis herpeti­ formis. Two cases have been attributed to vancomycin (84A,85A).

(SED-15, 1976; SEDA28, 281; SEDA-29, 262; SEDA-30, 301)

KETOLIDES Telithromycin

Telithromycin, the first marketed ketolide antibiotic, is a modification of the macro­ lide structure (86r). Like macrolides, teli­ thromycin blocks protein synthesis. However, compared with macrolides, it has increased affinity for the binding sites on domains II and V of the 50S ribosomal subunit. After oral administration, telithro­ mycin is widely distributed in the body, partly metabolized in the liver, and excreted primarily in the feces and urine. It is present in high concentrations in bronchial mucosa, epithelial lining fluid, alveolar macrophages, and polymorpho­ nuclear cells. Neuromuscular Telithromycin has been implicated in exacerbation or unmasking of myasthenia gravis. There has been a report of two cases, including a summary of eight other suspected cases notified to the French pharmacovigilance system, high­ lighting a potentially life-threatening risk of telithromycin treatment in patients with myasthenia (87Ar). An important common feature was that in seven cases the symp­ toms occurred within 2 hours of the first dose, notably in cases of severe exacerba­ tion. Another case has been described, in a 46-year-old woman who had an exacerba­ tion of myasthenia gravis while taking telithromycin (88A). Liver Telithromycin has been associated with rare cases of serious liver injury and liver failure, with four reported deaths and one liver transplantation (89r,90A).

Miscellaneous antibacterial drugs

Chapter 26

Drug–drug interactions Telithromycin in­ hibits CYP3A4. It is contraindicated in patients taking cisapride, pimozide, or class IA and class III antidysrhythmic agents in whom it can prolong the QT interval (86r). Digoxin Telithromycin increases plasma digoxin concentrations and can cause signs and symptoms of toxicity (91A).
A 58-year-old woman, who had been taking

digoxin 0.25 mg/day for more than 35 years for palpitation after mitral valve repair, was given telithromycin for acute bronchitis. After 6 days she complained of general malaise after three episodes of syncope over the previous 2 days. The plasma digoxin concentration was raised and electrocardiography showed several non­ specific repolarization anomalies.

437 rapid onset (48 hours) after treatment with aztreonam (500 mg 8-hourly) (94A).

Immunologic Clindamycin-related phylaxis is rare.

ana-


A 47-year-old man with buccal cancer who was

undergoing radical neck dissection developed life-threatening anaphylactic shock after receiving an intravenous infusion of clindamy­ cin 600 mg in 30 ml of lactated Ringer’s solution over about 10 minutes through a peripheral vein (95A). Within 3 minutes after the end of the infusion he developed bronchospasm, hypoten­ sion (systolic blood pressure under 40 mmHg), tachycardia, and wheals and erythema over almost all of the body but made an uneventful recovery with standard treatment.

The authors attributed this interaction to inhibition of renal P-glycoprotein by telithromycin.

Drug–drug interactions Paclitaxel In 16 patients with advanced ovarian cancer clindamycin altered paclitaxel pharmaco­ kinetics (92c). However, the changes were minimal and of questionable clinical rele­ vance.

(SED-15, 2063; SEDA-28, 281; SEDA-29, 263; SEDA-30, 302)

MACROLIDE ANTIBIOTICS

LINCOSAMIDES

Clindamycin Skin In a retrospective study of druginduced reactions among children with various ear, nose, and throat (ENT) infections, 7 of 62 reported cases with skin reactions were attributed to clindamycin (92c). Acute generalized exanthematous pustulosis (AGEP) involves numerous nonfollicular sterile pustular lesions associated with fever above 381C, neutrophilic leu­ kocytosis, an intensely pruritic rash, and in the later stages desquamation. AGEP was associated with clindamycin in a 38-year-old woman who was also undergoing therapy for systemic lupus erythematosus (93A).
Erythroderma occurred in 73-year-old woman

who developed intense pruritus, malaise, and chills 7 days after treatment with intravenous clindamycin (600 mg 6-hourly). Two years later she had a similar reaction with more

(SED-15, 2183; SEDA-28, 282; SEDA-29, 263; SEDA-30, 302)

Azithromycin

(SED-15, 389; SEDA-29, 264; SEDA-30, 302) Cardiovascular Azithromycin can cause prolongation of the QT interval (96A).


A 65-year-old man with idiopathic dilated

cardiomyopathy developed significant prolon­ gation of the QT interval after taking azithro­ mycin for 2 days for a community-acquired pneumonia. Three days after withdrawal the QT interval returned to normal.

Azithromycin can cause life-threatening bradycardia (97A).
A 9-month-old infant who was inadvertently

given azithromycin 50 mg/kg, taken from floor stock, instead of the prescribed ceftriaxone, became unresponsive and pulseless. The initial heart rhythm observed when cardiopulmonary resuscitation was started was a broad-complex bradycardia, with a prolonged rate-corrected

438 QT interval and complete heart block. She was resuscitated with adrenaline and atropine but suffered severe anoxic encephalopathy.

Skin After 10 days treatment with azithro­ mycin for an upper respiratory tract infec­ tion, a 62-year-old woman developed Stevens–Johnson syndrome, which improved during treatment with corticosteroids after few days (98A). Liver Severe liver damage can be caused by intravenous infusion of azithromycin (99A). Teratogenicity In a case–control study in 123 patients gestational exposure to azi­ thromycin was not associated with an increase in the rate of major malformations above the baseline of 1–3% (100C).

Clarithromycin (SED-15, 799; SEDA29, 265; SEDA-30, 302) Cardiovascular Clarithromycin caused modest but significant prolongation of the QTc interval in 28 children with respiratory tract infections after 24 hours of treatment (mean prolongation 22 ms; 95% CI ¼ 14, 30); in seven cases the QTc interval was over 440 ms, and in one case it was over 460 ms (101c). Psychiatric Delirium due to clarithromy­ cin is extremely uncommon.
A 63-year-old woman took clarithromycin for a

community-acquired pneumonia and had an episode of agitation and delirium; she recovered when the clarithromycin was stopped (102A).

Liver Severe progressively worsening cholestatic liver disease occurred in a 15-year-old girl after a 15-day course of clarithromycin 500 mg/day and nimesulide 100 mg/day (103A). Prednisone was started after 20 days after which there was prompt improvement. After 2 months she became symptom-free with normal liver function test results.

Chapter 26

N. Corti and A. Imhof

Urinary tract Drug-induced interstitial nephritis represents 4% of all cases studied histologically, with an estimated frequency of 8%. Granulomatous interstitial nephritis occurred in a 38-year-old woman who was given clarithromycin for pharyngitis (104A). Drug–drug interactions Cabergoline In 10 healthy men and seven patients with Parkinson’s disease, co-administration of cabergoline with clarithromycin increased the blood concentration of cabergoline (105c). Cisapride Concurrent administration of clarithromycin and cisapride prolongs the QTc interval by a mean effect of 25 ms (106cR). Paroxetine Serotonin syndrome has been reported in a patient taking paroxetine and clarithromycin (107A).
A 36-year-old woman who had taken parox­

etine 10 mg/day for mild anxiety for 3 months developed an upper respiratory tract infection and stopped taking paroxetine. Three days later she was given clarithromycin 500 mg bd and after the fourth dose developed acute ocular clonus, akathisia, and fever. She received intravenous fluids and lorazepam and clarithromycin was withdrawn; the syndrome abated within 24 hours.

Erythromycin

(SED-15, 1237; SEDA29, 265; SEDA-30, 302)

Cardiovascular Torsade de pointes occu­ rred in 16 of 23 patients who received intravenous erythromycin 3–4 g/day and 3 of 23 who received oral erythromycin 1.5–2 g/day (105cR). There were marked differences in exposure between the two regimens, with typical peak erythromycin concentrations of 30 mg/ml after intravenous administration versus 2–4 mg/ml after oral administration. Non-clinical models have shown a concentration-related effect of erythromycin on action potential duration over a wide range of concentrations. Drug–drug interactions When CYP3A4 inhibitors and erythromycin were

Miscellaneous antibacterial drugs

Chapter 26

concurrently prescribed, patients had a fivefold greater risk of cardiac sudden death. Ximelagatran There was a pharmaco­ kinetic interaction between erythromycin and ximelagatran in 16 healthy volunteers (mean age 24 years; seven men and nine women) (108cE). They took a single dose of ximelagatran 36 mg on day 1, erythromycin 500 mg tds on days 2–5, and a single dose of ximelagatran 36 mg plus erythromycin 500 mg on day 6. The ratio of AUCs of ximelagatran+erythromycin to ximelaga­ tran alone was 1.82 (95% CI ¼ 1.64, 2.01) and the ratio of Cmax values of melagatran, the active form of ximelagatran, was 1.74 (1.52, 2.00). Erythromycin inhibited P-glycoprotein-mediated transport of both ximelagatran and melagatran in vitro and reduced the biliary excretion of melagatran in rat.

439 (SED-15, 2542; SEDA-28, 284; SEDA-29, 266; SEDA-30, 303)

NITROFURANTOIN

Respiratory

DoTS classification: Reaction: Nitrofurantoin-induced lung disease Dose relation: Hypersusceptibility reaction Time course: Late Susceptibility factors: Female sex Nitrofurantoin has been associated with acute, subacute, and chronic pulmonary adverse reactions. The acute reaction occurs in about 1 in 5000 women after first exposure (113A,114r).

Roxithromycin

Liver A 67-year-old woman developed fulminant hepatitis after taking nitrofuran­ toin (115A).

Respiratory Roxithromycin can cause a hypersensitivity pneumonitis (109A).

Immunologic A 71-year-old woman deve­ loped a lupus-like syndrome associated with hepatitis 2 days after starting nitrofurantoin therapy. Her symptoms rapidly improved with systemic corticosteroids (116A).

(SED-15, 3083; SEDA29, 266; SEDA-30, 303)

Teratogenicity In a case–control study, roxithromycin was not a major teratogen (110c). Drug–drug interactions Cyclophosphamide Roxithromycin inhibits CYP3A4, which is involved in cyclophosphamide metabolism, and inhibits P-glycoprotein (111AE).
A 66-year-old man developed hepatic veno­

occlusive disease while taking immunosup­ pressive doses of cyclophosphamide 100 mg/ day and roxithromycin 600 mg/day; after all drugs were withdrawn he recovered within 2 weeks (112A).

In vitro, the combination of cyclophosphamide and roxithromycin, but not the individual compounds, was toxic to endothelial cells by inducing apoptosis.

(SED-15, 2645; SEDA-28, 284; SEDA-29, 266; SEDA-30, 304)

OXAZOLIDINONES

Linezolid was the first of an entirely new class of antibiotics, the oxazolidinones, in decades. It has a spectrum of activity against virtually all important Gram-positive patho­ gens. Its unique mechanism of action makes cross-resistance with other antimicrobial agents unlikely. Observational studies In a retrospective analysis in 44 patients taking linezolid (mean duration 29; range 8–185 days), the

440 clinical cure rate was 73%; 28 had adverse reactions (thrombocytopenia, n ¼ 13; anemia, n ¼ 7; gastrointestinal, n ¼ 12; peripheral neuropathy, n ¼ 1; serotonin syndrome, n ¼ 1) (117c). Nervous and sensory systems Long-term use of linezolid can be associated with severe peripheral and optic neuropathy. Eight patients with multidrug-resistant tuberculo­ sis were treated with linezolid 600 mg/day plus at least four other drugs (118c). Cultures became negative in all patients in an average of 82 days. Four patients developed a peripheral neuropathy, two developed an optic neuropathy, and one developed anemia. Although the optic neuropathy resolved after withdrawal of linezolid the peripheral neuropathy persisted. Three patients stopped taking linezolid after 7–9 months, two because of adverse effects and one for economic reasons. There have been several reports of optic and peripheral neuropathies (119A,120A).
A 65-year-old man who had taken linezolid

600 mg bd for 1 year because of an infection with a multidrug-resistant Staphylococcus aureus (MRSA) developed bilateral gradual loss of vision over 2 months. Linezolid was with­ drawn and his visual acuities returned to normal over 15 months.
A 40-year-old monocular woman with pyo­ derma gangrenosum who was taking long-term corticosteroids developed progressive, painless, loss of central vision in her remaining eye over 2 weeks after taking ciprofloxacin and linezolid 600 mg bd for recurrent meticillin-resistant Staphylococcus aureus (MRSA) infections for 6 months. At the same time she developed distal numbness and paresthesia. Linezolid was withdrawn and 1 month later her color vision had improved to 8/14. Four months later, there was 70% subjective improvement, a visual acuity of 20/40, normalization of the visual field, and mild nerve pallor. The peripheral numbness and tingling did not improve. Normal vision persisted 18 months later.
A 66-year-old man developed progressive, painless, bilateral loss of vision and peripheral numbness after taking rifampicin and linezolid 600 mg bd for 5 months. Both drugs were withdrawn and 3 months later his visual acuity was 20/25 in the right eye and 20/20 in the left and there was resolution of the disc edema. The peripheral numbness persisted.
A 79-year-old woman developed progressive, painless loss of vision, more in the left eye than the right over 1 month after taking linezolid for

Chapter 26

N. Corti and A. Imhof

10 months. There was also an axonal neuro­ pathy, which was attributed to linezolid that was withdrawn. Three months later, she reported subjective visual improvement, and the acuity in the left eye was 20/50. However, the acuity in the right amblyopic eye was unchanged. Six months later, the acuity in the left eye was 20/30. Color vision and Goldmann visual field improved. The neuropathy was unchanged.

Bell’s palsy has been reported in a 49-year-old man after 3 weeks of linezolid therapy; the symptoms recurred after rechallenge (121A). Hematologic In a retrospective case– control study of linezolid in 91 patients with end-stage renal disease, 28 of whom were receiving hemodialysis, and patients with non-end-stage renal disease, severe thrombocytopenia and anemia were signifi­ cantly more frequent in the former: 79% versus 43% and 71% versus 37% respec­ tively (122c). Survival analysis for the development of thrombocytopenia or death showed significant differences between the two groups. Metabolism Hyperlactatemia and metabolic acidosis are adverse effects of line­ zolid that could be related to its capacity for interfering with mitochondrial function. A 63-year-old woman developed an optic neuropathy, encephalopathy, skeletal myo­ pathy, lactic acidosis, and renal failure after taking linezolid for 4 months (123AE). Mitochondrial respiratory chain enzyme activity was reduced in affected tissues, without ultrastructural mitochondrial abno­ rmalities and without mutations or deple­ tion of mtDNA. In experimental animals, linezolid caused a dose- and time-related reduction in the activity of respiratory chain complexes containing mtDNA-encoded subunits and reduced the amount of protein in these complexes, whereas the amount of mtDNA was normal. These results provide direct evidence that linezolid inhibits mito­ chondrial protein synthesis, with potentially severe clinical consequences. Linezolid-induced hyperlactatemia has also been described in a 59-year-old patient during treatment with linezolid after liver transplantation (124A).

Miscellaneous antibacterial drugs

Chapter 26

Susceptibility factors Renal disease In 20 critically ill patients linezolid was signi­ ficantly eliminated by continuous veno­ venous hemofiltration (125r). The total clearance was 25% higher and the trough serum concentration was 50% lower than in normal conditions. There was large interindividual variability, and the authors con­ cluded that the standard dosage of 600 mg 12-hourly might be ineffective in some patients receiving continuous venovenous hemofiltration; that is, it might be ineffec­ tive for the least-susceptible pathogens that have an MIC of >4 mg/l. They also con­ cluded that increasing the dosage to 600 mg 8-hourly might be warranted in selected patients to assure optimal antibacterial activity. Both of the main metabolites of linezolid, PNU-142300 and PNU-142585, accumulated significantly in anuric patients receiving continuous venovenous hemofil­ tration. The clinical relevance of these inactive metabolites is unknown. However, because prolonged use of linezolid might be associated with severe hemopoietic and neurological adverse effects, special atten­ tion has to be paid to the potential toxicity associated with linezolid accumulation. In a 33-year-old man linezolid was not cleared significantly by continuous venove­ nous hemofiltration, which contributed 22 ml/minute of clearance to the total clearance (126A). Drug–drug interactions SSRIs The use of linezolid with medications that increase concentrations of serotonin in the central nervous system can result in serotonin toxicity (127r,128R,129r). Serotonin synd­ rome due to an interaction of linezolid with sertraline has been described (130A). In a retrospective chart review of 72 inpa­ tients at the Mayo Clinic, 52 received concomitant therapy with linezolid and an SSRI or venlafaxine within 14 days, and 20 did not but did receive linezolid and an SSRI separately within 14 days of each other (131c,132r). Overall, only two patients had a high probability of serotonin syn­ drome, and in both cases the symptoms rapidly resolved on withdrawal of the SSRI. An interaction of duloxetine 60 mg/day with noradrenaline and linezolid caused

441 serotonin syndrome man (127A).

in

a

55-year-old

Management of adverse reactions A 41-year-old woman who was allergic to oxazolidinones was successfully desensi­ tized with oral administration of an intra­ venous formulation of linezolid (133A).

POLYMYXINS Cardiovascular Transient hypotension occur­ red in a 62-year-old man after simultaneous administration of intravenous colistin 2 million IU and aerosolized colistin 2 million IU for the management of multidrug-resistant Pseudomonas aeruginosa (134A). Two possible explanations were considered. First, colistin is a relatively potent stimulator of degranulation of rat mast cells, and histamine released from mast cells reduces blood pressure. Secondly, colistin stimulates the activity of pseudomonal elastase, which might play a role in causing hypotension. Respiratory Treatment with aerosolized colistin can be complicated by bronchoconstriction and chest tightness (135R). However, treatment with aerosolized beta2­ adrenoceptor agonists before starting treat­ ment with aerosolized colistin could prevent this (136r). Nervous system The most common neuro­ logical adverse effect of colistin is paresthe­ sia, which occurs in about 27% and 7.3% of patients receiving intravenous and intramus­ cular colistimethate sodium respectively. This is associated with dizziness, muscle weakness, which can be generalized, facial and peripheral paresthesia, partial deafness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia, and neuromuscular blockade. The last of these usually produces a myasthenia-like clinical syn­ drome, as well as apnea due to respiratory muscle paralysis (135R). Neuromuscular function Neuromuscular blockade induced by polymyxins has been

442 attributed to a presynaptic action, through blockade of the release of acetylcholine into the synaptic gap (135R). Skin Hypersensitivity reactions, rash, urticaria, generalized itching, and fever have been described during therapy with colistin (135R). Urinary tract The incidence of nephro­ toxicity attributable to colistin was 36% in patients with pre-existing acute or chronic renal disease and 20% in a study of 288 patients. Additionally, in three studies intravenous colistimethate sodium was given for the treatment of patients with Gram-negative bacterial infections, 10.5% of patients had prolonged increase of blood urea nitrogen levels, 26.1% of patients experienced renal impairment during ther­ apy, and 50% had a fall in creatinine clearance and an increase in serum creati­ nine levels. Another interesting finding was the relatively high number of case reports that were published in the old literature, reporting patients who experienced acute renal failure during treatment with colisti­ methate sodium. However, in most of these cases the total daily dose of colistimethate sodium was considerably higher compared to the currently recommended dose. Of note, polymyxin B was reported in the old literature to be associated with a relatively increased incidence of toxicity compared to colistimethate sodium. However, these data were not verified in two recent studies that showed that the incidence of nephrotoxicity was 14% and 10% among patients receiving polymyxin B therapy. It has been suggested that the toxicity of polymyxins may be partly due to their d-amino acid content and fatty acid component. The proposed mechanism by which polymyxin B induces nephrotoxic events is by increasing mem­ brane permeability, resulting in an increased influx of cations, anions, and water, leading to cell swelling and lysis. Renal toxicity associated with the use of polymyxins is considered to be dosedependent (135R,137r). Drug formulations Dry powder inhalation may be an alternative to nebulization of colistin in the treatment of chest infections

Chapter 26

N. Corti and A. Imhof

in patients with cystic fibrosis. Colistin 25 mg of dry-by-dry powder inhaler (proto­ type Twincer) has been compared with 158 mg by nebulization in 10 patients with cystic fibrosis a randomized crossover study (138C). The dry powder was well tolerated and there was no significant reduction in FEV1. The relative availability of colistin by dry powder inhalation was about 140% based on actual dose. Similar results were reported in 10 healthy volunteers (139c). Drug–drug interactions The concurrent use of polymyxins with curariform muscle relaxants and other neurotoxic drugs such as ether, suxamethonium, decamethonium, and sodium citrate, must be avoided, since these agents can trigger neuromuscular blockade. Co-administration of sodium cephalothin and polymyxins can increase the risk of neurotoxicity (135R). Drug overdose Overdoses are mainly reported with colistimethate sodium (135R). There is no antidote for polymyxin overdose. Management requires early wiht­ drawal of the medication and appropriate supportive treatment. In the presence of established acute renal failure, hemodialysis and peritoneal dialysis can only manage renal complications, since they have little influence on the elimination of polymyxins. If apnea occurs, mechanical ventilatory support is needed.

(SED-15, 3182; SEDA-28, 285; SEDA-29, 269; SEDA-30, 307)

STREPTOGRAMINS

Pristinamycin Pristinamycin is a mixture of water-insolu­ ble pristinamycin IA and pristinamycin IIA, derived from Streptomyces pristinaespiralis. The former is a group B streptogramin (a peptidic macrolactone or depsipeptide) and the latter is a group A streptogramin (a polyunsaturated macrolactone). Sepa­ rately, group A and group B streptogramins

Miscellaneous antibacterial drugs

Chapter 26

are bacteriostatic, by reversible binding to the 50 S subunit of 70 S bacterial ribosomes. Together, however, streptogramins from each group are synergic and bactericidal. Skin Occupational airborne contact dermatitis from pristinamycin has been reported (140A).
A 23-year-old man was exposed to pristina­

mycin powder while working for a pharma­ ceutical company. He used rubber mask and gloves as protective equipment, but developed a pruritic dermatitis involving the neck, eye­ lids, and cheeks, characterized by erythema, edema, and scales. The skin lesions improved during holidays and with topical corticoster­ oids, and recurred when he restarted work. Patch testing with pristinamycin 1%, 5%, and 10% in equal volume mixtures of water and alcohol were negative at 20 minutes but positive at 2 and 4 days. Control tests in 10 patients were negative.

Quinupristin/dalfopristin Quinupristin/dalfopristin is a semisynthetic injectable streptogramin combination. Sev­ eral challenges to its use have emerged (141R). First, a substantial number of patients have developed myalgia, in many cases severe enough to necessitate with­ drawal of therapy. Some patients who had continue therapy did so only with the co­ administration of opioid analgesia. Sec­ ondly, quinupristin/dalfopristin can cause severe venous irritation, necessitating administration through a central venous catheter. Thirdly, resistance of vancomy­ cin-resistant enterococci to quinupristin/ dalfopristin emerged fairly rapidly after its clinical introduction. Finally, quinupristin/ dalfopristin interacts with drugs metabo­ lized by CYP isoenzymes, such as calci­ neurin inhibitors used in transplantation. Observational studies The safety profile of quinupristin/dalfopristin has been evaluated in more than 2000 patients (142R). The most common adverse effect was pain and inflammation at the infusion site. However, treat­ ment withdrawal was reported in o10% of patients. Other adverse effects include arthralgias (9%) and myalgias (6%), which

443 have led to the withdrawal of quinupristin/ dalfopristin in one-third to a half of affected patients. Other common systemic adverse events have been nausea (4.6%), diarrhea (2.7%), vomiting (2.7%), rash (2.5%), headache (1.6%), pruritus (1.5%), and pain (1.5%). Liver function abnormalities have occurred in about 1% of patients who received quinupristin/dalfopristin. However, these effects have generally been mild and transient. No significant effects on renal function have been reported and bone marrow toxicity has been rare. Musculoskeletal Arthralgias and myalgias have been reported in a retrospective study in 11 children (143c). Quinupristin/dalfopris­ tin was begun in a dose of 7.5 mg/kg 8-hourly intravenously. Treatment was planned for at least 14 days, or longer if there was no clinical improvement. Seven children com­ pleted the complete course without any adverse effects. In four children, treatment was stopped because of myalgia and arthral­ gia, and the median time to stopping treatment was 7 (range 7–35) days. All four children needed analgesics; three required additional narcotic analgesics, of whom two required continuous morphine infusion and intensive input from the pain team. In one child, in whom vancomycin-resistant enter­ ococci were isolated from the bile, mechan­ ical ventilation was considered in order that treatment could be maintained pain-free; this child died of overwhelming sepsis after withdrawal of the antibiotic. Of the other three, two were treated with linezolid and one completed the course of quinupristin/ dalfopristin while receiving mechanical ven­ tilation for respiratory deterioration. Cytotoxicity Infusion phlebitis is a com­ mon problem with quinupristin/dalfopristin. Cultured murine fibroblasts and immorta­ lized human endothelial cells were exposed to quinupristin/dalfopristin, erythromycin, and levofloxacin at clinically relevant con­ centrations to assess their toxic potential in two cytotoxicity assays (144E). Quinu­ pristin/dalfopristin and erythromycin had concentration-related cytotoxic effects in both cell cultures. Cytotoxic effects in both cell cultures occurred in the following

444

Chapter 26

N. Corti and A. Imhof

order: quinupristin/dalfopristin W erythro­ mycin WW levofloxacin. This ranking corre­ lates well with the frequency of local adverse effects observed with the infusion of these antibiotics.

of patients (146r). The most common are mild gastrointestinal distress and cutaneous events; a wide range of hematological abnormalities have also been ascribed to co-trimoxazole.

Monitoring therapy Quinupristin/dalfo­ pristin are active and are converted to active metabolites that contribute to the antimicrobial activity of the formulation (142R). The half-life of quinupristin and its metabolites is about 3 hours and the halflife of dalfopristin and its metabolites is about 1 hour. About 75% of a dose is eliminated by the gastrointestinal tract, and urinary excretion accounts for 15% of a dose of quinupristin and 19% of a dose of dalfopristin. The peak plasma concentra­ tion after a single intravenous dose of 7.5 mg/kg is 2.3 mg/l for quinupristin and 6.5 mg/l for dalfopristin. Both components penetrate well into interstitial fluid. There is a prolonged post-antibiotic effect of about 10 hours for Staphylococcus aureus and 9 hours for Streptococcus pneumoniae.

In a randomized comparison of co­ trimoxazole (800/160 mg/day of trimetho­ prim+sulfamethoxazole 5 days a week) versus norfloxacin (400 mg/day) in prevent­ ing spontaneous bacterial peritonitis in 54 patients with cirrhosis and ascites, adverse effects occurred only in patients using co­ trimoxazole (147C). There were five epi­ sodes. One patient had a rash, which disappeared spontaneously, two com­ plained of epigastric pain, and the other two had worsening of renal function unat­ tributable to other causes.

Virginiamycin

(SEDA-26, 293; SEDA28, 288; SEDA-29, 273; SEDA-30, 307)

Drug tolerance (antibacterial resistance) The use of virginiamycin has been linked with the selection of quinupristin/ dalfopristin-resistant Enterococcus faecium (145E). Because virginiamycin has been used in animals but streptogramins have been used infrequently in human medicine, an animal origin of resistance is suggested, and spread of resistance via the food chain to humans is probable.

SULFONAMIDES, TRIMETHOPRIM, AND CO-TRIMOXAZOLE (SED-15, 3216, 3510; SEDA-28, 285; SEDA-29, 270; SEDA-30, 308)

Comparative studies Adverse drug rea­ ctions due to co-trimoxazole occur in 6–8%

Psychiatric Acute psychosis is rarely asso­ ciated with co-trimoxazole.
An acute psychosis occurred in a 46-year-old

woman who had taken oral co-trimoxazole (160+800 mg bd) for a urinary tract infection (148A). She started to have psychotic symp­ toms with bizarre behavior 10 days after starting therapy. After withdrawal and anti­ psychotic drug treatment, her mental state resolved to a stable premorbid level within 36 hours.

Sensory systems Optic disc and retinal vasculitis is rarely associated with co­ trimoxazole.
A 53-year-old woman with recurrent painful

urticarial skin lesions associated with a vascu­ litis after using co-trimoxazole started to have visual disturbances in both eyes 2 years after the cutaneous manifestations, recurring at 1-year intervals (149A). Her ophthalmological findings were consistent with recurrent vascu­ litis of the optic nerve and retina. Treatment with high-dose corticosteroids and hydroxychloroquine resulted in the resolution of the cutaneous and ocular manifestations.

Hematologic In a placebo-controlled trial of co-trimoxazole prophylaxis in Cóte d’Ivoire, neutropenia was the most frequent short-term adverse effect (150C). In 533 HIV-infected adults receiving co­ trimoxazole (sulfamethoxazole 800 mg

Miscellaneous antibacterial drugs

Chapter 26

+trimethoprim 160 mg daily), followed-up for 1450 person-years, the probability of remaining free of neutropenia at 48 months was 0.29 (95% CI ¼ 0.23, 0.34) for grade 1 or worse, 0.64 (95% CI ¼ 0.60, 0.71) for grade 2 or worse, 0.82 (95% CI ¼ 0.77, 0.86) for grade 3 or worse, and 0.96 (95% CI ¼ 0.93, 0.99) for grade 4. The only factor that was significantly associated with a higher rate of all grades of neutropenia was a low baseline CD4 count. There was no association between any grade of neutro­ penia and the global risk of serious morbid­ ity during the study period.
A 40-year-old man developed early onset

neutropenia, thrombocytopenia, and a gener­ alized rash after taking co-trimoxazole for 5 days (146A). Despite thrombocyte transfu­ sions, whole blood transfusions, red cell con­ centrates, and filgrastim therapy he died.

Liver In a retrospective study of reports of suspected hepatic adverse drug reactions with fatal outcomes received by the Uppsala Monitoring Centre from 1968 to 2003, 52 patients who had taken co-trimoxazole died because of liver failure (151c). Skin Two cases of fixed drug eruption of the penis have been described in patients taking co-trimoxazole (152A,153A). In 81 Nigerian patients with fixed drug eruption there was an association with co­ trimoxazole in 23 (154c). Co-trimoxazole caused mainly genital and oral lesions, with a predilection for mucocutaneous junctions. A fixed drug eruption with polysensitivity to piroxicam and co-trimoxazole has been reported in a 38-year-old man (155A). Musculoskeletal Co-trimoxazole can cause rhabdomyolysis in HIV-positive patients.
A 39-year-old African–American man devel­

oped rhabdomyolysis after taking co-trimoxazole for 14 days (two double-strength tablets qds for presumed Pneumocystis jiroveci pneumonia); 6 months after co-trimoxazole withdrawal he had normal laboratory parameters (156A).

Metabolism In 14 cases of refractory hypoglycemia complicated by seizures

445 associated with co-trimoxazole, renal insuf­ ficiency was a predisposing risk factor in 13 (157c). The mean daily dose of co-trimox­ azole was 4.5 double-strength tablets per day (trimethoprim 160 mg+sulfamethoxa­ zole 800 mg). Serum insulin concentrations were increased or inappropriately normal in most of those in whom they were measured, suggesting a sulfonylurea-like effect of co-trimoxazole as the mechanism of hypo­ glycemia. All required intravenous glucose, and six had protracted hypoglycemia. Immunologic In a prospective observa­ tional study in 94 patients with reported sulfonamide allergies, co-trimoxazole allergy was reported by 42 patients, while 42 did not recall the drug to which they were allergic (158C). The allergy had caused a rash in 59 patients, anaphylaxis in 13, and Stevens– Johnson syndrome in two. The median time since the last reported allergic reaction to a sulfonamide-containing agent was 20 years. Forty patients had been taking a non­ antibiotic sulfonamide for an average of 6.2 years as outpatients; in 24 cases the sulfona­ mide was furosemide, and 16 reported an allergy to co-trimoxazole. Nine patients had received a non-antibiotic sulfonamide as inpatients (range 2–23 days), most commonly furosemide; there were no adverse events before admission or during the inpatient stay.
An 82-year-old woman with a history of

hypersensitivity reactions to co-trimoxazole, resulting in angioedema, developed angioe­ dema and severe dysphagia, shortness of breath, and rash after taking valsartan and hydrochlorothiazide for 4 months (159A). Valsartan was identified as the most likely cause of the symptoms and was withdrawn; however, she continued to have weekly episodes of angioedema and when hydrochlor­ othiazide withdrawn the angioedema disap­ peared. It recurred more severely after reintroduction of hydrochlorothiazide. Hydro­ chlorothiazide was permanently withdrawn and the angioedema did not recur.

Hypersensitivity syndrome in patients taking co-trimoxazole associated with the reactivation of herpesvirus (HHV)-6 infection has been described.
A 27-year-old man with a history of bronchial

asthma, eosinophilic enteritis, and eosinophilic

Chapter 26

446 pneumonia developed a fever, skin eruptions, cervical lymphadenopathy, hepatosplenome­ galy, atypical lymphocytosis, and eosinophilia 2 weeks after taking co-trimoxazole (160A). After withdrawal of co-trimoxazole and the administration of high-dose steroids, the sys­ temic symptoms gradually resolved. During the disease course, the patient had a transient increase in anti-human HHV-6 antibody titers and HHV-6 DNA in the peripheral blood, indicating reactivation of a latent HHV-6 infection.
HHV-6 encephalitis associated with hypersen­ sitivity syndrome induced by co-trimoxazole has been described in a 72-year-old woman (161A).

OTHER ANTIMICROBIAL DRUGS Daptomycin

(SED-15, 1053; SEDA-28, 287; SEDA-29, 271; SEDA-30, 309)

Daptomycin is a cyclic lipopeptide antibio­ tic used in the treatment of serious Grampositive infections, including those caused by meticillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Daptomycin was initially developed in the late 1980s and early 1990s but was ulti­ mately shelved owing to concerns regarding adverse effects, in particular drug-induced myopathy (162R,163R). In clinical trials, the most common adverse effects included gastrointestinal disorders, for example constipation (6%), nausea (6%), and diarrhea (5%), injection site reactions (6%), headache (5%), and rash (4%) (164R). Placebo-controlled studies Three cohorts of 12 healthy subjects each were given daptomycin 10 mg/kg or placebo once daily for 14 days, daptomycin 12 mg/kg or pla­ cebo once daily for 14 days, or daptomycin 6 or 8 mg/kg once daily for 4 days. Daptomy­ cin did not cause electrocardiographic abnormalities or electrophysiological evi­ dence of muscle or nerve toxicity (165C). Nervous system patients with

In a randomized trial, 120 Staphylococcus aureus

N. Corti and A. Imhof

bacteremia with or without endocarditis received daptomycin 6 mg/kg/day intrave­ nously and 115 received initial low-dose gentamicin plus either an antistaphylococ­ cal penicillin or vancomycin (166C). Eleven of the 120 patients who received daptomy­ cin (9.2%) had adverse events related to the peripheral nervous system (e.g., paresthesia, dysesthesia, and peripheral neuropathies) compared with two of 116 patients (1.7%) who received standard therapy. All of the events were classified as mild to moderate in intensity; most were short-lived and resolved during continued treatment. Musculoskeletal Daptomycin has been associated with raised creatine kinase activity, with a reported incidence of 2.8% in phase III clinical trials (167A). Rhabdomyolysis has also been described (168A).
A 45-year-old woman with refractory acute

myeloid leukemia was given intravenous daptomycin 550 mg (6 mg/kg) every 24 hours because of bacteremia due to vancomycinresistant enterococci. She was neutropenic (white cell count o400  106/l; absolute neu­ trophil count 10  106/l). Her creatine kinase activity was 108 U/l at baseline, but it gradually increased over the next 7 days, and on day 10 of daptomycin therapy had risen to 996 U/l. The blood urea nitrogen concentration was 26 mmol/l (73 mg/dl) and the serum creatinine 168 mmol/l (1.9 mg/dl). Myoglobin was present in a high concentration in the urine. Dapto­ mycin was withdrawn and she recovered over a period of 2 weeks with hydration.
A 53-year-old African–American woman with diabetes mellitus, hypertension, and peripheral vascular disease was given daptomycin 360 mg/ day (6 mg/kg/day) intravenously and after 10 days developed generalized muscle weak­ ness progressing to the point where she could not walk or even get out of bed, followed by non-oliguric acute renal failure with a serum creatinine rising to 239 mmol/l from a baseline of 80 ìmol/l. The serum creatine kinase activity was raised at 21 243 U/l, as were transaminase and lactate dehydrogenase activities. Urinaly­ sis was positive for red blood cells, hemoglo­ bin, and myoglobin. Daptomycin was withdrawn and she was given intravenous fluids with urine alkalinization. She progres­ sively recovered.

In a randomized trial, 120 patients with Staphylococcus aureus bacteremia with or without endocarditis received daptomycin 6 mg/kg/day intravenously and 115 received

Miscellaneous antibacterial drugs

Chapter 26

initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin (166C). Of the 120 who received daptomy­ cin, 62 (52%) had a serious adverse event. Rises in CK activity were significantly more common in the daptomycin group than the standard-therapy group (6.7% versus 0.9%). Among patients with normal baseline CK activity, there were rises in CK activity in 23 of 92 patients who received daptomycin compared with 12 of 96 patients who received standard therapy (25% versus 13%). Raised CK activity led to withdrawal of treatment in 3 of 120 patients treated with daptomycin (2.5%). In 20 of the 24 patients who received daptomycin and who had increased CK activity at baseline (83%), the CK activity returned to the reference range during treatment (n ¼ 18) or after treat­ ment (n ¼ 2). Three patients had small rises in CK (range 114–451 U/l) throughout the course of daptomycin therapy. Drug–drug interactions No drug–drug interactions have been reported with dapto­ mycin. Nevertheless, the manufacturer recommends giving consideration to tem­ porarily discontinuing HMG CoA reductase inhibitors while patients take daptomycin because of the potential confusion that could occur if a patient taking an HMG CoA reductase inhibitor were to experience myo­ pathy or an increase in CK activity (162R).

Fosmidomycin

(SED-15, 1450; SEDA28, 287; SEDA-29, 272; SEDA-30, 310)

Fosmidomycin inhibits 1-deoxy-d-xylulose 5-phosphate reductoisomerase, a key enzyme in the non-mevalonate pathway of

447 isoprenoid biosynthesis. It inhibits the synthesis of isoprenoids by Plasmodium falciparum and suppresses the growth of multidrug-resistant strains in vitro. Hematologic In a single-arm study of an oral 3-day fixed-ratio combination of fosmidomycin 30 mg/kg and clindamycin 10 mg/kg every 12 hours for uncomplicated Plasmodium falciparum malaria in 51 chil­ dren aged 1–14 years, one serious adverse event was reported in a boy aged 2.7 years who developed severe anemia on day 2 (169AC). His hemoglobin concentration fell from 9.2 g/dl on admission to 4.5 g/dl on day 2. He was given parenteral quinine but no blood transfusion. He made an uneventful recovery. In the whole group mean hemo­ globin concentration, mean leukocyte count, and mean alanine transaminase activity fell significantly from day 0 to day 2. In seven patients (including the patient described above) the hemoglobin concentration fell by 2 g/dl but remained above 8 g/dl in all but two patients and subsequently recovered by day 28. The glucose-6-phosphate dehydro­ genase status of these patients was not determined. The neutrophil counts in two of three patients with grade I neutropenia on admission recovered slightly by day 2 but fell further in the third patient from 1200 to 700  106/l, resulting in grade II neutropenia on day 2. Seven other patients aged 6–9 years developed transient asymptomatic neutro­ penia on day 2 (six grade I and one grade II). In four other patients, the neutrophil count fell below 1500  106/l (grade I) between days 7 and 14. Neutrophil counts returned to normal values by day 7 in all patients with day 2 neutropenia, without intervention. Neutropenia did not occur in children under 6 years old.

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454 142. Al-Tatari H, Abdel-Haq N, Chearskul P, Asmar B. Antibiotics for treatment of resistant Gram-positive coccal infections. Indian J Pediatr 2006;73(4):323–34. 143. Gupte G, Jyothi S, Beath SV, Kelly DA. Quinupristin–dalfopristin use in children is associated with arthralgias and myalgias. Pediatr Infect Dis J 2006;25(3):281. 144. Kruse M, Kilic B, Flick B, Stahlmann R. Effect of quinupristin/dalfopristin on 3T3 and Eahy926 cells in vitro in comparison to other antimicrobial agents with the poten­ tial to induce infusion phlebitis. Arch Toxicol 2007;81(6):447–52. 145. Kieke AL, Borchardt MA, Kieke BA, Spencer SK, Vandermause MF, Smith KE, Jawahir SL, Belongia EA. Use of streptogramin growth promoters in poultry and isolation of streptogramin-resistant Enterococcus faecium from humans. J Infect Dis 2006;194(9):1200–8. 146. Kocak Z, Hatipoglu CA, Ertem G, Kinikli S, Tufan A, Irmak H, Demiroz AP. Trimethoprim–sulfamethoxazole induced rash and fatal hematologic disorders. J Infect 2006;52(2):e49–52. 147. Alvarez RF, Mattos AA, Correa EB, Cotrim HP, Nascimento TV. Trimetho­ prim–sulfamethoxazole versus norfloxacin in the prophylaxis of spontaneous bacterial peritonitis in cirrhosis. Arq Gastroenterol 2005;42(4):256–62. 148. Weis S, Karagulle D, Kornhuber J, Bayer­ lein K. Cotrimoxazole-induced psychosis: a case report and review of literature. Pharmacopsychiatry 2006;39(6):236–7. 149. Batioglu F, Taner P, Aydintug OT, Heper AO, Ozmert E. Recurrent optic disc and retinal vasculitis in a patient with druginduced urticarial vasculitis. Cutan Ocul Toxicol 2006;25(4):281–5. 150. Toure S, Gabillard D, Inwoley A, Seyler C, Gourvellec G, Anglaret X. Incidence of neutropenia in HIV-infected African adults receiving co-trimoxazole prophy­ laxis: a 6-year cohort study in Abidjan, Cote d’Ivoire. Trans R Soc Trop Med Hyg 2006;100(8):785–90. 151. Bjornsson E, Olsson R. Suspected druginduced liver fatalities reported to the WHO database. Dig Liver Dis 2006;38(1): 33–8.

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N. Corti and A. Imhof

152. Lawrentschuk N, Pan D, Troy A. Fixed drug eruption of the penis secondary to sulfamethoxazole–trimethoprim. Sci World J 2006;:62319–22. 153. Rasi A, Khatami A. Unilateral nonpigmenting fixed drug eruption associated with cotrimoxazole. Dermatol Online J 2006;12(6):12. 154. Nnoruka EN, Ikeh VO, Mbah AU. Fixed drug eruption in Nigeria. Int J Dermatol 2006;45(9):1062–5. 155. Ozkaya E. Polysensitivity in fixed drug eruption due to a novel drug combinationindependent lesions due to piroxicam and cotrimoxazole. Eur J Dermatol 2006;16(5): 591–2. 156. Walker S, Norwood J, Thornton C, Scha­ berg D. Trimethoprim–sulfamethoxazole associated rhabdomyolysis in a patient with AIDS: case report and review of the literature. Am J Med Sci 2006;331(6): 339–41. 157. Strevel EL, Kuper A, Gold WL. Severe and protracted hypoglycaemia associated with co-trimoxazole use. Lancet Infect Dis 2006;6(3):178–82. 158. Hemstreet BA, Page 2nd. RL. Sulfona­ mide allergies and outcomes related to use of potentially cross-reactive drugs in hos­ pitalized patients. Pharmacotherapy 2006; 26(4):551–7. 159 Ruscin JM, Page 2nd. RL, Scoot J. Hydro­ chlorothiazide-induced angioedema in a patient allergic to sulfonamide antibiotics, evidence from a case report and a review of the literature. Am J Geriatr Pharmac­ other 2006;4(4):325–9. 160. Morimoto T, Sato T, Matsuoka A, Saka­ moto T, Ohta K, Ando T, Ikushima S, Hagiwara K, Matsuno H, Akiyama O, Oritsu M. Trimethoprim–sulfamethoxa­ zole-induced hypersensitivity syndrome associated with reactivation of human herpesvirus-6. Intern Med 2006;45(2): 101–5. 161. Mohammedi I, Mausservey C, Hot A, Najioullah F, Kanitakis J, Robert D. Asso­ ciation d’une encéphalite a herpes virus 6 et d’un syndrome d’hypersensibilité médica­ menteuse au triméthoprime–sulfaméthoxa­ zole. [Human herpesvirus 6 encephalitis in trimethoprim–sulfamethoxazole-induced

Miscellaneous antibacterial drugs

162.

163.

164.

165.

166.

Chapter 26

hypersensitivity syndrome.] Rev Med Interne 2006;27(6):499–501. Shoemaker DM, Simou J, Roland WE. A review of daptomycin for injection (Cubi­ cin) in the treatment of complicated skin and skin structure infections. Ther Clin Risk Manag 2006;2(2):169–74. Lee SY, Fan HW, Kuti JL, Nicolau DP. Update on daptomycin: the first approved lipopeptide antibiotic. Expert Opin Phar­ macother 2006;7(10):1381–97. Rybak MJ. The efficacy and safety of daptomycin: first in a new class of anti­ biotics for Gram-positive bacteria. Clin Microbiol Infect 2006;12(Suppl):124–32. Benvenuto M, Benziger DP, Yankelev S, Vigliani G. Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers. Antimicrob Agents Che­ mother 2006;50(10):3245–9. Fowler Jr. VG, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, Levine DP, Chambers HF, Tally FP, Vigliani GA, Cabell CH, Link AS,

455 DeMeyer I, Filler SG, Zervos M, Cook P, Parsonnet J, Bernstein JM, Price CS, Forrest GN, Fatkenheuer G, Gareca M, Rehm SJ, Brodt HR, Tice A, Cosgrove SE. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006;355(7):653–65. 167. Papadopoulos S, Ball AM, Liewer SE, Martin CA, Winstead PS, Murphy BS. Rhabdomyolysis during therapy with dapto­ mycin. Clin Infect Dis 2006;42(12):e108–10. 168. Kazory A, Dibadj K, Weiner ID. Rhabdo­ myolysis and acute renal failure in a patient treated with daptomycin. J Anti­ microb Chemother 2006;57(3):578–9. 169. Borrmann S, Lundgren I, Oyakhirome S, Impouma B, Matsiegui PB, Adegnika AA, Issifou S, Kun JF, Hutchinson D, Wiesner J, Jomaa H, Kremsner PG. Fosmidomycin plus clindamycin for treatment of pediatric patients aged 1 to 14 years with Plasmodium falciparum malaria. Antimicrob Agents Chemother 2006;50(8):2713–8.

J.K. Aronson

27

Antifungal drugs

(SEDA-28, 294; SEDA-29, 280; SEDA-30, 316)

ALLYLAMINES Terbinafine

(SED-15, 3316; SEDA-29, 280; SEDA-30, 316) Skin Acute generalized exanthematous pustulosis, despite corticosteroid therapy, has been attributed to terbinafine (1A).


A 62-year-old woman, who had been taking

prednisolone 10 mg/day for 18 months for bullous pemphigoid, was given terbinafine 250 mg/day for a toenail infection. After 8 days she developed a symmetrical papular eruption that began on the face and neck. The papules rapidly coalesced and within 2 days the rash became generalized, with targetoid lesions on the arms and pustules on the back. There was never any mucosal involvement. She was febrile, with a leukocytosis, neutrophilia, and a slightly raised creatinine of 162 mmol/l. She continued to take prednisolone 10 mg/day. A skin biopsy showed small subcorneal pustules, with neutrophils, underlying spongiosis, and an upper dermal lymphocytic infiltrate. Bacterial swabs and fungal scrapings from the pustules were negative. The eruption settled within 12 days of terbinafine withdrawal.

According to the scoring system devised by Sidoroff et al. (2RH) this was probably a case of acute generalized exanthematous pustulosis. This case suggests that steroids may not be effective in preventing the condition. Five patients developed severe rashes while taking oral terbinafine (3c). Splinter hemorrhages developed in fin­ gernails that were affected by Trichophyton rubrum infection 2 months after the start of Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03127-4 r 2009 Elsevier B.V. All rights reserved.

therapy with oral terbinafine 250 mg/day in a 45-year-old Chinese man; the fingernails that were not infected were not involved (4A). Three of the five fingernails resolved 3 months after switching to itraconazole. Musculoskeletal Rhabdomyolysis has been attributed to terbinafine (5A).
A 24-year-old man took terbinafine 250 mg/

day for sycosis barbae for 15 days and developed weakness, myalgia, and dark urine. His creatine kinase activity was 1120 U/l, and renal function was normal. He stopped taking terbinafine and the creatine kinase activity returned to normal.

Immunologic Terbinafine has occasionally been thought to have caused or exacerbated cutaneous lupus erythematosus. Several further cases have been reported.
A 59-year-old man with a history of cutaneous

lupus erythematosus, which had been in complete remission for 5 years, took oral terbinafine for onychomycosis and after 1 month developed cutaneous lupus erythe­ matosus, with typical papulosquamous lesions and a raised titer of antinuclear antibodies (6A). Terbinafine was withdrawn and systemic and topical steroids were given; the eruption resolved over several weeks.
A 50-year-old woman had a severe cutaneous flare-up of pre-existing systemic lupus erythe­ matosus 7 weeks after starting treatment with terbinafine (7A).
A 25-year-old woman with stable systemic lupus erythematosus, who was taking corticos­ teroids and chloroquine 200 mg/day, was given terbinafine for onychomycosis and 7 days later developed cheilitis and bilateral conjunctivitis followed by epidermolysis involving 10% of the skin (8A). There was massive hematuria and proteinuria, and a renal biopsy showed lupus glomerulonephritis. Antihistone antibo­ dies were strongly positive. She was given systemic corticosteroids, chloroquine, and cyclophosphamide and recovered.
A 39-year-old women with systemic lupus erythematosus took terbinafine 250 mg/day

457

458 for onychomycosis and after 7 days developed a widespread severe erythematous eruption (9A). Clinical, histological, and immunofluor­ escent investigations confirmed the diagnosis of co-existing subacute cutaneous and sys­ temic lupus erythematosus. Terbinafine was withdrawn.
Three patients with sicca syndrome, lung carcinoma, and Kikuchi disease were given terbinafine for suspected dermatophytic infec­ tions; each developed subacute cutaneous lupus erythematosus within 7 weeks (10Ar).

Drug–drug interactions Alfentanil In a randomized crossover study in 12 healthy volunteers terbinafine had no statistically significant effect on the pharmacokinetics of intravenous alfentanil 20 mg/kg (11C).

Chapter 27

J.K. Aronson

amphotericin; six occurred within 1 hour (13r). All except one had received a non-lipid-containing formulation.
A 19-year-old girl with acute lymphoblastic

leukemia developed sustained severe arterial hypertension shortly after being given ampho­ tericin and continuing for several hours after the infusion (14Ar).

Electrolyte balance Hypokalemia is a well-recognized adverse effect of ampho­ tericin, but it is rarely severe enough to cause rhabdomyolysis, which has only occasionally been reported (15A).
A 10-year-old boy receiving partial parenteral

Carbamazepine An interaction of terbi­ nafine with carbamazepine has been described (12A). 900 mg/day, bupropion 300 mg/day, and que­ tiapine 300 mg/day for bipolar affective dis­ order, among other drugs, was given terbinafine 250 mg/day. Within 2–3 days he felt dizzy, but continued to take his medica­ tions. Within 2 weeks, his terbinafine tablets ran out and his dizziness abated as well. About 1 month later he started to take terbinafine again and within 3 days his dizziness recurred, causing him to fall on two occasions. He also had blurred vision and double vision. There was nystagmus and numbness of the left face. A CT scan of the head showed no abnormality. His serum carbamazepine concentration was 73 mmol/l (usual target range 17–42).

nutrition was given amphotericin B 1 mg/kg/ day (formulation unspecified) for a catheterrelated infection with Candida albicans. After 6 days he developed hypokalemia (serum potassium 2.2–3.2 mmol/l) and was given daily potassium replacement. One week after a 2-week course of amphotericin B he devel­ oped fatigue, inability to walk, progressive weakness, and pain in the legs, particularly the calves. He was dehydrated and had abdominal distention and reduced bowel sounds. His deep tendon reflexes and muscle strength were markedly reduced, especially in the legs, and there was tenderness on palpation of the calves and thighs. His serum potassium concentration was 1.7 mmol/l, sodium 137 mmol/l, and magnesium 0.62 mmol/l; crea­ tine kinase activity was 3937 U/l, lactate dehydrogenase 432 U/l, aspartate transami­ nase 105 U/l, and alanine transaminase 105 U/l; there was a metabolic alkalosis and myoglobi­ nuria.

The authors pointed out that terbinafine and carbamazepine are both metabolized by CYP3A4, CYP2C9, CYP1A2, CYP2C19, and CYP2C8, and suggested that any of those isoenzymes could have been involved in this interaction.

The authors discussed three mechanisms whereby hypokalemia (below 2.0 mmol/l) can cause rhabdomyolysis: reduced blood flow to anerobic muscles, suppressed synthesis and storage of glycogen, and reduced transmembrane cation transport.

AMPHOTERICIN (SED-15, 192; SEDA-28, 295; SEDA-29, 280; SEDA-30, 317)

Urinary tract In a prospective observa­ tional study in 108 adults who received different formulations of amphotericin, nephrotoxicity was associated with acceler­ ated mortality and, among those who survived, increased duration of hospital stay (16c). There was at least one adverse event in 83 patients and 24% developed nephro­ toxicity, defined as a 50% increase in the


A 50-year-old man taking carbamazepine

Cardiovascular There have been eight cases of hypertension in patients receiving

Antifungal drugs

Chapter 27

baseline serum creatinine and a peak of at least 178 mmol/l (2 mg/dl).

Amphotericin B lipid complex (ABLC) Respiratory The adverse effect of aerosolized ABLC once daily for 4 days, and then once weekly for 13 weeks has been reported in 40 subjects undergoing allogeneic hemopoietic stem cell transplantation in an open noncomparative study (17c). Cough, nausea, taste disturbance, or vomiting occurred after 2.2% of 458 total inhalations; 5.2% of inhalations were associated with a 20% or more fall in FEV1 or forced vital capacity, but no patients required bronchodilators or withdrawal.

459 cumulative doses of amphotericin of 9.6, 14.4, and 25.2 mg/kg with saline compared with oral rehydration. The authors con­ cluded that oral rehydration was compar­ able to intravenous saline in preventing glomerular damage and was associated with less hypokalemia.

Liposomal amphotericin (L-AmB) Cardiovascular A subacute cardiomyo­ pathy occurred in a 37-year-old HIVpositive woman 48 hours after the start of therapy with liposomal amphotericin 200 mg/day for disseminated candidiasis (20A). Amphotericin was replaced by caspofungin 50 mg/day; she was given dobutamine 10 mg/kg/minute and recov­ ered in 9 days.

Amphotericin B deoxycholate (DAMB) Cardiovascular A 41-year-old woman with cryptococcal meningitis and no previous cardiac disease developed a fatal cardiac dysrhythmia, acute renal failure, and anemia after an acute overdose of amphotericin B deoxycholate (18A). The intention had been to give liposomal amphotericin 5 mg/kg/day; however, amphotericin B deoxycholate 5 mg/kg was inadvertently given instead, the usual dose of the deoxycholate formulation being 0.5–0.8 mg/kg/day. Urinary tract In an open randomized trial, an oral rehydration solution (3 l; sodium 90 mmol/l, chloride 104 mmol/l, bicarbonate 22 mmol/l, and potassium 12 mmol/l, osmo­ larity 290 mosm/l) has been compared with intravenous saline (1 l; sodium 153 mmol/l, chloride 153 mmol/l, osmolarity 306 mosm/ l) in the prevention of nephrotoxicity from amphotericin B deoxycholate in 48 adults with mucosal leishmaniasis (19c). There were no differences in serum creatinine, creatinine clearance, serum urea, or serum sodium during treatment. However, serum potassium concentrations were lower at

ANTIFUNGAL AZOLES (SED-15, 301; SEDA-28, 299; SEDA-29, 282; SEDA-30, 320)

Drug–drug interactions with antifungal azoles Mechanisms Drug–drug interactions with antifungal azoles are common and are usually based on two mechanisms, some­ times in combination—inhibition of meta­ bolism, usually by CYP3A4, and inhibition of transport by multidrug transporters. Both of these mechanisms were important in the case of a boy with toxicity from a che­ motherapeutic regimen containing drugs that are handled by these systems (21A).
A 14-year-old boy with Hodgkin’s lymphoma

was given vinblastine, doxorubicin, methotrex­ ate, and prednisone chemotherapy and low-dose radiotherapy. When he was given itraconazole for a presumed fungal infection during an episode of neutropenia, unexpectedly severe bone marrow toxicity and neuropathy suggested toxicity from the chemotherapy due to

460 enhancement by itraconazole. The itraconazole was withdrawn and the neutropenia and neuro­ pathic pain improved.

The authors suggested that itraconazole had interfered with the metabolism of vinblastine, resulting in neurotoxicity, and with the metabolism of doxorubicin and methotrex­ ate and the transport of doxorubicin, result­ ing in bone marrow suppression. A novel mechanism whereby azoles may take part in drug interactions has been described (22E). Drug metabolism is con­ trolled by a class of orphan nuclear receptors that regulate the expression of genes such as CYP3A4 and multidrug resistance-1 (MDR-1). Xenobiotic-mediated induction of CYP3A4 and MDR-1 gene transcription was inhibited by ketoconazole, which acted by inhibiting the activation of human preg­ nenolone X receptor and constitutive androstene receptor, which are involved in the regulation of CYP3A4 and MDR-1. The effect was specific to this group of nuclear receptors. Alfentanil In a randomized crossover study in 12 healthy volunteers, oral vorico­ nazole (400 mg twice on the first day and 200 mg twice on the second day) increased the AUC of intravenous alfentanil 20 mg/kg sixfold, reduced its mean plasma clearance by 85%, from 4.4 to 0.67 ml/minute/kg, and prolonged its half-life from 1.5 to 6.6 hours (11c). Alfentanil caused nausea in five subjects and vomiting in two, all when they were taking voriconazole. The authors attributed this interaction to inhibition of CYP3A by voriconazole. Ciclosporin The combined use of ketoco­ nazole with ciclosporin, by reducing the dose of ciclosporin, can reduce the costs of immunosuppression. In a retrospective study of 102 children with steroid-dependent nephrotic syndrome, 78 received daily keto­ conazole 50 mg dose and a reduced dose of ciclosporin and 24 received ciclosporin alone (23c). The mean duration of treatment was 23 months. Co-administration of ketocona­ zole significantly reduced the mean doses of ciclosporin by 48%, with a net cost saving of 38%. It also resulted in significant

Chapter 27

J.K. Aronson

improvement in the response to ciclosporin, increased success in the withdrawal of steroids, and a reduced frequency of renal impairment. Domperidone Domperidone prolongs the QT interval and increases the risk of serious cardiac dysrhythmias. It is metabolized by CYP3A4. In healthy volunteers ketocona­ zole increased domperidone Cmax and AUC 3–10-fold (24S). There was QT interval prolongation of about 10–20 milliseconds when domperidone 10 mg qds was given with ketoconazole 200 mg bd but not with domperidone alone. This is a potentially dangerous combination. Fentanyl Unintentional overdose of fenta­ nyl has been attributed to inhibition of its metabolism by ketoconazole (25A).
A 46-year-old man was given a Durogesic

(fentanyl) transdermal patch 150 mg/hour for pain, plus morphine 10 mg/day, diclofenac 50 mg tds, paracetamol 1 g tds, oxazepam 15 mg bd, zolpidem 5 mg at night, nystatin, lidocaine oral spray, lactulose, and metoclo­ pramide. Of these drugs, fentanyl, lidocaine, and paracetamol are partly metabolized by CYP3A4. He was then given fluconazole 50 mg/day and after 3 days died in his sleep. Forensic analysis of femoral blood showed a toxic concentration of fentanyl (0.017 ìg/g), high concentrations of fluconazole (2.4 ìg/g), lidocaine (1.6 ìg/g), and metoclopramide (0.15 ìg/g), and a therapeutic concentration of zolpidem (0.07 ìg/g). No ethanol or drugs of abuse were identified. There were no patholo­ gical findings other than pulmonary congestion and brain edema.

The coroner’s conclusion was that the cause of death was respiratory depression and circulatory failure due to fentanyl intoxica­ tion, since the concentration was within the range of other reported lethal intoxications, up to 48 ng/ml. Haloperidol The combined effects of the CYP3A4 inhibitor itraconazole 200 mg/day for 10 days and the CYP2D6�10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol 5 mg, a substrate of both CYP2D6 and CYP3A4, have been studied in 19 healthy subjects (9 CYP2D6�1/�1 and 10 CYP2D6�10/�10) (26C). Four

Antifungal drugs

Chapter 27

subjects (one CYP2D6�1/�1 and three CYP2D6�10/�10) did not complete this randomized placebo-controlled crossover study because of adverse events. Itraconazole increased the mean AUC of haloperidol by 55%. The subjects with the CYP2D6�10/�10 genotype had 81% higher values of AUC than those with the CYP2D6�1/�1 genotype. In the presence of itraconazole, those with the CYP2D6�10/�10 genotype had a threefold higher AUC of haloperidol than placebotreated subjects with the CYP2D6�1/�1 gen­ otype. The CYP2D6�10/�10 genotype and itraconazole pretreatment reduced the oral clearance of haloperidol by 24 and 25%, respectively, and in combination by 58%. The Barnes Akathisia Rating Scale (BARS) in CYP2D6�10/�10 subjects during itracona­ zole treatment was significantly higher than in CYP2D6�1/�1 subjects during placebo. Thus, the moderate effect of the CYP2D6�10/�10 genotype on the pharma­ cokinetics and pharmacodynamics of halo­ peridol is augmented by the presence of itraconazole. Ibuprofen The effects of voriconazole and fluconazole on the pharmacokinetics of S(+)-ibuprofen and R()-ibuprofen have been studied in 12 healthy men, who took a single oral dose of racemic ibuprofen 400 mg in randomized order either alone or 1 hour after voriconazole or fluconazole 400 mg bd on day 1 and 200 mg bd on day 2 (27C). Voriconazole increased the AUC of S-ibuprofen to 205% and the Cmax to 122%; the half-life was prolonged from 2.4 to 3.2 hours. Fluconazole increased the AUC of S-ibuprofen to 183% and the Cmax to 116%; the half-life was prolonged from 2.4 to 3.1 hours. These effects were attributed to inhibition of CYP2C9-mediated metabolism of S-ibuprofen. Voriconazole and flucona­ zole had minor effects on the pharmacoki­ netics of R-ibuprofen. The authors recommended that the dosage of ibuprofen should be reduced when it is co-administered with voriconazole or fluconazole, especially when the initial dose of ibuprofen is high. Loperamide Loperamide is metabolized by CYP2C8 and CYP3A4 and is a substrate

461 of P glycoprotein. Itraconazole inhibits CYP3A4 and P-glycoprotein and gemfibro­ zil inhibits CYP2C8. In a randomized crossover study 12 healthy volunteers took itraconazole 100 mg bd, gemfibrozil 600 mg bd, both itraconazole and gemfibrozil, or placebo for 5 days (28C). On day 3 they took a single dose of loperamide 4 mg. Itracona­ zole increased loperamide Cmax 2.9-fold and the AUC 3.8-fold and prolonged the half-life from 12 to 19 hours. Gemfibrozil increased the Cmax of loperamide 1.6-fold and its AUC 2.2-fold and prolonged its half-life to 17 hours. The combination of itraconazole and gemfibrozil increased the Cmax of loperamide 4.2-fold and its AUC 13-fold and prolonged the half-life to 37 hours. The amount of loperamide excreted into urine within 48 hours was increased 1.4-fold, 3.0­ fold, and 5.3-fold by gemfibrozil, itracona­ zole, and the combination, respectively, and the plasma AUC0-72 ratio of N-desmethyl­ loperamide to loperamide was reduced by 46, 65, and 88%. There were no significant differences in the Digit Symbol Substitution Test or subjective drowsiness between treat­ ments. Loratadine The effects of ketoconazole 600 mg on the pharmacokinetics of lorata­ dine in two oral formulations have been studied in 32 healthy volunteers in an open, randomized, two-period, crossover study (29c). The speed and extent of absorption of loratadine was not affected by ketocona­ zole. Methadone The pharmacokinetic inter­ action of voriconazole with methadone 30–100 mg/day at steady state has been studied in 23 men (30C). Voriconazole increased steady-state exposure to (R)­ methadone, the pharmacologically active enantiomer: the mean AUC0-24 increased by 47% (90% CI ¼ 38, 57%), and the mean Cmax increased by 31% (90% CI ¼ 22, 40%). The magnitude of increase in (S)-methadone exposure was even greater: the AUC0-24 increased by 103% (90% CI ¼ 85, 124%) and the Cmax by 65% (90% CI ¼ 53, 79%). Methadone had

Chapter 27

462 no effect on the steady-state pharmacoki­ netics of voriconazole. Ritonavir In a randomized, placebocontrolled crossover study in 20 healthy subjects, stratified according to CYP2C19 genotype, the apparent oral clearance of voriconazole after a single oral dose was 26% lower in CYP2C19�1/�2 individuals and 66% lower in CYP2C19 poor metaboli­ zers (31C). The addition of ritonavir reduced voriconazole apparent oral clearance (from 354 to 202 ml/minute); this occurred in all CYP2C19 genotypes (463 ml/minute versus 305 ml/minute for CYP2C19�1/�1; 343 ml/minute versus 190 ml/minute for CYP2C19�1/�2; 158 ml/minute versus 22 ml/minute for CYP2C19�2/�2). Sirolimus Voriconazole is contraindicated with sirolimus, because it substantially increases exposure. In a review of the medical records of all recipients of allogeneic hemo­ poietic stem cell, 11 patients had received voriconazole and sirolimus concomitantly for a median of 33 (range 3–100) days (32c). In eight patients whose sirolimus dosage was initially reduced by 90%, trough sirolimus concentrations were similar to those obtained before the administration of voriconazole; there were no adverse effects attributable to either drug during co-administration, but there were serious adverse events in two patients in whom sirolimus dosages were not adjusted during voriconazole administration. In a recipient of a stem cell transplant, a 20-year-old African-American man, co­ administration of itraconazole 200 mg bd with sirolimus increased trough sirolimus concentrations to over 17.5 ng/ml (usual target range 5–15 ng/ml) (33A). Sirolimus was withheld and the sirolimus trough concentration fell to 4.4 ng/ml. Solifenacin In an open crossover study in 17 healthy subjects aged 18–65 years, oral ketoconazole 200 mg/day prolonged the halflife of a single oral dose of solifenacin 10 mg from 49 to 78 hours and increased the Cmax 1.43 times and the AUC about twofold (34c). Solifenacin is metabolized by CYP3A4, which is inhibited by ketoconazole.

J.K. Aronson

Tacrolimus Ketoconazole inhibits the metabolism of tacrolimus and ciclosporin by inhibiting CYP isoenzymes. This has been put to good use in the long-term prevention of rejection of kidney trans­ plants by allowing the use of lower doses of tacrolimus. In a randomized study in 70 live-donor kidney transplant recipients the addition of ketoconazole 100 mg/day to tacrolimus therapy reduced the effec­ tive dose of the latter by 54% and the cost by 53%; there was also significant improvement in graft function (35C). No adverse effects of ketoconazole were noted.

Fluconazole

(SED-15, 1377; SEDA-29, 286; SEDA-30, 325)

Cardiovascular Torsade de pointes has been attributed to fluconazole.
A 33-year-old woman with systemic lupus

erythematosus was given intravenous fluco­ nazole 200 mg/day for C. albicans pneumonia (36A). She developed prolongation of the QTc interval and torsade de pointes. She had also been given domperidone, and both that and the fluconazole were withdrawn, the domperidone being suspected as the causa­ tive agent. However, torsade de pointes recurred several weeks later when she was given fluconazole again and resolved on withdrawal.
A 55-year-old woman with acute myelomono­ cytic leukemia with bone marrow eosinophilia who was receiving consolidation chemother­ apy had an episode of prolonged QT interval and torsade de pointes after being given fluconazole (37A). Intravenous magnesium sulfate and multiple attempts at electrocardio­ version led to recovery.

Endocrine Antifungal azoles inhibit the production of adrenal steroids and can cause acute adrenal insufficiency, as has been reported in a 38-year-old man who was treated with fluconazole and broadspectrum antibiotics (38A). Mouth An oral fixed drug eruption has been attributed to fluconazole (39A).

Antifungal drugs

Chapter 27


A 19-year-old boy developed redness and

swelling over the hard palate 7–8 hours after a dose of fluconazole 150 mg. There was mild pain and hypersalivation and the lesion gradually progressed to superficial erosion. He had had a similar episode about 1 year before after taking fluconazole for tinea cruris; he had stopped taking fluconazole and the oral lesion had healed by itself. The new erosion healed in about 15 days after treatment with chlorhexidine mouth rinse 0.12% 10 ml bd, warm saline rinses, oral cetirizine 10 mg/day, and topical triamcino­ lone in Orabase. Four weeks after the oral lesion had healed, oral provocation with fluconazole 50 mg caused the lesion to reappear in about 3 hours.

Biliary tract The use of fluconazole pro­ phylaxis for 6 weeks has been studied in a historical comparison in infants of extre­ mely low birth weight (40c). During pro­ phylaxis, 60/140 infants developed conjugated hyperbilirubinemia compared with 12/137 who did not have prophylaxis. However, fluconazole prevented several cases of candidiasis (none versus nine in the two groups) and the benefit to harm balance is probably favorable.

Itraconazole

(SED-15, 1932; SEDA-29, 286; SEDA-30, 326)

Observational studies In an open multicenter study in 156 Chinese patients who were given intravenous itraconazole for 2 weeks followed by 200 mg bd orally for 28 days, the most common adverse events were hypokalemia (14%), gastrointestinal disorders (13%), raised liver enzymes (11%), and raised bilirubin (8.3%) (41c). Liver In 49 patients with invasive fungal infections who were given intravenous itraconazole for 2–42 days, liver function tests were abnormal in 20 (42c). Those with liver enzyme abnormalities before treat­ ment were more likely to have liver damage during treatment. However,

463 hepatic damage was associated with itraco­ nazole in only two patients with mild liver function test abnormalities.

Posaconazole

(SED-15, 2905; SEDA­ 29, 286; SEDA-30, 327)

The pharmacokinetics, efficacy, and adverse effects of different dosing schedules of posaconazole oral suspension in patients with possible, probable, and proven refrac­ tory invasive fungal infections (n ¼ 32) or febrile neutropenia (n ¼ 66) have been evaluated in a multicenter, open, parallelgroup study (43c). Exposure in allogeneic bone marrow transplant recipients (n ¼ 12) was 52% lower than in others. There were treatment-related adverse effects in 24% of patients, mostly gastrointestinal.

Voriconazole (SED-15, 3688; SEDA-29, 287; SEDA-30, 328) The pharmacokinetics and pharmacody­ namics of voriconazole have been reviewed (44R). Liver Hepatotoxicity has been assessed in a retrospective observational study in 35 patients who took oral voriconazole com­ pared with 11 patients who received intra­ venous voriconazole during the first week followed by oral treatment (45c). The incidence of increased liver enzymes was comparable in the two groups. Voricona­ zole was withdrawn in two patients in the oral group and one patient in the intrave­ nous group because of hepatotoxicity. Liver enzyme rises in all 46 patients were higher than previously reported in a comparable study population. However, clinically sig­ nificant hepatotoxicity was infrequent (3/46, 6.5%). Biliary tract Cholelithiasis with cholecysti­ tis has been attributed to voriconazole in three cases (46A).

Chapter 27

464 Skin Seven cases of photosensitivity dur­ ing treatment with voriconazole have been reported (47c). All these patients had severe immunosuppression and were taking voriconazole for fungal infections. The photosensitivity reactions occurred within 5 weeks to 14 months after the start of treatment and in all cases followed expo­ sure to the sun, occasionally at low levels. The lesions disappeared rapidly on with­ drawal of voriconazole. Toxic epidermal necrolysis has been attributed to voriconazole (48A).
A 39-year-old man with metastatic breast

cancer, who was receiving cisplatin, epirubicin, and 5-fluorouracil, was given voriconazole for a fungal infection. After 5 days he developed a rash. All drugs were withdrawn. Within 3 days, he had a fever and diffuse erythema of the trunk, limbs, and face, with blistering skin lesions and a positive Nikolsky’s sign on erythematous areas, characteristic of toxic epidermal necrolysis and involving 85% of the body surface. The conjunctivae were injected and there were multiple bullae and ulcers on the lips and oropharyngeal mucosa. Biopsy showed necrosis of cells from the basal layer and stratum spinosum, resulting in detachment of the epidermis from the dermis. He recovered after 2 weeks of intensive therapy.

Drug formulations The intravenous for­ mulation of voriconazole includes the sol­ vent sulfobutylether b-cyclodextrin sodium, whose clearance is reduced in patients undergoing dialysis. Concentrations of vor­ iconazole and sulfobutylether b-cyclodex­ trin sodium have been measured in four patients with renal insufficiency undergoing intermittent dialysis (49c). Voriconazole plasma concentrations were generally below 1.5 mg/ml and there was no evidence of accumulation, in contrast to sulfobuty­ lether b-cyclodextrin sodium, which did accumulate.
A 75-year-old woman initially had a maximal

sulfobutylether b-cyclodextrin sodium plasma concentration of 145 mg/ml, but after a few days renal function recovered and the plasma concentration fell to under 20 mg/ml.
Sulfobutylether b-cyclodextrin sodium accumu­ lated in three patients with renal failure during intravenous administration of voriconazole;

J.K. Aronson

the maximum concentrations were 523 mg/ml in an 18-year-old man, 409 mg/ml in a 57-year-old man, and 581 mg/ml in a 47-year­ old man.

No adverse effects were observed in these cases, although the degree of exposure was comparable to that used in toxicity studies in animals, and the clinical relevance is uncertain. Monitoring drug therapy Of 26 patients 6 had neurological adverse events (visual and auditory hallucinations, encephalopathy, and visual disturbances) during treatment with voriconazole (50c). There was a significant difference between serum voriconazole con­ centrations in those who did and did not have adverse effects (median 5.7 mg/ml versus 1.4 mg/ml). The hazard ratio for adverse effects per 0.1 mg/ml increase in concentra­ tion was 2.27 (95% CI ¼ 1.45, 3.56). The relation between plasma voricona­ zole concentrations and the risk of visual adverse effects or abnormal liver function tests has been studied in 1053 patients (2925 plasma samples) (51c). There was a relation between plasma voriconazole concentra­ tions and the risk of visual adverse effects and a weaker, but still significant, association with the risk of abnormalities of bilirubin, alkaline phosphatase, or aspartate transami­ nase, but not alanine transaminase. How­ ever, receiver-operating characteristic curve analysis showed that individual plasma voriconazole concentrations cannot be used to predict abnormal liver function tests.

ECHINOCANDINS (SED-15, 1197; SEDA-28, 309; SEDA-29, 288; SEDA-30, 329) Micafungin

(SEDA-29, 290; SEDA-30, 331) Monitoring drug therapy The mean trough blood concentration of micafungin in patients with blood diseases in whom it was effective against pulmonary aspergillosis was 5.23 mg/ml in markedly improved cases, 4.08 mg/ml in improved cases, and 3.45 mg/ml

Antifungal drugs

Chapter 27

in successfully prevented cases, but there was no significant difference among the three groups (52c). The authors suggested a target

465 trough blood concentration of 5 mg/ml or higher in treating aspergillosis in patients with blood diseases.

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37. Tatetsu H, Asou N, Nakamura M, Hanaoka N, Matsuno F, Horikawa K, Mitsuya H. Torsades de pointes upon fluconazole administration in a patient with acute myeloblastic leukemia. Am J Hematol 2006;81(5):366–9. 38. Santhana Krishnan SG, Cobbs RK. Rever­ sible acute adrenal insufficiency caused by fluconazole in a critically ill patient. Post­ grad Med J 2006;82(971):e23. 39. Mahendra A, Gupta S, Gupta S, Sood S, Kumar P. Oral fixed drug eruption due to fluconazole. Indian J Dermatol Venereol Leprol 2006;72(5):391. 40. Aghai ZH, Mudduluru M, Nakhla TA, Amendolia B, Longo D, Kemble N, Kaki S, Sutsko R, Saslow JG, Stahl GE. Fluconazole prophylaxis in extremely low birth weight infants: association with cholestasis. J Perinatol 2006;26(9):550–5. 41. Wang A, Zhang Y, He L, Shen Z, Liao W, Han M, Li R, Liang D, Wu S, Hahn-Ast C, Glasmacher A, Liekwok WA. Clinical study on the efficacy and safety of intravenous itraconazole infusion for the treatment of invasive fungal infection in China. Jpn J Infect Dis 2006;59(6):370–6. 42. Zhu LP, Yang FF, Weng XH, Huang YX, Chen S, Shi GF, Lu Q, Zhang WH, Zhang YX. [Hepatic safety of itraconazole intravenous solution in treatment of invasive fungal infection.] Zhonghua Yi Xue Za Zhi 2006;86(29):2028–32. 43. Ullmann AJ, Cornely OA, Burchardt A, Hachem R, Kontoyiannis DP, Töpelt K, Courtney R, Wexler D, Krishna G, Mar­ tinho M, Corcoran G, Raad I. Pharmacokinetics, safety, and efficacy of posaconazole in patients with persistent febrile neutrope­ nia or refractory invasive fungal infection. Antimicrob Agents Chemother 2006;50(2): 658–66. 44. Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet 2006;45(7):649–63.

467 45. den Hollander JG, van Arkel C, Rijnders BJ, Lugtenburg PJ, de Marie S, Levin MD. Incidence of voriconazole hepatotoxicity during intravenous and oral treatment for invasive fungal infections. J Antimicrob Chemother 2006;57(6):1248–50. 46. Gérardin-Marais M, Allain-Veyrac G, Dan­ ner I, Jolliet P. Lithiase biliaire et cholecys­ tite au voriconazole (VFEND): à propos de 3 cas. [Biliary lithiasis and cholecystitis with voriconazole: à propos 3 cases.] Thérapie 2006;61(4):367–9. 47. Auffret N, Janssen F, Chevalier P, Guillemain R, Amrein C, Le Beller C. Photosensibilisation au voriconazole: 7 cas. [Voriconazole photosensitivity: 7 cases.] Ann Dermatol Venereol 2006;133(4):330–2. 48. Curigliano G, Formica V, De Pas T, Spitaleri G, Pietri E, Fazio N, de Braud F, Goldhirsch A. Life-threatening toxic epidermal necrolysis during voriconazole therapy for invasive aspergillosis after chemotherapy. Ann Oncol 2006;17(7): 1174–5. 49. von Mach MA, Burhenne J, Weilemann LS. Accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy. BMC Clin Pharmacol 2006;6:6. 50. Imhof A, Schaer DJ, Schanz U, Schwarz U. Neurological adverse events to voricona­ zole: evidence for therapeutic drug mon­ itoring. Swiss Med Wkly 2006;136(45–46): 739–42. 51. Tan K, Brayshaw N, Tomaszewski K, Troke P, Wood N. Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities. J Clin Pharmacol 2006;46(2):235–43. 52. Shimoeda S, Ohta S, Kobayashi H, Yamato S, Sasaki M, Kawano K. Effective blood concentration of micafungin for pulmonary aspergillosis. Biol Pharm Bull 2006;29 (9):1886–91.

Oscar Ozmund Simooya

28

Antiprotozoal drugs

ANTIMALARIAL DRUGS Although use of artemisinin-based combi­ nation therapies has increased rapidly in countries in which malaria is endemic, knowledge about the safety of artemisinin derivatives in special populations, such as pregnant women and young children, who bear the brunt of malaria, is limited. Most studies of the efficacy and safety of these compounds have been conducted in non­ pregnant adults. Consequently, sulfadox­ ine + pyrimethamine continues to be used for the treatment of malaria in pregnancy, despite widespread resistance of falciparum malaria. Attempts to find appropriate therapies for malaria in pregnancy are therefore an urgent priority (1r). The feasibility of reducing the burden of malaria in young children by intermittent presump­ tive treatment using various antimalarial compounds is also being studied (2r).

4-AMINOQUINOLINES (CHLOROQUINE AND CONGENERS) (SEDA-28, 315; SEDA-29, 294; SEDA-30, 336)

Amodiaquine

(SED-15, 178; SEDA-28,

315) Observational studies Amodiaquine has been suggested to be effective and safe in pregnancy, but its use has been limited Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03106.7 r 2009 Elsevier B.V. All rights reserved.

because of previous reports of neutropenia and lymphopenia. Amodiaquine has been studied alone or in combination with sulfadoxine + pyrimethamine in 900 women with P. falciparum malaria in Ghana, who were randomly assigned to chloroquine (n ¼ 225), sulfadoxine + pyrimethamine (n ¼ 225), amodiaquine (n ¼ 225), or amo­ diaquine plus sulfadoxine + pyrimethamine (n ¼ 225) (3C). The primary outcome measure was parasitological failure at day 28 of treatment. Parasitemia, hemoglobin concentration, white blood cell count, and liver function were assessed on days 3, 7, 14, and 28, and reports of adverse events were solicited at each visit. At day 28, parasitological failure was 14, 11, 3, and 0% in the women assigned chloroquine, sulfadoxine + pyrimethamine, amodiaquine, and amodiaquine with sulfadoxine + pyrimethamine, respectively. General weakness, vomiting, dizziness, and nausea were the most frequent adverse effects and were more common in those who took amodia­ quine and amodiaquine with sulfadoxine + pyrimethamine than in those who took sulfadoxine. However, there were no major changes in the white blood cell, bilirubin, and liver enzyme profiles during or at the end of the study. Of the 900 women, 711 (79%) were followed-up to delivery and for 6 weeks after. The proportion with peripheral parasitemia was significantly lower in those who took amodiaquine + sulfadoxine than in those who took chlor­ oquine (2% versus 10%), but there was no significant difference in the occurrence of placental parasitemia across the four treat­ ment groups. No maternal deaths were recorded and seven babies had extra digits (one chloroquine, five amodiaquine, and one amodiaquine with sulfadoxine + pyrimethamine).

469

470 This suggests that amodiaquine, alone or in combination with sulfadoxine + pyri­ methamine, is associated with minor adverse effects but is efficacious in malaria in pregnancy in places where falciparum malaria is still sensitive to these drugs, as is the case in much of West Africa.

Chloroquine and hydroxychloroquine

(SED-15, 722; SEDA-29, 294; SEDA-30, 336) Cardiovascular Toxic cardiac effects following acute ingestion of large doses of hydroxychloroquine have been reported before and include QRS widening, QT interval prolongation, torsade de pointes, other ventricular dysrhythmias, hypokale­ mia, and hypotension. Torsade de pointes following chronic use of hydroxychloro­ quine has been reported (4A).

Chapter 28

Oscar Ozmund Simooya

rheumatic diseases should be weighed against the risk of potentially lethal cardiac dysrhythmias. Skin Adverse skin reactions to chloro­ quine and hydoxychloroquine are not uncommon and include pruritus, pigment changes, photosensitivity, and provocation of some forms of porphyria and psoriasis. Some unusual dermatological effects after treatment with chloroquine and hydroxychloroquine have been reported. Pemphigus has been attributed to chlor­ oquine and hydroxychloroquine (5A).  A 52-year-old woman abruptly developed

generalized blisters 2 weeks after starting to take hydoxychloroquine for rheumatoid arthri­ tis. The eruption consisted of pruritic bullae and erosions on the head, trunk, limbs, and oral mucosa. She also had scattered urticarial lesions. She had had a previous similar but mild reaction following chloroquine therapy, which had cleared when the drug was withdrawn. Biopsy confirmed the diagnosis of pemphigus vulgaris with suprabasal slitting.

 A 67-year-old woman with systemic lupus

erythematosus and asthma who had taken prednisolone 15 mg/day, long-acting theo­ phylline 200 mg/day, and hydroxychloro­ quine 200 mg/day for 1 year developed sudden loss of consciousness and general­ ized rigidity. Moments later she regained consciousness with no residual symptoms, but the episode recurred several times. She had a past history of cirrhosis and hepatitis B virus-related hepatoma with portal vein thrombosis, an old myocardial infarction, and a small ventricular septal defect. An electrocardiogram showed multiple ventri­ cular extra beats and she had another syncopal attack, with documented torsade de pointes. After defibrillation and lidocaine 100 mg her cardiac rhythm reverted to normal with a prolonged QT interval (600 milliseconds). Cardiac enzymes were not raised. Hydroxychloroquine was sus­ pected as the cause of ventricular tachycar­ dia and was withdrawn. She was given intravenous magnesium sulfate 1 g followed by isoprenaline 2 mg/minute. After 4 days the ventricular dysrhythmia subsided but the QT interval was still prolonged (500– 530 milliseconds). After 3 weeks the ventri­ cular dysrhythmias abated.

It is not clear in this case whether congenital long QT interval could have contributed. Chronic use of hydroxychloroquine in

Drug-induced pemphigus is mainly caused by drugs containing a thiol (–SH) group, such as penicillamine, captopril, piroxicam, and ampicillin, or drugs with an active amide group, such as penicillin. In contrast, chloroquine and hydroxychloroquine are 4-aminoquinolines. A bullous skin eruption induced by radiotherapy after the use of chloroquine has been described (6A).  A 12-year-old girl with a diffuse pontine

glioma was treated with radiotherapy and developed a high-grade fever with chills. Although the blood smear was negative for malaria she was treated empirically with chloroquine 500 mg, 250 mg 6 hours later, and 250 mg/day for 2 days. On day 3 she developed localized bullous eruptions over the site of irradiation, which peeled in 6–7 hours leaving a patch of fulminant moist desquamation. The skin surrounding the patch was severely erythematous. Radiotherapy was withheld and she was treated with topical amniotic mem­ brane and gentian violet. One week later the fever had cleared and the desquamation had almost healed. Radiotherapy was restarted and completed uneventfully.

The combination of heat, chloroquine, and radiotherapy appears to have enhanced an

Antiprotozoal drugs

Chapter 28

aggressive skin reaction in this patient. Caution is recommended when using chloroquine in patients receiving radiotherapy. Drug resistance Chloroquine was with­ drawn in Malawi in 1993, but is once again an effective treatment for malaria in that country (7c). In 210 children with uncomplicated malaria randomized to chloroquine or sulfa­ doxine + pyrimethamine for 28 days, only 1 of those who were given chloroquine group had treatment failure compared with 71/87 of those who were given sulfadoxine + pyri­ methamine. Cumulative efficacy, defined using a proportional-hazards model, was 99% (95% CI ¼ 93, 100) with chloroquine compared with 21% (95% CI ¼ 13, 30) with sulfadoxine + pyrimethamine. There were no major adverse events related to the study drugs. This suggests that the advantage enjoyed by chloroquine-resistant malaria parasites was lost after the withdrawal of chloroquine. Drug pressure selectively favors the development of drug-resistant parasites. This promising result needs to be confirmed in larger studies and different locations.

Mefloquine

(SED-15, 2232; SEDA-29, 295; SEDA-30, 337)

Respiratory Interstitial pneumonia following mefloquine prophylaxis has been described (8A).  A 60-year-old Caucasian woman took meflo­

quine prophylaxis 250 mg/week 3 weeks before a trip to Kenya. One day after the first dose, she developed a high fever with chills and was given empirical unspecified antibiotic therapy. Four days later her condition wor­ sened and she developed a severe fever, progressive dyspnea, a productive cough, myalgia, and a headache. She had no history of pulmonary or allergic conditions and she had never taken malaria prophylaxis before. She was also taking low-dose aspirin, bisopro­ lol and ciprofibrate. Her temperature was 38.51C and there were bilateral crackles in the lungs. She had a leukocytosis, a raised Creactive protein concentration, and a raised lactate dehydrogenase activity. Blood and sputum cultures yielded no growth. Chest radiography showed bilateral interstitial infil­ trates, consistent with diffuse interstitial pneu­ monia. Without additional medication she

471 gradually improved and was discharged 20 days after admission. The trip to East Africa was cancelled. Four months later again she took mefloquine prophylaxis before traveling to Kenya and developed a similar illness, with high-grade fever and severe respiratory dis­ tress. The results of laboratory investigations and chest radiography were similar to those found in the first episode. A high-resolution CT scan confirmed the diagnosis of diffuse pulmonary infiltration. She was given gluco­ corticoids and made an uneventful recovery.

Mefloquine-induced respiratory pneumonia is rare. Nervous system Two cases of polyneuropathy following mefloquine treatment have been documented (9A).  A 50-year-old man developed an intermittent

fever of 3 weeks’ duration associated with chills and rigors. A blood smear showed Plasmodium vivax malaria, for which he was treated with oral chloroquine for 4–5 days. He became apyrexial after 2 days, and 9 days later, while still fever-free, he was given mefloquine 1000 mg on day 1 followed by 500 mg on the next day. Within 24 hours he developed tingling numbness and a burning sensation in both legs, followed by progressive weakness. Over the next 2 days these symp­ toms spread to both arms. He was unable to stand or perform fine motor activities, such as writing and eating. The next day an erythe­ matous rash appeared on both legs, especially on the shins and the dorsa of the feet. There was no muscle atrophy, but power was reduced around the knees and ankles and all deep reflexes were absent. Conduction studies showed increased latency, diminished ampli­ tudes, and decreased velocity, all suggestive of a sensory motor neuropathy in all four limbs. Within 3 weeks, he gradually improved and began walking; the rash began to disappear and the numbness and tingling sensation abated. He recovered after 6 months.  A 40-year-old housewife from Bihar, India, with a fever and impaired consciousness, was given parenteral artemisinin for 3 days for P. vivax malaria. The fever subsided and her conscious­ ness improved within 48 hours. A week later she was given mefloquine 1000 mg. Within 24 hours she developed a severe dermatitis and two large ulcers on the legs, one of which became infected. This was followed by paresthesia, progressive weakness, and inability to perform fine motor activities. Vital signs were normal and higher functions were intact. However, there was diminished tone and significantly reduced reflexes. Power was reduced and she could walk only with assistance. Nerve conduction studies

472 confirmed a sensory motor polyneuropathy. She improved gradually with vitamins and a course of co-trimoxazole for the septic ulcer. She recovered within 3 months.

Hematologic Bleeding disorders follow­ ing mefloquine are unusual (10A).  A 46-year-old nurse on a 2-week medical

assignment in Sri Lanka was given mefloquine in a single dose weekly for malaria prophy­ laxis. She was not taking any other medication and had not used mefloquine before. Three days after the first dose of mefloquine she developed bruising over her trunk and waist and had occasional per rectal bleeding. The bruising extended from the trunk to the buttocks. A full blood count was normal, the platelet count was 524  109 per liter, and the hemoglobin 12.4 g/dl. The coagulation profile and liver function tests were normal. Mefloquine was withdrawn and the bruising resolved. A repeat full blood count 6 months later was normal and the platelet count had normalized to 461  109 per liter.

Cutaneous reactions to mefloquine include pruritus and maculopapular rashes. The temporal relation between drug exposure and the bleeding episode in this case suggested a causal relation. Severe thrombotic thrombocytopenic purpura has been attributed to mefloquine (11A).  A 56-year-old Caucasian on a trip to Thailand

suddenly developed a fever, confusion, lethargy, and blurred vision 2 weeks after starting to take mefloquine prophylaxis 250 mg/week. He had leg petechiae and scleral jaundice. Chest radiography, electrocardiogra­ phy, abdominal echocardiography, and a cerebral CT scan showed no abnormalities. Laboratory tests showed thrombocytopenia (platelets 26 000  109 per liter), a leukocytosis (18.5  109 per liter), anemia (hemoglobin 10.1 g/dl with a high reticulocyte count), and raised lactate dehydrogenase activity and bilirubin concentration (total 55 mmol/l, indir­ ect 43 mmol/l). Coagulation profiles, creatinine, and urine examination were normal. Stool and blood cultures yielded no growth and serolo­ gical tests were negative. After plasmapheresis the neurological symptoms improved and the hematological profile gradually returned to normal.

Thrombocytopenia after mefloquine has been described before, but the severe neurological symptoms accompanied by

Chapter 28

Oscar Ozmund Simooya

fever, thrombocytopenia, and a microangiopathic anemia were unusual.

QUININE AND CONGENERS (SED-15, 3002: SEDA-29, 296)

Drug–drug interactions Atorvastatin Quinine-induced acute renal failure has been described as a result of a combination of hemolytic–uremic syndrome and rhabdomy­ oly sis with disseminated intravascular coagulation, thought to be secondary to an interaction with atorvastatin (12A).  A 54-year-old woman became acutely ill

within 1 hour of taking quinine 300 mg. She had a history of hypertension, dyslipidemia, chronic back pain, and a previous cholecys­ tectomy. She was currently taking atenolol 50 mg/day, aspirin 100 mg/day, glucosamine 750 mg bd, and atorvastatin 20 mg/day. Nau­ sea, vomiting, diarrhea, and abdominal pains were followed by rigors, myalgia, dizziness, and peripheral paresthesia. She was febrile (381C), with a tachycardia (101 per minute), tachypnea (26 per minute), and hypotension (100/60 mmHg). Electrocardiography showed widespread T wave inversion. Hemoglobin was 13 g/dl, white cell count 2.6  109 per liter, and platelets 247  109 per liter. Urea, electro­ lytes, and liver function tests were normal and a chest X-ray showed no active infection. She received intravenous fluids and ceftriaxone. Repeat biochemistry 18 hours later showed acute renal insufficiency (urea 13.5 mmol/l, creatinine 200 ìmol/l), rhabdomyolysis (CK 9300 U/l), and acute hepatitis (bilirubin 40 mmol/l, alkaline phosphatase 70 U/l, alanine transaminase 456 U/l, gamma glutamyl trans­ ferase 123 U/l). Urine microscopy was unhelp­ ful, but urine dipstick showed protein 4 + , blood 4 + , and myoglobin. She later developed a petechial rash and anemia (hemoglobin 9.5 g/ dl) and thrombocytopenia (61  109 per liter). There was a marked increase in lactate dehydrogenase, consistent with microangio­ pathic hemolysis. The international normal­ ized ratio of 2.1, activated partial thromboplastin time of 42, decreased fibrino­ gen concentration of 1.3 g/l (normal 2.0–4.0), and increased D-dimers pointed to dissemi­ nated intravascular coagulation. Following aggressive hydration, urinary alkalinization, and diuresis, her hematology and biochemistry gradually returned to normal. However, flow cytometry showed the presence of antiplatelet antibodies, which returned to normal by 12

Antiprotozoal drugs

Chapter 28

months. She had had a previous similar episode after taking a single quinine tablet along with atorvastatin.

This potentially fatal adverse event may have been triggered by quinine, a potent inhibitor of CYP3A4. Quinine may have increased the plasma concentrations of atorvastatin, by reducing its first-pass metabolism.

ENDOPEROXIDES (SED-15, 342; SEDA-28, 320; SEDA-29, 297; SEDA-30, 338) Observational studies In 32 pregnant women (mean gestation 30 weeks) with uncomplicated falciparum malaria, who were given a standard dose of artesunate (two tablets of 100 mg each) with sulfadoxine + pyrimethamine (sulfadoxine 500 mg plus pyrimethamine 25 mg) all as one dose, the treatments were well tolerated, the parasitemia cleared, and the patients were symptom-free within 2 days (13c). All delivered full-term live babies, although one baby died on the fourth day. None of the women died and there were no miscarriages, still births, or congenital anomalies in the neonates. Comparative studies There have been several comparisons of different formula­ tions and combinations of artemisinin com­ pounds. Children with severe malaria were ran­ domly assigned to either (a) artesunate suppositories (n ¼ 41) 8–16 mg/kg at 0 and 12 hours and then daily or (b) intramus­ cular artemether (n ¼ 38) 3.2 mg/kg fol­ lowed by 1.6 mg/kg/day; 1 died with multiple complications within 2 hours of admission, but the other 78 recovered uneventfully (14c). In a subset of 29 children, plasma concentrations of arte­ mether, artesunate, and their common metabolite dihydroartemisinin were mea­ sured for the first 12 hours. Primary end­ points included time to 50 and 90% parasite clearance and time to per os status. In those who received suppositories

473 the plasma concentrations of active meta­ bolite were higher at 2 hours and there were significantly earlier parasite clearance times, mirroring the higher plasma con­ centrations, which may offer a consider­ able advantage in the treatment of children with severe malaria, particularly when parenteral therapy is not possible. Patients with acute, uncomplicated falci­ parum malaria were randomly assigned to one of four regimens for 3 days: Group 1 (n ¼ 27) received azithromycin 750 mg bd + artesunate 100 mg bd; Group II (n ¼ 27) azithromycin 1000 mg bd + artesunate 200 mg/day; Group III (n ¼ 16) azithromy­ cin 750 mg bd + quinine 10 mg/kg bd; Group IV (n ¼ 26) azithromycin 500 mg tds + qui­ nine 10 mg/kg tds (15C). The 28-day cure rate was similarly high in Groups I, II, and IV. In Group III, there were three treat­ ment failures and recruitment was discon­ tinued. Artesunate combinations had faster clinical and parasitological outcomes than quinine combinations. There were no deaths or drug-related adverse events. Patients with uncomplicated malaria were randomly assigned to receive either dihydroartemisinin + piperaquine (n ¼ 327; 156 supervised treatment and 171 unsuper­ vised), 6.3 + 50 mg/kg for 3 days, or artesu­ nate + mefloquine (n ¼ 325; 162 and 163, respectively) 12 + 25 mg/kg (16c). The pri­ mary endpoint was PCR-confirmed para­ sitological failure rate on day 42. One patient died 22 days after receiving dihy­ droartemisinin + piperaquine and 16 patients were lost to follow-up. On day 42, the failure rate was 0.6% (95% CI ¼ 0.2, 2.5) for dihydroartemisinin + piperaquine and 0 (0, 1.2) for artesunate + mefloquine. No major adverse events were reported, although dizziness was the most frequent complaint. Adults and children with uncomplicated malaria were randomized to either a combined formulation of artesunate + mefloquine (n ¼ 251) or artesunate and mefloquine as separate tablets (n ¼ 249) (17C). The PCR cure rates after 63 days were 92% (95% CI ¼ 88, 96) with the combined formulation and 89% (85, 93) with the separate tablets. Patients who took the separate tablets had more vomiting.

474

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Oscar Ozmund Simooya

 A 46-year-old woman without as premorbid

DRUGS USED IN THE TREATMENT OF PNEUMOCYSTIS JIROVECI INFECTIONS Co-trimoxazole (trimethoprim + sulfamethoxazole) (SED-15, 3510; SEDA-28, 322; SEDA-29, 297; SEDA-30, 338; see also Chapter 26) Observational studies Co-trimoxazole has been recommended for prophylaxis against opportunistic infections in HIVinfected individuals living in sub-Saharan Africa. However, despite this recommenda­ tion, there has been limited use of co­ trimoxazole in these settings, partly because of concerns about hematological toxicity. The incidence of neutropenia in HIVinfected individuals taking co-trimoxazole prophylaxis has been reported (18C). In all, 533 HIV-infected individuals taking co­ trimoxazole prophylaxis were followed for 1450 person-years and examined for neu­ tropenia, which was graded as at least one absolute neutrophil count: below 1.5  109 per liter (severity grade 1), below 1.0  109 per liter (grade 2), below 750  106 per liter (grade 3), or below 500  106 per liter (grade 4). The probability of being free from neutropenia at 48 months was 0.29 (95% CI ¼ 0.23, 0.34) for grade 1; 0.64 (95% CI ¼ 0.60, 0.71) for grade 2; 0.82 (95% CI ¼ 0.77, 0.86) for grade 3; and 0.96 (95% CI ¼ 0.93, 0.99) for grade 4. There was a significant association between a higher rate of neutropenia and a low baseline CD4 count. However, there was no association between any grade of neutro­ penia and the overall risk of serious morbidity. These results confirm that mild neutropenia is common in patients taking co-trimoxazole prophylaxis, although there is no evidence of serious clinical conse­ quences. Psychiatry Psychosis following co­ trimoxazole therapy has been reported (19A).

history developed agitation, optic and acoustic hallucinations, delusions of persons and situa­ tions, lack of concentration, and incoherent thinking. She was alert and well oriented in time, person, and place, but her mood was labile and inappropriate. Her husband said that her mental state had gradually deterio­ rated over the 2 days before presentation. She had been started to take co-trimoxazole 12 days earlier for a urinary tract infection due to Escherichia coli. Co-trimoxazole was with­ drawn and she was given lorazepam 2.5 mg and haloperidol 5 mg. Her mental state improved within 36 hours.

Acute psychosis after antibiotic treatment has been reported before, but rarely with cotrimoxazole. Immunology Drug-induced hypersensitivity syndrome following reactivation of a latent viral infection is rare.  A 27-year-old man with a history of bronchial

asthma, eosinophilic enteritis, and eosinophilic pneumonia developed a fever, rash, cervical lymphadenopathy, hepatosplenomegaly, aty­ pical lymphocytosis, and eosinophilia 2 weeks after receiving co-trimoxazole (20A). After withdrawal of co-trimoxazole and the admin­ istration of high-dose steroids the symptoms gradually resolved. There was a transient increase in anti-human herpes virus (HHV-6) antibody titers and HHV-6 DNA in the peripheral blood, suggesting reactivation of a latent HHV-6 infection.

Sulfonamides

(SED-15, 3216)

Urinary tract Acute renal insufficiency secondary to crystalluria from sulfonamide use has been reported (21A).  A 48-year-old man with untreated HIV infec­

tion developed confusion and dyspnea. He had a history of ischemic heart disease and hepatitis C infection. His CD4 count was 50  106 per liter (reference range 400–1320). He was found to have P. jiroveci pneumonia and cerebral toxoplasmosis and was given oral co-trimoxazole (320/1600 qds) for the Pneumocystis pneumonia and sulfadiazine (1.5 g qds) for the toxoplasmosis. Baseline renal function was normal. Later, the co­ trimoxazole was withdrawn because of con­ current sulfadiazine treatment. On day 7, he developed macroscopic hematuria and profuse crystalluria. Renal function was normal, but 2 days later his creatinine rose to 250 mmol/l.

Antiprotozoal drugs

Chapter 28

Despite vigorous intravenous hydration the serum creatinine increased to 401 mmol/l. Renal tract ultrasound was normal but mor­ phological examination of crystals confirmed the presence of a sulfonamide. Sulfadiazine was withdrawn and he recovered uneventfully within 1 month.

Sulfadiazine is a weak acid that will precipitate as crystals in the tubular lumen at a urine pH below 5.5; patients taking doses over 4 g/day should maintain a high oral fluid intake or receive adequate intravenous hydration.

475 shin bilaterally. Deep tendon reflexes and power were preserved. Nerve conduction studies showed a peripheral neuropathy with reduced sensory nerve and compound muscle action potentials. Reproducible sympathetic skin potential responses could not be obtained in the hands and feet, providing evidence of a concurrent autonomic neuropathy. No other possible cause of her condition was found and nerve conduction and sympathetic skin poten­ tials gradually returned to normal over 6 months.

Skin Stevens–Johnson reaction after metronidazole has been reported (23A).  A 43-year-old

DRUGS USED IN THE TREATMENT OF OTHER PROTOZOAL INFECTIONS Metronidazole

(SED-15, 2323; SEDA28, 323; SEDA-30, 339)

Nervous system Peripheral neuropathy as an adverse effect of metronidazole has been reported before. A case of autonomic neuropathy has been described (22A).  A previously healthy 15-year-old girl devel­

oped burning feet after a short course of metronidazole for vaginitis. She could only obtain pain relief by submerging her feet in iced water. Her feet were cold and swollen and became erythematous and very warm when removed from the water. Temperature per­ ception was reduced to the upper third of the

woman developed bullous lesions and erosions of the lips, back, submammary and axillary areas, and groins, with generalized erythema and edema of the distal extremities. She also complained of general malaise and chills. Before the development of the skin lesions she had taken amoxicillin and metronidazole for gingivitis. A day later she developed pruritus, and amoxicillin was with­ drawn and replaced with cefuroxime. Histol­ ogy of her skin showed a reactive epidermis with numerous apoptotic cells, vacuolar degeneration of the dermoepidermal junction, a moderate cellular infiltrate with marked eosinophilia, and pigment incontinence, con­ sistent with Stevens–Johnson syndrome. Amoxicillin was withdrawn and she was given oral and topical steroids. The skin lesions regressed. Patch-testing with amoxicillin, cefuroxime, and metronidazole produced a vesicular reaction to metronidazole but no reaction to amoxicillin.

The positive patch test with metronidazole in this case suggests a causal relation.

References 1. D’Alessandro, ter Kuile FO. Amodiaquine, malaria, pregnancy: the old new drug. Lancet 2006;368:1306–7. 2. ter Kuile FO, Steketee RW. Intermittent preventive treatment in infants—adjusting expectations and seeing opportunity. J Infect Dis 2006;194:269–72. 3. Tagbor H, Bruce J, Browne E, Randal A, Greenwood B, Chandramohan D. Efficacy, safety, tolerability of amodiaquine plus sul­ phadoxine–pyrimethamine used alone or in

combination for malaria treatment in preg­ nancy: a randomized trial. Lancet 2006;368: 1349–56. 4. Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia. Clin Toxicol 2006;44:173–5. 5. Ghaffarpour G, Jalali MHA, Yaghmaii B, Mazloomi S, Soltani-Arabshahi R. Chloro­ quine/hydoxychloroquine-induced pemphi­ gus. Int Soc Dermatol 2006;45:1261–3.

Chapter 28

476 6. Rustogi A, Munshi A, Jalali R. Unexpected skin reaction induced by radiotherapy after chloroquine use. Lancet Oncol 2006;7: 608–9. 7. Laufer MK, Thesing PC, Edington ND, Masonga R, Dzinjalamala FK, Takala SL, Taylor TE, Plowe CV. Return of chloro­ quine antimalarial efficacy in Malawi. N Engl J Med 2006;355:1960–6. 8. Soentjens P, Delanote M, Van Gompel A. Mefloquine induced pneumonitis. J Travel Med 2006;13(3):172–4. 9. Jha S, Rajesh K, Raj K. Mefloquine toxicity presenting with polyneuropathy—a report of two cases in India. Trans R Soc Trop Med Hyg 2006;100:594–6. 10. Chin Chew H, Ponampalam R. An unusual cutaneous manifestation with mefloquine. Am J Emerg Med 2006;24:634–5. 11. Fiaccadori E, Maggiore U, Rotelli C, Giacosa R, Parenti E, Cabassi A, Ariya K, Wirote L. Thrombotic thrombocytopenic purpura following malaria prophylaxis with mefloquine. J Antimicrob Chemother 2006; 57:160–1. 12. Lim AKH, Ho L, Levidiotis V. Quinineinduced renal failure as a result of rhabdo­ myolysis, hemolytic uremic syndrome and disseminated intravascular coagulation. Intern Med J 2006;36:465–7. 13. Adam I, Ali DM, Abdalla MA. Artesunate plus sulfadoxine–pyrimethamine in the treatment of uncomplicated Plasmodium falciparum malaria during pregnancy in eastern Sudan. Trans R Soc Trop Med Hyg 2006;100:632–5. 14. Karunajeewa HA, Reeder J, Lorry K, Dabod E, Hamzah J, Page-Sharp M, Chiswell GM, Ilett KF, Davis TME. Artesunate suppositories versus intramuscular arte­ mether for treatment of severe malaria in children in Papua New Guinea. Antimicrob Agents Chemother 2006;50(3):968–74. 15. Noedl H, Krudsood S, Chalermratana K, Silachamroon U, Leowattana W, Tangpuk­ dee N, Looareesuwan S, Miller RS, Fukuda M, Jongsakul K, Sriwichai S, Rowan J, Bhattacharyya H, Ohrt C, Knirsch C. Azithromycin combination therapy with artesunate or quinine for the treatment of

16.

17.

18.

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20.

21.

22.

23.

Oscar Ozmund Simooya

uncomplicated Plasmodium falciparum malaria in adults: a randomized, phase 2 clinical trial in Thailand. Clin Infect Dis 2006;43(10):1264–71. Smithuis F, Kyaw MK, Phe O, Aye KZ, Htet L, Barends M, Lindegardh N, Sing­ toroj T, Ashley E, Lwin S, Stepniewska K, White NJ. Efficacy and effectiveness of dihydroartemisinin–piperaquine versus artesunate–mefloquine in falciparum malaria: an open-label randomized compar­ ison. Lancet 2006;367:2075–85. Ashley EA, Lwin KM, McGready R, Simon WH, Phaiphun L, Proux S, Wangseang N, Taylor W, Stepniewska K, Nawamaneerat W, Thwai KL, Barends M, Leowattana W, Olliaro P, Singhasivanon P, White NJ, Nosten F. An open label randomized comparison of mefloquine–artesunate as separate tablets vs. a new co-formulated combination for the treatment of uncomplicated multi-drug resis­ tant falciparum malaria in Thailand. Trop Med Int Health 2006;11:1653–60. Toure S, Gabillard D, Inwoley A, Seyler C, Gourvellec G, Anglaret X. Incidence of neutropenia in HIV-infected African adults receiving co-trimoxazole prophylaxis: a 6­ year cohort study in Abidjan, Cóte d’Ivoire. Trans R Soc Med Hyg 2006;100:785–90. Weis S, Karagulle D, Kornhuber J, Bayer­ lein K. Cotrimoxazole-psychosis: a case report and review of literature. Pharmacop­ sychiatry 2006;39:236–8. Morimoto T, Sato T, Matsuoka A, Sakamoto T, Ohta K, Ando T, Ikushima S, Hagiwara K, Matsuno H, Akiyama O, Oristu M. Trimethoprim–sulfamethoxazole induced hypersensitivity syndrome asso­ ciated with reactivation of human herpes­ virus-6. Int Med 2006;45:101–5. Swaminathan S, Pollett S, Loblay R, Macleod C. Sulfonamide crystals and acute renal failure. Int Med J 2006;36:399–402. Hobson-Webb LD, Roach ES, Donofrio PD. Metronidazole: newly recognized cause of autonomic neuropathy. J Child Neurol 2006;21(5):429–31. Piskin G, Mekkes JR. Stevens–Johnson syndrome from metronidazole. Contact Dermatitis 2006;55:192–3.

O. Koch, S. Sheehy, R. Serafino, and B.J. Angus

29 DRUGS ACTIVE AGAINST CYTOMEGALOVIRUS Cidofovir (SED-15, 771; SEDA-28, 326; SEDA-30, 343) Observational studies Topical intralaryn­ geal cidofovir has been used as an effective adjunct in treating recurrences of recurrent laryngeal papillomatosis, a benign laryngeal disease caused by human papilloma virus (1c). In 10 patients with recurrent papillo­ matosis, cidofovir was injected with a laryngeal needle during papilloma resec­ tion. There were no local or systemic adverse effects, but the median interval between recurrences increased significantly from 102 days before cidofovir to 239 days after treatment. Sensory systems Intrapleural cidofovir caused uveitis in a patient with pleural effusion lymphoma associated with herpesvirus-8, which usually has a poor prognosis (2A).
A 78-year-old Italian man with primary effu­

sion lymphoma received two cycles of conventional CHOP chemotherapy with sub­ stantial improvement. However, the effusions recurred and one cycle of DHAP and a short course of interferon alfa gave no benefit. He was then given intrapleural cidofovir into the right pleural space on five occasions. This was well tolerated except for mild uveitis.

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03129-8 r 2009 Elsevier B.V. All rights reserved.

Antiviral drugs Anterior uveitis has been described in 5 of 14 kidney transplant patients given cidofovir for polyomavirus-associated nephropathy (3c). The mean number of cidofovir doses given was 7 compared with 9 in patients who did not develop uveitis. Creatinine clearance when the nephropathy was diagnosed was lower in the patients with uveitis, and there was a graft survival of 40% versus 100% in the patients who did not have eye involve­ ment. Treatment was withdrawn in all of the affected patients, and topical steroids and cycloplegics were used; there was complete resolution in 80%. The authors recom­ mended that cidofovir should be used with caution in patients with creatinine clearances below 30 ml/minute. Urinary tract Two children with liver transplants and life-threatening dissemi­ nated adenoviral disease recovered after withdrawal of calcineurin inhibitor treat­ ment and the use of cidofovir; there were no dose-limiting adverse effects, apart from a slight transient rise in creatinine concentration and transient proteinuria in one and moderate neutropenia in the other (4A). The use of intravenous cidofovir has been studied in a retrospective analysis of the records of 57 patients, median age 8 years (range 0.5–26), with adenovirus infection after hemopoietic stem cell transplants (5c). Cidofovir 5 mg/kg was given by infusion once a week for 2 weeks and then every 2 weeks until three consecutive samples were negative for adenovirus. The patients were hydrated with isotonic saline before and after each infusion. Probenecid was given orally 3 hours before each infusion (1 g/m2) and then 2 and 8 hours after the infusion (500 mg/m2). When possible, other nephrotoxins, such as

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O. Koch, S. Sheehy, R. Serafino, and B.J. Angus

ciclosporin, aminoglycosides, pentamidine, and foscarnet, were avoided, but if the use of such a nephrotoxin was unavoidable, dosage adjustments were made to achieve a low therapeutic concentration of cidofovir. When indicated for antifungal therapy, lipo­ somal amphotericin B was used. In patients with compromised renal function the dosage of cidofovir was changed to 1 mg/kg given on 3 alternate days weekly for 2 weeks, and the same dose was repeated every other week until three consecutive specimens were nega­ tive for adenovirus from all previously involved sites. There were no cases of doselimiting nephrotoxicity.

probenecid and without nephrotoxicity (9c). Renal function improved in all three patients and they all had a marked fall in BK viral loads, with complete clearing of viremia in two.

478


A 48-year-old woman with HIV-related leu­

koencephalopathy was given intravenous aci­ clovir 500 mg tds for 15 days and had a partial remission. However, she deteriorated further due to infection with herpesvirus-6 and was given intravenous cidofovir 275 mg/week at first and then 275 mg every 2 weeks. Although her clinical condition gradually improved cidofovir had to be withdrawn because of Fanconi’s syndrome and replaced with oral valaciclovir (6A).
A 39-year-old African–American HIV- and HBV-positive man with worsening facial ver­ ruca vulgaris for several months, a CD4 count of 22  106/l, and a viral load of 58 000 copies/ mm3 was given intravenous cidofovir 300 mg in isotonic saline weekly for 2 weeks and then fortnightly, with pretreatment with probenecid and isotonic saline hydration (7A). Never­ theless, before the sixth cycles he developed mild proteinuria and the cidofovir was with­ held. The proteinuria resolved spontaneously within 1 month.

In 26 cases of BK virus allograft nephro­ pathy the rate of graft loss in cidofovir­ treated patients was 15% lower than the historic rate of graft loss before the use of cidofovir of 45% (8M). Although the viremia cleared in all but one case, and there was a large reduction in urinary viral load in 20 patients, the serum creatinine did not improve in 50% of cases. This was thought to be due to irreversible tissue damage with progression to chronic allo­ graft nephropathy. Three kidney transplant recipients with BK virus allograft nephropathy and raised serum creatinine concentrations were given infusions of intermediate-dose cidofovir (0.75–1.0 mg/kg) on 7–15 occasions without

DRUGS ACTIVE AGAINST HERPESVIRUSES (SEDA-28, 328; SEDA-29, 301; SEDA-30, 343)

Aciclovir Observational studies In a patient satis­ faction questionnaire during a comparison of once- and twice-daily oral suppressive therapy with aciclovir for genital herpes, adverse effects were rarely reported (10c). Psychiatric Aciclovir-related neuropsy­ chiatric symptoms have previously been associated with increased serum concentra­ tions of the main metabolite of aciclovir, 9­ carboxymethoxymethylguanine (CMMG) (Figure 1). In a further study of nine subjects with neuropsychiatric signs and symptoms (confusion, somnolence, hyper-reflexia, myoclonus, hallucinations, incoherence, and unresponsiveness) and 12 asymptomatic subjects, including 10 from a valaciclovir multiple sclerosis trial and 2 with recurrent herpes encephalitis, CSF aciclovir concen­ trations were measured. CMMG could only be detected in the CSF of those with neuropsychiatric symptoms and signs (med­ ian concentration 1.0, range 0.6–7.0 mmol/l). The concentration of CMMG was below the limit of quantification (o0.5 mmol/l) in the asymptomatic subjects. All those with neu­ ropsychiatric signs and symptoms, except one, had acute renal function impairment or chronic renal failure (11c). Reversible neurotoxicity in a 6-month­ old child after liver transplantation has been reported (12A).
A 6-month-old girl had liver transplantation

after liver failure secondary to an enterovirus infection, followed by initial immunosuppres­ sion with antilymphocyte serum, azathioprine, and glucocorticoids. Her renal function improved on day 3, and the antilymphocyte serum was switched to ciclosporin 10 mg/kg/day.

Antiviral drugs

Chapter 29

479 O

H

N

N

H2N

N

NH2

N O

O

CH3

Valaciclovir O

Valaciclovir hydrolase

O H

N

N

H2N

N

N OH

O Aciclovir

Alcohol dehydrogenase

O H

N

N

H2N

N

N O

C

H

Aciclovir aldehyde O

Aldehyde dehydrogenase

O H

N

N

H2N

N

N O

C

OH

CMMG O

Fig. 1. The metabolism of valaciclovir.

CH3

Chapter 29

O. Koch, S. Sheehy, R. Serafino, and B.J. Angus

Antimicrobial drug prophylaxis consisted of ticarcillin+clavulanic acid for 2 days, flucona­ zole 3 mg/kg/day from day 1, and aciclovir 250 mg/m2 from day 3, increased to 250 mg/m2 tds on day 5 to prevent Herpes simplex infection. On day 5 she became comatose and agitated, with choreoathetoid movements in all four limbs, random eye movements, and loss of eye contact. A brain CT scan was normal and electroencephalography showed slow waves with no evidence of seizures. The cerebrospinal fluid was normal. The trough plasma ciclosporin concentration was 87 ng/ml (below the target range of 200–250 ng/ml). The plasma aciclovir concentration was 4.5 mg/l on day 7, above the recommended target concen­ tration (2.3 mg/l). Aciclovir was withdrawn and the neurological effects resolved.

Reversible renal failure and encephalo­ pathy have been attributed to a higher dose of aciclovir (14A).

480

Urinary tract Reversible acute renal insufficiency has been described after intrave­ nous aciclovir, possibly related to changes in vascular resistance (13A).
A 28-year-old immunocompetent man who had

typical varicella infection, a serum creatinine concentration of 106 mmol/l, and normal urina­ lysis and chest X-ray. He was given intravenous aciclovir 8.5 mg/kg (340 mg/m2) every 8 hours. During the third infusion, he complained of mild pain in both loins. There was proteinuria (++) and hematuria (++) and his serum creatinine increased to 196 mmol/l. There were no crystals in the urine. Although aciclovir was withdrawn, the serum creatinine rose to 266 mmol/l on the second day. After 4 days renal function returned to normal. Aciclovir 5 mg/kg was then given again for 4 days without any problem. The patient refused renal biopsy.
A 21-year-old immunocompetent man who had a varicella infection was given intravenous aciclovir 10 mg/kg and during the third infusion complained of nausea and severe pain in both renal angles. He had proteinuria (++), hema­ turia (+), and reduced renal function (serum creatinine 238 mmol/l). There were no crystals in the urine. Although aciclovir was with­ drawn, the serum creatinine rose to 406 mmol/l without any alteration in urine output. A renal biopsy showed minimal changes in the cortex area; the glomeruli showed a small increase in the number of mesangial cells, with some vacuolation of the tubular epithelium; the medulla contained small foci of mononuclear cells and a few polymorphonuclear leukocytes in the interstitium; the tubules showed ische­ mia and focal epithelial regeneration, with a few epithelial deposits of hemosiderin. Seven days after withdrawal of aciclovir the renal function returned to normal.

The association with aciclovir in both of these cases was not strong.


A 42-year-old immunocompetent man with

herpetic encephalitis was given cefotaxime, fosfomycin, metronidazole, and aciclovir 15 mg/kg 8-hourly. His creatinine rose from 90 mmol/l to a peak of 381 mmol/l within 24 days. This was associated with proteinuria but normal renal ultrasonography. It reversed after with­ drawal of aciclovir and intravenous fluids.

Drug formulations A novel method of applying 5% aciclovir cream to cold sores using iontophoresis has been assessed in a randomized placebo-controlled trial in 200 patients with an incipient outbreak of Herpes labialis infection at the erythema or papular/edema lesion stage (15C). The median classic lesion healing time was 1.5 days shorter with the active treatment than with the vehicle (113 versus 148 hours). There were 17 adverse events in 12 patients who were given aciclovir, compared with 19 events in 13 patients who were given placebo. The most common adverse event was an electrical sensation (n ¼ 2 versus 1). There were also single instances each of mildly burned skin and mild erythema on the lip, both with aciclovir. In neither case was treatment required.

DRUGS ACTIVE AGAINST HEPATITIS VIRUSES Adefovir

(SED-15, 35; SEDA-30, 344)

Urinary tract The safety profile of the 10­ mg dose of adefovir was similar to that of placebo after 48 weeks of treatment in HBeAg-positive patients; there were renal laboratory abnormalities only at the 30-mg dose (16R).

Lamivudine (SED-15, 1989; SEDA-30, 344) Observational studies Reactivation of hepatitis B virus infection in asymptomatic hepatitis B surface antigen carriers undergoing

Antiviral drugs

Chapter 29

chemotherapy or immunosuppressive therapy was reduced by 4–7 times in patients who took lamivudine prophylaxis in a systematic review of nine prospective studies and one randomized-controlled trial (17M). Adverse effects included rises in amylase, lipase and creatine kinase, nausea, headache, dizziness, and pancreatitis. In 17 patients with severe acute or fulminant hepatitis B common adverse effects of lamivudine included headache, upper respiratory tract infection, nasopharyngitis, cough, pyrexia, dyspepsia, upper abdominal pain, fatigue, diarrhea, back pain, and myalgia, most of which were of mild-to-moderate intensity (18c). Comparative studies Oral entecavir 0.5 mg/day produced greater improvement in biochemical, histological, and virological outcomes than lamivudine 100 mg/day in HBeAg-positive and HBeAg-negative patients. Common adverse effects included headache, upper respiratory tract infections, nasopharyngitis, cough, pyrexia, dyspepsia, upper abdominal pain, fatigue, diarrhoea, back pain and myalgia; most were of mild­ to-moderate intensity. More patients had rises in alanine transaminase activity and there were more withdrawals due to adverse effects in those who took lamivu­ dine (19c,20c,21c,22c). Placebo-controlled studies In 276 HBeAg­ positive children the incidence of YMMD mutations (tyrosine, methionine, aspartate, aspartate) increased over time, resulting in lower response rates (23c). Common adverse effects included infections of the ear, nose and throat, headaches, cough, disturbances of temperature regulation, abdominal discomfort, nausea and vomiting. During continued treatment with lamivudine for up to 3 years there were no new or unexpected adverse events or laboratory abnormalities. Liver The reports of all suspected hepatic adverse drug reactions with a fatal outcome received by the Uppsala Monitoring Centre between 1968 and 2003 included 56 cases of lamivudine-associated hepatotoxicity (24c). Lamivudine, as part of an antiretroviral regimen was reported to have caused liver failure in four HIV-infected patients (25c).

481 Lamivudine given alone in hepatitis B cirrhosis was reported to have caused hepatic decompensation, postulated to be due to an intense immune response, with associated vigorous cytotoxic T cell activity. However, the role of lamivudine in causing further decompensation of the liver when used in patients with already decompen­ sated liver disease was impossible to assess (26A). In some cases lamivudine was associated with transient leukopenia, which recovered on withdrawal. Musculoskeletal There were persistent rises in creatine kinase activity (478– 1753 IU/l) with normal blood gases and lactate and no associated myalgia or other complaints in 2 of 20 HBe-Ag-positive children taking prolonged lamivudine ther­ apy. The activities normalized on with­ drawal of lamivudine (27c). Drug resistance Lamivudine is associated with a high rate of resistance (28C). Base­ line serum hepatitis B virus DNA W106 copies/ml was a strong predictor for break­ through disease because of drug-resistant mutations (29C).

Telbivudine Telbivudine is a synthetic l-nucleoside analog for the treatment of resistant HBV infection. Drug–drug interactions In phase 1 studies concomitant lamivudine or adefovir dipivoxil did not appear to have a significant effect on the steady-state plasma pharma­ cokinetics of telbivudine or vice versa (30c).

DRUGS ACTIVE AGAINST HIV: COMBINATIONS Comparative studies In an open noninferiority study 517 patients with HIV infection were randomly assigned to tenofovir+ emtricitabine+efavirenz once daily or fixeddose zidovudine+lamivudine bd+efavirenz od (31c). In the latter the following adverse events were noted: dizziness (7%), nausea

Chapter 29

O. Koch, S. Sheehy, R. Serafino, and B.J. Angus

(6%), diarrhea (4%), fatigue (6%), depression (7%), headache (4%), rash (4%), insomnia (5%), anemia (5%), raised amylase Z132 U/l (13%), raised triglycerides Z4.5 mmol/l (14%), raised creatine kinase Z499 U/l in men and Z424 U/l in women (15%), neutropenia o1.0  109/l (14%), hematuria (6%), and raised alanine transaminase Z109 U/l (7%). Significantly more patients in the zidovudine+lamivudine group had adverse events that resulted in drug withdrawal, most commonly marked anemia.

lipoatrophy, mainly after 15–18 months of therapy. The authors attributed this to the mitochondrial toxicity of didanosine (34c). There was one case of hyperlactatemia with peripheral neuropathy and diabetes melli­ tus, one case of cytolytic hepatitis, and one case of symptomatic pancreatitis. In 39 HIV-1-infected children who started treatment with stavudine, lamivu­ dine, and nevirapine, lipodystrophy occurred in 11 children after a median of 49 months (35c).

In another study, the most common adverse events in patients taking lamivu­ dine+zidovudine+efavirenz were dizziness (7%), nausea (7%), diarrhea (5%), fatigue (8%), depression (7%), headache (5%), rash (4%), insomnia (6%), vomiting (5%), anemia (5%); there were also laboratory abnormalities, including raised amylase Z132 U/l (14%), raised triglycerides Z4.5 mmol/l (16%), raised creatine kinase Z499 U/l in men and Z424 U/l in women (18%), neutropenia o1.0  109/l (15%), hematuria (7%), and raised alanine transaminase Z109 U/l (9%) (32c).

Liver In patients co-infected with HIV and hepatitis C, treatment with dideoxynu­ cleoside analogs, such as didanosine and stavudine, was associated with hepatic steatosis (OR ¼ 4.63; 95% CI ¼ 1.55, 14) (36C). The presence of steatosis was in turn associated with fibrosis (OR ¼ 1.37; 95% CI ¼ 1.03, 1.81).

482

Abacavir

(SED-15, 3; SEDA-29, 303; SEDA-30, 348) Psychiatric Psychiatric adverse effects have been reported in a child (37A).
An 11-year-old child had mood changes,

DRUGS ACTIVE AGAINST HIV: NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS (NRTI) (SED-15, 2586; SEDA-28, 332; SEDA-29, 304; SEDA-30, 349)

Observational studies In a retrospective observational cohort study of 730 patients who took abacavir+lamivudine+zidovudine, treatment was withdrawn in 104 patients because of severe adverse events; of these there were 30 hematological, 21 gastrointestinal, 6 hepatic, 4 due to malaise, 3 due to mitochondrial toxicity, 1 myopathy, 1 migraine, 1 fever, and 1 rash (33c). Metabolism In 60 patients taking a regi­ men containing stavudine+didanosine +nevirapine for 36 months, 10 developed

headaches, anxiety, and bad dreams 1 month after adding abacavir to his antiretroviral regimen and developed major depression. The symptoms completely resolved after abacavir was withdrawn.

Immunological Reports of abacavir hypersensitivity continue to appear (38A). In an open, multicenter, randomized trial 291 subjects received abacavir 300 mg/day plus lamivudine 150 mg bd, with a non-nucleoside reverse transcriptase inhibitor (efavirenz 600 mg/day), an enhanced protease inhibitor (amprenavir 1200 mg/day+ritonavir 200 mg/ day), or a third nucleoside reverse transcrip­ tase inhibitor (stavudine 30 or 40 mg bd) (39C). The rate of adverse effects, including abacavir hypersensitivity, was similar in all three arms. Abacavir hypersensitivity reac­ tions occurred in 21 subjects (7.3%). In a retrospective observational cohort study of 730 patients who took abacavir + lamivudine + zidovudine there were hyper­ sensitivity reactions to abacavir in 36 (5%) (40c).

Antiviral drugs

Chapter 29

In the SOLO study 16 of 211 patients (7.6%) had hypersensitivity reactions to abacavir (33C). Hypersensitivity reactions to abacavir have a strong genetic association with HLA B�5701. In a prospective study of 260 abacavir-naive individuals, 20 (7.7%) were positive for HLA-B�5701; there were no cases of abacavir hypersensitivity among 148 HLA-B�5701-negative recipients (41C). Nevertheless, hypersensitivity reactions to abacavir can occur in those who do not have HLA B�5701. In a retrospective study in acute HIV infection nine (18%) of 50 individuals treated with abacavir developed suspected hypersensitivity; only two of these nine and no controls were HLA­ B�5701 positive (42c). There were hypersensitivity reactions in 2 of 17 children who were given highdose abacavir (12 mg/kg bd, maximum 600 mg) for HIV-associated encephalopa­ thy (43c).

Didanosine

(SED-15, 1113; SEDA-29, 303; SEDA-30, 348)

Comparative studies In 44 patients with HIV infection, didanosine added to tenofo­ vir was associated with progressive loss of mtDNA content and reduced cyclo­ oxygenase activity over 12 months com­ pared with tenofovir alone (44c). In another study in 61 individuals didanosine+stavudine exposure was associated with mtDNA depletion in peripheral blood mononuclear cells and subcutaneous fat (45c). Psychiatric In a comparison of a regimen that contained a protease inhibitor with a switch to a once-daily combination of efavirenz+didanosine+emtricitabine, dida­ nosine was associated with a higher risk of depressive disorder, although this was not significant in a multivariate analysis (46c). Sensory systems Eyes Didanosine has been associated with retinopathy attributed to irreversible loss of retinal pigment epithelium accompanied by partial loss of

483 the choriocapillaris and neurosensory retina in the mid-periphery. In a single case of retinopathy the electrophysiological abnormalities improved after didanosine withdrawal (47A). Ears Hearing loss in HIV-infected people after beginning nucleoside reverse tran­ scriptase inhibitors has been reported. However, in a prospective observational pilot study to determine whether zidovu­ dine or didanosine, alone or in combina­ tion, are associated with sensorineural hearing loss in HIV-infected persons there was no association (48c). Metabolism In a cross-sectional study the use of a combination of medication contain­ ing stavudine and didanosine for longer than 1 year was significantly more often seen in children with lipoatrophy, although the numbers of patients were very small (4 versus 28 in the control group) (49c). Liver The reports of all suspected hepatic adverse drug reactions with a fatal outcome received by the Uppsala Monitoring Centre between 1968 and 2003 included over 50 cases of didanosine-associated hepatotoxi­ city (24c). Pancreas The combination of didanosine and tenofovir has been associated with unexpected reductions in CD4+ T cell counts and an increased risk of pancreatitis (50c). A direct toxic effect of didanosine, particularly when given in combination with tenofovir, on the pancreas has been sug­ gested as the cause for an increase in fasting blood glucose concentrations. In a retro­ spective comparison of patients taking dida­ nosine+tenofovir and either didanosine or tenofovir in combination with other antire­ troviral drugs, both hyperglycemia and diabetes mellitus were significantly more common in recipients of didanosine+tenofovir after 12 months compared with patients taking either tenofovir or didanosine alone; the effect was more pronounced in patients taking didanosine 400 mg/day. The recommended dose for didanosine when given in combina­ tion with tenofovir was reduced in 2003 to 250 mg/day for subjects weighing more than

Chapter 29

O. Koch, S. Sheehy, R. Serafino, and B.J. Angus

60 kg and 200 mg/day in those weighing less than 60 kg.

drug-related toxicity, adverse events, and treatment discontinuation than low-dose regimens. The adverse effects included peripheral neuropathy (12% on high-dose didanosine versus 4% on low-dose) and pancreatitis (6% versus 0%). However, few events were observed, and the differences between the two groups were not statisti­ cally significant (54c).

484

Urinary tract Renal insufficiency has been reported with both tenofovir and didanosine.
A 12-year-old girl developed nephrogenic

diabetes insipidus, renal insufficiency, and a Fanconi-like syndrome while taking tenofovir in combination with lopinavir+ritonavir and didanosine (51A).

The authors concluded that these symptoms might have been attributable to tenofovir or didanosine or the combination. In the BMS Study 045, once-daily ataza­ navir+ritonavir was compared with twicedaily lopinavir+ritonavir, each with tenofovir and one nucleoside reverse transcriptase inhibitor (52C). Adverse renal events were infrequent and occurred in five subjects, who were all taking lopinavir+ritonavir in combi­ nation with tenofovir and didanosine. Pregnancy Didanosine was thought to be safe when used in pregnancy after 34 weeks gestation to reduce mother-to-child transmis­ sion of HIV (53c). There were more grade 3 and 4 events when didanosine was given in combination with stavudine (18%) than with didanosine monotherapy (6%). In the same study treatment was continued for 6 weeks in infants after birth. Serious adverse events occurred less often with didanosine monotherapy (13%) than with other drugs (stavu­ dine or stavudine+didanosine or zidovudine), with which serious adverse events occurred in 22–29%. While the lowest mother-to-child transmission rate was seen in the stavudine +didanosine arm, the authors of this study warned that the combination of stavudine +didanosine should be used with caution during pregnancy. Drug dosage regimens In a retrospective analysis of patients in the HIV Outpatient Study who were taking didanosine+tenofo­ vir the rate of adverse events was studied in patients taking high-dose didanosine (400 mg/day) compared with low-dose dida­ nosine (100–250 mg/day). In keeping with previous findings, high-dose didanosine +tenofovir was more often associated with

Drug–food interactions It is usually recommended that didanosine be taken fasting. In a retrospective comparison of the effect of taking enteric-coated didano­ sine with or without food, those who took it with food had a higher virological failure rate (55c). However, those who took it with food but with over 80% adherence had similar virological failure rates to those who took it fasting with adherence over 80%.

Emtricitabine

(SEDA-29, 304)

The most common adverse events during the use of regimens containing emtricita­ bine in combination with tenofovir and efavirenz were dizziness (8%), nausea (8– 9%), diarrhea (7–8%), fatigue (7–8%), depression (4–7%), headache (5%), rash (5%), insomnia (4–5%), and hyperpigmentation (3%). Common laboratory abnorm­ alities included raised amylase Z132 U/l (17–18%), raised triglycerides Z 4.5 mmol/ l (13–15%), raised creatine kinase Z499 U/l in men and Z424 U/l in women (12–17%), neutropenia o1.0  109/l (7%), hematuria (8–9%), and raised alanine transaminase Z109 U/l (8%) (31c,32c).

Stavudine (SED-15, 3180; SEDA-30, 349) Observational studies In a subgroup ana­ lysis of 655 antiretroviral therapy-naive patients who took lamivudine, stavudine and nevirapine for 12 months, five had to stop taking stavudine because of neuropathy, two because of lipodystrophy, and two for unknown reasons (56c). Comparative studies In a comparison of efavirenz, ritonavir-boosted amprenavir, or

Antiviral drugs

Chapter 29

stavudine, with a backbone of abacavir and lamivudine in 98 patients, the following adverse events were reported in those who took stavudine: hypertriglyceridemia (7%), diarrhea (3%), nausea (6%), rashes (4%), peripheral neuropathy (6%, compared with 0–1% in the other arms), raised lactate (5% compared with 0% in the other arms) (39C). Liver The reports of all suspected hepatic adverse drug reactions with a fatal outcome received by the Uppsala Monitoring Centre between 1968 and 2003 included 120 cases of stavudine-associated hepatotoxicity (24c).

Zidovudine (SED-15, 3713; SEDA-28, 333) Observational studies In a retrospective study of patients co-infected with HIV and hepatitis C who were given peginterferon +ribavirin and concurrent zidovudine, signifi­ cant anemia, defined as a loss of W25% of hemoglobin concentration over the first 4 weeks of therapy, was associated with zido­ vudine (OR ¼ 4.4; 95% CI ¼ 2.3, 8.5) (57c). Hematologic In 740 adults who were given zidovudine+lamivudine+efavirenz, 28 interrupted treatment because of zido­ vudine-attributable adverse effects, includ­ ing 25 with severe anemia, 2 with severe neutropenia, and 1 with non-obstructive cardiomyopathy (58c). The rate of anemia in infants born to mothers receiving zidovudine for prevention of mother-to-child transmission was slightly higher than in those born to mothers receiv­ ing other nucleoside analogs (54C).

DRUGS ACTIVE AGAINST HIV: NUCLEOTIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS (NRTI) Tenofovir

(SED-15, 3314; SEDA-29, 304; SEDA-30, 349)

485 Hematologic Several reviews have focused on the fact that the combination of didanosine+tenofovir has been asso­ ciated with a paradoxical depletion of CD4+ T cells in the face of complete viral suppression (59R,60R). It has been speculated that this is due to interference with the activation pathways of these drugs. Electrolyte balance Hypokalemia in 40 patients taking tenofovir has been reviewed; susceptibility factors were treat­ ment with ritonavir or didanosine, lower weight, and longer duration of tenofovir therapy (61c). Pancreas See didanosine. Urinary tract Acute tubular necrosis occurred in 5 HIV-infected patients who were taking tenofovir and who were compared with 22 patients described in published reports (62cr). The mean serum creatinine concentration rose from 80 to 345 mmol/l, and fell to 106 mmol/l during recovery. The renal damage resolved in 22 of the 27 patients after withdrawal of tenofovir. The most common drugs given with tenofovir were ritonavir or lopinavir +ritonavir (n ¼ 21), atazanavir (n ¼ 5), and didanosine (n ¼ 9). The authors sug­ gested that multiple drug interactions with tenofovir can lead to an increased risk of acute tubular necrosis and that frequent monitoring of renal function is warranted in any patients who are taking these combinations. Tenofovir has been associated with acute renal failure and Fanconi’s syndrome (63A,64A). The risk seems to be increased in patients who are taking tenofovir con­ currently with ritonavir, lopinavir+ritona­ vir, didanosine, or atazanavir. In a cohort study the risk of nephro­ toxicity related to tenofovir was around 0.4% and was associated with other susceptibility factors for renal dysfunction (65c).

486

Chapter 29

DRUGS ACTIVE AGAINST HIV: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI) (SED-15, 2553; SEDA-28, 334; SEDA-29, 305; SEDA-30, 349)

Efavirenz (SED-15, 1204; SEDA-28, 334; SEDA-29, 305; SEDA-30, 349) Nervous system An efavirenz-containing HAART regimen was associated with altered dreams or sleep disorders in 14% of patients (39C). In another study, efavirenz had a modest but persistent impact on the time spent in several key sleep stages (66c). In 740 patients who took zidovudine +lamivudine+efavirenz, efavirenz was com­ monly associated with insomnia, vertigo, or nightmares, and less often with severe neuropsychiatric syndromes such as delirium (59c). In the same study there was one case of febrile rash, two of intolerable pruritus, and one of cytolytic cellulitis attributed to efavirenz. Psychiatric In a retrospective study the overall incidence of neuropsychiatric symp­ toms of any kind in patients taking an efavirenz-containing regimen was 30%; a previous history of depression was signifi­ cantly associated with depressive symptoms (67c). However, in a randomized trial efavir­ enz was not associated with depression significantly more often than a protease inhibitor-containing regimen (47C). In a single-centre, cross-sectional com­ parison of patients who had used efavirenz as part of their combination antiretroviral regimen for at least 6 months with a matched cohort who were stable on non­ efavirenz combination therapy, those who took efavirenz reported higher degrees of severe stress and anxiety and a higher rate of unusual dreams than patients who were not taking efavirenz (68c). Nutrition A man taking efavirenz devel­ oped vitamin D deficiency and the authors speculated that this could have been due to CYP450 enzyme induction by efavirenz (69A).

O. Koch, S. Sheehy, R. Serafino, and B.J. Angus

Hematologic A woman who had pre­ viously reacted to nevirapine in form of a rash with angioedema and systemic fea­ tures, developed an immune-mediated hemolytic anemia (70A). In a 48-year-old man who developed neutropenia while taking efavirenz, the neutrophil count recovered after withdra­ wal (71A). Mouth Burning mouth syndrome attribu­ ted to efavirenz resolved on withdrawal (72A). Skin In a retrospective study of 122 patients who had previously stopped taking nevirapine because of a rash and who took efavirenz instead, 10 (8.2%) developed a rash and required withdrawal of efavirenz (73c). Urinary tract There has been a report of urolithiasis suspected to be secondary to efavirenz based on the metabolic composi­ tion of the stone (74A). Immunologic A patient with HIV infec­ tion and disseminated tuberculosis devel­ oped an acute, severe, multiorgan hypersensitivity reaction to efavirenz, with acute hepatic, respiratory, and renal failure, in the absence of skin changes or eosino­ philia; the symptoms resolved on with­ drawal of efavirenz (75A). Drug–drug interactions In a population pharmacokinetic study in 87 patients, atazanavir clearance was significantly increased when efavirenz was co-adminis­ tered with atazanavir+ritonavir (76A).

Nevirapine Observational studies In 197 women exposed to nevirapine for more than 7 days, adverse effects occurred in 11 (5.6%), leading to drug withdrawal in 7 (77c). There was one case of Stevens–Johnson syndrome. There was no serious liver toxicity, except for one case of grade 4 cholestasis. Co­ infection with hepatitis C virus was asso­ ciated with toxicity.

Antiviral drugs

Chapter 29

487

In a retrospective analysis of 703 HIV-1­ positive pregnant women treated with a nevirapine-containing regimen, severe adverse reactions—hepatotoxicity, rashes, and Stevens–Johnson syndrome—occurred in 6.5%, 2.4%, and 1.1% respectively (78c).

each consisting of three periods of 14 days, in which subjects were to receive one of the following treatments with a washout period of 21–28 days between treatments:

Liver The reports of all suspected hepatic adverse drug reactions with a fatal outcome received by the Uppsala Monitoring Centre between 1968 and 2003 included over 50 cases of nevirapine-associated hepatotoxi­ city (24c). In a multicenter, cross-sectional, observa­ tion study 1.1% of patients (7/613) devel­ oped hepatic toxicity that led to withdrawal of nevirapine (79C). However, patients who had discontinued treatment within the first 2 years because of adverse events were excluded. The overall rate of hepatotoxicity may therefore have been underestimated. In a retrospective study of 123 pregnant women who took nevirapine as part of combination antiretroviral therapy, eight developed significant hepatotoxicity, includ­ ing two who died from fulminant hepatitis (80c). Women who had more severe hepato­ toxicity had higher pretreatment CD4 counts. In another case, fulminant liver failure requiring liver transplantation was attribu­ ted to nevirapine (81A).

bd+ritonavir

Drug–drug interactions There was a sig­ nificant increase in atazanavir clearance when either nevirapine was co-administered with atazanavir+ritonavir compared with patients treated with atazanavir+ritonavir and nucleoside reverse transcriptase inhibi­ tors (77C).

DRUGS ACTIVE AGAINST HIV: PROTEASE INHIBITORS (SED-15, 2586; SEDA-28, 332; SEDA-29, 306; SEDA-30, 351)

Amprenavir Metabolism In a phase 1, open, rando­ mized, crossover study 42 subjects were assigned to one of six treatment sequences,


foasamprenavir 700 mg 100 mg bd (treatment A);
foasamprenavir 1400 mg 100 mg bd (treatment B);
foasamprenavir 1400 mg 200 mg bd (treatment C).

bd+ritonavir

bd+ritonavir

In six subjects there were marked rises in serum transaminases, mostly in those who took treatment C (82c). Mean fasting serum triglycerides increased significantly during all treatments. Mean fasting serum cholesterol increased during treatment A and mean LDL fell during treatment B. Mean HDL cholesterol fell during all the treat­ ments. These lipid changes tended to abate or return to baseline during follow up. Gastrointestinal Nausea and vomiting were the main adverse effects that led to withdrawal (in 6%) in patients who were given ritonavir-boosted amprenavir 600/ 100 bd (83c).

Atazanavir Liver In a study of once-a-day ritonavir­ boosted atazanavir in 23 children and ado­ lescents total bilirubin increased significantly (to over 18 mmol/l) in 17 children (84c). This was attributed to competitive inhibition of uridine diphosphate glucuronyl transferase (UGT) activity by atazanavir. Drug–drug interactions In a population pharmacokinetic analysis in 87 patients, mean trough plasma concentrations of atazanavir were 27%, 32%, and 81% lower in patients taking atazanavir+ritonavir asso­ ciated with tenofovir, efavirenz, and nevir­ apine respectively (77C). However, these reductions in trough plasma concentrations were not significant, except for those taking atazanavir+ritonavir and nevirapine. The authors concluded that the risk of reduced plasma concentrations of atazanavir due to increased atazanavir clearance is significant when atazanavir is used in combination

Chapter 29

O. Koch, S. Sheehy, R. Serafino, and B.J. Angus

with nevirapine and that atazanavir concen­ trations should be monitoring. Atazanavir interacted with saquinavir hard gel 1600 mg/day+low-dose ritonavir 100 mg/day (85C). Atazanavir 150, 200, and 300 mg/day significantly increased the Cmax and AUC of saquinavir by 40–50% and 50– 60% respectively. Ritonavir Cmax and AUC were not affected by atazanavir 150 and 200 mg/day but were increased to 54% and 40% by atazanavir 300 mg/day. This sug­ gests that the dosage of atazanavir should be reduced when it is co-administered with saquinavir and ritonavir, if atazanavir- or ritonavir-related adverse effects occur.

and nelfinavir 1250 mg bd over 16 days, steady-state nelfinavir reduced exposure to pravastatin by 47%, suggesting that higher doses of pravastatin need to be pre­ scribed to achieve maximal lipid lowering activity (88c).

488

Indinavir Urinary tract Kidney stones and gastroin­ testinal intolerance were the main adverse effects in 8 of 35 patients who had to stop taking ritonavir-boosted indinavir (84c). Musculoskeletal Six patients taking stavu­ dine+lamivudine+indinavir developed adhesive capsulitis (86c). Based on previous evidence the authors suggested that this adverse effect might have been attributable to indinavir.

Lopinavir Gastrointestinal The most common adverse effect associated with ritonavir­ boosted lopinavir is diarrhea (84C). Drug–drug interactions The effect of lopi­ navir + ritonavir on the pharmacokinetics of lamotrigine and lamotrigine 2N-glucuronide and the effect of lamotrigine on the pharma­ cokinetics of lopinavir+ritonavir have been studied in 24 healthy subjects compared with historical controls (87c). Lopinavir+ritonavir caused a mean 55% reduction in lamotrigine concentration on day 20, probably by induc­ tion of glucuronidation.

Nelfinavir Drug–drug interactions In 14 healthy subjects who took pravastatin 40 mg/ day

Ritonavir Endocrine In 5 of 19 adolescents with HIV infection who took inhaled or intrana­ sal fluticasone and low-dose ritonavir there was associated laboratory evidence of adrenal suppression (89c). There were clinical features of Cushing syndrome, especially weight gain, in most of these patients, with laboratory evidence of adre­ nal suppression from exogenous corticos­ teroids. Both the laboratory abnormalities and the Cushingoid feature resolved when the fluticasone and/or ritonavir were with­ drawn in four of the five cases. Drug–drug interactions In a randomized double-blind study 20 healthy subjects, stratified according to CYP2C19 genotype, took oral ritonavir 300 mg bd or placebo for 2 days (90C). A single dose of voriconazole 400 mg was given together with the first dose of ritonavir or placebo. Ritonavir significantly reduced voriconazole apparent oral clearance by about 43%. The authors concluded that co-administration of ritona­ vir, a potent inhibitor of CYP3A4, leads to increased exposure to voriconazole, which might increase the risk of adverse reactions.

Saquinavir Gastrointestinal Nausea and vomiting were the main adverse effects that led to drug withdrawal in 8.6% of patients taking saquinavir+ritonavir 1000 + 100 mg bd. (84c). Liver Of 28 patients who took rifampicin 600 mg/day together with ritonavir 100 mg bd and saquinavir 100 mg bd for 28 days, 11 had significant hepatocellular damage (91c).

Antiviral drugs

Chapter 29

DRUGS ACTIVE AGAINST INFLUENZA VIRUSES: NEURAMINIDASE INHIBITORS (SED-15, 2436; SEDA-

489 the room; there were no neurological sequelae (92c).

Oseltamivir

Susceptibility factors Age Exposure (AUC) to both the parent drug and its active metabolite were more than 80% higher in five very elderly subjects com­ pared with young volunteers, but oseltami­ vir was well tolerated by all subjects (93c).

Psychiatric Oseltamivir was associated with abnormal behavior in four children, including meaningless speech, disorientation, fearful responses, and running around

Renal disease Gastrointestinal adverse effects and dizziness can occur with increas­ ing doses of oseltamivir, particularly in patients with renal failure (94r).

28, 337; SEDA-29, 310; SEDA-30, 352)

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approaches in HIV type 1-infected patients. AIDS Res Hum Retroviruses 2006;22(4): 321–9. Lyons F, Hopkins S, Kelleher B, McGeary A, Sheehan G, Geoghegan J, Bergin C, Mulcahy FM, McCormick PA. Maternal hepatotoxicity with nevirapine as part of combination antiretroviral therapy in preg­ nancy. HIV Med 2006;7(4):255–60. Buyse S, Vibert E, Sebagh M, Antonini T, Ichai P, Castaing D, Samuel D, DuclosVallée JC. Liver transplantation for fulmi­ nant hepatitis related to nevirapine therapy. Liver Transpl 2006;12(12):1880–2. Shelton MJ, Wire MB, Lou Y, Adamkie­ wicz B, Min SS. Pharmacokinetic and safety evaluation of high-dose combina­ tions of fosamprenavir and ritonavir. Anti­ microb Agents Chemother 2006;50(3): 928–34. de Mendoza C, Valer L, Ribera E, Barreiro P, Martín-Carbonero L, Ramirez G, Soriano V. Performance of six different ritonavir­ boosted protease inhibitor-based regimens in heavily antiretroviral-experienced HIVinfected patients. HIV Clin Trials 2006;7(4): 163–71. Macassa E, Delaugerre C, Teglas JP, Jullien V, Tréluyer JM, Veber F, Rouzioux C, Blanche S. Change to a once-daily combi­ nation including boosted atazanavir in HIV1-infected children. Pediatr Infect Dis J 2006;25(9):809–14. Boffito M, Maitland D, Dickinson L, Back D, Hill A, Fletcher C, Moyle G, Nelson M, Gazzard B, Pozniak A. Pharmacokinetics of saquinavir hard-gel/ritonavir and atazanavir when combined once daily in HIV Type 1­ infected individuals administered different atazanavir doses. AIDS Res Hum Retro­ viruses 2006;22(8):749–56. De Ponti A, Vigano MG, Taverna E, Sansone V. Adhesive capsulitis of the shoulder in human immunodeficiency virus-positive patients during highly active

antiretroviral therapy. J Shoulder Elbow Surg 2006;15(2):188–90. van der Leur MR, Burger DM, la Porte CJ, Koopmans PP. A retrospective TDM data­ base analysis of interpatient variability in the pharmacokinetics of lopinavir in HIVinfected adults. Ther Drug Monit 2006; 28(5):650–3. Aberg JA, Rosenkranz SL, Fichtenbaum CJ, Alston BL, Brobst SW, Segal Y, Gerber JG. ACTG A5108 team. Pharmacokinetic inter­ action between nelfinavir and pravastatin in HIV-seronegative volunteers: ACTG Study A5108. AIDS 2006;20(5):725–9. Arrington-Sanders R, Hutton N, Siberry GK. Ritonavir–fluticasone interaction caus­ ing Cushing syndrome in HIV-infected children and adolescents. Pediatr Infect Dis J 2006;25(11):1044–8. Mikus G, Schöwel V, Drzewinska M, Rengelshausen J, Ding R, Riedel KD, Burhenne J, Weiss J, Thomsen T, Haefeli WE. Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir. Clin Pharmacol Ther 2006;80(2):126–35. Gray A, Abdool Karim SS, Gengiah TN. Ritonavir/saquinavir safety concerns curtail antiretroviral therapy options for tuberculo­ sis-HIV-co-infected patients in resource-con­ strained settings. AIDS 2006;20(2):302–3. Okumura A, Kubota T, Kato T, Morishima T. Oseltamivir and delirious behavior in children with influenza. Pediatr Infect Dis J 2006;25(6):572. Abe M, Smith J, Urae A, Barrett J, Kinoshita H, Rayner CR. Pharmacokinetics of oseltamivir in young and very elderly subjects. Ann Pharmacother 2006;40(10): 1724–30. Karie S, Launay-Vacher V, Janus N, Izze­ dine H, Deray G. Pharmacokinetics and dosage adjustment of oseltamivir and zana­ mivir in patients with renal failure. Nephrol Dial Transplant 2006;21(12):3606–8.

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30

Drugs used in tuberculosis and leprosy

Hepatotoxicity of antituberculosis drugs The hepatotoxic potential of isoniazid, pyrazinamide, and rifampicin during antituberculosis chemotherapy has been reviewed (1R). DoTS classification: Reaction: Hepatotoxicity due to antituberculosis drugs Dose-relation: Mostly collateral, occasionally hypersusceptibility Time-course: Intermediate Susceptibility factors: Age (old age); other diseases (malnutrition, alcoholism, HIV infection, and chronic hepatitis B and C infections) Data on patients who died or were hospitalized for liver disease within 1 month after taking rifampicin + pyrazinamide for latent tuberculosis have been reported (2C). Liver injury was attributable to rifampicin + pyrazinamide in 50 patients reported, of whom 12 died. Rifampicin + pyrazinamide was the likeliest cause of liver injury in 47 patients. The median age was 44 (range 17– 73) years and 32 (64%) were men. Seven of 43 patients tested had hepatitis C virus antibodies, 1 of 45 had chronic hepatitis B, 3 of 22 had positive HIV serology, 34 of 48 had excess alcohol use, and 33 of 50 were Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03130-4 r 2009 Elsevier B.V. All rights reserved.

taking other hepatotoxic medications. Six patients, two of whom died, had no predictors of liver disease. Patients who died were older and had taken more medications than did those who recovered. Of 31 who were monitored according to guidelines, 9 died. Death was predicted by age and the use of other medications, but none of the cofactors was a promising predictor of severe liver injury. In another study the efficacy of weekly rifapentine + isoniazid was compared with daily rifampicin + pyrazinamide in preventing tuberculosis in 399 household contacts of patients with pulmonary tuberculosis in Brazil (3C). The median age was 34 years and the median weight 63 kg; 60% were female and only one patient was HIV infected. The trial was halted by the investigators before completion because of unanticipated hepatotoxicity in the rifampicin + pyrazinamide arm. Of 193 participants who received rifampicin + pyrazinamide 20 had grade 3 or 4 hepatotoxicity, compared with 2 of 206 participants who received rifapentine + isoniazid. There were no hospitalizations or deaths due to hepatotoxicity, and all the participants’ liver enzymes returned to normal during followup. During follow-up, there were four cases of active tuberculosis, three in the rifapentine + isoniazid group and one in the rifampicin + pyrazinamide group. The authors concluded that rifapentine + isoniazid was better tolerated than rifampicin + pyrazinamide and was associated with good protection against tuberculosis. In a retrospective comparison of isoniazid for 9 months (n ¼ 770) and rifampicin for 4 months (n ¼ 1379) for latent tuberculosis the percentages of patients who completed 80% or more of their prescribed treatment were

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53 and 72%, respectively (4C). Clinically recognized adverse reactions resulted in permanent treatment withdrawal in 4.6 and 1.9%, respectively. Clinically recognized hepatotoxicity was more common with isoniazid (1.8%) than rifampicin (0.08%). The American Thoracic Society has issued a statement on the hepatotoxicity of antituberculosis drugs (5S). The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of druginduced liver injury range from hepatic adaptation to hepatocellular injury. Systematic steps for preventing and managing liver damage include patient and regimen selection to optimize the benefits to harm balance, staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent tuberculosis, alanine transaminase monitoring is recommended for those who chronically take alcohol or concomitant hepatotoxic drugs, have viral hepatitis or other pre-existing liver disease or abnormal baseline transaminase activity, have had prior isoniazid-induced hepatitis, are pregnant, or are within 3 months postpartum. Treatment should be withdrawn and a modified or alternative regimen used for those with raised transaminase activity more than three times the upper limit of normal in the presence of hepatitis symptoms and/or jaundice, or five times the upper limit in the absence of symptoms.  A 19-year-old woman with ovarian and perito-

Soumya Swaminathan and V.V. Banu Rekha

is feasible and effective for antituberculosis drug-induced hepatic failure.

Susceptibility factors In a retrospective study of the adverse effects of antitubercu­ losis drugs and associated susceptibility factors in patients with active tuberculosis admitted to the Respiratory Ward of a University Clinic between 1984 and 2001, 95 of 1149 patients (8.3%) had adverse effects (7C). The frequency of adverse drug reactions increased from 0.6% at ages under 20 years to 5.2% at ages 20–40 years. There were no sex or age differences between patients who did and did not have adverse effects. There were asymptomatic liver function disturbances in 56 patients (4.9%) but the rate of hepatotoxicity was only 2.4%. There were no age or sex differences among those who had hepato­ toxicity and who had not. The major adverse effects were ototoxicity (1.7%), hepatotoxi­ city (0.8%), neuropsychiatric effects (0.7%), and hyperuricemia (0.6%). The authors concluded that severe adverse reactions to antituberculosis drugs are relatively com­ mon, especially among patients hospitalized for pulmonary tuberculosis.

Dapsone (SED-15, 1050; SEDA-28, 343; SEDA-29, 315; SEDA-30, 357)

neal tuberculosis was given isoniazid 300 mg/day, rifampicin 600 mg/day, ethambutol 1500 mg/day, and pyrazinamide 1500 mg/day (6A). On the third day she developed fatigue, malaise, and jaundice. Other causes were ruled out and the antituberculosis drug therapy was immediately withdrawn. The next day she became unconscious and icteric and did not respond to verbal or painful stimuli. Her serum aspartate transaminase activity was 1301 IU/l, alanine transaminase 1332 IU/l, total bilirubin 10.5 mg/dl, and prothrombin time 71 seconds. She underwent living-related partial liver transplantation and was then given nonhepatotoxic antituberculosis drugs and low-dose immunosuppressants.

Hematologic The medical records of 12 patients with ocular cicatricial disease, of whom 11, mean age 72 (range 55–89) years, were treated with dapsone 50 mg bd as first line therapy for 19 (range 1–60) months, were reviewed (8c). Six had reticulocytosis, including four with clinically significant hemolytic anemia. These patients were not checked for glucose-6-phosphate hydrogenase (G6PD) deficiency, which is a susceptibility factor for hemolytic anemia. Methemoglobinemia has been attributed to dapsone (9A).

The authors found four similar published cases and concluded that liver transplantation

 An immunocompromised child with chronic

immune thrombocytopenic purpura developed

Drugs used in tuberculosis and leprosy

Chapter 30

a fever, cough, perioral cyanosis, bilateral lower lobe coarse crackles, and a low O2 saturation by pulse oximetry (89%). His medications included prednisone and rituxi­ mab for chronic immune thrombocytopenic purpura, and dapsone for Pneumocystis jiroveci pneumonia prophylaxis. The methemo­ globin concentration was 9.6%.

Immunologic Sulfone syndrome is a rare effect of dapsone (10A).  A 51-year-old woman, with a history of

sulfonamide allergy, received a matched unre­ lated hemopoietic stem cell transplant for acute myelogenous leukemia. Dapsone 100 mg/day was started on day 28 for P. jiroveci prophylaxis. One month later she developed hepatitis, hemolytic anemia, fever, methemoglobinemia of 8%, and exfoliative dermatitis.

The sulfone syndrome is not a well-known effect of dapsone, but it can occur at doses of 50–300 mg/day. In all cases the syndrome occurs within 2 months of the start of therapy. Its clinical effects include fever, methemoglobinemia, hemolytic anemia, exfoliative dermatitis, and raised transami­ nase activities.

497 atelectasis of the middle lobe in the right lung 1 month later. Isoniazid, rifampicin, and pyrazi­ namide were restarted 14, 19, and 30 days later, respectively, and there was no recurrence. Rechallenge was not undertaken.

The authors concluded that the lung injury was due to ethambutol. Sensory systems Leber’s hereditary optic neuropathy has been attributed to etham­ butol (12Ar).  A 70-year-old woman with tuberculosis took

ethambutol, rifampicin, isoniazid, and pyrazi­ namide. She had marked reduction in visual acuity in both eyes after 3 months of treatment and ethambutol was withdrawn. Her corrected visual acuity was 0.03 in both eyes. There was no hyperemia, swelling of the optic disc, or capillary dilatation in either eye. Centrocecal scotomas were found bilaterally. After 1 month her visual acuity had further reduced to 0.01 and the scotomas had enlarged. Genetic analysis revealed a point mutation in mitochondrial DNA 11778.

The authors concluded that ethambutol could be a risk factor for Leber’s hereditary optic neuropathy and found three similar cases in a literature review. There was abnormal multifocal electroretinography in two cases of presumed ethambutol toxicity (13A).  An

Ethambutol

(SED-15, 1282; SEDA-29, 316; SEDA-30, 358)

Respiratory Acute lung injury has been attributed to ethambutol (11A).  A 78-year-old woman with active pulmonary

tuberculosis was given isoniazid, rifampicin, ethambutol, and pyrazinamide. After 10 days she developed a fever, dyspnea, left-sided pleuritic chest pain, and hypoxemia. A chest CT scan showed bilateral pleural effusions. A biopsy specimen from the anterior basal seg­ ment of the right lower lobe showed diffuse alveolar epithelial damage, focal hemorrhage, and alveolar wall thickening, with moderate infiltration of inflammatory cells. Drug-induced acute lung injury was suspected and the anti­ tuberculosis drugs were withdrawn after 34 days. The fever subsided and the dyspnea and general weakness improved. The chest X-ray showed significant clearing of the infiltration with reduced pleural effusions but persistent

81-year-old woman with Parkinson’s disease and hypothyroidism developed gra­ dual, bilateral, painless, progressive visual loss over 2–3 months. Her medications included clarithromycin, clopidogrel, oxybutynin, ome­ prazole, ciprofloxacin, levothyroxine, carbi­ dopa + levodopa, salbutamol, paracetamol, and ethambutol 400 mg bd. She had been taking ethambutol for 4 months when she noticed the visual changes. Her visual acuity was 20/250 in the right eye and 20/100 in the left eye. The pupils were equal and reactive without a relative afferent pupillary defect. Ophthalmoscopy showed minimal retinal pig­ ment epithelial changes in the macula and minimal temporal pallor of the optic discs. Goldmann visual fields showed a dense centrocecal scotoma with breakout to the superior temporal periphery. Ethambutol was withdrawn. The amplitudes of multifocal electroretinography were reduced by 1.1–4.5 standard deviations at different locations, and the change was greatest in the center of the visual fields. Over the next 2 months, her visual acuity gradually improved to 20/80 (right eye) and 20/50 (left eye) and after

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10 months 20/70 and 20/40; the visual fields showed markedly improved central scotomas.  A 60-year-old woman with Mycobacterium avium intracellulare pulmonary infection was given rifampicin 600 mg/day and ethambutol 1200 mg/day. After 9 months she developed reduced vision centrally in both eyes, which she described as a “shadow.” Her visual acuity was 20/25. Multifocal electroretinography showed a moderate diffuse reduction in amplitudes by 2.1–4.2 standard deviations. Ethambutol was continued, but after 1 month there was con­ tinued subjective visual loss and visual acuity was 20/50 with a new central scotoma. Multi­ focal electroretinography showed a reduction in amplitudes greater than 2 standard deviations and disproportionately in the center of the field. Ethambutol was withdrawn and her visual functions returned to normal within 6 months.

Multifocal electroretinography is useful in detecting retinal dysfunction caused by damage to photoreceptors or bipolar cells or their connections. The authors concluded that abnormal electroretinography with diffuse depression and additional central field depression could have contributed to the reduction in visual field sensitivity, in parti­ cular the central scotomas. This gives further evidence that ethambutol can produce toxi­ city in layers of the retina deep to the ganglion layer in addition to optic nerve toxicity. Musculoskeletal Crystal arthropathy, which is a rare and poorly recognized adverse effect of pyrazinamide and ethambutol, has been reported in a patient taking both drugs (14A).  A 76-year-old woman was given rifampicin,

ethambutol, isoniazid, and pyrazinamide for tuberculosis of the cervical spine and after 3 weeks developed an acute monoarthropathy of the right wrist associated with pyrexia. The wrist was swollen, erythematous, boggy, and tender. Active movement was impaired by pain and passive movement was limited. Radio­ graphy showed chondrocalcinosis. The CRP had risen to 600 g/l, there was a leukocytosis, and the serum uric acid concentration was 580 ìmol/l, having been normal on admission. From the joint 0.5 ml of “creamy” pus was aspirated. Synovial fluid analysis showed 50% neutrophils and 50% lymphocytes. The fluid was negative for Gram staining organisms and acid-fast bacilli. Polarized light microscopy showed urate and pyrophosphate crystals. She was treated with diclofenac sodium for 5 days and her symptoms subsided. She completed her course of antituberculosis drug therapy.

Soumya Swaminathan and V.V. Banu Rekha

A metabolite of pyrazinamide, pyrazinoic acid, inhibits the renal tubular secretion of uric acid and ethambutol also reduces its renal clearance. The resulting hyperuricemia can cause arthralgias and very rarely arthritis.

Isoniazid (SED-15, 1923; SEDA-28, 343; SEDA-29, 317, SEDA-30, 359) Nervous system Status epilepticus after overdose of isoniazid has been reported (15A).  A previously healthy 10-year-old was noticed to

have noisy irregular breathing during sleep. She vomited repeatedly and was agitated and not fully responsive to commands. Her only regular medication was isoniazid 400 mg/day because of recent contact with active tuberculosis. On the assumption that the child had taken an over­ dose of isoniazid, she was given activated charcoal via nasogastric tube and pyridoxine 5 mg/kg and sodium bicarbonate intravenously. There was rapid improvement and she recov­ ered full consciousness within a few hours.

Acute isoniazid intoxication is rare and is classically identified by a triad of signs and symptoms—seizures refractory to standard anticonvulsants, metabolic acidosis, and coma. The initial picture often mimics encephalitis. Laboratory findings often include metabolic acidosis, hyperglycemia, hypokalemia, glycosuria, and ketonuria, mimicking diabetic ketoacidosis. The ner­ vous system effects, particularly seizures, result from the ability of isoniazid to react with pyridoxine, a co-factor for the produc­ tion of gamma-aminobutyric acid (GABA). Isoniazid and pyridoxine form a compound that is rapidly excreted in the urine, resulting in acute GABA deficiency.

Rifampicin

(SED-15, 3040; SEDA-27, 324; SEDA-28, 344; SEDA-29, 317)

Cardiovascular The incidence of venous thromboembolic complications (deep vein thrombosis and pulmonary embolism) in

Drugs used in tuberculosis and leprosy

Chapter 30

patients being treated for tuberculosis has been reported (16r). In all, 1237 patients (mean age 44 years, 66% men, 41% immigrants, 75% new cases, 92% pulmonary cases, and 16% multidrug­ resistant cases) were followed up for a mean of 49 days after diagnosis and the immediate starting of an appropriate antituberculosis regimen. Five patients (0.4%) developed a proximal deep vein thrombosis after a mean interval of 20 days, complicated in two cases by pulmonary embolism. There were two other cases of pulmonary embolism without deep vein thrombosis in the first week of treatment. All cases of venous thromboembolism occurred among new cases of pulmonary tuberculosis, with rifampicin as part of the initial standardized treatment regimen. All except one case of venous thromboembolism occurred while the patients were in hospital in the absence of venous thrombopro­ phylaxis. The presence of a hypercoagulable state among patients with tuberculosis was postulated as a consequence of a raised plasma fibrinogen, reactive thrombocytosis, direct endothelial damage promoted by the tubercle bacillus, and the use of rifampicin. Skin Rifampicin-induced acute generalized exanthematous pustulosis (AGEP) has been reported (17A).  A 79-year-old woman with meticillin-sensitive

Staphylococcus aureus endocarditis was given vancomycin and rifampicin. Within 48 hours she developed a severe generalized erythema­ tous maculopapular rash, which worsened over the next 3 days. The rash was pruritic and non-tender and Nikolsky’s sign was negative. A biopsy of one of the pustules showed histological features consistent with AGEP. Given the intensity of the rash she was given a 5-day course of oral steroids (pre­ dnisolone 50 mg/day for 2 days, and then 25 mg/day). Over the next 7 days the rash resolved. She was given linezolid and success­ fully completed treatment.

AGEP is usually caused by systemic med­ ications with a typical onset within 48 hours of the start of treatment and less than 24 hours in 50% of cases. The most commonly implicated drugs are antibiotics, particularly penicillins and macrolides.

499

On withdrawal of the offending drug, the rash typically resolves within 2 weeks with­ out further complications. Immunologic Three patients taking rifam­ picin developed immediate urticarial reactions (18A). Only intradermal tests at a dilution of at least 1:10 000 (concentration of rifampicin approximately 6 mg/l) gave true positive results and in vitro tests (IgE, LTT, and CAST) did not correctly identify hypersensitive patients. All three patients were successfully desensitized with rifampi­ cin using a 7-day protocol. Rifampicin immediate hypersensitivity, which is rare, can be diagnosed by intradermal skin tests. In vitro tests did not contribute to the diagnosis and so an IgE-mediated mechan­ ism remains to be proven. Drug–drug interactions Atazanavir + ritonavir Rifampicin is contraindicated in combination with most HIV protease inhibitors. The pharmacokinetics of ataza­ navir in three regimens with atazanavir, ritonavir, and rifampicin has been evalu­ ated in 71 healthy subjects, 53 of whom took atazanavir 400 mg od on days 1–6 followed by atazanavir 300 mg and ritonavir 100 mg on days 7–16 (n ¼ 52) (19C). These subjects were then randomized to one of three regimens on days 17–26: atazanavir 300 + ritonavir 100 + rifampicin 600 (n ¼ 17), atazanavir 300 + ritonavir 200 + rifampicin 600 (n ¼ 17), or atazanavir 400 + ritonavir 200 + rifampicin 600 od (n ¼ 14) (all in mg/ day). Another 18 subjects underwent proce­ dures identical to those who received study drug on days 1–16, except that they did not receive the study drug or have a pharmaco­ kinetic evaluation on days 1–16. This group took rifampicin 600 alone on days 17–26 and underwent both trough and serial (day 26) pharmacokinetic sampling. With atazanavir 400 + ritonavir 200 + rifampicin 600, the ata­ zanavir AUCs were comparable, but the Cmin values were lower than with atazanavir 400 alone. Atazanavir exposure was sub­ stantially reduced with the other rifampicincontaining regimens relative to atazanavir 400 alone and with all regimens relative to atazanavir 300 + ritonavir 100. Rifampicin and des-rifampicin exposures were 1.6–2.5

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times higher than with rifampicin 600 alone. The authors concluded that atazanavir and rifampicin should not be co-administered in the doses studied, although atazanavir with rifampicin was safe. Mycophenolate mofetil In a prospective, open, non-randomized, controlled study of the interaction of rifampicin with mycophe­ nolate mofetil in eight stable renal allograft recipients total MPA AUC0-12 fell by 18% after rifampicin co-administration, partly attributable to induction of MPA glucur­ onidation (20c). This was mainly because of a 33% reduction in total MPA AUC6-12, attributable to reduced enterohepatic recir­ culation. Free MPA AUC6-12 fell by 22%. Total MPAG and AcMPAG AUC0-12 increased by 34 and 193%, respectively, attributable to altered in MRP2-mediated transport of MPAG and AcMPAG. Nevirapine In 140 HIV-infected Thai patients randomized nevirapine 400 mg/day as part of highly active antiretroviral therapy with or without rifampicin, mean plasma nevirapine concentrations at weeks 8 and 12 were 5.40 and 6.56 mg/l, respectively, attri­ butable to enzyme induction by rifampicin (21C). However, there was no significant difference in CD4 + cell count at 24 weeks, plasma alanine transaminase activity at 8 and 12 weeks, or the incidences of nevir­ apine-associated rashes (7.0% versus 8.6%). The effects of rifampicin 450/600 mg/day for 1 week on the steady-state pharmaco­ kinetics of nevirapine 200 mg bd have been studied in 13 HIV-infected patients (22c). Rifampicin caused a 42% reduction in Cmax, a 53% reduction in Cmin, and a 46% reduction in AUC of nevirapine. Increasing the dose of nevirapine to 300 mg/day in seven patients increased the Cmin to within the target range without exceeding the toxic concentration of 12 mg/ml.

Rifapentine Drug–drug interactions Isoniazid A well-known problem of using a fixed-dose

Soumya Swaminathan and V.V. Banu Rekha

combination of rifampicin and isoniazid is a reduction in the systemic availability of rifampicin. The same has been ascribed to hydrolysis of rifampicin to 3-formylrifamycin in gastric acid and reaction of the latter with isoniazid to form isonicotinyl hydrazone. The interaction of isoniazid with rifapentine, a newer long-acting rifamycin, which is structurally similar to rifampicin, has therefore been studied (23E). Rifapentine was converted to 3-formylrifamycin in acid conditions, and isonicotinyl hydrazone was therefore formed. Maximum decomposition occurred at pH 2, with 30% loss of rifapentine, similar to the value that has been reported for rifampicin. These results suggest that co-administration of rifapentine and isoniazid should be avoided and that the two drugs should not be formulated in a single fixed-dose formulation.

Newer drugs for tuberculosis Current management of tuberculosis involves taking at least four drugs and a minimum treatment duration of 6 months. Moreover, the emergence of newer strains of tuberculosis-like multidrug-resistant organisms (MDR-TB) and extremely resistant organisms (XDR-TB) has focused attention on the development of new antituberculosis drugs. There is now a pipeline of new compounds or classes of compounds that are being specifically tested for their potential effectiveness in the treatment of tuberculosis. Drug targets The most important aim in drug development is the identification of novel drug targets involved in vital aspects of bacterial growth, metabolism, and viability, the inactivation of which will lead to bacterial death or inability to persist (24R). The Mycobacterium tuberculosis genome sequence and mycobacterial genetic tools, such as transposon mutagenesis and signature-tagged mutagenesis, have been used to identify genes essential for growth of the organism in vitro and its survival in vivo (25E, 26E). Inhibition of the host tissue liquefaction process, which facilitates reduced

Drugs used in tuberculosis and leprosy

Chapter 30

transmission, represents a novel approach to the design of new drugs (25E). Targeted knockout of specific genes, whose disruption leads to non-viability of the bacilli, is a valuable approach to identifying essential gene products involved in mycobacterial persistence. Some enzymes, including isocitrate lyase (ICL), PcaA (a methyltransferase involved in the modification of mycolic acid), RelA (ppGpp synthase), and DosR (controlling a 48-gene regulon involved in mycobacterial survival under hypoxic conditions), have been identified as targets for the development of drugs to kill persistent bacilli (27E, 28E, 29E, 30E). Energy production pathways, such as the electron transport chain, glycolytic pathways (like the Embden–Meyerhof pathway), and fermentation pathways, could be good targets for drug development (24R). In identifying drugs that kill persistent organisms and thereby shortening the duration of treatment, novel drug screens that mimic in vivo conditions in lesions (i.e., acidic pH and hypoxia) and act against old stationary-phase non-growing bacilli could be important (31E, 32E). In addition, drug combination screens could be performed to identify drugs that have synergistic effects. The systems biology approach, which proposes using multiple compounds that hit multiple targets in different pathways to achieve the desired outcome, can be used for identifying novel drug combinations against tuberculosis (24R).

Newer antituberculosis drugs In the growing pipeline of potential new antituberculosis drugs there are currently seven novel compounds that are not yet approved for the treatment of tuberculosis and are in various stages of clinical development (33R). The most advanced of these are the fluoroquinolones, specifically gatifloxacin and moxifloxacin, which are currently being evaluated in phase 2 and 3 clinical trials. Two other compounds (TMC207 and OPC67683) have completed phase 1 clinical trials and early bactericidal activity (EBA) studies, PA824 has completed its phase 1 program, and two other compounds (LL3858 and SQ109) are currently being evaluated in phase 1 clinical studies.

501

Diarylquinoline (TMC207) A novel diarylquinoline TMC207 (previously referred to as “R207910”) is being developed by Tibotec, a Johnson & Johnson subsidiary. It has many characteristics, both in vitro and in vivo, that make it a very attractive antituberculosis drug candidate. It has very potent in vitro activity against both multidrug-resistant and drug-susceptible strains of M. tuberculosis (34E). The target for diarylquinoline has been proposed to be mycobacterial F1F0 proton ATP synthase, which is a new drug target in mycobacteria. TMC207 was more active than isoniazid and rifampicin in a mouse model and shortened therapy from 4 to 2 months in mice with established infection. In phase 1 studies in humans tolerability was good and the pharmacokinetics were linear over the dose range studied. In a phase 1 study of multiple ascending doses there was accumulation, with increases in the AUC by a factor of about two between days 1 and 14. The “effective halflife” was of the order of 24 hours. TMC207 is about to enter a randomized phase 2 study in a population of patients with MDR-TB (33R).

Nitroimidazoles (PA824 and OPC67683) Two nitroimidazoles are currently in clinical development, the nitroimidazo-oxazine PA824, which is being developed by the TB Alliance, and the dihydroimidazooxazole OPC67683, which is being developed by Otsuka Pharmaceutical (33R). PA824 has an MIC as low as 0.015– 0.250 mg/ml against drug-sensitive and multidrug-resistant M. tuberculosis (35E). PA824 is a prodrug that requires activation by a bacterial F420-depedent glucose-6phosphate dehydrogenase (Fgd) and nitroreductase to activate components that then inhibit bacterial mycolic acid and protein synthesis (35E). Pharmacokinetic studies of PA824 in rats have shown that it has excellent tissue penetration (36E). In animals, PA824 was active against non-growing bacilli, even in microaerophilic conditions, and its activity is comparable to that of

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isoniazid, rifampicin, and moxifloxacin (35E). PA824 had bactericidal activity in mice in the first 2 months of treatment and also in the continuation phase, which suggests that it has significant activity against non-growing persistent bacilli in vivo (36E). OPC67683 is extremely potent in vitro and in vivo against M. tuberculosis (37E). In a mouse model of chronic infection, OPC67683 was more efficacious that currently used antituberculosis drugs. The effective plasma concentration was 100 mg/l, which was achieved with an oral dose of 0.625 mg/kg. OPC67683 showed no crossresistance with any of the currently used antituberculosis drugs. MICs against multiple clinically isolated tuberculosis strains were of the order of 6 mg/l (38E).

New fluoroquinolones C-8-methoxy-FQ, moxifloxacin, and gatifloxacin have a longer half-life and are more active against M. tuberculosis than the older quinolones. Moxifloxacin, in combination with rifampicin and pyrazinamide, killed tubercle bacilli in mice more effectively than the standard regimen of isoniazid + rifampicin + pyrazinamide and achieved stable cures in 4 months without relapse (39E,40E). Moxifloxacin has EBA against tubercle bacilli comparable to that of isoniazid and was well tolerated in a preliminary human study (41c). In a clinical trial conducted by the TB Trials Consortium in patients with pulmonary tuberculosis substitution of

Soumya Swaminathan and V.V. Banu Rekha

moxifloxacin for ethambutol did not influence 2-month sputum culture status but did result in a higher frequency of negative cultures at earlier times, which suggests that moxifloxacin has good sterilizing activity (42C). There is a current trial by the TB Trials Consortium, in which moxifloxacin replaces isoniazid in patients with pulmonary tuberculosis. In addition, at the Tuberculosis Research Centre in Chennai, patients are being recruited for a randomized clinical study of the efficacy and tolerability of 3- and 4-month regimens containing moxifloxacin.

Pyrrole (LL3858) Pyrrole LL3858, developed by Lupin, is being evaluated in a multidose phase 1 trial in healthy volunteers in India. It has submicromolar MICs and was very active in a mouse model of tuberculosis. In combination with currently used antituberculosis drugs, LL3858 is reported to sterilize the lungs and spleens of infected animals more quickly than conventional therapy (43E).

Diamine (SQ109) The most recent compound to enter phase 1 clinical trials for tuberculosis is SQ109, which is being developed by Sequella. In in vitro and mouse in vivo studies the MIC against M. tuberculosis was 100–630 mg/l (44E). SQ109 has recently entered phase 1 studies in human volunteers.

References 1. Yew WW, Leung CC. Antituberculosis drugs and hepatotoxicity. Respirology 2006;11: 699–707. 2. Ijaz K, Jereb JA, Lambert LA, Bower WA, Spradling PR, McElroy PD, Iademarco MF, Navin TR, Castro KG. Severe or fatal liver injury in 50 patients in the United States taking rifampin and pyrazinamide for latent

tuberculosis infection. Clin Infect Dis 2006;42: 346–55. 3. Schechter M, Zajdenverg R, Falco G, Barnes G L, Faulhaber JC, Coberly JS, Moore RD, Chaisson RE. Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuber­ culosis in household contacts. Am J Respir Crit Care Med 2006;173:922–6.

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4. Page KR, Sifakis F, Montes de Oca R, Cronin WA, Doherty MC, Federline L, Bur S, Walsh T, Karney W, Milman J, Baruch N, Adelakun A, Dorman SE. Improved adherence and less toxicity with rifampin vs isoniazid for treatment of latent tuberculosis: a retrospective study. Arch Intern Med 2006;166:1863–70. 5. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan R, Sterling TR. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935–52. 6. Idilman R, Ersoz S, Coban S, Kumbasar O, Bozkaya H. Antituberculous therapyinduced fulminant hepatic failure: successful treatment with liver transplantation and nonstandard antituberculous therapy. Liver Transplant 2006;12(9):1427–30. 7. Gülbay BE, Gürkan OU, Yildiz OA, Onen ZP, Erkekol FO, Bac- c- iog?lu A, Acican T. Side effects due to primary antituberculosis drugs during the initial phase of therapy in 1149 hospitalized patients for tuberculosis. Respir Med 2006;100:1834–42. 8. Wertheim MS, Males JJ, Cook SD, Tole DM. Dapsone induced haemolytic anae­ mia in patients treated for ocular cicatricial pemphigoid. Br J Ophthalmol 2006;90:516. 9. Schiff DE, Roberts WD, Sue Y-J. Methemoglobinemia associated with dapsone ther­ apy in a child with pneumonia and chronic immune thrombocytopenic purpura. J Pediatr Hematol Oncol 2006;28:395–8. 10. Abidi MH, Kozlowski JR, Ibrahim RB, Peres E. The sulfone syndrome secondary to dapsone prophylaxis in a patient undergoing unrelated hematopoietic stem cell transplan­ tation. Hematol Oncol 2006;24:164–5. 11. Choi WI, June Jeon Y, Kwon KY, Ko SM, Keum DY, Kwon Park C. Acute lung injury caused by ethambutol. Respir Med Extra 2006;2:55–7. 12. Ikeda A, Ikeda T, Ikeda N, Kawakami Y, Mimura O. Leber’s hereditary optic neuro­ pathy precipitated by ethambutol. Jpn J Ophthalmol 2006;50:280–3. 13. Kardon RH, Morrisey MC, Lee AG. Abnormal multifocal electroretinogram (mfERG) in ethambutol toxicity. Semin Ophthalmol 2006;21(4):215–22.

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14. Abraham S, Mitchell A, Cope A. Antituberculous therapy-induced crystal arthropathy. Rheumatology 2006;45:1173–4. 15. Tibussek D, Mayatepek E, Distelmaier F, Rosenbaum T. Status epilepticus due to attempted suicide with isoniazid. Eur J Pediatr 2006;165(2):136–7. 16. Ambrosetti M, Ferrarese M, Codecasa LR, Besozzi G, Sarassi P, Viggiani P, Migliori GB. Incidence of venous thromboembolism in tuberculosis patients. Respiration 2006; 73:396. 17. Azad A, Connelly N. Case of rifampicininduced acute generalized exanthematous pustulosis. Int Med J 2006;36:619–20. 18. Buergin S, Scherer K, Hausermann P, Bircher AJ. Immediate hypersensitivity to rifampicin in 3 patients: diagnostic proce­ dures and induction of clinical tolerance. Int Arch Allergy Immunol 2006;140:20–6. 19. Burger DM, Agarwala S, Child M, BeenTiktak A, Wang Y, Bertz R. Effect of rifampin on steady-state pharmacokinetics of atazanavir with ritonavir in healthy volunteers. Antimicrob Agents Chemother 2006;50(10):3336–42. 20. Naesens M, Kuypers DRJ, Streit F, Armstrong VW, Oellerich M, Verbeke K, Vanrenterghem Y. Rifampin induces altera­ tions in mycophenolic acid glucuronidation and elimination: implications for drug exposure in renal allograft recipients. Clin Pharmacol Ther 2006;80:509–21. 21. Manosuthi W, Sungkanuparph S, Thakkins­ tian A, Rattanasiri S, Chaovavanich A, Prasithsirikul W, Likanonsakul S, Ruxrung­ tham K. Plasma nevirapine levels and 24­ week efficacy in HIV-infected patients receiving nevirapine-based highly active antiretroviral therapy with or without rifam­ picin. Clin Infect Dis 2006;43:253–5. 22. Ramachandran G, Hemanthkumar AK, Rajasekaran S, Padmapriyadarsini C, Narendran G, Sukumar B, Sathishnarayan S, Raja K, Kumaraswami V, Swaminathan S. Increasing nevirapine dose can overcome reduced bioavailability due to rifampicin coadministration. J Acquir Immune Defic Syndr 2006;42(1):36–41. 23. Prasad B, Bhutani H, Singh S. Study of the interaction between rifapentine and isonia­ zid under acid conditions. J Pharm Biomed Anal 2006;41(4):1438–41.

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24. Zhang Y, Post-Martens K, Denkin S. New drug candidates and therapeutic targets for tuberculosis therapy. Drug Discov Today 2006;11(1–2):21–7. 25. Lamichhane G, Zignol M, Blades NJ, Geiman DE, Dougherty A, Grosset J, Broman KW, Bishai WR. A postgenomic method for predicting essential genes at subsaturation levels of mutagenesis: application to Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2003;100:7213–8. 26. Sassetti CM, Rubin EJ. Genetic requirements for mycobacterial survival during infection. Proc Natl Acad Sci USA 2003;100:1298–9. 27. McKinney JD, Höner zu Bentrup K, ~ Munoz-Elías EJ, Miczak A, Chen B, Chan WT, Swenson D, Sacchettini JC, Jacobs Jr WR, Russell DG. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 2000;406 (6797):735–8. 28. Glickman MS, Cox JS, Jacobs WR. A novel mycolic acid cyclopropane synthetase is required for cording, persistence, and viru­ lence of Mycobacterium tuberculosis. Mol Cell 2000;5:717–27. 29. Dahl JL, Kraus CN, Boshoff HI, Doan B, Foley K, Avarbock D, Kaplan G, Mizrahi V, Rubin H, Barry 3rd CE. The role of RelMtb-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice. Proc Natl Acad Sci USA 2003;100(17):10026–31. 30. Dong PH, Guinn KM, Harrell MI, Liao R, Voskuil MI, Tompa M, Schoolnik GK, Sherman DR. Rv3133c/dosR is a transcrip­ tion factor that mediates the hypoxic response of Mycobacterium tuberculosis. Mol Micro­ biol 2003;48:833–43. 31. Zhang Y. The magic bullets and tubercu­ losis drug targets. Annu Rev Pharmacol Toxicol 2005;45:529–64. 32. Mitchison DA. The search for new steriliz­ ing anti-tuberculosis drugs. Front Biosci 2004;9:1059–72. 33. Spigelman MK. New tuberculosis thera­ peutics: a growing pipeline. J Infect Dis 2007;196:S28–34. 34. Andries K, Verhasselt P, Guillemont J, Göhlmann HWH, Neefs JM, Winkler H, Van Gestel J. A diarylquinoline drug active

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42.

on the ATP synthase of Mycobacterium tuberculosis. Science 2005;307:223–7. Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, Anderson SW, Towell JA, Yuan Y, McMurray DN, Kreiswirth BN, Barry CE, Baker WR. A small-molecule nitroimidazo­ pyran drug candidate for the treatment of tuberculosis. Nature 2000;405:962–6. Tyagi S, Nuermberger E, Yoshimatsu T, Williams K, Rosenthal I, Lounis N, Bishai W, Grosset J. Bactericidal activity of the nitroimidazopyran PA-824 in the murine model of tuberculosis. Antimicrob Agents Chemother 2005;49(6):2289–93. Matsumoto M, Hshizume H, Tomishige T, Kawasaki M. In vitro and in vivo efficacy of novel antituberculous candidate OPC-67683 [abstract F-1462]. In: Program and abstracts of the 45th interscience conference on anti­ microbial agents and chemotherapy (Washington, DC). Washington, DC: Amer­ ican Society for Microbiology; 2005. p. 204. Sasaki H, Haraguchi Y, Itotani M, Kuroda H, Hashizume H, Tomishige T, Kawasaki M, Matsumoto M, Komatsu M, Tsubouchi H. Synthesis and antituberculo­ sis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b] oxazoles. J Med Chem 2006;49(26):7854–60. Nuermberger EL, Yoshimatsu T, Tyagi S, O’Brien RJ, Vernon AN, Chaisson RE, Bishai WR, Grosset JH. Moxifloxacin-containing regimen greatly reduces time to culture con­ version in murine tuberculosis. Am J Respir Crit Care Med 2004;169:421–6. Nuermberger EL, Yoshimatsu T, Tyagi S, Williams K, Rosenthal I, O’Brien RJ, Vernon AA, Chaisson RE, Bishai WR, Grosset JH. Moxifloxacin-containing regi­ mens of reduced duration produce a stable cure in murine tuberculosis. Am J Respir Crit Care Med 2004;170:1131–4. Pletz MW, Roux AD, Roth A, Neumann KH, Mauch H, Lode H. Early bactericidal activity of moxifloxacin in treatment of pulmonary tuberculosis: a prospective, randomized study. Antimicrob Agents Chemother 2004;48:780–2. Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW, Choudhri S, Daley CL, Munsiff SS, Zhao Z,

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Vernon A, Chaisson RE. Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med 2006;174(3):331–8. 43. Sinha RK, Arora SK, Sinha N, Modak VM. In vivo activity of LL4858 against Mycobacterium tuberculosis [abstract F-1116]. In: Program and abstracts of the 44th interscience conference on antimicrobial agents

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31

Antihelminthic drugs

The Mazzotti reaction Presentation The Mazzotti reaction, first described in 1948 (1r), was originally described after treatment of onchocerciasis with diethylcarbamazine. It is characterized by fever, urticaria, swollen tender lymph nodes, tachycardia, hypotension, arthralgia, edema, and abdominal pain within 7 days of treatment of microfilariasis. The Mazzotti reaction to diethylcarbamazine in onchocerciasis is so common that it is the basis of a skin patch test used to confirm the diagnosis (2c, 3C). The drug patch is placed on the skin, and if the patient is infected with the microfilaria of Onchocerca volvulus, localized pruritus and urticaria occur at the site of application. Intense pruritus is most marked where microfilariae are concentrated. Hypotension, fever, adenitis, pruritus, and peripheral blood eosinopenia and neutrophilia all correlate with the intensity of the infection(4c).
A 13-year-old Liberian boy was given ivermec-

tin, praziquantel, and albendazole for intestinal parasitosis and 6 days later began to have midepigastric pain, vomiting, and urticaria (5Ar). He was treated with intravenous hydration and diphenhydramine and improved; however, on the next day his symptoms returned with the additional features of fever, generalized myalgia, swelling of his face, feet, and penis, and intense pruritus. His temperature was 38.61C, pulse 120/minute, respiratory rate 22/minute, and blood pressure 100/60 mmHg. There was a generalized urticaria was on the arms, legs, and trunk, bulbar and palpebral conjunctival injection, and angioedema of his face. He was given intravenous methylprednisolone (2 mg/kg bolus followed by 2 mg/kg/day) and diphenhydramine (1 mg/kg every 6 hours as needed for

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03131-6 r 2009 Elsevier B.V. All rights reserved.

itching) and all his symptoms resolved completely in 12 hours.

The Mazzotti reaction in this case was ascribed to the presence of undiagnosed onchocerciasis or Wuchereria bancrofti infection. Occurrence The incidence of the Mazzotti reaction during treatment of onchocerciasis with ivermectin is low, at about 10%(6C), and about 25% of patients have only fever or pruritus. Albendazole has not been reported to cause Mazzotti-like reactions. Praziquantel is associated with rare adverse effects in schistosomiasis, including fever, abdominal pain, and urticaria, as the following case shows, but it does not cause the typical Mazzotti reaction.
An 11-year-old African refugee was given prazi-

quantel for intestinal schistosomiasis and 2 hours after the first dose developed abdominal pain, high fever, and an intensely pruritic, urticarial rash on the arms and trunk. He looked unwell, was wheezy, but had no peripheral edema. He had tender hepatosplenomegaly, confirmed by ultrasonography. His stool was positive for Schistosoma mansoni. He had fluctuating high fevers and wheeze during the next 3 days but his symptoms improved with conservative management. His brother had a similar, although less severe, reaction to praziquantel.

Pathogenesis The Mazzotti reaction is generally ascribed to an inflammatory response, associated with eosinophil migration to the skin and degranulation (7). It is precipitated by abrupt release of parasite-specific antigens during cell death. Wolbachia bacteria, freeliving endosymbionts of Onchocerca volvulus, form degenerating parasites, which may contribute to the pathogenesis of severe Mazzotti reactions, as occur in patients with high microfilarial loads.
A 29-year-old New Zealand woman traveling

to Asia was exposed to Bancroftian filariasis and took ivermectin (200 mg/kg)(8A). She had

507

508 transient pruritus ani, especially at night, and took mebendazole for presumed Enterobius vermicularis infestation.

Management In patients receiving diethylcarbamazine a low dose of dexamethasone (3 mg/day), begun after the start of the reaction, modified its progression without interfering with the microfilaricidal efficacy of diethylcarbamazine (9c). Pretreatment with low-dose dexamethasone before diethylcarbamazine therapy prevented the reaction but also greatly reduced the microfilaricidal activity. Diphenhydramine, given after the start of the Mazzotti reaction, had no effect on the course or intensity of the Mazzotti reaction nor on microfilaricidal activity.

BENZIMIDAZOLES (SED-15, 424; SEDA-29, 320; SEDA-30, 364) Albendazole and mebendazole Uses Soil-transmitted helminth infections have been reviewed in two excellent papers (10R,11R). The benzimidazole antihelminthic drugs mebendazole and albendazole are commonly used to treat these infections. They bind to nematode b-tubulin and inhibit parasite microtubule polymerization, which causes death of adult worms after a few days. Although both albendazole and mebendazole are broad-spectrum antihelminthic drugs, their use differs substantially in clinical practice. Both are effective against ascariasis in a single dose. In hookworm infections, however, a single dose of mebendazole is associated with a low cure rate and albendazole is more effective. Conversely, a single dose of albendazole is not effective in many cases of trichuriasis. For both trichuriasis and hookworm infection, several doses of benzimidazoles are commonly needed. Another important difference between the two drugs is that mebendazole is poorly absorbed from the gastrointestinal tract. For this reason the therapeutic action is largely directed at intraluminal (adult) worms.

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P.J.J. van Genderen

Albendazole is better absorbed, especially when it is taken with a fatty meal. It is metabolized in the liver to a sulfoxide derivative, which is highly distributed to the tissues. It is therefore used to treat disorders caused by tissue-migrating larvae, such as visceral larva migrans caused by Toxocara canis. Systemic adverse effects, such as those on the liver and bone marrow, are usually rare with benzimidazoles in the doses used to treat soil-transmitted helminth infections. However, transient abdominal pain, diarrhea, nausea, dizziness, and headache can occur. Since deworming programs in endemic regions clearly improve child health and education as well as reducing the burden of disease attributed to soil-transmitted helminths, the use of these drugs is not limited to treatment of symptomatic infections, but also for prevention by mass deworming programs of morbidity in children living in endemic areas. Concerns about the sustainability of periodic deworming with benzimidazoles and the emergence of resistance have prompted efforts to develop and test new control tools (such as plant cysteine proteinases from various sources of latexbearing plants and fruits). Comparative studies The treatment of subarachnoid and intraventricular neurocysticercosis is controversial. In a randomized trial, 36 patients with subarachnoid and intraventricular cysticercosis were assigned to albendazole 15 (n ¼ 16) or 30 mg/kg/day (n ¼ 20) plus dexamethasone for 8 days (12C). The results were in favor of the higher dose, with larger cyst reduction on MRI scans at 90 and 180 days and higher albendazole sulfoxide concentrations in the plasma. A single dose was insufficient in intraventricular and giant cysts. Adverse effects were similar in the two groups. Three patients in each group had new headaches or an increase in headaches, one in each group had seizures, and one had focal paresthesia. Rash and hyperthermia occurred in two patients taking high-dose albendazole and each occurred in one patient taking low-dose albendazole. Six patients who took low-dose albendazole and nine who took the high dose developed a leukocytosis or increased alanine transaminase

Antihelminthic drugs

Chapter 31

activities to over three times the upper limit of normal. These laboratory abnormalities had disappeared by 30 days. One patient developed glucocorticoid-related hyperglycemia. Pediculosis capitis, caused by head lice, is one of the most common human ectoparasitic infections, infesting schoolchildren of all socioeconomic groups. In 150 children, the usefulness of albendazole was studied in the treatment of pediculosis capitis in combination with 1% permethrin or alone (13C). Group 1 (n ¼ 30) took a single dose of albendazole 400 mg; group 2 (n ¼ 30) took albendazole 400 mg for 3 days; group 3 (n ¼ 30) used permethrin 1%; group 4 (n ¼ 30) used permethrin 1% and took a single dose of albendazole 400 mg; and group 5 (n ¼ 30) used permethrin 1% and took albendazole 400 mg for 3 days. Those who took albendazole also took a dose of albendazole 400 mg 1 week later. The success rates after 2 weeks were 62%, 67%, 80%, 85%, and 82% respectively. There were no significant differences among the five groups. The results suggested that albendazole is effective against pediculosis capitis and that there is no synergistic effect between albendazole and 1% permethrin. Adverse effects were not reported in this study. Nervous system Worsening headache has been attributed to albendazole in neurocysticercosis (14A).
A 35-year-old Chinese woman with a 26-year

history of persistent headache as the dominant symptom of neurocysticercosis, relieved only by diuretic treatment, took albendazole 800 mg/day for 3 weeks. After 2 days she reported increased headache plus vertigo, nausea, and vomiting. Analysis of the cerebrospinal fluid showed increased white cell pleocytosis. Her headache improved after the addition of a glucocorticoid and 3 months after withdrawal of albendazole her headache had not recurred.

Pregnancy Women in hookworm-endemic areas may benefit from deworming during pregnancy by reducing hookwormattributable anemia. Whether the use of albendazole and mebendazole is associated with adverse birth outcomes has been studied in small observational studies only.

509 In Iquitos, Peru, a large double-blind, randomized, placebo-controlled trial was conducted to study the occurrence of adverse birth outcomes in 1042 pregnant women who were randomized to either a single 500 mg dose of mebendazole (n ¼ 522) or placebo (n ¼ 520) together with a 30-day supply of ferrous sulfate (60 mg elemental iron) (15C). There were no statistically significant differences between the mebendazole and placebo group in numbers of miscarriages, malformations, stillbirths, early neonatal deaths, or premature deliveries. These data suggest that deworming with mebendazole in hookworm-endemic areas can be safely carried out during pregnancy.

Ivermectin

(SED-15, 1946; SEDA-28, 349; SEDA-29, 323; SEDA-30, 365)

Uses The treatment of scabies has been reviewed (16R–18R). Topical treatments are poorly tolerated by some patients. An alternative approach is to use oral ivermectin, which has been used extensively for several parasitic infections, including onchocerciasis, lymphatic filariasis, and other nematode-related infestations. Ivermectin is thought to interrupt glutamate-induced and g-aminobutyric acid-induced neurotransmission in parasites, leading to nematode paralysis and death. In humans ivermectin does not cross the intact blood– brain barrier. The efficacy and effectiveness of oral ivermectin is equivalent to, or better than, that of topical lindane, benzylbenzoate, and permethrin. Cure rates are 70–74% with a single dose of ivermectin and 95% when a second dose is taken 2 weeks later. The poorer efficacy of a single dose may reflect the fact that ivermectin is not ovicidal. Observational studies Severe adverse events (e.g., the Mazzotti reaction) can occur after ivermectin treatment in patients with high Loa loa microfilarial densities. In the context of mass ivermectin distribution for onchocerciasis control in Africa, it is

510 crucial to define precisely the geographical distribution of Loa loa in relation to that of Onchocerca volvulus and predict the prevalence of heavy infections. To that end, the distribution of Loa loa microfilarial densities were determined in 4183 individuals living in 36 villages in the Lekie Division in central Cameroon, to predict prevalences of Loa loa-related postivermectin adverse events (19C). The value of k, an estimate of the degree of microfilarial overdispersion in Loa loa, varied around 0.3 independently of microfilarial intensity, host age, village, and endemicity. Based on these results a semi-empirical model was developed to predict the prevalence of heavy Loa loa microfilarial loads in a community, which could be useful in identifying areas and populations at risk of severe adverse events after ivermectin. Comparative studies No serious adverse effects were noted in a programme of mass treatment with ivermectin for children with scabies in the Solomon Islands (20C). In one study, there was an excess risk of deaths among elderly patients who took ivermectin for scabies, but selection bias and confounding factors were possible explanations; this observation has not been confirmed in other studies, including studies of residents in nursing homes. Drug resistance Resistance to oral ivermectin has been reported in two patients who had been treated over 50 times, which suggests that resistance can be induced by repetitive treatment (21R).

Levamisole

(SED-15, 2028; SEDA-28, 350; SEDA-29, 324; SEDA-30, 366)

Levamisole is an antihelminthic drug with immunomodulatory properties. Although its exact mechanism of action is unclear, levamisole may act by augmenting the type 1 response and reciprocally by downregulating the type 2 response by selective

Chapter 31

P.J.J. van Genderen

induction of gene transcription of key cytokines, such as interleukin-18. Levamisole may reduce the frequency of relapses and reduces steroid doses in steroiddependent patients. Comparative studies Levamisole has been studied as an immunomodulator in the treatment of frequently relapsing steroiddependent idiopathic nephrotic syndrome in a controlled study (22c). Levamisole 2.5 mg/kg on alternate days for 1 year (n ¼ 32) was compared with low-dose prednisolone o0.5 mg/kg on alternate days for 1 year (n ¼ 24). The mean relapse rate was reduced more by levamisole as was the mean cumulative dose of steroids. Therapy failed in three levamisole-treated individuals compared with 12 controls. There were no major adverse effects of levamisole, and in particular significant leukopenia was not encountered. One patient taking levamisole reported a mild transient gastrointestinal upset. Systematic reviews In a systematic review of the role of systemic adjuvant therapy in patients with high-risk resected primary melanoma the authors reported that based on four randomized controlled trials in which levamisole was studied (three placebo-controlled) there was no effect on survival when levamisole was used as an adjuvant (23M). Although morbidity from levamisole is generally mild, it was severe enough for therapy to be withdrawn in 16–44% of the patients who took part in the various trials. Hematological abnormalities were rare and there were no treatment-related deaths. Nervous system In a retrospective study in nine patients (three men, six women) aged 24–70 years with recurrent aphthous ulcers, the imaging and clinical findings of leukoencephalopathy induced by oral levamisole 700–2250 mg were described (24c). Intervals from the initial dose to the onset of symptoms were 37–144 (mean 76) days. All patients recovered to their baseline neurological status within 12 months after withdrawal of levamisole. In murine models, levamisole is not directly toxic to myelin.

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Chapter 31

However, when mice are infected with a demyelination-inducing virus, demyelination and inflammation are augmented and accelerated. Based on these observations, the authors speculated that levamisole may induce leukoencephalopathy in humans by stimulating a destructive immune response to a novel antigen that persists but does not cause symptoms, resulting in demyelination in susceptible individuals.

Myrrh

(Commiphora molmol) (SED-15,

2409) Myrrh, a purified oleo-resin extract from the Commiphora molmol tree, commercially known as mirazid, has been widely used to treat schistosomiasis in Egypt. However, it appears to be ineffective (25R).

Praziquantel

(SED-15, 2911; SEDA-28, 351; SEDA-29, 324; SEDA-30, 366)

The current chemotherapeutic armory for schistosomiasis has been reviewed (26R). Since the development of praziquantel in 1970, morbidity and mortality due to schistosomiasis has been significantly reduced. Nevertheless, praziquantel does not prevent reinfection, and repeated treatments are usually necessary in endemic areas. In addition, there are at least two threatening consequences of relying on single-drug therapy. One is the possibility of infection with a praziquantel-resistant strain and the other is increase in the frequency of acute manifestations of the disease, for which praziquantel is not effective. Its most common adverse effects are usually mild and include headache, dizziness, nausea, diarrhea, abdominal pain, and anorexia. Hematologic Treatment of human schistosomiasis rapidly causes eosinophilia and this provides an opportunity to study the development of eosinophilia in relation to other immunological events induced by the release

511 of worm antigens after treatment and the mechanisms that prevent systemic post-treatment hypersensitivity reactions, which might be expected to occur in the presence of high concentrations of circulating worm-specific IgE. This was studied in 69 fishermen (mean age 35, range 18–45 years), infected with S. mansoni, who had lived in Bugoigo, Uganda for at least 3 years (27c). After praziquantel 40 mg/kg, blood eosinophil numbers fell within 24 hours, and significant eosinophilia developed after 3 weeks. Data based on measurements of cellular eosinophil cationic protein content, cellular eosinophil protein X, interleukins 5, 6, and 10, and tumor necrosis factor alpha and eotaxin concentrations before treatment and 24 hours and 3 weeks after treatment suggested that blood eosinophils are activated during S. mansoni infection and that treatment induces a burst of released antigens, causing increased production of IL-5, IL-6, IL-10, and eotaxin and a fall in TNF-alpha production, combined with transient sequestration of eosinophils. The data suggested that infection intensitydependent concentrations of plasma IL-10, a major anti-inflammatory and regulatory cytokine that inhibits mast cell degranulation, may be involved in the prevention of treatmentinduced anaphylactic reactions. It is certainly noteworthy that severe allergic reactions to praziquantel in schistosomiasis are not as frequent as they are after treatment of filariasis, in which such reactions are significantly associated with microfilarial density and fluctuations in circulating eosinophil numbers.
A 46-year-old Korean woman developed

left upper quadrant pain after taking praziquantel for suspected hepatic fascioliasis (28A). Peripheral eosinophilia, hyperamylasemia, and hyperlipasemia were documented and ascribed to pancreatic fascioliasis. IgG antibodies to Fasciola hepatica were positive. Abdominal CT showed multiple hypodense foci, which had coalesced, forming irregular nodules in the left lobe of the liver and similar lesions in the pancreas. Treatment with biothionol resulted in reversal of the eosinophilia and improvement in the patient’s symptoms and laboratory findings. After 10 weeks imaging studies showed normal liver and pancreas.

512

Suramin

(SED-15, 3249; SEDA-28, 352; SEDA-29, 325; SEDA-30, 367)

Uses Because of serious toxicity suramin is nowadays rarely used as a macrofilaricidal drug in the treatment of onchocerciasis or African trypanosomiasis. However, it has antitumor effects, which have renewed interest in it. Suramin inhibits the binding of a number of growth factors to their specific cell-surface receptors. Because angiogenesis is tightly regulated by many pro-angiogenic and anti-angiogenic growth factors, suramin can block transduction of extracellular signals in not only tumor cells but also endothelial cells. This may explain some of its antitumor effects, in particular in the treatment of urological malignancies. Its complex pharmacokinetics, narrow thera-peutic margin, long half-life (55 days), and adverse effects (neuropathy, renal dysfunction, and myelosuppression), make it necessary to monitor blood suramin concentrations, aiming at concentrations of 200–250 mg/ml. Experience with suramin in antiangiogenic therapy for urinary cancer has been reviewed (29R). In advanced renal cell carcinoma, suramin yielded a response rate of only 0–4%. In 17 patients with hormone refractory prostate cancer, suramin produced a complete response in three and a partial response in three. In combination with glucocorticoids suramin produced a fall in prostate-specific antigen concentrations of at least 50% in 24–54% of eligible

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patients and yielded an objective response in 0–19% of patients with measurable disease. In patients with superficial bladder cancer, suramin can be administered intravesically which was tolerated well in phase I trials without serious toxicity. The paper did not contain further details of the adverse effects of suramin.

Monitoring therapy The pharmacokinetics of suramin have been studied in 62 patients with non-small-cell lung cancers with the aim of using it as a chemosensitizer for paclitaxel and carboplatin chemotherapy (30c). For this purpose, plasma suramin concentrations should be kept within the effective range (10–50 mmol/l) duration the time that the chemotherapeutic agents are present at therapeutically significant concentrations (e.g., 48 hours for paclitaxel and carboplatin). A dosing nomogram was developed by using pharmacokinetic data that were derived from 15 patients who had participated in phase I trials and evaluated in 47 patients in phase II trials. The chemosensitizing dose of suramin had a terminal half-life of 202 hours and a total body clearance of 29 ml/hour/m2. The dosing nomogram delivered the target concentration in more than 95% of treatments. There were no significant pharmacokinetic interactions between suramin, paclitaxel, and carboplatin, but the disposition of suramin was non-linear.

References 1. Mazzotti L. Onchocerciasis in Mexico. In: Proceedings of the 4th International Congress of Tropical Medicine: Malarias (Session 1 of 6). Washington DC, 1948: 948–956. 2. Stingl P, Ross M, Gibson DW, Ribas J, Connor DH. A diagnostic “patch test” for onchocerciasis using topical diethylcarbamazine. Trans R Soc Trop Med Hyg 1984;78(2): 254–8.

3. Kilian HD. The use of a topical Mazzotti test in the diagnosis of onchocerciasis. Trop Med Parasitol 1988;39(3):235–8. 4. Francis H, Awadzi K, Ottesen EA. The Mazzotti reaction following treatment of onchocerciasis with diethylcarbamazine: clinical severity as a function of infection intensity. Am J Trop Med Hyg 1985;34(3): 529–36.

Antihelminthic drugs

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5. Olson BG, Domachowske JB. Mazzotti reaction after presumptive treatment for schistosomiasis and strongyloidiasis in a Liberian refugee. Pediatr Infect Dis J 2006;25(5):466–8. 6. Chijioke CP, Okonkwo PO. Adverse events following mass ivermectin therapy for onchocerciasis. Trans R Soc Trop Med Hyg 1992;86(3):284–6. 7. Ackerman SJ, Kephart GM, Francis H, Awadzi K, Gleich GJ, Ottesen EA. Eosinophil degranulation. An immunologic determinant in the pathogenesis of the Mazzotti reaction in human onchocerciasis. J Immunol 1990;144(10):3961–9. 8. Shaw MTM, Leggat PA. A case of exposure to Bancroftian filariasis in a traveller to Thailand. Travel Med Infect Dis 2006;4: 290–3. 9. Stingl P, Pierce PF, Connor DH, Gibson DW, Straessle T, Ross MA, Ribas JL. Does dexamethasone suppress the Mazzotti reaction in patients with onchocerciasis? Acta Trop 1988;45(1):77–85. 10. Bethony J, Brooker S, Albonico M, Geiger SM, Loukas A, Diemert D, Hotez PJ. Soiltransmitted helminth infections: ascariasis, trichuriasis and hookworm. Lancet 2006; 367:1521–32. 11. Stepek G, Buttle DJ, Duce IR, Behnke JM. Human gastrointestinal nematode infections: are new control methods required? Int J Exp Pathol 2006;87:325–41. 12. Gongora-Rivera F, Soto-Hernandez JL, Gonzalez Esquivel D, Cook HJ, Marquez-Caraveo C, Hernandez Davila R, Santos-Zambrano J. Albendazole trial at 15 or 30 mg/kg/day for subarachnoid and intraventricular cysticercosis. Neurology 2006;66:436–8. 13. Akisu C, Delibas SB, Aksoy U. Albendazole: single or combination therapy with premethrin against pediculosis capitis. Pediatr Dermatol 2006;23(2):179–82. 14. Finsterer J, Li M, Rasmkogeler K, Auer H. Chronic long-standing headache due to neurocysticercosis. Headache 2006;46:523–4. 15. Gyorkos TW, Larocque R, Casapia M, Gotuzzo E. Lack of risk of adverse birth outcomes after deworming in pregnant women. Pediatr Infect Dis J 2006;25:791–4. 16. Guldbakke KK, Khachemoune A. Crusted scabies: a clinical review. J Drugs Dermatol 2006;5(3):221–7.

513 17. Heukelbach J, Feldmeier H. Scabies. Lancet 2006;367:1767–74. 18. Chosidow O. Scabies. N Engl J Med 2006; 354:1718–27. 19. Olson BG, Domachowske JB. Mazzotti reaction after presumptive treatment for schistosomiasis and stronglyloidiasis in a Liberian refugee. Pediatric Infect Dis J 2006;25(5):466–8. 20. Lawrence G, Leafasia J, Sheridan J, Hills S, Wate J, Wate C, Montgomery J, Pandeya N, Purdie D. Control of scabies, skin sores and haematuria in children in the Solomon Islands: another role for ivermectin. Bull World Health Organ 2005;83(1):34–42. 21. Burkhart CG. Recent immunologic considerations regarding the itch and treatment of scabies. Dermatol Online J 2006;12(7):7. 22. Al-Saran K, Mirza K, Al-Ghanam G, Abdelkarim M. Experience with levamisole in frequently relapsing, steroid-dependent nephrotic syndrome. Pediatr Nephrol 2006; 21:201–5. 23. Verma S, Quirt I, McCready D, Bak K, Charette M, Iscoe N. on behalf of the Melanoma Disease Site Group of Cancer Care Ontario’s Program in Evidence-Based Care. Systematic review of systemic adjuvant therapy for patients at high risk for recurrent melanoma. Cancer 2006;106: 1431–42. 24. Liu HM, Hsieh WJ, Yang CC, Wu VC, Wu KD. Leukoencephalopathy induced by levamisole alone for the treatment of recurrent aphthous ulcers. Neurology 2006;67: 1065–7. 25. Fenwick A, Webster JP. Schistosomiasis: challenges for control, treatment and drug resistance. Curr Opin Infect Dis 2006;19(6): 577–82. 26. Ribeiro dos Santos, Verjovski-Almeida S, Leite LCC. Schistosomiasis – a century searching for chemotherapeutic drugs. Parasitol Res 2006;99:505–21. 27. Reimert CM, Fitzsimmons CM, Joseph S, Mwatha JK, Jones FM, Kimani G, Hoffmann KF, Booth M, Kabatereine NB, Dunne DW, Vennervald BJ. Eosinophil activity in schistosoma mansoni infections in vivo and in vitro in relation to plasma cytokine profile pre- and posttreatment with praziquantel. Clin Vacc Immunol 2006;13(5):584–93.

514 28. Lee OJ, Kim TH. Indirect evidence of ectopic pancreatic fascioliasis in a human. J Gastroenterol Hepatol 2006;21(10):1631–3. 29. Kanda S, Miyata Y, Kanetake H. Current status and perspective of antiangiogenic therapy for cancer: urinary cancer. Int J Clin Oncol 2006;11:90–107.

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30. Chen D, Song SH, Wientjes MG, Yeh TK, Zhao L, Villalona-Calero M, Otterson GA, Jensen R, Grever M, Murgo AJ, Au JLS. Nontoxic suramin as a chemosensitizer in patients: dosing nomogram development. Pharm Res 2006;23(6):1265–74.

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32

Vaccines

Editor’s note: Abbreviations used in this and previous issues of SEDA:

Vaccines and Guillain–Barré syndrome


aP: acellular pertussis
HPV: human
BCG: bacillus Calmette papilloma virus
IPV: inactivated Guérin
DTaP: diphtheria polio vaccine
JE vaccine: Japanese +tetanus toxoids

The Global Advisory Committee on Vaccine Safety (GACVS) has discussed the possible relation between vaccines and Guillain–Barré syndrome, which is relatively rare (1–2 cases per 100 000 people annually)(1S). Guillain– Barré syndrome has occasionally been observed in temporal association with immu­ nization; this association has been considered as causal in cases after swine influenza vaccine (attributable risk 9.5 per million doses administered) as well as rabbit brain and other nervous-tissue-derived rabies vac­ cines. With conflicting evidence, cases of Guillain–Barré syndrome have been reported in temporal association with other vaccines, including seasonal influenza, tetanus, menin­ gococcal conjugates, and diphtheria–tetanus– pertussis (DTP). The GACVS considers that investigation of a possible causal relation could best be achieved by large-scale studies of the incidence of Guillain–Barré syndrome before and after an immunization program. All incident cases would need to be carefully ascertained and documented to ensure as accurate a diagnosis as possible. Improved understanding of the pathogenesis of all forms of the disease would assist the investi­ gation of possible associations between Guillain–Barré syndrome and immunization. In this context, the collection of serum samples from incident cases would contribute to the identification of the different forms of the disease and to understanding their possi­ ble relationship with vaccines. Recent advances in understanding the mechanisms of some of the Guillain–Barré syndrome subtypes should be considered when evaluating the possible relation with vaccines. Guillain–Barré syndrome consists of at least four subtypes of acute peri­ pheral neuropathy (2r). The histological

+acellular pertussis

encephalitis vaccine


DTaP–Hib–IPV–HB:
MMR: measles










diphtheria+tetanus
toxoids+acellular pertussis+IPV+Hib +hepatitis B
(hexavalent vaccine) DTwP: diphtheria
+ tetanus toxoids + whole cell pertussis HA[V]: hepatitis A (virus) HbOC (also called PRP-CRM): conjugated Hib vaccine (Hib capsular antigen polyribosylphosphate covalently linked to the
non-toxic diphtheria toxin variant CRM197)
HB[V]: hepatitis B (virus) Hib: Haemophilus
influenzae type b

+mumps+rubella MMRV: measles +mumps+rubella +varicella OPV: oral polio vaccine PRP-D-Hib: conjugated Hib vaccine (Hib capsular antigen polyribosyl­ phosphate covalently linked to a mutant polypeptide of diphtheria toxin) SV40: Simian virus 40 Td: diphtheria +tetanus toxoids (adult formulation) wP: whole cell pertussis
YF vaccine: yellow fever vaccine

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03132-8 r 2009 Elsevier B.V. All rights reserved.

515

516 appearance of the acute inflammatory demye­ linating polyradiculoneuropathy (AIDP) subtype resembles experimental autoimmune neuritis, which is predominantly caused by T cells directed against peptides from the myelin proteins P0, P2, and PMP22. The role of T-cell-mediated immunity in AIDP is unclear, and there is evidence for involve­ ment of antibodies and complement. Strong evidence now exists that axonal subtypes of Guillain–Barré syndrome, acute motor axo­ nal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN), are caused by antibodies to gangliosides on the axolemma that target macrophages to invade the axon at the node of Ranvier. About a quarter of patients with Guillain– Barré syndrome have had a recent Campy­ lobacter jejuni infection, and axonal forms of the disease are especially common in these people. The Fisher’s syndrome subtype is especially associated with antibodies to GQ1b, and similar cross-reactivity with ganglioside structures in the wall of C. jejuni has been discovered. Anti-GQ1b antibodies damage the motor nerve terminal in vitro by a complement-mediated mechanism. Whether influenza immunization (with the exception of the swine-flu immunization program in 1976 in the USA) is associated with Guillain–Barré syndrome remains uncertain (3C). In two studies using popu­ lation-based health-care data from the province of Ontario, Canada, from April 1, 1992 to March 31, 2004, there were 1601 incident hospital admissions because of Guillain–Barré syndrome. In 269 patients, the syndrome was diagnosed within 43 weeks of immunization against influenza. The estimated relative incidence during the pri­ mary risk interval (weeks 2–7) compared with the control interval (weeks 20–43) was 1.45 (95% CI ¼ 1.05, 1.99). This association persisted in several sensitivity analyses using risk and control intervals of different durations. However, a separate time-series analysis showed no evidence of seasonality and no statistically significant increase in hospital admissions because of Guillain– Barré syndrome after the introduction of the universal influenza immunization program. The authors concluded that influenza immu­ nization is associated with a small but

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significantly increased risk of hospitalization because of Guillain–Barré syndrome. In a prospective, multicenter study in 95 children with Guillain–Barré syndrome the frequency and causes of antecedent diseases were investigated (4C). All infections and immunizations that occurred within 6 weeks before the onset of Guillain–Barré syndrome were documented. Preceding infections were reported in 82% of children; the most frequently involved agents were Coxsackie viruses (15%), Chlamydia pneu­ moniae (8%), Cytomegalovirus (7%), and Mycoplasma pneumoniae (7%). There was serological evidence of a C. jejuni infection in six patients (7%). Eight children had been immunized during the 6 weeks preceding the onset of Guillain–Barré syndrome; in six of these children concomitant infectious dis­ eases were reported, and in one child the time between immunization and Guillain– Barré syndrome was extremely short. The authors concluded that Campylobacter spp. do not seem to play a major role in childhood Guillain–Barré syndrome, in con­ trast to adults. Most of the children who had been immunized had also concomitant infectious diseases.

Vaccines and autism Most studies, experts, and scientific commit­ tees have concluded that there is no proof of a causal tie between autism and thiomersal or the measles–mumps–rubella (MMR) vac­ cine (SED-15, 2207; SEDA-25, 387; SEDA­ 26, 350; SEDA-27, 338; SEDA-28, 363; SEDA-30, 375). Multiple independent lines of evidence all point in the same direction: vaccines in general, and thiomersal in particular, do not cause autism, which more probably has its roots in genetics. In the USA, 5 years after the removal of thiomersal from all childhood vaccines (except influ­ enza vaccines), autism diagnosis rates have continued to increase. In reality, the true reason for the huge increase in autism prevalence over the last 15–20 years is because of the broadening of the diagnostic criteria for a diagnosis of autism or autism spectrum disorder (ASD)

Vaccines

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517

beginning in the early 1990s, resulting in widespread diagnostic substitution. However, the controversy, particularly in the USA, is not over. Some doctors and scientists, some groups representing families with autistic children, and many parents fervently believe that there is a connection. More than 4800 such families (Autism Omnibus) have petitioned the (US) Federal Vaccine Injury Compensation Program (VICP) for compensation, based on the claim that their children’s autism was caused by vaccines. The VICP was adopted through legislation by the Congress in 1988.

mitochondrial disorder” and had resulted in a brain disorder “with features of autism spectrum disorder”(5S). The stakes for decision-makers are high, and not just for the 4800 families. If any of the petitioners win test cases based on hypothesis and despite the evidence, it will open the floodgates for the rest of the petitioners. This will probably bankrupt the VICP and will also risk the US vaccine infrastructure. Pharmaceutical companies will be reluctant to subject themselves to the liability of selling vaccines if even the truth cannot protect them from lawsuits (6r, 7R).

The Poling case Recently, the “Poling case” has provided some support for the claiming families. Given the volume of more than 4800 cases, the VICP adjudicators called Special Masters (judges trained in vaccine problems) decided to hear a small number of “test cases.” Why the case of Hannah Poling was settled separately is not known. When Hannah Poling was 19 months old, she received five vaccines (diphtheria– tetanus–acellular pertussis, Haemophilus influenzae type b, MMR, varicella, and inactivated polio). At that time, Hannah was interactive, playful, and communicative. Two days later, she was lethargic, irritable, and febrile. Ten days after immunization, she developed a rash consistent with vaccineinduced varicella. Months later, with delays in neurological and psychological develop­ ment, encephalopathy caused by a mito­ chondrial enzyme deficit was diagnosed. Hannah’s signs included problems with language, communication, and behavior— all features of ASD. Although it is not unusual for children with mitochondrial enzyme deficiencies to develop neurological signs between their first and second years of life, Hannah’s parents believed that vaccines had triggered her encephalopathy. They sued the Department of Health and Human Services (DHHS) for compensation under the VICP and won (beginning of 2008). According to the leaked document posted online, the Special Masters, Division of Vaccine Injury Compensation, concluded that five shots that Hannah had received in July 2000, when she was 19 months old, “significantly aggravated an underlying

Statement of GAVCS: mitochondrial diseases and immunization The Poling case offered advocates a new theory: that vaccines cause or contribute to an underlying mitochon­ drial disorder, which in turn causes autism. Although autism is common among children with mitochondrial disorders, several experts in the disorders dismissed the notion that vaccines may cause the disease, which is widely understood to have a genetic origin. Mitochondrial diseases result from failures of the mitochondria, specialized compart­ ments present in almost every type of cell in the body. Mitochondria are responsible for creat­ ing more than 90% of the energy needed by the body to sustain life and support growth. When they fail, less and less energy is generated within the cell. Cell injury and even cell death follow. If this process is repeated throughout the body, whole systems begin to fail, and the life of the person in whom this is happening is severely compromised. The disease primarily affects children, but adult onset is becoming more and more common. Diseases of the mitochondria appear to cause most damage to cells in the brain, heart, liver, skeletal muscle, kidneys, and the endocrine and respiratory systems. Depending on which cells are affected, symptoms may include loss of motor control, muscle weakness and pain, gastrointestinal disorders and swallowing difficulties, poor growth, cardiac disease, liver disease, diabetes, respiratory complications, seizures, visual/hearing problems, lactic acidosis, developmental delays, and suscept­ ibility to infection. At a meeting (June 18–19, 2008) of the GAVCS, an expert clinical and scientific

518 advisory body, established by the WHO to deal with vaccine safety problems of poten­ tial global importance independently from the WHO and with scientific rigor, discussed the hypothesis that immunization could affect patients with mitochondrial disease, leading to autism. The committee issued the following statement (8S): ‘Mitochondrial diseases are inherited dis­ orders of energy metabolism that tend to affect tissues with high energy requirements, such as the brain, heart, and liver. These diseases are associated with a variety of symptoms. They are often difficult to diag­ nose, and there is no effective treatment. Mitochondrial disorders can also lead to cognitive impairment and encephalopathy, resulting in blunted social interaction. Physiological stress triggered by external factors (e.g., fever, cold, heat, starvation, sleep deprivation) may result in a worsening of the metabolic situation which results in deteriora­ tion of affected organs. Additionally, inflam­ matory responses associated with most infectious diseases can precipitate a clinical deterioration in an underlying mitochondrial disease. While vaccines may cause fever, clinicians caring for children with mitochon­ drial disease recommend vaccinating their patients since the risk of developing an even more devastating clinical deterioration would be associated with natural infection. The GACVS concluded, on the basis of the limited data available from the United King­ dom and the United States, that there is no convincing evidence to support an association between vaccination and deterioration of mitochondrial disease. The topic will be reviewed further if new findings become available. GACVS supports the current practice standard: children with mitochon­ drial diseases should receive the immuniza­ tions recommended for healthy children.’

Information about vaccine safety A guide for evaluating vaccine safety concerns “Do Vaccines Cause That?” has been published by Myers and Pineda (9R). The book provides evidence-based infor­ mation about vaccine safety questions, such

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as suspected links between various vaccines and asthma, autism, damage to the immune system, diabetes, Guillain–Barré syndrome, arthritis, multiple sclerosis, inflammatory bowel disease, febrile seizures, encepha­ lopathy, sudden infant death (SIDS), AIDS, birth defects, mad cow disease, and cancers.

The Vaccine Safety and Public Confidence Assurance Act of 2007 On April 19, 2007 at a press conference two US representatives introduced a bill that would give responsibility for the nation’s vaccine safety to an independent agency within the DHHS, removing most vaccine safety research from the Centers for Dis­ ease Control and Prevention (CDC). Cur­ rently, the CDC has responsibility for both vaccine safety and promotion, which is an inherent conflict of interest increasingly garnering public criticism. The initiative is joined by several groups advocating vaccine safety reform, including the National Aut­ ism Association. The proposed legislation comes as the Senate considers legislation that reforms the way the federal govern­ ment conducts drug safety at the FDA but explicitly omits vaccines from further safety reviews (10S).

Surveillance of adverse events following immunization Cases reported to the post-marketing sur­ veillance system of the Kitasato Institute have been examined and categorized into two groups: allergic reactions and severe systemic illnesses (11R). Patients with ana­ phylaxis due to gelatin allergy after immu­ nization with live measles, rubella, and mumps monovalent vaccines have been reported since 1993, but the number of reported cases with anaphylaxis dramati­ cally fell after 1999, when gelatin was removed from all brands. The incidence of anaphylactic reactions was estimated to be 0.63 per million for Japanese encephalitis virus vaccine, 0.95 for DPT, and 0.68 for

Vaccines

Chapter 32

influenza vaccine, but the causative compo­ nent has not yet been specified. Among 67.2 million immunizations, there have been 6 cases of encephalitis or encephalopathy, 7 of acute disseminated encephalomyelitis (ADEM), 10 of Guillain–Barré syndrome, and 12 of idiopathic thrombocytopenic purpura (ITP). The wild-type measles virus genome was detected in a patient with encephalitis and in two of four bone marrow aspirates obtained from ITP after measles immunization. Enterovirus infec­ tion was identified in two patients after mumps immunization (one each with ence­ phalitis and ADEM), one patient with encephalitis after immunization with JEV vaccine, and one with aseptic meningitis after immunization with influenza vaccine. The total estimated incidence of serious neurological illness after immunization was 0.1–0.2 per million immunizations. It is noteworthy that enterovirus infection or wild-type measles virus infection was coin­ cidentally associated with immunization in several cases suspected of being vaccine adverse events.

Combination vaccines/multiple immunizations (SEDA-29, 327; SEDA­ 30, 369) Death SIDS following the administration of hexavalent vaccines (DTaP–Hib–IPV– HB) was discussed at length in SEDA-29 (p. 327) and updated with the results of a further study (SEDA-30, 370). The evi­ dence does not support a causal link between SIDS and hexavalent vaccines.
A 3-month-old girl died suddenly after being

given a hexavalent vaccine (12A). Investiga­ tion of the brainstem on serial sections showed bilateral hypoplasia of the arcuate nucleus. The cardiac conduction system had persistent fetal dispersion and resorptive degeneration.

The authors mentioned that autopsies in other cases of SIDS had not paid much attention to examination of brainstem and the cardiac conduction systems. They con­ cluded that their case offered a unique

519 insight into the possible role of hexavalent vaccine in triggering a lethal outcome in a vulnerable baby.

BACTERIAL VACCINES Meningococcal vaccine

(SED-15, 2250; SEDA-28, 359; SEDA-29, 331; SEDA-30, 372)

Safety of meningococcal B vaccines The GACVS has been presented with data relating to the safety of outer membranevesicle-based meningococcal B vaccines, based on their use in Cuba, Norway, New Zealand, and parts of France (13S). It has noted in particular the very carefully designed safety monitoring program that was set up in New Zealand to ascertain possible serious adverse events following immunization of around 1 million people aged under 20 years from July 2004 onwards, including 200 000 vaccinees monitored through linkages to hospital admission records. The various sur­ veillance methods used to detect potentially serious adverse events following immuni­ zation consistently found no evidence of such effects attributable to immunization. The most widely used meningococcal B vaccine has been that produced in Cuba. Over 55 million doses have been used in Cuba and other Latin American countries over the past 20 years. The committee was presented with data from the original Phase 3 study involving over 100 000 people, in which no evidence of an excess of serious adverse events following immunization had been identified in the immunized group. Nervous system In Norway during the 1970s there was extensive use of the vaccine in trials among teenagers and young adults. In some age groups, up to 40% of the population had been immunized. Despite media reports of a possible increased risk of myalgic encephalomyelitis, also called chronic fatigue syndrome, the results from these trials provided no specific causes for concern with respect to serious adverse events following immunization.

520 Hematologic The Norwegian-type vac­ cine had also been used in France in a three-dose schedule to immunize around 2700 children aged 12 months to 5 years in one administrative region (Department of Seine-Maritime), following an increased incidence of meningococcal disease in that department. Parents of vaccinees were sent a questionnaire to ascertain possible ad­ verse events. A high proportion of these were returned, and nine serious adverse events were identified, eight of which were purpura (one ITP, three Henoch–Schönlein purpura, four febrile purpura) and seven of which occurred after the second dose. All of these seven had received a third dose of vaccine with no reported ill effect. The significance of the cases of purpura follow­ ing immunization was difficult to evaluate, because of the absence of data on back­ ground rates of purpura in the general population.

Pertussis vaccine (including diphtheria–tetanus–whole-cell pertussis vaccine [DTwP]) (SED-15, 2780; SEDA-29, 331) Nervous system Whole-cell pertussis and measles vaccines have been suspected of increasing the risk of encephalopathy or encephalitis. Although many countries now use acellular pertussis vaccines, whole-cell pertussis vaccine is still widely used in the developing world. In a retrospective case– control study including four health maintenance organizations, records from January 1, 1981 to December 31, 1995 were examined to identify children aged 0–6 years old hospitalized with encephalo­ pathy or related conditions (14c). The cause of the encephalopathy was categorized as known, unknown, or suspected but unconfirmed. Up to three controls were matched to each case. Conditional logistic regression was used to analyze the relative risk of encephalopathy after immunization with DTwP or MMR vaccines in the 90 days before the onset of the disease, as defined

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by chart review, compared with an equivalent period among controls indexed by matching on case onset date. In all 452 cases were identified. Cases were no more likely than controls to have received either vaccine during the 90 days before the onset of the disease. When encephalopathies of known cause were excluded, the odds ratio for case children having received DTwP within 7 days before the onset of the disease was 1.22 (95% CI ¼ 0.45, 3.31) compared with control children. For MMR in the 90 days before onset of encephalopathy, the odds ratio was 1.23 (95% CI ¼ 0.51, 2.98). Thus, in this study of more than 2 million children, DTwP and MMR vaccines were not associated with an increased risk of encephalopathy after immunization. A 7-month-old boy developed acute transverse myelitis after DTwP immuniza­ tion with acellular pertussis vaccine (15A). The diagnosis was based on the clinical course and MRI findings.

VIRAL VACCINES Hepatitis B vaccine (including combination vaccines with HB component) (SED-15, 1600; SEDA-29, 332; SEDA-30, 374) Musculoskeletal The GACVS has consi­ dered the potential association of hepatitis B immunization and rheumatoid arthritis (16S). The committee was presented with a preliminary analysis of the interaction between hepatitis B virus and HLA status in respect of the occurrence of rheumatoid arthritis. This is the relevant question if the adverse effect is limited to or occurs largely among a particular genetically determined subgroup. It has the advantage that analysis can be done using cases of rheumatoid arthritis alone. These are compared between the genetically determined groups, which will not differ in regard to the likelihood of hepatitis B virus exposure. There are various subtypes of HLA DRB1�04; nine were found in this study,

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although analyses were limited to two of the subtypes. Hepatitis B virus exposure in the 90, 180, and 365 days before the onset of rheumatoid arthritis symptoms was examined. There was no statistically significant evidence of an increased risk in the genetic subgroups examined, and point estimates were less than unity. However, an increased risk in a subgroup could not be excluded, because of the low power of the study, given the small numbers of immunized cases. This is an inevitable limitation, but it also makes it clear that hepatitis B virus makes at most very little impact on the incidence of rheumatoid arthritis. In addition, whether HLA DRB1�04 is the best genetic marker for increased risk of development of rheumatoid arthritis is still unknown. The GACVS concluded, based on a review of the limited data available, that there was no convincing evidence to support an association between HBV and rheumatoid arthritis.

Horizontal transmission of the Leningrad-3 mumps vaccine strain from healthy vacci­ nes to six previously immunized contacts, resulting in symptomatic infection, has also been described (18c). In both reports, paro­ titis developed as a unique consequence of horizontal transmission of mumps vaccine strains. All patients were of childhood age. The first virologically confirmed cases of symptomatic mumps (causing parotitis as well as extrasalivary effects, including meningitis) have been described after hor­ izontal transmission of the Leningrad– Zagreb mumps vaccine strain in adults (19c). The possible sources of infection in the patients were their own children, who had been recently immunized with Leningrad–Zagreb mumps vaccine strain as a component of MMR vaccine. The first symptoms of disease in the parents appeared within 33–44 days after the immunization of their children.

Measles–mumps–rubella (MMR) vaccine (SED-15, 2207; SEDA-28, 363;

Rotavirus vaccine (SED-15, 3082; SEDA-27, 338; SEDA-28, 365; SEDA-30, 376)

SEDA-29, 335; SEDA-30, 375) MMR vaccine and autism has been dis­ cussed in the special review above. The role of measles vaccine in encephalopathies has been discussed in the section “Pertussis vaccine (including diphtheria–tetanus– whole cell pertussis vaccine [DTwP]) (SED-15, 2780; SEDA-29, 331).”

Mumps vaccine (SED-15, 2207; SEDA­ 30, 376) Infection risk Virus shedding after immunization with some live attenuated mumps vaccine strains has been well documented. However, it is generally accepted that horizontal transmission of vaccine strains is rare. Horizontal transmission of the Urabe AM9 vaccine strain from a symptomatic vaccinee to her younger sister was described in 1993 (17A).

Body temperature Administration of the first dose of rhesus rotavirus-based tetravalent vaccine in children aged 6 weeks and over is followed by a transient febrile reaction at 3–4 days in about one-third of vaccinees. It has been hypothesized that giving the first dose of the vaccine during the neonatal period might reduce its reacto­ genicity without compromising its use (20C). In a double-blind placebo-controlled trial 90 infants received the vaccine at 0–4–6, 0–2–4, or 2–4–6 months of age. The authors concluded that infants who received the first dose of the vaccine during the neonatal period did not have febrile reactions. The immune response in a three-dose schedule initiated in the neonatal period is somewhat dampened but still acceptable. Neonatal immunization might also reduce the very small risk of intussusception, which has been associated with administration of rotavirusbased tetravalent vaccine to older infants.

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Rotavirus vaccine and Kawasaki disease The GACVS has been presented with the latest information from the USA and the European Union on the potential association between Kawasaki disease and the adminis­ tration of rotavirus vaccines (21S). The US CDC have defined a case of Kawasaki disease as an illness in a patient with fever lasting 5 or more days associated with at least four of the following five clinical signs: rash, cervical lymphadenopathy (at least 1.5 cm in diameter), bilateral conjunctival injection, oral mucosal changes, and periph­ eral extremity changes. The possibility of an association had previously been raised after the observation of a non-statistically significant excess of Kawasaki disease in pre-licensure trials of Rotateqt vaccine (five cases in vaccinees versus one case in controls). In June 2007, the FDA amended the product information in the USA to note the occurrence of such cases, but stated that causality had not been established. Since June 2007 and as of October 14, 2007, a total of 16 cases of confirmed cases of Kawasaki disease had been reported to the US Vaccine Adverse Events Reporting System (VAERS) in the context of stimu­ lated reporting. The reported rate was 1.6 per 100 000 person-years compared with an estimated background rate of 17 per 100 000 person-years among children aged under 5 years. Active surveillance during the first year of life after immunization with Rotateqt was implemented in the Vaccine Safety Datalink. Preliminary results suggest that there has been no confirmed case of Kawasaki disease after the administration of over 125 000 doses. Further work is planned to extend the monitoring. In the European Union, where Rotarixt vaccine is licensed and in use, there have been no spontaneous reports of Kawasaki disease, with about 12 million doses administered in 6 million individuals. In clinical trials there has been a slight excess of cases in the Rotarixt groups, with a nonstatistically significant difference between the

S. Dittmann

Rotarixt and the placebo arms. Delay between immunization and the onset of Kawasaki disease varied from 2 weeks to 19 months. The overall conclusion of the GACVS was that the evidence for a causal association was not strong and that there was no reason for concern.

Varicella vaccine

(SED-15, 3606;

SEDA-26, 360) The GACVS has discussed the safety of varicella vaccines (22S). Some potential safety problems are common to other live attenuated viral vaccines, including the effect of immunization on pregnant women inadvertently immunized and the risk of secondary transmission of the attenuated virus vaccine strain from vaccinees to their contacts. To date, the data provide no cause for concern. An important safety question related to varicella vaccine is the impact on the epidemiology of herpes zoster, both in vaccinees and in individuals previously infected with wild-type varicella. Mathema­ tical models have predicted that the limited circulation of wild virus as a result of universal varicella immunization programs could lead to an increased incidence of herpes zoster for many years before an eventual decline over decades. The US data do not show signs of such an increase after 11 years of observation. However, given the natural history of reactivation, it is likely that decades of observation will be required before any conclusions can be drawn regarding the long-term impact on herpes zoster epidemiology. In view of the poten­ tial impact of these long-term effects, it is recommended that any countries planning to introduce varicella vaccine programs should collect baseline data on the agespecific incidence of herpes zoster. These observations should be shared and continu­ ously reviewed. Observational studies A subcutaneously administered, live, high-titer (18 700–60 000 plaque-forming units per dose) varicella zoster virus vaccine (zoster vaccine) of the Oka/Merck strain has been evaluated for

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the prevention of herpes zoster and the reduction of zoster-associated pain in adults aged 60 years and over (23C). Zoster vaccine reduced the burden of herpes zoster illness by 61% compared with placebo, the incidence of herpes zoster by 51%, and the incidence of postherpetic neuralgia by 67% during more than 3 years of surveillance. The most frequently reported adverse reactions after immuniza­ tion were injection-site reactions; the only systemic adverse event with zoster vaccine that differed significantly in incidence from that with placebo was headache.

Yellow fever vaccine (SED-15, 3703; SEDA-28, 366; SEDA-30, 336) A yellow fever immunization campaign was conducted in the Ica Region of Peru following the earthquake in September 2007. Four cases of vaccine-associated viscerotropic disease, all fatal, were reported among about 40 000 individuals who received one particular lot of yellow fever vaccine. As a result, the national authorities suspended the campaign. The rate of vaccine-associated viscerotropic dis­ ease was about 10 per 100 000 doses administered for this vaccine lot, compared with an expected rate of approximately 0.3 per 100 000 based on previous experience with yellow fever vaccines (24r).

OTHER COMPONENTS OF VACCINES Aluminium Musculoskeletal Macrophagic myofas­ ciitis is an uncommon inflammatory dis­ order of muscle, believed to be due to persistence of vaccine-derived aluminum hydroxide at the site of injection. The condition is characterized by diffuse mya­ lgia, arthralgia, and fatigue. In one case of histologically confirmed macrophagic

523 myofasciitis left chest and upper limb pain developed more than 10 years after immuni­ zation (25A). Treatment with steroids led to symptomatic improvement.

Squalene The GACVS has discussed the safety of squalene (26S). Squalene is commercially extracted from fish oil, in particular sharkliver oil, and is purified when used in pharmaceutical products and vaccines. Squalene alone is not an adjuvant, but emulsions of squalene with surfactants enhance the immune response when added to antigens. MF59, a proprietary adjuvant containing squalene, is included in some seasonal subunit influenza vaccines. The vaccine contains about 10 mg of squalene per dose. Since 1999, many million doses have been distributed. This vaccine has been administered primarily to individuals aged 65 years and older, for whom the vaccine was licensed. Reported rates of adverse events and local reactogenicity are not in excess of those that would be expected with other inactivated seasonal flu vaccines, suggesting that squalene in this vaccine poses no significant risk. Several experimental vaccines, including some pan­ demic flu vaccines, malaria vaccines, and various viral and bacterial vaccines, are also being developed with squalene-containing adjuvants, with the intention of enhancing immunogenicity and thereby efficacy. Clin­ ical studies of squalene-containing vaccines have been performed in infants and neo­ nates without evidence of safety concerns. A link between the health problems of Gulf War veterans and the possible presence of squalene in vaccines received by these soldiers has not been confirmed. The Committee concurred that fears about squalene are unfounded. It did note, however, that the experience of squalenecontaining vaccines has been primarily in older age groups and recommended that as squalene-containing vaccines are intro­ duced in other age groups, careful post-marketing follow-up to detect any vaccine-related adverse events needs to be performed.

524

Yeast Immunologic The preparation of recombinant hepatitis B vaccines involves using cellular cultures of Saccharomyces cerevisiae, otherwise known as baker’s yeast. Before vaccine licensure, clinical trials were performed to address whether residual yeast proteins in the vaccines could induce anaphylaxis, including testing for IgE antiyeast antibody titers. There were anti-yeast IgE antibodies in 1–2% of subjects before immunization, but there was no significant rise in IgE after hepatitis B immunization. The authors of a study searched reports in the VAERS for those that mentioned a history of allergy to yeast and then reviewed the adverse events described in these reports for potential anaphylactic reactions (27C). Probable anaphylaxis was defined as the presence of one or more skin symptoms and one or more respiratory, gastrointestinal, or cardiovascular symptoms with onset within 4 hours of hepatitis B immunization. Possible

Chapter 32

S. Dittmann

anaphylaxis was defined in one of two ways: (1) cases that described skin or respiratory symptoms (but not both) occurring within 4 hours of immunization; or (2) cases that described one or more skin and/or respiratory symptoms occurring 4–12 hours after immunization. Among the 107 reports of pre-existing “yeast allergies,” 11 reports described probable or possible anaphylaxis after hepatitis B immunization. Four additional cases were described after other vaccines. Most of the vaccinees who met the case definitions and had a history of yeast allergies were female, aged 10–64 years, and symptom onset ranged from 15 minutes to 5 hours after immunization. No deaths were reported. The small number of reports to VAERS may be partly because healthcare professionals observe current contraindications by not immunizing yeastsensitive individuals. Nevertheless, yeastassociated anaphylaxis after hepatitis B immunization in sensitized patients appears to be rare.

References 1. Global Advisory Committee on Vaccine Safety (GACVS), 12–13 December 2007. Guillain-Barre syndrome and vaccination. Wkly Epidemiol Rec 2008;83(4):37. 2. Hughes RAC, Cornblath DR. Guillain– Barré syndrome. Lancet 2005;366:1653–66. 3. Juurlin DN, Stukel TA, Jeffrey Kwong J. Guillain–Barré syndrome after influenza vaccination in adults. A population-based study. Arch Intern Med 2006;166:2217–21. 4. Schessl J, Luther B, Kirschner J, Mauff G, Korinthenberg R. Infections and vaccina­ tions preceding childhood Guillain–Barré syndrome: a prospective study. Eur J Pediatr 2006;165:605–12. 5. Chew K. The case of Hannah Poling, http:// www.blisstree.com/autismvox/the-case-of­ hannah-poling/ (accessed Oct 10, 2009). 6. Novella S. The antivaccine movement. Skep­ tical Inquirer 2007; November–December:31. 7. Offit PA. Thimerosal and vaccines—a cautionary tale. N Engl J Med 2007;357: 1278–9.

8. Global Advisory Committee on Vaccine Safety, 18–19 June 2008. Mitochondrial diseases and immunization. Wkly Epide­ miol Rec 2008;83(32):291. 9. Myers MG, Pineda D. Do vaccines cause that? Galveston, TX: Immunizations for Public Health; 2008. 10. Open Congress. Vaccine Safety and Public Confidence Assurance Act of 2007, http:// www.opencongress.org/bill/110-h1973/show. 11. Nakayama T, Onoda K. Vaccine adverse events in post-marketing study of the Kitasato Institute from 1994–2004. Vaccine 2007;25:570–6. 12. Ottaviani G, Lavezzi AM, Matturri L. Sudden infant death syndrome (SIDS) shortly after hexavalent vaccination: another pathology in suspected SIDS? Virchows Archiv 2006;448:100–4. 13. Global Advisory Committee on Vaccine Safety, 12–13 December 2007. Safety of meningococcal B vaccines. Wkly Epidemiol Rec 2008;83(4):42.

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14. Ray P, Hayward J, Michelson D, Lewis E, Schwalbe J, Black S, Shinefield H, Marcy M, Huff K, Ward J, Mullooly J, Chen R, Davis R. Encephalopathy after whole-cell pertus­ sis or measles vaccination: lack of evidence for a causal association in a retrospective case–control study. Pediatr Infect Dis J 2006;25:768–73. 15. Riel-Romero RMS. Acute transverse mye­ litis in a 7-month-old boy after diphtheria– tetanus–pertussis immunization. Spinal Cord 2006;44:688–91. 16. Global Advisory Committee on Vaccine Safety, 12–13 December 2007. Hepatitis B vaccination and rheumatoid arthritis. Wkly Epidemiol Rec 2008;83(4):39. 17. Sawada H, Yano S, Oka Y, Togashi T. Transmission of Urabe mumps vaccine between siblings. Lancet 1993;342:371. 18. Atrasheuskaya AV, Neverov AA, Rubin S, Ignatyev GM. Horizontal transmission of the Leningrad-3 live attenuated mumps vaccine virus. Vaccine 2006;24:1530–6. 19. Tesovi�c G, Poljak M, Lunar MM, Kocjan BJ, Seme K, Vuki�c BT, Sternak SL, Caji�c V, Vince A. Horizontal transmission of the Leningrad– Zagreb mumps vaccine strain: a report of three cases. Vaccine 2008;22(16):1922–5. 20. Vesikari T, Karvonen A, Forrest BD, Hoshino Y, Chanock RM, Kapikian AZ.

525

21.

22.

23.

24.

25.

26.

27.

Neonatal administration of rhesus rotavirus tetravalent vaccine. Pediatr Infect Dis J 2006;25:118–22. Global Advisory Committee on Vaccine Safety, 12–13 December 2007. Rotavirus vaccines and Kawasaki disease. Wkly Epi­ demiol Rec 2008;83(4):43. Global Advisory Committee on Vaccine Safety, 6–7 June 2006. Safety of varicella vaccines. Wkly Epidemiol Rec 2006;81 (28):277. Robinson DM, Perry CM. Zoster vaccine live (Oka/Merck). Drugs Aging 2006;23: 525–31. Global Advisory Committee on Vaccine Safety, 12–13 December 2007. Safety of yellow fever vaccines. Wkly Epidemiol Rec 2008;83(4):39. Ryan AM, Bermingham N, Harrington HJ, Keohane C. Atypical presentation of macro­ phagic myofasciitis 10 years post vaccination. Neuromuscul Disord 2006;16:867–9. Global Advisory Committee on Vaccine Safety, 6–7 June 2006. Safety of squalene. Wkly Epidemiol Rec 2006;81(28):274–5. DiMiceli L, Pool V, Kelso JM, Shadomy SV, Iskander J. Vaccination of yeast sensi­ tive individuals: review of safety data in the US vaccine adverse event reporting system (VAERS). Vaccine 2006;24:703–7.

P.F.W. Strengers and E. van Twuijver

33

Blood, blood components, plasma, and plasma products

(SED-15, 54; SEDA-28, 371; SEDA-29, 338; SEDA-30, 381)

ALBUMIN

Human serum albumin has a very low inci­ dence of immediate adverse effects (1M). Allergic and febrile reactions have been re­ ported, but are very rare and tend to be brandspecific, lot-specific, and/or patient-specific. Electrolyte balance In a nested cohort double-blind study within the SAFE (Saline and Albumin Fluid Evaluation) trial (2C), 691 critically ill patients in three general intensive care units were randomized to either 4% human albumin or isotonic saline for fluid resuscitation (3C). The authors concluded that the choice and amount of resuscitation fluid are independent predictors of acid–base status and serum electrolytes. When large volumes are given, albumin administration leads to a higher chloride concentration. However, overall differences between the types of fluid are minor, whereas the volume of fluid administered is a much stronger predictor of such changes, which are also influenced by illness severity and the passage of time. Respiratory In an unblinded randomized trial 100 consecutive patients were admitted for treatment of first-onset ascites with diuretics plus human albumin 25 g/week in the first year and 25 g every 2 weeks there­ after, or diuretics alone. After a median Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03133-X r 2009 Published by Elsevier B.V.

follow-up of 84 months, the albumin-treated patients had significantly greater cumulative survival rate and a lower probability of recurrence of ascites (51% versus 94%) (4c). Chronic albumin infusion resulted in a mean increase in survival of 16 months. There were no adverse effects attributed to albumin. The adverse effects of albumin have been studied in a multitier, open, dose-escalating study of its possible neuroprotective effects in 82 subjects after acute ischemic stroke (NIH Stroke Scale of 6 or above) who received a 2-hour infusion of 25% human albumin beginning 16 hours after the onset of the stroke (doses up to 2 g/kg) (5c). There were no major dose-limiting compli­ cations. The sole albumin-related adverse event was mild or moderate pulmonary edema in 11 subjects, which was readily managed with diuretics.

ANTICOAGULANT PROTEINS (SED-15, 266; SEDA-28, 371; SEDA-29, 338; SEDA-30, 381)

Drotrecogin alfa (recombinant human activated protein C) Hematologic The anticoagulant effects of drotrecogin alfa can cause bleeding. The manufacturers have supported a retrospec­ tive analysis of prospectively defined out­ comes from five integrated clinical studies of severe sepsis in 1659 surgical patients out of 4459 surgical patients from an interna­ tional integrated database for the evalua­ tion of severe sepsis and drotrecogin alfa

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(activated) therapy; 1659 surgical patients (1231 of whom received drotrecogin alfa and 428 placebo) were compared with 2800 non­ surgical patients (1995 of whom received drotrecogin alfa and 805 placebo) (6C). Drotrecogin alfa was infused at a rate of 24 mg/kg for 96 hours and standard care (antibiotics, fluid support, vasopressors, and oxygen) was given. The rate of serious ad­ verse events in those who received drotre­ cogin alfa was 7.5% versus 6.3% in the placebo group. Despite excluding patients at high risk of bleeding from enrollment in both the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial and the Administration of Drotrecogin Alfa (activated) in Early Severe Sepsis (ADDRESS) trial, treatment with drotrecogin alfa increased the risk of bleed­ ing, including intracranial bleeds, compared with placebo. The incidence of serious bleeding, defined as intracranial hemor­ rhage, life-threatening bleeding, or blood loss requiring transfusion of more than three units of packed red cells on 2 consecutive days, was almost twice as high with drotre­ cogin alfa (7R).

P.F.W. Strengers and E. van Twuijver

Haemovigilance Network and the Working Party on Haemovigilance of the International Society of Blood Transfusion, together with the US Biovigilance Initiative are collaborat­ ing on the development of common defini­ tions on adverse events after blood components transfusion (12S). The goal is to make comparison of data possible, and to prevent the occurrence and recurrence of these events which is one of the objectives of the European Blood Law. The Irish National Haemovigilance Office has reported the following incidences of complications:
acute hemolytic and other severe transfusion reactions: 1:5358 for red cell con­ centrates and 1:3955 for platelets;
acute severe allergic and anaphylactic reactions: 1:13 931 for red cell concen­ trates and 1:2197 for platelets;
delayed hemolytic transfusion reactions: 1:27 863 for red cell concentrates;
transfusion-associated circulatory overload: 1:7332 for red cell concentrates and 1:6407 for plasma for transfusion.

(SED-15, 529; SEDA-28, 369; SEDA-29, 338; SEDA-30, 381)

From the Greek database, the incidence of serious reactions over the period 1997–2005 was 0.9:10 000 blood units and 0.65:10 000 blood products; the frequency of non-serious adverse reactions was 12:10 000 blood units and 8.3:10 000 blood products (11R).

Observational studies The number of hae­ movigilance schemes worldwide continues to increase, and the collection of data related to adverse events following transfusion of blood components has improved significantly (8R– 11R). The reported transfusion reactions include acute and delayed hemolytic transfusion reactions, transfusion-related acute lung injury (TRALI), anaphylactic and other allergic reactions, circulatory overload, bacterial contamination, viral contamination, posttransfusion purpura, transfusion-associated graft-versus-host disease, hemosiderosis, new antibody formation, and mild fever. Adminis­ tration of the wrong blood component, other incidents, and near misses can cause morbid­ ity and even mortality. The European

Respiratory Transfusion of plasmacontaining blood components can be com­ plicated by life-threatening TRALI, defined as acute lung injury with no acute lung injury during or within 6 hours of a transfusion, with dyspnea, hypoxemia, fever, hypotension, and pulmonary infiltrates (13R). TRALI varies in severity, and death is not uncommon. It can occur in all age groups and has an equal sex distribution. All blood products, except albumin, have been implicated. TRALI accounts for 8% of all adverse transfusion reactions and overall mortality is 5–10%. Although fresh frozen plasma is considered as the main source of this event, it was not implicated in the six cases TRALI in the SHOT (Serious Hazards of Transfusion)

BLOOD TRANSFUSION

Blood, blood components, plasma, and plasma products

database, in which the reactions occurred after the use of platelets (n ¼ 3), red cells (n ¼ 2), and cryoprecipitate (n ¼ 1); in all the six cases, the donor of the implicated component was female (8r). In the TRIP (Transfusion Reactions in Patients) haemovigilance scheme, 15 cases of TRALI were reported. Eleven of these cases complied with the criteria for TRALI (dyspnoe and hypoxia within 6 hours after a transfusion and bilateral infiltrates on fron­ tal chest X-ray; no indications for hemoly­ sis, and no other explanation) after the use of red cells (n ¼ 3); red cells and fresh frozen plasma (n ¼ 6); fresh frozen plasma (n ¼ 1); and platelets (n ¼ 1) (9c). One patient died because of immunological reactions. In five cases an immunological cause was found: in two cases leukocyte serology was not performed, in two cases blood from the patient was not send in, and in one case blood was not cross-matched.
A 2-year-old girl with Down’s syndrome and

acute myeloid leukemia developed thrombocy­ topenia during her sixth cycle of chemotherapy and received four units of platelet concentrate. During infusion of the second unit of platelets, she developed acute respiratory distress with hypoxia and tachycardia. A chest X-ray showed bilateral interstitial infiltrates. The transfusion was stopped and she was given oxygen and a single dose of furosemide. There were no neutrophil reactive antibodies or HLA class I or II antibodies. Retrospective neutrophil compatibility testing between the patient’s and all four donor serum samples showed compat­ ibility with three units and incompatibility with one unit, by both GIFT and GAT techniques. The incompatible unit had antibodies to HLA­ B5, B15, and B35 and was from a female donor with six previous pregnancies (14A).
An 87-year-old woman was transfused with one unit of packed red cells for a hematocrit of 26%. She immediately developed symp­ toms of respiratory distress and died despite intensive treatment. The donor of the unit was female. After screening of the patient and the donor, the patient was found to be positive for the cognate HLA B13 antigen and the donor’s anti-B13 was present at a titer of 1:32 (15A).

Hematologic Massive transfusion as a consequence of post-traumatic and surgi­ cal hemorrhage due to hypothermia, dilu­ tional coagulopathy, platelet dysfunction,

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fibrinolysis, or hypofibrinogenemia may be followed by coagulopathy (16R). Immunologic Anaphylactic transfusion reactions are defined as serious reactions, occurring within seconds to minutes after the start of the transfusion, with expiratory stridor, wheeze, bronchospasm, laryngeal edema, hypotension, vomiting, diarrhea, back pain, and urticaria, in the absence of hemolysis and bacterial infection. From reports from The Netherlands, Spain, Den­ mark, and Canada, this is an important category of transfusion reactions. There have been 23 reports to TRIP: 5 occurred in association with platelets, 10 with plasma, 5 with red cells, 2 with red cells and plasma, and in one case the product was not mentioned. In three cases the patient was under 18 years of age; one patient with HLA and HPA antibodies had an anaphy­ lactic reaction twice after platelet transfu­ sion (9r). Infection risk Variant Creutzfeldt–Jakob disease Concerns have been raised that variant Creutzfeldt–Jakob disease (vCJD) might be transmissible by blood transfusion. UK experience with transfusion-acquired vCJD has been reviewed (17R). Three recipients of a transfusion derived from a vCJD-infected donor have developed vCJD, including two clinical cases and one of preclinical or subclinical infection. In view of the small size of the total at-risk recipient population and the background mortality rate for vCJD in the general UK population (0.24 per million per annum), these observa­ tions provide evidence that vCJD can be transmitted from person to person through blood transfusion. Cases of transmission of pathogenic prions by human plasma deriva­ tives have not been observed (18H). Two cases of prion infection in a group of known recipients of transfusion of donors who subsequently developed vCJD were reported in 2004, and a third report has appeared (19A).
A 31-year-old man developed progressive

difficulties with balance and impaired concen­ tration. He had incapacitating leg pains and increasing difficulty in walking. He had

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ulcerative colitis since a teenager and at age 23 had surgery with complications, including pelvic bleeding, and was given 22 units of red cells, 15 units of fresh frozen plasma, and three units of platelets. One of the donors of the non­ leukodepleted red cells developed vCJD 20 months after donation. The donor was homo­ zygous (MM) at the PRNP codon 129 and died after an 11-month illness with neuropathologi­ cal confirmation of vCJD. Six years after the transfusion, the patient developed fluctuating exertional fatigue and impaired concentration, which turned out to be the fist signs of vCJD. When he died, brain and tonsil tissue were obtained and assessed for the presence of disease-related PrP by immunoblotting and im­ munohistochemistry. The diagnosis was prob­ able vCJD.

The risk of transmission of vCJD via blood transfusion depends on potential levels of infectivity, the recipient’s exposure to infected donors, and individual suscept­ ibility. Based on animal models, infectivity is split roughly equally between leukocytes and plasma, with negligible levels associated with red cells and platelets. Exposure to infection depends on the prevalence of the infection in the population, which is unknown. The current precautionary assumption is that all recipients are susceptible to infection by transfusion, although incubation periods differ markedly (20H). Hepatitis B In a case of post-transfusion hepatitis B, the donor’s pretransfusion 50­ minipool hepatitis B virus (HBV) nucleic amplification technology (NAT) test result was negative, but retrospective testing of the same sample by individual-donation NAT was positive (21A). Hepatitis C In a study among Dutch donors, the prevalence and incidence rates of hepatitis C were extremely low, with a calculated residual risk of transmitting hepa­ titis C of 1 in 30 million donations. Former intravenous drug users (21%), transfusion recipients (30%), and immigrants (W12%) were major risk groups (22R). West Nile virus In 2002, West Nile virus became the first vector-borne flavivirus found to be transmitted through blood transfusion; three cases of West Nile virus

P.F.W. Strengers and E. van Twuijver

transfusion-associated transmission were documented in persons transfused with blood components from 16 viremic donors. In 2003–2005 more than 1400 potentially infectious blood donations in the United States were removed after national blood screening for West Nile virus (23R). How­ ever, some residual risk of transmission remained because of donations containing very low levels of virus. Death Five transfusion-related deaths have been attributed to an ABO incompa­ tible red cell transfusion (certain and con­ clusive), an anaphylactic reaction to fresh frozen plasma (evidence in favor) and one after red cells (possible), three possibly due to TRALI, and one possibly related to overtransfusion (8r, 9r). Medication errors In the SHOT database, including 485 reports, there were “wrong blood” events, when a patient receives a blood component intended for a different patient or an incorrect group, in 18% of cases (8r). In 4.5%, there were other pretransfusion errors, including incorrect D groups, based on missed allo-antibodies and missed serological incompatibility. In 0.5%, blood of the incorrect group was given to recipients of ABO mismatched peripheral blood stem cell or bone-marrow transplants. Failures to provide blood of appropriate specification or that did not meet the patient’s special requirements occurred in 29%. Inappropriate or unne­ cessary transfusions were given in 14%. In 16%, there was “unsafe” transfusion, when there were handling or storage errors. In 18%, events were related to the adminis­ tration of anti-D immunoglobulin. Hospital transfusion laboratory errors occurred in 180 cases (37%). In Ireland, of serious adverse events related to blood transfusion, incorrect blood compo­ nent transfusion accounted for 65% of incidents reported, an increase of 37% from 2004 (10R). The site of the first error was in the prescription/request (45%), cross-matching or issuing (24%), storage or handling (8%), initial clerking in the hospital (8%), adminis­ tration (7%), and sampling (7%).

Blood, blood components, plasma, and plasma products
Because of a bedside sampling error a patient

received a transfusion on the basis of a low hemoglobin and a cross-match sample taken from the wrong patient. The transfusion went ahead in spite of concerns that the hemoglobin was not correct. By chance, the patients were of the same blood group, so the patient suffered no ill effects.

BLOOD SUBSTITUTES (SEDA28, 370; SEDA-29, 340; SEDA-30, 383) Hemin

(SED-15, 1588)

Hemin is an iron-containing porphyrin, derived from red blood cells used for the treatment of acute porphyrias. In an open study, 111 patients received hemin, manu­ factured in a new facility, for treatment of 305 acute attacks of porphyria and 40 patients used it for prophylaxis (24c). Adverse events were more frequent in patients who were treated for attacks than for prophylaxis, 44% versus 16%. There were four serious adverse events: an adverse drug reaction, an injection site reaction, phlebitis and pyrexia, and bacteremia. The results of this study led to the commercial re-introduction of the drug, with FDA approval.

Hemoglobin-based oxygen carriers Nanobiotechnology, the assembling of bio­ logical molecules into nanodimension struc­ tures, is being used for the development of new generations of red blood cell sub­ stitutes. First-generation nanodimension polyhemoglobin (poly-Hb) and bovine polyhemoglobin have been successfully used in phase III clinical trials (25R). However, these products are merely oxygen carriers with short circulation times, lacking the enzyme activity of red blood cells, and therefore have limited clinical use. Other modified hemoglobin molecules, such as intramolecularly cross-linked hemoglobin and recombinant hemoglobin, can cause

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531

vasopressor effects and increased muscle contractions. New generations of modified hemoglobin are being developed that have potential clinical applications.

Perfluorocarbons Comparative studies Despite recent clinical trials demonstrating improved outcomes in acute respiratory distress syndrome (ARDS), mortality remains high. Partial liquid ventilation using perfluorocarbons improves oxygenation and reduces lung injury in various animal models. In order to determine if partial liquid ventilation would effect outcomes in patients with ARDS, 311 patients were randomized to conventional mechanical ventilation (n ¼ 107) and two doses of perfluorocarbon (10 ml/kg, n ¼ 99, and 20 ml/kg, n ¼ 105) (26R). The 28-day mortality after conventional mechanical ventilation was 15% versus 26% in the lowdose and versus 19% in the high-dose perfluorocarbon groups. There were more ventilator-free days after conventional mechanical ventilation compared with both the low-dose and high-dose groups (13, 7.4, and 9.9 days respectively). There were more episodes of pneumothorax, hypoxia, and hypotension in those who received perfluorocarbons. The authors therefore concluded that partial liquid ventilation with perfluorocarbons did not improve outcome in ARDS compared with conventional mechanical ventilation and cannot be recommended. Hematologic A new perfluorocarbon emulsion has been tested at two concentra­ tions (40 and 80 g/l) on plasma and whole blood viscosity in the presence of human albumin, hydroxyethyl starch, or modified fluid gelatine (27E). Addition of perfluor­ ocarbon, even at low, that is, clinically used concentrations, to volume expanders resul­ ted in increased blood viscosity. Clinicians should be cautious about using perfluoro­ carbon and colloids because of complex effects on blood rheology.

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(SED-15, 2847; SEDA-29, 340; SEDA-30, 383)

PLASMA PRODUCTS

Alpha1-proteinase inhibitor Drug formulations Alpha1-antitrypsin deficiency is an autosomally inherited dis­ order, which predispose to life-threatening lung and liver disease. In a multi-center, randomized, controlled study, the capability of a new plasma-derived alpha1-proteinase inhibitor (Zemairas) to achieve protective serum trough concentrations (W11 mmol/l) as well as to raise the concentration of alpha1-proteinase inhibitor in the lower lung was compared with the currently available alpha1-proteinase inhibitor, Prolastins (28c). There were adverse events related to Zemaira in 7% of the subjects and included injection site pain and paresthesia. Related adverse events in those who received Prolastin included an asymptomatic transient seroconversion for hepatitis B, vasodilatation, facial flushing, and parvovirus B19 infection.

Antithrombin III Drug–drug interactions The efficacy of high-dose antithrombin therapy with or without concomitant heparin has been tested in patients with severe sepsis (29C, 30C). Treatment with antithrombin III (30 000 IU in 4 days) may reduce 28-day mortality, but this effect was not observed in combination with heparin. There was a higher incidence of bleeding with anti­ thrombin plus heparin compared with antithrombin alone, but no difference in the rates of thromboembolic events. High-dose antithrombin alone may protect sufficiently against venous thromboembolism.

C1 inhibitor concentrate Intravenous self-administration of C1 inhi­ bitor concentrate is feasible and safe, resulting in a more rapid and more effective treatment or prevention of severe angioe­ dema attacks in patients with C1 inhibitor deficiency (31c).

P.F.W. Strengers and E. van Twuijver

Fresh Frozen Plasma Fresh frozen plasma is efficacious for coagu­ lopathies associated with massive hemor­ rhage, liver disease, and disseminated intravascular coagulation. In addition, it is the sole source of replacement for several rare coagulation protein deficiencies for which there are no available viral-inactivated, plasma-derived, or recombinant concen­ trates. Finally, reconstituted blood consisting of fresh frozen plasma and packed red blood cells is recommended for exchange transfu­ sion as well as for circuit priming. Systematic reviews Assessment of the evidence for the use of fresh frozen plasma showed 57 identified published trials, most of which enrolled small numbers of patients, resulting in inadequate informa­ tion on outcomes. Moreover, adverse effects might annul clinical benefits, and new trials therefore need to be conducted to determine the effectiveness of fresh frozen plasma (32M). Cardiovascular There is an increased risk of venous thromboembolism after treatment of thrombotic thrombocytopenic purpura with solvent-detergent fresh frozen plasma, probably due to a reduced protein S concentration (33R, 34R). Hematologic Because of its coagulant properties, fresh frozen plasma in combina­ tion with recombinant factor VIIa should be used with care (SEDA-30, 384).
A 13-year-old girl with hypofibrinogenemia

and von Willebrand disease developed a severe headache, vomiting, progressive right flaccid hemiplegia, and lethargy. Contrastenhanced computed tomography showed a subdural hematoma in the posterior parietal region of the brain and impending cerebellar herniation. She was given fresh frozen plasma and then activated factor VII (rFVIIa) 80 mg/ kg. The subdural hematoma was drained. She recovered in a few days, but 5 days after rFVIIa infusion developed a right middle cerebral arterial thrombosis.

The authors suggested that the thrombosis may have been due to infusion of rFVIIa and fresh frozen plasma (35A).

Blood, blood components, plasma, and plasma products

Fluid balance Fresh frozen plasma can cause fluid overload resulting in dyspnea, tachycardia, pulmonary crackles, and ankle/sacral edema (33r, 34r). Immunologic Administration of fresh fro­ zen plasma can lead to adverse reactions, among which immune-mediated reactions are the most common. These include allergic reactions, anaphylactic reactions, TRALI, and hemolysis, ranging from mild to fatal (33r). Infection risk Transmission of bacteria by transfusion of fresh frozen plasma is very rare. The risk of viral transmission has been reduced dramatically by a combination of strict donor selection and the use of extensive sensitive testing of donations (33r). Variant Creutzfeldt–Jakob disease Two suspected cases of transmission by transfu­ sion of vCJD have been reported in the United Kingdom. These cases reflected increased susceptibility to vCJD/prion infection in subjects who are methionine homozygous at codon 129 of the prion protein (33r). Susceptibility factors Age Fresh frozen plasma should not be infused into children except for specific indications; it is no longer used as a general adjuvant therapy in critically ill infants (36R). Drug formulations For orthotopic liver transplantation, often complicated by bleeding, fresh frozen plasma is the stan­ dard treatment for procoagulant factor deficiencies caused by end-stage liver dis­ ease. Solvent/detergent-treated fresh frozen plasma (Octaplas) products have been developed in an attempt to reduce the risk of viral transmission. Two of the 22 patients who received solvent/detergent-treated fresh frozen plasma during liver transplan­ tation died intraoperatively with rapid development of severe coagulopathy, excessive bleeding, fibrinolysis, and refractory hemodynamic instability (37c).

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533

PLASMA SUBSTITUTES (SEDA27, 353; SEDA-28, 371; SEDA-29, 340; SEDA-30, 384)

Etherified starches

(SED-15, 1237; SEDA-29, 340; SEDA-30, 384)

Comparative studies The effects of dif­ ferent volume expanders on cardiac output in a neonatal population with hemodynamic failure have been compared in a randomized clinical trial (38c). Hydroxyethyl starch is not more efficacious than isotonic saline or albumin. There were no adverse effects rela­ ted to fluid resuscitation. Hematologic Moderate doses of low molecular weight hydroxyethyl starch (130/0.4) in children undergoing cardiac surgery did not cause more bleeding or higher transfusion requirements than an infusion of fresh frozen plasma. The results suggested that hydroxyethyl starch does not have a negative effect on hemostasis, as assessed by INR and aPTT (39c). In another study hydroxyethyl starch (200/0.5) impaired clot formation and strength and increased fibrinolytic capacity after cardiopulmonary bypass; the effects could not be reversed by intravenous tranexamic acid (40c). Hemodilution significantly affects the var­ ious aspects of fibrinolysis in both human plasma in vitro and rabbit plasma after in vivo administration. Hydroxyethyl starch, compared with crystalloid or albumin solu­ tions, enhances fibrinolysis by reducing clot strength and time of onset of fibrinolysis (41E). Addition of fibrinogen improves coagulation after hemodilution with crystal­ loids and colloids (42E). These results are supported by another in vitro study (43E) and by results obtained from patients under­ going cardiac surgery receiving albumin, succinylated gelatine, or hydroxyethyl starch postoperatively. Both gelatine and hydro­ xyethyl starch impaired clot strength and fibrin formation, whereas albumin appeared to have the least effect on hemostatic variables (44c).
A 19-year-old man with a cerebral contusion

complicated by frequent and severe infectious

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complications required intermittent adminis­ tration of hydroxyethyl starch. Because of persistent thrombocytopenia and liver dys­ function a bone marrow and liver biopsy were performed and foamy cell degenerated macro­ phages were detected (45A).

Immunologic An immediate hypersensitivity reaction to hydroxyethyl starch has been reported (46A).
A

22-year-old man undergoing partial nephrectomy was infused with a solution of hydroxyethyl starch. Shortly after the start of the infusion, the peak inspiratory pressure suddenly increased and the blood pressure fell. Postoperatively, he had a diffuse urticarial rash on his torso and serum tryptase and urine N-methylhistamine concentrations were raised. Skin testing for possible allergy to latex 2 months later was negative.

Susceptibility factors Renal disease In a retrospective analysis of patients with impaired renal function receiving large amount of hydroxyethyl starch, there was an increase in chitotriosidase activity, excessive exposure to which can result in massive tissue infiltration with activated foamy macrophages, ultimately resulting in acquired lysosomal storage disease (47A).

Polygelines

(SED-15, 2888; SEDA-29, 341; SEDA-30, 384) Hematologic Resuscitation fluids, such as gelatine (Gelofusine), have an effect on clot formation, not shown by the conven­ tional coagulation screen (INR, thrombo­ plastin time, and aPTT), which seems to reflect the changes observed in vitro (48c, 49E). The results suggest that important changes in coagulation caused by resusci­ tation fluids may be unrecognized if clini­ cians rely on the conventional coagulation screen. Immunologic An anaphylactic reaction to Gelofusine has been reported (50A).
A 48-year-old woman received an infusion of

Gelofusine 3 hours after induction of anesthe­ sia and after 6 minutes developed increased

P.F.W. Strengers and E. van Twuijver

airway pressure with bronchospasm, reduced arterial blood pressure, and increased heart rate. There was erythema and goose flesh skin in both arms.

GLOBULINS Immunoglobulins

(SED-15, 1719; SEDA-28, 372; SEDA-29, 343; SEDA-30, 385)

In addition to immune deficiencies, intra­ venous immunoglobulin is used in a wide variety of disorders (51R–53R). The rapid expansion in the use of intravenous immu­ noglobulin has resulted in an increased number of adverse drug reactions, including fever, headache, myalgia, chills, nausea, vomiting, light-headedness, back pain, rash, flushing, pruritus, hypertension, hypotension, and fluid overload. Less common are chest tightness, chest pain, wheezing, aseptic meningitis, severe headaches, and renal failure. Renal failure was associated with high osmolarity sucrose-containing intravenous immunoglobulin formulations, whereas aseptic meningitis seems to be more com­ mon in patients with a history of migraine. Severe reactions have included thromboembolism, acute encephalopathy, bleeding disorders, stroke, neutropenia, hyponatremia, cryoglobulinemia, non-infectious hepatitis, and pleural effusion. Occasionally, vasculitis develops in pa­ tients treated with intravenous immunoglo­ bulin for rheumatic diseases, Guillain–Barré syndrome, chronic inflammatory demyelina­ ting polyneuropathy, or dys/hypogammaglo­ bulinemia. Autoimmune hemolytic anemia has been reported in several patients with Kawasaki disease and enhancement of the formation of cryoglobulins in individual patients with pre-existing cryoglobulinemia (54M). Current data suggest that high-dose intravenous immunoglobulin has a benefi­ cial effect on the reduction of anti-HLA antibodies with subsequent improvement in renal transplantation in highly HLAsensitized patients and is effective in the

Blood, blood components, plasma, and plasma products

treatment of antibody-mediated rejection episodes. Intravenous immunoglobulin has minor adverse effects in these patients, such as headaches, associated with the infusion rate (55c). It might also be a potential component of remission induction therapy for patients with myeloperoxidase–antineutrophil cyto­ plasmic antibody-associated rapidly progres­ sive glomerulonephritis. Only one out of 12 patients had transient hypertension and edema of the limbs during intravenous immu­ noglobulin infusion, which abated after low­ ering the infusion rate (56R). Placebo-controlled studies In a multi-cen­ ter, randomized, double-blind, place­ bo-controlled trial, the clinical effect of intravenous immunoglobulin 90 g on 3 consecutive days, twice at 3-month intervals was analyzed in patients with post-polio syndrome (57c). There were no serious adverse drug reactions. Headache was the most frequent adverse effect. Infusion site reactions, gastrointestinal, nervous system, skin, and subcutaneous disorders were more frequent in those who were given intravenous immunoglobulin. The potential beneficial effect of intrave­ nous immunoglobulin treatment for recur­ rent spontaneous pregnancy loss has been assessed in five randomized, controlled trials in 250 patients (58M). Intravenous immunoglobulin was not effective. Adverse events included transient rash and fever, but they were not frequent. Nervous system Two patients with Susac syndrome (a retinocochleocerebral microan­ giopathy) were treated with intravenous immunoglobulin and methylprednisolone, which resulted in no further relapses (59A). One had immediate and significant improve­ ment in hearing and MRI lesions. There was one potentially serious adverse event seizures during the intravenous immunoglo­ bulin infusion.
A 62-year-old woman with hemophagocytic

syndrome was treated with intravenous immu­ noglobulin (20 g/day for 3 days), followed by methylprednisolone (1 mg/kg/day). On day 8 she had an acute hemiplegia due to cerebral infarction.

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535

The authors question the association with intravenous immunoglobulin alone in the occurrence of the thrombotic event, since in most previous cases additional glucocorti­ coid therapy was given (60A).
A 3-year-old boy with Kawasaki disease

developed a cerebral infarction 4 days after high-dose intravenous immunoglobulin 2 g/kg. Concomitant aspirin 50 mg/kg did not prevent the stroke.

Based on numerous reports of thrombosis due to high-dose intravenous immunoglo­ bulin in older patients, caution should be taken when treating children with Kawasaki disease (61A). Urinary tract Two patients with chronic inflammatory demyelinating polyneuropa­ thy treated with intravenous immunoglobu­ lin developed acute renal insufficiency. The pathology was similar in the two cases, including tubular epithelial cell injury char­ acterized by isometric intracytoplasmic vacuolization and cellular swelling, attribu­ table to substances like sucrose and maltose in intravenous immunoglobulin formula­ tions (62A). High-dose intravenous immunoglobulin pulse therapy delayed disease progression in patients with progressive immunoglobulin A nephropathy, as assessed by glomerular filtration rate, proteinuria, and renal survival time; compared with the control group, renal survival time was prolonged by 3.5 years (63c). One patient developed acute renal insufficiency due to sucrose-containing intra­ venous immunoglobulin and was therefore switched to a sucrose-free formulation. Another patient had a deep vein thrombosis. Skin Four cases of severe extensive eczematous skin reactions occurred about 10 days after intravenous immunoglobulin infu­ sion for polyradiculoneuritis (64Ar). The onset was characterized by dyshydrotic lesions on the palms extending to the rest of the body. A literature review revealed 33 cases of cutaneous eruptions after infusion of intravenous immunoglobulin, with char­ acteristics similar to the four cases. Of these 37 cases, 35 had a neurological or

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neuromuscular disease, suggesting that neu­ rological disorders, which are often immuno­ logical and are often related to viral infections, could predispose patients to this type of adverse reaction. Other eczematous lesions have been reported.
A 7-year-old girl with Stevens–Johnson syn­

drome was given intravenous immunoglobulin 0.5 g/kg for 4 days (65A). Six days later she developed a vesicular eczema on her palms and forehead, which resolved after 3 weeks. However, new lesions on the plantar aspects of the feet then occurred.
A 33-year-old patient with multifocal motor neuropathy received intravenous immunoglo­ bulin 0.4 g/kg/day for 5 days and developed vesicular eczema on the fingers and palms; the vesicles progressed to bullae (66A). A slightly scaling erythema developed on the face and scalp. The lesions healed after treatment with topical glucocorticoids. In spite of systemic antihistamines during the following four courses of intravenous immunoglobulin, the vesicular eczema developed but with a mark­ edly milder course. Antihistamine treatment was stopped after the fourth course of intra­ venous immunoglobulin, resulting in slight aggravation of the eczema, which was transient and did not recur after the next courses.

A vasculitis has been attributed to intrave­ nous immunoglobulin (67A).
A previously healthy woman with progressive

bilateral paresthesia, weakness, and facial paralysis after chiropractic manipulation, initi­ ally treated with prednisone for 1 week, received a course of intravenous immunoglo­ bulin 2 mg/kg over 2 days. Two days later she developed asymptomatic erythematous papu­ lar eruptions on her shin, progressing to her feet, lower legs, hands, and arms. A skin biopsy showed that this was a thrombotic lymphocytic vasculitis which was attributed to intravenous immunoglobulin.

Drug formulations Intravenous immuno­ globulin products differ in salt and sugar content, pH, and osmolality. These differ­ ences have clinical implications. In a retro­ spective analysis, infusion-related adverse events were monitored during and after the administration of three intravenous immu­ noglobulin products, Gamimune 10% (n ¼ 76), Polygam (n ¼ 105), and Cari­ mune (n ¼ 98). Five patients (4.7%) in the Polygam group had acute myocardial

P.F.W. Strengers and E. van Twuijver

infarction, eight (8.2%) in the Carimune group developed acute renal insufficiency, whereas none of the patients in the Gamimune group developed either. All three products caused headaches. These results suggest that pre-existing susceptibil­ ity factors should be taken into account in the selection of an intravenous immunoglo­ bulin product (68R). A new 10% liquid intravenous immuno­ globulin has been evaluated in a prospective open study in patients with hypogammaglo­ bulinemia and agammaglobulinemia (69c). Its pharmacokinetics, efficacy, and safety were similar to the results obtained with other formulations. The most commonly reported drug-related adverse events were headache (9%), pyrexia (9%), and urticaria (5%). Its effects were also assessed in patients with primary immune deficiency (70c). A total of 826 infusions were adminis­ tered, with a median of 13 infusions per subject and a median dose per subject of 436 g. Drug-related adverse events were considered mild or moderate and consisted of headache, fatigue, pyrexia, rigors, and migraine, headache being the most frequent. Two serious adverse events were drug­ related—one subject had two episodes of aseptic meningitis. Intravenous anti-D immunoglobulin (n ¼ 18) has been compared to low-dose intravenous immunoglobulin (n ¼ 16) in children with chronic immune thrombocyto­ penic purpura (71c). There was intravascular hemolysis in 61% of the patients on day 3 and in 77% on day 7 after anti-D immu­ noglobulin infusion. Other less frequent adverse effects following anti-D immunoglo­ bulin infusion were low-grade fever (11%) and allergic skin rashes (5.5%). Low-dose intravenous immunoglobulin caused headache, mild fever, and skin rash; one patient developed aseptic meningitis and had seizures 24 hours after the infusion. Drug administration route Of 65 patients with primary immune deficiency diseases who self-administered subcutaneous immu­ noglobulin infusions at a mean weekly dose of 158 mg/kg for 12 months, 63 had adverse effects, attributable in 62 to a high rate of infusion-site reactions such as local swellings,

Blood, blood components, plasma, and plasma products

soreness, redness, and induration, most of mild or moderate intensity. Other treatmentrelated adverse events were headache, nausea, rash, weakness, and gastrointestinal disorders (72c). Diagnosis of adverse drug reactions The incidences of immediate and delayed adverse events after intravenous immuno­ globulin therapy in children have been determined in a prospective study in 33 patients with immunodeficiency and in 25 for immunomodulation of autoimmune and inflammatory diseases (73c). Immediate and delayed adverse events occurred in 6 and 24 children, respectively. The most common delayed adverse events were headache (n ¼ 13), fatigue (n ¼ 12), abdominal pain (n ¼ 8), and myalgia (n ¼ 4). In contrast, headache as an immediate adverse event was reported in only five patients. Delayed adverse events were the main cause of absence from school and a need for addi­ tional therapies and medical consultations.

COAGULATION PROTEINS (SED-15, 845; SEDA-28, 375; SEDA-29, 345; SEDA-30, 387)

Coagulation factor concentrates Immunologic Patients with hemophilia A or B can develop antibodies (inhibitors) that interfere with the function of the transfused factor (74r). Inhibitors are most common in severe hemophilia A. Inherited factors, a positive family history, racial (African) origin, environmental factors, the type of concentrate, and treatment early in life with high doses contribute to the development of inhibitors. There is some evidence that plasma-derived factor VIII concentrates containing von Willebrand factor are less immunogenic. Inhibitors in hemophilia B are uncommon but can be associated with severe anaphylaxis. Treatment of inhibitors comprises immune-tolerant protocols with plasmaderived or recombinant factor VIII, factor VIIa, and activated prothrombin complex

Chapter 33

537

concentrate (75c). Rituximab (an anti-CD20 monoclonal antibody) is investigational (76c). Infection risk Infectious agents can be transmitted when plasma-derived factors are used to treat hemophilia (SEDA-30, 397). Transmission of hepatitis C virus is pre­ vented by viral inactivation steps now used in the production of plasma-derived factor concentrates, but transmission remains a problem in many areas of the world where hemophilia is treated with cryoprecipitate and 80% of individuals using cryoprecipitate are estimated to be infected with hepatitis C (74r). Transmission of HIV ceased from 1986 with the introduction of effective steriliza­ tion methods. Regarding the potential trans­ mission of other blood-borne agents (e.g. West Nile virus or in the United Kingdom in particular vCJD), continued vigilance will be important. Drug administration route In a compar­ ison of continuous infusion and bolus injec­ tion, two of 43 patients, both with severe hemophilia A, developed a high-responding inhibitor after continuous infusion; two had mild thrombophlebitis or rash (77c).

Gene therapy In an open, dose-escalating study of gene therapy of hemophilia B with a recombinant adeno-associated viral vector (rAAV) expressing canine factor IX in seven patients with severe hemophilia B, vector infusion at doses up to 2  1012 vg/kg was not associated with acute or long-lasting toxicity (78c). None of the subjects had adverse reactions after vector infusion, but the gradual decline of factor IX was due to destruction of transduced hepatocytes by cell-mediated immunity tar­ geting antigens of the AAV capsid.

Prothrombin complex concentrate Hematologic In an open, prospective, randomized, controlled trial on the reversal of oral anticoagulant therapy with prothrombin complex concentrate in 93

538

Chapter 33

patients and comparing a standard dose with individualized treatment based on the initial International Normalized Ratio (INR), a target INR, and the patient’s body weight, the individualized treatment was more effective (79c). Two serious adverse events, non-hemorrhagic strokes, were possibly related to a combination of medical history, current illness, and the use of prothrombin complex concentrate.

ERYTHROPOIETIN AND DERIVATIVES (SED-15, 1243; SEDA-29, 346; SEDA-30, 388)

Recombinant human erythropoietin analogs (rHuEPO), epoetin alfa and epoetin beta (half-lives 8 hours), and the erythropoiesisstimulating glycoprotein darbepoetin alfa (half-life 49 hours) are used in the correction of anemia in adults and children with chronic kidney disease (80R), in anemia related to cancer or cytotoxic drugs (81R), and in heart failure, including chronic heart failure (82R), acute myocardial infraction (83c), and ane­ mia after cardiac transplantation (84c). Their use in the treatment of patients with strokes (85r), diabetes (86H), the reduction of red cell transfusions (87C), and in critically ill patients (88C) is experimental. The US FDA has warned health-care professionals and the public about the safety of the erythropoietin analogs darbe­ poetin alfa (Aranesp) and epoetin alfa (Epogen and Procrit), after four studies in patients with cancers showed a higher chance of serious adverse effects. (89S). These studies involved an unapproved dosage regimen, a patient population for which these drugs are not approved, or a new unapproved drug. The FDA therefore issued a Public Health Advisory with the following information:
There was a higher chance of death and an increased rate of tumor growth in patients with advanced head and neck cancers receiving radiotherapy and in patients with metastatic breast cancer receiving













P.F.W. Strengers and E. van Twuijver

chemotherapy, when erythropoietin ana­ logs were given to maintain the hemoglo­ bin at over 12 g/dl. There was a higher chance of death without a reduction in the need for blood transfusion when erythropoietin analogs were given to patients with cancer and anemia not receiving chemotherapy. There was a higher chance of death and an increased number of blood clots, heart attacks, heart failure, and strokes in patients with chronic renal insufficiency when erythropoietin analogs were given to maintain the hemoglobin at over 12 g/dl. There was a higher chance of blood clots in patients who were scheduled for major surgery and given erythropoietin analogs. Erythropoietin analogs are not approved for treatment of the symptoms of anemia such as fatigue in patients with cancer, in surgical patients, and in patients with HIV infection.

Studies in kidney disease In two studies, a change in the dose of darbepoetin alfa from once a week to once every 2 weeks was effective (90c, 91C). Renal anemia in stable hemodialysis patients can be treated with darbepoetin alfa more effectively intra­ venously than subcutaneously (92c), but a significantly higher dose is required to main­ tain the target hemoglobin concentration (93C, 94C). A regular dosing schedule of iron sucrose 50 mg/week will maintain stable iron stores and hemoglobin concentrations in hemo­ dialysed patients, allowing considerable reductions in the dosage of epoetin: the mean dose of darbepoetin alfa can be reduced from 0.75 to 0.46 mg/kg/week, and the mean dose of epoetin alfa from 101 to 74 IU/kg/week (95c). In an open trial in 1432 patients with chronic kidney disease, of whom 715 were randomly assigned to a dose of epoetin alfa targeted to achieve a hemoglobin concentra­ tion of 13.5 g/dl and 717 to a concentration of 11.3 g/dl, 55% of the high-dosage group and 49% of the low-dosage group had at least one serious adverse event (congestive heart failure, myocardial infarction, gastrointestinal hemorrhage, chest pain, cellulitis, pneumonia,

Blood, blood components, plasma, and plasma products

and renal insufficiency). The types of serious adverse events were similar in the two groups, with the exception of congestive heart failure, which occurred more fre­ quently in the high-dosage group (11% versus 7.4%) (80r). Studies in patients with cancers In an updated systematic review of 57 trials and 9353 patients with cancers on the effects of epoetin alfa and epoetin beta and darbepoe­ tin alfa, the use of epoetin and darbepoetin significantly reduced the need for red cell transfusions and improved hematological responses. However, treatment with epoetin or darbepoetin increased the risk of thromboembolic events. Uncertainties remain as to whether and how epoetin and darbepoetin affect overall survival. Caution is advised when using epoetin or darbepoetin in combination with thrombogenic chemother­ apeutic agents or for patients with cancers who are at high risk of thromboembolic events (96C). Cardiovascular There is frequently an association between hypertension and darbe­ poetin alfa or rHuEPO (82r). Adverse events include thromboembolic events, partly attrib­ uted to effects of increased hemoglobin on blood viscosity or platelet–erythrocyte inter­ actions or to direct effects of erythropoietin on platelets or vascular endothelial cells [Tang 2454R] (98C). Susceptibility factors Age In children and infants with kidney disease, the reported adverse events of rHuEpo and darbepoetin alfa include hypertension, thrombocytosis, and nausea. The highest percentages reported were for injection site pain, in particular for darbepoetin alfa, and for thrombosis of the vascular access (99c, 100c). Injection site pain may limit the subcutaneous use of this product in children (101c). An association has been described bet­ ween higher cumulative doses of rHuEPO used to reduce blood transfusions in pre­ mature infants and a risk of retinopathy of prematurity (102c).

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HEMATOLOGICAL GROWTH FACTORS Pegylated recombinant human megakaryo­ cyte growth and development factor (PEG-rHuMGDF) and granulocyte colonystimulating factor (G-CSF) promote hemopoietic progenitor cell maturation. Information has been reviewed about 3/538 volunteers who received PEG-rHuMGDF in clinical trials, and 2/200 donors who under­ went G-CSF mobilized stem cell harvesting procedures for sibling stem cell transplants (103c). Mantle cell lymphoma, diffuse large B cell lymphoma, and chronic lymphocytic leukemia were diagnosed 1–5 years after administration of PEG-rHuMGDF to three volunteers. One patient developed thrombocytopenia due to antibodies to PEG­ rHuMGDF. In two donors acute myeloid leukemia was diagnosed 4–5 years after G­ CSF mobilization. A causal relation between the administration of growth factors and the adverse events could not be demonstrated, but long-term follow-up of healthy indivi­ duals who receive hemopoietic growth factors is needed.

STEM CELLS (SEDA-29, 347; SEDA-30, 389)

Cord blood has several advantages over bone marrow, such as easy availability, a lower risk of transmission of infectious diseases, a lower risk of graft-versus-host disease, and less stringent criteria for HLA matching. How­ ever, collection strategies vary among cord blood banks, and improvement of cord blood hemopoietic content is of high importance. Evaluation of the benefits and disadvantages of cord blood collection before and after placental delivery in cesarean deliveries has shown that the two methods produce com­ parable total nucleated cells, CD34 counts and colony-forming unit counts in cord blood units (104E). The quality of immune reconstitution after unrelated cord blood transplantation in children with leukemia has been evaluated

540

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using T cell receptor Vb third complemen­ tary region spectratyping (105c). Within 12 months after transplantation, absolute num­ bers of lymphocyte subsets recovered, with generation of newly diversified CD4+ T lymphocyte subsets, indicative of successful reconstitution. Immunologic As after bone-marrow tra­ nsplantation, graft-versus-host disease can complicate transplantation of umbilical cord blood (106A).
A 12-year-old girl with acute lymphoblastic

leukemia received umbilical cord blood from a fully HLA-matched male donor. Six months after transplantation, she developed nephrotic syndrome, an autoimmune hemolytic anemia,

P.F.W. Strengers and E. van Twuijver

thrombocytopenia, and gastrointestinal symp­ toms. These symptoms manifested during taper­ ing of immunosuppressive therapy and a diagnosis of chronic graft-versus-host disease was made.

Susceptibility factors Late-onset non­ infectious pulmonary complications is a generic term for events that occur later than 3 months after hemopoietic stem cell transplantation, such as interstitial pneumo­ nia, bronchiolitis obliterans, and bronchio­ litis obliterans with organizing pneumonia. Extensive chronic graft-versus-host disease and transplants from unrelated donors are significant susceptibility factors, and result in a reduced survival rate (107C).

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6. Payen D, Sablotzki A, Barie PS, Ramsay G, Lowry S, Williams M, Sarwat S, Northrup J, Toland P, McL Booth FV. International integrated database for the evaluation of severe sepsis and drotrecogin alfa (activated) therapy: analysis of efficacy and safety data in a large surgical cohort. Surgery 2006; 140(5):726–39. Corrected and republished in: Surgery 2007; 141(4): 548–561. 7. Rice TW. Treatment of severe sepsis: where next? Current and future treatment app­ roaches after the introduction of drotrecogin alfa. Vasc Health Risk Manag 2006;2(1):3–18. 8. The Serious Hazards of Transfusion Steering Group. Serious Hazards of Transfusion (SHOT), Annual Report 2005. 30 Nov 2006; http://www.shotuk.org/SHOT%20report%20 2005.pdf. 9. TRIP Office, The Hague, The Netherlands. Transfusie Reacties in Patienten (TRIP), Rapport 2005. 2006; http://www.tripnet.nl/ pages/en/documents/64607-Rapport.pdf. 10. National Haemovigilance Office, Dublin. Annual Report 2005. http://www.giveblood.ie/ clinical_services/haemovigilance/publications/ nho_annual_report_2005.pdf. 11. Coordinating Haemovigilance Centre (SKAE). Annual Report. Athens, February 2007:1–22.

Blood, blood components, plasma, and plasma products 12. Strengers PFW. Is haemovigilance improv­ ing transfusion practice? The European Experience. In: Dax EM, Farrugia A, Vyas G, editors. Advances in transfusion safety. Volume IV. Dev Biol (Basel): Karger, 2007:215–224. 13. Swanson K, Dwyre DM, Krochmal J, Raife TJ. Transfusion-related acute lung injury (TRALI): current clinical and pathophysio­ logic considerations. Lung 2006;184(3): 177–85. 14. Fung YL, Williams BA. TRALI in 2 cases of leukemia. J Pediatr Hematol Oncol 2006;28(6):391–4. 15. Darabi K, Abdel-Wahab O, Stowell C, Sepehr A. An 87-year-old woman with respiratory distress and alveolar hemor­ rhage after transfusion. Chest 2006;130(5): 1612–6. 16. Levy JH. Massive transfusion coagulopa­ thy. Semin Hematol 2006;43(1 Suppl 1): S59–63. 17. Hewitt P. vCJD and blood transfusion in the United Kingdom. Transfus Clin Biol 2006;13(5):312–6. 18. Burnouf T, Padilla A. Current strategies to prevent transmission of prions by human plasma derivatives. Transfus Clin Biol 2006; 13(5):320–8. 19. Wroe SJ, Pal S, Siddique D, Hyare H, Macfarlane R, Joiner S, Linehan JM, Brandner S, Wadsworth JD, Hewitt P, Collinge J. Clinical presentation and pre­ mortem diagnosis of variant Creutzfeldt– Jakob disease associated with blood trans­ fusion: a case report. Lancet 2006;368 (9552):2061–7. 20. Dobra SA, Bennett PG. vCJD and blood transfusion: risk assessment in the United Kingdom. Transfus Clin Biol 2006; 13(5):307–11. 21. Inaba S, Ito A, Miyata Y, Ishii H, Kajimoto S, Tanaka M, Maruta A, Saito S, Yugi H, Hino M, Tadokoro K. Individual nucleic amplification technology does not prevent all hepatitis B virus transmission by blood transfusion. Transfusion 2006;46(11): 2028–9. 22. van de Laar TJ, Koppelman MH, van der Bij AK, Zaaijer HL, Cuijpers HT, van der Poel CL, Coutinho RA, Bruisten SM. Diversity and origin of hepatitis C virus infection among unpaid blood donors in the

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L, Czock D. High-dose intravenous immu­ noglobulin pulse therapy in patients with progressive immunoglobulin A nephropa­ thy: a long-term follow-up. Clin Exp Immu­ nol 2006;146(1):47–53. Vecchietti G, Kerl K, Prins C, Kaya G, Saurat JH, French LE. Severe eczematous skin reaction after high-dose intravenous immunoglobulin infusion: report of 4 cases and review of the literature. Arch Dermatol 2006;142(2):213–7. Young PK, Ruggeri SY, Galbraith S, Drolet BA. Vesicular eczema after intravenous immunoglobulin therapy for treatment of Stevens–Johnson syndrome. Arch Derma­ tol 2006;142(2):247–8. Maetzke J, Sperfeld AD, ScharffetterKochanek K, Sunderkotter C. Vesicular and bullous eczema in response to intrave­ nous immunoglobulins (IVIG). Allergy 2006;61(1):145–6. Bodemer AA, Longley BJ. Thrombotic lymphocytic vasculitic reaction to intrave­ nous immunoglobulin. J Am Acad Derma­ tol 2006;55(5 Suppl):S112–3. Vo AA, Cam V, Toyoda M, Puliyanda DP, Lukovsky M, Bunnapradist S, Peng A, Yang K, Jordan SC. Safety and adverse events profiles of intravenous gammaglobu­ lin products used for immunomodulation: a single-center experience. Clin J Am Soc Nephrol 2006;1(4):844–52. Björkander J, Nikoskelainen J, Leibl H, Lanbeck P, Wallvik J, Lumio JT, Braconier JH, Pavlova BG, Birthistle K, Engl W, Walter S, Ehrlich HJ. Prospective open-label study of pharmacokinetics, efficacy and safety of a new 10% liquid intravenous immunoglobulin in patients with hypo- or agammaglobulinemia. Vox Sang 2006;90(4): 286–93. Church JA, Leibl H, Stein MR, Melamed IR, Rubinstein A, Schneider LC, Wasser­ man RL, Pavlova BG, Birthistle K, Mancini M, Fritsch S, Patrone L, Moore-Perry K, Ehrlich HJ. US-PID-IGIV 10% -Study Group10. Efficacy, safety and tolerability of a new 10% liquid intravenous immune globulin [IGIV 10%] in patients with primary immunodeficiency. J Clin Immunol 2006;26(4):388–95. El Alfy MS, Mokhtar GM, El Laboudy MA, Khalifa AS. Randomized trial of

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Chapter 33 anti-D immunoglobulin versus low-dose intravenous immunoglobulin in the treat­ ment of childhood chronic idiopathic thrombocytopenic purpura. Acta Haematol 2006;115(1–2):46–52. Ochs HD, Gupta S, Kiessling P, Nicolay U, Berger M. Safety and efficacy of self-administered subcutaneous immuno­ globulin in patients with primary immuno­ deficiency diseases. J Clin Immunol 2006; 26(3):265–73. Singh-Grewal D, Kemp A, Wong M. A prospective study of the immediate and delayed adverse events following intrave­ nous immunoglobulin infusions. Arch Dis Child 2006;91(8):651–4. Bolton-Maggs PH. Optimal haemophilia care versus the reality. Br J Haematol 2006;132(6):671–82. Barnes C, Rivard GE, Poon MC, Teitel J, Pai M, Kern M, Blanchette VS. Carcao MInhi­ bitor Subcommittee of Association of Hemo­ philia Clinic Directors of Canada. Canadian multi-institutional survey of immune toler­ ance therapy (ITT)—experience with the use of recombinant factor VIII for ITT. Haemophilia 2006;12(1):1–6. Carcao M, St Louis J, Poon MC, Grune­ baum E, Lacroix S, Stain AM, Blanchette VS, Rivard GEInhibitor Subcommittee of Association of Hemophilia Clinic Directors of Canada. Rituximab for congenital hae­ mophiliacs with inhibitors: a Canadian experience. Haemophilia 2006;12(1):7–18. Bidlingmaier C, Deml MM, Kurnik K. Continuous infusion of factor concentrates in children with haemophilia A in compar­ ison with bolus injections. Haemophilia 2006;12(3):212–7. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, Ozelo MC, Hoots K, Blatt P, Konkle B, Dake M, Kaye R, Razavi M, Zajko A, Zehnder J, Rustagi PK, Nakai H, Chew A, Leonard D, Wright JF, Lessard RR, Sommer JM, Tigges M, Sabatino D, Luk A, Jiang H, Mingozzi F, Couto L, Ertl HC, High KA, Kay MA. Successful trans­ duction of liver in hemophilia by AAVFactor IX and limitations imposed by the host immune response. Nat Med 2006;12 (3):342–7. van Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk ME, Schouten TJ,

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umbilical cord blood units from caesarean deliveries. Gynecol Obstet Invest 2006; 61(1):34–9. 105. Finocchi A, Romiti ML, Di Cesare S, Puliafito P, Pensieroso S, Rana I, Pinto R, Cancrini C, De Rossi G, Caniglia M, Rossi P. Rapid T-cell receptor CD4+ repertoire reconstitution and immune recovery in unrelated umbilical cord blood trans­ planted pediatric leukemia patients. J Pediatr Hematol Oncol 2006;28(7): 403–11.

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M.C. Allwood and P.A. Ball

34

Vitamins, intravenous solutions, and drugs and formulations used in nutrition

VITAMINS IN GENERAL

(SED-

15, 3686)

Pregnancy Oxidative stress may play a part in pre-eclampsia, and there is some evidence to suggest that supplements of vitamins C and E could reduce the risk. However, this remains unproven. The potential benefit of these antioxidants in 2410 women with a range of clinical risk factors has been evaluated in a large multicenter randomized, placebo-controlled trial (1C). The women took vitamin C 1000 mg/day +vitamin E (RRR alpha tocopherol) 400 IU/ day (n ¼ 1199) or matched placebo (n ¼ 1205) from the second trimester until delivery. The primary end-point was preeclampsia. Secondary end-points were low birth weight (under 2.5 kg) and small size for gestational age (below the fifth customized birth weight centile). The incidence of preeclampsia was similar in the two placebo (15% versus 16%; RR ¼ 0.97; 95% CI ¼ 0.80, 1.17). More low birth weight babies were born to women who took antioxidants than to controls (28% versus 24%; RR ¼ 1.15; CI ¼ 1.02, 1.30), but small size for gestational age did not differ Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03134-1 r 2009 Elsevier B.V. All rights reserved.

between the groups (21% versus 19%; RR ¼ 1.12; CI ¼ 0.96, 1.31). The authors therefore concluded that concomitant supplementation with vitamins C and E does not prevent pre-eclampsia in women at risk, but does increase the rate of babies born with a low birth weight. They therefore recommended that the use of these highdose antioxidants is not justified in pregnancy. Susceptibility factors Liver disease Water-soluble and fat-soluble vitamin formulations for addition to total parenteral nutrition solutions have historically been formulated separately. By the addition of glycocholic acid, a vitamin formulation (Cernevitt, Baxter, Heidelberg, Germany) has been developed that combines all the necessary vitamins in one vial. However, there is little information about the possible consequences of the administration of bile acids such as glycocholic acid, especially if there is pre-existing liver disease. The effects of total parenteral nutrition with a vitamin formulation containing high doses of glycocholic acid in patients with and without liver disease have been studied in a prospective, randomized, controlled trial in 74 patients, of whom 36 had hepatobiliary disease (2c). They received total parenteral nutrition for an average of 16 days, with either Cernevit or separate

547

548 vitamin supplements. Serum glycocholic acid concentrations increased in the patients with liver disease treated with Cernevit, whereas total bile acids did not significantly change. Other liver function tests remained stable. There were no adverse events during Cernevit administration, except for a slight reversible increase in transaminases in one patient. The authors concluded that Cernevit was well tolerated after repeated dosing, even in patients with severe liver disease. They therefore recommended that, apart from standard controls of liver biochemistry, no specific surveillance is necessary during treatment with Cernevit. However, it should be noted that this was only a short-term study.

VITAMIN A (CAROTENOIDS) (SED-15, 3642; SEDA-28, 386)

Drug overdose Numerous vitamin supplements are available over the counter. Some are available as candy-like chewable formulations to encourage consumption by children. Three cases of overdose of such formulations have been reported (3A). Each child had taken an estimated 200 000– 300 000 IU of vitamin A. Their circulating vitamin A (retinol and retinyl palmitate) concentrations were monitored over 6 months. There were no clinical or biochemical complications. However, there were marked increases in both retinol and retinyl palmitate concentrations above the age-related reference ranges. In particular, it took 1–3 weeks for the serum retinol concentrations to peak and many months for them to normalize. The authors recommended that parents should be warned about the dangers of excessive vitamin A consumption. Clinicians should be aware of the late peak in serum retinol concentrations, which can lead to late complications of vitamin A overdose. There is a case for taking the chewable formulations off the market.

Chapter 34

M.C. Allwood and P.A. Ball

VITAMINS OF THE B GROUP Nicotinamide Gastrointestinal Nicotinamide has been recommended for the control of hyperphosphatemia in patients on dialysis; diarrhea occurred in a small proportion (7.8%) of patients in this study (4C). The preliminary observations from a prospective, open trial to test this proposal, using high doses of nicotinamide, have been reported (5A). Five of six patients on hemodialysis developed diarrhea after receiving nicotinamide in a mean dosage of 1050 mg/bag. The diarrhea stopped when the nicotinamide was withdrawn or the dose reduced (from a mean of 85 to 54 mg/l). The authors speculated that the higher incidence of diarrhea they observed may have been linked to the simultaneous use of calcium carbonate and/or a phosphate binder, the latter being excluded from the original study.

VITAMIN C (ASCORBIC ACID) (SED-15, 351; SEDA-30, 394) Urinary tract One risk associated with large doses of ascorbic acid is the formation and deposition of calcium oxalate crystals in the kidneys, as reported in a case of extreme oral vitamin C dosage (6A).  A 49-year-old woman, who had taken vitamin C

at least 4 g/day for several months, developed acute oliguric renal failure and a creatinine of 400 mmol/l (4.5 mg/dl). She had a history of migraine, for which she had been taking large doses of ibuprofen (up to 2000 mg/day). She also reported nausea and vomiting over the previous 24 hours. She had orthostatic hypotension and dry mucous membranes. There was marked proteinuria. Renal biopsy showed widespread tubular degenerative changes and interstitial edema, typical of acute tubular necrosis, with prominent tubular calcium oxalate deposition. The glomeruli were unremarkable. She became anuric, received four hemodialysis treatments, and began to recover renal function. Nine months later, her creatinine concentration was 97 mmol/l (1.1 mg/dl).

Vitamins, intravenous solutions, and drugs and formulations used in nutrition

The authors conclude that acute tubular necrosis observed in this patient was most likely related to dehydration and renal hypoperfusion in the setting of nausea, vomiting, and the use of high doses of non-steroidal anti-inflammatory drugs. Calcium oxalate deposition was presumably related to the very high vitamin C intake, since oxalate results from its metabolism.

VITAMIN D ANALOGUES (SED-15, 3669; SEDA-28, 388; SEDA-29, 354; SEDA-30, 394)

Pregnancy See Vitamins in general above. Mineral balance Absorption of calcium carbonate in the fasting state has been reported to be significantly compromised in subjects with achlorhydria. Although calcium carbonate malabsorption in the fasting state cannot be predicted, it might be corrected if the compound were administered with meals. However, administering calcium carbonate with meals is logistically challenging in long-term care facilities. A woman who was switched to calcium citrate subsequently had severe symptomatic hypercalcemia (7A).

Chapter 34

549

 A 7-year-old boy developed classic symptoms

of vitamin D intoxication after taking oral vitamin D (colecalciferol) 300 000 units/day for 15 days to treat suspected vitamin deficiency. There was turgor of the skin and dryness of the oral mucosa, consistent with moderate dehydration. Intravenous rehydration was begun and dietary calcium and vitamin D were restricted. The serum calcium concentration on day 2 was 4.7 mmol/l. The urinary calcium/creatinine ratio was initially high. Alendronate sodium 5 mg/day was given by mouth. The serum calcium fell slightly to 3.6 mmol/l on day 3, and the dose was increased to 10 mg/day. By day 16, the serum calcium had fallen to 2.6 mmol/l and treatment was withdrawn. The urinary calcium/creatinine ratio fell gradually to normal over 2 months.

This case suggests that oral bisphosphonates can be used to treat the effects of vitamin D intoxication. It also provides some pointers to dose and duration of treatment. The authors recommended that patients treated with a bisphosphonate in this way should be followed-up closely for several years.

VITAMIN E (SED-15, 3677; SEDA-29, 355; SEDA-30, 395)

Pregnancy See Vitamins in general above.

 An 89-year-old woman, resident in the Wis-

consin Veterans Home, a skilled nursing facility, was taking long-term ergocalciferol (vitamin D2) 50 000 IU/day and calcium carbonate supplements in the morning, and rarely ate breakfast. She was switched from calcium carbonate 2000 mg/day to calcium citrate 1230 mg/day, after which she developed severe symptomatic hypercalcemia (4.2 mmol/l).

The authors concluded that the primary cause of hypercalcemia in this case was the administration of an inappropriately high dose of vitamin D, manifested when calcium carbonate was replaced with calcium citrate. The management of hypercalcemia in children as a result of vitamin D intoxication is usually with intravenous bisphosphonates, such as pamidronate. Oral alendronate can also be used (8A).

PARENTERAL NUTRITION (SED-15, 2700; SEDA-28, 383; SEDA-29, 353)

Nervous system There has been yet another report of Wernicke’s encephalopathy associated with thiamine deficiency in a patient receiving parenteral nutrition, due to failure to include multivitamins in the regimen (9A).  A 30-year-old woman developed peritonitis

and a digestive tract fistula after elective surgery for a benign gastric tumor. She was given parenteral nutrition and antimicrobial drugs. After 30 days, she reported fatigue. Hyponatremia and hypophosphatemia were

550 corrected, but she became stuporose and was intubated and ventilated. Micronutrients (multivitamins and trace elements) were added. After 3 days, her neurological status improved, allowing extubation, but she had horizontal nystagmus and a lateral ophthalmoplegia. An MRI scan showed no sign of central pontine myelolysis but hyperintense lesions in the medial thalami. Thiamine was increased to 200 mg/day and the oculomotor signs and MRI scans regressed. However, a severe cognitive deficit with vertigo and loss of sphincter control persisted for at least 2 years. She remained totally dependent and disorientated with memory disturbances.

While the authors emphasized the difficulties in diagnosing Wernicke’s encephalopathy, this case clearly illustrates yet again the dangers of omitting micronutrients from parenteral nutrition. It also shows that the commonest manifestation of vitamin deficiency in parenteral nutrition when micronutrients have been excluded is likely to be thiamine deficiency, as has been previously reported. It has also provided some indication of the approximate time before such symptoms become evident. Susceptibility factors Blood glucose The effects of total parenteral nutrition-associated hyperglycemia on clinical outcomes in premature septic infants in the neonatal intensive care unit have been investigated (10c). The charts of all premature infants weighing less than 1500 g with sepsis, ventilator dependence, and feeding intolerance were studied; there were 37 of them. The average caloric intake at the time of blood culture-proven sepsis was 83 kcal/kg/day. The maximum

Chapter 34

M.C. Allwood and P.A. Ball

serum glucose concentration correlated positively with the duration of total parenteral nutrition, length of dependence on mechanical ventilation, and hospital length of stay. The average maximum serum glucose concentration was significantly higher in the nonsurviving infants (13.4 mmol/l versus 7.8 mmol/l). The tentative conclusion is that avoidance of excessive nutrient delivery and tight glycemic control during periods of acute metabolic stress may improve outcome in these patients.

Fat emulsions Liver Cholestasis is one of the most serious complications of parenteral nutrition in infants. Recently introduced fat emulsions containing fish oils, in particular omega-3 fatty acids, may be beneficial in reducing the incidence of liver-associated complications. Two infants with intestinal failure and parenteral nutrition-associated liver disease were given an intravenous fat emulsion containing primarily omega-3 fatty acids instead of the conventional emulsion (11A). Biochemical tests of liver function improved significantly. One child was removed from the liver transplantation list because of improved hepatic function, and the second child had complete resolution of cholestasis while solely on parenteral nutrition. This suggests that fat emulsions made from fish oils may be effective in treating and preventing this often fatal condition. A randomized, controlled trial is necessary.

References 1. Poston L, Briley A, Seed P, Kelly F, Shennan A. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006;367:1145–54. 2. Rifai K, Ockenga J, Manns MP, Bischoff SC. Repeated administration of a vitamin preparation containing glycocholic acid in patients with hepatobiliary disease. Aliment Pharmacol Ther 2006;23:1337–45.

3. Lam HS, Chung MC, Wing TP, Chi KL, Chan KCA, Wai LY, Hui J, Chan AYW, Pak CN. Risk of vitamin A toxicity from candy-like chewable vitamin supplements for children. Pediatrics 2006;118:820–4. 4. Takahashi Y, Nakamura T, Fukuwatari T, Shibata K, Shimada N, Ebihara I, Koide H. Nicotinamide suppresses hyperphosphatemia in hemodialysis patients. Kidney Int 2004;65: 1099–104.

Vitamins, intravenous solutions, and drugs and formulations used in nutrition 5. Delanaye P, Weekers L, Krzesinski JM. Diarrhea induced by high doses of nicotinamide in dialysis patients. Kidney Int 2006; 69:1914. 6. Nasr SH, Kashtanova Y, Levchuk V, Markowitz GS. Secondary oxalosis due to excess vitamin C intake. Kidney Int 2006;70: 1672. 7. Drinka PJ, Moore J, Boushon MC. Severe hypercalcemia after transition from calcium carbonate to calcium citrate in an elderly woman treated with ergocalciferol 50,000 IU per day. Am J Geriatr Pharmacother 2006;4: 70–4. 8. Orbak Z, Doneray H, Keskin F, Turgut A, Alp H, Karakelleoglu C. Vitamin D intoxication and therapy with alendronate (case report and review of literature). Eur J Pediatr 2006;165:583–4.

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9. Attard O, Dietemann JL, Diemunsch P, Pottecher T, Meyer A, Calon BL. Wernicke encephalopathy: a complication of parenteral nutrition diagnosed by magnetic resonance imaging. Anesthesiology 2006;105: 847–8. 10. Alaedeen DI, Walsh MC, Chwals WJ. Total parenteral nutrition-associated hyperglycemia correlates with prolonged mechanical ventilation and hospital stay in septic infants. J Pediatr Surg 2006;41:239–44. 11. Gura KM, Duggan CP, Collier SB, Jennings RW, Folkman J, Bistrian BR, Puder M. Reversal of parenteral nutritionassociated liver disease in two infants with short bowel syndrome using parenteral fish oil: implications for future management. Pediatrics 2006;118:e197–201.

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35

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

Editor’s note: The clotting factors, such as factor VIII, and anticoagulant proteins, such as activated factor C, are included in Chapter 33.

COUMARIN ANTICOAGULANTS

(SED-15, 983; SEDA-28, 391; SEDA-29, 358; SEDA30, 399)

Hematologic The relative risk of hemorrhage has been evaluated in a sample of 1.7 million health plan members who took warfarin together with a drug known to interact with it or who had liver disease or heart failure (1C). Of 17895 patients, 2634 (15%) had a hemorrhagic event within 1 week after filling a prescription for warfarin. The factors associated with an increased risk of hemorrhage included female sex (OR ¼ 1.15; 95% CI ¼ 1.05, 1.25), liver disease (OR ¼ 1.76; 95% CI ¼ 1.36, 2.29), and heart failure (OR ¼ 1.56; 95% CI ¼ 1.37, 1.77). Compared with warfarin Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03135-3 r 2009 Elsevier B.V. All rights reserved.

alone, cephalosporins (OR ¼ 1.16; 95% CI ¼ 1.04, 1.29) and metronidazole (OR ¼ 1.58; 95% CI ¼ 1.32, 1.89) were associated with increased risks of hemorrhage, but the risk of hemorrhage was not greater for concomitant use of warfarin with amiodarone, fibric acid derivatives, or non-steroidal anti­ inflammatory drugs (NSAIDs) including cyclo-oxygenase COX-2 inhibitors. There was no relation between estimated average daily warfarin dose and the prevalence of hemorrhage. Other variables associated with an increased risk of hemorrhage were increased patient age, female sex, 120 days or more of warfarin therapy during the year, two or more unique prescriber numbers, and the medical specialty of the first prescriber of warfarin. Many patients taking oral anticoagulants are exposed to a risk of hemorrhage after traumatic brain injury, and the effects of age and anticoagulation need to be assessed separately. In a retrospective analysis of consecutive series of patients aged 18 years and over, 1493 adults with blunt head trauma were analyzed; 159 were taking warfarin at the time of the trauma (2c). The mortality in the anticoagulated patients was significantly higher than in the controls (38/159, 24% versus 66/1334, 4.9%; OR ¼ 4.8). Mortality in patients over 70 years of age was signifi­ cantly higher than in the younger patients. Both mortality and the occurrence of intra­ cranial hemorrhage after head trauma were significantly increased at higher values of

553

554 international normalized ratio (INR), espe­ cially with INRs over 4.0 (mortality 50%, risk of intracranial hemorrhage 75%). Preinjury warfarin anticoagulation and age predicted survival. Addition of the Injury Severity Score and the initial Glasgow Coma Score to this model only modestly improved its predictive performance (95% correct prediction). Hematuria and abdominal pain are the most common complaints in coumadin­ induced renal and retroperitoneal hemor­ rhage, as has been described in three patients with retroperitoneal hemorrhage; one had hemorrhage in the renal pelvis and the jejunum, one had hemorrhage in the renal pelvis and the perirenal area, and one had hemorrhage in the perirenal area and retroperitoneally (3A). Another patient taking warfarin developed a massive retro­ peritoneal hematoma when she fractured her superior pubic ramus after a trivial fall at home and died (4A). Of the 367 patients undergoing trabecu­ lectomy for glaucoma, five patients taking warfarin had hemorrhagic complications and trabeculectomy failure (5c). In contrast, 55 who were taking aspirin did not have significant intraoperative or postoperative hemorrhage. Aspirin was associated with a significantly higher risk of hyphema, but this did not significantly affect control of intraocular pressure at 2 years. Skin Warfarin can cause skin necrosis clinically indistinguishable from that caused by purpura fulminans associated with dis­ seminated intravascular coagulation and heparin-induced thrombocytopenia (6A). Warfarin-induced skin necrosis predomi­ nantly affects obese women. Although it typically occurs within the first 10 days of warfarin therapy, some patients develop it after exposure for several years.  A 72-year-old woman with significant risk

factors for warfarin-induced skin necrosis, disseminated intravascular coagulation, and heparin-induced thrombocytopenia developed painful purpuric patches beginning on her feet and extending proximally before becoming hemorrhagic bullae (7A).  A 43-year-old Caucasian woman with recur­ rent thromboembolic disorders, protein S deficiency, and multiple exposures to warfarin developed worsening dermatitis over 15 hours

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J. Harenberg

(8A). She had multiple diffuse “lace-like” erythematous eruptions with superimposed lesions that were tender, ulcerated, and crusted. Histopathology was consistent with warfarin-induced skin necrosis.  A 44-year-old man with protein C deficiency developed skin necrosis twice within a short time as a result of delayed diagnosis (9A).

Early recognition of warfarin-induced skin necrosis has important implications. Since the treatment is generally supportive, prompt and prudent evaluation of suspi­ cious skin lesions is necessary to prevent serious sequelae. Susceptibility factors Genetic Further anecdotal data have shown that reduced CYP2C9 activity is associated with the presence of the rare CYP2C9�11 allele (10A).  An 18-year-old man, who was highly sensitive

to acenocoumarol, was genotyped for function­ ally defective alleles in the CYP2C9 and VKORC1 genes, as were members of his family. The proband had the CYP2C9�3 allele, a CYP2C9�11 allele, and the VKORC1 AA diplotype, which were all traced back through the parental lines. Thus, acenocoumarol sensi­ tivity in this subject resulted from inheritance of multiple functionally defective alleles in both the CYP2C9 and VKORC1 genes.

Age The association of older age with the risk of hemorrhage in patients with atrial fibrillation, whether or not they are taking warfarin, has been assessed in 13509 adults with non-valvular atrial fibrillation (11c). There were 170 major hemorrhages during 15300 person-years of warfarin therapy and 162 major hemorrhages during 15530 personyears without warfarin therapy. Rates of hemorrhage rose with older age, with an average increase of 1.2 (95% CI ¼ 1.0, 1.4) per older age category in patients taking warfarin and 1.5 (95% CI ¼ 1.3, 1.8) in those not taking warfarin. Rates of intracranial hemorrhage were significantly higher in those aged 80 and older (adjusted rate ratio ¼ 52; 95% CI ¼ 51, 53 for those taking warfarin; adjusted rate ratio ¼ 55; 95% CI ¼ 52, 59 for those not taking warfarin). Thus, older age increases the risk of major hemorrhage, particularly intracranial hemorrhage, in

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

patients with atrial fibrillation, whether or not they are taking warfarin. Antiphospholipid antibodies (lupus inhibitor) The presence of antiphospho­ lipid antibodies has been reported to increase the risk of hemorrhage in a patient taking warfarin (12A).  A 71-year-old man taking warfarin had a

massive spontaneous soft tissue bleed. He continued to bleed despite reversal of the effects of warfarin with large doses of intrave­ nous vitamin K and fresh frozen plasma and later died. The prothrombin time and acti­ vated partial thromboplastin time failed to correct with 50% normal plasma. He had a lupus inhibitor, with low concentrations of factors II, V, VII, and XI. The concentrations of factors II, V, and XI normalized when his plasma was diluted 1:16 in buffer, suggesting that the inhibitor may have been interfering with the assays of these factors, causing artefactually low results. However, the con­ centration of factor VII remained consistently low at all dilutions.

This case highlights the fact that patients with lupus inhibitors can develop severe hemorrhagic complications and illustrates the complexities involved in the investiga­ tion and treatment of abnormal bleeding in these patients. Thyroid disease Alterations in thyroid hormone concentrations by treatment with antithyroid drugs, such as thiamazole (methi­ mazole, the active metabolite of carbima­ zole), can alter sensitivity to warfarin, and frequent monitoring of both thyroid function and INR are required (13A).  A 54-year-old man with hyperthyroidism was

given methimazole 30 mg/day, metoprolol, enoxaparin, and warfarin 5 mg/day. Doses of warfarin and methimazole after discharge were adjusted over the next several months; methi­ mazole altered thyroid function and the inten­ sity of anticoagulation as measured by INR.

Drug–drug interactions Chamomile In a patient taking warfarin the INR increased after the use of chamomile tea (14A).  A 70-year-old woman, who was taking war­

farin, amiodarone, digoxin, levothyroxine, alendronate, metoprolol, and calcium plus

Chapter 35

555

vitamin D, developed pedal edema, which she treated at first with a chamomile-based skin lotion and then 4–5 cups per day of chamomile tea, prepared by adding water to a teaspoon of dried chamomile leaves. Five days later she was feeling weaker, was breathless on exer­ tion, and had bilateral pedal edema and ecchymoses in her perineal area, across her lower abdomen, and over her left hip. The INR was 7.9 and she had a retroperitoneal hematoma.

Although amiodarone potentiates the action of warfarin, this patient had taken both medications for 3 years without hemorrhage. The authors suggested that chamomile may have interacted with war­ farin by a pharmacodynamic effect, because of its coumarin content; they thought that a pharmacokinetic interaction was unlikely, since chamomile inhibits CYP1A2 and not CYP2C9. Clarithromycin Some macrolide antibio­ tics inhibit the metabolism of warfarin and this has again been reported with clarithro­ mycin (15A). Cranberry juice An interaction of cran­ berry juice with warfarin has been reported anecdotally, although a definite link could not be established. A man taking stable doses of warfarin developed major bleeding and a high INR soon after starting to take daily cranberry juice (16A). No other identifiable reasons for the high INR were apparent. He resumed his usual dose of warfarin after stopping the juice. Fluoroquinolones In 92 patients taking stable dosages of warfarin, levofloxacin increased the INR to above 4.0 in one of 54 patients and gatifloxacin increased it in eight of 38, of whom four needed vitamin K (17c). The authors concluded that close monitoring of warfarin therapy is warranted in those who are also taking gatifloxacin. Leflunomide Leflunomide has been reported to increase the INR in patients taking warfarin, a 61-year-old woman (18A) and a 49-year-old man (19A). The proposed mechanism for this interaction is inhibition of CYP2C9 by an active metabolite of leflunomide.

Chapter 35

556  A 61-year-old Caucasian woman taking long-

term warfarin started to take leflunomide. Her INR had been stable for 4 months before this but rose soon after. She required an overall reduction of 22% in her weekly dose of warfarin to maintain the INR within the target range of 2.0–3.0.

Prednisone Prednisone 10 mg/day for 3 months increased the INR in a 66-year-old white man taking warfarin 14 mg/week and thalidomide 300 mg/day (20A). His dietary intake of vitamin K was increased. Every time the INR was below the target range, the patient was not taking prednisone and every time it was above the target range he was taking prednisone. Tolterodine Modified-release tolterodine 4 mg/day increased the INR in a 53-year­ old woman taking warfarin (21A). How­ ever, in 20 healthy men oral tolterodine ltartrate 2 mg bd for 7 days had no effects on the pharmacokinetics or pharmacody­ namics of a single oral dose of warfarin 25 mg in a placebo-controlled study (22C). This suggests that if this is a true interac­ tion, it must be limited to a subgroup of individuals with a particular susceptibility. Management of adverse drug reactions In 65 patients with intracerebral hemorrhage secondary to warfarin, the median time from admission to administration of fresh frozen plasma was about 3 (1.5–4.5) hours, and from admission to fresh frozen plasma completion was 9.25 (5–12) hours (23c). The mean number of units of fresh frozen plasma administered was about five, and the average dose of vitamin K was 5.8 mg. Seven patients developed mild pulmonary complications and three developed moder­ ate-to-severe pulmonary edema. Many patients take warfarin for cardiac disease, which may not allow rapid infusion of fresh frozen plasma. The increase in colloid volume can cause circulatory overload and lead to pulmonary edema. Most of the patients who had pulmonary complications had atrial fibrillation, mechanical heart valves, or cardiomyopathy. A spinal epidural hematoma in an 8-year­ old boy taking an oral anticoagulant was

J. Harenberg

managed while maintaining therapeutic anticoagulation (24A).

(SED-15, 1590; SEDA-28, 391; SEDA-29, 361; SEDA-30, 404)

HEPARINS

Cardiovascular Heparin releases lipoprotein lipase from the capillary endothelial cell surface, resulting in increased plasma concentrations of free fatty acids, which can cause cardiac dysrhythmias. In 10 patients undergoing hemodialysis who had supraventricular and/or ventricular extra beats the frequency of dysrhythmias was significantly lower with the use of low­ molecular-weight heparin (LMWH) than with unfractionated heparin (UFH); LMWH was also associated with lower lipoprotein lipase activity and free fatty acid concentrations (25c). Hematologic Hemorrhage Enoxaparin is not associated with more major hemorrhagic complications in unselected medical patients than in controlled trials. In a prospective observational study of 549 consecutive patients who received enoxaparin 1 mg/kg bd for at least 24 hours (mean duration of therapy 3.8 days), there was hemorrhage in 94 (17%). There were major hemorrhages in 14 (2.6%), injection-site hemorrhages in 55 (10%), and minor (non-injection site) hemorrhages in 25 (4.7%) (26c). Two deaths were attributed to hemorrhage. Patients with major hemorrhages were older than patients with minor or no hemorrhage (76 versus 67 years). Major hemorrhages occurred in patients who received enoxaparin for a longer period (mean 5.1 days) than those with minor hemorrhages (4.0 days) or none (2.9 days). Major hemorrhages were significantly associated with impaired renal function, chronic liver disease, and concomitant treatment with warfarin or a proton pump inhibitor. Symptomatic hemorrhagic transforma­ tion is common in supratentorial and cerebellar infarction, but is rare in

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

brainstem infarction and is seldom reported in basilar artery occlusion. Although early arterial recanalization by thrombolytic agents has been widely used after cerebral infarction, some neurologists still prefer to use an anticoagulant in patients with basilar artery occlusion, especially in longerexisting ischemic deficits. However, massive pontine hemorrhage has been associated with enoxaparin in a patient with basilar artery occlusion (27A). Of 52 randomized controlled trials of prophylaxis of deep vein thrombosis, 33 quantified the bleeding complications in 33813 patients undergoing general surgery (28M). Of the minor complications, injec­ tion site bruising (6.9%), wound hematoma (5.7%), drainage site bleeding (2.0%), and hematuria (1.6%) were the most common. Major bleeding complications, such as gastrointestinal tract bleeding (0.2%) or retroperitoneal bleeding (>0.1%), were infrequent. Withdrawal was required in 2.0% of patients and subsequent operation in less than 1%. When analyzed by highdose versus low-dose UFH, the lower dose had a smaller rate of withdrawal and subsequent operation. The OASIS (Organization to Assess Strategies for Ischemic Syndromes)-5 study randomized 20078 patients with non-ST­ segment elevation acute coronary syn­ drome to subcutaneous fondaparinux 2.5 mg/day or enoxaparin 1 mg/kg for up to 8 days (29C). There was more major bleeding with enoxaparin (4.1% versus 2.2%), including fatal bleeding (22 versus 7 events). Endocrine glands are highly vascularized, but non-traumatic hemorrhage is extremely rare.  A 63-year-old woman developed an acute

painful mass in the neck due to a massive thyroid hematoma while she was receiving LMWH for deep vein thrombosis (30A). This was followed by an increase in serumfree thyroxine and free triiodothyronine concentrations and a fall in the concentration of serum thyroid-stimulating hormone (thyro­ tropin). Heparin was withdrawn and no antithyroid therapy was necessary. The serum thyroid hormone concentrations fell into the reference ranges as the hematoma shrank.

Chapter 35

557

Thrombocytopenia The incidence of immune heparin-induced thrombocytopenia (HIT type 2) is about 6.5% in patients receiving UFH after orthopedic surgery and 1% or less in other settings (31R). Its occurrence depends on the definition of HIT, the type of heparin used (bovine UFH > porcine UFH > LMWH), the duration of administration (the risk being highest on days 5–14), the patient’s sex (female >male), and the type of test used to detect heparindependent antibodies. It is due in most cases to an antibody response to the complex heparin/platelet factor 4, with secondary activation of platelets and coagulation, and finally increased thrombin generation. In a retrospective case–control study in 210 patients in a surgical intensive care unit (ICU) who had HIT antibody assays performed, 19 (9%) had positive tests (32c). Compared with 19 matched controls, the HIT antibody-positive patients had an increased risk of death or major thrombotic complications (seven versus two), and a prolonged length of stay in the ICU (20 days versus 10 days). Exposure to heparin via intravascular flushes alone was sufficient to generate HIT antibodies in 12 of 19 patients. Five patients received platelet transfusions after the diagnosis of HIT was made; four of them died. New or recurrent venous thromboembo­ lism can occur in patients who receive heparin if immune-mediated heparininduced thrombocytopenia occurs. There has been a comprehensive, systematic literature search for studies of the use of UFH or LMWH for thromboprophylaxis or treatment in which new or recurrent venous thromboembolism and serologically con­ firmed heparin-induced thrombocytopenia were reported (33M). Ten studies were identified, involving intravenous UFH, sub­ cutaneous UFH, or subcutaneous LMWH. There was venous thromboembolism in 386 of 6219 patients, including 32 who also had heparin-induced thrombocytopenia. There was no difference between intravenous and subcutaneous UFH (13% versus 12%; OR ¼ 1.07; 95% CI ¼ 0.50, 2.3), but a significant difference between UFH and LMWH (13% versus 0.7%; OR ¼ 21; 95% CI ¼ 2.8, 156).

558  A 27-year-old woman at 8 weeks gestation

developed a cerebral venous thrombosis invol­ ving the superior sagittal, rectus, and right transverse sinuses and was given intravenous UFH (34A). One week later, her clinical condition having improved, she was switched to enoxaparin 6000 units bd but soon after had a pulmonary embolism and was given intrave­ nous heparin. Nine days later her platelet count fell from 307 to 111  109/l. Her platelet factor 4-heparin enzyme immunoassay was positive. Heparin was withdrawn and she was given intravenous lepirudin 0.15 mg/kg/hour. Her platelet count recovered within 1 week.  A 43-year-old woman with myasthenia gravis underwent plasma exchange, during which a Gamcath central venous line was locked with heparin 5000 U/ml between procedures; 12 days later she developed type II heparininduced thrombocytopenia complicated by iliofemoral deep venous thrombosis and pul­ monary embolism (35A). Serology for heparin/ PF4 antibodies was positive. The line was removed and she was successfully managed with intravenous lepirudin.

Drotrecogin alpha (activated) has been used in the treatment of heparin-induced thrombocytopenia (36A). Thrombocytosis Thrombocytosis in a patient receiving enoxaparin did not occur with UFH (37A).  A 42-year-old man was given enoxaparin for 8

days and developed thrombocytosis. Enoxa­ parin was switched to UFH and the platelet count normalized within 6 days. Enoxaparin was restarted and the platelet count rose and peaked after 8 days at 920  109/l.

Skin In three patients tense hemorrhagic bullae appeared on uninflamed skin distant from sites of heparin injections on the limbs (38A). Skin necrosis caused by heparin is rare.  A 71-year-old white woman developed painful

diffuse skin lesions, most probably related to enoxaparin (39A). Other causes of skin necro­ sis, including heparin-induced thrombocytope­ nia, disseminated intravascular coagulation, protein C and protein S deficiencies, antipho­ spholipid antibodies, and vitamin K deficiency, were thought to be less likely.

Concomitant thrombophilia in this patient may have aggravated the problem. LMWHs can rarely cause an eczema-like type IV hypersensitivity reaction, as has

Chapter 35

J. Harenberg

been reported in three cases (40A). Fonda­ parinux sodium rarely cross-reacts and can be used instead. Alopecia Alopecia has been reported as an adverse effect of dalteparin and tinza­ parin, due to telogen effluvium. Extensive, patchy, non-scarring alopecia has now been reported in three women who received subcutaneous enoxaparin 1 mg/kg bd for 3 weeks; hair growth returned to normal within 1 month (41A). Musculoskeletal Osteoporosis The mechanism of heparin-induced osteoporosis is not known. It may involve parathyroid hormone-like effects, direct osteoclastic activity, or altered mineralization. In 98 pregnant women requiring throm­ boprophylaxis the incidence of clinically significant bone loss (at least 10%) in the femur was 2–2.5% and there was no difference in the changes in bone mineral density at the femoral neck or total proximal femur in those who were rando­ mized to either UFH or LMWH (42C). Immunologic Hypersensitivity reactions to heparin include heparin-induced immune thrombocytopenia, allergic vasculitis, hypereosinophilia, and immediate and delayed skin reactions (43R). Hypersensitivity to UFH and LMWH and semisynthetic heparinoids is increasingly common, but its pathogenesis is still not fully understood. Problems can arise because of cross-reactions between UFH and LMWH and between various heparins and heparinoids. In some patients with crossreactivity between various heparins and semisynthetic heparinoids, recombinant hir­ udins such as lepirudin may be safe and effective. However, combined allergy to recombinant hirudins and heparins has been reported. Therefore, there is an urgent need for therapeutic alternatives. Pregnancy Heparin can cause placental hemorrhage (44A).  A 30-year-old pregnant woman with an artificial

mitral valve and atrial fibrillation was given subcutaneous UFH 5000 IU/day followed by enoxaparin 60 mg bd and later 70 mg bd; however, she took 80 mg bd. At 19 weeks a fetal

Drugs affecting blood coagulation, fibrinolysis, and hemostasis scan showed a submembranous hematoma and the mother’s hemoglobin concentration was 7.8 g/dl. The dose of enoxaparin was reduced. At 35 weeks premature rupture of membranes led to a caesarean delivery, during which about 1000 ml of ruddy brown fluid gushed from the uterine incision before amniotomy. The pla­ centa showed no signs of abruption.

Susceptibility factors Obesity In a systematic review of publications retrieved from Medline, the Cochrane Database of Systematic Reviews, and LILACS from 1976 to 2006, 124 studies were found, of which 87 were excluded based on predefined criteria (45M). Obesity was associated with a higher risk of venous thromboembolism in medical patients and the risk exceeded that attributable to the surgical procedure alone in patients who underwent bariatric surgery. Only six studies evaluated prophylactic methods (UFH, LMWH, and sequential compression devices) in obese patients. The authors concluded that there have been too few prospective trials to allow a definitive conclusion about the most effective and safe form of thromboprophylaxis in obese patients.

DIRECT THROMBIN INHIBITORS (SED-15, 1142; SEDA29, 362; SEDA-30, 409)

Argatroban Hematologic Impaired coagulation can last longer than expected after argatroban withdrawal in some patients who are taking concomitant warfarin. Patients with liver dysfunction and obesity appear most likely to be affected.  A 32-year-old morbidly obese African–American

woman developed bilateral pulmonary emboli 12 days after undergoing Roux-en-Y gastric bypass surgery (46A). Three days later she developed heparin-induced thrombocytopenia type II. She was given argatroban 1.5 mg/kg/ minute by infusion for about 2.5 days and four doses of warfarin (total 37.5 mg). The argatroban was withdrawn when her INR was 4.36 and activated partial thromboplastin time (aPTT) 86 seconds. The aPTT and INR remained high

Chapter 35

559

for 19 days after the last dose of warfarin and for 20 days after argatroban withdrawal, but there were no bleeding complications.

Bivalirudin Bivalirudin is a 20-amino acid synthetic polypeptide analog of hirudin. Once bound, bivalirudin is cleaved by thrombin, thereby reducing its antithrombotic activity. Bivalir­ udin has a half-life of 25 minutes after intravenous injection and is partially cleared renally; there is no antidote.

Dabigatran Dabigatran etexilate is a prodrug of dabi­ gatran, a specific, competitive, and rever­ sible inhibitor of thrombin. Dabigatran etexilate is rapidly absorbed after oral administration and is converted to dabiga­ tran. Its half-life is about 8 hours after a single dose and 14–17 hours after multiple doses. It is cleared renally. Hematologic Prolongation of the activated partial thromboplastin time (aPTT) and ecarin clotting time (ECT) in 289 patients correlated directly with dabigatran concen­ trations (47C). Prolongation of blood coa­ gulation was most pronounced after surgery. The data suggest that ECT gives a more precise description of the anti­ coagulant effect than aPTT.

Lepirudin

(SEDA-29, 362; SEDA-30,

409) Hematologic The antithrombotic efficacy of lepirudin in patients with heparin-induced thrombocytopenia is compromised by an increased risk of bleeding. In a retrospective observational analysis of 181 patients (median age 67 years), lepirudin (mean dosage 0.06 mg/ kg/hour for a mean of 7.7 days) was associated with thrombotic or major bleeding events in 14% and 20%, respectively (48c). A mean dose of lepirudin greater than 0.07 mg/kg/hour, a long duration of lepirudin treatment, and moderate-to-severe renal impairment were significant positive factors for major bleeding.

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In a randomized, double-blind study of flushing central venous access devices with lepirudin or heparinized saline in 49 adults undergoing bone marrow transplantation, three patients who received heparin alone and five who were treated initially with lepirudin required alteplase instillation for an estimated relative risk with lepirudin versus heparin of 1.6 (95% CI ¼ 0.40, 14) (49c).

with warfarin alone (2.3% per year), aspirin plus ximelagatran (2.0% per year), or ximelagatran alone (1.9% per year). The rate of myocardial infarction with aspirin and warfarin (0.6% per year) was not significantly different from that with xime­ lagatran alone (1.0% per year), warfarin alone (1.0% per year), or aspirin and ximelagatran (1.4% per year).

 A 64-year-old woman with bilateral femoro­

Liver There were increases in serum alanine transaminase activity to over three times the upper limit of the reference range in 6–13% of patients who took ximelagatran (531/6948, mean 7.6%) com­ pared with 0–2% (68/6230, mean 1.1%) of patients who took comparators (53C). There were increases in bilirubin and alanine transaminase (to more than twice and thrice the upper limits of the reference ranges, respectively) in 0.53% (37/6948) of all patients who were exposed to ximela­ gatran for more than 35 days, compared with 0.08% (5/6230) of those who were exposed to comparators. The relative risk of severe liver damage with ximelagatran was 6.6 (95% CI ¼ 2.6, 17) compared with warfarin/placebo. Nine patients who took ximelagatran died; according to the food and drug administration (FDA), liver failure or toxicity due to ximelagatran might have caused or contributed to those deaths. Because 10% of individuals with severe liver damage progress to liver fail­ ure, liver transplantation, or death, the FDA speculated that fatal liver damage could occur in as many as one in 2000 patients taking long-term ximelagatran. Consistent with this estimation, the FDA’s Cardiovascular and Renal drug Advisory Committee (CRAC) noted that three deaths associated with severe liver damage occurred in the ximelagatran long-term exposure pool, i.e., a proportion of one fatal case in 2300 patients. The increase in alanine transaminase typically occurred at 1–6 months after the start of ximelagatran treatment. The mechanism of liver damage due to ximelagatran is not known. In the THRIVE (THRombin Inhibitor in Venous thromboEmbolism) studies of ximelagatran, alanine transaminase activity increased in 6.4–9.6% of patients (54C).

popliteal deep vein thrombosis and pulmonary embolism caused by heparin-induced throm­ bocytopenia type II resistant to danaparoid sodium was given lepirudin, which was not only ineffective but led to a further fall in platelet count (50A).

Management of adverse drug reactions Recombinant factor VIIa appears to be a suitable option as salvage therapy in patients with refractory bleeding secondary to anticoagulation with a direct thrombin inhibitor during cardiac surgery (51A).  A 56-year-old

man with heparin-induced thrombocytopenia and thrombosis received recombinant hirudin (lepirudin) for emer­ gency coronary artery bypass graft surgery and aortic valve replacement. After separation from bypass, he had a coagulopathy due to inability to reverse the effects of lepirudin and slowed elimination of the drug secondary to impaired renal function. As a result, he had excessive generalized oozing unresponsive to traditional therapies and blood transfusions. Recombinant factor VIIa 35 mg/kg slowed the rate of bleeding.

Ximelagatran

(SEDA-29, 363)

Ximelagatran is a prodrug of the active sitedirected thrombin inhibitor melagatran, which is eliminated via the kidneys. Xime­ lagatran has a half-life of 4–5 hours and is given orally twice a day. Hematologic Ischemic events and bleeding were compared in the SPORTIF III and IV randomized trials of anticoagulation with warfarin (INR 2–3) or fixed-dose ximelagatran (52C). Low-dose aspirin (o mg/day) was allowed. Major bleeding occurred significantly more often with aspirin plus warfarin (3.9% per year) than

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

Alanine transaminase activity was signifi­ cantly higher at week 2 for enoxaparin/ warfarin and at months 3 and 6 for ximelagatran. The effect of ximelagatran was dose related. There was a smaller effect on aspartate transaminase activity and that effect was not dose related. In 2004, the FDA’s CRAC reviewed ximelagatran (55S). Three indications were proposed: the prevention of venous thromboembolism in patients undergoing total knee replacement surgery, the pre­ vention of stroke and other thromboem­ bolic complications associated with atrial fibrillation, and the long-term secondary prevention of venous thromboembolism after standard treatment of an acute episode. The database consisted of 30698 subjects and included five phase III pivotal studies. During the advisory panel debate, there were widely divergent analyses of the benefits and risks of ximelagatran. However, hepatotoxicity was a key feature that led CRAC to conclude that the benefit to harm balance of ximelagatran was unfavorable for the three proposed indications. Drug–drug interactions Erythromycin A pharmacokinetic interaction between erythromycin and ximelagatran has been demonstrated in 16 healthy volunteers, mean age 24 years, who took a single dose of ximelagatran 36 mg on day 1, erythromycin 500 mg tds on days 2–5, and a single dose of ximelagatran 36 mg plus erythromycin 500 mg on day 6 (56c). The AUC and Cmax of melagatran were increased by erythromycin. However, the melagatran plasma concentration–effect relation for activated partial thromboplastin time was not affected. The proposed mechanism was inhibition of P glycoprotein, resulting in reduced melagatran biliary excretion. Food–drug interactions Food had no effects on the pharmacokinetics and phar­ macodynamics of melagatran after oral ximelagatran 48 mg in 24 young healthy Japanese men (57c).

Chapter 35

561

DIRECT FACTOR IXa INHIBITORS Both parenteral and oral inhibitors of factor IXa are being developed (58R). The most advanced is an RNA aptamer that binds factor IXa with high affinity and produces rapid anticoagulation. A unique aspect of this compound is its potential for rapid neutralization by a complementary oligo­ nucleotide. This drug–antidote pair is being developed for use in cardiopulmonary bypass surgery and for other indications for which rapid reversal of anticoagulation may be beneficial. An orally active direct factor IXa inhibitor (TTP889) has also been developed.

DIRECT FACTOR Xa INHIBITORS (SEDA-30, 411) Direct inhibitors of factor Xa bind to factor Xa with 1:1 stoichiometry and block the interaction of factor Xa with its substrates. Direct factor Xa inhibitors are reversible and not only inhibit free factor Xa but also inactivate factor Xa bound to platelets within the prothrombinase complex.

Apixaban Apixaban is a follow-up compound with high oral systemic availability (50–85%) and a half-life of about 12 hours. Apixaban is cleared through renal (25%) and fecal routes and is given twice daily. It is being tested in the prevention and treatment of venous thromboembolism, for the prevention of stroke or systemic embolism in patients with atrial fibrillation, and for the management of acute coronary syndrome (59c).

Otamixaban Otamixaban is a non-competitive inhibitor of factor Xa that is given parenterally and has a half-life of 2–3 hours.

Chapter 35

562 Hematologic In a double-blind, doubledummy, parallel-group, dose-ranging study, 947 patients were randomly assigned either to one of five weightadjusted otamixaban regimens or to weight-adjusted UFH before percutaneous coronary intervention (60C). Otamixaban (or placebo) was given as an intravenous bolus of 0.025–0.14 mg/kg followed by a 3­ hour infusion at a rate of 0.035–0.2 mg/kg/ hour. There was significant bleeding (major or minor) in 2.0%, 1.9%, 3.8%, 3.9%, and 2.6% of patients who received the increasing doses of otamixaban, and in 3.8% of patients who received UFH. There were four major bleeds. There was a significant dose–effect relation across the otamixaban dosage groups for the composite end point of major, minor, or minimal bleeding up to day 3 of hospital discharge (range 25–55%). There were significantly fewer cases of major, minor, or minimal bleeding with otamixaban dose 1 than UFH (25% versus 37%), but significantly more episodes of bleeding in the otamixaban dose 4 and 5 groups (50% and 55%, respectively). Almost all bleed­ ing events were minimal. The overall incidence of significant bleeding (major or minor) was 3.0% (2.8% with otamix­ aban pooled, 3.8% with UFH), with no dose effect in the otamixaban groups and no significant difference between any otamixaban group and UFH. There were only four major bleeding events (one with otamixaban dose 4, one with otamixaban dose 5, and two with UFH). Drug–drug interactions There was no interaction of otamixaban 0.3 and 0.5 mg/ kg with aspirin 300 mg/day in a doubleblind, placebo-controlled, three-way, cross­ over study in 68 healthy men (61c).

Razaxaban Razaxaban, a selective oral direct factor Xa inhibitor, was discontinued by the manufacturer after the three higher doses in a dose-ranging study in venous throm­ boembolism caused an increased risk of bleeding.

J. Harenberg

Rivaroxaban Rivaroxaban has high systemic availability (60–80%), is excreted by both renal (65%) and fecal routes, and is given once or twice daily. Maximum plasma drug concentrations occur 2–3 hours after oral administration, and the half-life is 6–9 hours. Comparative studies In a double-blind, double-dummy, randomized, active-com­ parator, dose-ranging comparison of oncedaily rivaroxaban and subcutaneous enoxaparin in 873 patients undergoing elective total hip replacement, there was major postoperative bleeding in 2.3%, 0.7%, 4.3%, 4.9%, 5.1%, and 1.9% of patients who received rivaroxaban 5, 10, 20, 30, and 40 mg, and enoxaparin 40 mg, respectively (62C,63C). One patient who took rivaroxaban 30 mg/day had a two-fold raised bilirubin concentration and three-fold raised alanine transaminase activity after his first dose. Bilirubin returned to within the reference range by the next day and alanine transaminase fell despite continued adminis­ tration. One patient taking rivaroxaban 10 mg/day had normal transaminase activities at baseline but raised activities 3 days after surgery; the transaminases continued to rise during follow-up and ultrasonography 99 days after the surgery showed cholelithiasis. Hematologic Rivaroxaban and enoxa­ parin have been compared in patients undergoing elective total hip replacement in a double-blind, double-dummy, doseranging study in 706 patients, who were randomized to oral rivaroxaban (2.5, 5, 10, 20, or 30 mg bd), starting 6–8 hours after surgery, or subcutaneous enoxaparin 40 mg/ day, starting on the evening before surgery (64C). The primary safety end point was major postoperative bleeding, and there was a significant increase in the frequency of events with increasing doses of rivarox­ aban, but no significant differences between individual doses of rivaroxaban and enoxaparin. Drug–drug interactions Aspirin In a randomized, two-way, crossover study in

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

14 healthy men, aspirin did not affect the pharmacokinetics of rivaroxaban (65c). Co-magaldrox In 12 healthy men co­ magaldrox had no significant effect on the Cmax and AUC of rivaroxaban (66c). Naproxen NSAIDs are often used in the patients who are likely to receive rivarox­ aban. There were no clinically relevant interactions in 11 healthy young men who took naproxen 500 mg on 2 consecutive days, a single dose of rivaroxaban 15 mg (67c). However, in one subject there was an increased bleeding time 3–4 hours after co­ administration of rivaroxaban and naproxen, suggesting that some individuals may be susceptible to an interaction. Ranitidine In 12 healthy men ranitidine had no significant effect on the Cmax and AUC of rivaroxaban (65c). Food–drug interactions In 10 healthy men food reduced the speed but increased the extent of absorption of rivaroxaban (65c).

INDIRECT FACTOR Xa INHIBITORS (SEDA-27, 359; SEDA28, 392; SEDA-29, 362; SEDA-30, 412)

Fondaparinux

(SED-15, 1437; SEDA29, 362; SEDA-30, 412)

Comparative studies In the OASIS-6 study 12 092 patients with ST-segment elevation myocardial infarction were randomized to subcutaneous fondaparinux 2.5 mg/day for up to 8 days or standard care with either placebo intravenous UFH for 48 hours (68C). The rate of bleeding was not increased by fondaparinux compared with controls (1.8% versus 2.1%). There was no difference in the numbers of total strokes (0.9% versus 1.1%) or hemorrhagic strokes (11 versus 10 events). Among patients who underwent primary percutaneous coronary intervention, there was an excess of

Chapter 35

563

catheter thrombosis in patients treated with fondaparinux and there was a non­ significant excess of ischemic outcomes and bleeding. There were no episodes of catheter thrombosis in patients who received UFH. Hematologic Fondaparinux shares many of the advantages of danaparoid, without the potential disadvantage of cross-reactivity in vitro with antibodies that are found in patients with heparin-induced thrombocytopenia (69R). Three patients were successfully treated for thromboembolic events with fondaparinux after developing heparininduced thrombocytopenia during therapy with UFH or LMWH (70R).  A 39-year-old pregnant woman with protein S

deficiency and previous severe skin reactions to heparin was initially treated with subcuta­ neous danaparoid sodium (71A) However, she soon developed severe skin reactions at injection sites. Danaparoid was withdrawn and she was given subcutaneous fondaparinux 2.5 mg/day uneventfully for 150 days until delivery. No adverse effects were observed in the neonate.

In two case series of patients with heparin-induced thrombocytopenia, fonda­ parinux did not alter platelet counts (69R). Finally, a retrospective review has shown that fondaparinux prevented thromboem­ bolic events or recurrent thrombocytopenia in patients with prior heparin-induced thrombocytopenia (69R). Questions remain regarding efficacy, safety, optimal doses, treatment duration, and incidence of throm­ boembolic events when fondaparinux is used in this setting. Prospective trials of the efficacy and safety of fondaparinux in this population need to be conducted.

Idraparinux Idraparinux is a synthetic analog of the unique pentasaccharide sequence that med­ iates the interaction of heparin with antith­ rombin (72R). It has a half-life of 130 hours and can be given once weekly subcuta­ neously. Idraparinux caused excessive bleeding in long-term treatment and is no longer

Chapter 35

564 being developed. A newer, biotinylated version of idraparinux (SSR12517E), which can be reversed by avidin infusion, is currently being evaluated.

J. Harenberg

DRUGS THAT ALTER PLATELET FUNCTION

[SEDA25, 412; SEDA-28, 396; SEDA-29, 363; SEDA-30, 413]

Anagrelide

(SEDA-29, 364; SEDA-30,

413)

THROMBOLYTIC AGENTS (SED-15, 3402; SEDA-28, 392; SEDA-29, 361; SEDA-30, 412)

Reteplase Hematologic In large randomized clinical trials of patients with ST-segment elevation myocardial infarction, reteplase was superior to alteplase in producing coronary artery patency at 60 and 90 minutes, but there was no significant difference in mortality and the incidence of intracranial bleeding (73R). The 35-day mortality rates were equivalent in reteplase and streptokinase recipients; there was a reduced incidence of some cardiac events with reteplase versus streptokinase, but a greater incidence of hemorrhagic strokes. Overall, the incidence of bleeding complications associated with reteplase appears to be similar to that associated with other thrombolytic agents.

Tenecteplase Hematologic Acute lower-limb ischemia was treated with tenecteplase 0.125 or 0.25 mg/hour for 20–27 hours in 43 limbs in 37 patients (74c). Tenecteplase-related complications, which occurred in five limbs, were related to the percentage reduction in fibrinogen concentration, the initial bolus dose, and abciximab administration. Initial bolus doses of 1.5 mg or less were associated with fewer complications than 3–5 mg. There were three major bleeding complications and no cases of intracranial hemorrhage. The authors concluded that the initial bolus dose of tenecteplase should be limited to 1.5 mg.

Anagrelide has been reviewed (75R). Its common adverse effects include headache, anemia, palpitation, fluid retention, tachycardia, abdominal pain, flatulence, vomiting, rash, fatigue, and nausea. Diarrhea has been attributed to lactose in the capsule formula­ tion. The adverse effects occur within 2 weeks of starting treatment and abate with time (i.e., they are probably early adverse effects with tolerance).

Dipyridamole

(SED-15, 1140; SEDA-28, 397; SEDA-29, 365; SEDA-30, 413)

Comparative studies Dipyridamole is a vasodilator and can cause hypotension, which can lead to myocardial ischemia in patients with coronary artery disease (76C). The effect of dipyridamole has been studied to determine whether it reduces the blood pressure after cerebral ischemia of presumed arterial origin more than 6 months after the start of treatment (77C). Patients were randomized to aspirin combined with dipyridamole, usually in a modified-release formulation (n ¼ 325) or aspirin-alone (n ¼ 341). After exclusion of those who did not adhere to therapy, 273 remained in the combination group and 318 in the group on aspirin-alone. Common reasons for non-adherence were headache and gastrointestinal complaints; dizziness and cardiac symptoms (palpitation or angina pectoris) also occurred; some switched to oral anticoagulation. There was no clinically important reduction in blood pressure. The results of other studies of aspirin plus dipyridamole versus aspirin-alone for

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

secondary prevention of vascular events after ischemic stroke of presumed arterial origin have been inconsistent. In a rando­ mized, single-blind trial patients were given aspirin (30–325, median 75, mg/day) with (n ¼ 1363) or without (n ¼ 1376) dipyr­ idamole 200 mg bd (83% modified-release) within 6 months of a transient ischemic attack or minor stroke of presumed arterial origin (78CM). The primary outcome was the composite of deaths from all vascular causes, non-fatal stroke, non-fatal myocar­ dial infraction, or major bleeding complica­ tions, whichever happened first. Primary analysis was by intention to treat. The mean follow up was 3.5 years. There were fewer primary outcome events in the patients who took the combination of aspirin plus dipyr­ idamole (hazard ratio ¼ 0.80; 95% CI ¼ 0.66, 0.98; absolute risk reduction 1.0% per year, 95% CI ¼ 0.1, 1.8). Addition of these data to a meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death, stroke, or myocardial infraction of 0.82 (95% CI ¼ 0.74, 0.91). Patients taking aspirin plus dipyridamole discontinued the trial medica­ tion more often than those taking aspirin alone (470 versus 184), mainly because of headache. Nervous system The most prominent adverse effect of dipyridamole is head­ ache, although the effect can be mitigated by starting with a low dose (79c). In a single-blind study in 10 healthy subjects and 10 patients with migraine without aura, intravenous dipyridamole 0.142 mg/ kg/minute caused headache in all the migraineurs and in eight of the healthy subjects, with no significant difference in intensity (80c). However, five migraineurs but only one healthy subject had the symptoms of migraine without aura within 12 hours. Four migraineurs reported photophobia compared with no healthy subjects. The authors suggested that the relatively low frequency of migraine, compared with nitric oxide donors and sildenafil, was probably due to the less specific action of dipyridamole on the cyclic guanosine monophosphate (GMP) signalling pathway, as well as a possible

Chapter 35

bidirectional effect migraine induction.

565 of

adenosine

on

Glycoprotein IIb-IIIa inhibitors (SED-15, 4; SEDA-28, 396; SEDA-29, 363; SEDA-30, 414) Hematologic Acute severe thrombocytopenia occurred 48 hours after the administration of tirofiban in a patient with an acute coronary syndrome; withdrawal caused resolution (81c). In another case thrombocytopenia occurred within 2 hours of administration (82c). Cross-reactivity between two glyco­ protein IIb-IIIa inhibitors, abciximab and tirofiban, has been reported, causing thrombocytopenia (83A).  A 62-year-old man underwent percutaneous

coronary intervention; 4 hours later he devel­ oped hematemesis and was found to have thrombocytopenia, presumably due to the abciximab infusion he had received during and shortly after the intervention. He had had a similar previous episode during a trial of tirofiban 11 years before.

The mechanism of this thrombocytopenia is not well understood but has been described as immune-mediated with both ligandmimetic agents (tirofiban and eptifibatide) and abciximab. This patient was unusual in that he developed thrombocytopenia from a ligand-mimetic agent and subsequently had a similar reaction to abciximab. To our knowledge, this is the first report of thrombocytopenia associated with both tirofiban and abciximab in the same patient, and it suggests that care should be given in administering glycoprotein IIb-IIIa inhibi­ tors of either type to patients with a history of thrombocytopenia due to one of these agents.  Acute profound thrombocytopenia (6  109/l)

occurred in an 86-year-old woman with angina who was given heparin and eptifibatide (84A). It resolved after drug withdrawal. In similar circumstances 4 months later she again developed acute profound thrombocytopenia (2  109/l).

Chapter 35

566 (SED-15, 821; SEDA-28, 397; SEDA-29, 365; SEDA30, 415)

THIENOPYRIDINES

Clopidogrel and ticlopidine Comparative studies The combination of clopidogrel plus aspirin has been explored in the Management of Atherothrombosis With Clopidogrel in High-Risk Patients trial, and compared with clopidogrel alone for secondary prevention in patients with transient ischemic attacks and strokes in a population with a high prevalence of other vascular risk factors. There was a non­ significant trend towards a reduction in the combined end-point of ischemic stroke, myocardial infarction, vascular death, and rehospitalization in the combination therapy group (85C). However, the frequency of lifethreatening bleeding was almost doubled in the combination arm. Hematologic A spinal–epidural hematoma occurring after combined spinal–epidural anesthesia in a patient who had been taking clopidogrel and had received perioperative dalteparin for thromboprophylaxis (86A). Skin Two patients developed maculopapular pruritic rashes that began on the abdomen and spread to the back, neck, and face after taking clopidogrel (87A). The rashes recurred during ticlopidine therapy, and the thienopyridines were withdrawn. One patient later took clopidogrel again and developed a rash. While there have been several reports of thienopyridine­ associated rashes, there have been only two reports of cross-sensitivity between oral clopidogrel and ticlopidine. Preliminary reports suggest that clopidogrel desensitiza­ tion can be accomplished in selected patients several months to years after the occurrence of a thienopyridine-associated rash using an allergy desensitization proto­ col, with close monitoring for anaphylaxis. Drug resistance Resistance to the actions of the thienopyridines has been reported (88A).

J. Harenberg

 A 67-year-old man underwent coronary angio­

graphy, during which he received aspirin, heparin, and eptifibatide. He was then given clopidogrel 300 mg and almost 1 hour later developed angina-like chest pain associated with hypotension, due to an acute inferolateral myocardial infarction.

After the patient had taken clopidogrel for 12 hours, platelet function tests were carried out. After stimulation with arachidonic acid there was less platelet aggregation than normal; however, the responses to ADP and collagen were similar to normal. These results were taken to indicate clopidogrel resistance. Platelet function was normal 24 hours after treatment with another thie­ nopyridine, ticlopidine.

HEMOSTATIC AGENTS Aprotinin

(SED-15, 331; SEDA-29, 367)

Cardiovascular Of nine patients with severe end-stage heart failure caused by dilated cardiomyopathy who underwent external cardiopulmonary bypass, seven received intravenous heparin which was reversed with intravenous protamine sulfate, eight received aprotinin, and one received aminocaproic acid (total dose 25 g) (89c). Of those who received aprotinin, four were given 1 ml (10 000 kallikrein inactivation units) as a test dose, 200 ml as a loading dose, and 50 ml/hour as a continuous infusion; at the start of the bypass an extra 200 ml was added to the priming fluid. In the other four patients, aprotinin was administered according to a weight-based protocol; the loading dose and priming dose were 100 ml each. Three of the eight patients who received aprotinin had a prior exposure to aprotinin, 3, 5, and 32 days earlier. Within minutes of protamine administration, pulmonary artery pressure increased dramatically. There was right ventricular distension and lack of right ventricular wall motion and eight of the nine patients died. At post­ mortem there were multiple recent fibrin thrombi in the capillaries and small and

Drugs affecting blood coagulation, fibrinolysis, and hemostasis

medium pulmonary arterioles throughout both lungs. Three patients also had microthrombi in the epicardial and intramyocardial microvasculature. Immunologic Acute anaphylaxis after a small dose of aprotinin has been reported (90A).  A 9-year-old boy with a history of severe milk

allergy was given a test dose of aprotinin 1 ml,

Chapter 35

567

containing 10KIU, during an operation for truncus arteriosus. Immediately after the dose he developed severe hypotension and increased airway pressure. The systolic blood pressure fell to 50 mmHg and remained low for 30 minutes, despite intravenous adrenaline in repeated doses and by infusion and 5% albumin. The serum tryptase concentration was 59 ìg/l (reference range below 11.5 ìg/l). He eventually recovered. A postoperative ELISA test was negative for latex and aprotinin-specific IgE but positive for aproti­ nin-specific IgG4.

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Chapter 35

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tirofiban: a case report. J Thromb Throm­ bolysis 2006;22(1):77–8. Dorsch MP, Montague D, Rodgers JE, Patterson C. Abciximab-associated throm­ bocytopenia after previous tirofiban-related thrombocytopenia. Pharmacotherapy 2006; 26(3):423–7. Cheema AA, TeklinskiAHia V, Chilukuri K, Frank JJ. Gosselin MO, Recurrent acute profound thrombocytopenia related to readministration of eptifibatide. J Interv Cardiol 2006;19(1):99–103. Fisher M. Results of the management of atherothrombosis with clopidogrel in highrisk patient trial: implications for the neurologist. Arch Neurol 2006;63(1):20–4. Tam NL, Pac-Soo C, Pretorius PM. Epi­ dural haematoma after a combined spinalepidural anaesthetic in a patient treated with clopidogrel and dalteparin. Br J Anaesth 2006;96(2):262–5. Makkar K, Wilensky R, Lien MB, Herrmann HC, Spinler SA. Rash with both clopidogrel and ticlopidine in two patients following percutaneous coronary interven­ tion with drug-eluting stents. Ann Pharmac­ other 2006;40(6):1204–7. Vats HS, Hocking WG, Rezkalla SH. Suspected clopidogrel resistance in a patient with acute stent thrombosis. Nat Clin Pract Cardiovasc Med 2006;3(4):226–30. Cooper Jr. JR, Abrams J, Frazier OH, Radovancevic R, Radovancevic B, Bracey AW, Kindo MJ, Gregoric ID. Fatal pul­ monary microthrombi during surgical ther­ apy for end-stage heart failure: possible association with antifibrinolytic therapy. J Thorac Cardiovasc Surg 2006;131(5):963–8. Zhang K, Young C, Berger J. Adminis­ trative claims analysis of the relationship between warfarin use and risk of hemor­ rhage including drug-drug and drug-disease interactions. J Manag Care Pharm 2006;12 (8):640–8.

R.J. Ali and H.R. Dalton

36

Gastrointestinal drugs

(SED-15, 243; SEDA-28, 401; SEDA-30, 423)

ANTACIDS

Sodium alginate and anhydrous magaldrate were compared in an open, randomized, parallel trial of 191 patients aged 18 years and over with symptoms of gastroesophageal reflux (1C). Sodium alginate had a statisti­ cally significant faster onset of action and was more efficacious. Diarrhea and nausea were noted in 5 of 93 patients who took alginate, and 7 of 98 who took magaldrate (2c). There were no drug-related serious adverse events. Sodium alginate, omeprazole, ranitidine, and placebo have been compared in a single-center, open, crossover study in 19 adults aged 18–70 years with gastroesopha­ geal reflux. Nausea attributed to ranitidine was the only adverse effect. No serious adverse events were reported.

ANTIEMETICS AND DRUGS THAT AFFECT GASTROINTESTINAL MOTILITY (SEDA-28, 401; SEDA-29, 371; SEDA-30, 423)

Cisapride (SEDA 28, 401; SEDA 29, 371) Comparative studies Functional dyspepsia is challenging to manage. Prokinetics have been compared with Helicobacter eradica­ tion in 130 patients in Singapore (3c). They took either triple therapy of lansoprazole Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03136-5 r 2009 Elsevier B.V. All rights reserved.

(60 mg/day), clarithromycin (1000 mg/day), and amoxicillin (2000 mg/day) or prokinetic therapy, either cisapride (15 mg/day) or domperidone (30 mg/day). In both arms of this study there was significant symptom improvement at 1 year. Very few adverse events were reported; the most common were minor GI disturbances in four patients in the eradication arm and three in the prokinetic arm. Nervous system Akathisia has been attrib­ uted to cisapride in a 2-year-old girl who developed it after starting cisapride in infancy (4A). The symptoms resolved on cessation of the drug. The authors sug­ gested this unusual and previously unre­ ported adverse event might have come about because cisapride is metabolized by CYP3A4, which is underdeveloped in neo­ nates, in the presence of an inadequate blood–brain barrier. This is an important adverse effect to note, as currently (in Europe and the USA) cisapride is only routinely prescribed in children.

Dronabinol

(SED-15, 1178)

The effects of dronabinol, a non-selective cannabinoid receptor agonist, on gastric emptying, small bowel and colonic transit, gastric volume, satiation, and postprandial symptoms have been investigated in 24 healthy volunteers in a double-blind, rando­ mized study (5c). There was a significant delay in gastric emptying in women, but not in men. There were no other significant findings. There were adverse events in 14 participants, including vasovagal episodes, drowsiness, dry mouth, headaches, lightheadedness, poor concentration, mild confusion, and nausea. With the exception of

573

574 drowsiness and headaches, all were thought to be drug-related. No serious events were reported.

Metoclopramide

(SED-15, 2317; SEDA-28, 401; SEDA-29, 371; SEDA-30, 423)

The evidence for using metoclopramide for gastroesophageal reflux in infants has been reviewed, resulting in an inconclusive recommendation for this indication (6M). There was marked heterogeneity in the populations, dosage regimens, and out­ comes in the 12 studies that met the review criteria, the available evidence substantiat­ ing neither significant benefit nor harm from metoclopramide. Adverse events were not reported in most of these studies. In the four that did report events, these included dystonic reactions, oculogyric crisis, irritability, drowsiness, emesis, and apnea. Skin A non-thrombocytopenic purpuric rash developed after 10 days of regular administration of intravenous metoclopra­ mide in a 62-year-old man (7A). The rash subsided on withdrawal. Nervous system A 27-year-old man with abdominal pain was given metoclopramide and had an abdominal dystonic reaction (8A). This was initially interpreted as peritonitis, but further symptoms developed in his limbs, pointing to the diagnosis. This has not apparently been described before. Orofacial tardive dyskinesia occurred in a 25-year-old woman taking metoclopramide (9A). Drug dosage regimens Different doses of metoclopramide (0, 10, 25, and 50 mg, all given with dexamethasone 8 mg) have been compared in a double-blind, randomized, controlled trial in postoperative nausea and vomiting in 3140 adults (10C). Both the 25 and 50 mg doses significantly reduced the incidence of early phase symptoms, but only the 50 mg dose reduced late phase symp­ toms. Adverse events were hypotension,

Chapter 36

R.J. Ali and H.R. Dalton

hypertension, dysrhythmias, skin reactions, headache, dizziness, sedation, dry mouth or altered taste, allergy, delirium, dyskinesias, and a central anticholinergic syndrome. Hypotension and tachycardia were clearly related to metoclopramide and dose-related, being significantly more common after 50 mg. Dyskinesia was also associated with metoclopramide, but with a non-significant NNTH of 156 (range 81–3333) at doses of 25 or 50 mg. The seven reported serious adverse events were not drug-related.

Renzapride Renzapride is a full 5-HT4 agonist and a partial 5-HT3 antagonist, which it is theorise will be effective for a wide range of the symptoms of irritable bowel syndrome. In a dose-escalating pilot study (placebo, 2 mg/ day, 2 mg bd) in 17 patients with constipa­ tion-predominant irritable bowel syndrome, renzapride reduced overall gastrointestinal tract transit time and accelerated colonic transit, reduced abdominal pain, and improved stool consistency (11c). Reported adverse events included abdominal pain, headache, constipation, and diarrhea. Five patients withdrew from the study owing to adverse effects that were thought to be drugrelated; these consisted of increased urinary frequency, urinary incontinence, bradycardia, headache, abdominal pain, and flatulence. There were no clinically significant changes in electrocardiography, body weight, or hematological or biochemical indices.

Tegaserod Tegaserod is a 5-HT4 receptor agonist that is efficacious in constipation-predominant irritable bowel syndrome and chronic con­ stipation. Observational studies Tegaserod has been studied in conjunction with a polyethylene glycol-based bowel preparation for colono­ scopy, to determine if its prokinetic effects would improve the quality of bowel pre­ paration (12c). Tegaserod (n ¼ 58) was no

Gastrointestinal drugs

Chapter 36

different from placebo in tolerance or quality of bowel preparation. Adverse events were similar in the two groups, most commonly nausea, vomiting, abdominal pain, and bloating. Placebo-controlled studies The effects of tegaserod 12 mg/day on gastric accommo­ dation and postprandial satiety have been investigated in 41 volunteers in a placebocontrolled study (13C). There was no significant change in gastric motor or sensory function. One subject taking tega­ serod had self-limiting diarrhea; no other adverse events were reported. Cardiovascular In China the production, sale, and use of tegaserod (Zelnorm) have been suspended by the Chinese State Food and Drug Administration (SFDA) (14c). It has been associated with an increased risk of strokes and heart attacks, this being the reason of the SFDA decision. According to the SFDA, local and international reports of adverse reactions have suggested a negative benefit to harm balance. By 2007 The National Centre for Adverse Drug Reaction Monitoring had received 98 adverse reaction reports involving tegaserod since the product was first marketed in China in 2003. Major reactions were reported to be diarrhea and nausea, but there was one case of tachycar­ dia, two of palpitation, and one of low blood pressure. In Switzerland, the Swiss Institute of Therapeutic Products, Swissmedic, has declined to extend the marketing author­ ization for tegaserod (Zelmac) after a new analysis of clinical data showed that tega­ serod increased the risk of cardiovascular disorders compared with placebo. Tega­ serod was authorized toward the end of October 2001 in Switzerland in the treat­ ment of irritable bowel syndrome in women. Swissmedic has advised that tega­ serod has an unfavorable benefit to harm balance. Novartis Pharma Schweiz AG will inform health-care professionals of the withdrawal in Switzerland. Finally, in the USA, the Food and Drug Administration (FDA) has permitting

575 restricted use of tegaserod (Zelnorm) as an investigational new drug for the treat­ ment of irritable bowel syndrome with constipation and chronic idiopathic consti­ pation. The use of tegaserod is restricted to women aged under 55 years whose physi­ cians decide that treatment with tegaserod is necessary. The FDA previously sus­ pended the sales and marketing of tega­ serod after a safety analysis that demonstrated an increased risk of myocar­ dial infarction, stroke, and unstable angina associated with tegaserod compared with placebo.

5-HT3 RECEPTOR ANTAGONISTS (SED-15, 1365; SEDA-28, 402; SEDA-29, 372; SEDA-30, 423)

Alosetron (SEDA-29, 372; SEDA-30, 423) Ischemic colitis has previously been reported in association with alosetron, and this has been confirmed in a large systematic review of clinical trials (316 882 patients in 26 trials) and postmarketing surveillance data (15M). However, metho­ dological problems with the review may make these figures questionable. Cases were excluded if confirmatory diagnostic results were unavailable; these should ordinarily be included. Also, the authors chose to combine postmarketing surveil­ lance data with RCT data, casting doubts on their methods, as the reporting of ischemic colitis in these two groups is not directly comparable.

Ondansetron

(SEDA 29; 372)

Comparative studies Droperidol 1.25 mg and ondansetron 4 mg reduced postopera­ tive nausea and vomiting in 394 patients by 58 and 60%, respectively (16c). When they were combined, there was a 78% reduction in symptoms. While the antiemetic effects

576 were additive, the adverse effects on the QTc interval were not. With combination therapy the mean increase in QTc interval was 13 milliseconds, similar to 11 and 10 milli­ seconds after droperidol and ondansetron separately. No other significant adverse events were noted. Placebo-controlled studies A method of optimizing oral rehydration in children with gastroenteritis using a single dose of oral dispersible ondansetron (2–8 mg depending on the child’s weight) has been investigated in a double-blind, placebo-controlled trial in 215 children aged 6 months to 10 years (17C). The frequency of vomiting was significantly reduced by ondansetron (RR ¼ 0.40). Significantly more children in the placebo group (31% versus 14%) went on to need intravenous rehydration. Hospi­ tal admission rates were similar in the two groups. Children who received ondansetron had significantly more episodes of diarrhea. No other adverse events were noted. In 12 children receiving highly emeto­ genic chemotherapy, metopimazine given with ondansetron was more effective than ondansetron alone in reducing the number of episodes of emesis and in reducing the children’s distress (18c). No adverse events were attributed to metopimazine.

Palonosetron Comparative studies Predose palonose­ tron and ondansetron have been compared in highly emetogenic chemotherapy in 673 patients (19C). Palonosetron was not inferior to ondansetron in the acute phase. The complete response rates (defined as no emetic episodes and no rescue antiemetics) for palonosetron (0.25 or 0.75 mg) and ondansetron (32 mg) in the delayed phase were 45, 48, and 39%, respectively. Those who had an incomplete response to palono­ setron also required significantly fewer rescue antiemetics. In the three groups there were adverse events in 72, 79, and 73%, respectively. Over 90% of these were mild or moderate, and 80% of all adverse events were judged not to be drug-related. Those that were drug-related included headache (8, 12, 11%, respectively) and constipation (4.4,

Chapter 36

R.J. Ali and H.R. Dalton

7.6, 2.2%, respectively). There were no serious drug-related adverse events.

Tropisetron Placebo-controlled studies In 310 patients given placebo, tropisetron 5 mg, dexa­ methasone 8 mg, or both drugs for postoperative nausea and vomiting, there was no significant difference between tropisetron and dexamethasone given individually (20c). However, in all three intervention groups there was significantly less postoperative nausea and vomiting than after placebo and there was a significant additive effect in those who were given both medications. There were similar adverse events in all the groups, including headache, pruritus, constipation, and hyperglycemia.

HISTAMINE H2 RECEPTOR ANTAGONISTS (SED-15, 1629; SEDA-28, 403; SEDA-29, 373; SEDA-30, 423)

Famotidine

(SEDA 28, 403)

Comparative studies Famotidine 20 mg/ day (n ¼ 66) and rebamipide 300 mg/day (n ¼ 63) for 4 weeks have been compared in 129 patients with gastric hemorrhage or erosions associated with non-steroidal anti­ inflammatory drugs (NSAIDs) (21c). They continued to take the NSAIDs throughout the study. There was a significant improve­ ment in gastric lesions with famotidine, but no change with rebamipide. Ten patients taking famotidine had adverse drug reac­ tions, including increased alanine transaminase activity (n ¼ 10) and increased blood urea nitrogen concentrations (n ¼ 2). Of those taking rebamipide 10 had an adverse drug reaction, including increased aspartate transaminase activity (n ¼ 2), increased blood urea nitrogen (n ¼ 2), and an increased white blood cell count (n ¼ 2). There were no serious adverse reactions. Endoscopic mucosal resection (EMR) of gastric tumors often results in iatrogenic ulcers. In 82 patients who took either

Gastrointestinal drugs

Chapter 36

famotidine 40 mg/day or omeprazole 20 mg/ day after EMR there was no difference in ulcer stage or reduction ratio at 28 days (22c). However, a subgroup analysis sug­ gested benefit with omeprazole in those who underwent endoscopic submucosal dissection. There were no adverse events in either group.

Ranitidine (SEDA 28, 403; SEDA 29, 373) Comparative studies A large multicenter comparison of intravenous pantoprazole and intravenous ranitidine in the preven­ tion of ulcer rebleeding was terminated early after only 149 had been entered, owing to slow enrollment (23c). The results showed a numerical but non-significant advantage with intravenous pantoprazole. There were adverse events in both groups, including headaches, abdominal pain, anemia, and pain with pantoprazole, and abdominal pain, headache, anemia, and infection with ranitidine. Non-bleeding ser­ ious adverse events were not significantly different between the groups and were all thought to be non-drug-related.

PROTON PUMP INHIBITORS (SED-15, 2973; SEDA-28, 403; SEDA-29, 373; SEDA-30, 424)

Comparative studies The effects of single doses of rabeprazole 20 mg and esomepra­ zole 40 mg on intragastric pH for 24 hours before have been evaluated in a crossover study in 24 subjects (24c). Rabeprazole was as effective as esomeprazole, although the time period when pH was most affected was different. Esomeprazole was significantly more effective during 0–14 hours, rabepra­ zole during 14–24 hours. Adverse events were infrequent; 13% reported gastrointestinal symptoms, 19% flu-like symptoms. When prescribing NSAIDs, it is common to recommend concomitant acid suppression to reduce the risk of gastroduodenal ulcera­ tion. Three proton pump inhibitors have

577 been compared in this setting—esomepra­ zole 40 mg, lansoprazole 30 mg, and panto­ prazole 40 mg—in an open crossover study in 90 subjects. Esomeprazole had the largest effect (25c). Very few adverse events were reported—nausea in four subjects, abdominal pain in three, and dyspepsia in three— and no patients discontinued treatment owing to these. In 595 patients requiring chronic NSAID treatment with additional risk factors for peptic ulcer disease, pantoprazole (20 or 40 mg/day) and omeprazole (20 mg/day) have been compared (26C). The three treatment regimens were equivalent. Adverse events were reported in 33% of subjects (29% of those taking pantoprazole 20 mg/day, 37% pantoprazole 40 mg/day, 33% omeprazole 20 mg/day) and were all either non-serious or not related to the study drug. In 1176 patients with erosive esophagitis, omeprazole 20 mg/day (n ¼ 588) and esomeprazole 20 mg/day (n ¼ 585) pro­ duced equivalent healing rates (88 and 91%, respectively) with similar tolerability profiles (27C). There were adverse events in 43% of those taking omeprazole and 44% of those taking esomeprazole, most com­ monly headache, gastritis, and diarrhea. When healing of moderate to severe erosive esophagitis was assessed in patients taking either esomeprazole 40 mg/day or omeprazole 20 mg/day, esomeprazole per­ formed significantly better (28C). In mild erosive esophagitis, no difference was found. The adverse events in the two groups (n ¼ 1148 total) were very similar (49% versus 45%); the most common were headache (10% versus 7%), diarrhea (6.6% versus 5.4%), and gastritis (4.9% versus 3.2%). In 717 patients with symptoms of gastro­ esophageal reflux disease randomized to either rabeprazole 20 mg/day or omepra­ zole 20 mg/day for 7 days, there was no significant difference in efficacy; the median time to achieve heartburn control was 1.5 days with both drugs (29C). There were similar numbers of adverse events in each group (with 15 and 13%, respectively). In 112 patients with active peptic ulcera­ tion rabeprazole 10 mg/day and omeprazole

578 20 mg/day produced similar healing rates and symptom resolution (30c). There were only three (non-serious) adverse events, headache in two and nausea in one. Mineral balance Hypochlorhydria due to proton pump inhibitors can affect calcium absorption and can also affect bone resorp­ tion by inhibiting osteoclastic vacuolar proton pumps. In a case–control study of over 1.8 million patients using the UKbased General Practice Research Database there was a significantly increased risk of hip fracture in patients taking long-term proton pump inhibitors (31C). The strength of this association increased with duration of therapy: at 1 year, the adjusted odds ratio was 1.44, increasing to 1.59 at 4 years. Gastrointestinal In a prospective study in 155 patients with Clostridium difficile-asso­ ciated diarrhea, acid suppression was inde­ pendently associated with diarrhea, as were antibiotic use and female sex (32c). The authors recommended vigilance in with­ holding proton pump inhibitors in hospital patients if there is no absolute indication for acid suppression, particularly if concomi­ tant antibiotics are prescribed.

Esomeprazole

(SED-15, 1252; SEDA28, 403; SEDA-29, 373; SEDA-30, 424)

Placebo-controlled studies Peptic ulcer formation has been investigated in patients taking regular NSAIDs in two very similar double-blind studies (VENUS, n ¼ 844 and PLUTO, n ¼ 585) of esomeprazole 20 or 40 mg/day or placebo (33C). Esomeprazole was associated with significantly reduced numbers of ulcers in both dosage groups. Reported adverse events were similar in all the groups, and were predominately gastrointestinal symptoms. More patients were withdrawn from the placebo group owing to adverse events than from either treat­ ment group. In a moderately sized study of esome­ prazole versus placebo there was no effect on symptom relief in functional dyspepsia at 8 weeks (34c). Adverse events were

Chapter 36

R.J. Ali and H.R. Dalton

similar in the two arms, most commonly nausea and headache, in 4.6% of subjects. Drug dosage regimens Three doses of esomeprazole (60, 80, and 120 mg/day) have been compared in a crossover study in 31 patients with Barrett’s esophagus who were given each dose of esomepra­ zole for 5 days, with a 10–14 day washout period between each (35c). Intragastric and intraesophageal pH monitoring was performed at baseline and at day 5 of each regimen. All three doses reduced intragastric pH; the 120 mg/day dose (40 mg qds) was significantly more effec­ tive than the lower doses. There were no dose-related trends in the types or sever­ ity of adverse events. The most common were diarrhea, headache, and vomiting.

Lansoprazole

(SEDA 28, 404)

Drug dosage regimens In a study of an intravenous formulation of lansoprazole in healthy volunteers, a bolus followed by continuous infusion effectively raised gas­ tric pH (36c). Two doses were studied: the lower dose (60 mg bolus, 6 mg/hour infu­ sion) produced similar acid suppression to the higher dose (90 mg bolus, 9 mg/hour infusion). Adverse events were mild (16/ 36 subjects), the most common being headache and loose stools, and no dose response effect was seen.

Omeprazole

(SED-15, 2615; SEDA-28, 403; SEDA-30, 425)

Biliary tract It has been postulated that proton pump inhibitors can cause gallbladder dysfunction. In a study of gall­ bladder ejection fraction before and after proton pump inhibitor therapy (omeprazole 40 mg/day for 4 weeks) reduced gall­ bladder motility was documented in 15 of 19 healthy volunteers (37c). In five patients there were symptoms consistent with biliary pathology (abdominal pain, nausea, vomiting, or increased flatulence).

Gastrointestinal drugs

Chapter 36

Skin Omeprazole-induced dermatomyositis has been described in an 81-year-old woman. All manifestations resolved on withdrawal (38A).

Pantoprazole

(SEDA 28, 404)

Sexual function A 34-year-old man with pyloric stenosis secondary to peptic ulcera­ tion was given intravenous pantoprazole 80 mg/day. After 72 hours he developed marked bilateral scrotal and penile edema. All investigations were normal and the edema resolved within 48 hours of with­ drawal of pantoprazole (39A). Drug dosage regimens Long-term acid suppression is required in most patients with Zollinger–Ellison syndrome and other hypersecretory conditions. In a 3-year study (40c) of oral pantoprazole in 35 such patients, doses of 40–120 mg bd were well tolerated. The most common adverse effect, reported in 49% of subjects, was headache, which was not dose-related. Also common were diarrhea (43%), nausea (40%), and abdominal pain (34%), all of which were dose-related. Drug administration route In 78 patients who were randomized to placebo, intrave­ nous pantoprazole, or oral pantoprazole for 7 days, gastric acid was suppressed as effectively by pantoprazole intravenously as orally (41c). In all three treatment groups the four most commonly reported adverse events were headache (8 cases), vasodilatation (6), nausea (9), and dizziness (10). One patient taking oral pantoprazole had treat­ ment withdrawn because of vomiting and diarrhea.

Rabeprazole

(SED-15, 3011; SEDA-28, 404; SEDA-29, 374; SEDA-30, 425)

Drug dosage regimens In an open cohort study in 1548 patients the speed of sympto­ matic relief using rabeprazole in patients with gastroesophageal reflux disease was studied according to Helicobacter pylori status (42C). There was no significant difference in speed or degree of symptom relief, but 241 patients reported adverse

579 events, most often headaches, nausea, diarrhea, and dry mouth. Most were considered to be mild (41%) or moderate (43%). In another study in 20 patients with Zollinger–Ellison syndrome, rabeprazole was effective and well tolerated at a median dose of 60 mg/day (43c). There was only one significant adverse event, which resulted in a single patient being withdrawn from the study: raised creatine kinase activity, which resolved on withdrawal of rabeprazole.

Tenatoprazole Tenatoprazole is an imidazopyridine-based proton pump inhibitor, in contrast to the benzimidazole-based first-generation drugs (omeprazole, lansoprazole, esomeprazole, rabeprazole, and pantoprazole). It has a much longer half-life in healthy volunteers, and consequent better control of night-time acid secretion. In a crossover study (44c) in 12 healthy subjects, the effects on gastric pH of three different dosing schedules of tenato­ prazole 40 mg were investigated: fasted 07:00 hours, fasted 19:00 hours, and fed 21:30 hours. Tenatoprazole provided pro­ longed acid suppression, particularly during the night, and neither feeding nor time of day significantly affected its efficacy. A total of 35 minor adverse events were reported, none of which was thought to be drug-related.

H. PYLORI ERADICATION REGIMENS (SED-15, 1586; SEDA-28, 405; SEDA-30, 425)

Comparative studies Failure of first-line eradication therapy is a common problem in areas with high levels of resistance to metronidazole and clarithromycin. In a randomized controlled trial in 106 such patients there was comparable efficacy between a quadruple regimen containing metronidazole 1200 mg/day + tetracycline 200 mg/day + bismuth subcitrate 480 mg/day + lansoprazole 60 mg/day and a triple regimen of lansoprazole 60 mg/day + amoxicillin 2000 mg/day + levofloxacin 1000 mg/day (45c).

580 The quadruple therapy had an eradication rate of 71%, the triple therapy 57%. The two regimens were associated with similar rates of adverse events (21 and 18 patients, respectively), most commonly nausea, vomiting, diarrhea, and dizziness. Bismuth salts are commonly recommended as a component of rescue therapy for failed Helicobacter eradication therapy but are not available world wide. In a prospective study of 93 patients who had failed eradication therapy esomeprazole + clarithromycin + tet­ racycline + metronidazole was compared with esomeprazole + bismuth subcitrate + tetracy­ cline + metronidazole (46c). There were simi­ lar eradication rates in the two groups (74% versus 77%). There were adverse events in 57 and 36%, respectively. This included signifi­ cantly more taste perversion (28 versus 16 patients) and vomiting (12 versus 4) in the clarithromycin group. Four patients withdrew (3 in the clarithromycin group, 1 in the bismuth group) because of adverse effects. Good adherence to therapy independently predicted treatment success in these groups (OR ¼ 22). In a randomized study of patients who had failed first-line eradication ther­ apy, rabeprazole 40 mg/day + amoxicillin 2000 mg/day was less effective than rabe­ prazole 20 mg/day + amoxicillin 1500 mg/ day + metronidazole 500 mg/day (74% versus 97%) (47c). Adverse events were similar in the two groups, the most common being diarrhea (n ¼ 4), abdominal bloating (2), and heartburn (3). In a pilot study of the use of rifamixin in eradication therapy in 48 patients, there were limited rates of eradication (58% when given with esomeprazole+clarithromycin, 42% with esomeprazole+levofloxacin) despite high degrees of adherence (48c). Adverse events were very similar in the two groups (13/24 and 10/24, respectively), the most common being taste disturbance.

Esomeprazole + amoxicillin + gatifloxacin In a pilot study (n ¼ 30) of sequential therapy with esomeprazole 120 mg/day

Chapter 36

R.J. Ali and H.R. Dalton

+amoxicillin 3000 mg/day for 12 days, add­ ing gatifloxacin 400 mg/day on days 6–12, there was an eradication rate of 80%; 13 patients reported adverse effects, of which diarrhea was the most common (49c).

Omeprazole + amoxicillin + clarithromycin In a comparative study (50c) of two H. pylori eradication regimens using ome­ prazole 40 mg/day+amoxicillin 1500 mg/day and two different doses of clarithromycin (400 and 800 mg/day, n ¼ 143 and 145, respectively) there were more adverse events in the higher dose group (52% versus 47%). The most common adverse events were diarrhea (33 and 49 patients, respectively) and altered taste (3 and 18 patients, respectively).

Pantoprazole + amoxicillin + rifabutin In 130 patients who had failed eradication therapy a regimen of low-dose rifabutin 150 mg/day, pantoprazole 240 mg/day, and amoxicillin 3000 or 4500 mg/day for (51c) 12 days was highly effective, with an eradica­ tion rate of 91% when amoxicillin 3000 mg/ day was used and 97% when 4500 mg/day was used. All reported adverse events (n ¼ 52) were mild and non-serious, the most common being diarrhea (8), nausea (5), and abdominal pain (5).

Rabeprazole + clarithromycin + amoxicillin In an open pilot study of eradication therapy using rabeprazole 40 mg/day + clarithromycin 1000 mg/day +amoxicillin 2000 mg/day in 111 patients there was a cure rate of 85% (52c). Of these 111 patients, 76 reported adverse events; the most common was a metallic taste in the mouth (44%) followed by abdominal pain in 15% (70% mild, 30% moderate).

Gastrointestinal drugs

Chapter 36

Rabeprazole + levofloxacin + tinidazole Duration of treatment has implications for adherence and consequently efficacy. In a pilot study of 169 patients (53c) comparing 4 and 7 days of eradication therapy with rabeprazole 40 mg/day +levofloxacin 1000 mg/day +tinidazole 1000 mg/day effi­ cacy was very similar for both durations of treatment (94% versus 95%, respectively). The 4-day treatment group, however, had significantly fewer adverse events (13% versus 29%) suggesting that it may be a preferable method for eradicating H. pylori.

Ranitidine bismuth citrate + amoxicillin + clarithromycin There are few validated treatment regimens for eradicating H. pylori in children. In 206 children (median age 12 years) 4-day and 7­ day eradication regimens with ranitidine bismuth citrate +amoxicillin +clarithromy­ cin were investigated (54c). The 7-day regimen was significantly more efficacious (89% eradication versus 78%). There were no significant differences in adverse effects, the most common of which was blackening of stools due to bismuth citrate; loose stools, dyspepsia, and headache were also fre­ quently noted.

LAXATIVES AND ORAL BOWEL PREPARATIONS (SED-15, 2008; SEDA-28, 406; SEDA-29, 374; SEDA-30, 426)

Bisacodyl Placebo-controlled studies Bisacodyl has been investigated in a placebo-controlled study in 27 patients with constipation (55c). It produced statistically significant improve­ ments in stool frequency and consistency. Of those who took bisacodyl, 15 reported a total of 37 adverse events, compared with 18 who reported 29 events in the placebo group.

581 There were no serious adverse events. Of the reported adverse events 24 (65%) were thought to be related to a concurrent condition, and only 10 (27%) were thought to be drug-related. These were mild and included constipation, an increase in blood urea nitrogen, and eosinophilia.

Phosphates

(SED-15, 2820; SEDA-29, 375; SEDA-30, 427)

Comparative studies Sodium phosphate and polyethylene glycol have been com­ pared in 94 adults undergoing colonoscopy (56c). Polyethylene glycol caused significant reductions in serum potassium, calcium, phosphorus, magnesium, bicarbonate, and blood urea nitrogen, and increases in sodium and phosphate. The proportional changes in those who used sodium phosphate were greater. In particular, in 37 of the patients who used sodium phosphate and 11 of those who used polyethylene glycol, phosphate concentrations increased by over 5%. Patients who took polyethylene glycol reported more adverse effects, including nausea, vomiting, abdominal cramps and distension, anal irritation, sleeplessness, and chills. All of these symptoms were also seen in the sodium phosphate group, but signifi­ cantly less often. The authors recommended that while sodium phosphate seemed to be more acceptable to patients, it should only be used with clinical supervision and after screening carefully for cardiovascular, hepa­ tic, and renal disease, and should not be used with medications that would exacerbate electrolyte disturbances, such as diuretics, or with drugs that electrolyte disturbances would affect, such as digoxin and lithium. In 340 patients undergoing elective colo­ noscopy, sodium phosphate was compared with polyethylene glycol with added ascor­ bic acid (57c). Polyethylene glycol was at least as efficacious as sodium phosphate. Of all adverse events reported 5 were in those who took polyethylene glycol and 24 in those who took sodium phosphate. The most common in the former was vomiting and in the latter hyperphosphatemia and hypokalemia; two cases of hypokalemia were classified as serious.

582 Systematic reviews Three types of bowel preparations for colonoscopy (sodium phos­ phate, polyethylene glycol, and sodium picosulfate) have been compared in a meta­ analysis of 29 trials in a total of 6459 patients (58M). Sodium phosphate was the most effective at cleansing the colon and was better tolerated than polyethylene glycol. Sodium picosulfate had similar efficacy to polyethylene glycol. There were adverse events in 1054/1662 patients who took polyethylene glycol and 902/1590 who took sodium phosphate. More patients developed dizziness with sodium phosphate than poly­ ethylene glycol, abdominal pain was more common with polyethylene glycol, and both groups had similar amounts of nausea, vomiting, and perianal pain. When polyethy­ lene glycol was compared with sodium picosulfate (104 and 112 patients, respec­ tively) polyethylene glycol produced more nausea, vomiting, abdominal pain, sleep disturbance, and perianal irritation than sodium picosulfate; 71% of patients who took polyethylene glycol reported adverse events compared with 48% of those who took sodium picosulfate. In comparisons of sodium phosphate and sodium picosulfate, there were similar amounts of nausea, vomiting, dizziness, and abdominal pain. Electrolyte balance Severe hyperphosphatemia can occur with phosphates (59A).  A 3-month-old infant was treated with an oral

laxative containing phosphate (Purgasol 2 ml every 8 hours) and developed hyperphospha­ temia, tachycardia, prolongation of the QTc interval, U waves, and tetany. Intravenous rehydration with calcium was required.

Phosphate toxicity from rectal preparations is well described, but has only once been previously attributed to an oral formulation in the absence of underlying renal or gastrointestinal disease (60A). Hyponatremia occurred after the use of an oral sodium phosphate bowel formula­ tion (61A).  A 64-year-old woman with a previous gastrect­

omy developed hyponatremia and had a con­ vulsion after using an oral sodium phosphate bowel formulation. She recovered after correc­ tion of the hyponatremia.

Chapter 36

R.J. Ali and H.R. Dalton

The gastrectomy was thought to have predisposed her to severe metabolic derangements, which have previously only been attributed to sodium phosphate in patients with renal, hepatic, or cardiac co-morbidity. Drug formulations A standard sodium phosphate bowel formulation has been compared with a residue-free formulation of sodium phosphate in 704 patients in a multicenter, randomized, blinded study (62C). The safety and efficacy data and patient preferences all significantly favored the residue-free formulation. There was a single serious adverse event in those who used the residue-free formulation: a man with a previous cardiac transplant and occlusive cardiovascular disease developed localized ischemic colitis, which resolved; this was thought to be due to dehydration, excess diarrhea, and a motility response to the purgative; there were no long-term consequences.

Polyethylene glycol

(SED-15, 1516; SEDA-29, 375; SEDA-30, 567; see also Phosphates)

Observational studies In order to assess the efficacy of polyethylene glycol solution as an oral contrast agent, 39 patients fasted from 12:00 hours and were given 500–750 ml of the oral contrast medium (one sachet of Norgine reconstituted in 1 l of water) 15 min­ utes before magnetic resonance imaging (63c). Norgine is a balanced mixture of polyethylene glycol and electrolytes, which when added to water produces a colorless, iso-osmotic solution. Visualization of the jejunum, ileal lips, and ileocecal region was excellent or sufficient in 87, 95, and 89%, respectively. The time taken to obtain complete visualization of the small bowel, from the jejunum to the ileocecal region, was (mean 65) 15–240 minutes, and in 74% of the patients imaging had to be delayed. Comparative studies Children with neuro­ genic constipation (n ¼ 67) were enrolled in a randomized comparative assessment of the

Gastrointestinal drugs

Chapter 36

efficacy and safety of polyethylene glycol 4000 and lactulose over 6 months (64c). Polyethylene glycol was more effective in treating constipation. There were no serious adverse events and no significant differences in overall adverse events between the groups. The reported symptoms included poor palatability, diarrhea, flatulence, nausea, and abdominal pain. Susceptibility factors Age Ferring and Casen Fleet Laboratories, in consultation with Afssaps, have revised the product monograph for sodium phosphates oral solution (Fleets Phospho-Sodas), advising prior evaluation of susceptibility factors and caution when using the product in elderly people, in whom it has been associated with rare but severe and potentially fatal cases of electrolyte disturbances (65S). Other patients in whom care should be taken are those with asymptomatic renal insufficiency or a history of acute myocardial infarction or unstable angina. Baseline electrolyte con­ centrations should be measured before and after administration and sufficient fluid replacement should be ensured, to prevent dehydration and serious electrolyte pro­ blems.

(SED-15, 138; SEDA-28, 408; SEDA-29, 377; SEDA30, 428)

AMINOSALICYLATES

Balsalazide

(SEDA 29, 377)

Skin Toxic epidermal necrolysis has been attributed to balsalazide (66A) in a patient who had previously had a severe reaction to sulfasalazine, with a purpuric rash, spleno­ megaly, lymphadenopathy, fever, raised liver enzymes and inflammatory markers, and a coagulopathy. This resolved on with­ drawal of sulfasalazine. Subsequent rechal­ lenge with balsalazide caused toxic epidermal necrolysis and required ventila­ tory support and a hospital stay of 28 days. The authors suggested that it may be illadvised to rechallenge patients with a mesalazine derivative after a documented reaction.

583

Mesalazine (5-aminosalicylic acid, mesalamine) (SEDA-28, 408; SEDA-29, 378; SEDA-30, 428) Comparative studies Alicaforsen is an antisense oligonucleotide inhibitor of expression of intracellular adhesion mole­ cule 1 protein, used in the treatment of ulcerative colitis. Mesalazine enemas and alicaforsen enemas have been compared in a randomized, double-blind, multicenter trial in 190 subjects (67c). There was no significant difference in efficacy. However, those who took alicaforsen seemed to have more durable improvement. There were no ser­ ious adverse events related to drug therapy in either group. Gastrointestinal adverse events were more common with mesalazine. Other adverse events included fatigue, sinusitis, arthralgia, headache, and rash. Overall 64% of subjects reported adverse events from mesalazine, 60% from alicaforsen. It has been suggested that probiotics may be beneficial in ulcerative colitis, since intestinal bacteria have been implicated in its pathogenesis. Mesalazine 2400 mg/day and Lactobacillus GG (18  109 viable bacteria/day) have been compared in 187 patients with quiescent ulcerative colitis (68c). There was no significant difference in relapse rate between the groups; patients who relapsed were likely to relapse sooner with mesalazine. Adverse events were not discussed, but it was noted that no patients withdrew early. Cardiovascular Acute myopericarditis has again been reported in patients taking mesalazine; in one case there was also mitral valve insufficiency (69A, 70A).

PREBIOTICS

(SEDA 29, 379)

Lactobacillus rhamnosus

Strains of L. rhamnosus have previously been shown to be effective in treating infectious diarrhea in children. A product called Lakcid L, which contains three strains of L. rhamnosus (573L/1, 573L/2,

584 573L/3), has been compared with placebo in 87 children with infectious diarrhea (71c). Lakcid L significantly reduced the duration of infectious diarrhea due to rotavirus, but

Chapter 36

R.J. Ali and H.R. Dalton

not in other infectious diarrheas. In all types of diarrhea, those who took Lakcid L required significantly less parenteral rehy­ dration. No adverse events were reported.

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preventing postoperative nausea and vomit­ ing. Anesth Analg 2006;103(5):1155–62. Freedman SB, Adler M, Seshadri R, Powell EC. Oral ondansetron for gastroenteritis in a pediatric emergency department. N Engl J Med 2006;354:1698–705. Nathan C, Tomlinson G, Dupuis LL, Greenberg ML, Ota S, Bartels U, Feldman BM. A pilot study of ondansetron plus metopimazine vs. ondansetron monother­ apy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial Nof-1 trials design. Support Care Cancer 2006;14:268–76. Aapro MS, Grunberg SM, Manikhas GM, Olivares G, Suarez T, Tijulandin SA, Bertoli LF, Yunus F, Morrica B, Lordick F, Macciocchi A. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemother­ apy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol 2006;17:1441–9. Eberhart LHJ, Büning EK, Folz B, May­ bauer DM, Kästner M, Kalder M, Koch T, Kranke P, Wulf H. Anti-emetic prophylaxis with oral tropisetron and/or dexametha­ sone. Eur J Clin Invest 2006;36:580–7. Yamao J, Kikuchi E, Matsumoto M, Nakayama M, Ann T, Kojima H, Mitoro A, Yoshida M, Yoshikawa M, Yajima H, Mayauchi Y, Ono H, Akiyama K, Sakurai G, Kinoshita Y, Haruma K, Takakura Y, Fukui H. Assessing the efficacy of famotidine and rebamipide in the treatment of gastric mucosal lesions in patients receiving long­ term NSAID therapy (FORCE—famotidine or rebamipide in comparison by endoscopy). J Gastroenterol 2006;41:1178–85. Ye BD, Cheon JH, Choi KD, Kim SG, Kim JS, Jung HC, et al. Omperazole may be superior to famotidine in the management of iatrogenic ulcer after endoscopic mucosal resection: a prospective randomized con­ trolled trial. Aliment Pharmacol Ther 2006; 24:837–43. Jensen DM, Pace SC, Soffer E, Comer GMMembers of the 315 Study Group. Continuous infusion of pantoprazole versus ranitidine for prevention of ulcer rebleeding: a U.S. multicenter randomized, double-blind study. Am J Gastroenterol 2006;101:1991–9.

585 24. Warrington S, Baisley K, Dunn K, Boyce M, Morocutti A. Effects of single doses of rabeprazole 20 mg and esomeprazole 40 mg on 24-h intragastric pH in healthy subjects. Eur J Clin Pharmacol 2006;62:685–91. 25. Goldstein JL, Miner Jr PB, Schlesinger PK, Liu S, Silberg DG. Intragastric acid control in non-steroidal anti-inflammatory drug users: comparison of esomeprazole, lanso­ prazole and pantoprazole. Aliment Phar­ macol Ther 2006;23:1189–96. 26. Regula J, Butruk E, Dekkers CPM, deBoer SY, Raps D, Simon L, et al. Prevention of NSAID-associated gastrointestinal lesions: a comparison study pantoprazole versus omeprazole. Am J Gastroenterol 2006;101: 1747–55. 27. Lightdale CJ, Schmitt C, Hwang C, Hame­ lin B. A multicenter, randomized, doubleblind, 8-week comparative trial of low-dose esomeprazole (20 mg) and standard-dose omeprazole (20 mg) in patients with erosive esophagitis. Dig Dis Sci 2006;51:852–7. 28. Schmitt C, Lightdale CJ, Hwang C, Hame­ lin B. A multicenter, randomized, doubleblind, 8-week comparative trial of standard doses of esomeprazole (40 mg) and ome­ prazole (20 mg) for the treatment of erosive esophagitis. Dig Dis Sci 2006;51:844–50. 29. Bytzer P, Morocutti A, Kennerly P, Ravic M, Miller N. Effect of rabeprazole and omeprazole on the onset of gastro-oesophageal reflux disease symptom relief during the first seven days of treatment. Scand J Gastroenterol 2006;41:1132–40. 30. Ji S, Kim HS, Kim JW, Jee MK, Park KW, Uh Y, et al. Comparison of the efficacy of rabeprazole 10 mg and omeprazole 20 mg for the healing rapidity of peptic ulcer diseases. J Gastroenterol Hepatol 2006;21:1381–7. 31. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pup inhibitor therapy and risk of hip fracture. JAMA 2006;296:2947–53. 32. Yearsley KA, Gilby LJ, Ramadas AV, Kubiak EM, Fone DL, Allison MC. Proton pump inhibitor therapy is a risk factor for Clostridium difficile-associated diarrhoea. Aliment Pharmacol Ther 2006;24:613–9. 33. Scheiman JM, Yeomans ND, Talley NJ, Vakil N, Chan FKL, Tulassay Z, et al. Prevention of ulcers by esomeprazole in atrisk patients using non-selective NSAIDs

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and COX-2 inhibitors. Am J Gastroenterol 2006;101:701–10. van Zanten SV, Armstrong D, Chiba N, Flook N, White RJ, Chakraborty B, Gasco A. Esomeprazole 40 mg once a day in patients with functional dyspepsia: the ran­ domized, placebo-controlled “ENTER” trial. Am J Gastroenterol 2006;101:2096–106. Spechler SJ, Sharma P, Traxler B, Levine D, Falk GW. Gastric and esophageal pH in patients with Barrett’s esophagus and trea­ ted with three esomeprazole dosages: a randomized, double-blind, crossover trial. Am J Gastroenterol 2006;101:1964–71. Howden CW, Metz DC, Hunt B, Vakily M, Kukulka M, Amer F, et al. Dose-response evaluation of the antisecretory effect of continuous infusion intravenous lansopra­ zole regimens over 48 h. Aliment Pharma­ col Ther 2006;23:975–84. Cahan MA, Balduf L, Colton K, Palacioz B, McCartney W, Farrell TM. Proton pump inhibitors reduce gallbladder function. Surg Endosc 2006;20:1364–7. Pan Y, Chong AH, Williams RA, Green J, Sinclair R. Omeprazole-induced dermato­ myositis. Br J Dermatol 2006;154:557–8. Sennaroglu E, Karakan S, Kayatas M, Akdur S, Genc H, Karakan T, et al. Reversible edema in a male patient taking parenteral pantoprazole infusion for pyloric stenosis. Dig Dis Sci 2006;51(1):121–2. Metz DC, Comer GM, Soffer E, Forsmark CE, Cryers B, Chey W, et al. Three-year oral pantoprazole administration is effective for patients with Zollinger–Ellison syn­ drome and other hypersecretory conditions. Aliment Pharmacol Ther 2006;23:437–44. Pratha V, Hogan DL, Lynn RB, Field B, Metz DC. Intravenous pantoprazole as initial treatment in patients with gastroeso­ phageal reflux disease and a history of erosive esophagitis: a randomized clinical trial. Dig Dis Sci 2006;51:1595–601. De Boer W, De Wit N, Geldof H, Hazelhoff B, Bergmans P, Smout A, et al. Does Helicobacter pylori infection influence response rate or speed of symptom control in patients with gastroesophageal reflux disease treated with rabeprazole?. Scan J Gastroenterol 2006;41:1147–54. Morocutti A, Merrouche M, Bjaaland T, Humphries T, Mignon M. An open-label

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study of rabeprazole in patients with Zollinger–Ellison syndrome or idiopathic gastric acid hypersecretion. Aliment Pharmacol Ther 2006;24:1439–44. Thomson ABR, Cohen P, Ficheux H, Fiorentini P, Domagala F, Homerin M, et al. Comparison of the effects of fasting morning, fasting evening and fed bedtime administration of tenatoprazole on intragastric pH in healthy volunteers: a rando­ mized three-way crossover study. Aliment Pharmacol Ther 2006;23:1179–87. Wong WM, Gu Q, Chu K-M, Yee YK, Fung FMY, Tong TSM, et al. Lansoprazole, levo­ floxacin and amoxicillin triple therapy vs. quadruple therapy as second-line treatment of resistant Helicobacter pylori infection. Aliment Pharmacol Ther 2006;23:421–7. Wu DC, Hsu PI, Chen A, Lai KH, Tsay FW, Wu CJ, et al. Randomized comparison of two rescue therapies for Helicobacter pylori infec­ tion. Eur J Clin Invest 2006;36(11):803–9. Kawai T, Kawakami K, Kataoka M, Taira S, Itoi T, Moriyaus F, et al. Comparison of efficacies of dual therapy and triple therapy using rabeprazole in second-line eradication of Helicobacter pylori in Japan. Aliment Pharmacol Ther 2006;24(Suppl 4):16–22. Gasbarrini A, Lauritano EC, Nista EC, Candelli M, Gabrielli M, Santoro M, et al. Rifaximin-based regimens for eradication of Helicobacter pylori: a pilot study. Dig Dis 2006;24:195–200. Graham DY, Abudayyeh S, El-Zimaity HMT, Hoffman J, Reddy R, Opekun AR. Sequential therapy using high-dose esome­ prazole-amoxicillin followed by gatifloxacin for Helicobacter pylori infection. Aliment Pharmacol Ther 2006;24:845–50. Higuchi K, Maekawa T, Nakagawa K, Chouno S, Hayakumo T, Tomono N, et al. Efficacy and safety of Helicobacter pylori eradication therapy with omeprazole, amoxicillin and high- and low-dose clari­ thromycin in Japanese patients. Clin Drug Invest 2006;26(7):403–4. Borody TJ, Pang G, Wettstein AR, Clancy R, Herdman K, Surace R, et al. Efficacy and safety of rifabutin-containing ‘rescue therapy’ for resistant Helicobacter pylori infection. Aliment Pharmacol Ther 2006;23:481–8. Cardenas VM, Graham DY, El-Zimaity HMT, Opekun AR, Campos A, Chavez

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A, et al. Rabeprazole containing triple therapy to eradicate Helicobacter pylori infection on the Texas–Mexican border. Aliment Pharmacol Ther 2006;23:295–301. Giannini EG, Bilardi C, Dulbecco P, Mamone M, Santi ML, Testa R, et al. Can Helicobacter pylori eradication regimens be shortened in clinical practice? An openlabel, randomized, pilot study of 4 and 7­ day triple therapy with rabeprazole, highdose levofloxacin, and tinidazole. J Clin Gastroenterol 2006;40:515–20. Tam YH, Yeung CK, Lee KH. Seven-day is more effective than 4-day ranitidine bis­ muth citrate-based triple therapy in eradi­ cation of Helicobacter pylori in children: a prospective randomized study. Aliment Pharmacol Ther 2006;24:81–6. Kienzle-Horn S, Vix JM, Schuijt C, Peil H, Jordan CC, Kamm MA. Efficacy and safety of bisacodyl in the acute treatment of constipation: a double-blind, randomized, placebo-controlled study. Aliment Pharmacol Ther 2006;23:1479–88. Mathus-Vliegen EMH, Kemble UM. A prospective randomized blinded comparison of sodium phosphate and polyethylene glycolelectrolyte solution for safe bowel cleansing. Aliment Pharmacol Ther 2006;23:543–52. Bitoun A, Ponchon T, Barthet M, Coffin B, Dugue C, Halphen M, et al. Results of a prospective randomised multicentre controlled trial comparing a new 2L ascorbic acid plus polyethylene glycol and electrolyte solution vs. sodium phosphate solution in patients undergoing elective colonoscopy. Aliment Pharmacol Ther 2006;24:1631–42. Tan JJY, Tjandra JJ. Which is the optimal bowel preparation for colonoscopy—a metaanalysis. Colorectal Dis 2006;8:247–58. Domico MB, Huynh V, Anand SK, Mink R. Severe hyperphosphatemia and hypocalce­ mic tetany after oral laxative administration in a 3-month-old infant. Pediatrics 2006;118: e1580–3. Levitt M, Gessert C, Finberg L. Inorganic phosphate (laxative) poisoning resulting in tetany in an infant. J Pediatr 1973;82:479–81. Liu SYW, Cheung FKY, Siu WT, Ng EKW. Hyponatraemic convulsion after oral sodium phosphate for bowel preparation in a patient with previous gastrectomy. Endoscopy 2006;38:854–5.

587 62. Rex DK, Schwartz H, Goldstein M, Popp J, Katz S, Barish C, et al. Safety and coloncleansing efficacy of a new residue-free formulation of sodium phosphate tablets. Am J Gastroenterol 2006;101:2594–604. 63. McKenna DA, Roche CJ, Murphy JMP, McCarthy PA. Polyethylene glycol solution as an oral contrast agent for MRI of the small bowel in a patient population. Clin Radiol 2006;61(11):966–70. 64. Rendeli C, Ausili E, Tabacco F, Focarelli B, Pantanella A, Di Rocco C, Genovese O, Fundarò C. Polyethylene glycol 4000 vs. lactulose for the treatment of neurogenic constipation in myelomeningocele children: a randomized-controlled clinical trial. Ali­ ment Pharmacol Ther 2006;23:1259–65. 65. Anonymous. Sodium phosphate oral solu­ tion. Electrolyte and renal function disturbances in the elderly. WHO Pharm Newslett 2007;1:3. 66. Iemoli E, Piconi S, Ardizzone S, Porro GB, Raimond F. Erythroderma and toxic epider­ mal necrolysis caused by 5-aminosalicylic acid. Inflamm Bowel Dis 2006;12:1007. 67. Miner Jr PB, Wedel MK, Xia S, Baker F. Safety and efficacy of two dose formulations of alicaforsen enema compared with mesalazine enema for treatment of mild to moderate left-sided ulcerative colitis: a randomized, double-blind, active-controlled trial. Aliment Pharmacol Ther 2006;23:1403–13. 68. Zocco MA, Zileri dal Verme L, Cremonini F, Piscaglia AC, Nista EC, Candelli M, et al. Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 2006;23:1567–74. 69. Garcia-Moran S, Sáez-Royuela F, Pérez­ Álvarez JC, Gento E, Téllez J. Myoper­ icarditis and mitral insufficiency associated with ulcerative colitis treated with mesalazine. Inflamm Bowel Dis 2006;12:334–5. 70. Dogannay L, Akinci B, Pekel N, Simsek I, Akpinar H. Mesalazine-induced myoperi­ carditis in a patient with ulcerative colitis. Int J Colorectal Dis 2006;21:199–200. 71. Szymanski H, Pejcz J, Jawien M, Chmie­ larczyk A, Strus M, Heczko PB. Treatment of acute infectious diarrhoea in infants and children with a mixture of three Lactobacillus rhamnosus strains—a randomized, double-blind, placebo-controlled trial. Aliment Pharmacol Ther 2006;23:247–53.

F.A. Goumas, F. Braun, D.C. Broering, and M. Behrend

37

Drugs that act on the immune system: cytokines and monoclonal antibodies

COLONY-STIMULATING FACTORS (SEDA-26, 398; SEDA-28, 415; SEDA-29, 383; SEDA-30, 435)

Granulocyte colony-stimulating factor (G-CSF) and granulocytemacrophage colony-stimulating factor (GM-CSF) (SED-15, 1542; SEDA-28, 415; SEDA-29, 383; SEDA-30, 435)

Guidelines Colony-stimulating factors improve granulocyte count in neutropenic patients, reduce the incidence and duration of neutropenia in patients receiving cytotoxic chemotherapy, and mobilize peripheral blood stem cells before leukapheresis in both autologous and allogeneic hemopoietic cell transplantation. In cancer chemotherapy, the use of guidelines should make it pos­ sible to target colony-stimulating factors to appropriate patients during the first cycle, when the risk of neutropenia is highest. Guidelines from the National Comprehensive Cancer Network on the use of myeloid growth factors with cancer chemotherapy include disease- and patientrelated factors along with the risks of the These chemotherapy regimen (1S). guidelines differ from previous guidelines, Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03137-7 r 2009 Elsevier B.V. All rights reserved.

in that they recommend the routine use of colony-stimulating factors in patients in whom the risk of neutropenia is over 20% (the previous threshold was 40%). This recommendation is based on data that show the clinical benefits of filgrastim and pegfilgrastim in studies in which the overall populations had risks of febrile neutropenia of 20–40%. The 2000 American Society of Clinical Oncology guidelines for the use of hematopoietic colony-stimulating factors were updated in 2006 (2S). The 2005 Update Committee agreed that a reduction in febrile neutropenia is an important clinical outcome that justifies the use of colony-stimulating factors, regardless of the impact on other factors, when the risk of febrile neutropenia is about 20% and there is no other equally effective regimen that does not require colony-stimulating factors. Primary prophylaxis is recommended for the prevention of febrile neutropenia in patients who are at high risk, based on age, medical history, disease characteristics, and the myelotoxicity of the chemotherapy regimen. The use of colony-stimulating factors allows a modest to moderate increase in chemotherapy dosage regimens. The prophylactic use of colony-stimulating factors for patients with diffuse aggressive lymphoma aged 65 years and older treated with curative chemotherapy (CHOP or more aggressive regimens) reduces the incidence of febrile neutropenia and infections. Current recommendations for the management of patients exposed to lethal doses of total body radiotherapy, but not doses high enough to lead to certain death through injury to other organs, includes the prompt

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administration of colony-stimulating factor or pegylated G-CSF. Observational studies The Severe Chronic Neutropenia International Registry (SCNIR) has collected data from patients with hematological disorders causing blood neu­ trophil counts below 500
106/l for months or years (3C). Of 1163 patients in the SCNIR, 1053 (91%) have been treated with G-CSF (median dose 3.33 mg/kg/day). Adverse effects included osteoporosis/ osteopenia (14%) and myelodysplastic syn­ drome or acute myelocytic leukemia (4.9%). Comparative studies In a preliminary randomized, blind, controlled comparison with usual care in 10 patients with acute cerebral infarction who presented within 7 days of onset, subcutaneous G-CSF 15 mg/kg/day for 5 days produced greater improvement in neurological function; there were no severe adverse effects (4c). However, concerns about the use of G-CSF in these circumstances have been raised because of the fears about transient hypercoagulability, which may be important for thrombophilic, atherosclerotic, or immobilized patients. (5r). This may be related to increased amounts of endothelial markers and thrombin generation or by stimulating tissue factor. There have been a few reports of acute arterial thrombo­ sis in patients receiving G-CSF, supporting the hypothesis of hypercoagulability. In addi­ tion, there have been cases of acute arterial thrombosis in healthy donors, possibly related to G-CSF. Hematologic Life-threatening adverse effects, such as splenic rupture, are supposed to be very rare during treatment with G-CSF, but several cases have been reported.  Spontaneous splenic rupture secondary to

high-dose G-CSF 20 mg/kg/day occurred in a healthy female allogeneic donor of peripheral blood stem cells (6Ar).  A patient with multiple myeloma undergoing autologous peripheral blood stem cell trans­ plantation developed splenic rupture after administration of pegfilgastrim (7A).

Hematological malignancies after the administration of PEG-rHuMGDF or G-CSF

occurred in three of 538 volunteers who received PEG-rHuMGDF in clinical trials and two of 200 donors who underwent GCSF-mobilized stem cell harvesting proce­ dures for sibling stem cell transplants (8c). Mantle cell lymphoma, diffuse large B cell lymphoma, and chronic lymphocytic leuke­ mia were diagnosed 1–5 years after PEG­ rHuMGDF exposure in three volunteers. One patient developed thrombocytopenia due to autoantibodies shortly after PEG­ rHuMGDF administration. Myeloid leuke­ mia was diagnosed 4 and 5 years after G-CSF mobilization in two donors who underwent peripheral blood stem cell donation for sibling allogeneic hemopoietic stem cell transplantation. After intensive chemother­ apy, one patient died from acute leukemia and the second achieved complete remission. There is controversy about the appropriate­ ness of giving hemopoietic growth factors to healthy individuals. While a causal relation to hematological malignancies cannot be demonstrated, long-term follow-up of healthy individuals who receive hemopoietic growth factors is needed. The long-term effects of in vivo G-CSF stimulation of the hemopoietic system during radiotherapy have been investigated in a prospective, randomized trial in 10 patients (mean age 51 years; 6 men, 4 women) with non­ Hodgkin’s lymphoma (n ¼ 7), Hodgkin’s lymphoma (n ¼ 1), or small-cell carcinomas of the lung (n ¼ 2) (9C). They were rando­ mized to either large-field radiotherapy alone or radiotherapy with simultaneous G­ CSF and were assessed for acute and late toxicity. Platelets and CD34 superset+ pro­ genitor cells fell significantly in the G-CSF treatment group and further treatment was stopped. Peripheral leukocyte counts were 2.8–4.4
109/l in 9/10 patients. In those who were given G-CSF mean platelet counts fell below 30
109/l and CD34 superset+ pro­ genitor cells to 50%. Hemoglobin did not vary. Differential blood smears showed differences in granulocyte counts and a higher proportion of neutrophils in those who were given G-CSF. Lymphocyte counts in patients who were not given G-CSF were significantly less than in those who were. Simultaneous treatment with G-CSF during radiotherapy reduced the mobilization of

Drugs that act on the immune system: cytokines and monoclonal antibodies

CD34+ progenitor cells and exhausted the bone marrow capacity, while peripheral leukocyte counts remained at baseline. A myelodysplastic syndrome has been reported after G-CSF treatment (10A).  A 42-year-old woman was given G-CSF for

severe neutropenia and subsequently devel­ oped a myelodysplastic syndrome with fibro­ sis, cervical lymphadenopathy, and cutaneous infiltration by extramedullary hemopoiesis. There was no hepatosplenomegaly. The extra­ medullary hemopoiesis disappeared after G­ CSF was withdrawn.

G-CSF may worsen anemia in breast cancer (11C). In 506 patients with stage I and stage II breast cancer who received epirubicin 120 mg/m2 + cyclophosphamide 600 mg/m2 only, epirubicin + cyclophospha­ mide + lonidamine, or epirubicin + cyclo­ phosphamide + lonidamine + G-CSF (n ¼ 246), more patients assigned to G­ CSF (39%) than those assigned to epirubi­ cin + cyclophosphamide (26%) had grade II anaemia or worse. After the third cycle of chemotherapy there was a significant over­ all reduction in mean hemoglobin concen­ tration in women who were given G-CSF. The mean hemoglobin concentration was lower in those who received four or seven injections of G-CSF than in those who received only two injections. Skin Sweet’s syndrome has been reported after G-CSF therapy (12M).  A 62-year-old man with chronic lymphocytic

leukemia developed neutropenic fever and sepsis. After treatment with G-CSF he devel­ oped Sweet’s syndrome (13A).  Four days after the start of treatment with G­ CSF 10 mg/kg/day a 29-year-old healthy donor developed signs of Sweet’s syndrome (14A). She had fatigue and developed exudative erythematous plaques on the neck, trunk, and arms. G-CSF was withdrawn and oral pre­ dnisolone was started, after which the symp­ toms improved.

Musculoskeletal “Hair-on-end” skull changes on plain skull radiographs and MRI have been reported in association with G-CSF in a child with severe con­ genital neutropenia (15A). The skull changes were probably caused by

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expansion of white blood cell precursors induced by long-term daily injections of recombinant human G-CSF. This symptom is typical in patients with thalassemia. Body temperature Two patients with malignant lymphoma developed high fevers (16A). One patient received stem cells mobilized with CHASER therapy (cyclo­ phosphamide, cytarabine, etoposide, dexa­ methasone, and rituximab) followed by subcutaneous filgrastim 600 mg/day. Serum CRP increased to 56 mg/l and the tempera­ ture to 38.91C. The other patient was given CHASE therapy followed by subcutaneous filgrastim 75 mg/day. Serum CRP increased to 122 mg/l and temperature to 38.91C. Neither had an infection. Multiple antibac­ terial agents were ineffective. After with­ drawal of G-CSF, the fever dissipated and the CRP returned to the reference range.

(SED-15, 1841; SEDA-28, 416; SEDA-29, 384; SEDA-30, 436)

INTERFERONS

Interferon alfa (SED-15, 1793; SEDA­ 29, 386; SEDA-30, 436) Psychiatric Interferon alfa can cause depressive symptoms and potentially dangerous psychiatric adverse effects (17b). Depressive symptoms were studied in 186 patients with chronic hepatitis C during treatment for 48 weeks with pegylated interferon alfa-2a and pegylated interferon alfa-2b. Depressive symptoms increased from 53% at baseline to 61% at 12 weeks with pegylated interferon alfa-2a and from 57% to 65% with pegylated interferon alfa-2b. Three patients had lifethreatening psychiatric symptoms with pegylated interferon alfa-2a (psychosis and delirium requiring withdrawal of antiviral therapy and admission to a psychiatric unit). This study underlines the fact that long-term interferon can be associated with serious psychiatric adverse effects. It is very important that psychiatric symptoms are

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diagnosed early during treatment in order to improve adherence to treatment and to prevent fatal and/or life-threatening adverse events. Urinary tract Interferon alfa and ribavirin combination therapy for chronic infection with hepatitis C virus produces a number of well-described adverse effects. Combina­ tion therapy with pegylated interferon yields an adverse event profile similar to that observed with standard interferon, although the frequency of certain adverse events varies according to the formula­ tion. Simultaneous thrombocytopenia and nephrotic syndrome has been reported (18A).  A 44-year-old man was given ribavirin and

pegylated interferon alfa-2b for chronic hepa­ titis C. After 16 weeks he simultaneously developed severe thrombocytopenia and nephrotic syndrome due to focal segmental glomerulosclerosis. Both are rare adverse effects. Antiviral treatment was immediately interrupted. He received immunosuppressive therapy and promptly recovered from the thrombocytopenia and partially and slowly from the nephrotic syndrome.

adjusted event rate of serious infections was higher in patients treated with anakinra for 0–3 years (5.4 events/100 patient-years) than for controls during the blinded phase (1.7 events/100 patient-years). However, if the patient was not receiving corticosteroid treatment at baseline, the serious infection rate was substantially lower (2.9 events/100 patient-years). Skin Metastatic malignant melanoma occurred in a patient taking anakinra (20A).  A 61-year-old man with rheumatoid arthritis

was given anakinra 100 mg/day and 3 years later a biopsy of a pigmented skin lesion behind his right ear showed a malignant melanoma with metastases in several cervical lymph nodes and in the right parotid gland. The stage was T3a, N3, M1.

TUMOR NECROSIS FACTOR ALPHA (TNF-a) ANTAGONISTS (SEDA-28, 425; SEDA-29, 395; SEDA-30, 439)

(SED-15, 1842; SEDA-28, 424; SEDA-29, 394; SEDA-30, 438)

INTERLEUKINS

Anakinra (interleukin-1 receptor antagonist) (SED-15, 215; SEDA-29, 394)

Infection risk Anakinra 100 mg/day has been compared with placebo in 1346 patients with rheumatoid arthritis in a 6­ month, randomized, double-blind study. The most frequent adverse events were injection site reactions (122 events/100 patient-years), rheumatoid arthritis progression (68 events/100 patient-years), and upper respiratory infections (26 events/ 100 patient-years) (19C). The exposure

The use of antagonists of TNF-a in the treatment of inflammatory bowel disease has been reviewed (21R). Observational studies In 95 patients with juvenile idiopathic arthritis, median age 14 (range 4–34) years, median duration of therapy 12 (range 1–40) months, who were given etanercept and 56 who were given infliximab, adverse effects that were defi­ nitely related to etanercept were severe headache and thrombocytopenia and those related to infliximab were infusion reactions and anti-dsDNA positivity (22c). Adverse effects that were probably related to both agents were behavioral changes and pain amplification syndrome. New Crohn’s dis­ ease was probably related to treatment with etanercept in three patients. Reactions that were possibly related to both agents were iridocyclitis, thyroid cancer, hypoglossal

Drugs that act on the immune system: cytokines and monoclonal antibodies

nerve paralysis, and a severe cytomegalo­ virus pulmonary infection. There were no cases of tuberculosis. Nervous system An acute or subacute demyelinating polyneuropathy may be an adverse effect of TNF-a antagonist therapy. Guillain–Barré syndrome and its variant, the Miller Fisher syndrome, during TNF-a antagonist therapy have been studied in a postmarketing study of the database of the Food and Drug Administration (FDA) after a patient with rheumatoid arthritis devel­ oped the Miller Fisher syndrome while he was receiving infliximab (23Ac) (see below under infliximab). The index patient had a neurological illness defined initially by ataxia and dysarthria, which fluctuated in relation to each subsequent infliximab infusion and after 6 months culminated in areflexic flaccid quadriplegia. In 15 other patients Guillain– Barré syndrome developed after TNF-a inhibitor therapy, infliximab in nine patients, etanercept in five, and adalimumab in one. Of the 13 patients with follow-up data, one had no resolution, nine had partial resolu­ tion, and three had complete resolution of Guillain–Barré syndrome after therapy. Skin Eruptive nevi have been described in patients receiving TNF-a antagonists (24A). One patient with Crohn’s disease was given azathioprine and infliximab and developed eruptive nevi, particularly on the palms and soles. Another patient had plaque psoriasis and developed eruptive nevi during two episodes of treatment with alefacept and etanercept. Immunologic A link between TNF-a antagonists and vasculitis has been sug­ gested. In a French nationwide survey between December 2004 and January 2005, 1200 hospital-based rheumatologists and internists identified 39 patients with vasculi­ tis during TNF-a antagonist therapy; 32 were women (25c). The joint disease was rheuma­ toid arthritis in 34 patients (including four without rheumatoid factor), juvenile idio­ pathic arthritis in two patients, ankylosing

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spondylitis in two patients, and psoriatic arthritis in one patient. The TNF-a antago­ nist was etanercept in 21 patients, infliximab in 15, adalimumab in two, and another drug in one; mean treatment duration was 9.6 months. The vasculitis involved the skin (n ¼ 32); peripheral nervous system (n ¼ 9); kidney (n ¼ 7); central nervous system (n ¼ 3); pleura (n ¼ 2); pericardium (n ¼ 2); and the lung, gallbladder, and heart (n ¼ 1 each). Antinuclear factor (ANF) was present in 22 patients, hypocomplementemia in six, and antineutrophil cytoplasmic anti­ bodies (ANCA) in five. Histology (30 biopsies from 27 patients) showed nonnecrotizing vasculitis in 12 patients, necrotiz­ ing vasculitis in seven, an inflammatory dermal infiltrate without vasculitis in three, extravascular necrotic granulomata in two, lupus in one, and cicatricial fibro-inflamma­ tory changes in one. Renal biopsy in three patients showed extracapillary glomerulone­ phritis with IgA deposits (n ¼ 2) or active floccular necrosis against a background of glomerulosclerosis (n ¼ 1). TNF-a antago­ nist therapy was withheld in 33 patients, of whom 18 recovered without further treat­ ment and 14 required high-dose glucocorti­ coids and/or immunosuppressants, with symptom resolution within a few weeks. The other patient died with multiple organ failure. Features that suggested a causal link between TNF-a antagonists and vasculitis included a short time from the start of treatment to the onset of the vasculitis; a favorable response to withdra­ wal; and systemic vasculitis in patients with rheumatoid factor-negative rheumatoid arthritis, in adults with juvenile-onset arthri­ tis, and in patients with spondyloarthro­ pathies. All exogenous proteins can cause antibody formation. Anti-infliximab antibo­ dies during treatment for ankylosing spon­ dylitis and rheumatoid arthritis have been demonstrated (26A,27c). The development of anti-infliximab antibodies is associated with a reduced response to treatment. Both acute and delayed hypersensitivity reactions have been associated with intrave­ nous infliximab (28A). The delayed forms can present as a serum sickness-like

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illness, and recognition of the clinical man­ ifestations becomes crucial for early diag­ nosis and treatment.

Infection risk from antagonists of TNF-a Since their approval, concerns have been raised regarding the safety of TNF-a antago­ nists (29R,30R). TNF-a plays a crucial role in host defences against bacterial infections. Immunological and clinical studies have suggested that there is a higher risk of infection in patients with rheumatoid arthri­ tis or ankylosing spondylitis who receive TNF-a antagonists, because they have active and more severe disease. They should, therefore, be closely monitored for serious infections, and rapid and adequate treatment of infections that are not mild and transient is recommended. Atypical signs and symp­ toms can occur and atypical pathogens can be involved. Patients should be educated about how to avoid infectious complications. All serious infections were analyzed in a national prospective observational study in 7664 patients with severe rheumatoid arthritis who were given TNF-a antagonists and 1354 who were given disease modifying antirheu­ matic drugs (DMARDs) (31C). There were 525 serious infections in those who received TNF-a antagonists and 56 in the comparison cohort (9868 and 1352 person-years of follow-up, respectively). The incidence rate ratio (IRR), adjusted for baseline risk, in those who received TNF-a antagonists com­ pared with those who did not was 1.03 (95% CI ¼ 0.68, 1.57). However, the frequency of serious skin and soft tissue infections was increased in those who received TNF-a antagonists, with an adjusted IRR of 4.28 (95% CI ¼ 1.06, 17). There was no difference in infection risk between the three main TNFa antagonists. There were 19 cases of serious bacterial intracellular infections, exclusively in patients who received TNF-a antagonists. In patients with active rheumatoid arthritis, TNF-a antagonists were not associated with an increased overall risk of serious infections compared with DMARDs, after adjustment

for baseline risk. In contrast, the rates of serious skin and soft tissue infections were increased, suggesting an important physiological role of TNF in host defences in the skin and soft tissues beyond that in other tissues. TNF inhibitor therapy may increase the risk of serious postoperative orthopedic infections in patients with rheumatoid arthritis (32c). The risk of infection was studied in 546 patients who underwent at least one orthope­ dic surgical procedure during January 1999 to March 2004. Seven of 21 patients were receiving TNF-a antagonists at the time of procedure and one developed an infection. All together 10 of 91 patients who underwent an orthopedic surgical procedure developed a serious postoperative orthopedic infection. The authors concluded that the prescription of TNF-a inhibitor therapy was significantly associated with the development of serious postoperative infections. This association persisted after adjusting for other susceptibil­ ity factors for infection, such as age, use of prednisone, diabetes mellitus, disease dura­ tion, and rheumatoid factor seropositivity. Data from randomized controlled trials of adalimumab, open extensions, and two phase IIIb open trials have been analyzed and postmarketing spontaneous reports of adverse events in the United States collected after FDA approval of adalimumab on 31 December 2002 (33M). As of 15 April 2005, the rheuma­ toid arthritis clinical trial safety database covered 10 050 patients, representing 12 506 patient-years of exposure. The rate of serious infections, 5.1/100 patient-years, was compar­ able to that reported on 31 August 2002 (4.9/ 100 patient-years), and to the rate in published reports from patients who have not received antitumor necrosis factor therapy. After imple­ mentation of tuberculosis screening in clinical trials, the rate of tuberculosis fell, but there were 34 cases in this analysis (0.27/100 patientyears). The standardized incidence ratio for lymphoma was 3.19 (95% CI ¼ 1.78, 5.26), consistent with the observed increased inci­ dence in patients with rheumatoid arthritis. As of 30 June 2005, there were an estimated 78 522 patient-years of exposure to adalimumab in the US postmarketing period. Seventeen cases of tuberculosis were spontaneously reported (0.02/100 patient-years) from the United States.

Drugs that act on the immune system: cytokines and monoclonal antibodies

Rates of other postmarketing events of interest, such as congestive heart failure, systemic lupus erythematosus, opportunistic infections, blood dyscrasias, lymphomas, and demyelinating disease, supported observations from clinical trials. The extent to which anti-TNF-a antibodies increase the risk of serious infections and malignancies has been assessed in patients with rheumatoid arthritis by performing a meta-analysis to derive estimates of sparse harmful events occurring in randomized trials of TNF-a antagonists (34M). From a systematic literature search (EMBASE, MEDLINE, Cochrane Library, and electro­ nic abstract databases, annual scientific meetings of both the European League Against Rheumatism and the American College of Rheumatology, interviews of the manufacturers of the two licensed anti-TNF-a antibodies, and randomized placebo-con­ trolled trials of infliximab and adalimumab), nine trials met the inclusion criteria; 3493 patients received TNF-a antagonists and 1512 patients received placebo. The pooled odds ratio for serious infections was 2.0 (95% CI ¼ 1.3, 3.1). For serious infections the number needed to treat for harm (NNTH) was 59 (95% CI ¼ 39, 125) during 3–12 months. From July 2001 to December 2003, all patients who received alemtuzumab for lym­ phoproliferative disorders at one institution were evaluated retrospectively to document infectious complications until death or the end of follow-up in October 2004 (35C). Alemtu­ zumab recipients who underwent allogeneic hemopoietic stem cell transplantation were compared with a concurrent cohort who also underwent allogeneic stem cell transplantation but did not receive alemtuzumab. There were 27 patients, 21 with chronic lymphocytic leukemia and six with plasma cell disorders. Overall mortality was 37%, seven of 10 deaths being related to infection. There were signifi­ cant opportunistic infections in nine patients with chronic lymphocytic leukemia, including cytomegalovirus and adenovirus infections, progressive multifocal leukoencephalopathy, toxoplasmosis, and acanthamebiasis. There were also 30 non-opportunistic infections in 22 patients, with three deaths, all involving Enterococcus species bacteremia. Of nine patients who received alemtuzumab six had

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cytomegalovirus reactivation compared with only 10 of 27 patients who did not receive alemtuzumab. Post-transplant opportunistic infections (excluding herpesviruses) occurred in 12/27 patients given alemtuzumab com­ pared with 8/27 controls. Of 449 consecutive transplant recipients who received alemtuzumab, 69 had at least one episode of bloodstream infection (36c). However, none had bacteremia with Streptococcus pneumoniae, Listeria monocy­ togenes, non-typhoidal Salmonella, or Myco­ bacterium avium complex. Fungemia occurred in 1.5% of patients. The most common organisms isolated from the blood were Staphylococcus aureus (21 episodes), coagulase-negative Staphylococcus (14), Klebsiella pneumoniae (12), Enterococcus faecium (11), Pseudomonas aeruginosa (10), Enterococcus faecalis (9), and Escherichia coli (7). The authors concluded that although alemtuzumab is associated with profound CD4 positive T lymphocyte depletion, it does not seem to be associated with an increased risk of bloodstream infection with pathogens that are typically seen in other disorders of CD4 cell depletion, such as acquired immu­ nodeficiency syndrome.  A 40-year-old Caucasian man with rheumatoid

arthritis received infliximab (37A) and 40 days after the 10th dose developed an acutely swollen, painful, erythematous left knee. Direct Gram stain showed Gram-negative pleo­ morphic coccobacilli in pairs or groups. The synovial fluid culture yielded a slow-growing Gram-negative coccobacillus, with pink pig­ mented mucoid colonies. The PCR product was sequenced as a strain of Roseomonas mucosa.  A 42-year-old man with a 13-year history of ankylosing spondylitis was enrolled in a rando­ mized controlled trial of the efficacy of inflix­ imab. After four doses he developed an orbital cellulitis. Culture of a swab from the left eye grew a flucloxacillin-sensitive Staphylococcus aureus (38A).

Tuberculosis There is an especial risk of granulomatous infections in patients treated with the monoclonal TNF-a antibodies infliximab and adalimumab, and TNF-a antagonists can increase the risk of reactiva­ tion of granulomatous diseases, especially tuberculosis. There are differences in the mechanisms of action of infliximab, etaner­ cept, and adalimumab, which might confer

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variations in their associated risks of infec­ tion. Tuberculosis in such patients frequently presents as extrapulmonary or disseminated disease, and clinicians should be vigilant for tuberculosis in any patient taking a TNF-a inhibitor who develops fever, weight loss, or cough. To prevent reactivation of latent tuberculosis infection during TNF-a inhibi­ tor therapy, clinicians should screen all patients for tuberculosis and begin treatment if latent infection is found, before therapy is started. Specific tuberculosis screening and treatment strategies vary between geographi­ cal regions. The screening strategies used in Europe and North America have reduced the occurrence of TNF-a inhibitor-associated tuberculosis and are to be recommended. However, the role of screening in preventing other opportunistic (e.g., fungal) infections is far less certain (39R). In a prospective study of 50 consecutive patients with rheu­ matoid arthritis who were given etanercept, there were serious infections, defined as requiring hospitalization and parenteral antibiotics, in six, including one patient with Streptococcus G septicemia, diverticular dis­ ease, and diabetic gangrene, two with strep­ tococcal pneumonia, two with Staphylococcal aureus soft tissue infections and ulceration, and one with Campylobacter jejuni diarrhea (40c). In 2001, the FDA reported 70 cases of tuberculosis among 147 000 patients treated with infliximab worldwide. This number increased to 117 within 2 months of the report. Tuberculosis associated with TNF-a antagonists has an unusual presentation; more than half of the cases had extrapulmonary disease and a quarter had disseminated disease (41c). Etanercept is also associated with tuber­ culosis and has a similar atypical presenta­ tion, with extrapulmonary disease in more than 50% of the cases. Adalimumab has also been associated with tuberculosis during clinical trials, predominantly at high doses. Viral infections Preliminary data suggest that TNF-a inhibitor therapy may be safe in chronic hepatitis C. However, TNF antago­ nists have resulted in reactivation of chronic hepatitis B if not given concurrently with antiviral therapy.

Fungal infections Pulmonary fungal infections have been reported with TNF-a antagonists (30c). The risk of histoplasmosis, which can be fatal, was reported as 27 per million with etanercept and 1990 per million with infliximab. Other pulmonary fungal infections include cryptococcal infection, invasive pulmonary aspergillosis, and cocci­ dioidomycosis. The incidence of aspergillus was reported as 86 per million with inflix­ imab and 62 per million with etanercept. Pneumocystis jiroveci pneumonia as a com­ plication from treatment with infliximab for rheumatoid arthritis has been reported in a 63-year-old woman (42A). There was no dyspnea and no typical observations on chest X-ray.

Tumorigenicity According to the Austra­ lian Adverse Drug Reactions Advisory Committee (ADRAC), TNF-a antagonists may predispose patients to an increased risk of malignancy or accelerate its development (43S). Since 2000, ADRAC has received 319 reports involving infliximab, etanercept, and adalimumab. The more serious reports were as follows: malignant melanoma (three reports), tuberculosis (n ¼ 4), lymphoma (n ¼ 5), anaphylaxis (n ¼ 9), sepsis (n ¼ 10), lupus or lupus-like syndrome (n ¼ 22), and pneumonia/lower respiratory tract infections (n ¼ 23). The Australian Product Information has advised caution when considering these drugs in patients with a history of malignancy, or when considering continued treatment in those who develop a malignancy. The extent to which TNF-a antibody antagonists increase the risk of serious malignancies has been assessed in patients with rheumatoid arthri­ tis by meta-analysis to derive estimates of sparse harmful events occurring in rando­ mized trials of TNF-a antagonists. From a systematic literature search (EMBASE, MEDLINE, Cochrane Library, and elec­ tronic abstract databases, annual scientific meetings of both the European League Against Rheumatism and the American College of Rheumatology, interviews of the manufacturers of the two licensed anti-TNF antibodies, and randomized

Drugs that act on the immune system: cytokines and monoclonal antibodies

placebo-controlled trials of infliximab and adalimumab), nine trials met the inclusion criteria; 3493 patients received anti-TNF antibody treatment and 1512 patients received placebo (34M). The pooled odds ratio for malignancy was 3.3 (95% CI ¼ 1.2, 9.1). Malignancies were significantly more common in patients taking higher doses than in patients who received lower doses of TNF-a antibody antagonists. For patients treated with TNF-a antagonists in the included trials, the number needed to treat for harm (NNTH) was 154 (95% CI ¼ 91, 500) for one additional malignancy during 6–12 months. In a multicenter matchedpairs study, the frequency of a new diagnosis of neoplasia in 404 patients with Crohn’s disease receiving infliximab was comparable with 404 who had never received infliximab (44C). There were nine patients with neo­ plasia (2.22%; one cholangiocarcinoma, three breast cancers, one skin cancer, one leukemia, one laryngeal cancer, and two anal carcinomas) among the former, com­ pared with seven (1.73%; three intestinal adenocarcinomas, one basalioma, one spina­ lioma, one non-Hodgkin’s lymphoma, and one breast cancer) among the latter. An unusual hepatocellular carcinoma and focal hepatic glycogenosis occurred in a noncirrhotic patient with Crohn’s disease who had received both azathioprine and inflix­ imab (45A). Whether infliximab directly or indirectly enhanced susceptibility to the development of hepatocellular carcinoma in this patient is not known. Susceptibility factors Age The risks of infections in elderly people taking TNF-a antagonists have been reviewed (46R). Compared with younger people, elderly patients have more co-morbidities and are likely to be taking more medications. Moreover, the aging process causes an increase in the rate of infections. In analyses of the databases of etanercept trials, the normalized incidence of adverse events, serious adverse events, medically important infections, and deaths was not increased in patients aged 65 years and over. However, these trials included patients who might have been healthier than elderly patients with rheumatoid

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arthritis and therefore not truly representa­ tive. Conflicting results have been reported in several observational studies. Taken together, the available data are reassuring for carefully selected populations, at least for etanercept, but it is not possible to claim that TNF-a antagonists do or do not pose a particular risk for the general population of older patients.

Adalimumab

(SED-15, 2380; SEDA-28, 426; SEDA-29, 397; SEDA-30, 439)

Placebo-controlled studies In a multicen­ ter, randomized, double-blind, placebo-con­ trolled study of subcutaneous adalimumab 40 mg every other week for 24 weeks, those who received adalimumab reported more adverse events (75% versus 60%), but there was no statistically significant difference in the incidence of infections; most adverse events were mild or moderate in intensity (47C). Respiratory Adalimumab-associated pul­ monary fibrosis can occur in patients with rheumatoid.  A 67-year-old man with rheumatoid arthritis

developed a non-productive cough and pro­ gressive dyspnea after being given subcuta­ neous adalimumab 40 mg every 2 weeks for 2 months. A CT scan showed extensive pulmonary fibrosis, with ground-glass lesions, honeycombing, and traction atelectasis. The dose of prednisone was increased to 90 mg/day, antibiotics were withdrawn, and 2 months later he was discharged in satisfac­ tory condition (48A).  A 76-year-old woman with severe rheumatoid arthritis and no respiratory symptoms was given adalimumab instead of sulfasalazine and hydroxycholoroquine. There was marked symptomatic improvement in her arthritis, but within 2.5 months she developed progressive shortness of breath. A CT scan showed extensive confluent reticular and honeycomb shadowing basally and posteriorly. Methotrex­ ate and adalimumab were both withdrawn and she was given oral prednisolone. Her symp­ toms improved and she was discharged to receive home oxygen therapy (49A).

A patient receiving adalimumab devel­ oped fatal exacerbation of fibrosing alveolitis associated with systemic sclerosis (50A).

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 A 74-year-old woman with severe Raynaud’s

syndrome, sclerodactyly, pulmonary fibrosis, abnormal esophageal peristalsis, and severe polyarthritis taking azathioprine was given adalimumab. After 7 months she developed respiratory failure and fever (39.31C). A CT scan angiogram showed lesions with extensive ground glass opacities. She was treated with oxygen, diuretics, azithromycin, and methyl­ prednisolone 1 g/day for 3 days, followed by prednisone 1 mg/kg/day and azathioprine. Adalimumab was withdrawn, but 3 months later her pulmonary function worsened and she died 2 months later from respiratory distress without infection.

Sensory systems Optic neuritis has been attributed to adalimumab (51A).  A 55-year-old man with psoriatic arthritis and

hyperlipidemia developed reduced central vision in his right eye; there was no pain on eye movement and there were no other visual or somatic complaints. Because the psoriatic rash was severe and associated with arthro­ pathy in the wrists and fingers, he received adalimumab injections 40 mg twice weekly over 4 months. After 3.5 months he noted visual loss. The best corrected visual acuity in the affected eye was 20/30 and there was a subtle right afferent pupillary defect. After treatment with methylprednisolone he recov­ ered completely.

Hematologic Reversible neutropenia has been associated with adalimumab (52A).  A 53-year-old woman with rheumatoid arthri­

tis taking many drugs, including non-steroidal anti-inflammatory drugs (NSAIDs), glucocor­ ticoids, hydroxychloroquine, methotrexate, and etanercept, had a poor response and was given adalimumab. She developed a neutro­ penia—1.5
109/l neutrophils and 3.8
109/l lymphocytes, of which 12% had typical large granular lymphocyte morphology. After with­ drawal of adalimumab the neutropenia recov­ ered within 3 weeks.

Skin New-onset psoriasis can develop dur­ ing TNF-a inhibitor treatment (53A,54A). Nine patients with rheumatoid arthritis who were treated with different types of TNF-a antago­ nists unexpectedly developed either newonset or worsened psoriatic skin lesions (55A).  A 49-year-old man with ankylosing spondylitis

was given infliximab and after 8 months developed an erythematosus pustular rash

over his back, histologically pustular psoriasis. The lesions resolved when the dose of methotrexate was increased.  A 68-year-old woman with plaque psoriasis and inflammatory arthritis was given infliximab and developed a new variant of psoriasis affecting her axillae and groins; she responded to topical treatments.  A 54-year-old woman with rheumatoid arthri­ tis was given adalimumab and after 10 months developed hyperkeratotic skin lesions consis­ tent with guttate psoriasis; with conservative management her rash resolved completely.  A 64-year-old woman with rheumatoid arthri­ tis was given adalimumab and 3 months later developed erythema at the injection site. After 18 months she developed a symmetrical psoriatic rash, with stable plaques involving the neck and elbows and thickening of the toenails. Histological examination showed psoriasiform dermatitis. She was given topical glucocorticoids. Adalimumab was continued and the rash improved significantly.

Eosinophilic cellulitis (Wells’ syndrome) has been attributed to adalimumab (56A).  A 72-year-old woman with rheumatoid arthritis

was given adalimumab and 6–8 hours after the first injection developed a mild reaction at the injection site; 4 hours after a second injection 2 weeks later she developed chest discomfort, fever, rigor, fatigue, and a 10
9 cm violaceous plaque. Skin biopsy showed eosinophilic cellu­ litis (Wells’ syndrome). She was given gluco­ corticoids and her other medications were withdrawn.

Alopecia areata can occur during treat­ ment with adalimumab (57A) (cf. efalizu­ mab and infliximab below).  A 23-year-old woman with a 2-year history of

patchy hair loss due to alopecia areata was given topical dexamethasone; the alopecia resolved within 4 months. She was given adalimumab for rheumatoid arthritis and the alopecia areata recurred and developed into alopecia totalis. Topical dexamethasone was ineffective.

An urticarial eruption occurred in a patient with psoriasis treated with adalimu­ mab (58A).  A 41-year-old woman with psoriasis was given

adalimumab. She had an injection site reaction with each injection, followed by a pruritic urticarial eruption, primarily on her neck and arms. She required no treatment for the eruption, which became less severe with each

Drugs that act on the immune system: cytokines and monoclonal antibodies injection. Her psoriasis responded dramati­ cally to adalimumab.

Immunologic The immunogenicity of ada­ limumab has been assessed in 15 patients with highly active rheumatoid arthritis (59c). Four were treated with adalimumab as monotherapy and 11 with concomitant DMARDs. Antiadalimumab antibodies were detected in four patients without concomitant DMARDs and in nine of the others. Five of seven patients with adverse drug reactions and all nine patients with lack of efficacy had antibodies. Two anti­ body-positive patients developed a rash. These results suggest that adalimumab, in spite of its fully human sequences, is immunogenic and induces antibody forma­ tion in a large number of patients. Visceral leishmaniasis has been reported in a patient with rheumatoid arthritis treated with adalimumab (60A).  A 69-year-old woman with rheumatoid arthri­

tis received adalimumab (40 mg every other week) plus methotrexate 7.5 mg weekly and prednisone 5 mg/day. After 2 years she devel­ oped an intermittent daily fever (maximum 38.51C) and severe weakness. Her CRP was 2400 mg/l and she had a pancytopenia. A CT scan did not show any localized infection. Giemsa-stained smears from a bone marrow aspirate showed Leishmania parasites. She was given intravenous amphotericin B and 2 weeks later PCR for Leishmania in the blood no longer showed parasites.

Tumorigenicity A meta-analysis of rando­ mized clinical trials of infliximab and adali­ mumab has found an increased risk of serious infections and malignancies. The malignancy rates were not higher than the expected rate in the general population, although they were increased compared with the randomized concurrent controls (61M). Drug dosage regimens The efficacy and safety of subcutaneous adalimumab has been analyzed in patients with moderateto-severe Crohn’s disease (62C). Patients received open induction therapy with ada­ limumab 80 mg in week 0 and 40 mg in week 2. In week 4 they were stratified by response (a reduction in the Crohn’s Dis­ ease Activity Index of at least 70 points from

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baseline) and randomized to double-blind treatment with placebo, adalimumab 40 mg every other week, or adalimumab 40 mg weekly for 56 weeks. More patients receiv­ ing placebo withdrew because of an adverse event (13%) than those who received adalimumab (4.7% and 6.9% in the weekly and every other week groups, respectively). Among patients who responded to adalimu­ mab, both adalimumab regimens were sig­ nificantly more effective than placebo in maintaining remission. Drug administration route Adalimumab is available for subcutaneous administration in two single-use injection devices, which provide bioequivalent amounts of adalimu­ mab: a ready-to-use prefilled syringe and an integrated disposable delivery system, the autoinjection pen. Although patients who require long-term subcutaneous administra­ tion of medications generally prefer pens, there are no data on preferences and pain in the use of biologics in patients with chronic inflammatory diseases. Injectionsite pain, overall tolerability, and patient preferences for two different adalimumab delivery systems have been studied in 52 patients with rheumatoid arthritis (mean age 54 years; 32 women, 20 men) in a phase II, multicenter, open, single-arm, sequential trial (63c). Patients self-administered a standard dose of subcutaneous adalimumab 40 mg every other week during each of the three monitored clinical visits: visit 1 (syringe), visits 2 and 3 (pen). At each visit they rated their pain on an 11-point scale (0 ¼ none to 10 ¼ pain as bad as it could be) immediately and 15–30 minutes after the injection and gave their impressions of and preferences for each delivery system. Adverse events were recorded throughout the study and 70 days after the final dose. Forty patients reported that the pen was less painful than the syringe, four found the syringe to be less painful, and eight had no preference. Injection-pain scores were sig­ nificantly lower from visit 1 to visit 2 and from visit 1 to visit 3. In all, 46 patients preferred the pen, three preferred the syringe, and three had no preference. Patients evaluated the pen as being easier to use (94%), more convenient (92%),

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requiring less time to inject (83%), and safer (89%).

Etanercept

(SED-15, 1279; SEDA-29, 397; SEDA-30, 440)

Respiratory Two patients receiving etanercept developed severe diffuse alveolar infiltrates culminating in groundglass changes on high-resolution CT scans of the lung (64A). Nervous system A 59-year-old woman with a 5-year history of seropositive erosive rheu­ matoid arthritis developed a demyelinating syndrome during etanercept therapy (65A). Sensory systems Four cases of optic neur­ itis associated with etanercept were revealed by a retrospective chart review between January 2003 and January 2005 in two Israeli medical centers (the Assaf Harofeh Medical Center and the Kaplan Medical Center) (66c). Urinary tract Henoch–Schönlein purpura with acute renal failure has been associated with an increase in the dose of etanercept after 11 months of use for psoriasis (67A). Withdrawal of the drug and treatment with a course of systemic glucocorticoids pro­ duced complete resolution of the vasculitis and improved renal function. Skin The dermatological adverse effects of etanercept have been reviewed (68R). Injec­ tion site reactions are common and usually self-limiting. Some patients have recall site reactions, in which rotated injection sites simultaneously develop a hypersensitivity reaction. In all cases, the rash has responded to antihistamines and etanercept therapy has been continued. Other injection site reac­ tions have included discoid lupus and cuta­ neous vasculitis, which respond to withdrawal of treatment and appropriate therapy. Skin reactions more distant from the injection site include erythema nodosum, widespread lupus rashes, infections, and skin tumors. One patient developed a purpuric rash at the site of the last injection associated with thrombocytopenia.

A rash has been attributed to etanercept (69A).  A 70-year-old woman long-standing erosive

seropositive rheumatoid arthritis was given etanercept 25 mg subcutaneously twice a week. After the fourth injection, she devel­ oped erythematous macular lesions, which were diagnosed as discoid eczema. Histo­ pathology was consistent with a drug-induced dermatitis.

Paradoxical new-onset psoriasis has been attributed to etanercept, as has paradoxical worsening of pre-existing psoriasis.  A 13-year-old girl developed new-onset psor­

iasis after starting to take etanercept for extending oligo-articular juvenile idiopathic arthritis (70A).  A 35-year-old man with severe plaque psor­ iasis and disabling psoriatic arthropathy, poorly controlled with conventional therapies, and recurrent episodes of erythroderma or pustular exanthematous psoriasis after inter­ current infections, was given subcutaneous. etanercept 25 mg twice a week (71A). After about 7 weeks of treatment he had flu-like symptoms with upper respiratory tract involve­ ment, followed 10 days later by sudden aggravation of his skin lesions, despite resolu­ tion of joint pain and stiffness. There were diffuse skin lesions and some pustules, sub­ mandibular lymphadenopathy, a mild pyrexia, a neutrophil leukocytosis, and a slight increase in erythrocyte sedimentation rate. No specific infection was identified. Etanercept was with­ drawn and he was given topical therapy and oral paracetamol for 1 week, when the fever abated. Methotrexate 10 mg weekly and ciclos­ porin 2.5 mg/kg then caused regression of the pustular lesions and erythema after 2 months, but the articular symptoms reappeared and etanercept was restarted with a good clinical response and no complications.

In the second case the authors proposed that exacerbation of psoriasis had resulted from an interaction between etanercept and an infection, an unproven association. Immunological Since 1998, there have been reports of vasculitic adverse events, including necrotizing vasculitis and leuko­ cytoclastic vasculitis, in patients taking etanercept. The adverse events reporting system of the US FDA has recorded 35 cases of leukocytoclastic vasculitis, 20 after etanercept and 15 after infliximab (72S). In

Drugs that act on the immune system: cytokines and monoclonal antibodies

most cases the symptoms developed within 3 months. In only one case was direct immunofluorescence performed on tissues and no specific immunoreactivity was found. Drug dosage regimens Two etanercept dosing regimens have been compared— 50 mg twice weekly and 100 mg once weekly, each for 12 weeks in 108 patients with moderate-to-severe recalcitrant psor­ iasis (73c). The two regimens caused com­ parable improvements after 4 weeks and 12 weeks. Treatment was well tolerated and adverse events were of similar type and frequency in the two groups. Etanercept and sulfasalazine, alone and in combination, have been compared in 254 adults with active rheumatoid arthritis, despite sulfasa­ lazine treatment, in a double-blind, rando­ mized study (74C). Lack of efficacy was the primary reason for withdrawal (sulfasala­ zine, n ¼ 12/50; etanercept, n ¼ 1/103; eta­ nercept and sulfasalazine, n ¼ 4/101). Several common adverse events (headache, nausea, weakness) were less common with etanercept alone than with the combination, but infections and injection site reactions were more common. In a prospective open study of added etanercept in 119 patients with active rheumatoid arthritis despite stable therapy with sulfasalazine (n ¼ 50), hydroxychloroquine (n ¼ 50), or intramus­ cular gold (n ¼ 19), withdrawals because of adverse effects by 48 weeks included protei­ nuria (etanercept + gold, n ¼ 1); septic wrist and bilateral pneumonia, rash, optic neuritis, breast cancer, and squamous cancer of the tongue (etanercept + hydroxychloroquine, n ¼ 5); and otitis media, abnormal liver function tests, pericarditis, rash, and gastro­ enteritis (etanercept + sulfasalazine, n ¼ 5) (75c). The most common adverse events not requiring withdrawal were injection site reactions (43%) and upper respiratory infec­ tions (34%). In 714 patients with rheuma­ toid arthritis refractory to DMARD who received etanercept for 8 years in one of seven initial trials or a long-term extension, the overall rate of serious adverse events was 15 events/100 patient-years. Other rates were: serious infections 4.2, cancers 1.0, and deaths 0.7 (76c).

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Tumorigenicity In 180 patients with active Wegener’s granulomatosis enrolled in the Wegener’s Granulomatosis Etanercept Trial (WGET) there were more solid malignancies in the etanercept group than in those treated with standard therapy alone (77c). All six solid malignancies were associated with etanercept treatment; they included two cases of mucinous adenocarci­ noma of the colon, one each of metastatic cholangiocarcinoma, renal cell carcinoma, and breast carcinoma, and one recurrent liposarcoma. Those who received etaner­ cept were older at baseline and those who developed solid tumors were older than those who did not. In addition, all etaner­ cept-treated patients who developed solid tumors had also received cyclophospha­ mide. This suggests that this combination may increase the risk of cancer beyond that observed with cyclophosphamide alone.

Infliximab

(SED-15, 1747; SEDA-29, 398; SEDA-30, 440)

Observational studies Data from 5000 patients with active rheumatoid arthritis treated with infliximab have been collected by Tanabe Seiyaku Co, Ltd (78c). The overall risk of adverse reactions was 28% and of serious adverse reactions 6.2%, including bacterial pneumonia 2.2%, tuberculosis (n ¼ 14), Pneumocystis pneumonia (n ¼ 22), interstitial pneumonitis (n ¼ 25), and serious infusion reactions (n ¼ 24); other adverse reactions included transient liver damage, gastroenteritis, and local skin infections. Most recovered after intensive treatment, but three patients (one with bacterial pneumonia and two with interstitial pneumonitis) died. There were 14 cases of tuberculosis in the early stages of treatment and half were extrapulmonary. Serious infusion reactions included anaphylactic reactions (n ¼ 8) and hypotension (n ¼ 9); all recovered completely. Respiratory Severe interstitial pneumoni­ tis has been attributed to infliximab.  A 22-year-old woman with colonic and peria­

nal Crohn’s disease developed a cough within hours of her first dose of infliximab (79A). It became worse after the second dose and

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5 weeks after the first infusion she was hospitalized with progressive breathlessness. A high-resolution CT scan of the thorax showed extensive ground glass shadowing with right apical peribronchial consolidation. Pul­ monary function tests showed a marked restrictive pattern. Bronchoscopy showed nor­ mal endobronchial appearances and bronchial washings were negative for Pneumocystis jiroveci, fungi, acid-fast bacilli, and viruses.  A 66-year-old woman developed non-infec­ tious interstitial pneumonitis after a second infusion of infliximab (80A).

Nervous system Various neurological abnormalities have been attributed to inflix­ imab.  A patient with rheumatoid arthritis developed

the Miller Fisher syndrome variant of the Guillain–Barré syndrome while receiving infliximab. He had ataxia and dysarthria, which fluctuated in relation to each subsequent infliximab infusion and after 6 months culmi­ nated in areflexic flaccid quadriplegia (81A).  A 55-year-old man with a 27 year history of ankylosing spondylitis received infliximab and developed back pain and a paraparesis. Radio­ graphy showed rapid exacerbation of preexist­ ing spinal pseudoarthrosis at T11–12. Although the myelopathy could have devel­ oped over time and been unrelated to inflix­ imab, the history and radiographic course suggested that suppression of inflammation by infliximab improved his activities of daily living, which paradoxically exacerbated preex­ isting spinal pseudoarthrosis and hastened the onset of subsequent myelopathy (82A).  A 47-year-old man with rheumatoid arthritis received monthly infusions of infliximab 300 mg for 2 years (83A). A brain MRI scan showed gadolinium enhancement of the cis­ ternal segment of the right oculomotor nerve. There were no white matter lesions and no dural enhancement. After withdrawal of inflix­ imab, the diplopia and ptosis gradually resolved over 3 months. The transient and isolated nature of the palsy described sug­ gested demyelination. There was no evidence of infection, inflammation, or migraine.

Psychiatric A 30-year-old woman with evolving ileocolonic Crohn’s disease received five intravenous infusions of infliximab 5 mg/ kg over 2 years (84A). About 2 hours after each infusion, she had a panic attack for 2– 48 hours. After the fourth infusion, she needed paroxetine and bromazepam. Hematologic A patient who had been treated for many years with classical

therapy for rheumatoid arthritis developed a refractory anaemia after treatment with infliximab + methotrexate (85A). Liver A 28-year-old man with refractory ulcerative colitis developed acute cholestatic liver damage after a single infusion of infliximab (86A). The liver damage resolved spontaneously within 6 weeks. Although a direct relation between infliximab and the acute liver damage could not be definitely established, this case suggests that infliximab can cause direct liver damage, the course of which is similar to acute cholestatic hepatitis and resolves after withdrawal of the drug. Skin Five patients developed erythema­ tous annular plaques on the trunk and limbs while receiving four different TNF-a antagonists (87c). One was taking lenalido­ mide for multiple myeloma, two were receiving infliximab, one was receiving etanercept for severe rheumatoid arthritis; and one was in a trial of adalimumab for psoriatic arthropathy. Skin biopsies showed diffuse interstitial granulomatous infiltra­ tion with lymphocytes, histiocytes, eosino­ phils, and palisading degenerated collagen. Withdrawal of the medications led to complete resolution of the skin lesions. Acute alopecia areata has been reported during treatment with infliximab in a sub­ ject who had never had it (cf. adalimumab above and efalizumab below) (88A).

MONOCLONAL ANTIBODIES (SED-15, 2380; SEDA-28, 434; SEDA-29, 404; SEDA-30, 442)

Adalimumab See TNF-a antagonists above.

Alemtuzumab (Campath-1Hs) (SED-15, 71; SEDA-29, 404; SEDA-30, 442) Endocrine A kidney recipient developed autoimmune thyroid disease after induction with alemtuzumab (89A).

Drugs that act on the immune system: cytokines and monoclonal antibodies  A 30-year-old woman underwent renal trans­

plantation because of renal failure due to tubulointerstitial nephritis. She received a live unrelated donor graft, alemtuzumab induction, and sirolimus 1 mg/day as maintenance immu­ nosuppression. Four years later she developed hyperthyroidism due to autoimmune thyroiditis with raised thyroid-stimulating autoantibodies. Her absolute lymphocyte count was 913
106/l, with low but appropriate numbers of CD4+ and CD8+ T cells (235 and 151
106/l). She responded to carbimazole.

Immunologic Acute cellular rejection of renal allografts in patients who receive alem­ tuzumab induction may be mediated by an atypical population of monocytes and not through “classical” T cell-dependent path­ ways of allorecognition. However, T cells with memory phenotype have been described in renal biopsies taken from alemtuzumab-trea­ ted patients with acute cellular rejection (90c). Twelve biopsies from patients who were given a single dose of alemtuzumab at the time of transplantation and subsequently developed acute cellular rejection were stained for the following cell markers: CD3 (T cells), CD68 (monocytes), CD20 (B cells), and CD45RO and CD45RA (memory and naive T cells). Biopsies from six patients who received no induction therapy were used as controls. In alemtuzumab-treated patients, there was acute cellular rejection despite profound lymphopenia. A consistent number of CD3+ T cells was found in all of these biopsies, and most of the infiltrating CD3+ T cells had a memory phenotype (CD45RO+, CD45RA–). The numbers of infiltrating CD3+ T cells and B cells (CD20+) were similar in the two groups, whereas there were more monocytes (CD68+) with alemtuzumab than in the controls. Despite profound peripheral T cell depletion by alemtuzumab, acute cellular rejection occurs and is associated with T cell, B cell, and monocyte infiltration of the kidney. Specifically, T cells express on their surface the memory phenotype, suggesting that memory T cells may have eluded the depleting agent.

Basiliximab

(SED-15, 418; SEDA-29, 407; SEDA-30, 443) Comparative studies Basiliximab and short courses of antithymocyte globulin have been compared in a randomized study

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in patients at high risk of acute rejection or delayed graft function who received a renal transplant from a dead donor (91C,92r). Patients taking ciclosporin, mycophenolate mofetil, and prednisone were randomly assigned to either rabbit antithymocyte globulin 1.5 mg/kg/day (n ¼ 141) during transplantation (day 0) and on days 1–4 or basiliximab 20 mg (n ¼ 137) on days 0 and 4. The primary end-point was a composite of acute rejection, delayed graft function, graft loss, and death. At 12 months, the incidence of the composite end-point was similar in the two groups. Basiliximab was associated with a higher incidence of acute rejection (26% versus 16%) and of acute rejection that required treatment with antibody (8.0% versus 1.4%). The two groups had similar incidences of graft loss (10.2% and 9.2%), delayed graft function (45% and 40%), and death (4.4% and 4.3%). Although the incidences of all adverse events, serious adverse events, and cancers were also similar in the two groups, the patients who received basiliximab had a lower incidence of infection (75% versus 86%) but a higher incidence of cytomegalovirus disease (18% versus 7.8%). The effects of adding basiliximab to a standard tacrolimus-based regimen in renal transplant recipients aged under 18 years have been studied in a 6­ month, multicenter, randomized, controlled, open, parallel-group trial (93c). Patients received tacrolimus + azathioprine + steroids (n ¼ 93) or tacrolimus + azathioprine + steroids + basiliximab (n ¼ 99). Target tacrolimus concentrations were 10–20 ng/ml during days 0–21 and 5– 15 ng/ml thereafter. The dose of basiliximab was 10 mg (o40 kg) or 20 mg within 4 hours of reperfusion and again on day 4. Biopsyproven acute rejection rates were 20% and 19%, respectively, and steroid-resistant acute rejection rates were 3.2% and 3.0%. Graft survival rates were 95% in both arms and all the patients survived. The nature and incidence of adverse events were similar in the two arms, except for toxic nephropathy and abdominal pain, which were more common with the addition of basiliximab (14% versus 4.3% and 11% versus 2.2%). Median serum creatinine concentrations at 6 months were 86 and 91 mmol/l and

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glomerular filtration rate was 79 and 78 ml/ minute/1.73 m2.

healing; and hematological (severe leukopenia, etc.).

Immunologic Monoclonal antibodies against the alpha-chain of the membranebound interleukin-2 receptor (IL-2Ra) cause characteristic changes in the concen­ trations of soluble interleukin-2 receptor (sIL-2R) in the serum and urine. The time course of changes in sIL-2R concentrations have been studied in 38 kidney transplant patients, of whom 28 received induction therapy with the IL-2R antibody basilix­ imab in addition to standard immunosup­ pression (94c). Of 18 patients with complications, 15 could be identified by raised sIL-2R concentrations, a sensitivity of 83%. Acute rejection, cytomegalovirus infection, extrarenal bacterial infection, and pyelonephritis in the transplant all caused a significant rise in sIL-2R concentration, even after the use of basiliximab.

Ear, nose, throat Bevacizumab can cause perforation of the nasal septum (101A,102A).

Bevacizumab (SED-15, 2380; SEDA-29, 407; SEDA-30, 444) The use of bevacizumab to target blood vessels in the treatment of solid tumors has been reviewed (95R), as have its many adverse effects (96R–98R). The most com­ mon adverse effects of the Vascular Endothelial Growth Factor (VEGF) inhibi­ tor bevacizumab include hypertension, hemorrhage, gastrointestinal perforation, arterial thromboembolism, wound healing, and proteinuria. Potentially life-threatening events (arterial thrombotic events and gas­ trointestinal perforation) have occurred in a small number of patients. Close monitoring, especially in patients who are at greater risk of adverse events, is important (99R). In three comparative trials there was an increase in median survival time of 3.7 months (18.8 versus 15.1 months) when bevacizumab was added to a fluorouracil + folinic acid combination (100R). When added to current chemotherapy protocols bevacizumab increased the frequency of some potentially serious reactions, such as cardiovascular disorders (hypertension, arterial thrombosis); tumor hemorrhage; intestinal perforation; impaired wound

disorders

Nervous system Reversible posterior leu­ koencephalopathy has been reported in patients receiving bevacizumab (103A, 104A+,105A). Hematologic Splenic infarction has been reported in association with bevacizumab (106A).  A 49-year-old man with metastatic sigmoid

adenocarcinoma who had received 6 cycles of chemotherapy with fluorouracil, folinic acid, irinotecan, and bevacizumab developed pain in the left upper abdominal quadrant. A CT scan showed liver metastases and several wedge-shaped defects in the spleen, consistent with splenic infarction. Physical examination, electrocardiography, laboratory tests, and blood cultures excluded common causes of splenic infarction and a Positron Emission Tomography (PET) scan ruled out splenic metastases. Bevacizumab was withdrawn. 2 months later, after further chemotherapy cycles without bevacizumab, a follow-up CT scan showed partial regression of the splenic infarcts.

Gastrointestinal The incidence, suscept­ ibility factors, typical presentation, and management of patients with bowel perfora­ tion due to bevacizumab have been described (107R). Three of 33 patients receiving bevacizumab developed severe bowel complications (108c). Two had acute ischemic colitis and one had a fatal gastro­ intestinal perforation. All three had under­ gone radiotherapy to the pelvis before receiving bevacizumab. None of the 30 patients without bowel complications had been pretreated with infradiaphragmatic irradiation. Histological evaluation of bowel biopsies and resection specimens showed severe ischemic bowel damage. Liver Partial portal vein thrombosis was observed during the course of preoperative chemotherapy with fluorouracil + folinic acid + bevacizumab for colorectal liver metastases, as was hepatic steatosis with lobular inflammation (109C).

Drugs that act on the immune system: cytokines and monoclonal antibodies

Skin A patient receiving bevacizumab in combination with intravenous 5-fluorouracil­ based chemotherapy for colorectal cancer developed a rash secondary to bevacizumab that correlated with response (110A).  A 40-year-old patient with stage IV colorectal

cancer received fluorouracil + leucovorin + bevacizumab (FOLFOX-4), which he toler­ ated very well, except for a skin rash related to bevacizumab. The rash cleared every time bevacizumab was eliminated from the regimen and recurred when it was reintroduced.

Trauma The incidence of wound healing complications was 1–2% in patients receiv­ ing bevacizumab for the treatment of colorectal cancer (111R). Death In early February 2006, Genentech Inc. issued a joint press release with the Roche Holding Corporation, explaining that their phase III early stage colon cancer trial of bevacizumab (Avastins) would be stopped after the deaths of four patients (112S). This announcement was the result of preliminary review of the data by the study’s Data Safety Monitoring Board.

Daclizumab

(SED-15, 1047; SEDA-29, 408; SEDA-30, 444)

Comparative studies In a single-centre, randomized, parallel group study of tacrolimus + sirolimus + prednisolone, tacrolimus + mycophenolate mofetil + prednisolone, and sirolimus + mycopheno­ late mofetil + daclizumab + prednisolone in 54 patients undergoing kidney transplantation, Kaplan–Meyer analysis showed rejectionfree survival rates of 82%, 76%, and 34%, respectively (113C). Calcineurin-free immunosuppression with 2 days of steroids was associated with an unacceptably high incidence of acute rejection and rerejection, and the study had to be stopped.

Efalizumab

(SEDA-29, 409; SEDA-30,

445) The adverse effects of efalizumab in clinical trials have been reviewed (114R). The most

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common adverse effects are a first-dose reaction complex that includes headache, chills, fever, nausea, and myalgia within 2 days after the first two injections. These reactions were mostly mild-to-moderate in intensity when a small dose of 0.7 mg/kg was used as the first dose. Adverse events that occurred at rates of 1–2% more with efalizumab than placebo were arthralgia, weakness, peripheral edema, and psoriasis. Withdrawal of efalizumab is associated with a rebound flare reaction in about 5% of patients. Antiefalizumab antibodies develop in about 5% of subjects, but their clinical significance is not known. Immunemediated thrombocytopenia (at or below 52
109/l) has been observed in 0.3% of cases, and monitoring of platelet counts monthly during the first 3 months and 3­ monthly thereafter is recommended. There have been four reports of hemolytic anae­ mia after 4–6 months. New-onset or recur­ rent severe arthritis, including psoriatic arthropathy, has been infrequently reported in clinical trials and postmarketing surveillance. Symptoms associated with hypersensitivity reactions (dyspnea, asthma, urticaria, angioedema, maculopapular rashes) were rare in the first 12 weeks of the controlled studies. The overall inci­ dence of malignancies of any kind was 1.8 per 100 patient-years with efalizumab com­ pared with 1.6 per 100 patient-years with placebo. One case each of the following serious adverse reactions was reported: transverse myelitis, bronchiolitis obliterans, aseptic meningitis, idiopathic hepatitis, siala­ denitis, and sensorineural hearing loss. The overall incidence of hospitalization for infections was 1.6 per 100 patient-years with efalizumab compared with 1.2 per 100 patient-years with placebo; the rates of infection were 29% and 26%, respectively. The most common laboratory findings in patients receiving efalizumab were reversi­ ble increases in lymphocyte and total white blood cell counts. Systematic reviews Clinical evaluation of efalizumab based on five double-blind, placebo-controlled trials has been analyzed (115M). In four of the trials the endpoint for efficacy was the number of patients who

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had an improvement of at least 75% in the psoriasis area severity index (PASI) score after 12 weeks of treatment. With efalizu­ mab 1 mg/kg per week, about 25% of patients reached this target, compared with about 4% of patients in the placebo group. Efficacy was not improved by doubling the dose of efalizumab. Another trial focused on adverse effects. Most of the patients relapsed within an average of 2 months after withdrawal of treatment. The most frequent short-term adverse effect is a flulike syndrome, which affects about 50% of the patients. Adverse events in clinical trials included skin cancers, severe infections, aggravation or rebound of psoriasis after withdrawal of treatment, thrombocytopenia, leukocytosis, hypersensitivity reactions, and raised liver enzymes. Hematologic Two patients developed unusual CD8+ cutaneous lymphoprolifera­ tive disorders after receiving efalizumab and infliximab (116A). Immune-mediated pancytopenia has been reported in a patient receiving efalizumab (117A). Skin Subacute cutaneous lupus erythema­ tosus has been attributed to efalizumab (118A).  A 65-year-old woman with oral and cutaneous

lichen planus was given efalizumab and after 8 weeks developed a new rash, clinically and histologically consistent with subacute cutaneous lupus erythematosus. Efalizumab was discontin­ ued and the rash resolved within 3 months.

Acute alopecia areata has been described during treatment with infliximab and efalizu­ mab, which caused a severe relapse in a patient with previous alopecia areata (cf adalimumab and infliximab above) (88A). Musculoskeletal During clinical trials, involving over 2700 subjects, arthralgia occurred at a rate of only 1–2% higher than in those who received placebo. Two cases of new-onset debilitating psoriatic arthropathy have been reported in patients with plaque psoriasis taking long-standing efalizumab, despite the fact that their skin disease was in remission (119A). These cases suggest that

efalizumab can “uncouple” the psoriatic arthritic component from the cutaneous disease. The authors speculated that a possible mechanism for efalizumab-induced psoriatic arthritis is via blockade of regula­ tory T cells from joint tissues. An arthro­ pathy was precipitated in a patient who was given efalizumab for psoriasis (120A).  A 38-year-old man with moderate-to-severe

plaque-type psoriasis affecting the scalp, geni­ tals, nails, and predilection sites on the body and limbs was given efalizumab 100 mg subcuta­ neously weekly. his initial response was good, but after 13 weeks he developed acute pain and stiffness in his lower back, feet, knees, left wrist, and fingers. There was synovitis in the feet, knees, left wrist, and several distal interphalan­ geal joints. The erythrocyte sedimentation rate and C-reactive protein were markedly raised and there was a mild monocytosis. Rheumatoid factor, antinuclear antibodies, and serum uric acid concentration were all negative or normal. Bone scintigraphy showed increased activity in several distal interphalangeal joints of the hands and feet, both knees, and the left wrist. Synovial fluid from the knees was sterile. Efalizumab was withdrawn and replaced by low-dose methotrexate and a non-steroidal anti-inflammatory drug. He did not improve during the next 2 weeks and was given oral prednisolone 50 mg/day and intra-articular steroid injections in both knees. He improved only moderately and was therefore given intravenous infliximab 500 mg at weeks 0, 2, and 6, to which he responded.

It was not clear in this case whether the arthropathy was coincidental or could be attributed to efalizumab. Immunologic Drug-induced lupus is asso­ ciated with biologics, and patients with systemic lupus erythematosus and lupus erythematosus tumidus have been described (121A–123A).  A 65-year-old white woman with oral and

cutaneous lichen planus was given efalizumab (124A). About 8 weeks later she developed a new rash, suggestive of subacute cutaneous lupus erythematosus. The antinuclear anti­ body titer was 1:160 with a speckled pattern, anti-SSA antibody and anti-double-stranded DNA antibody were positive, and antihistone antibodies were negative. She improved after withdrawal of efalizumab.

Tumorigenicity The incidence of malig­ nancies has been studied in patients with

Drugs that act on the immune system: cytokines and monoclonal antibodies

psoriasis receiving efalizumab during pla­ cebo-controlled open trials (125M). Efali­ zumab and placebo were associated with similar incidence rates of malignancy, including lymphoproliferative disease, solid tumors, malignant melanoma, and nonmelanoma skin cancers. The incidence of non-melanoma skin cancers, including basal cell and squamous cell carcinomas, in patients receiving efalizumab or placebo was increased compared with incidences in external databases. These results suggest that efalizumab treatment does not increase the risk of malignancies. The difference observed in the risk of nonmelanoma skin cancers may have been due to biases introduced by the clinical trial methods. Susceptibility factors Age Age-related changes in the pharmacokinetics of efalizu­ mab have been reviewed (126R). Reduced renal and hepatic function can be impor­ tant. Altered distribution as a result of changes in body composition can prolong the half-life.

Infliximab See TNF-a antagonists above.

Muromonab

(SED-15, 2397; SEDA-28,

437) Comparative studies Muromonab (OKT3) has been compared with basiliximab in a multicentre randomized study in 99 patients in the early period after heart transplantation (127C). There were no adverse events related to basiliximab but there were 23 adverse events among the patients who received muromonab. Fever, acute pulmonary edema, hypotension, and other complications accounted for most of the difference. After 1 year, there were biopsy-proven rejection episodes of at least grade 3A in 40% in both groups, with no differences in terms of severity and timing of episodes of acute rejection. The number of infectious episodes, complications not related to the study medication, and actuarial survival were similar.

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Rituximab

(SED-15, 3069; SEDA-29, 410; SEDA-30, 448)

Respiratory Most of the adverse effects of rituximab are due to an infusion-related symptom complex, and severe pulmonary complications are rare. A patient with non­ Hodgkin’s lymphoma received rituximab and developed symptomatic, biopsy-proven multinodular bronchiolitis obliterans with organizing pneumonia (BOOP) (128Ar). Hematologic Of 107 patients who received rituximab-containing chemother­ apy as primary treatment for CD20-positive B-cell lymphomas, 23 developed late-onset neutropenia after a median of 411 days (neutrophil count 1.0
109/l or less) at a median of 106 days after the last course of chemotherapy (129c). The median neutro­ phil count nadir was 0.61
109/l. These episodes were generally self-limiting; one patient was given filgrastim. There were no serious infectious episodes. Late-onset grade 4 neutropenia occurred in three of 54 patients with non-Hodgkin’s lymphoma treated with rituximab between September 2001 and March 2004 (130c). The neutrope­ nia occurred after 5–25 weeks and recurred 4 and 17 weeks after first onset in two patients. There were five episodes in a total of 332 cycles of rituximab therapy. The bone marrow showed neutrophil maturation arrest with or without reversible myeloid dysplasia in three episodes and selective depletion of the myeloid series in one. Neither circulating immune complexes nor antineutrophil antibodies were detected. Rituximab caused hemorrhagic thrombocy­ topenia in a patient with hairy cell leukemia (131A).  A 44-year-old man with hairy cell leukemia

developed an abscess in the right erector spinae muscle and was given intravenous antibiotics for Staphylococcus aureus infection and G-CSF. His neutropenia persisted and was given rituximab. Some hours later he devel­ oped severe knee-pain, hemorrhagic blisters in the mouth, petechiae on the legs, and gastro­ intestinal bleeding. The platelet count fell from 31 to 6
109/l. He developed raises D-dimer concentrations, which normalized within 6 days of treatment with interferon.

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Transient severe acute thrombocytope­ nia and neutropenia occurred a few days after rituximab infusion in two children with autoimmune hemolytic anaemia (132A). In both cases, the cytopenia resolved within a few days. Persistent B-cell depletion has been reported after the use of rituximab for thrombocytopenic purpura (133A).  A 14-year-old girl with autoimmune thrombo­

cytopenic purpura unresponsive to intrave­ nous immunoglobulin and high-dose steroids developed an intracranial hemorrhage and was given four weekly doses of rituximab 375 mg/m2. Her CD19+ cells became unde­ tectable after the second dose and her platelet count rapidly increased. She recovered com­ pletely.

All cases of unexplained delayed-onset peripheral blood cytopenias of WHO grades II–IV in an unselected series of patients receiving rituximab have been analysed (134c). There were 77 courses of rituximab (corresponding to 317 rituximab infusions) given to 72 consecutive patients with non­ Hodgkin’s lymphoma; nine received ritux­ imab alone, 50 were associated with che­ motherapy, and 18 were associated with autologous stem cell transplantation. There were 23 cases of cytopenias: neutropenia in 21 cases, thrombocytopenia in eight, and anemia in four. There were multiple cytope­ nias in nine cases. Neutropenia developed after a median of 10 weeks after the last dose of rituximab, anemia after 5 weeks, and thrombocytopenia after 4 weeks. There were severe infections in four of 21 neutropenic patients compared with two of 56 controls. The cytopenias eventually resolved in nine of 18 evaluable cases after a median of 10 (range 1–23) weeks. Of age, sex, histology, bone marrow infiltration, hypogamma­ globulinemia, previous chemotherapy, auto­ logous stem cell transplantation, and the dosage regimen of rituximab, only previous treatment with chemotherapy and more than four doses of rituximab were signifi­ cantly associated with a higher risk of cytopenias. Liver Fatal adenoviral hepatitis has been reported in a patient with Waldenstrom’s macroglobulinemia treated with rituximab

(135A). This case demonstrates the emer­ ging association between rituximab and fatal viral reactivation. Other cases have been reported with hepatitis viruses.  A woman with relapsed cutaneous follicular

center B-cell lymphoma and secondary lymphnode involvement had a complete remission with rituximab alone. However, 1 year later she had fatal hepatitis B virus reactivation (136A).  A 59-year-old man developed fatal acute hepatitis with reactivated hepatitis B virus after receiving rituximab for a malignant lymphoma; he developed a positive HBsAg titer (137A).  A patient with a diffuse large B-cell lymphoma and hepatitis C virus-related hepatic cirrhosis developed a mass in her left breast (138A). She was given rituximab monotherapy on 3 con­ secutive weeks, but treatment had to be withdrawn because of hematological toxicity. The hepatitis C viral load increased, but then fell gradually after rituximab was stopped.

Skin An urticarial reaction occurred in a patient with primary cutaneous B-cell lym­ phoma receiving rituximab (139A).  A 37-year-old man with a primary cutaneous

B-cell lymphoma was treated with 8 intrave­ nous doses of weekly rituximab and devel­ oped an urticarial reaction at the site of the tumor patches and excision scars 1 hour after the first dose. The lesions disappeared spon­ taneously after withdrawal of rituximab tem­ porarily for 1 hour. Rituximab was then given uneventfully.

Immunologic Rituximab can cause a leuko­ cytoclastic vasculitis (140A).  A 67-year-old woman with follicular non­

Hodgkin’s lymphoma received a standard course of rituximab. After the third dose she developed increasingly severe pruritus and a generalized rash. There were grouped hemor­ rhagic vesicles and bullae on the upper thighs and backs of the legs. A skin biopsy showed a leukocytoclastic vasculitis. Rituximab was withdrawn and she received a single dose of intravenous dexamethasone. The lesions regressed over 1 week.

Autacoids Cytokine release syndrome has been attributed to rituximab (141A).  A 14-year-old boy with acute lymphoblastic

leukemia had an anaplastic astrocytoma subtotally resected and was then treated

Drugs that act on the immune system: cytokines and monoclonal antibodies with irradiation and chemotherapy. A leu­ kemic relapse was refractory to salvage therapy and he was given rituximab. After a small fraction of the standard dose (375 mg/m2) the infusion had to be inter­ rupted because of acute lumbar pain. Two days later, after rituximab had been restarted, he developed a fatal systemic inflammatory response syndrome and died, possibly because of uncontrollable cytokine release syndrome associated with sepsis.

Infection risk The use of rituximab in immunosuppressed patients can cause lifethreatening infection (142c,143A), among which fatal enteroviral meningoencephalitis has been reported (144A).  A 75-year-old man with a long history of

recurrent lymphoplasmacytoid lymphoma developed a diffuse large-cell lymphoma affect­ ing the adrenal glands and causing severe hypoadrenalism. It responded to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy. Seven months later he developed signs of gastroenteritis, septicemia, and coma. PCR testing of the cerebrospinal fluid suggested enteroviral encephalitis and he initially responded to intravenous immunoglobulins but died after 14 weeks.

Cytomegalovirus gastritis has also been attributed to rituximab (145A).  A 65-year old woman was treated for a diffuse

large cell type non-Hodgkin’s lymphoma with six courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab, with a good partial response. Two weeks after radiotherapy (3000 cGy) to the parailiac and inguinal regions, she developed epigastric pain and diarrhea without blood and mucus. Upper gastrointestinal endoscopy showed multiple linear exudative gastric ulcers containing hyperchromatic epithelial cells with nuclear viral inclusions (owl’s eye), which were positive for monoclonal antibodies against cytomegalovirus. She responded to intravenous ganciclovir.

Caution may be needed when using rituximab in patients with a history of endocarditis (146A).  A 54-year-old woman with cerebral lupus

was treated successfully with rituximab, but developed a Streptococcus intermedius infec­ tion on valves that had been damaged by Libman–Sacks endocarditis more than 20 years before.

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Tumorigenicity Three cases of cutaneous squamous-cell carcinoma occurred during prolonged treatment with rituximab (147A).  An 80-year-old woman was treated with

rituximab 375 mg/m2 weekly after a second relapse of non-Hodgkin’s lymphoma. She had a history of a squamous cell carcinoma on the middle finger, which had been treated with surgery and radiotherapy. After a sixth cycle of rituximab, the carcinoma recurred, with multiple subcutaneous deposits on the back of the hand. Radiotherapy produced a complete response.  A 56-year-old man was treated at the time of a third relapse with rituximab 375 mg/m2 weekly for 4 weeks followed by maintenance therapy. After a fifth cycle he developed a rapidly growing area of unstable skin on his scalp. Histopathology showed a poorly differentiated squamous cell carcinoma.  A 64-year-old woman with follicular non­ Hodgkin’s lymphoma was given with rituximab 375 mg/m2 on three occasions. During the third course she developed a rapidly enlarging skin lesion on her nose requiring excision. Histo­ pathology showed a moderately differentiated squamous cell carcinoma.

A patient developed a rapidly growing Merkel cell carcinoma, an uncommon neu­ roendocrine carcinoma of the skin, after receiving rituximab for an acquired factor VIII inhibitor (148A). Pregnancy Very few cases of rituximab administration during pregnancy have been described. A woman with autoimmune hemolytic anaemia received rituximab dur­ ing her first trimester; there were no significant effects on B cell counts or the immune status of the neonate (149A). Monitoring therapy Infusion of immu­ notherapeutic monoclonal antibodies against normal or tumor cells can lead to loss of targeted epitopes, a phenomenon called antigenic modulation. In patients with chronic lymphocytic leukemia rituximab caused substantial loss of CD20 on B cells in the circulation, when rituximab plasma concentrations were high (150c). Such anti­ genic modulation can severely compromise therapeutic efficacy, and the authors postu­ lated that the B cells had been stripped of the rituximab/CD20 complex by monocytes or macrophages in a reaction mediated by

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FcgR. An in vitro model based on reacting rituximab-opsonized CD20(+) cells with acceptor THP-1 monocytes demonstrated this mechanism. After 45 minutes, rituximab and CD20 were removed from opsonized cells and both were demonstrable on accep­ tor THP-1 cells. The reaction occurred

equally well in the presence and absence of normal human serum, and monocytes iso­ lated from peripheral blood also promoted the stripping of CD20 from rituximab­ opsonized cells. The transfer of rituximab/ CD20 complexes to THP-1 cells was mediated by FcgR.

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regimen for metastatic colon cancer. Arch Neurol 2006;63(10):1475–8. Malka D, Van den Eynde M, Boige V, Dromain C, Ducreux M. Splenic infarction and bevacizumab. Lancet Oncol 2006;7 (12):1038. Heinzerling JH, Huerta S. Bowel perfora­ tion from bevacizumab for the treatment of metastatic colon cancer: incidence, etiol­ ogy, and management. Curr Surg 2006;63 (5):334–7. Lordick F, Geinitz H, Theisen J, Sendler A, Sarbia M. Increased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation: report of three cases. Int J Radiat Oncol Biol Phys 2006;64(5):1295–8. Donadon M, Vauthey JN, Loyer EM, Charnsangavej C, Abdalla EK. Portal thrombosis and steatosis after preoperative chemotherapy with FOLFIRI-bevacizu­ mab for colorectal liver metastases. World J Gastroenterol 2006;12(40): 6556–8. Gotlib V, Khaled S, Lapko I, Mar N, Saif MW. Skin rash secondary to bevacizumab in a patient with advanced colorectal cancer and relation to response. Antic­ ancer Drugs 2006;17(10):1227–9. Saif MW, Mehra R. Incidence and man­ agement of bevacizumab-related toxicities in colorectal cancer. Expert Opin Drug Saf 2006;5(4):553–66. McLemore MR. The role of the data safety monitoring board: why was the Avastin phase III clinical trial stopped?. Clin J Oncol Nurs 2006;10(2):153–4. Gelens MA, Christiaans MH, van Heurn EL, van den Berg-Loonen EP, PeutzKootstra CJ, van Hooff JP. High rejection rate during calcineurin inhibitor-free and early steroid withdrawal immunosuppres­ sion in renal transplantation. Transplanta­ tion 2006;82(9):1221–3. Scheinfeld N. Efalizumab: a review of events reported during clinical trials and side effects. Expert Opin Drug Saf 2006;5 (2):197–209. Woolacott N, Hawkins N, Mason A, Kainth A, Khadjesari Z, Vergel YB, Misso K, Light K, Chalmers R, Sculpher M, Riemsma R. Etanercept and efalizumab

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Drugs that act on the immune system: cytokines and monoclonal antibodies 127. Segovia J, Rodríguez-Lambert JL, CrespoLeiro MG, Almenar L, Roig E, GómezSánchez MA, Lage E, Manito N, AlonsoPulpón L. A randomized multicenter comparison of basiliximab and muromo­ nab (OKT3) in heart transplantation: SIMCOR study. Transplantation 2006;81 (11):1542–8. 128. Biehn SE, Kirk D, Rivera MP, Martinez AE, Khandani AH, Orlowski RZ. Bronch­ iolitis obliterans with organizing pneumo­ nia after rituximab therapy for non­ Hodgkin’s lymphoma. Hematol Oncol 2006;24(4):234–7. 129. Nitta E, Izutsu K, Sato T, Ota Y, Takeuchi K, Kamijo A, Takahashi K, Oshima K, Kanda Y, Chiba S, Motokura T, Kurokawa M. A high incidence of late-onset neutro­ penia following rituximab-containing che­ motherapy as a primary treatment of CD20-positive B-cell lymphoma: a singleinstitution study. Ann Oncol 2007;18(2): 364–9. 130. Fukuno K, Tsurumi H, Ando N, Kane­ mura N, Goto H, Tanabashi S, Okamoto K, Moriwaki H. Late-onset neutropenia in patients treated with rituximab for non­ Hodgkin’s lymphoma. Int J Hematol 2006; 84(3):242–7. 131. Thachil J, Mukherje K, Woodcock B. Rituximab-induced haemorrhagic throm­ bocytopenia in a patient with hairy cell leukaemia. Br J Haematol 2006;135(2): 273–4. 132. Larrar S, Guitton C, Willems M, BaderMeunier B. Severe hematological side effects following rituximab therapy in children. Haematologica 2006;91(8 Suppl):ECR36. 133. Bisogno G. Persistent B-cell depletion after rituximab for thrombocytopenic purpura. Eur J Pediatr 2007;166(1): 85–6. 134. Cattaneo C, Spedini P, Casari S, Re A, Tucci A, Borlenghi E, Ungari M, Ruggeri G, Rossi G. Delayed-onset peripheral blood cytopenia after rituximab: frequency and risk factor assessment in a consecutive series of 77 treatments. Leuk Lymphoma 2006;47(6):1013–7. 135. Iyer A, Mathur R, Deepak BV, Sinard J. Fatal adenoviral hepatitis after rituximab

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therapy. Arch Pathol Lab Med 2006;130 (10):1557–60. Perceau G, Diris N, Estines O, Derancourt C, Lévy S, Bernard P. Late lethal hepatitis B virus reactivation after rituximab treat­ ment of low-grade cutaneous B-cell lym­ phoma. Br J Dermatol 2006;155(5):1053–6. Sera T, Hiasa Y, Michitaka K, Konishi I, Matsuura K, Tokumoto Y, Matsuura B, Kajiwara T, Masumoto T, Horiike N, Onji M. Anti-HBs-positive liver failure due to hepatitis B virus reactivation induced by rituximab. Intern Med 2006;45(11):721–4. Aksoy S, Abali H, Kilickap S, Erman M, Kars A. Accelerated hepatitis C virus replication with rituximab treatment in a non-Hodgkin’s lymphoma patient. Clin Lab Haematol 2006;28(3):211–4. Errante D, Bernardi D, Bianco A, De Nardi S, Salvagno L. Rituximab-related urticarial reaction in a patient treated for primary cutaneous B-cell lymphoma. Ann Oncol 2006;17(11):1720–1. Kandula P, Kouides PA. Rituximab­ induced leukocytoclastic vasculitis: a case report. Arch Dermatol 2006;142(2):246–7. Seifert G, Reindl T, Lobitz S, Seeger K, Henze G. Fatal course after administration of rituximab in a boy with relapsed all: a case report and review of literature. Haematologica 2006;91(6 Suppl):ECR23. Basse G, Ribes D, Kamar N, Esposito L, Rostaing L. Life-threatening infections following rituximab therapy in renal trans­ plant patients with mixed cryoglobuline­ mia. Clin Nephrol 2006;66(5):395–6. van der Velden WJ, Blijlevens NM, Klont RR, Donnelly JP, Verweij PE. Primary hepatic invasive aspergillosis with progres­ sion after rituximab therapy for a post transplantation lymphoproliferative disor­ der. Ann Hematol 2006;85(9):621–3. Padate BP, Keidan J. Enteroviral menin­ goencephalitis in a patient with non-Hodg­ kin’s lymphoma treated previously with rituximab. Clin Lab Haematol 2006;28(1): 69–71. Unluturk U, Aksoy S, Yonem O, Bayr­ aktar Y, Tekuzman G. Cytomegalovirus gastritis after rituximab treatment in a non­ Hodgkin’s lymphoma patient. World J Gastroenterol 2006;12(12):1978–9.

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146. Armstrong D, Wright S, McVeigh C, Finch M. Infective endocarditis complicating rituximab (anti-CD20 monoclonal anti­ body) treatment in an SLE patient with a past history of Libman-Sacks endocarditis: a case for antibiotic prophylaxis?. Clin Rheumatol 2006;25(4):583–4. 147. Fogarty GB, Bayne M, Bedford P, Bond R, Kannourakis G. Three cases of activa­ tion of cutaneous squamous-cell carcinoma during treatment with prolonged adminis­ tration of rituximab. Clin Oncol (R Coll Radiol) 2006;18(2):155–6. 148. Wirges ML, Saporito F, Smith J. Rapid growth of Merkel cell carcinoma after

treatment with rituximab. J Drugs Derma­ tol 2006;5(2):180–1. 149. Ojeda-Uribe M, Gilliot C, Jung G, Drenou B, Brunot A. Administration of rituximab during the first trimester of pregnancy without consequences for the newborn. J Perinatol 2006;26(4): 252–5. 150. Beum PV, Kennedy AD, Williams ME, Lindorfer MA, Taylor RP. The shaving reaction: rituximab/CD20 complexes are removed from mantle cell lymphoma and chronic lymphocytic leukemia cells by THP-1 monocytes. J Immunol 2006;176(4): 2600–9.

Felix Braun, Freya A. Goumas, Dieter C. Broering, and Matthias Behrend

38

Drugs that act on the immune system: immunosuppressive and immunostimulatory drugs

Ciclosporin

(SED-15, 743; SEDA-28, 452; SEDA-29, 426; SEDA-30, 452) Cardiovascular Ischemic heart disease after renal transplantation has been reported to be three to four times higher than in the general population. The records of recipients of cadaveric kidneys between January 1985 and November 1999 have been reviewed in a multicenter study in Spain (1c). All received ciclosporin and steroids with or without azathioprine as initial therapy. There were 163 patients with ischemic heart disease and 362 control patients without ischemic heart disease. Of the patients with ischemic heart disease after transplantation, 38% had thexcardiac event during the first 12 months; 29 had previously been known to have ischemic heart disease, but all were asymptomatic at the time of transplantation. After transplantation 21 revascularization procedures were per­ formed, 8 during the first year and 13 thereafter. At the time the study was performed, 28% of the patients had lost the graft and 17% (86/525) had died, 34% (55/163) from the ischemic heart disease group and 8.6% (31/362) from the control group. Death was related to ischemic heart Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03138-9 r 2009 Elsevier B.V. All rights reserved.

disease in 66% of the patients with ischemic heart disease. Donor age was higher in the patients with ischemic heart disease than in the controls, as were hypercholesterolemia and hypertriglyceridemia after trans­ plantation. Graft function was similar in the two groups, measured by serum creatinine. Multivariate analysis showed that age at transplantation increased the risk of ischemic heart disease by 5% per year. Men had a more than twofold higher risk of ischemic heart disease than women. Body weight was associated with a 2% increased risk of ischemic heart disease. Other independent predictors were a previous history of cardiovascular disease and hypercholesterolemia before trans­ plantation. It has been suggested that the increase in blood pressure induced by calcineurin inhi­ bitors is mediated by excitation of the sympathetic nervous system. In 24 renal transplant patients who were randomly assigned to either withdrawal or con­ tinuation of ciclosporin, mean arterial pressure fell significantly during withdrawal but not during continued therapy (2c). Muscle sympathetic nerve activity and plasma noradrenaline concentrations did not change in either group, and graft function remained stable. Nervous system Ciclosporin-associated neurotoxicity is common but still poorly understood (3A).

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A

58-year-old man with severe chronic obstructive pulmonary disease underwent bilateral lung transplantation with allografts from a cytomegalovirus seropositive donor; the recipient was seronegative. Immunosup­ pression was maintained with ciclosporin, prednisone, and mycophenolate mofetil. The dose of ciclosporin was adjusted to achieve blood concentrations of 350–400 ng/ml. On postoperative day 2 he had a generalized tonic–clonic seizure, when the ciclosporin concentration was 52 ng/ml; he responded to lorazepam and valproic acid. On day 10 he was given intravenous ganciclovir for prophylaxis against cytomegalovirus. By day 12 he was drowsy and unable to move his limbs. He had bilateral ptosis with intact extraocular muscles. His motor strength in the arms and legs was 0/5, with absent deep tendon reflexes. There was a fivefold increase in CSF protein with no white cells or red cells; bacterial and viral cultures of the CSF, blood, and broncheoal­ veolar fluid were negative, including PCR for cytomegalovirus. Electromyography and nerve-conduction studies showed a lengthdependent, symmetrical, sensorimotor poly­ neuropathy with axonal features but no demyelination. An MRI scan of the cervical spinal cord was normal. Plasma exchange with albumin (30 ml/kg) every other day for a total of seven sessions was undertaken and ciclos­ porin was replaced with tacrolimus. After the first plasmapheresis his strength improved to 2/5 in the arms and 3/5 in the legs. Over the next several weeks he continued to have steady neurological improvement.

Ciclosporin can cause leukoencephalopathy in organ transplant recipients (4A).
A 43-year-old man with a history of chronic

renal insufficiency of unknown cause received a cadaveric kidney transplant and immuno­ suppression with antithymocyte globulin, mycophenolate mofetil, ciclosporin, and pre­ dnisone. Four months later, he developed pneumonia and received fluorquinolones for 14 days. His blood ciclosporin concentration was 659 ng/ml. Ten days after discharge, he had a headache, meningism, and a bilateral sixth nerve palsy. The cerebrospinal fluid was clear with 270 cells, including 60% polymor­ phonuclear leukocytes and 40% mononuclear cells and a glucose concentration of 3 mmol/l. There was no evidence of infection, but ceftriacone, vancomycin, ampicillin, and ganci­ clovir were given empirically. An MRI scan showed many hypersignals in the subcortical white matter, particularly in the broadcast crown and semioval centers. Ciclosporin was withdrawn, with complete clinical improvement.
A 50-year-old man with end-stage renal disease due to mesangiocapillary glomerulo­

nephritis received a cadaveric kidney trans­ plant and immunosuppression with azathiopr­ ine and prednisone. Because of gouty arthritis azathioprine was replaced by ciclosporin before treatment with allopurinol. Two weeks later he developed confusion, irritability, and personality changes. The blood ciclosporin concentration was 547 ng/ml. An MRI scan showed changes compatible with a leukoence­ phalopathy. He recovered quickly when myco­ phenolate mofetil replaced ciclosporin.
A 16-year-old man with chronic autoimmune hepatitis received a cadaveric orthotopic liver transplant and immunosuppression with prednisone, ciclosporin, and mycophenolate mofetil. Postoperatively he developed gener­ alized tonic–clonic seizures. His blood pres­ sure was normal and electroencephalography was inconclusive. The cerebrospinal fluid was clear, with 25 cells, a protein concentra­ tion of 2 g/l, and a glucose concentration of 3.3 mmol/l. Cultures were negative. The blood ciclosporin concentration was 405 ng/ml. An MRI scan showed changes compatible with a reversible posterior leukoencephalopathy. Ciclosporin was replaced with tacrolimus and he recovered.

In a study of kidney transplant recipients and children with kidney diseases, there were 20 cases (13 boys and 7 girls, aged 2–18 years) of the posterior reversible encephalopathy syndrome (5c). Of 177 kid­ ney transplant recipients, 6 of 127 patients who were given ciclosporin and 4 of 50 patients who were given tacrolimus devel­ oped the syndrome after transplantation. Seven had idiopathic nephrotic syndrome (all treated with ciclosporin), two had acute poststreptococcal glomerulonephritis, and one had diffuse mesangial sclerosis. The symptoms varied from headache to status epilepticus. All the patients had hyperten­ sion and had cerebellar lesions on CT or MRI scans. With the exception of one patient with a delayed diagnosis and a patient with developmental delay before transplantation, all recovered clinically and radiologically within 10 weeks, with optimal control of hypertension and seizures, as well as withdrawal of the calcineurin inhibitors. In three children with posterior reversible encephalopathy associated with tacrolimus (n ¼ 2) or ciclosporin (n ¼ 1), electro­ encephalography showed continuous focal rhythmic activity, which normalized after the clinical effects had resolved (6c).

Drugs that act on the immune system

Chapter 38

Psychiatric In a comparison of ciclosporin and tacrolimus, 45 of 128 patients developed complications attributed to immunosuppres­ sion (tacrolimus 36 patients; ciclosporin 7 patients) (7c). There was no difference between the type of immunosuppression and the presence of neuropsychiatric com­ plications. Patients with hepatitis C had a higher prevalence of psychiatric disorders, including depression, than other patients with different types of liver diseases. Hematologic Anemia is common after liver transplantation. Serum erythropoietin concentrations were measured in patients treated with ciclosporin and tacrolimus before and after liver transplantation (8c). At 14 months after liver transplantation (ciclosporin, n ¼ 14; tacrolimus, n ¼ 21) mean erythropoietin concentrations were significantly lower after than before trans­ plantation and in those who received ciclosporin the erythropoietin concentra­ tion was significantly lower than in those who received tacrolimus. Metabolism The incidence of diabetes mellitus has been investigated in a prospective multicenter study at 24 months after kidney transplantation in 1276 patients taking tacro­ limus, mycophenolate mofetil, and steroids and in 507 patients taking ciclosporin, mycophenolate mofetil, and steroids (9C). Significantly more of the patients who were taking tacrolimus (74/161, 46%) needed insulin than those who were taking ciclos­ porin (14/50, 28%). By multivariate Cox regression analysis, age over 60 years, a BMI over 30 kg/m2, and immunosuppression with tacrolimus were associated with diabetes mellitus after transplantation. Of 295 patients after renal transplanta­ tion, 76 were given tacrolimus and 126 ciclosporin (10c). Lipid concentrations were similar in the two groups at day 0. However, 12 months later, total cholesterol and LDL cholesterol were significantly higher in those who were taking ciclosporin; triglyceride concentrations were similar in the two groups. In 32 children (median age 14 years), all of whom received triple immunosuppressive

621 therapy (ciclosporin or tacrolimus, azathioprine or mycophenolate mofetil, and prednisone), 47% had hyperuricemia, with uric-acid concentrations above the agerelated reference range; 55% were taking ciclosporin, 30% tacrolimus (11C). Plasma uric-acid concentrations did not differ among patients taking ciclosporin or tacro­ limus. There was only one case of gout, 7.9 years after renal transplantation in a 15­ year-old boy who was also taking furosemide. Skin Ciclosporin-induced hemangiomas occurred in a patient with psoriatic arthro­ pathy (12A).
A 35-year-old man with psoriatic arthropathy

was given first methotrexate and methylpred­ nisolone and then ciclosporin in increasing doses starting at 2.3 mg/kg/day and increasing to 4.0 mg/kg/day when remission of arthritis was achieved. Gingival hyperplasia resolved after dosage reduction to 3 mg/kg/day. Three years later he developed two raised purple, hard, painless nodules 5 mm in diameter. Histology showed a vascular lesion without any features of hemangioma. During the next 2 months new nodules appeared on the limbs. The dose of ciclosporin was reduced but the nodules persisted and ciclosporin was with­ drawn. Over the next few months the nodules got smaller and finally disappeared, leaving small depigmented areas.

Musculoskeletal Ciclosporin muscle damage (13A).

can

cause


A 33-year-old man with severe psoriasis,

poorly controlled with calcipotriol, corticoster­ oids, tar and dithranol, and acitretin was given ciclosporin 3 mg/kg/day. After 5 months his blood pressure started to increase and the dose of ciclosporin was reduced to 1.5 mg/kg/day. He then began to have severe pain in his legs and back and was having difficulty getting out of bed or chair and in raising his arms above his head. He had severe proximal muscle weak­ ness in his shoulders and pelvis. Peripheral muscle power was good. There were no sensory abnormalities and his cranial nerves were normal. Electromyography confirmed myopathic changes, with an excess of shortduration action potentials. Ciclosporin was withdrawn and within 7 days his pain and weakness began to improve. A quadriceps muscle biopsy 2 weeks after the withdrawal of ciclosporin showed no evidence of

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mitochondrial abnormalities or type II fiber atrophy. After months his muscle strength was normal.

Bone metabolism has been studied in rats who were fed a powdered diet containing or lacking ciclosporin for 8–30 days (14E). Analyses were performed on days 8, 16, and 30. There was a reduction in bone volume in the rats who were fed ciclosporin after day 16. Histology showed that the number of osteoblasts and osteoclasts on the surface of trabecular bone in the ciclosporin-treated group had increased significantly. Plasma parathormone and osteocalcin concentrations were also signif­ icantly higher. However, in a clinical study ciclosporin was not associated with an increased risk of fractures (see the section “Azathioprine (SED-15, 377; SEDA-28, 450; SEDA-29, 424; SEDA-30, 459)”). Pregnancy Ciclosporin in therapeutic con­ centrations after renal transplantation inhi­ bits bile salt excretion pump function in rats and humans. Obstetric cholestasis leading to fetal distress and therefore to premature delivery has been reported (15c). Susceptibility factors Although the use of immunosuppression is controversial in posi­ tive patients (16c,17c), there was no differ­ ence between tacrolimus and ciclosporin in hepatitis C-positive patients in a rando­ mized controlled trial of tacrolimus versus microemulsified ciclosporin in liver trans­ plantation (18A). Drug–drug interactions Antiretroviral drugs Reduced clearance of ciclosporin has been attributed to antiretroviral drugs (19A).




A 43-year-old man with HIV infection taking tenofovir, lamivudine, and fosamprenavir was stable and underwent orthotopic liver trans­ plantation. Immunosuppression was started using ciclosporin 250–350 mg bd to maintain blood concentrations at 300–400 ng/ml. On day 12 HAART was resumed with fosamprenavir 1400 mg bd, lamivudine, and tenofovir. After 48 hours, the ciclosporin concentration rose from 400 to 600 ng/ml. The dosage of ciclos­ porin had to be reduced to 100 mg bd.

The authors concluded that the combina­ tion of amprenavir + ritonavir had a greater effect on ciclosporin clearance than fosam­ prenavir. Methoxsalen Methoxsalen causes a clini­ cally significant interaction with ciclosporin in some susceptible individuals; the reasons for this susceptibility and its clinical implications have not been established (20A). Statins Ciclosporin inhibits CYP3A4, P-glycoprotein, organic anion transporting polypeptide 1B1 (OATP1B1), and some other hepatic transporters. Gemfibrozil and its glucuronide inhibit CYP2C8 and OATP1B1. These effects explain the increased plasma statin concentrations and the increased risk of muscle toxicity when these drugs are co-administered with statins (21R). Monitoring therapy The single-dose and steady-state pharmacokinetics of a ciclos­ porin microemulsion formulation have been studied in six Chinese heart transplant recipients who also took everolimus, methyl­ prednisolone, and rabbit antithymocyte glo­ bulin (22c). The authors concluded that trough blood concentrations may be best for monitoring ciclosporin therapy.


A 45-year-old man taking lamivudine, tenofo­

vir, enfuvirtide, and amprenavir boosted with ritonavir was stable and underwent orthotopic liver transplantation from a cadaveric donor. Immunosuppression was induced with ciclos­ porin and steroids. The dosage of ciclosporin was 200–350 mg bd with ciclosporin blood concentrations of 200–300 ng/ml. Antiretro­ viral therapy was restarted and the ciclosporin trough concentration rose to more than 1000 ng/ml. The dosage of ciclosporin had to be reduced to 25 mg bd.

Everolimus (SDZ-RAD)

(SED-15, 1306; SEDA-28, 457; SEDA-29, 433; SEDA-30, 453)

Everolimus is a proliferation signal inhibi­ tor and a mammalian target of rapamycin (TOR) inhibitor, structurally similar to sirolimus, but with a number of important

Drugs that act on the immune system

Chapter 38

pharmacokinetic differences, including a shorter half-life (23R–25R). Comparative studies In a randomized, double-blind trial in 213 patients everoli­ mus 3 mg/day was compared with azathio­ prine 1–3 mg/kg/day in combination with ciclosporin and corticosteroids (26C). Treat­ ment withdrawal (particularly due to adverse events), serious adverse events, and high serum creatinine concentrations were more common with everolimus. How­ ever, everolimus significantly slowed the loss of lung function after transplantation, suggesting that patients may benefit from replacing azathioprine with everolimus 3 months after lung transplantation. Systematic reviews TOR inhibitors have been evaluated in four different primary immunosuppressive algorithms: as replace­ ment for calcineurin inhibitors and antime­ tabolites, in combination with calcineurin inhibitors in low and high doses, and with variable doses of calcineurin inhibitors. Generally, surrogate end-points for graft survival favor TOR inhibitors (a lower risk of acute rejection and better renal function) and adverse effects (bone marrow suppression and lipid disturbances) are worsened by TOR inhibitors. Long-term hard end­ point data from methodologically robust randomized trials are still required (27M). When evaluated as part of triple therapy with ciclosporin and corticosteroids, ever­ olimus had similar efficacy to mycopheno­ late mofetil after renal transplantation, and was better than azathioprine in cardiac transplant recipients, in terms of reducing efficacy failure after transplantation. Connective tissues In rats after small and large bowel resection everolimus caused a massive reduction in anastomotic strength, which the authors attributed to impaired deposition of collagen in the anastomotic area (28E). Immunologic Cutaneous leukocytoclastic vasculitis occurred in a patient with myelo­ dysplastic syndrome after therapy with everolimus (29A).

623 Tumorigenicity Recipients receiving siro­ limus or everolimus had an increased risk of lymphocele, with an incidence of 16% (30A). Drug dosage regimens The safety and tolerability of everolimus 0.5–2 mg bd has been studied in a placebo-controlled trial in 119 liver transplant recipients (31A). Co-immunosuppression consisted of pre­ dnisone and ciclosporin adjusted to trough concentrations of 150–400 ng/ml. Adverse events were more common with everolimus especially at the 4 mg/day dose, but there were no differences in the incidences of thrombocytopenia or leukopenia between the groups. Mean concentrations of choles­ terol and triglycerides rose from baseline in all groups, and maximum concentrations were seen at 6 months. Drug–drug interactions Everolimus is me­ tabolized by CYP3A, and co-administration of drugs that share this elimination pathway can lead to drug interactions. The CYP3A inhibitory classification system ranks inhi­ bitors according to the increase in the AUC of a probe substrate as follows:
strong (at least a fivefold increase in AUC);
moderate (a more than 2–4.9-fold increase in AUC);
weak (less than a twofold increase in AUC). This classification system has been used to characterize everolimus as a substrate of CYP3A in five open crossover studies in 12–16 healthy subjects each (32C). The strong inhibitor ketoconazole increased the everolimus AUC 15-fold after a single 2 mg dose; the increases with moderate inhibitors erythromycin, verapamil, and ciclosporin were 4.4, 3.5, and 2.7 times, respectively; the weak inhibitor atorvastatin had no effect. This systematic approach to drug interactions yielded clinically useful struc­ tured guidelines for everolimus dosage adjustment. Ciclosporin The effect of everolimus on single-dose and steady-state pharmacokine­ tics of ciclosporin in a microemulsion

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Felix Braun, Freya A. Goumas, Dieter C. Broering, and Matthias Behrend

formulation has been studied in six Chinese heart transplant recipients, all of whom took ciclosporin, everolimus, and rabbit antithymocyte globulin, compared with six age-matched recipients taking ciclosporin and azathioprine (33c). There was no significant difference between the ever­ olimus-based and the azathioprine-based regimens in dose-normalized ciclosporin AUC. The dose-normalized ciclosporin trough concentrations were significantly lower with everolimus than with azathiopr­ ine during the first 5 months after trans­ plantation, but the difference was not significant in month 6. Ciclosporin dosage requirements were not reduced by ever­ olimus. However, these results differed from reports from Western countries (34c,35c). Imatinib Imatinib is highly concentrated in red blood cells and this is increased by everolimus; this warrants routine erythro­ cyte versus plasma monitoring to prevent unexpected alterations in drug efficacy during long-term treatment (36c). Tacrolimus Conversion from mycopheno­ late mofetil to everolimus did not change exposure to tacrolimus in eight mainte­ nance renal transplant patients and there was no clinically relevant change in ever­ olimus exposure after tacrolimus dosage reduction (37c). Monitoring therapy Everolimus trough blood samples (n ¼ 826) were analyzed during a randomized, double-blind, multi­ center trial in 213 maintenance lung trans­ plant recipients taking everolimus 1.5 mg bd (n ¼ 101) or azathioprine 1–3 mg/kg/day (n ¼ 112) with ciclosporin and corticoster­ oids (38c). Trough everolimus concentra­ tions were 6.6 ng/ml (10–90th percentiles 2.8–12 ng/ml). Increases in serum choles­ terol (W6.5 mmol/l) and triglycerides (W2.9 mmol/l) and transient reductions in platelet count (o100  109 per liter) correlated with increasing trough everolimus concen­ trations. Infections and drug-related adverse events were not significantly related to exposure. A well-tolerated

and efficacious concentration range for everolimus in maintenance of lung trans­ plants appears to be 3–12 ng/ml when it is used in conjunction with ciclosporin and corticosteroids. A fluorescence polarization immunoas­ say (FPIA) was comparable to HPLC for measurement of everolimus concentrations in 113 trough blood samples from heart transplant recipients, but FPIA gave a mean overestimation of 24% compared with HPLC (39c). Cross-reactivity with sirolimus ranged from 85 to 138%. FPIA has been compared with HPLC– tandem mass spectrometry (HPLC–MS) for measurement of everolimus in 333 predose samples from 45 renal transplant recipients (40c). The two systems were comparable, but FPIA overestimated everolimus com­ pared with HPLC–MS, probably because of calibration differences between the meth­ ods and cross-reactivity of the FPIA anti­ body with everolimus metabolites. The Deming regression equation was FPIA ¼ 1.19  (HPLC–MS) + 0.51.

ISA 247 ISA 247 is a calcineurin inhibitor intended for use in the treatment of psoriasis, prevention of organ rejection after trans­ plantation, and the management of auto­ immune diseases (uveitis, arthritis, type I diabetes, and Crohn’s disease) (41R). Pre­ clinical observations suggest that it may be more potent and less toxic than other immunosuppressants in its class. Experi­ ments to date suggest that ISA 247 is about three times as potent as ciclosporin, and genotoxicity studies in animals suggest that it should cause significantly less renal toxicity. Urinary tract ISA247 (0.5 and 1.5 mg/kg/ day) has been evaluated in a placebocontrolled study in 201 patients with plaque psoriasis (42C). Those who took 1.5 mg/kg/ day had increased serum creatinine concentrations within the reference range.

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Chapter 38

Leflunomide

(SED-15, 2015; SEDA-28, 457; SEDA-29, 435; SEDA-30, 454)

Leflunomide inhibits dehydro-orotate dehy­ drogenase, a key enzyme in pyrimidine synthesis in activated lymphocytes. Comparative studies In 285 patients with rheumatoid arthritis leflunomide was discon­ tinued after 1 year in 57%, mainly because of adverse drug reactions (42%) (43A). The discontinuation rate because of toxicity was higher for leflunomide than for other DMARDs studied, while discontinuation for inefficacy was similar. Respiratory Rheumatoid lung nodulosis has been described during leflunomide therapy (44A).
A 77-year-old man with long-standing active

seropositive nodular rheumatoid arthritis had a complete remission during 2 months of leflunomide therapy. After 10 months he developed limb pain associated with intensive bone uptake on a bone scan, consistent with hypertrophic pulmonary osteopathy. After 13 months progressive cavitary nodules, pre­ dominantly involving the basal segments of the right lung, were detected on a CT scan. A lung biopsy showed necrosis surrounded by epithe­ lioid mononuclear inflammation with giant cells, consistent with rheumatoid disease.
A 66-year-old man with long-standing active seropositive nodular rheumatoid arthritis achieved a complete remission during 2 months of leflunomide therapy. After 3 months he developed a productive cough. After 7 months a CT scan showed progressive cavitary nodules, predominantly involving the basal segments of the right lung. A lung biopsy showed necrosis surrounded by epithelioid mononuclear inflammation with giant cells, consistent with rheumatoid disease.

In both cases withdrawal of leflunomide was followed by arrest in the growth of the lung nodules, resolution of the limb pain, and gradual improvement in the bone scan. The authors suggested that monocytopenia was involved in the pathogenesis of this rare complication. Interstitial pneumonitis has very rarely been observed in patients taking lefluno­ mide in clinical trials, but there is emer­ ging evidence that it is more frequent in clinical practice. The New Zealand

625 Pharmacovigilance Centre (NZPhvC) and the Australian Adverse Drug Reactions Unit (ADRU) have received 14 reports of supposed pneumonitis in patients taking leflunomide, 12 in combination with meth­ otrexate (45c). In 9 of these 12 patients pneumonitis occurred after leflunomide was added to methotrexate, usually within 12– 20 weeks. One of two patients who died had possible previous methotrexate-induced pneumonitis. Leflunomide washout with colestyramine was used to treat three patients, one with life-threatening illness, with good results. This report suggests that prompt recognition is important to avoid life-threatening disease and supports the use of colestyramine to remove leflu­ nomide, as has been reported in another case in which oral colestyramine was used (46A).
A

69-year-old woman with rheumatoid arthritis developed acute interstitial pneumo­ nia 3 months after starting to take lefluno­ mide. Methylprednisolone pulse therapy and colestyramine 24 g/day ameliorated her symptoms.

In 62 734 patients with rheumatoid arthri­ tis who had used a DMARD there were 74 cases of serious interstitial lung disease, corresponding to a rate of 8.1 per 10 000 patients per year (47C). Leflunomide increased the risk of interstitial lung disease (adjusted RR ¼ 1.9; 95% CI ¼ 1.1, 3.6). Among those who had not previously used methotrexate and without a history of interstitial lung disease, the risk associated with leflunomide was not increased (RR ¼ 1.2; 95% CI ¼ 0.4, 3.1), but it was increased among the others (RR ¼ 2.6; 95% CI ¼ 1.2, 5.6). Patients with a history of interstitial lung disease were twice as likely to have taken leflunomide as any other DMARD. Interstitial lung disease associated with the use of leflunomide is probably due to the fact that leflunomide is used in high-risk patients, particularly those who have used methotrexate or have pre­ existing interstitial lung disease. Fatal cases of leflunomide-related interstitial pneumonia have been reported.
A 75-year-old woman with rheumatoid arthri­

tis developed rapidly progressive interstitial

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pneumonia 45 days after starting to take leflunomide and died of respiratory failure (46A). Autopsy showed a mixed pattern of acute and organizing diffuse alveolar damage.
A 77-year-old woman with rheumatoid arthri­ tis and a history of methotrexate-induced pneumonitis suddenly developed dyspnea on exertion about 2 months after starting to take leflunomide and died (48A). For more than 3 weeks after withdrawal of the drug she had a high concentration of an active metabolite of leflunomide.

Pulmonary alveolar proteinosis is an uncommon disorder marked by abnormal accumulation of surfactant in the alveoli. Secondary pulmonary alveolar proteinosis can occur in patients who are immuno­ suppressed, usually with corticosteroids. Biopsy-proven pulmonary alveolar protei­ nosis has been reported in a patient taking leflunomide (49A). Treatment with whole lung lavage and withdrawal of leflunomide produced a good result. Sensory systems Endophthalmitis asso­ ciated with leflunomide and adalimumab has been reported (50A).
A 48-year-old woman taking leflunomide and

adalimumab for rheumatoid arthritis devel­ oped endophthalmitis caused by Propionibacterium acnes. The diagnosis was confirmed by polymerase chain reaction and positive cul­ tures. She underwent surgical treatment and was given intravitreal vancomycin, but devel­ oped retinal fibrosis and untreatable retinal detachment.

This report of endophthalmitis is consistent with previous reports associated with the use of TNF-a inhibitors. P. acnes can cause pathological reactions in immunocompro­ mised patients and can cause endophthal­ mitis, but only after ocular surgery or in intravenous drug users. Skin Leflunomide can cause skin ulceration. Two women, aged 59 and 63 years, were given leflunomide for rheumatoid arthritis and subsequently developed severe skin ulcers; after drug withdrawal the ulcers healed completely albeit very slowly (51A). Leflunomide has also been associated with toxic epidermal necrolysis (52A).

Connective tissues The risk of woundhealing complications after elective ortho­ pedic surgery has been studied in 201 patients with rheumatoid arthritis or psor­ iatic arthropathy receiving methotrexate, etanercept, infliximab, adalimumab, ana­ kinra, or leflunomide (53C). Compared with patients who received methotrexate (n ¼ 59), the risk of postoperative woundhealing complications in patients who received leflunomide (n ¼ 32) was signifi­ cantly increased: 14% versus 41%, respec­ tively. The authors recommended that leflunomide should be withdrawn preo­ peratively in patients with rheumatoid arthritis undergoing elective orthopedic surgical procedures, to reduce the risk of early wound-healing complications or infections. Immunologic Leflunomide caused severe skin reactions in five patients. All had taken leflunomide for rheumatoid arthritis 4– 6 weeks before the onset of the reactions and had fever, rash, and generalized weak­ ness (54c). All had delayed onset, wide­ spread and long-lasting rashes, and internal organ involvement. These features suggest a drug hypersensitivity syndrome. Infection risk A total of 10 614 patients with rheumatoid arthritis and 1721 with musculoskeletal disorders were screened for Herpes zoster by semiannual question­ naires (55C). Patients with prior Herpes zoster infection were excluded. The annual­ ized incidence rate per 1000 patient-years was 13 (95% CI ¼ 12, 15) in patients with rheumatoid arthritis and 15 (95% CI ¼ 11, 18) in those with musculoskeletal disorders; there was no effect of age and sex. The following significant hazard ratios predic­ tive of Herpes zoster were computed from multivariable analyses in patients with rheumatoid arthritis: cyclophosphamide 4.2 (95% CI ¼ 1.6, 12), azathioprine 2.0 (1.2, 3.3), prednisone 1.5 (1.2, 1.8), lefluno­ mide 1.4 (1.1, 1.8), and COX-2 inhibitory NSAIDs 1.3 (1.1, 1.6). Seven cases of tuberculosis have been reported in patients taking leflunomide (56c,57c).

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Chapter 38

Pregnancy Leflunomide must be prophy­ lactically withdrawn before a planned preg­ nancy (58R). Drug–drug interactions Warfarin An interaction between warfarin and lefluno­ mide has been reported (59A).
A

61-year-old Caucasian woman taking long-term warfarin for recurrent thromboem­ bolism and atrial fibrillation had a raised international normalized ratio (INR) after she started taking leflunomide for rheumatoid arthritis. Her INR had been stable for 4 months before this. She required an overall 22% reduction in her weekly warfarin dose to maintain the INR within the target range of 2.0–3.0 after adding leflunomide.

There has been a previous report of this interaction (60A). The frequency of INR monitoring should be increased in patients receiving leflunomide and warfarin.

Mycophenolate mofetil (SED-15, 2402; SEDA-28, 458; SEDA-29, 445; SEDA-30, 455) Respiratory system Mycophenolate mofe­ til can cause bronchiectasis (61R). Five kidney transplant patients developed cough, dyspnea, and abundant sputum production without an apparent cause 0–20 months after starting to take mycophenolate mofetil (62R). Chest radiography and CT scans showed evidence of bronchiectasis. After withdrawal of mycophenolate the pulmon­ ary complaints greatly diminished but repeated scans showed persistent lesions. Gastrointestinal Mycophenolate mofetil often causes dose-limiting gastrointestinal adverse effects. The underlying mechanisms are not fully understood. Using the US Renal Data System, 3675 adult recipients with gastrointestinal complications were identi­ fied; when mycophenolate was withdrawn or the dosage reduced as a result, there was an increased risk of graft loss (63R). In 39 stable kidney transplant patients therapeutically equivalent doses of an

627 enteric-coated formulation of mycophe­ nolate sodium reduced the incidence of adverse gastrointestinal events and produced higher concentrations of mycophenolic acid, probably because of better absorption (64c). This suggests that the gastrointestinal adverse effects of mycophenolate are due to a local action on the stomach. Urinary tract Mycophenolate mofetil may bee associated with acute graft pyelonephritis. Of 1022 renal transplant recipients, 169 (17%) developed acute graft pyelonephritis (65C). There were significant associations with the presence of a ureteric stent (OR ¼ 4.6), urological malformations in the original kidney (OR ¼ 2.1), cytomegalo­ virus infection (OR ¼ 2.0), mycophenolate mofetil (OR ¼ 1.9), and acute rejection episodes (OR ¼ 1.5). Age, sex, induction therapy, anti-CD3 treatment, and hypergly­ cemia were not associated. Infection risk There are contradictory reports of an association between myco­ phenolate mofetil and the risk of cytomegalovirus infection. In a review of 29 published studies immunosuppressive regi­ mens containing mycophenolate mofetil increased the likelihood of cytomegalovirus infection (66M). Tumorigenicity Of 3895 heart transplant recipients, 703 (18%) developed a malig­ nancy at any time during follow-up and 549 (14%) developed a malignancy within the first 5 years: skin (47%), lymphoprolifera­ tive (10%), and other malignancies (24%) (67M). Freedom from malignancy was greatest in those who took mycophenolate mofetil + tacrolimus, followed by mycophe­ nolate mofetil + ciclosporin, azathioprine + tacrolimus, and azathioprine + ciclosporin. A comparison of tacrolimus and ciclosporin showed no significant difference in survival. Freedom from malignancy was significantly higher with mycophenolate mofetil than with azathioprine. Mycophenolate mofetil was associated with a 27% adjusted risk reduction for any malignancy during followup. Female sex and blood group B were also associated with a reduced risk.

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Pregnancy Animal and limited human stu­ dies have raised concerns about the safety of in utero exposure to mycophenolate mofetil and sirolimus in transplant recipients. Outcomes in 39 pregnancies in 30 female transplant recipients with exposure to myco­ phenolate mofetil or sirolimus have been reported to the National Transplantation Pregnancy Registry (68M). Of 26 pregnancies in 18 kidney recipients exposed to mycophe­ nolate there were 15 live births and 11 spontaneous abortions. There were structural malformations in 4 of the 15 children, includ­ ing: hypoplastic nails and shortened fifth fingers, microtia with cleft lip and palate, microtia alone, and neonatal death with multiple malformations. One kidney/pan­ creas recipient reported a spontaneous abor­ tion. Three liver recipients reported three pregnancies with two live births (no malfor­ mations) and one second trimester sponta­ neous abortion. Two heart recipients reported one live birth (no malformations) and two spontaneous abortions. Among seven recipients (four kidney, one kidney/ pancreas, and two liver) with exposure to sirolimus there were four live births (one infant whose mother was switched from mycophenolate to sirolimus during late preg­ nancy had cleft lip and palate and microtia) and three spontaneous abortions. There was a higher incidence of structural malformations during pregnancy with exposure to mycophe­ nolate than in the overall kidney transplant recipient offspring. No structural defects have as yet been reported with exposure to sirolimus in early pregnancy.

patients co-treated with ciclosporin than with sirolimus, giving values of 1.8-fold, 2.6­ fold, and 4.3-fold for the phenyl-glucuronide, the acyl-glucuronide, and the phenyl-gluco­ side, respectively. Thus, patients who take mycophenolate mofetil and ciclosporin have less exposure to mycophenolic acid and greater exposure to its metabolites than those who take mycophenolate mofetil and sirolimus. This interaction is probably not caused by an effect on mycophenolic acid glucuronidation or glycosylation, but is more likely to be due to the effect of ciclosporin on the excretion of mycophe­ nolic acid metabolites into the bile.

Drug–drug interactions Iron There was no significant interaction between myco­ phenolate mofetil and iron supplements in 16 healthy men (69c).

The authors concluded that local immuno­ suppression may have promoted prolifera­ tion of Demodex folliculorum, a known trigger of rosacea.

Ciclosporin Mycophenolic acid pharma­ cokinetics have been studied in renal transplant patients taking either ciclosporin (n ¼ 19) or sirolimus (n ¼ 12) (70A). The mean mycophenolic acid AUC0-9 hours was 45 h mg/l in the sirolimus group and 31 h mg/l in the ciclosporin group, corresponding to a 1.5-fold dose-normalized difference. The metabolite/mycophenolic acid AUC09 hours ratios were significantly higher in

Valganciclovir The addition of mycophe­ nolate mofetil and co-trimoxazole may have increased the risk of leukopenia from valganciclovir in 16 kidney transplant reci­ pients, although in only one case was there increased exposure to mycophenolate, judged by the AUC (71c).

Pimecrolimus

(SED-15, 2833; SEDA28, 460; SEDA-29, 449; SEDA-30, 456)

Immunologic Local immunosuppression has been attributed to pimecrolimus (72A).
A 23-year-old woman with discoid lupus

developed a unilateral rosaceiform eruption on the right cheek after using pimecrolimus cream 1% bd for 2 months.

Sirolimus (rapamycin) (SED-15, 3148; SEDA-28, 460; SEDA-29, 449; SEDA-30, 457) Common adverse effects of TOR inhibitors, such as sirolimus, include hypertriglyceri­ demia, hypercholesterolemia, hypertension,

Drugs that act on the immune system

Chapter 38

rashes, diarrhea and abdominal discomfort, acne, pancytopenia, and oral ulcers. Respiratory tract Reversible sirolimus­ associated pneumonitis has been seen after heart, lung, and liver transplantation (73c–75c).
A 63-year-old Mexican underwent renal cada­

veric transplantation plus prednisone, ciclos­ porin, and sirolimus (76A). After 4 months he developed a productive cough, slowly progres­ sive exertional dyspnea, and occasional morn­ ing fevers; 2 months later he developed respiratory failure. Chest radiography showed a diffuse interstitial pattern and a CT scan showed patchy ground-glass opacities in the upper, middle, and central portions of the lungs. He was given broad antimicrobial therapy against Pneumocystis jiroveci and cytomegalovirus among others. Some symp­ toms improved but he remained severely hypoxic. An open lung biopsy showed that the alveolar spaces were filled with macro­ phages. After withdrawal of sirolimus, his symptoms and respiratory function quickly improved.

In a single center study in France in 217 patients who underwent kidney transplan­ tation, 128 switched from calcineurin inhi­ bitors to sirolimus to avoid calcineurin inhibitor nephrotoxicity and 89 received sirolimus initially after transplantation (77c). The targeted trough concentration was 12–20 ng/ml. There was presumed sirolimus-associated pneumonitis in 24 patients (10 men, 14 women) who had taken sirolimus for a median of 5.5 months. The most common presenting symptoms were cough (n ¼ 23), fatigue (n ¼ 20), fever (n ¼ 16), and dyspnea (n ¼ 8); two patients had hemoptysis. C-reactive protein concen­ trations were 6–344 mg/l. There was mod­ erate hypoxemia (mean PaO2 10 kPa) in 8 patients and 2 had a PaO2 below 8 kPa; the other 14 patients had normal saturations. All had pulmonary infiltrates on radio­ graphy. CT scans showed patchy bilateral asymmetrical peripheral consolidations (like bronchiolitis obliterans-organizing pneumonia) in 19 patients, reticular and ground-glass opacities in 4, and lobar consolidation in 1. Sirolimus withdrawn immediately in 9 patients and 4–12 days in 13 patients after ofloxacin and ceftriaxone

629 gave no improvement. Of 24 patients 19 improved spontaneously within 2 weeks after sirolimus withdrawal; 3 received corti­ costeroids for 2 weeks because of persis­ tence of pulmonary and general symptoms. Chest radiographs and CT scans returned to normal within 6 months in 22 patients. In two patients the dose of sirolimus was initially reduced, with clinical remission. Clinical relapse in one patient and persis­ tence of opacities on CT in another led to sirolimus withdrawal. Hematologic In 42 transplanted patients with biopsy-proven chronic allograft nephropathy, the dose of ciclosporin was either reduced (n ¼ 14) or it was replaced by sirolimus (n ¼ 28) (78c). In the former there was no change in hemoglobin or iron status, but in the latter hemoglobin fell significantly without any change in red blood cell count but a significant reduction in mean corpuscular volume and mean corpuscular hemoglobin concentration. Serum iron and transferring saturation concentrations were markedly reduced after the switch, while serum ferritin con­ centrations remained stable. Oral iron therapy did not affect hemoglobin or serum iron concentrations. Gastrointestinal Sirolimus can cause an intractable severe chronic secretory diarrhea (79A).
A 50-year-old Hispanic man who underwent

kidney transplantation was given sirolimus 2 mg/day plus prednisone and ciclosporin. One year later, the dose of sirolimus was increased to 5 mg/day and 1 month later he developed severe watery diarrhea with up to 20 bowel movements a day without mucus or blood. He had no abdominal pain, tenesmus, fecal urgency, nausea, vomiting, excessive flatu­ lence, hematemesis, melena, or anorexia. His vital signs were normal. There was no evi­ dence of a gastrointestinal infection. An MRI scan showed ascites and thickened colonic mucosal folds. Colonoscopy showed occa­ sional petechiae and diverticular disease. Colonic mucosa biopsy showed rare individual atrophic glands with negative viral cytopathic effect and granuloma. Upper gastrointestinal endoscopy showed duodenal melanosis. Duodenal mucosal biopsy showed mild epithelial reactive changes with no evidence of celiac disease, sprue, viral cytopathy, or

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granulomata. Sirolimus was withdrawn. Within 48 hours, he patient had formed stools and a dramatic reduction in the number of bowel movements. He recovered fully within 1 week.

Colonic perforation associated with leukocytoclastic vasculitis has been attributed to sirolimus toxicity (80A). Delayed gastric ulcer healing has been associated with sirolimus (81A). Urinary tract Sirolimus can cause heavy proteinuria (82A).
Within 10 days of receiving a living-related

kidney for focal segmental glomerulosclerosis a patient developed severe proteinuria, which disappeared completely after switching to tacrolimus. Allograft biopsy showed no evi­ dence of rejection, glomerulonephritis, or recurrent focal segmental glomerulosclerosis. Albumin re-absorption droplets could not be detected in the proximal tubular cells.

In 184 live donor kidney transplant recipi­ ents who received calcineurin inhibitorbased (n ¼ 106) or sirolimus-based (n ¼ 78) immunosuppression, the sirolimus­ treated patients had higher frequencies of proteinuria at 6 months (41% versus 21%) and 12 months (38% versus 18%) (83c). Skin The clinical characteristics of siroli­ mus-induced acne have been analyzed in 80 renal transplant recipients (84c). Acne devel­ oped in 36 of 48 men and 2 of 32 women. The locations of the lesion and the clinical, bacteriological, and histological features differentiated sirolimus-induced acne from acne vulgaris, but management was similar. Inhibition of epidermal growth factor by sirolimus is a plausible explanation. Nails Of 80 patients who took sirolimus after kidney transplantation 57 developed nail abnormalities, mostly matrix alterations, including slow growth, onychomalacia, onychorhexis, and leukonychia; there were nail bed changes in 42 cases and vascular phenomena and periungual anomalies in 19 (85c). Connective tissues In a study of wound healing 44 of 300 patients who took sirolimus were investigated; 14 developed

a lymphocele, bladder leak, wound dehiscence, cellulitis, or an abscess. Obesity was significantly associated with these problems. Those who took tacrolimus had fewer complications (14%) (86c). Tumorigenicity In 58 kidney transplant recipients 35 lymphoceles were detected. There was no significant difference in the incidence of lymphocele among the three immunosuppressive groups (tacrolimus 22%, ciclosporin 23%, sirolimus 22%) (87c). Pregnancy A 30-year-old woman who received a kidney transplant from a livingrelated donor and took low-dose sirolimus (4 mg/day) and ciclosporin (150 mg/day) de­ livered a child without abnormalities (88A). Drug–drug interactions Amiodarone Amiodarone increases trough blood siroli­ mus concentrations and sirolimus dosage reduction is required (89A).

Tacrolimus

(SED-15, 3279; SEDA-28, 463; SEDA-29, 453; SEDA-30, 458)

Cardiovascular Veno-occlusive disease is recognized as a complication of high-dose immunosuppressive therapy in solid-organ transplantation and has been reported with tacrolimus (90A).
A 60-year-old woman received a cadaveric

single lung transplant for severe chronic obstructive pulmonary disease and took tacro­ limus, mycophenolate mofetil, prednisone, and dapsone for immunosuppression. After about 6 months she developed night sweats, early satiety, abdominal bloating, and 4.5–6.8 kg of weight loss. She had new ascites and a palpable, tender, smooth liver edge 4–5 cm below the ribcage, with no splenomegaly. She had raised transaminases and hyperbilirubine­ mia. A CT scan showed ascites with portal hypertension. A liver biopsy showed centri­ lobular sinusoidal dilatation with hemorrhage and hepatocellular dropout. Trichrome staining showed areas of centrilobular fibrosis. The hepatic veno-occlusive disease was attributed to tacrolimus. Ciclosporin was used instead, and 3 weeks later her ascites, transaminases, and malaise had resolved.

Drugs that act on the immune system

Chapter 38

Ear, nose, throat Little is known about hearing impairment after organ transplan­ tation. A questionnaire was sent to 695 adults after liver transplantation and was completed by 75% (91c). Hearing impairment was reported by 35%: 8% had had hearing abnormalities before liver trans­ plantation and 27% developed hearing impairment after transplantation. Hearing loss (52%), tinnitus (38%), and otalgia (30%) were the main problems. In 43% the onset of the impairment was within 2 years after transplantation. Hearing loss was associated with the use of tacrolimus immunosuppression in univariate and mul­ tivariate analyses. Nervous system Tacrolimus-induced neu­ rotoxicity has been reported.

631 Sensory systems Optic neuropathy has been attributed to tacrolimus (94c).
A 51-year-old woman with type 1 diabetes

mellitus underwent islet cell transplantation followed by immunosuppression with tacroli­ mus 2 mg/day and sirolimus 0.1 mg/kg/day. Before transplantation, she had a stable retinopathy with a visual acuity of 8/10 in the right eye. Two weeks after transplantation she became insulin-free but 5 months later noted gradual deterioration in her visual acuity. The acuity in the right eye was 2/10. There were no retinal hemorrhages or infiltrates and there was no vitreous activity. Cytomegalovirus and mycobacterial serologies were negative. An MRI scan of the brain and orbits was normal. Visual-evoked potentials showed a delay in P100 latency and a decrease in amplitude in the right eye. Tacrolimus was withdrawn and mycophenolate mofetil started and 1 month later her visual acuity was 7/10.


A 20-year-old woman underwent renal trans­

plantation and took tacrolimus 7 mg bd and mycophenolate 750 mg bd for immunosup­ pression (92c). After 3 months she developed subacute truncal ataxia and mild appendicular ataxia, especially while reaching for objects. She also had dysarthria and tremulousness. She did not have any seizures. An MRI scan showed hyperintensities in the cerebellum, predominantly in the vermis. Electroencepha­ lography was normal. Tacrolimus was replaced by sirolimus. Her symptoms improved over the next 2 weeks and a repeat MRI scan 3 months later showed marked improvement in the cerebellum, but atrophy of the vermis.
A 62-year-old man underwent liver transplan­ tation and was given tacrolimus and low-dose prednisone for immunosuppression (93c). After 6 months he received influenza vaccine and 2 weeks later developed generalized weakness. He had bilateral facial weakness, dysphagia, hypophonia, and quadriplegia. Electrophysiology showed prolonged distal latencies and absent late responses in all limbs; the compound muscle action potentials were reduced throughout. Conduction velocities were reduced in the demyelinating range in the median nerves bilaterally and in the right ulnar and tibial nerves. These findings were consistent with an acute inflammatory demye­ linating polyneuropathy. He was given intra­ venous immunoglobulin 0.5 g/kg/day for 3 days without significant improvement. He died 3 weeks later from septic shock and acute renal insufficiency.

In the second case influenza vaccine probably played an important part, and it is not clear to what extent immunosuppres­ sion contributed.

Endocrine New-onset diabetes mellitus after kidney transplantation is an important co morbidity that is associated with inferior graft and patient survival. Of 15 309 adult kidney transplant recipients 1581 developed diabetes during follow-up. The independent susceptibility factors included age of the recipient (RR ¼ 1.29 for every 10-year age increment), obesity (RR ¼ 1.39 for BMI 25–30 and 1.85 for BMIW30), use of tacro­ limus (RR ¼ 1.50), hepatitis C virus positivity (RR ¼ 1.42), and African-American race (RR ¼ 1.32) (95c). Metal metabolism Hypomagnesemia is common in patients taking tacrolimus. In one study of 41 transplant patients and 10 healthy volunteers for correlation with tacrolimus level, 43% had hypomagnese­ mia, which was attributed to renal magne­ sium wasting (96c). The blood tacrolimus concentration was the best predictor of 24-hour urinary magnesium excretion and fractional urinary excretion of magnesium. Serum magnesium concentrations corre­ lated inversely with tacrolimus concentra­ tions and creatinine clearance. Hematologic Post-transplantation lymphoproliferative disorder is potentially fatal. In a chart review of 110 heart transplant

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recipients and 80 kidney transplant recipi­ ents 15 had post-transplantation lympho­ proliferative disorder, 6 after a heart transplant and 9 after a renal transplant. Pretransplant cytomegalovirus seropositiv­ ity was a strong predictor (97c). Sarcoidosis with hematologic effects has been reported in an immunosuppressed child (98A).
A 9-year-old boy who took tacrolimus and

mycophenolate mofetil for 9 years after heart transplantation developed a low-grade fever, hepatosplenomegaly, and enlarged axillary and mediastinal lymph nodes with a mild anemia and lymphocytopenia. Histology of a lymph node showed non-caseating epitheloid cell granulomata. He responded rapidly to steroid therapy.

It is not clear to what extent immuno­ suppression contributed in this case. Gastrointestinal In pediatric liver trans­ plant recipients taking tacrolimus eosinophilic gastroenterocolitis has been seen (99c). The patients had high serum immunoglobulin IgE concentrations, eosinophilia, and IgE-posi­ tive radioallergosorbent test for milk pro­ teins. The colitis appeared to be mediated by food allergy. Each patient had symptomatic improvement following reduced immunosup­ pression and a restricted diet. Biliary tract Tacrolimus can cause cholestasis after pediatric liver transplantation and steroid-resistant graft rejection. Cholestatic syndrome has been reported in six (5.4%) children receiving tacrolimus in therapeutic doses (100c). After re-conversion to ciclospo­ rin and prednisolone all recovered comple­ tely. The authors suggested that even therapeutic doses of tacrolimus after steroidresistant graft rejection can cause a chole­ static syndrome in pediatric liver transplant recipients. Urinary tract Tacrolimus-associated hemolytic–uremic syndrome is associated with high rates of kidney transplantation, graft loss, and death and has now been reported in a child (101c).
An 11-year-old girl developed hemolytic–

uremic syndrome, with renal failure, hemolytic

anemia, thrombocytopenia, hypertension, and erythrocyte casts in the urine, 4 days after receiving a living-related liver transplantation with concurrent splenectomy followed by methylprednisolone and tacrolimus immuno­ suppression. Antithymocyte globulin was used instead of tacrolimus. She recovered with daily plasmapheresis and intravenous immunoglo­ bulin. Sirolimus replaced the anithymocyte globulin at 16 days.

Tacrolimus-associated localized thrombotic microangiopathy in a transplanted kidney has been reported in a 14-year-old boy (102c). The immediate effects of ciclosporin and tacrolimus on renal arterial resistance have been investigated in 34 patients (16 taking ciclosporin, 18 tacrolimus) with stable graft function after renal transplantation (103c). Arterial resistance increased significantly 1 hour after administration of the calci­ neurin inhibitor and was still significantly raised after 2 hours; it reversed 30 minutes after administration of glyceryl trinitrate spray.
A 63-year-old woman developed acute renal

failure 8 months after receiving a cadaveric kidney transplant while taking tacrolimus, sirolimus, and prednisolone (104A). Doppler sonography showed reversed diastolic blood flow in all branches of the intrarenal vessels, suggesting severe narrowing. However, renal artery and vein MR angiography was normal. A renal biopsy showed no acute cellular or humoral rejection, chronic allograft vasculo­ pathy, or acute tubular necrosis. Within 1 week of reducing tacrolimus trough concentrations to 3–5 mg/l, the serum creatinine fell to 177 mmol/l and renal artery diastolic flow was orthograde. After 5 months the serum creati­ nine had fallen to 133 mmol/l.

In 24 adults with impaired renal function after intestinal transplantation the cumula­ tive tacrolimus concentration during the first year affected renal function at about 2 years (105c). Musculoskeletal Acute joint pain has been attributed to tacrolimus (106c).
A 49-year-old man received a cadaveric

kidney transplant and took tacrolimus 5 mg bd plus steroids. After 1 month he reported

Drugs that act on the immune system

Chapter 38

pain in his ankles, knees, feet, and hands, so intense as to require crutches. There was intense pain on movement, without edema, redness, increased temperature, or cutaneous trophic changes. Bone radiography showed widespread osteoporosis. MRI of the left knee showed an area of bone marrow edema in the external condyle of the femur and wearing of the cartilage. Computerized bone mineralo­ metry showed a slight reduction in bone mass, and bone scintigraphy showed increased radionuclide uptake in the affected joints. Tacrolimus was withdrawn and replaced by mycophenolate mofetil, with subsequent improvement. After acute rejection 5 months later, he was treated with steroid boluses and tacrolimus 2 mg bd was re-introduced; 8 months after the onset of the syndrome he was completely symptom-free.

Tumorigenicity Lareb, a Pharmacovigi­ lance Centre in the Netherlands, has received three reports of malignancies associated with topical tacrolimus 0.03% (Protopics) up to June 2006 (107S).
A child developed a T cell leukemia 2 years

after starting tacrolimus therapy and at the time of notification had not recovered.
A man developed a squamous cell carcinoma on the glans penis 1 year after starting tacrolimus; the outcome was unknown.
An elderly woman developed a malignant tumor of the tongue, which required surgical removal.

Topical tacrolimus is used in atopic derma­ titis. Lareb says that because topical tacro­ limus is often used for extended periods and off-label use is not uncommon, health professionals should be aware of a potential risk of malignancies. Susceptibility factors Of 174 patients after transplantation (120 cadaveric liver trans­ plantations, 54 living donor transplantations) 43 developed neurological complications (108c). Living donor transplants were asso­ ciated with a significantly lower incidence of neurological complications than cadaveric graft (11/54 versus 32/120). The cold ische­ mia time after living donor transplantation was significantly shorter than after cadaveric transplantation. There was no difference in the incidence of neurological symptoms between the patients treated with ciclosporin and tacrolimus.

633 Patients with Wilson disease and tyrosi­ nemia are more susceptible to neurological adverse effects of tacrolimus after liver transplantation (109c). Drug–drug interactions Fumagillin An interaction of tacrolimus with fumagillin, a drug used to treat microsporidiosis, has been reported in kidney transplant patients (110c).
A 49-year-old man received a second renal

transplant for amyloidosis and 2 months later developed intestinal microsporidiosis while taking tacrolimus 1 mg bd, corticosteroids, and mycophenolate mofetil 1 g bd. He was given fumagillin 20 mg tds and 1 week later the blood tacrolimus concentration fell from 10 to 3.5 ng/ml. The dose of tacrolimus was increased to 2 mg bd to maintain a blood concentration of around 10 ng/ml.
A 72-year-old woman received a renal transplant and took tacrolimus 2 mg bd and corticosteroids. After 10 days her tacrolimus concentrations were stable at 5–10 ng/ml. She developed intestinal microsporidiosis and was given fumagillin 20 mg tds; 2 days later her blood tacrolimus concentra­ tions fell by 50%. The dose of tacrolimus was increased to 3 mg bd.

Levofloxacin Levofloxacin partially inhibited the metabolism of both tacrolimus and ciclosporin in kidney transplant recipi­ ents (111c). Omeprazole Omeprazole is metabo­ lized to the major primary metabolites 5u­ hydroxyomeprazole, mediated by CYP2C19 with a minor contribution from CYP3A4. An interaction between tacroli­ mus and omeprazole in a pediatric liver transplant recipient has been reported (112c).
A 13-year-old child underwent liver transplan­

tation and took tacrolimus 12 mg/day and methylprednisolone 40 mg/day. Trough blood tacrolimus concentrations were stable at around 10 ng/ml. Nine days later he was given omeprazole 20 mg/day for gastroesophageal reflux. The trough tacrolimus concentration increased and peaked at 28 ng/ml. When omeprazole was withdrawn the blood tacroli­ mus concentration fell to 6 ng/ml. No mutation of CYP2C19 was detected. No other medica­ tion or clinical events such as diarrhea affecting the concentration of tacrolimus was reported.

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THIOPURINES Genetic susceptibility factors for thiopurine toxicity The association between thiopurine S-methyltransferase (TPMT) deficiency and myelosuppression with azathioprine is well recognized. The incidence of TPMT deficiency in Caucasians is 0.3–0.6% (113R,114R). TPMT catalyzes the S-methylation of thiopurines and has autosomal co-dominant polymorphism. Patients who carry a variant genotype have low TPMT activity and produce increased concentrations of 6-thioguanine nucleotides in their erythrocytes. Thioguanine nucleotide accumulation can result in azathioprine-induced bone marrow myelosuppression. It has also been suggested that the enzyme inosine triphosphate pyrophosphatase (ITPA) plays a role in the metabolism of thiopurines and that defective activity resulting from polymorphisms in the ITPA encoding genes may be associated with thiopurineinduced adverse effects. However, this has not been confirmed in relation to the ITPA 94CWA polymorphism in a meta-analysis of six studies in 751 patients (115M). Measurement techniques TPMT activity has been studied by a new rapid genetic PCR–RFLP screening test for the most prevalent mutant TPMT�3A and TPMT�3C alleles, which result in reduced TPMT enzyme activity (116A). Of 871 Caucasians, 8.6% carried the TPMT�3A allele and 0.23% were heterozygous for the TPMT�3C allele, which is in accord with previously reported allele frequencies. A non-radioactive method that uses HPLC with ion-trap mass detection has been developed to measure the activities of TPMT in erythrocytes and inosine 5u-monophosphate dehydrogenase (IMPDH) in peripheral blood mononuclear cells (117A). Clinical studies The relation between TPMT activity and the incidence of adverse effects has been studied in 788 patients with inflammatory bowel disease taking

azathioprine (118c). Erythrocyte TPMT activity was measured radiochemically. The mean TPMT activity was 19 (range 9–34) U/ml. No patient had low activity (o5), 7.1% had intermediate activity (5–14), and 93% had high activity (W14). Adverse effects were reported in 74 patients (19%), the most frequent being gastrointestinal intolerance (9.1%) and myelotoxicity (4.3%). No patient with adverse effects had low TPMT activity. However, mean TPMT activity was significantly lower in those with adverse effects (17 U/ml versus 19 U/ml). Moreover, the probability of myelotoxicity in the high TPMT group was only 3.5%, compared with 14% in the TPMT intermediate group (OR ¼ 4.5; 95% CI ¼ 1.37, 15). Of patients with Crohn’s disease (n ¼ 33) or ulcerative colitis (n ¼ 27) taking a thiopurine in a daily target dose at week 3 of 2.5 mg/kg of azathioprine or 1.25 mg/kg of mercaptopurine, 27 completed the study per protocol, 33 withdrew because of thiopurinerelated adverse events (n ¼ 27), early protocol violation (n ¼ 5), or TPMT deficiency (n ¼ 1) (119c). Of the patients with adverse effects 67% tolerated long-term treatment with a lower dose of azathioprine (median 1.32 mg/kg). TPMT activity did not change during the 20-week course of the study but there was a significant reduction in TPMT gene expression. Patients with methylthioinosine monophosphate concentrations over 11 450 pmol/8  108 erythrocytes during steady state at week 5 had an increased risk of myelotoxicity (OR ¼ 45). TPMT enzyme activity was not induced during thiopurine treatment, but TPMT gene expression fell. The development of different types of toxicity was unpredictable, but measurement of methylthioinosine monophosphate early in the steady-state phase helped to identify patients at risk of myelotoxicity. The frequency of TPMT deficiency has been assessed in 86 patients with autoimmune hepatitis taking azathioprine 50–150 mg/day compared with 89 similarly treated but untested patients (120C). There was low TPMT activity (11 (range 3.5–15) U/ml erythrocytes) in 13 tested patients. Azathioprine intolerance occurred as often in patients with normal or above normal

Drugs that act on the immune system

Chapter 38

enzyme activity as in patients with below normal activity (12% versus 15%). The frequency of complications was similar in the two groups (9% versus 13%). In this study routine screening of TPMT activity did not identify individual patients at risk of azathioprine toxicity during conventional low-dose therapy. In another study on patients with autoimmune hepatitis, azathioprine toxicity was predicted by the stage of fibrosis but not by TPMT genotype or activity (121A). In dialyzed patients, TPMT phenotype and genotype (�2, �3A, and �3C variant alleles), determined by HPLC, PCR–RFLP, and allele-specific PCR, were significantly correlated (122C). Median TPMT activity was 31 (12, 46) nmol of methylmercaptopurine/g of hemoglobin/hour. Heterozygous patients (12%) had significantly lower mean TPMT activity than wild homozygotes (17 versus 32). TPMT activities in heterozygous and wild-type homozygous patients did not overlap. TPMT activity after hemodialysis and TPMT genotyping were convergent in dialyzed patients, so both methods can be used to identify patients with lower TPMT activity before azathioprine therapy after renal transplantation. The pattern and frequency of the main mutant TPMT alleles (TPMT�2, �3A, �3B, and �3C) were similar in 122 transplant patients taking azathioprine and 210 healthy subjects (123C). TPMT heterozygosity was associated with significant reductions in hematologic indices and a significant reduction in ciclosporin plasma concentrations in the first year after renal transplantation. TPMT activity has been studied prospectively in 139 patients (35 men, 104 women) with systemic lupus erythematosus (n ¼ 38), progressive systemic sclerosis (n ¼ 13), Wegener’s granulomatosis (n ¼ 4), rheumatoid arthritis (n ¼ 5), and other chronic inflammatory diseases (n ¼ 79) (124c). Of 96 patients who took azathioprine, there were minor adverse effects in 11 (sickness, rash, and cholestasis) and severe adverse effects (bone marrow toxicity) in 7. Below a cut-off value of TPMT activity of 12 nmol/ml erythrocytes/hour, adverse effects were significantly more frequent.

635 An HPLC procedure has been developed to investigate the ITPA phenotype and phenotype–genotype correlation and a novel IVS2 + 68T W C mutation was found (125A). Mutations in the TPMT and ITPA genes have been associated with azathioprinerelated toxicity (126C). ITPA genotypes (94C W A, IVS2 + 21A W C) and TPMT genotypes (238G W C, 460G W A, and 719A W G) have been assessed in 262 patients with inflammatory bowel disease (159 women, 103 men; 67 patients with ulcerative colitis and 195 patients with Crohn’s disease) taking azathioprine and correlated with the development of leukopenia and hepatotoxicity. There was leukopenia (leukocyte count o 3.0  109 per liter) in 4.6%. Mutant ITPA 94C W A and TPMT alleles were significantly more common in those with leukopenia than in those without (17 and 5.4%, respectively, for ITPA 94C W A, and 21 and 4%, respectively, for TPMT). Moreover, the ITPA 94C W A and TPMT mutations predicted leukopenia: ITPA 94C W A OR ¼ 3.50 (95% CI ¼ 1.12, 10); TPMT OR ¼ 6.32 (2.14, 18). Neither TPMT nor ITPA genotypes predicted hepatotoxicity.

Azathioprine

(SED-15, 377; SEDA-28, 450; SEDA-29, 424; SEDA-30, 459) Respiratory Azathioprine-associated interstitial pneumonitis is a rare complication that can resolve after drug withdrawal (127A).


A 40-year-old man took azathioprine for

10 years for extensive ulcerative colitis. He then developed fever, cough, and catarrhal signs. Opportunistic infections were ruled out. Chest X-ray, a CT scan, and a lung biopsy showed interstitial inflammation. Azathioprine was withdrawn and he was given steroids; the pulmonary infiltrates gradually resolved.

Nervous system Neuritis multiplex occur­ red in a patient taking azathioprine for autoimmune hepatitis and resolved after conversion to cyclophosphamide (128A).

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Felix Braun, Freya A. Goumas, Dieter C. Broering, and Matthias Behrend


A 37-year-old woman with autoimmune hepa­

titis taking azathioprine and prednisolone developed a left-sided hemisensory deficit followed by right foot drop and bilateral paraesthesia in the ulnar nerve territory. An MRI scan and cerebral panangiography sug­ gested cerebral vasculitis. Neurological inves­ tigations and electromyography showed neuritis multiplex probably due to vasculitis. There were serum autoantibodies to extrac­ table nuclear antigens. Azathioprine was with­ drawn and oral cyclophosphamide 150 mg/day introduced. Almost complete motoric remis­ sion was achieved after 3 months, but sensa­ tion remained reduced in the right peroneal nerve distribution.

Azathioprine can cause a posterior leukoencephalopathy (129A).
A patient was given azathioprine for systemic

lupus erythematosus and after 3 weeks devel­ oped a posterior leukoencephalopathy with headache, tonic–clonic seizures, loss of con­ sciousness, bilateral loss of vision, and hyper­ tension. A CT scan showed hypodense lesions in both bilateral occipital lobes, mainly in the white matter. The symptoms and follow-up MRI scan improved after control of hyperten­ sion and withdrawal of azathioprine.

Neuromuscular function In two patients azathioprine caused profound muscular weakness, resulting in an inability to per­ form simple tasks, such as lifting even light objects, sitting upright, and walking a few steps (130A). Withdrawal of azathioprine resulted in prompt improvement, and rechallenge led to recurrence of similar symptoms within hours. Hematologic Among patients receiving mycophenolate mofetil or azathioprine the latter had lower hemoglobin concentrations after 1 and 6 months; mean corpuscular hemoglobin concentrations were also lower at 1 week and 1 months after transplantation but were comparable at 6 months (131R). Liver Thiopurines can cause hepatic nodular regenerative hyperplasia (132A). In vitro, glycyrrhizic acid and liquorice had a protective effect against azathioprine hepa­ totoxicity; glycyrrhizic acid protected human hepatocytes from intracellular glu­ tathione depletion on exposure to 1 mm azathioprine (133E). In another in vitro study a novel glutathione transferase

(GST)-dependent pathway in the biotrans­ formation of azathioprine was described (134E). GSTs A1-1, A2-2, and M1-1, all abundantly expressed in human liver, had the highest activity among the 14 isoen­ zymes tested. The uncatalyzed reaction of azathioprine with glutathione was less than 1% of the GST-catalyzed biotransforma­ tion. GST M1-1 is polymorphic, with a frequently occurring null allele, and GST A1-1 and GST A2-2 are variably expressed in humans, implying significant differences in the rate of mercaptopurine production from azathioprine. Individuals who express high GST activity are predisposed to adverse reactions to azathioprine, both by promoting excessively high concentrations of mercaptopurine and its toxic metabolites and by depleting cellular glutathione. Urinary tract A woman with Wegener’s granulomatosis progressed to renal failure within 10 days of starting azathioprine for vasculitis (135A). A renal biopsy showed acute tubulointerstitial nephritis and no active glomerulonephritis. Immunosuppression can lead to infections caused by Salmonella enteritidis (136A).
A

56-year-old man with systemic lupus erythematosus took azathioprine and predni­ solone and developed a urinary tract infection followed by bacteremia and epididymo­ orchitis. Both urine and blood cultures yielded S. enteritidis strains, which were typed by pulsed-field gel electrophoresis and were genotypically identical.

Musculoskeletal The risk of fractures has been studied in a case–control study in 124 655 patients. Azathioprine was asso­ ciated with an increase in overall risk of fractures, but not spine, hip, or forearm fractures (137C). Methotrexate and ciclos­ porin were not associated with a risk of fractures. This association might be related to the underlying disease for which azathioprine was being used. Reproductive system Sperm function has been studied in ejaculates from 37 immunocompromised kidney transplant recipients (20 taking tacrolimus and pre­ dnisolone, 17 ciclosporin, azathioprine, and

Drugs that act on the immune system

Chapter 38

prednisolone) compared with 15 healthy fertile men; there were no significant differ­ ences (138c). Immunologic Shock due to a hypersensitivity response to azathioprine is unpredict­ able and uncommon and can be fatal. It has been reported in a 46-year-old Caucasian man who rechallenged himself with azathioprine after having withdrawn it because of a persistent fever up to 401C, nausea, and vomiting (139A). Tumorigenicity The incidence of second­ ary myelodysplastic syndromes associated with a poor prognosis is increased in patients taking azathioprine for non-malignant disor­ ders. In a retrospective analysis of 317 patients with multiple sclerosis there was one case of myelodysplastic syndrome (cumulative dose 627 g) in a young patient and two further malignancies (cumulative doses 27 and 54 g) in those who had taken azathioprine (n ¼ 81; 3.7%). In those who had not taken azathioprine (n ¼ 236) there were five malignancies (2.1%) (140C). Three other cases of myelodysplastic syn­ dromes have been reported after long-term azathioprine therapy in multiple sclerosis. The cases suggest a time- and dose-depen­ dent risk of myelodysplastic syndromes during long-term therapy.
A woman with relapsing–remitting multiple

sclerosis took oral azathioprine for 4 years and subsequently switched to interferon-beta1a (141A). After 5 years, she developed a leukopenia, which resolved after interferon was withdrawn. She was given copolymer-1 instead, but recurrent pancytopenia subse­ quently led to a diagnosis of myelodysplastic syndrome with deletion of the long arm of chromosome 5. Within several months, which is unusually rapid for this subtype, the myelodysplasia progressed to secondary acute myeloid leukemia.

Azathioprine may have caused the chro­ mosomal deletion and myelodysplasia in this case. The etiology of diffuse large B cell lymphomas is unknown. Epstein–Barr virus may be involved and patients with immunodefi­ ciencies are primarily affected (142A). Two further cases have been reported (143A).

637
A 39-year-old woman developed an Epstein–

Barr virus-associated diffuse large B cell lymphoma of the plasmablastic subtype in the maxillary alveolar ridge in the region of teeth 11 and 21 after 24 years of immunosuppressive therapy with azathioprine for myasthenia gravis.
A 56-year-old man developed an Epstein–Barr virus-associated diffuse large B cell lymphoma of immunoblastic variant in the right maxillary edentulous alveolar ridge in the posterior region 7 weeks after cardiac transplantation and immunosuppressive therapy with aza­ thioprine and ciclosporin. There was a soft painless swelling measuring 1.5 cm  0.5 cm  0.5 cm with central ulceration. The tumor was excised followed by local radiotherapy and did not recur during 15 years of follow-up.

The demonstration of Epstein–Barr virus in the tumor cells in both of these cases underlines the involvement of this virus in the pathogenesis of oral diffuse large B cell lymphoma arising in the setting of immu­ nodeficiency. These tumors may dissemi­ nate early. Pregnancy The use of azathioprine in women of reproductive age at time of conception and during pregnancy has been reviewed (144A). Azathioprine can prob­ ably be safely used in systemic lupus erythematosus and rheumatoid arthritis, but the available evidence is scanty. In each case it must be decided whether the benefits outweigh the potential harms. The placenta forms a relative barrier to azathioprine and its metabolites, and intrauterine exposure to 6-thioguanine can be minimized by careful monitoring of the mother during pregnancy. This has been confirmed in three patients with autoim­ mune diseases who took azathioprine throughout their pregnancies (145c). The thiopurine metabolites (6-thioguaninenu­ cleotides and 6-methylmercaptopurine) were measured in the erythrocytes of the mother and infant directly after delivery. The erythrocyte concentration of thiogua­ nine nucleotides was slightly lower in the infant than the mother and methylmercap­ topurine could not be detected in the infant. Lactation Infant exposure to the metabo­ lites 6-thioguanine and 6-methylmercapto­ purine nucleotides has been determined

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Felix Braun, Freya A. Goumas, Dieter C. Broering, and Matthias Behrend

during maternal use of azathioprine (1.2– 2.1 mg/kg/day) in four breastfeeding women and their infants (146c). All the women had the wild-type TPMT genotype. Maternal thioguanine and methylmercaptopurine concentrations were 234–291 and 284– 1178 pmol/8  108 erythrocytes, comparable to those associated with improved thera­ peutic outcomes. Neither metabolite was detected in any of the infants. Thus, azathioprine may be safe during breastfeed­ ing in patients with wild-type TPMT geno­ type taking normal doses. Drug–drug interactions Warfarin An interaction between warfarin and azathioprine resulted in increased warfarin requirements (147A).
A 67-year-old woman took warfarin for

recurrent deep vein thrombosis associated with systemic lupus erythematosus. Azathiopr­ ine 150 mg/day was introduced for its steroidsparing effect and the dose of warfarin was titrated to a mean dose of 60–75 mg/week (8.5–10.5 mg/day) over the next 18 months. Her dose of azathioprine was then increased to 200 mg/day, after which subtherapeutic INRs required an increase in the dose of warfarin to a mean of 130 mg/week (18.5 mg/ day). Subsequent withdrawal of azathioprine resulted in a dramatic increase in her INR (from 1.8 to 14.0, 4 weeks after withdrawal).

An interaction between warfarin and azathioprine has been reported in seven other reports. The evidence suggests a clinically important inhibitory effect of azathioprine on warfarin and calls for close monitoring of the INR when doses of azathioprine are altered during concurrent administration of warfarin. Management of adverse drug reactions Desensitization has been successfully used in patients previously intolerant to azathioprine (148c). All had inflammatory bowel disease. Azathioprine was started at a low dose and thereafter gradually increased to a therapeutic dose. Nine of 14 patients were able to tolerate a full dose; the rest had recurrent adverse effects and were offered alternative treatment.

6-Thioguanine

(SEDA-30, 460)

Tumorigenicity Increased chemical reac­ tivity of DNA 6-thioguanine is an important contributor to its antileukemic effects. The same enhanced reactivity may contribute to the increased risk of acute myeloid leukemia and skin cancer in thiopurine-treated organ transplant patients (149R).

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Felix Braun, Freya A. Goumas, Dieter C. Broering, and Matthias Behrend

patient suffering from undifferentiated erosive oligoarthritis. Neth J Med 2006;64 (4):124–6. Putzki N, Knipp S, Ramczykowski T, Vago S, Germing U, Diener HC, Limmroth V. Secondary myelodysplastic syndrome fol­ lowing long-term treatment with azathiopr­ ine in patients with multiple sclerosis. Mult Scler 2006;12(3):363–6. Then Bergh F, Niklas A, Strauss A, von Ahsen N, Niederwieser D, Schwarz J, Wagner A, Al-Ali HK. Rapid progression of myelodysplastic syndrome to acute myeloid leukemia on sequential azathiopr­ ine, IFN-beta and copolymer-1 in a patient with multiple sclerosis. Acta Haematol 2006;116(3):207–10. Moss AC, Farrell RJ. Lymphoma risk with azathioprine/6-MP therapy—read beyond the headlines. Gastroenterology 2006;130 (4):1363–4. Rhinow K, Schirmer I, Loddenkemper C, Anagnostopoulos I, Stein H, Reichart PA. Orale Epstein–Barr-Virus-assoziierte dif­ fuse grosszellige B-Zell-Lymphome bei immunsupprimierten HIV-negativen Patienten. [Oral EBV-associated diffuse large B-cell lymphomas in HIV-negative immunocompromised patients.] Mund Kie­ fer Gesichtschir 2006;10(3):155–61.

144. Vroom F, de Walle HE, van de Laar MA, Brouwers JR, de Jong-van den Berg LT. Disease-modifying antirheumatic drugs in pregnancy: current status and implications for the future. Drug Saf 2006;29(10): 845–63. 145. de Boer NK, Jarbandhan SV, de Graaf P, Mulder CJ, van Elburg RM, van Bodegra­ ven AA. Azathioprine use during preg­ nancy: unexpected intrauterine exposure to metabolites. Am J Gastroenterol 2006;101 (6):1390–2. 146. Gardiner SJ, Gearry RB, Roberts RL, Zhang M, Barclay ML, Begg EJ. Exposure to thiopurine drugs through breast milk is low based on metabolite concentrations in mother–infant pairs. Br J Clin Pharmacol 2006;62(4):453–6. 147. Ng HJ, Crowther MA. Azathioprine and inhibition of the anticoagulant effect of warfarin: evidence from a case report and a literature review. Am J Geriatr Pharmac­ other 2006;4(1):75–7. 148. Green CJ, Mee AS. Re-introduction of azathioprine in previously intolerant patients. Eur J Gastroenterol Hepatol 2006;18(1):17–9. 149. Karran P. Thiopurines, DNA damage, DNA repair and therapy-related cancer. Br Med Bull 2006;79–80:153–70.

J. Costa and M. Farré

39

Corticotrophins, corticosteroids, and prostaglandins

Editor’s note: In this chapter adverse effects arising from the oral or intravenous administration of corticosteroids (glucocorticoids and mineralocorticoids) are covered in the section on systemic administration. Other routes of administration are dealt with in the sections after that; inhalation and nasal administration are dealt with in Chapter 16, topical administration to the skin in Chapter 14, and ocular administration in Chapter 47.

hypertension (65%), dysrhythmias (48%), irritability and increased muscle tone (17%), and hypokalemia (17%) (1c). Infection risk Corticotropin administration can increase the risk of infections, including those produced by opportunistic and rare pathogens, as can occur with glucocorticoids. A case of relapsing herpes simplex virus encephalitis has been attributed to corticotropin (2A).
A 7-month-old girl developed a fever, irrit-

CORTICOTROPHINS

(SED-15,

979; SEDA-27, 414)

Corticotropin (adrenocorticotropic hormone, ACTH) or its synthetic derivative tetracosactide is the treatment of choice of infantile spasms, including the West syndrome. Tetracosactide has been evaluated in a retrospective study using the medical records of 135 patients (73 boys and 62 girls) with West syndrome who had been treated and examined regularly for more than 1 year. There were adverse effects in 57 patients, leading to withdrawal of therapy in 23. The most common adverse effects that caused withdrawal were respiratory infections (74%), gastrointestinal infections (35%), Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03139-0 r 2009 Elsevier B.V. All rights reserved.

ability, and opisthotonus, followed by a tonic seizure. Her CSF showed signs of encephalitis and she was given aciclovir. She had herpes simplex virus encephalitis at age 14 days and was currently tapering corticotropin treatment (150 U/m2/day) for infantile spasms.

The authors suggested that corticotropin had caused a recurrence of the encephalitis in this case.

SYSTEMIC GLUCOCORTICOIDS

(SED-15, 906; SEDA-28, 471; SEDA-29, 480; SEDA-30, 463)

Sensory systems The ocular adverse effects of glucocorticoids are welldocumented. However, patients are now able to browse the Internet and purchase medications freely and are often not aware of their adverse effects.
A

64-year-old woman developed bilateral decreased vision and had evidence of

647

648 steroid-induced glaucoma and cataract (3A). She had been purchasing oral steroids via the internet for 4 years for a self-diagnosis of myalgic encephalomyelitis and had taken prednisolone 10–40 mg/day without medical advice.

Mouth and teeth Geographic tongue is a common condition, with prevalence of 0.28– 2.4% in adults. It is characteristically asymptomatic. There are multiple, well-demarcated erythematous areas of variable sizes, usually surrounded by a slightly elevated circinate linear border, usually on the anterior twothirds of the dorsum of the tongue. In a population-based case–control study, data from 16833 US adults who were examined during The Third National Health and Nutrition Examination Survey 1988–1994 (NHANES III) were included (4C). There was an overall prevalence of 1.8% of geographic tongue. Individuals who were taking glucocorticoids had a higher prevalence (5.7%; OR ¼ 3.3; 95% CI ¼ 1.3, 8.2) than those who were not (1.8%). There was no relation to the use of inhaled glucocorticoids. Multivariate logistic regression showed significant effects of current glucocorticoid therapy (adjusted OR ¼ 3.7; 95% CI ¼ 1.54, 8.6) and race (Whites and Afro– Americans versus Mexican–Americans) but not with age, sex, oral contraceptive use, diabetes mellitus, allergy or atopy, or psychological or dermatological conditions. Gastrointestinal In a study of 2061 patients with a first-time hospital discharge diagnosis of perforated peptic ulcer, using populationbased discharge registries in three Danish counties, 228 patients (11%) were exposed to glucocorticoids within 60 days of admission (5C). The overall 30-day mortality rate was 25%, the corresponding rate among current glucocorticoid users being 39%. Compared with “never users”, the adjusted mortality ratio among current users of oral glucocorticoids alone was 2.1 (95% CI ¼ 1.5, 3.1). Among current users of oral glucocorticoids in combination with other ulcerrelated drugs the mortality ratio was 1.5 (95% CI ¼ 1.1, 2.1). Thus, pre-admission use of oral glucocorticoids is associated with up to a twofold increase in 30-day mortality among patients hospitalized with perforated peptic ulcer.

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J. Costa and M. Farré

Liver Methylprednisolone-associated toxic hepatitis has been reported (6A).
A 47-year-old woman developed weakness,

fatigue, pruritus, and scleral icterus. She had been taking topiramate (dose not stated) for 1 year for chronic isolated central nervous system vasculitis. One week before her symptoms developed, she had completed a self-prescribed 7-day course of oral methylprednisolone (32 mg/day) for left arm weakness. She believed that methylprednisolone was appropriate, since it had been used previously for acute episodes of vasculitis. Her liver function tests were: alanine transaminase 2478 U/l (reference range 0–50), aspartate transaminase 1600 U/l (0–40), total bilirubin 10 mg/dl (0.2–1.2), direct bilirubin 8 mg/dl (0–0.4), alkaline phosphatase 138 U/l (40–150), and gamma-glutamyl transferase 242 U/l (5–64). Topiramate was withdrawn, and the liver function tests normalized within 45 days without treatment.

Based on the history and laboratory findings, the authors suggested that the hepatocellular and cholestatic liver injury had been caused by methylprednisolone, a rare adverse effect. Skin Linear hypopigmentation after intralesional or intra-articular injection of triamcinolone acetonide has been reported as a very rare adverse effect. The hypopigmentation is oriented linearly, spreads proximally, and may or may not be associated with skin atrophy. Another case has been reported (7A).
An 11-year-old girl had an elevated scar on

the back of her wrist, which had remained erythematous, gradually increasing in size. The scar had recurred after excision, and a silicon sheet was applied and triamcinolone injected intra-lesionally (20 mg in 0.5 ml) three times at intervals of 8 weeks. Hypopigmentation developed around the scar in the form of a halo about 2 weeks after the last injection and a linear hypopigmented streak progressed proximally over the forearm. At 4 weeks after the last injection, the hypopigmented streak stopped progressing and the lesion on the wrist started to repigment. At 6 months the perilesional halo of hypopigmentation and the linear streak were only very faintly discernible.

The authors commented that the hypopigmentation could have been due to lymphatic spread after inadvertent intra-dermal injection in the peripheral part of the keloid.

Corticotrophins, corticosteroids, and prostaglandins

Musculoskeletal Glucocorticoid therapy is associated with bone loss, resulting in osteoporosis and an increase in the risk of fractures. The pathogenesis, epidemiology, and management of glucocorticoid-induced osteoporosis have again been reviewed (8R) as has glucocorticoid-induced bone loss in patients with skin diseases (9R). The risk of fractures is increased in patients with rheumatoid arthritis. In a database study of 30262 patients with rheumatoid arthritis (older than 40 years) and 30783 controls with similar characteristics, followed for a mean of 7.6 years, there were 2460 fractures in the case group (10C). Compared with controls, the cases had an increased risk of hip fracture (RR ¼ 2.0; 95% CI ¼ 1.8, 2.3) and spine (RR ¼ 2.4; 95% CI ¼ 2.0, 2.8). Factors related to an increased risk of hip fracture included more than 10 years’ duration of rheumatoid arthritis (RR ¼ 3.4; 95% CI ¼ 3.0, 3.9), a low body mass index (RR ¼ 3.9; 95% CI ¼ 3.1, 4.9), and use of oral glucocorticoids (RR ¼ 3.4; 95% CI ¼ 3.0, 4.0). Vitamin D or calcitriol plus calcium did not prevent the bone loss associated with glucocorticoids in two studies, one in patients with asthma taking glucocorticoid therapy in a double-blind placebocontrolled trial (11C), and another in which a group of steroid-treated children with nephrotic syndrome were compared with a similar group without treatment (12c). In addition, calcitriol was less effective than alendronate in a randomized, double-blind, placebo-controlled trial that included patients with a rheumatic disease who took glucocorticoids in a daily dose that was equivalent to at least 7.5 mg of prednisone (mean dose equivalent to 23 mg) (13C). The 201 patients (mean age 61 years, 66% women) were randomized to alendronate (10 mg/day) or alfacalcidol (1 mg/day) for 18 months. The bone mineral density of the lumbar spine increased by 2.1% in the alendronate group (95% CI ¼ 1.1, 3.1) and fell by 1.9% in the alfacalcidol group (95% CI ¼ –3.1, –0.7). Three patients in the alendronate group had a new vertebral deformity, compared with eight patients in the alfacalcidol group (of whom three had symptomatic vertebral fractures).

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In a retrospective study of 13 infants with hemangiomas treated with systemic glucocorticoids, there was slowed linear growth but “catch-up” growth after the end of treatment (14c). Glucocorticoids did not affect bone mineralization adversely. Only one of 10 infants who had been treated with dexamethasone had clear evidence of adrenal insufficiency after the therapy was stopped. Avascular necrosis of the bilateral femoral head resulting from long-term steroid administration for radiation pneumonitis has been reported (15A).
A 50-year-old postmenopausal woman with

breast cancer and radiation pneumonitis was given oral glucocorticoids followed by steroid pulse administration and more oral therapy. She improved immediately, but the radiation pneumonitis relapsed when the steroid medication was stopped. The period of medication was 423 days and the cumulative dose of steroids was 7365 mg before complete resolution occurred. In the 19 months after therapy she developed bilateral avascular necrosis of the femoral heads.

Patients treated with long-term or high-dose glucocorticoids have been suggested to be at great risk of avascular necrosis, but this hypothesis is controversial. The probability of avascular necrosis may be very small, but it should be considered as one of the complications of glucocorticoids. Infection risk Glucocorticoid administration can increase the risk of infections, including those produced by opportunistic and rare pathogens. The risk of hospitalization for pneumonia in relation to drugs has been evaluated in 16788 patients with rheumatoid arthritis from the US National Data Bank for Rheumatic Diseases followed semiannually for 3.5 years (16C). In 644 patients hospitalization for pneumonia was required on 749 occasions. The use of prednisone increased the risk of pneumonia by 70% (HR ¼ 1.7; 95% CI ¼ 1.5, 2.1); leflunomide increased the risk by 30% (HR ¼ 1.3; 95% CI ¼ 1.0,1.5). There was a dose-related increase in the risk with prednisone: under 5 mg/day (HR ¼ 1.4, 95% CI ¼ 1.1, 1.6), 5– 10 mg/day (HR ¼ 2.1; 95% CI ¼ 1.7, 2.7), and over 10 mg/day (HR ¼ 2.3; 95% CI ¼ 1.6, 3.2). There was no increased risk with anti-TNF (tumor necrosis factor) therapy or methotrexate.

650 In a case–control study of the effects of glucocorticoids in a trauma Intensive Care Unit in 2002–2003, 100 patients were compared with 100 controls with similar APACHE II scores and medical histories (17C). Steroid use was associated in the multivariate analysis with an increased rate of pneumonia (OR ¼ 2.64; 95% CI ¼ 1.21, 5.75) and bloodstream infections (OR ¼ 3.25; 95% CI ¼ 1.26, 8.37). There was a trend towards increased urinary tract infections (OR ¼ 2.31; 95% CI ¼ 0.94, 5.69), other infections (OR ¼ 2.57; 95% CI ¼ 0.87, 7.67), and deaths (OR ¼ 1.89; 95% CI ¼ 0.81, 4.40). Pregnancy A single course of prenatal glucocorticoids given to the mother remains the most effective prenatal strategy for reducing the adverse results of preterm birth. However, repeated courses have been introduced without randomized clinical trials. Prenatal glucocorticoids given weekly to women at risk of preterm birth have been studied in 982 women who were randomly assigned to repeated intramuscular doses of either 11.4 mg betamethasone (as Celestone Chronodose) or saline (7 or more days after receiving a first course of prenatal glucocorticoids) (18C). The primary outcomes were the occurrence and severity of neonatal respiratory distress syndrome, the use and duration of oxygen and mechanical ventilation, and weight, length, and head circumference at birth and hospital discharge. Fewer babies exposed to repeated doses of corticosteroids had respiratory distress syndrome (33% versus 41%; RR ¼ 0.82; 95% CI ¼ 0.71, 0.95) and fewer had severe lung disease (12% versus 20%; RR ¼ 0.60; 95% CI ¼ 0.46, 0.79). Mean weight, length, and head circumference at birth and hospital discharge did not differ. There were no differences in adverse effects (chorioamnionitis, postpartum pyrexia, postnatal hypertension, and cesarean sections). Pending long-term outcomes, the short-term benefits support the use of repeat doses of glucocorticoids in women who are at risk of very preterm birth 7 or more days after an initial course. The adverse neonatal outcomes associated with antenatal dexamethasone or betamethasone have been studied

Chapter 39

J. Costa and M. Farré

retrospectively in 3600 infants (19C). Compared with betamethasone, dexamethasone was associated with a statistically significant increase in the risk of neonatal death (OR ¼ 1.66; 95% CI ¼ 1.07, 2.57). There were trends for greater risks associated with dexamethasone compared with betamethasone for intraventricular hemorrhage (OR ¼ 1.21; 95% CI ¼ 0.93, 1.59) and severe retinopathy of prematurity (OR ¼ 1.50; 95% CI ¼ 0.93, 2.42). Betamethasone seemed preferable to dexamethasone, but this must be confirmed in a comparative randomized trial. Drug–drug interactions Itraconazole Itraconazole inhibits CYP3A4 and inhibits the clearance of synthetic glucocorticoids. Cushing’s syndrome developed rapidly in a 55-year-old man who took itraconazole for 6 weeks in addition to inhaled fluticasone and resolved after withdrawal of itraconazole (20A). Cushing’s syndrome was attributed to increased systemic concentrations of fluticasone associated with adrenal insufficiency due to suppression of pituitary corticotropin secretion. Although itraconazole can also directly inhibit adrenal steroidogenesis, this usually happens at a much higher dose and there was no concomitant rise in corticotropin. Ritonavir Iatrogenic Cushing’s syndrome with secondary adrenal insufficiency has been described in two children (12- and 15year-old girls) with HIV infection taking oral ritonavir and inhaled fluticasone (21A). The combination of these drugs can cause Cushing syndrome and adrenal suppression in children, potentially leading to misdiagnosis of lipodystrophy syndrome and to an increased risk of adrenal crisis during acute illnesses (22A). Warfarin In a retrospective study using the medical records of 387 patients to evaluate a possible interaction between corticoids and warfarin (23c) 32 fulfilled the inclusion criteria of stable anticoagulation therapy, short-term oral glucocorticoid therapy, an international normalized ratio (INR) recorded within 30 days before the start of glucocorticoid therapy, and an INR recorded during corticosteroid therapy or

Corticotrophins, corticosteroids, and prostaglandins

within 14 days of withdrawal. Most of the patients had a raised INR after concomitant use of warfarin and glucocorticoids. The mean difference between pre- and postINR values was 1.24 (95% CI ¼ 0.86, 1.62). The change in INR occurred at a mean of 7 days after the first dose of glucocorticoid. Only one adverse event, minor epistaxis, was reported, and no visits or hospitalizations occurred as a consequence of the interaction. Thus, the use of oral glucocorticoids in patients taking long-term warfarin therapy may result in a clinically important interaction, which requires INR monitoring and possible warfarin dosage reduction.

PROSTAGLANDINS AND ANALOGUES (SED-15, 2955; SEDA-28, 476; SEDA-29, 487; SEDA-30 465)

Bimatoprost

(SED-15, 517)

Skin Periocular pigmentation due to bimatoprost has been studied retrospectively in 37 Caucasian patients (29 women), who had variable grades of periocular hyperpigmentation at presentation (arbitrary scale from 0 to 3; mean 1.27, range 1–2.5) (24c). The changes appeared most frequently at 3–6 months after the start of therapy. Resolution of the hyperpigmentation occurred most frequently at 3–12 months, and 33 patients had complete resolution. The efficacy of reducing the time of skin contact to prevent adverse effects of bimatoprost 0.03% topical therapy has been evaluated in a randomized, single-blind, internally controlled study (25c). The subjects started using bimatoprost 0.03% once at night in both eyes and were instructed to wipe only one eye (eye 1) with an absorbent pad during and after administration for 4 months. The fellow eye (eye 2) acted as the internal control. Eyelash growth, regional skin hypertrichosis, and pigmentation on the periocular skin were assessed at baseline and during the 4 months of follow-up. There was a lower incidence of eyelash growth and skin pigmentation in the inferonasal pericanthal region in eye 1. The

Chapter 39

651

incidence of pigmentation in the inferotemporal skin region and skin hypertrichosis were similar in the two eyes. The authors concluded that reducing the time of contact affects the regional incidence and the extent of skin changes that are related to bimatoprost 0.03% topical therapy.

Latanoprost

(SED-15, 2002; SEDA-28, 477; SEDA-29, 489; SEDA-30, 465)

Nervous system Latanoprost can produce darkening of the iris in green–brown, yellow– brown, and blue–brown eyes, whereas eyes with uniformly blue, gray, or green irises are much less affected. A group of Japanese ophthalmologists have shown that latanoprost can cause increased iris pigmentation in 50% of homogeneously brown eyes after 1 year (104 patient, 104 eyes) (26c). They used magnified iris color photographs and slitlamp microscopy, and both techniques were more sensitive that those used in previous studies. The percentage observed was higher than in Caucasian patients, possibly because of the method of evaluation.

Misoprostol

(SED-15, 2357; SEDA-28, 477; SEDA-29, 490; SEDA-30, 466)

Observational studies The Food and Drug Administration (FDA’s) Adverse Event Reporting System received 607 unique mifepristone adverse events reports over a 4-year period (27c). The most frequent adverse events were hemorrhage (n ¼ 237) and infections (n ¼ 66). Hemorrhages included one fatal, 42 life-threatening, and 168 other serious cases; 68 required transfusions. Infections included seven cases of septic shock (three fatal, four life-threatening) and 43 cases requiring parenteral antibiotics. There were 17 ectopic pregnancies (11 ruptured); second trimester viability was documented in 13 cases and three foetuses had serious malformations.

Travoprost

(SED-15, 3481; SEDA- 30,

466) Sensory system Bilateral anterior uveitis with synechiae formation associated with travoprost (after 5 days therapy) has been described (28A).

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References 1. Hamano S, Yamashita S, Tanaka M, Yoshinari S, Minamitani M, Eto Y. Therapeutic efficacy and adverse effects of adrenocorticotropic hormone therapy in West syndrome: differences in dosage of adrenocorticotropic hormone, onset of age, and cause. J Pediatr 2006;148(4):485–8. 2. Bonkowsky JL, Filloux FM, Byington CL. Herpes simplex virus central nervous system relapse during treatment of infantile spasms with corticotropin. Pediatrics 2006;117(5): e1045–8. 3. Sevem PS, Fraser SG. Bilateral cataracts and glaucoma induced by long-term use of oral prednisolone bought over the internet. Lancet 2006;386:618. 4. Shulman JD, Carpenter WM. Prevalence and risk factors associated with geographic tongue among US adults. Oral Dis 2006; 12(4):381–6. 5. Christensen S, Riis A, N§rgaard M, Thomsen RW, T§nnesen EM, Larsson A, Sorensen HT. Perforated peptic ulcer: use of pre-admission oral glucocorticoids and 30day mortality. Aliment Pharmacol Ther 2006;23(1):45–52. 6. Topal F, Özaslan E, Akbulut S, Küc- ükazman M, Yuksel O, Altiparmak E. Methylprednisolone-induced toxic hepatitis. Ann Pharmacother 2006;40(10):1868–71. 7. Nanda V, Parwaz MA, Handa S. Linear hypopigmentation after triamcinolone injection: a rare complication of a common procedure. Aesthetic Plast Surg 2006;30(1): 118–9. 8. van Staa TP. The pathogenesis, epidemiology and management of glucocorticoidinduced osteoporosis. Calcif Tissue Int 2006;79(3):129–37. 9. Summey BT, Yosipovitch G. Glucocorticoid-induced bone loss in dermatologic patients: an update. Arch Dermatol 2006;142(1):82–90. 10. van Staa TP, Geusens P, Bijlsma JW, Leufkens HG, Cooper C. Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum 2006;54(10):3104–12. 11. McDonald CF, Zebaze RM, Seeman E. Calcitriol does not prevent bone loss in

12.

13.

14.

15.

16.

17.

18.

19.

patients with asthma receiving corticosteroid therapy: a double-blind placebocontrolled trial. Osteoporos Int 2006;17(10): 1546–51. Bak M, Serdaroglu E, Guclu R. Prophylactic calcium and vitamin D treatments in steroid-treated children with nephrotic syndrome. Pediatr Nephrol 2006;21(3):350–4. de Nijs RN, Jacobs JW, Lems WF, Laan RF, Algra A, Huisman AM, Buskens E, de Laet CE, Oostveen AC, Geusens PP, Bruyn GA, Dijkmans BA, Bijlsma JWSTOP Investigators. Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. N Engl J Med 2006;355(7):675–84. Lomenick JP, Backeljauw PF, Lucky AW. Growth, bone mineral accretion, and adrenal function in glucocorticoid-treated infants with hemangiomas—a retrospective study. Pediatr Dermatol 2006;23(2):169–74. Kosaka Y, Mitsumori M, Araki N, Yamauchi C, Nagata Y, Hiraoka M, Kodama H. Avascular necrosis of bilateral femoral head as a result of long-term steroid administration for radiation pneumonitis after tangential irradiation of the breast. Int J Clin Oncol 2006;11(6):482–6. Wolfe F, Caplan L, Michaud K. Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum 2006;54(2): 628–34. Britt RC, Devine A, Swallen KC, Weireter LJ, Collins JN, Cole FJ, Britt LD. Corticosteroid use in the intensive care unit: at what cost? Arch Surg 2006;141(2):145–9. Crowther CA, Haslam RR, Hiller JE, Doyle LW, Robinson JSAustralasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet 2006;367(9526):1913–9. Lee BH, Stoll BJ, McDonald SA, Higgins RDNational Institute of Child Health and Human Development Neonatal Research Network. Adverse neonatal outcomes

Corticotrophins, corticosteroids, and prostaglandins

20.

21.

22.

23.

associated with antenatal dexamethasone versus antenatal betamethasone. Pediatrics 2006;117(5):1503–10. Woods DR, Arun CS, Corris PA, Perros P. Cushing’s syndrome without excess cortisol. BMJ 2006;332:469–70. Johnson SR, Marion AA, Vrchoticky T, Emmanuel PJ, Lujan-Zilbermann J. Cushing syndrome with secondary adrenal insufficiency from concomitant therapy with ritonavir and fluticasone. J Pediatr 2006; 148(3):386–8. Arrington-Sanders R, Hutton N, Siberry GK. Ritonavir–fluticasone interaction causing Cushing syndrome in HIV-infected children and adolescents. Pediatr Infect Dis J 2006;25(11):1044–8. Hazlewood KA, Fugate SE, Harrison DL. Effect of oral corticosteroids on chronic warfarin therapy. Ann Pharmacother 2006; 40(12):2101–6.

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24. Doshi M, Edward DP, Osmanovic S. Clinical course of bimatoprost-induced periocular skin changes in Caucasians. Ophthalmology 2006;113(11):1961–7. 25. Centofanti M, Oddone F, Chimenti S, Tanga L, Citarella L, Manni G. Prevention of dermatologic side effects of bimatoprost 0.03% topical therapy. Am J Ophthalmol 2006;142(6):1059–60. 26. Latanoprost-Induced Iris Pigmentation Study Group. Incidence of latanoprostinduced increase in iris pigmentation in Japanese eyes. Jpn J Ophthalmol 2006; 50(2):96–9. 27. Gary MM, Harrison DJ. Analysis of severe adverse events related to the use of mifepristone as an abortifacient. Ann Pharmacother 2006;40(2):191–7. 28. Suominen S, Välimäki J. Bilateral anterior uveitis associated with travoprost. Acta Ophthalmol Scand 2006;84(2):275–6.

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40

Sex hormones and related compounds, including hormonal contraceptives

Author’s note: Sex hormones, particularly estrogens and progestogens, can be used separately or in combination, and for various purposes. It is often not possible to determine to which compound or combination a particular adverse reaction can be attributed; information on particular types of adverse effects may therefore need to be sought under a series of differing headings.

Phytoestrogens in foodstuffs From time to time a suspicion arises that certain estrogen-like effects experienced by women and girls may be due to substances present in foods or in other non-medicinal products, or to the additive effects of these, either with physiological concentrations of sex hormones or with medicinal estrogens. An unpublished account presented at a medical meeting in The Netherlands concerned a girl who had pubertal development at the age of 8 years; in this case she had been given soya milk from early infancy onwards, because of milk allergy. Although precocious puberty can occur spontaneously, the hypothesis was advanced that phytoestrogens known to be present in soya might have accounted, at least in part, for the complication. A subsequent lay

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03140-7 r 2009 Elsevier B.V. All rights reserved.

contribution to a medical journal drew attention to the estrogen content not only of soya but also of a range of other foods, including alfalfa, lentils, chickpeas, yeast, sunflower seeds, seaweed, and various grain products (1r). Could it be, asked the author, that these should be contraindicated in sensitive subjects, such as women with a history of estrogen-dependent breast cancer? In the meantime, a series of consumer websites have sprung up, particularly in the USA, devoted to questioning the safety of soya (better known there as soy), for this and a series of other reasons, and the matter has been seriously reviewed in the quality lay press (2r–4r). It is a fact that a wide range of plants and the products derived from them, such as soya milk and tofu, contain estrogens (isoflavones or lignans) with some chemical affinity for estradiol; the concentrations of isoflavone are particularly high in soya. On the other hand, the isoflavones are of very low potency, estimated by one manufacturer at between 1:10 000 and 1:140 000 of the activity of estradiol itself. In 2001, Strom et al. published a retrospective multicenter cohort study of 811 adults aged 20–34 years who in their infancy had participated in controlled feeding studies at the University of Iowa (5M). Of these, 248 had been fed on soya-based breast-milk substitutes and 563 on dairy milk products. There were no differences between the groups as regards pubertal maturation or reproductive history, although women fed on soya as infants had had a very slightly longer duration of menstrual bleeding as adults. This study at least suggests that the use of soya as a breastmilk substitute has no serious effects on sexual

655

Chapter 40

656 maturation, but it leaves open the question of whether the continued intake of soya throughout childhood might have such an effect on young girls. Nor does the remaining literature adduced by manufacturers provide direct evidence on this last point. Some papers that exonerate soya, like that of Strom et al., relate to individuals who took soya only during the relatively brief period of breast-milk substitution (6c, 7R); some have used only nonhormonal measures to determine possible effects (8C); and others have highlighted an absence of significant undesirable effects in adult men (9c). Animal studies in which hormonal effects of phytoestrogens have been demonstrated are of little direct relevance to human subjects, especially because they have generally involved the administration of a single isoflavonoid (such as genistein) in exceptionally high doses, and because rodents metabolize these agents differently. However, there is no doubt that estrogenic effects exist, and while the phytoestrogens are of low potency the quantities administered through food are many times greater than the amounts of estrogen normally released into the system or administered medicinally. It has been pointed out that a 3-ounce serving of tofu contains about 23 mg of isoflavones, whereas the quantity of estrogen in an oral contraceptive may be as low as 30 mg. There is also some evidence, long emphasized in Asian medicine, that during the female climacteric a sufficient dose of phytoestrogens may provide relief from undesirable symptoms (10R); when Burke in North Carolina gave phytoestrogen 32 mg bd to menopausal women in the form of a soya drink, the severity of hot flushes (flashes) was noticeably reduced (11c). This is not the only evidence that soya in amounts that are commonly consumed can have an effect on the female system. British researchers have observed that eating some 60 g of soya powder (containing some 45 mg of isoflavones) daily for only 2 weeks stimulated the proliferation of epithelial breast cells in premenopausal women (12c). An earlier US study had showed an increase in breast cell proliferation in more than a quarter of women given a daily soya protein beverage containing 38 mg of isoflavones (13c). Dosage is

M.N.G. Dukes

obviously relevant, since estrogens in certain doses may have an antiestrogenic effect. All this matters a great deal, since world consumption of soya is growing rapidly; in 1965, global soya bean production was 30 million tonnes; by 1995 it had grown to 270 million tonnes, and it has continued to increase since. What is more, much of the human intake of soya is masked, since it is used as a component of many manufactured foods, and unless one reads the small print on the label one will not realize how much soya one is consuming daily. Finally, one has to consider possible additive effects with exogenous estrogens from other sources, especially in the course of oral contraception or hormone replacement. In this confusing situation, the food industry appears to be in two minds as to the type of sponsored research now deserving priority. Although allergy to cow’s milk protein commonly disappears within the first 2 years of life, about half the affected children still need an alternative to milk throughout their early years, and it would be helpful if more direct evidence were obtained about the safety of soya, particularly in girls, when so used. On the other hand, some parts of the trade are now clearly interested in the use of phytoestrogens (and hence of soya) for climacteric relief, an approach that seems to reflect a significant hormonal effect of nutrient doses of soya, even in adults. One can only hope that further evidence on both counts will emerge from uncommitted sources.

GONADOTROPINS AND OVULATION-INDUCING DRUGS (SED-15, 1536; SEDA-28, 480; SEDA-29, 493; SEDA-30, 468)

Estrogens

(SED-15, 1253; SEDA-28, 481; SEDA-29, 494; SEDA-30, 469)

Metabolism In a multicenter, doubleblind, placebo-controlled study, 152 hyster­ ectomized healthy postmenopausal women were randomized to receive daily trans­ dermal 17b-estradiol or oral micronized

Sex hormones and related compounds, including hormonal contraceptives

17b-estradiol (either unopposed or com­ bined with gestodene) for thirteen 28-day treatment cycles, to compare the effects of the forms of administration on asymme­ trical dimethylarginine (ADMA), an endo­ genous inhibitor of nitric oxide synthase (14C). After 13 cycles all the active treatment groups had significantly reduced ADMA concentrations compared with pla­ cebo. However, the reduction was more pronounced after oral than after transder­ mal administration. Adding gestodene to oral 17b-estradiol did not alter the reduc­ tion of ADMA. The authors admitted that the clinical implications of these findings remain uncertain. Tumorigenicity Breast cancer The risk of breast cancer as a complication of estrogen treatment has been reviewed. The authors concluded that the risk is now amply proven (15R). The mechanisms include the metabolism of estrogen to genotoxic mutagenic metabolites and sti­ mulation of tissue growth. Together, these processes cause initiation, promotion, and progression of carcinogenesis. Insight into the mechanisms of the causation of cancer by estrogen will identify the determinants of susceptibility to breast cancer and new targets for prevention and therapeutic intervention. Drug administration route Vaginal estrogen When aromatase inhibitors are accompanied by urogenital adverse effects due to atrophic vaginitis, the latter is often managed with vaginal estrogen formula­ tions, which are generally perceived to result in minimal systemic absorption of estrogen. This perception may not be correct. In seven postmenopausal women who used vaginal estrogens while taking aromatase inhibitors for breast cancer, serum estradiol concentrations rose from baseline concentrations of below 5 pmol/l, consistent with aromatase inhibitor therapy, to a mean of 72 pmol/l at 2 weeks; by 4 weeks this had fallen to the pretreatment concentration (16c). Both oral estrogen use and a high body mass index increase the risk of venous thromboembolism, but some data suggest

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that transdermal estrogen might be safer. In a series of women with a first documented idiopathic venous thromboembolism, 191 hospital cases were matched with 416 hospital controls and 62 out-patients were matched with 181 community controls (17C). Compared with non-users of normal weight, the combination of oral estrogen use and overweight or obesity further enhanced the risk of venous thromboem­ bolism. In this study at least, transdermal estrogen did not create an additional risk of idiopathic venous thromboembolism in women with increased body mass index. Drug–device interactions In a surgical study of the susceptibility factors for mesh erosion in patients undergoing abdominal sacral colpopexy, the only significant risk identified was concomitant estrogen treat­ ment (18c). In women using an estrogen, hysterectomy (OR ¼ 4.9, CI ¼ 1.2, 20) and anterior imbrication (OR ¼ 5.6, CI ¼ 1.1, 29) were associated with mesh erosion. No risk factors were identified in women not on estrogen.

Diethylstilbestrol

(SED-15, 1119)

Possible transgenerational effects of diethylstilbestrol Although diethylstilbestrol is long obsolete as a treatment for threatened or habitual abortion, evidence continues to emerge about changes in individuals who were exposed to the drug while in utero. Transgenerational epigenetic effects of diethylstilbestrol in the third generation, for which there is evidence from animal studies (19E–23E, 24R, 25R), are now also beginning to be reported in humans. Sensory systems Deafness has been reported in two children (one boy, one girl) in the second generation after intrauterine exposure to diethylstilbestrol; the two mothers who were exposed in utero to diethylstilbestrol had no hearing problems (26A). The same authors reported three cases

658 of limb reduction defects in children born to mothers who had taken diethylstilbestrol during pregnancy. Gastrointestinal The risks of esophageal atresia/tracheoesophageal fistula in the children of mothers who had been exposed in utero to diethylstilbestrol have been studied using three sources of information: questionnaires completed by members of the parents’ association of children with esophageal atresia/tracheoesophageal fistula; the records of patients with esophageal atresia/ tracheoesophageal fistula from a hospital database; and files from the Northern Netherlands EUROCAT birth defects registry (27c). Three of 124 mothers from the parents’ association and 6 of 192 from the hospital cases reported in utero exposure to diethylstilbestrol; 33 mothers of 8848 children registered by EUROCAT reported in utero exposure to diethylstilbestrol. Of 117 infants with esophageal atresia/tracheoesophageal fistula, 4 (3.4%) had a mother with in utero exposure to diethylstilbestrol, a statistically significant association. The authors concluded that there might be a contributory transgenerational effect of diethylstilbestrol in some cases of esophageal atresia/tracheoesophageal fistula. Sexual function After two case reports of hypospadias in the sons of women who had been exposed to diethylstilbestrol in utero a cohort study of the sons of 16284 Dutch women with a diagnosis of fertility problems was performed using a mailed questionnaire (response rate 67%) (28C). The mothers reported 8934 sons and 205 of these mothers reported exposure to diethylstilbestrol in utero. Four of the children of these 205 mothers were reported to have hypospadias. In the other 8729 children, there were only eight cases of hypospadias (prevalence ratio 21 (95% CI ¼ 6.5, 70)). All the cases of hypospadias were medically confirmed. Maternal age and fertility treatments did not affect the risk of hypospadias. Children conceived after assisted reproduction were not at increased risk. These findings suggest an increased risk of hypospadias in the sons of women who were exposed to diethylstilbestrol in utero.

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Reproductive system In 793 women whose mothers had documented information regarding in utero exposure to diethylstilbestrol the mean age at menarche was 12.6 years in both groups, but daughters of the exposed women attained menstrual regularization later than controls (16.2 years versus 15.8 years) and were more likely to report irregular menstrual periods (OR ¼ 1.54; 95% CI ¼ 1.02, 2.32) (29C). There was limited evidence that daughters of exposed women had more adverse reproductive outcomes, but they had fewer live births (1.6) than the daughters of unexposed women (1.9), suggesting possible infertility. Further follow-up is needed as the daughters of women who were exposed to diethylstilbestrol in utero start their own families. Tumorigenicity Small-cell ovarian carcinoma is rare in adolescents, and its occurrence in a young girl suggests the possibility of a transgenerational effect of diethylstilbestrol (30A).  A 15-year-old girl whose maternal grand-

mother had taken diethylstilbestrol while she was pregnant with the patient’s mother developed a small-cell carcinoma of the ovary.

The risk of cancer in the offspring of women who had been exposed prenatally to diethylstilbestrol has been assessed using two sources of information: mothers’ reports of cancers in 8216 sons and daughters and pathology-confirmed cancers and benign diagnoses self-reported by a subset of 793 daughters (31C). There was no overall increase in the risk of cancer in the sons or daughters of women exposed in utero to diethylstilbestrol nor an association with benign breast disease or reproductive tract conditions. However, based on three cases, the incidence of ovarian cancer was higher than expected in the daughters of women exposed prenatally to diethylstilbestrol. Mechanisms The mechanisms of possible transgenerational effects such as these are not known, but they may be genetic, that is, mediated by changes in DNA sequence, or epigenetic, that is, mediated by changes in gene expression without changes in DNA sequence. Epigenetic mechanisms include DNA methylation, histone modifications,

Sex hormones and related compounds, including hormonal contraceptives

and micro-RNA expression, which can change genome function (32R). Hypermethylation of the homeobox gene HOXA10, which controls uterine organogenesis, whose expression is increased in human endometrial cells after in utero exposure to diethylstilbestrol has been shown in mice (33E). There was also increased expression of DNA methyltransferases 1 and 3b. Changes in methylation did not occur after either in vitro or adult exposure to diethylstilbestrol. Other studies have shown altered DNA methylation in male and female mice in response to diethylstilbestrol (34E–37E). In one study, women who had been exposed to diethylstilbestrol in utero had chromatic aberrations in the cervical tissue; it may be such aberrations that account for the neoplasms that sometimes develop in these subjects (38c). If genetic or epigenetic changes occur in the germ line transgenerational effects could also occur.

Hormone replacement therapy (HRT) (SED-15, 1684, 1686, 1692; SEDA-28, 483; SEDA-29, 496; SEDA-30, 469)

Cardiovascular adverse effects of hormone replacement therapy In recent years, particularly since the publication of The Heart and Estrogen/Progestin Replacement Study and the Women’s Health Initiative (WHI) study, there has been a very marked decline in the use of HRT, in view of the impression that the risks outweigh any possible benefits. In a thoughtful review physicians have been urged to take a more considered view (39R). Until or unless the effectiveness of HRT for primary prevention of cardiovascular disease or Alzheimer’s disease is better established they agree with the current view that there is no justification for using it in asymptomatic postmenopausal women. However, symptomatic newly menopausal women might gain relief of their climacteric symptoms after

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using HRT without exposing themselves to unreasonable risks. One particular disappointment for proponents of HRT is that it has not reduced cardiovascular risk—rather the reverse. Cardiovascular disease is the leading cause of death among women in the USA, exceeding breast cancer mortality in women of all ages. Women develop cardiovascular disease a decade after men, and this has been attributed to a protective effect of female ovarian sex hormones that is lost after the menopause. Animal and observational studies have shown beneficial effects of hormone therapy when it is begun early in the perimenopausal period or before the development of significant atherosclerosis. However, randomized, placebo-controlled trials in older women have not shown any benefit in either primary prevention or secondary prevention of cardiovascular events, with a concerning trend toward harm (40R). It is at all events widely agreed at present that HRT should not be given for primary or secondary prevention of coronary heart disease. The question remains as to the approach to be adopted for patients during acute myocardial infarction who are already taking HRT? Is the “don’t stop don’t start” rule still true? The authors of a case study and review have concluded that it is not advisable to initiate HRT in women with established coronary heart disease for the sole purpose of preventing first or recurring coronary events (41cR). In line with the views of the American Heart Association, a decision to continue or stop HRT in women with cardiovascular disease should be based on established benefits and risks, taking each patient’s preference into account. The authors suggested that in the present state of knowledge existing HRT should be continued for some time (e.g., 3 months) and then withdrawn gradually. This policy is recommended until or unless a double-blind, placebo-controlled study becomes available to provide a firmer basis for judgment. It is after all a fact that, despite the disappointing findings to date with respect to HRT, there are investigators who have attributed the negative results in clinical trials to several flaws in study design, including the older age of study

660 participants and the introduction of estrogen late after the menopause. It remains impossible to make any adequate of the extent of any cardiological or circulatory risks that HRT may pose for a particular individual. As has been pointed out (42R), thrombosis, whether arterial or venous, has two requisites: a vascular anomaly and a response of the hemostatic system to the anomaly. Consequently, experimental approaches to understanding the pathophysiology of thrombosis require a definition of vascular anatomy and function, as well as characteristics of the blood within the context of genetic background, lifestyle choices, and environmental exposures, which influence gene expression. One must hope that increasing understanding of the interactions among factors that affect individual propensity to thrombosis will allow physicians to improve their ability to identify individuals at risk. A considerable number of women of menopausal age have now undergone coronary bypass surgery, and it is important to know the effects of HRT on the vessels concerned. Earlier work indicates that hormone therapy does not reduce cardiovascular disease events or the progression of angiographic coronary disease, but the effects of HRT on saphenous vein graft vessels have been uncertain. In a multicenter, randomized, placebo-controlled, angiographic study of the effects of estradiol with or without medroxyprogesterone, starting within 6 months of bypass surgery in 83 postmenopausal women, HRT significantly slowed the progression of saphenous vein graft disease, as assessed by mean percent stenosis, minimal lumen diameter, and total plaque volume (43Cr). However, HRT actually accelerated disease progression in non-bypassed native coronary arteries and saphenous vein grafts, and closure occurred in 38% subjects within 1 year after surgery. The two treatment groups had a similar frequency of cardiovascular events, except for angioplasty, which was required in eight of those who took HRT compared with one subject taking placebo. These results suggest that hormone treatment may slow saphenous vein grafts disease progression while accelerating atherosclerosis in non-bypassed native coronary arteries.

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M.N.G. Dukes

There is some reason to believe that when HRT involves the administration of esterified estrogens there is less risk of thrombotic events than when other types of estrogen are used. These apparent differences in risk, as well as the possible relation between the degree of risk and the genetic constitution of the individual, have been examined in a population-based, case–control study in postmenopausal women in a health maintenance organization; there were 328 women with a first venous thrombosis and 1591 controls; all were genotyped (44C). Factor II and Factor V Leiden variants were, respectively, associated with 2.1-fold and 3.7-fold increases in venous thrombotic risk. Overall, conjugated equine estrogens were associated with a 2.5-fold increase in risk compared with no hormone use, whereas esterified estrogens were not. Compared with no hormone use and no variant, joint exposure to conjugated equine estrogens and either prothrombotic variant was associated with an odds ratio of 9.1 (95% CI ¼ 4.5, 18), whereas joint exposure to esterified estrogens and either variant was associated with an odds ratio of 2.1 (0.6, 6.8). When analyses were restricted to hormone users with either variant, the use of conjugated equine estrogens was associated with an odds ratio of 5.3 (1.3, 22) compared with esterified estrogens. As the investigators themselves pointed out, these findings need replication, but they do seem to suggest once more that esterified estrogens are associated with a lower risk than conjugated equine estrogens, especially among the 5–10% of women who are carriers of a prothrombotic variant. In a comparison of postmenopausal women after myocardial infarction (n ¼ 1644) or stroke (n ¼ 1080) with 4205 controls, there was no difference in the risk of myocardial infarction or stroke associated with current use of conjugated equine estrogens or esterified estrogens compared with no treatment (45C). However, in an analysis restricted to hormone users, there was a suggestion of higher risk of ischemic stroke associated with conjugated equine estrogens alone (without progestogen) compared with esterified estrogens alone (OR ¼ 1.57; 95% CI ¼ 0.98, 2.53). There was also a suggestion that when initiated in the previous 6

Sex hormones and related compounds, including hormonal contraceptives

months, conjugated equine estrogens were associated with a higher risk of myocardial infarction than esterified estrogens (OR ¼ 2.33; 95% CI ¼ 0.93, 5.82).

Nervous system Benign paroxysmal positional vertigo is a fairly common vestibular end-organ disorder, resulting from detach­ ment of the utricular otoconia that float in the posterior or lateral semicircular canals. In most cases the precipitating cause is unknown. However, in a series of 289 cases, there were 10 in healthy women taking oral contraceptives; the symptom resolved after the treatment was withdrawn (46c). It has been hypothesized that impaired water and electrolyte balance, variation in endolym­ phatic pH, and impaired glucose or lipid metabolism induced by oral contraceptives may cause otoconial degeneration and subsequent detachment. Musculoskeletal There is accelerated bone loss and an increased risk of fractures after withdrawal of estrogens, and women who have stopped taking hormone therapy need to be monitored. Apart from nutritional treatment, which is obviously helpful, sev­ eral pharmacological agents, including the bisphosphonates and raloxifene, increase bone mass and reduce the risk of fractures, while themselves having reasonably accep­ table adverse effects profiles (47R). Tumorigenicity Breast cancer The risks of using HRT as regards the induction of breast cancer (see also the section “Estro­ gens”) vary to some extent with the population concerned, although the differ­ ences in incidence may be linked to physical characteristics (such as body weight) rather than to race. In a multiethnic cohort study in 55 371 African-American, Native Hawai­ ian, Japanese–American, Latina, and White postmenopausal women aged 45–75 years there were 1615 cases of invasive breast cancer (48C). Current use of estrogen + progestogen combinations was associated with a 29% increased risk of breast cancer per 5 years of use and current estrogen

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therapy with a 10% increase per 5 years of use. Both types of treatment were asso­ ciated with a greater risk among leaner women, but the increase in risk with EPT use was still very evident in women with BMI of 30 kg/m2 and over. There were no differences in risk associated with ethnicity. Opinion remains strongly divided as to whether women at increased risk of breast cancer because of a family history or highrisk benign breast conditions will be at additional risk if given HRT (49r). Because estrogen metabolism may affect breast cancer risk and can be altered by weight and HRT, it might play a role in the association between HRT, BMI, and breast cancer. In a nested case–control study as part of the Observational Study of the WHI baseline concentrations of 2- and 16-alpha­ hydroxyestrone (2-OHE1 and 16a-OHE1) were measured in 200 women who devel­ oped breast cancer during follow-up and in 200 healthy matched controls (50C). Con­ centrations of 16a-OHE1 were modestly but significantly higher in users of HRT among cases (median 356 pg/ml versus 315 pg/ml) and controls (354 pg/ml versus 298 pg/ml). Concentrations of 2-OHE1 were substantially and significantly higher in users of HRT among cases (369 pg/ml versus 125 pg/ml) and controls (347 pg/ml versus 134 pg/ml). For non-users only, a higher BMI and higher concentrations of 16a-OHE1 were individually and jointly associated with an increased risk of breast cancer (OR for women with a high BMI and high 16a-OHE1 concentrations com­ pared with those with a low BMI and low 16a-OHE1 concentrations ¼ 3.51, 95% CI ¼ 1.34, 9.16). There were no associa­ tions between BMI, estrogen metabolism, and the risk of breast cancer in users of HRT. Estrogen metabolism thus differs according to both BMI and use of HRT, potentially explaining the interaction. In a study in Finland, all women over 50 years of age using oral or transdermal estradiol (n ¼ 84 729), oral estriol (n ¼ 7941), or vaginal estrogens (n ¼ 18 314) for at least 6 months during 1994–2001 were identified from the national medical reimbursement register (51C). They included 2171 women with breast cancer.

662 The standardized incidence ratio for breast cancer with systemic estradiol for less than 5 years was 0.93 (95% CI ¼ 0.80, 1.04) and for estradiol 1.44 (1.29, 1.59). Oral and transdermal estradiol were accompanied by similar risks of breast cancer. The risk was most prominent with oral doses greater than 1.9 mg/day; the risk associated with the transdermal route was not dose-related. The standardized incidence ratio for the lobular type of breast cancer (1.58) was slightly higher than that for the ductal type (1.36). The use of estradiol was associated with both localized breast cancer (1.45; 1.26, 1.66) and cancer spread to regional nodes (1.35; 1.09, 1.65). The incidence of carcinoma in situ (n ¼ 32) was increased (2.43; 1.66, 3.42) among estradiol users. Use of oral estradiol for less than 5 years, oral estriol, or vaginal estrogens was not asso­ ciated with a risk of breast cancer. The fact that estrogens are used in the treatment of prostatic cancer (see also below) raises the concern that they might cause breast cancer in men. In an earlier population-based study in Sweden there was an increased risk of male breast cancer after prostate cancer; the same authors have now published a two-part investiga­ tion to determine whether treatment for prostate cancer and/or family history is responsible for this excess risk (52Cr). The first part of the investigation comprised a nested case–control study in 41 men who had previously been identified with prostate cancer followed by breast cancer; the 81 matched controls had prostate cancer only. The second part was a family study in the relatives of men with a diagnosis of prostate cancer and breast cancer, irrespective of which had come first. Men with prostate plus breast cancer had used estrogens more often than controls with prostate cancer only; the period of estrogen treatment was longer in the cases, but not significantly so. The mean time from diagnosis of prostate cancer to diagnosis of breast cancer was 4 years. In the family study there was an increased risk of prostate cancer in rela­ tives, but for other cancers there were no significantly increased risks. In two families there were estimated 100 and 49%

Chapter 40

M.N.G. Dukes

probabilities that the proband was a BRCA2 carrier. These data suggest that most of the increased risk of breast cancer after prostate cancer can be explained by estrogen treatment. However, in a small number of men with prostate and breast cancers, pedigree analysis suggests that the BRCA2 mutation might contribute. Endometrial cancer In one Japanese patient who took HRT for 2 years after hysterectomy and salpingo-oophorectomy, residual endometriotic tissue was found to have developed into an endometroid ade­ nocarcinoma (53A). Susceptibility factors Thrombocythemia In view of the well-documented association between estrogen-based hormone treat­ ment and thrombosis, the question arises as to the acceptability of such treatment in women with essential thrombocythemia. Experience in this matter has been retro­ spectively reviewed at the Mayo Clinic in 305 women who were followed for a median of 133 months (54C). Estrogenbased hormone treatment at diagnosis was documented in 59 women and was insti­ tuted at a variable time after diagnosis in 34 others. In this risk group estrogenbased hormone treatment in the form of oral contraception was associated with an increased risk of venous thrombosis. Other estrogen-based treatments did not increase the risk of either arterial or venous events. Drug administration route (see also the section “Estrogens”) Since many of the pharmacological effects of estradiol are mediated through the central nervous sys­ tem, there are several potential therapeutic applications for a system that could achieve brain-targeted delivery of this substance. In theory this could serve as a preferred means of treating hot flushes and possibly demen­ tia, without a significant risk of adverse effects elsewhere in the body (e.g., cancers). Preliminary results with one method cur­ rently under development that uses a redox CDS approach have been reviewed (55cr). Much more experience will however be

Sex hormones and related compounds, including hormonal contraceptives

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663

required to assess the efficacy/safety bal­ ance of this form of delivery.

HORMONAL CONTRACEPTIVES (SED-15, 1642

Intranasal estrogen In one randomized study, 29 healthy hysterectomized women received either intranasal 17b-estradiol or oral estrogens for 3 months and the effects on hemostatic markers were compared (56c). Nasal administration had no effect, except for a moderate increase in plasmino­ gen activator inhibitor-1 (PAI-1). Oral estrogens reduced factor VII-tissue factor complex (VIIa-rTF). However, none of the changes was outside the reference ranges.

et seq; SEDA-28, 487; SEDA-29, 499; SEDA-30, 473)

Transdermal estrogen Because almost all clinical trials use oral estrogen as the primary form of hormone supplementation, another question that has arisen is the importance of the route of estrogen admin­ istration with regards to cardiovascular out­ comes. During oral estrogen administration, the concentration of estradiol in the liver sinusoids is four to five times higher than that in the systemic circulation. This supraphysiological concentration of estrogen in the liver can modulate the expression of many hepatic-derived proteins, which are not observed in premenopausal women. In contrast, transdermal estrogen delivers the hormone directly into the systemic circula­ tion and thus avoids first-pass hepatic metabolism. Although oral estrogen has a more favorable effect than transdermal estrogen on traditional cardiovascular risk factors, such as high- and low-density lipoprotein cholesterol concentrations, there is evidence that oral estrogen adversely affects many emerging risk factors in ways that are not seen with transdermal estrogen. Oral estrogen significantly increases concentrations of acute-phase proteins, such as C-reactive protein and serum amyloid A; procoagulant factors, such as prothrombin fragments 1+2; and several key enzymes involved in plaque disruption. Transdermal estrogen does not have these adverse effects (57R). Whether the advan­ tages of transdermal estrogen with regards to these risks will translate into improved clinical outcomes remains to be determined.

Cardiovascular In a prospective surveil­ lance cohort study, adverse cardiovascular responses to low-dose combined oral contraceptives were examined in mainland Chinese women (58C). Women taking hormonal contraceptives (n ¼ 44 408) and women with an intrauterine device (n ¼ 75 230) were followed-up from July 1997 to June 2000 to study the difference in the incidence of stroke. Compared with users of intrauterine devices, current users of hormonal contraceptives had a higher RR of 4.20 (95% CI ¼ 2.11, 8.36) of hemorrhagic stroke and still reached 2.17 (95% CI ¼ 1.16, 4.06) among past users after they had stopped taking combined oral contraceptives for more than 10 years. The RR of hemorrhagic stroke was 3.09 (95% CI ¼ 1.26, 7.57) among women who had last used low-dose combined oral contraceptives during the previous 5 years. In women under 45 years of age, compared to users of intrauterine devices, hemor­ rhagic stroke was strongly associated with current use of low-dose combined norethisterone formulations (RR ¼ 19; 95% CI ¼ 3.08, 118). Spontaneous dissection of the left anterior descending coronary artery has been described in a 50-year-old woman who had taken an oral contraceptive for a decade (59Ar). The condition resolved within 6 months after conservative treatment. Four cases have been previously reported and it has been suggested that this complication is most likely to occur in the postpartum period and may be associated with female sex hormone function, although no credible mechanism has been proposed. Urinary tract Kidney angiomyolipomas are benign but progressive tumors com­ monly associated with tuberous sclerosis. They contain estrogen and progesterone

664 receptors and they have been reported to increase in size in pregnancy.  A 15-year-old girl with stable angiomyolipomas

and tuberous sclerosis took estrogen/progesto­ gen oral contraceptive tablets for menorrhagia for 12 months, during which time a new 4-cm exophytic angiomyolipoma developed and required selective arterial embolization to reduce the risk of spontaneous rupture (60Ar).

Drug administration route Vaginal ring Administration of hormonal contraceptives through a vaginal ring results in qualita­ tively different effects from oral adminis­ tration. The effects of local and oral ethinylestradiol and etonorgestrel through the “Niva Ring” for a single cycle on uterine tissue concentrations of these com­ pounds have been compared in a rando­ mized, open pharmacokinetic study in eight premenopausal women who were about to undergo hysterectomy (61c). Concentra­ tions of the two compounds were similar in uterine tissue taken from the upper myometrium and mid-myometrium and the cervical region. However, concentrations of both hormones were markedly lower in tissue samples from the endometrium of women who had used the ring.

ANTIESTROGENS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) (SEDA-28, 490; SEDA-29, 502; SEDA-30, 474)

Tamoxifen versus aromatase inhibitors Letrozole (Femars) and its congeners, notably anastrozole (Arimidexs) and exemestane (Aromasins), suppress aromatase-induced estrogen production in postmenopausal women and have been approved in many countries to treat both early and advanced breast cancer (62R). They cannot suppress estrogen production by the ovary and are therefore of no value in earlier life, but they now represent a serious alternative to tamoxifen in cases of

Chapter 40

M.N.G. Dukes

endometrial and mammary malignancy (63C, 64R). While tamoxifen was for many years the gold standard adjuvant endocrine therapy for early breast cancer, its role is being challenged by the newest aromatase inhibitors. Whatever its merits, tamoxifen increases the risk for endometrial cancer and cerebrovascular/thromboembolic events. In comparison, the major adverse effect of the inhibitors is bone loss, which may increase the risk of osteoporotic fractures and bone pain. Several studies have justified the conclu­ sion that aromatase inhibitors as monotherapy or sequentially to tamoxifen can improve the prospects of relapse-free survi­ val in postmenopausal women with early breast cancer (65R). Extensive studies of anastrozole in cases of hormone receptorpositive breast cancer suggest that it is closely similar to tamoxifen in both efficacy and safety (66Cr). Recent work also suggests that these treatments are costeffective (67M). The cost-effectiveness of long-term adjuvant letrozole after a course of tamoxifen has also been stressed by economists examining the matter on behalf of Britain’s National Health Service (68M). Several studies have compared the aroma­ tase inhibitors with tamoxifen as adjuvant hormone therapy in postmenopausal women. Using these drugs, either alone or after tamoxifen, reduces the risk of cancer recurrence more than tamoxifen alone for 5 years. For postmenopausal women whose cancers are estrogen and/or progesterone receptor-positive, most experts now recom­ mend using an aromatase inhibitor at some time during adjuvant therapy. Two separate meta-analyses of clinical trials have each reached the same conclusion. However, questions remain regarding the best treat­ ment regimen (69R, 70R). The aromatase inhibitors tend to have fewer serious adverse effects than tamox­ ifen, with no risk of uterine cancers and a low incidence of thrombosis. However, they can cause joint stiffness and/or pain invol­ ving a number of joints simultaneously, while the risk of osteoporosis and fractures may justify a prior bone density test in view of the possibility of corrective treatment, for example, with a bisphosphonate (71C).

Sex hormones and related compounds, including hormonal contraceptives

Whether under particular conditions tamoxifen or an aromatase inhibitor should be preferred is still disputed. However, at present both tamoxifen and aromatase inhibitors have their place and their propo­ nents (72R). Quality of life is generally good for up to 3 years of follow-up with either treatment. Vasomotor and sexual com­ plaints remain problematic, although they occur in only a small proportion of women. However, in one woman who had had amenorrhea for 5 years during tamoxifen treatment the introduction of letrozole in normally accepted doses resulted within 2 weeks in resumption of menstruation (73C). In a survey of 452 patients on long-term treatment the most troublesome symptoms in users of tamoxifen and aromatase inhi­ bitors included hot flushes (35% versus 30%, respectively), weight gain (14% ver­ sus 15%), insomnia (17% versus 17%), and joint aches (12% versus 23%); 48% of users of aromatase inhibitors switched medica­ tion to improve symptoms compared with only 37% of users of tamoxifen (74c). Musculoskeletal Bone loss remains a pro­ blem in some women taking adjuvant aro­ matase inhibitors. Investigators working with exemestane currently consider that it induces only minor bone loss compared with placebo and a non-significant increase in fracture rate compared with tamoxifen. This difference could be due to the bone-sparing effects of tamoxifen. The MA17 study showed a non-significant increase in fracture rate for letrozole compared with placebo. In contrast, both anastrozole and letrozole monotherapy or given sequentially signifi­ cantly increased fracture rate compared with tamoxifen. While an increased fracture rate may have detrimental effects, various cen­ ters consider that enhanced bone loss may be preventable through careful bone mineral density assessment and treatment with bisphosphonates (75R).

Clomifene (SED-15, 812; SEDA-30, 474) Sexual function More than a generation ago when the serious adverse effects of

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diethylstilbestrol on the unborn child were first clearly documented, concern was expressed regarding the safety of the closely related compound clomifene, used as a treat­ ment for infertility. Clomifene has a long halflife, its metabolites being detectable in the feces as much as 6 weeks after administration. Subsequent work has sometimes pointed to its supposed ability to induce hypospadias in male offspring, but results have been contradictory. A Europe-wide case–control study by EURO­ CAT appears to have provided an explanation for these discrepancies. It appears that the findings depend on the precise type of hypospadias studied. In the case of the severe but rare penoscrotal type of hypospadias there was a significant correlation with clomifene exposure, but for all other types of hypospa­ dias there was none (76C).

Exemestane Exemestane has been claimed to be parti­ cularly well tolerated, but as with the other agents in this group the possible detrimen­ tal effects of estrogen suppression on bone mineral density and cardiovascular risk require further investigation (77R).

Fulvestrant Fulvestrant (Faslodexs) is a synthetic estro­ gen receptor antagonist. Unlike tamoxifen (which has partial agonist effects) and the aromatase inhibitors (which reduce the estrogen available to tumor cells), fulves­ trant binds competitively to estrogen recep­ tors in breast cancer cells, resulting in estrogen receptor deformation and reduced estrogen binding. In vitro studies have shown that fulvestrant reversibly inhibits the growth of tamoxifen-resistant, estrogen-sen­ sitive, human breast cancer cell lines. It has been approved in some countries for advanced breast cancer. According to exist­ ing clinical reports and a review of data down to 2006 it has little effect on sex hormone endocrinology, bone metabolism, and lipid biochemistry and appears unlikely to be involved in CYP3A4-mediated drug–drug interactions (78R).

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Letrozole Placebo-controlled studies The first interim analysis of the MA.17 trial in 2003 identified letrozole as providing significant benefit in this follow-up phase, markedly reducing recurrence of the cancer. The final analysis has confirmed these findings: letro­ zole reduced the relative risk of recurrence by 42%, with no significant detrimental cardiovascular effects and lipid metabolism and global quality of life scores comparable with placebo (79R). Skin Toxic epidermal necrolysis in a patient taking letrozole for breast cancer may have been purely coincidental (80A). The condition has been associated with a wide range of drugs (notably sulfonamides, non-steroidal anti-inflammatory drugs, allopurinol, antiretroviral drugs, corticosteroids, and anticonvulsants) and it would not be entirely surprising if it were to be precipi­ tated in an occasional case by letrozole. Teratogenicity The incidence of congeni­ tal malformations among offspring of mothers who conceived with clomifene citrate or with letrozole for infertility has been examined retrospectively in 911 new­ born infants (81c). There were congenital malformations and chromosomal abnorm­ alities in 14 of 514 newborns in the letrozole group (2.4%) and in 19 of 397 newborns in the clomifene group (4.8%). The rate of major malformations with letrozole was 1.2% (6/514) and with clomifene 3.0% (12/397). One neonate in the letrozole group had a ventricular septal defect (0.2%) compared with four in the clomifene group (1.0%). In addition, the rate of all congenital cardiac anomalies was signifi­ cantly higher with clomifene (1.8%) than with letrozole (0.2%). There was no differ­ ence in the overall rates of major and minor congenital malformations among neonates from mothers who conceived after letrozole or clomifene treatment. Since the letrozole figures are similar to those for the popula­ tion at large, this study suggests that use of letrozole use for ovulation induction is not teratogenic.

M.N.G. Dukes

Susceptibility factors Genetic The response to sex hormone therapy may differ between racial groups, which is of considerable importance when clinical stu­ dies and experience from different parts of the world are considered together. In a study of various measures of response among 4708 Caucasian women and 352 women belonging to ethnic minorities, the therapeutic response was markedly better in the Caucasians but the women in the minority groups had a significantly lower incidence of hot flushes (49% versus 58%), fatigue (29% versus 39%), and arthritis (2% versus 7%) (82C).

Raloxifene

(SED-15, 3019; SEDA-29, 503; SEDA-30, 474)

Tumorigenicity In a double-blind, rando­ mized clinical study of raloxifene and tamoxifen in nearly 200 clinical centers throughout North America, there were 327 cases of invasive breast cancers (83C). The patients were 19 747 postmenopausal women, mean age 59 years, with an increased 5-year risk of breast cancer (mean risk 4.03%). There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (4.30 per 1000 versus 4.41 per 1000; RR ¼ 1.02; 95% CI ¼ 0.82, 1.28). There were fewer cases of non-invasive breast cancer with tamoxifen (n ¼ 57) than raloxifene (n ¼ 80). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene. There were no differences for other invasive cancer sites or for ischemic heart disease events or stroke. Throm­ boembolic events were less frequent with raloxifene (RR ¼ 0.70; 95% CI ¼ 0.54, 0.91). The numbers of osteoporotic frac­ tures in the groups were similar. There were fewer cases of cataracts (RR ¼ 0.79; 95% CI ¼ 0.68, 0.92) and operations for cataract (RR ¼ 0.82; 95% CI ¼ 0.68, 0.99) in the women taking raloxifene. There were no differences in the total numbers of deaths (101 versus 96 for tamoxifen versus ralox­ ifene) or in causes of death. The investiga­ tors concluded that raloxifene is as effective

Sex hormones and related compounds, including hormonal contraceptives

as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a non-statistically significant higher risk of non-invasive breast cancer.

Tamoxifen

(SED-15, 3296; SEDA-29, 503; SEDA-30, 475)

Sensory systems The eyes of 22 women who took tamoxifen 20 mg/day for at least 6 (range 13–44) months for adjuvant treat­ ment of breast cancer have been examined for corneal drug deposition by slit lamp after pupil dilatation and the findings compared with those in 15 healthy agematched women (84c). Drug deposition in the inferior paracentral cornea was identi­ fied by slit-lamp examination in 32 of the 44 exposed eyes. There were no significant differences between eyes with keratopathy, those without keratopathy, and control eyes in regard to the mean Schirmer test scores, mean central corneal thickness, mean endothelial cell count, mean basal epithe­ lium cell density, mean anterior and poster­ ior stromal keratocyte density, and mean endothelial cell density. There was no pathological change in structure with in vivo confocal microscopy at any corneal level in patients taking tamoxifen. The incidence of ocular toxicity after adjuvant chemoendocrine therapy in large randomized clinical trials has been analyzed (85M). In studies under the auspices of the International Breast Cancer Study Group (IBCSG) 4948 eligible patients were rando­ mized to tamoxifen or toremifene alone or in combination with chemotherapy (either concurrently or sequentially). Ocular toxi­ city at some stage was reported in 538 of 4948 patients (11%) during adjuvant treat­ ment, mainly during chemotherapy. Of 4948 patients 45 (0.9%) had ocular toxicity during hormone therapy alone, but 30 patients (0.6%) had ocular toxicity either without receiving any chemotherapy or beyond 3 months after completing che­ motherapy, and thus possibly related to tamoxifen or toremifene. In 3 cases, retinal alterations, without typical aspects of tamoxifen toxicity, were reported; 4

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patients had cataracts (2 bilaterally), 12 impaired visual acuity, 10 ocular irritation, and 1 optic neuritis; the rest had other symptoms. Ocular toxicity during adjuvant therapy therefore seems to be common. In contrast, ocular toxicity during hormonal therapy is rare and does not appear to justify a regular program of ocular exam­ ination. However, patients should be informed of this rare adverse effect so that they can seek prompt ophthalmological evaluation if they have ocular complaints. Psychiatric A 60-year old woman, who had had an episode of severe depression after the birth of her only child 32 years before, had a mastectomy for breast cancer followed by radiotherapy, chemotherapy, anastrozole for 6 weeks, and then letrozole (86A). While taking anastrozole she had a labile mood, increased activity, tremulous­ ness, and difficulty in sleeping. These symptoms disappeared after anastrozole was withdrawn. While taking letrozole she had an acute irritable activated mood elevation, which then subsided into pro­ longed major depression after withdrawal of letrozole. These effects occurred during co-prescription of amitriptyline at a low dose for increased urinary frequency. This case suggests the need for caution when employing aromatase inhibitors in women with a past history of postpartum affective disorder or bipolar disorder. As with post­ partum mania, the primary mechanism of the effect may be acute reduction in circulating estrogen concentrations. Mineral metabolism The most serious complication of tamoxifen treatment is flare hypercalcemia, which is a direct consequence of the treatment of breast carcinoma with skeletal metastases and can be life-threaten­ ing. There is now further evidence that the reaction can be controlled with an antihy­ percalcemic drug, gallium nitrate, while continuing tamoxifen therapy (87c). Pancreas Acute pancreatitis and hypertri­ glyceridemia has been attributed to tamox­ ifen, but hypertriglyceridemia is a wellknown risk factor for acute pancreatitis and may itself have been causal (88A). The

668 patient was successfully treated with insulin infusion and long-term gemfibrozil. Musculoskeletal Some centers have con­ tinued to use tamoxifen in men with gynecomastia who request treatment either for cosmetic reasons or because of local pain and tenderness. It is generally well tolerated at the variable doses needed to provide relief (e.g., 10 mg/day for 3 months), the only occasional complication described in one study being the rare occurrence of calf tenderness (89R). Reproductive system Uterus When menopausal patients with breast cancer have endometrial hyperplasia before treat­ ment with tamoxifen, early progression to atypical lesions during treatment is likely. In an Italian series of 25 such patients, there was progression from complex hyperplasia to complex atypical hyperplasia (n ¼ 1) and from complex and simple hyperplasia ade­ nocarcinomas (n ¼ 2) within 24 months of starting tamoxifen (90A). In two patients there was progression from simple to complex hyperplasia within 36 months of starting tamoxifen. In 13 patients there was stable histology of simple or complex hyperplasia, while 6 patients with focal hyperplasia in an endometrial polyp had normalization of endometrial histology after polyp resection. MRI scanning has been used to examine polypoid endometriosis and other benign gynecological complications associated with tamoxifen in one patient (91A). The variety of uterine abnormalities that can be associated with tamoxifen continues to grow as new cases are reported. A postmenopausal woman had bleeding asso­ ciated with villous papyraceous (sclerosed and mummified chorionic villi) in an other­ wise thin and atrophic endometrium (92A). Ovaries During postsurgical treatment with tamoxifen, bilateral ovarian cysts developed with consecutive unilateral cyst torsion and raised serum estradiol (93A). Drug resistance A problem with the longterm use of tamoxifen for breast cancer is that, while resistance to its wanted effects

Chapter 40

M.N.G. Dukes

apparently emerges, adverse events, such as thromboembolic disease and endometrial cancer, continue to occur (94C). For this reason, clinicians tend to limit the use of tamoxifen to 5 years and then switch to other treatments. Tumorigenicity Uterus More than onethird of women who take tamoxifen develop uterine cancer more than 12 months after discontinuing therapy. These women are at particular risk of developing moderately to poorly differentiated tumors, with a poor prognosis (95R). Therefore, women with a past history of tamoxifen therapy should have continued surveillance after comple­ tion of therapy to ensure early diagnosis of uterine cancer. Since the first reported case of tamox­ ifen-associated related uterine sarcoma in 1988, 68 more cases have described, 4 recent instances now being reported (96AR, 97A). A Japanese group has stressed the particular value of MRI in diagnosing this complication in the context of another case (98A). Although some of these investigators have pointed out that the low incidence of uterine sarcomas makes it difficult to establish a firm relation to the drug, it seems that a dose of 20 mg/day of tamoxifen over 1 year could be enough to promote the development of sarcomas in certain users. These tumors appear mainly during the first 8 years of treatment and tend to be aggressive. An unusual endometrial polyp occurred in a postmenopausal woman who took tamoxifen for 7 years after surgical resection of a breast carcinoma; the hysterectomy specimen showed florid adenomyosis and in the background, there were rare sex cordlike foci (99A). An unusual malignancy, perhaps related to this case, occurred in a 58-year-old postmenopausal women who had used tamoxifen for 4 years after surgery for breast cancer and who then presented with chronic pelvic pain (100A). Preopera­ tive investigations showed a uterine myoma and she underwent total abdominal hyster­ ectomy and bilateral salpingo-oophorect­ omy. Postoperative histological diagnosis unexpectedly showed a uterine tumor

Sex hormones and related compounds, including hormonal contraceptives

resembling ovarian sex cord tumors, an exceedingly rare entity. Gastrointestinal malignancies In view of earlier evidence regarding the occurrence of esophageal and gastric carcinomas as a consequence of tamoxifen treatment this potential association has been investigated in a study of data in the Swedish Cancer Registry from 1961 onwards (i.e., covering a considerable period before the availability of tamoxifen) (101C). Among 138 885 cohort members, who contributed 1 075 724 person-years of follow-up, there was a non-significant increase in the risk of esophageal adenocarcinoma during the potential tamoxifen exposure period (SIR ¼ 1.60, 95% CI ¼ 0.83, 3.08), but the risk estimates decreased with an increasing latency interval. There was no association during the unexposed period. There was no increased risk of adenocarcinoma of the gastric cardia in either period, but the risk of gastric adenocarcinoma in other sites was increased in the potential tamoxifen period (SIR ¼ 1.27, 95% CI ¼ 1.03, 1.57), and almost doubled in the period of longest latency (10–14 years) (SIR ¼ 1.86, 95% CI ¼ 1.10, 3.14). The corresponding overall SIR was also increased in the unexposed group, but here the SIR did not increase with longer latency intervals. There was an increased risk of tobacco-related tumors (esophageal squamous cell carcinoma and lung cancer) only in the unexposed cohort, suggesting that confounding by smoking might have explained the increased SIR during the unexposed period. The authors concluded that there might be a link between tamoxifen and a risk of gastric adenocarcinoma. The case has been described of a 44-year­ old premenopausal woman with breast cancer treated with adjuvant tamoxifen who presented with abdominal distension. Sur­ gery revealed a large retroperitoneal mass that was removed together with uterus and both adnexae and found to be a lymphan­ gioleiomyoma (102A). It seems possible, but it is not proven, that tamoxifen treatment can play a role in the development of this benign tumor.

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(SED-15, 2930; SEDA-28, 493; SEDA-29, 505; SEDA-30, 477)

PROGESTOGENS

Systematic reviews Half a century has elapsed since the belief was propagated, primarily on the basis of animal studies, that the administration of a progestogen was effective in the prevention of threatened or habitual abortion. At the time, very little critical evidence from sound clinical studies was available to support the belief, while there was increasing reason to doubt the safety of the approach, particularly because of the masculinizing effects that at least some of the progestogens used might have on a surviving fetus. However, the method retained some adherents for want of anything better to treat such cases (103r). Some have now argued for reacceptance of this approach and have suggested that further trials are desirable: “Progesterone is the primary factor of uterine quiescence that permits the physical distension of the uterine muscle throughout pregnancy” (104R). A meta-analysis of randomized controlled clinical trials has also suggested that progestational agents, initiated in the second trimester of pregnancy, can reduce the risk of delivery at less than 37 weeks when used in women at increased risk of spontaneous preterm birth (105M). However, only three trials were considered to merit inclusion, much other work being inadequately controlled or not at all. In these three trials, there was a significant reduction in the risk of delivery at less than 37 weeks with progestational agents (RR ¼ 0.57; 95% CI ¼ 0.36, 0.90). Larger randomized controlled trials are required to determine whether this treatment reduces perinatal mortality or serious neonatal morbidity. Psychiatric The association between pro­ gestogens and mood changes has long been puzzling, in connection with both changes of mood during the menstrual cycle and the effects of steroid treatment on the mental state of some users. A psychopharmacolo­ gical study in 43 postmenopausal women in Sweden has shown that there is a bimodal

Chapter 40

670 relation between mood and the circulating concentrations of the neuroactive steroid allopregnanolone (106c). During progester­ one treatment, women had significantly higher negative mood scores when allo­ pregnanolone serum concentrations were in the range 1.5–2 nmol/l compared with lower and higher concentrations. Allopregnano­ lone has several contradictory effects, including anesthetic, sedative, and anxioly­ tic effects, as well as aggressive and anxiogenic properties. Reproductive system It is unclear why some women who take progestogens con­ tinuously for endometrial disorders have breakthrough bleeding while others do not. In a pilot study, endometrial histology has been examined in both types of patients, in groups that had used depomedroxyproges­ terone acetate for shorter or longer periods (107c). Chronic endometritis was the most common histological finding and it occurred more often in women who had break­ through bleeding (35% versus 15%). The rate of bleeding was highest (45%) among women who had been treated for more than 12 months. As the investigators pointed out, chronic endometritis, which may indicate an underlying infectious or intracavitary ana­ tomical etiology, has not been previously reported as a frequent finding in users of depomedroxyprogesterone acetate, and may be related to ethnic or other socio­ demographic characteristics of the particu­ lar patient population studied. Drug administration route Intrauterine administration Although levonorgestrel­ releasing intrauterine systems were origin­ ally developed as a method of contracep­ tion in 1970, the only product approved for general use (Mirenas) releases 20 mg of levonorgestrel per day directly into the uterine cavity, and various efforts have been made to determine whether a lower rate of release would prove adequate, so far without clear results. However, research into the non-contraceptive uses of this type of product has become prominent and it appears to bear promise as a very welltolerated treatment for endometriosis,

M.N.G. Dukes

adenomyosis, fibroids, endometrial hyper­ plasia, and early stage endometrial cancer (when the patient is deemed unfit for primary surgical therapy) (108R). Although intrauterine administration of progestogens has generally been well toler­ ated, severe seborrheic dermatitis has been reported in a 36-year-old woman after insertion of a levonorgestrel intrauterine system; the complication resolved comple­ tely after removal of the system and topical treatment (109A).

Drospirenone Drospirenone is claimed to have character­ istics closer to those of natural progesterone than most synthetic progestogens. It has antimineralocorticoid properties, counter­ acts the estrogen-stimulated activity of the renin–angiotensin–aldosterone system, and is not androgenic. With its close structural relation to spironolactone it may lead to less water retention and breast tenderness while being less likely to cause acne. The authors of a review of the literature down to 2006 have concluded that drospirenone may have a benign effect on lipids, sig­ nificantly lowering total cholesterol and low-density lipoprotein concentrations while maintaining high-density lipoprotein and triglyceride concentrations (110R). Drospirenone also seems to differ from other progestogens in lowering blood pres­ sure in hypertensive patients while having a mild blood pressure-lowering effect in nonhypertensive patients. These conclusions will need to be tested against further clinical experience.

Megestrol acetate

(SED-15, 1679,

2932) Endocrine A Turkish group have very briefly reported on a woman who was being treated with megestrol acetate for endometrial cancer and who developed hypoadrenalism (111A).

Sex hormones and related compounds, including hormonal contraceptives

PROGESTERONE ANTAGONISTS (SEDA-28, 494; SEDA-29, 506; SEDA-30, 477)

CDB-2914 CDB-2914 is a selective progesterone receptor modulator, in effect a partial progesterone antagonist, which is being used experimentally for a series of possible indications. One of these is its use in emergency contraception as an alternative to an accepted product such as levonorges­ trel. In a direct comparison under rando­ mized double-blind conditions, healthy women seeking emergency contraception within 72 hours of unprotected intercourse took either a single dose of 50 mg of CDB­ 2914 plus a placebo 12 hours later or two doses of 0.75 mg of levonorgestrel taken 12 hours apart (112C). Efficacy was evalu­ able in 775 of those who took CDB-2914 and 774 of those who took levonorgestrel and appeared to be similar. Nausea was reported by a somewhat greater percentage of those who took CDB-2914 (29% versus 24%), but the distribution of other adverse effects was similar. Women in both groups had considerable variations in menstrual cycle length compared with their reported individual normal cycles.

Mifepristone

(SED-15, 2344; SEDA-29, 506; SEDA-30, 477)

In an assessment of mifepristone-associated mortality, morbidity, sentinel events, and the quality of postmarketing surveillance, 607 adverse event reports submitted to the FDA over 4 years were re-evaluated (113c). The most frequent reactions were hemor­ rhages (n ¼ 237) and infections (n ¼ 66). Hemorrhages included 1 fatal, 42 lifethreatening, and 168 serious cases; 68 required transfusion. Infections included 7 cases of septic shock (3 fatal, 4 lifethreatening) and 43 cases requiring parent­ eral antibiotics. Surgical interventions were required in 513 cases (235 drug-related, 278 not). The drug-related cases included 17

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ectopic pregnancies (11 ruptured). Second trimester viability was documented in 22 cases, of which 9 were lost to follow-up; of the 13 documented cases, 9 were termi­ nated without comment on fetal morphol­ ogy, 1 was enrolled in a fetal registry, and 3 fetuses had serious malformations, suggest­ ing a malformation rate of 23%. The authors concluded that hemorrhage and infection were the leading causes of mife­ pristone-related morbidity and mortality. However, these adverse reaction reports, relied upon by the FDA to monitor mifepristone’s postmarketing safety, were considered to be of extremely poor quality, and they have provided no information about the absolute frequency of adverse effects.

SEX HORMONE AGONISTS Tibolone (SEDA-28, 499; SEDA-29, 514; SEDA-30, 485) Cardiovascular Tibolone has several effects on cardiovascular risk factors and may exacerbate arteriosclerosis (114r). Tibolone 2.5 mg/day has been compared with combined conjugated equine estrogens +medroxyprogesterone acetate 0.625/ 2.5 mg/day in a 3-year double-blind, rando­ mized, placebo-controlled study of the progression of carotid intima media thick­ ness in 866 healthy postmenopausal women in Europe and the USA (115C). Annual progression rates of carotid intima media thickness in both groups were significantly faster than in the placebo group: HDL cholesterol was increased by estrogens +medroxyprogesterone and lowered by tibolone. However, translation of these effects into cardiovascular disease risk could not fully explain the observed increase in cardiovascular risk in the WHI study. This suggests that the net effect of tibolone and estrogens+medroxyprogester­ one on cardiovascular events may depend on combined effects on the arterial wall, clotting factors, and possibly inflammation.

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M.N.G. Dukes

SEX HORMONE ANTAGONISTS

of hemoglobin and the hematocrit should also be monitored.

Danazol

Tumorigenicity Ovaries A little-known but acknowledged use of androgens is their use in individuals undergoing a female-to­ male sex change. One such patient devel­ oped ovarian cancer during androgen sup­ port therapy; the tumor contained androgen receptors (119A). This is the second published case of such a complica­ tion, and these patients seem to be exposed to an increased risk of both ovarian cancer and endometrial cancer; however, the risk of such complications in trans-sexual patients not receiving androgen support is not known.

(SEDA-28, 496; SEDA-29, 514)

Liver The hepatotoxicity of danazol is well recognized. From Norway a further case of hepatocellular focal nodular hyperplasia has been reported after danazol treatment for hereditary angioedema (116C).

Gestrinone Gestrinone, like danazol, inhibits the synth­ esis of estrogens and progestogens, and has been used particularly to prepare patients with an endometrial disorder for hysterect­ omy. Its most common adverse effects are nausea, headache, changes of mood, rash, hot flushes, weight gain, and discomfort in the joints and muscles. In some cases there is evidence of masculinization. Some work­ ers have found it to be more effective or better tolerated than danazol (117C), but the two compounds have largely similar effects.

ANDROGENS, ANABOLIC STEROIDS, AND RELATED COMPOUNDS (SED-15, 216; SEDA28, 495; SEDA-29, 507; SEDA-30, 477)

Androgens Means of containing the risks of androgen therapy in elderly men with evidence of androgen deficiency have received increasing attention in view of its still apparently widespread use. It has been suggested that in the first year of testos­ terone treatment digital rectal examina­ tion of the prostate and measurement of prostate-specific antigen (PSA) should be performed every 3 months, and thereafter yearly (118R). The rate of increase of PSA concentration is more significant than its absolute values. Concentrations

Prostate In the lengthy controversy regarding the use of androgen replacement in elderly men, one constant concern has been that it might promote the develop­ ment of prostatic neoplasms. A critical review has provided no answers, but the authors suggested that in view of the rising popular demand for this treatment more attention needs to be devoted to this risk, the extent of which (if it truly exists) is uncertain (120R). Others, notably the group headed by Bhasin in Boston, claim that the approach has been wrongly rejected in the past because of an exaggerated emphasis on supposed risk, and that both testosterone itself and its synthetic “anabolic” deriva­ tives have a major role to play in the treatment of both aging and chronic illness (121R). Drug dosage regimens In treating locally advanced prostate cancer, neither androgen deprivation nor surgical castration is an attractive alternative (122R). Their adverse effects include severe osteoporosis, anemia, behavioral changes, and lack of sexual interest. There is some hope that intermit­ tent androgen replacement in surgically castrated patients with significant adverse effects may be helpful, but without the risk of promoting recurrence of the malignancy. However, studies to date have been limited in size and duration (e.g., to 6 months) and no firm conclusions can yet be drawn.

Sex hormones and related compounds, including hormonal contraceptives

Androgenic anabolic steroids Although the role once conceived for the use of anabolic steroids in seriously ill patients has been all but abandoned in most centers, it has been suggested that during the recovery phase, “when anabolism is critical for survival,” administration of ana­ bolic agents, such as testosterone or oxan­ drolone, may be useful and that a rational approach would be to limit anabolic treat­ ment to those patients who have (1) minimal signs of active inflammation or none; (2) a reasonable expectation of recovery with an acceptable quality of life; (3) biochemical hypotestosteronemia; (4) biochemical evi­ dence of decreased nitrogen; and (5) no contraindications (such as prostate cancer, male breast cancer, or a raised PSA requir­ ing further evaluation) (123R). Placebo-controlled studies There is some interest in using anabolic steroids in men with weight loss associated with HIV infection. When in one study 262 such men were randomized for 12 weeks to placebo or oxandrolone 20, 40, or 80 mg/ day, body weight increased in all groups, including those who took placebo (124C). Oxandrolone 40 mg/day caused a significant gain in weight compared with placebo and the gains in BCM at doses of 40 and 80 mg were greater than those in the placebo group. However, oxandrolone was associated with significant suppression of sex hormone-binding globulin, luteinizing hormone, follicle-stimulating hormone, and total and free testosterone concentrations. Treatment was accompanied by significant increases in transaminases and low-density lipoprotein as well as reduced high-density lipoprotein. Psychiatric Occasional investigators con­ tinue to examine the nature of the adverse effects of anabolic steroids, which by and large are those of the male hormone from which they are derived. These include the promotion of aggressive and hostile behaviors. In an unusual study in Greece involving two pairs of monozygotic male twins the mental effects of these drugs were

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examined (125A). One pair was 24 years old and the other 31 years old. They had absolute genomic and phenotypic similarity and living under similar conditions. One of the twins of each pair used an anabolic steroid and the other did not. Psychometric measures after 6 months of treatment showed high levels of aggressiveness, hosti­ lity, anxiety, and paranoid ideation in the twins who used an anabolic steroid, while there were no changes in the untreated twins.

Stanozolol Breasts A young male user of stanozolol developed breast cancer with gynecomastia (126A). This complication has been reported sufficiently often to suggest strongly that there is a causal association with anabolic treatment.

(SEDA-28, 497; SEDA-29, 510; SEDA-30, 479)

ANTIANDROGENS

Mason has reviewed the role of antiandro­ gens in the treatment of prostate cancer, arguing that with earlier initiation of therapy the long-term adverse effects of castration need to provide the standard by which the acceptability of drugs such as bicalutamide is judged (127R). There is now evidence that bicalutamide confers signifi­ cant overall survival benefit when used as an adjuvant to radiotherapy in patients with locally advanced disease. However, the survival data for bicalutamide are not as extensive as those available for LHRH agonists. Although they do not appear to have a significant impact on sexual and physical activity, non-steroidal antiandro­ gens are frequently associated with gyne­ comastia and breast pain, and some are associated with diarrhea. Against this background one can con­ sider the question posed by Gillatt in the same field: are all antiandrogen treatments

Chapter 40

674 in locally advanced prostate cancer the same (128R)? The most comprehensively investigated and reported antiandrogen is bicalutamide, which produces survival out­ comes similar to those observed with castration in patients with locally advanced prostate cancer. In contrast, only limited clinical data are available for the other non­ steroidal antiandrogens (flutamide and nilu­ tamide) and the steroidal antiandrogen cyproterone acetate in patients with locally advanced disease. Cyproterone is asso­ ciated with loss of libido and erectile dysfunction, cardiovascular risk; there have been occasional reports of fatal fulminant hepatitis and hepatocellular carcinoma. Gynecomastia is rare, in contrast to the non-steroidal antiandrogens. There are no direct comparisons between the three non­ steroidal antiandrogens in terms of quality of life, but the available evidence suggests that bicalutamide has a more favorable safety and tolerability profile than niluta­ mide and flutamide. Unlike cyproterone, non-steroidal antiandrogens appear to be better tolerated than castration, allowing patients to maintain sexual activity, physical ability, and bone mineral density; these agents have a higher incidence of gyneco­ mastia and breast pain (mild to moderate in over 90% of cases), but these are complica­ tions that can be effectively managed. Cardiovascular Although prostate cancerspecific mortality is falling, there is little effect on overall mortality, suggesting the possibility of an increased risk of death from non-prostate cancer-related causes, for example, androgen deprivation therapy could adversely affect cardiovascular health. An analysis of pooled data from three prospective clinical trials aimed at achieving medical castration by various methods has shown significant increases in total cholesterol, triglycerides, and HDL cholesterol in patients receiving leuprolide acetate or abarelix but not in patients receiving leuprolide acetate plus bicalutamide (129M). There were no consistent changes in low-density lipoprotein cholesterol. Increased total cholesterol was usually due to an increase in highdensity lipoprotein cholesterol. The authors concluded that short-term androgen

M.N.G. Dukes

deprivation therapy affects serum lipid and hemoglobin concentrations independent of statin therapy. Liver Although hepatotoxicity associated with antiandrogens has long been recog­ nized, its incidence is not clear. Data from a national reporting system are unlikely to solve this question, because of the generally very low reporting rate, but such a system can throw light on the characteristics of the complication. In a study using the Spanish adverse reaction reporting system liver disorders were the most common adverse reactions associated with flutamide and bicalutamide, but not specifically with cypro­ terone acetate (130c). “Hepatitis” and “cho­ lestatic hepatitis” were the most frequent terms coded. In 38% of the reports related to cyproterone acetate, 18% of those related to flutamide, and 33% of those related to bicalutamide the patient had simultaneously taken other hepatotoxic drugs. Dispropor­ tionality analysis showed a strong associa­ tion between hepatitis and flutamide and a weak association with bicalutamide and cyproterone acetate. Mean doses of fluta­ mide and bicalutamide were very close to their defined daily dose (DDD) to treat prostate cancer, although in the case of cyproterone acetate it was slightly higher. The latency period of hepatitis was 3–10 months for the three antiandrogens, and the recovery period was shorter (0.5–3 months). Most of the reported cases of hepatitis had favorable outcomes. These findings stress the hepatotoxic potential of flutamide com­ pared to cyproterone acetate.

Bicalutamide The third analysis of the bicalutamide Early Prostate Cancer (EPC) program was pub­ lished in 2006 and essentially confirmed earlier impressions of the acceptable benefit to harm balance of this compound in early prostate cancer treatment (131C, 132C), as have other studies. A typical dose is 150 mg/ day. However, much depends on the regi­ men that is used and the state of progres­ sion of the disorder.

Sex hormones and related compounds, including hormonal contraceptives

Dutasteride Finasteride is a selective inhibitor of 5a­ reductase type 2. Dutasteride (Avodarts) inhibits both types 1 and 2 and is approved for the treatment of symptomatic benign prostatic hyperplasia in a dose of 0.5 mg/ day. It is about 3 times more potent than finasteride at inhibiting 5a-reductase type 2 and more than 100 times more potent at inhibiting type 1. Of 416 subjects, 11 with­ drew because of adverse events including mild to moderate reduction in libido (133C).

Finasteride

(SEDA-30, 480)

Tumorigenicity Prostate The Prostate Cancer Prevention Trial (PCPT) was stopped in 2003 because, while it showed that finasteride significantly reduced the risk of prostate cancer by 25% compared with placebo, there seemed to be an increased incidence of high-grade tumors (Gleason score 7 or more) in the finasteride subgroup. However, a reanalysis of the findings has identified a number of potential biases in the original report (134R). They included an increased detection rate due to prostate volume reduction and improved PSA specificity and sensitivity for detecting prostate cancer. This suggests that there

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was improved detection of overall prostate cancer as well as high-grade prostate cancer in men treated with finasteride, rather than an increase in risk compared with placebo. Further analyses of the data from the PCPT together with other follow-up clinical findings have suggested that the increase in high-grade tumors in the finasteride arm was an artifact.

Flutamide

(SED-15, 1427; SEDA-29, 513; SEDA-30, 484)

Liver Another case of hepatitis in a patient taking flutamide alone has been reported (135A). The problem occurs in about 0.36% of patients. It is likely that the hepatotoxicity of flutamide is in part due to the presence of a hitherto unrecognized Noxidized metabolite known as N-[4-nitro-3­ (trifluoromethyl)phenyl]hydroxylamine. However, the correlation between hepatic complications and the formation of this metabolite is not complete, and other factors may be involved (136c). There is very limited case evidence that in low doses flutamide may not be hepatotoxic in hyperandrogenic women, even during long-term therapy (137c), but caution is still advisable.

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concentration and mood—a bimodal asso­ ciation in postmenopausal women treated with oral progesterone. Psychopharmacol­ ogy 2006;187:209–21. Thurman AR, Soper DE. Endometrial histology of depomedroxyprogesterone acetate users: a pilot study. Infect Dis Obstet Gynecol 2006;2006:69402. Varma R, Sinha D, Gupta JK. Non-contra­ ceptive uses of levonorgestrel-releasing hor­ mone system (LNG-IUS)—a systematic enquiry and overview. Eur J Obstet Gynecol Reprod Biol 2006;125(1):9–28. Karri K, Mowbray D, Adams S, Rendall JRS. Severe seborrhoeic dermatitis: sideeffect of the Mirena intra-uterine system. Eur J Contracept Reprod Health Care 2006;11(1):53–4. Shulman LP. A review of drospirenone for safety and tolerability and effects on endo­ metrial safety and lipid parameters con­ trasted with medroxyprogesterone acetate, levonorgestrel, and micronized progester­ one. J Womens Health 2006;15(5):584–90. Ozguroglu M, Yildiz O, Turna H, Kadioglu P. Megestrol acetate induced hypoadrenal­ ism with cushingoid phenotype in endome­ trial cancer. Gynecol Oncol 2006;101:183. Creinin MD, Schlaff W, Archer DF, Wan L, Frezieres R, Thomas M, Rosenberg M, Higgins J. Progesterone receptor modula­ tor for emergency contraception: a rando­ mized controlled trial. Obstet Gynecol 2006;108:1089–97. Gary MM, Harrison DJ. Analysis of severe adverse events related to the use of mifepristone as an abortifacient. Ann Pharmacother 2006;40:191–7. Clarkson TB. Does tibolone exacerbate atherosclerosis? Eur Heart J 2006;27: 635–7. Bots ML, Evans GW, Riley W, McBride KH, Paskett ED, Helmond FA, Grobbee DE. The effect of tibolone and continuous combined conjugated equine oestrogens plus medroxyprogesterone acetate on pro­ gression of carotid intima–media thickness: the Osteoporosis Prevention and Arterial effects of tibolone (OPAL) study. Eur Heart J 2006;27:746–55. Helsing P, Nielsen EW. Hepatocellular focal nodular hyperplasia after danazol

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treatment for hereditary angio-oedema. Acta Derm Venereol 1996;86:272–3. Triolo O, De Vivo A, Benedetto V, Falcone S, Antico F. Gestrinone versus danazol as preoperative treatment for hysteroscopic surgery: a prospective, ran­ domized evaluation. Fertil Steril 2006; 85(4):1027–31. Gooren L. Risks of androgen therapy. J Mens Health Gender 2006;3:404–9. Ockrim J, Lalani E-N, Abel P. Ovarian cancer associated with testosterone sup­ plementation in a female-to-male transsex­ ual patient. Gynecol Obstet Investig 2006; 62:226–8. Gould DC, Kirby RS. Testosterone repla­ cement therapy for late onset hypogonad­ ism. What is the risk of inducing prostate cancer? Prostate Cancer Prostatic Dis 2006;9:14–8. Bhasin S, Calof OM, Storer TW, Lee ML, Mazer NA, Jasuja R, Montori VM, Gao W, Dalton JT. Drug insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab 2006;2:146–59. Ferreira U, Leitao VA, Denardi F, Math­ eus WE, Stopiglia RM, Netto Jr NR. Intermittent androgen replacement for intense hypogonadism symptoms in castrated patients. Prostate Cancer Pro­ static Dis 2006;9:39–41. Mechanick JI, Nierman DM. Gonadal steroids in critical illness. Crit Care Clin 2006;22(1):87–103. Grunfeld C, Kotler DP, Dobs A, Glesby M, Bhasin S. Oxandrolone in the treatment of HIV-associated weight loss in men. J Acquir Immune Defic Syndr 2006;41:304–14. Pagonis TA, Angelopoulos NV, Koukoulis GN, Hadjichristodoulou CS, Toli PN. Psychiatric and hostility factors related to use of anabolic steroids in monozygotic twins. Eur Psychiatry 2006;21(8):563–9. Staerkle RF, Lenzlinger PM, Suter SL, Varga Z, Melcher A. Synchronous bilat­ eral ductal carcinoma in situ of the male breast associated with gynecomastia in a 30-year-old patient following repeated injections of stanozolol. Breast Cancer Res Treat 2006;97:173–6.

682 127. Mason MJ. What implications do the tolerability profiles of antiandrogens and other commonly used prostate cancer treatments have on patient care? Cancer Res Clin Oncol 2006;132:27–35. 128. Gillatt D. Antiandrogen treatments in locally advanced prostate cancer. Are they all the same? J Cancer Res Clin Oncol 2006;132:17–26. 129. Yannucci J, Manola J, Garnick MB, Bhat G, Bubley GJ. The effect of androgen depriva­ tion therapy on fasting serum lipid and glucose parameters. J Urol 2006;176:520–5. 130. Manso G, Thole Z, Salgueiro E, Revuelta P, Hidalgo A. Spontaneous reporting of hepa­ totoxicity associated with antiandrogens: data from the pharmacovigilance system. Pharmacoepidemiol Drug Saf 2006;15:253–9. 131. Iversen PEarly Prostate Cancer Pro­ gramme Investigators. The third analysis of the bicalutamide Early Prostate Cancer programme. BJU Int 2006;97(3):438–9. 132. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2005;97:247–54.

Chapter 40

M.N.G. Dukes

133. Olsen EA, Hordinsky M, Whiting D, Stough D, Hobbs S, Ellis ML, Wilson T, Rittmaster RS. The importance of dual 5a­ redutase inhibition in the treatment of male pattern hair loss: results of a rando­ mized placebo-controlled study of dutaste­ ride versus finasteride. J Am Acad Dermatol 2006;55:1014–23. 134. Akduman B, Crawford ED. The PCPT: new findings, new insights, and clinical implications for the prevention of prostate cancer. Eur Urol (Suppl) 2006;5:634–9. 135 Osculati A, Castiglioni C. Fatal liver complications with flutamide. Lancet 2006; 367:1140–1. 136. Goda R, Nagai D, Akiyama Y, Nishikawa K, Ikemoto I, Aizawa Y, Nagata K, Yamazoe Y. N-oxidized metabolite of flutamide, N-[4-nitro-3-(trifluoromethyl) phenyl]hydroxylamine, in human liver microsomes and urine of prostate cancer patients. Drug Metab Dispos 2006;34(5): 828–35. 137. Legro RS. Long-term, low-dose flutamide does not cause hepatotoxicity in hyperan­ drogenic women. Nat Clin Pract Endocri­ nol Metab 2006;2:188–9.

K. Boelaert

41

Thyroid hormones, iodine, and antithyroid drugs

Thyrotropin-releasing hormone (TRH, protirelin) Thyrotropin-releasing hormone (TRH) and TRH receptors are present through­ out the central nervous system and play a role in the regulation of neurotransmitters and neurological functions as well as endocrine secretion (1E). TRH is used as a therapeutic agent for various neurologi­ cal disorders (2E). Nervous system A small study has shown larger changes in cerebral blood flow after administration of TRH in patients with persistent disturbance of consciousness caused by childhood encephalitis or ence­ phalopathy (3c).

Thyroid-stimulating hormone (TSH, thyrotropin) Recombinant human thyrotropin (rhTSH) has been developed as a source of exogen­ ous thyrotropin to promote radioiodine uptake and thyroglobulin production by thyroid cells in patients with thyroid cancer (4c–6c). It has similar efficacy to hypothyr­ oidism induced by withdrawal of levothyr­ oxine in the diagnosis of thyroid cancer,

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03141-9 r 2009 Elsevier B.V. All rights reserved.

while at the same time improving patients’ quality of life (7R). In small studies, intramuscular rhTSH before treatment with radioiodine improved thyroid size reduction in patients under­ going treatment for benign non-toxic nodu­ lar goiter (8c–10c), and those with the lowest 131 I pre-treatment uptake benefit most from rhTSH stimulation (11R). However, it is associated with higher rates of hypothyroidism, cervical pain, transient thyrotoxicosis, and a sense of compression. The last of these may be due to a transient increase in thyroid volume, which has been seen in healthy individuals to the extent of 35%, attributed to an exaggerated vascular response, possi­ bly leading to an interstitial fluid accumula­ tion. Transient increases in thyroid size have also been reported in patients with nodular goiter: 10% after 24 hours, 24% after 48 hours, and 5% after 1 week (12c,13c). Serious adverse effects include tumor swelling and pain from metastases.

THYROID HORMONES (SED-15, 3409; SEDA-28, 505; SEDA-29, 520; SEDA-30, 490)

Systematic reviews Thyroid hormones, liothyronine (T3) and levothyroxine (T4), are prescribed for about 1% of the adult population in developed countries, and the prevalence of prescription rises to 5–10% in those aged over 60 years (14R,15c). Much controversy surrounds the effectiveness of T3 + T4 combination treatment versus

683

684 levothyroxine monotherapy for the treat­ ment of overt hypothyroidism. The authors of a meta-analysis of 11 studies in which 1216 patients were randomized concluded that levothyroxine monotherapy should remain the treatment of choice for clinical hypothyroidism (16M). Cardiovascular Large studies have shown that about 25% of those who use levothyr­ oxine take doses sufficient to suppress serum TSH (15C,17c) and much attention has focused on potential adverse effects of this degree of over-treatment. In a large casecontrol study thyroid replacement therapy was independently associated with an almost two-fold increased chance of atrial fibrillation in patients presenting with ischemic stroke; it was proposed that this increase in risk was mediated through induction of iatrogenic subclinical hyperthyroidism (18C). Psychiatric There is a well-recognized association between hypothyroidism and psychiatric illness. Two reports have shown significant improvements of remission rates (19c) or mood scores (20c) in euthyroid patients with SSRI (Selective serotonin re-uptake inhibitor)-resistant depression undergoing augmentation treatment with liothyronine. Musculoskeletal There have been many studies of the effects of levothyroxine in TSH-suppressive doses on bone mineral density and large meta-analyses have shown that levothyroxine is associated with a minor but statistically significant reduction in bone mineral density (21M,22M). However, the evidence that suppressive doses of levothyr­ oxine represent increase in the risk of clinically relevant end-points such as fracture incidence and mortality remains scanty (14R). Drug–drug interactions There has been a report of a novel interaction between the protease inhibitors lopinavir + ritonavir and levothyroxine, leading to the induction of glucuronyl transferase resulting in increased metabolism of levothyroxine (23A).

Chapter 41

K. Boelaert

The absorption kinetics of levothyroxine are not altered by proton pump inhibition (24c), although patients with impaired acid secretion require an increased dose of levothyroxine (25c).

IODINE AND IODIDES (SED-15, 1896; SEDA-28, 506; SEDA-30, 490)

Endocrine Iodine is an essential component of thyroid hormones with both low and high intake resulting in thyroid disease. In a study in more than 3000 Chinese patients, intake of iodized salt in more than adequate (median 243 mg/l) or excessive (median 651 mg/l) amounts led to hypothyroidism and autoimmune thyroiditis (26C). Iatrogenic iodine excess from iodinecontaining antiseptic solutions has resulted in hypothyroidism in infants undergoing peritoneal dialysis (27A) and in a neonate undergoing abdominal surgery for umbilical cord hernia (28A). In addition, iodineinduced hyperthyroidism leading to thyrotoxic periodic paralysis has been reported after cardiac catheterization (29A).

Radioactive iodine compounds Sexual function Oligospermia was present in eight of 22 patients who had received high cumulative doses of 131I (14 GBq or more) (30c). Tumorigenicity Radioactive iodine 131I is used to treat patients with hyperthyroidism or thyroid cancer. In one study there was an increased standardized incidence ratio for second primary cancers in patients with differentiated thyroid carcinoma but not for secondary cancers after administration of ablative 131I. These findings suggest a common causative and/or genetic mechan­ ism not related to the treatment of thyroid cancer with 131I (31c).

Thyroid hormones, iodine, and antithyroid drugs

Chapter 41

ANTITHYROID DRUGS

severe mixed hepatotoxicity, and severe cholestatic jaundice have been reported in a patient taking carbimazole; all the clinical signs and laboratory abnormalities resolved on withdrawal of the drug (36A).

(SED-15, 3387; SEDA -28, 506; SEDA-29 520; SEDA-30, 490)

Hematologic Drug-induced agranulocytosis remains the most serious disorder associated with thionamide therapy; it can be life-threatening, with a reported mortality of 5–15%. DoTS classification: Reaction: Agranulocytosis due to thionamides Dose-relation: Collateral Time-course: Intermediate Susceptibility factors: Not known

In a previous study, the incidences of idiosyncratic neutropenia and agranulocyto­ sis in England and Wales were estimated to be 120 and 7 cases per million per year respec­ tively (SEDA-30, 490). Current users of drugs classed as “thyroid inhibitors” had the highest adjusted odds ratios for neutropenia (adjusted OR ¼ 35; 95% CI ¼ 12, 100) and for agranulocytosis (OR ¼ 21; 95% CI ¼ 3.3, N) compared with other classes of drug associated with this complication (32C). There has been a report of a patient presenting with severe facial cellulitis sec­ ondary to carbimazole-induced agranulocy­ tosis (33A). Severe pancytopenia is a rare but severe complication of thyrotoxicosis, and this has to be remembered when patients under­ going treatment with thionamides present with agranulocytosis. Standard immunosup­ pressive therapy of thionamide-induced aplastic anemia can restore normal hemo­ poiesis (34A). Liver Cholestasis and hepatotoxicity have been reported after treatment with thiona­ mide drugs. There has been a case report of drug-induced cholestatic jaundice following treatment with carbimazole, which resolved on withdrawal of the drug; the patient was subsequently treated successfully with pro­ pylthiouracil (35A). Furthermore the con­ comitant presence of agranulocytosis,

685

Skin Carbimazole-induced toxic epidermal necrolysis has been reported in a 12-year-old girl. She received intensive systemic treat­ ment in a burns center and made a full recovery. Since her medical history included autoimmune cholangitis, persistent protei­ nuria, and antinuclear and antismooth mus­ cle cell antibodies, it is plausible that autoimmune processes were involved in the toxicity of carbimazole in this case (37A). Immunologic Antithyroid drugs, and especially propylthiouracil, can be asso­ ciated with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis, often manifesting as renal disease. Atypical pre­ sentations, with mouth ulcers (38A), sym­ metrical peripheral gangrene (39A), or massive pulmonary hemorrhage (40A), have been reported in subjects taking propylthiouracil. In a study of propylthiouracil-induced lupus-like syndrome or vasculitis in 42 patients, all had p-ANCA, but the patients with vasculitis were significantly older and had a longer duration of treatment com­ pared with those with lupus-like syndrome (41c). Musculoskeletal symptoms were pro­ minent in drug-induced lupus, while there was renal and pulmonary involvement in a significantly higher proportion of patients with propylthiouracil-induced vasculitis. Antinuclear, anti-DNA, and antihistone antibodies were predominantly found in drug-induced lupus, whereas c-ANCA was only detected in vasculitis. All patients with drug-induced lupus recovered (most after stopping propylthiouracil treatment), while about 50% of those with propylthiouracilinduced vasculitis needed steroid or immu­ nosuppressive drugs, including cyclopho­ sphamide and plamapheresis. Teratogenicity Concerns about the safety of carbimazole in pregnancy have been raised, but the association between antithyr­ oid drug administration in early pregnancy

Chapter 41

686 and congenital abnormalities remains unclear. Aplasia cutis congenita and choanal atresia have been reported in association with maternal carbimazole therapy, suggest­ ing a causative link either with the drug or with underlying hyperthyroidism. Pro­ pylthiouracil therefore remains the drug of choice in early pregnancy. However, one of the major hazards of antithyroid drug use in pregnancy is over-treatment, and hence induction of fetal hypothyroidism and goiter. It is therefore important to monitor maternal thyroid status carefully and to use the lowest possible dose of antithyroid drug sufficient to maintain maternal euthyroidism.

K. Boelaert

Drug dosage regimens Current treatment of thyrotoxicosis often includes antithyroid drugs, which usually restore euthyroidism after 1–3 months of therapy. Most centers use a titration regimen for the administra­ tion of antithyroid drugs, and several studies have favored this over a blockand-replace regimen (42M,43R). The authors of a further report have challenged this notion and have proposed that a blockand-replace regimen may be beneficial in those at risk of thyroid eye disease, those with fluctuant thyroid function tests, and those in whom regular thyroid function testing is difficult (44R).

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Winokur A, Utiger RD. Thyrotropinreleasing hormone: regional distribution in rat brain. Science 1974;185(147):265–7. Sobue I, Yamamoto H, Konagaya M, Iida M, Takayanagi T. Effect of thyrotropinreleasing hormone on ataxia of spinocer­ ebellar degeneration. Lancet 1980;1(8165): 418–9. Yoshinari S, Hamano S, Tanaka M, Minamitani M. Alteration of regional cerebral blood flow to thyrotropin-releas­ ing hormone therapy in acute encephalitis and encephalopathy during childhood. Eur J Paediatr Neurol 2006;10(3):124–8. Haugen BR, Pacini F, Reiners C, et al. A comparison of recombinant human thyro­ tropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999; 84(11):3877–85. Pacini F, Ladenson PW, Schlumberger M, et al. Radioiodine ablation of thyroid remnants after preparation with recombi­ nant human thyrotropin in differentiated thyroid carcinoma: results of an interna­ tional, randomized, controlled study. J Clin Endocrinol Metab 2006;91(3):926–32. Robbins RJ, Driedger A, Magner JUS and Canadian Thyrogen Compassionate Use Program Investigator Group. Recombinant human thyrotropin-assisted radioiodine

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therapy for patients with metastatic thyroid cancer who could not elevate endogenous thyrotropin or be withdrawn from thyrox­ ine. Thyroid 2006;16(11):1121–30. Rosário PW, Fagundes TA, Purisch S, Padra~o EL, Rezende LL, Barroso AL. TSH recombinante no tratamento e segui­ mento de pacientes com carcinoma difer­ enciado de tireoide: uso na pratica clinica. [Recombinant TSH in ablative therapy and follow-up of patients with differentiated thyroid carcinoma.] Arq Bras Endocrinol Metabol 2005;49(3):350–8. Cohen O, Ilany J, Hoffman C, et al. Lowdose recombinant human thyrotropinaided radioiodine treatment of large, mul­ tinodular goiters in elderly patients. Eur J Endocrinol 2006;154(2):243–52. Giusti M, Cappi C, Santaniello B, Ceresola E, Augeri C, Lagasio C, Minuto F. Safety and efficacy of administering 0.2 mg of recombinant human TSH for two consecutive days as an adjuvant to therapy with low radioiodine doses in elderly out-patients with large nontoxic multinodular goiter. Minerva Endocrinol 2006;31(3):191–209. Nielsen VE, Bonnema SJ, Boel-Jorgensen H, Grupe P, Hegedus L. Stimulation with 0.3-mg recombinant human thyrotropin prior to iodine 131 therapy to improve the

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size reduction of benign nontoxic nodular goiter: a prospective randomized doubleblind trial. Arch Intern Med 2006;166 (14):1476–82 Republished in Ugeskr Lae­ ger 2006; 168(47): 4098–4101. Bonnema SJ, Nielsen VE, Hegedüs L. Radioiodine therapy in non-toxic multi­ nodular goitre. The possibility of effectamplification with recombinant human TSH (rhTSH). Acta Oncol 2006;45(8):1051–8. Nielsen VE, Bonnema SJ, Hegedüs L. Transient goiter enlargement after admin­ istration of 0.3 mg of recombinant human thyrotropin in patients with benign non­ toxic nodular goiter: a randomized, dou­ ble-blind, crossover trial. J Clin Endocrinol Metab 2006;91(4):1317–22. Nieuwlaat WA, Huysmans DA, van den Bosch HC, Sweep CG, Ross HA, Corstens FH, Hermus AR. Pretreatment with a single, low dose of recombinant human thyrotropin allows dose reduction of radioiodine therapy in patients with nodular goiter. J Clin Endocrinol Metab 2003;88:3121–9. Boelaert K, Franklyn JA. Thyroid hor­ mone in health and disease. J Endocrinol 2005;187(1):1–15. Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC. Thyroxine prescription in the community: serum thyroid stimulat­ ing hormone level assays as an indicator of undertreatment or overtreatment. Br J Gen Pract 1993;43(368):107–9. Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine– triiodothyronine combination therapy ver­ sus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of rando­ mized controlled trials. J Clin Endocrinol Metab 2006;91(7):2592–9. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid dis­ ease prevalence study. Arch Intern Med 2000;160(4):526–34. O’Donnell MJ, Valens N, Lansberg MG, Wijman CA. Thyroid replacement therapy and atrial fibrillation in acute ischemic stroke. Neurology 2006;67(9):1714–5. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmen­ tation following two failed medication treat­ ments for depression: a STAR�D report. Am J Psychiatry 2006;163(9):1519–30.

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Abraham G, Milev R, Stuart LJ. T3 augmentation of SSRI resistant depres­ sion. J Affect Disord 2006;91(2–3):211–5. Faber J, Galloe AM. Changes in bone mass during prolonged subclinical hyperthyroidism due to L-thyroxine treat­ ment: a meta-analysis. Eur J Endocrinol 1994;130(4):350–6. Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret GY. Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis. J Clin Endo­ crinol Metab 1996;81(12):4278–89. Touzot M, Beller CL, Touzot F, Louet AL, Piketty C. Dramatic interaction between levothyroxine and lopinavir/ritonavir in a HIV-infected patient. AIDS 2006;20(8): 1210–2. Dietrich JW, Gieselbrecht K, Holl RW, Boehm BO. Absorption kinetics of levothyroxine is not altered by protonpump inhibitor therapy. Horm Metab Res 2006;38(1):57–9. Centanni M, Gargano L, Canettieri G, et al. Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis. N Engl J Med 2006;354(17):1787–95. Teng W, Shan Z, Teng X, et al. Effect of iodine intake on thyroid diseases in China. N Engl J Med 2006;354(26):2783–93. Brough R, Jones C. Iatrogenic iodine as a cause of hypothyroidism in infants with end-stage renal failure. Pediatr Nephrol 2006;21(3):400–2. Aliefendioglu D, Sanli C, Cakmak M, Agar A, Albayrak M, Evliyaoglu O. Wolff-Chaik­ off effect in a newborn: is it an overlooked problem? J Pediatr Surg 2006;41(12):e1–3. Kane MP, Busch RS. Drug-induced thyr­ otoxic periodic paralysis. Ann Pharmac­ other 2006;40(4):778–81. Rosario PW, Barroso AL, Rezende LL, et al. Testicular function after radioiodine therapy in patients with thyroid cancer. Thyroid 2006;16(7):667–70. Verkooijen RB, Smit JW, Romijn JA, Stokkel MP. The incidence of second primary tumors in thyroid cancer patients is increased, but not related to treatment of thyroid cancer. Eur J Endocrinol 2006;155 (6):801–6. van Staa TP, Boulton F, Cooper C, Hagenbeek A, Inskip H, Leufkens HG.

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Neutropenia and agranulocytosis in Eng­ land and Wales: incidence and risk factors. Am J Hematol 2003;72(4):248–54. del Giudice P, Cua E, Bernard E, et al. Pseudomonas aeruginosa ecthyma gang­ renosum and facial cellulitis complicating carbimazole-induced agranulocytosis. Arch Dermatol 2006;142(12):1663–4. Lima CS, Zantut Wittmann DE, Castro V, et al. Pancytopenia in untreated patients with Graves’ disease. Thyroid 2006;16(4): 403–9. Haboubi H, Harris D, Haboubi N. Chole­ static jaundice following carbimazole ther­ apy in an elderly thyrotoxic patient. Age Ageing 2006;35(3):319. Vilchez FJ, Torres I, Garcia-Valero A, Lopez-Tinoco C, de Los SA, AguilarDiosdado M. Concomitant agranulocytosis and hepatotoxicity after treatment with carbimazole. Ann Pharmacother 2006;40 (11):2059–63. Ziora K, Oswiecimska J, Broll-Waska K, et al. Methimazole-induced toxic epidermal necrolysis in a 12-year-old girl. J Paediatr Child Health 2006;42(7-8):472–3. Karincaoglu Y, Esrefoglu M, Aki T, Mizrak B. Propylthiouracil-induced vasculitic oral

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ulcers with anti-neutrophil cytoplasmic anti­ body. J Eur Acad Dermatol Venereol 2006; 20(1):120–2. Farah RE, Shay MD. Symmetrical periph­ eral gangrene and neutropenia following propylthiouracil. Ann Pharmacother 2006; 40(6):1211. Zhao MH, Chen M, Gao Y, Wang HY. Propylthiouracil-induced anti-neutrophil cytoplasmic antibody-associated vasculitis. Kidney Int 2006;69(8):1477–81. Aloush V, Litinsky I, Caspi D, Elkayam O. Propylthiouracil-induced autoimmune syn­ dromes: two distinct clinical presentations with different course and management. Semin Arthritis Rheum 2006;36(1):4–9. Abraham P, Avenell A, Park CM, Watson WA, Bevan JS. A systematic review of drug therapy for Graves’ hyperthyroidism. Eur J Endocrinol 2005;153(4):489–98. Cooper DS. Antithyroid drugs. N Engl J Med 2005;352(9):905–17. Razvi S, Vaidya B, Perros P, Pearce SH. What is the evidence behind the evidencebase? The premature death of blockreplace antithyroid drug regimens for Graves’ disease. Eur J Endocrinol 2006; 154(6):783–6.

R.C.L. Page

42

Insulin, other hypoglycemic drugs, and glucagon

GLUCAGON

(SED-15, 1510; SEDA-

28, 514)

Glucagon has been used to assess adrenal function in 215 children who had fasted overnight; 79 were aged 0.1–5 years, 28 were aged 5.1–10 years, 96 were aged 10.1– 15 years, and 12 were aged over 15 years (1c). The dose was 0.05 mg/kg (maximum 1.0 mg) subcutaneously. There was nausea in 25% and vomiting in 6%. Walking and drinking water minimized these adverse effects. No information was given as to whether adverse effects occurred more often in certain age groups.

(SED-15, 1761; SEDA-28, 509; SEDA-29, 523; SEDA-30, 494)

INSULIN

Metabolism Hypoglycemia The benefit of intensive treatment of blood glucose concentrations in patients who are critically ill continues to be debated (2r). In a prospective randomized study, patients who were thought to need a third day in a medical ICU received either intensive insulin therapy (n ¼ 595), starting when the blood glucose concentration was over 6.1 mmol/l and aiming for 4.4–6.1 mmol/l, or conventional insulin therapy, starting when the blood glucose concentration was 12 mmol/l and aiming for 10–11 mmol/l. There was no Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03142-0 r 2009 Elsevier B.V. All rights reserved.

difference in death rates between the two groups—24% versus 27%, respectively. However, of 433 patients who stayed for less than 3 days in the ICU, death rates were 56 (13%) compared with 42 (9.7%). There was a sixfold increase in the number of episodes of blood glucose below 2.2 mmol/l in those who received intensive insulin therapy (3C). The risk of hypoglycemia in ICU has been studied retrospectively in 2272 patients. Hypoglycemia was associated with diabetes, sepsis, a Sequential Organ Failures Assessment score of 1 or more, the use of bicarbonate in renal replacement, female sex, use of vasopressors or insulin, and impaired nutrition without altered insulin dosage (4r). Various protocols have been designed and studied to try to reduce the risk of hypoglycemia when infusing insulin to maintain normoglycemia in critically ill patients (5c,6c). Hypoglycemia when using insulin remains a barrier to achieving tight blood glucose control. In a review of severe hypoglycemia (requiring assistance) 11 studies of insulintreated patients with type 2 diabetes were analyzed; each included at least 50 patients followed for a minimum of 6 months (7M). The reporting of severe hypoglycemia varied enormously, from none at all to 73 episodes per 100 patient-years. Prospective and retrospective studies had different reporting rates, with lower rates in prospective studies. This may have been due to the study populations, with possible exclusions in prospective studies, including those with frequent hypoglycemia or hypoglycemia unawareness. Risk factors for severe hypoglycemia in type 2 diabetes were increasing age and duration of diabetes.

689

Chapter 42

690 The type of insulin used may influence the frequency of hypoglycemia. Insulin detemir and glargine may reduce the incidence of hypoglycemia compared with NPH insulin, although results are variable (8R). Studies in patients with type 2 diabetes tend not to be as significant. Studies in patients with type 1 diabetes show most benefit in reducing nocturnal hypoglycemia (9R,10R). The difference between patients with type 1 and type 2 diabetes may relate to the lower frequency with which hypoglycemia is experienced in patients with type 2 diabetes. Weight gain In comparisons of insulin detemir with NPH insulin, insulin detemir appears to be associated with less weight gain (8R). Immunologic Allergy to insulin is uncommon. Most reactions are of type 1, type III reactions rarely being reported.  A 31-year-old man with type 1 diabetes

developed a subcutaneous subdermal nodule within 6 hours of his first injection of insulin detemir (11A). On the following 2 days further nodules occurred 4–6 hours after insulin detemir. There was no reaction at the site of insulin aspart injection. The patient changed his insulin back to insulin glargine and the nodules resolved.

Route-dependent insulin been reported (12A).

allergy has

 A 24-year-old man with a 3-year history of

poorly controlled type 1 diabetes was allergic to insulin. Skin tests with all commercially available insulin and insulin analogs were positive. Desensitization using subcutaneous insulin resulted in frequent allergic symptoms, including shock and dyspnea. Skin tests to the solvents and additives were negative. When intravenous regular insulin was injected, there were no allergic symptoms. When he was given long-term intravenous insulin via a portable parenteral nutrition device all of his symptoms resolved and antiallergic agents were no longer required. Antihuman insulin IgE concentrations also returned to normal. Two years later despite normal antibody concentrations, subcutaneous regular insulin caused an immediate allergic response.

The route of administration appeared to be important in causing the allergic response in

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this case. The authors suggested that aggregation at the subcutaneous site might have been responsible. Drug administration route Subcutaneous injection Injection site pain has been reported to be more common with insulin glargine (2.7%) than with NPH insulin (0.7%); the pain is usually mild and does not require withdrawal of therapy (8R). Continuous subcutaneous insulin infusion (CSII) Several reviews have investigated the use of CSII in children. A review of seven non-randomized studies of children aged 1– 18 years showed a reduction in hypoglycemia, and the authors suggested that diabetic ketoacidosis is not more of a problem if guidelines are followed (13M). A further review showed that self-selection of patients in non-randomized studies weakens the results, but the authors concluded that some patients certainly have reduced frequency and severity of hypoglycemia using CSII. They highlighted the problem of accidental bolus doses, which can be given when the patient is asleep or confused, resulting in death or severe hypoglycemia. If this is thought to be a risk, putting the pump in a case or in remote control mode for boluses can help to prevent the problem (14M). The risk of diabetic ketoacidosis varies with the indication for CSII. In some countries CSII is recommended for children who are susceptible to ketoacidosis. In 1999 a population study in Sweden, where ketosis is an indication for CSII, showed that the incidence of diabetic ketoacidosis was 3.1/100 patient-years in pump users compared with 1.4 in non-pump users. Diabetic ketoacidosis occurred more often in the first year after starting to use a pump—in one study 75% of cases were reported in the first year. The authors concluded that results from CSII vary, but that it may be useful in reducing the incidence of diabetic ketoacidosis and hypoglycemia in some individuals and can be safely used in babies, children, and adolescents. Motivated patients and health-care teams are required and data should be collected continually.

Insulin, other hypoglycemic drugs, and glucagon

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Of 376 patients who were started on pump therapy between 1998 and 2003, 279 were under the age of 40 years, 23 were prepubertal (median age 5.4 years), 127 were adolescent (median age 14 years), and 129 were young adults (median age 23 years) (15c). The frequencies of episodes of severe hypoglycemia recorded in the year before starting CSII were 0, 37, and 58 per 100 patient-years in the three groups, respectively. During CSII the frequencies of episodes of severe hypoglycemic were 0, 11, and 23 per 100 patient-years. In the year before CSII, diabetic ketoacidosis occurred 0, 0.19, and 0.12 times per patientyear, respectively. During CSII there were 0.22, 0.17, and 0.09 events per patient-year. HbA1c concentrations improved with CSII. There was therefore a reduction in the frequency of episodes of severe hypoglycemia, but a small increase in the number of episodes of diabetic ketoacidosis in prepubertal children. The time it takes to develop increased concentrations of 3b-hydroxybutyrate when CSII is stopped for 4 hours has been studied in eight patients with type 1 diabetes (mean age 38 years), who stopped their CSII pumps at 0800 hours after an overnight fast (16c). Blood glucose concentrations rose from 8.3 to 12.5 mmol/l and 3b-hydroxybutyrate concentrations from 0.1 to 0.9 mmol/l (fasting reference range 0.03–0.3 mmol/l). Urine ketones changed from undetectable to +1. CSII was then re-established with an initial bolus; 3bhydroxybutyrate concentrations returned to normal more rapidly than blood glucose concentrations. This study highlights how rapidly 3b-hydroxybutyrate can increase on interruption of CSII and reinforces the important advice given to patients about frequent blood glucose monitoring and the action to take when blood glucose concentrations rise.

malfunctioned. A computerized model calculated insulin delivery rates. There were no episodes of severe hypoglycemia, but there were 13 episodes of biochemical hypoglycemia (o3.3 mmol/l), 8 of which occurred near the start of the closed loop system.

Closed loop insulin delivery Ten patients with type 1 diabetes using CSII had two subcutaneous glucose sensors inserted in the abdominal area (17c). The sensors were connected to radiofrequency transmitters able to communicate with a laptop computer. Two sensors were used in case one

691

Inhaled insulin Exubera, the first commercially available inhaled insulin, was withdrawn in January 2008, because of an insufficient market. In June 2008 six new cases of primary lung cancer in 4740 patients taking Exubera taking part in the clinical trial program were reported, compared with one new case in the comparison group, n ¼ 4292 (18S). All the cases had a previous history of cigarette smoking. Current smoking is a contraindication to the use of Exubera.

ALPHA-GLUCOSIDASE INHIBITORS (SED-15, 85; SEDA-28, 514; SEDA-29, 526; SEDA-30, 496)

Acarbose Observational studies In 20 people (age unknown) with impaired glucose tolerance, acarbose 100 mg/day was increased to three times daily (if tolerated) for 3 months (19c). All the patients also received dietary advice. Weight fell at 3 months from 72 to 69 kg; triglycerides from 1.7 to 1.2 mmol/l and HbA1c concentrations from about 6.1 to 5.9%; HDL cholesterol rose from 1.04 to 1.17 mmol/l. In contrast, 20 people in a control group did not have changes in weight, HbA1c, or triglycerides. Liver Liver damage has been attributed to acarbose (20A).  A 57-year-old woman with a 10-year history of

type 2 diabetes had used insulin for 6 months when acarbose 100 mg tds was added for poor glycemic control; 6 months later she developed gastrointestinal discomfort and reduced the dose to 50 mg tds. Her symptoms improved

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692 but her alanine transaminase activity rose to 640 U/l. She had also been taking an estrogen 0.625 mg/day for over 6 years and began taking Ginkgo biloba and other supplements after being informed of the abnormal liver function results. Both the estrogen and the nutritional supplements were withdrawn. There was some improvement in liver function but it was abnormal 6 months later. The alanine transaminase activity was about 2–3 times normal and the aspartate transaminase activity 1.5 times normal. Acarbose was withdrawn. The liver function tests returned to normal within 2 months and remained so.

There have been previous reports of liver function abnormalities with acarbose (SEDA30, 496). Abnormal liver function appears to be more commonly reported in women, with a peak onset at 2–6 months at dosages of 150– 300 mg/day.

(SEDA28, 514; SEDA-29, 526; SEDA-30, 496)

AMYLIN ANALOGUES Pramlintide

Metabolism Hypoglycemia, including severe hypoglycemic events, has occurred more commonly in studies in which pramlintide was combined with insulin in patients with both type 1 and type 2 diabetes, compared with placebo combined with insulin (21R). Pramlintide itself does not cause hypoglycemia. Reducing the meal-time dose of insulin by 30–50% combined with a gradual increase in pramlintide dose, depending on nausea, reduced the number of events of severe hypoglycemia to a similar level to that found with placebo. A review of longer-term placebocontrolled studies showed that pramlintide was associated with a small amount of weight loss, rather than weight gain, at 6 months and that weight reduction was sustained for up to 1 year (21R). Weight reduction appeared to be greater in those who were overweight, and was independent of nausea, which is common in patients taking pramlintide.

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(SED-15, 506; SEDA28, 514; SEDA-29, 526; SEDA-30, 497)

BIGUANIDES Metformin

Endocrine Four patients taking levothyroxine for hypothyroidism developed suppressed thyroid stimulating hormone concentrations when taking metformin (22A). In one patient the TSH concentrations returned to normal when the metformin was stopped. On reintroduction of metformin the TSH became suppressed, resolving once again after withdrawal. In this patient thyroid hormone concentrations were measured before and after metformin and were not significantly different. Metformin did not appear to interfere with the TSH assay when added to normal serum. In people taking metformin without levothyroxine, no changes in TSH concentrations have been found. This finding needs verification in a larger group of patients, as TSH concentrations can vary significantly depending on adherence to therapy. Nutrition Further reminders of vitamin B12 deficiency in patients taking metformin have been published. It has been speculated that this is due to an effect on the calcium-dependent action of ileal cell membrane receptors, interfering with the uptake of the vitamin B12– intrinsic factor complex (23A). In a nested case–control study in 155 patients with diabetes and vitamin B12 deficiency thought to be secondary to metformin, compared with 310 patients taking metformin without vitamin B12 deficiency, the risk of vitamin deficiency increased with increasing dose of metformin and duration of therapy (24c). There were slightly more vegetarians with vitamin B12 deficiency: 2.6% compared with 0.3%. Age did not differ between the groups: 73 years in cases and 71 in controls, although age was associated with an odds ratio of vitamin B12 deficiency of 1.36 for each 10-year increment. Skin Leukocytoclastic vasculitis has been attributed to metformin (25A).  A 33-year-old woman took metformin 850 mg/

day for weight loss. After 5 days she developed several petechial hemorrhagic lesions. A

Insulin, other hypoglycemic drugs, and glucagon drug-induced vasculitis was diagnosed and the drug discontinued. The rash disappeared within a few days. A month later she took metformin again. Within 1 day she developed a rash, which on biopsy was found to be a leukocytoclastic vasculitis. The drug was withdrawn. After 3 months of follow-up there had been no recurrence.

This is a rare adverse effect of metformin. The authors identified one previous report, which was associated with pneumonitis. Hair Alopecia has been attributed to metformin (26A).  After 4 months treatment with metformin for

anovulatory infertility caused by polycystic ovary syndrome a 36-year-old woman developed acute alopecia. She stopped taking the metformin and the problem resolved within 6 months. She had increased the dose of metformin to 1 g bd at 3 months.

The authors suggested that a reduction in vitamin B12 concentrations caused by metformin had been responsible. However, they gave no evidence to support the assumption that metformin had caused the alopecia or that the mechanism was via a reduction in vitamin B12 concentrations. Teratogenicity A review of a limited number of studies in women with polycystic ovary syndrome has shown no increase in major malformations when metformin was taken in the first trimester (27M). In 188 women aged 18–38 (mean 29) years, with 237 pregnancies treated with metformin for polycystic ovary syndrome who had taken metformin for about 7 months before pregnancy, half had taken additional therapy for infertility and most of them stopped taking metformin at the end of the first trimester (28C). Of the 237 pregnancies, 171 (72%) resulted in 184 live babies, of whom 4 had congenital abnormalities (congenital adrenal hyperplasia, cleft palate, Potter’s syndrome, and multiple abnormalities). In two other studies in women who took metformin for polycystic ovary syndrome until the end of the first trimester or sometimes longer, there were no increases in the frequencies of congenital malformations (29c,30c). Thus, the use of metformin for the management of infertility in women with

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polycystic ovary syndrome does not appear to increase the rate of congenital malformations, although further studies with longterm follow-up are still required to establish the safety of metformin in pregnancy.

DIPEPTIDYL PEPTIDASE IV INHIBITORS (SEDA-30, 498) Systematic reviews A meta-analysis has shown an increased risk of nasopharyngitis in patients taking dipeptidyl peptidase IV inhibitors: 6.4% compared with 6.1% in the comparison groups (31M). Urinary tract infection was also more common (3.2% compared with 2.4%). Of those taking dipeptidyl peptidase IV inhibitors especially vildagliptin, 5.1% reported headache compared with 3.9% in the comparison groups.

Sitagliptin Ear, nose, throat Nasopharyngitis and upper respiratory tract infection have been reported slightly more commonly in patients taking sitagliptin than placebo in 24-week placebo-controlled studies (32c–34c). The incidence of upper respiratory tract infections was 6.3% when pioglitazone was combined with sitagliptin (n ¼ 175) compared with 3.4% when pioglitazone was combined with placebo (n ¼ 178). Metabolism Hypoglycemia Hypoglycemia is no more frequent when taking sitagliptin (0.8%) compared with placebo (0.8%) when taken as monotherapy (32c), or in combination with metformin (1.3%) compared with placebo (2.1%) (33c). However, when combined with a sulfonylurea (n ¼ 222), the incidence of hypoglycemia was 12% compared with 2% in the placebo group (n ¼ 219) (35c). Body weight There was weight loss of 0.2 kg in a 24-week study (n ¼ 741) of sitagliptin monotherapy in patients with type 2 diabetes compared with 1.1 kg in the placebo group (32c). In further 24-week

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694 studies when sitagliptin was combined with metformin there was weight loss of 0.6 kg (n ¼ 464), similar to metformin combined with placebo (n ¼ 237) (33c). Patients who took pioglitazone plus sitagliptin had a placebo-adjusted weight gain of 0.2 kg (34c) and when sitagliptin was combined with a sulfonylurea there was a 1.1 kg placebo-adjusted weight gain (35c). Sitagliptin therefore appears to have a minor effect on body weight when taken alone or in combination with other therapies. Hematologic Sitagliptin reportedly caused a small increase in white cell count, due to an absolute increase in neutrophil count (354  106 per liter compared with 73 in the placebo group) (33c,35c). Gastrointestinal Adverse gastrointestinal effects (abdominal pain, nausea, diarrhea) were reported slightly more commonly when sitagliptin was taken as monotherapy (12% placebo, 16% sitagliptin) (32c), or combined with pioglitazone (6.2% placebo, 14% sitagliptin) (34c). Combination with metformin did not increase gastrointestinal effects (11% placebo, 12% sitagliptin) (33c). A meta-analysis suggested that overall there was no increase in gastrointestinal adverse effects (31M). Liver In a placebo-controlled crossover study in 28 patients, 1 patient was found to have abnormal liver function tests (alanine transaminase activity more than three times the upper limit of normal) after 4 weeks (36c). The activities returned to normal during the placebo phase. Sitagliptin could have been responsible. Immunologic Urticaria and angioedema occurred in a patient taking sitagliptin (34c). Details were not given, but the investigators thought that sitagliptin had possibly been responsible. Susceptibility factors Dosages of sitagliptin are not thought to be affected by the patient’s sex, age, and obesity. There were no significant pharmacokinetic differences when 8 healthy young non-obese women, 10 healthy elderly (65–80 years) non-obese men, 10 healthy elderly non-obese women, and 10 young obese (BMI 30–40 kg/m2)

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subjects were studied. In each group six to eight subjects received sitagliptin 50 mg and two received placebo (37R). Liver disease Moderate hepatic insufficiency has no significant effect on the pharmacokinetics of sitagliptin (38R). Renal disease Five groups of six patients with different levels of renal function took one dose of 50 mg of sitagliptin (39C). Renal function was defined using urinary creatinine excretion and calculated creatinine clearance (Cockcroft–Gault) in 145 historical controls. Normal renal function was defined as a creatinine clearance over 80 ml/minute, mild impairment 50–80 ml/minute, moderate impairment 30–50 ml/minute, severe impairment under 30 ml/minute, and end-stage renal disease on hemodialysis. Patients with mild renal impairment had an AUC of less than twice that of controls, moderate impairment 2–3 times higher, severe impairment 3.8 times, and end-stage renal failure 4.5 times higher. The patients on hemodialysis had been given their dose 48 hours before dialysis. After wash-out for 1 week they received a dose 4 hours before dialysis with further sampling to determine whether sitagliptin was removed. The fraction of the dose removed was 14% at 4 hours and 3.5% at 48 hours. The authors recommended that no dosage reduction is required in patients with mild renal impairment but that the dose should be reduced from 100 to 50 mg in those with moderate renal impairment, and to 25 mg in those with severe renal impairment or end-stage renal impairment. However, the manufacturer does not recommend using sitagliptin in patients with moderate or severe renal impairment.

Vildagliptin Placebo-controlled studies Vildagliptin was the second inhibitor of dipeptidyl peptidase IV to become available in the UK. In a 24-week study of patients with type 2 diabetes, vildagliptin 50 mg (n ¼ 177), vildagliptin 100 mg (n ¼ 185), or placebo (n ¼ 182) was added to metformin (40C). Gastrointestinal adverse events were slightly less frequent in those who took vildagliptin

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50 mg (9.6%) than in those taking vildagliptin 100 mg (15%) and in those taking placebo (18%). There was weight gain of more than 1 kg in 32% of those taking vildagliptin 50 mg, 37% of those taking 100 mg, and 16% of those taking placebo; relative to placebo there was no change in weight in those who took vildagliptin 50 mg, but an increase in those who took 100 mg (1.2 kg).

(median age 60 years; 2860 men) were reported; 3930 (76%) were taking therapy at 6 months (42C). The most common adverse events were diarrhea, malaise, nausea, and vomiting. Patients stopped taking repaglinide because of lack of effect (n ¼ 647), diarrhea (60), malaise (43), or nausea (44). There were 52 reports of diarrhea within the first month of therapy and 38 over months 2–6.

INCRETIN MIMETICS

(SEDA-29,

528; SEDA-30, 499)

Liraglutide Placebo-controlled studies A total of 144 patients with type 2 diabetes were randomized to metformin+liraglutide placebo, metformin +liraglutide, metformin+glimepiride, or liraglutide+metformin placebo. Liraglutide 0.5 mg was given as a subcutaneous injection once daily and the dose was increased weekly by 0.5 mg/day up to a dose of 2.0 mg/day or until the fasting glucose was less than 6.0 mmol/l. If liraglutide was not tolerated the dose was reduced by 0.25 mg increments. Over the 5-week study period, body weight fell by 2.2 and 2.1 kg in the liraglutide +metformin group and the liraglutide only group, respectively. The metformin only group lost 1.7 kg. Gastrointestinal adverse effects were more common in those taking liraglutide, especially nausea and diarrhea. Three of 72 subjects taking liraglutide withdrew and 4 required a dosage reduction (41c).

(SED-15, 2238; SEDA-26, 468; SEDA-27, 455; SEDA-28, 518)

MEGLITINIDES

Repaglinide Gastrointestinal In a postmarketing observational study of the use of repaglinide in general practice, 15 191 forms were sent out and data from 5731 patients

695

Drug–drug interactions Repaglinide is metabolized by CYP3A4 and CYP2C8 and ciclosporin and tacrolimus by CYP3A4. Repaglinide was given to 23 patients (mean age 49 years; BMI 25 kg/m2; 10 men) with new-onset diabetes mellitus after renal transplantation (43c). They were taking various combinations of immunosuppressive drugs, including prednisone, tacrolimus, ciclosporin, mycophenolate mofetil, and sirolimus. Repaglinide was usually given three times a day in doses depending on clinical need. Starting doses were 1– 3 mg/day. Blood concentrations of tacrolimus (n ¼ 17), ciclosporin (n ¼ 7), and sirolimus (n ¼ 5) were taken on the day of starting repaglinde and 3–7 days later. Patients who changed their immunosuppressive doses on the day of the first test were excluded (number unknown). Blood concentrations did not change significantly.

(SED-15, 3230; SEDA-28, 518; SEDA-29, 530; SEDA-30, 500)

SULFONYLUREAS

Metabolism Hypoglycemia due to sulfonylureas has been reviewed (44R). In one study up to 20% of patients with diabetes had suggestive symptoms. In the first year of the UKPDS study 30% of those taking glibenclamide (glyburide) reported problems. The annual incidence of severe events was 1.0% in those taking chlorpropamide and 1.4% in those taking glibenclamide. Although the figures are less than those reported for insulin, severe events in those taking sulfonylureas tend to be more protracted and

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696 more likely to be fatal. Susceptibility factors for hypoglycemia are older age and polypharmacy, especially concomitant use of insulin or drugs that inhibit the metabolism of sulfonylureas or potentiate their actions. Glibenclamide has been associated with a high risk of severe hypoglycemia and tolbutamide with one of the lowest. Although a long duration of action tends to increase the risk of hypoglycemia, glimepiride, a longacting sulfonylurea, carries a significantly lower risk than glibenclamide, and gliclazide MR an even lower risk. In the UKPDS hypoglycemia was graded 1–4; the lowest grade was used when there were transient symptoms that did not affect normal activity and the highest grade was used when medical attention or glucagon was required (45C). Hypoglycemia tended to be more frequent in younger patients (under 45 years), but patients over the age of 65 years were not enrolled. The annual frequency of at least one episode of hypoglycemia with a sulfonylurea was 1.2% for grades 2–4 and about 8% including all grades. Weight gain is associated with the use of sulfonylureas, but this effect has been suggested to have been overemphasized (44,46R). In a 27-week comparison of gliclazide MR and glimepiride, the mean gains in weight were 0.5 and 0.6 kg, respectively. In the UKPDS, the mean weight gain varied from 1.7 kg for glibenclamide to 2.6 kg for chlorpropamide, after 10 years of follow-up.

Glibenclamide Fetotoxicity The use of glibenclamide is increasing in the management of gestational diabetes. Of 235 women with gestational diabetes (Carpenter and Coustan diagnostic criteria), 101 (mean age 31 years; BMI 32 kg/m2) took glibenclamide in an initial dose of 2.5–5 mg depending on the prescriber (47c). Doses were titrated to a maximum of 10 mg bd and 80 women continued on glibenclamide and 21 required insulin to control blood glucose concentrations. When these two groups were compared, those who continued to take glibenclamide had a significantly higher

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rate of neonatal admissions—33% (n ¼ 26) compared with 10% (n ¼ 2). The most common indications for admission were hypoglycemia and respiratory distress. Further long-term studies that include outcome data on the future risk to the offspring are required. Management of adverse drug reactions Severe and prolonged hypoglycemia occurs when people overdose with sulfonylureas. Infusion of dextrose is used to maintain euglycemia. It is recommended that octreotide should be used to facilitate recovery. Different doses have been used. In one report a bolus dose of 50 mg intravenously followed by an infusion of 25–50 mg/hour was effective (48A).

Glipizide Skin Stevens–Johnson syndrome has been attributed to glipizide (49A).  A 31-year-old man developed painful wide-

spread red/purple macules, conjunctivitis, a mucoid discharge of the eyes, and erosions and exudates in and around the mouth. He had taken glipizide 5 mg/day for 1 year and had increased the dose to 10 mg/day 2 days earlier. The clinical and histological findings were consistent with Stevens–Johnson syndrome. On withdrawal of glipizide the lesions rapidly resolved.

Sulfonylureas are related to sulfonamides, which are associated with Stevens–Johnson syndrome. However, reports associated with sulfonylureas are rare. The authors speculated that in this case the change in drug dosage may have increased the concentration of drug metabolites, allowing an immune response to occur.

Gliquidone Observational studies The short half-life of gliquidone (1.5 hours) has been highlighted (50R). Gliquidone is metabolized by hydroxylation and demethylation in the liver to largely inactive metabolites, which are 95% excreted in the feces. In 3443 patients adverse events requiring withdrawal of therapy included allergic reactions

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(n ¼ 8), gastrointestinal intolerance (n ¼ 6), nausea (n ¼ 4), and vomiting (n ¼ 3). Hypoglycemia occurred in 0.13%. Weight gain after 1 year has been reported to be low (0.03 kg). Gliquidone was withdrawn from the UK in 2007 for commercial reasons.

The FDA have reported a time to first ischemic event analysis for rosiglitazone, in which there was a hazard ratio of 1.4 compared with control groups; a similar analysis for pioglitazone had a hazard ratio of 0.83 (54R). It appears therefore that the risk of ischemic events occurring when taking a thiazolidinedione is greater with rosiglitazone. This may be due to the different effects that pioglitazone and rosiglitazone have on plasma lipids. Patients (n ¼ 735) with type 2 diabetes, randomized to pioglitazone (30 mg for 12 weeks followed by 45 mg for 12 weeks), were compared with patients receiving rosiglitazone (4 mg once daily for 12 weeks followed by 4 mg twice daily for 12 weeks). Triglyceride concentrations decreased with pioglitazone and increased with rosiglitazone. Both drugs increased HDL cholesterol but the increase was greater with pioglitazone. LDL increased with both drugs but significantly more with rosiglitazone. Apoplipoprotein B concentrations were unchanged with pioglitazone and increased with rosiglitazone (55C). Pioglitazone has been studied in a randomized control trial in 5238 patients with type 2 diabetes, mean age 62 years, with evidence of macrovascular disease (56C). There was no difference between the two groups in the primary end-point, which was a composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention in the heart or leg, and amputation above the ankle. A meta-analysis of 19 trials in 8554 patients taking pioglitazone and 7836 in comparison groups showed no differences in death or myocardial infarction between the groups (57M).

THAZOLIDINEDIONES (GLITAZONES) (SED-15, 3380; SEDA-28, 519; SEDA-29, 531; SEDA-30, 501)

Risk of adverse cardiovascular effects in patients taking thiazolidinediones Ischemic heart disease The European Committee for Human use of Medicinal Products (CHMP) has recommended that rosiglitazone should be contraindicated in patients with acute coronary syndrome, as it has not been studied in this group of patients, and that it should not be recommended for use in patients with ischemic heart disease or peripheral arterial disease, because of concerns about its safety (51S). A meta-analysis of 42 trials that lasted more than 24 weeks included 15 565 patients taking rosiglitazone and 12 282 patients in comparison groups (52M). The mean age was 56 years. There were 86 cases of myocardial infarction and 39 cardiovascular deaths associated with rosiglitazone compared with 72 cases of myocardial infarction and 22 cardiovascular deaths in the controls. The odds ratio for myocardial infarction was 1.43 (95% CI ¼ 1.03, 1.98) and for death 1.64 (95% CI ¼ 0.98, 2.74). A meta-analysis of trials of at least 12 months using rosiglitazone showed an increased risk of myocardial infarction—94 of 6421 patients compared with 83 of 7870 in the comparison group; the odds ratio was 1.42 (95% CI ¼ 1.06, 1.91). There was no increase in cardiovascular mortality (53M). These meta-analyses included some patients without diabetes.

697

Congestive cardiac failure Patients taking thiazolidinediones have an increased risk of congestive cardiac failure. In a meta-analysis of 20 191 patients there were 214 events in the 9360 patients who took thiazolidinediones compared with 146 in the 10 831 patients in the comparison groups; this was reportedly a class effect (58M). In a meta-analysis of studies of rosiglitazone the relative risk of cardiac failure was 2.09 (95% CI ¼ 1.52, 2.88) (53M). For

698

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pioglitazone the risk of serious cardiac failure compared with control groups was 1.41 (95% CI ¼ 1.14, 1.76) (57M). Thiazolidinediones are contraindicated in patients with congestive cardiac failure.

papilledema associated with a normal MRI scan and raised intracranial pressure on lumbar puncture. Rosiglitazone was withdrawn. Within 2 weeks the headache had resolved and within 10 weeks the papilledema had disappeared.

 A 72-year-old obese hypertensive woman with a

The timing and resolution of symptoms suggested a causal relation, but the possible mechanism was unclear. The patient had no clinically apparent peripheral edema.

history of cardiac failure and type 2 diabetes had no echocardiographic evidence of failure and had a normal exercise capacity. She was taking isosorbide-5-mononitrate, losartan, hydrochlorothiazide, acarbose and gliclazide. She started to take rosiglitazone 4 mg/day; 2 weeks later she complained of leg edema and tiredness and after a further 2 weeks developed acute pulmonary edema (59A). She stopped taking rosiglitazone and was treated with diuretics. Two months later there were no clinical or echocardiographic signs of cardiac failure.

The time to development of heart failure in this case was short and it is likely that fluid retention due to rosiglitazone was important. Edema and thiazolidinediones has been reviewed (SEDA-29, 531).

Drug–drug interactions Reduced effects of warfarin have been reported in patients taking thiazolidinediones (60A).  An 84-year-old woman with atrial fibrillation

took warfarin for 1 year and then took pioglitazone 15 mg/day. Within 12 weeks her INR had fallen to 1.2 and an 88% increase in warfarin dose was required to achieve the target INR.  Within 4 weeks of starting to take rosiglitazone 4 mg/day, the INR in a 76-year-old man taking warfarin fell to 1.1; the dose of warfarin was increased by 75%.

The authors recommend close monitoring of the INR in the first few months of starting thiazolidinediones.

Rosiglitazone Nervous system Pseudotumor cerebri has been attributed to rosiglitazone (61A).  A 61-year-old man with type 2 diabetes who

had taken rosiglitazone 4 mg bd for 3 months developed a headache. Pseudotumor cerebri was diagnosed because of

Hematologic Thrombocytopenia has been attributed to rosiglitazone (62A).  A 66-year-old woman with type 2 diabetes,

hypertension, and arthritis, taking rabeprazole, enalapril, felodipine, ramipril, hydrochlorothiazide, and rosiglitazone, developed melena, anemia, and thrombocytopenia; the platelet count was 18  109 per liter. Each drug was screened for drug-mediated immune thrombocytopenia. Rosiglitazone, which had been started 2 weeks before, was the only positive drug. Ten days after withdrawal of rosiglitazone the platelet count resolved and the other therapies were reintroduced without recurrence.

Laboratory tests showed a rosiglitazone-dependent platelet reactive antibody that bound normal platelets in the presence of the drug. Thrombocytopenia has been reported in an adverse drug reaction reporting database as an adverse event in patients taking rosiglitazone (63r). Musculoskeletal Data from A Diabetes Outcome Prevention Trial (ADOPT), in which 4360 patients with type 2 diabetes were randomized to rosiglitazone, metformin, or glibenclamide, have shown an increased number of fractures in women taking rosiglitazone (64C). Upper limb fractures were increased in the humerus and hand and lower limb fractures in the foot. There were 2.74 fractures per 100 patient-years compared with 1.54 in those taking metformin and 1.29 in those taking glibenclamide. There was no difference in hip fractures between the groups. Men taking rosiglitazone did not have an increased fracture rate. Subsequently, the manufacturer of pioglitazone performed an analysis of the available data and also found

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an increased incidence of fractures. The increased risk of fractures in women was reportedly a class effect for thiazolidinediones.

diabetes randomized to 12 weeks of placebo, pioglitazone 45 mg, or one of five doses of tesaglitazar (0.1–3.0 mg/day), one patient taking tesaglitazar 3.0 mg/day developed anemia associated with gastrointestinal bleeding, and another developed neutropenia (0.8  109 per liter); both discontinued therapy (65C). There was a dose-related fall in hemoglobin. Patients were withdrawn when the hemoglobin fell by more than 2 g/ dl. Of those taking tesaglitazar 0.1, 0.5, 1.0, 2.0, and 3.0 mg/day, 0, 2, 6, 16, and 22 patients, respectively, had falls in hemoglobin. In those taking pioglitazone body weight rose by 1.5 kg compared with 1.1 kg in those taking tesaglitazar 0.5 and 1.0 mg/ day and by 2.3 and 2.9 kg in those taking tesaglitazar 2.0 and 3.0 mg/day. Four patients (one taking placebo, one tesaglitazar 0.5 mg/day, and two tesaglitazar 3.0 mg/ day) had asymptomatic increases in creatine kinase activity of between 5 and 10 times the upper limit of normal.

PEROXISOME PROLIFERATORACTIVATED RECEPTOR a/g AGONISTS Tesaglitazar Tesaglitazar is a peroxisome proliferatoractivated receptor (PPAR) a/g agonist. PPARa is expressed in liver, heart, kidney, and skeletal muscle. Placebo-controlled studies In 500 patients aged 30–80 (mean 57) years with type 2

699

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23. Liu KW, Dai LK, Jean W. Metforminrelated vitamin B12 deficiency. Age Aging 2006;35:200–1. 24. Ting RZ-W, Szeto CC, Chan MH-M, Ma KK, Chow KM. Risks factors of vitamin B12 deficiency in patients receiving metformin. Arch Intern Med 2006;166:1975–9. 25. Salem CB, Hmouda H, Slim R, Denguezli M, Belajouza C, Bouraoui K. Rare case of metformin induced leukocytoplastic vasculitis. Ann Pharmacother 2006;40:1685–7. 26. Jothilakshmi PK, Watson AJS, Jude E. Acute alopecia due to metformin treatment for polycystic ovarian syndrome. J Obstet Gynaecol 2006;26:584–5. 27. Gilbert C, Valois M, Koren G. Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis. Fertil Steril 2006;86:658–63. 28. Thatcher SS, Jackson EM. Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin. Fertil Steril 2006;85:1002–9. 29. Kovo M, Weissman A, Gur D, Levran D, Rotmensch S, Glezerman M. Neonatal outcome in polycystic ovarian syndrome patients treated with metformin during pregnancy. J Matern Fetal Neonatal Med 2006;19:415–9. 30. Turner MJ, Walsh J, Byrne KM, Murphy C, Langan H, Farah N. Outcome of clinical pregnancies after ovulation induction using metformin. J Obstet Gynaecol 2006;26:233–5. 31. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes. Systematic review and meta-analysis. JAMA 2007;298:194–206. 32. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DEfor the Sitagliptin Study 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006;29:2632–7. 33. Charbonnel B, Karasik A, Liu J, Wu M, Meininger Gfor the Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006;29:2638–43.

Insulin, other hypoglycemic drugs, and glucagon 34. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein Pfor the Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week multicenter randomized double-blind, placebo-controlled, parallelgroup study. Clin Ther 2006;28:1556–68. 35. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein Pfor the Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 2007;9:733–45. 36. Brazg R, Xu L, Man CD, Cobelli C, Thomas K, Stein PP. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24 hour glycaemic control and b-cell function in patients with type 2 diabetes. Diabetes Obes Metab 2007; 9:186–93. 37. Miller SA, St Onge EL. Sitagliptin: a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Ann Pharmacother 2006;40:1336–43. 38. Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int J Clin Pract 2006;60:1454–70. 39. Bergman AJ, Cote J, Yi B, Marbury T, Swan SK, Smith W, Gottesdiener K, Wagner J, Herman GA. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care 2007;30(7):1862–4. 40. Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007;30:890–5. 41. Nauck MA, Hompesch M, Filipczak R, Le TDT, Zdravkovic M, Gumprecht J. Five weeks of treatment with GLP-1 analogue liraglutide improves glycemic control and lowers body weight in subjects with type 2 diabetes. Exp Clin Endocrinol Diabetes 2006;114:417–23. 42. Marshall V, Wilton L, Shakir S. Safety profile of repaglinide as used in general practice in England: results of a

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702 54. Betteridge DJ, DeFronzo RA, Chilton RJ. PROactive: time for a critical appraisal. Eur Heart J 2008;29(8):969–83. 55. Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, Tan MH, Khan MA, Perez AT, Jacober SJfor the GLAI Study Investigators. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005;28:1547–54. 56. Dormandy JA, Charbonnel B, Eckland DJA, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton Jon behalf of the PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–89. 57. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus. A meta-analysis of randomised trials. JAMA 2007;298:1180–8. 58. Lago MR, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in

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patients with prediabetes and type 2 diabetes given thiazolidinediones: a metaanalysis of randomised clinical trials. Lancet 2007;370:1129–36. Cekmen N, Cesur M, Cetinbas R, Bedel P, Erdemli O. Acute pulmonary edema due to rosiglitazone use in a patient with diabetes mellitus. J Intensive Care Med 2006;21:47–50. Hoffmann TK, Parker DL, Buch HA, Balusu P. Suspected suppression of the INR by thiazolidinediones: interaction between warfarin and TZDs. Ann Pharmacother 2006;40:994–6. Dagdelen S, Gedik O. Rosiglitazone-associated pseudotumour cerebri. Diabetologia 2006;49:207–8. Liu X, Huang T, Sahud MA. Rosiglitazoneinduced immune thrombocytopenia. Platelets 2006;17:143–8. Hauben M, Younus M. Rosiglitazoneinduced immune thrombocytopenia. Platelets 2006;17:591–3. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill C, Zinman B, Viberti Gfor the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427–43. Goldstein BJ, Rosenstock J, Anzalone D, Tou C, Ohman P. Effect of tesaglitazar a dual PPARa/g agonist in patients with type 2 diabetes: a 12 week dose-ranging trial. Curr Med Res Opin 2006;22:2575–90.

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43

Miscellaneous hormones

Calcitonin

(SED-15, 595; SEDA-29, 539; SEDA-30, 507)

Comparative studies Teriparatide (n ¼ 34) and calcitonin 100 IU subcutaneously (n ¼ 29) have been compared in 63 postmenopausal Asian women aged 67.5 years (range 55–85) (1c). All received calcium 500 mg and vitamin D3 (colecalciferol) 400 IU throughout the 6-month study. Among those taking calcitonin there was one serious adverse effect, which was not documented but was not thought to be drug-related. The common adverse effects of calcitonin, dizziness, vasodilatation, and vomiting, were more frequent. Drug formulations Oral salmon calcitonin has been evaluated for 84 days in a rando­ mized placebo-controlled study in 53 patients (median age 67, range 55–80 years; 40 women and 13 men) with osteoarthritis, of whom 41 completed the study (2c). One of 14 who took placebo had headache and flushing compared with four of 13 who took calcito­ nin 0.5 mg/day and three of 14 who took 1 mg/day. Nausea and diarrhea occurred in three patients taking 1 mg of salmon calcito­ nin and in only one patient taking 0.5 mg and one patient taking placebo.

Gonadotropins (gonadorelin and analogues) (SED-15, 1536; SEDA-28, 528; SEDA-29, 539; SEDA-30, 507) The adverse effects of luteinizing hormonereleasing hormone agonists (n ¼ 299) Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03143-2 r 2009 Elsevier B.V. All rights reserved.

compared with those of bilateral orchidect­ omy (n ¼ 132) for prostate cancer have been reviewed (3R). Common adverse events in both groups were pain, lower urinary tract symptoms, and hot flushes. The incidence of hot flushes was higher with goserelin than after bilateral orchidectomy. Before treatment more individuals pre­ ferred to have medical treatment; however, the repeated injections were thought to be reminders of the disease. Endocrine Pituitary apoplexy has pre­ viously been reported in association with the use of gonadotropins and analogues. Two case reports remind us of the associa­ tion. Although pituitary tumors are com­ monly found on MRI scan and at post mortem, this is an infrequent problem, and routine screening before using these drugs is not justified, although the diagnosis should be considered in a patient reporting typical symptoms.  A 70-year-old, man developed a visual distur­

bance 10 days after his first injection of leuprolide 11.25 mg subcutaneously for prostate cancer (4A). An MRI scan showed a 22  26 mm pituitary adenoma. Subsequent histopathology showed a gonadotrophin secreting tumor.  A few hours after receiving leuprolide 30 mg, a 61-year-old man developed severe headache and neck pain (5A). A diagnosis of pituitary apoplexy was not made until 2 days later, when he developed ptosis and diplopia. An MRI scan showed a 20  18 pituitary adenoma, which was removed and found to be gonado­ troph secreting.

Although both these cases were in people with gonadotroph secreting tumors. there have been previous case reports in patients with nonfunctioning tumors. Skin Sterile abscesses have been reported after injection of leuprolide (6A).

703

704  A 72-year-old man who was receiving leupro­

lide 22.5 mg 3-monthly for prostate cancer developed a sterile abscess at the injection site 2.5 months after his third injection. The abscess was incised and drained. The next injection was given at a different site, but testosterone concentrations increased during the subsequent 3 months. A further injection then resulted in another sterile abscess. Testosterone concentrations failed to be sup­ pressed and goserelin was used instead. No further sterile abscesses occurred. However, the testosterone concentrations failed to sup­ press adequately and the patient underwent orchidectomy.

The mechanism of the failure of suppres­ sion in this case was uncertain. The authors suggested that local inflammation could stimulate a humoral response, resulting in antibodies cross-reacting with both leupro­ lide and goserelin. It is important that the response to therapy is monitored even in the absence of an abscess. There have been several previous reports of granulomatous reactions to leuprolide.  A 78-year-old man developed a suppurative

subcutaneous nodule on his right arm where he had received a subcutaneous injection of leuprolide (in a 3-month depot formulation) (7A). He went on to develop similar lesions on his buttock and left arm corresponding to injection sites. Patch, prick, and intradermal testing showed that he responded to the drug, but not when the synthetic polymers were removed.

Biodegradable highly lipophilic synthetic polymer microspheres (polylactic acid) are used to delay the release of leuprolide and are probably responsible for the reaction in this case. Sexual function Gonadorelin analogues can cause erectile dysfunction (8A).  Triptorelin was given to a 64-year-old man

with acute myeloid leukemia (AML-M4) thought to have metastatic prostate cancer. The leukemia improved and he continued to receive monthly triptorelin intramuscularly. Therapy was withdrawn after 1 year because of erectile dysfunction. At that time he felt well and declined further investigation. He was alive and well 4 years later.

Spontaneous remission of acute myeloid leukemia has been documented. However, leukemic cells contain steroid receptors, and the authors

Chapter 43

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suggested that the hormonal changes as a result of taking triptorelin could have had some effect. Reproductive system Goserelin 3.6 mg subcutaneously at least 1 week before the first cycle of chemotherapy for breast cancer was continued 4-weekly, the last injection being given before the last cycle of chemotherapy in 30 women with breast cancer (9c). Patients with hormone recep­ tor-positive tumors also received tamoxifen at the end of chemotherapy and restarted goserelin if menstrual activity occurred within 12 months. It was then continued for a further 2 years. Ovarian function was evaluated in 28 women during the 12 months after chemotherapy. Menstrual function appeared to return in 21. There was a trend towards a slower resumption with age, 2.7 months in those 35 years or under compared with 7.9 months in those 39 years or over. Goserelin therapy during chemotherapy by suppressing gonadal activity may be protective. In 125 premenopausal women (aged 27– 50 years) with adenocarcinoma of the breast goserelin was begun 1 week before che­ motherapy in a dose of 3.6 mg subcuta­ neously 4-weekly for 1 year and then 11.25 mg 12-weekly for 2 years (10c). Che­ motherapy varied depending on the tumor. After a median follow-up period of 75 months, when treatment was withdrawn, all women under the age of 40 years and 56% of those over 40 recovered normal menses. Immunologic There have been reports of systemic hypersensitivity reactions to goser­ elin and leuprolide.  An 8-year-old girl developed anaphylaxis after

a goserelin acetate implant (11A). Her symp­ toms continued for 4 days after the implant was removed. Less severe symptoms recurred 6 weeks later. She had a systemic allergic reaction to leuprolide acetate 3 years before.

The long half-lives of these agents in tissues requires clinicians to be aware of the possibility of continued and recurrent anaphylaxis. Drug formulations Eligards, a formula­ tion of leuprolide acetate, uses the Atrigels

Miscellaneous hormones

Chapter 43

delivery system, in which lyophilized sterile leuprolide acetate is in a second syringe and the two syringes are joined and the contents thoroughly mixed at the time of injection, allowing release of twice the dose of leuprolide as from conventional depot for­ mulations; the product (0.375 ml) is injected subcutaneously using a 19-gauge needle into the upper abdominal quadrants. The system consists of a polymeric formulation (non­ gelatin containing). It is biodegradable, poly-(DL-lactide-co-glycolide) (PLG), and N-methyl-2-pyrrolidone (NMP). The per­ centages vary depending on the formulation. The adverse effects of the 1-month and 3-month formulations were similar to those of other LHRH agonists (3r). The pharmacokinetics of leuprolide in LA-2585, a 6-month subcutaneous depot of leuprolide acetate (Atrix Laboratories), have been evaluated in a 12-month open study in a subset of 28 of 111 patients with prostate cancer (12c). LA-2585 uses the Atrigel delivery system. The mean Cmax was 82 ng/ml, 4.4 hours after the first injec­ tion and 102 ng/ml, 4.8 hours after the second injection. The concentrations then fell from day 3 to day 168. There were 211 adverse events reported by 82 of the 111 patients. The most common were hot flushes (58%), injection site burning (15%), fatigue (12%), testicular atrophy (5%), and gynecomastia (4%).

Somatropin (human growth hormone, hGH) (SED-15, 3163; SEDA-28, 528; SEDA-29, 540; SEDA-30, 508) Observational studies The KIGS database (Pfizer’s international growth database) includes 1909 children born small for gestational age from a number of countries. The adverse effects of growth hormone 0.48 mg/kg/week in children with short stature, born small for gestational age, were examined in 84 patients with a median birth weight of 1.78 kg at a median gestational age of 36.5 weeks (13c). At entry to the study,

705 mean age was 6.6 years and 65% were boys. None of the patients developed impaired glucose tolerance or diabetes mellitus at 1 year. Adverse events were similar in number to those with idiopathic short stature. There were 14 per 1000 serious adverse events compared with 10 in those with idiopathic short stature. Respiratory problems appeared to be more common in those born small for gestational age and endocrine problems more common in those with idiopathic short stature. Reporting of adverse events is variable and underreporting is likely. Cardiovascular Ten children who had received growth hormone for growth fail­ ure, mean age 7.8 years at the time of cardiac transplantation, were compared with eight controls, mean age 4 years at the time of transplantation (14c). The mean age at the time of starting growth hormone was 13 years and the duration of therapy was 2.5 years. Cardiac function was assessed using two-dimensional echocardio­ graphy. Left ventricular shortening fraction and left ventricular mass indexed to body surface area increased significantly from baseline during growth hormone therapy and returned to baseline on withdrawal. Left ventricular end-diastolic volume increased and remained high after with­ drawal of growth hormone. In controls there was no change in left ventricular shortening fraction or mass during the growth spurt, but left ventricular enddiastolic volume increased. The longer-term effects of these differences are not known. Reassuringly, rejection frequency did not alter during the growth hormone-induced or natural growth spurts. There was no difference in the frequency of rejection episodes between the groups, but the numbers were small. Gastrointestinal In a review of the use of growth hormone for adult short bowel syndrome, the authors recommended that patients with bowel cancer should be evaluated to ensure no recurrence and that at least 1 year should have elapsed after treatment (15R). Patients with residual colon should also have colonoscopy before

706 treatment. Patients with acromegaly have an increased risk of colon cancer. Pancreas Pancreatitis has been attributed to growth hormone (16A).  A 6-year-old girl with idiopathic partial growth

hormone deficiency was given growth hor­ mone 25 mg/kg/day and 2 weeks later devel­ oped acute abdominal pain and vomiting. Serum amylase was 1660 U/l and lipase 2736 / l. Pancreatitis was diagnosed, growth hormone was stopped, and she improved with conser­ vative management. Further investigation showed a mitochondrial cytopathy with muta­ tion T3231.

The authors discussed whether pancreatitis had occurred in relation to growth hormone therapy or the mitochondrial disorder. Timing and the lack of previous reports of acute pancreatitis in children with this mutation make growth hormone the more likely cause. Musculoskeletal Monozygotic twins with Turner’s syndrome were given growth hormone therapy at about 13 years of age (17A). Both twins developed slipped capital femoral epiphyses, twin A 16 months after starting, twin B 3 weeks later. Slipped capital femoral epiphysis occurs more com­ monly during growth hormone therapy and is also more common in Turner’s syndrome. It has also been previously described in twins. There are many contributing factors in these cases. Growth hormone was restarted 2 months after hip surgery and continued for a total of 3.5 years. Tumorigenicity The evidence supporting the importance of growth hormone and the somatotrophic axis in the development of cancer has been reviewed (18R). Whether growth hormone replacement is contribu­ tory is uncertain. There has been a retrospective study of 32 subjects, 22 men and 10 women aged 1–51 years at the time of diagnosis of craniopharyngioma(19c). They had received growth hormone for a mean of 6.3 (range 0.8–22) years. Children received 12–20 IU/ m2/week; adults received a dose titration regimen to maintain IGF-1 concentrations within the reference range. The patients

Chapter 43

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were compared with 53 patients who had not received growth hormone. The use of growth hormone did not predict recurrence. Four of those who received growth hormone and 22 of those who did not had tumor recurrence. Susceptibility factors Genetic In a study in Japan, 46 men and 27 women with growth hormone deficiency were randomized to growth hormone or placebo for 24 weeks (20C). The dose was 0.021 mg/kg/week, given as a daily dose subcutaneously, increasing after 4 weeks to 0.042 mg/kg/week and after a further 4 weeks to 0.084 mg/kg/week. The 37 patients who received growth hormone had a mean age of 38 years and those who received placebo 37 years (n ¼ 36). The most common adverse effects related to treatment were those previously reported in other studies: edema (n ¼ 8), arthralgia, and muscle weakness. Two patients who received growth hormone reported serious adverse events: acute gastroenteritis, which was not thought to be drug-related, and sudden deafness, which had not resolved 3 months after withdrawal from the study and was thought to be drug-related. The effects of growth hormone on body composition and lipids were similar to those found in other studies. Sex Growth hormone, adjusted to main­ tain serum IGF-1 concentrations within the reference range, was given for 6 months to 44 men and 44 women matched for age and body mass index (21c). The total daily dose of growth hormone was similar in the men and women but greater per kilogram body weight in women. The most common adverse effect was edema (50% women and 43% men). Body composition was determined by several different methods. Body mass index was reduced in the women; although there was no change in body mass index in the men, the difference was not significant. The sex differences in body composition in response to growth hormone treatment are small and different methods of measurement produce different results. HIV infection Of 25 men and one woman with mean age of 45 years with adult HIV-1

Miscellaneous hormones

Chapter 43

infection treated with HAART studied for 24 weeks, 12 received growth hormone 4 mg/day and 14 received 4 mg three times a week (22c). Adverse events were more common in those who took therapy daily (67%) compared with three times a week (29%). These included edema, myalgia, and arthralgia. In a review of HIV-associated wasting, patients who received growth hormone 0.1 mg/kg/day (about 6 mg/day) most com­ monly reported arthralgia, myalgia, and edema as adverse effects. Those who received alternate-day therapy had similar but less frequent adverse effects (23R). Adverse effects in those with HIV infection appear to be similar to those without and are dose-related in the therapeutic range. Drug formulations Six men and three women, mean age 56 (range 44–65) years received growth hormone replacement therapy for at least 4 months (24c). Mean weight was 89 kg and height 169 cm. The last dose of growth hormone was given 4 weeks before they were given subcuta­ neous LB03002 once weekly into the abdominal wall for 5 weeks. LB03002 is a dry powder consisting of growth hormone incorporated into sodium hyaluronate, which is then dispersed in an oil of medium-chain triglycerides before injec­ tion. Dosing was calculated based on the previous daily dose. The pharmacokinetics and pharmacodynamics were evaluated after the first and fifth injections. The Cmax was 2.7 mg/l for daily growth hormone, 6.1 mg/l after the first dose, and 4.5 mg/l after the fifth dose. The tmax was 3.5 hours for daily growth hormone, 7.5 hours after the first dose, and 15 hours after the fifth dose. The half-life was 5.1 hours for daily growth hormone, 12 hours after the first dose, and 17 hours after the fifth dose. The doseadjusted AUCs were 35 hours mg/l with daily growth hormone, 40 mg/l after the first dose, and 35 hours mg/l after the fifth dose. Five patients reported injection site reac­ tions, which resolved within 1–4 days with­ out intervention. Headaches were reported more often, four during the washout phase and seven while receiving LB03002. Daily injections can lead to poor adherence to

707 therapy, and weekly injections may be useful; however, the consequences of longterm growth hormone given by this method are unknown. Drug administration route Growth hor­ mone was given by a needle-free jet injection system (Medijector, by which growth hor­ mone is pushed into the subcutaneous space under high pressure) to 21 patients who had not previously received growth hormone, mean age 50 (range 20–73) years, and to 34 who had received growth hormone by daily subcutaneous injection, mean age 56 (range 25–80) years (25c). At 12 months, bruising was reported as occurring sometimes in 31% and often in 8%. At 24 months, bruising occurred with similar frequencies (33% sometimes and 9% often). IGF-1 and growth hormone concentrations increased in those who had not previously received therapy and remained stable in those who had. The authors did not report which device was preferred.

Growth hormone receptor antagonists (SEDA-28, 529; SEDA-30, 510) Liver Pegvisomant has been associated with liver damage (26A).  A 45-year-old man with acromegaly, who had

received monthly intramuscular injections of octreotide LAR 30 mg for 6 months, was given pegvisomant 60 mg subcutaneously weekly. At the start liver function was normal, but 5 months later the alkaline phosphatase activity increased to 149 /l, a~ ­ glutamyl transpeptidase to 372 U/l, aspartate transaminase to 467 U/l, and alanine transa­ minase to 1148 /l. Within 2 months of stop­ ping pegvisomant, while continuing octreotide LAR, liver function normalized. He was rechallenged with pegvisomant 20 mg daily, 2 months after stopping octreotide. Liver function became abnormal within 6 weeks and returned to normal within a few weeks of withdrawal.

This adverse effect appears to be unrelated to dose in the therapeutic range and can occur several months after the start of therapy.

708 Regular monitoring of liver function is advised in patients receiving pegvisomant.

Melatonin

(SED-15, 2245; SEDA-28, 531; SEDA-29, 542)

Melatonin has been given by different routes, including oral, intranasal, intrave­ nous, and transdermal. It is metabolized in the liver to hydroxymelatonin and 6-sulfa­ toxymelatonin, which are excreted in the urine. Very little unmetabolized melatonin is excreted. In the blood 50–75% of melatonin is bound reversibly to albumin and glycoproteins (27R, 28R). The role of melatonin in the management of disease remains to be established. There is little information about long-term adverse effects. Adverse effects associated with melatonin include drowsiness, fatigue, and headache. These effects were more likely at daily doses of 5 mg to 1 g compared with lower doses (0.5–1 mg/day). Although rare, doses of 10 mg/day or less have been associated with hypertension, nightmares, fits, constipation, and autoimmune hepatitis(29R). Gastrointestinal In an animal model of colitis, melatonin 2 mg/kg for 21 days worsened the colitis (27R). Drug–drug interactions Hormonal contraceptives Melatonin concentrations were measured 1.5 hours after melatonin 6 mg orally in 24 subjects; five were using hormonal contraceptives and had a signifi­ cantly higher concentration of melatonin (9.8 ng/ml) compared with 19 non-users (3.4 ng/ml) (30c).

Oxytocin and analogues

(SED-15, 2657; SEDA-28 531; SEDA-30, 511)

Comparative studies Carbetocin, a longacting oxytocin analogue, and syntometrine have been compared in a double-blind, randomized, controlled trial in 329 women with primary postpartum hemorrhage (31C). There were no differences in the fall in hemoglobin concentration in the first

Chapter 43

R.C.L. Page

48 hours, in the need for additional oxytocin, or the incidences of postpartum hemorrhage or retained placenta. Carbetocin was associated with significantly less nausea (RR ¼ 0.18; 95% CI ¼ 0.04, 0.78), vomiting (RR ¼ 0.1; 95% CI ¼ 0.01, 0.74), hypertension at 30 minutes (0 versus 8 cases) and 60 minutes (0 versus 6 cases) after delivery; however there was a higher incidence of maternal tachycardia (RR ¼ 1.68; 95% CI ¼ 1.03, 3.57). Oral misoprostol and intramuscular synto­ metrine have been compared in the manage­ ment of the third stage of labor in a doubleblind, randomized, controlled trial in 355 women (32C). There were no significant differences in hemoglobin concentrations and mean blood loss. Shivering was significantly more common with misoprostol and vomiting with syntometrine, but there were no differ­ ences in the incidences of nausea, headache, diarrhea, or pyrexia. Immunologic Anaphylaxis attributed to oxytocin (33A).

has

been

 Anaphylactic shock occurred in a 32-year-old

multigravida during elective cesarean section for partial placenta previa, when methylergo­ metrine was given intravenously and oxytocin was injected directly into the uterine muscle. She developed dyspnea and became agitated. Her systolic blood pressure fell to 50 mmHg and oxygen saturation to 87% even with 100% inspired oxygen. After a catecholamine infusion her respiratory function improved. Later serological tests were negative but skin tests showed that she was allergic to both drugs.

Pregnancy Intrapartum rupture of an unscarred uterus is uncommon, and is usually associated with factors such as high multiparity, malpresentation, a history of gestational trophoblastic disease, or instru­ mented delivery. Rupture during a first pregnancy is extremely rare but has been reported in the context of a high dosage of oxytocin (34A).  A 30-year-old primigravida was given oxytocin

during labor at 40.5 weeks. The infusion rate was increased during the first and second stages of labor, despite contractions about every 2 minutes. The uterus ruptured during the second stage and cesarean section was per­ formed. The baby was severely asphyxiated.

Miscellaneous hormones

Chapter 43

Acute severe pulmonary edema occurred postpartum in a 26-year-old primigravida who had been given oxytocin by infusion for induction of labor and to prevent postpartum hemorrhage (35A). The use of oxytocin in labor in women with cardiac disease is controversial. Some prefer not to use it, because it can cause profound falls in systemic vascular resistance, blood pressure, and cardiac output, increased pulmonary vascular resistance, and tachydysrhythmias (36A). At least one maternal death has been attributed to intravenous oxytocin in such circumstances (37S). However, others believe that the risks of not using it are greater than those of giving it (38r).

Thyrotropin-releasing hormone and thyrotropin See Chapter 41.

Parathyroid hormone

(SED-15, 2689; SEDA-28, 531; SEDA-29, 542)

Mineral balance Hypercalcemia occurred in 6% of Asian postmenopausal women receiving teriparatide 20 mg/day (n ¼ 34) compared with none of those who received calcitonin (n ¼ 29). All were taking elemental calcium 500 mg/day and vitamin D 400 IU/day (39c). Reviews have suggested that hypercalcemia is not a major problem, but that serum calcium should be measured 16 or more hours after parathormone injection within 1 month of starting therapy (40R, 41R). When hypercalcemia occurs, it usually resolves when calcium supplementation is reduced. Tumorigenicity In two reviews of teripara­ tide (PTH 1–34) and parathyroid hormone (PTH 1–84) the finding of osteosarcoma in rats receiving high doses of teriparatide or PTH 1–84 for prolonged periods has been discussed (40R, 41R). There are no compar­ isons of the two drugs. There have been no reports of osteosarcoma in humans. Rat bone continues to accrue throughout life and its different biology is likely to explain the observation.

709

Somatostatin (growth hormone release-inhibiting hormone) and analogues (SED-15, 3160; SEDA-28, 530; SEDA-29, 541; SEDA-30, 510) Biliary tract Six of 15 boys with tall stature, mean age 12 years, who had received somatostatin analogue 201–995 subcutaneously reported abdominal discomfort (42c). Three had asymptomatic microlithiasis of the gallbladder. The initial dose was 0.05 mg in the evening in prepubertal boys and 0.15 mg in pubertal boys. Dosing was increased but was limited by adverse effects.

Octreotide

(SEDA-30, 510)

Cardiovascular Bradycardia and hypotension have been attributed to octreotide (43A).  A 39-year-old man with no history of diabetes

mellitus presented with diabetic ketoacidosis. Acromegaly was diagnosed and he was given octreotide 50 mg subcutaneously tds, increasing to 300 mg /day after 4 days. Bradycardia (45/minute) and hypotension (70/40 mmHg) developed on day 7. The dose of octreotide was reduced to 150 mg /day but the bradycardia persisted and octreotide was withdrawn.

In patients with postural tachycardia syndrome and orthostatic intolerance octreotide 0.9 mg /kg subcutaneously 8 min­ utes before testing reduced heart rates from a mean of 114 to 91 in those with postural tachycardia syndrome (n ¼ 9) and from 100 to 85 in those with orthostatic intoler­ ance (n ¼ 6) (44c). Bradycardia and possi­ ble mechanisms have previously been reviewed (SEDA-29, 541). Gastrointestinal The gastrointestinal adverse effects of octreotide have been well documented. Studies in patients using octreotide for a variety of indications continue to report similar effects. Seven of 23 patients using octreotide therapy for postural tachycardia syndrome or ortho­ static intolerance reported nausea, vomiting, abdominal cramps, or diarrhea (44c).

Chapter 43

710 Of 34 patients mean age 50 years with acromegaly using octreotide LAR 20 mg every 28 days for 12 weeks and then 30 mg every 28 days, 27% reported diarrhea, 21% abdominal pain, 15% steatorrhea, 9% flatulence, and 9% biliary disorders (45c). In 172 adults (28 men and 144 women) rando­ mized to receive placebo or octreotide LAR 20, 40, or 60 mg monthly for 6 months for weight loss, diarrhea occurred in 36% of those receiving 20 mg, 29% of those receiv­ ing 40 mg, and 30% of those receiving 60 mg compared with 18% of those who received placebo (46C). Octreotide has been used as a treatment for patients with severe dumping symptoms. Of 34 patients only 14 were still using it after a mean of 7.5 years; seven withdrew because of lack of efficacy and nine because of adverse effects (five with diarrhea) (47c).

R.C.L. Page

Electrolyte balance The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has removed primary nocturnal enuresis as an indication for desmopressin spray products. About 15 cases of hyponatremia have been reported per 100 000 patient-years, compared with five cases associated with oral desmopressin (50S). Most cases were in patients under 18 years who were using it for primary nocturnal enuresis. The following advice was also given: all patients with primary nocturnal enuresis should start therapy at the lowest recommended dose and only increase if it is necessary to achieve symptom control; advice about fluid intake should be carefully followed. Hematologic Thrombotic thrombocytopenic purpura has been attributed to desmopressin (51A).  A 6-year-old Haitian child with Upshaw–

VASOPRESSIN AND ANALOGUES (SED-15, 3609; SEDA28, 531; SEDA-29, 542; SEDA-30, 511)

Gastrointestinal The role of vasopressinin splanchnic hypoperfusion has been reviewed (48R). High doses reduce gastrointestinal blood flow, which can lead to gut ischemia. Animal studies on terlipressin have suggested that adequate volume resuscitation is important, and that there is reduced splanchnic blood flow when resuscitation is inadequate.

Desmopressin (N-deamino-8-Darginine vasopressin, DDAVP) (SED-15, 1076; SEDA-29, 543; SEDA-30, 512) Ear, nose, and throat The effect of DDAVP nasal spray on nasal cytology and mucociliary clearance has been investigated for 6 months in 22 children aged 6–16 years (49c). The children were taking 10–40 mg each night for primary nocturnal enuresis. No statistically significant effects were found.

Schulman syndrome had episodes of throm­ botic thrombocytopenic purpura. Her mother had been giving her DDAVP for enuresis. No further relapses occurred after withdrawal of desmopressin.

Drug formulations A new oral lyophilisate formulation of desmopressin has been eval­ uated in a double-blind, randomized, parallelgroup study in 84 children with primary nocturnal enuresis, mean age 9 years (52C). The formulation is wafer-like and dissolves instantly in the mouth. Desmopressin was given in doses of 30, 60, 120, 240, 360, or 480 mg as a single dose. There were 24 adverse events in 15 patients. Two were considered serious, with diuresis remaining under 0.13 ml/minute until 29 hours after dosing. It was suggested that this could not be explained by pharmacokinetic mechanisms but was likely to be due to higher insensible losses of water compared with intake.

Terlipressin

(SEDA-29, 44;

SEDA-30, 512) Observational studies The adverse effects of terlipressin in hepatorenal syndrome have been confirmed in a review of 154 pooled patients, of whom 22 had abdominal

Miscellaneous hormones

Chapter 43

pain, three self-limiting cardiac dysrhythmias, and three cutaneous necrosis (53c). While cutaneous necrosis has been reported with terlipressin in septic shock, abdominal pain has not. Cardiovascular The adverse effects of terlipressin in septic shock have been

711 reviewed (54R). Reduced cardiac index and heart rate and increased pulmonary vascular resistance have been reported. Reduced oxygen delivery and utilization can occur. The dose was 1–2 mg as an intravenous bolus for 1 or 2 doses, which is similar to the dose used in hepatorenal syndrome.

References 1. Hwang JS, Tu St, Yang TS, Chen JF, Wang CJ, Tsai KS. Teriparatide vs calcitonin in the treatment of Asian postmenopausal women with established osteoporosis. Osteoporosis Int 2006;17:373–8. 2. Manicourt D-H, Azria M, Mindeholm L, Thonar E J-M, Devogelaer J-P. Oral salmon calcitonin reduces Lequesne’s algo­ functional index scores and decreases urin­ ary and serum levels of biomarkers of joint metabolism in knee osteoarthritis. Arthritis Rheum 2006;54:3205–11. 3. Tombal B, Berges R. Eligards: advantages for optimal testosterone control. Eur Urol Suppl 2006;5:900–4. 4. Massoud W, Paparel P, Lopez J-G, Perrin P, Daumont M, Ruffion A. Discovery of a pituitary adenoma following treatment with a gonadotropin-releasing hormone agonist in a patient with prostate cancer. Int J Urol 2006;13:87–8. 5. Davis A, Goel S, Picolos M, Wang M, Lavis V. Pituitary apoplexy after leuprolide. Pituitary 2006;9:263–5. 6. Daskivich TJ, Oh WK. Failure of gonadotropin-releasing hormone agonists with and without sterile abscess formation at depot sites: insight into mechanisms. Urology 2006;67:1084 e15–e17 7. Ferran M, Giménez-Arnau A, Toll A, Yébenes M, Baena V, Lloreta J, Pujol RM. Depot leuprorelin acetate-induced granulo­ mas manifested as persistent supporative nodules. Acta Derm Venereol 2006;86: 453–5. 8. Tsavaris N, Kopterides P, Kosmas C, Siakantaris M, Patsouris E, Pangalis G. Spontaneous remission of acute myeloid

9.

10.

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leukaemia associated with GnRH agonist treatment. Leuk Lymph 2006;47:557–60. Del Mastro L, Catzeddu T, Boni L, Bell C, Sertoli MR, Bighin C, Clavarezza M, Testa D, Venturini M. Prevention of chemotherapyinduced menopause by temporary ovarian suppression with goserelin in young, early breast cancer patients. Ann Oncol 2006; 17:74–8. Recchia F, Saggio G, Amiconi G, Di Blasio A, Cesta A, Candeloro G, Rea S. Gonado­ tropin-releasing hormone analogues added to adjuvant chemotherapy protect ovarian function and improve clinical outcomes in young women with early breast carcinoma. Cancer 2006;106:514–23. Lam C, Tjon J, Hamilton J, Ahmet AH. Recurrent anaphylaxis associated with gonadotropin-releasing hormone analogs: case report and review of the literature. Pharmacology 2006;26:1811–5. Crawford ED, Sartor O, Chu F, Perez R, Karlin G, Garrett JS. A 12-month clinical study of LA-2585 (45.0 MG): a new 6-month subcutaneous delivery system for leuprolide acetate for the treatment of prostate cancer. J Urol 2006;175:533–6. Cutfield WS, Lindberg A, Rapaport R, Wajnrajch MP, Saenger P. Safety of growth hormone treatment in children born small for gestational age: the US trial and KIGS analysis. Horm Res 2006;65 (Suppl 3):153–9. Mital S, Andron A, Lamour JM, Hsu DT, Addonizio LJ, Softness B. Effects of growth hormone therapy in children after cardiac transplantation. J Heart Lung Transplant 2006;25:772–7.

712 15. Steiger E, DiBaise JK, Messing B, Matarese LE, Blethen S. Indications and recommen­ dations for the use of recombinant human growth hormone in adult short bowel syndrome patients dependent on parenteral nutrition. J Clin Gastroenterol 2006;40: S99–106. 16. De Beaufort C, Beck P, Seligmann R, de Meirleir L, de Schepper J. Acute pancrea­ titis after growth hormone treatment: dis­ ease or treatment linked? Eur J Pediatr 2006;165:652–3. 17. Nabhan ZM, Eugster EA. Monozygotic twins with turner syndrome develop slipped capital femoral epiphysis on growth hormone therapy. Pediatrics 2006; 118:e1900–3. 18. Perry JK, Emerald BS, Mertani HC, Lobie PE. The oncogenic potential of growth hormone. Growth Horm IGF Res 2006; 16:277–89. 19. Karavitaki N, Warner JT, Marland A, Shine B, Ryan F, Arnold J, Turner HE, Wass JAH. GH replacement does not increase the risk of recurrence in patients with craniopharyngioma. Clin Endocrinol 2006;64:556–60. 20. Chihara K, Kato Y, Kohono H, Takano K, Tanaka T, Teramoto A, Shimatsu A. Efficacy and safety of growth hormone (GH) in the treatment of adult Japanese patients with GH deficiency: a randomised placebo-controlled study. Growth Horm IGF Res 2006;16:132–42. 21. Koranyi J, Bosaeus I, Alpsten M, Bengtsson B-A, Johannsson G. Body composition during GH replacement in adults – metho­ dological variations with respect to gender. Eur J Endocrinol 2006;154:545–53. 22. Bickel M, Zangos S, Jacobi V, Lutz T, Goebel F, Staszewski S, Klauke S. A randomised open-label study to compare the effects of two different doses of recombinant human growth hormone on fat reduction and fasting metabolic para­ meters in HIV-1-infected patients with lipodystrophy. HIV Med 2006;7(6): 397–403. 23. Goldsmith DR, Wagstaff AJ. Mammalian cell-derived somatropin. A review of its use in the management of HIV-associated wasting. Drugs 2006;66:387–401.

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24. Bidlingmaier M, Kim J, Savoy C, Kim MJ, Ebrecht N, de la Motte S, Strasburger CJ. Comparative pharmacokinetics and phar­ macodynamics of a new sustained-release growth hormone (GH), LB03002, versus daily GH in adults with GH deficiency. J Clin Endocrinol Metab 2006;91:2926–30. 25. Pereira AM, van der Klaauw AA, Kop­ peschaar HPF, Smit JWA, van Thiel SW, van Doorn J, Biermasz NR, Roelfsema F, Romijn JA. Efficacy of needle-free admin­ istration of recombinant human growth hormone in adults with growth hormone deficiency. Br J Clin Pharmacol 2006;61(4): 451–5. 26. Feenstra J, van Aken MO, de Herder WW, Feelders RA, van der Lely AJ. Druginduced hepatitis in an acromegalic patient during combined treatment with pegviso­ mant and octreotide long-acting repeatable attributed to the use of pegvisomant. Eur J Endocrinol 2006;154:805–6. 27. Giannoulia-Karantana A, Vlachou A, Poly­ chronopoulou S, Papassotiriou I, Chrousos GP. Melatonin and immunomodulation: connections and potential clinical applica­ tions. Neuroimmunomodulation 2006;13: 133–44. 28. Jung B, Ahmad N. Melatonin in cancer management: progress and promise. Cancer Res 2006;66:9789–93. 29. Fitzpatrick A. Melatonin in health and disease. Alternative and complementary therapies 2006;12:282–91. 30. Hartter S, Korhonen T, Lundgren S, Rane A, Tolonen A, Turpeinen M, Laine K. Effect of caffeine intake 12 or 24 hours prior to melatonin intake and CYP1A2�1F poly­ morphism on CYP1A2 phenotyping by melatonin. Basic Clin Pharmacol Toxicol 2006;99:300–4. 31. Leung SW, Ng PS, Wong WY, Cheung TH. A randomised trial of carbetocin versus syntometrine in the management of the third stage of labour. BJOG 2006;113(12): 1459–64. 32. Ng PS, Lai CY, Sahota DS, Yuen PM. A double-blind randomized controlled trial of oral misoprostol and intramuscular synto­ metrine in the management of the third stage of labor. Gynecol Obstet Invest 2007; 63(1):55–60.

Miscellaneous hormones

Chapter 43

33. Shimo T, Nishiike S, Masuoka M, Seki S, Tsuchida H. [Intraoperative anaphylactic shock induced by methylergometrine and oxytocin]. Masui 2006;55(4):447–50. 34. Catanzarite V, Cousins L, Dowling D, Daneshmand S. Oxytocin-associated rupture of an unscarred uterus in a primigravida. Obstet Gynecol 2006;108(3 Pt 2):723–5. 35. Ghai B, Vayjnath AM, Lal S. Acute pulmonary oedema following oxytocin administration: a life threatening complica­ tion. J Indian Med Assoc 2006;104(5): 261–2. 36. Hamlyn EL, Douglass CA, Plaat F, Cro­ whurst JA, Stocks GM. Low-dose sequential combined spinal-epidural: an anaesthetic technique for caesarean section in patients with significant cardiac disease. Int J Obst Anesth 2005;14:355–61. 37. Lewis G, Drife J. Why mothers die 1997– 1999. The fifth report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. London: RCOG Press; 2001. 38. Tamhane P, O’Sullivan G, Reynolds F. Oxytocin in parturients with cardiac dis­ ease. Int J Obstet Anesth 2006;15(4): 332–3. 39. Hwang JS, Tu St, Yang TS, Chen JF, Wang CJ, Tsai KS. Teriparatide vs calcitonin in the treatment of Asian postmenopausal women with established osteoporosis. Osteoporosis Int 2006;17:373–8. 40. Wagman RB, Miller PD. The use of teriparaide and PTH(1-84) for the treat­ ment of osteoporosis. Clin Rev Bone Mineral Metab 2006;4:277–90. 41. Girotra M, Rubin MR, Bilezikian JP. The use of parathyroid hormone in the treatment of osteoporosis. Rev Endocr Metab Disord 2006;7:113–21. 42. Noordam C, van Daalen S, Otten BJ. Treatment of tall stature in boys with somatostatin analogue 201–995: effect on final height. Eur J Endocrinol 2006;154: 253–7. 43. Erem C, Ersoz HO, Ukinc K, Avunduk AM, Hacihasanoglu A, Kocak M. Acrome­ galy presenting with diabetic ketoacidosis, associated with retinitis pigmentosa and octreotide-induced bradycardia. Endocrine 2006;30:145–9.

713 44. Hoeldtke RD, Bryner KD, Hoeldtke ME, Hobbs G. Treatment of postural tachycar­ dia syndrome: a comparison of octreotide and midodrine. Clin Autonom Res 2006; 16:390–5. 45. Colao A, Pivonello R, Rosato F, Tita P, De Menis E, Barreca A, Ferrara R, Mainini F, Arosio M, Lombardi G. First-line octreo­ tide-LAR therapy induced tumour shrinkage and controls hormone excess in patients with acromegaly: results from an open, prospective, mulicentre trial. Clin Endocri­ nol 2006;64:342–51. 46. Lustig RH, Greenway F, Velasquez-Mieyer P, Heimburger D, Schumacher, Smith D, Smith W, Soler N, Warsi G, Berg W, Maloney J, Benedetto J, Zhu W, Hohneker J. A multicenter, randomised, double blind, placebo controlled , dose finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion. Int J Obesity 2006; 30:331–41. 47. Didden P, Penning C, Masclee AM. Octreo­ tide therapy in dumping syndrome: analysis of long-term results. Aliment Pharmacol Ther 2006;24:1367–75. 48. Krismer AC, Dunser MW, Lindner KH, Stadlbauer KH, Mayr VD, Lienhart HG, Arntz RH, Wenzel V. Vasopressin during cardiopulmonary resuscitation and different shock states. A review of the litera­ ture. Am J Cardiovasc Drugs 2006;6: 51–68. 49. Akoglu E, Gorur S, Atik E, Okuyucu S, Sangun O. Effect of 1-deamino 8-D-arginine vasopressin spray on nasal cytology and mucociliary clearance in patients with noc­ turnal enuresis. Int J Pediatr Otorhinolaryn­ gol 2006;70:1919–22. 50. Medicines and Healthcare products Regu­ latory Agency. Desmopressin nasal spray: removal of nocturnal enuresis indication. Drug Safety Update 2007;1(2):7. 51. Veyradier A, Meyer D, loirat C. Desmopres­ sin an unexpected link between nocturnal enuresis and inherited thrombotic thrombocytopenic purpura (Upshaw-Schulman syn­ drome). J Thromb Haemost 2006;4: 700–1. 52. Van de Walle JGJ, Bogaert GA, Mattsson S, Schurmans T, hoebeke P, Deboe V,

714 Norgaard JP. A new fast-melting oral formulation of desmopressin: a pharmaco­ dynamic study in children with nocturnal enuresis. BJU Int 2006;97:603–9. 53. Fabrizi F, Dixit V, Martin P. Meta-analysis: terlipressin therapy for the hepatorenal

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syndrome. Aliment Pharmacol Ther 2006; 24:935–44. 54. Pesaturo AB, Jennings HR, Volis SA. Terlipressin: vasopressin analog and novel drug for septic shock. Ann Pharmacother 2006;40:2170–7.

I. Aursnes

44

Drugs that affect lipid metabolism

Ezetimibe

(SED-15, 1308; SEDA-28, 534; SEDA-29, 546; SEDA-30, 515)

Drug–drug interactions The long-term safety and efficacy of co-administering fenofibrate 160 mg/day and ezetimibe 10 mg/day has been investigated in a randomized, double-blind study in 576 patients with mixed hyperlipidemias compared with fenofibrate alone (1C). Both treatments were well tolerated. Consecutive rises in serum transaminase activities to more than three times the upper limit of normal were similar between the fenofibrate plus ezetimibe (1.2%) and fenofibrate (1.7%) groups. There were no rises in creatine kinase activity to more than 10 times the upper limit of normal and no cases of myopathy.

supported by a retrospective analysis of results from 50 randomized clinical trials of the use of atorvastatin in 5924 patients over 65 years of age (4M). However, since cerivastatin had to be withdrawn in 2001, because of an unacceptable frequency of rhabdomyolysis, it is best to be on guard. It is especially important to watch new drugs on the market (such as rosuvastatin) and to follow signals from spontaneous reporting of possible major adverse effects of older drugs. Differences between statins Some adverse effects may be related to specific statins, for instance, due to different degrees of lipid solubility and brain penetrability. In contrast to pravastatin, simvastatin, which is more lipid-soluble, significantly increased the activity of phospholipid transfer protein in the cerebrospinal fluid in 10 patients with hypercholesterolemia aged 34–87 years (5c).

HMG-CoA reductase inhibitors (SED-15, 1632; SEDA-28, 535; SEDA-29, 547; SEDA-30, 516) Statins have the reputation of ending the controversy over the lipid hypothesis of atherosclerosis, with claims that the range of adverse effects is minuscule (2r). A meta­ analysis of four high-dose statin therapy studies has shown that there is hardly any increase in severe adverse event rates in relation to dose (3M). This has been Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03144-4 r 2009 Elsevier B.V. All rights reserved.

Pancreas A systematic review of observa­ tional studies and spontaneous case reports has shown that therapy with statins can cause acute pancreatitis (6M).

DoTS classification: Reaction: Acute pancreatitis Dose-relation: Collateral or hypersusceptibility Time-course: Intermediate or delayed Susceptibility factors: None identified Altogether 20 published case reports and 33 spontaneous reports from the Canadian Adverse Drug Event Monitoring

715

716 System (CADRMP) database were identi­ fied. Two observational studies yielded an odds ratio of 1.41 (95% CI ¼ 1.15, 1.74) for the risk of acute pancreatitis in patients with a past history of exposure to statins. However, pancreatitis is relatively rare, with a quoted annual incidence varying up to 80 per 100 000 population. The data showed that pancreatitis can occur at both high and low doses; 12 patients developed pancreatitis at less than the dose equivalent of simvastatin 20 mg/day. Statin-induced pancreatitis can occur at any time but seems to be very uncommon early on and more likely to occur after many months of therapy. Its mechanism is unknown. Musculoskeletal Myopathy leading to rhabdomyolysis is a rare adverse effect of the statins, occurring in under 0.1% of patients (7r). The mortality rate is about 0.15 deaths per million prescriptions. How­ ever, the FDA has cited a mortality rate of 7.8% in patients with rhabdomyolysis (11r).

DoTS classification: Reaction: Myopathy and rhabdomyolysis due to statins Dose-relation: Collateral Time-course: Intermediate Susceptibility factors: Drug interactions (e.g., with fibrates); trauma and physical exertion Efforts have been made to compare the risk of rhabdomyolysis with the various statins, besides the well-recognized high risk with cerivastatin that led to its withdrawal. One report has stated that although data may indicate that atorvastatin is safer than simvastatin in the presence of risk factors, the data also suggest that there is a greater risk of rhabdomyolysis associated with ator­ vastatin in the absence of risk factors (8r). Trauma is a well-recognized risk factor for statin-induced rhabdomyolysis. That physical exertion can lead to localized rhabdomyolysis is a new observation (9A).  A 22-year-old man developed an acutely

swollen, tender left arm 2 years after orthotopic

Chapter 44

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cardiac transplantation. There was no history of trauma, but he had undertaken weighttraining four times during the preceding week. There was a marked increase in creatine kinase activity (5300 U/l). Pravastatin 40 mg/day, which he had taken since the transplantation, was withdrawn. Within 3 days the creatine kinase activity had fallen to 1200 U/l and the arm had returned to its normal size.

Drug–drug interactions Clopidogrel The evidence for and against a clinically impor­ tant interaction between clopidogrel and statins has been summarized (SEDA-30, 517). This interaction, thought to be mediated by competition for CYP3A4, is important, because these drugs are often taken by the same patients. It has been suggested that there is no such interaction, and that we have been misled by studies using inappropriate methods of platelet function assessment (10r). On the other hand, an observational study with clinical endpoints has not ruled out the possibility of an interaction (11c). As recorded in the administrative databases of the Province of Quebec, 2927 patients took clopidogrel after percutaneous coronary intervention. The odds ratio of a composite cardiovascular outcome within 30 days was 1.65 (95% CI ¼ 1.07, 2.54) for patients who took atorvastatin with clopidogrel compared with those who did not take atorvastatin. Because of the limitations of observational study designs, the clinical significance of this putative drug interaction remains uncertain but merits further investigation. Amiodarone A case report has suggested a significant interaction of simvastatin with amiodarone (12A).  A 72-year-old white man with diabetes melli­

tus, hyperlipidemia, hypertension, and mild uremia developed thigh weakness, aches, and dark urine for 7 days. Amiodarone 200 mg/day had been started 3 days after coronary artery bypass and 1 month later simvastatin 80 mg/ day. On admission the serum creatine kinase activity was 19 620 U/l (reference range 60– 224), blood urea nitrogen 18 mmol/l (50 mg/ dl), creatinine 230 mmol/l (2.6 mg/dl), aspartate transaminase (AsT) activity 912 U/l (30–60), alanine transaminase (AlT) activity 748 U/l (30–60), urine myoglobin 71 100 mg/l (o50), and serum myoglobin 13 877 mg/l (o110). Simvastatin and amiodarone were withdrawn

Drugs that affect lipid metabolism

Chapter 44

717

and the patient was hydrated with forced alkaline diuresis. After 13 days his creatine kinase activity was 323 U/l, creatinine 150 mmol/l (1.7 mg/dl), AlT 145 U/l, and AsT 37 U/l.

cholesterol fell significantly after withdra­ wal of phenytoin (15A).

Amiodarone suggests that and possibly related to an simvastatin.

inhibits CYP3A4. This case rhabdomyolysis, renal failure, hepatotoxicity were probably interaction of amiodarone with

Colchicine Severe rhabdomyolysis devel­ oped after a patient taking regular colchi­ cine took atorvastatin (13Ar).

 A 61-year-old man with familial hypercholes­

terolemia was taking aspirin 81 mg/day, fosi­ nopril 20 mg/day, phenobarbital 200 mg/day, and phenytoin 500 mg/day. As he had been seizure-free for over 15 years, the phenytoin was withdrawn, whereupon the low density lipoprotein cholesterol fell by 50%.

Quinine Quinine inhibits CYP3A4. Acute nausea, vomiting, diarrhea, and abdominal pain occurred in a 54-year-old woman after she took quinine 300 mg with atorvastatin 20 mg/day (16A).

 A 45-year-old man with nephrotic syndrome

and amyloidosis developed dyspnea, altered thinking, and severe fatigue. He had been taking colchicine 1.5 mg/day for amyloidosis for 3 years without adverse effects. Ator­ vastatin 10 mg/day was prescribed for hypercholesterolemia, and after 2 weeks he began to have myalgia and reduced muscle strength. The creatinine concentration and creatine kinase activity were 716 mmol/l and 9035 U/l, respectively. His muscle strength improved after withdrawal of atorvastatin and colchicine.

Despite atorvastatin’s proven safety, its use with certain drugs, such as colchicine, makes it potentially myotoxic. This might be because concomitant administration of P glycoprotein substrates, such as statins, and colchicine, which is a P glycoprotein inhibitor, increases the systemic availability and organ uptake of the substrates, leading to more adverse reactions. Nelfinavir Contrary to previous belief (SED-15, 1636) there is a negative interac­ tion between pravastatin and the HIV protease inhibitor nelfinavir (14c). There was a median reduction of 47% in pravas­ tatin AUC when 14 patients took nelfinavir 1250 mg bd. Phenytoin Phenytoin induces CYP3A4 and can reduce the systemic availability and thus the efficacy of statins that are metabolized by this enzyme, including atorvastatin and lovastatin. In a patient taking multiple lipid-lowering medications, including high-dose atorvastatin, the LDL

Fluvastatin Liver It has been debated whether HMGCoA reductase inhibitors can occasionally cause liver damage (SEDA-30, 516). DoTS classification: Reaction: Hepatitis and cholestatic hepatitis Dose-relation: Toxic Time-course: Intermediate Susceptibility factors: Sex (women taking fluvastatin) Pre- and postmarketing studies have shown rises in hepatic transaminase activity in 0.1– 3%. However, it is still unclear whether serious hepatic reactions are dose-related and occur more often than expected in the general population. The Italian Interregional Group of Pharmacovigilance (Gruppo Interregionale di Farmacovigilanza (GIF)) looks for signals in the Italian spontaneous ADR reporting system (17c). By December 31, 2004, the GIF had received 1260 reports of ADRs related to statins, including 178 of hepatic reactions; 69 were attributed to fluvastatin. Fluvastatin was associated with 33 serious reactions, mainly hepatitis and cholestatic hepatitis. The number of reports of severe hepatotoxicity associated with fluvastatin started to increase from 2002. About half of them did not report other

718 suspected or concomitant drugs and in onethird the hepatotoxicity occurred after less than 1 month of therapy. Of the 33 patients 27 were women, and the dose of fluvastatin was 80 mg/ day in 81% of the cases in whom complete data on drug dosages were available. This is a preliminary signal; further evaluation is needed to confirm it and to quantify the risk. Urinary tract Concerns have recently been raised regarding a potential harmful effect of statins on renal function. The effect of fluvastatin on renal function has been investigated in renal transplant reci­ pients enrolled in the Assessment of Lescol in Renal Transplantation (ALERT) trial (18C). This was a randomized, double-blind, placebo-controlled study in 1102 patients of the effect of fluvastatin 40–80 mg/day. Flu­ vastatin had no significant effect compared with placebo on renal function, assessed by serum creatinine, creatinine clearance, or proteinuria. An analysis of adverse events has also been performed on data from 30 completed clinical trials of fluvastatin in 11 815 patients (19M). Changes in creatinine clearance and serum creatinine from baseline were similar in fluvastatin-treated patients and placebotreated patients.

Rosuvastatin Although all safety and tolerability data obtained from phase II and phase III clinical studies of rosuvastatin have shown a profile in line with other statins, a

Chapter 44

I. Aursnes

pharmacoepidemiology program in three parts (studies of patient characteristics, safety evaluation, and prescription-event monitoring) has been implemented in order to monitor adverse events with rosuvastatin, planned to assess 500 000 patients (20S). Comparative studies A randomized, open, 16-week trial of rosuvastatin 20 mg/day in 1993 patients in 152 centers worldwide did not show any consistent differences in adverse effects compared with atorvastatin and simvastatin (21C). In a retrospective matched cohort study, the purpose of which was to compare the incidence rates of hospitalization associated with rhabdomyolysis, myopathy, renal dys­ function, or hepatic dysfunction, and of inhospital death, 11 249 patients took rosu­ vastatin and 37 282 took other statins (22c). The absolute incidence rates of rhabdo­ myolysis and myopathy were reassuringly low but were too small for firm conclusions to be drawn about any difference between the statins. The same conclusion has been drawn from a rosuvastatin historical cohort study in more than 45 000 Dutch statin users (23c), and from a comparison of the safety of rosuvastatin 10 mg/day and atorvastatin 20 mg/day in 996 randomized high-risk patients with hypercholesterolemia (24C). Both treatments were well tolerated, with a similar incidence of adverse events (rosu­ vastatin 28%; atorvastatin, 26%). There were no cases of rhabdomyolysis or hepatic or renal insufficiency.

References 1. McKenney JM, Farnier M, Lo KW, Bays HE, Perevozkaya I, Carlson G, Davies MJ, Mitchel YB, Gumbiner B. Safety and efficacy of long-term co-administration of fenofibrate and ezetimibe in patients with mixed hyperlipidemia. J Am Coll Cardiol 2006;47(8):1584–7. 2. Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An

interpretive history of the cholesterol con­ troversy, part V: the discovery of the statins and the end of the controversy. J Lipid Res 2006;47:1339–51. 3. Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006;48:438–45.

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719

4. Hey-Hadavi JH, Kuntze E, Luo D, Silver­ man P, Pittman D, Lepetri B. Tolerability of atorvastatin in a population aged > or ¼ 65 years: a retrospective pooled analy­ sis of results from fifty randomized clinical trials. Am J Geriatr Pharmacother 2006;4:112–22. 5. Vuletic S, Riekse RG, Marcovina SM, Peskind ER, Hazzard WR, Albers JJ. Statins of different brain penetrability differentially affect CSF PLTP activity. Dement Geriatr Cogn Disord 2006;22(5-6):392–8. 6. Singh S, Loke YK. Statins and pancreatitis: a systematic review of observational stu­ dies and spontaneous case reports. Drug Saf 2006;29:1123–32. 7. Schreiber DH, Anderson TR. Statin­ induced rhabdomyolysis. J Emerg Med 2006;31:177–80. 8. Ronaldson KJ, O’Shea JM, Boyd IW. Risk factors for rhabdomyolysis with simvasta­ tin and atorvastatin. Drug Saf 2006;29: 1061–7. 9. Biggs MJ, Bonser RS, Cram R. Localized rhabdomyolysis after exertion in a cardiac transplant recipient on statin therapy. J Heart Lung Transplant 2006;25:356–7. 10. Steinhubl SR, Akers WS. Clopidogrel– statin interaction: a mountain or a mole hill? Am Heart J 2006;152:200–3. 11. Brophy JM, Babapulle MN, Costa V, Rinfret S. A pharmacoepidemiology study of the interaction between atorvastatin and clopidogrel after percutaneous coronary intervention. Am Heart J 2006;152:263–9. 12. Ricaurte B, Guirguis A, Taylor HC, Zabriskie D. Simvastatin–amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother 2006;40:753–7. 13. Tufan A, Dede DS, Cavus S, Altintas ND, Iskit AB, Topeli A. Rhabdomyolysis in a patient treated with colchicine and atorvastatin. Ann Pharmacother 2006;40: 1466–9. 14. Aberg JA, Rosenkranz SL, Fichtenbaum CJ, Alston BL, Brobst SW, Segal Y, Gerber JGACTG A5108 team. Pharma­ cokinetic interaction between nelfinavir and pravastatin in HIV-seronegative volunteers: ACTG study A5108. AIDS 2006;20:725–9.

15. Khandwala HM. Lipid lowering inefficacy of high-dose statin therapy due to con­ current use of phenytoin. South Med J 2006;99:1385–7. 16. Lim AK, Ho L, Levidiotis V. Quinineinduced renal failure as a result of rhabdomyolysis, haemolytic uraemic syn­ drome and disseminated intravascular coagulation. Intern Med J 2006;36(7): 465–7. 17. Conforti A, Magro L, Moretti U, Scotto S, Motola D, Salvo F, Ros B, Leone R. Fluvastatin and hepatic reactions: a signal from spontaneous reporting in Italy. Drug Saf 2006;29(12):1163–72. 18. Fellstrom B, Abedini S, Holdaas H, Jardine AG, Staffler B, Gimpelewicz C. No detrimental effect on renal function during long-term use of fluvastatin in renal transplant recipients in the Assessment of Lescol in Renal Transplantation (ALERT) study. Clin Transplant 2006;20: 732–9. 19. Holdaas H, Wanner C, Abletshauser C, Gimpelewicz C, Isaacsohn J. The renal safety profile of fluvastatin: results of a pooled analysis. Ren Fail 2006;28(6): 487–92. 20. Johansson S, Ming EE, Wallander MA, Rodríguez LA, Herings RM, Goettsch WG, González-Pérez A, McAfee AT, Walker AM. Rosuvastatin safety: a com­ prehensive, international pharmacoepide­ miology programme. Pharmacoepidemiol Drug Saf 2006;15(7):454–61. 21. Ballantyne CM, Bertolami M, Hernandez Garcia HR, Nul D, Stein EA, Theroux P, Weiss R, Cain VA, Raichlen JS. Achieving LDL cholesterol, non-HDL cholesterol, and apolipoprotein B target levels in high-risk patients: Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY (MERCURY) II. Am Heart J 2006;151(5):975–9. 22. McAfee AT, Ming EE, Seeger JD, Quinn SG, Ng EW, Danielson JD, Cutone JA, Fox JC, Walker AM. The comparative safety of rosuvastatin: a retrospective matched cohort study in over 48,000 initiators of statin therapy. Pharmacoepi­ demiol Drug Saf 2006;15(7):444–53. 23. Goettsch WG, Heintjes EM, Kastelein JJ, Rabelink TJ, Johansson S, Herings

720 RM. Results from a rosuvastatin histor­ ical cohort study in more than 45,000 Dutch statin users, a PHARMO study. Pharmacoepidemiol Drug Saf 2006;15: 435–43. 24. Clearfield MB, Amerena J, Bassand JP, Hernández García HR, Miller SS, Sosef FF,

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Palmer MK, Bryzinski BS. Comparison of the efficacy and safety of rosuvastatin 10 mg and atorvastatin 20 mg in high-risk patients with hypercholesterolemia—Prospective study to evaluate the Use of Low doses of the Statins Atorvastatin and Rosuvastatin (PULSAR). Trials 2006;7:35.

H.-P. Lipp and J.T. Hartmann

45

Cytostatic and cytotoxic drugs

Editor’s note: The wide range of cytostatic and cytotoxic drugs, the multitude of their adverse effects, and the fact that they are generally used in combinations of several agents all make it impossible to provide as detailed a review of the adverse effects of all the drugs in this field as the Annual gives in others. This year this chapter is devoted to a special review of DNA alkylating N-Lost derivatives. Previous special reviews in the SEDA series have been as follows: � Anthracyclines (SEDA-25, 533) � Antimetabolites (SEDA-29, 551): Purine antagonists, pyrimidine antagonists, antifolate drugs, phosphatidylcholine antagonists, adenosine deaminase inhibitors � Fluorouracil (SEDA-23, 476) � Inhibitors of topoisomerase I and topoisomerase II (SEDA-27, 477) � Paclitaxel (SEDA-21, 463) � Platinum compounds (SEDA-26, 490) � Tyrosine kinase inhibitors (SEDA-30, 520) � Vinca alkaloids (SEDA-28, 538)

DNA alkylating N-Lost derivatives Mustard gas, bis(2-chloroethyl)sulfide (CH2CH2Cl)2 S, was invented in Germany during the First World War as an agent of

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03145-6 r 2009 Elsevier B.V. All rights reserved.

chemical warfare and was originally used in the third battle of Ypres (Passchendaele) in 1917. When it was further studied in the United States in the 1940s, it was noted to cause not only blistering of the skin and mucosae but also damage to the bone marrow, lymphoid tissues, and gastrointestinal epithelium (1R). Further experiments yielded the derivatives HN3 (2,2,2-trichlorotriethylamine) and HN2 (nitrogen mustard or mustine, later called mechlorethamine, chlormethine, or N-Lost). Nitrogen mustard derivatives contain the chemical group –N(CH2CH2Cl)2. The structures of chlormethine and its derivatives are shown overleaf.

Bendamustine In March 2008 the US Food and Drug Administration (FDA) approved bendamustine hydrochloride (Treanda) for the treatment of chronic lymphocytic leukemia, based on clinical trials that showed a median progression-free survival time of 18 months compared with 6 months in patients treated with chlorambucil. Bendamustine has an N-Lost moiety in its chemical structure, but it is also an antimetabolite, which may explain some lack of cross-resistance to other chemotherapeutic agents. In chronic lymphocytic leukemia it is given as a 28-day treatment cycle for up to six cycles of 70–100 mg/m2/day (days 1 + 2) (2R,3R). After intravenous administration, more than 95% of the dose is bound to plasma albumin. Bendamustine is extensively metabolised; its major metabolite, a hydroxyl derivative within the butyric acid side chain, is as active as the parent compound. Both, the unchanged drug and its active metabolite are predominantly

721

Chapter 45

722

H.-P. Lipp and J.T. Hartmann

H2C CH3

N

CH2CH2CI

+

CH3

CH2CH2CI

Mustine

N

CH2 CH2CH2CI

Ethylene immonium ion

H N COOH(CH2)3 N

N

CH2CH2CI CH2CH2CI

Bendamustine

N

COOH(CH2)3

CH2CH2CI CH2CH2CI

Chlorambucil

N

H2NCHCH2

CH2CH2CI CH2CH2CI

COOH Melphalan

O

O P

N

CH2CH2CI CH2CH2CI

N H Cyclophosphamide O

O P

N

H CH2CH2CI

N CH2CH2CI Ifosfamide O

O P

N

CH2CH2CI CH2CH2CI

N CH2CH2CI Trofosfamide Fig. 1. Structures of DNA alkalating N-LOST derivatives.

Cytostatic and cytotoxic drugs

Chapter 45

excreted in the urine; however, dosage modification does not appear to be warranted even in patients with a glomerular filtration rate (GFR) below 10 ml/minute or on dialysis (4c). Further metabolic pathways include N-demethylation and oxidative reactions mediated by CYP1A2 and phase II conjugation reactions resulting in cysteine Sconjugates. The half-life is 28 minutes (5c). Only 50% of the dose should be given to patients with a higher tumor burden in the liver and moderate liver dysfunction (e.g., serum bilirubin 20–50 mmol/l). Non-hematological adverse effects are uncommon during bendamustine therapy. Hematologic Myelosuppression and febrile neutropenia are hematological dose-limiting adverse effects of bendamustine (3R,4c). � A 48-year-old woman received intravenous

bendamustine 150 mg/m2/day on two consecutive days for advanced progressive breast cancer (6A). The cycle was repeated every 4 weeks. After five courses, she developed Pneumocystis jiroveci pneumonia. The CD4/CD8 ratio of 0.82 (near normal) fell to 0.05 during bendamustine treatment, mainly due to a marked fall in CD4 ( + ) lymphocytes. The patient was HIV seronegative. In spite of highdose intravenous co-trimoxazole and methylprednisolone, she died of respiratory failure 3 days later.

Hair In contrast to other alkylating agents, bendamustine does not cause alopecia in therapeutic doses (4c). Immunologic Hypersensitivity reactions (of WHO severity 1–2) occur frequently, but drug-associated anaphylaxis has not yet been described (7C).

Chlorambucil Chlorambucil, a bifunctional alkylating agent, has long been used in the treatment of chronic lymphocytic leukemia and advanced non-Hodgkin`s lymphoma (e.g., 0.1–0.2 mg/ kg/day orally). However, it has been replaced by novel drugs for those indications. It is rapidly and completely absorbed from the gastrointestinal tract. There is some evidence that concomitant food reduces the Area under

723 the curve (AUC) and lengthens the time to Cmax. In the plasma, chlorambucil is highly bound (nearly 99%) to albumin. Its major metabolite, phenylacetic acid mustard, which has considerable antineoplastic activity, is primarily formed by beta-oxidation of the butyric acid side chain. The half-life of chlorambucil and its major metabolite average 92 minutes and 2.5 hours, respectively. Chlorambucil and its major metabolite hydrolyze spontaneously in plasma, resulting in the formation of inactive monohydroxy and dihydroxy derivatives, which lack bifunctional alkylating activity. About 60% of the dose is excreted in the urine within 24 hours, and 99% resembles hydrolyzed degradation products (8R). The adverse effects of chlorambucil include hematological effects, mild nausea and vomiting (incidence o10%), allergic reactions, and cumulative pulmonary effects. Nervous system Nervous system toxicity is uncommon and dose-related. Myoclonus has been reported (9A). � An 81-year-old man with stage IVB diffuse

small lymphocytic lymphoma (low grade) was given chlorambucil 0.28 mg/kg/day for 14 days. On day 3 he developed a gastrointestinal upset, jerking movements, and stiffness without fever, which persisted for 3 days, worse at night, and experienced even while he was asleep. The dose was reduced to 8 mg/day, which resulted in reduced symptoms. Resolution of the myoclonus occurred after withdrawal of chlorambucil. The tremor recurred when he was rechallenged with 14 mg/day. In contrast, when oral cyclophosphamide was substituted for the remaining cycles, myoclonus did not recur.

Chlormethine Chlormethine (rINN) has been used in combination with vincristine, procarbazine, and prednisone in the MOPP regimen [mechlorethamine + vincristine (Oncovin) + procarbazine + prednisolone] developed for Hodgkin`s disease; however, chlormethine has been replaced by cyclophosphamide and the MOPP regimen by ABVD [doxorubicin (Adriamycin) + bleomycin + vinblastine + dacarbazine]. In vivo, chlormethine is rapidly converted to the ethylene immonium ion (Figure 1),

724 which alkylates various nucleophilic binding sites. Its cytotoxic effect is primarily based on covalent binding to the N-7 position of guanine, which results in interstrand and intrastrand cross-links within the DNA. Chlormethine undergoes rapid non-enzymatic degradation reactions in aqueous solution. Thus, unchanged chlormethine is undetectable in the blood within minutes after intravenous administration. Less than 0.01% of an intravenous dose is excreted unchanged in the urine (9A). Besides dose-limiting myelosuppression and gastrointestinal adverse effects, severe painful ulceration has been observed in the cases of accidental drug extravasation. Some recommend isotonic sodium thiosulfate and cold compresses for 6–12 hours in order to reduce local painful inflammation and induration (10A).

Melphalan The alkylating agent melphalan has been used for more than 50 years for a variety of malignant tumors. Conventional dosages of 16 mg/m2 intravenously every two weeks or 0.15–0.25 mg/kg/day orally for 4–7 days are commonly used for different indications. Based on a clear dose–response relation, intensified melphalan regimens 200 mg/m2 intravenously followed by autologous peripheral blood derived stem-cell rescue prolong survival in patients with multiple myeloma (9A). The clearance of melphalan is reduced in underweight patients, elderly people, and those with poor renal function. In these patients higher exposure to melphalan may predispose to more severe forms of gastrointestinal toxicity (e.g., mucositis) and pneumonitis (11c,12c). The recommendations of the International Society of Geriatric Oncology (SIOG) therefore include using 75% and 50% of the planned conventional or intensified dose in patients with creatinine clearance values of 15–60 ml/minute and under 15 ml/minute respectively (13S). Immunologic Melphalan has been associated with hypersensitivity reactions, including urticarial rashes, pruritus, dyspnea, bronchospasm, hypotension, and anaphylaxis (14A).

Chapter 45

H.-P. Lipp and J.T. Hartmann

OxIazaphosphorines The oxazaphosphorines cyclophosphamide and ifosfamide are prodrugs whose antineoplastic activity resides in metabolites that are formed by cytochrome P450 isoenzymes. However, besides the active compound that results, equimolar amounts of acrolein are released by biotransformation and this causes oxazaphosphorine-associated acute hemorrhagic cystitis. The thiol derivative mesna non-enzymatically neutralizes acrolein in the bladder and so protects against this adverse effect (15R,16E,17E). The oxazaphosphorine trofosfamide has been used in the palliative treatment of several solid and hematologic malignancies and soft tissue sarcomas. In contrast to cyclophosphamide and ifosfamide, it is exclusively used orally. It is activated by cytochrome P450 isoenzyme activity (18R). In Hodgkin`s disease, non-Hodgkin’s lymphoma, ovarian cancer, and breast cancer, cyclophosphamide can be given either intravenously (e.g., 500–1000 mg/m2/ cycle) or orally (e.g., 1–5 mg/kg/day as a maintenance dose). During intensified regimens after peripheral blood stem cell transplantation, dosages average 60 mg/kg/day on 2 consecutive days. Cyclophosphamide is well-absorbed from the gastrointestinal tract and has an absolute systemic availability greater than 75%. The parent compound and its metabolites are widely distributed throughout the body, including the brain. The half-life of cyclophosphamide is 3–12 hours and the half-lives of its metabolites are up to 72 hours. Activation is primarily mediated by CYP2B6, resulting in the formation of 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide, the acyclic tautomer. The latter can undergo further metabolism, including oxidation to carboxyphosphamide, but the main process is release of phosphoramide mustard. About 36–99% of a dose is eliminated within 48 hours in the urine, 5–30% as unchanged drug. Conventional dosages of the structurally related ifosfamide are higher than those of cyclophosphamide: 1.2–2.4 g/m2/day on 3–5 consecutive days or 5–8 g/m2 as a 24-hour continuous infusion during treatment of

Cytostatic and cytotoxic drugs

Chapter 45

testicular neoplasms, bone and soft tissue sarcomas, and bladder, lung, and cervical cancers. In contrast to cyclophosphamide, ifosfamide cannot be given orally, because of the risk of intolerable neurotoxicity by this route of administration. Ifosfamide and its metabolites are widely distributed throughout the body, including the brain. Ifosfamide undergoes hepatic bioactivation via CYP3A4. The corresponding aldofosfamide splits spontaneously into ifosfamide mustard and acrolein. In contrast to cyclophosphamide, CYP-mediated side-chain dealkylation is of high quantitative importance during ifosfamide metabolism. The half-life of ifosfamide is 3–10 hours and about 34% of the dose is excreted in the urine as unchanged drug (15R,16E,17E). There are marked differences between the adverse effects of cyclophosphamide and ifosfamide. Both drugs cause dose-dependent hematologic effects, alopecia, gastrointestinal disorders, and genitourinary effects, particularly sterile hemorrhagic cystitis. High-dose cyclophosphamide also has cardiac adverse effects, and hepatic, respiratory, and sensory disorders occur in individual patients. Ifosfamide can cause potentially serious nephrotoxicity and extensive nerve dysfunction. Cardiovascular High-dose cyclophosphamide is widely established in transplant conditioning regimens (e.g., together with intensified busulfan). Doses exceeding 7 g/m2 (or even 200 mg/kg) have not been recommended because of a risk of acute fatal cardiotoxicity. However, even with doses up to 60 mg/kg/day for 2 days patients may develop irreversible and fatal cardiomyopathy. Acute fatal restrictive cardiomyopathy is associated with myocardial edema, progressive unresponsive hypertension, reduced left ventricular stroke volume, and markedly reduced systemic and pulmonary vascular resistances (19A). Cellular mechanisms include increased oxygen-free radicals via intracellular phosphoramide mustard. Patients who develop congestive heart failure may have a lower AUC of total cyclophosphamide than patients who do not develop cardiotoxicity, which suggests that the extent of metabolites rather than the parent compound may be responsible for increased end-organ toxicity (20C). According to a case

725 series, corrected QT dispersion may be a useful predictor of acute heart failure after high-dose cyclophosphamide (21c). Respiratory Lung damage caused by cyclophosphamide can occur at any time and does not appear to be dose-related. It can be difficult to recognize because of confounding variables, such as the concomitant use of other cytotoxic drugs, opportunistic infections, diffuse pulmonary malignancy, radiation pneumonitis, and oxygen toxicity. In a retrospective study of six patients with cyclophosphamide-induced lung disease aged 42–78 years, the clinical features included dyspnea, fever, cough, new parenchymal infiltrates, gas exchange abnormalities on pulmonary function tests, and pleural thickening on chest X-ray (22A). There were two patterns of cyclophosphamide-induced lung toxicity. One patient developed early-onset pneumonitis and responded to drug withdrawal. The other five had late-onset pneumonitis with progressive pulmonary fibrosis and bilateral pleural thickening; they did not respond to drug withdrawal and corticosteroids; three died of respiratory failure. The authors reviewed 12 other reported cases and confirmed their own findings. Early-onset pneumonitis is reversible and may respond to corticosteroids. Late-onset pneumonitis, which is often associated with pleural thickening, is clinically distinct from idiopathic pulmonary fibrosis but has a chronically progressive course. It is unresponsive to corticosteroids. Cyclophosphamide-induced lung disease may be more common in patients who have used other potentially pneumotoxic drugs (e.g., amiodarone) (23A). � A 73-year-old Caucasian woman with follicular

center non-Hodgkin’s lymphoma (grade 2, stage III) was given R-CHOP—intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincris2 tine 1 mg/m on day 1 plus oral prednisone 100 mg/day on days 1–5. She had also been taking amiodarone 300 mg bd for 4 years, simvastatin 40 mg/day, atenolol 100 mg/day, and warfarin. Two days after the first treatment cycle she developed acute respiratory distress and profound hypoxia, with an oxygen saturation of 77%. She required intubation and underwent bronchoscopy. No pathogen was

726 identified and she was given dexamethasone 8 mg every 6 hours for presumed cyclophosphamide-induced acute lung injury. However, 2 weeks later, she developed septicemia with Pseudomonas and vancomycin-resistant Enterococcus and died.

Ifosfamide and cyclophosphamide can cause interstitial pneumonitis, particularly after intensified treatment regimens. Trofosfamide has also been associated with a hypersensitivity pneumonitis (18R). � A 83-year-old woman with an advanced

malignant peripheral nerve sheath tumor of the right femur was given trofosfamide 300 mg/day for 7 days, followed by 150 mg/day. She then developed progressive dyspnea on exertion. Withdrawal of trofosfamide and the addition of prednisolone 1 mg/kg resulted in rapid improvement (24A).

Nervous system In 5–30% of cases ifosfamide causes a broad spectrum of nervous system adverse effects, including hallucinations, personality changes, confusion, lethargy, somnolence, cerebellar dysfunction, seizures, and rarely coma. � A 55-year-old woman with a diffuse large B cell

lymphoma received ifosfamide 1000 mg/m2 (as a 1-hour infusion on days 1–5 with mesna), idarubicin 10 mg/m2 (as a 1-hour infusion on days 1 and 2), and etoposide 150 mg/m2 (as a 3hour infusion on days 1–3) (25A). On the third day of chemotherapy she became confused and lethargic. Her speech deteriorated and after several hours she became mute. Cranial tomography was normal but an electroencephalogram showed slow background activity and epileptiform anomalies. Diazepam 10 mg and levetiracetam 500 mg bd produced improvement. She regained consciousness on the following day.

The mechanism of ifosfamide-related neutrotoxicity has not been fully elucidated, but susceptibility factors include shorter infusion times, hypoalbuminemia, impaired renal function, previous treatment with cisplatin, poor performance status, bulky abdominal disease, and pre-existing neurological disorders (26R,27A,28R). Based on the observation that oral ifosfamide was associated with a higher incidence of nervous system toxicity, metabolites rather than the parent compound may play a pivotal role in pathogenesis, because oral administration,

Chapter 45

H.-P. Lipp and J.T. Hartmann

even in very small amounts, results in a different pattern of metabolites from the intravenous route. In addition, poor metabolizers of carbocysteine, based on lower amounts of endogenous cysteine, appear to have a higher risk of ifosfamide-related nervous system toxicity (29A). Finally, the parent compound may not mediate neurotoxicity, because the structurally related cyclophosphamide does not cause nervous system toxicity, even during high-dose chemotherapy. Whether chloroacetic aldehyde, which is released during ifosfamide biotransformation, triggers neurotoxicity is controversial (30H). Whereas mesna has no effect on ifosfamide-related nervous system toxicity, methylthioninium chloride (methylene blue) has been suggested to be beneficial; however, there have been no controlled studies (31R). Thiamine supplementation (e.g., 100 mg intravenously every 4 hours) has been reported to be beneficial in patients with ifosfamide encephalopathy, based on the observation that reduced thiamine concentrations correlate to some extent with ifosfamide nervous system adverse effects; however, controlled trials are needed to prove this hypothesis (32c). Sensory systems The mechanism of cyclophosphamide-induced facial discomfort or upper respiratory symptoms, including facial burning, sneezing, oropharyngeal tingling, rhinorrhea, and lacrimation, has not been elucidated, but may be at least in part vagally mediated. Some authors have suggested that rapid administration predisposes to facial discomfort. However, prolonging the duration of administration during high-dose cyclophosphamide, e.g., by infusing over 2 hours rather than 1 hour, led to some improvement in 20 patients but not consistently (33c). Further considerations include the use of anticholinergic agents. � A 72-year-old woman received carboplatin and

intravenous cyclophosphamide 930 mg over 15 minutes for ovarian carcinoma(34A). Immediately after cyclophosphamide administration, she experienced nasal burning, nasal stuffiness, and profuse lacrimation. The symptoms resolved spontaneously within 15 minutes. The preceded supportive use of intranasal

Cytostatic and cytotoxic drugs

Chapter 45

ipratropium bromide markedly reduced the intensity of symptoms in the following cycles.

Liver High-dose cyclophosphamide as a single agent appears to be insufficient to produce extensive sinusoidal injury in the liver; however, intensified cyclophosphamide dosages followed by total body irradiation act synergistically in producing hepatotoxicity. Among several metabolites, carboxyethylphosphoramide mustard (CEPM) might be related to sinusoidal obstruction syndrome (veno-occlusive disease) and raised bilirubin concentrations. Whether of the second dose of high-dose cyclophosphamide should be adjusted depending on exposure to CEPM on the first day needs investigation (35A). Urinary tract Potentially serious nephrotoxicity can limit the use of ifosfamide. Its pathogenesis has not been elucidated in detail. The most common susceptibility factors include age and cumulative ifosfamide dose (e.g., 45 g/m2). Fanconi syndrome can occur, with severe impairment of amino acid and phosphate reabsorption (36C). In addition, experimental results suggest that lower concentrations of glutathione (GSH) predispose the kidneys to damage by ifosfamide, which supports the prophylactic use of N-acetylcysteine (37E). In experimental animals taurine and glycine attenuate ifosfamide-related Fanconi syndrome, but controlled clinical trials are lacking (38E,39E). The same is true for lcarnitine, which has been suggested to be able to detoxify chloroacetaldehyde-CoA (40E).

727 Based on the fact that cyclophosphamide does not cause nephrotoxicity, even in higher doses, CYP3A4-mediated biotransformation of ifosfamide may be important in nephrotoxicity. Ifosfamide undergoes extensive side-chain dealkylation (up to 48% of a dose), with formation of 2-dechloroethylifosfamide, 3-dechloroethylifosfamide (3DCE), and chloroacetaldehyde (2-DCE). Higher median 14-hour plasma concentrations of ifosfamide, 2-DCE, and 3-DCE correlate with different grades of drugassociated renal dysfunction (41C). It has been suggested that ifosfamideinduced nephrotoxicity is associated with a CYP3A5 polymorphism, because donors carrying the CYP3A5-wild-type have a more pronounced rate of ifosfamide N-dechloroethylation than donors who are homozygous for the mutant CYP3A5�3/�3 allele, which results in an aberrant CYP3A5 mRNA and a truncated non-functional protein. This hypothesis has been strengthened by the observation that ifosfamide Ndechlorethylation may be mediated locally at the site of toxicity in proximal renal tubules. This phenomenon may account for the difficulty in explaining drug-related nephrotoxicity by quantitative assessment of ifosfamide metabolites in plasma or serum (42E,43E). Cyclophosphamide can cause bladder and kidney cancers, particularly if cumulative doses exceed 20–50 g or more. Consequently, the risk of secondary malignancies must be carefully weighed against the potential benefit (44c).

References 1. Sneader W. Drug discovery: the evolution of modern medicines. Chichester: John Wiley & Sons; 1985;335–42. 2. Leoni LM, Bailey B, Reifert J, Bendall HH, Zeller RW, Corbeil J, Elliott G, Niemeyer CC. Bendamustine (Treanda) displays a dis­ tinct pattern of cytotoxicity and unique

mechanistic features compared with other alkylating agents. Clin Cancer Res 2008;14 (1):309–16. 3. Rummel MJ, Mitron PS, Hoelzer D. Bend­ amustine in the treatment of non-Hodgkin`s lymphoma: results and future perspectives. Semin Oncol 2002;4(Suppl.3):27–32.

728 4. Preiss R, Sohr R, Matthias M, Brockmann B, Hüller H. Untersuchungen zur Pharmakoki­ netik von Bendamustin (Cytostasans) am Menschen. Pharmazie 1985;40(11):782–4. 5. Teichert J, Sohr R, Baumann F, Hennig L, Merkle K, Caca K, Preiss R. Synthesis and characterization of some new phase II metabolites of the alkylator bendamustine and their identification in human bile, urine, and plasma from patients with cholangio­ carcinoma. Drug Metab Dispos 2005;33: 984–92. 6. Klippstein A, Schneider CP, Sayer HG, Höffken K. Pneumocystis carinii pneumo­ nia as a complication of bendamustine monotherapy in a patient with advanced progressive breast cancer. J Cancer Res Clin Oncol 2003;5:316–9. 7. Weidmann E, Kim SZ, Rost A, Schuppert H, Seipelt G, Hoelzer D, Mitrou PS. Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin`s lym­ phoma. Ann Oncol 2002;13:1285–9. 8. Lind MJ, Ardiet C. Pharmacokinetics of alkylating agents. Cancer Surv 1993;17: 157–88. 9. Wyllie ARJ, Bayliff CD, Kovacs MJ. Myoclonus due to chlorambucil in two adults with lymphoma. Ann Pharmacother 1997;31:171–4. 10. Schulmeister L. Extravasation manage­ ment. Semin Oncol Nurs 2007;23:184–90. 11. Carlson K. Melphalan 200 mg/m2 with blood stem cell support as first-line myeloma therapy: impact of glomerular filtration rate on engraftment, transplantation-related toxicity and survival. Bone Marrow Trans­ plant 2005;35:985–90. 12. Akasheh MS, Freytes CO, Vesole DH. Melphalan-associated pulmonary toxicity following high-dose therapy with autolo­ gous hematopoietic stem cell transplanta­ tion. Bone Marrow Transplant 2000;26: 1107–9. 13. Lichtman ST, Wildiers H, Launay-Vacher V, Steer C, Chatelut E, Aapro M. Interna­ tional Society of Geriatric Oncology (SIOG) recommendations for the adjustment of dosing in elderly cancer patients with renal insufficiency. Eur J Cancer 2007;43:14–34. 14. Bleichner F, Mende S. Allergische Reak­ tion auf Melphalan? Onkologie 1982;5:195.

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15. Kerbusch T, de Kraker J, Keizer HJ, van Putten JW, Groen HJ, Jansen RL, Schellens JH, Beijnen JH. Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites. Clin Pharmacokin 2001;40(1): 41–2. 16. Chang T, Weber GF, Crespi CL, Waxman DJ. Differential activation of cyclophospha­ mide and ifosphamide by cytochromes P-450 2B and 3A in human liver micro­ somes. Cancer Res 1993;53(23):5629–37. 17. Ducharme MP, Bernstein ML, Granvil C, Gehrcke B, Wainer IW. Phenytoin-induced alteration in the N-dechloroethylation of ifosfamide stereoisomers. Cancer Che­ mother Pharmacol 1997;40(6):531–3. 18. Latz D, Nassar N, Frank R. Trofosfamide in the palliative treatment of cancer: a review of the literature. Onkologie 2004;27:572–6. 19. Lee C-K, Harman GS, Hohl RJ, Gingrich RD. Fatal cyclophosphamide cardiomyopa­ thy: its clinical course and treatment. Bone Marrow Transplant 1996;18(3):573–7. 20. Ayash L, Wright J, Tretyokov O, Gonin R, Elias A, Wheeler C, Eder JP, Rosowsky A, Antman K, Frei 3rd E. Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response. J Clin Oncol 1992;10(6):995–1000. 21. Nakamae H, Tsumura K, Hino M, Hayashi T, Tatsumi N. QT dispersion as a predictor of acute heart failure after high-dose cyclophosphamide. Lancet 2000;355(9206): 805–6. 22. Malik S, Myers J, Deremee R, Specks U. Lung toxicity associated with cyclopho­ sphamide use. Am J Respir Crit Care Med 1996;154:1851–6. 23. Gupta S, Mahipal A. Fatal pulmonary toxicity after a single dose of cyclopho­ sphamide. Pharmacotherapy 2007;27:616–8. 24. Kopp HG, Kanz L, Hartmann JT. Hyper­ sensitivity pneumonitis associated with the use of trofosfamide. Anti-Cancer Drugs 2004;15:603–4. 25. Kilickap S, Cakar M, Onal I, Tufan A, Akoglu H, Aksoy S, Erman M, Tekuzman G. Nonconvulsive status epilepticus due to ifosfamide. Ann Pharmacother 2006;40(2): 332–5. 26. Nicolao P, Giometto B. Neurological toxi­ city of ifosfamide. Oncology 2003;2:11–6.

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27. Miller L, Eatan V. A case report and review of the literature. Ann Pharmacother 1992;26: 183–7. 28. Rieger C, Fiegl M, Tischer J, Ostermann H, Schiel X. Incidence and severity of ifosfa­ mide-induced encephalopathy. Anticancer Drugs 2004;15(4):347–50. 29. Chatton JY, Idle JR, Vågbø CB, Magistretti PJ. Insights into the mechanisms of ifosfa­ mide encephalopathy: drug metabolites have agonistic effects on alpha-amino-3­ hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors and induce cel­ lular acidification in mouse cortical neurons. J Pharmacol Exp Ther 2001;299(3):1161–8. 30. Wagner T. Mode of action of ifospha­ mide—new aspects. Onkologie 1998;21 (Suppl.2):1–4. 31. Patel PN. Methylene blue for management of ifosfamide-induced encephalopathy. Ann Pharmacother 2006;40:299–303. 32. Buesa JM, Garcia-Teijdo P, Losa R, Fra J. Treatment of ifosfamide encephalopathy with intravenous thiamine. Clin Cancer Res 2003;9:4636–7. 33. Schwinghammer T, Wiggins L, Burgunder M, Michell TE, Bailey WL. Adverse reac­ tions related to i.v. infusion of high-dose cyclophosphamide in bone marrow trans­ plant patients. Am J Hosp Pharm 1994;51 (19):2419–21. 34. Kosirog-Glowacki J, Bressler L. Cyclopho­ sphamide-induced facial discomfort. Ann Pharmacother 1994;28:197–9. 35. Goldberg J, Lidsky M. Cyclophosphamideassociated hepatotoxicity. South Med J 1985;2:222–3. 36. Rossi R, Pleyer J, Schäfers P, Kuhn N, Kleta R, Deufel T, Jürgens H. Development of

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38.

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ifosfamide-induced nephrotoxicity: prospec­ tive follow-up in 75 patients. Med Paediatr Oncol 1999;32(3):177–82. Chen N, Aleksa K, Woodland C, Rieder M, Koren G. N-acetylcysteine prevents ifosfa­ mide-induced nephrotoxicity in rats. Br J Clin Pharmacol 2008;153(7):1364–72. Badary OA. Taurine attenuates Fanconi syndrome induced by ifosfamide without compromising its antitumor activity. Oncol Res 1998;10:355–60. Nissim I, Weinberg J. Glycine attenuates Fanconi syndrome induced by maleate or ifosfamide in rats. Kidney Int 1996;684–95. Marthaler N, Visarius T, Küpfer A, Lauter­ burg BH. Increased urinary losses of carni­ tine during ifosfamide chemotherapy. Cancer Chemother Pharmacol 1999;44(2):170–2. Chugh R, Wagner T, Griffith KA, Taylor JM, Thomas DG, Worden FP, Leu KM, Zalupski MM, Baker LH. Assessment of ifosfamide pharmacokinetics, toxicity, and relation to CYP3A4 activity as measured by the erythromycin breath test in patients with sarcoma. Cancer 2007;109(11):2315–22. McCune J, Risler L, Phillips B, Thummel KE, Blough D, Shen DD. Contribution of CYP3A5 to hepatic and renal ifosfamide N­ dechloroethylation. Drug Metab Dispos 2005;33(7):1074–81. Aleksa K, Ita S, Koren G. Renal-tubule metabolism of ifosfamide to the nephro­ toxic chloracetaldehyde: pharmacokinetic modelling for estimation of intracellular levels. Clin Med 2004;143:159–62. DeLair SM, White RW, Kurzrock EA. Secondary transitional cell carcinoma and nitrogen mustard treatment. Urology 2005; 65:1226–7.

Sameh K. Morcos

46 Radiological contrast agents TYPES OF CONTRAST AGENTS Iodinated water-soluble contrast media are used to enhance diagnostic information provided by radiographic examinations. They are of four types: (a) high-osmolar ionic monomers (e.g., diatrizoate, iothalamate, metrizoate); (b) low-osmolar ionic dimers (e.g., ioxaglate); (c) low-osmolar non-ionic monomers (e.g., iobitridol, iopitridole, iohexol, iomeprole, iopamidol, iopromide, ioversol); (d) iso-osmolar non-ionic dimers (e.g., iodixanol, iotrolan).

Adverse reactions to contrast media are generally few, and serious reactions are uncommon. Ultrasound contrast agents are particularly safe.

Water-soluble intravascular iodinated contrast agents (SED-15, 1848; SEDA-28, 552; SEDA-29, 573; SEDA-30, 533) Cardiovascular Significant bradycardia has been reported after a single bolus administration of an iodinated contrast medium into a peripheral artery (1A).
A 68-year-old patient with pre-existing atrio-

They are mainly used intravascularly, but can also be injected into body cavities, particularly the low-osmolar contrast agents. They are also suitable for oral or rectal administration. The high-osmolar water-soluble contrast agent diatrizoate (Gastrografin) is suitable only for oral or rectal administration. Low-osmolar and isoosmolar iodinated contrast media have almost completely replaced high-osmolar agents for intravascular use and administration into body cavities. Ultrasound contrast agents are microbubbles that provide acoustic enhancement. Contrast agents that enhance the diagnostic information provided by magnetic resonance imaging are mainly gadolinium-based, but new non-gadolinium paramagnetic contrast agents have also become available.

The authors suggested that the administration of the contrast medium might have caused transient ischemia in the obstructed vessel, increasing endogenous adenosine, which could have caused transient third-degree heart block in the presence of a previously damaged AV node.

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03146-8 r 2009 Elsevier B.V. All rights reserved.

Contrast medium-induced nephrotoxicity has been extensively covered in previous issues of SEDA, and only reports with important new information have been included here.

ventricular block, Wenckebach type, developed complete heart block after a single intra-arterial bolus injection of an iodinated contrast medium during percutaneous transluminal angioplasty of the left superficial femoral artery.

Contrast medium-induced nephrotoxicity

731

732 DoTS classification: Reaction: Contrast medium-induced nephrotoxicity Dose-relation: collateral Time-course: intermediate Susceptibility factors: endogenous factors (pre-existing renal insufficiency, particularly if it is secondary to diabetes mellitus, congestive heart failure, dehydration); drugs (nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs; metformin; mannitol and diuretics, particularly loop diuretics); multiple repeat exposures to contrast media within a short period of time (72 hours) Large numbers of articles on the subject of nephrotoxicity induced by iodinated contrast media continue to appear, reflecting the importance of this adverse effect. This is particularly important for cardiologists, who may have to perform life-saving angiography in patients at high risk of nephrotoxicity. Several reports have shown a high incidence of non-renal complications, including major adverse cardiac events, among patients who had developed nephrotoxicity. In addition, these patients have a high mortality within 1 year after angiography. The importance of prophylactic use of drugs such as acetylcysteine, fenoldopam, theophylline, or iloprost in preventing nephrotoxicity in high-risk patients remains contentious, with no conclusive data of consistent benefit. Choice of agent Whether iso-osmolar iodinated contrast media are safer than lowosmolar ones has not been confirmed. It is currently generally acknowledged that all iodinated contrast media, including the isoosmolar agent iodixanol, are potentially nephrotoxic in patients with risk factors for nephrotoxicity, particularly those with greatly reduced renal function before contrast administration. Prophylaxis Nephrotoxic drugs should be avoided for at least 48 hours before and after the administration of an iodinated contrast medium.

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Sameh K. Morcos

The use of sodium bicarbonate infusion alone or in combination with a large dose of acetylcysteine (1200 mg bd for 2–3 days starting 24 hours before the procedure) in preference to isotonic saline has not been conclusively confirmed. The standard approach to reducing the risk of nephrotoxicity is that patients at high risk should receive volume expansion with intravenous isotonic saline (100 ml/hour) for at least 4– 6 hours before and after administration of the contrast medium and the smallest possible dose of an iso-osmolar or lowosmolar agent. Oral hydration with 1000 ml of clear fluid over 4–6 hours before and another 1000 ml over 4–6 hours after administration could replace intravenous saline in patients with a moderate degree of renal impairment (eGFR around 45 ml/ minute) who receive 100 ml or less of the contrast medium intravenously. Susceptibility factors ACE inhibitors The available data on the use of angiotensin-converting enzyme (ACE) inhibitors and the associated risks of nephrotoxicity are sparse and conflicting. In 230 patients with renal insufficiency aged 65 years and over, divided into two groups according to prior use of ACE inhibitors (ACE inhibitor group, n ¼ 109; control group, n ¼ 121) nephrotoxicity occurred in 17 of the former and 7 of the latter (2c). The mean serum creatinine concentration increased from 1.34 mg/dl (119 mmol/l) to 1.53 mg/dl (135 mmol/l) in the former and from 1.33 mg/dl (118 mmol/l) to 1.45 mg/dl (128 mmol/l) in the latter. The authors concluded that chronic administration of an ACE inhibitor increases the risk of nephrotoxicity from iodinated contrast media in elderly patients with renal insufficiency. Dialysis Preserving residual renal function is crucial and an independent predictor of survival in patients on peritoneal dialysis. There are few data on the effect of iodinated contrast media in such patients. Residual renal function was monitored in 10 patients on continuous ambulatory peritoneal dialysis (CAPD) who received intravenous or intraarterial iopromide, a low-osmolar iodinated contrast medium, median dose 108 ml/patient

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Chapter 46

(3c). Residual renal function (calculated as the average of renal creatinine and renal urea clearance) was measured on the day before the intervention (baseline), on days 1–7, 10, and 30. Eight patients on CAPD without exposure to an iodinated contrast medium acted as the control group. There was no significant difference between the two groups in age, sex, diabetes, duration of dialysis, and renal clearance at baseline. There was a temporary fall in residual renal clearance after administration of iopromide. However, on day 30, clearances were not significantly different from baseline. In the control group, there was no significant change in residual clearance. Repeated measures ANOVA showed no significant difference in the course of residual renal function between the groups. The fall in residual renal clearance between baseline and a routine visit after 4 months was comparable. The authors concluded that administration of iodinated contrast medium did not lead to persistent reduction in residual renal function in patients on CAPD. However, they emphasized the importance of using the lowest possible dose of a non-ionic iodinated contrast medium and of giving the contrast medium only if there is a real clinical indication. The evolution of residual renal function 2 weeks after iodinated contrast medium administration has been evaluated in 36 patients on stable peritoneal dialysis, and compared with that in a control group of 36 patients who did not receive contrast medium (4c). In the iodinated contrast medium group (28 intra-arterial and 8 intravenous) the mean volume of iodinated contrast medium was 104 ml (iodixanol, an iso-osmolar non-ionic dimeric iodinated contrast medium in 27 cases, and iohexol, a low-osmolarity non-ionic monomeric iodinated contrast medium in 9 cases). All the patients received adequate intravenous hydration with isotonic saline. Variations in residual renal function were comparable in the two groups. Creatinine clearance at baseline and after 2 weeks in those who were given an iodinated contrast medium was 7.07 and 7.20 ml/minute, respectively, and in the control group 6.5 and 6.62 ml/ minute, respectively. The authors concluded that iodinated contrast media did not

733 accelerate the decline in residual renal function in patients on stable peritoneal dialysis who received adequate hydration.

Immunologic There are very few data concerning systematic skin testing to iodinated contrast media. Patients (n ¼ 44; 15 male, 29 female) with previous hypersensitivity reactions to iodinated contrast media were skin tested in an immunology center in France for (a) the implicated iodinated contrast medium and (b) a set of iodinated contrast media if they were positive for the implicated contrast medium or if its name was unknown (5c). The skin tests were positive in 10 patients: 1 had a positive skin prick test, 7 an immediate positive intradermal test, and 2 a delayed positive intradermal test. Skin tests were more often positive in patients with immediate (9/32) compared with non-immediate reactions (1/ 11). The time interval between the reaction to the contrast medium and skin testing was shorter in those patients with an immediate reaction and a positive skin test (mean 3 months) compared with those with an immediate reaction and a negative skin test (mean 48 months). Respiratory allergy was more frequent in the positive group (6/10 versus 7/34). The authors recommended that those with a previous history of an apparently allergic reaction to an iodinated contrast medium should be skin tested, as a proportion of reactions could really be allergic (Type I and Type IV) in nature. They also indicated that cross-reactivity occurs, since five patients in the study had two or more positive skin tests. They concluded that skin tests with iodinated contrast media are positive in a subgroup of patients with hypersensitivity reactions and may play an important role in the diagnosis of iodinated contrast medium allergy. Death Adverse reaction to intravascular low-osmolar and iso-osmolar iodinated contrast media can be minor, intermediate, or life-threatening. Fortunately, very serious or fatal reactions to low-osmolar contrast media are very rare. Deaths attributed to iodinated contrast media on US death

734 certificates from 1999 to 2001 occurred at the rate of 1.1–1.2 per million contrast media packages distributed (6R). An analysis of 1999 death certificates indicated that most deaths attributed to contrast media were associated with renal failure and allergic reactions. Risk assessment of the comparative safety of classes or agents was limited by lack of specific contrast media names. The authors recommended that the names of contrast agents that have been used should be recorded in patients’ medical records and communicated to primarycare physicians and certifiers of death in the event of serious sequelae. Susceptibility factors The safety of the low-osmolar contrast medium iobitridol in the general population and at-risk patients (those with renal impairment, heart failure NYHA classes III or IV, hypotension or hypertension, coronary artery disease, previous reactions to contrast media, asthma and/or allergies, dehydration, diabetes mellitus, poor general condition) has been investigated in a post-marketing surveillance study of 52 057 patients (7C). The adverse event rate was 0.96% in all patients and 1.39% in at-risk patients. The rate of serious adverse events was 0.044% in all patients and 0.057% in at-risk patients. Adverse events occurred more often in women than in men. In patients who had previously reacted to a contrast medium, adverse events were reported in 3.43%, with mild to moderate symptoms. Drug dosage regimens In a prospective comparison of contrast media containing moderate and high concentrations of iodine in 945 patients undergoing computed tomography, iopamidol was used in a high concentration (370 mg I/ml) or a moderate concentration (300 mg I/ml) (8c). There were similar numbers of acute adverse reactions: 2.4% (11/458) in the moderate-concentration group and 3.11% (15/482) in the highconcentration group. Most were mild, but one patient in the high-concentration group had a moderate adverse reaction. There was no correlation between the incidence of adverse reactions and patient characteristics such as sex, age, weight, flow amount, and

Chapter 46

Sameh K. Morcos

flow rate. The incidence of pain was not significantly different, but the incidence of heat sensation was significantly higher in the high-concentration group. The authors concluded that the incidence and severity of acute adverse reactions were not significantly different between the two groups, and there were no severe adverse reactions in either group. Drug administration route The routine use of a power injector for contrastenhanced CT examinations performed with modern multidetector equipment has led to an increase in the incidence of extravasation of iodinated contrast media, particularly if meticulous technique in placing the intravenous cannula in an appropriate size vein has not been followed. The safety of using a power injector for peripheral intravenous injections during CT examinations in 557 children, aged 13 days to 20 years (mean 10 years), has been investigated by measuring the incidence of contrast extravasation (9c). The size of catheter most commonly used was 22 gauge (n ¼ 443). The dorsum of the hand was the most common site of venous access (n ¼ 373). The mean flow rate was 1.48 ml/second. There were only two episodes of extravasation (0.3%), which were treated conservatively. The authors concluded that the use of power injectors through 18–24-gauge catheters in children is safe when meticulous technique is used and personnel are appropriately trained.

MRI CONTRAST MEDIA Gadolinium salts (SED-15, 1469; SEDA-28, 561; SEDA-29, 578; SEDA-30, 538) Systematic reviews The safety of gadobenate dimeglumine (MultiHance) has been studied in 3092 subjects who received MultiHance in 79 clinical trials (10M). Postmarketing surveillance data after more than 1.5 million applications were also evaluated. In all, 413 (14%) of 2982 adults who received

Radiological contrast agents

Chapter 46

MultiHance reported at least one adverse event that was definitely or potentially related to MultiHance, an incidence that was similar to that observed with placebo (21/127, 17%). In crossover studies, 23 (8%) of 287 subjects who received MultiHance had an adverse event compared with 25 (9%) of 295 who received gadopentetate dimeglumine (Magnevist). The rate of adverse events was not increased in children and there was no worsening of renal or liver function in subjects with hepatic or renal impairment. There was no detrimental effect on cardiac electrophysiology in a retrospective electrocardiographic analysis in more than 1000 patients and healthy volunteers. The adverse event reporting rate from postmarketing surveillance of MultiHance was 0.05%. Serious adverse events were rarely reported and included dyspnea, nausea, urticaria, hypotension, and non-IgEmediated anaphylactic (anaphylactoid) reactions. Adverse events in phase II and phase III trials of gadofosveset (Vasovist, MS-325) 0.03 mmol/kg (n ¼ 767) compared with placebo (n ¼ 49) have been pooled from eight studies, including adverse event monitoring, clinical laboratory assays, vital signs, oxygen saturation, physical examination, and electrocardiography (11M). Events were monitored for 72–96 hours after injection and were compared with events in 318 subjects who underwent X-ray angiography using iodinated contrast media. In the phase II trial, five doses of gadofosveset 0.03 mmol/kg (n ¼ 39) and placebo (n ¼ 38) were evaluated, and treatmentrelated adverse events were reported by 13 of the 39 patients who received gadofosveset and 9 of the 38 patients who received placebo; there were no severe or serious adverse events. In the pooled data set, treatment-related adverse events were reported by 176 (23%) of those who received gadofosveset and 16 (33%) of those who received placebo; there were no clinically significant trends in adverse events, laboratory assays, vital signs, or oxygen saturation. The adverse events profile of gadofosveset is comparable to that reported with other gadolinium contrast agents.

735

Gadolinium-based contrast agents and nephrogenic systemic fibrosis DoTS classification: Reaction: Gadolinium induced toxicity Dose-relation: Collateral Time-course: Late Susceptibility factors: endogenous factors (advanced renal insufficiency, inflammatory events, acidosis, hyperphosphatemia); drugs (epoetin therapy) Nephrogenic systemic fibrosis is a fibrosing disorder that can develop in patients with severely reduced renal function. A causal relation between gadolinium-based contrast agents and nephrogenic systemic fibrosis is probable and supported by accumulating data and significantly more common after gadodiamide (Omniscan) than any other gadolinium-based agent. Gadolinium-based contrast agents are either linear or macrocyclic chelates available as ionic or non-ionic preparations. The molecular structure whether cyclic or linear and ionicity determines their stability. Linear chelates are flexible open chains, which do not bind strongly to Gd+++. In contrast, the macrocyclic chelates bind with high affinity to Gd+++ by virtue of being pre-organized rigid rings of almost optimal size to cage gadolinium atoms. Non-ionic preparations are also less stable compared with ionic ones, particularly in the linear chelates, as the binding of Gd+++ to the negatively charged carboxyl groups is stronger than binding to amides or alcohols in the non-ionic preparations. According to stability constants and kinetic measurements, the most stable gadolinium-based contrast agent is the ionic-macrocyclic chelate Gd-DOTA and the least stable are the non-ionic linear chelates gadodiamide and gadoversetamide. The stability of gadolinium-based contrast agents seems to be an important factor in the pathogenesis of nephrogenic systemic

736 fibrosis. Gadolinium-based contrast agents of low stability are likely to undergo transmetallation and release free gadolinium ions, which can deposit in the tissues and attract circulating fibrocytes. There have been no reported cases of nephrogenic systemic fibrosis in the peer-reviewed literature associated with the exclusive use of the stable macrocyclic gadolinium-based contrast agents. There have been 23 cases (20 with Magnevist, 3 with Omniscan) of nephrogenic systemic fibrosis but without skin biopsies (12r). The reported cases of nephrogenic systemic fibrosis are summarized in Table 1. The strong association with gadodiamide was also observed in cases reported to regulatory authorities in the USA and Europe and in the records of the International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR) at Yale University. The strong association of nephrogenic systemic fibrosis with Omniscan (83% of cases reported in the literature) cannot be explained by the market share, which in the USA (from July 2005 to September 2007) was around 26%. Magnevist had the highest market share in the USA, about 54% in the same period (13r). Current recommendations In the USA the Food and Drug Administration (FDA) has asked manufacturers of all gadoliniumbased contrast to include a new boxed warning on the product labeling (14S):

Chapter 46

Sameh K. Morcos

In Europe, the UK Commission on Human Medicines (CHM) together with the European Pharmacovigilance Working Party (PhVWP) of the Committee for Medicinal Products for Human Use (CHMP) have recommended that: Use of Omniscan (gadodiamide) is contraindicated in patients with severe renal impairment (i.e. GFR or eGFR below 30 ml/min/1.73 m2) or in patients with renal dysfunction who have had, or who are awaiting, liver transplantation. For patients with moderate renal impairment (i.e. GFR or eGFR 30–59 ml/min/ 1.73 m2) or neonates and infants up to 1 year of age, Omniscan should be used only after careful consideration. Use of Magnevist (gadopentetic acid) is contraindicated in patients with severe renal impairment (i.e. GFR or eGFR under 30 ml/min/1.73 m2). Magnevist should be used with caution in patients with moderate renal impairment (i.e. GFR or eGFR 30–59 ml/min/1.73 m2), and should be used in neonates and infants up to 1 year of age only after careful consideration. All patients, particularly those older than 65 years, should be screened for renal dysfunction by obtaining a history and/or laboratory tests before these contrast agents are used. Careful consideration should be given to the use of the other gadolinium-containing MRI contrast agents in patients with severe renal impairment (i.e. GFR or eGFR under 30 ml/min/1.73 m2).

Patients with severe kidney insufficiency who receive gadolinium-based agents are at risk for developing a debilitating, and a potentially fatal disease known as nephrogenic systemic fibrosis (NSF). In addition, it would state that patients just before or just after liver transplantation, or those with chronic liver disease, are also at risk for developing NSF if they are experiencing kidney insufficiency of any severity.

Further information can be found at the websites of the FDA (15S), the Medicines and Healthcare products Regulatory Agency (MHRA) (16S,17S), the European Society of Urogenital Radiology (ESUR) (18S), and the ICNFDR (19S).

The FDA also recommends that patients should be screened for kidney problems before receiving any gadolinium-based contrast agents. The recommended dose should not be exceeded and enough time should elapse before the agent is used again.

Susceptibility factors Age Gadoversetamide (OptiMARK) 0.1 mmol/kg has been studied in 100 children aged 2–18 years referred for MRI scans of the central nervous system in an open multicenter study; patients under 2 years of

Radiological contrast agents

Chapter 46

737

Table 1 Biopsy-proven cases of nephrogenic systemic fibrosis published in peer-reviewed literature associated with gadolinium contrast agents up to February 2008 (12r) Gadolinium contrast agent

Number of patients

Omniscan (GE Healthcare, USA) Magnevist (Bayer Schering Pharma AG, Germany) OptiMARK (Covidien, USA) Unspecified More than one agent

157 8 3 18 4

age were excluded (20c). Adverse events were evaluated by physical examination and monitoring of laboratory values, vital signs, and electrocardiography before and after drug administration. Four adverse events in four patients were thought to be probably related to gadoversetamide. All were mild and clinically insignificant; there were no drug-related moderate or serious adverse events. The most common adverse events, regardless of a relation to the drug, were injection-site reactions and minor prolongation of the QT interval. Drug dosage regimens Gd-DTPA-DeA, an MR contrast agent for imaging liver tumors, has been assessed (21c). In a phase I trial, 33 healthy volunteers were given a single intravenous dose of 0.03–10 mmol/kg and reported no adverse events. In a nationwide phase II trial, 80 patients were divided into three dosage groups: 2.5, 5.0, or 7.5 mmol/kg; there were no serious adverse events.

Polyethylene glycol

(SED-15, 1516; SEDA-29, 375; SEDA-30, 567)

Observational studies In order to assess the efficacy of polyethylene glycol solution as an oral contrast agent, 39 patients fasted from 12.00 hours and were given 500–750 ml of the oral contrast medium (one sachet of Norgine reconstituted in 1 l of water) 15 minutes before magnetic resonance imaging (22c). Norgine is a balanced mixture of polyethylene glycol and electrolytes, which when added to water produces a colorless isoosmotic solution. Visualization of the jejunum, ileal lips, and ileocecal region was excellent or sufficient in 87, 95, and 89%, respectively. The time taken to obtain complete visualization of the small bowel, from the jejunum to the ileocecal region, was (mean 65) 15–240 minutes, and in 74% of the patients imaging had to be delayed.

References 1. Brodmann M, Seinost G, Stark G, Pilger E. Aggravation of pre-existing atrioventricular block, Wenckebach type, provoked by application of X-ray contrast medium. Cardiovasc Intervent Radiol 2006;29:1114–6. 2. Cirit M, Toprak O, Yesil M, Bayata S, Postaci N, Pupim L, Esi E. Angiotensin-converting enzyme inhibitors as a risk factor for contrastinduced nephropathy. Nephron Clin Pract 2006;104:c20–7.

3. Dittrich E, Puttinger H, Schillinger M, Lang I, Stefenelli T, Horl WH, Vychytil A. Effect of radio contrast media on residual renal function in peritoneal dialysis patients—a prospective study. Nephrol Dial Transplant 2006; 21:1334–9. 4. Moranne O, Willoteaux S, Pagniez D, Dequiedt P, Boulanger E. Effect of iodinated contrast agents on residual renal function in PD patients. Nephrol Dial Transplant 2006;21:1040–5.

Chapter 46

738 5. Kvedariene V, Martins P, Rouanet L, Demoly P. Diagnosis of iodinated contrast media hypersensitivity: results of a 6-year period. Clin Exp Allergy 2006;36:1072–7. 6. Wysowski DK, Nourjah P. Deaths attributed to X-ray contrast media on U.S. death certificates. AJR 2006;186:613–5. 7. Vogl TJ, Honold E, Wolf M, Mohajeri H, Hammerstingl R. Safety of iobitridol in the general population and at-risk patients. Eur Radiol 2006;16:1288–97. 8. Nagamoto M, Gomi T, Terada H, Terada S, Kohda E. Evaluation of the acute adverse reaction of contrast medium with high and moderate iodine concentration in patients undergoing computed tomography. Radiat Med 2006;24:669–74. 9. Amaral JG, Traubici J, BenDavid G, Reintamm G, Daneman A. Safety of power injector use in children as measured by incidence of extravasation. Am J Roentgenol 2006;187:580–3. 10. Shellock FG, Parker JR, Venetianer C, Pirovano G, Spinazzi A. Safety of gadobenate dimeglumine (MultiHance): summary of findings from clinical studies and postmarketing surveillance. Invest Radiol 2006;41:500–9. 11. Shamsi K, Yucel EK, Chamberlin P. A summary of safety of gadofosveset (MS325) at 0.03 mmol/kg body weight dose: phase II and phase III clinical trials data. Invest Radiol 2006;41:822–30. 12. Broome DR. Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting. Eur J Radiol 2008;66:230–4. 13. Penfield JG, Reilly RF. Nephrogenic systemic fibrosis risk: is there a difference between gadolinium-based contrast agents? Semin Dial 2008;21:129–34. 14. Anonymous. Gadolinium-based contrast agents. Boxed warning about risk of

15.

16.

17.

18.

19.

20.

21.

22.

Sameh K. Morcos

nephrogenic systemic fibrosis. WHO Pharm Newslett 2007;3:1. US Food and Drug Administration. Information on gadolinium-containing contrast agents, http://www.fda.gov/drugs/drugsafety/ PostmarketdrugsafetyInformationforPatientsandProviders/ucm142882.htm. 2007. Duff G. Gadolinium-containing MRI contrast agents and nephrogenic systemic fibrosis (NSF), http://www.mhra.gov.uk/home/ groups/pl-p/documents/websiteresources/con 2030231.pdf. 7 February, 2007. Public Assessment Report. Increased risk of nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis and gadoliniumcontaining MRI contrast agents, http://www. mhra.gov.uk/home/groups/pl-p/documents/ websiteresources/con2030232.pdf. 2006. European Society of Urogenital Radiology. Nephrogenic fibrosis! http://www.esur.org/ Nephrogenic_Fibrosis.39.0.html. updated 22 September, 2009. International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR). http://www.icnfdr.org. Lowe LH, Kearns GL, Wible Jr JH. The safety and efficacy of neuroimaging with gadoversetamide injection in pediatric patients. Curr Med Res Opin 2006;22: 2515–24. Tanimoto A, Kadoya M, Kawamura Y, Kuwatsuru R, Gokan T, Hirohashi S. Safety and efficacy of a novel hepatobiliary MR contrast agent, Gd-DTPA-DeA: results of phase I and phase II clinical trials. J Magn Reson Imaging 2006;23: 499–508. McKenna DA, Roche CJ, Murphy JMP, McCarthy PA. Polyethylene glycol solution as an oral contrast agent for MRI of the small bowel in a patient population. Clin Radiol 2006;61(11):966–70.

J.S.A.G. Schouten

47

Drugs used in ocular treatment

DRUGS USED IN THE MANAGEMENT OF AGE­ RELATED MACULAR DEGENERATION Pegaptanib Observational studies The adverse effects of intravitreal injection of pegaptanib (0.3, 1, or 3 mg every 6 weeks) over 2 years have been reported in 1190 patients who took part in two concurrent, prospective, rando­ mized, multicenter, double-masked, shamcontrolled studies (1M). The major adverse events in year 1 were: endophthalmitis (0.16% per injection), traumatic cataracts (0.07%), and retinal detachment (0.08%). In year 1 there was no difference in serious thromboembolic adverse events, vascular hypertensive disorders, or serious hemor­ rhagic adverse events between 892 patients who received pegaptanib and 298 who received sham treatment. There was no increase in the numbers of deaths. Sensory systems Two patients with occult choroidal revascularization and associated serous pigment epithelial detachment devel­ oped a retinal pigment epithelium tear 1 week and 8 weeks after intravitreal injections pegaptanib (2A). This can also occur during the course of the natural history.

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03147-X r 2009 Elsevier B.V. All rights reserved.

Ranibizumab

(SEDA-30, 545)

Comparative studies In a phase I/II ran­ domized controlled trial 64 patients received either ranibizumab 0.3 or 0.5 mg (n ¼ 53) or usual care (n ¼ 11) (3C). The most commonly reported adverse event was sterile, painless, reversible inflammation, most often occurring the day after admin­ istration and resolving without treatment after 14 days. Minor scleral and conjunctival hemorrhage was the second most common adverse event. Three patients had a poten­ tially sight-threatening adverse event; the first had a recurrent severe iridocyclitis, the second had a culture-proven infectious endophthalmitis, and the third had a central retinal vein occlusion. Increases in intraocular pressure were transient and mostly mild and resolved without treatment. Vitreous hemorrhage occurred in five patients and a retinal tear in one. There was only one nonocular adverse event judged to be due to ranibizumab, a metallic taste.

Verteporfin and photodynamic therapy (SEDA-30, 545) Patients receiving photodynamic therapy with verteporfin have been compared with patients receiving anecortave 15 mg under Tenon’s capsule at baseline and at 6 months as a periocular posterior juxtascleral depot (4C). There were no differences between the two groups. The most frequently reported adverse event was reduced visual acuity, but there was no difference between the two groups. There were 15 deaths, which were assessed as being unrelated to the treatment. A total of 97 (18%) reported a non-fatal

739

Chapter 47

740 serious adverse event in 12 months, of whom 45 (17%) received verteporfin. These were unrelated to the therapy or the injection procedure. Treatment had to be withdrawn because of adverse events in 13 patients (5%) who received verteporfin.

ACETYLCHOLINE RECEPTOR AGONISTS Pilocarpine

(SED-15, 2830;

SEDA-28, 568) Sensory systems Crystalline lens opacification occurred in a 46-year-old man immediately after the instillation of pilocarpine into an eye with a hyperopic phakic intraocular lens due to posterior chamber flattening (5A).

ADRENOCEPTOR AGONISTS Phenylephrine

(SED-15, 2808;

SEDA-28 570) Cardiovascular Phenylephrine eye-drops are used to dilate the pupils to enable fundoscopy and are used in neonates when an ophthalmic examination is conducted to assess the presence of retinopathy of pre­ maturity. However, it can cause serious cardiovascular adverse events. In 42 neo­ nates there were no adverse effects of phenylephrine 2.5%, in combination with tropicamide 0.5% eye-drops, on heart rate or blood pressure (6c).

ANTIBIOTICS Fluoroquinolones Sensory systems Two cases of sterile corneal ulcers have been reported during the use of topical moxifloxacin (7A).

J.S.A.G. Schouten

 A 41-year-old woman with a corneal abra­

sion developed recurrent corneal erosions and keratitis consistent with bacterial infec­ tion, although all cultures for bacteria and fungi were negative. She was given moxi­ floxacin eye-drops 0.5% and fluorometho­ lone and erythromycin were added. Over the next 4 weeks, the epithelial defect persisted and the corneal edema worsened. There were no infiltrates or hypopyon. There was no evidence of Herpes simplex infection. Moxifloxacin was withdrawn and gatifloxacin and topical prednisolone were started. The epithelial defect finally closed after 70 days and the corneal edema had already resolved.  A 84-year-old man had a corneal ulcer and bacterial and fungal cultures were negative. The condition did not respond to a bandage lens and artificial tears and moxifloxacin was started. Over the next 5 weeks his vision declined and after 5 weeks there was an ulcer with an epithelial defect. The appearance was that of a corneal melt. Moxifloxacin was withdrawn. Topical gatifloxacin, doxycycline (for blepharitis), and artificial tears were started. The corneal edema resolved and the epithelium healed within 50 days.

ARTIFICIAL TEARS Systane Systane is an artificial tear solution that contains the pH-dependent gelling polymer hydroxypropylguar. In an open study in 32 subjects it reduced the symptoms of dry eyes but blurred vision was a complication in many of the participants (8c).

BETA-ADRENOCEPTOR ANTAGONISTS (SEDA-26, 525; SEDA-27, 509)

Psychiatric Beta-adrenoceptor antagonists are associated with an increased risk of depression. The data from electronic medical records of a health maintenance organization have been used to analyze the relation between antiglaucoma prescriptions and anti­ depressant prescriptions (9C). Among patients with glaucoma there was no differ­ ence in prescriptions for antidepressants

Drugs used in ocular treatment

Chapter 47

between those who were using beta-adreno­ ceptor antagonists (12.7% of 5846) and those who were not (12.2% of 751). Skin Drugs in eye-drops can cause allergic periorbital contact dermatitis. Data on 112 430 patch-tested patients during 1993– 2004 from a network of departments of dermatology have been analyzed to assess whether patients had positive patch-tests for beta-adrenoceptor antagonists (10C). Of 332 patients who used betaxolol, carteolol, levobunolol, metipranolol, or timolol eyedrops, 43 (13%) tested positive. Allergic contact dermatitis was strongly suspected in 59% of the patients before patch-testing. Based on the prescription rate of beta­ adrenoceptor antagonist and the extrapo­ lated number of cases who tested positive to the beta-adrenoceptor antagonist that they were using, it was estimated that the incidence is one per million defined daily doses.

Timolol

741 glucocorticoid receptor-mediated activity. Patients who received anecortave 15 mg under Tenon’s capsule at baseline and at 6 months as a periocular posterior juxtascl­ eral depot have been compared with patients who received photodynamic ther­ apy with verteporfin (4C). There were no differences between the two groups. The most frequently reported adverse event was reduced visual acuity, but there was no difference between the two groups. There were 15 deaths, which were assessed as being unrelated to the treatment. A total of 97 (18%) reported a non-fatal serious adverse event in 12 months, of whom 52 (20%) received anecortave. These were unrelated to the therapy or the injection procedure. Treatment had to be withdrawn because of adverse events in 19 patients (7%) who received anecortave. Only one adverse event, retinal artery occlusion, was possibly related to anecortave.

Dexamethasone (SED-15, 3428)

Drug formulations In an 8-week rando­ mized, double-blind, crossover, multicenter study in 25 patients there were more pro­ nounced drug-induced changes in peak heart rate and head-up tilt test and higher plasma concentrations of timolol in patients who used timolol 0.5% aqueous solution compared with topical 0.1% timolol gel (11C).

Metabolism Glucocorticoids can cause hyperglycemia. In 25 patients with type 2 diabetes who received a subconjunctival (n ¼ 11) or peribulbar injection (n ¼ 14) of dexamethasone disodium 4 mg/day for three consecutive days there was a median doubling of the blood glucose concentration 6 hours after the injection; 21 patients were given a rapid acting insulin (12c).

CARBONIC ANHYDRASE INHIBITORS

NON-STEROIDAL ANTI­ INFLAMMATORY DRUGS

See Chapter 21.

Bromfenac

GLUCOCORTICOSTEROIDS (SED-15, 906; SEDA-30, 548) Anecortave acetate Anecortave acetate is an angiostatic steroid derived from cortisol but without

(SED-15, 558)

Bromfenac sodium ophthalmic solution 0.1%, a non-steroidal anti-inflammatory drug (NSAID) for ophthalmic use, has been reviewed (13R). It is the most potent ophthalmic NSAID in inhibiting COX-2. Its penetration into ocular tissue is rapid and extensive. Peak concentrations in rabbit eyes occurred after 2 hours in aqueous humor and were present after 24 hours in every ocular tissue, including the retina. In

Chapter 47

742 humans, the peak concentration occurred after 150–180 minutes. The effective con­ centration remained in the eye for 12 hours. Bromfenac reduced ocular inflammation after cataract surgery. Ocular adverse events in phase III clinical trials were not more common in the treatment arms compared with patients who received the vehicle. Of 3425 patients, 89% received bromfenac twice a day. Treatment periods of more than 28 days accounted for 32%. There were 56 patients (1.64%) with a total of 66 adverse events. The most frequently reported adverse events were corneal erosions (14 cases, 0.41%), blepharitis (6 cases, 0.18%), superficial punctate keratitis, irritation, local pain, and pruritus (5 each, 0.15%). There were three serious ocular adverse events: endophthalmitis, ocular hypertension, and branch retinal vein occlusion; these were predictable from concurrent diseases. Data were also collected from spontaneously reported adverse events in 7.8 million patients who had used bromfenac 0.1%; there were 16 (0.0002%) adverse events: corneal ulcers (n ¼ 4), corneal erosions (n ¼ 3), corneal perforations (n ¼ 3), corneal infiltrates (n ¼ 3), corneal thinning (n ¼ 2), and a defect of the corneal epithelium (n ¼ 1). Systemic absorption seems to be negligible and no systemic adverse events have been reported. After 14 days of twice-daily dosing, liver function tests were normal in over 90% of the subjects and there was no evidence of hepatotoxi­ city. In 39 subjects with documented dis­ orders of hepatic function before starting bromfenac, none had worsening of hepatic function or serious adverse events. Sensory systems There have been three cases of corneal melting attributed to bromfenac sodium (14A).  A 58-year-old man with bullous keratopathy

caused by Fuchs’ corneal dystrophy was treated for episcleritis with topical bromfenac sodium. After 15 days, melting (80% depth) developed inferiorly in the paracentral cornea.  A 71-year-old man underwent uncomplicated pterygium surgery, followed by treatment with topical bromfenac sodium. After 40 days, a 60%-depth corneal melt developed in the nasal limbus.



J.S.A.G. Schouten

A 76-year-old woman had a suspected bacterial corneal ulcer that resolved with topical oflox­ acin; however, after 5 days of treatment with topical bromfenac sodium, a perforation occurred in the inferonasal cornea.

Conservative treatment, including the use of a bandage soft contact lens and/or antibiotics and lubrication, led to resolution in all cases. These reports were criticized because the use of bromfenac was inappropriate (no indication, combined with bandage lens, inappropriate dose frequency), the melting could have been caused by other eye-drops used (corticosteroids), and the complications of the underlying disease could have been masked by bromfenac (15r,16r). However, after stopping bromfenac recovery occurred, suggesting a causal role (17r).

Ketorolac

(SED-15, 1978)

Sensory systems Corneal perforation has been attributed to ketorolac (18A).  A 31-year-old man presented 5 days after

photorefractive keratectomy in the left eye with corneal ulceration and perforation requir­ ing penetrating keratoplasty. He had used ketorolac every hour, ciprofloxacin every hour, and prednisolone acetate 1% qds post­ operatively. Corneal cultures were negative.

PROSTAGLANDIN ANALOGUES See also Chapter 39.

Bimatoprost (SED-15, 517; SEDA-26, 526) Skin In 37 patients using bimatoprost periocular skin pigmentation occurred most often at 3–6 weeks (19c). Resolution was noted most frequently at 3–12 months (range 61–472 days). There was complete resolution in 33 patients.

Travoprost

(SED-15, 3481)

Sensory systems A 76-year-old woman with no previous history of anterior uveitis developed bilateral anterior uveitis 5 days after starting to use travoprost (20A).

Drugs used in ocular treatment

Chapter 47

743

References 1. VEGF Inhibition Study in Ocular Neovas­ cularization (VISION) Clinical Trial Group. D’Amico DJ, Masonson HN, Patel M, Adamis AP, Cunningham Jr ET, Guyer DR, Katz B. Pegaptanib sodium for neo­ vascular age-related macular degeneration. Two-year safety results of the two prospec­ tive, multicenter, controlled clinical trials. Ophthalmology 2006;113(6):992–1001. 2. Dhalla MS, Blinder KJ, Tewari A, Haripra­ sad SM, Apte RS. Retinal pigment epithe­ lial tear following intravitreal pegaptanib sodium. Am J Ophthalmol 2006;141:752–4. 3. Heir JS, Antoszyk AN, Reed Pavan P, Leff SR, Rosenfeld PJ, Ciulla TA, Dreyer RF, Gentile RC, Sy JP, Hantsbarger G, Shams N. Ranibizumab for treatment of neovascular age-related macular degeneration. A phase I/II multicenter, controlled, multidose study. Ophthalmology 2006;113:633–42. 4. Slakter JS, Bochow T, D’Amico, Marks B, Jerdan J, Sullivan KAnecortave Acetate Clinical Study Group. Anecortave acetate (15 milligrams) versus photodynamic ther­ apy for treatment of subfoveal neovascular­ ization in age-related macular degeneration. Ophthalmology 2006;113:3–13. 5. Maldonado MJ, García-Feijoó J, Benítez Del Castillo JM, Teutsch P. Cataractous changes due to posterior chamber flattening with a posterior chamber phakic intraocular lens secondary to the administration of pilocar­ pine. Ophthalmology 2006;113:1283–8. 6. Willems L, Allegaert K, Casteels I. Prospec­ tive assessment of systematic side effects of topical ophthalmic drug administration for screening for retinopathy of prematurity. Paed Perinat Drug Ther 2006;7(3):121–2. 7. Walter K, Tyler ME. Severe corneal toxi­ city after topical fluoroquinolone therapy. Cornea 2006;25:855–7. 8. Gifford P, Evans BJW, Morris J. A clinical evaluation of systane. Cont Lens Anterior Eye 2006;29(1):31–40. 9. Kaiserman I, Kaiserman N, Elhayany A, Vinker S. Topical beta-blockers are not associated with an increased risk of treat­ ment for depression. Ophthalmology 2006; 113:1077–80.

10. Jappe U, Uter W, Menezes de Padua CA, Herbst RA, Schnuch A. Allergic contact dermatitis due to beta-blockers in eye drops: a retrospective analysis of multicentre surveillance data 1993–2004. Acta Derm Venereol 2006;86(6):509–14. 11. Uusitalo H, Kähönen M, Ropo A, Mäenpää J, Bjärnhall G, Hedenström H, Turjanmaa V. Improved systemic safety and risk benefit ratio of topical 0.1% timolol hydrogel compared with 0.5% timolol aqueous solution in the treatment of glaucoma. Graefes Arch Clin Exp Ophthalmol 2006; 244(11):1491–6. 12. Feldman-Billard S, Du Pasquier-Fediaevsky L, Héron E. Hyperglycemia after repeated periocular dexamethasone injections in patients with diabetes. Ophthalmology 2006;113:1720–3. 13. Donnenfeld ED, Donnenfeld A. Global experience with Xibrom (bromfenac ophthalmic solution) 0.09%: the first twice-daily ophthalmic nonsteroidal anti­ inflammatory drug. Int Ophthalmol Clin 2006;46(4):21–40. 14. Asai T, Nakagami T, Mochizuki M, Hata N, Tsuchiya T, Hotta Y. Three cases of corneal melting after instillation of a new nonsteroidal anti-inflammatory drug. Cornea 2006; 25:224–7. 15. Flach AJ. Misuse and abuse of topically nonsteroidal anti-inflammatory drugs. Cornea 2006;25:1265. 16. Rho DS. Three cases of corneal melting after instillation of a new nonsteroidal anti-inflam­ matory drug. Cornea 2006;25:1266. 17. Asai T, Nakagami T, Hotta Y. Authors’ reply. Cornea 2006;25:1267. 18. Mian SI, Gupta A, Pineda II R. Corneal ulceration and perforation with ketorolac tromethamine (Aculars) use after PRK. Cornea 2006;25:232–4. 19. Doshi M, Edward DP, Osmanovic S. Clinical course of bimatoprost-induced periocular skin changes in caucasians. Ophthalmology 2006;113:1961–7. 20. Suominen S, Välimäki J. Bilateral anterior uveitis associated with travoprost. Acta Ophthalmol Scand 2005;83:275.

K. Chan and T.X. Lin

48

Treatments used in complementary and alternative medicine

GENERAL Susceptibility factors HIV infection In a cross-sectional study of the use of complementary and alternative medicines in 682 participants with HIV infection among the 47% ever-users, vitamins/minerals (81%), meditation/yoga (36%), massage (31%), marijuana (30%), dietary supplements (24%), and herbal medicines (19%) were the most commonly used (1C). Users were less likely to be poorly educated, more likely to be unemployed, more likely to have been taking antiretroviral drugs for longer, and more likely to have objective, action-requiring adverse effects.

(SED-15, 1609; SEDA-27, 512; SEDA-28, 573; SEDA-29, 583)

HERBAL MEDICINES

Observational studies In an audit of 100 patients admitted to a UK hospital for acute medical emergencies, 24 were taking herbal remedies (a total of 40 products); the most popular product was garlic (2cA). Of these 24 patients 20 were also taking prescription medications and 11 were taking herbal remedies that have either documented toxicity or known interactions with Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03148-1 r 2009 Elsevier B.V. All rights reserved.

prescription drugs. However, the use of a herbal preparation was documented in the case notes in only one case. In a 5-month survey on the use of phytomedicines by 1063 patients, based on a prestructured questionnaire, in the out­ patient department of an urban university general hospital in Italy, of the 1044 women who completed the interview 491 (47%) reported taking at least one herbal com­ pound (3R). Of these 491 patients, 272 (55%) consumed only one phytomedicine, while 219 (45%) also took traditional drugs. Adverse effects were reported by 47 (9.6%), including: gastrointestinal (due to dandelion, propolis, and fennel); cardiovas­ cular (after liquorice, ginseng, and green tea); dermatological (after propolis, thyme, arnica, and passion-flower); and neurological (after guaraná and liquorice). Conventional medicines that were taken simultaneously and were potentially involved in adverse effects were antihypertensive drugs, benzo­ diazepines, non-steroidal anti-inflammatory drugs, antibiotics, and oral contraceptives. In five cases adverse effects were sufficiently serious to justify admission to hospital. In 29/ 47 cases the adverse effect was not commu­ nicated to the doctor. The authors confirmed previous observations (4R) that consumers of herbal remedies act differently with regard to reporting an adverse reaction (serious or minor) to their physician, and that many adverse manifestations to herbal remedies are not monitored. Perioperative events in 601 patients undergoing major elective surgery who had taken traditional Chinese herbal medicines presurgically have been studied in a teaching

745

746 hospital in Hong Kong (5CA). Of these patients, 483 (80%) had taken self-pre­ scribed herbal medicines and 47 (8%) had taken herbal medicines prescribed by practi­ tioners of traditional Chinese medicine in the 2 weeks before surgery. The crude incidences of any combined end-points of preoperative, intraoperative, and post­ operative events were 23% (19–26%), 74% (71–78%), and 63% (59–66%), respectively. Compared with non-users, patients who took traditional Chinese herbal medicines by prescription were more likely to have a preoperative event. The authors presented four case reports to highlight the effect of traditional Chinese herbal medicines by prescription on preoperative prolongation of the activated partial thromboplastin time and hypokalemia. In contrast, there was no significant association between the use of any type of traditional Chinese herbal medicines and the occurrence of either intraoperative or postoperative events. They emphasized that the use of traditional Chinese herbal medicines by prescription near the time of surgery should be discour­ aged, because of the increased risk of adverse events in the preoperative period. Gastrointestinal Number Ten is a dietary supplement that contains rhubarb, ginger, astragalus, red sage, and turmeric. It has been used to reduce food intake and cause weight loss in a pilot study in 24 healthy women aged 18–60 years, body mass index 25–35 kg/m2, who were taking no long-term medications, but was ineffective (6c). Doserelated loose stools was the main adverse effect, which was not surprising, as Number Ten was found to contain sennosides, known laxatives, and gallic acid, which causes weight loss in rodents. Liver Xiao-chai-hu-tang (syo-saiko-to in Japanese), a herbal remedy (consisting of bupleurum root, pinellia tuber, scutellaria root, jubube fruit, ginseng root, glycyrrhiza root, and ginger root), widely used in China for treatment of respiratory, hepa­ tobiliary, and gastrointestinal diseases, particularly among patients with chronic liver disease, has been reported to cause acute hepatitis (7A).

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K. Chan and T.X. Lin


A 52-year-old woman developed weakness,

fatigue, and tea-colored urine after repeated consumption of a decoction of xiao-chai-hu-tang for 1.5 months. Laboratory studies showed acute hepatitis and all markers of viral hepatitis were negative. Liver biopsy showed a picture of acute hepatocellular hepatitis. The symptoms improved after withdrawal of the drug, and liver biochemical tests normalized 2 months later.

This case report reminds us of the possibility of hepatotoxic effects of herbs, even from some that are claimed to have hepatoprotective effects. Hepatotoxicity has also been attributed to traditional medicines in patients with hepa­ titis B infection (8c). In a pilot study to review the clinical course of drug-induced liver damage in a Singapore tertiary hospital 29 patients were identified, of whom 15 had consumed traditional Chinese medicines and 4 had taken antituberculosis drugs (9c). Drug contamination Legislation to control the quality of traditional Chinese medicines was implemented in Hong Kong in 1989, since when proprietary Chinese medicines have been recalled by government bodies after inspection of products available on the market (10S). This information can be used as an alert when these products are re­ distributed to other regions. Heavy metals Heavy metals, such as lead, can cause anemia, kidney failure, and adverse effects on the nervous system, gastrointestinal system, and cardiovascular system. The public have been advised not to purchase contaminated products with the brand names listed in Table 1 and to stop using them or to dispose of the product or surrender it to the Pharmaceutical Service of Department of Health, as the lead content of the products concerned exceeded the maximum permitted limit. Microbial counts The Department of Health in Hong Kong has ordered the immediate recall of 17 proprietary Chinese medicines after laboratory tests showed that the total bacterial count exceeded the maximum permitted limit for registration of such medicines in both Hong Kong and Macau (Table 1). Some of these products are intended for pediatric use.

Treatments used in complementary and alternative medicine

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Table 1. Herbal preparations contaminated with lead or with excess bacterial counts Preparations containing lead Chung San Brand Po Ling Brand (production batch numbers 040607 and Fung Sen Brand 050607) Golden Ship Brand Tin Fung Brand Green Leaf Brand Wintex Tong Brand Proprietary Chinese medicines recalled after laboratory tests showed that the total bacterial count exceeded the maximum permitted limit Bao Zhu Brand Bo Ying Pills Chu Pai Chut Lee San Bao Zhu Brand Chut Lee San Chu Pai Hou Tsao San Bao Zhu Brand Hou Tsao San Hou Tsao San Bo Ying Pills Hung Win Bo Ying Pills Chi Chun Tang Chu Pai Bo Ying Dan Kui Hua Chut Lee San Bird’s Nest & Pearl Chi Chun Tang Chu Pai Chut Lee San Po Wo Tong Ging Fung San Chi Chun Tang Chu Pai Hou Tsao San Po Wo Tong Hou Tsao San Chi Chun Tang Pearl Bat Po Keng Foong Po Wo Tong Wui Chun Tan for Children Powder Xian Cao Tang Chu Pai Hou Tsao San

Pharmaceutical drugs Adulteration of herbal medicines with pharmaceutical drugs continues to be reported.

NSAIDs The Department of Health of Hong Kong has urged members of the public not to buy or take two brands of proprietary Chinese medicines containing NSAIDs (11S):
Chuifong Toukuwan and Nan Lien Chui­ fong Toukuwan, which were marketed for treatment of rheumatoid arthritis and contained diclofenac;
Jin Feng Brand Gallinaci Bak Foong Pills, Baozhitang Gallinaci Pai Feng Pills, Pujitang Gallinaci Pai Feng Pill, Jinbei Brand Gallinaci Pai Feng Pills, and Tongjitang Gallinaci Pai Feng Pills; all contained diclofenac and paracetamol.

Sibutramine Adulteration of a herbal medicine with sibutramine has been reported (12A).
A young healthy woman took a Chinese

herbal medicine called LiDa Dai Dai Hua Jiao Nang and on the second day developed a severe headache, vertigo, and numbness. She stopped taking it and the symptoms disap­ peared within 2 days. Sibutramine was identi­ fied in her urine sample and the capsules each contained 27.4 mg of sibutramine base, about

twice the amount of the highest single dosage form available on the market in Germany.

Drug–drug interactions Multiple interac­ tions can occur if a patient is taking several different herbal preparations (2Ac).
A 77-year-old lady developed epigastric pain

and hematemesis. Her clotting was normal. After identical symptoms 4 months before, a gastroscopy had shown a large sliding intrathoracic hiatus hernia with severe eso­ phagitis. She had been given lansoprazole 30 mg/day. She had also taken garlic, St John’s wort, feverfew, Echinacea, and ginseng. The herbal remedies were withdrawn.

Garlic, feverfew, and ginseng all inhibit platelet aggregation and could have increased the risk of bleeding in this case, particularly since they were taken in com­ bination. An interaction between lansopra­ zole and St John’s wort may also have contributed, since lansoprazole is metabo­ lized by CYP2C19, which is induced by St John’s wort. In a cross-sectional survey of the use of herbal medicines that might interfere with the effects of antiplatelet drugs or antic­ oagulants among 250 patients, 106 (42%) were taking herbs, of whom 76 (72%) had been using them for the past 12 months (13C). Overall, almost 31% were taking one

748 or more herbal medicines that are thought to interact with antiplatelet drugs or antic­ oagulants: ginseng (Panax ginseng), garlic (Allium sativum), and ginkgo (Ginkgo biloba). A large proportion of respondents involved in potential drug–herb interaction were elderly (63%). However, more than 90% of herbal users did not disclose the use of herbal medicines to their health profes­ sionals.

ANTHROPOSOPHIC MEDICINES Patient-reported and physician-assessed adverse drug reactions to anthroposophic medications for chronic diseases have been prospectively assessed over 2 years in 662 consecutive outpatients aged 1–75 years in 131 German medical practices (14C). Con­ firmed adverse reactions to any anthropo­ sophic medication occurred in 2.2% of medications (21 of 949) and 3.0% of users (20 of 662); there was one adverse reaction per 382 patient-months of use. The origins of the medicines were mineral (n ¼ 77, 8.1%), botanical (n ¼ 397, 42%), zoological (n ¼ 74, 7.8%), chemically defined (n ¼ 100, 11%), and mixed (n ¼ 301, 32%). There were 1861 adverse events, of which the most frequent were non-specific (513 of 1861 events, 28%), including mus­ culoskeletal (17%), respiratory (8.2%), and digestive problems (6.6%). There were no serious adverse events attributable to any medication. Of the 1861 reported adverse events, 284 (15%) in 29 patients were suspected by the physician or the patient to be an adverse reaction to a non-medication therapy. Of these, 20 had confirmed reac­ tions to 21 anthroposophic medications: local reactions to topical application (n ¼ 6), systemic hypersensitivity (n ¼ 1), and aggravation of pre-existing symptoms (n ¼ 13). In 10 patients the medication was withdrawn because of an adverse reaction; 2 patients had reactions of severe intensity. All the reactions resolved after withdrawal; none was serious.

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K. Chan and T.X. Lin

SPECIFIC PLANTS Aconitum spp. (Ranunculaceae) The Hospital Authority Toxicology Refer­ ence Laboratory, Princess Margaret Hospital, Hong Kong, confirmed 10 cases of aconite poisoning from March 2004 to May 2006 (15c). In 4 of these 10 cases, the aconite herb was not listed in the written prescription. The authors reported four cases to highlight the problem of “hidden” aconite poisoning. They reported that yunaconitine, a newly identified alkaloid, was detected by HLPC-MS in all four cases. It is not one of the common toxins (aconitine, hypaconitine, and mesaconitine) seen in aconite poisoning. The diagnosis would have been missed in these four cases if laboratory screening for yunaconitine had not been included. The presence of yunaconitine sug­ gests that the mix-up occurred in aconitum species of Yunnan origin. The frequent occurrence of “hidden” aconite poisoning has public health significance for the community in Hong Kong. This mistaken substitution with aconite herbs can occur randomly and result in severe poisoning. It also highlights the importance of quality assurance in herbs with low margins of safety. Efforts should be made to enhance the safety of herbs through the promotion of Good Agricultural Practice and Good Manufacturing Practice (16R,17R).
A 20-year-old man took a decoction of a

prescribed mixture of 17 Chinese medicinal materials for low back pain and developed sudden weakness, sweating, vomiting, and shortness of breath. He had impaired con­ sciousness, circulatory failure, a systolic blood pressure of 70 mmHg, and ventricular tachy­ cardia. Cardioversion was attempted unsuc­ cessfully. Amiodarone was given immediately but the cardiac dysrhythmia was refractory to standard therapy. During bouts of ventricular tachycardia his pulse became imperceptible. Following prolonged cardiopulmonary resus­ citation, aggressive supportive management, and temporary pacing, he recovered fully. He had taken a similar decoction 2 months before the event without problem and a Chinese medicine pharmacist found that it did not include any cardiotoxic herbs. Leftover herbal

Treatments used in complementary and alternative medicine broth and a urine sample collected on the day of admission were screened for common toxins and yunaconitine was found in both samples; its source was a mystery.
A 27-year-old woman developed chest dis­ comfort, dizziness, numbness, and weakness 1 hour after taking a decoction of Chinese herbal medicines containing 19 components. She was unwell. Her blood pressure was 95/ 73 mmHg and her pulse rate 55 per minute because of sinus bradycardia with first-degree heart block. Her symptoms resolved comple­ tely in 24 hours with supportive therapy alone. This patient had enjoyed good health and had no history of cardiac disease. The herbal remnants were examined and one item did not match any of the prescribed herbs but appeared to be a piece of aconitum rootstock. Yunaconitine was detected in both the leftover herbal broth and the patient’s urine.
A 51-year-old woman, with a history of optic neuritis, suddenly developed neck rigidity, dizziness, numbness of the extremities, and weakness 2 hours after taking a bowl of herbal decoction that contained 15 herbs. She had taken the same herbal mixture before without problems. Her blood pressure was 105/ 63 mmHg and her pulse rate 63 per minute in sinus rhythm. The hypotension responded to fluid therapy. Routine laboratory investiga­ tions were unremarkable. Her symptoms resolved spontaneously the next day. Leftover herbal decoction and a urine specimen were analyzed and yunaconitine was found in both.
A 45-year-old woman became ill 1 hour after taking a herbal broth containing 11 ingredients for a menstrual problem. She had tongue numbness, nausea, dizziness, and generalized weakness. Her blood pressure was 91/ 44 mmHg and her pulse rate 58 per minute, with a junctional bradycardia. Her symptoms improved with supportive treatment. Leftover herbal broth and a urine sample collected on the day of admission were analyzed and yunaconitine was found in both.

Aconite has also been implicated in a case of murder (18A).

Cimicifuga racemosa (Ranunculaceae, black cohosh) Liver Black cohosh has been linked to fulminant hepatic failure that required liver transplantation (19A). Musculoskeletal Muscle damage has been attributed to black cohosh (20A).
A 54-year-old woman took a herbal product

derived from black cohosh (Remifemins) for

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menopausal vasomotor symptoms. She took one tablet bd for 1 year, stopped taking it, and then started taking it again 2 months later. Each tablet contains 20 mg of dried rhizome and root extracts, standardized to contain 1 mg of 27­ deoxyactein. After 2 months she started to feel weak. She had increased activities of creatine kinase (247 U/l; reference range 24–170) and lactate dehydrogenase (987 U/l; 230–460). The black cohosh was withdrawn and her symptoms improved within 10 days; the enzyme activities fell and were normal after 20 days.

There may have been very mild muscle damage in this case, but the increases in enzymes were much less than one usually sees in cases of rhabdomyolysis. Pregnancy and lactation The use of black cohosh in pregnancy and lactation has been reviewed. There is weak evidence based on theory and expert opinion that black cohosh has the following effects during pregnancy: labor-inducing effects, hormo­ nal effects, emmenagogue properties, and anovulatory effects (21A). The authors concluded that black cohosh should be used with caution during pregnancy.

Citrus aurantium (Rutaceae, bitter orange) (SED-15, 3087; SEDA29, 586)

After the US marketing ban of Ephedracontaining supplements in April 2004, many manufacturers used C. aurantium instead and marketed the products as “ephedra-free” supplements. However, extracts of C. aurantium contain synephr­ ine, an alpha-adrenoceptor agonist. In the 2004 California Behavioral Risk Factor Surveillance Survey, 70 of 4140 respon­ dents reported having taken a dietary supplement containing C. aurantium during 2003 (22S). Compared with non-users, they were more likely to be single, aged 18–34 years, and Hispanic and to have a heavier body mass index. Five users reported adverse events that they attributed to the supplement. Between March 1, 2004 and October 31, 2006, Health Canada received 21 domestic reports of adverse reactions suspected of being associated with C. aurantium (22S).

750 Of these, 15 reports were of cardiovascular adverse reactions, 10 of which were serious and included 1 report of myocardial infrac­ tion. According to Health Canada, synephr­ ine found in bitter orange can have serious adverse effects on heart rate and blood pressure; these effects are significantly potentiated by caffeine. Synephrine is found in various natural health products that are promoted for weight loss. Health Canada has cautioned that the following people may be particularly at risk of adverse reactions from synephrine-contain­ ing products:
those with heart conditions, central ner­ vous system disorders, diabetes mellitus, enlarged prostate, glaucoma, hyperten­ sion, pheochromocytoma, thyroid disease, or known risk factors for cardiovascular disease;
those taking caffeine-containing pro­ ducts, monoamine oxidase inhibitors, thyroid hormones, or medications to control blood pressure or heart rate;
underweight people. Immunologic Eosinophilic gastroenteritis has been linked to citrus fruit allergy (23Ar).

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K. Chan and T.X. Lin

Ephedra See Chapter 13.

Ginkgo biloba (Ginkgoaceae; maidenhair tree) (SED-15, 1507; SEDA-28, 576; SEDA-29, 587; SEDA-30, 553)

Skin Acute generalized exanthematous pustulosis (AGEP), which is commonly caused by systemic antibacterial drugs, has been attributed to G. biloba (24A).
A 45-year-old man developed a symmetrical

maculopapular eruption on his limbs. Within 2 days the rash generalized to involve the face. Disseminated non-follicular small pustules on erythematous skin were predominant. The palms, soles, and mucous membranes were spared. His temperature was 38.81C. The rash had developed 48 hours after starting oral G. biloba treatment for tinnitus. He denied previously having taken G. biloba and was not taking any other medications. He reported no previous adverse drug reactions and no history of psoriasis. A skin biopsy showed neutrophil-containing spongiotic pustules in the epidermis and a mixed cellular infiltrate with edema in the papillary dermis, consistent with AGEP. The rash cleared within 10 days after withdrawal of G. biloba.


A 46-year-old man developed non-bloody

loose stools 16 times a day associated with abdominal cramping and nausea but no vomiting. Ten years before he had had urticaria and wheezing, but no gastrointestinal symptoms, after taking lemons or grapefruit followed by exercise, and had avoided citrus fruits since then. A CT scan of the abdomen showed colonic, ileal, and duodenal wall thickening. Colonoscopy showed terminal ileitis and pancolonic reduced vascular mark­ ings, suggesting chronic inflammation. Histol­ ogy showed acute colitis and ileitis with eosinophil infiltration. Specific IgE against the following foods was found; lemon, grapefruit, tomato, carrot, potato, coconut, banana, pars­ ley, yeast, garlic, onion, hazelnut, peanut, sesame, and corn. He responded to non­ enteric-coated budesonide and mesalazine. Montelukast was added when the peripheral eosinophilia persisted and prednisolone when he had a recurrence 1 year later.

The authors diagnosed eosinophilic gastro­ enteritis, which they classified into four types, in three of which food allergies are common.

Pregnancy and lactation The use of ginkgo in pregnancy and lactation has been reviewed (25M). There is weak evidence from animal and in vitro studies that ginkgo has antiplatelet activity and might therefore prolong bleeding time during labor. There is also weak evidence that it may be an emmenagogue. The authors concluded that ginkgo should be used with caution during pregnancy, particularly around the time of labor. Its safety during lactation is unknown and it should be avoided. Drug contamination In a study of human placental blood a factor that affected human neutrophils and their adherence was discovered and turned out to be colchicine (26c). Significant concentrations of colchicine (49–763 mg/l) were then found in the placental blood of patients who had used non-prescription herbal dietary supplements during pregnancy,

Treatments used in complementary and alternative medicine

and colchicine was found in commercial preparations of G. biloba. Drug overdose Poisoning with ginkgo nuts has been reported in a child (27A).
A 2-year-old boy took about 50 ginkgo nuts

and 4 hours later started vomiting and had an afebrile generalized tonic seizure. There was a large volume of ginkgo nuts in the vomitus. He was given diazepam 0.4 mg/kg and pyridoxal phosphate 8 mg/kg intravenously and recov­ ered. Sleep electroencephalography 12 hours after admission showed irregular spikes and high-voltage slow waves in the left central, parietal, occipital, and posterior temporal regions; 6 months later electroencephalogra­ phy was normal.

Drug–drug interactions The possible interactions of G. biloba extract with several commonly used drugs have been investi­ gated in a number of pharmacokinetic studies. In healthy subjects there was no interaction with diclofenac (28c), metformin (29c), ticlopidine (30c), or warfarin (31c). For tolbutamide the data were not consistent (27c,32c) and for midazolam there was a slight reduction in clearance (31c). Aspirin In a double-blind, double-dummy study in 50 healthy men (aged 20–44 years) aspirin alone (500 mg/day for 7 days) prolonged bleeding time and altered plate­ let aggregation; the addition of an extract of G. biloba, EGb 761, had no additional significant effect (33C). Cilostazol Co-administration of G. biloba with either cilostazol or clopidogrel did not enhance ex vivo antiplatelet activity compared with individual agents in a pharmacodynamic interaction study in male volunteers. How­ ever, there was significant potentiation of the prolongation of the bleeding time with the combination of cilostazol+G. biloba com­ pared with the two drugs individually (34c).

Glycyrrhiza spp. (Fabaceae, liquorice or liquorice root) (SED-15, 1311; SEDA-24, 538; SEDA-25, 569; SEDA-26, 531)

Endocrine Extracts of liquorice and glycyrrhizin, its principal component, have

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extensive use in foods, tobacco, and in both traditional and herbal medicines (35R). It is estimated that consumption of liquorice and glycyrrhizin by the US public ranges from 0.027 to 3.6 mg/kg/day of glycyrrhizin. Both products have been approved for use in foods by most national and supranational regulatory agencies. Glycyrrhizinates inhibit 11-hydroxysteroid dehydrogenase, the enzyme responsible for inactivating cortisol. As a result, continuous high exposure to glycyrrhizin compounds can produce mineralocorticoid-like effects in both animals and humans. The effects may be greater in men than in women (36c) and are reversible. Pseudoaldosteronism occurred in a 77-year-old Japanese man who took two Chinese herbal medicines containing gly­ cyrrhizin (Arejin for chronic allergic rhinitis and Daiokanzo-to as a laxative). The condition became manifest only when he developed symptoms related to hypokale­ mia when his dosage of enalapril was reduced (37A). In a study of the effects of liquorice in nine healthy women aged 22–26 years during the luteal phase of the menstrual cycle after 2 months consumption of 3.5 g/day of a commercial preparation of licorice (containing 7.6%, w/w, of glycyr­ rhizic acid), plasma renin activity, aldosterone, cortisol, serum parathyroid hormone (PTH), 1,25-dihydroxycolecalci­ ferol (1,25OHD), 25-hydroxycolecalciferol (25OHD), estradiol, FHS, LH, alkaline phosphatase, calcium, phosphate, and crea­ tinine, urinary calcium and phosphate, and mineralometry were measured (38c). PTH, 25OHD, and urinary calcium increased significantly from baseline after 2 months of therapy, while 1,25OHD and alkaline phosphatase did not change. All these parameters returned to pretreatment values 1 month after withdrawal of licorice. Plasma rennin activity and aldosterone were depressed during therapy, but blood pres­ sure and plasma cortisol were unchanged. The effects of liquorice on calcium metabo­ lism are probably mediated by several components of the root, which have aldos­ terone-like, estrogen-like, and antiandrogen activity.

752 Mutagenicity and teratogenicity Various studies have shown that glycyrrhizin is neither teratogenic nor mutagenic, and that it may even have antigenotoxic properties under certain conditions (34R).

Harpagophytum procumbens (Passifloraceae, Devil’s claw) The effect of Devil’s claw in osteoarthritis has been studied in a meta-analysis of 14 pub­ lished clinical trials (39M). Many of the published trials lacked important methodolo­ gical quality criteria, although the data from the higher-quality studies suggested that Devil’s claw reduces pain. Devil’s claw appears to be associated with minor risks relative to NSAIDs. However, the clinical evidence to date cannot provide a definitive answer to its claimed efficacy and safety. Further better designed clinical investigations are warranted.

Hydroxycut Hydroxycut formerly contained ma huang, an Ephedra-type alkaloid. However, since restrictions on the use of Ephedra as a dietary supplement were introduced in 2004, it has been reformulated as a caffeine-based Ephedra-free preparation. A 42-year-old man, previously healthy, developed malignant hypertension and hypertensive retinopathy while taking Hydroxycut (40A). Given the lack of investigative studies in regard to their safety and efficacy, judicious care should be taken with the use of all herbal supple­ ments, including those designated as Ephedra-free.

Morinda citrifolia (Rubiaceae, noni) (SED-15, 3085; SEDA-30, 554) Liver Noni, a Polynesian herbal remedy, is a tropical fruit that has been implicated in liver damage (41A).
A 24-year-old woman with multiple sclerosis

drank noni juice for 4 weeks and developed a mildly raised bilirubin concentration and

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K. Chan and T.X. Lin

serum transaminase activity after treatment with interferon beta-1a for 6 weeks. Interferon was withdrawn because of the possibility of drug-induced hepatitis, after exclusion of viral hepatitis due to hepatitis A–E. One week later she developed severe icterus, greatly raised bilirubin and transaminases, and a reduced prothrombin time, indicating impaired liver function with a suspicion of incipient acute liver failure. There was no evidence of hepatotoxic viruses, alcoholic hepatitis, Budd–Chiari syndrome, hemochromatosis, or Wilson’s disease. Fine-needle aspiration biopsy of the liver ruled out autoimmune hepatitis but showed signs of drug-induced toxicity. After withdrawal of the noni juice, her transaminase activities fell and were in the reference range within 1 month.

Several animal and human studies have shown that high doses of noni juice (up to 750 ml/day), many times greater than in any case reports, have not caused liver damage, as judged by liver function tests and histology (42r). The anthraquinones in noni juice, identified as causative agents in case reports, are of the wrong type and quantity to be of toxicological relevance. In reply the authors of the paper stated that it was not possible to rule out idiosyncratic noni-induced hepatotoxicity. This type of drug reaction is not doserelated in the therapeutic range of doses, is not reproducible in healthy volunteers or in animals, and can present with immu­ noallergic features.

Piper methysticum (Piperaceae; kava kava) (SED-15, 2837; SEDA-28, 578; SEDA-30, 554)

The effects of kava kava have been reviewed (43R). Its chief adverse effects are a dermopathy and liver damage. The efficacy and safety of kava kava (P. methysticum) have been analyzed in three double-blind, randomized, placebocontrolled trials in generalized anxiety dis­ order in 64 adult outpatients, including one study with an active comparator (venlafax­ ine) (44M). Since the study designs were comparable, the kava and placebo data were then pooled for further efficacy and safety analyses. There were no significant

Treatments used in complementary and alternative medicine

differences between the groups in any of the trials. In the pooled analyses, kava had no effects, while there was a significant effect in favor of placebo in participants with higher anxiety at baseline. There was no evidence of hepatotoxicity with kava.

PLANT TOXINS Anthraquinones Anthraquinones are found in rhubarb root, senna leaf and pod, Cascara sagrada, buckhorn, and aloe, all common components of herbal slimming regimens. Anthraquinones have several biological effects and adverse effects have been reported. The root contains a complex mixture of 2–5% anthraquinone derivatives (anthranoids), of which most are present as glycosides. After ingestion, colo­ nic bacteria metabolize the anthraquinone glycosides to anthranols, which are absorbed to a moderate degree and are excreted in the bile, saliva, milk, and urine. Rhubarb root has mainly been used traditionally for its laxative properties and in short-term ther­ apy. Since 1996 the Federal Institute for Drugs and Medical Devices in Germany has recommended that anthraquinone-contain­ ing laxatives should not be used continuously for periods exceeding 1–2 weeks. Urinary tract Acute renal failure has been associated with anthraquinones (45A).
A 23-year-old woman developed acute renal

failure with hypocellular interstitial fibrosis after prolonged use of a proprietary Chinese herbal slimming pill that contained anthraqui­ none derivatives, extracted from rhubarb. The renal damage was probably aggravated by concomitant use of diclofenac. Her renal function recovered after withdrawal of the slimming pills, but mild interstitial fibrosis and tubular atrophy was still evident histologically 4 months later.

Although a causal relation between the anthraquinone-containing agents and renal damage remains to be proven, phytother­ apy-associated interstitial nephropathy

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should be considered in patients who present with unexplained renal failure.

AROMATHERPY Aromatherapy uses essential oils created by distilling various plant-derived chemicals to create a concentration as great as 100 times. It should be used with caution. Aromatherapy preferences and complications in 3000 otolar­ yngology patients have been studied (46M). Among these patients, 1.67% had some form of complication induced by essential oils used in aromatherapy, including skin eruptions, respiratory distress, and other symptoms. Some patients (0.93%) refused aromatherapy because of individual preference and unplea­ sant smell. People should follow instructions at all times and should never use these oils for an extended period or overuse them.

CUPPING Skin Cupping, the therapeutic application of heated cups to the skin, is an East Asian and Oriental tradition, still in use in many cultures. Alcohol-soaked cotton in the cup is ignited and the cup immediately pressed tightly against the skin. The procedure usually lasts 5–20 minutes. The vacuum created during cupping breaks superficial capillaries and can cause circular erythema, edema, ecchymoses, purpura, burns, keloid, and factitious panniculitis.
A 57-year-old woman with a tender red patch on

her lower back reported that cupping had been performed 2 weeks before to relieve back pain (47A). However, the cup had been held on her skin for over 40 minutes. She experienced intense pain soon after the procedure, and bullae and crusting developed over the area during the following week. There was a 50-mm, circular, red patch on the right lumbar area, with several uniform intact vesicles, serous exudation, and crusting on the surface. Routine laboratory parameters were normal, except for a raised white blood cell count (14  109 per liter) and fasting blood glucose (9.28 mmol/l). Wet dressings and an antibiotic ointment led to complete resolution of the crusts and vesicles within 10 days.

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References 1. Dhalla S, Chan KJ, Montaner JSG, Hogg RS. Complementary and alternative med­ icine use in British Columbia—a survey of HIV positive people. Compl Ther Clin Pract 2006;12:242–8. 2. Constable S, Ham A, Pirmohamed M. Herbal medicines and acute medical emer­ gency admissions to hospital. Br J Clin Pharmacol 2007;63(2):247–8. 3. Cuzzolin L, Zaffani S, Benoni G. Safety implications regarding use of phytomedi­ cines. Eur J Clin Pharmacol 2006;62:37–42. 4. Barnes J, Mills SY, Abbot NC, Willoughby M, Ernst E. Different standards for reporting ADRs to herbal remedies and conven­ tional OTC medicines: face-to-face interviews with 515 users of herbal remedies. Br J Clin Pharmacol 1998;45:496–500. 5. Lee A, Chiu PT, Aun ST, Angel SC, Lau BSN, Gin T. Incidence and risk of adverse perioperative events among surgical patients taking traditional Chinese herbal medicines. Anesthesiology 2006;105: 454–61. 6. Greenway FL, Martin CK, Kai-yuen W, Nofzger J, Rood JC, Yu Y, Amen RJ. Safety and efficacy of NT, an herbal supplement, in treating human obesity. Int J Obes 2006;30:1737–41. 7. Hsu L-H, Huang Y-S, Tsay S-H, Chang F-Y, Lee S-D. Acute hepatitis induced by Chinese hepatoprotective herb, xiao-chai­ hu-tang. J Chin Med Assoc 2006;69(2): 86–8. 8. Yuen M-F, Tam S, Fung J, Wong DK-H, Wong BC-Y, Lai C-L. Traditional Chinese medicine causing hepatotoxicity in patients with chronic hepatitis B infection: a 1-year prospective study. Aliment Pharmacol Ther 2006;24:1179–86. 9. Wai CT. Presentation of drug-induced liver injury in Singapore. Singapore Med J 2006; 47(2):116–20. 10. Chinese Medicine Council of Hong Kong. http://www.cmchk.org.hk/pcm/eng/index.htm. 11. Department of Health. The Government of the Hong Kong Special Administrative Region. Recall of proprietary Chinese medicines with Western drug ingredient;

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9 June 2006, http://www.dh.gov.hk/english/ press/2006/060609.html. Jung J, Hermanns-Clausen M, Weinmann W. Anorectic sibutramine detected in a Chinese herbal drug for weight loss. Forensic Sci Int 2006;161(2–3):221–2. Saw JT, Baharia MB, Ang HH, Lim YH. Potential drug–herb interaction with antiplatelet/anticoagulant drugs. Compl Ther Clin Pract 2006;12:236–41. Hamre HJ, Witt CM, Glockmann A, Troger W, Willich SN, Kiene H. Use and safety of anthroposophic medications in chronic disease: a 2-year prospective ana­ lysis. Drug Saf 2006;29(12):1173–89. Poon WT, Lai CK, Ching CK, Tse KY, So YC, Chan YC, Hau LM, Mark TWL, Chan YW. Aconite poisoning in camouflage. Hong Kong Med J 2006;12:456–9. Chan K. Chinese medicinal materials and their interface with Western medical concepts. J Ethnopharmacol 2005;96:1–18. Chan K. Some aspects of toxic contami­ nants in herbal medicines. Chemosphere 2003;52:1361–71. Ohno Y. Experimental approach to murder by aconite poisoning from the viewpoint of medicolegal toxicology. Nihon Hoigaku Zasshi 2006;60(2):101–9. Lynch CR, Folkers ME, Huston WR. Fulminant hepatic failure associated with the use of black cohosh: a case report. Liver Transpl 2006;12(6):989–92. Minciullo PL, Saija A, Patafi M, Marotta G, Ferlazzo B, Gangemi S. Muscle damage induced by black cohosh (Cimicifuga racemosa). Phytomedicine 2006;13(1–2):115–8. Dugoua JJ, Seely D, Perri D, Koren G, Mills E. Safety and efficacy of black cohosh (Cimicifuga racemosa) during pregnancy and lactation. Can J Clin Pharmacol 2006; 13(3):e257–61. Anonymous. Citrus aurantium (bitter orange). Reports of adverse cardiovascular effects. WHO Pharm Newslett 2007;3:4. Kumar A, Teuber SS, Naguwa S, Prindi­ ville T, Gershwin ME. Eosinophilic gastroenteritis and citrus-induced urticaria. Clin Rev Allergy Immunol 2006;30(1):61–70.

Treatments used in complementary and alternative medicine 24. Pennisi RS. Acute generalized exanthema­ tous pustulosis induced by the herbal remedy Ginkgo biloba. Med J Aust 2006;184(11): 583–4. 25. Dugoua JJ, Mills E, Perri D, Koren G. Safety and efficacy of ginkgo (Ginkgo biloba) during pregnancy and lactation. Can J Clin Pharmacol 2006;13(3):e277–84. 26. Petty HR, Fernando M, Kindzelskii AL, Zarewych BN, Ksebati MB, Hryhorczuk LM, Mobashery S. Identification of colchi­ cine in placental blood from patients using herbal medicines. Chem Res Toxicol 2001; 14(9):1254–8. 27. Dugoua JJ, Mills E, Perri D, Koren G. Safety and efficacy of ginkgo (Ginkgo biloba) during pregnancy and lactation. Can J Clin Pharmacol 2006;13(3): e277–84. 28. Mohutsky MA, Anderson GD, Miller JW, Elmer GW. Ginkgo biloba: evaluation of CYP2C9 drug interactions in vitro and in vivo. Am J Ther 2006;13:24–31. 29. Kudolo GB, Wang W, Javors M, Blodgett J. The effect of the ingestion of Ginkgo biloba extract (EGb 761) on the pharma­ cokinetics of metformin in non-diabetic and type 2 diabetic subjects—a double blind placebo-controlled, crossover study. Clin Nutr 2006;25:606–16. 30. Lu WJ, Huang JD, Lai ML. The effects of ergoloid mesylates and Ginkgo biloba on the pharmacokinetics of ticlopidine. J Clin Pharmacol 2006;46:628–34. 31. Jiang X, Blair EY, McLachlan AJ. Inves­ tigation of the effects of herbal medicines on warfarin response in healthy subjects: a population pharmacokinetic–pharmacody­ namic modeling approach. J Clin Pharma­ col 2006;46:1370–8. 32. Uchida S, Yamada H, Li XD, Maruyama S, Ohmori Y, Oki T, Watanabe H, Umegaki K, ohaski K, Yamada S. Effects of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in healthy volunteers. J Clin Pharmacol 2006;46:1290–8. 33. Wolf HR. Does Ginkgo biloba special extract EGb 761 provide additional effects on coagulation and bleeding when added to acetylsalicylic acid 500 mg daily? Drugs R D 2006;7(3):163–72.

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34. Aruna D, Naidu MJ. Pharmacodynamic interaction studies of Ginkgo biloba with cilostazol and clopidogrel in healthy human subjects. Br J Clin Pharmacol 2007;63: 333–8. 35. Isbrucker RA, Burdock GA. Risk and safety assessment on the consumption of licorice root its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin. Regul Toxicol Pharmacol 2006;46:167–92. 36. Sigurjonsdottir HA, Axelson M, Johanns­ son G, Manhem K, Nyström E, Wallerstedt S. The liquorice effect on the RAAS differs between the genders. Blood Press 2006;15 (3):169–72. 37. Iida R, Otsuka Y, Matsumoto K, Kuriyama S, Hosoya T. Pseudoaldosteronism due to the concurrent use of two herbal medicines containing glycyrrhizin: interaction of gly­ cyrrhizin with angiotensin-converting enzyme inhibitor. Clin Exp Nephrol 2006; 10:131–5. 38. Mattarello MJ, Benedini S, Fiore C, Camozzi V, Sartorato P, Luisetto G, Armanini D. Effect of licorice on PTH levels in healthy women. Steroids 2006;71:403–8. 39. Brien S, Lewith GT, McGregor G. Devil’s claw (Harpagophytum procumbens) as a treatment for osteoarthritis: a review of efficacy and safety. J Altern Complement Med 2006;12(10):981–93. 40. Willis SL, Moawad FJ, Hartzell JD, Iglesias M, Jackson W. Hypertensive retinopathy associated with use of the Ephedra-free weight-loss herbal supplement Hydroxycut. Med Gen Med 2006;8(3):82. 41. Yüce B, Gülberg V, Diebold J, Gerbes AL. Hepatitis induced by noni juice from Morinda citrifolia: a rare cause of hepato­ toxicity or the tip of the iceberg? Digestion 2006;73:167–70. 42. West BJ. Hepatotoxicity from interferonbeta, not noni juice. Digestion 2006;74(1): 47–8. 43. Gounder R. Kava consumption and its health effects. Pac Health Dialog 2006;13 (2):131–5. 44. Connor KM, Payne V, Davidson JRT. Kava in generalized anxiety disorder: three placebo-controlled trials. Int Clin Psycho­ pharmacol 2006;21:249–53.

756 45. Kwan TH, Tang MKH, Lai CK, Poon WT, Chan YW, Au TC. Acute renal failure associated with prolonged intake of slim­ ming pills containing anthraquinones. Hong Kong Med J 2006;12(5):394–7. 46. Yoo K-M. Statistical analysis of aromather­ apy preferences and complications for 3000

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otolaryngology patients. Int J Aromather 2006;16:181–5. 47. Tuncez F, Bagci Y, Kurtipek GS, Erkek E. Suction bullae as a complication of pro­ longed cupping. Clin Exp Dermatol 2006;31: 281–305.

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49

Miscellaneous drugs, materials, medical devices, and techniques

Alcohol Nervous system The association between blood alcohol concentration and the presence and degree of amnesia has been investigated in actively drinking subjects (1C). A questionnaire was administered regarding any recent alcohol-associated arrest with a documented blood alcohol concentration over 80 mg/dl (14.3 mmol/l) for public intoxication, driving under the influence, or under-age drinking. Memory of the drinking episode was evaluated to determine if there had been either a grayout (partial anterograde amnesia) or a blackout (complete anterograde amnesia). There were differences in (1) the mean total number of drinks ingested before the arrest; (2) gulping of drinks; and (3) blood alcohol concentration at the time of arrest for those who had blackouts compared with no amnesia; while there were differences in drinking more than planned between those without amnesia and those with grayouts. There was a strong linear relation between blood alcohol concentration and the predicted probability of memory loss, particularly for blackouts. Subjects with a blood alcohol concentration of 310 g/dl or greater have a 0.50 or greater probability of having an alcoholic blackout. Gastrointestinal The role of alcohol in irritable bowel syndrome and dyspepsia is Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03149-3 r 2009 Elsevier B.V. All rights reserved.

not well understood. It has been hypothesized that people with psychological distress who drink no alcohol, or excess alcohol, are at increased risk. Gastrointestinal symptom surveys were mailed to randomly selected community residents to assess associations between alcohol use and irritable bowel syndrome, dyspepsia, and abdominal pain, using logistic regression adjusted for a Somatic Symptom Checklist (SSC) score (2C). A total of 4390 (80%) responded; of these, 11% reported irritable bowel syndrome, 2% dyspepsia, and 22% abdominal pain. Alcohol consumption of over seven drinks per week was associated with a higher chance of dyspepsia but not irritable bowel syndrome. However, there were significant interactions among sex, alcohol use, and SSC scores. In women with a low SSC score, consuming at least seven drinks per week increased the odds of irritable bowel syndrome compared with moderate consumption. Alcohol consumption was associated with dyspepsia and abdominal pain. There was a relation to irritable bowel syndrome when interactions with somatization and sex were appropriately considered. Whether these associations are due to the effects of alcohol on the gut or to a common central mechanism remains to be determined. Immunologic A 47-year-old man developed anaphylaxis, including generalized urticaria and swelling of the lips, after taking alcohol beverages (3A). He had previously been able to consume alcohol without problems. His serum IgE concentration was slightly raised (210 iu/ml). In a prick test, acetaldehyde produced slight erythema, but

757

758 only acetic acid produced a positive wheal in the patient but not in healthy volunteers. On the other hand, ethanol only caused erythema and no wheal, even in the scratch test. A mouthwash test with diluted ethanol was negative, suggesting that these urticarial reactions were not due to contact urticaria. The administration of 20% ethanol caused pruritus of the lips after 7 minutes and this symptom abated within 30 minutes. After oral challenge it became difficult for the patient to continue administration of ethanol because his tongue was irritated. The administration of 60 ml of 8% diluted Shochu (Japanese distilled alcohol from rice or wheat) caused pruritus of his lips after 10 minutes. When his symptoms started to improve another 60 ml of Shochu was added and this caused swelling of his lips and pruritus of the oral cavity. Drug abuse and dependence Alcohol abuse and dependence are among the most common psychiatric disorders in adolescents. Research on the development, diagnosis, course, treatment, and adult outcomes of adolescent alcohol use disorders has been reviewed (4R). A developmental history of childhood mental disorders, reflecting psychological dysregulation, predicts adolescent alcohol use disorders. The DSM-IV definitions of alcohol use disorders developed for adults are generally valid for adolescents, although some adolescents with significant alcohol problems are not identified by this diagnostic system. Adolescents with alcohol use disorders typically have other substance involvements, co-morbid mental disorders, and problematic family relationships. While the medical complications seen in adults with chronic alcoholism are typically absent, acute complications of intoxication, such as alcohol poisoning or traumatic injury, can contribute to excess mortality in adolescents. Psychosocial interventions promoting abstinence are the most common treatments for alcohol use disorders, and there is credible empirical support for family-based approaches. While few drug trials have been completed for adolescents with alcohol use disorders, pharmacological interventions are available for alcohol withdrawal, craving, and co-morbid mental disorders. Some

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adolescents with alcohol use disorders develop chronic alcoholism in adulthood; many others switch to abstinence or normative drinking. Alcohol abstinence is the primary treatment focus, although other complications need to be addressed and treated to foster optimal outcomes. Tumorigenicity Alcohol consumption is increasing in many countries and is an important cause of cancer worldwide. A causal association has been established with cancers of the oral cavity, pharynx, larynx, esophagus, liver, colon, rectum, and (in women) breast; an association is suspected for cancers of the pancreas and lung. Evidence suggests that the effect of alcohol is modulated by polymorphisms in genes that encode enzymes for ethanol metabolism (e.g. alcohol dehydrogenases, aldehyde dehydrogenases, and CYP2E1), folate metabolism, and DNA repair (5C). The mechanisms by which alcohol consumption is carcinogenic have not been defined, although plausible events include: a genotoxic effect of acetaldehyde, the main metabolite of ethanol; increased estrogen concentration, important for breast carcinogenesis; a role as solvent for tobacco carcinogens; production of reactive oxygen species and nitrogen species; and changes in folate metabolism. The numbers of cancer cases and deaths attributable to alcohol drinking in 2002 by sex and WHO subregion have been estimated, based on the relative risks of cancers of the oral cavity, pharynx, esophagus, liver, colon, rectum, larynx, and female breast obtained from recent meta-analyses and pooled analyses and from data on the prevalence of drinkers obtained from the WHO Global Burden of Disease project (6S). A total of 38 9100 cases of cancer are attributable to alcohol drinking worldwide, representing 3.6% of all cancers (5.2% in men, 1.7% in women). The corresponding figure for mortality is 232 900 deaths (3.5% of all cancer deaths). This proportion is particularly high among men in Central and Eastern Europe. Among women, breast cancer comprises 60% of alcohol-attributable cancers. Although these estimates are based on simplified assumptions, the burden of alcohol-associated cancer appears to be substantial and needs to be considered when

Miscellaneous drugs, materials, medical devices, and techniques

making public health recommendations about drinking alcohol. Teratogenicity The adverse effects of alcohol on the developing fetus comprise a spectrum of structural anomalies and behavioral and neurocognitive disabilities, most accurately termed fetal alcohol spectrum disorders (fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopment disorder). An international consortium of projects aimed at more complete characterization of the teratogenic spectrum of alcohol has been established; one of the project’s sites is in Finland (7A). The aims of this project were: (1) to characterize completely the structural and learning/behavioral phenotypes of a large group of older children and adolescents with moderate to severe disability within the fetal alcohol spectrum disorders continuum; (2) to correlate fetal alcohol dysmorphology and behavioral phenotypes with nervous system structure and function; (3) to compare the phenotype of a genetically homogeneous population of Finnish children with fetal alcohol spectrum disorders to that observed in other populations. The sex ratio of the cohort was 0.38 (male:female) and ages were 8–20 (mean 13) years. After application of the Revised IOM Diagnostic Criteria, 53% of the subjects were diagnosed as having fetal alcohol syndrome, 30% partial fetal alcohol syndrome, 12% alcohol-related neurodevelopment disorder, and 5% other diagnoses. Although a family history of mental retardation of birth defects was rare, 43% of the children had one or more sibling with a diagnosis of fetal alcohol syndrome. Most of the mothers (89%) smoked cigarettes during gestation; other teratogenic exposures were rare. Almost none had undergone genetic evaluation in the past. Almost all of the subjects had resided in multiple foster placement since early childhood and had been followed regularly by pediatric specialists. Although 11% were born prematurely, 70% had prenatal growth deficiency and 45% were microcephalic. Other than growth deficits and cardinal facial features, the most common major and minor anomalies were: camptodactyly (55%), “hockey stick” or other altered palmar creases (51%), refractive errors (40%), strabismus (38%), dental

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crowding (42%), nail hypoplasia (38%), genitourinary anomalies (22%), and congenital heart defects (18%). “Railroad track” ears were not observed in this population.

Antimisting agents Sensory systems Ocular epithelial damage has been attributed to an antimisting agent in swim goggles (8A).
A 47-year-old man felt sudden ocular pain and

grit after pool water flooded his goggles while swimming. Before the swim he had sprayed a copious amount of an antimisting agent inside his goggles. There was a severe corneal epithelial defect and stromal edema in the right eye. Best-corrected visual acuity was 20/40. Right eye corneal thickness was 625 mm. He was given topical glucocorticoids, antibiotic eye-drops, and oral tetracycline. After 1 week, the epithelial defect in the right cornea and the stromal edema improved slightly; the epithe­ lial defect healed completely after 3 months with a residual mild diffuse superficial stromal opacity, which later resolved. However, at 1 year there were white subepithelial plaques in the corneae, which responded to a topical glucocorticoid.

The antimisting agent was a mixture of chemicals, including methanol, ethanol, and surfactants, and had been stored for 3 years; the culprit in this case was not clear.

Calabash chalk Pregnancy Calabash chalk, which is generally sold loose, is not authorized for sale in Canada, but is used there by some pregnant women for alleviation of morning sickness. Health Canada has issued an Advisory notice, warning Canadians not use calabash chalk, especially women who are pregnant or breast-feeding. The chalk contains arsenic and large amounts of lead, both of which have been associated with adverse effects (9S). The Agency has warned that after exposure to lead, the developing child is at particular risk of adverse effects on the nervous system and

Chapter 49

760 neurological development, and that the adverse effects associated with excessive long-term arsenic exposure include urinary, bladder, skin, and lung cancers.

Disulfiram

(SED-15, 1148)

Liver There are few systematic data on the incidence of drug-induced hepatotoxicity due to disulfiram and the most important prognostic markers. The nature and the frequency of suspected disulfiram hepa­ totoxicity has been studied in a review of all reports of suspected hepatic adverse drug reactions associated with disulfiram received by the Swedish Adverse Drug Reactions Advisory Committee [SADRAC] during 1966–2002 (10S). Causality assessment was based on the International Consensus Criteria. There was a possible causal relationship in 82 reports. Eight patients died or underwent liver transplantation. Mortality or transplantation was 16% in patients with jaundice. The median age of the patients (65% men) was 45 years and the median duration of treatment was 42 days. Bilirubin concentration was higher in the diseased/ transplanted patients compared with the surviving patients. There was no difference in age or duration of therapy between those who died or needed a transplant and those who recovered. Eosinophilic infiltration in liver biopsies was associated with a favorable outcome and hepatocyte drop-out with a poor outcome. The authors concluded that disulfiram-associated hepatitis has a considerable mortality risk. Histological signs of immunoallergy are common.

DYESTUFFS Indocyanine green

(SED-15, 2595;

SEDA-30, 566) Indocyanine green is a dye that has been used to measure cardiac output, liver function, and in ophthalmic angiography.

N.H. Choulis

Indocyanine green is used to staining the anterior capsule and internal limiting membrane of the eye to facilitate their removal. The safety of intraocular indo­ cyanine is still of concern. There have been six cases of indocyanine-related toxicity after indocyanine-assisted peeling of the internal limiting membrane (11A). In five cases there was a preoperative diagnosis of a macular hole; one had preoperative rhegmatogenous retinal detachment complicated by proliferative vitreoretinopathy. All underwent vitrect­ omy, indocyanine-assisted peeling of the internal limiting membrane, and air–fluid exchange. All the eyes contained residual indocyanine at the end of surgery. The patients were followed up with indirect ophthalmoscopy, visual acuity measure­ ment, color fundus photography, fluores­ cein angiography, and ocular coherence tomography. There was circular foveal retinal pigment epithelium atrophy larger than the area of the macular hole and the surrounding cuff in four of the five cases with a preoperative macular hole. The other eye had a shallow anterior chamber and a low intraocular pressure for 1 week postoperatively. There was diffuse retinal pigment epithelial atrophy in the eye with preoperative proliferative vitreoretinopa­ thy. Four eyes had optic atrophy post­ operatively. To prevent toxicity, residual indocyanine and indocyanine-stained internal limiting membrane must be removed as completely as possible. Another patient had indocyanine green staining of the anterior capsule for pha­ coemulsification of a traumatic cataract (12A). Intraoperatively, the indocyanine extended into the posterior segment. Post­ operatively, the patient developed indo­ cyanine toxicity in the retina and had a vitrectomy to remove the indocyanine. It is believed that indocyanine extended into the vitreous through an area of zonular dehiscence. The kinetics of indocyanine after intrao­ cular surgery has been examined in nine eyes of seven patients with white cataracts and 14 eyes of 14 patients with idiopathic holes, using the indocyanine angiographic mode of a scanning laser ophthalmoscope

Miscellaneous drugs, materials, medical devices, and techniques

(in vivo) and fluorescence microscopy (in vitro) after circular curvilinear capsulorhexis with indocyanine staining during cataract surgery and peeling of the internal limiting membrane with indocyanine staining during macular hole surgery (13A). Scanning laser ophthalmoscopy showed fluorescence in the anterior segments of the eyes of patients with cataracts on the first postoperative day, and fluorescence remained for a mean of 6 days postoperatively. Scanning laser ophthalmoscopy also showed fluorescence in the posterior pole of the eyes of patients with macular holes, and it remained for a mean of 2.7 months postoperatively. Fluor­ escence microscopy showed fluorescence of the entire tissue, suggesting that indocyanine had not only stained the surface of the membranes but had also entered them. In both operations, visual outcomes were not significantly different from the results obtained without indocyanine. Because entire tissues were stained, the differences in indocyanine kinetics might also be caused by factors other than differences in stain­ ability, such as the environment surrounding the tissues or molecular structural differ­ ences between the lens capsule and the internal limiting membrane. Although the fluorescence completely disappeared and there was good functional recovery, the longer resident time of the dye after macular hole surgery suggests a potential risk to intraocular tissues.

Hydrogen peroxide

(SEDA-29, 379)

Gastrointestinal After taking an amount of 3% hydrogen peroxide solution, a 25-year-old woman developed epigastric pain and vomiting (14A). Endoscopy and CT imaging showed hemorrhagic gastritis and portal venous gas emboli. While gas emboli have been described with hydrogen peroxide ingestion, it is unusual to develop this complication from a solution of low concentration. There is no specific treatment for ingestion of hydrogen peroxide, but in patients with symptoms a careful examination to exclude gastrointestinal injury and gas emboli should be performed.

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Latex allergy Allergy to natural rubber latex proteins continues to be an important medical problem not only among health-care professionals, but also in children who have undergone many operations. Clinical manifestations range from urticaria to angioedema, rhinoconjunctivitis, bronchial asthma, and anaphylactic shock. Latex allergy has again been reviewed (15R–17R,18r). Medical devices that can cause a risk of reactions include elastic bandages, tourniquets, urinary catheters, drainage tubes, and taping; domestic devices include rubber insoles, toy balloons, latex mattresses, household rubber gloves, work gloves, inflatable floating mattresses (19E). There is also an association with allergies to certain fruits (avocado, banana, chestnut, fig, kiwi, mango, melon, papaya, passion fruit, peach, pineapple, and tomato) (20R). This may be associated with the enzyme endo-beta-1,3-glucanase, since the glucanase in bananas has allergenic properties mediated by well-conserved IgE-binding epitopes on the surface of the enzyme, which might account for the IgE-binding cross-reactivity that is often reported in people with the latex–fruit syndrome (21E). Prevalence The prevalence of latex allergy depends on the method used to identify it. Latex allergy has been studied in 182 children using a standardized questionnaire, skin prick testing with a battery of common aeroallergens as well as latex, and measurement of serum total IgE, Phadiatop, F x 5E, and latex-specific IgE; specific IgE to fruits that cross-react with latex was determined in latex-sensitized children (22C). Based on the questionnaire, the prevalence of latex allergy was 0.5%; based solely on skin prick testing the prevalence was 3.8%; based on latex-specific IgE, it was 12% at a threshold of 0.35 IU/ml and 6.6% at a threshold of 0.70 IU/ml. Based on positive results for either test, the prevalence of latex sensitization was 14%. All the latexsensitized children were atopic. There was

762 sensitivity to foodstuffs that cross-react with latex in 16 of 26 latex-sensitized children. The authors concluded that assessment of latex allergy and sensitization should always include skin prick testing and determination of serum IgE. There is an increased risk of latex allergy among health-care workers. In a metaanalysis of studies in French health-care workers, latex allergy was found in 4.32% (range 4.01–4.63%) of health-care workers and in 1.37% (range 0.43–2.31%) of the general population (23M). Latex-positive skin prick test responses ranged from 2.1% to 3.7% in the general population and from 6.9% to 7.8% in health-care workers. In health-care workers exposed to latex there was an increased risk of hand dermatitis (OR ¼ 2.46; 95% CI ¼ 2.11, 2.86), asthma or wheezing (OR ¼ 1.55; 95% CI ¼ 1.15, 2.08), rhinoconjunctivitis (OR ¼ 2.73; 95% CI ¼ 1.97, 3.81), and at least one generic symptom (OR ¼ 1.27; 95% CI ¼ 1.09, 1.47). Sensitization to latex was significantly associated with asthma and rhinoconjunctivitis. In contrast, exposure to latex was not associated with a significantly increased risk of positive skin prick test responses to latex (OR ¼ 1.47; 95% CI ¼ 0.94, 2.30). In three hospitals in Dakar, Senegal, 140 health-care workers were required to use latex gloves in their work (median age 39 years, sex ratio 0.57); 66 (47%) had familial atopic dermatitis, 13 (9.6%) had atopic dermatitis, and four (2.9%) had food allergies (banana, avocado) (24c). There was irritant dermatitis in 57 (41%) and 112 (81%) used bleach and water to clean their hands. Antiseptics were often used: 76% of those examined used them more than three times a day. None of the health-care workers was allergic to latex condoms. In 15 cases, of whom 12 were women, latex gloves caused contact urticaria or immediate pruritus (n ¼ 8), contact dermatitis (n ¼ 6), combined contact dermatitis and contact urticaria (n ¼ 2), allergic conjunctivitis (n ¼ 1), allergic rhinitis (n ¼ 2), and asthma (n ¼ 2). Rechallenge tests were performed in seven cases—2/3 prick tests and 1/4 patch tests (standard European battery) were positive. Allergy to latex gloves was significantly associated with atopy and irritant dermatitis.

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These results underline the importance of prophylactic measures to avoid exposure, not only in the sanitary environment, with adoption of latex-safe routes, but also in daily life, to prevent potentially serious allergic reactions. In a questionnaire study of ambulance workers in South Australia and Western Australia, 2716 forms were distributed and 1099 (41%) were returned (25c). Atopy was identified in 15%, hand dermatitis in 9.4%, and latex allergy in 6.4%. In full-time ambulance officers, there was a significantly higher incidence of hand dermatitis and latex allergy. There was a significant relation between latex allergy and both dermatitis and glove usage. In 130 nurses assigned to operating theaters and intensive care units, the serum total IgE concentration was raised in 22, three of whom had increased latex-specific IgE (26c). Susceptibility factors Children with spina bifida have a high degree of exposure to latex products as a consequence of repeated surgical procedures, implantation of latex-containing materials, and catheterization. They therefore have a higher incidence of latex-allergic reactions. The prevalence of latex sensitization and allergy and the associated susceptibility factors have been studied in 60 children with myelomeningocele (27c). There was latex sensitization with specific IgE W0.7 kU/l in 29 (48%), while nine were allergic to latex (specific IgE W0.7 Ku/l and clinical manifestations). The principal factor that correlated with allergy to latex was latex-specific serum IgE. Between 1998 and 2004, of 6832 patients who underwent 7333 operations, 26 had latex allergy (28C). The major susceptibility factors were atopy, congenital malformations that are often associated with latex allergy, and five or more surgical procedures. Six of the 26 patients had only one risk factor (atopy) and eight had simultaneously nine of the 10 factors that were analyzed. Management Avoidance of unnecessary use of gloves, the use of non-powdered latex gloves, and the use of non-latex gloves by sensitized subjects can stop the progression

Miscellaneous drugs, materials, medical devices, and techniques

of symptoms of latex allergy and reduce the risk of new cases of sensitization. In 1040 health-care workers a change to a glove powder-free environment significantly improved or eliminated symptoms (29C). Latex-specific immunotherapy has been studied in 23 sensitized patients, most often health-care workers, 20 of whom also had asthma, in a randomized, double-blind, placebo-controlled trial (30C). Conjunctival provocation tests and quantitative skin prick tests were also performed. The clinical index (derived by combining changes from baseline of six efficacy variables during the treatment period) did not differ significantly between the groups. Changes from baseline in rhinitis, conjunctivitis, skin symptoms, asthma symptoms, medication score, and skin reactivity were not significantly different. There was a non-significant difference in conjunctival reactivity in favor of the active treatment. Systemic reactions were much commoner with the specific immunotherapy than placebo. The failure of this study to show significant improvement in symptoms and medication scores was probably due to the low level of symptoms at baseline and the low maintenance dose of therapy, even if allergen-specific conjunctival reactivity improved in the active group. Moreover, the incidence of systematic reactions was very high in the active group. Latex desensitization has been attempted in 10 children aged 4–16 years with a history of multiple surgical procedures and latex allergy (31c). They had adverse reactions to latex and positive skin tests to latex and/or specific immunoglobulin E (IgE). The diagnosis was confirmed by specific provocation tests (cutaneous, sublingual, mucous, and conjunctival). Sublingual desensitization was performed over 4 days with increasing doses of latex extract up to 500 mg, followed by 10 drops of undiluted solution three times a week. For over 2 years there were no significant variations in mean concentrations of specific IgG4 and IgE, total IgE, or eosinophilic cationic protein. There were no adverse effects during the initial phase and only two patients had mild local symptoms during maintenance therapy. The results of challenge tests showed reduced percentage positivity and mean scores, and patients who underwent dental examination or surgery had no symptoms.

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Methylthioninium chloride (methylene blue) (SED-15, 2314; SEDA-28, 595; SEDA-29, 610; SEDA-30, 569) Systematic reviews In a systematic review to determine if methylthioninium chloride improves hemodynamic status and/ or outcomes in patients with septic shock, studies were identified from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials database (32M). Methylthioninium chloride increased mean arterial pressure and systemic vascular resistance and reduced vasopressor requirements. Increased pulmonary vascular resistance can occur with bolus administration but might be avoided by continuous infusion. No other ill effects were reported. Effects on mortality have not been adequately evaluated. Sensory systems Corneal endothelial decompensation and iris pigment dispersion have been reported after the inadvertent use of methylthioninium chloride 1% for cap­ sular staining during cataract surgery (33A).
During an otherwise routine phacoemulsifica­

tion cataract operation, inadvertent anterior capsule staining was performed with methylthioninium chloride 1% instead of trypan blue 0.025%. The anterior chamber with balanced salt solution was copiously irrigated as soon as the wrong dye was identified. The operation was completed with minimal ultra­ sound energy without complications. Iris dis­ coloration and severe corneal edema developed in the early postoperative period, resulting in severe visual loss. The patient developed a bullous keratopathy and under­ went penetrating keratoplasty 16 months later.

Nicotine

(SED-15, 2508; SEDA-28, 596; SEDA-29, 610; SEDA-30, 571)

Psychological When smokers who have been briefly deprived of cigarettes are given

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764 nicotine, they display a range of psychobiological “gains”, with improved cognitive performance, feelings of contentment, and reduced feelings of stress or depression. However, abstinence leads to reductions in all these functions. The balance between the deficits of nicotine deprivation and the gains of reinstatement has been long debated, but it is still controversial whether nicotine is beneficial, neutral, or detrimental (34r). Beginning to smoke during adolescence is often followed by increased feelings of stress and depression, whereas quitting is often associated with mood gains. Short-term prospective studies have shown that the essence of nicotine dependence is repetitive vacillation. Mood gains from smoke inhalation represent temporary reversal of abstinence effects, and the frequent experience of negative states in between cigarettes explains why smoking can increase distress. This may also be linked to Diathesis–Stress models. If withdrawal symptoms reflect the exacerbation of natural predispositions, “disadvantaged” smokers will suffer the worst abstinence symptoms and develop the strongest nicotine dependence. This explanation contrasts with the self-medication model, which focuses on the immediate benefits of smoke inhalation, rather than the overall costs of nicotine use, and the frequently experienced negative psychological states in between cigarettes therefore help to explain why nicotine dependence is associated with a range of problems. Chronic smoking and nicotine exposure are accompanied by impaired cognitive task performance, modulated cerebral activity in brain imaging studies, and neuritic damage in experimental animals. The profile of the described dysfunctions matches frontal lobe circuits, which also play a role in reward processing and reinforcement behavior. However, it is largely unknown whether cerebral dys­ function is reversible or persists during long-term abstinence. For this reason cortical activation during auditory target processing (oddball task, P300 component) was recorded with 32-channel electroence­ phalography in 247 healthy subjects (84 smokers, 53 former smokers, mean

N.H. Choulis

time of abstinence 12 years, and 110 never smokers) (35c). Both current smokers and former smokers had significantly reduced P300 amplitudes relative to the never smo­ kers. Neuroelectric source analysis (low resolution brain electromagnetic tomogra­ phy) showed hypoactivation of the anterior cingulate, orbitofrontal, and prefrontal cortex in smokers compared with never smokers. There was a similar profile of hypoactivation in former smokers. The authors therefore concluded that dysfunctional activation of frontal lobe networks in smokers is also present in long-term abstainers. The differential effects of nicotine on alcohol consumption in 22 men and 12 women have been studied in a three-session, double-blind, within-subject study (36C). They were pretreated with transdermal nicotine (7 or 14 mg) or placebo, followed 2 hours later by an alcoholic beverage and subsequent opportunities to “purchase” and consume more of the same drink. Nicotine increased alcohol consumption in men, but reduced it in women. These effects were even more pronounced after excluding those who reported nausea after nicotine. Nicotine alone increased subjective arousal in men but impaired positive mood in women. Nicotine increased the sedative-like effects of alcohol in both sexes. These findings suggest that both the subjective effects of nicotine and the effects of nicotine on alcohol consumption differ markedly in men and women.

Paraffins

(SED-15, 2693)

Respiratory Exogenous lipid pneumonia is uncommon and most cases are related to aspiration of liquid paraffin taken for constipation. Occupational lipid pneumonia is rare—only four of 44 cases reported in a French nationwide retrospective study (37c). Very few well-documented cases have been published. Severe interstitial pulmonary disease induced by occupational exposure to paraffin, leading to delayed fibrosis over 25 years, despite cessation of exposure, has been reported (38A).

Miscellaneous drugs, materials, medical devices, and techniques

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A 35-year-old non-smoking woman devel­

oped exertional dyspnea, purulent sputum, and weight loss. She had no significant medical history and did not take any medicines. She was an unskilled worker in a cardboard crockery factory, tending and refilling a machine that covered cardboard plates and cups with paraffin for water­ proofing. Solid blocks of paraffin were introduced into the machine and heated, with subsequent release of fumes and projection of paraffin droplets. The work­ shop contained several of these machines, with no ventilation system. Pipes were covered by a thick coat of paraffin. At the end of the shift, the workers had white hair, due to deposition of aerosolized paraffin. Paraffin was the only form of occupational exposure in this workshop. She had bilateral crackles at both lung bases. Pulmonary function tests showed a restrictive pattern (vital capacity 45% of predicted, total lung capacity 66% of predicted); the diffusion capacity for CO was 30% of predicted, PaO2 was normal (12.4 kPa, 93 mmHg), but PaCO2 was slightly reduced (4.3 kPa, 32 mgHg). A chest X-ray was normal. Bronchoalveolar lavage showed an increased total cell count, with a high percentage of lymphocytes (58%); alveolar macrophages contained numerous large empty vacuoles that stained with oil red. Exposure to paraffin was discontinued and she was given a glucocorticoid. Her respira­ tory function improved (vital capacity 70%, total lung capacity 75%), but the exertional dyspnea, cough, and sputum production persisted, with frequent exacerbations. Radiological investigations remained normal or near normal for 10 years, after which a slight interstitial infiltrate appeared on the chest X-ray, characterized by discrete bilat­ eral ill-defined reticulonodular opacities, mainly in the lower lungs; a small sub­ pleural condensation in the right lower lobe was also detected on high-resolution com­ puted tomography. Progressive fibrosis appeared, with loss of volume, haziness, and a diffuse reticulonodular pattern. There was also progressive deterioration of pul­ monary function tests and blood gases, despite continued glucocorticoid therapy.

Repeated occupational inhalation of paraffin can lead to severe pulmonary fibrosis. In the absence of curative treatment, primary prevention in the workplace remains essential. The various forms of exposure should be carefully monitored by occupational physicians, especially when paraffin may be aerosolized, particularly in cardboard crockery factories and the automobile industry.

Phosphatidylcholine Subcutaneous injections of phosphatidyl­ choline are used internationally for loca­ lized subcutaneous fat reduction on the face and body. Observational studies In a retrospective assessment of the treatment outcomes and adverse effects associated with the use of subcutaneous phosphatidylcholine, 39 UK doctors specifically trained and experienced in this treatment completed questionnaires related to 10581 treatments that had been administered over a mean duration of 13 months (39c). Localized adverse effects (swelling, erythema, burning/stinging, pain, tenderness, and bruising) were described by most patients as “very mild” (18%) or “mild” (39%). The total incidence of systemic adverse effects was 3%: diarrhea, nausea, dizziness/light-headedness, and intermenstrual bleeding were described by most patients as “very mild” (36%) or “mild” (55%). Only 15 (0.14%) “unex­ pected, unusually severe, or prolonged” adverse reactions (commonly pain and/or swelling) were reported, all self-limiting and none serious. Other studies have been carried out on orbital fat tissue, which, while important in protecting the eye, can protrude during aging (“baggy eyes”), making a patient look “tired”. Surgical correction, although traditionally the treatment of choice, can lead to scarring, Phosphatidylcholine reduces the size of these fat pads after direct injection. However, there is a dearth of clinical data relating to efficacy and adverse effects. In an open study in 21 subjects, who had injections of phosphati­ dylcholine, 0.4 ml every 6 weeks, into infraorbital fat pads 74% had significant improvement after two or three treatments (40c). Five had no response after two or more procedures and treatment was dis­ continued. None had adverse effects other than mild burning, erythema, and swelling at the injection site.

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766

Silicone

(SED-15, 3137; SEDA-29, 611)

Two patients presented with orbital cysts 5 and 7 years after their orbital blowout fractures had been repaired with silicone plate implants (41A). The orbital cysts caused significant exophthalmos and restricted ocular motility. Surgical excision revealed thick-walled cysts that were displa­ cing the globe and encapsulating the silicone implant. Histopathology showed that the cysts were lined with both stratified squa­ mous and ciliated columnar (respiratory) epithelia. The authors proposed that squa­ mous and respiratory epithelial cells may have been deposited during surgery from the conjunctival and sinus epithelia, respectively. A transconjunctival surgical approach is a possible risk factor.

Talc

(SED-15, 3592; SEDA-29, 612)

Talc is currently the preferred agent for pleurodesis, but there are growing concerns about its safety. In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) has stated that talc formulations for pleurodesis are to be treated as medicinal products, because they promote an inflammatory reaction in the tissues through a metabolic/immunological response after exposure (42S). The MHRA has, therefore, treated these products as medicines that will require a manufacturing authorization from 1 January 2008. Urinary tract The prevalence of renal insufficiency in patients undergoing thoraco­ scopy with talc poudrage pleurodesis has been examined in a retrospective chart review of 120 patients who underwent thoracoscopy with talc pleurodesis from August 1995 to March 2004 (43A). There was a malignant pleural effusion in 110 cases, the most common malignancies being lung and breast cancer. Nine patients (7.5%)

N.H. Choulis

developed renal insufficiency, four recov­ ered to baseline renal function, three had persistent renal insufficiency, and two devel­ oped anuric renal failure. All had a malig­ nant pleural effusion. The mean amount of talc used was 7.5 (range 1–12) g. Comparing the affected patients with the rest, there were no statistical differences in age, sex, or race, the amount of talc used, fluid balance, or the mean arterial pressure in the operating room and on postoperative day 1. Whether renal insufficiency in such cases is due to a systemic inflammatory reaction or to systemic distri­ bution of talc itself is not known. Skin A boy developed multiple facial granulomas, which persisted for more than 6 months, related to the use of topical antipruriginous talc powder applied to papuloex­ udative lesions caused by varicella (44A). Talc was identified in the lesions by examination with polarized light and electron microscopy.

DEVICES Drug-eluting stents The Swedish Medical Products Agency, in conjunction with the National Board of Health and Welfare and the Swedish Society of Cardiology, has recommended utmost restraint in the use of drug-eluting stents. The recommendation was based on the results of clinical studies, including the Swedish Coronary and Angioplasty Regis­ try (SCAAR) study, in which there was an increased risk of thrombosis associated with the use of drug-eluting stents (45S). The results of the SCAAR study and four other randomized studies showed that drug-elut­ ing stents have no advantages in terms of myocardial infarction or mortality, com­ pared with bare metal stents; indeed, there was a small long-term increased risk of these events. According to the Medical Products Agency, drug-eluting stents must not be used in patients unless no alternative exists or in patients who are at greatly increased risk of restenosis and for whom the effect of restenosis is expected to be severe.

Miscellaneous drugs, materials, medical devices, and techniques

Syringes A foreign body was found in a propofol syringe into which lidocaine was aspirated

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767

(46A). The foreign body consisted of sheared material from the syringe plunger. Pieces of the plunger can easily be sheared into a syringe by passing a needle through it.

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32. Kwok ES, Howes D. Use of methylene blue in sepsis: a systematic review. J Intensive Care Med 2006;21(6):359–63. 33. Brousas D, Droutsas D, Charakidas A, Malias I, Georgiadou E, Apostolopoulos M, Moschos M. Severe toxic effect of methylene blue 1% on iris epithelium and corneal endothelium. Cornea 2006;25(4): 470–1. 34. Parrott AC. Nicotine psychobiology: how chronic-dose prospective studies can illuminate some of the theoretical issues from acute-dose research. Psychopharmacology 2006;184(3):567–76. 35. Neuhaus A, Bajbouj M, Kienast T, Kalus P, Von Haebler D, Winterer G, Gallinat J. Persistent dysfunctional frontal lobe activa­ tion in former smokers. Psychopharmacology 2006;186(2):191–200. 36. Acheson A, Mahler SV, Chi H, De Wit H. Differential effects of nicotine on alcohol consumption in men and women. Psychopharmacology 2006;186(1):54–63. 37. Gondouin A, Manzoni P, Ranfaing E, Brun J, Cadranel J, Sadoun D. Exogenous lipid pneumonia: a retrospective multicenter study of 44 cases in France. Eur Respir J 1996;9:1463–9. 38. Descatha A, Mompoint D, Ameille J. Occupational paraffin-induced pulmonary fibrosis: a 25-year follow-up. Occup Med 2006;56(7):504–7. 39. Palmer M, Curran J, Bowler P. Clinical experience and safety using phosphatidylcholine injections for the localized reduction of subcutaneous fat: a multicenter, retrospective UK study. J Cosmet Dermatol 2006;5(3):218–26. 40. Treacy PJ, Goldberg DJ. Use of phos­ phatidylcholine for the correction of lower lid bulging due to prominent fat pads. J Cosmet Laser Ther 2006;8(3): 129–32. 41. Tan CSH, Ang LPK, Choo CT, Cheah EST, Chee SP. Orbital cysts lined with both stratified squamous and columnar epithelia: a late complication of silicon implants. Ophthal Plastic Reconstr Surg 2006;22(5): 398–400. 42. Anonymous. Talc preparations for pleuro­ desis. To be treated as medicines. WHO Pharm Newslett 2007;5:5.

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45. Anonymous. Drug-eluting stents. To be used with utmost restraint. WHO Pharm Newlett 2007;2:1. 46. Cohen S, Prieto N, Hunter CH. A foreign body in propofol syringe. Anesth Analg 2006;103(3):784.

Index of drugs Note. Boldface page numbers refer to main discussions. A abacavir, 482 comparative studies, 480 hypersensitivity, 482–483 immunologic effects, 482 therapy, + lamivudine + zidovudine, 482 acarbose and gliclazide, 698 liver effects, 691–692 observational studies, 691 acebutolol, 261–262 aceclofenac, 186 ACE inhibitors, see also specific drugs angioedema, 350, 352–354 and calcium channel blockers, 349 and cough, 354, 360 drug–drug interactions, 354–355 dual therapy with, 371 electrolyte balance, 350 lithium toxicity, 26 pancreas effects, 350 renoprotective effect of, 351 respiratory effects, 350 safety aspects of, 351 treatment, early in pregnancy, 354 teratogenicity, 354 urinary tract, 351–352 acetaminophen see paracetamol acetazolamide placebo-controlled studies, 371 urinary tract, 371 acetylcholinesterase inhibitors, 272–273 acetylsalicylic acid, 193 drug–drug interactions, 200 exacerbated respiratory disease, 193–196 gastrointestinal effects, 198 hematologic effects, 197–198 nervous system effects, 196–197 not associated with risk, 150 overdose, 200 during pregnancy, 199 resistance, 198–199 respiratory disease, 193–196

susceptibility factors, 199–200 urinary tract, 198 aciclovir formulations, 480 observational studies, 478 psychiatric effect, 478–475 urinary tract, 480 acitretin, 291 Aconitum spp., 748–745 adalimumab administration route, 599 dosage regimens, 599 FDA approval, 594 granulomatous diseases, 595 hematologic effects, 598 immunologic effects, 599 placebo-controlled studies, 597 randomized controlled trials, 594 respiratory effect, 597–598 sensory system effects, 598 skin, 598 tumorigenicity, 599 adefovir urinary tract, 480 adenosine and analogues, 323 cardiovascular effects, 323 respiratory effects, 323–324 adenosine receptor agonists placebo-controlled studies, 324 adrenaline, 259 administration route, 261 cardiovascular effects, 261 for dental extraction, 241 drug–drug interactions, 261–262 gastrointestinal injection, 260 injection in finger, 261 lidocaine, 159 myocardial infarction, 259–260 overdose, 261 penile injection, 260 aescin respiratory effects, 345 albendazole comparative studies, 508–509 and mebendazole, 508 nervous system effects, 509

praziquantel, and, 507 during pregnancy, 509 usage, 508 albumin electrolyte balance, 527 general effects, 527 respiratory effects, 527 alcohol drug abuse and dependence, 758 effects of nicotine on, 764 gastrointestinal, role of, 757 immunologic effects, 757 nervous system effects, 757 teratogenicity, 759 tumorigenicity, 758–759 aldehydes respiratory effects, 409 alemtuzumab endocrine, 602 immunologic effects, 603 alpha-glucosidase inhibitors, 691 alfentanil administration route, 154 comparative studies, 153 drug dosage regimens, 154 alfuzosin formulations, 363 sensory system effects, 363–364 sexual function, 364 skin effects, 363 aliskiren, 360 drug–drug interactions, 375 Allium sativum (garlic), 748 allopurinol skin effects, 201–202 urinary tract, 201 allylamines, 457 alosetron, 575 clinical trials, 575 alpha1-proteinase inhibitor, 532 alprazolam drug withdrawal, 57 formulations, 57 nervous system effects, 118 psychiatric effects, 57 aluminium musculoskeletal effects, 383, 523 tumorigenicity, 383

771

Index of drugs

772 aluminum see aluminium amantadine nervous system effects, 269–270 skin effects, 270 ambrisentan placebo-controlled studies, 361 amethocaine interference with diagnostic tests, 239 amfebutamone see bupropion amikacin cardiovascular effect, 427 aminolevulinic acid genotoxicity, 291 4-aminoquinolines, 469 5-aminosalicyclic acid see mesalazine amiodarone cardiovascular effects, 324–325 case report, 716 death, 329 drug–drug interactions, 329 endocrine, 326–327 induced thyrotoxicosis, management, 327–329 liver effects, 329 monitoring therapy, 329–330 musculoskeletal effects, 329 observational studies, 324 potentiating action of warfarin, 555 respiratory effects, 325–326 sensory systems effects, 326 skin effects, 329 systematic reviews, 324 amisulpride comparative studies, 69–70 drug–drug interactions, 134 endocrine, 76 nervous system effects, 70, 268 amlodipine overdose, 0 amodiaquine observational studies, 469 amoxicillin esomeprazole + gatifloxacin, 580 omeprazole + clarithromycin, 580 pantoprazole + rifabutin, 581 rabeprazole + clarithromycin, 580 ranitidine bismuth citrate + clarithromycin, 581 teeth, effects on, 418 amphetamines nervous system effects, 1, 41

amphotericin cardiovascular effects, 458 electrolyte balance, 458 urinary tract, 458–459 amphotericin B deoxycholate (DAMB) cardiovascular effects, 459 urinary tract, 459 amphotericin B lipid complex (ABLC) respiratory effects, 459 amprenavir gastrointestinal effects, 487 metabolism, 487 and ritonavir, 622 anagrelide, 564 anakinra infection risk, 592 skin risk, 592 androgenic anabolic steroids placebo-controlled studies, 673 psychiatric effects, 673 androgens dosage regimens, 672 prostate, 672 tumorigenicity, 672 anecortave acetate, 741 anesthesia brachial plexus, 233 dental, 237 epidural, 234–235 ocular, 237–238 peripheral nerve block, 238 spinal (intrathecal), 235–237 tonsillar, 238 topical, 238 anesthetics, local, 231 angiotensin converting enzyme inhibitors see ACE inhibitors angiotensin II receptor antagonists cardiovascular effects, 358 dosage regimens, 358 fetotoxic effects, 358, 360 aniline derivatives, 181, see also specific drugs antacid, 573 drug–drug interactions, 435 anthraquinones, 753 anthroposophic medicines, 748 antiandrogens, 673 cardiovascular effects, 674 endocrine, 751 liver effects, 674 antibiotics, 740, see also specific drugs anticholinergic drugs, 273 adverse effects, 273–276 cardiovascular effects, 276 comparative studies, 274–275 dosage regimen, 277 drug–drug interactions, 277

musculoskeletal effects, 277 placebo-controlled studies, 275 psychological effects, 276 observational studies, 274 sensory system effects, 276 skin, 277 susceptibility factors, 277 anticoagulants bleeding, 527 hemorrhage, 553 non-steroidal antiinflammatory drugs (NSAIDs), 553 antidepressants drugs general effects, 17 during pregnancy, 18 antidysrhythmic drugs, 330 antiepileptic drugs, see also specific drugs endocrine, 105 drug–drug interactions, 107 general effects, 105 metabolic effects, 105 musculoskeletal effects, 105–106 during pregnancy, 106–107 antifungal azoles, 459 drug–drug interactions, 192, 459–462 endocrine, 462 antihistamines (H1), 297, see also specific drugs antihypertensive agents, see also specific drugs drug–drug interactions, 350 drug withdrawal, 349 endocrine, 349 sexual function, 349 susceptibility factors, 349 antimalarial drugs, 469 antimony observational studies, 384–385 antipsychotic drugs comparative studies, 65–66 death, 69 endocrine, 67 metabolic effects, 68 nervous system effects, 67 off-label use, 65 sexual function, 68–69 systematic reviews, 66–67 tumorigenicity, 69 antiretroviral drugs, 169, 622 antithrombin III C1 inhibitor concentrate, 532 drug–drug interactions, 532 antithyroid drugs dosage regimens, 686 hematologic effects, 685 immunologic effects, 685–686 liver effects, 685 skin effects, 685 teratogenicity, 686

Index of drugs antituberculosis drugs, hepatotoxicity, 495–496 apixaban, 561 appetite suppressants, 9 aprotinin cardiovascular effects, 566 immunologic effects, 567 aromatase inhibitor comparative studies, 664–665 argatroban hematologic effects, 559 aripiprazole cardiovascular effects, 93 comparative studies, 71–73 drug–drug interactions, 77–78 endocrine, 76 formulations, 77 metabolic effects, 76–77 musculoskeletal effects, 77 nervous system effects, 75–76 observational studies, 70–71 overdose, 77 placebo-controlled studies, 73 systematic reviews, 75 arsenic musculoskeletal effects, 385 during pregnancy, 759 Artecollt, 287 artemisinin, 469, 473 articaine nervous system effects, 237 sensory system effects, 237 ASA see acetylsalicylic acid ascorbic acid urinary tract, 548–549 aspirin see acetylsalicylic acid atazanavir drug–drug interactions, 487–488 liver effects, 487 ritonavir + , 499 atenolol breasts effects, 339 atomoxetine, 2–3 atorvastatin, 472 with clopidogrel, 716 fatal adverse event, 473 and lovastatin, 717 vs. simvastatin, 716 azathioprine adverse drug reactions, management, 638 drug–drug interactions, 638 hematologic effects, 636 immunologic effects, 637 lactation, 637 liver effects, 636 musculoskeletal effects, 636–637 nervous system effects, 635 neuromuscular function, 636

773 during pregnancy, 637 reproductive system, 636 respiratory effects, 635 tumorigenicity, 637 urinary tract, 636 azithromycin cardiovascular effects, 437 liver effects, 438 skin effects, 438 teratogenicity, 438 aztreonam immunologic effects, 417 B baclofen administration route, 251 gastrointestinal effects, 250 infection risk, 250 musculoskeletal effects, 250 nervous system effects, 250 overdose, 251–252 psychiatric effects, 50 susceptibility factors, 251 withdrawal, 250–251 bacterial vaccines, 519 balsalazide skin effects, 583 basiliximab comparative studies, 603 immunologic effects, 604 bendamustine hair effects, 723 hematologic effects, 723 immunologic effects, 723 treatment, 721 benzimidazoles comparative studies, 508 nervous system effects, 509 during pregnancy, 509 benzocaine hematologic effects, 239 immunologic effects, 239 benzodiazepines, 57 bepridil respiratory effects, 330 beta2-adrenoceptor agonists adverse effects of, 309–310 cardiovascular effects, 308–309 comparative studies, 308 dosage regimens, 311 respiratory effects, 441 susceptibility factors, 310–311 beta-adrenoceptor antagonists, 339, 740 cardiovascular effects, 339 endocrine, 349 psychiatric effects, 740 skin effects, 339, 741 beta-lactam antibiotics immunologic effects, 414 nervous system effects, 418 skin effects, 414

bevacizumab gastrointestinal effects, 604 hematologic effects, 604 liver effects, 604 nervous system effects, 604 skin effects, 605 trauma, 605 bicalutamide breast, 673 prostate cancer, 674 bimatoprost skin effects, 651, 742 bisacodyl placebo-controlled studies, 581 bisbiguanides, 410 bismuth immunologic effects, 385 bitter orange see Citrus aurantium bivalirudin, 559 black cohosh see Cimicifuga racemosa blood transfusion general effects, 528 hematologic effects, 529 immunologic effects, 529 infection risk, 529–530 observational studies, 528 respiratory effects, 528–529 transfusion-related acute lung injury (TRALI), 528–529 bosentan drug–drug interactions, 361 liver effects, 361 skin effects, 361 susceptibility factors, 361 botulinum toxins endocrine, 252 formulations, 253 gastrointestinal effects, 253 infection risk, 253 interference with tests, 253 nervous system effects, 252 during pregnancy, 253 sensory systems effects, 252 systematic reviews, 252 brachial plexus anesthesia, 233 nervous system effects, 233–234 brinzolamide comparative studies, 371 observational studies, 371 bromfenac, 741 sensory systems, 742 bucillamine, 403 bupivacaine cardiovascular effects, 239 buprenorphine drug–drug interactions, 169–170 lactation, 169 musculoskeletal effects, 169

Index of drugs

774 during pregnancy, 169 susceptibility factors, 169 bupropion sexual function, 22 butorphanol observational studies, 170 C C1 inhibitor concentrate, 532 caffeine Ephedra, 262–263 fluvoxamine + propafenone, 8, 21 calabash chalk in pregnancy, 759 calcipotriol skin, 293 calcitonin comparative studies, 703 formulations, 703 calcium channel blockers, 340 calcium salts, 417 candesartan autacoid, 358 fetotoxicity, 359 musculoskeletal effects, 358 cannabinoids cardiovascular effects, 33 fetotoxicity, 36 gastrointestinal effects, 35 psychological effects, 34–35 reproductive system effects, 35–36 respiratory effects, 33–34 sensory systems effects, 35 skin effects, 35 teratogenicity, 36 tumorigenicity, 36–37 captopril pemphigus, 470 respiratory effects, 355 carbamazepine comparative studies, 107 drug–drug interactions, 110 drug withdrawal effect, 109 hematologic effects, 108 immunologic effects, 108–109 metabolism, 107–108 musculoskeletal effects, 108 nervous system effects, 107 overdose, 110 during pregnancy, 109 psychological effects, 107 skin effects, 108 susceptibility factors, 109–110 teratogenicity, 109 withdrawal, 108 carbapenems, 414–415 cardiac glycosides adverse drug reactions, management, 322–323 cardiovascular effects, 321 drug–drug interactions, 322

gastrointestinal effects, 322 nervous system effects, 321 placebo-controlled studies, 321 sensory systems effects, 321 carisoprodol psychiatric effects, 253 carotenoids overdose, 548 CDB-2914, 671 cefaclor anaphylactic reaction, 416 cefdinir gastrointestinal effects, 416 red stools, 416 cefepime nervous system effects, 416 cefprozil liver effects, 417 ceftriaxone drug–drug interactions, 417 topical provocation, 416 celecoxib cardiovascular effects, 190 lactation, 190 overdose, 190–191 cephalosporins immunologic effects, 416 skin effects, 416 cerium see lanthanoids cerium nitrate, 388 hematologic effects, 389 skin, 389 cesium cardiovascular effects, 386 cetirizine drug–drug interactions, 297–298 nervous system effects, 297 chloral hydrate observational studies, 60 tumorigenicity, 61 chlorambucil nervous system effects, 723 chloramphenicol blood dyscrasias, 429 hematologic effects, 429 chlorhexidine immunologic effects, 411 mouth hygiene, 410 observational studies, 410 urinary tract, 410 chlormethine combination with drugs, 723 degradation, 724 chloroquine cardiovascular effects, 470 resistance, 471 skin effects, 470 chlortalidone metabolism, 372–373 chlorzoxazone liver effect, 253–254

chromium in local groundwater, 390 urinary tract, 386 cibenzoline respiratory effect, 330 ciclesonide, 305–306 placebo-controlled study, 306 ciclosporin cardiovascular effects, 619 drug–drug interactions, 622 hematologic effects, 621 metabolism, 621 monitoring therapy, 622 musculoskeletal effects, 621–622 nervous system effects, 619 during pregnancy, 622 psychiatric effects, 621 skin effects, 621 susceptibility factors, 622 cidofovir observational studies, 477 sensory systems effects, 477 urinary tract, 477–478 cilomilast gastrointestinal effects, 313 cilostazol, 751 Cimicifuga racemosa (black cohosh) general effects, 749 cinnarizine overdose, 345 sensory systems effects, 345 ciprofloxacin cardiovascular effects, 429 drug–drug interactions, 431 hematologic effects, 430 immunologic effects, 430–431 musculoskeletal effects, 430 psychiatric effects, 430 skin, 430 urinary tract, 430 cisapride comparative studies, 573 nervous system effects, 573 citalopram lactation, 20 monotherapy, 89 Citrus aurantium (bitter orange), 749 clarithromycin cardiovascular effects, 438 drug–drug interactions, 438 liver effects, 438 psychiatric effects, 438 therapy, + clarithromycin, 580 urinary tract, 438 clavulanic acid immunologic effects, 419 prophylaxis, + ticarcillin, 478 clindamycin drug–drug interactions, 437 erythroderma, 437

Index of drugs immunologic effects, 437 skin, 437 clomifene sexual function, 665 clonidine overdose, 363 psychiatric effects, 363 clopidogrel comparative studies, 566 drug–drug interactions, 716 hematologic effects, 566 resistance, 566 skin, 566 clozapine cardiovascular effects, 78 comparative studies, 78 drug–drug interactions, 80 gastrointestinal effects, 80 hematologic effects, 79–80 metabolism, 79 nervous system effects, 79 salivary glands, 80 smoking, 80 susceptibility factors, 80 coagulation proteins administration route, 537 immunologic effects, 537 infection risk, 537 co-amoxiclav immunologic effects, 419 cobalt sensory systems effects, 386 cocaine abuse, 165 cardiovascular effects, 37, 240 drug–drug interactions, 41 endocrine, 40 for ENT procedures, 244 fetotoxicity, 41 nervous system effects, 38, 41 during pregnancy, 40–41 psychiatric effects, 40 sensory systems effects, 40 sleep, 39 codeine, 154–155 colchicine drug–drug interactions, 202–203 nervous system effects, 202 psychological effects, 202 skin, 202 cold medicines, non­ prescription, 314 colistin, 441 nebulization, 442 skin, 442 colony-stimulating factors, see granulocyte-colony stimulating factor colophony immunologic effects, 291 combination vaccines, 519

775 contraceptives see hormonal contraceptives copper liver effects, 387 corticotrophins infection risk, 647 cosmetics allergy to, 287 eyelash tint, 287 hair dyes, 288 hyaluronic acid-based skin fillers, 288 synthetic cosmetic filler substance, 287 co-trimoxazole (trimetho­ prim + sulfamethoxazole) comparative studies, 444 hematologic effects, 444–445 immunologic effects, 445, 774 liver effects, 445 metabolism, 445 musculoskeletal effects, 445 observational studies, 774 psychiatric effects, 438, 444 sensory systems effects, 444 skin, 445 cough medicines, non-prescription, 314 coumarin anticoagulants, 553 adverse drug reactions, management, 556 drug–drug interactions, 555–556 hematologic effects, 553 skin, 554 susceptibility factors, 554–555 COX-2 selective inhibitors, 190 crack see cocaine cupping skin, 753 cyclizine cardiovascular effects, 298 respiratory effects, 298 cyclobenzaprine drug–drug interactions, 254 cyclophosphamide, see oxazaphosphorines D dabigatran hematologic effects, 559 daclizumab comparative studies, 605 dalbavancin preclinical studies, 435 danazol liver effects, 672 dapsone hematologic effects, 496 immunologic effects, 497 methemoglobinemia, 496

daptomycin drug–drug interactions, 447 musculoskeletal effects, 446 nervous system effects, 446 placebo-controlled studies, 446 N-deamino-8-D-arginine vasopressin (DDAVP) see desmopressin deferasirox agranulocytosis, 402 comparative studies, 401 high doses, 401 skin rash, 401 deferiprone observational studies, 402 deferoxamine comparative studies, 403 infection risk, 403 observational studies, 402 sensory systems, 403 tumorigenicity, 403 deflazacort see glucocorticoids dental anesthesia sensory systems, 237 desflurane adverse reactions management, 217 cytotoxicity, 217 respiratory effects, 217 susceptibility factors, 217 desloratadine susceptibility factors, 298 desmopressin electrolyte balance, 710 formulations, 710 hematologic effects, 710 Devil’s claw see Harpagophytum procumbens dexamethasone metabolism, 741 dexketoprofen skin, 186 dextromethorphan comparative studies, 156 nervous system, 156 susceptibility factors, 156 systematic reviews, 156 dextropropoxyphene musculoskeletal effects, 156 diamine (SQ109), 502 diaminopyridine, 254 diamorphine immunologic effects, 156 nervous system effects, 156 overdose, 156–157 susceptibility factors, 157 diarylquinoline (TMC207), 501 diazepam comparative studies, 57 psychological effects, 58

Index of drugs

776 diclofenac administration route, 187 gastrointestinal effects, 187 hematologic effects, 186 liver effects, 187 sensory systems, 186 skin, 187 didanosine comparative studies, 483 dosage regimens, 484 drug–food interactions, 484 liver effects, 483 metabolism, 483 pancreas effects, 483 during pregnancy, 484 psychiatric effects, 483 sensory systems effects, 483 urinary tract, 484 diethylstilbestrol gastrointestinal effects, 658 mechanisms, 658–659 reproductive system effects, 658 sexual function, 658 transgenerational effects, 657–658 tumorigenicity, 658 digoxin, 21 cardiovascular effects, 321 drug–drug interactions, 322 gastrointestinal effects, 322 nervous and sensory effects, 321–322 placebo-controlled studies, 321 diltiazem skin, 341 dipeptidyl peptidase IV inhibitors systematic reviews, 693 diphenhydramine overdose, 298 diphtheria–tetanus–whole-cell pertussis vaccine (DTP), 520 dipyridamole comparative studies, 564 nervous system effects, 565 dipyrone hematologic effects, 192 overdose, 192–193 during pregnancy, 192 di-2-pyridylketone-4,4­ dimethyl-3­ thiosemicarbazone (Dp44mT), 404 disulfiram liver effects, 760 diuretics, 371 divalproex, see also valproate sodium vs. lithium, 28 dobutamine cardiovascular effects, 265 myocardial damage, 266

domperidone, 460 donepezil, 10 cardiovascular effects, 11 comparative studies, 10 gastrointestinal effects, 11 monitoring therapy, 11 nervous system effects, 11 observational studies, 10 placebo-controlled studies, 10–11 psychiatric effects, 11 dopamine receptor agonists cardiovascular effects, 268 gambling, 269 hair, 269 nervous system effects, 268 psychiatric effects, 268 doripenem nervous system effects, 415 dorzolamide sensory systems effects, 371 taste, 372 doxazosin, 363 doxycycline placebo-controlled studies, 420 skin, 420 doxylamine interference with diagnostic tests, 299 mechanism, 299 overdose, 298 surveys, 299 susceptibility factors, 299 Dp44mT, 404 dronabinol, 573, see also cannabinoids drospirenone, 670 drotrecogin alfa hematologic effects, 527–528 dutasteride, 675 E echinocandins, 464 ecstasy, 41 liver damage, 47 nervous system effects, 41 neurocognition, 45–47 overdose, 47–48 psychological effects, 42 subjective effects, 43–45 EDTA see ethylene diamine tetraacetic acid efalizumab hematologic effects, 606 immunologic effects, 606 musculoskeletal effects, 606 skin, 606 susceptibility factors, 607 systematic reviews, 605–606 tumorigenicity, 607 efavirenz comparative studies, 484

drug–drug interactions, 433, 486 hematologic effects, 486 immunologic effects, 486 mouth, 486 nervous system effects, 486 nutrition, 486 psychiatric effects, 486 skin, 486 urinary tract, 486 emla cream immunologic effects, 240 emtricitabine, 481, 483, 484 enalapril adverse reactions management, 356 drug–drug interactions, 356 fetotoxicity, 356 hematologic effects, 356 overdose, 356 respiratory effects, 355 endoperoxides comparative studies, 473 observational studies, 473 endothelin receptor antagonists, 360 Ephedra and ephedrine, 262 cardiovascular effects, 262 musculoskeletal effects, 263 psychiatric effects, 263 sensory systems effects, 263 epidural anesthesia cardiovascular effects, 234 nervous system effects, 234 reproductive system effects, 235 systematic reviews, 234 epinephrine see adrenaline epoetins see erythropoietin ergot alkaloids cardiovascular, 345 ertapenem seizures, 415 erythromycin cardiovascular effects, 438 drug–drug interactions, 438–439 erythropoietin and epoetins, 538 cancer patients, studies in, 539 cardiovascular effects, 539 kidney disease, studies in, 539 susceptibility factors, 539 esomeprazole comparative studies, 580 dosage regimens, 578 placebo-controlled studies, 578 estrogens administration route, 657 drug–device interactions, 657

Index of drugs metabolism, 656–657 tumorigenicity, 657 etanercept dosage regimens, 601 immunological effects, 600 nervous system effects, 600 respiratory effects, 600 sensory systems effects, 600 skin, 600 tumorigenicity, 601 urinary tract, 600 ethambutol musculoskeletal effects, 498 respiratory effects, 497 sensory systems effects, 497 etherified starches comparative studies, 533 hematologic effects, 533 immunologic effects, 534 susceptibility factors, 534 ethylene diamine tetra-acetic acid (EDTA) general effects, 405 etomidate nervous system effects, 221–222 etoricoxib skin, 191 everolimus, 622 comparative studies, 623 connective tissues effects, 623 dosage regimens, 623 drug–drug interactions, 623–624 immunologic effects, 623 monitoring therapy, 624 systematic reviews, 623 tumorigenicity, 623 exemestane, 665 eyelash tint, 287–288 ezetimibe drug–drug interactions, 715 F factor Xa inhibitors, 561, 563 factor IXa inhibitors, 561 famotidine comparative studies, 576–577 fat emulsions liver effects, 550 fenfluramines withdrawal from market, 9 fentanyl administration route, 159 adverse reactions management, 159–160 cardiovascular effects, 157–158 comparative studies, 157 dosage regimens, 169 drug–drug interactions, 159 formulations, 158–159 gastrointestinal effects, 158 observational studies, 157

777 placebo-controlled studies, 157 respiratory effects, 158 susceptibility factors, 158 fexofenadine skin, 299–300 systematic reviews, 299 finasteride tumorigenicity, 675 fish oils liver effects, 550 flecainide cardiovascular effects, 330 observational studies, 330 fluconazole, 159, 462 flunarizine see cinnarizine flunitrazepam monitoring therapy, 58 psychological effects, 58 fluoroquinolones comparative studies, 429 immunologic effects, 429 new, 502 sensory systems effects, 740 flutamide liver effects, 675 fluvoxamine, 8, 85 fluvastatin liver effects, 716 urinary tract, 717 fondaparinux comparative studies, 563 hematologic effects, 563 formaldehyde tumorigenicity, 409 formoterol, 308, 309 fosmidomycin hematologic effects, 447 fosphenytoin see phenytoin frakefamide placebo-controlled studies, 160 fresh frozen plasma cardiovascular effects, 532 fluid balance, 532 formulations, 533 hematologic effects, 532 immunologic effects, 533 infection risk, 533 susceptibility factors, 533 systematic reviews, 532 fulvestrant, 665 G gabapentin fluid balance, 113 nervous system effects, 113 observational studies, 110–111 overdose, 113 placebo-controlled studies, 111–112 systematic reviews, 112–113

gadolinium-based contrast agents nephrogenic systemic fibrosis, 735–736 gadolinium salts systematic reviews, 734 garlic see Allium sativum gatifloxacin drug–drug interactions, 432 interference, with diagnostic tests, 432 metabolism, 431–432 nervous system effects, 431 psychiatric effects, 431 sensory systems effects, 431 susceptibility factors, 432 G-CSF see granulocyte-colony stimulating factor gelatine (gelofusine), 534 gemfibrozil, 62 gentamicin sensory systems effects, 427 urinary tract, 428 gestrinone, 672 Ginkgo biloba, 750–751 ginseng (Panax ginseng), 745–748 glibenclamide fetotoxicity, 696 pancreatic beta-cells effects, 432 glipizide skin, 696 gliquidone observational studies, 696 glitazones drug–drug interactions, 698 risk, 697–698 globulins, 536 glucagon, 689 glucocorticoids see inhaled glucocorticoids; systemic glucocorticoids; topical glucocorticoids glutaral see glutaraldehyde glutaraldehyde gastrointestinal effects, 409 tumorigenicity, 409 glyburide see glibenclamide glycoprotein IIb-IIIa inhibitors, 565 hematologic effects, 565 gold and gold salts skin, 387 gonadotropins, 656, 703 endocrine, 703 formulations, 705 immunologic effects, 704 reproductive system effects, 704

Index of drugs

778 sexual function, 704 skin, 704 granulocyte-colony stimulating factor (G-CSF), 589 comparative studies, 590 guidelines, 589 hematologic effects, 590–591 observational studies, 590 musculoskeletal effects, 591 skin, 591 granulocyte macrophage colony-stimulating factor (GM-CSF) see granulocyte colonystimulating factor (G-CSF) H Helicobacter pylori eradication regimens comparative studies, 579–581 hair dyes, see also cosmetics skin, 289 tumorigenicity, 288–289 halogenated vapors, 217 haloperidol combined effects, 460 dose, 2 endocrine, 67 mania, 72 placebo-controlled studies, 80 Harpagophytum procumbens (Devil’s claw), 752 hemin, 531 heparins cardiovascular effects, 556 hematologic effects, 556–558 immunologic effects, 558 during pregnancy, 558 skin, 558 susceptibility factors, 559 hepatitis B vaccine musculoskeletal effects, 520–521 herbal medicines, 745 contamination, 746–747 drug–drug interactions, 747–748 gastrointestinal effects, 746 observational studies, 745–746 heroin see diamorphine histamine H2 receptor antagonists, 578, see also specific drugs HMG-CoA reductase inhibitors, 715 drug–drug interactions, 716–717 liver damage, 717 musculoskeletal effects, 716 pancreas effects, 715 statins, differences between, 715–716

hormonal contraceptives administration route, 664 cardiovascular effects, 663 urinary tract, 663–664 hormone replacement therapy (HRT) administration route, 662–663 cardiovascular, adverse effects, 659–661 musculoskeletal effects, 661 nervous system effects, 661 susceptibility factors, 662 tumorigenicity, 661–662 hyaluronic acid, 288 hydralazine respiratory effects, 365 hydrochlorothiazide drug–drug interactions, 375 electrolyte balance, 373 genotoxicity, 375 non-cardiogenic pulmonary edema, management, 373–375 skin, 373 hydrocodone comparative studies, 160 therapy, + paracetamol, 162 hydrogen peroxide gastrointestinal effects, 761 hydromorphone comparative studies, 160 neuromuscular function effects, 161 hydroquinone, 288 hydroxychloroquine, see also chloroquine cardiovascular effects, 470 resistance, 471 skin, 470 Hydroxycut, 752 hydroxyzine rash, 385 skin, 298 I ibuprofen body temperature, 188 cardiovascular, 187 drug–drug interactions, 188–189 immunologic effects, 188 musculoskeletal effects, 188 nervous system effects, 189 overdose, 188 pancreas effects, 188 sensory systems effects, 187–188 skin, 188 urinary tract, 188 idraparinux, 563–564 ifosfamide, see oxazaphosphorines imatinib, 624

imidapril comparative studies, 357 immunoglobulins, 534 administration route, 538–539 adverse drug reactions diagnosis, 539 formulations, 538 nervous system effects, 537 placebo-controlled studies, 537 skin, 537–538 urinary tract, 537 indinavir musculoskeletal effects, 488 urinary tract, 488 indocyanine green visual field defects, 760–761 indometacin fetotoxicity, 189 gastrointestinal effects, 189 hematologic effects, 189 pancreas effects, 189 respiratory effects, 189 infliximab hematologic effects, 602 liver damage, 602 nervous system effects, 602 observational studies, 601, 607 psychiatric effects, 602 respiratory effects, 601–602 skin, 602 inhaled glucocorticoids, 305 general effects, 305–306 musculoskeletal effects, 306–307 risk of fracture, 307–308 insulin administration route, 690 hypoglycaemia, 689–690 immunologic effects, 690 interferon alpha psychiatric effects, 591–592 skin, 592 urinary tract, 592 interleukin-1 receptor antagonist infection risk, 592 skin, 592 iodine and iodides endocrine, 684 iodine compounds, radioactive sexual function, 684 tumorigenicity, 684 iodophors, 411 irbesartan skin eruption, 359 teratogenicity, 359 iron chelators combining, 399 efficacy, 404 with phlebotomy, 402 susceptibility factors, 401–402

Index of drugs iron salts hematologic effects, 387 infection risk, 388 ISA 247 (calcineurin inhibitor) preclinical observations, 623 urinary tract, 624 isoflurane liver effects, 218 isoniazid co-administration, 500 intoxication, 498 nervous system effects, 498 standard regimen, + rifampicin + pyrazinamide, 502 with pyridoxine, 498 isotretinoin autacoids, 292 infection risk, 292 gastrointestinal effects, 292 metabolism, 292 musculoskeletal effects, 292 psychiatric effects, 292 itraconazole clearance, 650 interfere with vinblastine, 460 liver damage, 463 observational studies, 463 ivermectin comparative studies, 510 observational studies, 509–510 resistance, 510 uses, 509 K kava kava see Piper methysticum ketamine nervous system effects, 222 ketoprofen skin, 189–190 ketorolac concomitant morphine, 163 sensory systems effects, 742 khat cardiovascular effects, 48 liver damage, 48 psychiatric effects, 48 L lamivudine comparative studies, 481 liver damage, 481 musculoskeletal effects, 481 observational studies, 480–481 placebo-controlled studies, 481 resistance, 481 lamotrigine co-administration, 116 comparative studies, 113

779 drug–drug interactions, 116 fetotoxicity, 115–116 lactation, 116 vs. lithium, 25–26 metabolism, 114–115 monotherapy, 107 nervous system effects, 115 during pregnancy, 115 psychiatric effects, 114 psychological effects, 113–114 skin, 115 vs. valproate, 107 lansoprazole dosage regimens, 578 lanthanoids acute toxicity, 388 biological properties, 388 use in, 388 lanthanum carbonate gastrointestinal effects, 390 liver effects, 389–390 latanoprost for eye, 371 nervous system effects, 651 laxatives, 581 leflunomide comparative studies, 625 connective tissues, 626 drug–drug interactions, 627 immunologic effects, 626 infection risk, 626 during pregnancy, 627 respiratory effects, 625–626 sensory systems effects, 626 skin, 626 lepirudin adverse reactions management, 560 hematologic effects, 559 letrozole breast, 664 monotherapy, 667 placebo-controlled studies, 666 skin, 666 susceptibility factors, 666 teratogenicity, 666 levamisole comparative studies, 510 nervous system effects, 510–511 systematic reviews, 510 levetiracetam metabolism, 118 nervous system effects, 118 observational studies, 116–117 placebo-controlled trials, 117–118 psychiatric effects, 118 psychological effects, 118 teratogenicity, 118

levocetirizine vs. cetirizine, 301 skin, 300 levodopa melanoma, 267 nervous system effects, 266 psychological effects, 266 susceptibility factors, 267–268 levofloxacin drug–drug interactions, 433–434, 633 gastrointestinal effects, 433 hematologic effects, 433 metabolism, 433 musculoskeletal effects, 433 nervous system effects, 433 respiratory effects, 432 urinary tract, 433 LiDa Dai Dai Hua Jiao Nang, 747 lidocaine (lignocaine) drug–drug interactions, 330–331 effect on sex hormones, 331 immunologic effects, 240 nervous system effects, 240 overdose, 240, 330 placebo-controlled studies, 330 linezolid, see also oxazolidinones adverse effects, 440 hematologic effects, 440 nervous system effects, 440 observational studies, 439–440 sensory systems effects, 440 susceptibility factors, 441 liposomal amphotericin (LAmB) cardiovascular effects, 459 liraglutide placebo-controlled studies, 695 lisinopril drug–drug interactions, 357 pancreas effects, 357 skin, 357 lithium cardiovascular effects, 26 digoxin and, 581 drug–drug interactions, 28, 77 endocrine, 27 metabolism, 27–28 monitoring therapy, 28–29 nervous system effects, 26 neuroprotection, 25 observational studies, 25 placebo-controlled studies, 26 psychiatric effects, 26–27 psychological effects, 26

Index of drugs

780 reproductive system effects, 28 respiratory effects, 26 sensory systems effects, 27 skin, 28 teratogenicity, 28 toxicity management, 29 local anesthetics, 231 loop diuretics dosages, 375 drug–drug interactions, 375 skin, 375 urinary tract, 375 lopinavir drug–drug interactions, 488 gastrointestinal effects, 488 lopinavir + ritonavir, 488 lorazepam bipolar disorder, 74 dosage regimen, 59 psychiatric effects, 58–59 losartan fetotoxicity, 359 nervous system effects, 359 respiratory effects, 359 susceptibility factors, 359 urinary tract, 359 M magnesium salts cardiovascular effects, 390 musculoskeletal effects, 391 Ma huang see Ephedra/ephedrine mannitol electrolyte balance, 376 nervous system effects, 376 marijuana see cannabinoids MDMA see ecstasy measles-mumps-rubella (MMR) vaccine, 521 mebendazole comparative studies, 508 nervous system effects, 509 during pregnancy, 509 uses, 508 mefloquine hematologic effects, 472 nervous system effects, 471 respiratory effects, 471 megestrol acetate endocrine, 670 melatonin drug–drug interactions, 708 gastrointestinal effects, 708 meloxicam reproductive system effects, 192 respiratory effects, 192 skin, 192 melphalan immunologic effects, 724

meningococcal vaccine hematologic effects, 520 nervous system effects, 519 safety, 519 meperidine see pethidine mercury and mercurial salts nervous system effects, 391 mesalazine (mesalamine) cardiovascular, 583 comparative studies, 583 metamfetamine adverse reactions management, 2 cardiovascular effects, 1 susceptibility factors, 2 metamizole (dipyrone), 192 hematologic effects, 192 overdose, 192–193 during pregnancy, 192 metformin, 692 endocrine, 692 hair, 693 nutrition, 692 skin, 692–693 teratogenicity, 693 treatment combination, 355 methadone cardiovascular effects, 161 drug–drug interactions, 162 endocrine, 161–162 fetotoxicity, 162 infection risk, 162 lactation, 162 musculoskeletal effects, 162 nervous system effects, 161 observational studies, 161 tolerance, 162 methotrexate, 362 methyldopa hematologic effects, 363 methylene blue see methylthioninium chloride 3,4-methylenediox­ ymetamfetamine see ecstasy methylphenidate adverse effects, 6–7 cardiovascular effects, 3 drug–drug interactions, 7 nervous system effects, 3 observational studies, 3 psychiatric effects, 4 susceptibility factors, 4 methylthioninium chloride sensory systems effects, 763 systematic reviews, 763 methylxanthines, 8 methysergide cardiovascular effects, 272 metoclopramide dosage regimens, 574

nervous system, 574 skin, 574 metoprolol drug–drug interactions, 339 metronidazole nervous system effects, 475 skin, 475 mexiletine immunologic effects, 331 micafungin monitoring therapy, 464 midazolam comparative studies, 59 formulations, 59–60 observational studies, 59 sensory systems, 60 midodrine urinary tract, 264 mifepristone (RU-486) hemorrhage, 671 observational studies, 671 milrinone adverse drug reactions management, 323 minocycline immunologic effects, 420–421 mirazid see myrrh misoprostol observational studies, 651 MMR vaccine, 521 modafinil placebo-controlled studies, 7 susceptibility factors, 8 montelukast musculoskeletal effects, 312 susceptibility factors, 312–313 Morinda citrifolia (noni) liver effects, 752 morphine administration route, 165 cardiovascular effects, 163 comparative studies, 163 dosage regimens, 165 gastrointestinal effects, 164 nervous system effects, 164 neuromuscular function effects, 164 observational studies, 162–163 psychological effects, 164 respiratory effects, 163–164 skin, 164 susceptibility factors, 164–165 morphine-6-glucuronide, 165 moxifloxacin cardiovascular effects, 436 gastrointestinal effects, 436 sensory systems effects, 436 susceptibility factors, 436 multiple immunizations death, 519

Index of drugs mumps vaccine infection risk, 521 muromonab comparative studies, 607 mycophenolate mofetil drug–drug interactions, 628 gastrointestinal effects, 627 infection risk, 627 during pregnancy, 628 respiratory system effects, 627 tumorigenicity, 627 urinary tract, 627 mycophenolate sodium gastrointestinal effects, 627 myrrh, 511 N nafcillin drug–drug interactions, 419 urinary tract, 419 naloxone administration route, 170 naltrexone comparative studies, 170 formulations, 171 nervous system effects, 171 placebo-controlled studies, 170 systematic reviews, 170 naproxen pancreas effects, 190 skin, 190 teratogenicity, 190 nelfinavir drug–drug interactions, 488 neomycin ointment, 300 sensory systems effects, 428 neuraminidase inhibitors, 489 nevirapine drug–drug interactions, 487 gastrointestinal effects, 487 liver effects, 487 observational studies, 486 nickel immunologic effects, 392 nicorandil skin, 340 nicotinamide gastrointestinal effects, 548 nicotine psychological effects, 763–764 nifedipine, 341 nimodipine placebo-controlled studies, 341 nitrofurantoin acute reaction, 439 immunologic effects, 439 liver damage, 439 nitroimidazoles (PA824/ OPC67683), 501

781 nitrous oxide abuse, 221 adverse drug reactions, management, 221 management, 221 nervous system effects, 221 observational studies, 221 noni see Morinda citrifolia non-steroidal antiinflammatory drugs (NSAIDs), see also specific drugs autoacids, 185 cardiovascular effects, 183–185 drug–drug interactions, 186 liver effects, 185 pancreas effects, 185 teratogenicity, 186 O octreotide cardiovascular effect, 709 gastrointestinal effect, 709 ocular anesthesia musculoskeletal effects, 238 nervous system effects, 237 sensory systems effects, 237–238 ofloxacin musculoskeletal effects, 435 sensory systems effects, 434 skin, 435 olanzapine comparative studies, 81–82 drug–drug interactions, 85 endocrine, 84 hematologic effects, 85 metabolic effects, 84–85 nervous system effects, 83 observational studies, 81 placebo-controlled studies, 82–83 psychiatric effects, 83–84 teratogenicity, 85 omeprazole benefit, 577 biliary tract, 578 drug-drug interactions, 633 pediatric liver, 633 skin, 579 ondansetron comparative studies, 575 placebo-controlled studies, 576 opioids abuse, 152 administration route, 152–153 drug–drug interactions, 153 gastrointestinal effect, 150 infection risk, 151 immunologic effects, 151 musculoskeletal effects, 150–151

observational studies, 149 psychological effects, 149 related deaths, 151–152 systematic reviews, 149 oral contraceptives see hormonal contraceptives oseltamivir psychiatric effects, 489 susceptibility factors, 489 osmotic diuretics, 376 otamixaban drug–drug interactions, 562 hematologic effects, 561–562 oxandrolone, 673 oxazaphosphorines cardiovascular effects, 725 dosages, 724 liver effects, 727 nervous system effects, 726 respiratory effects, 725 sensory systems effects, 726 urinary tract, 727 oxazolidinones, see also linezolid drug–drug interactions, 441 hematologic effects, 440 metabolism, 440 nervous and sensory systems effects, 440 observational studies, 439 susceptibility factors, 441 oxcarbazepine comparative studies, 119 electrolyte balance, 120 endocrine, 120 observational studies, 118–119 monitoring therapy, 120 overdose, 120 placebo-controlled studies, 119–120 psychological effects, 120 oxybutynin, 275 comparative studies, 274, 275 oxycodone drug–drug interactions, 165–166 overdose, 165 susceptibility factors, 165 oxymorphone administration route, 166 general information, 166 susceptibility factors, 166 oxytocin comparative studies, 708 during pregnancy, 708–709 immunologic effects, 708 P paclitaxel drug–drug interactions, 437 palonosetron comparative studies, 576

Index of drugs

782 pantoprazole administration route, 579 dosage regimens, 579 sexual function, 579 therapy, + amoxicillin + rifabutin, 579 papaverine sensory systems effects, 166 paracetamol acid–base balance, 182 drug–drug interactions, 183 gastrointestinal effects, 181 liver damage, 181–182 overdose, 182 respiratory effects, 181 skin, 182 tumorigenicity, 182 paraffins respiratory effects, 764 para-phenylenediamine skin, 289–290 parathyroid hormone (PTH) mineral balance, 709 tumorigenicity, 709 parecoxib urinary tract, 191 parenteral nutrition nervous system effects, 549 susceptibility factors, 550 paroxetine drug–drug interactions, 322, 438 pegaptanib observational studies, 739 sensory systems effects, 739 pegvisomant liver damage, 707 penicillamine, 403 comparative studies, 404 sensory systems effects, 404 systematic reviews, 404 urinary tract effects, 404 penicillins interference with diagnostic tests, 418 nervous system effects, 418 perfluorocarbons comparative studies, 531 hematologic effects, 531 peripheral nerve block anesthesia nervous system effects, 238 observational studies, 238 pertussis vaccine nervous system effects, 520 pethidine musculoskeletal effects, 166 observational studies, 166 during pregnancy, 166 phenoxybenzamine tumorigenicity, 364 phenylephrine cardiovascular effects, 264, 740

phenylpropanolamine cardiovascular, 264–265 during pregnancy, 265 teratogenicity, 265 phenytoin comparative studies, 120–121 overdose, 121 skin, 121 pholcodine, 249 phosphates comparative studies, 581 electrolyte balance, 582 formulations, 582 systematic reviews, 582 phosphatidylcholine observational studies, 765–766 phosphodiesterase type IV inhibitors, 313 phosphodiesterase type V inhibitors cardiovascular effects, 346 nasal congestion, 346 nervous system effects, 347 sensory systems effects, 347 photodynamic therapy see verteporfin physostigmine, 272 phytoestrogens, 655–656 pilocarpine sensory systems effects, 740 pimecrolimus immunologic effects, 628 Piper methysticum (kava kava), 752 piroxicam pancreas effects, 192 plasma substitutes comparative studies, 533 hematologic effects, 533, 534 immunologic effects, 534 susceptibility factors, 534 polyethylene glycol comparative studies, 582 observational studies, 582, 737 susceptibility factors, 583 polygelines hematologic effects, 534 immunologic effects, 534 polymyxins cardiovascular effects, 442 drug–drug interactions, 442 formulations, 442 nervous system effects, 441 neuromuscular function, 441–442 overdose, 442 respiratory effects, 441 skin, 442 urinary tract, 442 polyvinylpyrrolidone endocrine, 411

observational studies, 411 skin, 411 posaconazole, 463 postsynaptic a-adrenoceptor antagonists, 363–366, see also specific drugs potassium channel activators, 340 potassium salts electrolyte balance, 392 pramlintide metabolism, 692 praziquantel hematologic effects, 511 prebiotics, 583–584 pregabalin breasts, 123 comparative studies, 121–122 observational studies, 121 placebo-controlled trials, 122 psychiatric effects, 122–123 prilocaine hematologic effects, 240 immunologic effects, 240 pristinamycin, 442 skin, 443 probenecid lactation, 203 procainamide hematologic effects, 332 progesterone antagonists, 671 progestogens administration route, 670 psychiatric effects, 669–670 reproductive system effects, 670 systematic reviews, 669 propafenone cardiovascular effects, 331 immunologic effects, 332–332 overdose, 332 propofol administration route, 226 adverse drug reactions, management, 226 cardiovascular effects, 222–223 formulation, 225–226 lactation, 224–225 liver effects, 224 metabolism, 223–224 nervous system effects, 223 respiratory effects, 223 susceptibility factors, 225 propranolol skin, 340 proton pump inhibitors, 577–579 comparative studies, 577 gastrointestinal effects, 578 mineral balance, 578 pseudoephedrine see also Ephedra/ephedrine cardiovascular effects, 263

Index of drugs nervous system effects, 264 in pregnancy, 264 skin, 264 psilocybin, 49 abuse and tolerance, 50 adverse effects, 50–51 adverse drug reactions, management, 52 body temperature, 51 cardiovascular effects, 50 death, 51 electrolyte balance, 51 endocrine, 51 interference, with diagnostic tests, 51 liver effects, 51 psychiatric effects, 50 trauma, 51 usage in OCD, 50 PTH see parathyroid hormone PUVA observational studies, 291 skin, 291 pyrrole (LL3858), 502 Q quazepam drug–food interactions, 60 quetiapine comparative studies, 87 drug–drug interactions, 88 endocrine, 87 musculoskeletal effects, 88 nervous system effects, 87 observational studies, 86 overdose, 88 psychiatric effects, 87 sexual function, 88 quinapril overdose, 357 quinidine susceptibility factors, 332 quinine drug–drug interactions, 472 quinupristin/dalfopristin cytotoxicity, 443–444 monitoring therapy, 444 musculoskeletal effects, 443 observational studies, 443 R rabeprazole dosage regimens, 579 therapy, + levofloxacin + tinidazole, 581 raloxifene tumorigenicity, 666–667 ramipril mouth and teeth, 357 skin, 358 ranibizumab comparative studies, 739

783 ranitidine comparative studies, 577 rapamycin see sirolimus rasagiline drug–drug interactions, 272 placebo-controlled studies, 270–272 rasburicase comparative studies, 204 hematologic effects, 205–206 mineral metabolism, 204 nervous system effects, 204 observational studies, 203 respiratory effects, 204 razaxaban, 562 reboxetine urinary tract, 22 remifentanil cardiovascular effects, 167 comparative studies, 166 drug–drug interactions, 167 nervous system effects, 167 placebo-controlled studies, 167 respiratory effects, 167 sexual function, 167 susceptibility factors, 167 renin inhibitors, 360, see also specific drugs renzapride, 574 repaglinide drug–drug interactions, 695 gastrointestinal effects, 695 reteplase hematologic effects, 564 retinoids, 291 rifampicin cardiovascular effects, 498–499 drug–drug interactions, 499–500 immunologic effects, 499 skin, 499 rifapentine drug–drug interactions, 500 risperidone, 28, 68 comparative studies, 89 dose response, 91–92 drug–drug interactions, 92 endocrine, 90 formulations, 91 hematologic effects, 90–91 metabolism, 90 observational studies, 88 placebo-controlled studies, 89–90 skin, 91 susceptibility factors, 91 systematic reviews, 90 ritonavir drug–drug interactions, 488 endocrine, 488

rituximab autacoids, 608 hematologic effects, 607–608 immunologic effects, 608 infection risk, 609 liver effects, 608 monitoring therapy, 609–610 during pregnancy, 609 respiratory effects, 607 skin, 608 tumorigenicity, 609 rivaroxaban comparative studies, 562 drug–drug interactions, 562–563 food–drug interactions, 563 hematologic effects, 562 rivastigmine, 11 monitoring therapy, 11 rocuronium hypersensitivity reactions, 249 neuromuscular effects, 248–249 systematic reviews, 248 rofecoxib drug–drug interactions, 191 liver damage, 191 psychiatric effects, 191 roflumilast comparative studies, 314 dose-ranging studies, 313–314 placebo-controlled studies, 314 ropivacaine cardiovascular effects, 240–241 rosiglitazone hematologic effects, 698 musculoskeletal effects, 698–699 nervous system effects, 698 rosuvastatin comparative studies, 718 rotavirus vaccine body temperature, 521 Kawasaki disease, 522 roxithromycin drug–drug interactions, 439 respiratory effects, 439 teratogenicity, 439 S salmeterol, 309 saquinavir gastrointestinal effects, 488 liver damage, 488 sarcosine (N-methylglycine), 92 selective serotonin re-uptake inhibitors (SSRIs), 17, 18 drug–drug interactions, 21, 186, 441 fetotoxicity, 20

Index of drugs

784 gastrointestinal effects, 19 lactation, 20 suicidal behavior, 18–19 teratogenicity, 19–20 selegiline psychiatric effects, 270 selenium multiorgan failure, 392–393 serotonin and noradrenaline reuptake inhibitors (SNRIs), 22, see also specific drugs sevoflurane cardiovascular effects, 218 musculoskeletal effects, 219 nervous system effects, 219 psychological effects, 219 sensory systems effects, 219 sibutramine cardiovascular effects, 9–10 contaminants for herbal medicines, 747 hematological effects, 10 silicone, 766 silver salts and derivatives argyria, 393 renal insufficiency, 394 sirolimus connective tissues, 630 drug–drug interactions, 630 gastrointestinal effects, 629–630 hematologic effects, 629 nails, 630 during pregnancy, 630 respiratory tract effects, 629 skin, 630 tumorigenicity, 630 urinary tract, 630 sitagliptin gastrointestinal effects, 692 hematologic, 692 immunologic effects, 692 liver damage, 692 metabolism, 693 nasopharyngitis, 693 renal disease, 694 susceptibility factors, 694 sitaxsentan placebo-controlled studies, 362 sodium nitroprusside hematologic effects, 365 somatostatin biliary tract effects, 709 somatropin (human growth hormone, hGH), 705 administration route, 707 cardiovascular effects, 705 formulations, 707 gastrointestinal effects, 705–706 musculoskeletal effects, 706 nervous system effects, 661 observational studies, 705

pancreas effects, 706 susceptibility factors, 706 tumorigenicity, 706 sparfloxacin drug–drug interactions, 435 spinal (intrathecal) anesthesia cardiovascular effects, 235–236 formulations, 237 nervous system effects, 236 during pregnancy, 236–237 systematic reviews, 235 spironolactone breasts, 376 electrolyte balance, 375 gastrointestinal effects, 376 structural relation, 670 squalene, 523–524 SSRIs see selective serotonin reuptake inhibitors stanozolol breasts, 673 statins see HMG-CoA reductase inhibitors stavudine comparative studies, 484–485 liver effect, 485 observational studies, 484 stem cells immunologic effects, 540 susceptibility factors, 540 sufentanil susceptibility factors, 167–168 therapy, + propofol, 219 sugammadex, 249–250 sulfamethoxazole see co-trimoxazole sulfonamides urinary tract, 474 sulfonylureas metabolism, 695–696 overdose, 696 sunscreens immunologic effects, 291 suramin monitoring therapy, 512 uses, 512 suxamethonium administration route, 248 electrolyte balance, 247 immunologic effects, 247 musculoskeletal effects, 247 susceptibility factors, 247–248 systane, 740 systemic glucocorticoids drug–drug interactions, 650–651 gastrointestinal effects, 648 infection risk, 649–650 liver effects, 648

mouth and teeth, 648 musculoskeletal effects, 649 during pregnancy, 650 sensory systems effects, 647 skin, 648 T tacrolimus biliary tract effects, 632 cardiovascular effects, 630 drug–drug interactions, 633 endocrine, 631 gastrointestinal effects, 632 hearing impairment, 631 hematologic effects, 631–632 metal metabolism, 631 musculoskeletal effects, 632–633 nervous system effects, 631 sensory systems effects, 631 susceptibility factors, 633 tumorigenicity, 633 urinary tract, 632 talc skin, 766 urinary tract, 766 tamoxifen vs. aromatase inhibitors, 664–665 gastrointestinal malignancies, 669 mineral metabolism, 667 musculoskeletal effects, 668 pancreas effects, 667 psychiatric effects, 667 reproductive system effects, 668 resistance, 668 sensory systems effects, 664, 667 tumorigenicity, 668–669 tamsulosin liver effects, 364 nervous system effects, 364 sensory systems effects, 364 sexual function, 364–365 skin, 363 tazarotene, 292 tebipenem pivoxil drug–drug interactions, 415–416 nutrition, 415 tegaserod cardiovascular effects, 575 observational studies, 574–575 placebo-controlled studies, 575 teicoplanin immunologic, 435 telbivudine drug–drug interactions, 481 telithromycin drug–drug interactions, 437

Index of drugs liver effects, 436–437 neuromuscular, 436 telmisartan skin, 360 temazepam, 60 tenatoprazole, 579 tenecteplase hematologic effects, 564 tenofovir electrolyte balance, 485 hematologic, 485 pancreas effects (see didanosine) urinary tract, 485 terbinafine drug–drug interactions, 458 immunologic effects, 457–458 musculoskeletal effects, 457 skin, 457 terlipressin cardiovascular effects, 711 observational studies, 711 tesaglitazar placebo-controlled studies, 699 tetracaine hematologic effects, 241 tetracyclines chemically modified, 419 minocycline, 419–420 urinary tract, 421 theophylline nervous system, 8 susceptibility factors, 8–9 thiamphenicol immunologic effects, 429 respiratory effects, 429 thiazide diuretics, 349 electrolyte balance, 372 metabolism, 372 thiazolidinediones cardiac failure, 697 drug–drug interactions, 698 6-thioguanine, 638 thiomersal, 411–412 thiopental sodium monitoring therapy, 226 thiopurines clinical studies, 634 measurement, 634 toxicity, 635 thyroid hormones cardiovascular effects, 684 drug–drug interactions, 684 musculoskeletal effects, 684 psychiatric effects, 684 systematic reviews, 683 thyroid-stimulating hormone (TSH), 683 thyrotropin-releasing hormone (TRH) nervous system effects, 683 tiagabine nervous system effects, 123

785 observational studies, 123 psychological effects, 123–124 tibolone cardiovascular effects, 671 ticlopidine see clopidogrel comparative studies, 566 hematologic effects, 566 resistance, 566 skin, 566 tigecycline drug–drug interactions, 421 timolol cardiovascular effects, 340 formulations, 741 sensory systems effects, 340 tiotropium bromide, 311–312 titanium immunologic effects, 394 tobramycin sensory systems effects, 428 urinary tract, 428 tolterodine, 274, 275, 556 tonsillar anesthesia, 238 topical anesthesia, 238 nervous system effects, 228 sexual function, 229 skin, 229 topical glucocorticoids immunologic effects, 290 skin, 290–291 topiramate acid–base balance, 126 cardiovascular effects, 125 comparative studies, 124 dosage regimens, 126 drug–drug interactions, 126 nervous system effects, 125–126 observational studies, 124 placebo-controlled studies, 124–125 psychiatric effects, 126 psychological effects, 126 systematic reviews, 125 tramadol comparative studies, 168 gastrointestinal effects, 168 observational studies, 168 placebo-controlled studies, 168 psychiatric effects, 168 skin, 168–169 susceptibility factors, 169 travoprost sensory system effects, 651, 743 Triapinet immunologic effects, 405 hematologic effects, 405 triazolam drug–food interactions, 60 trichloroethylene

nervous system effects, 219 respiratory effects, 219 skin, 219–210 teratogenicity, 221 tumorigenicity, 220 trimethoprim, 444 see also co­ trimoxazole triptans cardiovascular effects, 346 nervous system effects, 346 trofosfamide, see oxazaphosphorines tropisetron placebo-controlled studies, 576 tumor necrosis factor alpha (TNF-a) antagonists, 592 immunologic effects, 593 infection risk from antagonists, 594–595 nervous system effects, 593 observational studies, 592–593 skin, 593 susceptibility factors, 597 tumorigenicity, 596–597 U ultrasound contrast agents, 731 V vaccines, 515 autism, 516–518 components, 523–524 Guillain–Barré syndrome, 515 safety, 518 surveillance of adverse events, 518–519 valdecoxib overdose, 191 valproate sodium, 126 cardiovascular effects, 127 comparative studies, 126–127 drug–drug interactions, 134–136 fertility, 132 formulations, 134 hematologic effects, 130 liver effects, 130 metabolism, 128–129 monitoring therapy, 136 nervous system effects, 128 overdose, 134 pancreas effects, 131 during pregnancy, 132–133 reproductive system effects, 131–132 skin, 131 susceptibility factors, 133–134 systematic reviews, 127 teratogenicity, 133 valproic acid, 80, 415

Index of drugs

786 valsartan psychological effects, 360 vancomycin hematologic effects, 436 liver effects, 436 skin, 436 urinary tract, 436 varicella vaccine, 522 observational studies, 522–523 vasopressin gastrointestinal effects, 710 vs. noradrenaline, 323 venlafaxine fetotoxicity, 22 verapamil cardiovascular effects, 342 verteporfin, 739–740 vigabatrin nervous system effects, 136–137 sensory systems effects, 137 vildagliptin placebo-controlled studies, 694–695 virginiamycin tolerance, 444 vitamin A see carotenoids vitamin C see ascorbic acid vitamin D analogues, 549

vitamins, see also specific names during pregnancy, 547 susceptibility factors, 547–548 voriconazole biliary tract, 463 formulations, 464 liver effects, 463 monitoring drug therapy, 464 skin, 463–464 W warfarin, 110, 419, 432, 553, 554, 627, 650, 751, see also coumarin anticoagulants water-soluble intravascular iodinated contrast agents, 731 administration route, 734 cardiovascular effects, 731 death, 733–734 dosage regimens, 734 immunologic effects, 733 nephrotoxicity, 731–732 susceptibility factors, 734 X ximelagatran drug–drug interactions, 561 food–drug interactions, 561

hematologic effects, 560 liver effects, 560–561 Y yeast, 524 yellow fever vaccine, 523 Z zidovudine hematologic effects, 485 observational studies, 485 zinc metabolism, 394 ziprasidone cardiovascular effects, 93 immunologic effects, 94 musculoskeletal effects, 94 nervous system effects, 93–94 observational studies, 92–93 zolpidem dependence, 61–62 formulations, 62 psychological effects, 61 zonisamide observational studies, 138 placebo-controlled trials, 138–139 psychiatric effects, 139 zopiclone drug–drug interactions, 62

Index of adverse effects A abdominal cramps enalapril, 353 octreotide, 710 polyethylene glycol, 581 abdominal discomfort codeine, 182 deferiprone, 400 lamivudine, 481 paracetamol, 182 sirolimus, 628 somatostatin, 709 abdominal pain alcohol, 757 basiliximab, 603 benzimidazoles, 508 cilomilast, 313 cocaine, 38 coumarin, 554 deferasirox, 401 lamivudine, 481 lamotrigine, 114 lisinopril, 353 methylphenidate, 7 naproxen, 190 octretide, 710 omeprazole, 577 pantoprazole, 579 pantoprazole+amoxicillin +rifabutin, 580 phosphates, 581, 582 polyethylene glycol, 583 praziquantel, 511 quinine, 717 rabeprazole, 577 rabeprazole+clarithromycin +amoxicillin, 580 ranitidine, 577 renzapride, 574 sitagliptin, 694 tegaserod, 575 terlipressin, 711 tiagabine, 123 abnormal liver function etanercept, 601 valproate, 127 abnormal smell benzylisoquinolinium, 249 acanthosis clobetazole, 290 acidosis see metabolic acidosis acne valproate, 131 zonisamide, 138

acquired lysosomal storage disease etherified starches, 534 activated partial thromboplastin time, prolongation herbal medicines, 746 acute alopecia areata infliximab, 602, 606 acute anaphylaxis aprotinin, 567 acute dystonia ziprasidone, 94 acute encephalopathy immunoglobulin, 534 theophylline, 8 valproate, 128 acute generalized exanthematous pustulosis clindamycin, 437 furosemide, 375 Ginkgo biloba, 750 morphine, 164 pseudoephedrine, 264 rifampicin, 499 terbinafine, 457 acute graft pyelonephritis mycophenolate mofetil, 627 acute hepatitis ecstasy, 47 tamsulosin, 364 xiao-chai-hu-tang, 746 acute joint pain tacrolimus, 632 acute leukemia paracetamol, 182 acute lung damage ethambutol, 497 trichloroethylene, 219 acute mania zonisamide, 139 acute meningeal syndrome ibuprofen, 187 acute myelopathy amphetamines+heroin, 41 acute myocardial infarction aspirin, 198, 199 cannabis, 33 HRT, 659 immunoglobulin, 536 magnesium, 390–391 NSAIDs, 184 acute myoclonic reaction rasburicase, 204

acute myopericarditis mesalazine, 583 acute non-ketotic hyperglycemia methadone, 161 acute ocular clonus paroxetine, 21 acute pancreatitis ACE inhibitors, 350 ibuprofen, 188 indometacin, 189 naproxen, 190 NSAIDs, 185 piroxicam, 192 statins, 716 tamoxifen, 667 acute papillary necrosis ibuprofen, 188 acute promyelocytic leukemia differentiation syndrome arsenic, 385 acute psychosis co-trimoxazole, 444 acute psychotic syndromes rofecoxib, 191 acute pulmonary edema hydrochlorothiazide, 373 muromonab, 607 acute renal failure amphotericin B deoxycholate, 459 anthraquinones, 753 iron dextran, 387 losartan, 359 tenofovir, 485 acute renal insufficiency aciclovir, 480 digoxin, 322 doxylamine,299 sulfonamide, 474 tetracyclines, 421 acute respiratory distress syndrome (ARDS) amiodarone, 325 perfluorocarbons, 531 propofol, 224 quetiapine, 88 acute tubular necrosis chromium picolinate, 386 non-steroidal anti-inflammatory drugs, 549 tenofovir, 485 adenoviral hepatitis rituximab, 608

787

Index of adverse effects

788 ADHD amfetamine salts +methylphenidate, 5 atomoxetine, 2 cocaine, 41 methylphenidate, 3, 5, 6 adhesive capsulitis stavudine+lamivudine +indinavir, 488 adrenal insufficiency azoles, 462 dexamethasone, 649 fluticasone, 650 adrenal suppression ritonavir, 488 adult respiratory distress syndrome see acute respiratory distress syndrome AGEP see acute generalized exanthematous pustulosis aggravate idiopathic generalized epilepsy syndromes antiepileptic drugs, 107 agitation antipsychotic drugs, 66 fentanyl, 157 fluoxetine, 167 levetiracetam, 118 olanzapine, 81 pethidine, 166 pregabalin, 122 quetiapine, 86 topiramate, 124 zonisamide, 138, 139 agranulocytosis see also leukopenia, neutropenia antithyroid drugs, 685 carbimazole, 685 clozapine, 76, 78 deferiprone, 399, 400 thionamides, 685 airway compromise propofol, 223 airway obstruction chloral hydrate, 61 akathisia antipsychotic drug, 67 aripiprazole, 71, 74 cisapride, 573 haloperidol, 81 quetiapine, 87 risperidone, 90 ziprasidone, 94 zonisamide, 138 alcohol syndrome alcohol, 759 allergic contact dermatitis aceclofenac, 186 diclofenac, 187 emla cream, 240

ethylenediamine, 300 hyoscine, 277 allergic rash see rash allergic reactions amoxicillin+clavulanic acid, 419 beta-lactams, 418 glucocorticoids, 290 leuprolide acetate, 704 sulfonamide, 445 allergic vasculitis heparin, 558 allergy chlorhexidine, 411 citrus fruit, 750 clavulanic acid, 419 co-trimoxazole, 445 gabapentin, 112 insulin, 690 irbesartan, 359 ketoprofen, 190 latex, 761–762 metoclopramide, 574 nickel, 392 alopecia see hair loss alopecia areata see also hair loss adalimumab, 598 efalizumab, 6o6 altered dreams efavirenz, 486 altered tastes topiramates, 125 Alzheimer’s disease donepezil, 11, 358 amenorrhea haloperidol, 76 penicillamine, 404 risperidone,89 tamoxifen, 665 amnesia alcohol, 757 lamotrigine, 114 sevo flurane–nitrous oxide, 219 silver compounds, 393 topiramate, 114 anaemia infliximab+methotrexate, 602 anaphylactic reactions fresh frozen plasma, 533 gelofusine, 534 infliximab, 601 meloxicam, 192 non-IgE-mediated, 429 anaphylaxis clindamycin, 437 co-trimoxazole, 445 diamorphine, 156 fluoroquinolone, 429 melphalan, 724

oxytocin, 708 TNF-a antagonist, 596 yeast, 524 ANCA see antineutrophil cytoplasmic antibodies (ANCA) anemia ACE inhibitors, 356 amphotericin B deoxycholate, 459 anagrelide, 564 androgens, 678 antiepileptic drugs, 110, 132 ciclosporin, 672 dapsone, 496 daptomycin, 446 endothelin receptor antagonists, 361 G-CSF, 591 heavy metals, 746 lamivudine, 482 linezolid, 440 methyldopa, 363 quinine, 472 ranitidine, 577 rituximab, 608 tesaglitazar, 699 zidovudine, 485 zinc, 394 anergia naltrexone, 170 Angelman syndrome vigabatrin, 136 angina see also myocardial infarction adrenaline, 264 aspirin, 570 NSAIDs, 188 topiramate, 127 angioedema ACE inhibitors, 356, 357 benazepril, 357 captopril, 362 COX-2 selective inhibitors, 189 efalizumab, 611 isotretinoin, 296 nevirapine, 492 propafenone, 336 rasburicase, 207 sitagliptin, 700 anhydrosis epidural anesthetic, 240 ankle/sacral edema fresh frozen plasma, 539 anorexia see appetite loss anterior uveitis cidofovir, 483 methadone, 164 travoprost, 657

Index of adverse effects antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis antithyroid drugs, 691 antiphospholipid syndrome aspirin, 200 anxiety alprazolam, 57 aripiprazole, 72 cannabis, 34, 46 efavirenz, 492 levetiracetam, 120 lorazepam, 59 methylphenidate, 3, 7 modafinil, 8 naltrexone, 172 pregabalin, 124 psilocybin, 51 anxiolysis gabapentin, 115 aphasia lamotrigine, 117 aplasia cutis congenita antithyroid drugs, 692 aplastic anemia see also anemia antiepileptic drugs, 130 carbamazepine, 108 chloramphenicol, 429 appetite loss levetiracetam, 117 methylphenidate, 7 praziquantel, 511 tiagabine, 123 topiramate, 124, 126 zonisamide, 138, 139 apnea ACE inhibitors, 350, 353, 355 chloral hydrate, 61 codeine, 155 colistin, 441 fentanyl, 217 metoclopramide, 574 midazolam, 59 morphine, 164 polymyxins, 441 argyria-like symptoms silver sulfadiazine, 393 arterial hypertension methylphenidate, 3 arterial thromboembolism bevacizumab, 604 arteriosclerosis tibolone, 671 arthralgia aluminium, 523 antimony, 384 deferiprone, 402 efalizumab, 606 isotretinoin, 292 mesalazine, 583 quinupristin/dalfopristin, 443 arthritis arsenic trioxide, 385

789 isotretinoin, 292 letrozole, 666 rubella vaccine, 109 arthropathy deferiprone, 402 efalizumab, 606 aseptic meningitis baclofen, 250 efalizumab, 605 ibuprofen, 187 immunoglobulins, 534 asphyxia naloxone, 170 asthma aescin, 345 aspirin, 192 formoterol, 308 glucocorticoid, 305, 649 montelukast, 311 paracetamol, 181 roflumilast, 314 salmeterol, 308 theophylline, 8 thiamphenicol inhalation, 429 ataxia colistin, 441 gabapentin, 111 lamotrigine, 113 oxcarbazepine, 119 polymyxins, 441 pregabalin, 122 zonisamide, 138 atherosclerosis cocaine, 37 HRT, 660 magnesium, 390 athetosis pregabalin, 121 tiagabine, 123 atrial fibrillation adenosine, 323 amiodarone, 324 aspirin, 201 caffeine, 8 dobutamine, 266 propafenone, 331 thyroid hormones, 684 auditory hallucinations quetiapine, 88 autism clonidine, 363 mercury, 391 autoimmune disorder ibuprofen, 187 autoimmune hemolytic anemia immunoglobulin, 534 methyldopa, 363 rasburicase, 204 stem cells, 540 autoimmune hepatitis melatonin, 708 autonomic neuropathy fentanyl, 158

autoimmune thyroid disease alemtuzumab, 602 autoimmune thyroiditis iodine, 684 B B-cell depletion rituximab, 608 back pain blood transfusion, 531 immunoglobulin, 534 lamivudine, 481 opioids, 158 topiramate, 125 back spasm methylphenidate, 3 bacterial pneumonia infliximab, 601 behavioral effects donepezil, 11 nitrous oxide, 221 TNF-a antagonist therapy, 592 topiramate, 124 zonisamide, 138 Bell’s palsy linezolid, 440 biliary disorders octretide, 710 bladder leak sirolimus, 630 bladder tumor marijuana, 37 bleeding anticoagulants, 201 clopidogrel+aspirin, 566 donepezil, 11 idraparinux, 566 immunoglobulin, 534 lepirudin, 559 mefloquine, 472 otamixaban, 562 razaxaban, 562 SSRIs, 19 tenecteplase, 564 blepharitis bromfenac, 742 bloating tegaserod, 575 blood dyscrasias chloramphenicol, 429 blood pressure, increase see also hypertension alprazolam, 57 amphetamines, 7 ciclosporin, 619 ecstasy, 42 ketamine, 222 NSAIDs, 184 olanzapine, 52 bloody stools gabapentin, 110 blurred vision see vision, blurred

Index of adverse effects

790 bone loss adjuvant aromatase inhibitors, 665 glucocorticoid therapy, 649 HRT, 661 bone marrow necrosis diclofenac, 186 bone marrow suppression everolimus, 623 bone mineral density reduction carbamazepine, 108 methadone, 162 thyroid hormones, 684 bone volume, reduction ciclosporin, 622 Bong lung cannabinoids, 33 bradycardia amiodarone, 324 antimony, 384 azithromycin, 437 beta-adrenoceptor antagonists, 339 bupivacaine, 233 clonidine, 362 codeine, 155 diamorphine (heroin), 157 donepezil, 11 iodinated contrast agents, 731 lithium, 26 methadone, 161 octreotide, 709 propofol, 224 renzapride, 574 ropivacaine, 241 bradykinesia levetiracetam, 118 ziprasidone, 94 breast cancer etanercept, 601 HRT, 661 stanozolol, 673 breast feeding codeine, 154, 155 breast pain atenolol, 339 bronchiolitis obliterans efalizumab, 605 bronchopulmonary dysplasia indometacin, 189 bronchospasm blood transfusion, 534 brown staining of teeth chlorhexidine, 410 bruising cupping, 753 growth hormones, 707 heparins, 557 mefloquine, 472 phosphatidylcholine, 765 restylane/perlane, 288 sibutramine, 10 Brugada syndrome bupivacaine, 239

flecainide, 330 ropivacaine, 241 bullous pemphigoid furosemide, 375 lisinopril, 357 bullous skin eruption chloroquine, 470 burning mouth syndrome efavirenz, 486 burning, erythema phosphatidylcholine, 765 burns cupping, 753 iodopovidone, 411 isotretinoin, 292 morphine, 164 C calcium oxalate crystals vitamin C, 548 calf pain gabapentin, 111 cardiac arrest see also myocardial infarction bupivacaine, 231 doxylamine +pyridoxine, 299 heroin, 157 propofol, 226 ropivacaine, 241 sibutramine, 9 tiotropium bromide, 312 cardiac conduction abnormalities nefazodone+gabapentin, 113 cardiac dysrhythmias adenosine, 323 amiodarone, 748 amphotericin B deoxycholate, 459 anesthetic creams, 233 chlorphenamine, 9 cocaine, 38 disodium edetate, 405 domperidone, 460 ecstasy, 43 heparin, 556 methadone, 161 phentermine, 9 phenytoin, 121 ziprasidone, 93 cardiac myocyte apoptosis cocaine, 38 cardiomyopathy lithium, 26 cardiovascular abnormalities SSRIs, 19, 20 cataracts deferiprone, 403 pilocarpine, 276 cauda equina syndrome spinal epidural anesthetic, 236

cellulitis recombinant human erythropoietin analogues, 538 sirolimus, 630 cerebellar dysfunction ifosfamide, 726 cerebellar syndrome lithium, 26 cerebral pseudoatrophy valproate, 128 cerebrospinal fluid leakage dopamine receptor agonists, 268 cervical pain recombinant human thyrotropin (rhTSH), 683 cheilitis chloroquine, 457 chemosis gatifloxacin, 431 chest pain cannabis, 33 gabapentin, 110 immunoglobulin, 534 iodopovidone, 411 recombinant human erythropoietin analogues, 538 chest tightness immunoglobulin, 534 chills doxycycline, 420 immunoglobulin, 536 polyethylene glycol, 581 choanal atresia antithyroid drugs, 686 cholelithiasis voriconazole, 463 cholestasis nevirapine, 486 parenteral nutrition, 550 tacrolimus, 632 cholestatic liver disease clarithromycin, 438 choroidal hemorrhage tadalafil, 346 chronic granulomatous interstitial nephritis allopurinol, 201 chronic secretory diarrhea sirolimus, 629 chronic thromboembolic pulmonary hypertension metamfetamine, 1 chrysiasis gold therapy, 389 circular erythema cupping, 753 circular foveal retinal pigment epithelium atrophy indocyanine green, 760

Index of adverse effects cleft palate carbamazepine, 109 coagulopathy balsalazide, 583 blood transfusion, 529 cognitive complaints lamotrigine, 114 cognitive disorder/problems ecstasy, 45 levetiracetam, 118 mood stabilizers, 26 trichloroethylene, 221 cognitive performance, impaired alprazolam, 57 ecstasy, 46 levetiracetam, 115 opioids, 149 pethidine, 149 topiramate, 125, 126 valproate, 128 zonisamide, 138 colitis, ischemic alosetron, 575 bevacizumab, 604 sodium phosphate, 582 colitis, non-specific diclofenac, 187 colon cancer somatropin, 705 coma baclofen, 251 carbamazepine, 110 doxylamine, 298 methadone, 161 topical anesthetics, 233 confusion aciclovir, 478 alprazolam, 57 gabapentin, 110 ifosfamide, 726 lithium, 26 morphine, 163, 165 pregabalin, 121–124 rasagiline, 272 tiagabine, 123–124 topiramate, 124 zonisamide, 138 congenital malformations ACE inhibitors, 352 carbamazepine, 107, 109 decongestants, 269 lamotrigine, 115 letrozole, 666 levetiracetam, 118 trichloroethylene, 221 valproate, 133 recombinant human erythropoietin analogues, 538, 539 conjunctival hemorrhage gatifloxacin, 431 conjunctival hyperemia ropivacaine, 236 timolol, 373

791 conjunctival irritation gatifloxacin, 431 constipation anticholinergic drugs, 271 bisacodyl, 581 botulinum toxins, 251 clozapine, 80 deferoxamine, 407 gabapentin, 111 ipratropium bromide, 312 melatonin, 708 morphine, 164 opioids, 149, 150, 158 oxcarbazepine, 120 palonosetron, 576 renzapride, 574 solifenacin, 275 tramadol, 168 tropisetron, 576 trospium, 275 zonisamide, 138 contact dermatitis antiglaucoma agents, 339 cannabis, 35 pristinamycin, 443 trichloroethylene, 221 convulsions cinnarizine, 345 SSRIs, 20 corneal drug deposition amiodarone, 324 ofloxacin, topical, 434 tamoxifen, 667 corneal disturbances cocaine, 40 corneal erosions bromfenac, 742 corneal infiltrates bromfenac, 742 corneal melting bromfenac, 742 corneal perforations bromfenac, 742 corneal thinning bromfenac, 742 coronary artery spasm dobutamine, 265 coronary vasospasm adenosine, 323 coronary heart disease NSAIDs and paracetamol, 184, 185 coryza lamotrigine, 114 cough ACE inhibitors, 350, 355 arsenic, 385 bucillamine, 410 levetiracetam, 117 losartan, 359 mycophenolate mofetil, 627 craniopharyngioma growth hormone, 706

Creutzfeldt–Jakob disease (vCJD) blood transfusion, 529 Crohn’s disease etanercept, 592 infliximab, 601 cryoglobulinemia immunoglobulin, 534 crystal arthropathy ethambutol, 498 cutaneous leishmaniasis antimony, 384 cutaneous lupus erythematosus terbinafine, 458 cutaneous squamous-cell carcinoma rituximab, 609 cutaneous vasculitis etanercept, 600 cyanosis codeine, 155 cytokine release syndrome rituximab, 608 cytolytic cellulitis efavirenz, 486 cytomegalovirus gastritis rituximab, 609 cytomegalovirus infection alemtuzumab, 603 basiliximab, 603 mycophenolate mofetil, 627 TNF-a antagonist therapy, 593 D dark urine khat, 47 deafness colistimethate sodium, 441 deferasirox, 401 deferoxamine, 403 sildenafil, 347 death alcohol, 758 atomoxetine, 2 blood transfusion, 530 etanercept, 601 fentanyl, 460 iodinated contrast agents, 733 naltrexone, 171 opioids, 151 selenium toxicity, 393 ziprasidone, 93 decision-making capacity ecstasy+alcohol, 43 methylphenidate, 4 delayed gastric ulcer healing sirolimus, 630 delayed hypersensitivity reactions TNF- a antagonist therapy, 593 delayed myeloid engraftment vancomycin, 436

Index of adverse effects

792 delirium antipsychotic drugs, 66 baclofen, 251 clarithromycin, 438 efavirenz, 486 lorazepam, 58 opioids, 149 delusional jealousy quetiapine, 89 delusions bupropion, 22 clozapine+aripiprazole, 71 nitrous oxide, 221 dementia lithium, 27–28 olanzapine, 85 quetiapine, 87 demodex folliculorum pimecrolimus, 628 demyelinating disease etanercept, 600 depersonalization psilocybin, 51 depression ciclosporin, 621 clonidine, 362 digoxin, 21 efavirenz+didanosine +emtricitabine, 483 emtricitabine, 484 levetiracetam, 117, 118 risperidone, 90 tamoxifen, 667 zonisamide, 138 derealization psilocybin, 49 dermatitis latex proteins, 762 tazarotene, 292 dermatomyositis omeprazole, 579 desaturation midazolam, 59 diabetes olanzapine, 85 diabetes insipidus lithium, 27 vasopressin, 27 diabetes mellitus antipsychotic drugs, 65 ciclosporin, 627 risperidone, 90–91 tacrolimus, 631 thiazide diuretics, 372 diarrhea alginate, 573 anagrelide, 564 aripiprazole, 71 arsenic, 385 benzimidazoles, 508 blood transfusion, 529 calcitonin, 703 cilomilast, 313 daptomycin, 446

deferoxamine, 401 emtricitabine, 484 esomeprazole, 577 esomeprazole+amoxicillin +gatifloxacin, 580 gabapentin, 71, 112 Helicobacter pylori eradication regimens, 580 lamivudine, 481 levofloxacin, 433 liraglutide, 7695 lopinavir, 488 modafinil, 8 moxifloxacin, 434 nicotinamide, 548 octreotide, 710 omeprazole, 579 omeprazole+amoxicillin +clarithromycin, 580 ondansetron, 576 pantoprazole, 579 pantoprazole+amoxicillin +rifabutin, 580 phosphatidylcholine, 765 polyethylene glycol, 583 praziquantel, 511 quinupristin/dalfopristin, 443 renzapride, 574 roflumilast, 313 sirolimus, 629 sitagliptin, 694 stavudine, 485 DIC see disseminated intravascular coagulation (DIC) diffuse retinal pigment epithelial atrophy indocyanine green, 760 digitalis intoxication paroxetine, 21 diplopia botulinum toxins, 252 lamotrigine, 113 oxcarbazepine, 119 zonisamide, 138, 139 discoid lupus etanercept, 600 disorientation gabapentin, 112 oseltamivir, 489 disseminated intravascular coagulation (DIC) atorvastatin, 472 fresh frozen plasma, 532 heparin, 558 warfarin, 554 disturbed attention lamotrigine, 114 topiramate, 114, 125 dizziness alfentanil, 153 alfuzosin, 363 amodiaquine, 469

aripiprazole, 74 calcitonin, 703 cannabis, 33 chloroquine, 469 colistin, 441, 442 dextromethorphan, 156 dipyridamole, 564 efavirenz, 484 emtricitabine, 484 gabapentin, 110–113 lamivudine, 481, 488 lamotrigine, 113, 114 levetiracetam, 116–118 methylphenidate, 3 morphine, 163 naltrexone, 170, 171 oseltamivir, 489 oxcarbazepine, 119, 120 phosphatidylcholine, 765 praziquantel, 511 pregabalin, 121, 122 quetiapine, 88 risperidone, 90 tiagabine, 124 topiramate, 125 tramadol, 168 zonisamide, 138, 139 DRESS dreams, altered efavirenz, 486 see drug rash with eosinophilia and systemic symptoms (DRESS) drowsiness antihistamines, 301 celecoxib, 192, 193 codeine, 155 dronabinol, 573 levetiracetam, 118 levocetirizine, 300 melatonin, 708 metoclopramide, 574 morphine, 163 naltrexone, 170 oxcarbazepine, 119, 120 topiramate, 125, 126 drug eruption, fixed co-trimoxazole, 445 ibuprofen, 190 etoricoxib, 193 drug hypersensitivity syndrome leflunomide, 626 drug rash with eosinophilia and systemic symptoms (DRESS) syndrome antiepileptic drugs, 108, 121 anticonvulsants, 133 cephalosporins, 416 citalopram, 110 phenytoin, 121

Index of adverse effects dry eyes gatifloxacin, 431 dry mouth anticholinergic drugs, 273 benzylisoquinolinium, 249 botulinum toxins, 252 dronabinol, 573 gabapentin, 112 ipratropium bromide, 312 methylphenidate, 7 morphine, 164 olanzapine, 82 oxybutynin, 276 rabeprazole, 579 risperidone, 90 solifenacin, 273, 274 tiotropium bromide, 312 tolterodine, 273 trospium, 273 zonisamide, 138 dry skin antiepileptic drugs, 120 oxcarbazepine, 120 ductus arteriosus, premature closure indometacin, 193 dysesthesia daptomycin, 446 dyskinesia levetiracetam, 118 metoclopramide, 574 olanzapine, 84 dyspepsia lamivudine, 481 ranitidine bismuth citrate +amoxicillin +clarithromycin, 581 tolterodine, 275 topiramate, 124 dysphagia see also swallowing difficulty alfuzosin, 363 amantadine, 88 botulinum toxins, 253 dysphonia salmeterol+fluticasone propionate, 3182 dysphoria topiramate, 125 dyspnea blood transfusion, 528 fresh frozen plasma, 533 gadolinium salts, 735 methadone, 161 tiotropium bromide, 312 dysrhythmias antipsychotic drugs, 67 beta2-adrenoceptor agonists, 308 corticotropin, 647 naloxone, 170 olanzapine, 85, 86 propofol, 224

793 dystonia cannabinoids, 33–35 levetiracetam, 118 metoclopramide, 574 olanzapine, 82, 85, 86 ziprasidone, 134 E Ebstein’s anomaly lithium, 28 ecchymosis see bruising echolalia morphine, 164 ectopic pregnancies misoprostol, 651 eczema corticosteroids, topical, 204 hair dyes, 289 immunoglobulin, 535 levocetirizine, 300 edema alfuzosin, 362 cupping, 753 gabapentin, 112, 113 isosulfan, 218 lanthanoids, 388 pregabalin, 121, 122 emesis see vomiting emotional instability methylphenidate, 6 emphysema cannabinoids, 33–35 encephalopathy cocaine, 39 measles vaccines, 520 methadone, 161 pregabalin, 121–122 theophylline, 8 valproate, 128 endocarditis rituximab, 607 endophthalmitis bromfenac, 742 leflunomide, 626 pegaptanib, 739 entactogenesis ecstasy, 44 enteroviral meningoencephalitis rituximab, 606 eosinophilia bisacodyl, 581 carbamazepine, 108 clozapine, 78 eosinophilic cellulitis adalimumab, 598 eosinophilic gastroenteritis citrus fruit allergy, 750 eosinophilic gastroenterocolitis tacrolimus, 632

epigastric pain co-trimoxazole, 446 hydrogen peroxide, 761 epistaxis topiramate, 125 erectile dysfunction antihypertensive treatment, 349 gonadorelin analogues, 704 erosive esophagitis omeprazole, 579 eruptive nevi TNF-a antagonist therapy, 593 erythema diltiazem, 339 irbesartan, 359 erythema multiforme minor risperidone, 91 erythema nodosum etanercept, 600 erythematous annular plaques infliximab, 602 euphoria khat, 48 modafinil, 8 pregabalin, 121, 122 exfoliative dermatitis fosphenytoin, 120 phenytoin, 120 exogenous lipid pneumonia paraffin, 764 extrapyramidal effects antipsychotic drugs, 67 aripiprazole, 73, 76 ecstasy, 46 haloperidol, 66, 74 quetiapine, 87, 88 risperidone, 92 tiagabine, 123 ziprasidone, 93 extrapyramidal symptoms antipsychotic drugs, 67 aripiprazole, 72, 74 olanzapine, 72 perphenazine, 72 eye irritation brinzolamide, 371 gatifloxacin, 431 eyelid edema gatifloxacin, 431 eye pain gatifloxacin, 431 F facial dyskinesia aripiprazole, 71 facial flushing prolastin, 532 factitious panniculitis cupping, 753 factor XIII deficiency valproate, 130

Index of adverse effects

794 Fanconi’s syndrome tenofovir, 485 valproate, 126 fasciculations topiramate, 125 fatigue see also malaise, tiredness, weakness alprazolam, 57 anagrelide, 564 arsenic, 385 emtricitabine, 484 gabapentin, 110–112 immunoglobulin, 536, 537 lamivudine, 481 lamotrigine, 112 letrozole, 666 levetiracetam, 116–118 melatonin, 708 mesalazine, 583 oxcarbazepine, 119, 120 risperidone, 90, 91 somatropin, 705 topiramate, 124–126 zonisamide, 139 fearful responses oseltamivir, 489 febrile rash efavirenz, 486 feeding problems serotonin toxicity, 20 SSRIs, 20 fetal death antiepileptic drugs, 106, 115 fever abacavir+lamivudine +zidovudine, 482 albendazole, 508 antimony, 384 azathioprine, 637 baclofen, 250 balsalazide, 583 blood transfusion, 528 colistin, 442 dapsone, 497 doxycycline, 420 ecstasy, 47 efalizumab, 605 hemin, 531 immunoglobulins, 534–2 irbesartan, 359 lamivudine, 480 mefloquine, 481 metamizole (dipyrone), 192 muromonab, 607 propofol, 224 rotavirus vaccine, 521 fibromyalgia olanzapine, 82 fits melatonin, 708 flares penicillins, 418

flatulence anagrelide, 564 octretide, 710 orlistat, 90 oxymorphone, 166 polyethylene glycol, 583 fluid overload immunoglobulin, 534 fluid retention anagrelide, 564 flu-like symptoms tiagabine, 123 topiramate, 125, 126 flushing alfentanil, 153 aspirin, 198 endothelin receptor antagonists, 359 immunoglobulin, 534 naltrexone, 171 prolastin, 532 focal brain edema pregabalin, 121, 122 folliculitis allopurinol, 204 fracture antiepileptic drugs, 105, 106 ibuprofen, 190 HRT, 661 opioids, 150 fulminant hepatic failure black cohosh, 749 fulminant hepatitis paracetamol, 183, 184 nevirapine, 487 nitrofurantoin, 439 G gait disturbance gabapentin, 112 gentamicin, 427 levetiracetam, 116, 117 ziprasidone, 95, 96 galactorrhea amisulpride, 69 antipsychotic drugs, 69 aripiprazole, 76, 77 risperidone, 88, 89 gamma-glutamyl transpeptidase activity, neonatal lamotrigine, 115, 116 gastric disturbance tiagabine, 123, 126 gastric emptying, slowing of dronabinol, 35 gastritis esomeprazole, 577 khat, 48 spironolactone, 376 gastroenteritis etanercept, 601 infliximab, 601

gastrointestinal bleeding donepezil, 11 SSRIs, 19 gastrointestinal discomfort amiodarone, 324 buprenorphine, 171 cisapride, 573 co-trimoxazole, 444 dipyridamole, 564 gabapentin, 112 liraglutide, 695 oxcarbazepine, 119 topiramate, 125 vildagliptin, 694 ziprasidone, 92 gastrointestinal disorders deferiprone, 403 immunoglobulin, 537 itraconazole, 463 liraglutide, 695 nitrous oxide, 221 paracetamol, 184 quetiapine, 88 topiramate, 124 vildagliptin, 694 gastrointestinal hemorrhage recombinant human erythropoietin analogues, 538 gastrointestinal infections corticotropin, 647 gastrointestinal perforation bevacizumab, 604 gastroschisis decongestant, 265 generalized dermatitis trichloroethylene, 221 generalized eosinophilic pustular folliculitis allopurinol, 202 generalized itching colistin, 442 generalized itchy eczematous plaques zyloric, 202 generalized pustular psoriasis aceclofenac, 186 giddiness cocaine, 38 glandular hyperplasia antiepileptic drugs, 123 glaucoma cannabinoids, 33, 34 topiramate, 125, 126 glossitis bucillamine, 404 granulocytopenia metamizole, 192 granulomatous reactions leuprolide, 704 granulomatous stomatitis ramipril, 355 gut ischemia vasopressin, 710

Index of adverse effects gynecomastia antiandrogens, 673 antipsychotic drugs, 65, 66 diazepam, 123 leuprolide, 705 phenytoin, 123 risperidone, 89 spironolactone, 376 stanozolol, 673 zonisamide, 123 H hair loss dalteparin, 558 metformin, 693 pramipexole, 269 valproate, 120, 127 hallucinations aciclovir, 478 clonidine, 362 ecstasy, 44 gatifloxacin, 431 ifosfamide, 726 propofol, 224 topiramate, 126 tramadol, 168 hallucinogen persisting perceptual disorder (HPDD) psilocybin, 50, 51 HDL cholesterol, increased carbamazepine, 107 headache albendazole, 508 alfuzosin, 364 anagrelide, 564 antimony, 384 arsenic, 385 aripiprazole, 72 benzimidazoles, 508 buprenorphine, 169 cannabinoids, 33, 35 cilomilast, 313 dextromethorphan, 156 dipyridamole, 564 doxycycline, 420 dronabinol, 573 emtricitabine, 484 endothelin receptor antagonists, 361 formoterol+budesonide, 308 gabapentin, 110, 112 gestrinone, 672 khat, 48 lamivudine, 481 lamotrigine, 113 lansoprazole, 578 levetiracetam, 117 methylphenidate, 3, 7 modafinil, 8 montelukast, 316 naltrexone, 170 olanzapine, 82 omeprazole, 577 oxcarbazepine, 119, 120

795 palonosetron, 576 pantoprazole, 579 PDE-5 inhibitors, 347 praziquantel, 511 pregabalin, 121 psilocybin, 50 quetiapine, 68 ranitidine, 577 ranitidine bismuth citrate +amoxicillin +clarithromycin, 581 renzapride, 574 risperidone, 90, 92 roflumilast, 313, 314 salmeterol+fluticasone propionate, 318 sibutramine, 9, 10 sitaxsentan, 362 tiagabine, 123, 124 TNF-a antagonist therapy, 593 topiramate, 125 tropisetron, 576 valproate, 124 ziprasidone, 93 zonisamide, 138 hearing impairment clarithromycin, 44 loop diuretics, 375 psilocybin, 49, 50 hearing loss cobalt poisoning, 386 didanosine, 483 oscillopsia, 427 heart beat see cardiac dysrhythmias heart rate, increase regadenoson, 324 verapamil, 342 heart rate, reduction donepezil, 11 hemangioma ciclosporin, 621 valproate, 126–128 hematuria ciprofloxacin, 430 coumarin, 553 emtricitabine, 484 heparin, 557 lamivudine, 482 hemolysis blood transfusion, 529 fresh frozen plasma, 533 iron dextran, 388 rasburicase, 204 hemolytic anemia efalizumab, 605 rasburicase, 204 hemolytic–uremic syndrome tacrolimus, 632 hemorrhage bevacizumab, 604 misoprostol, 651 ranibizumab, 739

warfarin, 553, 554 hemorrhagic stroke phenylpropanolamine, 264 hemorrhagic thrombocytopenia rituximab, 607 Henoch–Schönlein purpura etanercept, 600 paracetamol + codeine, 182 hepatic disorder bromfenac, 182 diclofenac, 182, 185 nimesulide, 182, 185 sulindac, 182, 185 hepatic impairment arsenic, 385 hepatic insufficiency sitagliptin, 694 hepatic nodular regenerative hyperplasia thiopurines, 636 hepatic steatosis didanosine, 482 stavudine, 482 hepatitis antiandrogens, 674 blood transfusion, 530 buprenorphine, 169 cocaine, 40, 41 khat, 48 rofecoxib, 191 hepatocellular damage saquinavir, 488 hepatocellular focal nodular hyperplasia danazo, 672 hepatotoxicity amiodarone, 329 disulfiram, 760 isoflurane, 218 lanthanoids, 388 sevoflurane, 218 hip dysplasia olanzapine, 86 hoarseness isotretinoin, 291 salmeterol+fluticasone propionate, 308 Horner’s syndrome bupivacaine, 236 spinal epidural anesthetic, 236 hostility androgens, 673 levetiracetam, 117 tiagabine, 123 hot flushes gestrinone, 672 gonadotropins, 703 letrozole, 666 Helicobacter pylori eradication regimens omeprazole+amoxicillin +clarithromycin, 580

Index of adverse effects

796 hydrocephalus methadone, 161 hyperalgesia opioids, 149 remifentanil, 167 hyperammonemia valproate, 128 hyperandrogenism anticonvulsants, 132 valproate, 131 hypercalcemia parathormone, 709 tamoxifen, 667 vitamin D, 549 hyperemia dorzolamide+timolol, 372 hypereosinophilia heparin, 558 hyperglycemia arsenic, 385 methadone, 161, 162 risperidone, 90, 91 tropisetron, 576 hyperhomocysteinemia antiepileptic drugs, 105 nitrous oxide, 221 hyperkalemia mannitol, 376 propofol, 224 thiopental sodium, 226 hyperkinetic movement disorders modafinil, 8 hyperlactatemia linezolid, 440 zopiclone, 8 hypernatremia lithium, 27 hyperparathyroidism lithium, 27 hyperphagia oxcarbazepine, 119 hyperphosphatemia phosphate, 581 hyperpigmentation emtricitabine, 484 hyperprolactinemia antipsychotic drugs, 65, 69 olanzapine, 84 risperidone, 90 hyper-reflexia aciclovir, 478 hypersalivation clozapine, 80 olanzapine +fluvoxamine, 86 hypersensitivity reactions azathioprine, 637 cephalosporins, 416 colistin, 442 efalizumab, 605, 606 efavirenz, 486 hydroxyethyl starch, 534 ibuprofen, 188

leuprolide, 704 trichloroethylene, 219 hypersensitivity syndrome, drug-induced see also DRESS carbamazepine, 108, 109 co-trimoxazole, 445 hypersexuality quetiapine, 89 hypertension see also blood pressure increase acetazolamide, 371 adrenaline (epinephrine), 261 baclofen, 251 beta2-adrenoceptor agonists, 308 bevacizumab, 604 cannabinoids, 33, 34 carbetocin, 708 corticotropin, 647 ecstasy, 47 immunoglobulins, 534, 535 infliximab, 602 isoflurane, 218 melatonin, 708 methadone, 161 methylphenidate, 3 midazolam, 59 naloxone, 170 recombinant human erythropoietin analogues, 539 sirolimus, 628 hypertensive encephalopathy Ephedra+caffeine, 262 hyperthermia see fever hyperthyroidism amiodarone, 324 hypertriglyceridemia propofol, 224 hyperuricemia ciclosporin, 621 hyphema aspirin, 554 hypoacusis deferiprone, 403 hypocalcemia disodium edetate, 405 rasburicase, 204 hypofibrinogenemia valproate sodium, 130 hypoglossal nerve paralysis TNF-a antagonist therapy, 592, 593 hypoglycemia fluoroquinolones, 431 levofloxacin, 433 pramlintide, 692 sitagliptin, 693 SSRIs, 20 sulfonylureas, 695

hypokalemia amphotericin, 458 corticotropin, 647 herbal medicines, 746 itraconazole, 463 methadone, 161 spironolactone, 392 tenofovir, 485 thiazide diuretics, 372 valproate, 129 hypomagnesemia tacrolimus, 631 hypomania lamotrigine, 113 zonisamide, 138 hyponatremia desmopressin, 710 immunoglobulin, 534 oxcarbazepine, 119, 120 phosphate, 582 thiazide, 372 hypopigmentation glucocorticoids, 650 hypospadias clomifene, 665 hypotension amikacin, 427 baclofen, 251 benzylisoquinolinium, 249 blood transfusion, 529, 529 cannabinoids, 33, 34 chloral hydrate, 61 clonidine, 363 cocaine, 40, 41 dipyridamole, 564 endothelin receptor antagonists, 361 fentanyl, 157, 158 gadolinium salts, 735 immunoglobulin, 534 iodopovidone, 411 morphine+midazolam, 163 muromonab, 607 perfluorocarbons, 531 pethidine and midazolam, 166 phenytoin, 121 propofol, 224, 226 quetiapine, 87 remifentanil, 167 trichloroethylene, 220 ziprasidone, 93, 94 hypothermia blood transfusion, 529 SSRIs, 20 hypothyroidism amiodarone, 324 iodine, 684 iodopovidone, 411 lithium, 27 oxcarbazepine, 120 quetiapine, 89 recombinant human thyrotropin (rhTSH), 683

Index of adverse effects hypovitaminosis D carbamazepine, 106 valproate, 106 hypoxemia blood transfusion, 528 hypoxia chloral hydrate, 61 morphine+midazolam, 162–163 perfluorocarbons, 531 sevoflurane, 218 I iatrogenic ulcers famotidine, 576 IBCT see incorrect blood component transfusion (IBCT) idiopathic hepatitis efalizumab, 605 idiopathic generalized epilepsy syndromes antiepileptic drugs, 136 idiopathic pulmonary arterial hypertension (PAH) metamfetamine, 1, 2 IFIS see intraoperative floppy iris syndrome (IFIS) ileus midazolam+fentanyl, 158 opioids, 150 immune-mediated pancytopenia efalizumab, 606 immunosuppression ecstasy, 45–47 opioids, 151 impaired coagulation argatroban, 559 impaired wound healing bevacizumab, 604 impotence sildenafil, 346 incorrect blood component transfusion (IBCT) blood transfusion, 530 infection basiliximab, 603 efalizumab, 606 etanercept, 600 misoprostol, 651 pregabalin, 121, 122 infectious endophthalmitis ranibizumab, 739 inflammatory bowel disease isotretinoin, 292 infusion phlebitis quinupristin/dalfopristin, 443 infusion reactions infliximab, 601 injection site reactions anakinra, 592

797 insomnia antimony, 384 aripiprazole, 72 arsenic, 385 buprenorphine, 169 citalopram, 89 efavirenz, 486 emtricitabine, 484 enoxacin, 429 lamivudine, 482 methadone, 161, 162 methylphenidate, 7 naltrexone, 170 olanzapine, 81 risperidone, 92 rufloxacin, 429 topiramate, 122–126 ziprasidone, 91, 93 zonisamide, 138 insulin resistance olanzapine, 85 intermenstrual bleeding phosphatidylcholine, 765 interstitial nephritis celecoxib, 193, 196 ciprofloxacin, 430 rofecoxib, 193 interstitial pneumonitis amiodarone, 324 azathioprine, 635 cyclophosphamide, 726 ifosfamide, 726 infliximab, 601 lamotrigine, 113, 116 leflunomide, 625 intestinal perforation bevacizumab, 606 dexamethasone +indometacin, 189 intracranial bleeding SSRIs, 19 intracranial pressure papaverine, 166 intrahepatic cholestasis ecstasy, 41 intraocular pressure, increase ranibizumab, 739 intraoperative floppy iris syndrome (IFIS) alpha-adrenoceptor antagonists, 363 intravascular hemolysis iron dextran, 388 intraventricular cysticercosis albendazole, 508 intraventricular hemorrhage indometacin, 189 morphine, 163 iridocyclitis ranibizumab, 739 TNF-a antagonist therapy, 593 iris pigment dispersion methylthioninium chloride, 763

irritability bromfenac, 742 methylphenidate, 6 metoclopramide, 574 tiagabine, 123 zonisamide, 138 itching see also pruritus alfentanil, 153 doxycycline, 420 fondaparinux, 563 lamotrigine, 115 levetiracetam+diazepam, 118 rofecoxib, 193 sufentanil, 167, 168 talc, 288 J jaundice see also liver carbimazole, 685 cocaine, 40, 41 rofecoxib, 193 jitteriness naltrexone, 171 SSRIs, 20 K Kawasaki disease vaccines, 522 keloid cupping, 753 keratitis bromfenac, 748 cocaine, 40 gatifloxacin, 431 NSAIDs, 742 keratolysis diclofenac, 186 kidney cancers benzo(a)pyrene, 384 cyclophosphamide, 727 kidney stones indinavir, 488 zonisamide, 140 L lacrimation gatifloxacin, 431 lactation reduction khat, 48 lactic acidosis see also metabolic acidosis linezolid, 440 propofol +catecholamines, 224 metformin + ACE inhibitors, 353 language impairment topiramate, 124 laryngeal edema blood transfusion, 529 laryngeal dystonia antipsychotic drugs, 65

Index of adverse effects

798 LDL cholesterol, increased carbamazepine, 108 Leber’s hereditary optic neuropathy ethambutol, 497 left ventricular dysfunction propofol, 222 leg cramps oxcarbazepine, 119 leg pain donepezil, 11 pregabalin, 123 Lennox–Gastaut syndrome levetiracetam, 116 lens abscess methadone, 162 lethargy aripiprazole, 70 oxcarbazepine, 120 phentermine, 9 leukemia formaldehyde, 409 valproate, 126, 127 leukocytoclastic vasculitis etanercept, 600 everolimus, 623 ibuprofen, 190 metformin, 692 rituximab, 608 sirolimus, 630 leukocytosis arsenic, 385 carbamazepine, 108, 109 efalizumab, 606 leukoencephalopathy ciclosporin, 620 levamisole, 510 morphine, 164 leukocytosis arsenic, 385 efalizumab, 606 leukoencephalopathy ciclosporin, 620 levamisole, 510 leukonychia sirolimus, 630 leukopenia clozapine, 80 everolimus, 623 levamisole, 510 risperidone, 90 Lewy-body dementia quetiapine, 88 libido, increased quetiapine, 89 libido, loss dutasteride, 675 methadone, 161, 162 lichenoid hydrochlorothiazide, 373 irbesartan, 359, 373 lichenoid eruptions diltiazem, 341

lichen planus pemphigoides naproxen, 190 lightheadedness dronabinol, 573 immunoglobulin, 534 lorazepam, 58, 59 phosphatidylcholine, 765 linear hypopigmentation glucocorticoids, 648 linear IgA bullous dermatosis vancomycin, 436 lipid disturbances everolimus, 622 lipodystrophy lamivudine, 482 nevirapine, 482 stavudine, 482 liposarcoma etanercept, 601 livedoid dermatitis NSAIDs, 187 livedo reticularis amantadine, 270 liver damage acarbose, 691 chlorzoxazone, 253, 254 infliximab, 602 kava kava, 752 pegvisomant, 707 telithromycin, 436 liver failure co-trimoxazole, 445 lamivudine, 481 nevirapine, 487 telithromycin, 436 liver function abnormalities quinupristin/dalfopristin, 443 local pain bromfenac, 742 local skin infections infliximab, 601 loose stools lansoprazole, 578 ranitidine bismuth citrate +amoxicillin +clarithromycin, 581 loss of vision cobalt poisoning, 386 low birth weight antiepileptic drug, 106 decongestants, 265 vitamins C/E, 547 SSRIs, 20 lower respiratory tract infections TNF-a antagonist, 596 lower urinary tract symptoms gonadotropins, 703 lung cancer calabash chalk, 759 cannabis, 36, 37 lupus erythematosus tumidus efalizumab, 606

lupus-like syndrome antithyroid drugs, 685 penicillamine, 404 TNF-a antagonist, 596 lupus pneumonitis hydralazine, 365 lupus rashes etanercept, 600 lymphocele everolimus, 622 sirolimus, 630 lymphocytosis carbamazepine, 108 lymphoma azathioprine, 637 TNF-a antagonist, 596 lymphoproliferative disorder alemtuzumab, 595 efalizumab, 607 M macrophagic myofasciitis vaccine-derived aluminium hydroxide, 385 maculopapular pruritic rashes clopidogrel, 566 malaise abacavir+lamivudine +zidovudine, 482 antimony, 384 moxifloxacin, 434 repaglinide, 695 telithromycin, 322 topiramate, 124 malformations see also congenital malformations ACE inhibitors, 352 antiepileptic drugs, 118, 133 carbamazepine, 109 efalizumab, 605 metformin, 693 misoprostol, 651 mycophenolate, 628 phenobarbital, 106 valproate, 106, 133 mania antidepressants, 114 aripiprazole, 73 bromocriptine, 269 lamotrigine, 26, 114 methylphenidate, 4 quetiapine, 87 valproate, 136 maternal tachycardia carbetocin, 708 meaningless speech oseltamivir, 489 memory problems diazepam, 58 topiramate, 125 memory deficits ecstasy, 45, 46 zolpidem, 61

Index of adverse effects memory impairment cannabis, 34, 45 topiramate, 125 valproate, 126 zonisamide, 138 memory loss gabapentin, 111 oxcarbazepine, 119 meningitis see aseptic meningitis menometrorrhagia lithium, 28 mental sluggishness zonisamide, 138 Merkel cell carcinoma rituximab, 609 metabolic acidosis cocaine, 37 ibuprofen, 188 linezolid, 440 paracetamol, 184 pethidine, 166 topiramate, 126 metallic taste rabeprazole+ clarithromycin+ amoxicillin, 580 ranibizumab, 739 methemoglobinemia cerium nitrate, 389 dapsone, 496 rasburicase, 204 triapine, 405 microangiopathy tacrolimus, 632 microhematuria penicillamine, 404 microlithiasis of gallbladder somatostatin, 709 migraine haloperidol, 81 mild confusion dronabinol, 574 mineralization of teeth tetracyclines, 418 mood disorder atomoxetine, 2 cannabis, 34 ecstasy, 44 gestrinone, 672 levetiracetam, 116 progestogen, 669 ziprasidone, 93 mood, dysphoric alprazolam, 57 cannabis, 51 moodiness methylphenidate, 7 tiagabine, 123 mouth ulcer antithyroid drugs, 685 levetiracetam, 116 mucormycosis deferiprone, 403

799 mucous leishmaniasis antimony, 384 multinodular bronchiolitis obliterans rituximab, 607 multiorgan hypersensitivity reaction efavirenz, 486 multiple sclerosis baclofen, 169 gabapentin, 111 minocycline, 419 muscle cramps deferoxamine, 402 muscle damage black cohosh, 749 ciclosporin, 621 muscle rigidity ecstasy, 45 remifentanil, 167 sevoflurane, 219 muscle weakness azathioprine, 636 colistin, 441 myalgia antimony, 384 aripiprazole, 71 frakefamide, 162 isotretinoin, 292 lamivudine, 481 levetiracetam, 118 quinupristin/dalfopristin, 443 myalgic encephalomyelitis vaccine, 520 myasthenia gravis lithium, 26 telithromycin, 436 mydriasis dosylamine, 298 myelodysplastic syndrome azathioprine, 637 G-CSF, 591 myelopathy amphetamines, 41 nitrous oxide, 221 myelosuppression suramin, 512 myocardial adrenergic stress cocaine, 38 myocardial infarction adrenaline, 262, 264 angiotensin II receptor antagonists, 358 aspirin, 198, 199 beta2-adrenoceptor agonists, 308 cannabis, 33 celecoxib, 190 cocaine, 37, 240 dobutamine, 266 endothelin receptor antagonists, 361 ephedrine, 262 epoetin alfa, 538

HRT, 660, 661 khat, 48 magnesium, 390, 391 NSAIDs+paracetamol, 184, 185 pseudoephedrine, 263 psilocybin, 50 recombinant human erythropoietin analogues, 538 tegaserod, 575 tiotropium bromide, 310 myocardial depression propofol, 223 myocarditis clozapine, 78 cocaine, 38 myoclonic activity etomidate, 222 SSRIs, 20 myoclonic cramps topiramate, 125 myoclonic epilepsy levetiracetam, 116 myoclonic jerks lithium, 26 sevoflurane, 222 myoclonic movements etomidate, 222 propofol, 222 myoclonic status epilepticus vigabatrin, 136 myoclonus etomidate, 222 gabapentin, 113 opioids, 161 myopathy daptomycin, 446 N NAION see non-arteritic anterior ischemic optic neuropathy (NAION) narrow-angle glaucoma ipratropium bromide, 311 nasal congestion immunoglobulin, 78 nasopharyngitis sitagliptin, 693 nausea alfentanil, 460 alginate, 573 amphotericin B lipid complex (ABLC), 459 anagrelide, 570 aripiprazole, 71 arsenic, 385 benzimidazoles, 508 benzylisoquinolinium, 249 botulinum toxins, 252 butorphanol, 170 carbetocin, 708 chloroquine, 469

Index of adverse effects

800 cilomilast, 313, 314 citalopram, 20 cocaine, 40 dextromethorphan, 156 donepezil, 10 dronabinol, 573 emtricitabine, 484 esomeprazole, 578 fentanyl, 157, 158 gabapentin, 110, 111 gadolinium salts, 734 gestrinone, 672 glucagon, 689 lamivudine, 481 lamotrigine, 113, 114 levetiracetam, 118 modafinil, 7, 8 morphine, 153, 163, 164 naltrexone, 170, 171 nevirapine, 487 octreotide, 710 omeprazole, 578 opioids, 48, 150, 153 oxcarbazepine, 119, 120 oxymorphone, 168 pantoprazole+amoxicillin +rifabutin, 580 pethidine, 166 phosphatidylcholine, 765 polyethylene glycol, 581 praziquantel, 511 pregabalin, 122, 123 quetiapine, 60 quinupristin/dalfopristin, 449 rabeprazole, 577 ranitidine, 573 repaglinide, 695 roflumilast, 313, 314 saquinavir+ritonavir, 488 tegaserod, 575 tiagabine, 124 topiramate, 124, 125 tramadol, 168 valproate, 126, 127 ziprasidone, 95, 96 zonisamide, 137–139 neonatal abstinence syndrome buprenorphine, 169 nephrolithiasis zonisamide, 138 nephrotic syndrome colchicine, 203 nephrotoxicity ACE inhibitor, 732 hydroquinone, 288 nerve injury ropivacaine, 238 nervousness cocaine, 38 ecstasy, 41 levetiracetam, 116–118 modafinil, 8 nervous system impairment dextromethorphan, 156

neuritis multiplex azathioprine, 636 neuroleptic malignant syndrome amantadine, 87 antipsychotic drugs, 67 aripiprazole, 71, 76 lithium, 26 quetiapine, 88 ziprasidone, 92 neuromuscular blockade colistin, 441 polymyxins, 441 neuromyopathy colchicines, 202 neuropathy arsenic, 385 gabapentin, 113 suramin, 512 neuropsychiatric disorders efavirenz, 486 nitrous oxide, 221 neurorestorative effect lithium, 25 neurosensory deafness deferiprone, 403 neurotoxicity lithium, 26 trichloroethylene, 219 neutropenia adalimumab, 598 clozapine, 79 deferiprone, 402 immunoglobulin, 534 indometacin, 189 olanzapine, 86 vancomycin, 436 zidovudine, 485 Nicolau syndrome NSAIDs+corticosteroids +penicillins, 187 nightmares efavirenz, 486 gabapentin, 111 melatonin, 708 sevoflurane, 219 valsartan, 360 non-arteritic anterior ischemic optic neuropathy (NAION) amiodarone, 324 non-hemorrhagic strokes prothrombin, 537 non-Hodgkin’s lymphoma trichloroethylene, 220 non-IgEmediated anaphylactic reaction gadolinium salts, 734 non-infectious hepatitis immunoglobulin, 536 non-melanoma skin cancers efalizumab, 607 non-obstructive cardiomyopathy zidovudine, 485

non-occlusive acute mesenteric ischemia digoxin, 322 numbness gabapentin, 111 nystagmus oxcarbazepine, 120 O obesity sitagliptin, 694 topiramate, 125 obsessive-compulsive disorder quetiapine, 87 ziprasidone, 93 obsessiveness olanzapine, 84 obstructive sleep apnea ACE inhibitors, 353 occult insomnia cocaine, 39 ocular argyrosis silver-containing compounds, 287 ocular epithelial damage antimisting agent, 761 ocular hyperemia brinzolamide, 371 ocular hypertension cannabinoids, 35 ocular irritation tamoxifen, 667 oculogyric crisis metoclopramide, 574 oligohydramnios metamizole, 192 oligomenorrhea lithium, 132 valproate, 132, 133 oligospermia radioactive iodine compounds, 684 Onchocerca volvulus ivermectin, 510 onychomalacia sirolimus, 630 onychorhexis sirolimus, 630 opioid withdrawal syndrome buprenorphine, 169 optic atrophy indocyanine green, 760 optic neuritis adalimumab, 598 etanercept, 600, 601 ibuprofen, 189 lithium, 27 tamoxifen, 667 optic neuropathy amiodarone, 324 linezolid, 440 tacrolimus, 631 oral fixed drug eruption fluconazole, 462

Index of adverse effects orofacial tardive dyskinesia metoclopramide, 574 orthostatic hypotension quetiapine, 86 oscillopsia gentamicin, 427 osteomalacia magnesium-containing antacids, 391 osteopenia antiepileptic drug, 106 carbamazepine, 108 osteoporosis heparin, 558 otitis media etanercept, 601 oxidative stress desflurane, 219 8-hydroxydeoxyguanosine, 8 valproate, 130, 131 P painful gynecomastia see also gynecomastia antiepileptic drugs, 123 pregabalin, 123 spironolactone, 376 pain amplification syndrome TNF-a antagonist therapy, 592 pain on injection etomidate, 221 propofol, 226 pain sensitization remifentanil, 167 palpitation anagrelide, 564 ipratropium bromide, 312 methylphenidate, 3 pancreatitis didanosine, 483, 484 growth hormone, 706 indometacin, 191 lamivudine, 481 valproate, 126, 131 pancytopenia levofloxacin, 433 risperidone, 90, 130 valproate, 130 panic attack ecstasy, 45 papillary conjunctivitis gatifloxacin, 431 papular rash doxycycline, 420 paranoia cocaine, 40 khat, 48 psilocybin, 50 paraphilia selegiline, 270 paraplegia nitrous oxide, 221

801 paresthesia daptomycin, 446 risperidone, 91 topiramate, 124–127 parkinsonism amphetamines, 1 antipsychotic drugs, 65 levetiracetam, 118 losartan, 359 risperidone, 89 valproate, 126, 127 ziprasidone, 93 pedal edema immunoglobulin E, 94 pemphigus vulgaris chloroquine, 470 hydroxychloroquine, 470 penile erection remifentanil, 167 penile ischemia adrenaline, 260 perceptual alterations ecstasy, 44 pericarditis etanercept, 601 periodic thyrotoxic hypokalemic paralysis amiodarone, 325 peripheral edema efalizumab, 605 endothelin receptor antagonists, 360 peripheral neuropathies didanosine, 484 linezolid, 439 metronidazole, 475 periungual anomalies sirolimus, 630 persistent pulmonary hypertension of newborn (PPHN) metamfetamine, 2 SSRIs, 20 pharyngitis lamotrigine, 114 levetiracetam, 117 olanzapine, 82 phlebitis antimony, 384 hemin, 531 quinupristin/dalfopristin, 443 photoallergic contact dermatitis dexketoprofen, 186 diclofenac, 187 photoallergic reactions NSAIDs, 193 photophobia cardiac glycosides, 320 dipyridamole, 565 photopsia cardiac glycosides, 320 phototoxicity amiodarone, 322

pituitary apoplexy gonadotropins, 703 pituitary tumors antipsychotic drugs, 69 risperidone, 69 pityriasis rosea bismuth subsalicylate, 385 placental hemorrhage heparin, 558 platelet dysfunction valproate, 130 pleural effusion immunoglobulin, 534 plexopathy heroin, 156 Pneumocystis pneumonia infliximab, 601 pneumonia recombinant human erythropoietin analogues, 538 TNF-a antagonist, 596 pneumonitis amiodarone, 324 bepridil, 325 cibenzoline, 330 levofloxacin, 432 pimecrolimus, 628 roxithromycin, 439 pneumothorax perfluorocarbons, 531 polycystic ovarian syndrome (PCOS) valproate, 131, 132 polydipsia ziprasidone, 94 polyneuropathy gabapentin, 113 polyradiculopathy heroin, 156 polyps aspirin, 196 portopulmonary hypertension amfetamine, 2 cocaine, 2 posterior leukoencephalopathy azathioprine, 636 posterior reversible encephalopathy syndrome ciclosporin, 620 posthypoxic leukoencephalopathy morphine, 164 post-transplantation lymphoproliferative disorder tacrolimus, 632 preterm birth SSRIs, 20 priapism alpha-adrenoceptor antagonists, 363 PR interval, increase donepezil, 11

Index of adverse effects

802 prolonged QT interval see QT interval prolongation propofol infusion syndrome propofol, 223 pro-social effects ecstasy, 44 proteinuria bevacizumab, 604 etanercept+gold, 601 penicillamine, 404 pruritus see also itching antimony, 384 bromfenac, 742 celecoxib, 191 diazepam +levetiracetam, 118 diltiazem, 341 efavirenz, 486 fentanyl, 152, 156, 164 gabapentin, 111, 118 hydromorphone, 160 hydoxychloroquine, 470 immunoglobulin, 536 mefloquine, 472 melphalan, 724 morphine, 152, 163, 164 opioids, 149, 159 ondansetron, 164 quinupristin/dalfopristin, 443 tropisetron, 576 psoriasis efalizumab, 605 fexofenadine, 299 meloxicam, 192 TNF-a antagonist, 598 psoriatic arthropathy efalizumab, 606 psychometric performance, impaired flurazepam, 61 psychosis antipsychotic drugs, 66 baclofen, 250 cannabis, 35 ciprofloxacin, 430 co-trimoxazole, 474 doxylamine, 298 gatifloxacin, 431 khat, 48 levetiracetam, 118 levodopa, 268 metamfetamine, 2 methylphenidate, 4 oxybutynin, 276 psilocybin, 50 ropinirole, 268 topiramate, 126 psychotic symptoms pregabalin, 122 topiramate, 124 pulmonary alveolar proteinosis leflunomide, 626

pulmonary crackles fresh frozen plasma, 533 pulmonary edema albumin, 527 hydrochlorothiazide, 374 naloxone, 170 oxytocin, 709 pulmonary embolism methadone, 161 pulmonary fibrosis adalimumab, 597 pulmonary hypertension fenfluramine, 9 ibuprofen, 189 lithium, 26 metamfetamine, 2 pupillary dilatation papaverine, 166 purpura ciprofloxacin, 430 cupping, 753 lamotrigine, 115 pustulosis morphine, 164 pyrexia see fever Q QT interval prolongation antipsychotic drugs, 65 arsenic, 385 azithromycin, 437 cesium chloride, 386 digoxin, 321 domperidone, 460 gadoversetamide, 737 hydroxychloroquine, 470 lithium, 26 quinidine, 332 sevoflurane, 22, 221 sibutramine, 9 telithromycin, 437 ziprasidone, 93 QT variability cocaine, 37 R rabbit syndrome methylphenidate, 3 rabies minocycline, 420 rashes albendazole, 508 allopurinol, 203 amisulpride, 69, 70 anagrelide, 564 bucillamine, 404 celecoxib, 190, 191 co-trimoxazole, 444, 445 colistin, 442 deferoxamine, 401 ecstasy, 43 emtricitabine, 484 etanercept, 601

fentanyl, 155 gestrinone, 672 immunoglobulin, 534 lamivudine, 482 lamotrigine, 113–115 lithium, 28 midazolam, 59 naltrexone, 170 oxcarbazepine, 119 plasma-derived factor VIII, 543 quinupristin/dalfopristin, 443 terbinafine, 457 red eye gatifloxacin, 427 relapsing Herpes simplex virus encephalitis corticotropin, 647 renal cell carcinoma etanercept, 601 renal dysfunction nafcillin, 419 suramin, 512 renal failure acetazolamide, 371 amphetamines, 41 azathioprine, 636 co-efferalgan, 182 immunoglobulin, 536 rasburicase, 206 renal impairment amantadine toxicity, 270 arsenic, 385 renal insufficiency didanosine, 484 recombinant human erythropoietin analogues, 538 talc, 766 tenofovir, 484 renal stones see nephrolithiasis renal tubular acidosis topiramate, 126 renal tubular dysfunction aminoglycoside, 428 renal tubular dysgenesis naproxen sodium, 190 renal vasculitis ciprofloxacin, 430 respiratory infection aspirin, 193, 194 corticotropin, 647 somatropin, 705 topiramate, 124 respiratory depression buprenorphine, 169 fentanyl+fluconazole, 159 gabapentin, 111 morphine, 163 opioids, 160 phenytoin, 121, 127 remifentanil, 167 valproate, 127

Index of adverse effects respiratory distress aromatherapy, 753 respiratory failure cyclizine, 298 respiratory problems corticotropin, 647 somatropin, 705 restlessness methylphenidate, 3 SSRIs, 20 retinal artery occlusion timolol, 741 retinal detachment pegaptanib, 739 retinal vasculitis co-trimoxazole, 444 retinal vein occlusion ranibizumab, 739 retinopathy didanosine, 483 penicillamine, 404 reversible inflammation ranibizumab, 739 rhabdomyolysis buprenorphine, 169 cocaine, 39 colchicine, 717 colchicine +statins, 202 heroin, 156 levofloxacin, 433 quetiapine, 88 statins, 202, 716 terbinafine, 457 ziprasidone, 94 rheumatoid arthritis see also arthritis anakinra, 592 arsenic trioxide, 385 vaccines, 520 rheumatoid lung nodulosis leflunomide, 625 rhinitis aspirin, 196 endothelin receptor antagonists, 361 frakefamide, 160 levetiracetam, 119 paracetamol, 181 thiamphenicol inhalation, 429 S sarcoidosis tacrolimus, 632 sedation alprazolam, 57 aripiprazole, 70 chloral hydrate, 60 gabapentin, 110, 112 haloperidol, 80 levetiracetam+diazepam, 118 levocetirizine, 300 methadone, 161, 162 morphine, 163

803 naltrexone, 171 olanzapine, 86, 87 opioids, 149 oxcarbazepine, 119, 120 quetiapine, 88 risperidone, 90, 91 seizures albendazole, 508 amitriptyline, 3, 4 beta-lactams, 418 cannabinoids, 33, 34 carbapenems, 415 colistin, 441 co-trimoxazole, 445 ecstasy, 45, 46 ifosfamide, 726 ketamine, 222 naloxone, 170 olanzapine, 84 sildenafil, 347 SSRIs, 20 tamsulosin, 364 valproate, 126 venlafaxine, 22 selective serotonin re-uptake inhibitors melperone, 92 sensorineural hearing loss efalizumab, 605 tadalafil, 347 sepsis propofol, 224 TNF-a antagonist, 596 septicemia deferiprone, 403 septic shock misoprostol, 651 septic wrist etanercept, 601 serotonin syndrome chlorzoxazone, 254 linezolid, 440 oxycodone, 165 triptans, 346 venlafaxine+lithium, 22, 28 sexual dysfunction baclofen, 252 bupropion, 22 methadone, 161 risperidone, 88 SSRIs, 22 shivering misoprostol, 708 shock crack cocaine, 38 sialorrhea clozapine, 78, 80 sialadenitis efalizumab, 605 sinoatrial block lithium, 26 skin atrophy calcipotriol, 293

skin cancers calabash chalk, 759 efalizumab, 606 skin eruption aromatherapy, 753 skin necrosis amiodarone, 329 warfarin, 554 skin tumors etanercept, 600 sleep disorder cocaine, 39 efavirenz, 486 lamotrigine, 113 quetiapine, 86 topiramate, 124 sleepiness aripiprazole, 71 naltrexone, 170 oxcarbazepine, 119 polyethylene glycol, 581 zonisamide, 138 slipped capital femoral epiphyses growth hormone, 706 slow growth sirolimus, 630 small bowel atresia decongestant, 265 phenylpropanolamine, 264 solid tumors efalizumab, 607 somnolence aciclovir, 478 alprazolam, 57 amantadine, 270 aripiprazole, 74 clonidine, 363 doxylamine, 298 fentanyl, 157 fexofenadine, 299 gabapentin, 111 general anesthesia, 235 ifosfamide, 726 levetiracetam, 116–118 olanzapine, 82 oxcarbazepine, 121 pregabalin, 121, 123 risperidone, 89 tiagabine, 123 topiramate, 124–126 valproate, 127 ziprasidone, 92 zonisamide, 138, 139 sore throat phenytoin, 121 speech disorder vigabatrin, 136 splenic rupture G-CSF, 590 spongiform leukoencephalopathy heroin, 156

Index of adverse effects

804 squamous cancer, of tongue etanercept +hydroxychloroquine, 601 steatorrhea octreotide, 710 sterile abscesses leuprolide, 704 sterile corneal ulcers moxifloxacin, 740 topical moxifloxacin, 740 Stevens–Johnson syndrome co-trimoxazole, 445 glipizide, 696 lamotrigine, 115 stomach ache gabapentin, 111 stomatitis bucillamine, 404 khat, 48 stroke amphetamines, 1 ecstasy, 42 immunoglobulin, 534 khat, 48 NSAIDs and paracetamol, 184 pseudoephedrine, 268 quetiapine, 89 subacute cutaneous lupus erythematosus efalizumab, 606 subacute prurigo olanzapine, 81 subcutaneous nodules tramadol, 168 subjective sedation alprazolam, 57 sudden cardiac death amiodarone, 325 suicidal ideation atomoxetine, 2, 3 SSRIS, 18 suicide alcohol, 134 aripiprazole, 77 sulfone syndrome dapsone, 497 superficial punctate keratitis bromfenac, 742 superficial punctate keratopathy brinzolamide, 371 supraventricular tachycardia adrenaline, 261 swallowing difficulty botulinum toxin, 251 quetiapine, 87, 88 tramadol, 168 sweating buprenorphine, 169 lamotrigine, 113 latanoprost, 373 methadone, 163, 164 tramadol, 168

Sweet’s syndrome doxycycline, 420 G-CSF, 591 ofloxacin, 435 swelling atenolol, 339 phosphatidylcholine, 765 symptomatic hyperprolactinemia aripiprazole, 76 syncope timolol, 340 systemic lupus erythematosus efalizumab, 606 T tachycardia anagrelide, 564 arsenic, 385 carbetocin, 708 clozapine, 79 dosylamine, 298 ecstasy, 47 fresh frozen plasma, 533 ipratropium bromide, 312 ketamine, 59 midazolam, 59 tachydysrhythmias oxytocin, 709 TA-GVHD see transfusion-associated graft-versus-host disease Takotsubo cardiomyopathy adrenaline, 261 tardive dyskinesia amisulpride, 70 clozapine, 79 haloperido, 79 metoclopramide, 574 taste disturbance amphotericin B lipid complex (ABLC), 459 dorzolamide+timolol, 372 omeprazole + amoxicilin + clarithromycin, 580 rabeprazole + clarithromycin + amoxicilin, 580 topiramate, 124 teeth, brown staining chlorhexidine, 410 /tendon rupture ciprofloxacin, 430 throat irritation naproxen + ibuprofen, 196 thrombocytopenia co-efferalgan, 182 efalizumab, 605 estrogen-based hormone treatment, 662 everolimus, 623 glycoprotein IIb-IIIa inhibitors, 565 heparin, 558 interferon alpha, 592

rituximab, 609 rosiglitazone, 698 stem cells, 540 TNF-a antagonist therapy, 590 valproate, 130 thromboembolism celecoxib, 190 immunoglobulin, 534 recombinant human erythropoietin analogues, 539 thrombophlebitis amiodarone, 324 plasma-derived factor VIII, 537 thrombosis cannabinoids, 33 thrombotic cardiovascular events etoricoxib +diclofenac, 184 thrombotic thrombocytopenic purpura desmopressin, 71 mefloquine, 472 thyroid cancer TNF-a antagonist therapy, 592 thyrotoxicosis amiodarone, 324 thyrotoxic periodic paralysis iodine, 684 tingling gabapentin, 111 tiredness alfentanil, 153 gabapentin, 110 levetiracetam, 117 oxcarbazepine, 119 zonisamide, 138 tonic-clonic movements midazolam, 222 tonic-clonic seizures ecstasy, 47 vigabatrin, 136 torsade de pointes amiodarone, 325 ciprofloxacin, 429 erythromycin, 438 fluconazole, 462 hydroxychloroquine, 470 methadone, 161 sevoflurane, 218 ziprasidone, 93 torticollis ziprasidone, 94 toxic encephalopathy lithium+risperidone, 28 methadone, 161 toxic epidermal necrolysis alfuzosin, 363 balsalazide, 583 letrozole, 666

Index of adverse effects phenytoin, 121 voriconazole, 464 toxic nephropathy basiliximab, 603 toxic retinopathy deferiprone, 403 toxic shock syndrome acetylsalicylic acid, 194 transfusion associated graft­ versus-host disease blood transfusion, 528 transient liver damage infliximab, 601 transient thyrotoxicosis recombinant human thyrotropin (rhTSH), 683 transitional cell carcinoma cannabis, 37 transverse myelitis efalizumab, 605 traumatic cataracts pegaptanib, 739 tremor amiodarone, 323 diazepam, 57 oxcarbazepine, 118 quetiapine, 87 topiramate, 125, 126 zonisamide, 140 Tourette’s syndrome, exacerbation lamotrigine, 113 tuberculosis infliximab, 601 TNF-a antagonist, 595 tumor hemorrhage bevacizumab, 604 tumor swelling recombinant human thyrotropin (rhTSH), 683 type 2 diabetes mellitus olanzapine, 68 U ulcerative keratitis crack-cocaine, 40 ulcers spironolactone, 376 unipolar depression lithium, 26 upper respiratory infections anakinra, 592 etanercept, 601 interferon alpha, 592 sitagliptin, 693 tiotropium bromide, 312 urinary cancers calabash chalk, 760 urinary hesitancy quetiapine, 78 reboxetine, 22 urinary incontinence renzapride, 574

805 urinary retention anticholinergic agents, 67 gabapentin, 111 ipratropium bromide, 312 opioids, 153 tiotropium, 312 urticaria aspirin, 199, 200 blood transfusion, 529 colistin, 442 gadolinium salts, 735 meloxicam, 192 piperazine, 301 propafenone, 332 rituximab, 610 sitagliptin, 694 uveitis cidofovir, 477 timolol, 340 travoprost, 652 V vascular phenomena sirolimus, 630 vasculitis antithyroid drugs, 685 everolimus, 623 immunoglobulin, 534, 536 TNF-a antagonist therapy, 593 vasoconstriction of aorta, fatal cocaine, 38 vasodilatation calcitonin, 703 prolastin, 532 vasospasm adrenaline, 50, 260 psilocybin, 50 vasovagal episodes dronabinol, 573 veno-occlusive disease tacrolimus, 630 venous thromboembolism prolastin, 532 ventricular septal defect letrozole, 666 ventricular tachycardia anesthesia, 158 vertigo antimony, 384 colistin, 441 efavirenz, 486 flunarizine, 345 gentamicin, 427 oscillopsia, 427 sibutramine, 10 vestibular toxicity neomycin, 428 visceral leishmaniasis adalimumab, 599 viscerotropic disease vaccine, 523 vision, blurred brinzolamide, 371

cannabinoids, 34 ibuprofen, 188 lamotrigine, 113 naltrexone, 171 oxcarbazepine, 119, 120 polysubstance, 40 pregabalin, 122 risperidone, 92 solifenacin, 274 systane, 748 zonisamide, 138 visual acuity zonisamide, 137 tamoxifen, 667 verteporfin, 739 visual field constriction vigabatrin, 137 visual hallucinations paroxetine, 21 pregabalin, 122 rofecoxib, 191 vitreous hemorrhage ranibizumab, 739 vomiting amphotericin B lipid complex (ABLC), 459 anagrelide, 564 antimony, 384 arsenic, 385 benzylisoquinolinium, 249 blood transfusion, 529 calcitonin, 703 carbetocin, 708 chloroquine, 469 general anesthesia, 235 glucagon, 689 hydrogen peroxide, 761 immunoglobulin, 534 metoclopramide, 574 nevirapine, 487 octreotide, 710 omeprazole, 578 polyethylene glycol, 581 quinupristin/dalfopristin, 443 repaglinide, 695 saquinavir + ritonavir, 488 sulfadoxine + pyrimethamine, 469 tegaserod, 575 von Willebrand disease valproate, 130 vulvar fixed drug eruptions telmisartan, 360 W Wallerian degeneration ecstasy, 42 weakness see also fatigue, malaise, tiredness amodiaquine, 469 azathioprine, 636 baclofen, 251

Index of adverse effects

806 botulinum toxins, 252 colchicine, 202 colistimethate sodium, 441 doxazosin, 364 efalizumab, 605 etanercept, 601 gabapentin, 112 immunoglobulins, 536 leflunomide, 626 levetiracetam, 117 pregabalin, 122 tiagabine, 123 weight gain antipsychotic drugs, 68 clozapine, 79 gabapentin, 112 gestrinone, 672 haloperidol, 73 lamotrigine, 114, 115 lithium, 27

methadone, 161 olanzapine, 82, 85 pregabalin, 122 quetiapine, 27 risperidone, 89, 90 valproate, 27, 127 zonisamide, 138 weight loss antimony, 384 fenfluramines, 9 risperidone, 90 topiramate, 124, 125, 126 zonisamide, 138 Wernicke’s encephalopathy thiamine, 549 West Nile virus blood transfusion, 530 wheezing immunoglobulin, 534 paracetamol, 181

white cell count, increase sitagliptin, 694 wound dehiscence sirolimus, 630 wound healing complications bevacizumab, 605 leflunomide, 626 X xerosis tazarotene, 292 Y Yersinia enterocolitica enteritis deferoxamine, 400 Z Zollinger–Ellison syndrome pantoprazole, 579