• 1
    Towbin JA, Wang Z, Li H. Genotype and severity of long QT syndrome. Arch Pathol Laboratory Med 2001; 125: 116121.
  • 2
    Dessertenne F. La tachycardie ventriculaire á deux foyers oppośes variable. Arch Mal Coeur Vaiss 1966; 59: 263272.
  • 3
    Bauman JL, Bauernfeind RA, Hoff JV, Strasberg B, Swiryn S, Rosen KM. Torsade de pointes due to quinidine: observations in 31 patients. Am Heart J 1984; 107: 425430.
  • 4
    MacNeil DJ, Davies RO, Deitchman D. Clinical safety profile of sotalol in the treatment of arrhythmias. Am J Cardiol 1993; 72: 44A50A.
  • 5
    McKibbin JK, Pocock WA, Barlow JB, Millar RN, Obel IW. Sotalol, hypokalaemia, syncope, and torsade de pointes. Br Heart J 1984; 2: 157162.
  • 6
    Milon D, Daubert JC, Saint-Marc C, Gouffault J. Torsade de pointes. Apropos of 54 cases. [Article in French]. Ann Fr Anesth Reanim 1982; 1: 513520.
  • 7
    Salle P, Rey JL, Bernasconi P, Quiret JC, Lombaert M. Torsades de pointe. Apropos of 60 cases. Ann Cardiol Angeiol (Paris), 1985; 34: 381388.
  • 8
    Fung MC, Hsiao-hui Wu H, Kwong K, Hornbuckle K, Muniz E. Evaluation of the profile of patients with QTc prolongation in spontaneous adverse event reporting over the past three decades – 1969–98. Pharmacoepidemiol Drug Safety 2000; 9(Suppl 1): S24.
  • 9
    Thompson D, Oster G. Use of terfenadine and contraindicated drugs. JAMA 1996; 275: 13391341.
  • 10
    Burkhart GA, Sevka MJ, Temple R, Honig PK. Temporal decline in filling prescriptions for terfenadine closely in time with those for either ketoconazole or erythromycin. Clin Pharmacol Ther 1997; 61: 9396.
  • 11
    Smalley W, Shatin D, Wysowski DK, et al. Contraindicated use of cisapride: impact of Food and Drug Administration regulatory action. JAMA 2000; 284: 30363039.
  • 12
    Krasucki C, McFarlane F. Electrocardiograms, high-dose antipsychotic treatment and College guidelines. Psychiatric Bull 1996; 20: 326330.
  • 13
    Geelen P, Drolet B, Rail J, et al. Sildenafil (Viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current. Circulation 2000; 102: 275277.
  • 14
    Sofowora G, Dishy V, Roden D, Wood AJJ, Stein CM. The effect of sildenafil on QT interval in healthy men. Clin Pharmacol Ther 2001; 69: P67 (abstract PIII−11).
  • 15
    Bonate PL, Russell T. Assessment of QTc prolongations for non-cardiac-related drugs from a drug development perspective. J Clin Pharmacol 1999; 39: 349358.
  • 16
    Shah RR. ‘Withdrawal of terodiline. A tale of two toxicities'. In Pharmacovigilance, 1st edn, eds MannRD, AndrewsEB. London: John Wiley and Sons Ltd. in press, 2002.
  • 17
    Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR Jr. Torsades de pointes occurring in association with terfenadine use. JAMA 1990; 264: 27882790.
  • 18
    Anon. Ventricular arrhythmias due to terfenadine and astemizole. Committee on Safety of Medicines London, Current Problems. November 1992; 35: 12.
  • 19
    Anon. J & J. hit by new Propulsid warnings. Scrip p19, 2509, 28 January 2000, England.
  • 20
    Anon. FDA warns of interactions with Orap. Scrip p22, 2477, 1 October 1999, England.
  • 21
    Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR Jr. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther 1992; 52: 231238.
  • 22
    Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine–ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. JAMA 1993; 269: 15131518.
  • 23
    Flockhart DA, Drici MD, Kerbusch T, et al. Studies on the mechanism of a fatal clarithromycin–pimozide interaction in a patient with Tourette syndrome. J Clin Psychopharmacol 2000; 20: 317324.
  • 24
    Tsai WC, Tsai LM, Chen JH. Combined use of astemizole and ketoconazole resulting in torsade de pointes. J Formos Med Assoc 1997; 96: 144146.
  • 25
    Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000; 38: 4157.
  • 26
    Renwick AG. The metabolism of antihistamines and drug interactions: the role of cytochrome P450 enzymes. Clin Exp Allergy 1999; 29(Suppl 3): 116124.
  • 27
    Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993; 269: 15321536.
  • 28
    Rampe D, Wible B, Brown AM, Dage RC. Effects of terfenadine and its metabolites on a delayed rectifier K+ channel cloned from human heart. Mol Pharmacol 1993; 44: 12401245.
  • 29
    Zhou Z, Volperian VR, Gong Q, Zhang S, January CT. Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. J Cardiovasc Electrophysiol 1999; 10: 836843.
  • 30
    Volperian VR, Zhou Z, Mohammad S, Hoon TJ, Studenik C, January CT. Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole. J Am Coll Cardiol 1996; 28: 15561561.
  • 31
    Anon. ‘Propulsid limited access program allows off-label use to continue. F-D-C Report ‘the Pink Sheet’ 2000; 62: 3.
  • 32
    Craft TM. Torsade de pointes after astemizole overdose. Br Med J 1986; 292: 660.
  • 33
    Davies AJ, Harindra V, McEwan A, Ghose RR. Cardiotoxic effect with convulsions in terfenadine overdose. Br Med J 1989; 298: 325.
  • 34
    Anon. Cardiotoxicity of astemizole in overdose-Dosing is critical. Committee on Safety of Medicines London, Current Problems. March 1987; 19: 12.
  • 35
    Fulop G, Phillips RA, Shapiro AK, Gomes JA, Shapiro E, Nordlie JW. ECG changes during haloperidol and pimozide treatment of Tourette's disorder. Am J Psychiatry 1987; 144: 673675.
  • 36
    Vanhoutte F, Vereecke J, Verbeke N, Carmeliet E. Stereoselective effects of the enantiomers of bupivacaine on the electrophysiological properties of guinea-pig papillary muscle. Br J Pharmacol 1991; 103: 12751281.
  • 37
    Valenzuela C, Delpon E, Tamkun MM, Tamargo J, Snyders DJ. Stereoselective block of a human cardiac potassium channel (Kv1.5) by bupivacaine enantiomers. Biophys J 1995; 69: 418427.
  • 38
    Wesche DL, Schuster BG, Wang W-X, Woosley RL. Mechanism of cardiotoxicity of halofantrine. Clin Pharmacol Ther 2000; 67: 521529.
  • 39
    Abernethy DR, Wesche DL, Barbey JT, et al. Stereoselective halofantrine disposition and effect: concentration-related QTc prolongation. Br J Clin Pharmacol 2001; 51: 231237.
  • 40
    Hartigan-Go K, Bateman ND, Daly AK, Thomas SHL. Stereoselective cardiotoxic effects of terodiline. Clin Pharmacol Ther 1996; 60: 8998.
  • 41
    Bayer R, Schwarzmaler J, Pernice R. Basic mechanism underlying prenylamine-induced torsade de pointes: differences between prenylamine and fendiline due to basic actions of the isomers. Curr Med Res Opin 1988; 11: 254272.
  • 42
    Haehl M. Roxane Laboratories Inc ‘Dear Healthcare Professional’ letter dated 11 April 2001. Also EMEA Press Release announcing suspension of ‘Orlaam’.
  • 43
    Anon. Lilly pulls out of R-fluoxetine deal. Scrip p24, 2586, 25 October 2000, England.
  • 44
    Wong SL, Menacherry S, Mulford D, Schmitz PJ, Locke C, Granneman GR. Pharmacokinetics of sertindole and dehydrosertindole in volunteers with normal or impaired renal function. Eur J Clin Pharmacol 1997; 52: 223227.
  • 45
    Von Bahr C, Movin G, Nordin C, et al. Plasma levels of thioridazine and metabolites are influended by the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther 1991; 49: 234240.
  • 46
    Scordo MG, Spina E, Facciola G, Avenoso A, Johansson I, Dahl ML. Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone. Psychopharmacology (Berl) 1999; 147: 300305.
  • 47
    Pierce DM, Smith SE, Franklin RA. The pharmacokinetics of indoramin and 6-hydroxyindoramin in poor and extensive hydroxylators of debrisoquine. Eur J Clin Pharmacol 1987; 33: 5965.
  • 48
    Dahl ML, Bertilsson L, Nordin C. Steady-state plasma levels of nortriptyline and its 10-hydroxy metabolite: relationship to the CYP2D6 genotype. Psychopharmacology (Berl) 1996; 123: 315319.
  • 49
    Billon N, Funck-Brentano C, Cohen A, Chauvel C, Le Liboux A, Jaillon P. Influence of CYP2D6 genetic polymorphism on the pharmacokinetics and pharmacodynamic effects of terikalant, a new K+ channel blocker. Fundam Clin Pharmacol 1995; 9: 88.
  • 50
    Escande D. Pharmacogenetics of cardiac K+ channels. Eur J Pharmacol 2000; 410: 281287.
  • 51
    Saarinen K, Swan H, Kainulainen K, Toivonen L, Viitasalo M, Kontula K. Molecular genetics of the long QT syndrome: two novel mutations of the KVLQT1 gene and phenotypic expression of the mutant gene in a large kindred. Hum Mutat 1998; 11: 158165.
  • 52
    Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long–QT syndrome: clinical impact. Circulation 1999; 99: 529533.
  • 53
    Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270: 25902597.
  • 54
    Rodriguez I, Kilborn MJ, Liu XK, Pezzullo JC, Woosley RL. Drug-induced QT prolongation in women during the menstrual cycle. JAMA 2001; 285: 13221326.
  • 55
    Gupta PR, Somani PN, Avasthey P, Singh VP. Prolonged QT and hypertrophic cardiomyopathy in two families with 10 sudden deaths. J Assoc Physicians India 1985; 33: 353355.
  • 56
    Martin AB, Garson A Jr, Perry JC. Prolonged QT interval in hypertrophic and dilated cardiomyopathy in children. Am Heart J 1994; 127: 6470.
  • 57
    Peters S, Rust H, Trummel M, Brattstrom A. Familial hypertrophic cardiomyopathy associated with prolongation of the QT interval. Z Kardiol 2000; 89: 624629.
  • 58
    Kaab S, Dixon J, Duc J, et al. Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. Circulation 1998; 98: 13831393.
  • 59
    Schwartz PJ, Wolf S. QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation 1978; 57: 10741077.
  • 60
    Schwartz PJ, Stramba-Badiale M, Segantini A, et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998; 338: 17091714.
  • 61
    Veglio M, Sivieri R, Chinaglia A, Scaglione L, Cavallo-Perin P. QT interval prolongation and mortality in type 1 diabetic patients: a 5-year cohort prospective study. Neuropathy Study Group of the Italian Society of the Study of Diabetes, Piemonte Affiliate. Diabetes Care 2000; 23: 13811383.
  • 62
    Whitsel EA, Boyko EJ, Siscovick DS. Reassessing the role of QTc in the diagnosis of autonomic failure among patients with diabetes: a meta-analysis. Diabetes Care 2000; 23: 241247.
  • 63
    Rossing P, Breum L, Major-Pedersen A, et al. Prolonged QTc interval predicts mortality in patients with Type 1 diabetes mellitus. Diabet Med 2001; 18: 199205.
  • 64
    Marques JL, George E, Peacey SR, et al. Altered ventricular repolarization during hypoglycaemia in patients with diabetes. Diabet Med 1997; 14: 648654.
  • 65
    Bernardi M, Calandra S, Colantoni A, et al. Q-T interval prolongation in cirrhosis: prevalence, relationship with severity, and etiology of the disease and possible pathogenetic factors. Hepatology 1998; 27: 2834.
  • 66
    Choy AM, Lang CC, Roden DM, et al. Abnormalities of the QT interval in primary disorders of autonomic failure. Am Heart J 1998; 136: 664671.
  • 67
    Ishizaki F, Harada T, Yoshinaga H, Nakayama T, Yamamura Y, Nakamura S. Prolonged QTc intervals in Parkinson's disease – relation to sudden death and autonomic dysfunction. [Article in Japanese]. No To Shinkei 1996; 48: 443448.
  • 68
    Nabauer M, Kaab S. Potassium channel down-regulation in heart failure. Cardiovasc Res 1998; 37: 324334.
  • 69
    Anon. Severe cardiac arrhythmia on cisapride. Prescrire International 2000; 9: 144145.
  • 70
    Hani EH, Boutin P, Durand E, et al. Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians. Diabetologia 1998; 41: 15111515.
  • 71
    Anon. Points to consider: The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. Committee for Proprietary Medicinal Products (CPMP/986/96). EMEA, 17 December 1997, London.
  • 72
    Anon. Note for Guidance on the Investigation of Drug Interactions. Committee for Proprietary Medicinal Products (CPMP/EWP/560/95) EMEA, 17 December 1997, London.
  • 73
    Priori SG. Exploring the hidden danger of noncardiac drugs. J Cardiovasc Electrophysiol 1998; 9: 11141116.
  • 74
    Davis AS. The pre-clinical assessment of QT interval prolongation: a comparison of in vitro and in vivo methods. Hum Exp Toxicol 1998; 17: 677680.
  • 75
    Hammond TG, Carlsson L, Davis AS, et al. Methods of collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical industry: results of an international survey. Cardiovasc Res 2001; 49: 741750.
  • 76
    Gralinski MR. The assessment of potential for QT interval prolongation with new pharmaceuticals: impact on drug development. J Pharmacol Toxicol Meth 2000; 43: 9199.
  • 77
    Anon. Position Paper: ‘Replacement of animal studies by In Vitro models’. Committee for Proprietary Medicinal Products (CPMP/SWP/728/95). EMEA, 19 February 1997, London.
  • 78
    Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995; 80: 795803.
  • 79
    Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 1995; 81: 299307.
  • 80
    McDonald TV, Yu Z, Ming Z, et al. A minK-HERG complex regulates the cardiac potassium current I (Kr). Nature 1997; 388: 289292.
  • 81
    Taglialatela M, Castaldo P, Pannaccione A, Giorgio G, Annunziato L. Human ether-a-gogo related gene (HERG) K+ channels as pharmacological targets: present and future implications. Biochem Pharmacol 1998; 55: 17411746.
  • 82
    Crumb W, Cavero I. QT interval prolongation by non-cardiovascular drugs: issues and solutions for novel drug development. Pharm Sci Technol Today 1999; 2: 270280.
  • 83
    Gintant GA, Limberis JT, McDermott JS, Wegner CD, Cox BF. The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis. J Cardiovasc Pharmacol 2001; 37: 607618.
  • 84
    Anon. The extent of population exposure to assess clinical safety for drugs intended for long-term treatment of non-Iife-threatening conditions CPMP Guideline (CPMP/ICH/375/95). In ‘The Rules Governing Medicinal Products in the European Union’ EUDRALEX, Vol. 3C. ‘Efficacy Guidelines’ p121–125. European Commission, Brussels, 1998.
  • 85
    Hartigan-Go K, Bateman DN, Nyberg G, Martensson E, Thomas SH. Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans. Clin Pharmacol Ther 1996; 60: 543553.
  • 86
    Démolis J-L, Kubitza D, Tennezé L, Funck-Brentano C. Effect of a single oral dose of moxifloxacin (400 mg and 800 mg) on ventricular repolarization in healthy subjects. Clin Pharmacol Ther 2000; 68: 658666.
  • 87
    Démolis J-L, Charransol A, Funck-Brentano C, Jaillon P. Effects of a single oral dose of sparfloxacin on ventricular repolarization in healthy volunteers. Br J Clin Pharmacol 1996; 41: 499503.
  • 88
    Desta Z, Kerbusch T, Flockhart DA. Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). Clin Pharmacol Ther 1999; 65: 1020.
  • 89
    Shapiro E, Shapiro AK, Fulop G, et al. Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette's syndrome. Arch General Psychiatry 1989; 46: 722730.
  • 90
    Morganroth J, Hunt T, Dorr MB, Magner D, Talbot GH. The cardiac pharmacodynamics of therapeutic doses of sparfloxacin. Clin Ther 1999; 21: 11711181.
  • 91
    Morganroth J, Talbot GH, Dorr MB, Johnson RD, Geary W, Magner D. Effect of signle ascending supratherapeutic doses of sparfloxacin on cardiac repolarisation (QTc interval). Clin Ther 1999; 21: 818828.
  • 92
    Jaillon P, Morganroth J, Brumpt I, Talbot G and the Sparfloxacin Safety Group. Overview of electrocardiographic and cardiovascular safety data for sparfloxacin. J Antimicrob Chemotherap 1996; 37(Suppl A): 161167.
  • 93
    Morganroth J, Brozovich FV, McDonald JT, Jacobs RA. Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 1991; 67: 774776.
  • 94
    Pratt CM, Ruberg S, Morganroth J, et al. Dose–response relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram: distinguishing a drug effect from spontaneous variability. Am Heart J 1996; 131: 472480.
  • 95
    Haverkamp W, Hördt M, Hindricks G, et al. Torsade de pointes induced by d,l-sotalol. Circulation 1993; 88(Suppl): 1872.
  • 96
    Malik M. Problems of heart rate correction in assessment of drug-induced QT interval prolongation. J Cardiovasc Electrophysiol 2001; 12: 411420.