title: Limited induction of torsade de pointes by terikalant and erythromycin in an in vivo model.
abstract: The proarrhythmic activities of the selective I(Kr) blocker erythromycin and the less selective K(+) channel blockers, terikalant and clofilium, have been compared in an alpha(1)-adrenoceptor-stimulated, anaesthetized rabbit model. Terikalant (2.5, 7.5 and 25 nmol kg(-1) min(-1); n = 10), erythromycin (133, 400 and 1330 nmol kg(-1) min(-1); n = 8), clofilium (20, 60 and 200 nmol kg(-1) min(-1); n=10) or vehicle (n = 8) was infused intravenously over 19 min and there was a 15-min interval between each infusion [corrected]. QT and QTc intervals, and epicardial monophasic action potential duration were prolonged significantly (and to a similar extent) only by clofilium and terikalant. The total incidences of torsade de pointes were 60%*, 20%, 0% and 0% in clofilium-, terikalant-, erythromycin- and vehicle-treated animals, respectively (*P < 0.05 compared to vehicle control). In conclusion, terikalant exerted mild proarrhythmic activity though it prolonged repolarisation markedly. Despite being given in high doses, erythromycin neither prolonged repolarisation nor induced proarrhythmia.
authors.affiliation: Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, Liverpool L69 3GE, UK. coker@liv.ac.uk
authors.forename: András
authors.initials: A
authors.lastname: Farkas
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Coker
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002839:Chromans / Q000633:toxicity*; D004562:Electrocardiography / Q000187:drug effects; D004917:Erythromycin / Q000633:toxicity*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D010880:Piperidines / Q000633:toxicity*; D000644:Quaternary Ammonium Compounds / Q000633:toxicity; D011817:Rabbits; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000473:pathology
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D002839:Chromans; D010880:Piperidines; D000644:Quaternary Ammonium Compounds; D004917:Erythromycin; C022799:clofilium; C063899:terikalant