Limited induction of torsade de pointes by terikalant and erythromycin in an in vivo model.
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.
Farkas
András
A
Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street, Liverpool L69 3GE, UK. coker@liv.ac.uk
Coker
Susan J
SJ
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
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