Limited induction of torsade de pointes by terikalant and erythromycin in an in vivo model

Abstract

The proarrhythmic activities of the selective IKr blocker erythromycin and the less selective K+ channel blockers, terikalant and clofilium, have been compared in an α1-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 mg 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. 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.