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

Farkas, A. and Coker, Susan J. (2002) Limited induction of torsade de pointes by terikalant and erythromycin in an in vivo model. European Journal of Pharmacology, 449 (1-2). pp. 143-153. ISSN 0014-2999

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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.