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: András Farkas, Susan J Coker
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 449 Issue 1-2 Pg. 143-53 (Aug 02 2002) ISSN: 0014-2999 [Print] Netherlands
• PMID: 12163118 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic alpha-1 Receptor Agonists
• Anti-Arrhythmia Agents
• Anti-Bacterial Agents
• Chromans
• Piperidines
• Quaternary Ammonium Compounds
• Erythromycin
• clofilium
• terikalant

Topics

• Action Potentials (drug effects)
• Adrenergic alpha-1 Receptor Agonists
• Animals
• Anti-Arrhythmia Agents (toxicity)
• Anti-Bacterial Agents (toxicity)
• Arrhythmias, Cardiac (chemically induced, physiopathology)
• Blood Gas Analysis
• Blood Pressure (drug effects)
• Body Temperature (drug effects)
• Chromans (toxicity)
• Electrocardiography (drug effects)
• Erythromycin (toxicity)
• Heart Rate (drug effects)
• Male
• Piperidines (toxicity)
• Quaternary Ammonium Compounds (toxicity)
• Rabbits
• Torsades de Pointes (chemically induced, pathology)