Proarrhythmia of azimilide and other class III antiarrhythmic agents in the adrenergically stimulated rabbit

The ventricular proarrhythmic actions of five class III antiarrhythmic agen ts were compared in the Carlsson rabbit model. In adrenergically stimulated anesthetized rabbits, azimilide, clofilium, dofetilide, sematilide, and d, I-sotalol caused premature ventricular contractions and nonsustained and su stained ventricular tachyarrhythmias (NSVT and SVT) at pharmacologically eq uivalent intravenous doses that increased QTc intervals 200% (ED20). There were no significant differences between agents in the percentage of rabbits with serious arrhyhthmias at the ED20 doses of 5.2, 0.033, 0.015, 0.66, an d 2.8 mg/kg iv, respectively, Proarrhythmia was dose-dependent. Linear regr ession analysis of arrhythmia score versus log dose estimated the NSVT dose s as 6.2, 0.055, 0.0089, 1.5, and 5.7, respectively. Analysis of arrhythmia states during a 10-min window after infusion when QTc prolongation was 20% showed that the compounds differed significantly in the proportion of time treated rabbits spent in SVT and combined NSVT and SVT. Rabbits treated wi th azimilide spent significantly less time in SVT and combined NSVT and SVT , followed in order of increasing time by d,l-sotalol, sematilide, clofiliu m, and dofetilide.