Hemodynamic and electrophysiologic effects of ontazolast in dogs

Objective-To determine whether QT interval is prolonged or sudden death is caused by ventricular fibrillation resulting from torsades de pointes and t o identify hemodynamic effects of ontazolast. Animals-28 Beagles. Procedure-Physiologic variables were measured for 2 hours in conscious dogs given ontazolast (0, 1. or 3 mg/kg of body weight, IV) and for 1 hour in a nesthetized dogs given cumulative doses of ontazolast (0, 1, 3, 6, or 8 mg/ kg, IV). Results-Ontazolast prolonged QT interval and QT interval corrected for hear t rate (QTc) at doses of 6 mg/kg in anesthetized dogs. At 8 mg/kg, both var iables remained prolonged but tended to decrease. In conscious dogs, antazo last increased QT interval and QTc 15 minutes after administration, but bot h variables returned to reference ranges by 60 minutes. In conscious dogs, ontazolast increased maximum rate of increase of left ventricular pressure and maximal velocity of fiber shortening, indicators of inotropy, and incre ased tau, indicating a decreased rate of relaxation. One conscious dog rece iving 3 mg/kg developed nonfatal torsades de pointes, but another conscious dog developed ventricular fibrillation. Two anesthetized dogs receiving 6 mg/kg developed early afterdepolarizations, and all dogs developed secondar y components in their T waves. Conclusion and Clinical Relevance-Ontazolast possesses potent class-ill ant iarrhythmic properties and induces prolongation of QTc in a dose-dependent fashion. Because there was a clear dose-dependent prolongation of QT Interv al in all instances, ontazolast may serve as a positive-control compound fo r studying other compounds that are believed to prolong the QT interval.