CANINE PLASMA CONCENTRATION-CARDIOVASCULAR EFFECT RELATIONSHIPS FOR BIDISOMIDE, A NEW ANTIARRHYTHMIC DRUG, AND DISOPYRAMIDE, CIBENZOLINE, AND PROPAFENONE

Bidisomide (SC-40230) is a unique new antiarrhythmic agent. In this st udy the canine intravenous (i.v.) antiarrhythmic doses of bidisomide ( 9 +/- 1 mg/kg), disopyramide (8 +/- 1 mg/kg), cibenzoline (8 +/- 2 mg/ kg), and propafenone (6 +/- 0.5 mg/kg) were established in a 24 h coro nary ligation ventricular arrhythmia model. Based on the canine therap eutic doses of the four agents, three cumulative i.v. doses (load/main tenance infusions) of each of these drugs and placebo were then studie d in normal anesthetized dogs to evaluate their general cardiovascular effects. Propafenone (0.7-3.0 mu g/ml plasma concentration) caused po tent reductions in cardiac output and increases in QRS duration relati ve to the other agents. Cibenzoline (0.9-7.0 mu g/ml) and disopyramide (1.4-12.9 mu g/ml), at matched plasma concentrations, caused very sim ilar cardiac output reductions, but cibenzoline caused nearly double t he QRS increase. Bidisomide (1.9-16.1 mu g/ml) had the least potent ef fects on cardiac output and QRS duration. All four drugs increased PR and QT in addition to QRS, but only disopyramide and propafenone incre ased JT (QT-QRS). These experiments suggest that the antiarrhythmic pl asma concentrations of bidisomide, in contrast to those of selected re ference agents, do not cause prominent ventricular conduction slowing or prolongation of ventricular repolarization, and in addition, cause only modest hemodynamic effects in normal dogs. (C) 1995 Wiley-Liss, I nc.