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 study 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 coronary ligation ventricular arrhythmia model. Based on the canine therapeutic doses of the four agents, three cumulative i.v. doses (load/maintenance infusions) of each of these drugs and placebo were then studied in normal anesthetized dogs to evaluate their general cardiovascular effects. Propafenone (0.7–3.0 μg/ml plasma concentration) caused potent reductions in cardiac output and increases in QRS duration relative to the other agents. Cibenzoline (0.9–7.0 μg/ml) and disopyramide (1.4–12.9 μg/ml), at matched plasma concentrations, caused very similar cardiac output reductions, but cibenzoline caused nearly double the QRS increase. Bidisomide (1.9–16.1 μg/ml) had the least potent effects on cardiac output and QRS duration. All four drugs increased PR and QT in addition to QRS, but only disopyramide and propafenone increased JT (QT‐QRS). These experiments suggest that the antiarrhythmic plasma concentrations of bidisomide, in contrast to those of selected reference agents, do not cause prominent ventricular conduction slowing or prolongation of ventricular repolarization, and in addition, cause only modest hemodynamic effects in normal dogs.