Canine plasma concentration‐cardiovascular effect relationships for bidisomide, a new antiarrhythmic drug, and disopyramide, cibenzoline, and propafenone

Abstract

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 mgikg), cibenzoline (8 -+ 2 mg/kg), and propafenone (6 k 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 @ml plasma concentration) caused potent reductions in cardiac output and increases in QRS duration relative to the other agents. Cibenzoline (0.S7.0 pgiml) and disopyramide (1.4-12.9 pgiml), at matched plasma concentrations, caused very similar cardiac output reductions, but cibenzoline caused nearly double the QRS increase. Bidisomide (1.9-16.1 pg/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 bidisornide, in contrast t o 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. @ 1995 ~i l e y -~i s s , Inc