Effects of a new class I antiarrhythmic drug bidisomide on canine ventricular arrhythmia models

Abstract

The antiarrhythmic and direct cardiovascular effects of a new antiarrhythmic agent, bidisomide, alpha-(2-[acetyl(1-methylethyl)amino]ethyl)-alpha-(2- chlorophenyl)-1-piperidinebutanamide, were investigated. To determine the anti-arrhythmic effects, spontaneously occurring adrenaline-, digitalis- and two-stage coronary ligation-induced arrhythmias were used. Bidisomide suppressed these three arrhythmia models. The antiarrhythmic plasma concentration, IC50, of bidisomide for digitalis-induced arrhythmia was 22.1 micrograms/ml, and those calculated for intravenous bidisomide in 24 h and 48 h coronary ligation-arrhythmias were 15.1 and 11.6 micrograms/ml and that calculated for oral bidisomide in 24 h coronary ligation-arrhythmia was 5.4 micrograms/ml and that for adrenaline induced arrhythmia was 58.7 micrograms/ml. In the blood perfused sinoatrial node and papillary muscle preparations, bidisomide decreased the sinoatrial rate and contractile force and increased the intraventricular conduction time and coronary blood flow. These results indicate that bidisomide is similar to other class I antiarrhythmic agents such as pirmenol and KW-3401 in its antiarrhythmic profile and is expected to become a clinically useful antiarrhythmic drug.

Bidisomide: An Investigational Antiarrhythmic Agent

“…eliminated the ventricular arrhythmia. Oral doses (15,25, and 35 mg/kg) of bidisomide resulted in more sustained (>lo0 min) antiarrhythrnic activity (20,51). A plasma concentration of at least 3 kg/ml resulted in an ectopic rate reduction of at least 25% in this model (20).…”

“…Bidisomide (SC-40230) is an investigational antiarrhythmic drug. In preclinical and clinical testing bidisomide has been shown to be effective against both atrial (23,47) and ventricular (20,21,36,43,51) arrhythmias. Because of its distinctive atrial effects (22,35), the potential of bidisomide for treatment of atrial fibrillation has been extensively probed.…”

Electrophysiologic Effects of an Antiarrhythmic Agent, Bidisomide, on Sodium Current in Isolated Rat Ventricular Myocytes: Comparison With Mexiletine and Disopyramide

“…The pyridyl residue of disopyramide was replaced with a pyperidine residue in bidisomide and a halogen (chloride) was introduced to the ortho position of the benzene ring. These chemical changes produced a beneficial property; i.e., little side effect on the cardiovascular profile because of the weak negative inotropic effect and the low anticholinergic effect (1,2). Although disopyramide is an established and widely-used class I antiarrhythmic agent, congestive heart failure and/or anticholinergic actions, such as urinary retention, dry mouth and constipation, are its side effects, which limited the clinical efficacy of disopyramide.…”