Effect of SC‐40230, a new class I antiarrhythmic agent, on canine ventricular tachycardias

Abstract

Garthwaite, S., F. Hatley, L. Frederick, J. Ruby, and C. Cook: Effect of SC-40230, A new class I antiarrhythmic agent, on canine ventricular tachycardias. Drug Dev. Res. 17:119-133, 1989. SC-40230, a-[2-[acetyl( 1 -methylethyl)amino]ethyl]-tr-(2-chlorophenyl)-l -piperidinebutanamide, a new class I antiarrhythmic agent, was tested for efficacy against coronary ligation-induced arrhythmias and ouabain toxicity arrhythmias in dogs. Doses of 9 mg/kg i.v. and 15, 25, and 35 mgikg p.0. significantly reduced ectopic rate in conscious dogs that had undergone ligation of the left anterior descending coronary artery 24 hr prior to testing. Plasma concentrations of SC-40230 ranging from 3 to 9 pg/ml corresponded with ectopic rate reductions of 10-82% in the coronary ligation model. was well tolerated at all doses tested in the conscious dogs. A 5 mgikg i.v. dose of SC-40230 converted ouabain-induced ventricular tachycardias to normal sinus rhythm in anesthetized dogs. The antiarrhythmic effect of SC-40230 in the ouabain toxicity model was reversed by large ( 5 240 U) doses of insulin. The experiments described in this study demonstrated that SC-40230 is a well-tolerated new class I antiarrhythmic agent with intravenous and oral effectiveness against ventricular arrhythmias.

Effects of bidisomide (SC-40230), a new class I antiarrhythmic agent, on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats; comparison with mexiletine and disopyramide

“…SC-40230 has been found to be effective in models of adrenaline-induced, digitalis-induced, two-stage coronary ligation-induced arrhythmias [10,11], and electrical stimulation-induced arrhythmias [12]. However, to our knowledge, no study has examined the effects of SC-40230 on early-phase occlusion and reperfusion arrhythmias.…”

Electropharmacology of bidisomide in the normal intact canine heart

“…In preclinical studies bidisomide was shown to be effective against both ventricular [Garthwaite et al, 1989a,b] and atrial [Spinelli and Hoffman, 19891 arrhythmias in dogs. Bidisomide's bioavailability and acute tolerability were demonstrated in both animals [Garthwaite et al, 1989a;Ames et al, 19891 and humans [Page et al., 19901. The hemodynamic effects of bidisomide were minimal in normal dogs [Frederick et al, 19891 and in dogs with large myocardial infarctions [Garthwaite et al,3989bl.…”

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

“…In conscious dogs with myocardial infarctions all of these drugs were well tolerated and consistently antiarrhythrriic when judiciously infused to achieve a canine thcrapeutie dose. Thc arrhythmia experiments also confirmed the relative canine therapeutic potency of these drngs [Garthwaite et al, 1989b[Garthwaite et al, , 1994Mokler and Van Arman, 1962;Patterson et al, 1979;Hashimoto et al, 1982;Bergey et al, 198:3;Kaplan et al, 1984;Gomoll, 1987;Frederick et al, 1988;IIinscli et al, 1983;Dangman, 1984;Hashimoto et al, 19871. Harris dogs resiilts in rapid achievenierit of very high plasma coriccntrations of tcst agents, followed by very rapid declines in plasma concentrations [Garthwaite et al, 1989a,b]. In the i.v.…”

“…We first cletermined the canine antiarrhythinic dose for these agents in the IIarris [ 19501 dog model to ensure that our model, in which the canine dose of bidisomide was originally established [Garthwaite et al, 1989b], would also confirm the doses of the other agents as reported in the literature. Based on the canine therapeutic doses of the four test agents, three cumulative doses of each agent were infused using a loadiniaintenancc protocol, as opposcd to the constant rate infusion methods we previously nsed [Frederick et al, 19891 to study bidisoniide.…”