Pharmacology of sematilide, a non‐quaternary class III antiarrhythmic agent

Abstract

Greenberg, S.S., A. Luisi, J.P. Long, and H.E. Williamson: Pharmacology of sematalide, a non-quaternary class Ill antiarrhythmic agent. Drug Dev. Res. 25:283-302, 1992. Sematilide is a new, non-quaternary class Ill antiarrhythmic agent currently undergoing clinical trials. We showed that a quaternary ammonium class Ill antiarrhythmic agent exhibits few extracardiac effects (Greenberg et al., Drug Dev. Res. 25107-123, 1992). However, the extracardiac effects of a non-quaternary, pure class Ill antiarrhythmic agent are unknown. Sematilide, a pure class Ill antiarrhythmic agent, is effective in a canine model of arrhythmia at 0.3-1 .O mg/kg, intravenously (i.v.). We compared the nervous system and extracardiac effects of sematilide to acecainide (a class 1/111) and several class I antiarrhythmic agents to evaluate the potential side effects of this new drug. Sematilide was devoid of neuropharmacologic activity in the mouse and rat, devoid of gastrointestinal activity in the mouse fed a charcoal meal, and without effect in the rat carrageenan-induced paw edema test. Ten to 30 times the average antiarrhythmic dose or plasma levels of sematilide were devoid of a,, muscarinic, nicotinic, and p-adrenoceptor blocking activities in a variety of preparations. Moreover, sematilide was devoid of depressant activity on 1) cholinergic, nicotinic, and sympathetic neurotransmission; 2) vascular and non-vascular smooth muscle reactivity and contractility; 3) aggregation of human platelets; 4) responses of the anesthetized dog to i.v. acetylcholine, isoproterenol, and nicotine; and 5) displacement of quinuclidinyl benzilate (QNB) binding to dog atrial membranes. Sematilide (1 0-30 mg/kg, i.v.) inhibited vagal nerve stimulation in the dog and slightly enhanced free water clearance in

IK independent class III actions of MS‐551 compared with sematilide and dofetilide during reperfusion in anaesthetized rats

“…It is not clear what produced such different results on the blood pressure and whether they are related to the K channel blockade. Even though the effects on MAP of the three drugs indicate the existence of some other cardiovascular effects, changes in haemodynamics have been found to be transient and minimal in conscious dogs and man (Greenberg et al, 1992). Because maximal doses were used in our experiments, these effects should be of little importance in the clinical use of these drugs.…”

“…Sematilide had a biphasic effect on the MAP, namely an increase was produced by a low dose, whereas a decrease was produced by a high dose. There have been several reports (Chi et al, 1990;Fish et al, 1990;Greenberg et al, 1992) showing similar transient decreases in MAP, but there were no reports of an increasing effect. It is not clear what produced such different results on the blood pressure and whether they are related to the K channel blockade.…”

General pharmacology of CK‐1649C: A new quaternary class III antiarrhythmic agent

“…Twenty-eight mongrel dogs of either sex, weighing 9-17 kg, were anesthetized with pentobarbital sodium (35 mg/kg, i.v. ); the anterior mesenteric artery was prepared for TNS and isometric recording of force development as described previously in detail [Greenberg et al, 1981[Greenberg et al, , 1991Greenberg and Luisi, 19891. Responses of mesenteric arteries to TNS (0.5-32 Hz, in 0.3-log increments) were obtained before and during a 30-min exposure to cumulative concentrations (0.1-100 pM in 1-log M increments) of CK-1649C, clofilium, acecainide, or vehicle. The magnitude of inhibition of the responses of TNS at each concentration of test compound or vehicle was determined.…”