PHARMACOLOGY OF SEMATILIDE, A NONQUATERNARY CLASS-III ANTIARRHYTHMIC AGENT

Sematilide is a new, non-quaternary class III antiarrhythmic agent currently undergoing clinical trials. We showed that a quaternary ammonium class III antiarrhythmic agent exhibits few extracardiac effects (Greenberg et al., Drug Dev. Res. 25:107-123, 1992). However, the extracardiac effects of a non-quaternary, pure class III antiarrhythmic agent are unknown. Sematilide, a pure class III antiarrhythmic agent, is effective in a canine model of arrhythmia at 0.3-1.0 mg/kg, intravenously (i.v.). We compared the nervous system and extracardiac effects of sematilide to acecainide (a class I/III) 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 alpha-1, muscarinic, nicotinic, and beta-adrenoceptor blocking activities in a variety ot 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 (10-30 mg/kg, i.v.) inhibited vagal nerve stimulation in the dog and slightly enhanced free water clearance in water-loaded dogs. The data show that effective antiarrhythmic doses and concentrations of sematilide are devoid of significant, injurious neural, hemodynamic, or smooth muscle side effects.