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

Abstract

AbstractCK‐1649C is a new quaternary ammonium class III antiarrhythmic agent undergoing clinical trials. The side effect profile of a class III antiarrhythmic agent is generally unknown. This study compared CK‐1649C with quinidine and lidocaine (class I), acecainide (class I/III), and clofilium (class III), in several models of smooth muscle, platelet, skeletal muscle, and central and peripheral nervous system function, to evaluate the potential side effects of this new drug. CK‐1649C was devoid of neuropharmacologic activity in the mouse and rat. CK.‐1649C did not promote gastrointestinal hypermotility in the mouse fed a charcoal meal and was also inactive in the rat carrageenan‐induced paw edema test. Ten to 30 times the antiarrhythmic dose of concentration of CK‐1649C was devoid of activity on transmural nerve stimulation and did not exhibit α1‐muscarinic, nicotinic, or β‐adrenoceptor blocking activity in canine vascular and guinea pig nonvascular smooth muscle. CK‐1649C was devoid of effects on human platelets, nonvascular smooth muscle of guinea pig vas deferens and uteri, and rabbit bronchi, responses of the anesthetized dog to intravenous acetylcholine (ACh), isoproterenol, and nicotine; cervical sympathetic transmission to the nictitating membrane of dog; and free water clearance in water‐loaded dogs. CK‐1649C (30mg/kg, i.v.) was devoid of all but transient inhibitory activity against vagal nerve stimulation in the dog. CK‐1649C should not have significant hemodynamic, neural, or smooth muscle side effects at proposed therapeutic doses of 1–3 mg/kg in man.