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

Abstract

CK-1649C is a new quaternary ammonium class Ill antiarrhythmic agent undergoing clinical trials. The side effect profile of a class Ill antiarrhythmic agent is generally unknown. This study compared CK-1649C with quinidine and lidocaine (class I), acecainide (class l/lll), and clofilium (class Ill), 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-I 649C did not promote gastrointestinal hypermotility in the mouse fed a charcoal meal and was also inactive in the rat carrageenaninduced 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 a,-muscarinic, nicotinic, or p-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 (30 mg/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.

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

“…Twenty-one mongrel dogs of either sex, weighing 9-17 kg, were anesthetized with pentobarbital sodium (35 mgikg, i.v.) and the anterior mesenteric artery prepared for TNS and isometric recording of force development as described previously in detail [Greenberg et al, 1981[Greenberg et al, , 1989b[Greenberg et al, , 1992Greenberg 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 increasing, cumulative concentrations (0.1-100 pM in 1 Log intervals) of sematilide, acecainide, or vehicle.…”

“…Guinea pig vas deferens and uteri. Seventeen male and 17 female Hartley strain guinea pigs (300-550 g) were sacrificed by cervical dislocation, the vas deferens and uteri removed and prepared for study as described previously in detail [Van Rossum, 1962;Greenberg et al, 1973Greenberg et al, , 1992Greenberg and Luisi, 19891. The composition of the Tyrode's solution (guinea pig) was (mM): NaCl(l36.9), KC1 (2.68), CaCl, (0.9), NaHCO, (1 1.9), MgC1, (2.…”

“…The side effects of a non-quaternary, pure class 111 antiarrhythmic agent are currently unknown. CK-1649C is almost devoid of extracardiac activity in vitro and in vivo (Greenberg et al, 1992). However, this may simply reflect the inability of quaternary ammonium salts to easily move across cell membranes.…”