Pharmacology of azimilide dihydrochloride (NE-10064), a class III antiarrhythmic agent

Azimilide, a new class III antiarrhythmic agent with structural uniqueness, prolongs APD in Purkinje or ventricular muscle fibers of six species, including humans. Prolongation involves selective block of delayed rectifier potassium currents, primarily the rapid I(Kr) and slow I(Ks) components. Azimilide was the first class III agent to significantly block I(Ks). In vivo azimilide provides rate-independent increases in refractoriness. In vitro, the compound's ability to increase refractoriness is little affected over a broad range of cycle lengths (500 to 2000 ms) but decreases at the fastest rates. Even at the fastest rates tested, it maintains the ability to prolong repolarization. Azimilide's class III action was confirmed in isolated guinea pig hearts as a concentration-dependent increase in the electro-cardiographic QT interval and ERP. Antiarrhythmic efficacy (i.v. and p.o.) was demonstrated in a rat model of ischemic ventricular arrhythmias induced by ligation and reperfusion of the left anterior descending coronary artery. In anesthetized dogs, i.v. azimilide increased ERP as a function of dose (0.3 to 30 mg/kg) and prevented or ameliorated electrically induced arrhythmias in postinfarction dogs treated intravenously (1 to 30 mg/kg). In a conscious dog model of sudden cardiac death, azimilide 10 mg/kg i.v. protected the majority of animals from spontaneous VF induced by imposition of a second ischemic event distant from a previous infarct. In three dog models of AF, azimilide 10 mg/kg i.v. or less was highly effective in terminating and preventing supraventricular arrhythmia. In a dog model of AFib, azimilide terminated the arrhythmia at both 10 and 20 mg/kg i.v. Oral administration in dogs produced significant increases in ERP. Azimilide caused little or no effect on mean blood pressure or cardiac output at doses that significantly increased the QT interval in anesthetized dogs. It also modestly increased HCF. The compound was well tolerated hemodynamically in most dogs at doses several times higher than those needed for maximal pharmacologic effects (QTc prolongation). Azimilide appears to have minimal arrhythmogenic or proarrhythmic actions in animal studies and may bring new properties to bear on the treatment of both atrial and ventricular arrhythmias in the clinic.