UK‐68,798, A Class III Antiarrhythmic Drug with Antifibrillatory Properties

Sudden cardiac death is a significant cause of mortality in the United States, with an estimated 400,000 cases per year (1 1). Discovery of an effective antiarrhythmic drug capable of reducing the incidence of sudden cardiac death by as little as 10% would result in the saving of approximately 40,000 lives annually. Obviously, there is a need for an effective form of therapy capable of safely treating patients at risk of sudden cardiac death. The Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that antiarrhythmic therapy that successfully prevented asymptomatic and mildly symptomatic ventricular arrhythmias in post-myocardial infarction patients was associated with an increased risk of sudden cardiac death (32). Iatrogenic death is untenable and, therefore, an active search is underway for an antiarrhythmic drug that prevents (ideally), or reduces the probability of (at least), ventricular fibrillation or sudden cardiac death. Since certain currently available antiarrhythmic drugs (i.e., flecainide, encainide, and ethmozine) have proven to be inefficacious against sudden cardiac death (32), several antiarrhythmic drugs are currently under development. According to the Vaughan-Williams classification scheme, class I11 antiarrhythmic drugs increase the refractory period via an increase in the action potential duration, without altering the maximal rate of depolarization (33). Such an electrophysiologic mechanism may be ideal for the prevention of re-entrant arrhythmias, which constitute the predominant mechanism for life-threatening arrhythmias in humans (4). This review focuses on the recently developed class I11 drug, UK-68,798, a potent and efficacious antiarrhythmic agent with antifibrillatory properties. The review will discuss the chemistry, in vitro and in vivo cardiovascular pharmacology, mechanism of action, and pharmacokinetics of UK-68,798.