AZIMILIDE DIHYDROCHLORIDE, A NOVEL ANTIARRHYTHMIC AGENT

Azimilide, a novel class III antiarrhythmic agent, blocks both the slo wly activating (I-Ks) and rapidly activating (I-Kr) components of the delayed rectifier potassium current, which distinguishes it from conve ntional potassium channel blockers such as sotalol and dofetilide, whi ch block only I-Kr. Azimilide is being developed to prolong the time t o recurrence of atrial fibrillation, atrial flutter, and paroxysmal su praventricular tachycardia in patients with and without structural hea rt disease. Azimilide is also being studied for its role in prevention of sudden cardiac death in high-risk patients after myocardial infarc tion (MI). Preclinical and clinical studies indicate that azimilide pr olongs cardiac refractory period in a dose-dependent manner, as manife sted by increases in action potential duration, QT(c) interval, and ef fective refractory period. Azimilide does not affect PR or QRS interva l and minimally affects hemodynamic properties such as blood pressure and heart rate. Its in vivo effects appear to be race-independent and are maintained under ischemic or hypoxic conditions, properties of pot ential clinical significance. Azimilide has shown excellent efficacy ( > 85%) in suppressing supraventricular arrhythmias in a variety of dog models. It also suppressed complex ventricular arrhythmias in infarct ed dogs and, in a sudden death cardiac model, decreased mortality. Azi milide pharmacokinetics are very predictable. The drug is completely a bsorbed, and the extent of absorption is not affected by food. It can be administered once daily. Clinical data suggest that dose adjustment s of azimilide are not required for age, gender, hepatic or renal func tion, or concomitant use of digoxin or warfarin. Azimilide has a good safety profile in open-label safety studies in > 800 supraventricular arrhythmia patients, most with structural heart disease. The incidence of serious adverse events, including torsade de pointes, is low. The rate of patient withdrawal from long-term studies is also encouragingl y low. Unlike amiodarone, azimilide has shown no evidence of pulmonary or ocular toxicity. Azimilide is expected to provide a unique new the rapy for the prevention of supraventricular arrhythmias and sudden car diac death when Phase III clinical trials are complete and safety and efficacy are confirmed. (C) 1998 by Excerpta Medica, Inc.