Proarrhythmia of azimilide and other class III antiarrhythmic agents in the adrenergically stimulated rabbit.

The ventricular proarrhythmic actions of five class III antiarrhythmic agents were compared in the Carlsson rabbit model. In adrenergically stimulated anesthetized rabbits, azimilide, clofilium, dofetilide, sematilide, and d,l-sotalol caused premature ventricular contractions and nonsustained and sustained ventricular tachyarrhythmias (NSVT and SVT) at pharmacologically equivalent intravenous doses that increased QTc intervals 20% (ED20). There were no significant differences between agents in the percentage of rabbits with serious arrhyhthmias at the ED20 doses of 5.2, 0.033, 0.015, 0.66, and 2.8 mg/kg i.v., respectively. Proarrhythmia was dose-dependent. Linear regression analysis of arrhythmia score versus log dose estimated the NSVT doses as 6.2, 0.055, 0.0089, 1.5, and 5.7, respectively. Analysis of arrhythmia states during a 10-min window after infusion when QTc prolongation was 20% showed that the compounds differed significantly in the proportion of time treated rabbits spent in SVT and combined NSVT and SVT. Rabbits treated with azimilide spent significantly less time in SVT and combined NSVT and SVT, followed in order of increasing time by d,l-sotalol, sematilide, clofilium, and dofetilide.

Suppression of inducible ventricular arrhythmias by intravenous azimilide in dogs with previous myocardial infarction.

The class III antiarrhythmics azimilide dihydrochloride and dl-sotalol were evaluated for ability to suppress induction of ventricular tachyarrhythmias (VT) in anesthetized, male mongrel dogs 4-6 days after surgical infarction of the left ventricle (LV) produced by ligation/reperfusion of the left anterior descending coronary artery. Postmortem infarcts averaged 28.2 +/- 3.3% and 27.5 +/- 3.9% of the LV for azimilide- and sotalol-treated dogs, respectively. Both agents (0.3-30 mg/kg i.v.) increased ventricular effective refractory period as a function of dose in LV normal and infarcted zones without increasing conduction time. Azimilide was well tolerated hemodynamically up to 30 mg/kg i.v., whereas sotalol produced a significant and dose-related decrease in both blood pressure and heart rate. Azimilide was effective in five (56%) of nine dogs in preventing induction of ventricular arrhythmias by programmed electrical stimulation (PES) at doses from 1 to 30 mg/kg. Efficacy was seen for nonsustained and sustained VT and for ventricular fibrillation. Although sotalol (0.3-10 mg/kg) was effective in all five VT dogs tested, one of two nonsustained ventricular tachyarrhythmia (NSVT) dogs and two of three sustained ventricular tachyarrhythmia (SVT) dogs were reinducible with the baseline arrhythmia at doses higher than the effective dose, and one dog died after 30 mg/kg of sotalol. Both agents increased the cycle length of VT. Thus azimilide simultaneously increased refractoriness and provided antiarrhythmic efficacy as suppression of PES-induced ventricular arrhythmias in infarcted dogs without the hemodynamic depression seen with sotalol.

Comparison of the effects of intravenous LNC-834, a new antiarrhythmic agent, and quinidine in canine models of arrhythmia.

The effects of intravenous LNC-834, a new antiarrhythmic agent, and quinidine sulfate were evaluated and compared in 24-h infarction, programmed electrical stimulation (PES), and ventricular fibrillation threshold (VFT) canine models of cardiac arrhythmias. In the 24-h infarction model (24 h after myocardial infarction), animals averaged 85% arrhythmic beats before treatment. LNC-834 gave greater suppression of these spontaneous arrhythmias (97%) and had a longer duration of action (150 min) than did quinidine (70% and 85 min, respectively) at 10 mg of base/kg, although plasma levels were comparable (1.82 +/- 0.19 and 1.50 +/- 0.27 micrograms/ml of plasma for LNC-834 and quinidine, respectively). At 10 mg of base/kg, LNC-834 and quinidine increased effective refractory periods by 9 and 7%, respectively. In the PES model, LNC-834 (3 mg of base/kg) suppressed ventricular tachycardia (VT) in 33% (2/6) of the dogs tested: none of the six quinidine-treated animals displayed suppression of VT at cumulative doses of 0.3 to 30 mg of base/kg. In PES dogs, inducible and noninducible, mortality was less with LNC-834 treatment than with quinidine [9% (1/11) and 36% (4/11), respectively]. Neither LNC-834 nor quinidine elevated VFT in naive, anesthetized dogs. Although no treatment significantly affected the intrinsic heart rate in VFT dogs, both LNC-834 and quinidine produced significant hypotension; however, LNC-834 caused less hypotension than did quinidine at equal doses. This study demonstrates that LNC-834 may be a useful antiarrhythmic agent with efficacy comparable to and hemodynamic advantages over quinidine.