Amiodarone is one of the most effective
antiarrhythmic drugs. However, poor solubility of this compound has limited its intravenous application. SAR11464A is a water-soluble
amiodarone-like drug that lacks
iodine and inhibits multiple cardiac
ion channels in vitro. This study evaluated the antiarrhythmic efficacy of this drug in vivo. In porcine studies, atrial effective refractory period (AERP) was measured in
pentobarbital-anesthetized thoracotomized pigs and
atrial fibrillation (AF) was induced by a
premature beat.
Ventricular fibrillation (VF) was induced via either burst pacing or programmed electrical stimulation (a series of progressively shorter beats, S1-S5). In canine studies, VF was induced by a 2-min occlusion of the left circumflex coronary artery during the last minute of exercise in dogs with healed
myocardial infarctions (n = 8). One week later, this test was repeated after pretreatment with
SAR114646A (3.0 mg/kg, i.v., slow bolus).
SAR114646A produced a significant dose-dependent prolongation of AERP, inhibited AF induced by a premature stimulus, and electrically induced VF in anesthetized pigs. At 1.0 and 3.0 mg/kg, i.v., it was superior to
amiodarone,
dofetilide, and
flecainide. In dogs,
SAR114646A did not alter any ECG parameter including QTc (control, 236.9 ± 8.5 ms vs. SAR, 237.2 ± 3.5 ms) but significantly reduced the incidence of VF, protecting six of eight animals (Fisher's exact test, P = 0.01).
SAR114646A was effective against both atrial and ventricular arrhythmias without altering ventricular repolarization. These data suggest that the
amiodarone-like drug
SAR114646A may be an effective antiarrhythmic intervention that does not adversely prolong ventricular repolarization.