Effects of a novel amiodarone-like compound SAR114646A on the pig atrium and susceptibility to ventricular fibrillation in dogs and pigs

Abstract

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.

Effects of the novel amiodarone-like compound SAR114646A on cardiac ion channels and ventricular arrhythmias in rats

“…Moreover, the transient outward K + current I to and the ATP-sensitive channel K ATP , which play a role in ventricular arrhythmias, are also more potently blocked by SAR114646A than by amiodarone. Therefore, promising antiarrhythmic potency of SAR114646A is expected, as it was demonstrated in rats (the present study), in a porcine model of atrial fibrillation , and in a dog model of sudden cardiac death (Billman et al 2008). Unlike amiodarone, the chemical structure of SAR114646A is devoid of iodine and therefore, less chronic side effects are expected.…”

Pleiotropic actions of amiodarone: still puzzling after half a century

“…In addition, the PALLAS trial was recently halted due to excess mortality in the dronedarone-treated arm, raising concerns about the usefulness of dronedarone (Nattel 2011). Other amiodarone derivatives with improved water solubility (e.g., budiodarone) are being developed and have shown a promise as antiarrhythmic agents for both atrial and ventricular arrhythmias Billman et al 2012;Ezekowitz et al 2012). …”