title: 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.
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University, 304 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA. billman.1@osu.edu
authors.forename: George E
authors.initials: GE
authors.lastname: Billman
authors.forename: Heinz
authors.initials: H
authors.lastname: Gögelein
authors.forename: Hartmut
authors.initials: H
authors.lastname: Ruetten
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Wirth
mesh_terms: D000638:Amiodarone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D004558:Electric Stimulation; D004562:Electrocardiography; D005260:Female; D006325:Heart Atria / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D013552:Swine; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; C569040:SAR114646A; D000638:Amiodarone