Vanoxerine, a new drug for terminating atrial fibrillation and flutter.
BACKGROUND
Vanoxerine produces potent block of cardiac hERG, sodium, and L-type calcium channels. Block is strongly frequency dependent, is unassociated with transmural dispersion of repolarization, and occurs at concentrations safe in humans. Therefore, we proposed that vanoxerine might be antiarrhythmic. In these studies, we tested the hypothesis that vanoxerine would terminate induced atrial fibrillation (AF) and atrial flutter (AFL) in dogs with sterile pericarditis (SP).


RESULTS
In 9 SP dogs, 11 episodes each of sustained (>10 minutes) AF and AFL were induced. Electrophysiological studies were performed before and after infusion of vanoxerine, which effectively terminated AF and AFL in 19 of 22 episodes. Simultaneous multisite mapping during 3 AF and 3 AFL episodes demonstrated that termination of each arrhythmia occurred with termination of the driver (a reentrant circuit) following an increase in tachycardia CL. Except for conduction in an area of slow conduction in the driver's reentrant circuit, vanoxerine did not significantly affect intraatrial or atrioventricular conduction time, QRS duration, or QT/QTc intervals. Ventricular refractoriness prolonged minimally during ventricular pacing at 400 and 333 ms (176 +/- 16 ms to 182 +/- 16 ms; 173 +/- 11 ms to 178 +/- 18 ms, respectively). Vanoxerine minimally increased (mean 0.7 mA) atrial stimulus threshold for capture.


CONCLUSIONS
Vanoxerine effectively terminated induced, sustained AF and AFL in the canine SP model, and produced insignificant or minimal changes in refractoriness, conduction time, or stimulus threshold, consistent with little proarrhythmic risk.
Matsumoto
Naomichi
N
Department of Medicine, Division of Cardiology, Case Western Reserve University, School of Medicine, University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
Khrestian
Celeen M
CM
Ryu
Kyungmoo
K
Lacerda
Antonio E
AE
Brown
Arthur M
AM
Waldo
Albert L
AL
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D001282:Atrial Flutter / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects*; D006339:Heart Rate / Q000528:radiation effects*; D010879:Piperazines / Q000008:administration & dosage*; D016896:Treatment Outcome
D018927:Anti-Asthmatic Agents; D010879:Piperazines; C043425:vanoxerine