Vanoxerine, a New Drug for Terminating Atrial Fibrillation and Flutter

Authors

  • NAOMICHI MATSUMOTO M.D.,

    1. Department of Medicine, Division of Cardiology, Case Western Reserve University, School of Medicine, University Hospitals of Cleveland and ChanTest Inc., Cleveland, Ohio, USA
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  • CELEEN M. KHRESTIAN B.S.,

    1. Department of Medicine, Division of Cardiology, Case Western Reserve University, School of Medicine, University Hospitals of Cleveland and ChanTest Inc., Cleveland, Ohio, USA
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  • KYUNGMOO RYU Ph.D.,

    1. Department of Medicine, Division of Cardiology, Case Western Reserve University, School of Medicine, University Hospitals of Cleveland and ChanTest Inc., Cleveland, Ohio, USA
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  • ANTONIO E. LACERDA Ph.D.,

    1. Department of Medicine, Division of Cardiology, Case Western Reserve University, School of Medicine, University Hospitals of Cleveland and ChanTest Inc., Cleveland, Ohio, USA
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  • ARTHUR M. BROWN M.D., Ph.D.,

    1. Department of Medicine, Division of Cardiology, Case Western Reserve University, School of Medicine, University Hospitals of Cleveland and ChanTest Inc., Cleveland, Ohio, USA
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  • ALBERT L. WALDO M.D.

    1. Department of Medicine, Division of Cardiology, Case Western Reserve University, School of Medicine, University Hospitals of Cleveland and ChanTest Inc., Cleveland, Ohio, USA
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  • Supported in part by Grant HL067503 from the National Institutes of Health.

  • Dr. Lacerda is an employee of Chan Test Inc, which holds a use patent for vanoxerine. Dr. Brown is a coinventor on the patent and a majority owner of the company. Dr. Waldo reports participation in research grants supported by CV Therapeutics and Sequel Pharmaceuticals; compensation for participation in a speaker's bureau relevant to this topic from GlaxoSmithKline; honoraria from Sanofi-Aventis and participation on the advisory board for dronedarone.

Address for correspondence: Albert L. Waldo, M.D., Division of Cardiology, MS LKS 5038, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106, USA. Fax: 216-844-7196; E-mail: alw2@po.cwru.edu

Abstract

Vanoxerine Terminates AF and AFL. 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).

Methods and 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. (J Cardiovasc Electrophysiol, Vol. 21, pp. 311–319, March 2010)

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