The Experts below are selected from a list of 90 Experts worldwide ranked by ideXlab platform
John A Camm - One of the best experts on this subject based on the ideXlab platform.
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randomized double blind placebo controlled study to evaluate the safety and efficacy of a single oral dose of Vanoxerine for the conversion of subjects with recent onset atrial fibrillation or flutter to normal sinus rhythm restore sr
Heart Rhythm, 2016Co-Authors: Jonathan P Piccini, Edward L C Pritchett, Beth A Davison, Gad Cotter, Laura Elizabeth Wiener, Gary G Koch, Gregory K Feld, Albert L Waldo, Isabelle C Van Gelder, John A CammAbstract:Background Vanoxerine is an oral, 1,4-dialkylpiperazine derivative antiarrhythmic drug being evaluated for pharmacological cardioversion of atrial fibrillation (AF). Objective The purpose of this study was to evaluate the safety and efficacy of Vanoxerine for the restoration of sinus rhythm in subjects with recent onset AF or atrial flutter (AFL). Methods RESTORE SR ( r andomized, double-blind, placebo-controlled study to e valuate the s afety and efficacy of a single oral dose of Vanoxerine for t he conversion o f subjects with re cent onset atrial fibrillation or flutter to normal s inus r hythm) was a prospective, multinational, randomized, double-blind, placebo-controlled trial that randomized subjects to a single oral dose of Vanoxerine 400 mg or placebo (2:1 allocation). Results A total of 41 subjects were randomized in the study (placebo [n = 15] and Vanoxerine [n = 26]). The study was terminated prematurely because of safety concerns. Overall, 61% (23 of 38) of the treated cohort had a history of AF/AFL and 66% (27 of 41) had structural heart disease (SHD). The primary efficacy end point—conversion to sinus rhythm through 24 hours—occurred in 20% (3 of 15) in the placebo arm vs 69% (18 of 26) in the Vanoxerine arm ( P = .0024). The mean length of stay was 4.2 ± 2.9 days in the placebo arm vs 4.7 ± 3.2 days in the Vanoxerine arm ( P = .6561). The primary safety end point (all-cause death, ventricular fibrillation/tachycardia requiring intervention, or torsades de pointes) occurred in no patient in the placebo arm vs 11.5% (3 of 26) in the Vanoxerine arm. All 3 patients had torsades de pointes and underlying SHD. Conclusion Vanoxerine is an oral, mixed ion channel blocker with I Kr , I Na , and L-type calcium channel activity. While oral therapy with 400 mg of Vanoxerine appears effective for the termination of recent onset AF/AFL, its use was associated with a significant risk of ventricular proarrhythmia in patients with SHD.
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cor art a multicenter randomized double blind placebo controlled dose ranging study to evaluate single oral doses of Vanoxerine for conversion of recent onset atrial fibrillation or flutter to normal sinus rhythm
Heart Rhythm, 2015Co-Authors: Howard C. Dittrich, Gregory K Feld, Albert L Waldo, John A Camm, Tristram D Bahnson, Sergey Golitsyn, Amos Katz, Jason I Koontz, Peter R Kowey, Arthur M. BrownAbstract:Background Restoration of sinus rhythm (SR) in patients with atrial fibrillation/atrial flutter (AF/AFL) is limited principally to direct current cardioversion. The multi-ion channel blocker Vanoxerine may prove an effective alternative. Objective The purpose of this study was to assess Vanoxerine, a 1,4-dialkylpiperazine derivative, for acute conversion of recent-onset, symptomatic AF and AFL. Methods One hundred four subjects with symptomatic AF/AFL for Results Conversion to SR was dose related: 18.2%, 44.0%, and 52.0% within 4 hours, and 59.1%, 64.0%, and 84.0% within 24 hours, for the 200-, 300-, and 400-mg groups, respectively. This was significantly higher than placebo for the 300- and 400-mg groups within 4 hours (12.5% for placebo; P = .0138 and P = .0028, respectively) and for all doses within 24 hours (31.3% for placebo; P = .0421, P = .0138, P = .0001 for 200-, 300-, and 400-mg Vanoxerine groups, respectively). Although Vanoxerine caused significant dose-dependent QTcF (QT correction by Fridericia) prolongation, monomorphic or polymorphic ventricular tachycardia did not occur. Adverse events were mild and self-limited, with only the highest dose having a greater frequency than placebo. Conclusion Oral Vanoxerine converted AF/AFL to SR at a high rate, was well tolerated, and caused no ventricular proarrhythmia.
Arthur M. Brown - One of the best experts on this subject based on the ideXlab platform.
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Quantitative Profiling of the Effects of Vanoxerine on Human Cardiac Ion Channels and its Application to Cardiac Risk
Scientific Reports, 2015Co-Authors: Carlos A. Obejero-paz, Andrew Bruening-wright, James Kramer, Peter Hawryluk, Milos Tatalovic, Howard C. Dittrich, Arthur M. BrownAbstract:Vanoxerine has been in clinical trials for Parkinsonism, depression and cocaine addiction but lacked efficacy. Although a potent blocker of hERG, it produced no serious adverse events. We attributed the unexpected result to offsetting Multiple Ion Channel Effects (MICE). Vanoxerine’s effects were strongly frequency-dependent and we repositioned it for treatment of atrial fibrillation and flutter. Vanoxerine terminated AF/AFL in an animal model and a dose-ranging clinical trial. Reversion to normal rhythm was associated with QT prolongation yet absent proarrhythmia markers for Torsade de Pointes (TdP). To understand the QT/TdP discordance, we used quantitative profiling and compared Vanoxerine with dofetilide, a selective hERG-blocking torsadogen used for intractable AF, verapamil, a non-torsadogenic MICE comparator and bepridil, a torsadogenic MICE comparator. At clinically relevant concentrations, verapamil blocked hCav1.2 and hERG, as did Vanoxerine and bepridil both of which also blocked hNav1.5. In acute experiments and simulations, dofetilide produced early after depolarizations (EADs) and arrhythmias, whereas verapamil, Vanoxerine and bepridil produced no proarrhythmia markers. Of the MICE drugs only bepridil inhibited hERG trafficking following overnight exposure. The results are consistent with the emphasis on MICE of the CiPA assay. Additionally we propose that trafficking inhibition of hERG be added to CiPA.
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cor art a multicenter randomized double blind placebo controlled dose ranging study to evaluate single oral doses of Vanoxerine for conversion of recent onset atrial fibrillation or flutter to normal sinus rhythm
Heart Rhythm, 2015Co-Authors: Howard C. Dittrich, Gregory K Feld, Albert L Waldo, John A Camm, Tristram D Bahnson, Sergey Golitsyn, Amos Katz, Jason I Koontz, Peter R Kowey, Arthur M. BrownAbstract:Background Restoration of sinus rhythm (SR) in patients with atrial fibrillation/atrial flutter (AF/AFL) is limited principally to direct current cardioversion. The multi-ion channel blocker Vanoxerine may prove an effective alternative. Objective The purpose of this study was to assess Vanoxerine, a 1,4-dialkylpiperazine derivative, for acute conversion of recent-onset, symptomatic AF and AFL. Methods One hundred four subjects with symptomatic AF/AFL for Results Conversion to SR was dose related: 18.2%, 44.0%, and 52.0% within 4 hours, and 59.1%, 64.0%, and 84.0% within 24 hours, for the 200-, 300-, and 400-mg groups, respectively. This was significantly higher than placebo for the 300- and 400-mg groups within 4 hours (12.5% for placebo; P = .0138 and P = .0028, respectively) and for all doses within 24 hours (31.3% for placebo; P = .0421, P = .0138, P = .0001 for 200-, 300-, and 400-mg Vanoxerine groups, respectively). Although Vanoxerine caused significant dose-dependent QTcF (QT correction by Fridericia) prolongation, monomorphic or polymorphic ventricular tachycardia did not occur. Adverse events were mild and self-limited, with only the highest dose having a greater frequency than placebo. Conclusion Oral Vanoxerine converted AF/AFL to SR at a high rate, was well tolerated, and caused no ventricular proarrhythmia.
Gregory K Feld - One of the best experts on this subject based on the ideXlab platform.
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randomized double blind placebo controlled study to evaluate the safety and efficacy of a single oral dose of Vanoxerine for the conversion of subjects with recent onset atrial fibrillation or flutter to normal sinus rhythm restore sr
Heart Rhythm, 2016Co-Authors: Jonathan P Piccini, Edward L C Pritchett, Beth A Davison, Gad Cotter, Laura Elizabeth Wiener, Gary G Koch, Gregory K Feld, Albert L Waldo, Isabelle C Van Gelder, John A CammAbstract:Background Vanoxerine is an oral, 1,4-dialkylpiperazine derivative antiarrhythmic drug being evaluated for pharmacological cardioversion of atrial fibrillation (AF). Objective The purpose of this study was to evaluate the safety and efficacy of Vanoxerine for the restoration of sinus rhythm in subjects with recent onset AF or atrial flutter (AFL). Methods RESTORE SR ( r andomized, double-blind, placebo-controlled study to e valuate the s afety and efficacy of a single oral dose of Vanoxerine for t he conversion o f subjects with re cent onset atrial fibrillation or flutter to normal s inus r hythm) was a prospective, multinational, randomized, double-blind, placebo-controlled trial that randomized subjects to a single oral dose of Vanoxerine 400 mg or placebo (2:1 allocation). Results A total of 41 subjects were randomized in the study (placebo [n = 15] and Vanoxerine [n = 26]). The study was terminated prematurely because of safety concerns. Overall, 61% (23 of 38) of the treated cohort had a history of AF/AFL and 66% (27 of 41) had structural heart disease (SHD). The primary efficacy end point—conversion to sinus rhythm through 24 hours—occurred in 20% (3 of 15) in the placebo arm vs 69% (18 of 26) in the Vanoxerine arm ( P = .0024). The mean length of stay was 4.2 ± 2.9 days in the placebo arm vs 4.7 ± 3.2 days in the Vanoxerine arm ( P = .6561). The primary safety end point (all-cause death, ventricular fibrillation/tachycardia requiring intervention, or torsades de pointes) occurred in no patient in the placebo arm vs 11.5% (3 of 26) in the Vanoxerine arm. All 3 patients had torsades de pointes and underlying SHD. Conclusion Vanoxerine is an oral, mixed ion channel blocker with I Kr , I Na , and L-type calcium channel activity. While oral therapy with 400 mg of Vanoxerine appears effective for the termination of recent onset AF/AFL, its use was associated with a significant risk of ventricular proarrhythmia in patients with SHD.
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cor art a multicenter randomized double blind placebo controlled dose ranging study to evaluate single oral doses of Vanoxerine for conversion of recent onset atrial fibrillation or flutter to normal sinus rhythm
Heart Rhythm, 2015Co-Authors: Howard C. Dittrich, Gregory K Feld, Albert L Waldo, John A Camm, Tristram D Bahnson, Sergey Golitsyn, Amos Katz, Jason I Koontz, Peter R Kowey, Arthur M. BrownAbstract:Background Restoration of sinus rhythm (SR) in patients with atrial fibrillation/atrial flutter (AF/AFL) is limited principally to direct current cardioversion. The multi-ion channel blocker Vanoxerine may prove an effective alternative. Objective The purpose of this study was to assess Vanoxerine, a 1,4-dialkylpiperazine derivative, for acute conversion of recent-onset, symptomatic AF and AFL. Methods One hundred four subjects with symptomatic AF/AFL for Results Conversion to SR was dose related: 18.2%, 44.0%, and 52.0% within 4 hours, and 59.1%, 64.0%, and 84.0% within 24 hours, for the 200-, 300-, and 400-mg groups, respectively. This was significantly higher than placebo for the 300- and 400-mg groups within 4 hours (12.5% for placebo; P = .0138 and P = .0028, respectively) and for all doses within 24 hours (31.3% for placebo; P = .0421, P = .0138, P = .0001 for 200-, 300-, and 400-mg Vanoxerine groups, respectively). Although Vanoxerine caused significant dose-dependent QTcF (QT correction by Fridericia) prolongation, monomorphic or polymorphic ventricular tachycardia did not occur. Adverse events were mild and self-limited, with only the highest dose having a greater frequency than placebo. Conclusion Oral Vanoxerine converted AF/AFL to SR at a high rate, was well tolerated, and caused no ventricular proarrhythmia.
Albert L Waldo - One of the best experts on this subject based on the ideXlab platform.
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randomized double blind placebo controlled study to evaluate the safety and efficacy of a single oral dose of Vanoxerine for the conversion of subjects with recent onset atrial fibrillation or flutter to normal sinus rhythm restore sr
Heart Rhythm, 2016Co-Authors: Jonathan P Piccini, Edward L C Pritchett, Beth A Davison, Gad Cotter, Laura Elizabeth Wiener, Gary G Koch, Gregory K Feld, Albert L Waldo, Isabelle C Van Gelder, John A CammAbstract:Background Vanoxerine is an oral, 1,4-dialkylpiperazine derivative antiarrhythmic drug being evaluated for pharmacological cardioversion of atrial fibrillation (AF). Objective The purpose of this study was to evaluate the safety and efficacy of Vanoxerine for the restoration of sinus rhythm in subjects with recent onset AF or atrial flutter (AFL). Methods RESTORE SR ( r andomized, double-blind, placebo-controlled study to e valuate the s afety and efficacy of a single oral dose of Vanoxerine for t he conversion o f subjects with re cent onset atrial fibrillation or flutter to normal s inus r hythm) was a prospective, multinational, randomized, double-blind, placebo-controlled trial that randomized subjects to a single oral dose of Vanoxerine 400 mg or placebo (2:1 allocation). Results A total of 41 subjects were randomized in the study (placebo [n = 15] and Vanoxerine [n = 26]). The study was terminated prematurely because of safety concerns. Overall, 61% (23 of 38) of the treated cohort had a history of AF/AFL and 66% (27 of 41) had structural heart disease (SHD). The primary efficacy end point—conversion to sinus rhythm through 24 hours—occurred in 20% (3 of 15) in the placebo arm vs 69% (18 of 26) in the Vanoxerine arm ( P = .0024). The mean length of stay was 4.2 ± 2.9 days in the placebo arm vs 4.7 ± 3.2 days in the Vanoxerine arm ( P = .6561). The primary safety end point (all-cause death, ventricular fibrillation/tachycardia requiring intervention, or torsades de pointes) occurred in no patient in the placebo arm vs 11.5% (3 of 26) in the Vanoxerine arm. All 3 patients had torsades de pointes and underlying SHD. Conclusion Vanoxerine is an oral, mixed ion channel blocker with I Kr , I Na , and L-type calcium channel activity. While oral therapy with 400 mg of Vanoxerine appears effective for the termination of recent onset AF/AFL, its use was associated with a significant risk of ventricular proarrhythmia in patients with SHD.
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cor art a multicenter randomized double blind placebo controlled dose ranging study to evaluate single oral doses of Vanoxerine for conversion of recent onset atrial fibrillation or flutter to normal sinus rhythm
Heart Rhythm, 2015Co-Authors: Howard C. Dittrich, Gregory K Feld, Albert L Waldo, John A Camm, Tristram D Bahnson, Sergey Golitsyn, Amos Katz, Jason I Koontz, Peter R Kowey, Arthur M. BrownAbstract:Background Restoration of sinus rhythm (SR) in patients with atrial fibrillation/atrial flutter (AF/AFL) is limited principally to direct current cardioversion. The multi-ion channel blocker Vanoxerine may prove an effective alternative. Objective The purpose of this study was to assess Vanoxerine, a 1,4-dialkylpiperazine derivative, for acute conversion of recent-onset, symptomatic AF and AFL. Methods One hundred four subjects with symptomatic AF/AFL for Results Conversion to SR was dose related: 18.2%, 44.0%, and 52.0% within 4 hours, and 59.1%, 64.0%, and 84.0% within 24 hours, for the 200-, 300-, and 400-mg groups, respectively. This was significantly higher than placebo for the 300- and 400-mg groups within 4 hours (12.5% for placebo; P = .0138 and P = .0028, respectively) and for all doses within 24 hours (31.3% for placebo; P = .0421, P = .0138, P = .0001 for 200-, 300-, and 400-mg Vanoxerine groups, respectively). Although Vanoxerine caused significant dose-dependent QTcF (QT correction by Fridericia) prolongation, monomorphic or polymorphic ventricular tachycardia did not occur. Adverse events were mild and self-limited, with only the highest dose having a greater frequency than placebo. Conclusion Oral Vanoxerine converted AF/AFL to SR at a high rate, was well tolerated, and caused no ventricular proarrhythmia.
Howard C. Dittrich - One of the best experts on this subject based on the ideXlab platform.
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Quantitative Profiling of the Effects of Vanoxerine on Human Cardiac Ion Channels and its Application to Cardiac Risk
Scientific Reports, 2015Co-Authors: Carlos A. Obejero-paz, Andrew Bruening-wright, James Kramer, Peter Hawryluk, Milos Tatalovic, Howard C. Dittrich, Arthur M. BrownAbstract:Vanoxerine has been in clinical trials for Parkinsonism, depression and cocaine addiction but lacked efficacy. Although a potent blocker of hERG, it produced no serious adverse events. We attributed the unexpected result to offsetting Multiple Ion Channel Effects (MICE). Vanoxerine’s effects were strongly frequency-dependent and we repositioned it for treatment of atrial fibrillation and flutter. Vanoxerine terminated AF/AFL in an animal model and a dose-ranging clinical trial. Reversion to normal rhythm was associated with QT prolongation yet absent proarrhythmia markers for Torsade de Pointes (TdP). To understand the QT/TdP discordance, we used quantitative profiling and compared Vanoxerine with dofetilide, a selective hERG-blocking torsadogen used for intractable AF, verapamil, a non-torsadogenic MICE comparator and bepridil, a torsadogenic MICE comparator. At clinically relevant concentrations, verapamil blocked hCav1.2 and hERG, as did Vanoxerine and bepridil both of which also blocked hNav1.5. In acute experiments and simulations, dofetilide produced early after depolarizations (EADs) and arrhythmias, whereas verapamil, Vanoxerine and bepridil produced no proarrhythmia markers. Of the MICE drugs only bepridil inhibited hERG trafficking following overnight exposure. The results are consistent with the emphasis on MICE of the CiPA assay. Additionally we propose that trafficking inhibition of hERG be added to CiPA.
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cor art a multicenter randomized double blind placebo controlled dose ranging study to evaluate single oral doses of Vanoxerine for conversion of recent onset atrial fibrillation or flutter to normal sinus rhythm
Heart Rhythm, 2015Co-Authors: Howard C. Dittrich, Gregory K Feld, Albert L Waldo, John A Camm, Tristram D Bahnson, Sergey Golitsyn, Amos Katz, Jason I Koontz, Peter R Kowey, Arthur M. BrownAbstract:Background Restoration of sinus rhythm (SR) in patients with atrial fibrillation/atrial flutter (AF/AFL) is limited principally to direct current cardioversion. The multi-ion channel blocker Vanoxerine may prove an effective alternative. Objective The purpose of this study was to assess Vanoxerine, a 1,4-dialkylpiperazine derivative, for acute conversion of recent-onset, symptomatic AF and AFL. Methods One hundred four subjects with symptomatic AF/AFL for Results Conversion to SR was dose related: 18.2%, 44.0%, and 52.0% within 4 hours, and 59.1%, 64.0%, and 84.0% within 24 hours, for the 200-, 300-, and 400-mg groups, respectively. This was significantly higher than placebo for the 300- and 400-mg groups within 4 hours (12.5% for placebo; P = .0138 and P = .0028, respectively) and for all doses within 24 hours (31.3% for placebo; P = .0421, P = .0138, P = .0001 for 200-, 300-, and 400-mg Vanoxerine groups, respectively). Although Vanoxerine caused significant dose-dependent QTcF (QT correction by Fridericia) prolongation, monomorphic or polymorphic ventricular tachycardia did not occur. Adverse events were mild and self-limited, with only the highest dose having a greater frequency than placebo. Conclusion Oral Vanoxerine converted AF/AFL to SR at a high rate, was well tolerated, and caused no ventricular proarrhythmia.
