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Quantitative Profiling of the Effects of Vanoxerine on Human Cardiac Ion Channels and its Application to Cardiac Risk.

Obejero-Paz CA, Bruening-Wright A, Kramer J, Hawryluk P, Tatalovic M, Dittrich HC, Brown AM - Sci Rep (2015)

Bottom Line: 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.Additionally we propose that trafficking inhibition of hERG be added to CiPA.

View Article: PubMed Central - PubMed

Affiliation: ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Effect of vanoxerine, bepridil, dofetilide and verapamil on spontaneously beating SC-CMAPs.Spontaneous frequency was ~1 Hz. Note the reduction in action potential amplitude in vanoxerine, bepridil and verapamil and the depolarization of the maximum diastolic potential membrane potential in dofetilide.
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f3: Effect of vanoxerine, bepridil, dofetilide and verapamil on spontaneously beating SC-CMAPs.Spontaneous frequency was ~1 Hz. Note the reduction in action potential amplitude in vanoxerine, bepridil and verapamil and the depolarization of the maximum diastolic potential membrane potential in dofetilide.

Mentions: Figure 3 shows the effects of vanoxerine and comparators on action potentials measured after at least 5 min exposure to different concentrations and after washout. The time course of changes in membrane potential and APD30, 60 and 90 are shown in Supplementary Figure 3. We restricted our measurements to beat rates between 0.5 and 1.5 Hz.


Quantitative Profiling of the Effects of Vanoxerine on Human Cardiac Ion Channels and its Application to Cardiac Risk.

Obejero-Paz CA, Bruening-Wright A, Kramer J, Hawryluk P, Tatalovic M, Dittrich HC, Brown AM - Sci Rep (2015)

Effect of vanoxerine, bepridil, dofetilide and verapamil on spontaneously beating SC-CMAPs.Spontaneous frequency was ~1 Hz. Note the reduction in action potential amplitude in vanoxerine, bepridil and verapamil and the depolarization of the maximum diastolic potential membrane potential in dofetilide.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663487&req=5

f3: Effect of vanoxerine, bepridil, dofetilide and verapamil on spontaneously beating SC-CMAPs.Spontaneous frequency was ~1 Hz. Note the reduction in action potential amplitude in vanoxerine, bepridil and verapamil and the depolarization of the maximum diastolic potential membrane potential in dofetilide.
Mentions: Figure 3 shows the effects of vanoxerine and comparators on action potentials measured after at least 5 min exposure to different concentrations and after washout. The time course of changes in membrane potential and APD30, 60 and 90 are shown in Supplementary Figure 3. We restricted our measurements to beat rates between 0.5 and 1.5 Hz.

Bottom Line: 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.Additionally we propose that trafficking inhibition of hERG be added to CiPA.

View Article: PubMed Central - PubMed

Affiliation: ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus