Limits...
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

Change in hERG surface expression relative to vehicle control for vanoxerine, bepridil, verapamil and dofetilide.Symbols indicate mean values ± sem from at least 2 independent plates. The data is plotted as a function of the experimental concentration divided by the total Cmax8. Asterisks indicate that the change in relative surface expression is significantly different from the relative surface expression of the lower concentration tested for each drug.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4663487&req=5

f5: Change in hERG surface expression relative to vehicle control for vanoxerine, bepridil, verapamil and dofetilide.Symbols indicate mean values ± sem from at least 2 independent plates. The data is plotted as a function of the experimental concentration divided by the total Cmax8. Asterisks indicate that the change in relative surface expression is significantly different from the relative surface expression of the lower concentration tested for each drug.

Mentions: We tested concentrations of bepridil and vanoxerine at 10 to 30 times the total plasma concentrations. These concentrations were at least one order of magnitude smaller than the concentrations reached in rabbit myocardium after direct perfusion with vanoxerine or bepridil which were concentrated 43020 and 91421 times above the plasma concentrations. Figure 5 shows the percentage changes in surface hERG expression relative to vehicle controls as a function of the experimental concentration normalized to the total effective therapeutic plasma concentration. In the presence of bepridil hERG surface expression was decreased significantly to 38% at ~10 times the total plasma concentration. Over the same concentration range, vanoxerine increased surface expression of wild type hERG by 30% and dofetilide by 26%. The increase in hERG surface expression by dofetilide is consistent with the increased trafficking efficiency observed by Varkevisser et al. (2013)22. Verapamil did not affect hERG surface expression.


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)

Change in hERG surface expression relative to vehicle control for vanoxerine, bepridil, verapamil and dofetilide.Symbols indicate mean values ± sem from at least 2 independent plates. The data is plotted as a function of the experimental concentration divided by the total Cmax8. Asterisks indicate that the change in relative surface expression is significantly different from the relative surface expression of the lower concentration tested for each drug.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Change in hERG surface expression relative to vehicle control for vanoxerine, bepridil, verapamil and dofetilide.Symbols indicate mean values ± sem from at least 2 independent plates. The data is plotted as a function of the experimental concentration divided by the total Cmax8. Asterisks indicate that the change in relative surface expression is significantly different from the relative surface expression of the lower concentration tested for each drug.
Mentions: We tested concentrations of bepridil and vanoxerine at 10 to 30 times the total plasma concentrations. These concentrations were at least one order of magnitude smaller than the concentrations reached in rabbit myocardium after direct perfusion with vanoxerine or bepridil which were concentrated 43020 and 91421 times above the plasma concentrations. Figure 5 shows the percentage changes in surface hERG expression relative to vehicle controls as a function of the experimental concentration normalized to the total effective therapeutic plasma concentration. In the presence of bepridil hERG surface expression was decreased significantly to 38% at ~10 times the total plasma concentration. Over the same concentration range, vanoxerine increased surface expression of wild type hERG by 30% and dofetilide by 26%. The increase in hERG surface expression by dofetilide is consistent with the increased trafficking efficiency observed by Varkevisser et al. (2013)22. Verapamil did not affect hERG surface expression.

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