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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

Steady state simulations of action potentials at drug concentrations indicated in the Figure.Indicated simulations were paced at 1 Hz (top panel) and 0.5 Hz (Bottom panel). Records in dofetilide are control (no drug), last record in the series without EADs (blue line, 80 nM at 1 Hz and 40 nM at 0.5 Hz), first record in the series showing EADs (green line, 80 nM at 1 Hz, 45 nM at 0.5 Hz) and maximal tested concentration (red line, 100 nM). Records in verapamil are simulations at the same concentrations used in the stem cell action potentials.
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f4: Steady state simulations of action potentials at drug concentrations indicated in the Figure.Indicated simulations were paced at 1 Hz (top panel) and 0.5 Hz (Bottom panel). Records in dofetilide are control (no drug), last record in the series without EADs (blue line, 80 nM at 1 Hz and 40 nM at 0.5 Hz), first record in the series showing EADs (green line, 80 nM at 1 Hz, 45 nM at 0.5 Hz) and maximal tested concentration (red line, 100 nM). Records in verapamil are simulations at the same concentrations used in the stem cell action potentials.

Mentions: Figure 4 shows simulated potentials at 1 and 2 s periods (top and bottom panels, respectively). Supplementary Figure 4 shows the functional relationships between concentration, frequency and APD90 for vanoxerine and its comparators. From inspection of Fig. 4 for dofetilide EADs appear followed by triggered ectopic beats. The threshold of 40 nM at 2 s periods approximates the 10 nM threshold for triggered activity observed experimentally in SC-CMAPs (Supplementary Table S4). By contrast, vanoxerine, bepridil and verapamil were free of EADs and triggered arrhythmias over the same range of frequencies. The simulation in Fig. 4a shows the reduction in plateau due to vanoxerine block of hCav 1.2 and hNav 1.5 and prolongation of APD90 due to hERG block observed experimentally. For verapamil and bepridil, the simulations resembled the experimental observations with decreased plateau potential and changes in APD90. Supplementary Figure 5 shows single simulated action potentials which compare favorably to the single experimental action potentials of text Fig. 3.


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)

Steady state simulations of action potentials at drug concentrations indicated in the Figure.Indicated simulations were paced at 1 Hz (top panel) and 0.5 Hz (Bottom panel). Records in dofetilide are control (no drug), last record in the series without EADs (blue line, 80 nM at 1 Hz and 40 nM at 0.5 Hz), first record in the series showing EADs (green line, 80 nM at 1 Hz, 45 nM at 0.5 Hz) and maximal tested concentration (red line, 100 nM). Records in verapamil are simulations at the same concentrations used in the stem cell action potentials.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Steady state simulations of action potentials at drug concentrations indicated in the Figure.Indicated simulations were paced at 1 Hz (top panel) and 0.5 Hz (Bottom panel). Records in dofetilide are control (no drug), last record in the series without EADs (blue line, 80 nM at 1 Hz and 40 nM at 0.5 Hz), first record in the series showing EADs (green line, 80 nM at 1 Hz, 45 nM at 0.5 Hz) and maximal tested concentration (red line, 100 nM). Records in verapamil are simulations at the same concentrations used in the stem cell action potentials.
Mentions: Figure 4 shows simulated potentials at 1 and 2 s periods (top and bottom panels, respectively). Supplementary Figure 4 shows the functional relationships between concentration, frequency and APD90 for vanoxerine and its comparators. From inspection of Fig. 4 for dofetilide EADs appear followed by triggered ectopic beats. The threshold of 40 nM at 2 s periods approximates the 10 nM threshold for triggered activity observed experimentally in SC-CMAPs (Supplementary Table S4). By contrast, vanoxerine, bepridil and verapamil were free of EADs and triggered arrhythmias over the same range of frequencies. The simulation in Fig. 4a shows the reduction in plateau due to vanoxerine block of hCav 1.2 and hNav 1.5 and prolongation of APD90 due to hERG block observed experimentally. For verapamil and bepridil, the simulations resembled the experimental observations with decreased plateau potential and changes in APD90. Supplementary Figure 5 shows single simulated action potentials which compare favorably to the single experimental action potentials of text Fig. 3.

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