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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

(a) CRs for block of hERG, hCav1.2, and peak and late hNav1.5 channel currents by vanoxerine; (b) CRs for block of hERG, hCav1.2, peak and late hNav1.5 by bepridil; (c) CRs for block of hERG, hCav1.2 and hNav1.5 by verapamil; (d) CRs for block of hERG, hCav1.2 and hNav1.5 by dofetilide. Continuous lines indicate data obtained using the step-ramp protocol and are new. Dashed lines in the dofetilide panel indicate CRs for hCav1.2 and hNav1.5 block from Kramer et al. (2013). The dashed line in the verapamil panel is the CRs for late hNav1.5 block measured with a pulse protocol. Measured IC50 values are shown. The gray region in the vanoxerine CRs extends from the peak clinical Cmax of 831 nM1 to the calculated free concentration assuming 99% plasma protein binding4. The respective gray areas in the bepridil, dofetilide and verapamil CRs were calculated from data in Kramer et al. (2013). Insets show SaVety™ plots. Blue segments indicate the SM difference between block of hCav1.2 and hERG. Orange segments indicate the SM difference between block of peak hNav1.5 and hERG. SM for hERG is at the intercept of hCav 1.2 and hNav 1.5 segments. Vertical lines indicate the 95% confidence intervals of the ETPC indexes. The dashed line is at a margin of 30 which has been used to identify torsadogenicity due to hERG block alone14.
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f2: (a) CRs for block of hERG, hCav1.2, and peak and late hNav1.5 channel currents by vanoxerine; (b) CRs for block of hERG, hCav1.2, peak and late hNav1.5 by bepridil; (c) CRs for block of hERG, hCav1.2 and hNav1.5 by verapamil; (d) CRs for block of hERG, hCav1.2 and hNav1.5 by dofetilide. Continuous lines indicate data obtained using the step-ramp protocol and are new. Dashed lines in the dofetilide panel indicate CRs for hCav1.2 and hNav1.5 block from Kramer et al. (2013). The dashed line in the verapamil panel is the CRs for late hNav1.5 block measured with a pulse protocol. Measured IC50 values are shown. The gray region in the vanoxerine CRs extends from the peak clinical Cmax of 831 nM1 to the calculated free concentration assuming 99% plasma protein binding4. The respective gray areas in the bepridil, dofetilide and verapamil CRs were calculated from data in Kramer et al. (2013). Insets show SaVety™ plots. Blue segments indicate the SM difference between block of hCav1.2 and hERG. Orange segments indicate the SM difference between block of peak hNav1.5 and hERG. SM for hERG is at the intercept of hCav 1.2 and hNav 1.5 segments. Vertical lines indicate the 95% confidence intervals of the ETPC indexes. The dashed line is at a margin of 30 which has been used to identify torsadogenicity due to hERG block alone14.

Mentions: To compare MICE effects, we measured block of hERG, hCav 1.2 and hNav 1.5 channel currents using concentrations related to drug exposure levels. Figure 2 shows the CRs of vanoxerine and the comparators bepridil, dofetilide and verapamil for hERG, hCav 1.2 and peak and late hNav 1.5 currents. Continuous lines are binding isotherms from data measured using step-ramp protocols whereas dashed lines are binding isotherms measured using step pulses. The measured IC50s and Hill coefficients for the four currents and four drugs are compiled in Table 1. The number of experiments associated with the data points that were used for fitting the CRs is shown in Supplementary Figure 2.


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)

(a) CRs for block of hERG, hCav1.2, and peak and late hNav1.5 channel currents by vanoxerine; (b) CRs for block of hERG, hCav1.2, peak and late hNav1.5 by bepridil; (c) CRs for block of hERG, hCav1.2 and hNav1.5 by verapamil; (d) CRs for block of hERG, hCav1.2 and hNav1.5 by dofetilide. Continuous lines indicate data obtained using the step-ramp protocol and are new. Dashed lines in the dofetilide panel indicate CRs for hCav1.2 and hNav1.5 block from Kramer et al. (2013). The dashed line in the verapamil panel is the CRs for late hNav1.5 block measured with a pulse protocol. Measured IC50 values are shown. The gray region in the vanoxerine CRs extends from the peak clinical Cmax of 831 nM1 to the calculated free concentration assuming 99% plasma protein binding4. The respective gray areas in the bepridil, dofetilide and verapamil CRs were calculated from data in Kramer et al. (2013). Insets show SaVety™ plots. Blue segments indicate the SM difference between block of hCav1.2 and hERG. Orange segments indicate the SM difference between block of peak hNav1.5 and hERG. SM for hERG is at the intercept of hCav 1.2 and hNav 1.5 segments. Vertical lines indicate the 95% confidence intervals of the ETPC indexes. The dashed line is at a margin of 30 which has been used to identify torsadogenicity due to hERG block alone14.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: (a) CRs for block of hERG, hCav1.2, and peak and late hNav1.5 channel currents by vanoxerine; (b) CRs for block of hERG, hCav1.2, peak and late hNav1.5 by bepridil; (c) CRs for block of hERG, hCav1.2 and hNav1.5 by verapamil; (d) CRs for block of hERG, hCav1.2 and hNav1.5 by dofetilide. Continuous lines indicate data obtained using the step-ramp protocol and are new. Dashed lines in the dofetilide panel indicate CRs for hCav1.2 and hNav1.5 block from Kramer et al. (2013). The dashed line in the verapamil panel is the CRs for late hNav1.5 block measured with a pulse protocol. Measured IC50 values are shown. The gray region in the vanoxerine CRs extends from the peak clinical Cmax of 831 nM1 to the calculated free concentration assuming 99% plasma protein binding4. The respective gray areas in the bepridil, dofetilide and verapamil CRs were calculated from data in Kramer et al. (2013). Insets show SaVety™ plots. Blue segments indicate the SM difference between block of hCav1.2 and hERG. Orange segments indicate the SM difference between block of peak hNav1.5 and hERG. SM for hERG is at the intercept of hCav 1.2 and hNav 1.5 segments. Vertical lines indicate the 95% confidence intervals of the ETPC indexes. The dashed line is at a margin of 30 which has been used to identify torsadogenicity due to hERG block alone14.
Mentions: To compare MICE effects, we measured block of hERG, hCav 1.2 and hNav 1.5 channel currents using concentrations related to drug exposure levels. Figure 2 shows the CRs of vanoxerine and the comparators bepridil, dofetilide and verapamil for hERG, hCav 1.2 and peak and late hNav 1.5 currents. Continuous lines are binding isotherms from data measured using step-ramp protocols whereas dashed lines are binding isotherms measured using step pulses. The measured IC50s and Hill coefficients for the four currents and four drugs are compiled in Table 1. The number of experiments associated with the data points that were used for fitting the CRs is shown in Supplementary Figure 2.

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