title: Quantitative Profiling of the Effects of Vanoxerine on Human Cardiac Ion Channels and its Application to Cardiac Risk.
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.
authors.affiliation: ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Obejero-Paz
authors.affiliation: ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bruening-Wright
authors.affiliation: ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.
authors.forename: James
authors.initials: J
authors.lastname: Kramer
authors.affiliation: ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hawryluk
authors.affiliation: ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.
authors.forename: Milos
authors.initials: M
authors.lastname: Tatalovic
authors.affiliation: Laguna Pharmaceuticals, 4225 Executive Square, Suite 960, La Jolla, CA 92037, USA.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Dittrich
authors.affiliation: ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.|Laguna Pharmaceuticals, 4225 Executive Square, Suite 960, La Jolla, CA 92037, USA.
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Brown
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D015764:Bepridil / Q000494:pharmacology; D016466:CHO Cells; D003198:Computer Simulation; D003412:Cricetulus; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D007473:Ion Channels / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D007473:Ion Channels; D010627:Phenethylamines; D010879:Piperazines; D013449:Sulfonamides; D015764:Bepridil; C043425:vanoxerine; D014700:Verapamil; C063533:dofetilide