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Quantitative Profiling of the Effects of Vanoxerine on Human Cardiac Ion Channels and its Application to Cardiac Risk.
Obejero-Paz, Carlos A; Bruening-Wright, Andrew; Kramer, James; Hawryluk, Peter; Tatalovic, Milos; Dittrich, Howard C; Brown, Arthur M.
Afiliación
  • Obejero-Paz CA; ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.
  • Bruening-Wright A; ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.
  • Kramer J; ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.
  • Hawryluk P; ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.
  • Tatalovic M; ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.
  • Dittrich HC; Laguna Pharmaceuticals, 4225 Executive Square, Suite 960, La Jolla, CA 92037, USA.
  • Brown AM; ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.
Sci Rep ; 5: 17623, 2015 Nov 30.
Article en En | MEDLINE | ID: mdl-26616666
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperazinas / Corazón / Canales Iónicos / Miocardio Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Sci Rep Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperazinas / Corazón / Canales Iónicos / Miocardio Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Sci Rep Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido