title: Double pharmacological challenge on repolarization opens new avenues for drug safety research.
abstract: The pharmaceutical industry is testing new potential drugs for their propensity to prolong human cardiac repolarization, and regards this as a sign of proarrhythmic risk. Many studies have dethroned the common perception that prolonged repolarization is a reliable surrogate marker for torsades de pointes (TdP) arrhythmia. Both the pharmaceutical industry and the regulatory bodies are neglecting the available proarrhythmia models. In vitro studies have suggested that combined pharmacological hits on repolarization will produce a superior substrate for in vivo proarrhythmia, compared to the single-drug assessment. By using consecutive pharmacological challenges, a simple model is proposed, in which combinatorial pharmacology is employed to provoke TdP in the conscious dog. The pharmaceutical industry interested in evaluating the proarrhythmic potential of their present and future drugs now has a simple means of doing so.
authors.affiliation: Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 W. 168th Street, NY 10032, USA. mbt2117@columbia.edu
authors.forename: M B
authors.initials: MB
authors.lastname: Thomsen
mesh_terms: D000818:Animals; D002839:Chromans / Q000008:administration & dosage / Q000633:toxicity; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D004285:Dogs; D004357:Drug Synergism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000517:prevention & control; D004562:Electrocardiography / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D010627:Phenethylamines / Q000008:administration & dosage / Q000633:toxicity; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000633:toxicity; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000502:physiology*; D011817:Rabbits; D012307:Risk Factors; D013449:Sulfonamides / Q000008:administration & dosage / Q000633:toxicity; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; C420023:HMR 1556; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C059983:potassium channel protein I(sk); C063533:dofetilide