title: Effects of the antitussive drug cloperastine on ventricular repolarization in halothane-anesthetized guinea pigs.
abstract: Cloperastine is an antitussive drug, which can be received as an over-the-counter cold medicine. The chemical structure of cloperastine is quite similar to that of the antihistamine drug diphenhydramine, which is reported to inhibit hERG K⁺ channels and clinically induce long QT syndrome after overdose. To analyze its proarrhythmic potential, we compared effects of cloperastine and diphenhydramine on the hERG K⁺ channels expressed in HEK293 cells. We further assessed their effects on the halothane-anesthetized guinea-pig heart under the monitoring of monophasic action potential (MAP) of the ventricle. Cloperastine inhibited the hERG K⁺ currents in a concentration-dependent manner with an IC₅₀ value of 0.027 μM, whose potency was 100 times greater than that of diphenhydramine (IC₅₀; 2.7 μM). In the anesthetized guinea pigs, cloperastine at a therapeutic dose of 1 mg/kg prolonged the QT interval and MAP duration without affecting PR interval or QRS width. Diphenhydramine at a therapeutic dose of 10 mg/kg prolonged the QT interval and MAP duration together with increase in PR interval and QRS width. The present results suggest that cloperastine may be categorized as a QT-prolonging drug that possibly induces arrhythmia at overdoses like diphenhydramine does.
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, Japan. akirat@phar.toho-u.ac.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Takahara
authors.forename: Kaori
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsuki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Oka
authors.forename: Iyuki
authors.initials: I
authors.lastname: Namekata
authors.forename: Hikaru
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000605:Amino Alcohols / Q000494:pharmacology / Q000506:poisoning; D000818:Animals; D017849:Animals, Inbred Strains; D000889:Anti-Arrhythmia Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000996:Antitussive Agents / Q000494:pharmacology* / Q000506:poisoning; D004155:Diphenhydramine / Q000494:pharmacology / Q000506:poisoning; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006168:Guinea Pigs; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008564:Membrane Potentials / Q000187:drug effects; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology* / Q000506:poisoning; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000506:poisoning; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000605:Amino Alcohols; D000889:Anti-Arrhythmia Agents; D000996:Antitussive Agents; D051638:Ether-A-Go-Go Potassium Channels; D010880:Piperidines; D026902:Potassium Channel Blockers; D011994:Recombinant Proteins; C017135:clobutinol; C040282:cloperastine; D004155:Diphenhydramine