title: Cardiohemodynamic and electrophysiological effects of anti-influenza drug oseltamivir in vivo and in vitro.
abstract: Electropharmacological effects of oseltamivir were studied in comparison with pilsicainide using halothane-anesthetized dogs (n = 4) and isolated left atrium of guinea pigs (n = 5). Oseltamivir (0.3, 3 and 30 mg/kg, i.v.) or pilsicainide (1 and 3 mg/kg, i.v.) was additionally administered to the dogs. The low dose of oseltamivir provided clinically relevant plasma concentrations with C max of 4 μM. The low and middle doses of oseltamivir increased cardiac output, whereas the middle dose increased blood pressure and delayed intra-atrial conduction and ventricular repolarization. The high dose of oseltamivir exerted negative chronotropic, inotropic and hypotensive effects, while it delayed intra-atrial, atrioventricular nodal and intra-ventricular conduction and ventricular repolarization. Use-dependent delay of ventricular repolarization was observed after oseltamivir, whereas reverse use-dependent prolongation was induced by pilsicainide. Moreover, oseltamivir more selectively suppressed intra-atrial conduction than intra-ventricular conduction, which was less selective for pilsicainide. Action potential assay using isolated atrium indicated that oseltamivir (10 μM) decreased V max more than pilsicainide (10 μM) and that oseltamivir (10-100 μM) prolonged action potential duration, which was not induced by pilsicainide (1-10 μM). Thus, oseltamivir in clinically relevant to its 10 times higher doses is relatively safe, whereas 10-100 times higher doses possess unique electrophysiological profile.
authors: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan.
authors: Ken
authors: K
authors: Kitahara
authors: Yuji
authors: Y
authors: Nakamura
authors: Yayoi
authors: Y
authors: Tsuneoka
authors: Satomi
authors: S
authors: Adachi-Akahane
authors: Hikaru
authors: H
authors: Tanaka
authors: Hiroshi
authors: H
authors: Yamazaki
authors: Akira
authors: A
authors: Takahara
authors: Junichi
authors: J
authors: Yamazaki
authors: Takanori
authors: T
authors: Ikeda
authors: Atsushi
authors: A
authors: Sugiyama
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000097:blood / Q000494:pharmacology*; D062186:Arterial Pressure / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D003326:Coronary Circulation / Q000187:drug effects*; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007251:Influenza, Human / Q000188:drug therapy; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D053139:Oseltamivir / Q000097:blood / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological
chemical_list: D000889:Anti-Arrhythmia Agents; D000998:Antiviral Agents; D053139:Oseltamivir; D008012:Lidocaine; C042288:pilsicainide