Cardiohemodynamic and Electrophysiological Effects of Anti-influenza Drug Oseltamivir In Vivo and In Vitro
Cardiohemodynamic and Electrophysiological Effects of Anti-influenza Drug Oseltamivir In Vivo and In Vitro
复制标题
DOI：
10.1007/s12012-013-9202-6
复制
发表时间：
2013-09-01
影响因子：
3.2
通讯作者：
Sugiyama, Atsushi
中科院分区：
文献类型：
--
作者：
Kitahara, Ken;Nakamura, Yuji;Sugiyama, Atsushi
用氟烷麻醉的狗（n = 4）和离体豚鼠左心房（n = 5）研究了奥司他韦的电药理作用，并与吡西卡尼进行了比较。奥司他韦（0.3、3和30 mg/kg，i. v.）或吡西卡尼（1和3 mg/kg，i. v.）另外对狗给药。低剂量奥司他韦提供临床相关的血浆浓度，C（max）为4 μ M。低剂量和中等剂量的奥司他韦增加心输出量，而中等剂量的奥司他韦增加血压，延迟心房内传导和心室复极。高剂量奥司他韦具有负性变时、变力和降压作用，同时延迟心房内、房室结和心室内传导以及心室复极。在奥司他韦后观察到心室复极的剂量依赖性延迟，而吡西卡尼诱导了反向使用依赖性延长。此外，奥司他韦抑制心房内传导的选择性高于心室内传导，而心室内传导对匹西卡尼的选择性较低。用离体心房进行的动作电位测定表明，奥司他韦（10 μ M）比匹西卡尼（10 μ M）更能降低V（max），奥司他韦（10-100 μ M）延长动作电位时程，而匹西卡尼（1-10 μ M）不能诱导这种作用。因此，奥司他韦在临床相关的10倍以上的剂量是相对安全的，而10-100倍以上的剂量具有独特的电生理特征。
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 mu M. 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 mu M) decreased V (max) more than pilsicainide (10 mu M) and that oseltamivir (10-100 mu M) prolonged action potential duration, which was not induced by pilsicainide (1-10 mu M). Thus, oseltamivir in clinically relevant to its 10 times higher doses is relatively safe, whereas 10-100 times higher doses possess unique electrophysiological profile.