Chiba K, Sugiyama A, Satoh Y, Shiina H, Hashimoto K
Department of Pharmacology, Yamanashi Medical University, Tamaho-cho, Nakakoma-gun, Yamanashi 409-3898, Japan.
Toxicol Appl Pharmacol. 2000 Nov 15;169(1):8-16. doi: 10.1006/taap.2000.9041.
Drug-induced prolongation of the QT interval is often associated with the onset of Torsades de Pointes (TdP) resulting in a life-threatening ventricular arrhythmia. The potential of the proarrhythmic effects of the new fluoroquinolone antibacterial agents, levofloxacin and sparfloxacin, was examined in the chronic complete atrioventricular block dogs with stable idioventricular automaticity using Holter ECG monitoring in conscious state (Experiment 1). Next, to better analyze the mechanisms of the proarrhythmic property, the cardiovascular effects of these two drugs were compared in the halothane-anesthetized dogs under the monitoring of ECG, His bundle electrogram, systemic and left ventricular pressure, monophasic action potential, cardiac output, and effective refractory period (Experiment 2). In Experiment 1, oral administration of 6 mg/kg (n = 4) as well as 60 mg/kg (n = 4) of levofloxacin did not induce any ventricular premature depolarization. On the other hand, oral administration of 60 mg/kg of sparfloxacin (n = 4) induced TdP leading to ventricular fibrillation in all animals within 24 h, while 6 mg/kg of sparfloxacin (n = 4) did not induce any ventricular premature depolarization. In Experiment 2, intravenous administration of 0.3 mg/kg as well as 3.0 mg/kg of levofloxacin slightly increased cardiac output, but no significant changes were detected in the other parameters (n = 6). On the other hand, intravenous administration of 0.3 mg/kg of sparfloxacin prolonged the effective refractory period. Additional administration of 3.0 mg/kg of sparfloxacin decreased the heart rate and prolonged the effective refractory period and ventricular repolarization phase in a similar extent, but no significant changes were detected in the other parameters (n = 6). These results suggest that backward shift of the relative repolarization period in a cardiac cycle may be the mechanism responsible for the torsadegenic effect of sparfloxacin.
药物引起的QT间期延长常与尖端扭转型室速（TdP）的发作相关，可导致危及生命的室性心律失常。在清醒状态下使用动态心电图监测，对具有稳定室性自主节律的慢性完全性房室传导阻滞犬，研究新型氟喹诺酮类抗菌药物左氧氟沙星和司帕沙星的促心律失常作用潜力（实验1）。接下来，为了更好地分析促心律失常特性的机制，在氟烷麻醉的犬中，在监测心电图、希氏束电图、体循环和左心室压力、单相动作电位、心输出量和有效不应期的情况下，比较这两种药物的心血管效应（实验2）。在实验1中，口服6mg/kg（n = 4）以及60mg/kg（n = 4）的左氧氟沙星未诱发任何室性早搏。另一方面，口服60mg/kg的司帕沙星（n = 4）在24小时内使所有动物诱发TdP并导致心室颤动，而6mg/kg的司帕沙星（n = 4）未诱发任何室性早搏。在实验2中，静脉注射0.3mg/kg以及3.0mg/kg的左氧氟沙星使心输出量略有增加，但其他参数未检测到显著变化（n = 6）。另一方面，静脉注射0.3mg/kg的司帕沙星使有效不应期延长。额外注射3.0mg/kg的司帕沙星使心率降低，并使有效不应期和心室复极期延长程度相似，但其他参数未检测到显著变化（n = 6）。这些结果表明，心动周期中相对复极期的后移可能是司帕沙星致扭转型室速效应的机制。
