Proarrhythmic effects of fluoroquinolone antibacterial agents: in vivo effects as physiologic substrate for torsades.
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.
Chiba
K
K
Department of Pharmacology, Yamanashi Medical University, Tamaho-cho, Nakakoma-gun, Yamanashi 409-3898, Japan.
Sugiyama
A
A
Satoh
Y
Y
Shiina
H
H
Hashimoto
K
K
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D004285:Dogs; D015716:Electrocardiography, Ambulatory / Q000187:drug effects; D005260:Female; D024841:Fluoroquinolones; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006327:Heart Block / Q000503:physiopathology; D064704:Levofloxacin; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D023421:Models, Animal; D015242:Ofloxacin / Q000633:toxicity*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology; D018497:Ventricular Dysfunction, Right / Q000139:chemically induced / Q000503:physiopathology
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D064704:Levofloxacin; D015242:Ofloxacin; C061363:sparfloxacin