Comparison of sensitivity of surrogate markers of drug-induced torsades de pointes in canine hearts.
Given a limited information regarding the difference of the sensitivity of surrogate markers of drug-induced torsades de pointes, including early afterdepolarization, ectopic beats, phase 3 repolarization and dispersion of ventricular repolarization, we simultaneously analyzed them in the halothane-anesthetized canine model (n=5). A non-specific IKr channel blocker sparfloxacin, which has been known to induce torsades de pointes in animals and clinical patients, prolonged the repolarization process in a dose-related and reverse use-dependent manner. No significant change was detected in any of the proarrhythmic markers except for the backward parallel shift of phase 3 repolarization in the cardiac cycle with the QT interval prolongation, which would be the most sensitive marker in predicting the potential arrhythmogenic property of sparfloxacin in the "non-remodeled" normal heart.
Chiba
Katsuyoshi
K
New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd. 16-13, Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan.
Sugiyama
Atsushi
A
Takasuna
Kiyoshi
K
Hashimoto
Keitaro
K
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects / Q000633:toxicity; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology*
D015415:Biomarkers; D024841:Fluoroquinolones; C061363:sparfloxacin