Wisialowski Todd, Crimin Kimberly, Engtrakul Juntyma, O'Donnell John, Fermini Bernard, Fossa Anthony A
Pfizer Global Research and Development, Eastern Point Rd., Building 274, Groton, CT 06340, USA.
J Pharmacol Exp Ther. 2006 Jul;318(1):352-9. doi: 10.1124/jpet.106.101881. Epub 2006 Apr 13.
Antibacterial drugs are known to have varying degrees of cardiovascular liability associated with QT prolongation that can lead to the ventricular arrhythmia torsade de pointes. The purpose of these studies was to compare the assessment for the arrhythmogenic risk of moxifloxacin, erythromycin, and telithromycin. Each drug caused dose-dependent inhibition of the rapidly activating delayed rectifier potassium current encoded by the human ether-á-go-go-related gene (hERG) with IC20 concentrations of 31 microM (moxifloxacin), 21 microM (erythromycin), and 11 microM (telithromycin). These drugs were also evaluated in an anesthetized guinea pig model to measure changes in monophasic action potential duration (MAPD) and to quantify beat-to-beat alternations in MAPD during rapid ventricular pacing. Moxifloxacin dose dependently increased MAPD and caused a rate-dependent increase in alternans at the highest achieved free drug concentration (41 microM). Erythromycin also increased MAPD at its highest free drug concentration (58 microM), but alternans occurred at a relatively lower therapeutic multiple (13.9 microM), and the magnitude of alternans at higher concentrations was independent of pacing rate. Further analysis of the data showed that the beat-to-beat pattern of alternans with erythromycin was less stable than that with moxifloxacin and suggestive of greater arrhythmogenic liability. In contrast to erythromycin and moxifloxacin, telithromycin decreased both MAPD and alternans at the highest achievable drug concentration (7.9 microM). The relative risk at therapeutic concentrations is erythromycin>moxifloxacin>telithromycin and appears to be consistent with clinical observations of torsade de pointes in patients.
已知抗菌药物与QT间期延长相关，具有不同程度的心血管不良反应，可导致室性心律失常尖端扭转型室速。这些研究的目的是比较莫西沙星、红霉素和泰利霉素致心律失常风险的评估。每种药物均导致对人醚 - 去极化相关基因（hERG）编码的快速激活延迟整流钾电流呈剂量依赖性抑制，IC20浓度分别为31微摩尔（莫西沙星）、21微摩尔（红霉素）和11微摩尔（泰利霉素）。还在麻醉豚鼠模型中对这些药物进行评估，以测量单相动作电位时程（MAPD）的变化，并量化快速心室起搏期间MAPD的逐搏交替。在达到的最高游离药物浓度（41微摩尔）时，莫西沙星剂量依赖性增加MAPD，并导致交替现象呈心率依赖性增加。红霉素在其最高游离药物浓度（58微摩尔）时也增加MAPD，但交替现象出现在相对较低的治疗倍数（13.9微摩尔）时，且较高浓度时交替现象的幅度与起搏速率无关。对数据的进一步分析表明，红霉素的逐搏交替模式比莫西沙星的更不稳定，提示更大的致心律失常可能性。与红霉素和莫西沙星相反，泰利霉素在可达到的最高药物浓度（7.9微摩尔）时降低了MAPD和交替现象。治疗浓度下的相对风险为红霉素>莫西沙星>泰利霉素，这似乎与患者尖端扭转型室速的临床观察结果一致。
