Lu Hua Rong, Vlaminckx Eddy, Van de Water Andre, Rohrbacher Jutta, Hermans An, Gallacher David J
Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research and Development, Division of Janssen Pharmaceutica N.V. B-2340, Beerse, Belgium.
Eur J Pharmacol. 2007 Dec 22;577(1-3):222-32. doi: 10.1016/j.ejphar.2007.07.070.
The prolongation of the ventricular repolarization and proarrhythmic effects (Torsade de Pointes: TdP) of five reference antibiotics were compared in four in-vitro models. 1. Using the patch clamp technique on the human ether-a-gogo-related gene (HERG) current, the rank order for blockade of the HERG-current (IC(50)) was: sparfloxacin (44 microM)>telithromycin=moxifloxacin=erythromycin (+/-100 microM). 2. Assessing their effects on action potential duration (APD(90)) and incidence of early afterdepolarizations in isolated rabbit Purkinje fibers, the rank order was: sparfloxacin>moxifloxacin>telithromycin>erythromycin (prolongation of APD(90) at 100 microM: 83%, 48%, 33% and 17% from baseline compared to +5% with solvent, P<0.05, respectively). 3. Assessing the drug effects on the APD(60), triangulation, reverse use-dependency, and instability in isolated Langendorff-perfused rabbit hearts, the rank order was: moxifloxacin>erythromycin>sparfloxacin>telithromycin. 4. Assessing their torsadogenic potentials (scores of effects on QT-interval, peak of the T wave to end of T wave: T(p-e), T(p-e)/QT ratio, R wave on T wave (R on T) and TdP in isolated rabbit left ventricular wedge preparations, the rank order for their TdP risk score was: sparfloxacin>erythromycin>moxifloxacin>telithromycin. Additional experiments with grepafloxacin indicate that the rank order to detect grepafloxacin-induced long QT was the wedge preparation>the Purkinje fiber>HERG>the isolated heart, where the isolated heart was unable to detect grepafloxacin-induced APD prolongation. The present study demonstrates that the first three in-vitro models can be used to assess the ability of antibiotic compounds to delay ventricular repolarization. However, with respect to their known clinical effects on QT and TdP incidence, the wedge preparation appears to be more predictive and suitable for detecting torsadogenic action of antibiotics.
在四种体外模型中比较了五种参考抗生素的心室复极延长和促心律失常作用（尖端扭转型室速：TdP）。1. 使用膜片钳技术研究人醚 - 去极化相关基因（HERG）电流，HERG电流阻断（IC(50)）的排序为：司帕沙星（44 microM）>泰利霉素 = 莫西沙星 = 红霉素（±100 microM）。2. 评估它们对离体兔浦肯野纤维动作电位时程（APD(90)）和早期后去极化发生率的影响，排序为：司帕沙星>莫西沙星>泰利霉素>红霉素（100 microM时APD(90)的延长：与溶剂组相比，基线时分别为83%、48%、33%和17%，而溶剂组为 +5%，P<0.05）。3. 评估药物对离体Langendorff灌注兔心脏的APD(60)、三角化、反向使用依赖性和不稳定性的影响，排序为：莫西沙星>红霉素>司帕沙星>泰利霉素。4. 评估它们的致扭转型室速潜力（对QT间期、T波峰至T波终点（T(p - e)）、T(p - e)/QT比值、T波上的R波（R on T）和离体兔左心室楔形标本中TdP的影响评分），它们的TdP风险评分排序为：司帕沙星>红霉素>莫西沙星>泰利霉素。加替沙星的额外实验表明，检测加替沙星诱导的长QT的排序为：楔形标本>浦肯野纤维>HERG>离体心脏，其中离体心脏无法检测到加替沙星诱导的APD延长。本研究表明，前三种体外模型可用于评估抗生素化合物延迟心室复极的能力。然而，就它们对QT和TdP发生率的已知临床影响而言，楔形标本似乎更具预测性，更适合检测抗生素的致扭转型室速作用。
