Frommeyer Gerrit, Fischer Christina, Lange Philipp S, Leitz Patrick, Fehr Michael, Bogossian Harilaos, Milberg Peter, Eckardt Lars
Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
Eur J Pharmacol. 2016 Apr 5;776:185-90. doi: 10.1016/j.ejphar.2016.02.051. Epub 2016 Feb 19.
In several case reports a prolongation of the QT-interval and even proarrhythmic effects of fluconazole and voriconazole were reported. The aim of the present study was to investigate if application of fluconazole or voriconazole has the potential to provoke polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In female rabbits, fluconazole (10, 30 and 50 µM, n=6) and voriconazole (10, 30 and 50 µM, n=6) were infused after obtaining baseline data. Eight endocardial and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant QT prolongation after application of fluconazole as compared with baseline (10 µM:+12 ms, 30 µM:+22 ms, 50 µM:+37 ms; P<0.05) accompanied by an increase of action potential duration (APD90). Administration of voriconazole also induced QT prolongation (30 µM:+10 ms, 50 µM:+20 ms, P<0.05). Spatial dispersion of repolarization remained stable in voriconazole-treated hearts while fluconazole induced a significant increase (30 µM:+15 ms, 50 µM:+16 ms; P<0.05). Lowering of potassium concentration in bradycardic AV-blocked hearts did not provoke any early afterdepolarizations (EADs) or polymorphic ventricular tachycardia in voriconazole-treated hearts. Application of fluconazole led to the reproducible induction of EADs in 4 of 6 hearts and polymorphic ventricular tachycardia in 3 of 6 hearts (36 episodes). In the present study, voriconazole demonstrated a safe electrophysiologic profile despite significant QT prolongation. In contrast, fluconazole led to a more marked prolongation of myocardial repolarization combined with a more marked increase of dispersion of repolarization. These results imply that application of fluconazole might be torsadogenic and the QT-interval should be closely monitored.
在多篇病例报告中，有关于氟康唑和伏立康唑导致QT间期延长甚至促心律失常作用的报道。本研究的目的是在一个对心律失常敏感的模型中，研究应用氟康唑或伏立康唑是否有可能诱发多形性室性心动过速。在雌性兔中，获取基线数据后输注氟康唑（10、30和50 μM，n = 6）和伏立康唑（10、30和50 μM，n = 6）。八通道心内膜和心外膜单相动作电位以及同步记录的12导联心电图显示，与基线相比，应用氟康唑后QT间期显著延长（10 μM：+12 ms，30 μM：+22 ms，50 μM：+37 ms；P<0.05），同时动作电位时程（APD90）增加。应用伏立康唑也导致QT间期延长（30 μM：+10 ms，50 μM：+20 ms，P<0.05）。在伏立康唑治疗的心脏中，复极的空间离散度保持稳定，而氟康唑导致显著增加（30 μM：+15 ms，50 μM：+16 ms；P<0.05）。在心动过缓的房室传导阻滞心脏中降低钾浓度，在伏立康唑治疗的心脏中未诱发任何早期后除极（EADs）或多形性室性心动过速。应用氟康唑导致6只心脏中的4只可重复诱发EADs，6只心脏中的3只诱发多形性室性心动过速（36次发作）。在本研究中，尽管QT间期显著延长，但伏立康唑显示出安全的电生理特征。相比之下，氟康唑导致心肌复极更明显的延长，并伴有复极离散度更明显的增加。这些结果表明，应用氟康唑可能具有致扭转型室性心动过速的作用，应密切监测QT间期。
