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题名:No proarrhythmic properties of the antibiotics Moxifloxacin or Azithromycin in anaesthetized dogs with chronic-AV block
作者:M B Thomsen, J D M Beekman,...
来源:British Journal of Pharmacology (06 Nov 2006) Research Paper
URL :http://dx.doi.org/10.1038/sj.bjp.0706900
日期:061130
摘要:M B Thomsen1, J D M Beekman1, N J M Attevelt1, A Takahara2, A Sugiyama2, K Chiba3 and M A Vos1

1Department of Medical Physiology, Heart Lung Centre Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands 2Department of Pharmacology, University of Yamanashi, Yamanashi, Japan
3New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd, Tokyo, Japan
Correspondence: Dr MA Vos, Department of Medical Physiology, Heart Lung Centre Utrecht, Yalelaan 50, NL 3584 CM Utrecht, The Netherlands. E-mail: m.a.vos@umcutrecht.nl


Abstract

Background & purpose: The therapeutically available quinolone antibiotic moxifloxacin has been used as a positive control for prolonging the QT interval in both clinical and non-clinical studies designed to assess the potential of new drugs to delay cardiac repolarization. Despite moxifloxacin prolonging QT, it has not been shown to cause torsades de pointes arrhythmias (TdP). Azithromycin is a macrolide antibiotic that has rarely been associated, clinically, with cases of proarrhythmia. As there is a lack of clinical data available, the cardiac safety of these drugs was assessed in a TdP-susceptible animal model by evaluating their repolarization and proarrhythmia effects.

Experimental approach & Key results: In transfected HEK cells, the IC50s for I hERG were 456 and 856259 g ml-1 for moxifloxacin and azithromycin, respectively. Intravenous administration of 2 and 8 mg kg-1 moxifloxacin (total peak-plasma concentrations 4.61.5 and 22.96.8 g ml-1) prolonged the QTc in 6 anaesthetized dogs with chronic AV block by 73 and 2119%, respectively. Similar intravenous doses of azithromycin (total peak-plasma concentrations 5.41.3 and 20.84.9 g ml-1) had no electrophysiological effects in the same dogs. The reference compound, dofetilide (25 g kg-1 i.v.) caused QTc prolongation (2915%) and TdP in all dogs. Beat-to-beat variability of repolarization (BVR), quantified as short-term variability of the left ventricular monophasic action potential duration, was only increased after dofetilide (1.80.7 to 3.81.5 ms; P<0.05).

Conclusion & implications: As neither moxifloxacin nor azithromycin caused TdP or an increase in the BVR, we conclude that both drugs can be used safely in clinical situations.

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