利用人诱导多能干细胞分化的心肌细胞评价莫西沙星和左氧氟沙星与抗心律失常药物联用的心脏毒性风险  

Cardiotoxicity Evaluation of Moxifloxacin and Levofloxacin Used in Conjunction with Antiarrhythmic Drugs through HiPSC-CM

作　　者：汪祺[1] 颜玉静 任璐 文海若 郭建[2] WANG Qi;YAN Yujing;REN Lu;WEN Hairuo;GUO Jian(National Institutes for Food and Drug Control,Beijing 100050,China;Emergency Department,Beijing Tongren Hospital Affiliated to Capital Medical University,Beijing,100730,China)

机构地区：[1]中国食品药品检定研究院,北京100050 [2]首都医科大学附属北京同仁医院急诊科,北京100730

出　　处：《中国药物警戒》2020年第9期553-558,共6页Chinese Journal of Pharmacovigilance

基　　金：国家自然科学基金项目(81503068,81503347);国家十三五“重大新药创制”(2018ZX09201017)。

摘　　要：目的利用人诱导多能干细胞分化的心肌细胞和实时细胞分析系统评价喹诺酮类抗生素莫西沙星和左氧氟沙星与抗心律失常药物奎尼丁、普鲁卡因胺和胺碘酮联用的心脏毒性风险。方法人诱导多能干细胞分化的心肌细胞接种于实时细胞分析系统Cardio E-Plate 96孔板并给予不同浓度的莫西沙星、左氧氟沙星、奎尼丁、普鲁卡因胺和胺碘酮,根据人诱导多能干细胞分化的心肌细胞的标准化细胞指数及标准化搏动频率筛选毒性浓度。以莫西沙星和左氧氟沙星最高无毒性浓度和最低有毒性浓度预处理24 h后,分别给予不同浓度的奎尼丁、普鲁卡因胺和胺碘酮,比较各组间标准化细胞指数的差异。结果莫西沙星、左氧氟沙星、奎尼丁、普鲁卡因胺和胺碘酮均可诱导标准化细胞指数降低(P<0.05)。莫西沙星与奎尼丁或普鲁卡因胺联合给药后可导致标准化细胞指数降低(P<0.05);左氧氟沙星与胺碘酮联合给药后可导致标准化细胞指数降低(P<0.05)。结论莫西沙星和左氧氟沙星与抗心律失常药物联用后可增加心脏毒性风险,基于人诱导多能干细胞分化的心肌细胞和实时细胞分析系统的体外评价模型在药物心脏毒性预测上具有应用前景。Objective To evaluate the cardiotoxicity of quinolone antibiotics used in combination with antiarrhythmic drugs using human induced pluripotent stem cell derived cardiac myocytes(hiPSC-CM)and the real-time cell analyzer(RTCA).Methods The hiPSC-CM was seeded onto the RTCA Cardio E-Plate 96 and treated with moxifloxacin,levofloxacin,quinidine,procainamide,and amiodarone of different concentrations,while the normalized cell index(NCI)and normalized beat rate(NBR)were used for the screening of toxic concentrations.After 24 hours of pretreatment with the highest non-toxic concentration and the lowest toxic concentration of moxifloxacin or levofloxacin,different concentrations of quinidine,procainamide,and amiodarone were used to treat the cells,and the difference in the NCI between the groups was compared.Results Moxifloxacin,levofloxacin,quinidine,procainamide,and amiodarone all decreased the NCI when used alone to treat the cells(P<0.05).Moxifloxacin combined with quinidine or procainamide reduced the NCI of cells(P<0.05),so did levofloxacin combined with amiodarone(P<0.05).Conclusion This study suggests that the combination of moxifloxacin and levofloxacin with antiarrhythmic drugs could increase the risk of cardiotoxicity,and that the in vitro evaluation model based on hiPSC-CM and RTCA is applicable to the prediction of risks of drug cardiotoxicity.

关 键 词：莫西沙星 左氧氟沙星 心律失常 人诱导多能干细胞 心肌细胞 实时细胞分析 心脏毒性 奎尼丁 普鲁卡因胺 胺碘酮 

分 类 号：R96[医药卫生—药理学]