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

doi:10.19803/j.1672-8629.2020.09.02

Abstract

Abstract: 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.

Key words: moxifloxacin, levofloxacin, arrhythmia, human induced pluripotent stem cell, cardiac myocytes, cardial, real-time cell analysis, cardiotoxicity, quinidine, procainamidel, amiodarone

CLC Number:

WANG Qi, YAN Yujing, REN Lu, WEN Hairuo, GUO Jian. Cardiotoxicity Evaluation of Moxifloxacin and Levofloxacin Used in Conjunction with Antiarrhythmic Drugs through HiPSC-CM[J]. Chinese Journal of Pharmacovigilance, 2020, 17(9): 553-558.

References

[1] 刘蓓菁. 药物心脏毒性反应与药物警戒[J]. 药物流行病学杂志, 2011, 20(4):205-208.
[2] ICH. ICH Guidance for Industry ICH S7A: Safety pharmacology studies for human pharmaceut-icals [EB/OL]. (2000-11-08)[2019-10-28].http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelin-es/Safety/S7A/Step4/S7A_Guideline. pdf.
[3] ICH. ICH Guidance for Industry ICH S7B: The nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals [EB/OL]. (2005-05-12)[2019-10-28].http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7B/Step4/S7B_ Guideline.pdf.
[4] 陈高建, 黄芝瑛, 王三龙, 等. 诱导多能干细胞分化的心肌细胞在心脏毒性评价中的应用[J]. 药物分析杂志, 2018, 38(5):758-764.
[5] Jonsson MKB, Wang QD, Becker B.Impedance-Based Detection of Beating Rhythm and Proarrhythmic Effects of Compounds on Stem Cell-Derived Cardiomyocytes[J]. Assay Drug Dev Technol, 2011, 9(6):589-599.
[6] 胡碧君. 氟喹诺酮类药物不良反应分析[J]. 海峡药学, 2018, 30(12):280-281.
[7] 国家药品监督管理局. 总局关于修订全身用氟喹诺酮类药品说明书的公告[EB/OL]. (2017-07-05)[2019-10-28].http://www.nmpa.gov.cn/WS04/CL2115/286700.html.
[8] Zhou P, Wu FJ, Zhou TC, et al.Simple and versatile synthetic polydopamine-based surface supports reprogramming of human somatic cells and long-term self-renewal of human pluripotent stem cells under defined conditions[J]. Biomaterials, 2016, 5(87):1-17.
[9] 张真真, 王三龙, 赵亚,等. 人胚胎干细胞分化的心肌细胞心脏毒性评价模型的建立及应用[J]. 中国新药杂志, 2017, 26(7):795-803.
[10] Selzer A, Wray HW.Quinidine Syncope: Paroxysmal Ventricular Fibrillation Occurring during Treatment of Chronic Atrial Arrhythmias[J]. Circulation, 1964, 30(1):17-26.
[11] 张婧, 王金华, 刘璐,等. 65例β-内酰胺类药物致心血管不良反应的文献分析[J].中国药物警戒, 2013, 10(4):238-241.
[12] Li M, Ramos LG.Drug-Induced QT Prolongation and Torsades de Pointes[J]. P&T, 2017, 42(7):473-477.
[13] 杨倩, 汪小涧, 尤启冬.药物心脏毒副作用及其产生机制与防治策略[J].中国药师, 2008, 11(6):641-643.
[14] Somasundaram S, Manivannan K.An Overview of Fluoroquinolones[J]. Annual Review & Research in Biology, 2013, 3(3):296-313.
[15] 谭莉莉. 喹诺酮类抗菌药物的临床不良反应[J]. 中国药物警戒, 2013, 10(2):92-95.
[16] Noel GJ, Natarajan J, Chien S, et al.Effects of three fluoroquinol ones on QT interval in healthy adults after single doses[J]. Clinical Pharmacology & Therapeutics, 2003, 73(4):292-303.
[17] Wilhelm H, Frank K, Anna F, et al.Update on the Cardiac Safety of Moxifloxacin[J]. Current Drug Safety, 2012, 7(2):149-163.
[18] Giovanni BM, Emanuele P, Giovanni S, et al.Combined Use of Delamanid and Bedaquiline to Treat Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: A Systematic Review[J]. International Journal of Molecular Science, 2017,18(2):341-350.
[19] Yang YY, Shen NS, Shi FW, et al.Liensinine- and Neferine-Induced Cardiotoxicity in Primary Neonatal Rat Cardiomyocytes and Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes[J]. International Journal of Molecular Sciences, 2016, 17(2):186-199.