In vitro safety "clinical trial" of the cardiac liability of drug polytherapy.
In vitro safety "clinical trial" of the cardiac liability of drug polytherapy.
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DOI：
10.1111/cts.13038
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Healy KE
中科院分区：
文献类型：
--
作者：
Charrez B;Charwat V;Siemons B;Finsberg H;Miller EW;Edwards AG;Healy KE
只有少数美国食品和药物管理局（FDA）紧急使用授权存在用于治疗严重急性呼吸综合征-冠状病毒2（SARS-CoV-2）感染的药物和生物治疗剂。潜在的治疗方法包括重新利用药物，其中一些具有心脏负担。我们报告了一个慢性临床前药物筛选平台，心脏微生理系统（MPS），以评估心脏毒性与再利用羟氯喹（HCQ）和阿奇霉素（AZM）多药治疗在模拟I期安全性临床试验。MPS含有来自诱导多能干细胞的人类心肌。使用与临床测量相关的输出（如QT间期（动作电位持续时间）和药物-生物标志物配对）测量药物反应的影响。慢性暴露（10天）心肌单独HCQ引起早期后除极和增加QT间期过去5天。AZM单药从第7天开始引起QT间期延长，在第8天和第10天观察到心律失常。单药治疗结果与临床试验结果相似。在长期暴露于HCQ和AZM多药治疗后，我们观察到QT间期在第4-8天增加。有趣的是，与已发表的临床试验一致，在多药治疗中观察到心律失常和不稳定性相对于单药治疗减少。生物标志物，其中大部分可在患者血清中测量，被确定为单药治疗或多药治疗对组织收缩功能、形态学和抗氧化保护的负面影响。心脏MPS可正确预测与QT间期延长和心律不稳定相关的临床心律失常。这个高内容的系统可以帮助临床医生设计他们的试验，快速预测心脏结局，并定义新的监测生物标志物，以加速患者获得安全的2019冠状病毒病（COVID-19）治疗方法。
Only a handful of US Food and Drug Administration (FDA) Emergency Use Authorizations exist for drug and biologic therapeutics that treat severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) infection. Potential therapeutics include repurposed drugs, some with cardiac liabilities. We report on a chronic preclinical drug screening platform, a cardiac microphysiological system (MPS), to assess cardiotoxicity associated with repurposed hydroxychloroquine (HCQ) and azithromycin (AZM) polytherapy in a mock phase I safety clinical trial. The MPS contained human heart muscle derived from induced pluripotent stem cells. The effect of drug response was measured using outputs that correlate with clinical measurements, such as QT interval (action potential duration) and drug‐biomarker pairing. Chronic exposure (10 days) of heart muscle to HCQ alone elicited early afterdepolarizations and increased QT interval past 5 days. AZM alone elicited an increase in QT interval from day 7 onward, and arrhythmias were observed at days 8 and 10. Monotherapy results mimicked clinical trial outcomes. Upon chronic exposure to HCQ and AZM polytherapy, we observed an increase in QT interval on days 4–8. Interestingly, a decrease in arrhythmias and instabilities was observed in polytherapy relative to monotherapy, in concordance with published clinical trials. Biomarkers, most of them measurable in patients’ serum, were identified for negative effects of monotherapy or polytherapy on tissue contractile function, morphology, and antioxidant protection. The cardiac MPS correctly predicted clinical arrhythmias associated with QT prolongation and rhythm instabilities. This high content system can help clinicians design their trials, rapidly project cardiac outcomes, and define new monitoring biomarkers to accelerate access of patients to safe coronavirus disease 2019 (COVID‐19) therapeutics.
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影响因子：
5.6
作者：
Jæger KH;Charwat V;Wall S;Healy KE;Tveito A
通讯作者：
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影响因子：
15.1
作者：
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影响因子：
4.6
作者：
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通讯作者：
Healy KE
DOI：
10.1016/j.ijantimicag.2020.105949
发表时间：
2020-07-01
影响因子：
10.8
作者：
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通讯作者：
Raoult, Didier
影响因子：
4.9
作者：
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通讯作者：
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