ZeGlobalTox: An Innovative Approach to Address Organ Drug Toxicity Using Zebrafish.
ZeGlobalTox: An Innovative Approach to Address Organ Drug Toxicity Using Zebrafish.
复制标题
DOI：
10.3390/ijms18040864
复制
发表时间：
2017-04-19
影响因子：
5.6
通讯作者：
Terriente J
中科院分区：
文献类型：
--
作者：
Cornet C;Calzolari S;Miñana-Prieto R;Dyballa S;van Doornmalen E;Rutjes H;Savy T;D'Amico D;Terriente J
毒性是药物开发过程中的主要损耗原因之一。在这方面，心脏、神经和肝脏毒性是临床阶段药物退役和上市后撤回的主要原因。斑马鱼在高通量药物筛选中的应用正成为评价新药毒性和疗效的重要工具。从生理学角度来看，该动物模型从早期发育阶段就具有功能齐全的器官。因此，可以在幼虫阶段检测到药物诱导的器官毒性，从而对可能的人类药物诱导的责任具有较高的预测能力。因此，斑马鱼可以以快速且具有成本效益的方式弥合临床前体外安全性测定和啮齿动物模型之间的差距。ZeGlobalTox是一种创新的检测方法，它在同一动物中依次整合了体内心脏、神经和肝脏毒性评估，从而对3Rs原则产生了强烈的影响。它减少了多达三分之一的动物数量，需要评估这些器官的毒性。它通过新的生理参数来改进药物毒性评价。最后，由于其高预测性（特异性：89%，灵敏度：68%，准确度：78%），它可能允许替代经典物种，如啮齿动物和大型哺乳动物。
Toxicity is one of the major attrition causes during the drug development process. In that line, cardio-, neuro-, and hepatotoxicities are among the main reasons behind the retirement of drugs in clinical phases and post market withdrawal. Zebrafish exploitation in high-throughput drug screening is becoming an important tool to assess the toxicity and efficacy of novel drugs. This animal model has, from early developmental stages, fully functional organs from a physiological point of view. Thus, drug-induced organ-toxicity can be detected in larval stages, allowing a high predictive power on possible human drug-induced liabilities. Hence, zebrafish can bridge the gap between preclinical in vitro safety assays and rodent models in a fast and cost-effective manner. ZeGlobalTox is an innovative assay that sequentially integrates in vivo cardio-, neuro-, and hepatotoxicity assessment in the same animal, thus impacting strongly in the 3Rs principles. It Reduces, by up to a third, the number of animals required to assess toxicity in those organs. It Refines the drug toxicity evaluation through novel physiological parameters. Finally, it might allow the Replacement of classical species, such as rodents and larger mammals, thanks to its high predictivity (Specificity: 89%, Sensitivity: 68% and Accuracy: 78%).