Off-target drug effects on platelet function: Protecting an Achilles heel of drug development

IF 4.6 Current opinion in toxicology Pub Date : 2019-10-01 DOI:10.1016/j.cotox.2019.09.004

James D. McFadyen , Himawan Fernando , Karlheinz Peter

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引用次数: 1

Abstract

The development of new drugs is often limited or even halted by their side effects on platelet number or function. This review introduces the signalling pathways and the role of various platelet receptors, such as GPIIb/IIIa, GPIb-IX-V, GPVI and P-selectin. The large scope of platelet function tests are described, including aggregometry, flow cytometry, VerifyNow, adhesion and in vivo thrombosis and haemostasis assays. Several important examples of drugs that have off-target effects influencing platelet function are discussed, including GPIIb/IIIa inhibitors, oligonucleotides, BH3 mimetics and Bruton tyrosine kinase inhibitors. Finally, challenges for future drug development with regards to platelet function are outlined, including the conclusion that no single assay can fully predict drug effects and thus a combination of platelet function tests is often required to assess platelet function in the context of newly developed therapeutics.

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脱靶药物对血小板功能的影响:保护药物开发的致命弱点

新药的开发常常因其对血小板数量或功能的副作用而受到限制甚至停止。本文综述了血小板受体GPIIb/IIIa、GPIb-IX-V、GPVI和p -选择素等的信号通路及其作用。描述了大范围的血小板功能测试，包括聚集、流式细胞术、VerifyNow、粘连和体内血栓形成和止血试验。本文讨论了几种具有脱靶效应影响血小板功能的药物，包括GPIIb/IIIa抑制剂、寡核苷酸、BH3模拟物和布鲁顿酪氨酸激酶抑制剂。最后，概述了未来药物开发中血小板功能方面的挑战，包括没有单一的检测方法可以完全预测药物作用的结论，因此在新开发的治疗方法中，通常需要结合血小板功能测试来评估血小板功能。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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