摘要
新药研发是一个迷人的学科包括医学的各个方面,例如药理学,生物技术和化学。在人类患者中新的临床申请的有效性和安全性使得新药研发受到限制。药品监管当局为安全的新化学成分提供了不同的指导方针,必须在临床试验中严格遵守。尽管如此,各种药物在临床试验中失败或退出市场,因为与人类相关的毒性、肝毒性、神经毒性和致畸性问题。安全预测的失败是指物种特异性问题,缺乏机械的毒性数据和临床试验的不足。这些药物不仅影响人类健康,而且造成资源和时间的损失。该物种特异性问题主要利用人体细胞解决但他们的可用性是非常有限的。人类胚胎干细胞(为)和诱导多能干细胞(hiPSCs)提供无限数量的人体细胞的产生来源。毒性测试机械模型的出现为设计新的人类相关测试策略铺平了道路设计新的人类相关的测试策略,这种机械模型基于胚胎干细胞和人iPS细胞的蛋白质组学研究与转录组学,毒代动力学读数同步。在体外药代动力学研究中及在平行的导线选择和优化的时间内,这些模型的引入通过安全先导分子的选择将大大降低复合损耗率。我们专注于即将到来的胚胎干细胞和人iPS细胞的毒性试验模型和未来的角色来解决目前药物发现和开发的安全漏洞。
关键词: 多能干细胞、致畸性、毒性、肝毒性、神经毒性、新药发现、选择测试策略。
Current Medicinal Chemistry
Title:Human Embryonic and Induced Pluripotent Stem Cell Based Toxicity Testing Models: Future Applications in New Drug Discovery
Volume: 23 Issue: 30
Author(s): Vaibhav Shinde, Poornima Sureshkumar, Isaia Sotiriadou, Jurgen Hescheler, Agapios Sachinidis
Affiliation:
关键词: 多能干细胞、致畸性、毒性、肝毒性、神经毒性、新药发现、选择测试策略。
摘要: New drug discovery (NDD) is a fascinating discipline encompassing different facets of medicine, pharmacology, biotechnology and chemistry. NDD is very often restricted by efficacy or safety problems of the new clinical candidate in human patients. Drug regulatory authorities have provided various guidelines for advancement of safe new chemical entities (NCEs) in clinical trials which must be strictly followed. In spite of this, various drugs have failed in clinical trials or withdrawn from market because of human safety issues related to cardiotoxicity, hepatotoxicity, neurotoxicity and teratogenicity. The failure of safety prediction was pointed to species specificity issues, lack of mechanistic toxicity data and inadequate clinical trials. These drugs not only affect human health but also cause loss of resources and time. The species specificity issues are partially addressed by use of primary human cells but their availability is very limited. Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) offer sources for generation of an unlimited number of human somatic cells. The emergence of mechanistic models for toxicity testing with transcriptomics, proteomics along with toxicokinetics readouts based on hESCs and hiPSCs is paving the way to design new human relevant testing strategies. Introduction of these models at the timeframe of lead selection and optimization in parallel with in vitro pharmacokinetic studies will significantly reduce compound attrition rate by selection of safer lead molecules. We focused on upcoming hESCs and hiPSCs based toxicity testing models and their future role to address safety gaps of present drug discovery and development.
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Cite this article as:
Vaibhav Shinde, Poornima Sureshkumar, Isaia Sotiriadou, Jurgen Hescheler, Agapios Sachinidis , Human Embryonic and Induced Pluripotent Stem Cell Based Toxicity Testing Models: Future Applications in New Drug Discovery, Current Medicinal Chemistry 2016; 23 (30) . https://dx.doi.org/10.2174/0929867323666160627113436
DOI https://dx.doi.org/10.2174/0929867323666160627113436 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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