论文部分内容阅读
随着3Rs原则的实施,药物非临床生殖发育毒性研究中的整体动物试验面临严重挑战,体外替代研究逐步成为研究热点。生殖发育毒性周期长,涵盖面广,现有的任何一种体外方法无法全面模拟药物在体内作用的全过程,无法全面反映其对于生殖发育周期中性成熟、受精、配子发生、合子发育、出生后发育及性功能等方面的影响。形成一套完整的生殖发育毒性体外替代法评价是解决体外替代法预测结果接近体内检测结果的关键,在整合体外替代研究时,应考虑体细胞与生殖细胞,不同进化阶段的物种,多个生殖毒性周期,体内外代谢活化差异等因素。根据受试物特性、分布、用途、适用范围,其他毒理学实验及毒代动力学资料,技术水平,管理部门的要求等特点进行实验设计,通过一系列反应不同试验终点的组合实验(Integrated testing strategy,ITS)综合评定药物体外生殖发育毒性,但目前尚无最合理的组合方案。对生殖发育毒性体外试验研究进展及应用策略需考虑要点进行综述,以推动替代技术在药物非临床安全性评价中的应用。
With the implementation of the 3Rs principle, overall animal testing in non-clinical reproductive and developmental toxicology research is facing serious challenges. In vitro replacement research has gradually become a research hotspot. Reproductive and developmental toxicity of a long cycle, covering a wide range of existing in vitro methods can not fully simulate the whole process of drug action in vivo, can not fully reflect the reproductive cycle of sexual maturation, fertilization, gametogenesis, zygotes, birth After development and sexual function and other aspects of the impact. The formation of a complete set of reproductive and developmental toxicology in vitro surrogate evaluation is the key to solve the in vitro surrogate prediction results close to the in vivo test results. When integrating in vitro surrogate studies, consideration should be given to somatic and germ cells, species at different stages of evolution, multiple reproductive Toxicity cycle, metabolic activation differences in vivo and in vitro and other factors. According to the characteristics, distribution, use, scope of application, other toxicology experiments and toxicokinetics data, technical level, management requirements and other characteristics of the experimental design, through a series of experiments that reflect the end of different combinations (Integrated testing strategy, ITS) comprehensive evaluation of reproductive and developmental toxicity of drugs in vitro, but at present there is no most reasonable combination of programs. The progress of in vitro test on reproductive and developmental toxicity and its application strategies need to be considered in order to promote the application of alternative technology in non-clinical safety evaluation of drugs.