如何成功开展药物非临床生殖毒性试验  

How to successfully carry out nonclinical reproductive toxicity study on new drugs

作　　者：孙祖越[1] 周莉[1] 闫晗[1] 何桂林[1] 

机构地区：[1]上海市计划生育科学研究所药理毒理学研究室,中国生育调节药物毒理检测中心,上海200032

出　　处：《中国新药杂志》2011年第22期2195-2204,共10页Chinese Journal of New Drugs

基　　金：国家“重大新药创制”科技重大专项(2011ZX09301-005);上海市实验动物创新行动计划项目(09140900500);上海市人才发展基金(2010031)

摘　　要：本文围绕如何成功开展药物非临床生殖毒性试验展开讨论,认为:①在大鼠生育力与早期胚胎发育毒性试验(Ⅰ段)中,应该选用年轻、性成熟的成年动物,雌性动物需未经产;雄鼠交配前给药期限超过9周比较稳妥;不建议利用医院使用的人类精子质量分析系统,人工镜检或动物精子分析系统都可行,后者较客观。②在胚胎-胎仔发育毒性试验(Ⅱ段)中,一般不建议采用从饲养场购买的孕兔开展研究;交配笼的使用有利于提高实验用兔的交配成功率。③在围产期毒性试验(Ⅲ段)中,受试物为生育调节和细胞毒性药物时,应该观察到F2代的行为,甚至F2代生育力和F3代的行为,以检测生殖毒性有可能的延续性;应避免F1代的"兄妹(或姐弟)"交配。④选择在易发情季节,挑选性成熟的动物,特别是在Ⅱ和Ⅲ段试验中选用有交配经验的雄性动物,是提高实验动物交配成功率的主要关键点。最好设立阳性对照组,增加激素水平的检测,如雌、雄激素等。适当增加与性功能、性活动有关的检测指标以及对于生殖相关的器官进行组织病理学检查。这些都是能够成功开展药物非临床生殖毒性试验的关键技术。This paper focused on how to successfully carry out nonclinical reproductive toxicity study on drugs.The following issues are principally argued.① In the rat fertility and early embryonic development toxicity test（I section）,sexually mature young adult animals and nulliparous female animals should be selected.Male drug administration period more than nine weeks is more reliable before mated.The use of hospital human sperm quality analysis system is not recommended;manual microscopy or animal sperm analysis system is feasible,however the latter is more objective.② In the embryo-fetal developmental toxicity study（II section）,pregnant rabbits purchased from farms are generally not recommended for research;the use of mating cage is helpful to improve the rabbit mating success.③ In pre-and postnatal toxicity tests（III section）,in order to detect possible continuity of reproductive toxicity,for test targets that are fertility regulation and cytotoxic drugs the behavior of the F2 generation should be observed,and even the F2 and F3 generations of fertility behavior;＂brothers and sisters（or siblings）＂ mated of F1 should be avoided.④ The selection of sexually mature animals in rut season,especially in sections II and III trial experience in the selection of mating male animals,is the key point to improve the animal mating rate of success.It is highly recommended to establish positive control group and append hormone level testing,such as male and female hormones.More testing on sexual function,sexual activity and the detection of targets related to the reproductive organs and histopathological examination is suggested.These are the key technology to the successful conduction of clinical reproductive toxicity test on drugs.

关 键 词：非临床 生殖毒性 关键技术 药物生殖毒理学 

分 类 号：R965.1[医药卫生—药理学]