摘要
目的采用三段式幼龄动物试验(JAS)系统考察馥感啉口服液(FGLOL)在幼龄SD大鼠长期给药后的潜在发育毒性和延迟毒性。方法第一阶段:根据1岁内婴幼儿临床拟用剂量,每天分别ig给予出生后4日龄(PND4)大鼠FGLOL 3.88,11.64和38.75 g·kg^(-1),共18 d,停药恢复3周。第二阶段:根据1~6岁儿童临床拟用剂量,分别ig给予PND15大鼠FGLOL 3.88,11.64和38.75 g·kg^(-1),共31 d,停药恢复3周。第三阶段:根据7~12岁儿童临床拟用剂量,每天分别ig给予PND40大鼠FGLOL 29.06,58.13和116.25 g·kg^(-1)共66 d,停药恢复4周。上述试验均设溶剂对照组,ig给予等体积纯水。考察FGLOL对幼龄大鼠一般状况、摄食量、体重、生长发育、神经反射发育、学习记忆功能(总运动距离,中心、角落和边缘运动距离,潜伏期,工作记忆错误和参考记忆错误)、体格发育(体长)、骨骼发育(骨密度)、血液学(白细胞数、红细胞数和血小板数)和凝血、血液生化(谷氨酸脱氢酶、尿素氮和甘油三酯)以及组织病理变化等的影响。结果三段式JAS中,ig给予FGLOL均未造成大鼠死亡。与溶剂对照组相比,FGLOL组大鼠一般状况无异常,体重、生长发育、神经反射发育、体格发育、骨骼发育、血液学和凝血、血液生化以及组织病理等变化均未见有毒理学意义差异。结论FGLOL对相当于人类<6岁年龄段幼龄大鼠的JAS试验的未见不良反应剂量(NOAEL)为38.75 g·kg^(-1),对相当于人类7~12岁年龄段幼龄大鼠JAS和重复给药毒性试验的NOAEL为116.25 g·kg^(-1)。
OBJECTIVE To investigate the potential developmental toxicity and delayed toxicity of Fuganline oral liquid(FGLOL)after long-term administration in juvenile SD rats via a three-stage juve⁃nile animal study(JAS).METHODS Stage 1:according to the proposed clinical dose for infants within one year of age,FGLOL 3.88,11.64,38.75 g·kg^(-1)was orally administered to rats of postnatal day 4(PND4)rats for 18 days,and the drug was stopped for 3 weeks.Stage 2:according to the proposed clinical dose for children ages 1 to 6,FGLOL 3.88,11.64,38.75 g·kg^(-1)was orally administered to PND15 rats for 31 d,and the drug was discontinued for 3 weeks.Stage 3:according to the proposed clinical dose for children aged 7 to 12,FGLOL 29.06,58.13,116.25 g·kg^(-1)was orally administered to PND40 rats for 66 d,and the drug was stopped for 4 weeks.The effects of FGLOL on health status,food intake,body mass,growth and development,nerve reflex development,learning and memory ability,physical development(body length),bone development(bone mineral density),hematology and coagulation(white blood cells,red blood cells and platelet count),blood biochemistry(glutamate dehydrogenase,urea nitrogen and triglycerides)and histopathology were investigated in young rats.RESULTS In the three-stage JAS test,long-term administration of FGLOL did not cause rat death,and no toxicological effects were observed on body mass,growth and development,nerve reflex development,physical development,bone development,hematology and coagulation,blood biochemistry and histopathology of juvenile rats compared with the vehicle control group.CONCLUSION The no observed adverse effect level(NOAEL)of FGLOL is 38.75 g·kg^(-1)for the JAS test corresponding to humans between 1 and 6 years old,while the NOAEL of FGLOL is 116.25 g·kg^(-1)for the JAS test and repeated drug toxicity test corresponding to humans aged 7 to 12.
作者
郭健敏
张文强
邓应华
蒙飞彪
梁纯
杨威
GUO Jianmin;ZHANG Wenqiang;DENG Yinghua;MENG Feibiao;LIANG Chun;YANG Wei(Guangzhou Bay Area Institute of Biomedicine,Guangdong Lewwin Pharmaceutical Research Institute Co.,Ltd.,Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and Research,TCM Non-clinic Evaluation Branch of National Engineering Research Center for Modernization of Traditional Chinese Medicine,Guangdong Engineering Research Center for Innovative Drug Evaluation and Research,Guangzhou 510990,China;Division of Life Sciences,Hong Kong University of Science and Technology,Hongkong 999077,China)
出处
《中国药理学与毒理学杂志》
CAS
北大核心
2023年第12期895-903,共9页
Chinese Journal of Pharmacology and Toxicology
基金
国家科技重大专项(2018ZX09721003-009-025)
广东省实验室建设项目(2023B1212070029)
广东省领军人才工程项目(210183503006)
广东省重点领域研发计划(2020B1111030005)。
关键词
馥感啉口服液
幼龄动物试验
幼龄大鼠
发育毒性
Fuganlin oral liquid
juvenile animal study
juvenile rats
developmental toxicity
