摘要
目的依据国内外药品监管部门关于儿科用药非临床安全性评价技术指导原则要求,考察幼龄大鼠重复给予复方蒲公英制剂后的毒性反应,为儿童临床试验提供参考。方法144只幼龄(27日龄,Postnatal Day(PND)27)SD大鼠,随机分为溶媒对照组、低、中和高剂量组,每组36只,雌雄各半,分别每天灌胃(ig)给予纯水、复方蒲公英制剂1.2、3.8、12 g/kg,给药体积均为1 mL/100 g,每天2次,连续给药4周(28 d),恢复观察4周;于给药结束、恢复期结束检查时每组雌雄分别剖检10/18只、8/18只的动物。检测指标包括:常规毒性指标、生长发育、骨骼发育、行为学、性激素、免疫系统发育等。结果高剂量(12 g/kg)组大鼠出现流涎,雄性体重及顶臀长增长减缓、摄食量降低,以及红细胞系部分指标异常(红细胞、血红蛋白降低,网织红细胞升高等),血清生化学部分脂代谢、糖代谢相关指标异常(总胆固醇、甘油三酯、血糖下降),部分尿液指标异常(酮体、蛋白质、白细胞、比重、pH值、微白蛋白升高),脾重量及系数升高,雄鼠IgG升高;脾、肝轻微/轻度髓外造血以及骨髓红系造血细胞轻度增生等,上述现象均在给药结束4周后恢复正常;对性征发育、骨骼系统发育、生长激素、行为记忆、眼科、性激素、骨髓细胞形态学等指标均未见明显毒性影响;中、低剂量组未见明显毒性影响。结论在本剂量条件下,复方蒲公英制剂对幼龄大鼠(PND27~PND54)未观察到不良作用剂量(NOAEL)为3.8 g/kg;高剂量(12 g/kg)有一定的可逆性的毒性影响,主要毒性靶组织为血液红细胞。
Objective According to the technical guidelines for non-clinical safety evaluation of pediatric drugs by both domestic and foreign drug regulatory authorities,this study regarding repeated dose toxicity of compound Taraxacum mongolicum extract(CTME)in juvenile rats was performed to provide reference for clinical trials.Methods One hundred and forty-four juvenile Sprague-Dawley rats(postnatal day(PND)27)were randomly divided into four groups with 18 of each gender per group.The rats were orally administered twice daily with CTME at doses of 0,1.2,3.8,12 g/kg for 4 weeks in a dosage volume of 1 mL/100 g.Eighty rats were necropsied after the last administration,and the remaining animals were observed for 4 weeks after drug cessation.Test indicators included routine toxicology indexes,growth development,skeletal development,behavioral testing,sex hormones and immune system development.Results In the high dose group,the male juvenile rats slowly grew,reduced food intake and the juvenile rats of both genders demonstrated salivation,some changes in hematology(decreased red blood cell count and hemoglobin levels,increased numbers and percentage of reticulocytes),biochemistry(decreased total carbohydrates,triglycerides and glucose levels),urine(increased ketones,protein,leukocytes,specific gravity,p H and microalbumin),immunology(increased spleen weight and coefficient,and increased IgG in male rats),mild extramedullary hematopoiesis in spleen and liver,and mild proliferation of erythroid hematopoietic cells in bone marrow.The influence could be reversed after 4 weeks of withdrawal.There were no obvious toxic effects on sexual development,skeletal development,growth hormone,behavior,memory,ophthalmology,sex hormones,or bone marrow cell morphology.No significant toxic effects were observed in the middle or low dose groups.Conclusions Under these test conditions,the no observed adverse effect level(NOAEL)of CTME in juvenile rats(PND27~PND54)was 3.8 g/kg.However,a dose of 12 g/kg resulted in reversible changes in some indexes,with red blood cells being the main toxicity target.
作者
张城达
宋翼升
扈荣
白海波
谢锋
黄敏聪
陈云祥
郑高利
张立将
ZHANG Chengda;SONG Yisheng;HU Rong;BAI Haibo;XIE Feng;HUANG Mincong;CHEN Yunxiang;ZHENG Gaoli;ZHANG Lijiang(Center of Safety Evaluation,Zhejiang Academy of Medical Sciences,Hangzhou 310053,China;Drug R&D institute of HZ HD Pharm,Hangzhou 310005)
出处
《中国比较医学杂志》
CAS
北大核心
2020年第2期33-42,共10页
Chinese Journal of Comparative Medicine
基金
浙江省基础公益研究计划项目(LGF18H310004)
浙江省实验动物科技计划项目(2018C37127).
关键词
儿科药物
复方蒲公英制剂
幼龄动物实验
重复给药毒性
paediatric drugs
compound Taraxacum mongolicum extract
juvenile animal study(JAS)
repeated dose toxicity
作者简介
张城达(1983—),男,助理研究员,在读硕士研究生,研究方向:药物安全性评价研究。E-mail:zcdhd@163.com;通信作者:张立将(1981—),男,研究员,博士,研究方向:药物毒理学研究和评价。E-mail:zhanglj127@163.com
