重组人促红素注射液(CHO细胞)食蟹猴重复给药毒性试验研究  

Study on repeated administration toxic effect of recombinant human erythromycin injection(CHO cells)in cynomolgus monkey

作　　者：吴玉娥[1] 贾欢欢[1] 李云峰 李航[1] 高洪彬 龚宝勇[1] 罗挺[1] 刘晓霖[1] 梁十 黄仨 凌雪荧 郭扬清 麦冬梅 刘婵 曾业文 梁金强 关业枝[1] WU Yu'e;JIA Huanhuan;LI Yunfeng;LI Hang;GAO Hongbin;GONG Baoyong;LUO Ting;LIU Xiaolin;LIANG Shi;HUANG Sa;LING Xueying;GUO Yangqing;MAI Dongmei;LIU Chan;ZENG Yewen;LIANG Jinqiang;GAUN Yezhi(Guangdong Laboratory Animals Monitoring Insitute,Guangzhou 510663,China)

机构地区：[1]广东省实验动物监测所,广东省实验动物重点实验室,广东广州510663

出　　处：《药物评价研究》2020年第7期1289-1293,共5页Drug Evaluation Research

基　　金：广东省科技计划项目(2017B020231001、2017A070701003、2017A070702001)。

摘　　要：目的研究重组人促红素注射液(CHO细胞)对食蟹猴的长期毒性,预测各组织器官的潜在毒性反应。方法18只普通级成年食蟹猴根据体质量随机分为阴性对照组(生理盐水)和重组人促红素注射液(CHO细胞)低(每周500 IU/kg)、高剂量(每周1500 IU/kg)组,每组6只,雌雄各半;受试品经后肢大腿外侧sc注射给药,每周3次,连续4周;给药结束后,每组处死4只动物(雌雄各半),其余动物停药后进行4周恢复期观察;观察指标包括动物外观体征、行为活动、精神状态等情况,并进行体质量、体温、眼科、心电图、血常规、凝血指标、血生化、免疫细胞检测及组织病理学检查。结果在8周观察期内,各组动物外观体征、行为活动、精神状态、体质量、体温、眼科、心电图、凝血指标、血生化、大体解剖等均未见异常;血常规检查发现,与阴性对照组比较,受试品低、高剂量组红细胞(RBC)、网织红细胞(RET)、血红蛋白(HGB)、红细胞压积(HCT)、血小板数(PLT)给药后显著升高(P<0.05),淋巴细胞数(LYMPH)显著降低(P<0.05),停药4周后RET、PLT及LYMPH恢复正常水平,而RBC、HGB及HCT仍维持较高水平;免疫细胞检查发现,与阴性对照组比较,给药4周后高剂量组CD3+T细胞比例显著减少,4周后恢复正常水平;病理检查发现,高剂量组3只动物出现股骨骨髓轻度红系增生。结论给予食蟹猴每周1500 IU/kg(相当于10倍临床剂量)重组人促红素注射液(CHO细胞)未发现明显毒性反应,血常规指标及病理学的改变与其药理作用相关。Objective To study the four week repeated dose toxicity of recombinant human erythromycin injection(CHO cells)in cynomolgus monkey.Methods Eighteen monkeys were randomly divided into three groups(six each,half male and half female)to receive the dose of 0,500,1500 IU/kg of EPO by sc injection three times a week for four weeks.On dosing termination,one third of the animals in each group were left to observe four weeks recovery.Daily observation of animal appearance and sign,behavior and mental state were carried out.And body weights,body temperature,ophthalmology,ECG,hematology,clinical chemistry,T lymphocyte subset and histopathology were examined in different points in administration period and recovery period.Results No abnormalities were found in the exarninations of clinical symptoms,body weight,body temperature,opthalmology,ECG,coagulation index,clinical chemistry and gross anatomy.RBC,RET,HGB,HCT and PLT were observed signifieantly increased and LYMPH obviously decreased in high and medium dose groups after four weeks dosing as compared to control group.RET and PLT returned to normal level and RBC,HGB and HCT remained at a high level after four weeks recovery.The proportion of CD3+T cells decreased significantly in high dose groups and returned to normal level after 4 weeks recovery,the mild erythroid hyperplasia of femur were abserved in high dose group in three animals after 4 weeks dosingon histopathology exarnination.Conclusion The dose of 1500 IU/kg of Recombinant human erythromycin injection(CHO cells)for 4 weeks shows no obvious toxic effect in cynomolgus monkey.The changes of hematology and pathology are related to their pharmacological effects.

关 键 词：重组人促红素注射液(CHO细胞) 食蟹猴 重复给药毒性试验 

分 类 号：R965.3[医药卫生—药理学]