间充质干细胞注射液关节腔及静脉单次注射给药急性毒性及局部刺激性  

Local irritation and acute toxicities of mesenchymal stem cell injection following single intra-articular injection and intravenous injection

作　　者：侯衍豹 肖海蓉 康玮 张海娇 付合明 刘冰 张金晓 HOU Yan-bao;XIAO Hai-rong;KANG Wei;ZHANG Hai-jiao;FU He-ming;LIU Bing;ZHANG Jin-xiao(Tianjin Tiancheng Drug Assessment Co.,Ltd.,Tianjin 300301,China;Tianjin Engineering Research Center for Drug Preclinical Assessment Technology,Tianjin 300301,China;Research Unit for Drug Metabolism,Chinese Academy of Medical Sciences,Tianjin Institute of Pharmaceutical Research,Tianjin 300301,China;State Key Laboratory of Drug Delivery Technology and Pharmacokinetics,Tianjin Institute of Pharmaceutical Research,Tianjin 300301,China;BoyaLife Group Ltd.,Wuxi 214000,China)

机构地区：[1]天津天诚新药评价有限公司,天津300301 [2]天津市新药非临床评价技术工程中心,天津300301 [3]中国医学科学院药物代谢新技术创新单元,天津300301 [4]释药技术与药代动力学国家重点实验室,天津300301 [5]博雅干细胞科技有限公司,无锡214000

出　　处：《中国药理学与毒理学杂志》2023年第3期185-190,共6页Chinese Journal of Pharmacology and Toxicology

基　　金：天津市科技计划项目(17ZXXYSY00020);中国医学科学院医学与健康科技创新工程项目资助(2019-I2M-5-020)。

摘　　要：目的 选取兔和大鼠,通过关节腔及静脉单次注射评价间充质干细胞(MSC)注射液的急性毒性及刺激性,以期为其临床安全用药提供参考依据。方法 (1)急性毒性试验:SD大鼠,关节腔注射和静脉注射MSC注射液(给药剂量分别为5.0×107和1.0×108kg^(-1)),单次给药,同时设正常对照组,每组10只,雌雄各半,给药后观察30 d。试验期间每日进行1次临床观察,给药前(d 0)及给药后d 1(给药当天),3,7,14,21和28测体重,恢复期结束次日(d 31)解剖,对体表及皮下、头部、颈部、胸腔及胸腔脏器、盆腔及盆腔脏器、腹腔及腹腔脏器及给药部位等采用肉眼逐项进行详细大体观察。(2)刺激性试验:4只日本大耳白家兔,雌雄各半,采用同体左右侧对比法分为正常对照侧和给药侧,用关节腔注射及静脉注射(给药剂量分别为4.0×106和6.0×106kg^(-1))单次给药,给药后观察14 d。试验期间每日观察全身及注射部位,d 3和d 14进行解剖检查及组织病理学检查。结果 (1)急性毒性:与正常对照组相比,静脉注射给药组SD大鼠临床观察和体重均未见明显异常;关节腔注射给药组出现给药侧后肢蜷缩,呈跛行,并给药部位逐渐出现膝关节肿胀,恢复期后可陆续恢复;关节腔注射给药组雄性大鼠给药后d 1和d 3体重显著降低(P<0.05),其余各检查时间点平均体重无明显差异,雌性大鼠体重无差异。试验期间无动物死亡;静脉注射及关节腔注射组动物解剖检查均无异常。(2)刺激性试验:与正常对照侧比较,关节腔注射给药家兔膝关节周围组织可见明显的充血、红肿,经恢复期可陆续恢复;3 d解剖检查可见关节腔内有淡粉色浓稠积液溢出,组织病理学检查可见滑膜中度病变,对局部组织有一定的刺激性;14 d,病变程度明显减轻,但未完全恢复正常。静脉注射给药组家兔临床观察及组织病理学检查均未见明显异常。结论 大鼠单次关节腔及静脉注射给�OBJECTIVE To evaluate the acute toxicity(in rats)and irritation(in rabbits)of mesenchymal stem cell injection by single intra-articular injection and intravenous injection so as to provide reference for clinical safety use.METHODS①Acute toxicity test:SD rats were administered by intraarticular injection and intravenous injection(the doses were 5.0×107 kg-1 and 1.0×108 kg-1,respectively).SD rats were randomly divided into 4 groups including two blank control groups with different routes of administration(n=10 in each group).SD rats were allowed to recover for 30 d after administration of a single dose.Clinical observation was conducted once a day during the trial.On the day before administration(d 0)and 1,3,7,14,21 and 28 d after administration,the body mass was recorded,anatomy was performed the next day after recovery(d 31),and detailed gross observation was carried out of the body surface and subcutaneous tissues,head,neck,chest and thoracic organs,pelvic and pelvic organs,abdominal cavity and abdominal organs,and drug administration sites with naked eyes.②Irritation test:using isomorphism(left-right)contrast method,four Japanese white rabbits(half male and half female)were divided into two groups(the control group and the administration group).Both were administered by intra-articular injection and intravenous injection(the doses were 4.0×106 kg-1 and 6.0×106 kg-1,respectively).Rabbits were allowed to recover for 14 d after administration of a single dose.The whole body and the injection sites were observed once a day during the test.Anatomic and histopathological examinations were performed at the end of 72 h and 14 d restoration.RESULTS①Acute toxicity:No obvious abnormalities were observed during body mass examination and clinical observation of SD rats with intravenous injection.In the intra-articular injection group,the hind limbs of the administration side were cured up and limped,and knee joint swelling at the administration site gradually appeared,which recovered in succession during recovery.

关 键 词：间充质干细胞注射液 关节腔注射 静脉注射 急性毒性 刺激性 

分 类 号：R99[医药卫生—毒理学]