pUDKH基因治疗制剂临床前安全性初步分析  

Safety evaluation of pUDKH preparation for gene therapy

作　　者：哈小琴[1] 吴祖泽[2] 袁丽珍[2] 李元敏[2] 毕建进[2] 张庆林[2] 

机构地区：[1]兰州军区总医院医学实验中心,兰州730050 [2]军事医学科学院放射与辐射医学研究所,北京100850

出　　处：《军事医学科学院院刊》2006年第2期156-158,165,共4页Bulletin of the Academy of Military Medical Sciences

基　　金：国家高技术研究发展计划资助项目(2001AA217061)

摘　　要：目的:观察大鼠肌肉注射pUDKH后,出现毒性反应的时间、性质和程度,为临床毒副反应的监测和确定初始安全剂量提供依据。方法:实验设3个组,即正常对照组、pUDKH小剂量(0.63 mg/kg)和大剂量(2.50 mg/kg)组,给药途径为肌肉注射,且每只大鼠的给药方式相同,每只大鼠共给药14次,停药后观察16周。试验期间观测一般药物反应,分析尿液生化和血清生化,测定大鼠血清中抗人肝细胞生长因子(HGF)的抗体,目的基因HGF在多种组织内的分布,病理组织学检查各脏器的组织结构。结果:试验中给药组动物未见药物毒性反应,尿生化指标基本无有意义的变化,各时间点血清生化也无明显有意义的改变。各时间点血清样品中未检测到抗HGF抗体。除了注射局部的肌肉组织检测到高表达的HGF外,其他组织未见到高表达的HGF。各脏器病理学检查均未见异常改变。结论:大鼠肌注pUDKH剂量为0.63 mg/kg和2.5 mg/kg两种,分别是大鼠起始有效剂量的3倍和12.5倍,各项观测指标未见明显有意义的改变,故在本试验条件下可视2.50 mg/kg以下为安全剂量,pUDKH基因治疗大鼠肢体缺血是安全、可行的。Objective ：To investigate the primary occurrence time, character and degree of toxic reaction in rats after im injection of pUDKH, in order to supply a basis for monitoring toxic reaction and determining primary safety dosage clinically. Methods： The animals were divided into three groups： normal group, pUDKH 0. 63 mg/kg group, and pUDKH 2.50 mg/kg group, then injected intramuscularly with pUDKH for 14 times, and observed for 16 weeks after discontinuation of drug administration. During the test, the general drug reaction was observed, urine and blood biochemistry was analyzed, the antibody against human hepatocyte growth factor （HGF） and the distribution of HGF gene in tissues were examined,and the tissue morphology of main organs was observed. Results： No drug toxic reaction was observed in rats from pUDKH groups, and no significant change was found in urine and serum biochemical examination. High HGF expression was only observed in muscular tissue at the local area of im injection of pUDKH, but wasn＇t observed in the other distant tissues（including blood） and no anti-HGF antibody in serum was detected at different time points, In addition, there was no significant change in morphology of local muscle and remote tissues. Conclusion：The dosage of pUDKH injected intramuscularly to rats was 0, 63 mg/kg or 2.5 mg/kg, which was 3 or 12.5 times that of the lowest effective pUDKH dosage in rat , respectively, There was no significant change in almost all examinations, suggesting that the dosage less than 2, 50 mg/ kg was safe under this test conditions, and pUDKH gene therapy is safe and feasible for treatment of limb ischemia.

关 键 词：pUDKH 基因治疗 制剂 基因剂量 安全性 评价 

分 类 号：R96[医药卫生—药理学]