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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 observe the time, nature and degree of toxicity of pUDKH after intramuscular injection of pUDKH in rats, and provide basis for monitoring clinical side effects and determining the initial safe dose. Methods: Three groups were randomly divided into three groups: normal control group, pUDKH low dose (0.63 mg / kg) and high dose (2.50 mg / kg). The route of administration was intramuscular injection, Each rat was administered 14 times in total and observed for 16 weeks after withdrawal. General drug reactions were observed during the experiment, urine biochemical analysis and serum biochemical analysis of anti-human hepatocyte growth factor (HGF) antibody in rat serum, the distribution of the target gene HGF in a variety of tissues, histopathological examination of various organs The organizational structure. Results: There was no drug toxicity in the test group and no significant changes in biochemical parameters of urine. Serum biochemistry did not change significantly at all time points. Anti-HGF antibodies were not detected in serum samples at each time point. Except HGF, which was highly expressed in the local muscle tissues injected by injection, no other tissues showed high expression of HGF. Pathological examination of the organs showed no abnormal changes. CONCLUSION: The intramuscular injection of pUDKH is 0.63 mg / kg and 2.5 mg / kg respectively, which are 3 and 12.5 times of the initial effective dose in rats, respectively. There is no significant change in all the observed indexes Under the test conditions visual safety 2.50 mg / kg below the dose, pUDKH gene therapy of limb ischemia in rats is safe and feasible.