重组人尿激酶原急性毒性和长期毒性的研究  

Acute and Chronic Toxicology of Recombinant Human Prourokinase

作　　者：张培祥[1] 刘蓓钫[2] 方泰慧[1] 张菁[2] 徐立[1] 陈于红[2] 罗炳辉[1] 孙自勇[2] 杨世华[1] 朱德煦[2] 刘建宁[2] 

机构地区：[1]南京中医药大学药理教研室,南京210029 [2]南京大学分子医学研究所,南京210093

出　　处：《南京大学学报（自然科学版）》2001年第4期458-472,共15页Journal of Nanjing University（Natural Science）

摘　　要：(1)重组人尿激酶原 (prouk)单剂量分别经静脉和腹腔注射给药均未测出小鼠的LD50 ,因此改作其最大给药量 .结果表明 ,prouk单剂量经静脉及腹腔注射给药小鼠的最大给药量不低于 9,0 0 0万IU /kg .(2 ) prouk 36 .0万IU/kg、6 7.5万IU/kg、135 .0万IU/kg和 2 70 .0万IU/kg四个剂量组连续给食蟹猴静脉滴注 14d ,每组 4只猴 ,雌雄各半 .实验过程中未见动物死亡 .prouk 36 .0万IU/kg剂量组的食蟹猴给药期及恢复期 ,精神状态良好 ,一般行为活动正常 ,体重、分泌物、食欲及摄食量、心电图、血常规、血液生化、体表观察、尿常规和粪便隐血试验等基本正常 ,无明显变化 .给药第 14天和恢复期的脏器系数与病理组织学检查表明 ,动物的脏器、组织均未见由药物引起的异常病理改变 ,与生理盐水组或赋形剂组之间比较均无明显差异 .而prouk 6 7.5万IU/kg、135 .0万IU/kg、2 70 .0万IU /kg剂量组的食蟹猴出现皮下出血、充血、紫癜、尿、粪便隐血反应阳性、贫血以及心率加快等症状 .给药期及恢复期 ,血清中检测出少量prouk抗体 .结果表明 ,prouk的无毒安全剂量不低于 36 .0万IU/kg .Since the medial lethal dose (LD 50 ) of rhprouk was not detected from either a single intraceous injection or an intraperitiounal one the lethal dose (LD) of rhprouk was investigated in mice. Our data indicates that the LD was above 9×10 7 IU/kg via either a single intravenous injection or a single intraperitoneal injection of rhpro-UK in mice. In four random assigned groups of monkeys (2 males and 2 females in each group), rhprouk was infused intravenously for 14 days at a daily dose of 3.6×10 5 IU/kg, 6.75×10 5 IU/kg, 13.5×10 5 IU/kg, and 27×10 5 IU/kg respectively. No monkey was found dead during the experiment. During the treatment and recovery periods of the dose group of 3.6×10 5 IU/kg rhprouk, the behavior and motor activities of monkey subjects were normal. The body weight, excretion, food intake, ECG, blood status, skin observation, urine and feces examination did not change significantly after the drug application. Compared with the control group receiving saline or vehicle treatments, there was no pathological changes caused by drugs in the organ and tissue samples of the experimental subjects in the 14 day rhprouk treatment period. However, in dose groups of 6.75×10 5 IU/kg, 13.5×10 5 IU/kg, and 27×10 5 IU/kg, we observed the drug related subcutaneous hemorrhage, congestion, purpura, positive feces and urine blood test, anemia and tachycardia in experimental subjects. The immunological examination revealed that a minor amount of prouk antibody was detected in the serum during the treatment and recovery period. Therefore our data indicated that the sub lethal dose of rhprouk was no lower than 3.6×10 5 IU/kg.

关 键 词：重组人尿激酶原 急性毒性 长期毒性 溶栓药物 毒性反应 安全剂量 

分 类 号：R972[医药卫生—药品] R994.1[医药卫生—药学]