【摘要】 目的研究重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白(TNFR-Fc)对大鼠的长期毒性。方法将120只大鼠随机分4组,各30只:TNFR-Fc低剂量组(5 mg.kg-1)、中剂量组(15 mg.kg-1)和高剂量组(45 mg.kg-1)和溶媒对照组(溶媒2.0 mL.kg-1)。每只大鼠每100 g体重给药的容量0.2 mL。途径:sc,给药期:180 d。每周给药2次。给药90,180 d和停药后30 d,分别观察一般临床体征,检测11项血液指标、10项血液生化指标和24项器官或组织病理检查,测定抗体和抗体中和能力。结果一般体征和血液学及临床生化指标在实验组与对照组之间未见明显改变。实验组自第4周开始有大鼠产生抗体,第8周所有用药大鼠均产生抗体,各剂量组均未产生中和抗体。病理组织学检查发现给药各组动物的肝、肾有轻重不等的瘀血和轻度细胞水肿;可能为受试大鼠自身感染性病变或动物处死及组织处理过程产生的人为性损害。肺脏病变有灶性或片块分布的肺泡腔内出血,是由于动物处死挣扎所致。结论各剂量组大鼠均未出现明显的由药物导致的生理生化改变和病理损害,也未发现明显的毒性反应,各组大鼠抗体均无中和TNFR-Fc活性能力,大鼠皮下注射TNFR-Fc的安全剂量为45 mg.kg-1。更多还原

【Abstract】 Objective To study the long term toxicity of recombinant human tumor necrosis factor receptor class Ⅱ-antibody confused protein（TNFR-Fc） in rats. Methods Animals were randomly divided to receive twice weekly dose of 0,5,15 or 45 mg·kg^-1 of TNFR-Fc given by sc for 180 days.General clinic signs,11 hematological indices,10 blood biochemical indices,specific antibodies,and 24 pathological exams of organs were observed at 90,180, 210 days. Results The general signs,all hematological and biochemical indices between treatment and control groups had no significant change.Specific antibodies in all TNFR-Fc groups began to appear from the 4^th week.All TNFR-Fc groups didn’t produce any neutralizing antibody.Histopathological examination showed that there were hepatic and renal blood stases and mild cell edema of some animals in each group.Perhaps these were induced by silent infection in animals. Conclusion There isn’t any seriously biochemical or pathological damage and toxicity reaction found in TNFR-Fc groups.All the antibodies produced in rats can’t neutralize TNFR-Fc activity.The safety dosage of TNFR-Fc for rats is 45 mg·kg^-1.更多还原