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目的观察重组人白介素-1受体拮抗剂(rhIL-1Ra)的毒性靶器官及毒性的严重程度。方法32只成年恒河猴分为rhIL-1Ra 2mg/(kg·d)(n=6)、10mg/(kg·d)(n=6)和50mg/(kg·d)(n=6)连续给药90天组,10mg/(kg·d)(n=4)连续给药30天组,正常对照组(n=5)和溶剂对照组(n=5)。rhIL-1Ra为皮下注射给药,每日1次。观察指标包括一般药物反应、尿八项、心电图、眼底检查、外周血细胞计数及白细胞分类、凝血时间、血清生化、外周血T细胞亚群和猴抗rhIL-1Ra抗体测定、脏器重量和脏器系数、常规病理组织学检查。结果给药后30天各给药组动物血清非特异性抗体明显升高。rhIL-1Ra 2mg/(kg·d)组其他检测指标均未见明显地改变。rhIL-1Ra 10mg/(kg·d)组给药后90天肾小球毛细血管基底膜明显增厚,但此剂量给药时间为30天时未见任何异常。rhIL-1Ra 50mg/(kg·d)组肾小球及肾小管中蛋白性液体量多,小球毛细血管基底膜增厚更为严重,且停药30天后基底膜增厚程度仍未见明显减轻或改善。结论rhIL-1Ra的主要毒性靶器官为肾脏。2mg/(kg·d)为安全剂量,10mg/(kg·d)给药30天时为安全剂量,给药90天为恒河猴中毒性剂量,而50mg/(kg·d)为明显的毒性反应剂量,可产生难以恢复的肾脏纤维化。
Objective To observe the toxicity of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) and its toxicity. Methods Thirty-two adult Rhesus macaques were divided into rhIL-1Ra 2 mg / (kg · d) (n = 6), 10 mg / kg · d (n = 6) and 50 mg / (kg · d) The rats in the 90-day continuous administration group were administrated with 10 mg / (kg · d) (n = 4) for 30 consecutive days, normal control group (n = 5) and solvent control group (n = 5). rhIL-1Ra is administered subcutaneously once daily. Observations included general drug reaction, eight urines, electrocardiogram, fundus examination, peripheral blood cell count and leukocyte classification, clotting time, serum biochemistry, peripheral blood T cell subsets and monkeys anti-rhIL-1Ra antibody assay, organ weights and organs Coefficients, routine histopathological examination. Results The serum non-specific antibody in each administration group was significantly increased 30 days after administration. rhIL-1Ra 2mg / (kg · d) group of other test indicators have not changed significantly. The glomerular capillary basement membrane was significantly thicker at 90 days after rhIL-1Ra 10 mg / (kg · d) administration, but no abnormalities were observed at this dose of 30 days. RhIL-1Ra 50mg / (kg · d) group of glomerular and tubular protein in the liquid volume, capillary capillary basement membrane thickening more serious, and 30 days after stopping the basement membrane thickening has not yet been seen Reduce or improve. Conclusion The main target organ of rhIL-1Ra is kidney. 2mg / (kg · d) is a safe dose, 10mg / (kg · d) administered 30 days as a safe dose, administered for 90 days rhesus poisoning dose, and 50mg / (kg · d) for obvious toxicity The amount of the reaction can produce refractory kidney fibrosis.