重组人白介素-11对猕猴的长期毒性实验

目的：观察重组人白介素-11（rhIL-11)对猕猴的长期毒性。方法：18只猕猴分别按体质量随机分为4组，高剂量组6只，余均为4只。低、中、高剂量分别为0.1、0.3和1.0mg/kg.每天sc给药1次,连续90d.停药观察30d.观察症状和检测项目有:一般状况、心电图、血液学及生化指标、尿液、免疫、骨髓、脏器质量、组织学检查。结果：所有给药组猴猴食量明显减少。体质量有所减轻，并有短暂性发热，低剂量组有1只猕猴肢全活动受限，震颤，高剂量组1只猕猴出现呕吐，1只死亡，给药组RBC、Hb、Hct、MCV、MCH和MCHC均明显降低，Plat则明显增高。ALT、SAT、LDH活性明显下降，TP和Alb含量明显下降，ALP活性明显升高，给药90d各给药组猕猴均出现抗IL-11抗体，免疫复合物也明显增高。高、中剂量组骨髓有核细胞增生明显活跃。给药组心、肝的绝对质量有增大的趋势，相对质量明显增大，给药90d时，给药组猕猴肝、肾出现明显的细胞变性，中、高剂量组重于低剂量组，停药后30d上述变化的均趋向恢复。结论：rhIL-11对猕猴的毒性靶器官及系统有：血液系统、肝脏、肾脏、肾脏、免疫系统、骨髓。其毒性损害均为可逆性。rhIL-11对猕猴的3个月长期毒性安全剂量为每次0.1mg/kg。

Long-term toxicity test of rhIL-11 in cynomolgus

Objective:To investigate the long-term toxicity of recombinant human interleukin-11(rhIL-11) in cynomolgus. Methods: Eighteen cynomolgus were randomized into 4 groups: control group(2/sex), low dose group(2/sex), medium dose group(2/sex)， and high dose group(3/sex). The drug groups were sc adminstered 0.1, 0.3 and 1.0 mg/kg of rhIL-11 for 90 days with a 30-day recovery period. The clinical signs were observed, electrocardiogram, hematological, biochemical, urinary and immunological parameters were measured, organ masses were weighed, bone marrow and pathological histology were observed. Results: The food consumption, body mass of the drug groups were decreased, the body temperature was increased transiently. One of the low dose group showed restricted movements and tremors. One of the high dose group vomited and another died. Reduced red blood cell(RBC) count, hemoglobin(Hb) concentration, hematocrit(Hct), mean corpuscular volume(MCV), mean corpuscular hemoglobin(MCH), and mean corpuscular hemoglobin concentration(MCHC), dose-related increase of platelet(Plat) counts were present in drug groups. Biochemical examinations revealed dose-related decreases in serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), lactate dehydrogenase(LDH), total proteins(TP) and albumin(Alb) increases in serum alkaline phosphatase(ALP) levels. Positive antibody responses were seen and circulatory immune complex(CIC) was significantly increased in all drug groups. Hypertropy of marrow megakaryocyocytes was noted in the medium and high dose groups. The heart and liver masses were slightly increased in all treatment groups. Treatment-related microscopic findings included dose-related degeneration in the liver and the kidney. The adverse effects were reversed by the end of the recovery period. Conclusion: The target organs and systems are blood, liver, kidney, immmue system and bone marrow. The toxicity injuries were reversible and the no-toxic-effect level is 0.1 mg/kg.