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目的探讨阿达木单抗类似药SMMU-16重复皮下注射对食蟹猴的安全性。方法 30只健康食蟹猴按体重随机分为溶媒对照组,阳性对照组,SMMU-16低、中、高剂量组,其中SMMU-16低、中、高剂量组分别给予SMMU-16 10、33、200 mg/kg,每组6只,雌雄各半。阳性对照组给予33.0 mg/kg阿达木单抗,溶媒对照组给予SMMU-16空白溶液。给药体积均为4.0 ml/kg(分4个点注射)。每周1次皮下注射给药,共给药4周,恢复期4周,期间进行各项毒理学指标检测。结果与自身给药前(d0)相比,给药期间中剂量组、高剂量组及阳性对照组的红细胞计数、Hb定量、红细胞压积(HCT)降低(P均<0.05),中、高剂量组网织红细胞比例升高(P<0.05)。骨髓检查发现SMMU-16中、高剂量组及阳性对照组食蟹猴骨髓红细胞系轻度增生。组织病理学检查发现d28时阳性对照组和高剂量组各3只、中剂量组2只动物出现胸腺萎缩和脾脏萎缩。上述变化在恢复期结束时可逐渐恢复。各组动物肝脏和肾脏未见明显病理改变。其余指标包括一般症状、呼吸、体温、瞳孔、尿液、心电图、免疫和生化指标等未见明显与供试品相关的异常变化和量效、时效关系。结论 SMMU-16主要毒性靶器官为免疫系统(胸腺和脾脏)和血液系统,毒性作用具有一定的可逆性。此毒性作用考虑与SMMU-16免疫抑制药理作用的延伸和放大有关。SMMU-16皮下注射对食蟹猴的无毒性剂量为10 mg/kg。SMMU-16与等剂量阳性对照药在本实验条件下出现的毒性反应基本类似。
Objective To investigate the safety of adalimumab-like SMMU-16 repeated subcutaneous injection in cynomolgus monkeys. Methods Thirty healthy cynomolgus monkeys were randomly divided into two groups: SMMU-16 low dose, middle dose and high dose SMMCU-16 low dose group, SMMU-16 low dose group, , 200 mg / kg, each group 6, male and female half. The positive control group was given adalimumab 33.0 mg / kg, and the vehicle control group was given SMMU-16 blank solution. The volume of administration was 4.0 ml / kg (4 injections). Subcutaneous injection administration once a week for a total of 4 weeks, recovery period of 4 weeks, during the detection of various toxicological indicators. Results The red blood cell count, Hb quantitation and hematocrit (HCT) of middle dose group, high dose group and positive control group were lower than those before dosing (d0) (all P <0.05) The proportion of reticulocytes increased (P <0.05). Bone marrow examination found that SMMU-16, high-dose group and positive control group, cynomolgus monkey bone marrow erythroid cell hyperplasia. Histopathological examination found that the d28 positive control group and high-dose group of three, two doses of the group of animals showed thymus atrophy and spleen atrophy. The above changes can be gradually restored at the end of the recovery period. No significant pathological changes were found in the liver and kidney of each group of animals. The remaining indicators, including general symptoms, respiratory, body temperature, pupil, urine, ECG, immune and biochemical indicators were not significantly related to the test-related abnormal changes and dose-effect, time-effect relationship. Conclusion The main target organs of SMMU-16 are immune system (thymus and spleen) and blood system, and the toxic effect of SMMU-16 is reversible. This toxicological effect is related to the extension and enlargement of the pharmacological effects of SMMU-16 immunosuppression. The non-toxic dose of SMMU-16 subcutaneously to cynomolgus monkeys is 10 mg / kg. The toxic effects of SMMU-16 and isodose positive control were similar in this experiment.