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目的:评价栗色猕猴皮下注射重复给予胰高血糖素样肽-1类似物PEX-168的安全性。方法:猕猴随机分为溶媒对照组,PEX-168低、中和高剂量组(0.5,1.5,3.0 mg.kg-1),每组8只,皮下注射给药,每周1次,连续180 d,恢复期30 d,进行各项毒理学指标检测。结果:给药前期,各剂量组动物给药后大部分拒食,其后逐渐恢复;给药后期,动物拒食现象逐渐好转;首次给药后,各剂量组体重均有不同程度下降。高剂量组d 180丙氨酸氨基转移酶与d 0或同期各组间均有显著差异。组织病理学结果提示PEX-168的靶器官为淋巴结。其余指标包括一般症状、呼吸、体温、瞳孔、尿液、心电图、血液学、骨髓象等未见明显与供试品相关的异常。结论:PEX-168皮下注射180 d(每周1次)主要毒性靶器官是消化系统和免疫系统。PEX-168皮下注射对猕猴的无明显毒性剂量为1.5 mg.kg-1,提示临床使用时应密切注意PEX-168对肝功能和免疫系统的影响。
OBJECTIVE: To evaluate the safety of repeated administration of the glucagon-like peptide-1 analogue PEX-168 subcutaneously in maroon macaque. Methods: The cynomolgus monkeys were randomly divided into the vehicle control group, PEX-168 low, medium and high dose groups (0.5, 1.5, 3.0 mg.kg-1), 8 in each group, administered subcutaneously once a week for 180 d, the recovery period of 30 d, the toxicological indicators of detection. Results: At the early stage of administration, most of the animals in each dose group refused to take food after they were administered, and then recovered gradually. After the drug was administered, the antifeedant food gradually improved. After the first dose, the body weight of each dose group dropped to some extent. High dose group d 180 alanine aminotransferase and d 0 or the same period between the groups were significantly different. Histopathological findings suggest that the target organ of PEX-168 is lymph node. The remaining indicators include general symptoms, respiratory, body temperature, pupil, urine, electrocardiogram, hematology, bone marrow, etc. No obvious test-related abnormalities. CONCLUSION: The main toxic target organ of PEX-168 administered subcutaneously 180 d once a week is digestive system and immune system. PEX-168 subcutaneous injection of rhesus macaque no apparent toxic dose of 1.5 mg.kg-1, suggesting that clinical use should pay close attention to PEX-168 on liver function and immune system.