GLP-1类似物聚乙二醇洛塞那肽对猕猴的重复给药毒性研究

Toxicity of PEX-168,a new glucagon-like peptide-1,for Maroon macaques following repeated administration

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 PEX-168, a new glucagon-like peptide-1, following repeated subcutaneous injection for 180 days in Maroon macaques. Methods： Maroon macaques were randomly divided into four groups （0, 0.5, 1.5, 3.0 mg· kg^-1 ）. All animals were subcutaneously injected with vehicle or PEX-168 weekly for 180 days followed by 30-day recovery. Toxicological parameters such as clinical sighs, hematological, biochemical, urinary, immunological indices, serum antibody, organ masses, the bone marrow and pathol- ogy were determined. Results： Decrease in body weight and food consumption was found in all dosage groups during the first period of administration, and then a gradual recovery of food consumption was observed during the end of dosing period. On the other hand, increased ALT was observed on day 180 in 3.0 mg· kg^-1 group, which was statistically significant when compared with day 0 or other groups during the same period. Furthermore, the results of pathology indicated lymph nodes might be the target organ of the test substance. All of these changes reversed after a 30-day recovery period. There was no obvious abnormality induced by test substance in other parameters such as clinical symptoms, respiration, body temperature, urine, pupils, electrocardiogram, hematological index and bone marrow cell counts, and so on. Conclusion： The target toxicity organs and systems for PEX-168 in Maroon macaque are digestive and immune systems. The no-observed-adverse-effect level （NOAEL） is 1.5 mg· kg^-1 More attention should be paid to PEX-168 effects on liver and immune systems.