目的 研究重組人促紅素注射液（CHO細(xì)胞）對食蟹猴的長期毒性，預(yù)測各組織器官的潛在毒性反應(yīng)。方法 18只普通級成年食蟹猴根據(jù)體質(zhì)量隨機(jī)分為陰性對照組（生理鹽水）和重組人促紅素注射液（CHO細(xì)胞）低（每周500 IU/kg）、高劑量（每周1500 IU/kg）組，每組6只，雌雄各半；受試品經(jīng)后肢大腿外側(cè)sc注射給藥，每周3次，連續(xù)4周；給藥結(jié)束后，每組處死4只動物（雌雄各半），其余動物停藥后進(jìn)行4周恢復(fù)期觀察；觀察指標(biāo)包括動物外觀體征、行為活動、精神狀態(tài)等情況，并進(jìn)行體質(zhì)量、體溫、眼科、心電圖、血常規(guī)、凝血指標(biāo)、血生化、免疫細(xì)胞檢測及組織病理學(xué)檢查。結(jié)果 在8周觀察期內(nèi)，各組動物外觀體征、行為活動、精神狀態(tài)、體質(zhì)量、體溫、眼科、心電圖、凝血指標(biāo)、血生化、大體解剖等均未見異常；血常規(guī)檢查發(fā)現(xiàn)，與陰性對照組比較，受試品低、高劑量組紅細(xì)胞（RBC）、網(wǎng)織紅細(xì)胞（RET）、血紅蛋白（HGB）、紅細(xì)胞壓積（HCT）、血小板數(shù)（PLT）給藥后顯著升高（P<0.05），淋巴細(xì)胞數(shù)（LYMPH）顯著降低（P<0.05），停藥4周后RET、PLT及LYMPH恢復(fù)正常水平，而RBC、HGB及HCT仍維持較高水平；免疫細(xì)胞檢查發(fā)現(xiàn)，與陰性對照組比較，給藥4周后高劑量組CD3⁺T細(xì)胞比例顯著減少，4周后恢復(fù)正常水平；病理檢查發(fā)現(xiàn)，高劑量組3只動物出現(xiàn)股骨骨髓輕度紅系增生。結(jié)論 給予食蟹猴每周1 500 IU/kg（相當(dāng)于10倍臨床劑量）重組人促紅素注射液（CHO細(xì)胞）未發(fā)現(xiàn)明顯毒性反應(yīng)，血常規(guī)指標(biāo)及病理學(xué)的改變與其藥理作用相關(guān)。

Objective To study the four week repeated dose toxicity of recombinant human erythromycin injection(CHO cells) in cynomolgus monkey. Methods Eighteen monkeys were randomly divided into three groups (six each, half male and half female) to receive the dose of 0, 500, 1 500 IU/kg of EPO by sc injection three times a week for four weeks. On dosing termination, one third of the animals in each group were left to observe four weeks recovery. Daily observation of animal appearance and sign, behavior and mental state were carried out. And body weights, body temperature, ophthalmology, ECG, hematology, clinical chemistry, T lymphocyte subset and histopathology were examined in different points in administration period and recovery period. Results No abnormalities were found in the exarninations of clinical symptoms, body weight, body temperature, opthalmology, ECG, coagulation index, clinical chemistry and gross anatomy. RBC, RET, HGB, HCT and PLT were observed signifieantly increased and LYMPH obviously decreased in high and medium dose groups after four weeks dosing as compared to control group. RET and PLT returned to normal level and RBC, HGB and HCT remained at a high level after four weeks recovery. The proportion of CD3⁺T cells decreased significantly in high dose groups and returned to normal level after 4 weeks recovery, the mild erythroid hyperplasia of femur were abserved in high dose group in three animals after 4 weeks dosingon histopathology exarnination. Conclusion The dose of 15 00 IU/kg of Recombinant human erythromycin injection (CHO cells) for 4 weeks shows no obvious toxic effect in cynomolgus monkey. The changes of hematology and pathology are related to their pharmacological effects.

R965.3

廣東省科技計劃項目（2017B020231001、2017A070701003、2017A070702001）#共同