目的 研究重組人干擾素β-1a （rhIFN β-1a）注射液的毒副反應(yīng)靶器官及其恢復(fù)情況，預(yù)測(cè)可能引起的臨床不良反應(yīng)，為臨床用藥提供參考。方法 食蟹猴sc重復(fù)給予rhIFN β-1a注射液3.9、13.2、45.0 μg/kg，連續(xù)30 d，每組6只動(dòng)物，雌雄各半，停藥后恢復(fù)16 d。觀察藥物對(duì)一般體征、飲食、肛溫、體質(zhì)量的影響，同時(shí)進(jìn)行尿液分析、血液學(xué)、血液生化、心電圖、眼科檢查、骨髓涂片、免疫學(xué)指標(biāo)、免疫原性檢查，在給藥結(jié)束和恢復(fù)結(jié)束進(jìn)行大體剖檢并進(jìn)行組織病理學(xué)檢查。結(jié)果 45.0 μg/kg rhIFN β-1a組動(dòng)物出現(xiàn)一過性肛溫升高，以及活化部分凝血活酶時(shí)間（APTT）、凝血酶時(shí)間（TT）延長(zhǎng)，血漿纖維蛋白原（FIB）濃度降低，該變化在給藥期內(nèi)能恢復(fù)。其余一般指標(biāo)、心電圖、血液生化、尿液生化、骨髓檢查、大體解剖、臟器質(zhì)量及系數(shù)、組織學(xué)檢查、免疫學(xué)指標(biāo)檢查未見異常。免疫原性試驗(yàn)可見給藥20 d后絕大部分動(dòng)物開始出現(xiàn)抗體，給藥30 d時(shí)所有動(dòng)物均出現(xiàn)抗體，各劑量組絕大多數(shù)產(chǎn)生結(jié)合抗體的動(dòng)物血清可檢測(cè)到具有中和rhIFN β-1a注射液活性的抗體，結(jié)合抗體以及中和抗體的滴度均與劑量呈非相關(guān)性關(guān)系，具有隨給藥時(shí)間延長(zhǎng)抗體強(qiáng)度增強(qiáng)的趨勢(shì)。結(jié)論 食蟹猴連續(xù)sc重復(fù)給予rhIFN β-1a注射液30 d，無可見有害作用水平（NOAEL）為13.2 μg/kg，該劑量為人臨床擬用劑量0.135 μg/kg的97.8倍。rhIFN β-1a注射液對(duì)食蟹猴具有一定的免疫原性。

Objective We conducted a 30-day long-term toxicity test of cynomolgus monkey subcutaneously in order to study the target organs of toxicity and side effects of recombinant human interferonβ-1a (rhIFN β-1a) injection and its recovery, predict the possible clinical adverse reactions, and provide reference for clinical medication. Methods RhIFN β -1a injection was given subcutaneously for 30 days at doses of 3.9, 13.2 and 45.0 μg/kg for 6 animals in each group, male and female in half. Then there was a 16-day recovery time. We observed the effects of drugs on general signs, diet, rectal temperature and body weight. At the same time, urine analysis, hematology, blood biochemistry, electrocardiogram, ophthalmological examination, bone marrow smears, immunological indicators, immunogenicity were carried out. General anatomy and histopathological examination were performed at the end of administration and recovery.Results In the 45.0 μg/kg dosage group, there was a transient increase of anal temperature, prolonged time of APTT and TT, and decreased concentration of FIB, which could be recovered in the period of administration. The other general indexes, electrocardiogram, blood biochemistry, urine biochemistry, bone marrow examination, general anatomy, organ weight and coefficient, histological examination and immunological index were normal. Immunogenicity test showed that most animals began to show antibodies 20 days after administration, and all animals showed antibodies 30 days after administration. Most of the sera of animals producing binding antibodies in each dose group could detect antibodies that neutralize rhIFN β-1a injection. The titers of binding antibodies and neutralizing antibodies were independent of the dose and the intensity of antibody had enhanced trend with the prolongation of administration time.Conclusions Cynomolgus monkeys were subcutaneously administered rhIFN β-1a injection for 30 consecutive days, and NOAEL was 13.2 μg/kg. The dose was 97.8 times that of human clinical dosage of 0.135 μg/kg. RhIFN β-1a injection has certain immunogenicity to cynomolgus monkeys.

國家科技重大新藥創(chuàng)制項(xiàng)目（2015ZX09501004）；天津市科技計(jì)劃項(xiàng)目（16PTGCCX00090）