徐德璐,胡雷,兰天龙,钟飞,刘艳菊,周博宇.食蟹猴sc重组人干扰素β-1a注射液30 d安全性评价[J].药物评价研究,2019,42(8):1537-1543
食蟹猴sc重组人干扰素β-1a注射液30 d安全性评价
A 30-days subcutaneous safety evaluation of recombinant human interferon β-1a injection in cynomolgus monkeys
投稿时间:2019-01-17  
DOI:10.7501/j.issn.1674-6376.2019.08.009
中文关键词:  重组人干扰素β-1a;长期毒性试验;食蟹猴;安全性评价
英文关键词:recombinant human interferon β-1a;long-term toxicity;cynomolgus monkeys;safety evaluation
基金项目:国家科技重大新药创制项目(2015ZX09501004);天津市科技计划项目(16PTGCCX00090)
作者单位E-mail
徐德璐 天津药物研究院新药评价有限公司, 天津 300301
天津市新药非临床评价技术工程中心, 天津 300301 
 
胡雷 天津药物研究院新药评价有限公司, 天津 300301
天津市新药非临床评价技术工程中心, 天津 300301 
hul@tjipr.com 
兰天龙 天津药物研究院新药评价有限公司, 天津 300301  
钟飞 天津药物研究院新药评价有限公司, 天津 300301  
刘艳菊 天津药物研究院新药评价有限公司, 天津 300301  
周博宇 天津药物研究院新药评价有限公司, 天津 300301  
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中文摘要:
      目的 研究重组人干扰素β-1a (rhIFN β-1a)注射液的毒副反应靶器官及其恢复情况,预测可能引起的临床不良反应,为临床用药提供参考。方法 食蟹猴sc重复给予rhIFN β-1a注射液3.9、13.2、45.0 μg/kg,连续30 d,每组6只动物,雌雄各半,停药后恢复16 d。观察药物对一般体征、饮食、肛温、体质量的影响,同时进行尿液分析、血液学、血液生化、心电图、眼科检查、骨髓涂片、免疫学指标、免疫原性检查,在给药结束和恢复结束进行大体剖检并进行组织病理学检查。结果 45.0 μg/kg rhIFN β-1a组动物出现一过性肛温升高,以及活化部分凝血活酶时间(APTT)、凝血酶时间(TT)延长,血浆纤维蛋白原(FIB)浓度降低,该变化在给药期内能恢复。其余一般指标、心电图、血液生化、尿液生化、骨髓检查、大体解剖、脏器质量及系数、组织学检查、免疫学指标检查未见异常。免疫原性试验可见给药20 d后绝大部分动物开始出现抗体,给药30 d时所有动物均出现抗体,各剂量组绝大多数产生结合抗体的动物血清可检测到具有中和rhIFN β-1a注射液活性的抗体,结合抗体以及中和抗体的滴度均与剂量呈非相关性关系,具有随给药时间延长抗体强度增强的趋势。结论 食蟹猴连续sc重复给予rhIFN β-1a注射液30 d,无可见有害作用水平(NOAEL)为13.2 μg/kg,该剂量为人临床拟用剂量0.135 μg/kg的97.8倍。rhIFN β-1a注射液对食蟹猴具有一定的免疫原性。
英文摘要:
      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.
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