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目的:寻找高效低毒的抗禽流感病毒药物。方法:体外实验选用狗肾细胞(MDCK),实验分为正常对照组、病毒对照组和受试化合物组,采用细胞病变法结合MTT法检测金刚烷胺修饰物(NAM)对MDCK细胞的半数中毒浓度、对禽流感病毒的半数抑制浓度和治疗指数;体内实验采用NAM对禽流感病毒H5N1亚型小鼠感染模型的治疗实验,检测小鼠的死亡率、存活率、死亡保护率和延长生命率。结果:体外实验,NAM对MDCK细胞的最大无毒浓度为235.09mg.L-1,半数致死浓度为1582.78mg.L-1,NAM对禽流感病毒半数抑制浓度(IC50)为15.32mg.L-1,治疗指数(TI,103.31)高于金刚烷胺对照组(TI,48.48);体内实验,NAM100mg.kg-1剂量组对H5N1感染小鼠的死亡率(12.5%)明显低于病毒对照组小鼠死亡率(87.5%)(P<0.05),平均生存日数(13.38d)明显高于病毒对照组平均生存日数(9.63d)(P<0.05),肺炎抑制率(99.15%)和生命延长率(26.79%)均高于金刚烷胺对照组肺炎抑制率(69.18%)和生命延长率(13.39%)(P<0.05)。结论:NAM体外毒性和抗病毒活性均优于阳性对照金刚烷胺;体内抗病毒活性较好,可显著降低禽流感病毒感染小鼠的死亡率、提高平均生存日数和延长生命率。
Objective: To find high-effective and low-toxic anti-avian influenza virus drugs. Methods: Dogs kidney cells (MDCK) were selected in vitro. The experiment was divided into normal control group, virus control group and test compound group. Cytotoxicity assay and MTT assay were used to detect the half-poisoning effect of amantadine modification (NAM) on MDCK cells Concentration, the median inhibitory concentration against the bird flu virus and the therapeutic index. The in vivo experiments used NAM to treat the H5N1 subtype mice infected by the avian influenza virus. The mice were tested for mortality, survival rate, death protection rate and life prolongation rate . Results: In vitro, the maximum non-toxic concentration of NAM on MDCK cells was 235.09 mg.L-1 and the median lethal concentration was 1582.78 mg.L-1. The IC50 of NAM against avian influenza virus was 15.32 mg.L- 1, the therapeutic index (TI, 103.31) was higher than the amantadine control group (TI, 48.48); in vivo, the mortality of H5N1-infected mice was significantly lower than that of the virus control group The mortality of mice was 87.5% (P <0.05). The mean number of days of survival (13.38 days) was significantly higher than that of virus control (9.63 days) (P <0.05) (26.79%) were higher than the control group of amantadine pneumonia inhibition rate (69.18%) and the life extension rate (13.39%) (P <0.05). Conclusion: The in vitro and in vivo antiviral activity of NAM are better than that of the positive control amantadine. The antiviral activity in vivo is good, which can significantly reduce the mortality of mice infected with avian influenza virus, improve the average survival days and prolong the survival rate.