流感泰得在小鼠模型中抗流感病毒活性研究

In vivo anti-influenza virus activity of flutide, a novel phosphorothioate antisense oligonucleotides

为了在动物整体水平评价流感泰得 (flutide ,FT)抗流感病毒活性 ,建立了流感病毒感染小鼠实验模型 ,并测定了FT在小鼠模型中的抗病毒活性和对小鼠的急性毒性作用。结果表明 ,流感病毒A 京防 86 1(H1N1)和A 沪防 93 9(H3N2 )在小鼠体内连续传代 6次时即对小鼠具有感染性 ,表现为小鼠体重下降 ,小鼠肺脏湿重增加并能检测到很高的病毒滴度。在小鼠模型中FT具有较高的抗病毒活性 ,表现在FT能明显提高病毒感染小鼠的存活率 ,抑制病毒感染引起的小鼠体重下降和肺湿重增加。当FT剂量为 6.5× 10 -4μmol g和 32 .5× 10 -4μmol g滴鼻给药时 ,小鼠存活率分别提高30 %和 5 0 % (P <0 .0 5 ) ;给药途径对FT抗病毒作用有一定影响 ,静脉注射高于腹腔注射和滴鼻给药 ;当接种剂量为 5 2× 10 -4μmol g时 ,FT对小鼠的生长状态、体重和肺脏湿重等均无影响。以上结果为抗流感病毒反义寡核苷酸药物研究向临床前试验过渡提供了试验依据。

In order to evaluate in vivo anti?influenza virus activity of Flutide(FT),a novel phosphorothioate antisense oligonucleotides,mouse model of influenza virus infection was established and then in vivo anti?influenza virus activity and topical toxicity of FT were assayed.It was found that when influenza virus A/JingFang/86?1(H 1N 1) and A/HuFang/93?9(H 3N 2) were passaged in Bal b/c mouse for at least 6 times these mouse?adapted influenza virus showed significant infectivity in mouse,which was indicated by body weight decrease,lung humid weight increase and high detected virus titer in lung.When administred for treatment of influenza virus infection,FT had significant inhibitory effects on infections in mice induced by influenza virus.Antiviral effects were seen as prevention of death,inhibition of decline of body weight of mouse,lessened lung consolidation and inhibition of infection virus recovered from the lungs. when FT was administered intranasally at doses of 6.5×10 -4 μmol/g,32.5×10 -4 μmol/g for treatment,the survival rate of mouse was increased respectively by 30% and 50%(P<0.05).But the anti?influenza virus activity of FT was not seen in a good dose?dependent manner.The administration route of FT had effects on its antiviral activity.When administered intravenously FT exhibited more antiviral activity.No toxicity was seen when phosphorothioate FT administered intranasally in dosage up to 52×10 -4 μmol/g (the highest evaluated).These data provide strong evidence of the potential of Flutide using for treatment of influenza virus infection in humans.