【作者】 浦昀；

【导师】 李娟；

【作者基本信息】 吉林大学 ， 劳动卫生与环境卫生学， 2005， 硕士

【摘要】 流感是对人类健康威胁较大的传染病之一。甲型流感病毒是引起流感全球流行的重要病原体。化学药物在流感的预防和治疗中占有重要的地位。寻找活性高、毒性低、选择性好的抗流感病毒药物已成为世界各国医学领域研究的重要课题。由于多酸化合物具有独特的抗病毒活性及较低的毒性,使其日益成为抗病毒新药研究的热点。本研究中的Tg-A、Tb-A 、Ts-A 和Mo-A,是以具有抗病毒活性的多金属氧酸盐为化学母体(Tg),抗甲型流感病毒药物金刚烷胺(AMA)为有机配体,经分子自组装合成的有机-无机杂化的ET 电荷转移盐,是未见报道的四种新型多金属氧酸盐。本文采用体内外实验方法,分别从毒理学、药效学和免疫学等方面研究了四种新型多金属氧酸盐的体内外毒性、体内外抗甲型流感病毒活性和免疫调节活性,探讨其抗甲型流感病毒作用机理,并对其抗病毒谱进行了初步研究。实验结果表明:Tg-A、Tb-A 、Ts-A 和Mo-A 的体外毒性低于Tg 和AMA。Tg-A 对小鼠的半数致死剂量LD50>5000 mg·kg-1,Tg-A 属于低毒化学物质。Tg-A、Tb-A 、Ts-A 和Mo-A 体外抗甲型流感病毒的活性均高于Tg 和AMA,其中Tg-A 细胞内和鸡胚内的TI 值分别达到了98.58 和60.76。Tg-A能有效抑制流感病毒感染导致小鼠死亡和导致小鼠肺炎的效应。Tg-A对脾细胞、胸腺细胞、T 淋巴细胞、NK 细胞和LAK 细胞的免疫活性均有不同程度的促进作用。Tg-A 可通过直接和间接两条途径抑制流感病毒复制。Tg-A、Tb-A 、Ts-A 和Mo-A 对RNA 病毒和DNA 病毒均有抑制活性。提示:四种新型多金属氧酸盐具有较低的毒性和较高的抗甲型流感病毒活性,抗病毒谱较广,其中Tg-A 抗甲型流感病毒活性最佳,并具有免疫调节活性,抗病毒机制初步明确。Tg-A 已申请国家发明专利,是具有我国自主知识产权的化学新药,其合成原料易得,价格低廉,相关开发和应用前景广阔。更多还原

【Abstract】 Influenza is an acute, hyperinfected disease caused by influenza virus and spreads broadly in human and animals.Up to now, influenza is still a viral infectious disease that is the most invasion, the fastest infect and the most broadly spread, epidemic outbreak sine die in human and animals,is pandemic infection that can’t control effectively by now. Influenza A virus is the most important pathogen ,which epidemic repeatedly and frequently and evoke influenza epidemic globally. Antigenic variation of influenza virus confines the use of influenza vaccine.At present, drugs treated influenza in clinical application have lower effcts,higher adverse reactions and drug resistances. Consequently,it is urgent to find new drugs that have high performance,low toxicities and independent intellectual property rights of China. Polyoxometallates possess distinct antiviral effects and low toxicities,become the hot spot of researching antiviral new drug increasely. This thesis adopted Tg-A,Tb-A,Ts-A and Mo-A which were synthesized via molecule self-assembly based on chemical mother nuclide polyoxometallates which have antiviral activities and organo-ligand AMA, which has anti-influenza A virus activity . Tg-A,Tb-A,Ts-A and Mo-A are neotype polyoxometallates that haven’t reported. In this thesis, toxicities,anti-viral activities, immunoregulatory activities,anti-influenza A virus mechanism and antiviral spectra of four neotype polyoxometallates were measured in vitro and in vivo. 1.Toxicities of Tg-A,Tb-A ,Ts-A and Mo-A in vitro: Toxicities of po-lyoxometallates in vitro were measured by the methods of cultivation in cells and cultivation in chick embryo.The results showed that TC50, TC0 in cells and LD50 in chick embryo of Tg-A,Tb-A ,Ts-A and Mo-A are higher than Tg and AMA ,respectively.Hint:toxicities in cells and chick embryo of Tg-A,Tb-A,Ts-A and Mo-A in vitro are both lower than chemical mo-ther nuclide Tg and organo-ligand AMA, four neotype polyoxometallates synthesized by molecule self-assembled with amantadine have lower toxicities. 2. Toxicities of Tg-A in vivo: Toxicities of Tg-A in vivo were measured by the methods of acute toxicity testing and maximum tolerated dose testing. The results showed that median lethal dose (LD50)of Tg-A is larger than 5000 mg·kg-1, maximal tolerance dose of Tg-A is 15000 mg·kg-1. Hint: Tg-A is lowly toxic chemical materials. 3. Anti-influenza A virus activities of Tg-A,Tb-A ,Ts-A and Mo-A in vitro: Anti-influenza A virus activities of compounds in vitro were measured by the methods of cultivation in cells and cultivation in chick embryo. The results showed that TI of Tg-A,Tb-A ,Ts-A and Mo-A are higher than Tg and AMA ,respectively.TI of Tg-A in cells and in chick embryo is 98.58 and 60.76, respectively. Hint: Tg-A,Tb-A ,Ts-A and Mo-A all possess anti-influenza A virus activities in vitro,and antiviral activities are higher than Tg and AMA. Safety margin are wider than Tg and AMA. Furthermore, Tg-A has the best anti-influenza A virus activity. 4. Anti-influenza A virus activities of Tg-A in vivo: Anti-influenza A virus activities of Tg-A in vivo were measured in mice infected with influenza A virus. The results showed that Tg-A depressed death rate ,elevated survival rate, extended average living days, elevated death protect rate and extention living rate of mice infected with influenza A virus significantly. Tg-A inhibited death potency and depressing of body weight of mice infected with influenza A virus effectively. Tg-A depressed lung humid weight , lung pathological degree, virus multiplicationof lung lung and pathological change of mice infected with influenza A virus significantly. Tg-A inhibited pneumonic potency of mice infected with influenza A virus effectively. Hint: Tg-A possess anti-influenza A virus activities in vivo,and antiviral activities are higher than Tg and AMA. 5. Immunoregulatory activities of Tg-A: Immunoregulatory activities of Tg-A were measured by the methods of organ weighter,T Lymphocytetransformation NK,LAK cytotoxicity study and thymocyte absorption 3H-TdR. The results showed that Tg-A stimulate spleen cells and thymocyte cells proliferation, promoted T Lymphocyte transformation function, NK,LAK cytotoxicities and thymocyte cells activities.Hint: Tg-A possesses immunoregulatory activities,elevated organism immunologic function,adjust antiviral activities. 6. Anti-influenza A virus mechanism of Tg-A: Anti-influenza A virus mechanism of Tg-A was measured by the methods of cultivation in cells and immune empirical method. The results showed that Tg-A had better antiviral activities to influenza A virus entered cells,and killed virus straightly.Hint: Tg-A inhibits influenza A virus by direct and indirect ways, obstruct viral replication and activate immunological effect of antiviral infection, elevated organism immunologic function,adjust antiviral activities. 7. Antiviral spectra of Tg-A,Tb-A,Ts-A and Mo-A: Antiviral spectra of Tg-A,Tb-A,Ts-A and Mo-A wesr measured by the methods of cultivation in cells. The results showed that Tg-A,Tb-A,Ts-A and Mo-A have inhibition effects to tunicary minor strand RNA virus-influenza A virus and Respiratory styncytial virus,also have inhibition effects to nonencapsulated double strands DNA virus-Adenovirus.Hint: Tg-A,Tb-A,Ts-A and Mo-A have wide anti-virus spectra, have inhibition effects to both RNA virus and DNA virus,and have better antiviral activities to tunicary minor strand RNA virus than to nonencapsulated double strands DNA virus. Review articles, on inhibiting virus effects,polyoxometallates possess some characteristas follow:(1) polyoxometallates possess low toxicities;(2) polyoxometallates possess better antiviral effects,inhibit replication of viruses effectively;(3) polyoxometallates possesses immunoregulatory activities,elevated organism immunologic function,adjust antiviral activities;(4) polyoxometallates have wide antiviral spectra.更多还原