转移贴-Favipiravir（T-705）对于耐药流感病毒及2009H1N1在体外...

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本帖最后由 cloud 于 2010-5-25 17:48 编辑 In Vitro Antiviral Activity of Favipiravir (T-705) against Drug-Resistant Influenza and 2009 A(H1N1) Viruses Katrina Sleeman,1 Vasiliy P. Mishin,1 Varough M. Deyde,1 Yousuke Furuta,2 Alexander I. Klimov,1 and Larisa V. Gubareva1*     Favipiravir (T-705) has previously been shown to have a potent antiviral effect against influenza virus and some other RNA viruses in both cell culture and in animal models. Currently, favipiravir is undergoing clinical evaluation for the treatment of influenza A and B virus infections. In this study, favipiravir was evaluated in vitro for its ability to inhibit the replication of a representative panel of seasonal influenza viruses, the 2009 A(H1N1) strains, and animal viruses with pandemic (pdm) potential (swine triple reassortants, H2N2, H4N2, avian H7N2, and avian H5N1), including viruses which are resistant to the currently licensed anti-influenza drugs. All viruses were tested in a plaque reduction assay with MDCK cells, and a subset was also tested in both yield reduction and focus inhibition (FI) assays. For the majority of viruses tested, favipiravir significantly inhibited plaque formation at 3.2  M (0.5  g/ml) (50% effective concentrations [EC50s] of 0.19 to 22.48  M and 0.03 to 3.53  g/ml), and for all viruses, with the exception of a single dually resistant 2009 A(H1N1) virus, complete inhibition of plaque formation was seen at 3.2  M (0.5  g/ml). Due to the 2009 pandemic and increased drug resistance in circulating seasonal influenza viruses, there is an urgent need for new drugs which target influenza. This study demonstrates that favipiravir inhibits in vitro replication of a wide range of influenza viruses, including those resistant to currently available drugs.

rojjer

高江河 回复：
日本人的？
挺好一个药物啊，有谁能突破其专利，抢仿了才好咧。

rojjer

zhangtao1012450
呵呵，怎么可能抢仿呢，T705在2002年人家就开始做了，而且这个药物至少进入了临床II期试验，人家专利几年前就申请了，药物做的效果非常的好，而且这个通讯作者在流感领域非常的牛，同时在日本和美国有两个实验室，平均每个月都会有一两篇影响因子在10左右的文章，可以说是流感领域最高产的专家，同时该实验室做的流感的抗病毒药物目前有几个非常好的，CS8598大概也进入临床试验，在2006年nature对其就有一个专访。
不过中国也有一个华人夫妇，房芳 很牛的，在美国圣地亚哥有自己的公司，好像从美国政府拿到了6000多万美金用于流感抗病毒药物DAS181的研究

rojjer

zhangtao1012450

新药流感酶为应对甲流感或提前上市
　抗流感新药“Fludase”（流感酶）不会产生抗药性，并且能对抗目前所知的所有流感病毒变种，包括甲型H1N1 流感。

　　近日，美国华裔生物科学家余芒研制的抗流感新药“Fludase”(流感酶)取得了突破性进展。这种新药针对患者本身，通过阻止病毒与人体结合的方式来达到治病的目的。它比“达菲”等常规药物更出色的地方在于，它不会产生抗药性，并且能对抗目前所知的所有流感病毒变种，包括甲型H1N1流感。

　　文/Margo

　　美国NexBio生物制药公司的首席执行官余芒博士又在案头上添了几叠资料，浏览完世界卫生组织每周更新的检测资料之后，便起身走向了实验室。七年前，为研发预防流感蛋白药物，华裔生物科学家余芒和妻子房芳一同创立了这间公司。在美国政府6300万美元的大力资助下，应对流感病毒的蛋白药物 “Fludase”在近日取得了突破性进展，NexBio也因此被《科学美国人》杂志列为“最有影响力的50家公司”之一。

　　余芒在接受媒体采访时表示，“Fludase”的主要成分是唾液酸酶融合蛋白，它由人体内自有的细菌中提取并加工合成。药物并不直接杀灭病毒，而是通过切断呼吸道上皮细胞表面的糖链受体，以阻止病毒与该人体的结合，从而达到防病治病的目的。“Fludase”的中文名为“流感酶”。在解释为何有如此中文名称时，他开玩笑说，“流感酶”，也就是“流感没了”的意思。

　　为降低抗药性而进行的研究

　　9月11日，一名来自珀斯的38岁男子被送进了西澳大利亚州立医院，在被确诊染上甲型H1N1后，医护人员让他服下了“达菲”，这是目前有效应对H1N1病毒的首选药物。然而，由于较弱的免疫系统，最初服药产生效果后不久，咳嗽与发热的病症再次复发，医生发现，病人产生了抗药性反应，这是澳洲出现首例对抗病毒药物达菲产生抗药性的甲流病例。

　　事实上，最先的病例早在6月30日已经出现，丹麦一名甲型H1N1流感患者对“达菲”产生了同样的耐药反应，这是科学家首次检测到甲型H1N1 流感病毒的抗药变异。之后，美国、加拿大、香港、日本、澳大利亚相继发现了对“达菲”有抗药性的甲流病例。根据瑞士罗氏公司最近公布的统计数字，全球范围内，对达菲产生耐药性的甲型H1N1流感病例已达26例。

　　在甲型H1N1流感治疗手段方面，余芒表示，目前有效的首选药物是“达菲”和“乐感清”，它们属于同类药物，其中以“达菲”为主，根据临床试验，大约有0.5%的病例会出现抗药性。因为过度使用，抗药性H1N1甲型流感病毒的菌株很可能开始出现了。如产出抗药性，则意味着人们将没有现成的有效药物，流感也将成为无药可治的疾病，对人类威胁极大。

　　正是“达菲”等药物潜在的抗药性，促使余芒进行新流感药物的研究。在禽流感肆虐全球的一年多以前，余芒的NexBio公司与联邦疾病控制中心联合，在小鼠生物模型上完成了“流感酶”防治H5N1病毒的实验。该实验证实“流感酶”可以保护小鼠抵御致命性禽流感病毒H5N1的感染。而在刚刚完成的一期临床实验中，结果也显示了药物在人体中的安全性。

　　对预防和治病都有效的“流感酶”

　　余芒与联邦疾病控制中心的洁奎琳。卡茨博士(Dr.Jacqueline Katz)及其同事将实验分为预防和治疗两大类。在防病实验中，从接触传染源之前一天起，每日以滴鼻方式给以“流感酶”(每公斤体重给一毫克)，连续给药七天，结果小白鼠均得以存活，并减少因病毒感染而出现的体重下降。反之，对照组中未给药的小白鼠都在感染后七天内陆续死亡，并在感染后第五天平均减重 16%。

　　在治病的实验中，研究人员将小鼠分3档，它们分别在接触病毒后24小时、48小时和72小时后开始接受药物治疗。结果显示，药物虽不能保护小鼠免于病毒感染，但却能减少它们的体重下降和延长它们的寿命。小鼠的存活率随开始治疗时间的早晚呈下滑趋势，分别为70%(24小时)、35%(48小时) 以及15%(72小时)。

　　NexBio公司与疾病控制中心专家都认为，“流感酶”代表治疗呼吸道病毒感染的新进展，它不同于当前用于治疗禽流感的各种药物，它所针对的不是病毒，而是患病者自身，作用于保护人体细胞不受流感病毒侵害，因而比一般药物更有“治本”的功效。并且，“流感酶”还具有广泛的抗病毒活性以及降低抗药性的潜力，能有效识别同一宿主受体的呼吸道流感病毒，从而对抗目前所知的所有流感病毒变种，包括在全球范围内徘徊了五个月之久的甲型H1N1流感。对于已对达菲产生耐药性的流感病毒毒株，“流感酶”也能抵御其入侵细胞。美国国家卫生研究院(NIH)已高度肯定该项研究成果，一再提供高额经费，推动相关的研发进程。

　　将在紧急情况下批准使用

　　“流感酶”目前已完成“合标制造程序”(cGMP)的生产，并顺利结束一期临床实验。根据美国食品药物管理局(FDA)的规定，通常药物要完成三期临床试验后才有可能被批准上市。这往往需要花费数年甚至更长的时间。也许实验还未来得及完成，因H1N1变异引起的人类流感就会暴发。对此，余芒表示，迄今尚未发现真正意义上的“甲流”病毒变异并传染的案例。已经发现的“甲流”病毒抗药性病例，均为孤立现象。如果甲型H1N1流感对现有药物真的产生了抗药性，那么公司将申请美国食品和药品管理局(FDA)的紧急用药许可证，由政府购买药物进行战略储备。根据美国法律规定，在紧急情况下，如果实验药物满足动物实验有效且人体使用安全两个条件，那么FDA将准许使用该药物。

　　余芒认为，病毒毒力及其变异方向存在不确定性，没有人能够确保甲型H1N1流感的耐药性病毒变体是否会产生，并大范围地传播。甲型H1N1流感可以在几周内肆虐全球，影响到每个人。有些人会自己痊愈，但对有些人却会是致命的。人们必须充分认清流感病毒潜在的杀伤力，提高防范意识，而作为研究者的他们也将加快实验进程，让“流感酶”尽快生产问世。

rojjer

这是2006年nature做的专访，做流感病毒的不能不知道这个人
Nature Medicine - 12, 489 (2006)
Profile: Yoshihiro Kawaoka
  If people make comments, I don't say a word. I don't care what other people think.
Even in a constant state of jetlag, Yoshihiro Kawaoka is a fiercely productive flu researcher. Wonder what he could accomplish with a little bit of sleep?
If Yoshihiro Kawaoka owned a country, its citizens would be well protected from a bird flu pandemic.
Confronted with a pandemic, Kawaoka says he would close his country's borders and release a vaccine based on the live, but weakened, bird flu virus. Some people might fall ill from the vaccine strain, but far greater numbers would benefit. "The immune response provided by live virus, that is going to be the one that really protects humans," Kawaoka says.
He is only half-serious. Kawaoka knows that closing borders is impractical and would at best only stall the pandemic. But when it comes to a vaccine, he knows of what he speaks.
Kawaoka engineered a method to generate entire viruses from genetic sequences, a technology that's now used to make flu vaccines. He has published paper after high-profile paper describing what makes certain flu viruses lethal and how they acquire resistance to available drugs. Most recently, he suggested that the H5N1 virus prefers to bind receptors far down in the lungs, making it more difficult for the virus to jump between people (Nature 440, 435–436; 2006).
Since 1999, Kawaoka has juggled dual appointments at the University of Tokyo and the University of Wisconsin in Madison. Full-sized labs at each institution churn out top-notch publications, 27 in 2005 alone.
"I'm glad that I work with him and don't have to compete with him," says Heinz Feldmann, chief of special pathogen programs at Canada's National Microbiology Laboratory, and Kawaoka's collaborator on Ebola virus research.
Kawaoka became interested in Ebola after reading The Hot Zone, the only English novel he says he has ever read. But soon after he began working in the field, "Yoshi really came on the scene with a bang," recalls Tom Geisbert, chair of viral pathology at the US Army Medical Research Institute of Infectious Diseases in Fort Detrick, Maryland.
How Kawaoka has the energy to do so much is a mystery. He doesn't eat much, sleeps even less and is perpetually jetlagged. To keep up his dual appointment, he often travels to Tokyo, sometimes for just a day.
Even as a postdoc at St. Jude Children's Research Hospital in Memphis, Tennessee, Kawaoka was in the lab when the cleaning lady arrived in the early evening, would go home to sleep at some point and be back again, ready to start the next day, before she left. "We're all amazed at how he can physically manage to function so well in two different time zones," says Krisna Wells, who has worked with Kawaoka since 1987