给战友点希望－－硝唑尼特治疗慢肝

lemonades

Discussion

In this report, we present the first in vitro demonstrations of the activity of nitazoxanide and its active circulating metabolite, tizoxanide, against both HBV and HCV replication. Inhibition of both viruses was dose-dependent and selective relative to cytotoxicity under the conditions of the antiviral assays. Concentrations of tizoxanide required to inhibit viral replication, even those observed in the presence of additional human serum, are readily achieved in human plasma following oral administration of nitazoxanide (Broekhuysen et al., 2000; Stockis et al., 2002). Four of six other thiazolides tested exhibited selective activity against HBV replication, and two exhibited selective activity against HCV replication.

Nitazoxanide was active against both genotypes 1a and 1b HCV, commonly observed LMV and ADV-resistant HBV mutants, as well as representative HCV mutants resistant to telaprevir and 2'CmeC. Activity against genotype 2a HCV as well as additional drug-resistant HCV remains to be evaluated. If TIZ exerts its observed antiviral effects by targeting cellular processes, it is possible that resistance may not be as significant a problem for thiazolides as it is typically for direct-acting antiviral agents. The lack of diminished activity against several clinically relevant drug-resistant HBV and HCV variants presents the potential for use in rescue therapy or in combination with existing agents, and is consistent with an indirect mechanism of antiviral activity.

Nitazoxanide exhibited synergistic activity in combination with LMV or ADV against HBV, and with IFNa or 2'CmeC against HCV, consistent with a mechanism of action that is different from these antiviral agents. Pre-treatment of HCV replicon cells with nitazoxanide potentiated the effect of subsequent treatment with combinations containing IFNa, but not 2'CmeC, suggesting an interesting complementary activity with IFNa. Thiazolides may offer the possibility of new more effective combination treatments for chronic hepatitis C, whether used as additions to current standard-of- care, as replacements for ribavirin, or as part of novel combination regimens with other anti-HCV drugs in development. The activity of nitazoxanide against HBV proteins could prove to be advantageous in treating chronic hepatitis B. Reductions in HBV protein levels, especially HBsAg and HBeAg, are of critical importance in elucidating long term antiviral responses in vivo (Menne et al., 2002; Korba et al., 2004;Wong and Lok, 2006).

While the mechanism of antiviral activity of nitazoxanide, tizoxanide, and the other thiazolides has not been fully elucidated, our findings are indicative of a mechanism that differs from direct-acting antiviral drugs and involves cellular processes.

It is not at all apparent if the mechanisms of antiviral effectiveness and cytotoxicity involve similar cellular targets. The lack of an effect on levels of HBV RNA transcription indicates a post-transcriptional (possibly post-translational) mechanism. We propose that thiazolides may alter cellular processes required for virus protein production/maturation and/or assembly. Consistent with this hypothesis is the observation that the relative potencies of NTZ against secreted and intracellular HBV proteins are similar to that against secreted HBV virions and intracellular HBV RI, respectively. Given the substantial differences in the roles of these viral proteins, effects on more than one cell process are likely involved. Further studies are ongoing in our laboratories to more fully characterize the mechanism of activity of these drugs against HBV and HCV replication, and the potential for development of resistance.

The limited panel of thiazolides examined provides some initial clues into which components of TIZ are important for its anti-HBV and anti-HCV activities. The observation that the dual anti-hepatitis activity of TIZ can be separated into compounds that possess only anti-HBV or anti HCV activity has the potential to further elucidate the mechanism of action and identify the critical cellular targets involved. There will be a need to examine additional thiazolides for antiviral and cytotoxicity profiles.

Nitazoxanide, tizoxanide and other drugs from the thiazolide class are promising new antiviral agents that may enhance current or future therapies for viral hepatitis caused by HBV or HCV. NTZ is undergoing phase II clinical development for hepatitis C, and NTZ other thiazolides are also being developed for treating either hepatitis B or hepatitis C. The implications of a new class of antiviral drugs with the properties described herein could be significant from a clinical perspective.

[ 本帖最后由 lemonades 于 2010-3-15 03:57 编辑 ]

lemonades

虽然我只标了部分，但觉得整篇文章都挺重要的。
最好能看懂。

好消息是，最长有4年的试验证明其安全性，与拉米阿德有协同作用，对拉米阿德耐药的效果依然很好。

不太好的消息是，虽然觉得硝唑尼特的耐药性不太可能是问题，但他们还没有证实。还有，alinia对HBV RNA没有作用，当然了，拉米等对HBV RNA也没作用。

总的来说是好消息。事实上，在药代动力学前面的那篇英文也重要。

还有，不是所有的人都从Romark实验室得到了回复。我非常感激他们的回复。

[ 本帖最后由 lemonades 于 2010-3-15 04:55 编辑 ]

hatecccdna

感谢 lemonades !

蔑视大三阳

感谢分享！感谢 lemonades !

走遍四方

xiexie, lemon，我能大致看得懂的。。。

走遍四方

928 贴翻译如下：Lemon 看看，重大错误 更正一下。
Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication...

Nitazoxanide, tizoxanide 和其他thiazolides 是强有力的HBV/HCV病毒抑制剂
  
  There were 4 presentations at EASL. I'll be reporting them to you in detail.
这里有4篇EASL上的报告，详细如下：
Antiviral Research抗病毒研究
Volume 77, Issue 1, January 2008, Pages 56-63
卷，。。。略

These are extracts from the publication leaving out Methods.
下面是公开发行物中的摘要（略去方法）
Brent E. Korba a,, Abigail B. Montero a, Kristine Farrar a, Karen Gayea, Sampa Mukerjee a, Marc S. Ayers b, Jean-Franc黲is Rossignol b,c a Department of Microbiology and Immunology, Georgetown University Medical Center, 3900 Reservoir Rd. Washington, DC20007 USA b The Romark Institute for Medical Research, 3000 Bayport Drive, Tampa, FL 33607 USA c Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305, USA
作者：XXXXX 乔至顿大学医学中心，微生物免疫部门，USA 华盛顿
和Romark实验室，史坦福大学医学部，肠胃肝部。
"...In this report, we present the first in vitro demonstrations of the activity of nitazoxanide and its active circulating metabolite, tizoxanide, against both HBV and HCV replication.....在本报告中，首先陈述的是NTZ在生物体内对抑制HBV/HCV复制的活性和循环代谢的示范证明。
Nitazoxanide was active against both genotypes 1a and 1b HCV, commonly observed LMV and ADV-resistant HBV mutants, as well as representative HCV mutants resistant to telaprevir.....Nitazoxanide对HCV基因型1a和1b都有作用，这在对LMV和ADV耐药HBV变异株和典型的HCV对telaprevir变异株的研究观察中证实。
If TIZ exerts its observed antiviral effects by targeting cellular processes, it is possible that resistance may not be as significant a problem for thiazolides as it is typically for direct-acting antiviral agents.
如果TIZ发挥其以观察的定向细胞代谢过程的抗病毒功效，那么耐药将不是一个严重问题对于TIZ来说，因为它是典型的直接作用的抗病毒剂。
The lack of diminished activity against several clinically relevant drug-resistant HBV and HCV variants presents the potential for use in rescue therapy or in combination with existing agents, and is consistent with an indirect mechanism of antiviral activity.....
基于目前对HBV/HCV耐药变异株的有力抑制剂的缺失，NIT将是有力的援救疗法或单用或联合现有制剂且与其他间接抗病毒机制协调统一。

....Nitazoxanide exhibited synergistic activity in combination with LMV or ADV against HBV, and with IFNa or 2'CmeC against HCV, consistent with a mechanism of action that is different from these antiviral agents.
在联合LMV或ADV对抗HBV 和联合 干扰素或2‘CmeC 对抗HCVz中，NIT展现出增效作用，表现出与这样抗病毒制剂不同的作用机制。
Pre-treatment of HCV replicon cells with nitazoxanide potentiated the effect of subsequent treatment with combinations containing IFNa.....Thiazolides may offer the possibility of new more effective combination treatments for chronic hepatitis C, whether used as additions to current standard-of- care, as replacements for ribavirin, or as part of novel combination regimens with other anti-HCV drugs in development......
针对HCV复制细胞如先用NIT治疗之后，再联用干扰素治疗，NIT显示更强的增效作用，后面略：：：都是对HCV的

Nitazoxanide, tizoxanide and other drugs from the thiazolide class are promising new antiviral agents that may enhance current or future therapies for viral hepatitis caused by HBV or HCV.
NIT， TIZ 以及其他的thiazolide族药物均显示潜在增强现有和将来的HBV/HCV抗病毒疗法的抗病毒剂。
NTZ is undergoing phase II clinical development for hepatitis C, and NTZ other thiazolides are also being developed for treating either hepatitis B or hepatitis C. The implications of a new class of antiviral drugs with the properties described herein could be significant from a clinical perspective."
NTZ 正在2期HCV研究中，新型抗病毒药物（含这里描述的属性）对临床医疗意义重大

wtd.2009

支持蔡老师,相信蔡老师,感谢蔡老师!......期待蔡老师的药。

lemonades

挺好的，谢谢了！

fromdesert34

原帖由 lemonades 于 2010-3-15 04:05 发表
虽然我只标了部分，但觉得整篇文章都挺重要的。
最好能看懂。

好消息是，最长有4年的试验证明其安全性，与拉米阿德有协同作用，对拉米阿德耐药的效果依然很好。

不太好的消息是，虽然觉得硝唑尼特的耐药性不太可能是问题，但他 ...

不能清除hbv RNA是不是就是意味着这个并不是作用于免疫系统的？

lemonades

不懂，只听有些丙肝的病人讨论，这个药给病毒营造了个不好的环境，使其难以生存。另外就是清除病毒蛋白，这个与拉米等不同。
Romark实验室认为可能是干扰了病毒蛋白的复制，组装的过程。

[ 本帖最后由 lemonades 于 2010-3-15 11:32 编辑 ]