Understanding silibinin鈥檚 modes of action against HCV using viral kinetic modeling

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• 作者：Jeremie Guedj¹ ; ^鈦庘亷 ; Harel Dahari¹ ; ² ; ^鈦庘亷 ; Ralf T. Pohl³ ; Peter Ferenci⁴ ; Alan S. Perelson¹ ; ^asp@lanl.gov
• 关键词：Hepatitis C ; Silibinin ; Viral kinetics ; Mathematical modeling
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：May, 2012
• 卷：56
• 期：5
• 页码：1019-1024
• 文件大小：639 K

摘要

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class="h4">Background & Aims

Legalon庐 SIL (SIL) is a chemically hydrophilized version of silibinin that has exhibited high antiviral effectiveness against hepatitis C virus (HCV). Its main mode of action (MOA) remains unclear, with contradicting in vitro studies supporting either suppression of entry and cell-to-cell spread or suppression of viral RNA synthesis as the main MOA. We sought to provide new insights into SIL鈥檚 MOA in HCV genotype-1/4 patients receiving intravenous SIL monotherapy for 7 days via mathematical modeling.

class="h4">Methods

Changes in HCV RNA in 25 patients receiving 10, 15, or 20 mg/kg/day of SIL were analyzed and modeled using viral kinetic methods.

class="h4">Results

In 15 patients, the virus declined in a biphasic manner, in which a sharp drop between days 0 and 2 was followed by a slower second phase of decline. In 10 patients, the initial decline was weaker and the virus declined in a single phase over the 7-day period. The blocking production effectiveness, 蔚, was dose-dependent with mean 蔚 = 0.49 and 0.89 in the 10 or 15 and 20 mg/kg/day dosing groups, respectively (p = 0.02). The effectiveness of blocking viral infection, 畏, was estimated as 0.60 with no significant differences across dosing groups. For all patients, the mean rate of viral load decline measured between days 2 and 7 was high (0.3 log₁₀ IU/ml/day), i.e., 4-fold higher than typically observed during the 2nd phase of (pegylated)-interferon-伪 卤 ribavirin treatment.

class="h4">Conclusions

Modeling HCV kinetics in vivo suggests that SIL may block both viral infection and viral production/release with its main dose-dependent effect being blocking viral production/release.