Understanding silibinin¡¯s modes of action against HCV using viral kinetic modeling

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• 作者：Jeremie Guedj¹ ; ^?? ; Harel Dahari¹ ; ² ; ^?? ; 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
• 出版时间：May, 2012
• 年：2012
• 卷：56
• 期：5
• 页码：1019-1024
• 全文大小：639 K

文摘

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Background & Aims

Legalon? 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¡¯s MOA in HCV genotype-1/4 patients receiving intravenous SIL monotherapy for 7 days via mathematical modeling.

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.

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, ¦Å, was dose-dependent with mean ¦Å = 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, ¦Ç, 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-¦Á ¡À ribavirin treatment.

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.