title: Understanding silibinin's modes of action against HCV using viral kinetic modeling.
abstract: OBJECTIVE
  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 20mg/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, ε, was dose-dependent with mean ε=0.49 and 0.89 in the 10 or 15 and 20mg/kg/day dosing groups, respectively (p=0.02). The effectiveness of blocking viral infection, η, 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 log(10)IU/ml/day), i.e., 4-fold higher than typically observed during the 2nd phase of (pegylated)-interferon-α±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.
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Guedj
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA; Department of Medicine, University of Illinois at Chicago, IL 60612, USA.
authors.forename: Harel
authors.initials: H
authors.lastname: Dahari
authors.affiliation: Rottapharm Madaus, Madaus GmbH, Colonia Allee 15, Cologne 51067, Germany.
authors.forename: Ralf T
authors.initials: RT
authors.lastname: Pohl
authors.affiliation: Internal Medicine 3, Department of Gastroenterology and Hepatology, Medical University of Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Ferenci
authors.affiliation: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA. Electronic address: asp@lanl.gov.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D008962:Models, Theoretical; D012367:RNA, Viral / Q000097:blood; D000077385:Silybin; D012838:Silymarin / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load; D014779:Virus Replication / Q000502:physiology*
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D012838:Silymarin; D000077385:Silybin