(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Hepatitis-C

Cholesterol biosynthesis suppresses the replication of HCV-1b replicons, thus influencing hepatitis C virus (HCV) natural history. This study aimed at comparing the efficacy and safety of fluvastatin (FLV) as an adjuvant therapy to the standard of care (SOC) therapy, i.e., pegylated interferon (PEG-IFN) and ribavirin, for the treatment of HCV patients.. Sixty HCV patients were enrolled and allocated to either group I, who received the triple therapy (fluvastatin + SOC), or group II, who received SOC; the duration for both treatments was 48 weeks. All patients were subjected to pretreatment liver biopsy and monthly biochemical tests (liver profile, CBC), and quantitative HCV-RNA test was performed at weeks 0, 4, 12, 48, and 72.. All virological responses were higher in group I than in group II, with no statistical difference. Group I showed no manifestations of hepatotoxicity.. Fluvastatin yielded a borderline, significantly higher complete early virological response than SOC; therefore, it is a safe adjuvant to the SOC therapy.

Topics: Adult; Antiviral Agents; Blood Cell Count; Drug Therapy, Combination; Egypt; Fatty Acids, Monounsaturated; Female; Fluvastatin; Hepacivirus; Hepatitis C; Humans; Indoles; Interferon-alpha; Liver Function Tests; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Ribavirin; RNA, Viral; Standard of Care; Treatment Outcome

Fluvastatin or simvastatin has demonstrable antiviral activity against hepatitis C virus (HCV) as monotherapy. The safety and efficacy of adding fluvastatin or simvastatin to peginterferon/ribavirin for 48 weeks was tested in HCV genotype 1 naïve-to-treatment veterans. Thirty-seven naïve-to-treatment genotype 1 HCV patients were randomized to either a control group (n = 20) to receive peginterferon alfa plus ribavirin or an experimental group (n = 18) to similarly receive peginterferon alfa plus ribavirin as well as fluvastatin 20 mg/day. In addition, seven patients who presented for HCV treatment already were on simvastatin and could not be withdrawn. These simvastatin users were not randomized but were entered into a concurrent prospective pilot arm. There were no unique safety issues with fluvastatin or simvastatin when these drugs were given with peginterferon/ribavirin for 48 weeks. Thirteen of 25 statin patients achieved sustained viral response (SVR), while 5 of 20 control patients achieved SVR. Analysis of SVR by intention-to-treat showed P = 0.078. In this phase 2 study, there were no safety issues with the addition of fluvastatin or simvastatin to peginterferon and ribavirin for 48 weeks. There was a trend towards improvement in SVR when fluvastatin or simvastatin was administered with peginterferon/ribavirin. The size of the groups did not reach the prestudy size thought needed to show significant difference (type II error). These results support the significant results of two other larger randomized controlled trials reported using the same dose of fluvastatin in naïve-to-treatment genotype 1 HCV patients.

Topics: Adult; Aged; Antiviral Agents; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Fatty Acids, Monounsaturated; Fluvastatin; Genotype; Hepacivirus; Hepatitis C; Humans; Indoles; Interferon-alpha; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Treatment Outcome

Hepatitis C virus (HCV) nonstructural protein 5B (NS5B) is an RNA-dependent RNA polymerase that plays a key role in HCV replication, and, hence, NS5B is an attractive target for hepatitis C drug discovery. Hepatitis C is a chronic liver disease affecting the global population significantly. Many NS5B inhibitors targeting active site were launched in recent years, however, still there exists a pressing need for cost-effective therapies with pan genotypic activity and therapies targeting niche HCV population with comorbities and resistant to earlier therapies. The objective of the current study is to identify potential anti-HCV agents from FDA approved drugs that are already in the market for a different disease-Drug repurposing approach. A combination of computational chemistry and computational biology techniques was used to discover potential therapies for hepatitis C targeting the NS5B Thumb I allosteric site. Computational chemistry analysis emphasized the fact that fluvastatin, a lipid lowering agent, and olopatadine, an antihistamine, exhibited good binding affinity to NS5B. In addition, gene set enrichment analysis brought to light the significant overlap between disease characteristic features and the mechanism of action of fluvastatin and olopatadine. The current study concludes the potentially beneficial use of fluvastatin in niche hepatitis C patient population suffering from nonalcoholic fatty liver diseases.

Topics: Allosteric Site; Antiviral Agents; Computational Biology; Drug Repositioning; Fluvastatin; Hepacivirus; Hepatitis C; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Ligands; Metabolic Networks and Pathways; Molecular Docking Simulation; Molecular Dynamics Simulation; Olopatadine Hydrochloride; Protein Binding; Protein Structure, Secondary; Transcriptome; User-Computer Interface; Viral Nonstructural Proteins

Topics: Antiviral Agents; Fatty Acids, Monounsaturated; Fluvastatin; Hepacivirus; Hepatitis C; HIV Infections; Humans; Indoles; RNA, Viral; Viral Load; Virus Replication

Topics: Antiviral Agents; Fatty Acids, Monounsaturated; Fluvastatin; Hepacivirus; Hepatitis C; HIV Infections; Humans; Indoles; Randomized Controlled Trials as Topic; RNA, Viral; Viral Load; Virus Replication