The potential anti-hBV effect of amantadine in combination with ursodeoxycholic acid and biphenyl dimethyl dicarboxylate in hepG2 2.2.15 cells.
Experimental studies have demonstrated that the triple combination of amantadine (A)/ ursodeoxycholic acid (UDCA, U)/ biphenyl dimethyl dicarboxylate (DDB, D) might have a preferential antiviral effect compared with that observed in interferon-induced antiviral signal pathways, such as those of STAT1alpha and the 6-16 genes. To confirm the result, this study examined whether the signal transduction for the antiviral activity in HepG2 2.2.15 was induced dependently or independently of interferon. To accomplish this, the correlation between the STAT1alpha and 6-16 genes, and nitric oxide, for the mediation of the antiviral activity was assessed. The increase in nitric oxide in the UDCA groups suggests that the inhibition of viral gene replication was enhanced by the amantadine combinations (AU and AUD), and might be more effective if incubated for longer periods. It was found that STAT1alpha was activated by the amantadine combination, although to a lesser extent than that of interferon-alpha, and the primary endpoints examined for the inhibition of gene expression (HBsAg and HBcAg) were remarkably well regulated. This suggests that the amantadine triple, or at least the double, combination had better clinical benefits than those of IFN-alpha and the nucleoside analogue single treatment. This demonstrates that the amantadine combination might be a substitute for the existing HBV therapy if the results of in vivo and in vitro studies concur.
Joo
Seong Soo
SS
Department of Immunology, College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea.
Lee
Do Ik
DI
D000547:Amantadine / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000096:biosynthesis; D004149:Dioxoles / Q000494:pharmacology; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006514:Hepatitis B Surface Antigens / Q000096:biosynthesis; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D024101:Mitochondrial Proteins; D009569:Nitric Oxide / Q000096:biosynthesis*; D011506:Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D014580:Ursodeoxycholic Acid / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D004279:DNA, Viral; D004149:Dioxoles; D006514:Hepatitis B Surface Antigens; C468762:IFI6 protein, human; D050832:Interferon-Stimulated Gene Factor 3; D024101:Mitochondrial Proteins; D011506:Proteins; D014157:Transcription Factors; C079868:gamma interferon activation factor; D009569:Nitric Oxide; D014580:Ursodeoxycholic Acid; C041398:7,7'-dimethoxy-(4,4'-bi-1,3-benzodioxole)-5,5'-dicarboxylic acid dimethyl ester; D000547:Amantadine