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本帖最后由 StephenW 于 2012-3-12 23:05 编辑
http://www.ncbi.nlm.nih.gov/pubmed/22368233
Antivir Ther. 2012 Feb 27. doi: 10.3851/IMP2075. [Epub ahead of print]
Strong antiviral activity of the new l-hydroxycytidine derivative, l-Hyd4FC, in HBV-infected human chimeric uPA/SCID mice.Volz T, Lütgehetmann M, Allweiss L, Warlich M, Bierwolf J, Pollok JM, Petersen J, Matthes E, Dandri M.
Source
Department of Internal Medicine, University Medical Center Hamburg, Hamburg, Germany.
Abstract
BACKGROUND: Suppression of viral replication with nucleoside/nucleotide inhibitors has been shown to greatly improve the outcome of chronic HBV infection. β-l-nucleoside analogues, especially β-l-deoxycytidine derivatives represent one of the most efficient groups of antiretroviral compounds. We recently described that hydroxylation of the amino group of these β-l-deoxycytidine derivatives preserved their strong HBV inhibitory activity in vitro, but strongly reduced their cytotoxicity. From this new group of compounds we selected β-l-2',3'-didehydro-2',3'-dideoxy-N(4)-hydroxy-5-fluorocytidine (l-Hyd4FC) for a first in vivo investigation. The aim of this study was to determine the antiviral activity of l-Hyd4FC in HBV-infected human liver chimeric urokinase plasminogen activator (uPA)/SCID mice.
METHODS: Stably infected animals (median 6×10(7) HBV DNA/ml) were injected daily with either l-Hyd4FC (50 mg/kg) or saline as controls. Mice treated with lamivudine served to compare the in vivo antiviral potency of l-Hyd4FC. Virological changes were determined by quantitative PCR.
RESULTS: Treatment with l-Hyd4FC for 4 weeks induced a 2-log reduction of viraemia, while a median 1.5-log decline was achieved with lamivudine. Intrahepatically, l-Hyd4FC induced a median eightfold decline of viral activity (relaxed circular DNA/covalently closed circular DNA), and threefold reduction of pregenomic RNA/GAPDH levels. No significant decline of subgenomic HBV transcripts, as well as of circulating hepatitis B e antigen and hepatitis B surface antigen was detected. Maintenance of human serum albumin concentrations throughout the study, negative TUNEL staining and occurrence of viral rebound after drug withdrawal indicated that l-Hyd4FC was not toxic in human hepatocytes.
CONCLUSIONS: Administration of l-Hyd4FC in uPA/SCID mice harbouring HBV-infected human hepatocytes demonstrated the high antiviral potency of this drug in vivo. Such characteristics make l-Hyd4FC a good candidate for further investigations a as potential HBV therapeutic agent.
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