Disease relevance of Clevudine

• We determined the frequency of integrated viral DNA in the livers of three woodchucks chronically infected with the woodchuck hepatitis virus before and during 30 weeks of therapy with the nucleoside analog L-FMAU [1-(2-fluoro-5-methyl-beta, L-arabinofuranosyl)uracil, clevudine] [1].
• Median serum hepatitis B virus DNA reductions from baseline at week 12 were 0.20, 4.49, and 4.45 log10 copies/mL in the placebo, 30-mg clevudine, and 50-mg clevudine groups, respectively (P < .0001) [2].
• A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B [3].
• Clevudine was well tolerated, with no dose-limiting toxicities [3].
• The reduction in viremia was remarkably rapid at the higher doses of L-FMAU, with greater than 1,000-fold reductions in WHV-DNA serum levels observed after as little as 2 to 3 days of therapy [4].
• We describe two cases of drug-induced myopathy during long-term treatment of chronic hepatitis B with clevudine [5].
• Myopathy associated with clevudine is characterized by a weakness in proximal muscles of the lower extremities with elevated muscle enzymes and presumably caused by mitochondrial toxicities [6].

High impact information on Clevudine

• Clevudine therapy with vaccine inhibits progression of chronic hepatitis and delays onset of hepatocellular carcinoma in chronic woodchuck hepatitis virus infection [7].
• A total of 98 patients with HBeAg-positive chronic hepatitis B were randomized to placebo (n=32), 30-mg clevudine (n=32), and 50-mg clevudine (n=34) groups [2].
• Moreover, L-FMAU inhibited preferentially HBV plus strand DNA synthesis in these cell lines [8].
• Four weeks of once-daily oral administration of L-FMAU significantly reduced viremia, antigenemia, intrahepatic WHV replication, and intrahepatic expression of woodchuck hepatitis virus core antigen (WHcAg) in a dose-dependent manner [4].
• Antiviral activity of clevudine [L-FMAU, (1-(2-fluoro-5-methyl-beta, L-arabinofuranosyl) uracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks (Marmota monax) [4].

Chemical compound and disease context of Clevudine

• The following anti-hepatitis B virus drugs are currently undergoing clinical testing: telbivudine, emtricitabine, tenofovir disoproxil fumarate, clevudine and thymosin-+/-1 [9].
• Mutations of the woodchuck hepatitis virus polymerase gene that confer resistance to lamivudine and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil [10].
• Recent disclosures from several laboratories clearly demonstrated that L-Fd4C was the most potent anti-HBV agent reported to date (vs. 3TC, L-FddC, L-FMAU, etc.). In fact, L-Fd4C proved to be at least 10 times more potent than Lamivudine on HBV DNA synthesis in the hepatoma cell line HepG2 2.2.15 [11].
• Repeated treatments of HepG2 cells with L-FMAU at a 1 microM concentration for 9 days did not result in any decrease in the total mitochondrial DNA content, suggesting that a mode of toxicity similar to that produced by 2',3'-dideoxycytidine is unlikely [12].
• Also at concentrations as high as 200 microM, L-FMAU did not adversely affect mitochondrial function as determined by lactic acid production by L-FMAU-treated hepatoma cells [12].

Biological context of Clevudine

• Phosphorylation of L-OddC, L-SddC, L-Fd4C, L-FMAU, and L-ddC were compared with D-deoxynucleoside analogs, AraC, dFdC, and D-FMAU, and D-dideoxynucleoside analogs, ddC and d4T [13].
• The humoral and cellular immunity associated with the combination of L-FMAU and vaccine resembled that observed in self-limited WHV infection [14].
• Carriers treated first with L-FMAU to reduce serum WHV DNA and surface antigen and then vaccinated had a similar low-level antibody response to surface antigen [14].
• Immunization with surface antigen vaccine alone and after treatment with 1-(2-fluoro-5-methyl-beta-L-arabinofuranosyl)-uracil (L-FMAU) breaks humoral and cell-mediated immune tolerance in chronic woodchuck hepatitis virus infection [14].
• Absorption of L-FMAU after oral administration was incomplete, and bioavailability was approximately 20% [15].

Anatomical context of Clevudine

• L-FMAU administration in primary duck hepatocyte cultures infected with DHBV induced a dose-dependent inhibition of both virion release in culture supernatants and intracellular viral DNA synthesis, without clearance of viral covalently closed circular DNA [16].
• 19F NMR study of the uptake of 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil in erythrocytes: evidence of transport by facilitated and nonfacilitated pathways [17].

Associations of Clevudine with other chemical compounds

• The interactions of the anti-HBV compounds 2',3'-dideoxy-2',3'-didehydro-beta-L(-)-5-fluorode-oxycytidine and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil triphosphate with HBV DP and its L(-)SddC-associated mutants have not been studied [18].
• The X-ray structure of the 5-iodocytosine analog showed a 2'-exo/3'-endo conformation for the carbohydrate moiety, which is different from those of the biologically active compounds (-)-FTC and L-FMAU [19].
• We examined the behavior of its monophosphate metabolite with human recombinant thymidylate kinase (TMPK) and showed that L-FMAU monophosphate (L-FMAUMP) is a poorer substrate than its D-configuration anomer (D-FMAUMP) [20].

Gene context of Clevudine

• Behavior of thymidylate kinase toward monophosphate metabolites and its role in the metabolism of 1-(2'-deoxy-2'-fluoro-beta-L-arabinofuranosyl)-5-methyluracil (Clevudine) and 2',3'-didehydro-2',3'-dideoxythymidine in cells [20].
• L-FMAU was metabolized in the cells to its mono-, di-, and triphosphates, A dose-dependent inhibition of HBV DNA synthesis by L-FMAU triphosphate was observed in the DNA polymerase assays with isolated HBV particles, suggesting that the mode of action of this compound could involve viral polymerase [12].
• Unique metabolism of a novel antiviral L-nucleoside analog, 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil: a substrate for both thymidine kinase and deoxycytidine kinase [21].
• In vitro cytotoxicity in MT2, CEM, 2.2.15, and H1 cells was also assessed, and the results indicated high antiviral selectivities of L-FMAU in these cells [22].
• With the introduction of new nucleoside/nucleotide analogs such as entacavir, clevudine, LFd4C,tenofovir, and immunomodulatory agents such as pegylated IFN, new treatment options, either alone or in combination, are being investigated to increase the response rate in treatment-naïve and treatment-experienced chronic hepatitis B patients [23].

Analytical, diagnostic and therapeutic context of Clevudine

• Following vaccinations, cell-mediated immunity to surface antigen was demonstrated in both groups, independent of serum viral and antigen load, but was significantly enhanced in woodchucks treated with L-FMAU and was broadened to include other viral antigens (core, e, and x antigens and selected core peptides) [14].
• Long-term administration of L-FMAU for the eradication of viral infection in animal models of HBV infection should be evaluated [16].
• Concentrations of L-FMAU in urine and plasma were determined by high-performance liquid chromatography [15].
• Six woodchuck hepatitis virus (WHV)-infected woodchucks received L-FMAU (10 mg/kg) plus FTC (30 mg/kg) intraperitoneally for 8 weeks; six other animals received in addition an intravenous injection of a recombinant adenovirus vector expressing woodchuck IFN-gamma (Ad-IFN) at weeks 4 and 8 [24].
• Adenovirus-based gene therapy during clevudine treatment of woodchucks chronically infected with woodchuck hepatitis virus [25].

References