Efficiency of oxetanocin-G, a novel nucleoside against the woodchuck hepatitis virus

Ikeda, Naoki; Kaneko, Shuichi; Shimoda, Akihiro; Inagaki, Yutaka; Unoura, Masashi; Okada, Mineaki; Yonekawa, Yoshiaki; Takahashi, K.; Kobayashi, Kenichi

doi:10.1093/jac/33.1.83

Cited by 9 publications

(8 citation statements)

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“…To date, no nucleosides with efficacies approaching that of BMS-200475 appear to have been reported on in the published studies of antiviral agents in woodchucks (11,13,15,19,30,34,39,41). While efficacy has been seen with 2'-fluorinated arabinosyl-pyrimidine nucleosides (15,41), there was also manifest toxicity marked by anorexia and death.…”

Section: Discussionmentioning

confidence: 99%

“…The efficacy of BMS-200475 against hepadnavirus infection in woodchucks (Marmota monax) chronically infected with woodchuck hepatitis virus (WHV) was determined. This animal model (35,40) of HBV infection is widely accepted and has proved to be useful for the evaluation of antiviral agents directed against HBV (7,11,13,15,19,30,34,35,39,41). Daily oral administration of BMS-200475 at doses as low as 0.02 mg/kg of body weight markedly reduced serum WHV DNA levels in woodchucks with no evidence of toxicity at the dose levels used.…”

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confidence: 99%

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Efficacy of the Carbocyclic 2′-Deoxyguanosine Nucleoside BMS-200475 in the Woodchuck Model of Hepatitis B Virus Infection

Genovesi

Lamb

Medina

et al. 1998

Antimicrob Agents Chemother

110

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Daily oral treatment with the cyclopentyl 2′-deoxyguanosine nucleoside BMS-200475 at doses ranging from 0.02 to 0.5 mg/kg of body weight for 1 to 3 months effectively reduced the level of woodchuck hepatitis virus (WHV) viremia in chronically infected woodchucks as measured by reductions in serum WHV DNA levels and endogenous hepadnaviral polymerase activity. Within 4 weeks of daily therapy with 0.5 or 0.1 mg of BMS-200475 per kg, endogenous viral polymerase levels in serum were reduced about 1,000-fold compared to pretreatment levels. Serum WHV DNA levels determined by a dot blot hybridization technique were comparably decreased in these treated animals. In the 3-month study, the sera of animals that had undetectable levels of WHV DNA by the dot blot technique were further analyzed by a highly sensitive semiquantitative PCR assay. The results indicate that BMS-200475 therapy reduced mean WHV titers by 107- to 108-fold, down to levels as low as 102 to 103 virions/ml of serum. Southern blot hybridization analysis of liver biopsy samples taken from animals during and after BMS-200475 treatment showed remarkable reductions in the levels of WHV DNA replicative intermediates and in the levels of covalently closed circular viral DNA. WHV viremia in BMS-200475-treated WHV carriers eventually returned to pretreatment levels after therapy was stopped. These results indicate that BMS-200475 should be evaluated in clinical trials for the therapy of chronic human hepatitis B virus infections.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Efficacy of the Carbocyclic 2′-Deoxyguanosine Nucleoside BMS-200475 in the Woodchuck Model of Hepatitis B Virus Infection

Genovesi

Lamb

Medina

et al. 1998

Antimicrob Agents Chemother

110

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“…DAPD was selected for these studies since it is more potent against HBV in vitro than DXG, and because it is more water soluble. The woodchuck (Marmota monax) has been shown to be an excellent animal model for studying the efficacy of antiviral agents against HBV in vivo (Fourel et a/., 1993;Ikeda et a/., 1994). However, there are no reports concerning drug disposition in this animal model.…”

Section: Discussionmentioning

confidence: 99%

“…A comparison of HBV and WHV endogenous DNA polymerase properties shows remarkable similarities in conditions required for optimal activity, and these enzymes are inhibited by certain nucleotide triphosphates to the same extent (Hantz et al, 1984). The woodchuck model has also been shown to be a sLiitable animal model for studying the efficacy of antiviral agents against HBV in vivo (Fourel et al, 1990;Ikeda et al, 1994). However, there are no reports concerning drug disposition in this animal model.…”

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confidence: 99%

Pharmacokinetics of (-)-β-D-2,6-Diaminopurine Dioxolane and its Metabolite, Dioxolane Guanosine, in Woodchucks (Marmota Monax)

Rajagopalan

Boudinot

Chu

et al. 1996

Antivir Chem Chemother

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SummaryThe woodchuck (Marmota monax) is a useful animal model for evaluating the in-vivo efficacy of antiviral agents against hepatitis B viral infection (HBV). The pharmacokinetics of a newly synthesized antiviral agent (-H-o-2,6-diaminopurine dioxolane (DAPD) in woodchucks is reported. DAPD is a nucleoside analogue, having potent and selective activity against human immunodeficiency virus and HBV in vitro. DAPD is susceptible to deamination in vivo by the ubiquitously present enzyme adenosine deaminase yielding the active metabolite dioxolane guanosine (DXG). The pharmacokinetics of DAPD and DXG were characterized following intravenous (Lv.) and oral (p.o.) administration of 20 mg kg-1 of DAPD to woodchucks. Plasma and urine samples were collected, and nucleoside concentrations were determined by HPLC. Following intravenous administration, the halflife of DAPD averaged 6.7 ± 4.3 h, and that of DXG averaged 17.6 ± 14.5 h. The mean total clearance and steady state volume of distribution of DAPD were 0.33 ± 0.14 L h kg-1 and 1.76 ± 0.65 L kg-\ respectively. The oral bioavailability of DAPD ranged from 3.7-8.2%; however, the apparent availability of DXG following oral administration of DAPD was 10.5-53%.

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“…A comparison of the endogenous DNA polymerase properties of HBV and WHV shows striking similarities in terms of the conditions required for optimal activity, and these enzymes are inhibited by certain nucleotide triphosphates to the same extent in vitro (12). The woodchuck model has also been shown to be a suitable animal model for studying the efficacy of antiviral agents against HBV in vivo (10,17). However, there are no reports concerning drug disposition in this animal model.…”

mentioning

confidence: 99%

Pharmacokinetics of (-)-2'-3'-dideoxy-3'-thiacytidine in woodchucks

Rajagopalan

Boudinot

Chu

et al. 1996

Antimicrob Agents Chemother

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The woodchuck (Marmota monax) has proven to be a suitable animal model for studying hepatitis B virus (HBV) infection owing to similarities in the course of infection between woodchuck hepatitis virus (WHV) in woodchucks and HBV in humans. (-)-beta-L-2',3'-Dideoxy-3'-thiacytidine (3TC; lamivudine) is a nucleoside analog which has demonstrated antiviral activity against HBV as well as human immunodeficiency virus (HIV). The purpose of the present investigation was to characterize the pharmacokinetics of 3TC following intravenous and oral administration of 20 mg of 3TC per kg of body weight to woodchucks. Following intravenous administration, the concentrations of 3TC in plasma declined, with a terminal half-life of 2.84 +/- 0.85 h (mean +/- standard deviation). The systemic clearance and steady-state volume of distribution of 3TC were 0.22 +/- 0.078 liters/h/kg and 0.75 +/- 0.13 liters/kg, respectively. The renal clearance of the nucleoside analog was 0.063 +/- 0.016 liters/h/kg. The oral bioavailability of 3TC ranged from 18 to 54%. Allometric relationships between pharmacokinetic parameters and body weight developed by Hussey et al. (E.K. Hussey, K.H. Donn, M.J. Daniel, S.T. Hall, A.J. Harker, and G.L. Evans, J. Clin. Pharmacol. 34:975-977, 1994) were augmented by including data from woodchucks, monkeys (S.M. Blaney, M.J. Daniel, A.J. Harker, K. Godwin, and F.M. Balis, Antimicrob. Agents Chemother. 39:2779-2782, 1995), and additional data from rats (P. Rajagopalan, L. Moore, C.K. Chu, R.F. Schinazi, and F.D. Boudinot, submitted for publication). Interspecies scaling of the pharmacokinetic parameters of 3TC demonstrated a good correlation between clearance (0.74 . W0.76 [where W is body weight]; r = 0.93; P < 0.025), apparent volume of distribution (1.62 . W0.81; r = 0.98; P < 0.005), and steady-state volume of distribution (1.09 . W0.94; r = 0.99; P < 0.05) and species body weight. The allometric relationships for clearance and volume of distribution at steady state predicted the observed pharmacokinetic parameters in humans quite well; however, the apparent volume of distribution was underestimated in humans. Thus, the pharmacokinetic data obtained with the woodchuck HBV animal model should be useful for designing clinical trials.

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Efficiency of oxetanocin-G, a novel nucleoside against the woodchuck hepatitis virus

Cited by 9 publications

References 0 publications

Efficacy of the Carbocyclic 2′-Deoxyguanosine Nucleoside BMS-200475 in the Woodchuck Model of Hepatitis B Virus Infection

Efficacy of the Carbocyclic 2′-Deoxyguanosine Nucleoside BMS-200475 in the Woodchuck Model of Hepatitis B Virus Infection

Pharmacokinetics of (-)-β-D-2,6-Diaminopurine Dioxolane and its Metabolite, Dioxolane Guanosine, in Woodchucks (Marmota Monax)

Pharmacokinetics of (-)-2'-3'-dideoxy-3'-thiacytidine in woodchucks

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