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Antimicrobial Agents and Chemotherapy, December 1998, p. 3209-3217, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

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

E. V. Genovesi,* L. Lamb, I. Medina, D. Taylor, M. Seifer,dagger S. Innaimo, R. J. Colonno, D. N. Standring,dagger and J. M. Clark

Pharmaceutical Research Institute, Bristol-Myers Squibb, Wallingford, Connecticut 06492

Received 8 May 1998/Returned for modification 1 July 1998/Accepted 11 September 1998

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.

* Corresponding author. Mailing address: Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660. Phone: (203) 677-6570. Fax: (203) 677-6771. E-mail: eugene_v_genovesi{at}ccmail.bms.com.

dagger Present address: Schering Plough Pharmaceutical Research Institute, Kenilworth, N.J. 07033.

Antimicrobial Agents and Chemotherapy, December 1998, p. 3209-3217, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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