Antiviral Activities and Pharmacokinetics of Penciclovir and Famciclovir in Pekin Ducks Chronically Infected with Duck Hepatitis B Virus

Tsiquaye, K. N.; Sutton, David; Maung, Mala; Boyd, M R

doi:10.1177/095632029600700305

Cited by 27 publications

(16 citation statements)

References 33 publications

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“…These data confirm the activity of their respective nucleosides, which have a validated anti-HBV action in vivo and in tissue culture (Schalm et al, 1985;Ueda et al, 1989;Shaw et al, 1994;Tsiquaye et al, 1994Tsiquaye et al, , 1996Howe etal., 1996;Korba and Boyd, 1996;Kruger et al, 1996;Main et al, 1996). Penciclovir is a highly selective antiviral agent, having activity against herpesviruses (Boyd et al, 1987) and hepadnaviruses (Shaw et al, 1994;Tsiquaye et al, 1994) but being non-toxic to replicating cells (Vere Hodge and Perkins 1989;Boyd et al, 1993).…”

Section: Inhibitory Effect Of Guanosine Analogue Triphosphates On Thesupporting

confidence: 66%

“…tured hepatocytes, and in vivo in animal models ofHBV infection (Shaw et al, 1994;Tsiquaye et al, 1994Tsiquaye et al, , 1996Korba and Boyd, 1996;Lin et al, 1996). It was also shown that K i for HBV DNA polymerase contrast with high K., for cellular polymerase giving rise to high selectivity (Korba and Boyd, 1996).…”

Section: Inhibitory Effect Of Guanosine Analogue Triphosphates On Thementioning

confidence: 99%

“…Furthermore, results of in vivo experiments showed that the intraperitoneal administration ofpenciclovir induced a profound inhibition of viral DNA and protein synthesis in ducks congenitally infected with DHBV . Famciclovir, its oral form, was also shown to inhibit viral replication in congenitally DHBV-infected ducklings (Tsiquaye et al, 1994(Tsiquaye et al, , 1996. Preliminary evidence suggests that famciclovir may have clinical utility in the treatment of chronic HBV-infected patients (Main et al, 1996) and of HBV recurrence after orthotopic liver transplantation (Kruger et al,1996) In view of the low cytotoxicity of penciclovir and its potent antiviral activity against HBV, it is important to gain a better understanding of the mechanism of inhibition of HBV replication.…”

Section: Introductionmentioning

confidence: 99%

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Inhibitory Effect of Penciclovir-Triphosphate on Duck Hepatitis B Virus Reverse Transcription

Dannaoui

Trépo

Zoulim

1997

Antivir Chem Chemother

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H 13, P182. SummaryTheaim of this studywas to investigate the mechanism of inhibition of hepatitis B virus replication by pencic1ovir-triphosphate, the active metabolite of famcic1ovir. A recently developed in vitro translation assay for the expression of an enzymatically active duck hepatitis B virus (DHBYj reverse transcriptase was used to assess the inhibitory activity of penciclovirtriphosphate (PCV-TPj in comparison with other guanosine analogue triphosphates. Acyclovir-triphosphate (ACV-TP), the chiral triphosphates of penciclovir (PCV), (Rj-PCV-TP and (Sj-PCV-TP, and carbocyclic 2'-deoxyguanosine-TP (CDG-TPj did inhibit reproducibly minus strand DNAsynthesis to differentextents. CDG-TP was the most potent inhibitor of dGTP incorporation. The inhibitory effect of these compounds against the incorporation of the first nucleotide of minus strand DNA, dGMP, was similar to that observed with DNA chain elongation. 2',3'-dideoxyguanosine-TP (ddG-TP), ACV-TP and both (R) and (Sj-PCV-TP inhibited the incorporation of the next nucleotides in the short DNA primer, whereas CDG-TP did not. These results demonstrate that PCV-TP inhibits hepadnavirus reverse transcription by inhibiting the synthesis of the short DNA primer. The data obtained with the inhibition of the enzymatic activity ofthe DHBV polymerase provides a new insightinto the mechanismofaction of penciclovir-triphosphate on HBV replication.

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Section: Inhibitory Effect Of Guanosine Analogue Triphosphates On Thesupporting

confidence: 66%

Section: Inhibitory Effect Of Guanosine Analogue Triphosphates On Thementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibitory Effect of Penciclovir-Triphosphate on Duck Hepatitis B Virus Reverse Transcription

Dannaoui

Trépo

Zoulim

1997

Antivir Chem Chemother

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“…16,17 Later, famciclovir was shown to have activity against human and duck hepatitis B viruses in enzymatic and cell culture assays and in animal models of infection. 15,[18][19][20][21] Clinical studies subsequently showed that famciclovir can reduce serum HBV levels in patients chronically infected with HBV. 5,10,11 In analogous fashion to the treatment of human immunodeficiency virus (HIV) infection, HBV infection also requires prolonged administration of nucleoside analogs to eliminate the virus from patients' sera, and emergence of drug-resistant HBV during extended monotherapy appears to be a factor that may ultimately limit treatment efficacy.…”

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confidence: 99%

In vitro evaluation of hepatitis B virus polymerase mutations associated with famciclovir resistance

et al. 2000

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Several mutations (V521L, P525L, L528M, T532S, and V555I) in the gene for hepatitis B virus (HBV) polymerase have been identified in HBV isolated from patients that displayed break-through viremia during famciclovir treatment. To determine whether these mutations cause phenotypic resistance to famciclovir, we compared the inhibition constants (K i ) of penciclovir triphosphate (PCVTP, the active metabolite of famciclovir) for recombinant wild-type and mutant HBV polymerases containing these mutations. In in vitro enzymatic assays, the V555I mutation displayed the most resistance (with K i increased by 6.2-fold) to PCVTP. The V521L and L528M mutations showed moderately decreased sensitivity to PCVTP (K i increased by G3-fold). We also analyzed the cross-resistance profiles of these variants for adefovir and lamivudine, two other antiviral agents that also inhibit DNA replication by HBV polymerase. All 5 famciclovir-associated mutations were sensitive to adefovir diphosphate (ADVDP) in in vitro enzymatic assays (F2.3-fold decreased sensitivity). The V521L, L528M, and T532S mutations were also sensitive to lamivudine triphosphate (LAMTP); however, the P525L and V555I mutations displayed moderately decreased sensitivity to LAMTP in enzymatic assays (3.6-fold decreased sensitivity). The lamivudine-resistant mutations M552I, M552V, and L528M؉M552V, which were previously shown to display 8-to 25-fold resistance to LAMTP, were less resistant (I3.1-fold) to PCVTP. (HEPATOLOGY 2000;31:219-224.)Hepatitis B viral infection is a major cause of acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma, and it is one of the 10 most common causes of death worldwide. 1 Current treatment regimens rely primarily on interferon alfa therapy. However, interferon has limited efficacy, is expensive, requires parenteral administration, and is associated with frequent and unpleasant side effects. Nucleoside or nucleotide analogs, which inhibit DNA replication through hepatitis B virus (HBV) polymerase, represent a new class of promising anti-HBV therapeutics. In addition to lamivudine, 2-9 which was approved recently for the treatment of hepatitis B infection in the United States, several nucleoside and nucleotide analogs including famciclovir 5,10,11 and adefovir dipivoxil 12-14 are currently being evaluated in late stage clinical trials. These compounds have been shown to be well tolerated and can produce rapid and marked decreases in serum HBV-DNA levels.Famciclovir is the oral prodrug of penciclovir, which has to be converted to penciclovir triphosphate by cellular enzymes to become an active inhibitor against HBV polymerase by competing with the natural substrate deoxyguanosine triphosphate (dGTP). 15 Famciclovir was originally approved for the treatment of herpes simplex virus and herpes zoster virus. 16,17 Later, famciclovir was shown to have activity against human and duck hepatitis B viruses in enzymatic and cell culture assays and in animal models of infection. 15,[18][19][20][21] Clinical studies subsequently showed...

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Section: Purine Analogsmentioning

confidence: 85%

New Antiviral Agents for the Therapy of Chronic Hepatitis B Virus Infection

Zoulim

Trépo²

1999

Intervirology

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The development of new antiviral strategies for the treatment of chronic hepatitis B remains a major goal since hepatitis virus (HBV) is resistant to interferon treatment as well as to new nucleoside analogs. HBV is a small DNA virus that replicates its genome via a reverse transcription step. The viral polymerase has been the main viral target that was studied to design new antiviral treatments. Active research has led to the discovery of new nucleoside analogs that are potent inhibitors of the viral reverse transcriptase. Among them, lamivudine has also proven antiviral efficacy in clinical trials with a sustained inhibition of viral replication. However, due to the kinetics of viral clearance, long-term antiviral therapy is necessary to eradicate viral infection. These prolonged regimens are associated with the emergence of drug-resistant strains that harbor mutations in the viral polymerase gene within the conserved B and C domains. New approaches using combinations of nucleoside analogs or other strategies, such as immune intervention (DNA vaccine, stimulation of the TH1 response ) or gene therapy (antisense oligonucleotides, dominant negative mutants), should therefore be evaluated in animal models to optimize the current antiviral protocols.

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Antiviral Activities and Pharmacokinetics of Penciclovir and Famciclovir in Pekin Ducks Chronically Infected with Duck Hepatitis B Virus

Cited by 27 publications

References 33 publications

Inhibitory Effect of Penciclovir-Triphosphate on Duck Hepatitis B Virus Reverse Transcription

Inhibitory Effect of Penciclovir-Triphosphate on Duck Hepatitis B Virus Reverse Transcription

In vitro evaluation of hepatitis B virus polymerase mutations associated with famciclovir resistance

New Antiviral Agents for the Therapy of Chronic Hepatitis B Virus Infection

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