Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Famciclovir (FCV) and lamivudine (LAM) reduce viral replication in patients with recurrent hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT). Eighteen of 20 patients with insufficient response to FCV were treated with 100 mg LAM daily after OLT. These patients had shown nonresponse (n = 5), partial response (n = 7), or breakthrough (n = 6) during FCV therapy. Despite passive immunoprophylaxis with hepatitis B immunoglobulin after liver transplantation, HBV reinfection had occurred in 14 of 15 transplanted patients. HBV-DNA levels and the regions A to E of the HBV-DNA polymerase gene were analyzed before and after treatment failure to either therapy. Within 4 weeks on LAM, all but 1 patient showed a 95% average reduction of the HBV-DNA level. As with FCV, we did not observe any severe side-effects attributable to LAM. However, 7 patients developed a breakthrough within 12, 29 (n = 2), 32, 37, 54, and 145 weeks under treatment with LAM associated with the methionine-to-valine signature mutation (M552V) in the YMDD motif in all. With FCV, no unique, but a dominant, resistance pattern with the L528M mutation was identified for patients with breakthrough under FCV. In contrast, nonresponders or patients with partial response to FCV did not exhibit such mutations. Our results indicate that the L528M mutation is a risk factor for LAM breakthrough, because breakthrough during LAM occurred earlier in patients with this mutation (50 +/- 10 weeks vs. 120 +/- 21 weeks). Because breakthrough on either treatment is frequent for this specific group of patients, the use of combination therapy should be explored.
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PMID:Mutational pattern of hepatitis B virus on sequential therapy with famciclovir and lamivudine in patients with hepatitis B virus reinfection occurring under HBIg immunoglobulin after liver transplantation. 1038 63

Hepatitis B virus (HBV) infection is a major cause of chronic liver disease worldwide. Famciclovir is a nucleoside analogue with potent antiviral activity that appears promising in the management of patients with HBV infection. No data exist regarding the safety of nucleoside analogue withdrawal in patients treated for HBV cirrhosis. The authors describe a 41-year-old man with compensated HBV cirrhosis who developed fatal hepatic decompensation due to a rebound in viral replication within six weeks of discontinuing famciclovir therapy. Although several mutations in the HBV DNA polymerase gene have been documented, none has been associated with famciclovir resistance or adverse clinical outcomes. Clinicians should consider the risk of inducing serious flares in hepatic inflammation as a result of abrupt nucleoside analogue withdrawal. Until further data are available regarding the safety of withdrawal of these agents, indefinite treatment may be required in patients with established cirrhosis.
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PMID:Fatal hepatic decompensation in a patient with hepatitis B cirrhosis following famciclovir withdrawal. 1118 39

Famciclovir is converted rapidly and efficiently after oral administration to the selective antiviral compound, penciclovir. In cell culture, penciclovir is a potent inhibitor of herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV) and hepatitis B virus (HBV). Phosphorylation of penciclovir and aciclovir in uninfected cells is limited, and penciclovir, like aciclovir, has minimal effect on replicating cells in culture as expected for a selective antiviral agent. Mode of action studies with VZV and HSV have shown that the phosphorylation of penciclovir in infected cells is far more efficient than for aciclovir. This compensates for differences observed between penciclovir triphosphate and aciclovir triphosphate in the inhibition of HSV and VZV DNA polymerases. Because HBV is not known to encode a thymidine kinase, a different rationale for the selective inhibition of this virus by penciclovir is required. Recent data indicate that the DNA polymerase of HBV is far more sensitive to inhibition by penciclovir triphosphate than cellular DNA polymerases, suggesting that for this virus, selectivity operates at the DNA polymerase. Penciclovir triphosphate is more stable within infected cells than aciclovir triphosphate, and consequently penciclovir has more prolonged antiviral activity than aciclovir. Similarly, famciclovir is more effective than aciclovir or valaciclovir in suppressing HSV replication when given at a lower dosing frequency in certain animal models. These preclinical properties have helped to provide the foundation for the famciclovir clinical programme.
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PMID:Famciclovir, from the bench to the patient--a comprehensive review of preclinical data. 1861 46