penciclovir and Herpes-Zoster

The discovery of acyclovir and penciclovir has led to the development of a successful systemic therapy for treating herpes simplex virus infection and varicella-zoster virus infection, and the orally available prodrugs, valacyclovir and famciclovir, have improved antiviral treatment compliance. Acyclovir and penciclovir are phosphorylated by viral thymidine kinase and are incorporated into the DNA chain by viral DNA polymerase, resulting in chain termination. Helicase-primase plays an initial step in DNA synthesis to separate the double strand into two single strands (replication fork) and is a new target of antiviral therapy. The helicase-primase inhibitors (HPIs) pritelivir and amenamevir have novel mechanisms of action, drug resistance properties, pharmacokinetic characteristics, and clinical efficacy for treating genital herpes. The clinical study of amenamevir in herpes zoster has been completed, and amenamevir has been submitted for approval for treating herpes zoster in Japan. The clinical use of HPIs will be the beginning of a new era of anti-herpes therapy.

Topics: Acyclovir; Animals; Antiviral Agents; Clinical Trials as Topic; Guanine; Herpes Simplex; Herpes Zoster; Herpesvirus 3, Human; Humans; Oxadiazoles; Simplexvirus

The herpesviruses continue to produce considerable morbidity in man. Once infected with herpes simplex (HSV), the virus remains dormant within the nervous system and may reactivate if provoked by stress, trauma and/or other factors. To date, there is no cure, but antiviral medication can reduce duration and severity of symptoms and prophylaxis can suppress recurrent episodes of disease. The second-generation guanosine nucleosides, acyclovir and penciclovir, are effective inhibitors with low toxicity; both, however, have relatively low oral bioavailability. Subsequently, the orally bioavailable prodrugs valaciclovir and famciclovir have been introduced. These compounds offer high oral bioavailabilty and deliver acyclovir and penciclovir, respectively, to the target cells by means of more convenient dosing schedules. This short review points to recent experience with famciclovir in the management of HSV and varicella-zoster virus.

Topics: 2-Aminopurine; Acyclovir; Antiviral Agents; Biological Availability; Clinical Trials as Topic; Famciclovir; Guanine; Herpes Genitalis; Herpes Zoster; Humans; Male; Nervous System; Prodrugs

Topics: 2-Aminopurine; Acyclovir; Antiviral Agents; Famciclovir; Guanine; Herpes Genitalis; Herpes Labialis; Herpes Simplex; Herpes Zoster; Herpesvirus 3, Human; Humans; Immunocompromised Host; Prodrugs; Simplexvirus; Virus Replication

Topics: 2-Aminopurine; Acyclovir; Adrenal Cortex Hormones; Antiviral Agents; Chickenpox; Famciclovir; Guanine; Herpes Zoster; Humans; Immunocompromised Host; Prodrugs; Valacyclovir; Valine

Topics: 2-Aminopurine; Acyclovir; Antiviral Agents; Famciclovir; Guanine; Herpes Zoster; Herpesviridae Infections; Humans

Famciclovir is the well-absorbed oral form of penciclovir, a potent and selective antiviral agent, with activity against members of the herpesvirus family, including varicella-zoster virus (VZV), and herpes simplex virus-1 (HSV-1) and HSV-2. Famciclovir is rapidly absorbed and converted to penciclovir. Penciclovir has excellent bioavailability (77%) after oral administration of 500 mg of famciclovir. Similar to acyclovir, famciclovir is converted by phosphorylation to its active metabolite, penciclovir-triphosphate. Penciclovir-triphosphate has a prolonged in vitro intracellular half-life of 10 to 20 hours in HSV-1-and HSV-2-infected cells, respectively, and 9 to 14 hours in VZV-infected cells. In contrast, the in vitro intracellular half-life of acyclovir is substantially shorter at 0.7 and 1 hours in HSV-1- and HSV-2-infected cells, respectively, and 0.8 hours in VZV-infected cells. Famciclovir is eliminated primarily via the kidneys. Dosage adjustment is not required for famciclovir in elderly patients with normal or mildly impaired renal function, and the extent of penciclovir availability is not affected by food. The excellent bioavailability ensures that adequate drug reaches virus-infected cells, and the prolonged intracellular half-life of the active form of famciclovir results in persistent antiviral activity.

Topics: 2-Aminopurine; Acyclovir; Aged; Antiviral Agents; Drug Interactions; Famciclovir; Guanine; Herpes Zoster; Humans

In comparison to the range of antibiotics used in medicine, the spectrum of antifungal and antiviral drugs used in primary dental care is relatively limited. In practical terms, there are only three antifungal agents and two antiviral agents that have a role. This paper will describe the clinical presentation of orofacial candidal and viral infections and the use of antimicrobial drugs in their management.

Topics: Acyclovir; Amphotericin B; Antifungal Agents; Antiviral Agents; Candidiasis, Oral; Cheilitis; Dental Care; Fluconazole; Glossitis; Guanine; Herpes Zoster; Humans; Miconazole; Mouth Diseases; Nystatin; Primary Health Care; Stomatitis, Herpetic

Topics: 2-Aminopurine; Acyclovir; Antiviral Agents; Cytomegalovirus Infections; Drug Resistance, Viral; Famciclovir; Guanine; Hepatitis B; Hepatitis C; Herpes Simplex; Herpes Zoster; Humans; Influenza, Human; Valacyclovir; Valine; Virus Diseases

We have characterized the differential actions of acyclovir and penciclovir against varicella-zoster virus (VZV) in cell culture by comparing the frequency of appearance of resistant viruses followed by their characterization. Cells were infected with cell-free virus and the cultures were successively treated with increasing concentrations of acyclovir or penciclovir. Drug-resistant viruses were selected in the presence of 6 microg/ml of acyclovir or penciclovir. The emergence frequency of resistant viruses was significantly higher following acyclovir exposure than following penciclovir exposure (Fisher's exact test, P<0.0001), possibly reflecting virus growth differences under these experimental conditions. Based on antiviral drug susceptibility and thymidine kinase (TK) activity assays, 11 acyclovir-resistant variants from seven experiments using three virus strains (Kawaguchi strain, Oka varicella vaccine strain and a clinical isolate from a zoster patient) were found to be TK-deficient. Sequence analysis of TK-deficient variants of the Kawaguchi strain revealed deletions that caused frameshifts, resulting in premature termination in the TK gene.

Topics: Acyclovir; Antiviral Agents; Cells, Cultured; DNA, Viral; Drug Resistance, Microbial; Genes, Viral; Guanine; Herpes Zoster; Herpesvirus 3, Human; Humans; Lung; Microbial Sensitivity Tests; Sequence Analysis, DNA; Thymidine Kinase; Viral Plaque Assay

Topics: 2-Aminopurine; Acetamides; Acyclovir; Aged; Amantadine; Animals; Anti-HIV Agents; Antiviral Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Resistance, Microbial; Enzyme Inhibitors; Famciclovir; Ganciclovir; Guanidines; Guanine; Herpes Simplex; Herpes Zoster; History, 18th Century; HIV Infections; Humans; Injections, Intravenous; Interferon-alpha; Lamivudine; Neuraminidase; Oseltamivir; Pyrans; Rats; Ribavirin; Sialic Acids; Teratogens; Valacyclovir; Valine; Zanamivir

Topics: 2-Aminopurine; Acyclovir; Antiviral Agents; Famciclovir; Guanine; Herpes Labialis; Herpes Zoster; Humans; Valacyclovir; Valine

The metabolism and mode of action of penciclovir [9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine; BRL 39123] were studied and compared with those of acyclovir. In uninfected MRC-5 cells, low concentrations of the triphosphates of penciclovir and acyclovir were occasionally just detectable, the limit of detection being about 1 pmol/10(6) cells. In contrast, in cells infected with either herpes simplex virus type 2 (HSV-2) or varicella-zoster virus (VZV), penciclovir was phosphorylated quickly to give high concentrations of the triphosphate ester. Following the removal of penciclovir from the culture medium, penciclovir-triphosphate remained trapped within the cells for a long time (half-lives, 20 and 7 h in HSV-2- and VZV-infected cells, respectively). In HSV-2-infected cells, acyclovir was phosphorylated to a lesser extent and the half-life of the triphosphate ester was only 1 h. We were unable to detect any phosphates of acyclovir in VZV-infected cells. (S)-Penciclovir-triphosphate inhibited HSV-1 and HSV-2 DNA polymerase competitively with dGTP, the Ki values being 8.5 and 5.8 microM, respectively, whereas for acyclovir-triphosphate, the Ki value was 0.07 microM for the two enzymes. Both compounds had relatively low levels of activity against the cellular DNA polymerase alpha, with Ki values of 175 and 3.8 microM, respectively. (S)-Penciclovir-triphosphate did inhibit DNA synthesis by HSV-2 DNA polymerase with a defined template-primer, although it was not an obligate chain terminator like acyclovir-triphosphate. These results provide a biochemical rationale for the highly selective and effective inhibition of HSV-2 and VZV DNA synthesis by penciclovir and for the greater activity of penciclovir than that of acyclovir when HSV-2-infected cells were treated for a short time.

Topics: Acyclovir; Base Sequence; Cell Line; DNA-Directed DNA Polymerase; DNA, Viral; Esterification; Guanine; Herpes Simplex; Herpes Zoster; Herpesvirus 3, Human; Humans; Molecular Sequence Data; Nucleic Acid Hybridization; Nucleic Acid Synthesis Inhibitors; Phosphates; Phosphorylation; Simplexvirus; Time Factors