Inhibition of Varicella-Zoster Virus by Penciclovir in Cell Culture and Mechanism of Action

Bacon, Teresa H.; Gilbart, J.; Howard, Barbara A.; Standring-Cox, Ruth

doi:10.1177/095632029600700203

Cited by 16 publications

(9 citation statements)

References 21 publications

(23 reference statements)

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“…The withdrawal of aciclovir for 18h in each 24-hour period therefore resulted in greater virus replication when measured 72h after infection than in parallel cultures treated with penciclovir. Similarly, pulse treatment with penciclovir was significantly more effective than with aciclovir in MRC-5 cells infected with clinical isolates of VZV (Bacon et al 1996a). With HSV-2 strains, pulse treatment with penciclovir was marginally more effective than aciclovir (Table 5; Inhibition of HSV by penciclovir 135 p = 0.062; n = 6 strains), although results from a preliminary study with one HSV-2 strain revealed that penciclovir was significantly more active than aciclovir at 1~g mr' (Fig.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Further Characterization of the Potent and Prolonged Inhibition of Herpes Simplex Virus Replication in Human Cell Lines by Penciclovir

Bacon

Howard

1996

Antivir Chem Chemother

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SummaryThe replication of herpes simplex virus type 1 (HSV-1) or HSV-2 in MRC-5 cells infected at 0.01 pfu ceni and treated continuously for 72 h, was inhibited more efficiently by penciclovir than aciclovir (p =0.0001).However, multiple cycles of replication were required in order to distinguish the compounds. Virus from cultures treated for 72 h with either compound, at 3 or 10 /1g mr", was resistant to penciclovir and aciclovir (50% effective concentrations> 10 /1g mr"), but infectivity titres of supernatants from these aciclovirtreated cultures were higher than for penciclovir. Increased production of resistant virus in aclclovlrtreated cultures may be the consequence of the less potent inhibition of virus replication by aciclovir. Penciclovir caused prolonged inhibition of HSV-1 and HSV-2 replication in three human cell lines infected at 1 pfu celr" following treatment for 18 h, whereas virus replication resumed rapidly after withdrawal of aclclovir. Neither compound showed prolonged activity after 18 h treatment, when the multiplicity of infection was reduced to 0.01 pfu ceir'. This surprising observation prompted experiments testing the effect of repeated pulse treatment in cultures infected at low multiplicity. Penciclovir inhibited HSV-1 replication significantly more effectively than aciclovir in MRC-5 cells infected at 10-4 pfu ceni and treated daily for 6 h (p < 0.001, n =5) but only a trend was observed for HSV-2 (p =0.06, n =6).

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Section: Discussionmentioning

confidence: 99%

“…As with aciclovir (ACV), penciclovir also inhibits varicellazoster virus replication (Boyd et al, 1993;Bacon et al 1996a). Famciclovir, the oral form of penciclovir (Pue and Benet, 1993), has been approved for the treatment of herpes zoster and acute genital herpes infections.…”

Section: Introductionmentioning

confidence: 99%

Further Characterization of the Potent and Prolonged Inhibition of Herpes Simplex Virus Replication in Human Cell Lines by Penciclovir

Bacon

Howard

1996

Antivir Chem Chemother

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“…Therefore, higher doses and/or increased administration frequency of valacyclovir or famciclovir would be required for efficient treatment for EHV-1 infection. However, it has been reported that the intracellular half-lives of penciclovir triphosphate are much longer than those of acyclovir triphosphate in human cells infected with herpes simplex virus type 1 (HSV-1), type 2 (HSV-2), or varicella-zoster virus (VZV) (10 hr vs. 0.7 hr, 20 hr vs. 1 hr, and 9.1 hr vs. 0.8 hr, respectively) [3,10,33]. Additionally, in both tissue culture [2] and animal infection [6,28], penciclovir has a more sustained antiviral effect than acyclovir against HSV-1 and -2, a finding that may be correlated with the difference in the stability of the 2 compounds in infected cells.…”

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confidence: 99%

Pharmacokinetics of Penciclovir after Oral Administration of its Prodrug Famciclovir to Horses

Tsujimura

Yamada

Nagata

et al. 2010

The Journal of Veterinary Medical Science

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ABSTRACT. We investigated the pharmacokinetics of penciclovir after oral administration of its prodrug famciclovir to horses. Following an oral dose of famciclovir at 20 mg/kg, maximum plasma concentrations of penciclovir occurred between 0.75 and 1.5 hr (mean 0.94  0.38 hr) after dosing and were in the range 2.22 to 3.56 g/ml (mean 2.87  0.61 g/ml). The concentrations of penciclovir declined in a biphasic manner after the peak concentration was attained. The mean half-life of the rapid elimination phase was 1.73  0.34 hr whereas that of the slow elimination phase was 34.34  13.93 hr. These pharmacokinetic profiles observed were similar to those of another antiherpesvirus drug, acyclovir, previously reported in horses following oral dosing of its prodrug valacyclovir.KEY WORDS: equine, famciclovir, penciclovir, pharmacokinetics.J. Vet. Med. Sci. 72(3): 357-361, 2010 Equine herpesvirus type 1 (EHV-1) is a major causative agent of respiratory disease in horses and can also lead to abortion and neurological disease [1]. In particular, the recent increase in neurological EHV-1 outbreaks among horses in the U.S.A., the U.K. and Europe is of major concern to the horse industry worldwide, since affected animals often have a poor prognosis [7,8,[17][18][19][20]. The antiherpesvirus drug acyclovir has been used for the treatment of EHV-1-associated neurological disorders [13,20,36]. Oral administration is preferable to intravenous infusion during outbreaks, but pharmacokinetic studies have revealed that acyclovir given orally to horses is poorly bioavailable and reaches low plasma concentrations [4,15,35] that do not exceed the 50% effective concentration (EC 50 ) against EHV-1 strains, as determined by in vitro plaque reduction assay [16]. In contrast, oral administration of valacyclovir, the prodrug of acyclovir, achieves concentrations within the sensitivity range of EHV-1 [15,23]. Therefore, valacyclovir is now considered to be an attractive candidate for treatment of EHV-1-associated neurological disorders, even though its therapeutic efficacy has not been proven in a controlled study.Another antiherpesvirus drug, famciclovir, is the oral prodrug of penciclovir. Like acyclovir, penciclovir is a guanine analogue. It is phosphorylated to penciclovir monophosphate by the viral thymidine kinase, and then to penciclovir diphosphate and triphosphate by cellular enzymes in virusinfected cells [32,33]. Penciclovir triphosphate inhibits viral DNA synthesis through competitive inhibition of DNA polymerase; consequently, viral replication in herpesvirusinfected cells is inhibited, with no effect on DNA synthesis in uninfected cells [10,32]. However, like acyclovir, penciclovir is very poorly absorbed when administered orally to rodents [6,34] and humans [5]. Famciclovir is the diacetyl ester of 6-deoxy penciclovir and has good bioavailability in humans [5,12,24,34]. After oral administration, famciclovir is converted to penciclovir through di-deacetylation in the intestinal wall and liver and oxidation in the liver [3...

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“…The clinical advantages of these prodrugs, particularly famciclovir, relative to aciclovir are also discussed. Data from VereHodge & Cheng (1993) and Bacon et al (1996).…”

Section: Clinical Efficacymentioning

confidence: 99%

Antiviral Treatment: From Concept to Reality

Boon

1997

Antivir Chem Chemother

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The initial development of antiviral compounds was slow, with the first clinical antiviral agent not available until the 1960s. Early development was hindered by the lack of understanding of virus life-cycles and the absence of an assay system for antiviral activity. The appearance of the first assay system, the fertilized egg yolk sac, led to the identification of methisazone. This was the first antiviral agent to be used clinically. The improvement in antiviral assay systems, and the start of directed research programmes led to the development of the first antiherpes agents idoxuridine, trifluorothymidine (TFT) and vidarabine. However, all of these agents were associated with significant adverse effects. Antiherpes therapy took a major step forward with the development of the acyclic nucleoside analogue, aciclovir. Aciclovir is much more potent than previous antiherpesvirus agents. Its mode of action results in selectivity for herpesvirus-infected cells, thus significantly reducing the side-effects seen with earlier agents. Because of this, it became the standard therapy for herpes simplex virus type 1 (HSV-1), HSV-2 and varicella zoster virus infections. However, the bioavailability of oral aciclovir is poor, requiring high and frequent doses. This led to the search for better absorbed agents and to the development of two prodrugs, famciclovir and valaciclovir. Both famciclovir and valaciclovir offer much improved bioavailability of the nucleosides penciclovir and aciclovir, compared with aciclovir. Once in the body the conversion of valaciclovir to aciclovir means that the two agents have similar pharmacokinetic properties. Similarly, famciclovir is converted to penciclovir in the body. Penciclovir, when phosphorylated in virus-infected cells, persists within the cell for a much longer period than aciclovir triphosphate. Over the last 10 years we have seen an acceleration in the development of antiviral agents and some major advances in antiviral therapy. Many challenges, however, still lie ahead.

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Inhibition of Varicella-Zoster Virus by Penciclovir in Cell Culture and Mechanism of Action

Cited by 16 publications

References 21 publications

Further Characterization of the Potent and Prolonged Inhibition of Herpes Simplex Virus Replication in Human Cell Lines by Penciclovir

Further Characterization of the Potent and Prolonged Inhibition of Herpes Simplex Virus Replication in Human Cell Lines by Penciclovir

Pharmacokinetics of Penciclovir after Oral Administration of its Prodrug Famciclovir to Horses

Antiviral Treatment: From Concept to Reality

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