The Effects of Delayed-Onset Chemotherapy using Famciclovir or Valaciclovir in a Murine Immunosuppression Model for HSV-1

Field, Hugh J.; Thackray, Alana M.

doi:10.1177/095632029500600402

Cited by 26 publications

(18 citation statements)

References 22 publications

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“…This stage of infection might be comparable 18 Intervirology 1997:40:15-21 W utzler/U lbricht/Färhcr Recently, encouraging results in favor of FCV have also been reported by Field et al [12], In a comparative study, in which the compounds were orally administered at 100 mg/kg per day (divided into two doses) for 5 or 10 days to treat HSV-1 infection in immunosuppressed mice, FVC proved to be more effective than VACV at clearing the virus from the ear pinna and brain stem and at preventing the recurrence of infectious virus on cessa tion of therapy. Very similar results were found when the start of treatment was delayed until 5 days after infection -a time when virus replication in the brain stem and ear pinna was well established [19]. The better therapeutic effect of FCV may be due to the prolonged suppression of virus replication after cessation of therapy, an effect that has been shown by Sutton and Boyd [20] for PCV but not for ACV in an experimental HSV-1 infection.…”

Section: Effect O F Antiviral Treatment On Mortalitysupporting

confidence: 68%

Antiviral Efficacies of Famciclovir, Valaciclovir, and Brivudin in Disseminated Herpes Simplex Virus Type 1 Infection in Mice

Wutzler¹,

Ulbricht²,

Färber³

1997

Intervirology

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The animal model of necrotic hepatitis caused by HSV-1 infection in juvenile mice was used to compare the efficacies of the oral antiherpes agents famciclovir (FCV), valaciclovir (VACV) and brivudin (BVDU). The experimental infection allows the measurement of viral replication in the liver by macroscopic lesions and the evaluation of mortality from encephalitis. Mice intravenously inoculated with a highly virulent clinical HSV-1 isolate were orally treated by gavage over a period of 3 days starting on day 2 post infection. The reference drug acyclovir (ACV) was administered subcutaneously. Necrotic hepatitis was significantly (p < 0.01) reduced by treatment with FCV, VACV and ACV at a dose of 50 mg/kg per day divided into 3 doses. No significant effect was achieved with BVDU at 200 mg/kg per day. Treatment with FCV at 50 mg/kg per day, ACV at 100 mg/kg per day, and VACV at 200 mg/kg per day significantly (p < 0.001) decreased mortality in mice. BVDU treatment at 200 mg/kg per day did not reduce mortality but significantly prolonged (p < 0.05) the survival time.

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Section: Effect O F Antiviral Treatment On Mortalitysupporting

confidence: 68%

Antiviral Efficacies of Famciclovir, Valaciclovir, and Brivudin in Disseminated Herpes Simplex Virus Type 1 Infection in Mice

Wutzler¹,

Ulbricht²,

Färber³

1997

Intervirology

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“…We confirmed previous observations that the daily water consumption of each mouse was about 1.8 ml of water. The drug was supplied as a 1-mg/ml solution, corresponding to an average daily intake of 100 mg/kg (9). The drug ameliorated negative effects of the viral infection on the general health of the mice as measured by weight loss (Table 1).…”

Section: Methodsmentioning

confidence: 99%

Axonal Transport and Sorting of Herpes Simplex Virus Components in a Mature Mouse Visual System

LaVail

Tauscher²,

Aghaian³

et al. 2003

J Virol

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The time course for delivery and transport of two major proteins of herpes simplex virus (HSV) has been determined for mature mouse retinal ganglion cell axons in vivo. Twenty-four hours after intravitreal injection of HSV, valacyclovir was introduced into the drinking water of the mice to inhibit subsequent viral replication. Without treatment, viral spread and replication in periaxonal glial cells confound study of axonal transport. At 2 to 5 days after infection, the animals were sacrificed and contiguous segments of the optic pathway were removed. Immunofluorescence microscopy indicated that the number of infected astrocytes was reduced in the proximal optic nerve and eliminated in the optic tract. Western blots of the retina with antibodies for envelope and capsid components, glycoprotein D (gD) and VP5, respectively, revealed that both components were expressed in retinal homogenates by 2 days. Results of reverse transcription-PCR indicated that there was no gD mRNA present in the treated optic tract 5 days after infection. Therefore, we conclude that gD is transcribed from viral mRNA in the retinal ganglion cell bodies. The gD accumulated in the proximal ganglion cell axon by 2 days and reached the most distal segment after 3 days. The VP5 first appeared in the proximal axons at 4 days, about 48 h after the appearance of gD. Thus, gD entered the axon earlier and independent of VP5. These finding confirm the subassembly model of viral transport in neurons and suggest that there is a 4-to 5-day window for initiation of effective antiviral treatment with valacyclovir.

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“…Also, for patients with less severe disease, an agent that will achieve a better reduction of lesion duration with episodic treatment beyond the 1 to 2 days' reduction achieved with current medications is urgently required (16). Furthermore, a drug which continues to show profound efficacy when given at later stages of herpetic disease would be a new and highly desired standard in the treatment of herpes (10). BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide) ( Fig.…”

mentioning

confidence: 99%

Potent In Vivo Antiviral Activity of the Herpes Simplex Virus Primase-Helicase Inhibitor BAY 57-1293

Betz

Fischer

Kleymann

et al. 2002

Antimicrob Agents Chemother

123

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BAY 57-1293 belongs to a new class of antiviral compounds and inhibits replication of herpes simplex virus (HSV) type 1 and type 2 in the nanomolar range in vitro by abrogating the enzymatic activity of the viral primase-helicase complex. In various rodent models of HSV infection the antiviral activity of BAY 57-1293 in vivo was found to be superior compared to all compounds currently used to treat HSV infections. The compound shows profound antiviral activity in murine and rat lethal challenge models of disseminated herpes, in a murine zosteriform spread model of cutaneous disease, and in a murine ocular herpes model. It is active in parenteral, oral, and topical formulations. BAY 57-1293 continued to demonstrate efficacy when the onset of treatment was initiated after symptoms of herpetic disease were already apparent.During the last 50 years, the treatment of herpesvirus infections has been continuously refined. Following the discovery of iodoxuridine in the mid-1950s and its successful demonstration as a topical therapeutic agent for herpes simplex virus (HSV) keratoconjunctivitis, vidarabine was licensed for systemic use and approved for the treatment of HSV encephalitis in 1978.Since it was first approved in 1981, the guanosine analogue acyclovir and later its L-valyl ester prodrug valacyclovir have been widely used in the treatment of HSV infections. Additional compounds used to treat HSV infections are famciclovir, the prodrug of penciclovir; ganciclovir; foscarnet; and cidofovir.Nevertheless, a high medical need exists for improved antiherpetic drugs for the treatment of severe disease. Encephalitis in newborns, for example, results in 15% mortality, and only 29% of survivors develop normally after acyclovir therapy (22). Also, for patients with less severe disease, an agent that will achieve a better reduction of lesion duration with episodic treatment beyond the 1 to 2 days' reduction achieved with current medications is urgently required (16). Furthermore, a drug which continues to show profound efficacy when given at later stages of herpetic disease would be a new and highly desired standard in the treatment of herpes (10). BAY 57-1293 (Fig. 1) is a member of the thiazolylsulfonamides, a recently discovered class of nonnucleosidic compounds with potent antiherpetic activity in vitro and in vivo, based on a novel mechanism of action (11a). It inhibited the replication of HSV type 1 (HSV-1) and HSV-2 in Vero cells with a 50% inhibitory concentration (IC 50 ) of 20 nM and a selectivity index of 2,500 and had about equal potencies against different strains and clinical isolates, while under the same assay conditions, acyclovir exhibited an IC 50 of 1 M and a selectivity index of 250. BAY 57-1293 targets the viral primase-helicase complex and inhibits its ATPase activity in a dose-dependent manner with an IC 50 of 30 nM. Resistant viral mutants exhibited amino acid substitutions in viral UL5 and/or UL52, which code for components of the viral primasehelicase complex. Accordingly, BAY 57-1293 also is acti...

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The Effects of Delayed-Onset Chemotherapy using Famciclovir or Valaciclovir in a Murine Immunosuppression Model for HSV-1

Cited by 26 publications

References 22 publications

Antiviral Efficacies of Famciclovir, Valaciclovir, and Brivudin in Disseminated Herpes Simplex Virus Type 1 Infection in Mice

Antiviral Efficacies of Famciclovir, Valaciclovir, and Brivudin in Disseminated Herpes Simplex Virus Type 1 Infection in Mice

Axonal Transport and Sorting of Herpes Simplex Virus Components in a Mature Mouse Visual System

Potent In Vivo Antiviral Activity of the Herpes Simplex Virus Primase-Helicase Inhibitor BAY 57-1293

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