Intranasal Challenge of Mice with Herpes Simplex Vims: An Experimental Model for Evaluation of the Efficacy of Antiviral Drugs

Clercq, Erik De; M, Luczak

doi:10.1093/infdis/133.supplement_2.a226

Cited by 49 publications

(22 citation statements)

References 36 publications

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“…The activities of orally administered BAY 57-1293 for the treatment of acute HSV-1 and HSV-2 infections were assessed in a murine lethal challenge model of disseminated herpes, including herpes encephalitis. This model is widely used for the evaluation of antiviral agents (4,9). Mice were infected intranasally and were treated 6 h later with the compounds under evaluation for 5 consecutive days three times a day (t.i.d.).…”

Section: Resultsmentioning

confidence: 99%

“…The plate was sealed and incubated for 24 h at 4°C. After the addition of 50 l of diluted guinea pig complement (Calbiochem) (1 part complement, 3 parts PBS), the plates were resealed and incubated for 1 h at 37°C, and then 10 4 Vero cells in 50 l of medium were added. After 3 days of incubation, the medium was removed, and the cells were washed once with PBS and finally incubated for 30 min at room temperature with 10 g of fluorescein diacetate per ml in PBS.…”

Section: Methodsmentioning

confidence: 99%

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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

125

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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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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

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

125

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“…We postulated that the reason for failure of drug therapy to protect the animals was the inability of treatment to prevent direct neural spread of the virus from nasopharynx to the CNS. In contrast, De Clercq and co-workers, using 10-day-old mice inoculated intranasally with H. hominis type 1, reported that these same drugs appeared to have some effectiveness (5). One possible explanation for the difference between these studies is that the type 2 strain we utilized has a greater capacity for neurovirulence than the type 1 strain used by De Clercq et al The present studies appear to confirm our original hypothesis (15)(16)(17) that failure of therapy is due to inability of drug treatment to prevent direct neural spread to the CNS.…”

Section: Discussionmentioning

confidence: 93%

“…Successful therapy with ara-AMP in the present study was associated with a significant reduction in the titers of virus in all tissues of the CNS. Virus titers in the CNS of treated animals continued to decline through day 5 and presumably would have been eliminated had the experiment been extended for additional days. A similar reduction of virus in the brains of mice inoculated i.c.…”

Section: Discussionmentioning

confidence: 99%

“…One of the major problems associated with systemic administration of ara-A is its water insolubility, which has necessitated the use of large volumes of fluid for its delivery. A phosphorylated derivative of ara-A, adenine arabinoside 5 in experimental animals (18,29,30,32). Both drugs have been active when given systemically; however, with the exception of infections of the eye (26), they have not been effective when applied topically (1,12,18).…”

mentioning

confidence: 99%

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Alteration of Mortality and Pathogenesis of Three Experimental Herpesvirus hominis Infections of Mice with Adenine Arabinoside 5′-Monophosphate, Adenine Arabinoside, and Phosphonoacetic Acid

Kern

Richards

Overall

et al. 1978

Antimicrob Agents Chemother

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The therapeutic effectiveness of adenine arabinoside 5′-monophosphate (ara-AMP), adenine arabinoside (ara-A), and phosphonoacetic acid (PAA) was compared in three experimental Herpesvirus hominis type 2 infections of mice. In animals inoculated with H. hominis by the intracerebral or intraperitoneal route, both ara-AMP and ara-A were highly effective in reducing mortality even when treatment was begun 48 to 96 h after viral inoculation. ara-AMP was the most effective in both models in that treatment could be initiated 24 to 48 h later in the course of infection than with ara-A and still confer significant protection. In mice inoculated intraperitoneally, protection due to ara-AMP therapy was associated with reduced replication of virus in visceral organs and complete inhibition of transmission of virus to the brain. PAA treatment of mice inoculated intraperitoneally was effective in reducing mortality only if initiated shortly after infection. Treatment with PAA did not reduce mortality of mice inoculated intracerebrally but did prolong the mean day of death. When mice were inoculated intranasally with H. hominis , none of the three drugs altered final mortality; however, treatment with ara-AMP did prolong the mean day of death. Treatment with ara-AMP effectively reduced viral replication in the lung and liver in this model infection, but failed to prevent transmission of virus through the trigeminal nerves from the nasopharynx to the brain.

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A simple method for typing clinical isolates of herpesvirus simplex: replication in the presence of 2h‐1,3‐oxazine‐2,6 (3h)‐dione (oxauracil)

Seal

Jamison

1980

Journal of Medical Virology

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A rapid simple method for the typing of wild HSV isolates based on selective inhibition of HSV-2 replication by the pyrimidine analogue oxauracil (2H-1,3-oxazine-2,6(3H)-dione) has been developed. Chi-square analysis of the results of typing of 30 wild strains by serum neutralization tests, immunofluorescence, and oxauracil-inhibition indicates no significant differences in assignment of types to the isolates. The oxauracil-inhibition test obviates confusion of typing resulting from use of immune sera containing cross-reactive antibodies. We conclude oxauracil typing is a simple, rapid, and precise test which can be performed in any laboratory capable of isolating HSV.

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Intranasal Challenge of Mice with Herpes Simplex Vims: An Experimental Model for Evaluation of the Efficacy of Antiviral Drugs

Cited by 49 publications

References 36 publications

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

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

Alteration of Mortality and Pathogenesis of Three Experimental Herpesvirus hominis Infections of Mice with Adenine Arabinoside 5′-Monophosphate, Adenine Arabinoside, and Phosphonoacetic Acid

A simple method for typing clinical isolates of herpesvirus simplex: replication in the presence of 2h‐1,3‐oxazine‐2,6 (3h)‐dione (oxauracil)

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