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

Penciclovir [PCV; 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine; BRL 39123] is a potent and selective inhibitor of herpes simplex virus and varicella-zoster virus in human cell culture. We have compared the activities of PCV and acyclovir (ACV) in DBA/2 mice infected intraperitoneally with herpes simplex virus type 1 SC16 by measuring the amount of virus in peritoneal washings. In untreated mice after an eclipse phase, virus titers are maximum at 48 h after infection and decline thereafter. PCV and ACV reduced virus replication to a similar extent when given ad libitum in drinking water, even though ACV had better oral bioavailability and greater potency in murine cells. Thus, PCV was more active than had been predicted. In dose-response experiments, PCV given as a single subcutaneous dose 24 h after infection was active at a 10-fold-lower dose than ACV (P < 0.01). A single subcutaneous dose of PCV at 5 h after infection prevented virus replication for 3 days and was more effective than three doses of ACV given 1, 5, and 20 h after infection (P < 0.05). The superior activity of PCV following discrete dosing is not due to pharmacokinetic differences but is probably a reflection of the known stability of the intracellular triphosphate. In this model, the maintenance of high concentrations in blood is less important for PCV than for ACV and may lead to less-frequent doses in clinical use.We have previously demonstrated that penciclovir [PCV; 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine; BRL 39123] is a potent and selective inhibitor of herpesvirus replication both in cell culture (2) and in animal models (1). Cell culture studies have shown that, unlike acyclovir (ACV), the continuous presence of PCV in extracellular medium is unnecessary for prolonged inhibition of virus replication (2). This prolonged activity is thought to be due to the greater stability of PCV-triphosphate (PCV-TP) within cells infected with herpes simplex virus (HSV) compared with that of . If the same is true for herpesvirus infections in animals, the maintenance of a high PCV concentration in blood may be unnecessary and PCV could therefore be administered less frequently than ACV. This is supported by results from studies carried out in mice infected with HSV by both intranasal and intraperitoneal routes (1,3,10). We have now confirmed and extended these findings by studying in more detail the activity of PCV against an HSV type 1 (HSV-1) intraperitoneal infection in mice. in 0.1 ml of phosphate-buffered saline. At various times after inoculation, groups of five mice were killed and peritoneal washings were collected by injecting 2.0 ml of ice-cold Eagle's minimal essential medium with 10% newborn calf serum into the peritoneal cavity. The abdomen of the mouse was gently massaged, and a sample of fluid was withdrawn. After three freeze-thaw cycles, the virus contents of the samples were determined by plaque assay in Vero cells (2). MATERIALS AND METHODS MiceBioavailability studies. At each time point (15, 60, and 180 min) after drug administ...

Section: Antiviral Activity In Murine Cells a Plaque Reduction Assaymentioning

confidence: 99%

Comparative activity of penciclovir and acyclovir in mice infected intraperitoneally with herpes simplex virus type 1 SC16

Sutton¹,

Boyd²

1993

“…This was demonstrated when the results of studies on the effect of vidarabine (ara-A) or 5-iodo-2'-deoxyuridine in mice infected intracerebrally with herpes simplex virus (HSV) (10,12) were compared with those for humans with HSV encephalitis (2,26). Whereas ara-A was effective in mice and in humans, 5-iodo-2'-deoxyuridine was shown to be inactive.…”

Section: -(2-fluoro-2-deoxy-3-d-arabinofuranosyl)-5-iodocytosine > Vmentioning

confidence: 99%

Therapeutic activities of 1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)-5-iodocytosine and -thymine alone and in combination with acyclovir and vidarabine in mice infected intracerebrally with herpes simplex virus

Schinazi¹,

Peters²,

Sokol³

et al. 1983

The therapeutic effectiveness of two new antiviral agents, 1-(2-fluoro-2-deoxy-P-D-arabinofuranosyl)-5-iodocytosine and 1-(2-fluoro-2-deoxy-p-D-arabinofuranosyl)thymine, was compared with that of acyclovir and vidarabine. In mice inoculated intracerebrally with high 50% lethal doses of herpes simplex virus type 2, nontoxic intraperitoneal or oral treatments with the two new fluorinated antiviral agents were highly effective in reducing mortality. The two drugs were also effective when treatment was begun as late as 48 h after virus inoculation. The relative order of potencies of the drugs when compared on a molar basis or in terms of therapeutic index was 1-(2-fluoro-2-deoxy-3-D-arabinofuranosyl)thymineacyclovir. The new pyrimidine analogs were also found to lack immunosuppressive activity in mice. The combination of 1-(2-fluoro-2-deoxy-p-D-arabinofuranosyl)-5-iodocytosine and vidarabine was the most effective; significantly greater reduction in mortality was achieved with this combination than with either drug alone. Thirty minutes after intraperitoneal treatment with the fluorinated analogs, the drugs (or their metabolites) were transported to the brains of virus-inoculated and normal mice at levels about one-third to two-thirds those in the blood. The levels of 1-(2-fluoro-2-deoxy-3-D-arabinofuranosyl)thymine in the blood or brain were consistently higher than those found with equivalent intraperitoneal doses of the 5-iodocytosine analog.The mouse encephalitis mnodel has been a useful indicator of drug efficacy in the treatment of human herpes encephalitis. This was demonstrated when the results of studies on the effect of vidarabine (ara-A) or 5-iodo-2'-deoxyuridine in mice infected intracerebrally with herpes simplex virus (HSV) (10,12) were compared with those for humans with HSV encephalitis (2,26). Whereas ara-A was effective in mice and in humans, 5-iodo-2'-deoxyuridine was shown to be inactive. Pharmacokinetic studies in mice and humans (at autopsy) later revealed that 5-iodo-2'-deoxyuridine does not cross the blood-brain barrier (10, 13). Two new antiviral agents, 1-(2-fluoro-2-deoxy-,B-D-arabinofuranosyl)-5-iodocytosine (2'-fluoro-5-iodoaracytosine; FIAC) and its thymine analog (2'-fluoro&5-mfthylarauracil; FMAUJ), were previously shown to have potent antiviral activities in cell culture and in mice inoculated intraperitoneally with HSV' type 1 (HSV-1) (8,9,14,24). It was therefore of interest to determine whether these drugs are also effective when virus is inoculated intracerebrally. Other than the route of infection, the efficacy of antiviral agents in the mouse encephalitis model depends on the (i) viral strain; (ii) infectious dose; (iii) time of initiation of treatment; (iv) route of treatment; (v) drug dose and schedule; and (vi) animal species, weight, and age. Several of these variables were examined in this report. In addition, since any evaluation of new antiviral agents in the treatment of human encephalitis within the United States will probably necessitate a comparative double-blind stu...

“…The antiviral drug vidarabine (9-p-D-arabinofuranosyladenine; ara-A) is highly effective in the systemic treatment of herpes simplex virus (HSV) encephalitis both in laboratory animals (11,12,17,25,29,30) and in humans (33,34,36,37). This clinically effective purine nucleoside analog is rapidly deaminated in biological systems by the enzyme adenosine deaminase (2,4,6,9,40).…”

mentioning

confidence: 99%

Comparison of the efficacy of vidarabine, its carbocyclic analog (cyclaradine), and cyclaradine-5'-methoxyacetate in the treatment of herpes simplex virus type 1 encephalitis in mice

Shannon¹,

Westbrook²,

Arnett³

et al. 1983

The relative therapeutic effects of vidarabine (9-,-D-arabinofuranosyladenine), cyclaradine (the adenosine deaminase-resistant carbocyclic analog of vidarabine), and cyclaradine-5'-methoxyacetate in the parenteral treatment of systemic herpes simplex virus type 1 infections in Swiss mice were determined. Among control mice inoculated intraperitoneally with virus, a mortality rate of 95% was observed. The intraperitoneal administration of nontoxic doses of vidarabine (125 to 250 mg/kg per day) or cyclaradine (113 to 450 mg/kg per day), by daily injections for 7 days beginning 4 h after virus inoculation, reduced mortality to 0 to 10%, Amnong control animals inoculated intracerebrally with 32 50% lethal doses of virus, 100%to mortality was observed, with a mean survival time of 4.6 days.Treatment with either drug at equimolar dose levels ranging from ca. 32 to 750 mg/kg per day produced significant (P < 0.0005), dose-dependent increases in the mean survival time of animals dying of herpesvirus encephalitis. Mice inoculated intracerebraily with 10 50o lethal doses of virus exhibited 97% mortality and a mean survival time of 5.5 to 6.4 days. Treatment with vidarabine, cyclaradine, or cyclaradine-5'-methoxyacetate significantly increased the mean survival time of dying animals and, at doses ranging from 250 to 750 mg/kg per day, produced significant increases in survival. The three drugs displayed equivalent antiviral efficacy in vivo. Drug toxicity (measured by weight loss) was not detected in mice treated with cyclaradine or cyclaradine-5'-methoxyacetate at 750 mg/kg per day, whereas severe toxicity (weight loss of -3 g) was observed in mice treated with vidarabine at an equivalent dose level. Thus, cyclaradine or its 5'-methoxyacetic acid ester may possess some advantage over vidarabine in the treatment of severe herpesvirus infections and should therefore be considered for clinical trials in humans.