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

Abstract

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...

Comparison of efficacies of famciclovir and valaciclovir against herpes simplex virus type 1 in a murine immunosuppression model

“…It was reported that the recurrence of infection was reproducible and, while the generation of resistance was ruled out, no other explanation was forthcoming. In addition, Sutton and Boyd (21) have reported that PCV therapy, but not ACV therapy, led to prolonged suppression of virus replication on cessation of therapy. These data were obtained in an intraperitoneal HSV-1 infection model in DBA-2 mice.…”

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

“…This has been accounted for by the greater stability of PCV triphosphate within herpesvirus-infected cells, this compound having a longer intracellular half-life (t1l2 = 7-20 h) than ACVtriphosphate (t1/2 = 0.7-1 h) (Vere Hodge and Perkins, 1989;Earnshaw et al, 1992;Vere Hodge and Cheng, 1993). Prolonged suppression of virus replication in vivo by PCV, but not ACV, has also been reported previously (Sutton and Boyd, 1993). Subsequently, Ashton et al (1994) …”

“…This strain of virus has been extensively characterized in mice (Hill et al, 1975) and has been widely used previously for studying antiviral compounds (Field et et., 1979;Boyd et al, 1988;Sutton and Boyd, 1993). The virus working stocks were produced at a low multiplicity of infection in baby hamster kidney cells (BHK-21) and stored in small aliquots at -70°C.…”

2-[4,5-Difluoro-2-(2-Fluorobenzoylamino)-Benzoylamino]Benzoic Acid, an Antiviral Compound with Activity against Acyclovir-Resistant Isolates of Herpes Simplex Virus Types 1 and 2

“…The ester prodrug of acyclovir, valacyclovir, has higher absorption characteristics and a bioavailability of up to 54% (25,64). The guanine analog, penciclovir, has an activity similar to that of acyclovir, but it is poorly absorbed after oral administration and is therefore not commercially available as an oral agent (4,9,56). Famciclovir, the ester prodrug of penciclovir, increases the absolute bioavailability of penciclovir when administered orally (59).…”