Activity of Penciclovir ( Denavir ) in antiviral assays against herpes simplex virus.

The effect of Penciclovir ( Denavir ) and Acyclovir / Aciclovir on the replication of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) strains was determined in MRC-5 cells infected with 0.01 pfu/cell and exposed to the drugs for 72 h to allow multiple cycles of replication. Penciclovir ( Denavir ) was significantly more active than Acyclovir / Aciclovir against three strains of HSV-1 and three strains of HSV-2 at 1 mg/L (P = 0.009), 3 mg/L (P < 0.001) and 10 mg/L (P = 0.001). Further comparisons between the compounds were made in MRC-5 cells infected with HSV-1 strain SC16 using four different antiviral assays namely, the 24 h virus yield reduction assay, plaque reduction assay, viral antigen inhibition assay, and a viral DNA inhibition assay, to determine the relative merits of each. Penciclovir ( Denavir ) and Acyclovir / Aciclovir shared similar activities in the plaque reduction assay (with 50% effective concentrations, EC50, being 0.8 and 0.6 mg/L, respectively) and in the viral antigen inhibition assay (EC50s. 0.6 and 0.7 mg/L, respectively). The EC50 of Penciclovir ( Denavir ) in the 24 h viral DNA inhibition assay was 0.01 mg/L compared with 0.06 mg/L of Acyclovir / Aciclovir. In the 24 h virus yield reduction assay in which MRC-5 cells were infected with 0.3 pfu/cell, Penciclovir ( Denavir ) was more active than Acyclovir / Aciclovir with 99% effective concentrations of 0.6 mg/L and 1.1 mg/L, respectively. The activity of Penciclovir ( Denavir ) in the 24 h virus yield reduction and antigen inhibition assays was inversely related to the multiplicity of infection, whereas this had considerably less effect on the inhibition of viral DNA synthesis. These results suggest that Famciclovir ( Famvir ), which is the oral form of Penciclovir ( Denavir ), will be at least as effective as Acyclovir / Aciclovir in treating infections caused by HSV-1 and HSV-2.

L-Valacyclovir ( Valtrex ), a prodrug of Acyclovir / Aciclovir, is a substrate for the peptide transporter (PepT1) in the intestinal mucosa, which accounts for its higher than expected oral bioavailability. The substrate activity of L-Valacyclovir ( Valtrex ) for PepT1 is surprising, particularly when one considers that the molecule has the structural features of a nucleoside rather than a peptide. In an attempt to better understand the structure-transport relationships (STR) for the interactions of L-Valacyclovir ( Valtrex ) with PepT1, analogs of this molecule with structural changes in the guanine moiety were synthesized and their substrate activity for PepT1 in Caco-2 cell monolayers was determined. The analogs synthesized include those that had the guanine moiety of L-Valacyclovir ( Valtrex ) substituted with purine, benzimidazole, and 7-azaindole. All three analogs (purine, benzimidazole, and 7-azaindole) exhibited affinity for PepT1 in binding studies, but only the purine analog (as the L-valine ester) showed PepT1-associated transcellular transport across Caco-2 cell monolayers. The benzimidazole and 7-azaindole analogs (as their L-valine esters) were rapidly metabolized by esterase when applied to the apical surface of Caco-2 cells, which probably explains their low penetration as the intact prodrugs via PepT1.

Cost-effectiveness of Acyclovir / Aciclovir suppression to prevent recurrent genital herpes in term pregnancy.

The objective of this paper is to determine whether Acyclovir / Aciclovir suppression provides a greater cost savings over no medical therapy in the management of recurrent genital herpes (HSV) in pregnancy. Estimates of the risk of HSV recurrence and cesarean delivery rates in Acyclovir / Aciclovir-treated and -untreated patients and frequency of neonatal Acyclovir / Aciclovir treatment were derived from literature reviews, prospective surveillance, and practices at our institution. Estimates of costs were derived from average hospital and outpatient clinic charges at our institution. Calculations were run separately for four different groups of patients: women whose first diagnosis of genital herpes occurred during the pregnancy, women whose diagnosis antedated pregnancy and who had infrequent recurrences, women whose diagnosis antedated pregnancy and had frequent recurrences, and all women with a history of genital herpes regardless of timing of diagnosis or frequency of recurrences. Suppressive Acyclovir / Aciclovir treatment of all term pregnant women with a history of genital herpes resulted in an estimated savings of $183.00 per patient or $36,600,000 per year. Women with their first episode of herpes diagnosed during pregnancy or with frequent recurrences benefitted even more, achieving a savings of $455.00 and $391.00 per patient, respectively. Assuming that prenatal Acyclovir / Aciclovir treatment is safe for the fetus, utilizing this management for all patients with recurrent HSV in pregnancy could immediately save $183 per patient. On a national level, this translates to $36,600,000 per year just in reduced obstetrical costs. If indirect costs associated with cesarean deliveries had been included in these calculations, the estimated savings would be even more substantial.

The efficacy of early versus late treatment with Acyclovir / Aciclovir and valAcyclovir / Aciclovir on zoster-associated pain was assessed from two databases (1076 patients) that were compiled from randomized trials. Early treatment was started < 48 h and late treatment was started 48-72 h after the onset of cutaneous herpes zoster. Median times to complete resolution of zoster-associated pain were 28 and 62 days, respectively, for patients (> or = 18 years of age) treated with Acyclovir / Aciclovir and placebo within 48 h (hazard ratio [HR], 1.68; 95% confidence limit [95% CL], 1.19, 2.38) and 28 and 58 days, respectively, for those treated later (HR, 2.20; 95% CL, 1.03, 4.71). In the valAcyclovir / Aciclovir versus Acyclovir / Aciclovir study (in patients > or = 50 years of age), the corresponding figures were 44 and 51 days for patients treated early (HR, 1.28; 95% CL, 1.03, 1.60) and 36 and 48 days for those treated later (HR, 1.40; 95% CL, 1.04, 1.87). Acyclovir / Aciclovir significantly shortened the time to complete resolution of zoster-associated pain compared with placebo (and valAcyclovir / Aciclovir was superior to Acyclovir / Aciclovir in this regard) even when therapy was delayed up to 72 h after rash onset.