Suppression of generation and replication of Acyclovir / Aciclovir-resistant herpes simplex virus by a sensitive virus.

The role of Acyclovir / Aciclovir-sensitive herpes simplex virus (HSV) was analyzed in the process of its replacement by a resistant virus in vitro and in vivo in the aspect of Acyclovir / Aciclovir therapy. The mode of replacement of Acyclovir / Aciclovir-sensitive HSV with Acyclovir / Aciclovir-resistant HSV was examined by the passages of Acyclovir / Aciclovir-sensitive wild type HSV in Vero cells under Acyclovir / Aciclovir-treatment. The development of resistance was monitored more adequately by counting the number of Acyclovir / Aciclovir-resistant viruses in 10,000 plaque forming units than by the conventional susceptibility assay. The resistance increased with the proportion of thymidine kinase-deficient (TK(-)) viruses, when the susceptibilities of Acyclovir / Aciclovir-treated HSV population to 5'-iodo-2'deoxyuridine and phosphonoacetic acid were examined. The increased resistance was due to the increased proportion of Acyclovir / Aciclovir-resistant virus but not intermediately resistant virus. Infection with mixtures of TK(-) and Acyclovir / Aciclovir-sensitive strains rendered TK(-) sensitive to Acyclovir / Aciclovir, and virus yields were reduced to the levels of Acyclovir / Aciclovir-sensitive virus in Vero cells. Their yield reduction depended on the proportion of Acyclovir / Aciclovir-sensitive viruses and induction of TK activity. This reduction in virus yields of the mixture of TK(-) and Acyclovir / Aciclovir-sensitive strains was confirmed by Acyclovir / Aciclovir treatment in the skin of mice with cutaneous infection. Acyclovir / Aciclovir treatment combined with superinfection of Acyclovir / Aciclovir-sensitive virus delayed the development of herpetic skin lesions due to Acyclovir / Aciclovir-resistant virus and reduced virus yields in the infected skin. Acyclovir / Aciclovir-sensitive virus plays an important role in suppressing the generation and replication of Acyclovir / Aciclovir-resistant virus during Acyclovir / Aciclovir therapy.

The synthesis and in vitro anti-hepatitis B virus (HBV) activity of two mononucleoside phosphotriester derivatives of Acyclovir / Aciclovir incorporating S-acyl-2-thioethyl (SATE) groups are reported. In contrast to the parent nucleoside, the described phosphotriesters emerged as potent and selective inhibitors of HBV replication in HepG2.2.15 cells. This result can be attributed to the unique cellular metabolism of the SATE pronucleotides giving rise to the delivery to Acyclovir / Aciclovir 5'-monophosphate inside the infected cells. Moreover, the in vitro anti-HBV activities of one of these bis(SATE)phosphotriesters and of (-)-beta-L-2',3'-dideoxy-3'-thiacytidine (lamivudine, 3TC) were compared alone and in combination. Analysis of the combination data indicates that 3TC and the studied SATE pronucleotide of Acyclovir / Aciclovir exhibited strong synergistic interactions. The present study provides an example where the use of a pronucleotide approach extends the antiviral spectrum of a nucleoside analogue. Given the potency of SATE pronucleotides of Acyclovir / Aciclovir against HBV in HepG2.2.15 cells, further studies including animal experiments seem warranted to evaluate the potential of these compounds as anti-HBV agents.

Recognition of L-amino acid ester compounds by rat peptide transporters PEPT1 and PEPT2.

Peptide transporters (PEPT1 and PEPT2) in epithelia play an important role in the absorption of small peptides and peptide-like drugs. Recently, it was demonstrated that various nonpeptidic compounds can be transported by these transporters. In the present study, we focused on the L-amino acid ester compounds and examined the mechanisms of their interaction with rat PEPTs (rPEPTs) using stable transfectants. Valacyclovir ( Valtrex ), the L-valyl ester prodrug of the antiherpetic agent Acyclovir / Aciclovir, competitively inhibited [(14)C]glycylsarcosine uptake in the rPEPT1- or rPEPT2-expressing cells. Dixon plot analyses showed that the inhibition constant (K(i)) values of Valacyclovir ( Valtrex ) were 2.7 and 0.22 mM for rPEPT1 and rPEPT2, respectively, suggesting that rPEPT2 had higher affinity for this agent. Various L-valine alkyl esters significantly inhibited [(14)C]glycylsarcosine uptake. L-Valine methyl ester (Val-OMe) competitively inhibited [(14)C]glycylsarcosine uptake with K(i) values of 3.6 and 0.83 mM for rPEPT1 and rPEPT2, respectively, indicating that Val-OMe is also a high-affinity substrate for rPEPT2. Val-OMe had a trans-stimulation effect on [(14)C]glycylsarcosine efflux from both transfectants, suggesting the translocation of L-valine methyl ester via rPEPTs. Val-OMe showed the most potent inhibitory effect among the several L-amino acid methyl esters examined. We conclude that Val-OMe, as well as Valacyclovir ( Valtrex ), could be recognized and transported by rPEPT1 and rPEPT2 and that these L-valyl esters showed higher affinity for rPEPT2 as do most substrates of these transporters. Our results suggest that L-valine is a desirable L-amino acid for the esterification of poorly permeable drugs to enhance their oral bioavailability targeting intestinal PEPT1.

Valacyclovir ( Valtrex ). New indication: for genital herpes, simpler administration.

Valacyclovir ( Valtrex ), the metabolic precursor of Acyclovir / Aciclovir, is now approved for treatment and prevention of genital infection with herpes simplex viruses. The clinical file is bulky and methodologically sound. For treatment of a first episode of genital herpes, a large comparative trial has shown that Valacyclovir ( Valtrex ) (1 g twice a day) is as effective as Acyclovir / Aciclovir (200 mg five times a day) when given for 10 days. For treating recurrences, two trials show that Valacyclovir ( Valtrex ) is as effective as Acyclovir / Aciclovir (200 mg five times a day) with a treatment period of 5 days. A daily dose of 1 g of Valacyclovir ( Valtrex ) is as effective as 2 g daily. Valacyclovir ( Valtrex ) can be administered once a day. For prevention among patients with frequent recurrences, the efficacy of Valacyclovir ( Valtrex ) (500 mg/d in a single dose) has been proven in a placebo-controlled trial lasting 4 months. In these trials, Valacyclovir ( Valtrex ) and Acyclovir / Aciclovir were both well tolerated, with no major differences between the two drugs.