Denavir
The role of stratum corneum and dermal microvascular perfusion in penetration and tissue levels of water-soluble drugs investigated by microdialysis.

Morgan CJ, Renwick AG, Friedmann PS.

Dermatopharmacology Unit, Southampton General Hospital, Southampton SO16 6YD, UK.

BACKGROUND: Hydrophilic drugs are poorly absorbed when applied topically, due to low partitioning through the lipid matrix of the stratum corneum. Cutaneous blood flow rapidly clears the absorbed drug, which may result in low tissue levels. This is of importance for topically applied drugs whose site of action is within the epidermis or dermis. Dermal drug levels can be measured using cutaneous microdialysis, which is a means of continuously sampling substances from the dermal extracellular fluid. OBJECTIVES: To measure the contribution of stratum corneum barrier and microvascular perfusion in determining dermal tissue levels of hydrophilic drugs (aciclovir and penciclovir) in vivo. METHODS: Studies were performed using microdialysis of the volar surface of the forearm of healthy volunteers (n = 55) over a 5-h collection period. Stratum corneum was removed by tape stripping, and barrier disruption quantified by measurement of transepidermal water loss (TEWL); dermal microvascular perfusion was modulated by inclusion of noradrenaline in the microdialysis perfusate. RESULTS: With intact skin and normal cutaneous blood flow the concentration of penciclovir recovered was below assay threshold (0.05 ng x mL(-1). With noradrenaline-induced local vasoconstriction, the area under the curve of drug absorbed through normal skin (+/- SEM) was 13.3 +/- 2.9 ng mL(-1) h(0-5) for penciclovir and 27.6 +/- 10.6 ng mL(-1) h(0-5) for aciclovir. Removal of the stratum corneum (to glistening) by tape stripping increased penciclovir absorption by 1300-fold and aciclovir absorption by 440-fold, confirming the stratum corneum as the major barrier to hydrophilic drug absorption. Sequential barrier disruption by tape stripping gave a close correlation between penciclovir concentration absorbed per hour and barrier disruption measured by TEWL (r2 = 0.9283). There was a 15.6-fold difference in the recovery of penciclovir through barrier-deficient skin with and without cutaneous blood flow. There was no relationship between fibre depth and amount of drug dialysed, which suggests free movement of antiviral drug on reaching the aqueous environment of the dermis. CONCLUSIONS: This study defines for the first time the relationship between the degree of mechanical barrier impairment and drug absorption at the same anatomical site in humans, and the role of blood flow in drug clearance in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12653734&dopt=Abstract penciclovir Denavir



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Differential mutation patterns in thymidine kinase and DNA polymerase genes of herpes simplex virus type 1 clones passaged in the presence of acyclovir or penciclovir.

Suzutani T, Ishioka K, De Clercq E, Ishibashi K, Kaneko H, Kira T, Hashimoto K, Ogasawara M, Ohtani K, Wakamiya N, Saijo M.

Department of Microbiology, Fukushima Medical University, Fukushima, Tokyo, Japan. suzutani fmu.ac.jp

A total of 21 clones of acyclovir (ACV)-resistant (ACV(r)) herpes simplex virus type 1 (HSV-1) and 23 clones of penciclovir (PCV)-resistant (PCV(r)) HSV-1, emerging during serial passages in the presence of ACV or PCV, were isolated under conditions excluding contamination of resistant mutants in the starting virus culture, and their mutations in the thymidine kinase (TK) and DNA polymerase (DNA Pol) genes were analyzed comparatively. Mutations in the TK genes from ACV(r) mutants consisted of 50% single nucleotide substitutions and 50% frameshift mutations, while the corresponding figures for the PCV(r) mutants were 4 and 96%, respectively (P < 0.001). Eight of the 21 ACV(r) clones, but none of the 23 PCV(r) clones, had mutations in DNA Pol. Only nucleotide substitution(s) could be detected in the DNA Pol gene, as the gene is essential for virus replication. Therefore, the results for the DNA Pol mutants are concordant with those for the TK mutants in that a single nucleotide substitution was commonly observed in the ACV(r), but not in the PCV(r), mutants. These results clearly point to differential mutation patterns between ACV(r) and PCV(r) HSV-1 clones.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12709344&dopt=Abstract penciclovir Denavir



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Ganciclovir and penciclovir, but not acyclovir, induce apoptosis in herpes simplex virus thymidine kinase-transformed baby hamster kidney cells.

Shaw MM, Gurr WK, Watts PA, Littler E, Field HJ.

Centre for Veterinary Science, University of Cambridge, Cambridge, UK.

The efficacies of ganciclovir (GCV), penciclovir (PCV) and acyclovir (ACV) in inducing cell death in the herpes simplex virus thymidine kinase (HSVTK) system were compared. HSVTK-transformed baby hamster kidney cells treated with GCV, PCV or ACV were monitored for growth by viable count, and for death by TUNEL assay, propidium iodide staining, detection of phosphatidyl serine translocation and detection of DNA laddering. All compounds delayed growth or reduced viability of HSVTK-transformed cells. Drug treatment reduced levels of cyclin B1 message (which normally peaks in G2/M-phase of the cell cycle) and induced a four- to fivefold upregulation of GADD45 message. Treatment with GCV or PCV induced rapid accumulation of cells in S-phase and apoptotic death. Treatment with ACV, however, was associated with sustained S-phase arrest. GCV (and to a lesser extent PCV) increased phosphatidyl serine translocation, induced positive TUNEL results with alterations in cell morphology, caused marked propidium iodide staining and induced DNA laddering. By contrast, up to 7 days' exposure to ACV did not induce DNA laddering, with very little TUNEL staining. ACV treatment had little effect on phosphatidyl serine translocation and propidium iodide staining was markedly reduced compared with treatment with the other compounds. Thus, by all criteria, GCV was the most potent inducer of cell death. The current theories regarding apoptosis or necrosis as the preferred form of cell death in prodrug gene therapy are considered and the suitability of PCV or ACV as potential alternatives to GCV in the HSVTK system is discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12959326&dopt=Abstract penciclovir Denavir



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In vitro activities of penciclovir and acyclovir against herpes simplex virus types 1 and 2.

Weinberg A, Bate BJ, Masters HB, Schneider SA, Clark JC, Wren CG, Allaman JA, Levin MJ.

Pediatric Infectious Diseases, University of Colorado School of Medicine, Denver 80262.

Penciclovir (PCV) and acyclovir are acyclic guanine analogs which inhibit herpes simplex virus (HSV) DNA polymerase. Their 50% infective doses were 0.5 to 0.8 microgram/ml for clinical isolates of HSV-1 and 1.3 to 2.2 micrograms/ml for HSV-2. Furthermore, HSV-infected cultures receiving 2-h pulses of PCV had 2- to 50-fold less HSV than acyclovir-treated cultures, consistent with the prolonged intracellular half-life of PCV triphosphate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1329640&dopt=Abstract penciclovir Denavir



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The acyclic nucleoside analogue penciclovir is a potent inhibitor of equine herpesvirus type 1 (EHV-1) in tissue culture and in a murine model.

de la Fuente R, Awan AR, Field HJ.

Department of Clinical Veterinary Medicine, University of Cambridge, UK.

Equine herpesvirus type 1 (EHV-1) was sensitive to the nucleoside analogue penciclovir (PCV) when tested in tissue culture; the ED50 was 1.6 micrograms/ml. Drug-resistant mutants were selected which were found to be TK-defective and approx. 45-fold less sensitive to PCV compared with the parental strain. PCV was compared with the phosphonyl derivative, HPMPA in mice infected with EHV-1. Both drugs were shown to be effective in vivo, limiting wild-type virus replication in respiratory tissues, and reducing viraemia. The treated mice also showed less clinical signs and reduced histopathology compared with placebo-treated controls. The establishment of latent EHV-1 in the mice, however, was not prevented. The results obtained with mice suggest that antiviral chemotherapy may be practical in the horse and that this possibility is worthy of further investigation in the natural host.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1329646&dopt=Abstract penciclovir Denavir