Denavir
Penciclovir: new preparation. Slightly effective.

[No authors listed]

(1) A penciclovir skin cream has been approved in France for local treatment of herpes simplex labialis. (2) The clinical file is limited to a single trial versus the excipient. This double-blind trial showed that, even when started immediately after the first manifestations occur, penciclovir cream failed to prevent the emergence of skin lesions. The only effect was a reduction in the duration of the lesions and associated pain by a few hours. In the absence of any specific assessment, there is no evidence that penciclovir improves overall patient satisfaction. (3) Penciclovir has not been compared with aciclovir skin cream.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11503816&dopt=Abstract penciclovir Denavir



Denavir
Lack of effect of treatment with penciclovir or acyclovir on the establishment of latent HSV-1 in primary sensory neurons in culture.

Smith RL, Morroni J, Wilcox CL.

Department of Neurology and Pediatrics, University of Colorado Health Sciences Center, Denver, CO, USA.

Recent studies suggest reductions in establishment of herpes simplex virus, type 1 (HSV-1) latency using the nucleoside analog penciclovir compared with acyclovir in the murine model. These observations raise the possibility that the new analogs may have novel activities that directly interfere with the establishment of the latent infection, suggesting a mechanism other than simply blocking the productive infection. To determine if penciclovir has a direct action on the establishment of latency, we compared the effects of penciclovir versus acyclovir in an in vitro model of HSV-1 latency in rat dorsal root ganglia neurons in culture. In neurons in culture, both penciclovir and acyclovir were highly effective in blocking the productive infection. However, neither penciclovir nor acyclovir blocked establishment of latency as demonstrated by similar percentages of neurons expressing the latency-associated transcript (LAT). Following removal of the respective nucleoside analog, latency was maintained until reactivation was induced by nerve growth factor deprivation. Similar virus titers were recovered after induction of reactivation of latent infections, which were established in the presence of either penciclovir or acyclovir. These results indicate that neither penciclovir nor acyclovir treatment directly prevents the establishment of latent HSV-1 infections in primary sensory neurons in culture.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11530184&dopt=Abstract penciclovir Denavir



Denavir
Comparison of new topical treatments for herpes labialis: efficacy of penciclovir cream, acyclovir cream, and n-docosanol cream against experimental cutaneous herpes simplex virus type 1 infection.

McKeough MB, Spruance SL.

Department of Medicine, School of Medicine, Room 4B319, University of Utah, 50 North Medical Dr, Salt Lake City, UT 84132, USA.

BACKGROUND: There are 3 new topical treatments for herpes labialis that have either been approved by the US Food and Drug Administration (penciclovir cream [Denavir] and n-docosanol cream [Abreva]) or recently undergone extensive clinical evaluation (acyclovir cream). The relative efficacy of these products is unknown. OBJECTIVE: To compare the efficacy of penciclovir cream, acyclovir cream, n-docosanol cream, and acyclovir ointment in an experimental animal model of cutaneous herpes simplex virus type 1 (HSV-1) disease. DESIGN: The backs of guinea pigs were infected with HSV-1 using a vaccination instrument. Active treatments and corresponding vehicle controls were applied for 3 to 5 days beginning 24 hours after inoculation. MAIN OUTCOME MEASURES: After completion of treatment, the animals were killed and the severity of the infection assessed from the number of lesions, the total lesion area, and the lesion virus titer. RESULTS: Penciclovir cream effected modest reductions in lesion number (19%), area (38%), and virus titer (88%) compared with its vehicle control, and each of these differences was significantly greater (P<.05) than the reductions effected by acyclovir ointment (0%, 21%, and 75%, respectively). The acyclovir cream effect (reductions of 4%, 28%, and 77%, respectively) was less than that of penciclovir cream, and this difference was confirmed by 2 additional head-to-head experiments. Two experiments with n-docosanol cream failed to show statistically significant differences by any parameter between n-docasonol cream and vehicle control-treated sites or between n-docosanol and untreated infection sites. CONCLUSIONS: In this model, the efficacy of penciclovir cream was greater than acyclovir cream, acyclovir cream was greater than or equal to acyclovir ointment, and acyclovir ointment was greater than n-docosanol cream. Since our model was designed to evaluate compounds that function primarily through antiviral activity, the negative findings with n-docosanol in these studies do not exclude that it might work clinically through other mechanisms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11559210&dopt=Abstract penciclovir Denavir



Denavir
Absence of rapid selection for acyclovir or penciclovir resistance following suboptimal oral prodrug therapy of HSV-infected mice.

Sarisky RT, Bartus HR, Dennis SA, Quail MR, Nguyen TT, Wittrock RJ, Halsey WS, Bacon TH, Leary JJ, Sutton D.

Department of Host Defense, The Antimicrobial and Host Defense Center of Excellence for Drug Discovery, USA. robert_t_sarisky gsk.com

BACKGROUND: Acyclovir (ACV) resistant herpes simplex virus (HSV) isolates can be readily selected in animal infection models receiving suboptimal ACV treatment, however no comparative studies of the emergence of resistance following suboptimal treatment with valacyclovir (VCV) or famciclovir (FCV), the prodrugs of acyclovir and penciclovir, respectively, have been reported. METHODS: Mice (n = 30) were infected with HSV type 1 or 2 in the ear pinnae and administered oral prodrugs at one fifth a dose previously shown to be effective. To select and amplify drug-resistant HSV, a total of seven consecutive in vivo passages with suboptimal treatment were performed for each virus sample and progeny virus from each passage was characterized by the plaque reduction (PRA) and plating efficiency assays (PEA). RESULTS: No drug-resistant HSV-2 and only a single drug-resistant HSV-1 variant were identified. Virus recovered from the first three sequential passages of this HSV-1 sample was susceptible by PRA, although the proportion of resistant virus recovered gradually increased upon passage. The resistant HSV-1 phenotype was confirmed by PRA after four sequential passages in mice. Unexpectedly, this in vivo-selected drug-resistant HSV-1 failed to yield an infection completely refractory to treatment in subsequent passages. CONCLUSIONS: Sub-optimal therapy of immunocompetent mice with either VCV or FCV did not readily select for HSV-mutants resistant to either ACV or PCV, suggesting that selection of resistance with either prodrug remains difficult using this system. Futhermore, this study suggests that the PEA may represent a useful adjunct to the PRA for monitoring alterations in the proportion of drug-resistant virus even when no change in IC50 is apparent.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11749671&dopt=Abstract penciclovir Denavir



Denavir
Susceptibilities of herpes simplex viruses to penciclovir and acyclovir in eight cell lines.

Leary JJ, Wittrock R, Sarisky RT, Weinberg A, Levin MJ.

GlaxoSmithKline, The Antimicrobial and Host Defense Center of Excellence for Drug Discovery, Department of Host Defense, Collegeville, Pennsylvania, USA. jjl27773 glaxowellcome.com

The commonly used antiviral drugs acyclovir (ACV) and penciclovir (PCV) possess similarly potent antiviral activities in vivo against herpes simplex virus (HSV). Assay methods for sensitivity to ACV are not necessarily transferable to PCV, even though the two drugs have similar in vivo potencies and mechanisms of action. We determined by plaque reduction assay the relative activities of ACV and PCV against five laboratory-adapted strains of HSV types 1 and 2 (including sensitive and resistant strains) in seven human cell lines and one nonhuman primate cell line. Seven characteristics were used to evaluate the cell lines. All cell lines were similar in their plating efficiencies and abilities to discriminate between sensitive and resistant HSV isolates. Vero and MRC-5 cells yielded the most discordant 50% inhibitory concentrations (IC50s) for the two HSV types, while Vero and WI-38 VA-13 cells yielded large differences in the IC50s of ACV and PCV. The limited life spans and poor plaque morphologies of the fibroblast lines were undesirable characteristics. Among the transformed cell lines producing well-defined plaques, A549 cells provided the best concordance between IC50s for the two HSV types and two antiherpes drugs. Comparison experiments with a yield reduction format indicated that the use of assays of this type might allow some of the cell-specific properties observed in plaque reduction assays to be avoided.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11850259&dopt=Abstract penciclovir Denavir