Denavir
Inhibitory action of acyclovir (ACV) and penciclovir (PCV) on plaque formation and partial cross-resistance of ACV-resistant varicella-zoster virus to PCV.

Hasegawa T, Kurokawa M, Yukawa TA, Horii M, Shiraki K.

Department of Virology, Toyama Medical and Pharmaceutical University, Japan.

Penciclovir has potent antiviral activity against varicella-zoster virus (VZV). We have characterized the inhibitory effects of penciclovir and acyclovir on the plaque formation of cell-free VZV and cross-resistance of acyclovir-resistant VZV to penciclovir. The apparent effective concentration for 50% plaque reduction (EC50) of penciclovir determined on the third day was significantly lower than that determined on the fourth or fifth day. The size of plaques was smaller in the presence of penciclovir than in the presence of acyclovir. The effective concentrations for 50% reduction of the number of infected cells per plaque were 1.40 and 5.00 micrograms/ml for penciclovir and acyclovir, respectively. Thus penciclovir suppressed spread of infection within developing plaques more efficiently than acyclovir. Five acyclovir-resistant VZV strains with altered DNA polymerase selected by acyclovir were examined for cross-resistance to penciclovir. They were 11- to 18-fold more resistant to ACV than the parent strain, but only 4- to 5-fold more resistant to PCV. Penciclovir-triphosphate carrying the 3'-hydroxyl group of 2'-deoxyribose might have better affinity to the altered viral DNA polymerase than acyclovir-triphosphate without the 3'-hydroxyl group.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8540749&dopt=Abstract penciclovir Denavir



Denavir
Comparison of a DNA probe assay with the plaque reduction assay for measuring the sensitivity of herpes simplex virus and varicella-zoster virus to penciclovir and acyclovir.

Standring-Cox R, Bacon TH, Howard BA.

SmithKline Beecham Pharmaceuticals, Betchworth Surrey, UK.

A DNA probe assay was compared with the plaque reduction assay to determine the sensitivity of clinical isolates of herpes simplex virus (HSV) and varicella-zoster virus (VZV) to penciclovir and acyclovir in MRC-5 cells. In both assays, penciclovir and acyclovir shared comparable activity against cell-free virus (CFV) preparations of VZV and herpes simplex virus type 1 (HSV-1) isolates, whilst acyclovir was significantly more active than penciclovir against herpes simplex virus type 2 (HSV-2) isolates in both the DNA probe assay (P < or = 0.01) and the plaque reduction assay (P < or = 0.01). However, the 50% effective concentrations (EC50s) were generally lower in the DNA probe assay and the correlation between the plaque reduction and DNA probe assays was poor for either compound. Six acyclovir-resistant strains of HSV-1 derived in cell culture were also tested for susceptibility to penciclovir and acyclovir, in the DNA probe and plaque reduction assays. The relative susceptibilities of these strains were comparable, for example, one ACV-resistant strain was susceptible to penciclovir in both assays. Further comparisons of the assay methods were made using cell-associated VZV (CAV). As with CFV the EC50s were significantly lower in the DNA probe assay than the plaque reduction assay for penciclovir (P < or = 0.01) and acyclovir (P < or = 0.01). In the DNA probe assay there was no significant difference in the EC50s for either penciclovir or acyclovir when comparing CAV with CFV. However, in the plaque reduction assay the EC50s for CAV were significantly higher than those for CFV for both penciclovir (P < or = 0.01) and acyclovir (P < or = 0.01). Overall the DNA probe assay is objective, does not require prior titration of isolates and provides opportunities for automation. It is more suitable for sensitivity testing of large numbers of clinical isolates than the well-established plaque reduction assay.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8690764&dopt=Abstract penciclovir Denavir



Denavir
Comparative in-vivo genotoxicity of antiviral nucleoside analogues; penciclovir, acyclovir, ganciclovir and the xanthine analogue, caffeine, in the mouse bone marrow micronucleus assay.

Haynes P, Lambert TR, Mitchell ID.

SmithKline Beecham Pharmaceuticals, Welwyn, Herts, UK.

Three purine nucleoside analogues, penciclovir (PCV), acyclovir (ACV) and ganciclovir (GCV), were assessed for in-vivo genotoxicity in the mouse bone marrow micronucleus assay, together with the xanthine (purine) analogue, caffeine (CAF). All these compounds exhibit anti-viral properties and the first three are marketed anti-viral drugs. All have been shown to be genotoxic in separate in-vitro and in-vivo studies. Because of their widespread use, we considered it important to directly compare their relative in-vivo genotoxic potencies as an aid to assessing their relative genotoxic risk to humans. Accordingly, two-dose (0 and 24 h)/single sample mouse micronucleus assays were performed on all four compounds. PCV and ACV appeared to give essentially arithmetic increases in induction of micronucleated polychromatic erythrocytes (MNPCE) with arithmetic increases in dose with apparent thresholds at approx. 1078 mumols/kg per day and 316 mumols/kg per day, respectively. The dose-response curve for GCV appeared more exponential, without a threshold, but with a no-effect dose of around 150 mumols/kg per day. With CAF, systemic toxicity allowed the assessment of only very weak effects, such that our estimate of a no-effect dose of 388 mumols/kg per day is subject to large errors. Taking into account magnitude of response, slope of dose-response curve and no-effect doses, the order of potency was GCV > ACV > (CAF?) > PCV. The relevance of these findings in terms of risk is uncertain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8700184&dopt=Abstract penciclovir Denavir



Denavir
Activity of penciclovir in antiviral assays against herpes simplex virus.

Bacon TH, Howard BA, Spender LC, Boyd MR.

SmithKline Beecham Pharmaceuticals, Betchworth, Surrey, UK.

The effect of penciclovir and acyclovir 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 was significantly more active than acyclovir 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 and acyclovir 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 in the 24 h viral DNA inhibition assay was 0.01 mg/L compared with 0.06 mg/L of acyclovir. In the 24 h virus yield reduction assay in which MRC-5 cells were infected with 0.3 pfu/cell, penciclovir was more active than acyclovir with 99% effective concentrations of 0.6 mg/L and 1.1 mg/L, respectively. The activity of penciclovir 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, which is the oral form of penciclovir, will be at least as effective as acyclovir in treating infections caused by HSV-1 and HSV-2.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8707740&dopt=Abstract penciclovir Denavir



Denavir
Penciclovir is a selective inhibitor of hepatitis B virus replication in cultured human hepatoblastoma cells.

Korba BE, Boyd MR.

Division of Molecular Virology and Immunology, Georgetown University, Rockville, Maryland, USA.

Penciclovir [9-(4-hydroxy-3-hydroxymethylbut-1-yI)guanine], an effective antiherpesvirus agent, was found to be a potent and selective antiviral agent against intracellular hepatitis B virus (HBV) replication (drug concentration at which a 10-fold decrease in HBV DNA from the average level in an untreated culture was observed [EC90], 1.6 microM) and extracellular virion release (EC90, 0.7 microM) by cultured human hepatoblastoma (2.2.15) cells. Acyclovir and three other related 9-alkoxypurines with activity against either herpesviruses or human immunodeficiency virus were uniformly inactive against HBV. The activity of penciclovir is discussed in relation to recent findings related to its mode of action against HBV.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8723485&dopt=Abstract penciclovir Denavir