Acyclovir Topical Therapy of Cutaneous Herpes Simplex Virus Infection in Guinea Pigs

Park, No-Hee; Pavan-Langston, Deborah; McLean, Sandra L.; Lass, Jonathan H.

doi:10.1001/archderm.1980.01640300060018

Cited by 31 publications

(4 citation statements)

References 28 publications

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“…In the guinea pig genital model, ACV may have achieved significant systemic levels by absorption across the introital or vaginal mucosa (11). The study on the guinea pig dorsum by Park et al (18) was similar to ours. However, if inoculation stabs were close together or superimposed, more damage to the skin may have occurred than with the widely spaced injections we employed, or increased drug penetration may have resulted from their repeated use of a depilatory (28).…”

Section: Discussionsupporting

confidence: 85%

“…Since the drug is a potent antiviral agent effective against herpes simplex virus disease under other clinical circumstances, we have attributed the failure of topical therapy in recurrent infections to either late initiation of treatment or inadequate penetration of the drug through the stratum corneum (24). A recently completed trial of topical ACV-PEG against prodromal and erythema-stage herpes labialis has yielded negative results, which makes it unlikely that late treatment alone is responsible for the lack of efficacy (S. (1), topical ACV-PEG was highly effective in a variety of animal models of cutaneous HSV disease, including the guinea pig dorsum (18,22), female guinea pig genitalia (11), mouse lip (17), lumbosacral and orofacial skin of hairless mice (12), and lumbar skin of athymic nude mice (9). Topical ACV-PEG may have succeeded in these studies because the inoculation process altered the integrity of the stratum corneum or alternate routes of absorption were available, so that the ability of the formulation to penetrate stratum corneum was not a critical determinant of the outcome.…”

Section: Discussionmentioning

confidence: 99%

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Penetration of guinea pig skin by acyclovir in different vehicles and correlation with the efficacy of topical therapy of experimental cutaneous herpes simplex virus infection

Spruance¹,

McKeough²,

Cardinal³

1984

Antimicrob Agents Chemother

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Inadequate penetration of antiviral agents through the stratum corneum of the skin may be one of the limiting factors in the topical therapy of recurrent cutaneous herpes simplex virus infections in humans. In vitro studies of the penetration of the nucleoside analog acyclovir (ACV) through guinea pig skin demonstrated a marked increase in drug flux when ACV was formulated in dimethyl sulfoxide (DMSO), compared with water or polyethylene glycol (PEG) as the vehicle. To examine whether the increased transcutaneous flux of ACV effected by DMSO was meaningful in vivo, topical 5% ACV in DMSO was evaluated for the treatment of cutaneous herpes simplex virus infection in guinea pigs and compared with topical 5% ACV in PEG. When compared with infection sites treated with the vehicle alone, ACV in DMSO produced a greater percent reduction than did ACV in PEG in median lesion number (8 versus 58%; P < 0.001), median lesion area (35 versus 73%; P = 0.001), and median lesion virus titer (21 versus 84%; P = 0.08). We conclude that DMSO is a highly effective vehicle for topical administration of ACV and is superior to PEG in our model. Careful choice of vehicle and consideration of transcutaneous penetration may be important for realization of the full potential of topical antiviral therapy in humans.Development of an effective topical therapy for recurrent mucocutaneous herpes simplex virus (HSV) infections in immunologically normal humans has been difficult (16). Acyclovir (ACV) is a new anti-herpesvirus compound which is 10-to 150-fold more potent in vitro than older drugs such as vidarabine or iodoxuridine (IDU). In addition, ACV is phosphorylated selectively to an active form in virus-infected cells and is nontoxic to uninfected mammalian cells over a wide range of concentrations (22). The value of ACV applied intravenously, orally, and topically in the treatment of severe HSV infections in immunosuppressed hosts and in primary genital HSV infections has been documented (5,7,15,25,27). However, the results of treatment of recurrent mucocutaneous HSV infections in normal subjects with topical 5% ACV in polyethylene glycol (PEG; Zovirax) were disappointing. Topical treatment of recurrent herpes simplex labialis and recurrent herpes genitalis effected a reduction in the excretion of virus from the lesions, but there was no change in the clinical course of infection (7, 24).Assessment of the reasons for the clinical failure of topical ACV therapy in the treatment of recurrent herpes labialis and genitalis has led to the conclusion that either ACV was applied too late to affect the natural course of recurrent HSV disease or that it did not penetrate the stratum corneum and reach infected cells in the lower layers of the epidermis in adequate concentrations (24). To evaluate the latter possibility, we studied the flux of ACV through guinea pig skin in vitro from different drug vehicles and have compared these findings with the in vivo efficacy of two drug vehicle combinations in the topical treatment of an experimental HSV in...

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Penetration of guinea pig skin by acyclovir in different vehicles and correlation with the efficacy of topical therapy of experimental cutaneous herpes simplex virus infection

Spruance¹,

McKeough²,

Cardinal³

1984

Antimicrob Agents Chemother

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“…In this system, several antiherpetic drugs had a therapeutic effect, notably phosphonoacetic acid (PAA), PFA, and ACG Helgstrand et al, 1979;Alenius, 1980;Park et al, 1980;Alenius et al, 19821.…”

Section: Introductionmentioning

confidence: 99%

“…Since the studies by Hubler et al [ 19771 and Schafer et al [ 19771 , skin infection of white guinea pig has lent itself as a model for cutaneous HSV infection. In this system, several antiherpetic drugs had a therapeutic effect, notably phosphonoacetic acid (PAA), PFA, and ACG Helgstrand et al, 1979;Alenius, 1980;Park et al, 1980;Alenius et al, 19821. One approach to antiviral chemotherapy is the combination of two inhibiting substances, with the aim of minimizing toxic effects and avoiding the emergence of resistant mutants. In cell culture experiments, we combined six antiherpetic substances and human fibroblast interferon with each other and observed many instances of synergistic interaction [Jam and Wigand, 19821.…”

Section: Introductionmentioning

confidence: 99%

Combined chemotherapy of cutaneous herpes simplex infection of the guinea pig

Burkhardt

Wigand

1983

Journal of Medical Virology

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Cutaneous infection of guinea pigs with HSV1 was topically treated from 2 to 6 days post infection with 7 antiherpetic substances. Phosphonoformic acid and acyclovir were found to be highly effective; trifluorothymidine, thymine arabinoside, ethyldeoxyuridine, and adenine arabinoside monophosphate all had some therapeutic effect in decreasing order, whereas iododeoxyuridine was ineffective. The efficacy of treatment was evaluated from cutaneous lesion scores by the Wilcoxon rank test. The substances were combined in marginally effective concentrations. From the 21 combinations, acyclovir + phosphonoformic acid, acyclovir + thymine arabinoside, and phosphonoformic acid + thymine arabinoside suggested a synergistic interaction, which appeared significant for acyclovir + phosphonoformic acid.

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Treatment of Eczema Herpeticum With Acyclovir

Swart¹

1983

Arch Dermatol

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Acyclovir Topical Therapy of Cutaneous Herpes Simplex Virus Infection in Guinea Pigs

Cited by 31 publications

References 28 publications

Penetration of guinea pig skin by acyclovir in different vehicles and correlation with the efficacy of topical therapy of experimental cutaneous herpes simplex virus infection

Penetration of guinea pig skin by acyclovir in different vehicles and correlation with the efficacy of topical therapy of experimental cutaneous herpes simplex virus infection

Combined chemotherapy of cutaneous herpes simplex infection of the guinea pig

Treatment of Eczema Herpeticum With Acyclovir

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