Efficacies of topical formulations of foscarnet and acyclovir and of 5-percent acyclovir ointment (Zovirax) in a murine model of cutaneous herpes simplex virus type 1 infection

Abstract

The topical efficacies of foscarnet and acyclovir incorporated into a polyoxypropylene-polyoxyethylene polymer were evaluated and compared to that of 5% acyclovir ointment (Zovirax) by use of a murine model of cutaneous herpes simplex virus type 1 infection. All three treatments given three times daily for 4 days and initiated 24 h after infection prevented the development of the zosteriform rash in mice. The acyclovir formulation and the acyclovir ointment reduced the virus titers below detectable levels in skin samples from the majority of mice, whereas the foscarnet formulation has less of an antiviral effect. Reducing the number of treatments to a single application given 24 h postinfection resulted in a significantly higher efficacy of the formulation of acyclovir than of the acyclovir ointment. Acyclovir incorporated within the polymer was also significantly more effective than the acyclovir ointment when treatment was initiated on day 5 postinfection. The higher efficacy of the acyclovir formulation than of the acyclovir ointment is attributed to the semiviscous character of the polymer, which allows better penetration of the drug into the skin.

FIG. 1

Time evolution of the mean lesion score and survival of hairless mice infected cutaneously with HSV-1 strain F and treated soon after infection with the polymer alone (●), the polymer containing 3% foscarnet (■), the polymer containing 5% acyclovir (▴), or the acyclovir ointment (▵). Untreated infected mice (○) were used as controls. Treatment was started 24 h after the infection and was repeated three times daily for 4 days. Values represent the means for 7 to 10 animals per group.

FIG. 2

Effect of formulations on titers of HSV-1 in the skin of hairless mice. Treatment was started 24 h after the infection and was repeated three times daily for 4 days. Viral titers in skin samples corresponding to the inoculation site (A) and to the lower flank (B) were determined on day 5 postinfection. Broken lines show the limit of detection of the assay. PFA, foscarnet; ACV, acyclovir. Values represent the means ± standard errors of the means for 7 to 10 animals per group. P values were <0.05 (∗), <0.005 (∗∗), and <0.001 (∗∗∗).

FIG. 3

Time evolution of the mean lesion score and survival of hairless mice infected cutaneously with HSV-1 strain F and treated 24 h postinfection with a single application of the polymer containing 3% foscarnet (■), the polymer containing 5% acyclovir (▴), or the acyclovir ointment (▵). Untreated infected mice (○) were used as controls. Values represent the means for 7 to 13 animals per group.

FIG. 4

Time evolution of the mean lesion score and survival of hairless mice infected cutaneously with HSV-1 strain F and treated later after infection with the polymer alone (●), the polymer containing 3% foscarnet (■), the polymer containing 5% acyclovir (▴), or the acyclovir ointment (▵). Untreated infected mice (○) were used as controls. Treatment was started on day 5 postinfection and was repeated three times daily for 4 days. Values represent the means for 7 to 10 animals per group.

FIG. 5

Distribution of foscarnet (▵ and ▴) and acyclovir (○ and ●) in skin tissues of uninfected (A, C, and E) and infected (B, D, and F) mice at 24 h after topical application either in phosphate buffer (open symbols) or in the polymer matrix (filled symbols). (A and B) Distributions of foscarnet and acyclovir in the stratum corneum tape strips. (C and D) Concentrations of foscarnet and acyclovir in the epidermis. (E and F) Concentrations of foscarnet and acyclovir in the dermis. Values represent the means for four to six animals per group. Error bars show standard errors of the means. P values were <0.05 (∗) and <0.001 (∗∗∗).

FIG. 6

Concentration of acyclovir in plasma of uninfected and infected mice at 24 h after topical application either in phosphate buffer (open bars) or in the polymer matrix (filled bars). Values represent the means for four to six animals per group. Error bars show standard errors of the means. The P value was <0.001 (∗∗∗).