Topical acyclovir (ACV) in polyethylene glycol (PEG) ointment has been disappointing in the treatment of recurrent herpes simplex virus infections in immunocompetent patients. To investigate the possible role of poor drug delivery from this formulation, we studied the penetration of ACV through excised human skin from three vehicles; PEG ointment, modified aqueous cream, and dimethyl sulfoxide. A second antiviral agent, idoxuridine, was studied in the same formulations, and drug delivery through excised guinea pig skin was also assessed for comparison. The delivery of ACV from PEG ointment was very slow for both human and guinea pig skin (drug flux, 0.055 and 0.047 tLg/cm2 per h, respectively). Formulation of ACV in modified aqueous cream and in dimethyl sulfoxide resulted in an 8-and 60-fold increase, respectively, in the flux of ACV through human skin. Idoxuridine behaved similarly to ACV in the three vehicles. The poor clinical results seen with topical use of ACV ointment may be due in part to retarded drug delivery from this formulation.Topically administered acyclovir (ACV) in polyethylene glycol (PEG; Zovirax Ointment; Burroughs Wellcome Co., Research Triangle Park, N.C.) has proved disappointing in the therapy of recurrent herpes simplex virus (HSV) infections in immunocompetent patients, including trials in which therapy was patient initiated (3,10,12,15,17). Investigators have speculated from this experience that the failure of topical ACV therapy is due in part to the inability of ACV to penetrate the stratum corneum barrier layer of the skin (10,11,15,20).In this study we examined this question by measuring the penetration of ACV and idoxuridine (IDU) through excised human and guinea pig skin from three different vehicles: PEG, a modified aqueous cream (MAC), and dimethyl sulfoxide (DMSO). The results show that PEG is an inferior vehicle for the percutaneous delivery of nucleoside antiviral agents and that drug delivery is markedly enhanced by formulation in other vehicles. Skin specimens were mounted with the epidermal side up in single-chamber, jacketed diffusion cells. The temperature of the receiver chamber was controlled by circulating 37°C water through the external jacket, and the epidermal surface was left exposed to ambient conditions. Single doses of drugs were applied to the epidermal surface as either 100 pul of solution or 200 mg of ointment or cream; these quantities were sufficient to completely cover the exposed epidermal surface. MATERIALS AND METHODSDrug concentration in the receiver chamber was determined by withdrawing samples over time and measuring labeled drug by scintillation counting. Drug flux (J; in micrograms per square centimeter per hour) was calculated from the slope of a plot of drug concentration versus time, the area of the treated skin, and the volume of the receiver chamber (16).

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Topical foscarnet (PFA) and acyclovir (ACV) were compared in the dorsal cutaneous guinea pig model of herpes simplex virus type 1 infection. The relative order of efficacy was PFA cream>ACV cream>ACV ointment. In vitro studies demonstrated that PFA and ACV formulated in cream vehicles penetrated through guinea pig skin 7-to 10-fold faster than did ACV in ointment.Foscarnet cream (sodium phosphonoformate [PFA]), acyclovir (ACV) cream, and ACV ointment are topical antiviral preparations which have received extensive clinical evaluation as treatments for recurrent herpes simplex labialis and genitalis in normal, nonimmunocompromised subjects. Modest success has been claimed for PFA cream (19,26) and ACV cream (6,7,15,25), while the majority of studies with ACV ointment in recurrent disease have failed to demonstrate any clinical benefit (3,17,20,21,24,27 (8) were 14.2 and 0.14 ,ug/ml, respectively. Sixteen Hartley strain, outbred female albino guinea pigs weighing 350 to 400 g each were inoculated with HSV-1 E115 in six different areas on the depilated dorsum by multiple shallow punctures as originally described by Hubler et al. (14). Treatment of each infection site with 200 to 250 mg of cream or ointment was begun 24 h after inoculation and continued once per day for 3 days. The frequency of dosing was limited because some formulations were irritating to the skin. This protocol allowed for 12 comparisons between each drug and its contralaterally applied vehicle as well as comparisons of efficacy between each of the four different antiviral formulations. The severity of the infection at each treatment site was evaluated on the day after completion of the treatment regimen by examining the number of lesions, the diameter of lesions, the total lesion area, and the quantity of virus in excised skin. Further details of these procedures have been previously described (8,22 Drug flux was determined from a steady-state plot of drug concentration versus time. Further details of these procedures are available elsewhere (8,22,23).Lesion severity between drug and vehicle control-treated sites were compared by the Wilcoxon signed-rank test. The percent efficacies of different drug formulations were compared by the Mann-Whitney rank-sum procedure and in vitro flux values by Student's t test. All probability determinations were two tailed, and a P of c 0.05 was considered to be significant.The results of the in vivo studies are shown in Table 1. Compared with lesion severity at vehicle control-treated sites, reductions of the mean number of lesions by 3% PFA, 0.3% PFA, ACV cream, and ACV ointment were 54, 36, 19, and -8%, respectively; reductions in the mean lesion area were 73, 52, 31, and 19%; and the reductions in mean lesion virus titer effected by these treatments were 90, 80, 75, and 60%. The greater reduction in number of lesions by 3% PFA, 0.3% PFA, and ACV cream compared with that of ACV ointment was statistically significant (P c 0.03). Both 3% and 0.3% PFA were significantly more effective in reducing lesion area t...

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Three percent 5-ethyl-2'-deoxyuridine (EdU) in an aqueous cream base was compared with 5% acyclovir (ACV) in polyethylene glycol ointment and 3% EdU in 95% dimethyl sulfoxide (DMSO) for efficacy in the topical treatment of an experimental dorsal cutaneous herpes simplex virus type 1 infection in guinea pigs. Topical ACV treatment reduced the mean lesion number by 15%, the lesion area by 32%, and the lesion virus titer by 60% when compared with measurements at contralateral sites treated with the vehicle alone. Application of 3% EdU cream was more beneficial, effecting reductions of 29, 44, and 68% in the same measurements. EdU in DMSO was even more effective, reducing the lesion measurements by 39, 60, and 90%, respectively. The penetration of EdU and ACV through guinea pig skin was compared in single-chamber diffusion cells. In the aqueous cream, EdU readily penetrated excised skin and exhibited rates of flux 10-fold greater than those shown by ACV in ointment formnulation (0.56 versus 0.05 pg/cm2 per h; P = 0.05). The flux of EdU in DMSO was 3.39 jig/cm2 per h, six times higher than the flux in the cream vehicle. EdU was more effective than ACV in this experimental animal model, most likely due to better percutaneous drug delivery of EdU from the cream and DMSO vehicles.The activity of 5-ethyl-2'-deoxyuridine (EdU) against infection with herpes simplex virus (HSV) was first recognized in 1967 (13). In vitro testing by reduction in cytopathic effect has identified the mean 50% inhibitory dose against HSV type 1 (HSV-1) and HSV type 2 (HSV-2) to be 0.3 to 0.5