Comparison of New Topical Treatments for Herpes Labialis

STUDY 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 Mark B. McKeough, BA; Spotswood L. Spruance, MD Background: There are 3 new topical treatments for her- compared with its vehicle control, and each of these dif- pes labialis that have either been approved by the US Food ferences was significantly greater (P,.05) than the re- and Drug Administration (penciclovir cream [Denavir] ductions effected by acyclovir ointment (0%, 21%, and and n-docosanol cream [Abreva]) or recently under- 75%, respectively). The acyclovir cream effect (reduc- gone extensive clinical evaluation (acyclovir cream). The tions of 4%, 28%, and 77%, respectively) was less than relative efficacy of these products is unknown. that of penciclovir cream, and this difference was con- firmed by 2 additional head-to-head experiments. Two Objective: To compare the efficacy of penciclovir cream, experiments with n-docosanol cream failed to show sta- acyclovir cream, n-docosanol cream, and acyclovir oint- tistically significant differences by any parameter be- ment in an experimental animal model of cutaneous her- tween n-docasonol cream and vehicle control–treated sites pes simplex virus type 1 (HSV-1) disease. or between n-docosanol and untreated infection sites. Design: The backs of guinea pigs were infected with Conclusions: In this model, the efficacy of penciclovir HSV-1 using a vaccination instrument. Active treat- cream was greater than acyclovir cream, acyclovir ments and corresponding vehicle controls were applied cream was greater than or equal to acyclovir ointment, for 3 to 5 days beginning 24 hours after inoculation. and acyclovir ointment was greater than n-docosanol cream. Since our model was designed to evaluate com- Main Outcome Measures: After completion of treat- pounds that function primarily through antiviral activ- ment, the animals were killed and the severity of the in- ity, the negative findings with n-docosanol in these fection assessed from the number of lesions, the total le- studies do not exclude that it might work clinically sion area, and the lesion virus titer. through other mechanisms. Results: Penciclovir cream effected modest reductions in lesion number (19%), area (38%), and virus titer (88%) Arch Dermatol. 2001;137:1153-1158 OLLOWING a period of uncer- tions of drug to the site of the infection.7 tainty regarding efficacy,1,2 A multitude of treatments are available antiviral treatments for her- over the counter, with claims based on the pes labialis have been ap- potential of the ingredients to reduce le- proved by regulatory agen- sion pain or promote wound healing Fcies in the United States and other through occlusion. countries. In the United States, acyclovir ointment (Zovirax Ointment) is ap- See also page 1232 proved for use in immunocompromised patients and penciclovir cream (Denavir) Because of the large number of pa- From the Departments of for use in otherwise healthy adults.3,4 In tients and the expense required to con- Medicine (Mr McKeough and other countries, 1 or more ethical drug duct a therapeutic trial in herpes labialis, Dr Spruance) and Dermatology treatments, including penciclovir cream, it is unlikely that the relative clinical effi- (Dr Spruance), School of acyclovir cream,5 and idoxuridine in di- cacy of these various treatments will ever Medicine, and the Department 6 of Pharmaceutics and methyl sulfoxide, are generally avail- be determined. The dorsal cutaneous guinea Pharmaceutical Chemistry able. There is experimental evidence that pig model is a well-standardized animal (Dr Spruance), College of high-dose peroral nucleoside analogue model of cutaneous herpes disease and per- Pharmacy, University of Utah, therapy may be highly effective, possibly mits an experimental approach to this ques- Salt Lake City. because of delivery of high concentra- tion. Drug efficacy in the model correlates (REPRINTED) ARCH DERMATOL / VOL 137, SEP 2001 WWW.ARCHDERMATOL.COM 1153 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 MATERIALS AND METHODS and their vehicles were each applied at 3 different sites once per day, 2 times per day, and 4 times per day for 3 days and evaluated for irritation on the morning of the ANTIVIRAL AGENTS fourth day using an irritation score of 0 to 4. A score of 4 indicated severe erythema with punctate bleeding. Both 10% and 12% n-docosanol cream and 10% and 12% A mean score of 2.5 or greater indicated that the com- stearic acid–supplemented vehicle controls were pro- pound and/or its vehicle at that dosing frequency caused vided by Lidak Pharmaceuticals (La Jolla, Calif). The 10% sufficient irritation to compromise assessment of the viral n-docosanol cream is now marketed over the counter as infection and potentially affect the outcome of the experi- Abreva by GlaxoSmithKline (Research Triangle Park, NC). ment. The 5% acyclovir cream (Zovirax Cream [Europe]), 5% acyclovir ointment (Zovirax Ointment), and their correspond- ANIMAL INOCULATION ing vehicles were provided by GlaxoWellcome (Research AND TREATMENT Triangle Park, NC). The 1% penciclovir cream (Denavir [United States], Vectavir [Europe]) and its vehicle were pro- Guinea pigs were inoculated with HSV-1 E115 (day 0) in vided by SmithKline Beecham (King of Prussia, Pa). 4 different areas on the depilated dorsum, right and left midback, and right and left rump by multiple shallow EXPERIMENTAL VIRUS STRAIN punctures with a vaccination instrument as originally per- formed by Hubler et al.13 Between 40 and 60 discrete le- The virus was the laboratory strain HSV-1 E115, origi- sions developed at each of the 4 infection sites. Test treat- nally obtained from Andre Nahmias, MD, MPH (Emory, ments were begun 24 hours after inoculation (day 1) and Ga), and used in our model since 1980.11,12 Virus stock for given 1 to 4 times per day at 8 AM, noon, 4 PM, and 8 PM, inoculation of guinea pigs contained 13108 plaque- depending on dermal irritation, for a total of 3 days. The forming unit (pfu)/mL and was prepared in mink lung cells day after completion of treatment (day 4), the dorsum of (MV-1-Lu, American Type Culture Collection). each animal was again depilated, and the severity of infection at each site was assessed from the number of lesions, EXPERIMENTAL ANIMALS the total lesion area, and titer of virus in the excised infection site. The procedures have been described in detail Hartley strain, outbred, female, albino guinea pigs, weigh- elsewhere.12 ing approximately 500 g each, were obtained from Charles River Breeding Laboratories Inc, Wilmington, Mass. Dur- STATISTICAL PROCEDURES ing treatment, animals were housed in individual cages. Be- fore inoculation and again immediately before experimen- Paired data (drug and drug vehicle) were evaluated by the tal virus lesion assessment, the hair was removed from the Wilcoxon signed rank test. To compare 2 drugs with one animal dorsum with a chemical depilatory. another, efficacies were expressed as the percent difference in a lesion severity measure (lesion number, area, or ASSESSMENT OF DERMAL IRRITATION virus titer) between the active formulation and its control and tested by a Mann-Whitney rank sum procedure. All Test compounds were evaluated for irritation on the depi- probability determinations were 2-tailed, and P#.05 was lated, uninfected dorsum of guinea pigs. Test compounds considered significant. with antiviral activity and skin penetration.8,9 Guinea pig which were applied at contralateral infection sites. Acy- skin is generally more permeable to nucleoside drugs than clovir ointment and the ointment vehicle were studied human skin, but the relative order of permeation of dif- concurrently as a control. The different drug formula- ferent compounds appears to be the same.10,11 tions were compared with one another using the per- The present report describes 2 sets of experiments centage of improvement in lesion severity measures in the guinea pig model. In the first experiment, we com- from the drug vs drug vehicle assessments. Each treat- pared penciclovir cream, acyclovir cream, and acyclovir ment was evaluated at 12 different infection sites on the ointment with vehicle controls. In the second group of guinea pig dorsum as described in the “Materials and experiments, we examined the efficacy of a new over- Methods” section. Treatments were only applied once a the-counter agent, n-docosanol cream (Abreva). The re- day because both cream formulations were irritating to sults are correlated with the efficacy of other treatments guinea pig skin. The results are shown in Table 1. in the model and the outcome of clinical trials. Penciclovir cream had the greatest effect. Reduc- tions in lesion number (19%), area (38%), and virus ti- RESULTS ter (88%) were demonstrated in comparison to the vehicle, and each of these differences was significantly greater PENCICLOVIR CREAM, ACYCLOVIR CREAM, (P,.05) than the reductions effected by acyclovir oint- AND ACYCLOVIR OINTMENT VS ment (0%, 21%, and 75%, respectively). The acyclovir VEHICLE CONTROLS cream effect on lesion parameters (reductions of 4%, 28%, and 77%, respectively) was less than that of penciclovir Penciclovir and acyclovir creams were examined for ef- cream and similar in magnitude and not significantly dif- ficacy in relationship to their corresponding vehicles, ferent from those of acyclovir ointment. The differences (REPRINTED) ARCH DERMATOL / VOL 137, SEP 2001 WWW.ARCHDERMATOL.COM 1154 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 1. Penciclovir Cream Treatment vs Vehicle Control Treatment in the Guinea Pig Model* Difference Difference Difference Between Between Between Penciclovir Means, % Vehicle Acyclovir Means, % Vehicle Acyclovir Means, % Vehicle Variable Cream (P Value) Control Cream (P Value) Control Ointment (P Value) Control No. of lesions Mean 39 19 (.04)† 48 50 4 (.67) 52 49 −6 (.18) 46 SD 11 ..

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