Measurement of the stratum corneum drug reservoir to predict the therapeutic efficacy of topical iododeoxyuridine for herpes simplex virus infection.
A rapid, in vivo measurement of the penetration of antiviral compounds into the skin would improve our ability to predict the therapeutic efficacy of topical treatments for herpes simplex virus (HSV) infection. We have studied the concentration of iododeoxyuridine (IDU) in the stratum corneum of guinea pig skin by tape stripping at different time points after single and multiple topical doses of the drug. These results were correlated with the efficacy of topical IDU against an experimental cutaneous HSV infection. Ten adhesive tape strippings were performed on depilated guinea pig dorsum in vivo at serial intervals after a single topical dose of [3H]IDU. Iododeoxyuridine levels in the stratum corneum peaked at 1-3 h (67-70 mg/g of tissue) and then gradually declined over the next 3-24 h. We hypothesized that the peak IDU stratum corneum concentration would correlate with therapeutic efficacy. Accordingly, we determined the quantity of IDU in guinea pig stratum corneum 2 h after a topical application of seven different concentrations of IDU in dimethylsulfoxide (DMSO) and examined the in vivo efficacy of these formulations in an experimental dorsal cutaneous HSV-1 infection in guinea pigs. The results showed an excellent correlation between the quantity of IDU in the stratum corneum and reduction in lesion severity (r = 0.95-0.97). Fifteen percent IDU in DMSO provided the highest therapeutic efficacy (90-94%). We also studied the relationship between the clinical efficacy of different dosing frequencies and the amount of IDU in the stratum corneum. Serial IDU stratum corneum concentrations were measured over 24 h following 1, 2, 3, or 4 applications per day of 1, 3, and 15% IDU in DMSO treatments and parallel efficacy studies of the different regimens were conducted in the animal model. Within each dosing frequency, the cumulative amount of drug in the stratum corneum correlated with the strength of the test formulation and with efficacy in the animal model. For each of the three formulations, increasing the number of daily doses from one up to three led to progressive increases in cumulative stratum corneum IDU levels and clinical efficacy. An increase in the number of daily applications to four had little effect on drug efficacy and was associated with a plateau in stratum corneum IDU levels. Stratum corneum IDU concentrations were rapid and easy to determine and correlated well with clinical events.(ABSTRACT TRUNCATED AT 400 WORDS)
Sheth
N V
NV
Department of Medicine, School of Medicine, University of Utah, Salt Lake City 84132.
McKeough
M B
MB
Spruance
S L
SL
D000287:Administration, Topical; D000818:Animals; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage; D005260:Female; D006168:Guinea Pigs; D006561:Herpes Simplex / Q000188:drug therapy* / Q000473:pathology; D007065:Idoxuridine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014677:Pharmaceutical Vehicles; D012867:Skin / Q000032:analysis*
D014677:Pharmaceutical Vehicles; D007065:Idoxuridine; D004121:Dimethyl Sulfoxide