Some ultraviolet spectroscopic characteristics sensitive to the polarity of the medium have been used to determine the average polarities of the microenvironments of benzene, several of its derivatives, Triton X-100, and naphthalene when solubilized in micelles at low solubilizate to surfactant ratios. Concordant results are obtained using several parameters and, for benzene, a micelle-water distribution coefficient is obtained in good agreement with literature values. The polarity parameters show little dependence on the charge of the micelles. The microenvironment of benzene is polar and roughly comparable with that of Triton X-100, used as a solubilizate, for which the chromophore is located at the micelle-water interface. The polarity of the microenvironment decreases systematically on progressive alkyl substitution. A two-state model for the solubilized species involving a distribution between a nonpolar "dissolved state", associated with the hydrocarbon core, and a polar "adsorbed state", associated with the micelle-water interface, provides a satisfactory description. The adsorption can be ascribed to the surface activity of the aromatic species using an "oil-drop" model for the micelle. Although interfacial tension data indicate that benzene is only mildly surface active at hydrocarbon-water interfaces, the adsorption effects are greatly magnified by the extremely high surface to volume ratios of micelles. The interfacial tensions of alkyl benzenes against water are higher than that of benzene; the reduced adsorption expected is in agreement with the observed lowering of the microenvironmental polarity. The fractional adsorption is also expected to be lower at high mole fractions of the solubilizates in the micelles. Some apparently contradictory results in the literature are rationalized on this basis. The implications of the surface activity of solubilized species for biological membranes, for understanding the solubilizing capacity of micelles, as also for the use of surface active species as microenvironmental "probes" are discussed.

No abstract

Tokiwa and K. Nagase for their encouragements and permission to publish this paper. They also thank Messrs. Y. Teramoto and T. Saito of Daini Seikosha for their help in DSC measurements.

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...

No abstract