sm-8668 and Tinea

Sch 39304 is a new broad spectrum triazole antifungal agent that is active, orally and topically, against superficial Trichophyton mentagrophytes and vaginal Candida albicans infections. Sch 39304 was compared to fluconazole (FLZ) in a T. mentagrophytes infection model in guinea pigs. Following topical administration, Sch 39304 (0.125%, twice daily, 10 days), was 5-8-fold more effective than FLZ, based on culture and lesion score results. Following oral administration, Sch 39304 (2.5 mg kg-1, once daily, 10 days) produced a dramatic reduction in lesion scores and was 20-fold more active than FLZ; however, due to the length of time it takes for the drugs to reach the infected area of the skin and eradicate the infections, most animals remained culture positive with both drugs. Sch 39304 was also compared with FLZ in a vaginal C. albicans infection in hamsters. Following oral administration (4 days), Sch 39304 (1.6 mg kg-1), cured all hamsters and was 4-fold more active than FLZ. In addition, Sch 39304 as a single oral dose (10 mg kg-1) also cured all hamsters. When treatment was intravaginal (8 days), Sch 39304 was again more active than FLZ (2-fold), and also micronazole (8-fold), with 100% of the hamsters cured at concentrations as low at 0.025%.

Topics: Administration, Oral; Administration, Topical; Animals; Antifungal Agents; Candidiasis, Vulvovaginal; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fluconazole; Guinea Pigs; Miconazole; Tinea; Triazoles

The topical antifungal Sch-39304 is a racemic compound comprised of two enantiomers, Sch-42427 and Sch-42426, only one of which (Sch-42427) is pharmacologically active. The pure enantiomers have a lower melting point and, therefore, a higher solubility than the racemic compound. Because of these differences in physicochemical properties, the concentration of the pure enantiomers in vehicles and in the skin was predicted to be an order of magnitude higher than the racemic compound. It was hoped that the pharmacological activity would also be higher. By measuring the flux of the chiral forms through human cadaver skin, the expected differences in skin solubility were confirmed. However, only a minimal difference between racemate and active enantiomer was observed in the lesion scores using a guinea pig dermatophyte model. By fitting the data to the Emax pharmacodynamic model, it is demonstrated that the maximum effect occurs at a concentration lower than the saturated concentration of the less soluble racemic compound. The data illustrate that the efficacy of topically active compounds may not be linearly related to drug concentration in either the vehicle or the skin.

Topics: Adult; Animals; Antifungal Agents; Chemical Phenomena; Chemistry, Physical; Chromatography, High Pressure Liquid; Guinea Pigs; Humans; In Vitro Techniques; Male; Microbial Sensitivity Tests; Skin; Skin Absorption; Solubility; Stereoisomerism; Tinea; Triazoles; Trichophyton

SM-8668 (Sch 39304) is a new oral antifungal agent which we evaluated in comparison with fluconazole in various fungal infection models. The prophylactic effect of SM-8668 was excellent against systemic candidiasis, aspergillosis, and cryptococcosis in mice. The 50% effective dose for SM-8668 was assessed at 10 days after infection and was 0.18, 3.7, and 5.9 mg/kg (body weight), respectively, for the above-mentioned fungal diseases. Fluconazole was about four times less effective than SM-8668 against systemic candidiasis and was only slightly effective at doses of 80 and 25 mg/kg against systemic aspergilosis and cryptococcosis, respectively. SM-8668 was also about four to eight times more active than fluconazole against vaginal candidiasis in rats and against dermatophytic infection in guinea pigs. In addition, topical SM-8668 was as effective as topical miconazole or tioconazole against skin mycosis in guinea pigs. After oral administration, SM-8668 showed a maximum concentration in serum similar to that of fluconazole in both mice and rats, but the elimination half-life and area under the serum concentration-time curve for SM-8668 were twice those for fluconazole.

Topics: Administration, Cutaneous; Administration, Oral; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Candidiasis, Vulvovaginal; Cryptococcosis; Female; Fluconazole; Guinea Pigs; Male; Mice; Mice, Inbred Strains; Rats; Rats, Inbred Strains; Tinea; Triazoles