Untitled

Abstract

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.

Animal Model of Dermatophytosis

“…The methods of abrading back skin include the use of sandpaper [22, 23, 25, 31, 33, 45, 47, 48, 54, 58], a roughened pestle [40, 41], a steel brush [50], pumice stone [17], shaving [51, 57, 59], and tape stripping [21, 26–30, 32, 35, 36, 46, 51, 52]. The abrasion techniques using sandpaper, a roughened pestle, and a pumice stone are simple and easy; however, such techniques may lead to skin wounds such as an ulcer, which subsequently can be confused with lesions produced during dermatophyte infections [51].…”

“…The tinea corporis animal model was used to estimate the efficacy of antifungal agents like bifonazole [21, 22, 25, 26, 35, 46, 52], clotrimazole [22, 23, 25, 35, 37, 40, 46, 52], miconazole [37, 44], tolnaftate [12, 22, 25, 37, 40], griseofulvin [28, 29, 37, 40, 65], ketoconazole [12, 18, 20, 29, 37, 40], omoconazole [32, 36], terbinafine [26, 29, 40, 41, 47, 48, 50, 58, 65], econazole [40], butenafine [22, 23, 33], naftifine [22], itraconazole [20, 27, 41, 50, 51, 59, 65], amorolfine [21, 65], sertaconazole [44], saperconazole [24], latoconazole [25], fluconazole [27, 28, 31, 41, 65], SCH 39304 [31, 54], lanoconazole [30, 33, 48], mupirocin [18], laudamonium [17], KP-103 [33], neticonazole [33], R126638 [59], voriconazole [57], ciclopirox [58], pramiconazole [50], luliconazole [48], and Astragalus verus Olivier [45]. …”

Enantiomeric separation of norgestrel by reversed phase high-performance liquid chromatography using eluents containing hydroxypropyl-beta-cyclodextrin in stereoselective skin permeation study

“…The differences in permeation rate between d-(±)-norgestrel and levonorgestrel do not have to be related to stereoselective interactions, which may mainly contributed to the discrepancy in melting point (the difference was about 30 • C). The phenomena of differences in permeation rate between racemate and enantiomers had also been reported for other chiral drugs such as ketoprofen [15], ketorolac [16], a new antifungal Sch-39304 [17] and nivaldipine [18].…”

Chiral Recognition R- and RS- of New Antifungal: Complexation/Solubilization/Dissolution Thermodynamics and Permeability Assay

“…For example, Li et al [13] disclosed a role of difference in binding energy in the enantioseparation process by the example of complex formation of 12 new triadimenol and seven new triazole antifungal active compounds with heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin. In their turn, Wearley et al [14] estimated the relationship between physicochemical properties (melting point, solubility), including skin permeation of the racemic and pure enantiomers of topical antifungal of 1,2,4-triazole class, and found no linear correlation between the efficacy of topically active drugs and the thermodynamic activity in the vehicle or the skin.…”