Preclinical antimycotic activity of SDZ 89–485: a new orally and topically effective triazole

Abstract

SDZ 89-485 is a new orally and topically active triazole antifungal with efficacy superior to reference compounds in most animal infection models used for preclinical comparison of antifungals.The compound inhibits mycelial transformation of Candida albicans in vitro at MIC50 concentrations of 0.006 and 0.00019 mgl -~ in MEM and NYP medium, respectively.In rodent models of vaginal candidosis SDZ 89-485 was significantly more active than reference compounds after various oral or topical treatment regimens, with ED50 values ranging from 0-09 to 0.79 mgkg -J and 0.01% active ingredient, respectively. When administered orally, the efficacy of SDZ 89-485 was superior to, or as good as that of the reference compounds in several murine models of systemic candidosis, sporotrichosis and histoplasmosis. In murine aspergillosis, using the kidney as the target organ, SDZ 89-485 was as active as itraconazole. Guinea pig trichophytosis was more responsive to oral tluconazole and itraconazole than to oral SDZ 89-485.Fungal infections, particularly systemic mycoses caused by opportunistic pathogens, are a growing problem in patients with impaired immune defence mechanisms and successful therapy of these infections presents difficulties [5,16,20,30,31]. The recently developed triazole antimycotics, fluconazole and itraconazole are under clinical evaluation for the treatment of these mycoses and early results with these drugs look promising [3-7, 12, 19, 22]. SDZ 89-485, a new triazole derivative [11] is the result of a research programme aimed at the development of a new azole-derivative, which has not only an improved antimycotic efficacy but also high selectivity for the target enzyme of fungal sterol biosynthesis [29], and no teratogenic potential [2].The antifungal activity of this compound (Fig. 1) in vitro against a broad spectrum of medically important fungi has already been reported [28]. The minimum inhibitory concentrations (MICs) of SDZ 89-485 against Candida blastospores were consistently within the same range as those of ketoconazole and itraconazole. Since MIC tests targeting yeast blastospores do not accurately reflect the activity of azole antimycotics

Experimental models in antifungal chemotherapy

“…Itraconazole has also shown high activity against sporotrichosis in the testis model performed at Janssen Pharmaceuticals [S]. In the chamber model [ 1581, amphotericin B, ketoconazole and the three triazoles itraconazole, ICI 153066 and SD89485 showed high efficacy [163].…”

Rodent Models of Invasive Aspergillosis due to Aspergillus fumigatus: Still a Long Path toward Standardization

“…It appeared to be well-tolerated by all animals as no mortality was observed during the first 12 h after injection (Zimmerli et al, 2007 ). For a nephritis model, 1.0 × 10 3 spores were injected into the intra-medullar kidney (Walzl et al, 1987 ; Schaude et al, 1990 ). Cutaneous abscesses were generated in murine soft tissues by sc injections, mainly into the thigh after fur removal (Lupetti et al, 2002 ; Ruiz-Cabello et al, 2002 ; Donat et al, 2012 ), or by intradermal injections into the ears (Petersen et al, 2002 ; Goebel et al, 2005 ; Stein et al, 2013 ).…”