In vitro and in vivo antifungal activities of D0870, a new triazole agent

Abstract

In vitro and in vivo antifungal activities of D0870 were evaluated in comparison with those of fluconazole. D0870, which is the R-enantiomer of IC1195,739, was found to be the mycologically active enantiomer by comparing the activities of D0870 with those of M16355 (S-enantiomer of IC1195,739). D0870 showed a broad spectrum of antifungal activity and MICs and minimum antibiotic concentrations 4-to 2,000-fold lower in synthetic amino acid medium (fungal) agar than those of fluconazole for various fungi. Although MICs of D0870 were affected by variation of the test conditions, such as type of medium, inoculum size of fungi, supplementation with fetal bovine serum, and pH of medium, they were consistently much lower than those of fluconazole under any condition. In vivo activities of D0870 in the systemic infection models with Candida albicans, Cryptococcus neoformans, and Aspergillus fiumigatus in normal mice and in the mice immunosuppressed with cyclophosphamide or cortisone acetate were 2-to 7-fold and 3-to 89-fold greater than those of fluconazole, respectively. In these infection models in immunosuppressed mice, the therapeutic efficacy of D0870 was almost equivalent to that in normal mice, whereas the efficacy of fluconazole was 2-to 50-fold lower than that in normal mice.It has been reported that the recent rise in the number of patients with systemic fungal infections closely relates to therapy using immunosuppressive or anticancer agents (6, 7). These kinds of agents reportedly cause the destruction of the cellular or humoral host defense system, and that destruction inevitably raises the frequency of opportunistic infections caused by fungi such as Candida, Aspergillus, or Cryptococcus species. Under these circumstances, the need for potent systemic antifungal agents has been increasing recently. Six systemic antifungal agents, amphotericin B (AMPH), flucytosine, miconazole (MCZ), ketoconazole, fluconazole (FCZ), and itraconazole, have been developed so far for clinical use. However, the clinical values of these agents have been limited primarily by their relatively high risks of toxicity, emergence of drug resistance, pharmacokinetic deficiencies, and/or insufficiency of their antifungal activities (7,8,14). Thus, much effort still has been made to develop novel potent antifungal agents which are safe and systemically effective against various deep-seated mycoses. D0870 (Fig. 1) is the R-enantiomer of IC1195,739, which has excellent in vitro and in vivo antifungal activities (4,16 In vitro antifungal activity. MICs and minimum antibiotic concentrations (MACs) were determined by the twofold agar dilution method with synthetic amino acid medium (fungal)

Efficacy of D0870 compared with those of itraconazole and amphotericin B in two murine models of invasive aspergillosis

“…(1, 7, 10, 11, 13), Cryptococcus neoformans (10,13), Histoplasma capsulatum (11), Blastomyces dermatitidis (12), and Coccidioides immitis (2). It has shown activity against human oropharyngeal candidosis even in a few patients with fluconazole-resistant disease (1,7).…”

D0870, an Antifungal Agent, Induces Reverse Use-dependent QQT Prolongation in Dogs.

“…1H-1, 2, 4-triazol-1-yl]-3-(1H-1, 2, 4-triazol-1-yl) propan-2-ol, is a new antifungal agent that is active orally and parenterally against a wide range of systemic mycosis, even in the immunocompromised models [31]. We previously reported that D0870 induced plasma concentrationdependent QT prolongation and sudden death due to ventricular fibrillation (VF) associated with torsades de pointes (TdP) in a dog study using loading (50 mg/kg) and maintenance (5 mg/kg/day) doses with long-term ambulatory electrocardiographic monitoring [19].…”

Activities of D0870, a novel triazole, against Candida lusitaniae and Trichosporon beigelii in experimental murine infections

“…Several models of experimental murine infections were used for the in vivo testing of D0870. Vaginal (11,17) and disseminated (11,12,23) candidiasis caused by C. albicans, disseminated (12,23) and pulmonary (17) cryptococcosis, cryptococcal meningitis (9), pulmonary blastomycosis (7), hematogenous aspergillosis (23), and coccidiodomycosis (8) in normal and immunosuppressed mice responded more favorably to D0870 than to fluconazole. The activity of D0870 in experimental candidiasis caused by Candida species other than C. albicans was variable.…”

“…Nevertheless, our study is in agreement with recent favorable reports on the activity of D0870 against various fungi. D0870 has a broad spectrum of in vitro antifungal activity against Candida species (12,19,23), Cryptococcus neoformans (12,19,23), Blastomyces dermatitidis (7,20), Aspergillus fumigatus (18,20,23), and other molds (20). The MICs of D0870 against Candida krusei (19) and Torulopsis glabrata (4,20) were higher than those against various Candida species.…”