Treatment of murine pulmonary blastomycosis with SCH 51048, a broad-spectrum triazole antifungal agent

Sugar, Alan M.; Picard, Michele

doi:10.1128/aac.39.4.996

Cited by 14 publications

(8 citation statements)

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“…Itraconazole at 150 mg/kg/day divided into two doses afforded a survival rate of 30% when it was delivered in PEG 400, with minimal effects on the colony counts in the lungs (13). However, itraconazole absorption is not optimal when the compound is suspended in PEG, and blood itraconazole levels were not determined in that study.…”

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confidence: 70%

“…However, itraconazole absorption is not optimal when the compound is suspended in PEG, and blood itraconazole levels were not determined in that study. In contrast, amphotericin B at 1 mg/kg/day provided complete protection in terms of survival and sterilized the lungs of these mice (13). Thus, voriconazole, especially when it is administered at 40 mg/kg/day, com- Itraconazole has become the major antifungal drug for use in the oral treatment of blastomycosis in humans (3).…”

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confidence: 99%

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Efficacy of Voriconazole in Treatment of Murine Pulmonary Blastomycosis

Sugar

Liu

2001

Antimicrob Agents Chemother

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We evaluated the efficacy of voriconazole, a new broad-spectrum triazole antifungal compound, in the treatment of murine pulmonary blastomycosis. Since mice metabolize voriconazole rapidly, we took advantage of our previous observation that administration of grapefruit juice to mice resulted in suitable serum voriconazole concentrations so that treatment studies with mice could be done (A. M. Sugar and X.-P. Liu, Med. Mycol. 38:209-121, 2000). Our results show that voriconazole prolonged survival in a dose-dependent fashion and that the fungal burden in the lungs was decreased by voriconazole administered at 40 mg/kg of body weight/day. Voriconazole should be studied in humans with blastomycosis.Blastomycosis is a fungal infection that occurs primarily in specific areas of the United States. While several antifungals have been useful in the treatment of patients with the disease, including itraconazole, amphotericin B, and fluconazole, additional options would be welcome. In the study described here, we used a well-described murine model of pulmonary blastomycosis to evaluate the antifungal efficacy of voriconazole, a new broad-spectrum triazole antifungal drug (5-7, 10).Early work with voriconazole documented that serum voriconazole concentrations were very low to undetectable in mice. This necessitated a switch to other animals, such as guinea pigs, in order to continue the preclinical development of voriconazole. Unfortunately, guinea pigs are resistant to the development of pulmonary blastomycosis. We then found that grapefruit juice could increase the concentrations of voriconazole in serum in the mouse to suitable levels to conduct treatment studies (14). In the present study, we made use of this pharmacokinetic interaction to study the efficacy of voriconazole in the treatment of murine pulmonary blastomycosis.Male specific-pathogen-free BALB/cByJ mice were obtained from Jackson Laboratories. Mice were housed at 10 mice per cage. They were fed mouse chow and water ad libitum. Five days before infection, the water was replaced with grapefruit juice in the water bottle and was provided to the mice ad libitum. On average, mice ingested 2 to 3 ml of grapefruit juice/day, as determined in our previous study (14).Blastomyces dermatitidis ATCC 26199 was obtained as a new culture from the American Type Culture Collection (Manassas, Va.) and was maintained in the yeast form in 1% sterile milk in yeast nitrogen broth at Ϫ70°C. Prior to an experiment, a loopful was plated on blood agar and the plate was incubated at 37°C for 4 to 6 days. A 4-to 6-day growth from a subculture of this was used to prepare inocula for infection of mice.The susceptibility of the yeast form of B. dermatitidis to voriconazole was tested according to NCCLS guidelines (11), using the microtiter plate format. The (MIC) was read at 48 h and was defined as the first clear well. The minimal fungicidal concentration (MFC) was obtained by culturing the entire contents of the clear wells, with the well showing no growth representing the MFC. The pu...

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confidence: 99%

Efficacy of Voriconazole in Treatment of Murine Pulmonary Blastomycosis

Sugar

Liu

2001

Antimicrob Agents Chemother

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“…13 SCH 51048 is a novel orally active azole antifungal having improved therapeutic potential over existing agents in immunocompromised animal models. 13 In an effort to further improve the oral absorption properties of SCH 51048, the synthesis of novel analogs having polar side chains was undertaken. While introduction of relatively basic or acidic side chains resulted in loss of activity, incorporation of hydroxyl groups led to greatly improved in vivo activity.…”

Section: Discussionmentioning

confidence: 99%

Chiral high-performance liquid chromatographic analysis of antifungal SCH 56592 and evaluation of its chiral inversion in animals and humans

Kim¹,

Lin²,

Laughlin³

et al. 2000

Chirality

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SCH 56592 is a novel triazole antifungal agent that is active both orally and intravenously in animal models of infection. This compound is in Phase II-III clinical trials for the treatment of systemic fungal infections. SCH 56592 is a single enantiomer with four stereogenic centers; therefore, it was necessary to evaluate the possible chiral inversion of this drug candidate in animals and humans. Thus, chiral high-performance liquid chromatographic (HPLC) methods have been developed to separate SCH 56592 from its diastereomers and to evaluate its chiral inversion in rats, dogs, cynomolgus monkeys, and humans. Chiral HPLC analysis involved the use of a Chiralcel OD column set at 39 degrees C with a mobile phase of hexane-ethanol-diethylamine and a fluorescence detector set at an excitation wavelength of 270 nm and an emission wavelength of 390 nm. Plasma or serum samples were subjected to solid phase extraction on a C(2) cartridge followed by HPLC analysis. The method was sensitive with a limit of quantitation of 0.1 microg/ml in dog serum. The linearity was satisfactory, as shown by correlations of >0.997 and by visual examination of the calibration curves. The precision and accuracy were satisfactory, as indicated by coefficients of variation (CV) ranging from 1.1 to 12.1% and bias values ranging from -11.0 to 9.0%. Chiral HPLC analysis indicated that SCH 56592 was not subjected to chiral inversion in rats, dogs, cynomolgus monkeys, and humans.

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“…Historically, when there were few antifungal options and combination antifungal therapy for IA was in its infancy, the most debated combination scheme for treatment of IA was AmB + itraconazole and the theoretical risks of antagonism with this combination have been reviewed [29]. The proposed mechanism of antagonism stems from the very aspect that is often the foundation of potential synergy: different methods of action.…”

Section: Polyene Combinationsmentioning

confidence: 99%

“…Clinical therapy with AmB and azoles has been extensively reviewed [29]. Despite those continuously heard concerns of AmB with azoles, a retrospective clinical case series of 21 patients examining concurrent therapy of AmB (1 mg/kg/d) + itraconazole (400 mg/kg/d, capsules or suspension) demonstrated no clinical antagonism, with 82% (9/11) cure or improvement rate in the combination arm and only 50% (5/10) improvement with AmB monotherapy.…”

Section: Polyene Combinationsmentioning

confidence: 99%

Combination Antifungal Therapy for Invasive Aspergillosis: Utilizing New Targeting Strategies

Steinbach

2005

CDTID

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The optimal therapy for invasive aspergillosis (IA) is unknown, and there is little agreement on the exact antifungal management of IA. The previously stagnant landscape of antifungal choices for IA is rapidly changing with newer antifungals and newer targets. While amphotericin B has historically been the preferred therapy, recent studies support voriconazole as primary therapy or caspofungin as salvage therapy. However, even these newer therapies have only elevated clinical response rates to approximately 50%. Recent in vitro studies, animal models, and limited clinical reports suggest that combination antifungal therapy utilizing novel targeting strategies might offer improved outcome. Until very recently, combination antifungal therapy for IA was of little consequence since there were a limited number of possible permutations available. There has been a great deal of new data published exploring the possibilities of combination therapy, but clinicians need to be aware of the potential advantages and disadvantages of combination antifungal therapy for IA.

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Treatment of murine pulmonary blastomycosis with SCH 51048, a broad-spectrum triazole antifungal agent

Cited by 14 publications

References 4 publications

Efficacy of Voriconazole in Treatment of Murine Pulmonary Blastomycosis

Efficacy of Voriconazole in Treatment of Murine Pulmonary Blastomycosis

Chiral high-performance liquid chromatographic analysis of antifungal SCH 56592 and evaluation of its chiral inversion in animals and humans

Combination Antifungal Therapy for Invasive Aspergillosis: Utilizing New Targeting Strategies

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