Oral Therapy for Experimental Coccidioidomycosis with R41 400 (Ketoconazole), a New Imidazole<sup>1,</sup><sup>2</sup>

Levine, Howard B.; Cobb, J.M.

doi:10.1164/arrd.1978.118.4.715

Cited by 69 publications

(14 citation statements)

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“…dichlorophenyl)-2-( lH-imidazol-1-ylmethyl) -1, 3-dioxalan-4-yl]methoxy]phenyl} piperazine) orally active agent with broad-spectrum activity against a variety of yeasts, dermatophytes, and dimorphous fungi (1,4,11,13,14).…”

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confidence: 99%

In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis

Bossche¹,

Willemsens²,

Cools³

et al. 1980

Antimicrob Agents Chemother

264

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Ketoconazole, an orally active antimycotic drug, is a potent inhibitor of ergosterol biosynthesis in Candida albicans when added to culture media which support yeast or mycelial growth or to cultures containing outgrown mycelium. This inhibition coincides with accumulation of sterols with a methyl group at C-14 and can thus be attributed to an interference with one of the reactions involved in the removal of the 14 alpha-methyl group of lanosterol. When administered to rats infected with C. albicans, ketocanazole also inhibits fungal synthesis of ergosterol. A six-times-higher dose is required to effect cholesterol synthesis by rat liver.

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confidence: 99%

In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis

Bossche¹,

Willemsens²,

Cools³

et al. 1980

Antimicrob Agents Chemother

264

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“…It is soluble in dilute acid and shows a broad spectrum of antifungal activity. When orally administered it yields satisfactory blood levels and should, therefore, prove to be a major advance in the treatment of both topical and systemic mycotic infections (3,6,8).The potential usefulness of ketoconazole in the treatment of fungal diseases justifies indepth studies into its pharmacokinetics, metabolism, toxicity, and mode of action. A rapid and accurate assay method is essential to such studies, however, and liquid chromatography seems to be a logical methodology for such assays.…”

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Liquid chromatographic assay of ketoconazole

Andrews¹,

Peterson²,

Beggs³

et al. 1981

Antimicrob Agents Chemother

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A reverse-phase, high-pressure liquid chromatographic method for the rapid and quantitative determination of ketoconazole has been developed. Drug levels from 0.5 to 10,ug/ml can be determined in either yeast nitrogen base medium or human serum by using an octadecylsilane column. A retention time of 4.9 ± 0.1 min resulted when the drug was eluted from a column with 75% methanol-25% 0.02 M (pH 7.5) phosphate buffer at a flow rate of 2 ml/min. Optimum sensitivity was obtained at a wavelength of 231 nm.Ketoconazole is a recent addition to the imidazole class of antifungal drugs (5). It is soluble in dilute acid and shows a broad spectrum of antifungal activity. When orally administered it yields satisfactory blood levels and should, therefore, prove to be a major advance in the treatment of both topical and systemic mycotic infections (3,6,8).The potential usefulness of ketoconazole in the treatment of fungal diseases justifies indepth studies into its pharmacokinetics, metabolism, toxicity, and mode of action. A rapid and accurate assay method is essential to such studies, however, and liquid chromatography seems to be a logical methodology for such assays. This report describes a rapid, quantitative assay for ketoconazole, using reverse-phase high-pressure liquid chromatography. In the Varian 5020, the weak-and strong-phase solvents are degassed and mixed in the instrument; however, we routinely filter sterilized (and degassed) the phosphate buffer (weak phase) to eliminate any possibility of microbial contamination. MATERIALS AND METHODSKetoconazole standards. Calibration standards of ketoconazole were prepared by dilution in the mobile phase and were injected directly into the chromatograph. Stock solutions of ketoconazole (1 mg/ml) were prepared in 0.006 N phosphoric acid and, after appropriate dilution in water, were used to spike either serum or yeast nitrogen base medium, at levels ranging from 0.25 to 10 yg/ml. Sample preparation. Yeast nitrogen base solutions of ketoconazole were diluted (1:1) with methanol before injection into the chromatograph.Serum samples spiked with ketoconazole after gentle stirring were left at ambient temperature for 1 h before deproteinization. Deproteinization was accomplished by passing sera through Sep-Pak C18 cartridges. The cartridges were conditioned by pumping 2-column volumes of methanol through the cartridge three times, followed by three similar washings with deionized water. The pH of the cartridges was made alkaline by addition of 0.2 ml of 0.1 M sodium carbonate. A 1-ml amount of serum was then pumped through the cartridge, and this was followed by three washes of water (2 column volumes) and one wash with 0.2 ml of methanol. Ketoconazole was eluted from the cartridge by using two 1-ml washes with methanol, and 100 pl of the eluate was injected into the chromatograph.

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“…The transformation of arthroconidia into mycelium was fully prevented after treatment. Mycelial cells were most susceptible to the antifungals for necrosis was induced in a substantial part of the hyphae after exposure for 24 h.The imidazole drugs, miconazole and ketoconazole, interfere markedly with progressive murine coccidioidomycosis [13][14][15]17]. Treatment, after intranasal instillation of arthrocondia, limits the subsequent replication of the spheruleendospore phase of Coccidioides immitis in the lungs.…”

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Ultrastructure ofCoccidioides immitisafter exposure to the imidazole antifungals miconazole and ketoconazole

Borgers¹,

Levine²,

Cobb³

1981

Med Mycol

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Scanning and transmission electron microscopy was performed on the various phases ofCoccidioides immitis, exposed for different periods of time to the imidazole antifungals miconazole and ketoconazole.The development of spherules into endospores, which takes place in cultures under normal growth conditions, was suppressed in the drug treated cultures.Typical ultrastructural changes were localized at the cell periphery and in the vacuolar system. The drugs did induce changes in mature, resting endospore cultures and in cultures incubated statically at room temperature. Aerobically growing endospores were not susceptible to either drug. The transformation of arthroconidia into mycelium was fully prevented after treatment. Mycelial cells were most susceptible to the antifungals for necrosis was induced in a substantial part of the hyphae after exposure for 24 h.The imidazole drugs, miconazole and ketoconazole, interfere markedly with progressive murine coccidioidomycosis [13][14][15]17]. Treatment, after intranasal instillation of arthrocondia, limits the subsequent replication of the spheruleendospore phase of Coccidioides immitis in the lungs. Early ketoconazole treatment, in particular, markedly reduces dissemination 1-13, 15] characterized by fungal invasion of the peritoneal organs. These activities are associated with high rates of survival in appropriately treated animals. Corresponding findings in man [12,20,23] also indicate that the drugs are effective in local and in disseminated coccidioidomycosis. However, in animals, as in man, biocure rates are low and prolonged therapy is required.In animals it was apparent that exposure of endospores to plasma concentrations of ketoconazole of 10#gml-1 was therapeutically beneficial [15]. We sought therefore to determine in the present study if this concentration of ketoconazole or miconazole altered the structure of the different morphologic phases of C. immitis. Recent publications [21,22] have described the saprobic and parasitic forms of C. immitis in clear detail and have updated earlier morphologic studies [5, 6, 10, 19] on C. immitis.On the other hand, surface characteristics of C. immitis, as seen with scanning electron microscopy, have not been reported in detail. We have therefore limited our descriptions in this paper to developmental changes in fungal structure during normal growth and to alterations that occur after exposure of the organism to miconazole and ketoconazole.

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Oral Therapy for Experimental Coccidioidomycosis with R41 400 (Ketoconazole), a New Imidazole^1,²

Cited by 69 publications

References 0 publications

In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis

In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis

Liquid chromatographic assay of ketoconazole

Ultrastructure ofCoccidioides immitisafter exposure to the imidazole antifungals miconazole and ketoconazole

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Oral Therapy for Experimental Coccidioidomycosis with R41 400 (Ketoconazole), a New Imidazole1,2

Cited by 69 publications

References 0 publications

In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis

In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis

Liquid chromatographic assay of ketoconazole

Ultrastructure ofCoccidioides immitisafter exposure to the imidazole antifungals miconazole and ketoconazole

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Oral Therapy for Experimental Coccidioidomycosis with R41 400 (Ketoconazole), a New Imidazole^1,²