Biomedical subjects
Publications and source records attributed to J Van Cutsem.
Results with ketoconazole were studied in 281 non-pregnant patients with acute and chronic Candida-vaginitis. Several dose regimens were evaluated. The 5-day regimens (200 mg b.i.d. or 400 mg once daily) seem to be the most appropriate schedules in this infection. Side effects were minor. Relapse rates are not different from those, historically known, with topical antifungals.
The preparation and antifungal properties of cis-1-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1, 3-dioxolan-4-yl]methoxy]phenyl]-4-(1-methylethyl)piperazine are reported. Terconazole has a high topical in vivo activity against vaginal candidosis in rats and against dermatophytosis in guinea pigs.
Terconazole, a new triazole ketal, is found to be highly active in vitro on a wide range of yeasts and mycelium-forming fungi. The in vitro activity depends largely on the medium used. In vitro it is a potent antifungal agent in preventing the morphogenetic transformation of the yeast into the (pseudo-)mycelium form of Candida albicans. In vivo terconazole is highly active in topical treatment of various experimental models of dermatophytosis and candidosis. It also possesses moderate oral broad-spectrum activity. No side effects were observed.
Staphylococcus aureus can be protected by unsaturated unesterified fatty acids against the growth inhibitory effects of miconazole and ketoconazole observed at concentrations greater than 10(-6) M and greater than 10(-5) M, respectively. Miconazole's fungicidal activity is partly antagonized by oleic acid. However, the effect of ketoconazole on the viability of Candida albicans was not affected by this fatty acid. Cytochrome oxidase and ATPase activities are more sensitive to miconazole (10(-5) M) than to ketoconazole (greater than 10(-4) M) and also liposomes are more susceptible to lysis induced by miconazole. Using differential scanning calorimetry it is shown that high concentrations of miconazole shift the lipid transition temperature of multilamellar vesicles to lower values without affecting the enthalpy of melting. Ketoconazole induces a broadening of the main transition peak only. It is suggested that miconazole changes the lipid organization without binding to the lipids, whereas ketoconazole is localized in the multilayer without having an important direct effect on the lipid organization. The results indicate that miconazole, and to a lesser extent ketoconazole, at doses that can be reached by topical application only, interfere with a third target (the two others are ergosterol synthesis and fatty acid elongation plus desaturation). It is hypothesized that the induced change in lipid organization may play some role in miconazole's topical antibacterial and fungicidal activity, whereas it does not seem to play a significant role in ketoconazole's activities.
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The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.
Ketoconazole (100 mg, orally, once daily) was investigated in nine patients with extensive dermatophyte infections. After treatment ranging between one week and three months, clinical cures (healing of lesions and negative cultures) were observed in all cases. In vitro growth of Trichophyton rubrum, T. mentagrophytes, and T. verrucosum isolated from infected skin scales were completely inhibited by concentrations of ketoconazole of 10 microgram/ml and above. No evidence for the development of drug resistance was obtained from regular in vitro sensitivity tests.
A series of in vitro experiments with imazalil is described. It is demonstrated that the compound has fungistatic, fungicidal and even sporocidal activity in the vapour phase against a wide variety of fungal species, e.g., dermatophytes, Candida albicans, and plant-pathogenic fungi. Possible practical applications are discussed.
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1-[2-(2,4-Dichlorophenyl)-2-(2-propenyloxy)-ethyl]-1H-imidazole (imazalil) base and different salts were tested in vitro on various pathogenic fungi and bacteria; in vivo on guinea-pigs, rats and turkeys experimentally infected with dermatophytes and Candida albicans. In vitro the dermatophytes were the most sensitive. The plant-pathogenic fungi were more sensitive to the base than to the salts. The antibacterial activity was low. The in vivo antifungal activity was high for the dermatophytes and rather low for Candida. The acute, subacute and chronic toxicity studies in rats and dogs showed that imazalil wa a well tolerated substance. Ocular and dermal irritation were not seen at therapeutic doses. Fertility and reproductive capacity were not affected and embryotoxicity and teratogenicity were not seen. No mutagenic or cancerogenic potential was found.
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Oral treatment with ketoconazole prevented and cured artificial crop candidosis of the turkey, vaginal candidosis of the rat and skin candidosis of the guinea-pig. It was also highly effective against artificial systemic candidosis of the guinea-pig and chicken as well as against dermatophytoses of the guinea-pig.
The efficacy of a new, orally active antimycotic, ketoconazole, in the treatment of vaginal candidiasis was studied at different doses involving 63 patients. All patients had subjective complaints and were mycologically positive. There was no significant difference in the cure rates of the different doses. The oral treatment was successful in 55 out of 63 patients (87.3%). No correlation was found between the relapse rate of vaginal candidiasis and the dose regimen. There were no serious side-effects, and no significant changes were reported in hematological and biochemical parameters.
The preparation and antifungal properties of cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine (I) are described. Ketoconazole has, at low oral doses, a high in vivi activity against vaginal candidosis in rats and against cutaneous candidosis in guinea pigs.
The effects of miconazole and its new derivative ketoconazole on Candida albicans have been evaluated by light and electron microscopy. The growth characteristics and morphology of C. albicans in culture for various periods of time in a solution consisting of Eagle's minimum essential medium supplemented with amino acids and fetal calf serum are emphasized. This medium, normally used for culturing mammalian cells, promotes a rather fast growth of C. albicans and favours the development of pseudomycelium. The obvious interest in using such culture conditions for drug evaluation is the prevalence of pseudomycelium, which in vivo is the predominant pathological form of C. albicans. Suppression of pseudomycelium formation is found in the 10-9 to 10-7 M concentration range of the imidazoles. Growth retardation and the destruction of both yeast and pseudomycelial forms brought about by incubating the cells with 10-9 to 10-4 M of the drugs are reported. At low doses these changes include the alteration of cell division, an increase in cell volume and a progressive deterioration of subcellular organelles at the cell periphery. At higher doses the involvement of all other organelles is observed finally leading to complete cell necrosis.
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