J. Van Cutsem

The Clinical Pharmacokinetics of Itraconazole: An Overview

Summary: Itraconazole (R 51211) is the prototype of a class of triazole antifungals characterized by a high lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic triazole antifungal fluconazole.

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

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.

Miconazole, a Broad-Spectrum Antimycotic Agent with Antibacterial Activity

Miconazole tested in vitro against the most important fungi pathogenic for man and animals, and against gram-positive bacteria has proved to be highly potent. The dermatophytes, yea

Posttreatment itraconazole levels in the nail: New implications for treatment in onychomycosis

BACKGROUND A problem in the treatment of onychomycosis is the lengthy duration of therapy. The pharmacokinetics of itraconazole suggest a potential for briefer treatment. OBJECTIVE This study was designed to investigate itraconazole nail kinetics in 39 patients with onychomycosis in relation to their therapeutic outcome. METHODS All patients received itraconazole for 3 months at a dose of 100 or 200 mg daily. Itraconazole levels of distal nail clippings were determined during a 6-month posttherapy period. RESULTS Therapeutic itraconazole concentrations were found in the nail plates of fingernails and toenails for up to 6 months after treatment. Cure of the toenails was observed in 79% of the patients treated with the 200 mg dosage and in 26% of those treated with 100 mg at 6 months after therapy. CONCLUSION The data suggest that the drug reaches the nail via incorporation into the matrix and by diffusion from the nail bed and is eliminated with regrowth of the nail after discontinuation of treatment.

Itraconazole, a new triazole that is orally active in aspergillosis.

Itraconazole is a new orally active triazole derivative with broad-spectrum antifungal activity. This drug is effective in experimental aspergillosis and possesses in vitro activity against various species and strains of Aspergillus. Morphological destruction of inoculated hyphae and complete inhibition of hyphal outgrowth in culture is obtained from 0.07 micrograms ml-1 (10(-7)M) onward. These properties make itraconazole a likely candidate for clinical evaluation in disseminated aspergillosis. Images

The in-vitro antifungal spectrum of itraconazole.

Summary: The activity of itraconazole on 6113 fungal strains belonging to 252 species was evaluated in fluid media. The test medium was brain heart infusion broth for all fungi, except for Pityrosporum ovale, for which it was Dixon broth.

Ketoconazole -- a new broad spectrum orally active antimycotic.

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.

Promotion of pseudomycelium formation of Candida albicans in culture: a morphological study of the effects of miconazole and ketoconazole.

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 Eagles 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.

The in vitro antifungal activity of ketoconazole, zinc pyrithione, and selenium sulfide against Pityrosporum and their efficacy as a shampoo in the treatment of experimental pityrosporosis in guinea pigs

The fungistatic and fungicidal activity of ketoconazole, zinc pyrithione, and selenium sulfide against Pityrosporum, a yeast thought to play a pathogenic role in seborrheic dermatitis and dandruff, was assessed in Dixon broth for Pityrosporum ovale and Sabouraud broth for Pityrosporum pachydermatis. Ketoconazole inhibited growth at concentrations ranging from 0.001 to 1 micrograms/ml. For zinc pyrithione and selenium sulfide higher concentrations were needed. In a guinea pig model the efficacy of treatment with four shampoos (Nizoral [Jansen], EDS Zinc [Schering], Zinkan [Lederle], and Selsun [Abbott]) was compared. The animals were inoculated for 7 consecutive days on intact skin. The lesions were scored for erythema, folliculitis, and hyperkeratosis 24 hours after the last inoculation and after treatment. Final evaluations were made 13 days after infection (10 days after last shampoo application). Treatment with undiluted and diluted (1:10) shampoos showed consistently superior clinical and mycologic results for Nizoral shampoo. None of the shampoos produced side effects.

Detection of circulating galactomannan by Pastorex Aspergillus in experimental invasive aspergillosis

The performance of Pastorex Aspergillus, a new latex agglutination test for the detection of circulating galactomannan in the serum of patients with invasive aspergillosis, was evaluated in a blind trial in standardized guinea‐pig models of invasive aspergillosis and other invasive mycoses. In these animal models, the invasive nature of the fungal infection was confirmed by re‐isolation of the etiologic agent from the organs of every animal.