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Biomedical subjects

J Van Cutsem

Publications and source records attributed to J Van Cutsem.

At least 37 records · Page 2Linked to original sources
PubMed1990

Itraconazole in the treatment of superficial mycoses--a double-blind study vs. placebo.

Ninety-four patients with dermatophytosis and 16 patients with pityriasis versicolor were assigned under double-blind conditions to oral itraconazole (100 mg once daily) or placebo. The medication consisted of two capsules, each containing 50 mg of active substance, or placebo and was given for 15 or 30 days in patients with dermatophytosis and for 15 days in patients with pityriasis versicolor. Patients with pityriasis versicolor who had not responded at the end of the double-blind period were treated on an open basis with itraconazole (100 mg once daily) for 15 days. In the treatment of dermatophyte infections for 30 days, both clinical response and mycological cure were significantly superior in the itraconazole group compared with placebo. Oral administration of itraconazole (100 mg once daily) was also highly efficacious in the treatment of pityriasis versicolor. None of the placebo patients was clinically or mycologically cured at the end of the double-blind phase compared to seven out of eight itraconazole patients. All placebo patients who entered the open phase responded to itraconazole treatment. Three itraconazole-treated patients and nine placebo-treated patients reported side-effects.

Adolescent↗
PubMed1990

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. Ninety-two plasma samples from 42 animals with invasive aspergillosis were submitted to the test. In 41 of these animals, at least one plasma sample was positive with the latex test (sensitivity 97.6%), titers ranging from 1/1 to 1/512. In general, antigen titers increased as a function of time, reaching the highest values shortly before death. Guinea-pigs infected with Penicillium marneffei also yielded positive agglutination reactions but antigen titers were lower (maximal titer 1/8). Plasma samples from animals with invasive candidosis (23), disseminated trichophytosis (11) and cryptococcosis (23) were all negative with the latex test. In 80 guinea-pigs without fungal infection, 3 false positive results (titers 1/1) were observed, which means a specificity of 96.2% in this control group.

Animals↗
PubMed1990

Oral and parenteral treatment with itraconazole in various superficial and systemic experimental fungal infections. Comparisons with other antifungals and combination therapy.

Itraconazole has been tested in vitro against 6,113 different strains of a total of 252 fungal species. Almost all medically important fungi are apparently sensitive to itraconazole. Topical and oral treatment with itraconazole was found to be successful in microsporosis, trichophytosis, vulvovaginal, gastrointestinal and systemic candidosis, pityrosporosis, sporotrichosis, histoplasmosis, aspergillosis and cryptococcosis induced in a number of animal models. Vulvovaginal candidosis responded well to itraconazole, with a one-day topical or oral treatment resulting in a complete cure. The same results could not be achieved with the same concentration or dosage of either ketoconazole or fluconazole. Biologically active antifungal levels were present in plasma and vaginal fluid of rats after one dose of itraconazole 10 mg/kg for at least 72 hours. Itraconazole was also found to be successful in immunodepressed animals infected with a number of different diseases and in disseminated and systemic infections, such as candidosis, aspergillosis and cryptococcosis. Oral and parenteral itraconazole treatment was compared with oral and parenteral fluconazole treatment and parenteral amphotericin B in a number of models. Results overall were better with itraconazole. Combination therapy of itraconazole with fluconazole was not found to be superior to treatment with itraconazole alone. No side-effects were observed with itraconazole treatment.

Animals↗
PubMed1989

Effects of deferoxamine, feroxamine and iron on experimental mucormycosis (zygomycosis).

Mucormycosis was induced in healthy guinea pigs by the i.v. injection of spores from Rhizopus microsporus var. rhizopodiformis or from Rhizopus oryzae, leading to a reproducible mortality. Pretreatment with one dose of 50 mg of deferoxamine (DFO) shortened animal survival from 4.2 +/- 0.4 to 3.3 +/- 0.5 days for Rh. rhizopodiformis and from 8.8 +/- 0.4 to 7.3 +/- 1.9 days for Rh. oryzae (P less than 0.05). Survival was shortened even more after 4 doses of DFO (P = 0.0013 for Rh. rhizopodiformis and P = 0.002 for Rh. oryzae). After Rh. oryzae infection, animal survival decreased similarly after DFO, feroxamine or DFO combined with Fe3+ citrate (P less than 0.001). Fe3+ citrate also decreased survival (P = 0.0011), although significantly less than DFO either alone or combined with Fe3+. In vitro growth of both fungal strains was enhanced by addition of either DFO or Fe3+ at 0.001 to 1 mmol in the medium. DFO abolished the prolonged survival induced by amphotericin B in vivo and in vitro. Indeed, four doses of DFO abolished the improved survival due to amphotericin B (P = 0.0019 for Rh. rhizopodiformis and P = 0.002 for Rh. oryzae); DFO combined with Fe3+ at greater than or equal to 0.1 mmol decreased the antifungal activity of amphotericin B in vitro. These results point to a major role of DFO in the pathogenesis of mucormycosis in dialysis patients and suggest that DFO behaves as a siderophore for Rhizopus strains, stimulating their growth.

Amphotericin B↗
PubMed1989

Oral, topical and parenteral antifungal treatment with itraconazole in normal and in immunocompromised animals.

Itraconazole was dissolved in polyethylene glycol for oral and topical treatment and in hydroxypropyl-beta-cyclodextrin for oral, topical or parenteral treatment. Topical and oral treatment was successful in microsporosis, trichophytosis, skin-and vaginal candidosis, pityrosporosis and eye mycosis by Candida, Fusarium and Aspergillus. Vaginal candidosis could be cured with a one-day topical or oral treatment. The same results could not be obtained with any of the reference compounds (griseofulvin, terbinafine, ketoconazole or fluconazole) on a mg per kg body weight base, nor on a % concentration base. Antifungal levels were determined by bioassay: biologically active antifungal levels were present in plasma and vaginal fluid of rats, after one oral dose of 10 mg.kg-1, for at least 72 and 96 hours respectively. This was in good correlation with findings on prophylaxis of vaginal candidosis. Itraconazole was also successfully used, in normal animals and animals immunodepressed with various agents, in disseminated and systemic diseases: trichophytosis, sporotrichosis, histoplasmosis, candidosis, aspergillosis and cryptococcosis. Oral and parenteral treatment with itraconazole was compared in various models to oral and parenteral fluconazole and to parenteral amphotericin B. The outcome with itraconazole was better than with the other antifungals. Meningeal cryptococcosis responded very well to itraconazole. Combination therapy of itraconazole and fluconazole was not superior to treatment with itraconazole alone. No side-effects were observed in relation to itraconazole treatment.

Administration, Oral↗
PubMed1989

The clinical pharmacokinetics of itraconazole: an overview.

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. The pharmacokinetics of itraconazole in man are characterized by a good oral absorption, an extensive tissue distribution with tissue concentrations many times higher than in plasma, a relatively long elimination half-life of about one day and a biotransformation into a large number of metabolites. One of them, hydroxy-itraconazole, is antifungally active and explains why antifungal plasma levels, when measured by bioassay, are about three times the itraconazole levels measured by a specific HPLC-method. Distribution studies have shown that therapeutically active levels of itraconazole are maintained much longer in some infected tissues than in plasma. For instance, active levels persist for four days in the vaginal epithelium after a one-day treatment and for 3 weeks in the stratum corneum of the skin after treatment has been stopped. Unlike fluconazole, itraconazole does not interfere with mammalian drug metabolizing enzymes, minimizing the risk of interaction with concomitantly administered drugs. These pharmacokinetic properties may contribute to the high efficacy and safety of itraconazole in patients with various mycotic infections. New pharmaceutical formulations are being explored in order to broaden the application field of itraconazole to intravenous and oral therapy of patients with malabsorption.

Absorption↗
PubMed1989

Oral and parenteral therapy with saperconazole (R 66905) of invasive aspergillosis in normal and immunocompromised animals.

Saperconazole (R 66905) is a broad-spectrum antifungal triazole with potent in vitro activity against Aspergillus spp. A total of 279 strains were tested in brain heart infusion broth. Development of the Aspergillus spp. was completely inhibited at 0.1 and 1 microgram of saperconazole per ml for 80.3 and 99.6% of the strains, respectively. Normal and immunocompromised guinea pigs were infected intravenously with Aspergillus fumigatus and treated orally, intravenously, or intraperitoneally with saperconazole or intraperitoneally with amphotericin B. Leukopenia, neutropenia, lymphocytosis, and monocytosis were obtained with mechlorethamine hydrochloride; leukopenia, neutrophilia, and lymphopenia were obtained with cyclophosphamide. Saperconazole was dissolved for oral treatment in polyethylene glycol and for parenteral treatment in cyclodextrins. Amphotericin B was given parenterally as Fungizone (E.R. Squibb & Sons). Treatment was given once daily for 14 days. An early starting treatment was efficacious, but the activity of saperconazole was maintained even when the onset of the treatment was delayed to the moribund state. The activity of saperconazole was not altered in immunocompromised animals. Saperconazole was clearly superior to amphotericin B and free of side effects. The oral and parenteral formulations of saperconazole were equipotent. The systemic activity of saperconazole in guinea pigs was confirmed in invasive aspergillosis in pigeons.

Administration, Oral↗
PubMed1989

Treatment of experimental zygomycosis in guinea pigs with azoles and with amphotericin B.

Nonpredisposed Albino guinea pigs were infected intravenously with Rhizopus microsporus var. rhizopodiformis or with Rhizopus oryzae. Both strains were highly pathogenic. They killed all control animals between days 4 and 7 and between days 5 and 9 after infection, respectively. All animals presented invasion of almost all internal organs and skin eruptions developing into ulcers. Oral treatment with ketoconazole, itraconazole, fluconazole or saperconazole was inefficacious. Parenteral treatment with amphotericin B prolonged survival and was life-saving in 9 out of 12 guinea pigs infected with Rh. microsporus var. rhizopodiformis and in 5 out of 12 infected with Rh. oryzae. More active therapy is needed.

Amphotericin B↗
PubMed1989

The in-vitro antifungal spectrum of itraconazole.

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. Most of the human and animal pathogens and a large number of saprophytes were highly sensitive: dermatophytes, Candida, Cryptococcus, Torulopsis, Pityrosporum, Aspergillus, Penicillium, Sporothrix, dimorphic fungi, phaeohyphomycetes, agents of eufungal mycetoma, Entomophtorales and various others. The majority of Fusarium species and the Zygomycetes were poorly sensitive. Itraconazole was not only fungistatic at low concentrations, but also fungicidal for the tested organisms, such as Microsporum canis, Trichophyton mentagrophytes, Candida albicans, C. tropicalis, Aspergillus fumigatus, P. ovale and Cryptococcus neoformans with or without replenishment. Itraconazole was able to block the morphogenetic transformation of C. albicans from the yeast phase into the (pseudo)-mycelium phase.

Animals↗
PubMed1989

Structural degeneration of Aspergillus fumigatus after exposure to saperconazole.

Saperconazole is a newly synthesized triazole antifungal with potent activity against Aspergillus fumigatus. Exposure of spores inoculated into BHI agar medium to saperconazole doses as low as 35 ng ml-1, resulted in complete suppression of germination (hyphal outgrowth) when treatment started simultaneously with inoculation. Cultures which were grown for 24 or 48 h in the absence of drug and were then exposed to saperconazole showed a block in the development of hyphae, sporophores, vesicles, sterigmata and spores. Moreover, a substantial proportion of the pre-existent hyphae became necrotic during exposure to the drug. The latter was most obvious with the 70 ng ml-1 dose. Although treatment with lower doses yielded severely altered but non-necrotic cells, an abolishment of further outgrowth and differentiation was achieved.

Antifungal Agents↗
PubMed1988

Role of animal and human pharmacology in antifungal drug design.

Since the late sixties, several new antifungal drugs have become available. Initially, they were all intended for topical use, and, consequently, animal and human pharmacology always primarily aimed at confirming therapeutic efficacy. With the new tendency for the development of orally active antifungal drugs, human and animal pharmacology have significantly gained in importance. Indeed, not only is it now necessary to demonstrate the presence of adequate antifungal concentrations at the site of infection, but the systemic availability of the antifungal drug also necessitates an in-depth study of the effects of the drug on the function of several organs. As a result, human and animal pharmacology have become the cornerstones in the selection of orally active antifungal drugs. The development of ketoconazole has been an example of the need for optimized pharmacological screening. The choice of itraconazole--with its improved tissue affinity, its lower therapeutic dose requirements, and its increased selectivity for fungal cytochrome P-450--demonstrates very well that the use of animal and human pharmacology helps in the design of an antifungal drug with as much effect as possible on the fungus and as little effect as possible on the host.

Animals↗
PubMed1987

Therapeutic efficacy of itraconazole in systemic candidosis in guinea pigs.

Fifty non-immunocompromised guinea pigs were infected by the intravenous route with 8,000 blastospores of Candida albicans per gram body weight: 26 were treated orally with the excipient, 12 with itraconazole at 1.25 mg X kg-1 and 12 at 5 mg X kg-1, once daily for 14 days starting on the day of infection. Hematology was checked for all animals before infection and on days 7, 14 and 17 after infection. Histopathological examinations were done for 2 animals of each group on days 7, 14 and 17. The infection and the therapeutic efficacy were checked by clinical observation, at autopsy and by cultures of organs. Itraconazole was highly active at both concentrations, resulting in clinical cure, negativation of cultures, normalisation of the blood picture and absence of fungal elements and presence of only small remnants of lesions on days 14 and 17 in some organs. No drug-related side effects were observed.

Animals↗