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M Plempel

Publications and source records attributed to M Plempel.

At least 19 recordsLinked to original sources
PubMed1990

Therapeutic effect of the triazole Bay R 3783 in mouse models of coccidioidomycosis, blastomycosis, and histoplasmosis.

A new triazole, Bay R 3783, was compared with ketoconazole, itraconazole, and fluconazole, which were given via the alimentary tract at three dosages, and amphotericin B, which was given at 1 mg/kg intraperitoneally, in murine models of the systemic mycoses coccidioidomycosis, histoplasmosis, and blastomycosis. In a pulmonary coccidioidomycosis model, Bay R 3783, fluconazole, and itraconazole were essentially equally efficacious and more active than ketoconazole in protecting mice against death; but they were inferior to amphotericin B. In a short-term organ load experiment, Bay R 3783 and amphotericin B were equally effective and were more effective than the other drugs in reducing the amount of Coccidioides immitis in the lungs. Against meningocerebral coccidioidomycosis, Bay R 3783, itraconazole, and fluconazole at 25 mg/kg and amphotericin B prevented death only during therapy, with mortalities ensuing shortly thereafter. In mice with systemic histoplasmosis, Bay R 3783 and itraconazole at 25 mg/kg and amphotericin B prevented death in all mice through a 44-day observation period. Clearance of Histoplasma capsulatum from organs was similar in mice treated with Bay R 3783 and itraconazole; this clearance was greater than that in mice treated with ketoconazole and fluconazole but less than that in mice treated with amphotericin B. In mice with systemic blastomycosis, Bay R 3783 at 25 mg/kg yielded 90% survivors at 60 days, which was greater than that achieved with amphotericin B (60%) or itraconazole (30%). Clearance of Blastomyces dermatitidis from the lungs was greatest with Bay R 3783, followed by that with amphotericin B, itraconazole, fluconazole, and ketoconazole, in that order. Therefore, Bay R 3783 showed effectiveness comparable to or exceeding those of itraconazole and fluconazole and exceeding that of ketoconazole against these systemic mycoses in mice.

Animals↗
PubMed1989

[Current topics in mycology].

There is an urgent need of in vitro test methods with a good in vivo predictability both for the search of new antimycotics moderate in price and for the susceptibility testing of yeasts in antimycotic therapy. We discuss the problems of agar dilution test methods. Usually, the minimal inhibitory concentration (MIC) is measured. This parameter does not only depend on the susceptibility of the test fungus, but is greatly influenced by other factors such as inoculum size, incubation time, and culture medium. Thus the MIC of azoles can vary considerably. Moreover, the current test methods are not adjusted to the different ways of fungus growing in vitro and in vivo.

Antifungal Agents↗
PubMed1988

Sterol biosynthesis inhibitors. Secondary effects and enhanced in vivo efficacy.

Sterol biosynthesis inhibitors such as the imidazoles and 1,2,4-triazoles are generally regarded as inhibitors of sterol C-14 demethylation. Neither the MIC values nor the data for direct interaction with the cytochrome P-450 responsible for oxidative C-14 methyl removal, however, fully explain the observed in vivo efficacy. The first generation of azoles, which includes clotrimazole and miconazole, has been supplemented by a second generation, and azoles of the new generation are capable of additional effects on sterol biosynthesis. With the new azoles, for example, delta 5 sterols may accumulate, the accumulation being due to additional sites of inhibition in sterol biosynthesis or to direct membrane-azole interactions. Ketoconazole, itraconazole, and vibunazole are representative of the azoles of the second generation. Finally, a third generation of azoles has been discovered. Azoles of this generation, which include fluconazole, show almost negligible in vitro potency against saprophytically grown fungi but excellent in vivo efficacy. These compounds specifically affect parasitic forms of fungi, thus blocking invasion processes, and interfere directly with the plasma membrane, as shown in leakage experiments. Such secondary effects obviously enhance in vivo potency.

Antifungal Agents↗
PubMed1984

Antimycotic activity of BAY N 7133 in animal experiments.

The triazole derivative BAY N 7133 has been tested for its antimycotic efficacy on oral administration in vivo and compared with ketoconazole in mice infected with Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans and in guinea pig trichophytosis. On starting administration at the same time as infection and using daily doses between 25 and 100 mg/kg, the agent protected the mice in all experimental models, even mouse aspergillosis for which ketoconazole was not adequately effective. BAY N 7133 was also effective for mouse candidosis by parenteral administration and was effective for guinea pig trichophytosis on topical application.

Administration, Oral↗
PubMed1984

Pharmacokinetics of the oral triazole antimycotic vibunazole in animals.

Methods of assay of the oral triazole antimycotic vibunazole (BAY n 7133) in body fluids by GLC, HPTLC and by a microbiological assay are described and compared. Bioassay data of vibunazole concentrations in mice and rats are lower than those of the chemical methods, probably due to a species-dependent difference in protein binding. The pharmacokinetics of vibunazole was studied after administration to mice, rats, rabbits, beagle dogs and rhesus monkeys. Peak concentrations of 14 to 16 mg/l were found in plasma of mice after oral administration of 25 mg/kg as an aqueous suspension. After the first oral dose the mean plasma half-life was 4.8 h. After the fifth dose, plasma levels were lower and declined with a half-life of 1.2 h which may indicate enzyme induction. Signs of enzyme induction after multiple oral doses were also seen in beagle dogs but not in rhesus monkeys. After intravenous administration to one beagle dog, vibunazole plasma half-life was 1.8 h. The absolute bioavailability of oral vibunazole in the dog was estimated to be about 70%.

Administration, Oral↗
PubMed1984

Reduction of the in vivo virulence of Candida albicans by pretreatment with subinhibitory azole concentrations in vitro.

Cells of Candida albicans exposed to subinhibitory concentrations of clotrimazole or bifonazole in shake cultures were found to have a reduced capacity to divide normally or produce germ tubes and mycelia under appropriate conditions, although treated cultures produced a cell mass equivalent to that of the untreated controls. The long-term morphological effects are considered to be due to azole-caused disturbances in ergosterol biosynthesis. When cells, pretreated with subinhibitory concentrations of the azole compounds, were injected intravenously in mice, the resultant infections were of reduced severity in comparison to controls, as measured by mortalities and colony forming units in kidneys.

Animals↗
PubMed1984

Bifonazole and clotrimazole. Their mode of action and the possible reason for the fungicidal behaviour of bifonazole.

Bifonazole (Bay h 4502, Mycospor) and clotrimazole (Bay b 5097, Canesten) are potent inhibitors of ergosterol synthesis in yeasts and dermatophytes. Inhibition of demethylation of 4,4',14-trimethylsterols is accepted as primary mode of action responsible for their fungistatic efficacy. In Candida albicans, Microsporum canis, Trichophyton mentagrophytes as well as in Epidermophyton floccosum the ergosterol precursor 24-methylendihydrolanosterol accumulates, whereas in Torulopsis glabrata lanosterol accumulation occurs, due to the fact that in this organism side chain alkylation proceeds after demethylation reactions. Bifonazole additionally leads to a generally decreased rate of sterol biosynthesis as compared to clotrimazole, due to a direct inhibition of microsomal HMG-CoA-reductase. The additional fungicidal effects of bifonazole are considered to originate from a sequential action by inhibition of HMG-CoA-reductase and of cytochrome P450.

Antifungal Agents↗
PubMed1984

Bifonazole, a biochemist's view.

Bifonazole, a new broad-spectrum antimycotic, interferes with sterol biosynthesis. Compared to clotrimazole, the primary mode of action of these two antimycotics is accepted to represent inhibition of the cytochrome P450-dependent hydroxylation at the sterol-C14-methyl group, which is the first step in C14-demethylation reaction. At least in dermatophytes bifonazole additionally inhibits directly HMG-CoA-reductase, the starting and regulatory enzyme in terpenoid biosynthesis, whereas after application of clotrimazole the activity of HMG-CoA-reductase is only decreased by feed-back control, resulting from accumulation of dihydrolanosterol. The inhibition of HMG-CoA-reductase obviously is pathogen specific as the mammalian enzyme is not affected. By this, in contrast to clotrimazole, bifonazole possesses a sequential mode of action, namely inhibition of cytochrome P450-dependent C14-demethylation of sterols and direct inhibition of HMG-CoA-reductase. In vitro bifonazole shows a strongly pH-dependent efficacy. The uptake kinetics of bifonazole have been measured with different pathogens. With respect to budding cells of Candida albicans it can be shown that the pH dependence of efficacy is due to a parallel pH dependence of the intracellular concentration of active ingredient. Even sublethal concentrations of bifonazole cause prior damages of young cells of C. albicans. These effects might explain the loss of infectivity of C. albicans after incubation with sublethal concentrations of bifonazole.

Animals↗
PubMed1983

In-vitro studies of a new oral azole antimycotic, BAY N 7133.

The in-vitro antifungal activities of BAY N 7133, a new orally absorbed synthetic azole derivative against 364 strains of fungal pathogens were studied in direct comparison with another orally active azole compound ketoconazole, using an agar dilution procedure. BAY N 7133 was found to have a broad spectrum of antifungal activity and to inhibit most pathogenic yeasts and fungi at concentrations ranging from less than or equal to 0.04 to 10 mg/1, with the exception only of some strains of zygomycetic pathogens. It was equal to or even greater than ketoconazole in activity against most of the fungal pathogens tested. Composition and pH of culture media and inoculum size altered the effect of BAY N 7133. No in-vitro development of drug resistance was demonstrated. BAY N 7133 can be considered to have a possible usefulness in the treatment of human mycoses.

Antifungal Agents↗
PubMed1983

Antimycotic efficacy of bifonazole in vitro and in vivo.

The new imadozolyl derivative 1-(p, alpha-diphenyl-benzyl)imidazole (bifonazole, Bay h 4502, Mycospor) shows in vitro the broad spectrum of activity characteristic of azole antimycotics. The intensity of activity under conventional test conditions is equivalent to that of clotrimazole. Further, concentrations of less than or equal to 5 micrograms/ml bifonazole have a fungicidal effect on dermatophytes, and a MIC value of less than or equal to 0.25 micrograms/ml has a maximal effect on Torulopsis glabrata. In ng concentrations bifonazole is effective on proliferating dermatophytes and pseudomycelia of Candida albicans. The resistance situation regarding bifonazole is favourable--as is typical of azole antimycotics. In animal experiments, topical application of concentrations of between 0.05 and 1% bifonazole as a cream or solution are extremely effective on guinea-pig trichophytosis. This is attributed to the therapeutically achievable fungicidal effect on dermatophytes and the long period of time the substance is retained in the skin. The sum of the experimental properties of bifonazole make it possible to recommend the active drug to be applied, once every 24 h, as a 1% cream or solution and the duration of therapy for these indications being reduced to 2-3 weeks.

Animals↗
PubMed1983

In vitro studies of a new imidazole antimycotic, bifonazole, in comparison with clotrimazole and miconazole.

The in vitro activity of 1-[(4-Biphenylyl)-phenylmethyl]-1H-imidazole bifonazole, Bay h 4502, Mycospor) a new antifungal imidazole derivative, against a variety of medically important fungi were studied using an agar dilution procedure. Two imidazole drugs which have already appeared on the market as topical antimycotics, clotrimazole and miconazole, were also tested as reference drugs. MIC values of bifonazole to a range of pathogenic fungi and yeasts ranged from 0.04 to 80 micrograms/ml, but mostly were less than 2.5 micrograms/ml. The antifungal potency of bifonazole relative to that of clotrimazole and miconazole varied from strains to strains or from species to species. For example, almost all strains of dermatophytes were less susceptible to bifonazole than clotrimazole and the least susceptible to miconazole. Against most other fungi tested bifonazole was similar to or greater than clotrimazole and/or miconazole in inhibitory activity. The activity against Candida species increased in the order of bifonazole, miconazole and clotrimazole. When tested against other pathogenic yeasts such as T. glabrata and C. neoformans, bifonazole was more active than clotrimazole, and compared favorably with miconazole. Bifonazole and the other two imidazole derivatives inhibited the growth of most fungi at concentrations well below their quoted MICs. Composition and pH of culture medium, as well as fungal inoculum size, significantly altered the activity of bifonazole. A brief discussion of the possible clinical usefulness of bifonazole is given.

Antifungal Agents↗
PubMed1983

The effect of bifonazole on the structure of Trichophyton.

The effect of a new azole antimycotic, 1-[(4-biphenylyl)-phenylmethyl]-1H-imidazole (bifonazole, Bay h 4502, Mycospor) on the morphology of hyphae of Trichophyton mentagrophytes grown in a liquid medium was studied by high-resolution scanning electron microscopy. With bifonazole at concentrations ranging from 1 to 10 ng/ml that were much lower than the MIC value of the drug for this test strain (630 ng/ml), the hyphal growth was significantly inhibited and several morphological changes of the hyphae were produced. They were characterized by: (1) development of wavy or curled hyphae, (2) occasional formation of swollen cells often arranging in chain; (3) partial exfoliation of hyphal walls; and (4) excretion of fibrillar materials. These morphological changes of the hyphae became more prominent with increasing drug concentrations up to 200 ng/ml, and many hyphae were collapsed and distorted. These results strongly suggest that subinhibitory concentrations of bifonazole profoundly affected the normal growth and induced degenerative changes of the hyphae of T. mentagrophytes probably by damaging the cell membrane.

Antifungal Agents↗