Manfred Plempel

Test Methods for Antifungal Agents—a Critical Review/ Wirksamkeitsuntersuchungen an antimykotischen Substanzen

Summary: The research for new antimycotic agents is markedly hampered by a lack of alternative fungus‐specific test methods in vitro and a limited number of reproducible infection models in vivo.

Antimycotic sterol biosynthesis inhibitors

Abstract The last decade or so has seen the development and increased use of the antifungal azoles. D. Berg and colleagues describe the pharmacology and medicinal chemistry of these compounds which has allowed research in this field to move towards the development of analogues with reduced toxicity suitable for oral and parenteral administration.

Sexualreaktion und Carotin-Synthese bei Zygomyceten

SummaryIn the Zygomycetes Mucor mucedo, Blakeslea trispora and Phycomyces Blakesleeanus, gamon formation and carotene synthesis are coupled reactions. The gamon formation goes parallel with the carotene biosynthesis. This provides a way by which gamon synthesis can be elucidated.ZusammenfassungGamonbildung und Carotinsynthese sind bei den Zygomyceten Mucor mucedo, Blakeslea trispora und Phycomyces Blakesleeanus gekoppelte Reaktionen. Die Gamonbildung verläuft parallel zur Carotinbiosynthese. Damit kann ein Weg zur Klärung der Gamonsynthese gefunden werden.

Sterol Biosynthesis Inhibitors

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.

Action Mechanisms of Cell-Division-Arresting Benzimidazoles and of Sterol Biosynthesis-Inhibiting Imidazoles, 1, 2, 4-Triazoles, and Pyrimidines

Summary: In spite of a formal similarity between benzimidazoles and azoles, two completely different action mechanisms are in operation, namely inhibition of tubuline association by the benzimidazoles, and inhibition of ergosterol biosynthesis at the stage of C14 demethylation by imidazoles, 1, 2, 4‐triazoles, and pyrimidines.

Modulation of leukotriene metabolism from human polymorphonuclear granulocytes by bifonazole

Summary. The influence of bifonazole and other azoles on the leukotriene‐metabolism of human neu‐trophil granulocytes (PMN) was investigated. The cells were stimulated with the Ca‐ionophore A23187 over 15 minutes in the presence of the azoles. Subsequently the supernatants were analyzed for their leukotriene content by reversed‐phase HPLC. In order to confirm that the observed effects are not due to cytotoxic phenomena tests were performed to evaluate the viability of the granulocytes. The chemotactic active leukotriene B4 (LTB4) and its inactive omega‐metabolites were detected and quantified by HPLC analysis. The results clearly demonstrated that bifonazole inhibited the omega‐oxidation already at concentrations as low as 0.5 μg ml‐1. As a consequence the LTB4‐level became elevated. At concentrations up to 64 μg ml‐1 bifonazole totally blocked the formation of leukotrienes in human granulocytes. Identical experiments were performed with other azoles and with various anti‐inflammatory drugs just to have a comparison with bifonazole. It is evident that bifonazole in addition to its well known antimycotic action shows a unique modulation of the leukotriene‐metabolism, which is important for its anti‐inflammatory potency.

Erste klinische Erfahrungen bei Systemmykosen mit einem neuen oralen Antimykoticum

Aus einer Reihe erster klinischer Therapieversuche wird über die Behandlung eines sekundären Aspergilloms, einer Candidainfektion der Bronchien und einer Sycosis barbae candidamycetica mit einem neuen Antimykoticum (BAY b 5097) berichtet. Hierbei hat sich die Substanz als sehr wirksam erwiesen. Die Verträglichkeit, beurteilt an Leber‐ und Nierenfunktion wie Blutbild war auch nach langfristiger Anwendung zufriedenstellend. Die Substanz verhält sich in dieser Hinsicht wie ein Placebo. Intestinale Störungen können auftreten. Diese scheinen durch Verabreichung von BAY b 5097 in dünndarmlöslichen Kapseln geringer zu sein. Zum Therapieerfolg sind relativ hohe Dosen erforderlich. Diese werden in den besprochenen Fällen aus der Relation, der MHK der Pilze in vitro zum Serumspiegel errechnet. Der fungistatische Wirkungstyp von BAY b 5097 kann bei zu kurzer Therapiedauer zu Recidiven führen. In einer später folgenden Mitteilung wird über weitere therapeutische Erfahrungen berichtet.