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Mechanism of action of antifungals and combination therapy

1995; Wiley; Volume: 4; Issue: 1 Linguagem: Inglês

10.1016/0926-9959(94)00074-a

1468-3083

A. Polak-Wyss,

Plant Pathogens and Fungal Diseases

Abstract Biochemical studies have identified a number of potential targets for antifungal chemotherapy, including cell wall synthesis, membrane sterol biosynthesis, nucleic acid synthesis, metabolic inhibition and macromolecular biosynthesis. The inhibition of cell wall synthesis would be in theory highly specific since only fungal cells build their cell wall with chitin and glucan. Despite this defined specificity, none of the clinically available drugs act there. Most antifungals interfere with enzymatic steps involved in the complicated synthesis of ergosterol. Allylamines interfere with the squalene epoxidation leading to an intracellular accumulation of squalene. The imidazole and triazole derivatives interact with the cytochrom P-450-dependent C14-demethylase system. C14-methyl-sterols like lanosterol are accumulated within the fungal cell. Under treatment of morpholine derivatives like amorolfine, ignosterol a sterol containing a Δ14 double bond is accumulated. Amorolfine inhibits two steps in the pathway of ergosterol biosynthesis namely the Δ14 reductase and the Δ7,8 isomerase. Amorolfine possesses a broad antimycotic spectrum against fungi pathogenic to plants and humans. The drug not only inhibits the fungal growth, it also shows a strong fungicidal activity which is both concentration- and time-dependent. The fungicidal activity against dermatophytes is in the same order as the one of terbinafine. Amorolfine also shows good fungicidal activity against yeasts, dimorphic and dematiaceous fungi. Amorolfine exerts synergistic activity in combination with several other antifungals such as ketoconazole, terbinafine, itraconazole and griseofulvin. The fungistatic activity of all these antifungals against dermatophytes is slightly increased by addition of amorolfine. The synergistic effect seen in vitro is, however, more pronounced in an animal model. Combination therapy of amorolfine with terbinafine, itraconazole and griseofulvin was studied in a murine trichophytosis model. Murine trichophytosis is self-healing, the course of infection reaches a plateau on day 7 and declines thereafter throughout the second week. Mice infected with trichophyton and treated with various antifungal drugs generally responded to the treatment in a dose-dependent manner, showing a significant reduction in the appearance of mycotic foci in comparison to untreated animals. The combinations of amorolfine with griseofulvin, terbinafine, itraconazole and fluconazole were always more efficient than the individual drug treatment alone, provided that the single therapy is not overwhelmingly efficacious per se. Antagonism was never observed.