Abstract

Since the 1960s, there has been such a rapid evolution in the pharmacotherapy of mycoses that three phases of the development of antimycotic agents can be distinguished: compounds that existed before griseofulvin (1939); compounds presently available on the market, including itraconazole (1987); and new antimycotics that are being studied now and will be prescribed tomorrow. Both milestones (griseofulvin and itraconazole) are intended for oral administration. Topical treatment of superficial dermatomycoses (trichophytosis, favus, and microsporosis) has been complemented by systemic oral treatment. The world market for antimycotics in 1980 was valued at a total of $350 million. About 10% of this came from the sale of systemic (intravenous or oral) antifungals. In 1990, the antifungal world market was estimated at $1560 million of which almost $280 million was accounted for by systemic antifungals. This important increase in market value has induced more interest in research activities in the field of antifungals leading to more and more costly new treatment modalities. Among most prescribed antifungals are miconazole, clotrimazole, ketoconazole, nystatin, and econazole. Among topical antimycotic antibiotics, the polyene antimycotics include nystatin, natamycin (C₃₃H₄₇NO₁₃), amphotericin B (C₄₇H₇₃NO₁₇), candicidin, filipin, homycin, etruscomycin (C₃₆H₅₃NO₁₃), and trichomycin. Nystatin is mainly used to treat vaginal and oral infections and localized skin lesions. Natamycin, indicated for skin and nail infections with C. albicans, intertrigo and fissures at the corners of the mouth (perleche) caused by C. albicans, Candida vulvitis, and vaginitis, also plays an important role in the treatment of mycotic keratitis. Amphotericin B, an important polyene antibiotic, is administered almost exclusively via the intravenous route. Because of their limited activity, small spectrum, and side effects, the older topical antimycotics have generally been surpassed by newer, synthetic antimycotic chemotherapeutic agents. These antimycotics for topical use include the azole derivatives clotrimazole (C₂₂H₁₇ClN₂), miconazole (C₁₈H₁₄Cl₄N₂O), econazole (C₁₈H₁₅C₃N₂O), isoconazole (C₁₈H₁₄Cl₄N₂O), ketoconazole (C₂₆H₂₈Cl₂N₄O₄), butoconazole (C₁₉H₁₇Cl₃N₂S), oxiconazole (C₁₈H₁₃Cl₄N₃O), omoconazole (C₂₀H₁₇Cl₃N₂O₂), sulconazole (C₁₈H₁₅Cl₃N₂S), itraconazole (C₃₅H₃₈Cl₂N₈O₄), fluconazole (C₁₃H₁₂F₂N₆O), saperconazole, fenticonazole (C₂₄H₂₀Cl₂N₂OS), bifonazole (C₂₂H₁₈N₂), terconazole (C₂₆H₃₁Cl₂N₅O₃), tioconazole (C₁₆H₁₃Cl₃N₂OS), and zinoconazole. The introduction of the azole derivatives represents a milestone in the treatment of mycoses. Clotrimazole exhibits a broad-spectrum activity against mycoses of the skin and the vagina. Miconazole is indicated for infections of skin and nails due to dermatophytes or Candida species and vulvovaginal infections due to Candida species. Econazole and isoconazole are structurally very similar to miconazole. Good results in treating seborrheic eczema and dandruff led to the development of a 2% cream and a 2% shampoo (scalp gel) of ketoconazole. Included among systemic antimycotics are potassium iodide, griseofulvin, amphotericin B, flucytosin, miconazole, ketoconazole, itraconazole, and fluconazole. Two new antimycotics for systemic use are a triazole and fluoride analogue of itraconazole, named saperconazole.