Michael Barry Gravestock

Experimental approaches to antifungal chemotherapy.

Publisher Summary This chapter discusses the experimental approaches to antifungal chemotherapy. Fungal diseases in general occur in all parts of the world and affect all ages, though a number of particular species are restricted geographically in their incidence. It goes without saying that a systemic fungal infection will require systemic treatment. When however the fungus is confined to the skin or mucosal membranes, then the possibility exists of applying a topical treatment to the affected area, or alternatively treating the infection systemically, getting the parasite from “behind.” With a topical treatment the patient may feel he is doing something positive by applying the medication to the lesion whereas an oral treatment may give the feeling of irrelevance. On the other hand there would seem little point in applying a messy treatment to an already messy lesion if an alternative oral treatment were available.

Synthesis and Structure‐Activity Relationships of a Novel Antifungal Agent, ICI 195,739

Antifungal azole derivatives are known to have potential for inhibition of host P-450 systems, and, in the attempts to increase the antifungal specificity of the inhibitor by identification of extra receptor binding within the enzyme complex, initial synthesis was guided by the structural requirements of the natural lanosterol substrate. With the aid of computer graphics, the 3-styryl functionality was identified as a key structural element. For metabolically stable systems, in vitro-in vivo correlations exist, but optimizing oral activity resulted in the production of compounds with unacceptably long elimination half-lives. A disconnection of this relationship was achieved in pairs of structural isosteres with metabolic nonequivalence (CN:CONH2/OCH3:OCF3) and led to the identification of ICI 195,739, a novel 3-tetrafluoropropoxystyryl-substituted bistriazole tertiary alcohol, as the compound of choice.

Chapter 13. Antifungal Chemotherapy

Publisher Summary Ketoconazole (KC) as the first systemically-active azole antifungal has been the subject of a number of reviews including the general management of fungal disease, and its efficacy in superficial and systemic infections. The clinical pharmacokinetics of the systemic anti-fungals amphotericin B (AMB), 5-fluorocytosine (5-Fc), miconazole (MC), and Ketoconazole (KC) were reviewed with their individual limitations and preferred protocols for administration. A monograph on fungal infection in the compromised patient provides timely information on this area of increasing clinical concern. Bifonazole showed a broad spectrum of activity in vitro with particularly marked fungicidal effects on dermatophytes. Topical applications of the drug were extremely effective against trichophytosis in guinea pigs. Comparison of the drug in vitro with MC and clotrimazole (CL) showed that potency relative to both varied from strain to strain and species to species of yeasts and dematophytes. An evaluation of oxiconazole showed a broad fungistatic spectrum and fungicidal activity in selected species: Asperaillus fumigatus , C . neoformans , C. albicans, and T. mentagzophytes ; DNA synthesis was more sensitive at sub-inhibitory concentrations than RNA, protein, or carbohydrate synthesis. The potential for anti-fungal drugs to stimulate the host defenses as a possible component of their fungicidal action has been considered in earlier work, particularly for the polyenes. The relationship between adjuvant and mitogenic effects for amphotericin B methyl ester (AME) has been considered. Dose-dependent ultrastructural changes in C. parapsilosis include increased accumulation of lipid particles in the cytoplasm, thickening of the cell wall, and alterations of the plasma membrane.