Screening and Evaluation In Vivo
If, as has been suggested, screening in vitro can be misleading and unreliable, it is even more important that in vivo screens should be relevant and that they should be able to cope with large numbers of compounds in restricted quantity. Although topical activity may be achievable in a new compound, a profusion of topical antifungals of differing chemical types is already available. As the current medical need is rather for safer and more effective drugs which can be given by mouth or by injection, the following discussion will be mostly concerned with systemic activity. The purpose of the screen is firstly to detect in vivo antifungal activity and then to indicate whether or not that activity is worth further investigation (as systemic activity in vivo is rare, it will be worth further investigation!). Because of varying fungal susceptibilities, compounded by the distribution patterns of compounds in the body and the different sites of fungal location, some indication of the effective spectrum of activity is desirable; e.g. although Candida albicans is basically susceptible to amphotericin B and systemic infections do show a response to treatment, vaginal ones do not. Other compounds will be basically narrow in their spectrum of activity, e.g. griseofulvin and terbinafine only have utility against dermatophytes, 5-fluorocytosine only against yeasts and cilofungin (LY 121019) only against two species of Candida. As there appears to be commercial viability in narrow spectrum antifungal agents as well as a medical need, the screen should be able to detect both types of activity. Extrapolation from mice to humans is never easy, and so comparison with already established antifungals will be important in assessing the possible significance of activity detected in the screen.
KeywordsCandida Albicans Antimicrob Agent Cryptococcal Meningitis Minimum Effective Dose Fungal Count
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