1996 Volume 37 Issue 4 Pages 199-205
Preclinical experiments are extremely important for predicting the results of clinical trials in the development of novel antifungal agents. The methods of preclinical therapeutic evaluation of agents for treating dermatophytosis were discussed.
The agar plate dilution method has been conventionally used to determine in vitro antifungal activities. In 1995, the Committee Laboratory Standards, the Japanese Society for Medical Mycology proposed adoption of the micro broth dilution method used in testing drugs against deep-seated mycosis as the standard sensitivity testing method for yeast-like fungi. Although a final evaluation of the usefulness of this method remains to be made, its adoption in preclinical experiments in the near future is anticipated. Many problems, however, remain unresolved with regard to the standardization of sensitivity testing for filamentous fungi. In the micro broth dilution method, various end-point determination techniques have been used, such as mycelial ATP determination by bioluminescence measurement and spectrophotometric method based on the reduction of redox dye. The results of these techniques in sensitivity testing against dermatophytes were described.
Guinea pig infection models are commonly used to assess the in vivo therapeutic effects of agents against dermatophytosis. The usefulness of a tinea pedis model produced by infecting the foodplanta of guinea pigs with Trichophyton mentagrophytes, and the results of therapeutic effect and recurrence prevention assessments were presented. The assessment of recurrence prevention illustrated its importance as a model to study follow-up of drug effect in clinical trials.
Studies of drug retention in the epidermal corneum and persistence of drug effect are indispensable in the evaluation of antifungal agents against dermatophytosis. Methods for analyzing the pharmacokinetics of these drugs include affinity of the drug to keratin in vitro, prevention of symptom onset in animal models and cutaneous distribution of isotope-labelled drugs. Results of local pharmacokinetics in infected tissues together with antifungal activities of the agent allow a certain degree of prediction of therapeutic effectiveness in the skin.
Many antifungal agents that were evaluated favorably in these preclinical experiments have been confirmed to be effective in subsequent clinical trials.
