Evaluation of activity and toxicity of combining clioquinol with ciclopirox and terbinafine in alternative models of dermatophytosis.

Dermatophytosis is a superficial fungal infection that affects humans and is very common in small animals. The treatment using the most commonly used antifungals is failing, and new therapeutic alternatives are required to combat the resistance of these fungal infections. Previous studies by the group have shown that clioquinol is an important therapeutic alternative in the treatment of dermatophytosis. The object was to conduct studies of antidermatophytic activity and the irritant potential from the double and triple combinations of clioquinol, terbinafine and ciclopirox in ex vivo and in vivo alternative models. To evaluate the irritant potential of antifungal combinations, the alternative HET-CAM method (chicken egg test chorioallantoic membrane) was used. Ex vivo models were used to assess the effectiveness of antifungal combinations, using pig hooves and veterinary fur. Any possible tissue damage was to assess through in histopathology of swine ears. HET-CAM results showed that all combinations can be classified as non-irritating, corroborated by the results of the histopathological evaluation of the pig's ear skin. Only the double combinations managed to remove 100% of the colony-forming units (CFU) formed on the pig's hooves. The clioquinol + terbinafine combination and the triple combination were more effective than clioquinol + ciclopirox in eradicating the preformed biofilm in fur of veterinary origin. These results show the potential of formulations of clioquinol in combination with antifungals for use in humans and in the veterinary field to combat dermatophytosis, as an important alternative therapy, for use in the near future.

Synergistic association of clioquinol with antifungal drugs against biofilm forms of clinical Fusarium isolates.

BACKGROUND: The influence of biofilm on the complexity of fungal diseases has been reported in recent years, especially in non-invasive mycoses such as keratitis and onychomycosis. The difficulty in treating cases of fusariosis in the human medical clinic exemplifies this situation, because when Fusarium spp. are present in the form of biofilm, the permeation of antifungal agents is compromised. OBJECTIVES: This study proposes an association of clioquinol, an inhibitor of fungal cells with antifungal drugs prescribed to combat fusariosis in humans. METHODS: Susceptibility was assessed by microdilution in broth. Formation of biofilm by staining with violet crystal. Inhibition and removal of biofilm using the MTT colorimetric reagent. Time-kill combination, hypoallergenicity test, cytotoxicity test and toxicity prediction by computer analysis were also performed. RESULTS: Clioquinol associated with voriconazole and ciclopirox inhibited biofilm formation. Possibly, clioquinol acts in the germination and elongation of hyphae, while voriconazole prevents cell adhesion and ciclopirox the formation of the extracellular polymeric matrix. The CLIO-VRC association reduced the biofilm formation by more than 90%, while the CLIO-CPX association prevented over 95%. None of the association was irritating, and over 90% of the leucocytes remained viable. Computational analysis does not reveal toxicity relevant to CLIO, whereas VRC and CPX showed some risks for systemic use, but suitable for topical formulations. CONCLUSIONS: The combination of CLIO-VRC or CLIO-CPX proved to be a promising association strategy in the medical clinic, both in combating fungal keratitis and onychomycosis, since they prevent the initial process of establishing an infection, the formation of biofilm.

Consideraçöes sobre o clioquinol / Clioquinol

Os autores apresentam uma revisäo sobre a neurotoxicidade do clioquinol e seus aspectos históricos em outros países. Concluem que näo há indicaçäo para o uso desta droga na atualidade. Sua popularidade e baixo custo näo säo fatores de relevância para a manutençäo de uma terapêutica sujeita a efeitos adversos graves. Recomendaçöes alternativas säo apresentadas para a terapêutica das enterocolites, com ênfase â orientaçäo sanitária