Efeito in vitro do cetoconazol e de sua combinação com antimonial em Leishmania (Leishmania) amazonensis

• Ano de defesa: 2016
• Autor(a) principal: Nunes, Débora Cristina de Oliveira
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Uberlândia; Brasil; Programa de Pós-graduação em Genética e Bioquímica
• Palavras-chave em Português: Bioquímica; Leishmania amazonensis; Leishmaniose; Antimonial; Cetoconazol; Isobolograma; Antimoyl; Ketoconazole; Isobolgram; CNPQ::CIENCIAS BIOLOGICAS::GENETICA
• Link de acesso: https://repositorio.ufu.br/handle/123456789/19055; https://doi.org/10.14393/ufu.te.2016.97

Leishmaniasis is caused by protozoa of the Leishmania genus and belongs to the group of neglected diseases prevalent in developing countries. The available treatments for this disease present several limitations, which have directed efforts to search for new drugs or new therapeutic combinations aimed at the effectiveness and reduction of cost, parasite resistance and toxicity of the currently used treatments. Thus, the main objective of this study was to evaluate the in vitro effects of ketoconazole, an oral anti-fungal with antileishmanial potential, alone or in combination with antimony, the first choice drug for the leishmaniasis treatment. In order to determine the in vitro nature of the association between ketoconazole and antimony on Leishmania (Leishmania) amazonensis amastigote, the fixed-rate isobologram method was used and the following analyzes were performed: (1) evaluation of cytotoxicity of ketoconazole and antimony alone or in combination on amastigote form as well as in murine macrophages cell line RAW264.7, by measuring mitochondrial dehydrogenases activity; (2) evaluation of the effect of ketoconazole and antimonial alone or in combination on the infectivity of amastigote forms in murine macrophages RAW264.7. The results suggested that the nature of ketoconazole-antimony combination appears to be additive.For the study of a probable mechanism of action for ketoconazole against L. (L.) amazonensis promastigotes, the drug effects were evaluated on: (1) promastigote proliferation; (2) parasitic morphology and ultrastructure; (3) mitochondrial damage; (4) the development of autophagic vacuoles; (5) the cell death; and (6) the cell cycle. The study concluded that the mode of action of the ketoconazole on L. (L.) amazonensis promastigote forms appears to be cytostatic and noncytotoxic, since the drug had no effect on the mitochondrial membrane potential of the parasite, did not induce cell death (necrosis, apoptosis or autophagy) and was able to cause an arrest in the G0-G1 phases of the cell cycle.