Research Article: In vitro additive interaction between ketoconazole and antimony against intramacrophage Leishmania (Leishmania) amazonensis amastigotes

Date Published: June 29, 2017

Publisher: Public Library of Science

Author(s): Débora Cristina de Oliveira Nunes, Luiz Borges Bispo-da-Silva, Danielle Reis Napolitano, Mônica Soares Costa, Márcia Moura Nunes Rocha Figueira, Renata Santos Rodrigues, Veridiana de Melo Rodrigues, Kelly Aparecida Geraldo Yoneyama, Luis Eduardo M Quintas.


Leishmaniasis is a group of diseases caused by protozoa of Leishmania genus. The currently available treatments for this disease are expensive, present high toxicity and are associated to difficulties of healing and parasite resistance. Therefore, the development of strategies for leishmaniasis treatment is indispensable and includes reposition of existing drugs, as well as drug combination therapy. The aim of this study was to assess the nature of ketoconazole and antimony association on the cytotoxic effect against Leishmania (Leishmania) amazonensis amastigotes. The calculated mean sum of fractional 50% inhibitory concentration (x¯ΣFIC50) was 2.54 and 1.43 for free and intracellular amastigotes, respectively, values that suggest an additive interaction between ketoconazole and antimony concerning to Leishmania toxicity only in the intramacrophage parasite form. Despite the clinical efficacy of ketoconazole-antimony combination has been shown in the literature, our study is the first to describe the nature of ketoconazole-antimony interaction against L. (L.) amazonensis amastigotes. Moreover, our results point out the need for future in vivo studies to confirm the nature of ketoconazole-antimony interaction and also to determine possible effective dosage regimens related to ketoconazole administration in association with the optimal lower dose of antimony.

Partial Text

Parasitic protozoan diseases are commonly found in the poorest countries of the world and constitute one of the most widely spread human health problem [1]. These diseases are still neglected and unfortunately have received little attention from the pharmaceutical industry and scientific funding agencies [2]. Despite several therapeutic options are available to treat different forms of leishmaniasis, the current chemotherapy of cutaneous leishmaniasis usually relies on antimony-based drugs. However, these drugs produce many side effects and their toxicity associated to the drug-resistant strains have limited therapeutic uses of antimony-based agents [3].

Ketoconazole- and antimony-induced Leishmania toxicity appears to be related to the inhibitory effects of these drugs on different parasite metabolic pathways [4, 14]. Therefore, in the present study we tested the hypothesis that the combination of ketoconazole with antimony could improve the antileishmanial effect of these agents. It has been shown that Sb5+ should be reduced by the host cells to Sb3+, the active form against parasites [15, 16]. Thus, since both intramacrophage or free parasites were analyzed, and to avoid biases due to variability in macrophage drug conversion, antimonyl tartrate (Sb3+) was used instead meglumine antimoniate (Sb5+). Despite ketoconazole was less potent than antimony in inducing L. (L.) amazonensis free (ca. 40 times) and intracellular (ca. 50 times) amastigotes death in vitro, ketoconazole was much less toxic to macrophages than antimony. These data strongly suggest that this azole compound may be used against parasite-infected macrophages ensuring safety and efficacy.




0 0 vote
Article Rating
Notify of
Inline Feedbacks
View all comments