Efficacy of tamoxifen and miltefosine combined therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis

Autor(es)

Trinconi, Cristiana T. ^[1] ; Reimao, Juliana Q. ^[1] ; Coelho, Adriano C. ^[1] ; Uliana, Silvia R. B. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, Av Prof Lineu Prestes 1374, BR-05508000 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Antimicrobial Chemotherapy; v. 71, n. 5, p. 1314-1322, MAY 2016.
• Citações Web of Science: 14

Resumo

The objective of this study was to characterize in vitro interactions and evaluate the antileishmanial activity of tamoxifen and miltefosine combinations. Interactions between drugs were evaluated in vitro against Leishmania amazonensis promastigotes and intracellular amastigotes by a modified isobologram method. Four different drug ratios were used to calculate the FIC index (FICI) and the mean sum of FICI. Treatment of L. amazonensis-infected BALB/c mice was initiated 4 weeks post-infection. Mice were treated with the half-maximal effective dose (ED50) or half the ED50 of tamoxifen and miltefosine orally for 15 days. Efficacy was evaluated by lesion growth and parasite burden measured through luciferase detection at the end of treatment and 30 days later. Characterization of growth curves and stepwise increase in drug concentrations in vitro were used to measure survival and resistance selection of parasite populations submitted to combination treatment. No in vitro interactions between tamoxifen and miltefosine were found. In infected mice, the combination of tamoxifen and miltefosine at doses corresponding to half the ED50 was more effective than monotherapy with either tamoxifen or miltefosine. When the ED50 was employed, the efficacy of the combination was equivalent to miltefosine monotherapy. In vitro, tamoxifen was able to retard or suppress the growth of parasites treated with miltefosine. In vitro and in vivo studies revealed no interaction between tamoxifen and miltefosine. Tamoxifen was able to hinder the emergence of miltefosine resistance. (AU)

• Processo FAPESP: 11/18858-6 - Tamoxifeno como droga anti-leishmania: atividade em esquemas terapêuticos combinados e estudo do mecanismo de ação
• Beneficiário: Cristiana de Melo Trinconi Tronco
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/14629-5 - Mecanismos de ação e resistência à Miltefosina Leishmania spp.
• Beneficiário: Adriano Cappellazzo Coelho
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 15/09080-2 - Avaliação de candidatos a fármacos para o tratamento de leishmaniose no Brasil
• Beneficiário: Silvia Reni Bortolin Uliana
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/20484-7 - Tamoxifeno no tratamento de leishmaniose: avaliação de eficácia em esquemas de combinação de drogas e estudo do mecanismo de ação
• Beneficiário: Silvia Reni Bortolin Uliana
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/21970-2 - Moduladores seletivos de receptores de estrógeno como candidatos a fármacos para leishmaniose visceral: avaliação de associações de fármacos e investigação de mecanismos de ação leishmanicida
• Beneficiário: Juliana Quero Reimão Dalla Zanna
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado