title: Efficacy of tamoxifen and miltefosine combined therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis.
abstract: OBJECTIVE
  The objective of this study was to characterize in vitro interactions and evaluate the antileishmanial activity of tamoxifen and miltefosine combinations.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  In vitro and in vivo studies revealed no interaction between tamoxifen and miltefosine. Tamoxifen was able to hinder the emergence of miltefosine resistance.
authors: Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes 1374, 05508-000 São Paulo, Brazil.
authors: Cristiana T
authors: CT
authors: Trinconi
authors: Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes 1374, 05508-000 São Paulo, Brazil.
authors: Juliana Q
authors: JQ
authors: Reimão
authors: Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes 1374, 05508-000 São Paulo, Brazil.
authors: Adriano C
authors: AC
authors: Coelho
authors: Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes 1374, 05508-000 São Paulo, Brazil srbulian@icb.usp.br.
authors: Silvia R B
authors: SR
authors: Uliana
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D007891:Leishmania / Q000187:drug effects*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D008807:Mice, Inbred BALB C; D059208:Parasite Load; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013629:Tamoxifen / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000981:Antiprotozoal Agents; D013629:Tamoxifen; D010767:Phosphorylcholine; C039128:miltefosine