Histamine H1-receptor antagonists against Leishmania (L.) infantum: an in vitro and in vivo evaluation using phosphatidylserine-liposomes

Autor(es)

Pinto, Erika G. ^{[1, 2]} ; da Costa-Silva, Thais A. ^[1] ; Tempone, Andre Gustavo ^[1]

Afiliação do(s) autor(es)

^[1] Ctr Parasitol & Mycol, Inst Adolfo Lutz, BR-01246 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Med Trop Sao Paulo, BR-05403 Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Acta Tropica; v. 137, p. 206-210, SEP 2014.
• Citações Web of Science: 10

Resumo

Considering the limited and toxic therapeutic arsenal available for visceral leishmaniasis (VL), the drug repositioning approach could represent a promising tool to the introduction of alternative therapies. Histamine H1-receptor antagonists are drugs belonging to different therapeutic classes, including antiallergics and anxyolitics. In this work, we described for the first time the activity of H1-antagonists against L. (L) infantum and their potential effectiveness in an experimental hamster model. The evaluation against promastigotes demonstrated that chlorpheniramine, cinnarizine, hydroxyzine, ketotifen, loratadine, quetiapine and risperidone exerted a leishmanicidal effect against promastigotes, with IC50 values in the range of 13-84 mu M. The antihistaminic drug cinnarizine demonstrated effectiveness against the intracellular amastigotes, with an IC50 value of 21 mu M. The mammalian cytotoxicity was investigated in NCTC cells, resulting in IC50 values in the range of 57-229 mu M. Cinnarizine was in vivo studied as a free formulation and entrapped into phosphatidylserine-liposomes. The free drug was administered for eight consecutive days at 50 mg/kg by intraperitoneal route (i.p.) and at 100 mg/kg by oral route to L. infantum-infected hamsters, but showed lack of effectiveness in both regimens, as detected by real time PCR. The liposomal formulation was administered by i.p. route at 3 mg/kg for eight days and reduced the parasite burden to 54% in liver when compared to untreated group; no improvement was observed in the spleen of infected hamsters. Cinnarizine is the first antihistaminic drug with antileishmanial activity and could be used as scaffold for drug design studies for VL. (C) 2014 Elsevier B.V. All rights reserved. (AU)

• Processo FAPESP: 11/23703-1 - Estudo do potencial terapêutico de fármacos e compostos sintéticos, livres ou incluídos em nanolipossomos: uma abordagem in vitro e experimental
• Beneficiário: Érika Gracielle Pinto
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/18756-1 - Avaliação de novas alternativas terapêuticas com fármacos sintéticos em modelos in vitro e experimentais de Leishmania (L.) infantum chagasi
• Beneficiário: André Gustavo Tempone Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular