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

Author(s)

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

Affiliation

^[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

• Document type: Journal article
• Source: Acta Tropica; v. 137, p. 206-210, SEP 2014.
• Web of Science Citations: 10

Abstract

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)

• FAPESP's process: 11/23703-1 - Study of the therapeutic potential of drugs and synthetic compounds, free or loaded into nanoliposomes: in vitro and experimental approach
• Grantee: Érika Gracielle Pinto
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 12/18756-1 - Evaluation of novel alternative therapies with synthetic drugs using in vitro and experimental models of Leishmania (L.) infantum chagasi
• Grantee: André Gustavo Tempone Cardoso
• Support Opportunities: Regular Research Grants