title: Histamine H1-receptor antagonists against Leishmania (L.) infantum: an in vitro and in vivo evaluation using phosphatidylserine-liposomes.
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 13-84μM. The antihistaminic drug cinnarizine demonstrated effectiveness against the intracellular amastigotes, with an IC50 value of 21μM. The mammalian cytotoxicity was investigated in NCTC cells, resulting in IC50 values in the range of 57-229μM. Cinnarizine was in vivo studied as a free formulation and entrapped into phosphatidylserine-liposomes. The free drug was administered for eight consecutive days at 50mg/kg by intraperitoneal route (i.p.) and at 100mg/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 3mg/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.
authors.affiliation: Center for Parasitology and Mycology, Instituto Adolfo Lutz, Av. Dr. Arnaldo, 351, 01246-900, São Paulo SP, Brazil; Instituto de Medicina Tropical de São Paulo, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 470, 05403-000, São Paulo SP, Brazil.
authors.forename: Erika G
authors.initials: EG
authors.lastname: Pinto
authors.affiliation: Center for Parasitology and Mycology, Instituto Adolfo Lutz, Av. Dr. Arnaldo, 351, 01246-900, São Paulo SP, Brazil.
authors.forename: Thais A
authors.initials: TA
authors.lastname: da Costa-Silva
authors.affiliation: Center for Parasitology and Mycology, Instituto Adolfo Lutz, Av. Dr. Arnaldo, 351, 01246-900, São Paulo SP, Brazil. Electronic address: atempone@usp.br.
authors.forename: Andre Gustavo
authors.initials: AG
authors.lastname: Tempone
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D058492:Drug Repositioning; D006634:Histamine H1 Antagonists / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D006801:Humans; D020128:Inhibitory Concentration 50; D018314:Leishmania infantum / Q000187:drug effects* / Q000502:physiology; D007896:Leishmaniasis / Q000188:drug therapy*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008297:Male; D008647:Mesocricetus; D008807:Mice, Inbred BALB C; D059208:Parasite Load; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000981:Antiprotozoal Agents; D006634:Histamine H1 Antagonists
keywords: Cinnarizine; H1 antagonist; Histamine; Leishmania; Liposomes; Therapy