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Therapeutic combinations for visceral leishmaniasis: the antileishmanial potential of calcium channel blockers and the use of liposomal nanoformulations


Visceral Leishmaniasis (VL) is a parasitic tropical disease, resulting in a progressive and fatal infection. The increase in the number of cases in non-endemic areas and the high toxicity of the chemotherapy demonstrate the urgent necessity of novel drugs. The study of clinically available drugs has been an important tool for the introduction of new chemotherapeutics against VL. Based on the restricted therapeutic arsenal against VL, drug combinations have been studied, as it is a common practice in the therapy of viral and bacterial infections, as for other parasitic diseases. The use of drug delivery systems as liposomes has been demonstrating a potential in the pharmaceutical field. These technologies could improve the Therapeutic Indexes of drugs and a marked reduction of adverse effects, through a sustained drug release and targetability. Based in this proposal, we have identified for the first time in literature, the in vitro potential of the calcium channel blocker, nimodipine, against Leishmania (L.) chagasi. Thus, this project will study the antileishmanial potential of clinically available calcium channel blockers. Drug combinations will be studied, by using nimodipine and pentamidine, amphotericin B and pentavalent antimony. The in vitro and in vivo synergism or antagonism of drug combinations will be studied as its potential in vitro cytotoxicity. The project will develop a nanoformulation of nimodipine, loaded in phosphatidylserine rich liposomes for targeting macrophages in major organs: spleen, liver and bone marrow. The in vitro uptake by macrophages of liposomal nimodipine will be studied, as other pharmacokinetics parameters as bioavailability and biodistribution by using liquid chromatography techniques. Besides it will be studied the effectiveness of the liposomal nimodipine in in vivo experimental assays. Finally, it will also be in vitro screened other calcium channel blockers against L chagasi. The goal of this project is to obtain a novel drug or drug combination and a novel liposomal formulation of nimodipine to be used in the treatment of VL, through the use of clinically available drugs. Consequently, it could reduce the costs and time of Research & Development of novel chemotherapeutics against a neglected disease as Visceral Leishmaniasis. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:
Pesquisa colaborativa amplia terapêutica para leishmaniose visceral 
Collaborative research augments therapy for visceral leishmaniasis 

Scientific publications (8)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
PINTO, ERIKA GRACIELLE; ANTONIAZZI, MARTA MARIA; JARED, CARLOS; TEMPONE, ANDRE GUSTAVO. Antileishmanial and antitrypanosomal activity of the cutaneous secretion of Siphonops annulatus. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 20, NOV 24 2014. Web of Science Citations: 5.
PINTO, ERIKA GRACIELLE; PIMENTA, DANIEL C.; ANTONIAZZI, MARTA MARIA; JARED, CARLOS; TEMPONE, ANDRE GUSTAVO. Antimicrobial peptides isolated from Phyllomedusa nordestina (Amphibia) alter the permeability of plasma membrane of Leishmania and Trypanosoma cruzi. Experimental Parasitology, v. 135, n. 4, p. 655-660, DEC 2013. Web of Science Citations: 22.
REIMAO, JULIANA Q.; COLOMBO, FABIO A.; PEREIRA-CHIOCCOLA, VERA L.; TEMPONE, ANDRE G. Effectiveness of liposomal buparvaquone in an experimental hamster model of Leishmania (L.) infantum chagasi. Experimental Parasitology, v. 130, n. 3, p. 195-199, MAR 2012. Web of Science Citations: 26.
REIMAO, JULIANA QUERO; TEMPONE, ANDRE GUSTAVO. Investigation into in vitro anti-leishmanial combinations of calcium channel blockers and current anti-leishmanial drugs. Memórias do Instituto Oswaldo Cruz, v. 106, n. 8, p. 1032-1038, DEC 2011. Web of Science Citations: 8.
REIMAO, JULIANA Q.; COLOMBO, FABIO A.; PEREIRA-CHIOCCOLA, VERA L.; TEMPONE, ANDRE G. In vitro and experimental therapeutic studies of the calcium channel blocker bepridil.: Detection of viable Leishmania (L.) chagasi by real-time PCR. Experimental Parasitology, v. 128, n. 2, p. 111-115, JUN 2011. Web of Science Citations: 24.
REIMAO, JULIANA Q.; SCOTTI, MARCUS T.; TEMPONE, ANDRE G. Anti-leishmanial and anti-trypanosomal activities of 1,4-dihydropyridines: In vitro evaluation and structure-activity relationship study. Bioorganic & Medicinal Chemistry, v. 18, n. 22, p. 8044-8053, NOV 15 2010. Web of Science Citations: 41.
TEMPONE, ANDRE GUSTAVO; MORTARA, RENATO ARRUDA; DE ANDRADE, JR., HEITOR FRANCO; REIMAO, JULIANA QUERO. Therapeutic evaluation of free and liposome-loaded furazolidone in experimental visceral leishmaniasis. INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, v. 36, n. 2, p. 159-163, AUG 2010. Web of Science Citations: 19.
TEMPONE, ANDRE GUSTAVO; TANIWAKI, NOEMI NOSOMI; REIMAO, JULIANA QUERO. Antileishmanial activity and ultrastructural alterations of Leishmania (L.) chagasi treated with the calcium channel blocker nimodipine. Parasitology Research, v. 105, n. 2, p. 499-505, 2009. Web of Science Citations: 28.

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