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Rational Pre-Clinical Study of New Drug Candidates Against Neglected Protozoan Diseases Using Pharmacokinetic Approaches

Abstract

Neglected protozoosis as leishmaniasis and Chagas disease, afflict more than 20 million people mainly in developing countries, with a limited, highly toxic and inefficient therapeutic arsenal. Using two approaches in Drug Discovery, as the drug repositioning and combination therapy, this proposal aims to study oral antidepressant drugs, with focus mainly on sertraline, as a potential alternative therapy for visceral leishmaniasis, cutaneous, and Chagas disease. There will be performed a comprehensive study addressing the following objcetives: i) metabolomics study, cellular and in silico chemogenomics to evaluate the mechanism of action of sertraline in Leishmania and / or T. cruzi; ii) in vivo pharmacokinetic study of sertraline and miltefosine in murine model; iii) oral combination of sertraline with miltefosine (Leishmania), and benznidazole (T. cruzi), using in vitro and in vivo models of L. infantum, L. amazonensis and T. cruzi; iv) development of an oral formulation containing sertraline alone or associated; v) histopathological sub-chronic toxicity profile of the association in mice, vi) in vitro evaluation of the immunomodulatory potential of sertraline; vii) assessment of in vitro toxicity of most promising association; viii) in vitro evaluation of antiparasitic activity of the metabolite desmethylsertraline in intracellular amastigotes and cytotoxicity; ix) In vitro screening of oral second-generation antidepressants on intracellular amastigotes. The implementation of pharmacokinetic analyzes in the early stages of Drug Discovery will provide the most appropriate intervals of doses in animal models, and also optimize the experimental studies to increase their chances of success. Thus, the identification of an oral combination therapy of short duration and well tolerated, could significantly contribute to new treatments for leishmaniasis and Chagas disease. (AU)

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Scientific publications (15)
(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)
CUNHA-JUNIOR, EDEZIO FERREIRA; ANDRADE-NETO, VALTER VIANA; LIMA, MARTA LOPES; DA COSTA-SILVA, THAIS ALVES; GALISTEO JUNIOR, ANDRES J.; ABENGOZAR, MARIA A.; BARBAS, CORAL; RIVAS, LUIS; ALMEIDA-AMARAL, ELMO EDUARDO; TEMPONE, ANDRE GUSTAVO; et al. Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice. PLoS Neglected Tropical Diseases, v. 11, n. 1, . (15/23403-9)
ALVES CONSERVA, GEANNE A.; DA COSTA-SILVA, THAIS A.; AMARAL, MAIARA; ANTAR, GUILHERME M.; NEVES, BRUNO J.; ANDRADE, CAROLINA H.; TEMPONE, ANDRE G.; LAGO, JOAO HENRIQUE G.. Butenolides from Nectandra oppositifolia (Lauraceae) displayed anti-Trypanosoma cruzi activity via deregulation of mitochondria. Phytomedicine, v. 54, p. 302-307, . (15/23403-9, 16/20633-6, 18/07885-1)
GRECCO, SIMONE S.; COSTA-SILVA, THAIS A.; SOUSA, FERNANDA S.; CARGNELUTTI, STEFANO B.; UMEHARA, ERIC; MENDONCA, POLIANA S.; TEMPONE, ANDRE G.; LAGO, JOAO HENRIQUE G.. Neolignans isolated from twigs of Nectandra leucantha Ness & Mart (Lauraceae) displayed in vitro antileishmanial activity. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 24, . (18/07885-1, 15/23403-9)
LIMA, MARTA L.; ABENGOZAR, MARIA A.; NACHER-VAZQUEZ, MONTSERRAT; MARTINEZ-ALCAZAR, MARIA P.; BARBAS, CORAL; TEMPONE, ANDRE G.; LOPEZ-GONZALVEZ, ANGELES; RIVAS, LUIS. Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate. Antimicrobial Agents and Chemotherapy, v. 62, n. 12, . (15/23403-9)
VARELA, MARINA T.; COSTA-SILVA, THAIS A.; LAGO, JOAO HENRIQUE G.; TEMPONE, ANDRE G.; FERNANDES, JOAO PAULO S.. Evaluation of the antitrypanosoma activity and SAR study of novel LINS03 derivatives. BIOORGANIC CHEMISTRY, v. 89, . (18/03918-2, 16/25028-3, 18/07885-1, 15/23403-9)
ERIKA G. PINTO; ANDRE G. TEMPONE. Activity of the antiarrhythmic drug amiodarone against Leishmania (L.) infantum: an in vitro and in vivo approach. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 24, . (15/23403-9)
UENO, ANDERSON K.; BARCELLOS, ALINE F.; COSTA-SILVA, THAIS A.; MESQUITA, JULIANA T.; FERREIRA, DAIANE D.; TEMPONE, ANDRE G.; ROMOFF, PAULETE; ANTAR, GUILHERME M.; LAGO, JOAO HENRIQUE G.. Antitrypanosomal activity and evaluation of the mechanism of action of diterpenes from aerial parts of Baccharis retusa (Asteraceae). Fitoterapia, v. 125, p. 55-58, . (14/08961-2, 15/23403-9, 15/11936-2)
DA COSTA-SILVA, THAIS ALVES; GALISTEO, JR., ANDRES JIMENEZ; LAULETTA LINDOSO, JOSE ANGELO; BARBOSA, LEANDRO R. S.; TEMPONE, ANDRE GUSTAVO. Nanoliposomal Buparvaquone Immunomodulates Leishmania infantum-Infected Macrophages and Is Highly Effective in a Murine Model. Antimicrobial Agents and Chemotherapy, v. 61, n. 4, . (15/15822-1, 15/23403-9, 13/07275-5, 13/50228-8)
MESQUITA, JULIANA TONINI; ROMANELLI, MAIARA MARIA; TRINCONI TRINCONI, CRISTIANA DE MELO C. M.; GUERRA, JULIANA MARIOTTI; TANIWAKI, NOEMI NOSOMI; BORTOLIN ULIANA, SILVIA RENI; REIMAO, JULIANA QUERO; TEMPONE, ANDRE GUSTAVO. Repurposing topical triclosan for cutaneous leishmaniasis: Preclinical efficacy in a murineLeishmania (L.) amazonensismodel. Drug Development Research, . (18/10279-6, 15/23403-9)
ALVES CONSERVA, GEANNE A.; QUIROS-GUERRERO, LUIS M.; COSTA-SILVA, THAIS A.; MARCOURT, LAURENCE; PINTO, ERIKA G.; TEMPONE, ANDRE G.; FERNANDES, JOAO PAULO S.; WOLFENDER, JEAN-LUC; QUEIROZ, EMERSON F.; LAGO, JOAO HENRIQUE G.. Metabolite profile of Nectandra oppositifolia Nees & Mart. and assessment of antitrypanosomal activity of bioactive compounds through efficiency analyses. PLoS One, v. 16, n. 2, . (15/23403-9, 16/20633-6, 18/07885-1, 18/18975-1, 18/10279-6)
ROMANELLI, MAIARA MARIA; DA COSTA-SILVA, THAIS ALVES; CUNHA-JUNIOR, EDEZIO; DIAS FERREIRA, DAIANE; GUERRA, JULIANA M.; GALISTEO, JR., ANDRES JIMENEZ; PINTO, ERIKA GRACIELLE; BARBOSA, LEANDRO R. S.; TORRES-SANTOS, EDUARDO CAIO; TEMPONE, ANDRE GUSTAVO. Sertraline Delivered in Phosphatidylserine Liposomes Is Effective in an Experimental Model of Visceral Leishmaniasis. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 9, . (18/10279-6, 15/15822-1, 13/07275-5, 15/23403-9)
VARELA, MARINA T.; ROMANELI, MAIARA M.; LIMA, MARTA L.; BORBOREMA, SAMANTA E. T.; TEMPONE, ANDRE G.; FERNANDES, JOAO P. S.. Antiparasitic activity of new gibbilimbol analogues and SAR analysis through efficiency and statistical methods. European Journal of Pharmaceutical Sciences, v. 122, p. 31-41, . (16/00195-4, 15/23403-9, 16/25028-3)
LONDERO, VINICIUS S.; DA COSTA-SILVA, THAIS A.; GOMES, KAIO S.; FERREIRA, DAIANE D.; MESQUITA, JULIANA T.; TEMPONE, ANDRE G.; YOUNG, MARIA CLAUDIA M.; JERZ, GEROLD; LAGO, JOAO HENRIQUE G.. Acetylenic fatty acids from Porcelia macrocarpa (Annonaceae) against trypomastigotes of Trypanosoma cruzi: Effect of octadec-9-ynoic acid in plasma membrane electric potential. BIOORGANIC CHEMISTRY, v. 78, p. 307-311, . (15/23403-9)
TEMPONE, ANDRE GUSTAVO; FERREIRA, DAIANE DIAS; LIMA, MARTA LOPES; COSTA SILVA, THAIS ALVES; BORBOREMA, SAMANTA E. T.; REIMAO, JULIANA QUERO; GALUPPO, MARIANA K.; GUERRA, JULIANA MARIOTTI; RUSSELL, ANGELIE J.; WYNNE, GRAHAM M.; et al. Efficacy of a series of alpha-pyrone derivatives against Leishmania (L.) infantum and Trypanosoma cruzi. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 139, p. 947-960, . (13/07275-5, 15/23403-9, 15/50075-2)
GUIMARAES GONCALVES, GIULIA ELISA; MORAIS, THIAGO RAHAL; GOMES, KAIO DE SOUZA; COSTA-SILVA, THAIS ALVES; TEMPONE, ANDRE GUSTAVO; GHILARDI LAGO, JOAO HENRIQUE; CASELI, LUCIANO. Antitrypanosomal activity of epi-polygodial from Drimys brasiliensis and its effects in cellular membrane models at the air-water interface. BIOORGANIC CHEMISTRY, v. 84, p. 186-191, . (15/23446-0, 13/14262-7, 18/07885-1, 15/23403-9)

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