title: Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis.
abstract: Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is the second major cause of death by parasites, after malaria. The arsenal of drugs against leishmaniasis is small, and each has a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. Our group has focused on studying new drug candidates as alternatives to current treatments. The pterocarpanquinone LQB-118 was designed and synthesized based on molecular hybridization, and it exhibited antiprotozoal and anti-leukemic cell line activities. Our previous work demonstrated that LQB-118 was an effective treatment for experimental cutaneous leishmaniasis. In this study, we observed that treatment with 10 mg/kg of body weight/day LQB-118 orally inhibited the development of hepatosplenomegaly with a 99% reduction in parasite load. An in vivo toxicological analysis showed no change in the clinical, biochemical, or hematological parameters. Histologically, all of the analyzed organs were normal, with the exception of the liver, where focal points of necrosis with leukocytic infiltration were observed at treatment doses 5 times higher than the therapeutic dose; however, these changes were not accompanied by an increase in transaminases. Our findings indicate that LQB-118 is effective at treating different clinical forms of leishmaniasis and presents no relevant signs of toxicity at therapeutic doses; thus, this framework is demonstrated suitable for developing promising drug candidates for the oral treatment of leishmaniasis.
authors.affiliation: Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Edézio Ferreira
authors.initials: EF
authors.lastname: Cunha-Júnior
authors.affiliation: Laboratório de Imunologia Aplicada e Bioquimica de Proteínas e Produtos Naturais, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Thiago Martino
authors.initials: TM
authors.lastname: Martins
authors.affiliation: Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Marilene Marcuzzo
authors.initials: MM
authors.lastname: Canto-Cavalheiro
authors.affiliation: Laboratório de Imunologia Aplicada e Bioquimica de Proteínas e Produtos Naturais, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Paulo Roberto
authors.initials: PR
authors.lastname: Marques
authors.affiliation: Departamento de Patologia e Laboratórios, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Elyzabeth Avvad
authors.initials: EA
authors.lastname: Portari
authors.affiliation: Laboratório de Imunologia Aplicada e Bioquimica de Proteínas e Produtos Naturais, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Marsen Garcia Pinto
authors.initials: MG
authors.lastname: Coelho
authors.affiliation: Laboratório de Química, Universidade Federal do Rio de Janeiro, Macaé, RJ, Brazil.
authors.forename: Chaquip Daher
authors.initials: CD
authors.lastname: Netto
authors.affiliation: Instituto de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Paulo Roberto Ribeiro
authors.initials: PR
authors.lastname: Costa
authors.affiliation: Laboratório de Imunologia Aplicada e Bioquimica de Proteínas e Produtos Naturais, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Katia Costa de Carvalho
authors.initials: KC
authors.lastname: Sabino
authors.affiliation: Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, RJ, Brazil ects@ioc.fiocruz.br.
authors.forename: Eduardo Caio
authors.initials: EC
authors.lastname: Torres-Santos
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D065570:Gastric Absorption; D006529:Hepatomegaly / Q000517:prevention & control*; D006801:Humans; D020128:Inhibitory Concentration 50; D007441:Intubation, Gastrointestinal; D018314:Leishmania infantum / Q000187:drug effects* / Q000254:growth & development; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009285:Naphthoquinones / Q000494:pharmacology*; D009928:Organ Specificity; D018512:Parasitemia / Q000517:prevention & control*; D036343:Pterocarpans / Q000494:pharmacology*; D013163:Splenomegaly / Q000517:prevention & control*; D059551:Toxicity Tests, Subacute
chemical_list: D000981:Antiprotozoal Agents; C569361:LQB 118; D009285:Naphthoquinones; D036343:Pterocarpans