title: Hepatotoxicity of pentavalent antimonial drug: possible role of residual Sb(III) and protective effect of ascorbic acid.
abstract: Pentavalent antimonial drugs such as meglumine antimoniate (Glucantime [Glu; Sanofi-Aventis, São Paulo, Brazil]) produce severe side effects, including cardiotoxicity and hepatotoxicity, during the treatment of leishmaniasis. We evaluated the role of residual Sb(III) in the hepatotoxicity of meglumine antimoniate, as well as the protective effect of the antioxidant ascorbic acid (AA) during antimonial chemotherapy in a murine model of visceral leishmaniasis. BALB/c mice infected with Leishmania infantum were treated intraperitoneally at 80 mg of Sb/kg/day with commercial meglumine antimoniate (Glu) or a synthetic meglumine antimoniate with lower Sb(III) level (MA), in association or not with AA (15 mg/kg/day), for a 20-day period. Control groups received saline or saline plus AA. Livers were evaluated for hepatocytes histological alterations, peroxidase activity, and apoptosis. Increased proportions of swollen and apoptotic hepatocytes were observed in animals treated with Glu compared to animals treated with saline or MA. The peroxidase activity was also enhanced in the liver of animals that received Glu. Cotreatment with AA reduced the extent of histological changes, the apoptotic index, and the peroxidase activity to levels corresponding to the control group. Moreover, the association with AA did not affect the hepatic uptake of Sb and the ability of Glu to reduce the liver and spleen parasite loads in infected mice. In conclusion, our data supports the use of pentavalent antimonials with low residue of Sb(III) and the association of pentavalent antimonials with AA, as effective strategies to reduce side effects in antimonial therapy.
authors.affiliation: Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Pampulha, Belo Horizonte, Brazil.
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Kato
authors.forename: Eliane
authors.initials: E
authors.lastname: Morais-Teixeira
authors.forename: Priscila G
authors.initials: PG
authors.lastname: Reis
authors.forename: Neila M
authors.initials: NM
authors.lastname: Silva-Barcellos
authors.forename: Pascal
authors.initials: P
authors.lastname: Salaün
authors.forename: Paula P
authors.initials: PP
authors.lastname: Campos
authors.forename: José
authors.initials: J
authors.lastname: Dias Corrêa-Junior
authors.forename: Ana
authors.initials: A
authors.lastname: Rabello
authors.forename: Cynthia
authors.initials: C
authors.lastname: Demicheli
authors.forename: Frédéric
authors.initials: F
authors.lastname: Frézard
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000627:therapeutic use*; D005260:Female; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D008099:Liver / Q000187:drug effects*; D008536:Meglumine / Q000009:adverse effects* / Q000627:therapeutic use*; D000077485:Meglumine Antimoniate; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000009:adverse effects* / Q000627:therapeutic use*
chemical_list: D009942:Organometallic Compounds; D008536:Meglumine; D000077485:Meglumine Antimoniate; D001205:Ascorbic Acid