Genotoxic effects of the antileishmanial drug glucantime®

Abstract

Leishmaniasis is caused by species of the protozoan parasite Leishmania. It is the third most important vector-borne disease and is widely distributed throughout the world. The World Health Organization recommends pentavalent antimonials as drugs of first choice in its treatment. Although Glucantime has traditionally been used to treat leishmaniasis, there are still many questions about its structure, mechanisms of action and ability to induce damage in DNA. In this study, the genotoxic activity of this drug was evaluated in vitro using human lymphocytes treated for 3 and 24 h (comet assay) and 48 h (apoptosis assay) with 3.25, 7.5 and 15 mg/ml of Glucantime, respectively, corresponding to 1.06, 2.12 and 4.25 mg/ml of pentavalent antimony. In the in vivo tests, Swiss mice received acute treatment with three doses (212.5, 425 and 850 mg/kg) of pentavalent antimony. All the treatments were administered intraperitoneally in the volumes of 0.1 ml/10 g of body weight, adapting human exposure to murine conditions. The animals were treated for 3 h in the comet assay using resident peritoneal exudate macrophages, for 24 h in the comet assay using peripheral blood leukocytes and for 24 h in the bone marrow erythrocyte micronucleus test. While no genotoxic effect was observed in the in vitro tests, the in vivo tests showed that Glucantime induces DNA damage. These findings indicate that Glucantime is a promutagenic compound that causes damage to DNA after reduction of pentavalent antimony (SbV) into the more toxic trivalent antimony (SbIII) in the antimonial drug meglumine antimoniate.

Distribution of Human Leishmaniasis (VL) and Its Associated Risk Factors, in Metemma, Ethiopia

“…Due to side effects such as high cardiotoxicity, pancreatitis, and nephrotoxicity, patients should be hospitalized and monitored, as treatment may need to be suspended [5,6]. Antimonials seem to have a broad mechanism of action [7].…”

Protective effects of the antileishmanial extract of Tephrosia cinerea (L.) Pers. (Fabaceae) against cyclophosphamide-induced damage

“…Indeed, the drug of choice that is recommended by the World Health Organization and the Brazilian Ministry of Health, Glucantime ® , an antimonite of N-methylglucamine, has genotoxic and mutagenic activities in vivo (Lima et al, 2010). We showed that the antileishmanial hydroalcoholic extract of T. cinerea (L.) Pers.…”

“…Leishmaniasis is an endemic disease in Brazil that is generally treated with Glucantime ® despite its known genotoxic and mutagenic activities in vivo (Lima et al, 2010). To aid the search for new leishmaniasis treatments, we extended a previous study showing that hydroalcoholic extracts of T. cinerea leaves exert a potent antileishmanial activity (Bezerra et al, 2006).…”

Evaluation of genotoxic and cytotoxic effects of antileishmanial extract from Julocroton triqueter (Euphorbiaceae)

“…It is known that an agent's capacity to induce genetic damage can be directly related to its metabolism, so the genotoxic effects in vitro may be different than those seen in in vivo assays (Lima et al, 2010). To test whether components in the extract would have a different effect on DNA after metabolism, the genotoxic potential of the extract was tested in Swiss mice.…”

“…var. triqueter is a promising phytotherapeutic product for treating leishmaniasis, as it does not show genotoxic effects in vitro or in vivo, contrary to Glucantime ® , the drug currently used to treat this disease, which has a proven mutagenic effect (Lima et al, 2010). In addition, this hydroalcoholic extract is capable of reducing apoptotic cell death and inducing necrotic cell death at anti-leishmanial concentrations.…”