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.

The need for daily parenteral administration is an important limitation in the clinical use of pentavalent antimonial drugs against leishmaniasis. In this study, amphiphilic antimony(V) complexes were prepared from alkylmethylglucamides (L8 and L10, with carbon chain lengths of 8 and 10, respectively), and their potential for the oral treatment of visceral leishmaniasis (VL) was evaluated. Complexes of Sb and ligand at 1:3 (SbL8 and SbL10) were obtained from the reaction of antimony(V) with L8 and L10, as evidenced by elemental and electrospray ionization-tandem mass spectrometry (ESI-MS) analyses. Fluorescence probing of hydrophobic environment and negative-staining transmission electron microscopy showed that SbL8 forms kinetically stabilized nanoassemblies in water. Pharmacokinetic studies with mice in which the compound was administered by the oral route at 200 mg of Sb/kg of body weight indicated that the SbL8 complex promoted greater and more sustained Sb levels in serum and liver than the levels obtained for the conventional antimonial drug meglumine antimoniate (Glucantime [Glu]). The efficacy of SbL8 and SbL10 administered by the oral route was evaluated in BALB/c mice infected withLeishmania infantumafter a daily dose of 200 mg of Sb/kg for 20 days. Both complexes promoted significant reduction in the liver and spleen parasite burdens in relation to those in the saline-treated control group. The extent of parasite suppression (>99.96%) was similar to that achieved after Glu given intraperitoneally at 80 mg of Sb/kg/day. As expected, there was no significant reduction in the parasitic load in the group treated orally with Glu at 200 mg of Sb/(kg day). In conclusion, amphiphilic antimony(V) complexes emerge as an innovative and promising strategy for the oral treatment of VL.

Antimonial drugs have been used for a century in the therapy of the parasitic disease leishmaniasis. Even though pentavalent antimonials are still first-line drugs, they exhibit several limitations, including severe side effects, the need for daily parenteral administration and drug resistance. The molecular structure of pentavalent antimonials, their metabolism and mechanism of action, are still being investigated. Previous studies suggest that pentavalent antimony acts as a prodrug which is converted to the active and more toxic trivalent antimony. Other works support the direct involvement of pentavalent antimony. Recent data indicate that thiols and ribose-containing biomolecules may mediate the pharmacological action of these drugs. Trypanothione reductase and zinc-finger proteins were identified as possible molecular targets. This review summarizes the progress achieved to date on the chemistry of antimonial drugs in biological systems.

The dry roots of Polygonum cuspidatum contain resveratrol, a compound known for its antimicrobial and protective effects against oxidative stress, which is associated with impaired wound healing. In this study, titanium dioxide nanoparticles (TiO₂NPs) were loaded with a P. cuspidatum extract (TiO₂-loaded extract NPs), and the resveratrol release profile, hemocompatibility, antioxidant, cytotoxic, and antimicrobial activities were evaluated. The results demonstrated that TiO₂-loaded extract NPs exhibited antioxidant activity for DPPH (Inhibitory Concentration 50 (IC₅₀) = 62.31 mg Trolox Equivalent (TE)/mL) and ABTS⁺ (IC₅₀ = 4.8 mg TE/mL) assays, along with suitable hemocompatibility (3.02% at 10 mg/mL), in comparison with bulk TiO₂ NPs. Additionally, temperature influenced the resveratrol release over time. The P. cuspidatum extract alone showed strong antibacterial activity, with a Minimal Inhibitory Concentration (MIC) of 5 µg/mL, TiO₂-loaded extract NPs showed MIC values about 50 mg/mL, while bulk TiO₂ NPs exhibited no antibacterial effect against the tested strains. In contrast, the P. cuspidatum extract, the TiO₂-loaded extract NPs, and the bulk TiO₂ NPs did not demonstrate antifungal activity against Candida albicans and C. glabrata. Moreover, TiO₂-loaded extract NPs showed no cytotoxicity against the L-929 cell line at concentrations ranging from 1.5 to 150 µg/mL, unlike TiO₂ NPs, which exhibited high cytotoxic concentrations between 9.4 and 300 µg/mL. These findings suggest that TiO₂-loaded extract NPs effectively control the release of resveratrol and hold promises for applications in skin management and wound healing.