Enhanced oral delivery of antimony from meglumine antimoniate/beta-cyclodextrin nanoassemblies.

The composition comprising the highly water-soluble drug meglumine antimoniate (MA) and beta-cyclodextrin (beta-CD) was shown previously to enhance the absorption of Sb by oral route and render MA orally active in a murine model of cutaneous leishmaniasis. This unexpected behaviour was attributed, in part, to the fact that the heating of equimolar mixture of MA and beta-CD (first step of preparation of MA/beta-CD composition) induced the depolymerization of MA from high-molecular weight Sb complexes into 1:1 Sb-meglumine complex, resulting in an enhanced oral bioavailability of Sb. In the present work, we demonstrate that the heated MA+beta-CD mixture still produced significantly lower serum Sb levels when compared to the MA/beta-CD composition, indicating that the freeze-drying process (second step of preparation of MA/beta-CD composition) is required for achieving a high absorption of Sb by oral route. To get insight into the physicochemical alterations induced by the freeze-drying step, the MA/beta-CD composition was further characterized by circular dichroism, (1)H NMR and ESI(-)-MS and photon correlation spectroscopy. The freeze-drying process was found to promote the formation of supramolecular nanoassemblies with a mean hydrodynamic diameter of 190 nm, comprising 1:2:1, 2:2:1 and 2:2:2 NMG-Sb-beta-CD complexes. Another important observation was the ability of the MA/beta-CD composition to act as a sustained release system of the antimonial drug MA, suggesting that this property may result in the change of the drug absorption site in the gastrointestinal tract. A model is proposed for the mechanisms involved in the enhanced absorption of Sb from the MA/beta-CD composition.

Mode of action of beta-cyclodextrin as an absorption enhancer of the water-soluble drug meglumine antimoniate.

It has been previously reported that beta-cyclodextrin (beta-CD) enhances the oral absorption of the pentavalent antimony (Sb) drug, meglumine antimoniate (MA). Contrary to the drugs commonly used in association with beta-CD, MA is highly soluble in water (solubility >300 mg/mL) and, therefore, the mode of action of beta-CD in this system requires clarification. ESI(-)-MS analysis of MA and of the MA/beta-CD composition indicated the formation of a 1:1 association compound between 1:1 Sb-meglumine complex and beta-CD. A stability constant on the order of 100 Lmol(-1) was determined for this association compound. When MA solution was heated for 48 h at 55 degrees C to mimic the conditions used to prepare MA/beta-CD, MA was found to suffer dissociation, from high molecular weight Sb complexes into species of lower molecular weight. Strikingly, heated MA was found to be more extensively absorbed in mice by the oral route than MA freshly prepared at room temperature. In vitro skin permeation experiments using MA and MA/beta-CD indicated a two-fold increase in the Sb flux for MA/beta-CD. These findings support the hypothesis that the improved oral absorption of Sb arises from the increased permeation of MA across lipid bilayers, as a result of the enhanced availability of 1:1 Sb-meglumine complex.

What the Erythrocytic Nuclear Alteration Frequencies Could Tell Us about Genotoxicity and Macrophage Iron Storage?

Erythrocytic nuclear alterations have been considered as an indicative of organism's exposure to genotoxic agents. Due to their close relationship among their frequencies and DNA damages, they are considered excellent markers of exposure in eukaryotes. However, poor data has been found in literature concerning their genesis, differential occurrence and their life span. In this study, we use markers of cell viability; genotoxicity and cellular turn over in order to shed light to these events. Tilapia and their blood were exposed to cadmium in acute exposure and in vitro assays. They were analyzed using flow cytometry for oxidative stress and membrane disruption, optical microscopy for erythrocytic nuclear alteration, graphite furnace atomic absorption spectrometry for cadmium content in aquaria water, blood and cytochemical and analytical electron microscopy techniques for the hemocateretic aspects. The results showed a close relationship among the total nuclear alterations and cadmium content in the total blood and melanomacrophage centres area, mismatching reactive oxygen species and membrane damages. Moreover, nuclear alterations frequencies (vacuolated, condensed and blebbed) showed to be associated to cadmium exposure whereas others (lobed and bud) were associated to depuration period. Decrease on nuclear alterations frequencies was also associated with hemosiderin increase inside spleen and head kidney macrophages mainly during depurative processes. These data disclosure in temporal fashion the main processes that drive the nuclear alterations frequencies and their relationship with some cellular and systemic biomarkers.

Oral delivery of meglumine antimoniate-beta-cyclodextrin complex for treatment of leishmaniasis.

The need for daily parenteral administration represents one of the most serious limitations in the clinical use of pentavalent antimonials against leishmaniasis. In this work, we investigated the ability of beta-cyclodextrin to enhance the oral absorption of antimony and to promote the oral efficacy of meglumine antimoniate against experimental cutaneous leishmaniasis. The occurrence of interactions between beta-cyclodextrin and meglumine antimoniate was demonstrated through the changes induced in the spin lattice relaxation times of protons in both compounds. When free and complexed meglumine antimoniate were given orally to Swiss mice, plasma antimony levels were found to be about three times higher for the meglumine antimoniate-beta-cyclodextrin complex than for the free drug. Antileishmanial efficacy was evaluated in BALB/c mice experimentally infected with Leishmania amazonensis. Animals treated daily with the complex (32 mg of Sb/kg of body weight) by the oral route developed significantly smaller lesions than those treated with meglumine antimoniate (120 mg of Sb/kg) and control animals (treated with saline). The effectiveness of the complex given orally was equivalent to that of meglumine antimoniate given intraperitoneally at a twofold-higher antimony dose. The antileishmanial efficacy of the complex was confirmed by the significantly lower parasite load in the lesions of treated animals than in saline-treated controls. This work reports for the first time the effectiveness of an oral formulation for pentavalent antimonials.