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 ␤-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 ␤-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-␤-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.Pentavalent antimonials, including meglumine antimoniate, are the main drugs used in the treatment of all forms of leishmaniasis (1, 2, 9). These highly water-soluble compounds are considered inactive when given enterally and are subject to rapid renal clearance after parenteral administration, requiring a multiple-dosing regimen. Antimony (Sb) therapy is often accompanied by local pain during and just after intramuscular injections and by severe systemic side effects requiring very careful medical supervision. All these factors contribute to high cost and compliance difficulties that may ultimately lead to treatment failures. This also explains why so much effort is being devoted to the search for orally active antileishmanial drugs (4, 7, 13).The association of drugs with carrier systems is a feasible strategy to improve oral absorption. Among drug carrier systems, cyclodextrins, which are cyclic oligosaccharides composed of glucose units joined through ␣-1,4 glucosidic bonds, have been one of the most successful drug absorption enhancers for oral delivery (5, 14).We show here that ␤-cyclodextrin forms a complex with meglumine antimoniate and report the impact of this association on the oral absorption of antimony in mice and on the efficacy of meglumine antimoniate in an experimental model of cutaneous leishmaniasis. The meglumine antimoniate-␤-cyclodextrin complex was prepared by mixing ␤-cyclodextrin and meglumine antimoniate in distilled water at a 1:1 cyclodextrin/Sb molar ratio, heati...

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Two simple and efficient procedures for the preparation of pentavalent antimony derivatives are described, using either antimony pentachloride (SbCl 5 ) or potassium hexahydroxoantimonate (KSb(OH) 6 ) as sources of antimony(V). These two new methods are evaluated for the synthesis of an important anti-leishmanial drug: meglumine antimonate. Using elemental (carbon, hydrogen, nitrogen) and thermal analysis, atomic absorption (antimony), proton NMR spectroscopy and highresolution positive-ion electrospray ionization mass spectrometry (ESI(+)-MS), products for the reaction with N-methyl-D-glucamine (NMG) using both the SbCl 5 and KSb(OH) 6 methods were characterized and found to be similar to a commercial sample of the drug. The only notable difference was observed for the ESI-MS spectrum of the KSb(OH) 6 product; it displays the same pattern of ESI-generated ions as those of both the SbCl 5 product and the commercial drug, but with significantly different abundance ratios. NMR data indicate that the NMG molecules coordinate antimony in two different fashions, which suggests either the coexistence of two different complexes or the existence of a single major complex in which two NMG molecules are coordinated with antimony in an asymmetrical geometry.