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Leishmaniasis is a parasitic disease that threatens 350 million people worldwide. In a search for new antileishmanial drugs, the in vitro activity of flavonoids from Kalanchoe pinnata (Crassulaceae) was previously demonstrated in infected cells. In order to demonstrate the safety and oral activity of K. pinnata, flavonoids were evaluated in vivo in a murine model of cutaneous leishmaniasis. Daily oral doses of quercetin 3-O-alpha-L-arabinopyranosyl (1-->2)-alpha-L-rhamnopyranoside, quercetin 3-O-alpha-L-rhamnopyranoside, and free quercetin (16 mg/kg body weight) all were able to control the lesion growth caused by Leishmania amazonensis and to significantly reduce parasite load. These flavonoids were as effective as the crude K. pinnata aqueous extract given at 320 mg/kg body weight. HPLC-DAD-MS analysis of the plasma of extract-treated mice suggested that quercetin and quercetin glucuronides are the main metabolites of K. pinnata quercetin glycosides. Our results indicate that K. pinnata quercetin glycosides are important active components of the aqueous extract and that they possess potent oral efficacy against cutaneous leishmaniasis.

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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...

Conventional chemotherapy of cutaneous leishmaniasis (CL) is based on multiple parenteral or intralesional injections with systemically toxic drugs. Aiming at a single-dose localized therapy, biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles loaded with 7.8% of an antileishmanial nitrochalcone named CH8 (CH8/PLGA) were constructed to promote sustained subcutaneous release. , murine macrophages avidly phagocytosed CH8/PLGA smaller than 6 μm without triggering oxidative mechanisms. Upon 48 h of incubation, both CH8 and CH8/PLGA were 40 times more toxic to intracellular than to macrophages. , BALB/c were given one or three subcutaneous injections in the infected ear with 1.2 mg/kg of CH8 in free or CH8/PLGA forms, whereas controls received three CH8-equivalent doses of naked PLGA microparticles or meglumine antimoniate (Glucantime; Sanofi-Aventis). Although a single injection with CH8/PLGA reduced the parasite loads by 91%, triple injections with free CH8 or CH8/PLGA caused 80 and 97% reductions, respectively, in relation to saline controls. Meglumine antimoniate treatment was the least effective (only 36% reduction) and the most toxic, as indicated by elevated alanine aminotransferase serum levels. Together, these findings show that CH8/PLGA microparticles can be effectively and safely used for single-dose treatment of CL.