Efficacy of Meglumine Antimoniate under Low Polymerization State Orally Administrated in Murine Model of Visceral Leishmaniasis [PublishAheadOfPrint]

Progress towards the improvement of meglumine antimoniate (MA) commercially known as Glucantime®, a highly effective but also toxic antileishmanial drug, has been hindered by the lack of knowledge and control on its chemical composition. Here, MA was manipulated chemically with the aim of achieving an orally effective drug. MA compounds were synthesized from either antimony pentachloride (MA-SbCl₅) or potassium hexahydroxyantimonate (MA-KSb(OH)₆) and prepared under low polymerization state. Those were compared to Glucantime® regarding chemical composition, permeation properties across cellulose membrane and Caco-2 cell monolayer and uptake by peritoneal macrophages. MA-SbCl₅ and MA-KSb(OH)₆ were characterized as less polymerized and more permeable 2:2 Sb-meglumine complexes, when compared to Glucantime® that consisted in a mixture of 2:3 and 3:3 Sb-meglumine complexes. The antileishmanial activity and hepatic uptake of all compounds were evaluated after oral administration in BALB/c mice infected with Leishmania infantum chagasi, as model of visceral leishmaniasis (VL). The synthetic MA compounds given at 300 mg Sb/kg/12h for 30 days reduced significantly spleen and liver parasite burdens, in contrast to Glucantime® at the same dose. The greater activity of synthetic compounds could be attributed to their higher intestinal absorption and accumulation efficiency in the liver. MA-SbCl₅ given orally was as efficacious as Glucantime® by parenteral route (80 mg Sb/kg/24h IP). This data taken altogether suggests that treatment with less polymerized form of MA by oral route may be effective for the treatment of VL.

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