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Cutaneous leishmaniasis (CL) is a major health problem in many countries and its current treatment involves multiple parenteral injections with toxic drugs and requires intensive health services. Previously, the efficacy of a single subcutaneous injection with a slow-release formulation consisting of poly(lactide-co-glycolide) (PLGA) microparticles loaded with an antileishmanial 3-nitro-2-hydroxy-4,6-dimethoxychalcone (CH8) was demonstrated in mice model. In the search for more easily synthesized active chalcone derivatives, and improved microparticle loading, CH8 analogues were synthesized and tested for antileishmanial activity in vitro and in vivo. The 3-nitro-2′,4′,6′-trimethoxychalcone (NAT22) analogue was chosen for its higher selectivity against intracellular amastigotes (selectivity index = 1489, as compared with 317 for CH8) and more efficient synthesis (89% yield, as compared with 18% for CH8). NAT22 was loaded into PLGA / polyvinylpyrrolidone (PVP) polymeric blend microspheres (NAT22-PLGAk) with average diameter of 1.9 μm. Although NAT22-PLGAk showed similar activity to free NAT22 in killing intracellular parasites in vitro (IC50 ~ 0.2 μm), in vivo studies in Leishmania amazonensis – infected mice demonstrated the significant superior efficacy of NAT22-PLGAk to reduce the parasite load. A single intralesional injection with NAT22-PLGAk was more effective than eight injections with free NAT22. Together, these results show that NAT22-PLGAk is a promising alternative for single-dose localized treatment of CL.
Leishmaniasis is a vector-borne neglected tropical disease caused by protozoan parasites of the genus Leishmania for which there is a paucity of effective viable non-toxic drugs. There are 1·3 million new cases each year causing considerable socio-economic hardship, best measured in 2·4 million disability adjusted life years, with greatest impact on the poorest communities, which means that desperately needed new antileishmanial treatments have to be both affordable and accessible. Established medicines with cheaper and faster development times may hold the cure for this neglected tropical disease. This concept of using old drugs for new diseases may not be novel but, with the ambitious target of controlling or eradicating tropical diseases by 2020, this strategy is still an important one. In this review, we will explore the current state-of-the-art of drug repurposing strategies in the search for new treatments for leishmaniasis.
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