Abstract
Translational studies involving the reuse and association of drugs are approaches that can result in higher success rates in the discovery and development of drugs for serious public health problems, including leishmaniasis. If we consider the number of pathogenic species in relation to therapeutic options, this arsenal is still small, and each drug possesses a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. In the search for new drugs, we performed a drug screening of L. amazonensis promastigotes and intracellular amastigotes of fifty available drugs belonging to several classes according to their pharmacophoric group. Spironolactone, a potassium-sparing diuretic, proved to be the most promising drug candidate. After demonstrating the in vitro antileishmanial activity, we evaluated the efficacy on a murine experimental model with L. amazonensis and L. infantum. The treatment controlled the cutaneous lesion and reduced the parasite burden of L. amazonensis significantly, as effectively as meglumine antimoniate. The treatment of experimental visceral leishmaniasis was effective in reducing the parasite load on the main affected organs (spleen and liver) via high doses of spironolactone. The association between spironolactone and meglumine antimoniate promoted better control of the parasite load in the spleen and liver compared to the group treated with meglumine antimoniate alone. These results reveal a possible benefit of the concomitant use of spironolactone and meglumine antimoniate that should be studied more in depth for the future possibility of repositioning for leishmaniasis co-therapy.
Highlights
In 2018, among the 200 countries or territories that sent reports to the World Health Organization, 88 were considered endemic for cutaneous leishmaniasis (CL) and 78 were considered endemic for visceral leishmaniasis (VL) (WHO Control of Neglected Tropical Diseases, 2020)
The direct antileishmanial activity of spironolactone was first evaluated by incubating L. amazonensis or L. infantum promastigotes with the drug for 72 h
Spironolactone was found to be active against intracellular amastigotes, with an IC50 of 1.8 μM for L. amazonensis and 18.0 μM for L. infantum (Table 1)
Summary
In 2018, among the 200 countries or territories that sent reports to the World Health Organization, 88 were considered endemic for cutaneous leishmaniasis (CL) and 78 were considered endemic for visceral leishmaniasis (VL) (WHO Control of Neglected Tropical Diseases, 2020). It is considered the third most common parasitic disease, after schistosomiasis and malaria, based on morbidity and disability-adjusted life years (DALYs) (GBD 2015 DALYs and HALE Collaborators, 2016). Leishmaniasis is treated with a small arsenal of drugs, including pentavalent antimonials, amphotericin B deoxycholate, lipid formulations of amphotericin B, miltefosine, and paromomycin, all of which have disadvantages in terms of toxicity, efficacy, price, or treatment regimen (Agil, 2015). One recent example of the successful use of this approach is the demonstration of fexinidazole’s leishmanicidal activity in vitro and in vivo against Leishmania infantum, L. amazonensis, and L. braziliensis (Wyllie et al, 2012; de Morais-Teixeira et al, 2019)
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