TY - JOUR
T1 - Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis
AU - Andrade-Neto, Valter Viana
AU - da Silva Pacheco, Juliana
AU - Inácio, Job Domingos
AU - Almeida-Amaral, Elmo Eduardo
AU - Torres-Santos, Eduardo Caio
AU - Cunha-Junior, Edezio Ferreira
N1 - This work was supported by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) through fellowships E-26/202.348/2017 awarded to VVAN and E-26/202.371/2019 awarded to EFCJ (pós-doutorado nota 10), grant E-26/202.918/2018 awarded to ECTS (Cientista do Nosso Estado), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) grant 438858/2018-2 awarded to EFCJ, and Fundação Oswaldo Cruz (FIOCRUZ). E.E.A-A. was the recipient of a research fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). J.D.F.I. was a recipient of a postdoctoral fellowship from Fundação Oswaldo Cruz (FIOCRUZ). All funders are governmental non-profit foundations that support research in Brazil.
PY - 2021/4/13
Y1 - 2021/4/13
N2 - 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.
AB - 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.
KW - spironolactone
KW - drug repositioning
KW - leishmania
KW - visceral leishmaniasis
KW - pentavalent antimonial
UR - http://www.scopus.com/inward/record.url?scp=85104937045&partnerID=8YFLogxK
U2 - 10.3389/fphar.2021.636265
DO - 10.3389/fphar.2021.636265
M3 - Article
C2 - 33927619
SN - 1663-9812
VL - 12
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 636265
ER -