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Miltefosine-Lopinavir Combination Therapy Against Leishmania infantum Infection: In vitro and in vivo Approaches

Concurrently, leishmaniasis and AIDS are global public health issues and the overlap between these diseases adds additional treats to the management of co-infected patients. Lopinavir (LPV) has a well characterized anti-HIV and leishmanicidal action, and to analyze its combined action with miltefosi...

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Autores principales: Rebello, Karina M., Andrade-Neto, Valter V., Gomes, Claudia Regina B., de Souza, Marcos Vinícius N., Branquinha, Marta H., Santos, André L. S., Torres-Santos, Eduardo Caio, d'Avila-Levy, Claudia M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611157/
https://www.ncbi.nlm.nih.gov/pubmed/31316919
http://dx.doi.org/10.3389/fcimb.2019.00229
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author Rebello, Karina M.
Andrade-Neto, Valter V.
Gomes, Claudia Regina B.
de Souza, Marcos Vinícius N.
Branquinha, Marta H.
Santos, André L. S.
Torres-Santos, Eduardo Caio
d'Avila-Levy, Claudia M.
author_facet Rebello, Karina M.
Andrade-Neto, Valter V.
Gomes, Claudia Regina B.
de Souza, Marcos Vinícius N.
Branquinha, Marta H.
Santos, André L. S.
Torres-Santos, Eduardo Caio
d'Avila-Levy, Claudia M.
author_sort Rebello, Karina M.
collection PubMed
description Concurrently, leishmaniasis and AIDS are global public health issues and the overlap between these diseases adds additional treats to the management of co-infected patients. Lopinavir (LPV) has a well characterized anti-HIV and leishmanicidal action, and to analyze its combined action with miltefosine (MFS) could help to envisage strategies to the management of co-infected patients. Here, we evaluate the interaction between LPV and MFS against Leishmania infantum infection by in vitro and in vivo approaches. The effect of the compounds alone or in association was assessed for 72 h in mouse peritoneal macrophages infected with L. infantum by the determination of the IC(50)s and FICIs. Subsequently, mice were orally treated twice daily during 5 days with the compounds alone or in association and evaluated after 30 days. The in vitro assays revealed an IC(50) of 0.24 μM and 9.89 μM of MFS and LPV, respectively, and an additive effect of the compounds (FICI 1.28). The in vivo assays revealed that LPV alone reduced the parasite load in the spleen and liver by 52 and 40%, respectively. The combined treatment of infected BALB/c mice revealed that the compounds alone required at least two times higher doses than when administered in association to virtually eliminate the parasite. Mice plasma biochemical parameters assessed revealed that the combined therapy did not present any relevant hepatotoxicity. In conclusion, the association of MFS with LPV allowed a reduction in each compound concentration to achieve the same outcome in the treatment of visceral leishmaniasis. Although a pronounced synergistic effect was not evidenced, it does not discard that such combination could be useful in humans co-infected with HIV and Leishmania parasites.
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spelling pubmed-66111572019-07-17 Miltefosine-Lopinavir Combination Therapy Against Leishmania infantum Infection: In vitro and in vivo Approaches Rebello, Karina M. Andrade-Neto, Valter V. Gomes, Claudia Regina B. de Souza, Marcos Vinícius N. Branquinha, Marta H. Santos, André L. S. Torres-Santos, Eduardo Caio d'Avila-Levy, Claudia M. Front Cell Infect Microbiol Cellular and Infection Microbiology Concurrently, leishmaniasis and AIDS are global public health issues and the overlap between these diseases adds additional treats to the management of co-infected patients. Lopinavir (LPV) has a well characterized anti-HIV and leishmanicidal action, and to analyze its combined action with miltefosine (MFS) could help to envisage strategies to the management of co-infected patients. Here, we evaluate the interaction between LPV and MFS against Leishmania infantum infection by in vitro and in vivo approaches. The effect of the compounds alone or in association was assessed for 72 h in mouse peritoneal macrophages infected with L. infantum by the determination of the IC(50)s and FICIs. Subsequently, mice were orally treated twice daily during 5 days with the compounds alone or in association and evaluated after 30 days. The in vitro assays revealed an IC(50) of 0.24 μM and 9.89 μM of MFS and LPV, respectively, and an additive effect of the compounds (FICI 1.28). The in vivo assays revealed that LPV alone reduced the parasite load in the spleen and liver by 52 and 40%, respectively. The combined treatment of infected BALB/c mice revealed that the compounds alone required at least two times higher doses than when administered in association to virtually eliminate the parasite. Mice plasma biochemical parameters assessed revealed that the combined therapy did not present any relevant hepatotoxicity. In conclusion, the association of MFS with LPV allowed a reduction in each compound concentration to achieve the same outcome in the treatment of visceral leishmaniasis. Although a pronounced synergistic effect was not evidenced, it does not discard that such combination could be useful in humans co-infected with HIV and Leishmania parasites. Frontiers Media S.A. 2019-06-28 /pmc/articles/PMC6611157/ /pubmed/31316919 http://dx.doi.org/10.3389/fcimb.2019.00229 Text en Copyright © 2019 Rebello, Andrade-Neto, Gomes, de Souza, Branquinha, Santos, Torres-Santos and d'Avila-Levy. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular and Infection Microbiology
Rebello, Karina M.
Andrade-Neto, Valter V.
Gomes, Claudia Regina B.
de Souza, Marcos Vinícius N.
Branquinha, Marta H.
Santos, André L. S.
Torres-Santos, Eduardo Caio
d'Avila-Levy, Claudia M.
Miltefosine-Lopinavir Combination Therapy Against Leishmania infantum Infection: In vitro and in vivo Approaches
title Miltefosine-Lopinavir Combination Therapy Against Leishmania infantum Infection: In vitro and in vivo Approaches
title_full Miltefosine-Lopinavir Combination Therapy Against Leishmania infantum Infection: In vitro and in vivo Approaches
title_fullStr Miltefosine-Lopinavir Combination Therapy Against Leishmania infantum Infection: In vitro and in vivo Approaches
title_full_unstemmed Miltefosine-Lopinavir Combination Therapy Against Leishmania infantum Infection: In vitro and in vivo Approaches
title_short Miltefosine-Lopinavir Combination Therapy Against Leishmania infantum Infection: In vitro and in vivo Approaches
title_sort miltefosine-lopinavir combination therapy against leishmania infantum infection: in vitro and in vivo approaches
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611157/
https://www.ncbi.nlm.nih.gov/pubmed/31316919
http://dx.doi.org/10.3389/fcimb.2019.00229
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