Efecto de la combinación de Anfotericina-B y fármacos tricíclicos frente a promastigotes de Leishmania braziliensis
The treatment of cutaneous leishmaniasis caused by Leishmania amazonensis and Leishmania braziliensis remains challenging due to drug toxicity, cost, and the emergence of resistant strains. Amphotericin B (AmB), in its various formulations, represents a relevant therapeutic alternative, but its...
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Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología
2025
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| Acceso en línea: | https://revistas.unc.edu.ar/index.php/med/article/view/50594 |
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I10-R327-article-50594 |
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ojs |
| institution |
Universidad Nacional de Córdoba |
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I-10 |
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R-327 |
| container_title_str |
Revista de la Facultad de Ciencias Médicas de Córdoba |
| language |
Español |
| format |
Artículo revista |
| topic |
combination therapy leishmania braziliensis antagonism terapia combinada leishmania braziliensis antagonismo |
| spellingShingle |
combination therapy leishmania braziliensis antagonism terapia combinada leishmania braziliensis antagonismo Barrionuevo, CN Dimmer, JA Campagno , LP Tempesti, TC Rivarola, HW Efecto de la combinación de Anfotericina-B y fármacos tricíclicos frente a promastigotes de Leishmania braziliensis |
| topic_facet |
combination therapy leishmania braziliensis antagonism terapia combinada leishmania braziliensis antagonismo |
| author |
Barrionuevo, CN Dimmer, JA Campagno , LP Tempesti, TC Rivarola, HW |
| author_facet |
Barrionuevo, CN Dimmer, JA Campagno , LP Tempesti, TC Rivarola, HW |
| author_sort |
Barrionuevo, CN |
| title |
Efecto de la combinación de Anfotericina-B y fármacos tricíclicos frente a promastigotes de Leishmania braziliensis |
| title_short |
Efecto de la combinación de Anfotericina-B y fármacos tricíclicos frente a promastigotes de Leishmania braziliensis |
| title_full |
Efecto de la combinación de Anfotericina-B y fármacos tricíclicos frente a promastigotes de Leishmania braziliensis |
| title_fullStr |
Efecto de la combinación de Anfotericina-B y fármacos tricíclicos frente a promastigotes de Leishmania braziliensis |
| title_full_unstemmed |
Efecto de la combinación de Anfotericina-B y fármacos tricíclicos frente a promastigotes de Leishmania braziliensis |
| title_sort |
efecto de la combinación de anfotericina-b y fármacos tricíclicos frente a promastigotes de leishmania braziliensis |
| description |
The treatment of cutaneous leishmaniasis caused by Leishmania amazonensis and Leishmania braziliensis remains challenging due to drug toxicity, cost, and the emergence of resistant strains. Amphotericin B (AmB), in its various formulations, represents a relevant therapeutic alternative, but its efficacy and tolerability vary by species and clinical context. In this regard, the combination of drugs with different mechanisms of action has emerged as a promising strategy. AmB exerts its effect by binding to ergosterol in the parasite membrane, while clomipramine (Clo) and thioridazine (Thio), clinically used psychotropic drugs, have been shown to inhibit, at subtherapeutic concentrations, trypanothione reductase—a peroxide-reducing enzyme specific to the parasite. The aim of this study was to evaluate the in vitro effect of combined AmB-Clo and AmB-Thio therapy on L. braziliensis promastigotes.
Promastigotes (3 × 10⁶/mL) were incubated with individual and combined drug concentrations (AmB = 0.02–0.62 μg/mL; Clo/Thio = 0.8–15 μg/mL). After 72 hours, parasite counts were performed, and the 50% inhibitory concentration (IC₅₀) and the Combination Index (CI; CI > 1 = antagonistic, CI = 1 = additive, CI < 1 = synergistic) were determined. An isobologram was then constructed using the IC₅₀ values of each drug and their combinations.
In the AmB-Clo assay, the IC₅₀ values for individual drugs were: AmB = 0.09 μg/mL and Clo = 8.96 μg/mL. Combinations with Clo yielded CI values of 2.4, 1.87, 1.43, 1.32, and 1.22, all above the additivity line in the isobologram, indicating antagonism. Similar results were observed in the AmB-Thio assays, where the IC₅₀ values for individual drugs were: AmB = 0.38 μg/mL and Thio = 7.8 μg/mL, while CI values were 2.34, 1.5, 1.31, 1.61, and 1.87—all antagonistic.
These results indicate that the susceptibility of L. braziliensis to AmB was not enhanced by combination with the tricyclic drugs, showing an opposite effect to that previously observed in studies involving L. amazonensis. These differences may be attributed to the biological, clinical, and immunological particularities of each species, which significantly influence their susceptibility to different therapeutic agents.
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| publisher |
Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología |
| publishDate |
2025 |
| url |
https://revistas.unc.edu.ar/index.php/med/article/view/50594 |
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I10-R327-article-505942025-11-13T12:04:31Z Efecto de la combinación de Anfotericina-B y fármacos tricíclicos frente a promastigotes de Leishmania braziliensis Effect of the Combination of Amphotericin B and Tricyclic Drugs on Promastigotes of Leishmania braziliensis Barrionuevo, CN Dimmer, JA Campagno , LP Tempesti, TC Rivarola, HW combination therapy leishmania braziliensis antagonism terapia combinada leishmania braziliensis antagonismo The treatment of cutaneous leishmaniasis caused by Leishmania amazonensis and Leishmania braziliensis remains challenging due to drug toxicity, cost, and the emergence of resistant strains. Amphotericin B (AmB), in its various formulations, represents a relevant therapeutic alternative, but its efficacy and tolerability vary by species and clinical context. In this regard, the combination of drugs with different mechanisms of action has emerged as a promising strategy. AmB exerts its effect by binding to ergosterol in the parasite membrane, while clomipramine (Clo) and thioridazine (Thio), clinically used psychotropic drugs, have been shown to inhibit, at subtherapeutic concentrations, trypanothione reductase—a peroxide-reducing enzyme specific to the parasite. The aim of this study was to evaluate the in vitro effect of combined AmB-Clo and AmB-Thio therapy on L. braziliensis promastigotes. Promastigotes (3 × 10⁶/mL) were incubated with individual and combined drug concentrations (AmB = 0.02–0.62 μg/mL; Clo/Thio = 0.8–15 μg/mL). After 72 hours, parasite counts were performed, and the 50% inhibitory concentration (IC₅₀) and the Combination Index (CI; CI > 1 = antagonistic, CI = 1 = additive, CI < 1 = synergistic) were determined. An isobologram was then constructed using the IC₅₀ values of each drug and their combinations. In the AmB-Clo assay, the IC₅₀ values for individual drugs were: AmB = 0.09 μg/mL and Clo = 8.96 μg/mL. Combinations with Clo yielded CI values of 2.4, 1.87, 1.43, 1.32, and 1.22, all above the additivity line in the isobologram, indicating antagonism. Similar results were observed in the AmB-Thio assays, where the IC₅₀ values for individual drugs were: AmB = 0.38 μg/mL and Thio = 7.8 μg/mL, while CI values were 2.34, 1.5, 1.31, 1.61, and 1.87—all antagonistic. These results indicate that the susceptibility of L. braziliensis to AmB was not enhanced by combination with the tricyclic drugs, showing an opposite effect to that previously observed in studies involving L. amazonensis. These differences may be attributed to the biological, clinical, and immunological particularities of each species, which significantly influence their susceptibility to different therapeutic agents. El tratamiento de la leishmaniasis cutánea causada por Leishmania amazonensis y Leishmania braziliensis continúa siendo un desafío debido a la toxicidad, el costo y la aparición de cepas resistentes a los fármacos convencionales. La anfotericina B (Anf), en sus distintas formulaciones, representa una alternativa terapéutica de relevancia, pero su eficacia y tolerancia varían según la especie y el contexto clínico. En este marco, la combinación de fármacos con distintos mecanismos de acción emerge como una estrategia prometedora. Anf actúa mediante su unión al ergosterol de la membrana del parásito; mientras que clomipramina (Clo) y tioridazina (Tio), psicofármacos de uso clínico, han demostrado inhibir a concentraciones subterapéuticas la tripanotiona reductasa, enzima reductora de peróxidos y específica del parásito. El objetivo de este trabajo fue analizar la terapia combinada “in vitro” de Anf-Clo y Anf-Tio sobre promastigotes de L. braziliensis. Se incubaron 3x106 promastigotes/ml con concentraciones de los fármacos solos y combinados (Anf=0,02-0,62 μg/ml y Clo /Tio=0,8-15 μg/ml). Luego de 72 h, se realizó el recuento de parásitos y se determinó la concentración inhibitoria del 50% (CI50) y el Índice de Combinación (IC: IC>1 antagónico; IC=1 aditivo; IC<1 sinérgico). Por último, se realizó el isobolograma correspondiente a los valores de CI50 de cada uno de los fármacos y sus combinaciones. Los valores de CI50 en fármacos solos en el ensayo Anf-Clo fueron: Anf=0,09 μg/mL y Clo=8,96 μg/ml. Las combinaciones con Clo mostraron los siguientes IC= 2,4; 1,87; 1,43; 1,32 y 1,22, ubicándose todas por encima de la línea de aditividad en el isobolograma, indicando un efecto antagonista. Lo mismo fue observado en los ensayos Anf-Tio donde los CI50 en fármacos solos fueron: Anf=0,38 μg/ml y Tio=7,8 μg/ml, mientras que los IC= 2,34; 1,5; 1,31; 1,61 y 1,87, todos antagonistas. Estos resultados indican que la susceptibilidad de L. braziliensis frente a Anf no se vio incrementada mediante la combinación con los fármacos tricíclicos, evidenciando un efecto opuesto al observado, en trabajos previos, con L. amazonensis. Estas diferencias podrían atribuirse a las particularidades biológicas, clínicas e inmunológicas entre ambas especies, que influyen significativamente en su susceptibilidad frente a distintos agentes terapéuticos. Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología 2025-11-12 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion application/pdf https://revistas.unc.edu.ar/index.php/med/article/view/50594 Revista de la Facultad de Ciencias Médicas de Córdoba.; Vol. 82 (2025): Suplemento JIC XXVI Revista de la Facultad de Ciencias Médicas de Córdoba; Vol. 82 (2025): Suplemento JIC XXVI Revista da Faculdade de Ciências Médicas de Córdoba; v. 82 (2025): Suplemento JIC XXVI 1853-0605 0014-6722 spa https://revistas.unc.edu.ar/index.php/med/article/view/50594/50697 Derechos de autor 2025 Universidad Nacional de Córdoba https://creativecommons.org/licenses/by-nc/4.0 |