Caenorhabditis elegans as a valuable model for the study of anthelmintic pharmacodynamics and drug-drug interactions: The case of ivermectin and eprinomectin
Caenorhabditis elegans is a free-living nematode that has been validated for anthelmintic drug screening. However, this model has not been used to address anthelmintic dose-response-time and drug-drug interactions through matrix array methodology. Eprinomectin (EPM) and Ivermectin (IVM) are macrocyc...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.984905/full |
| _version_ | 1811237695314198528 |
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| author | Gonzalo Suárez Ignacio Alcántara Gustavo Salinas Gustavo Salinas |
| author_facet | Gonzalo Suárez Ignacio Alcántara Gustavo Salinas Gustavo Salinas |
| author_sort | Gonzalo Suárez |
| collection | DOAJ |
| description | Caenorhabditis elegans is a free-living nematode that has been validated for anthelmintic drug screening. However, this model has not been used to address anthelmintic dose-response-time and drug-drug interactions through matrix array methodology. Eprinomectin (EPM) and Ivermectin (IVM) are macrocyclic lactones widely used as anthelmintics. Despite being very similar, EPM and IVM are combined in commercial formulations or mixed by farmers, under the assumption that the combination would increase their efficacy. However, there is no data reported on the pharmacological evaluation of the combination of both drugs. In this study, we assessed the pharmacodynamics and drug-drug interactions of these two anthelmintic drugs. Since the action of these drugs causes worm paralysis, we used an infrared motility assay to measure EPM and IVM effects on worm movement over time. The results showed that EPM was slightly more potent than IVM, that drug potency increased with drug time exposure, and that once paralyzed, worms did not recover. Different EPM/IVM concentration ratios were used and synergy and combination sensitivity scores were determined at different exposure times, applying Highest Single Agent (HSA), Loewe additivity, Bliss and Zero Interaction Potency (ZIP) models. The results clearly indicate that there is neither synergy nor antagonism between both macrocyclic lactones. This study shows that it is more relevant to prioritize the exposure time of each individual drug than to combine them to improve their effects. The results highlight the utility of C. elegans to address pharmacodynamics studies, particularly for drug-drug interactions. Models in vitro can be integrated to facilitate preclinical and clinical translational studies and help researchers to understand drug-drug interactions and achieve rational therapeutic regimes. |
| first_indexed | 2024-04-12T12:27:49Z |
| format | Article |
| id | doaj.art-8cf702049b8742438f8664fbc36210d8 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T12:27:49Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-8cf702049b8742438f8664fbc36210d82022-12-22T03:33:06ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-10-011310.3389/fphar.2022.984905984905Caenorhabditis elegans as a valuable model for the study of anthelmintic pharmacodynamics and drug-drug interactions: The case of ivermectin and eprinomectinGonzalo Suárez0Ignacio Alcántara1Gustavo Salinas2Gustavo Salinas3Unidad de Farmacología y Terapéutica, Departamento Hospital y Clínicas Veterinarias, Facultad de Veterinaria, Universidad de la República, Montevideo, UruguayUnidad de Bioestadística, Departamento de Salud Pública Veterinaria, Facultad de Veterinaria, Universidad de la República, Montevideo, UruguayWorm Biology Laboratory, Institut Pasteur de Montevideo, Montevideo, UruguayDepartamento de Biociencias, Facultad de Química, Universidad de la República, Montevideo, UruguayCaenorhabditis elegans is a free-living nematode that has been validated for anthelmintic drug screening. However, this model has not been used to address anthelmintic dose-response-time and drug-drug interactions through matrix array methodology. Eprinomectin (EPM) and Ivermectin (IVM) are macrocyclic lactones widely used as anthelmintics. Despite being very similar, EPM and IVM are combined in commercial formulations or mixed by farmers, under the assumption that the combination would increase their efficacy. However, there is no data reported on the pharmacological evaluation of the combination of both drugs. In this study, we assessed the pharmacodynamics and drug-drug interactions of these two anthelmintic drugs. Since the action of these drugs causes worm paralysis, we used an infrared motility assay to measure EPM and IVM effects on worm movement over time. The results showed that EPM was slightly more potent than IVM, that drug potency increased with drug time exposure, and that once paralyzed, worms did not recover. Different EPM/IVM concentration ratios were used and synergy and combination sensitivity scores were determined at different exposure times, applying Highest Single Agent (HSA), Loewe additivity, Bliss and Zero Interaction Potency (ZIP) models. The results clearly indicate that there is neither synergy nor antagonism between both macrocyclic lactones. This study shows that it is more relevant to prioritize the exposure time of each individual drug than to combine them to improve their effects. The results highlight the utility of C. elegans to address pharmacodynamics studies, particularly for drug-drug interactions. Models in vitro can be integrated to facilitate preclinical and clinical translational studies and help researchers to understand drug-drug interactions and achieve rational therapeutic regimes.https://www.frontiersin.org/articles/10.3389/fphar.2022.984905/fulldrug combinationantiparasitic resistanceEC50pharmacologysynergismnematode |
| spellingShingle | Gonzalo Suárez Ignacio Alcántara Gustavo Salinas Gustavo Salinas Caenorhabditis elegans as a valuable model for the study of anthelmintic pharmacodynamics and drug-drug interactions: The case of ivermectin and eprinomectin Frontiers in Pharmacology drug combination antiparasitic resistance EC50 pharmacology synergism nematode |
| title | Caenorhabditis elegans as a valuable model for the study of anthelmintic pharmacodynamics and drug-drug interactions: The case of ivermectin and eprinomectin |
| title_full | Caenorhabditis elegans as a valuable model for the study of anthelmintic pharmacodynamics and drug-drug interactions: The case of ivermectin and eprinomectin |
| title_fullStr | Caenorhabditis elegans as a valuable model for the study of anthelmintic pharmacodynamics and drug-drug interactions: The case of ivermectin and eprinomectin |
| title_full_unstemmed | Caenorhabditis elegans as a valuable model for the study of anthelmintic pharmacodynamics and drug-drug interactions: The case of ivermectin and eprinomectin |
| title_short | Caenorhabditis elegans as a valuable model for the study of anthelmintic pharmacodynamics and drug-drug interactions: The case of ivermectin and eprinomectin |
| title_sort | caenorhabditis elegans as a valuable model for the study of anthelmintic pharmacodynamics and drug drug interactions the case of ivermectin and eprinomectin |
| topic | drug combination antiparasitic resistance EC50 pharmacology synergism nematode |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.984905/full |
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