Suárez Gonzalo, Alcántara Ignacio, Salinas Gustavo
Unidad de Farmacología y Terapéutica, Departamento Hospital y Clínicas Veterinarias, Facultad de Veterinaria, Universidad de la República, Montevideo, Uruguay.
Unidad de Bioestadística, Departamento de Salud Pública Veterinaria, Facultad de Veterinaria, Universidad de la República, Montevideo, Uruguay.
Front Pharmacol. 2022 Oct 19;13:984905. doi: 10.3389/fphar.2022.984905. eCollection 2022.
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 to address pharmacodynamics studies, particularly for drug-drug interactions. Models can be integrated to facilitate preclinical and clinical translational studies and help researchers to understand drug-drug interactions and achieve rational therapeutic regimes.
是一种已被验证可用于驱虫药物筛选的自由生活线虫。然而，该模型尚未用于通过矩阵阵列方法解决驱虫剂量 - 反应时间和药物 - 药物相互作用问题。埃普利诺菌素（EPM）和伊维菌素（IVM）是广泛用作驱虫剂的大环内酯类药物。尽管非常相似，但EPM和IVM在商业配方中组合使用，或者在农民的假设下混合使用，即这种组合会提高它们的疗效。然而，没有关于这两种药物组合的药理学评估数据报道。在本研究中，我们评估了这两种驱虫药物的药效学和药物 - 药物相互作用。由于这些药物的作用会导致蠕虫麻痹，我们使用红外运动测定法来测量EPM和IVM随时间对蠕虫运动的影响。结果表明，EPM的效力略高于IVM，药物效力随药物暴露时间增加，并且一旦麻痹，蠕虫就不会恢复。使用不同的EPM/IVM浓度比，并在不同暴露时间确定协同作用和组合敏感性评分，应用最高单药（HSA）、洛氏加和性、布利斯和零相互作用效力（ZIP）模型。结果清楚地表明，这两种大环内酯类药物之间既没有协同作用也没有拮抗作用。这项研究表明，优先考虑每种药物的暴露时间比将它们组合以提高效果更重要。结果突出了用于解决药效学研究，特别是药物 - 药物相互作用的实用性。模型可以整合以促进临床前和临床转化研究，并帮助研究人员理解药物 - 药物相互作用并实现合理的治疗方案。
