Faculdade de Medicina Veterinária e Zootecnia, Universidade Federal de Mato Grosso do Sul, Avenida Senador Filinto Müller 2443, Ipiranga, MS, 79074-460, Campo Grande, Brazil.
Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grosso do Sul, Cidade Universitária, MS, 79070-900, Campo Grande, Brazil.
Parasitol Res. 2023 Mar;122(3):867-876. doi: 10.1007/s00436-023-07790-x. Epub 2023 Feb 11.
A possible synergistic effect of macrocyclic lactones' (MLs) combination has been previously described against resistant gastrointestinal nematodes of cattle. In addition to synergism, drug-drug interactions between MLs can also result in additive or antagonistic effect, considering the different MLs pharmacokinetics, pharmacodynamics, and interactions with molecular mechanisms of resistance. Therefore, the aim of the current work was evaluated the effect of different MLs combinations against Haemonchus contortus. Infecting larvae of two isolates (one susceptible and one resistant to ivermectin) were used in the larval migration inhibition test. After estimating the half maximal effective concentration of abamectin (ABA), eprinomectin, (EPR), ivermectin (IVM), and moxidectin (MOX) for both isolates, combinations were delineated by a simplex-centroid mixture experiment, and the mixture regression analysis was applied to the special cubic model. A synergistic effect was found for the EPR + MOX against the susceptible isolate as well as the EPR + MOX, IVM + MOX, and ABA + EPR + IVM against the resistant isolate. An antagonistic effect of ABA + IVM + MOX was found against the susceptible isolate. For the susceptible isolate, a higher inhibition was found with greater proportions of EPR and lower proportions of the other drugs compared to the reference mixture. For the resistant isolate, inhibition greater than that of the reference mixture was found with higher proportions of IVM as well as lower proportions of the other drugs. The synergistic and antagonistic effects were dependent on the following: (a) parasite drug resistance profile, (b) the composition of the combination, and (c) the proportions used, with EPR and IVM exerting a greater impact on these effects.
大环内酯类药物（MLs）联合使用可能具有协同作用，此前已被描述可用于治疗牛的耐药胃肠道线虫。除了协同作用之外，MLs 之间的药物相互作用也可能导致相加或拮抗作用，这取决于不同 MLs 的药代动力学、药效学以及与耐药分子机制的相互作用。因此，本研究旨在评估不同 MLs 组合对捻转血矛线虫的作用。使用两种分离株（一种对伊维菌素敏感，一种对伊维菌素耐药）的感染幼虫进行幼虫迁移抑制试验。在估计阿维菌素（ABA）、依普菌素（EPR）、伊维菌素（IVM）和莫昔克丁（MOX）对两种分离株的半数有效浓度后，通过单纯形质心混合物实验设计组合，并应用混合物回归分析特殊三次模型。发现 EPR+MOX 对敏感分离株以及 EPR+MOX、IVM+MOX 和 ABA+EPR+IVM 对耐药分离株具有协同作用。发现 ABA+IVM+MOX 对敏感分离株具有拮抗作用。对于敏感分离株，与参考混合物相比，EPR 的比例较高而其他药物的比例较低时，抑制作用更高。对于耐药分离株，发现 IVM 的比例较高且其他药物的比例较低时，抑制作用大于参考混合物。协同和拮抗作用取决于以下因素：（a）寄生虫耐药谱，（b）组合成分，以及（c）使用比例，其中 EPR 和 IVM 对这些作用的影响更大。
