Laboratorio de Farmacología, Centro de Investigación Veterinaria de Tandil (CIVETAN), (CONICET-CICPBA-UNCPBA) Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario, 7000 Tandil, Argentina.
Laboratorio de Farmacología, Centro de Investigación Veterinaria de Tandil (CIVETAN), (CONICET-CICPBA-UNCPBA) Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario, 7000 Tandil, Argentina.
Vet Parasitol. 2020 Mar;279:109010. doi: 10.1016/j.vetpar.2019.109010. Epub 2019 Dec 10.
In a context of nematodicidal resistance, anthelmintic combinations have emerged as a reliable pharmacological strategy to control gastrointestinal nematodes in grazing systems of livestock production. The current work evaluated the potential drug-drug interactions following the coadministration of two macrocyclic lactones (ML) ivermectin (IVM) and abamectin (ABM) to parasitized cattle using a pharmacokinetic/pharmacodynamic (PK/PD) approach. The kinetic behavior of both compounds administered either separately or coadministered was assessed and the therapeutic response of the combination was evaluated under different resistance scenarios. In the pharmacological trial, calves received a single subcutaneous (s.c.) injection of IVM (100 μg/Kg); a single s.c. injection of ABM (100 μg/Kg) or IVM + ABM (50 μg/Kg each) administered in different injection sites to reach a final ML dose of 100 μg/Kg (Farm 1). Plasma samples were taken from those animals up to 20 days post-treatment. IVM and ABM plasma concentrations were quantified by HPLC. A parasitological trial was carried out in three farms with different status of nematodes resistance to IVM. Experimental animals received IVM (200 μg/Kg), ABM (200 μg/Kg) or IVM + ABM (100 μg/Kg each) in Farm 2, and IVM + ABM (200 μg/Kg each) in Farms 3 and 4. The anthelmintic efficacy was determined by fecal egg count reduction test (FECRT). PK analysis showed similar trends for IVM kinetic behavior after coadministration with ABM. Conversely, the ABM elimination half-life was prolonged and the systemic exposure during the elimination phase was increased in the presence of IVM. Although IVM alone failed to control Cooperia spp., the combination IVM + ABM was the only treatment that achieved an efficacy higher than 95% against resistant Cooperia spp. in all farms. In fact, when Cooperia spp. was the main genus within the nematode population and Haemonchus spp. was susceptible or slightly resistant to ML (Farms 2 and 4), the total FECR for the combination IVM + ABM was higher than 90%. Instead, when the predominant nematode genus was a highly resistant Haemonchus spp. (Farm 3), the total FECR after the combined treatment was as low as the single treatments. Therefore, the rational use of these pharmacological tools should be mainly based on the knowledge of the epidemiology and the nematode susceptibility status in each cattle farm.
在抗线虫药物的背景下，驱虫药联合使用已成为控制放牧系统中家畜胃肠道线虫的可靠药理学策略。本研究采用药代动力学/药效学（PK/PD）方法，评估了两种大环内酯类药物（ML）伊维菌素（IVM）和阿维菌素（ABM）联合给药时的潜在药物相互作用。评估了单独或联合给药时两种化合物的动力学行为，并在不同的耐药情况下评估了联合治疗的治疗反应。在药理试验中，小牛接受了单次皮下（sc）注射伊维菌素（100μg/kg）；单次 sc 注射阿维菌素（100μg/kg）或 IVM+ABM（各 50μg/kg），注射到不同的注射部位，以达到最终 ML 剂量为 100μg/kg（农场 1）。从这些动物身上采集到治疗后 20 天的血浆样本。通过 HPLC 定量检测 IVM 和 ABM 的血浆浓度。在三个具有不同伊维菌素耐药性线虫状况的农场进行了寄生虫学试验。实验动物在农场 2 接受伊维菌素（200μg/kg）、阿维菌素（200μg/kg）或 IVM+ABM（各 100μg/kg），在农场 3 和 4 接受 IVM+ABM（各 200μg/kg）。通过粪便卵计数减少试验（FECRT）确定驱虫效果。PK 分析表明，伊维菌素与阿维菌素联合使用后，伊维菌素的动力学行为呈现相似趋势。相反，阿维菌素的消除半衰期延长，在伊维菌素存在的情况下，消除阶段的系统暴露增加。尽管单独使用伊维菌素不能控制库珀线虫，但 IVM+ABM 联合治疗是唯一一种对所有农场中耐药库珀线虫的疗效高于 95%的治疗方法。事实上，当库珀线虫是线虫种群中的主要属，而 Haemonchus spp. 对 ML 敏感或轻度耐药（农场 2 和 4）时，伊维菌素+阿维菌素联合治疗的总 FECR 高于 90%。相反，当主要线虫属是高度耐药的 Haemonchus spp.（农场 3）时，联合治疗后的总 FECR 与单一治疗一样低。因此，这些药理学工具的合理使用应主要基于对每个牛场的流行病学和线虫易感性状况的了解。
