Lespine Anne, Ménez Cécile, Bourguinat Catherine, Prichard Roger K
INRA UMR1331, Université de Toulouse, INP, TOXALIM, F-31027 Toulouse, France.
Institute of Parasitology, McGill University, Montreal, Canada.
Int J Parasitol Drugs Drug Resist. 2011 Nov 7;2:58-75. doi: 10.1016/j.ijpddr.2011.10.001. eCollection 2012 Dec.
Parasitic helminths cause significant disease in animals and humans. In the absence of alternative treatments, anthelmintics remain the principal agents for their control. Resistance extends to the most important class of anthelmintics, the macrocyclic lactone endectocides (MLs), such as ivermectin, and presents serious problems for the livestock industries and threatens to severely limit current parasite control strategies in humans. Understanding drug resistance is important for optimizing and monitoring control, and reducing further selection for resistance. Multidrug resistance (MDR) ABC transporters have been implicated in ML resistance and contribute to resistance to a number of other anthelmintics. MDR transporters, such as P-glycoproteins, are essential for many cellular processes that require the transport of substrates across cell membranes. Being overexpressed in response to chemotherapy in tumour cells and to ML-based treatment in nematodes, they lead to therapy failure by decreasing drug concentration at the target. Several anthelmintics are inhibitors of these efflux pumps and appropriate combinations can result in higher treatment efficacy against parasites and reversal of resistance. However, this needs to be balanced against possible increased toxicity to the host, or the components of the combination selecting on the same genes involved in the resistance. Increased efficacy could result from modifying anthelmintic pharmacokinetics in the host or by blocking parasite transporters involved in resistance. Combination of anthelmintics can be beneficial for delaying selection for resistance. However, it should be based on knowledge of resistance mechanisms and not simply on mode of action classes, and is best started before resistance has been selected to any member of the combination. Increasing knowledge of the MDR transporters involved in anthelmintic resistance in helminths will play an important role in allowing for the identification of markers to monitor the spread of resistance and to evaluate new tools and management practices aimed at delaying its spread.
寄生性蠕虫在动物和人类中引发严重疾病。在缺乏替代治疗方法的情况下，驱虫药仍然是控制这些疾病的主要药物。耐药性已扩展到最重要的一类驱虫药，即大环内酯类体内外寄生虫杀虫剂（MLs），如伊维菌素，这给畜牧业带来了严重问题，并有可能严重限制目前人类寄生虫控制策略。了解耐药性对于优化和监测控制措施以及减少耐药性的进一步选择非常重要。多药耐药（MDR）ABC转运蛋白与ML耐药性有关，并导致对许多其他驱虫药产生耐药性。MDR转运蛋白，如P-糖蛋白，对于许多需要将底物跨细胞膜运输的细胞过程至关重要。它们在肿瘤细胞的化疗和线虫基于ML的治疗中会过度表达，通过降低靶点处的药物浓度导致治疗失败。几种驱虫药是这些外排泵的抑制剂，适当的组合可提高对寄生虫的治疗效果并逆转耐药性。然而，这需要与对宿主可能增加的毒性或组合成分对参与耐药性的相同基因的选择相平衡。提高疗效可通过改变宿主中驱虫药的药代动力学或通过阻断参与耐药性的寄生虫转运蛋白来实现。驱虫药的联合使用可能有助于延缓耐药性的选择。然而，这应基于对耐药机制的了解，而不仅仅基于作用方式类别，并且最好在对联合用药中的任何一种药物产生耐药性之前开始。对参与蠕虫驱虫药耐药性的MDR转运蛋白的了解不断增加，将在识别监测耐药性传播的标志物以及评估旨在延缓其传播的新工具和管理实践方面发挥重要作用。
