Buxton Samuel K, Robertson Alan P, Martin Richard J
Department of Biomedical Sciences, Iowa State University, Ames, Iowa, United States of America.
PLoS Negl Trop Dis. 2014 Nov 20;8(11):e3276. doi: 10.1371/journal.pntd.0003276. eCollection 2014.
Diethylcarbamazine is a drug that is used for the treatment of filariasis in humans and animals; it also has effects on intestinal nematodes, but its mechanism of action remains unclear. Emodepside is a resistance-busting anthelmintic approved for treating intestinal parasitic nematodes in animals. The novel mode of action and resistance-breaking properties of emodepside has led to its use against intestinal nematodes of animals, and as a candidate drug for treating filarial parasites. We have previously demonstrated effects of emodepside on SLO-1 K+-like currents in Ascaris suum. Here, we demonstrate that diethylcarbamazine, which has been proposed to work through host mediated effects, has direct effects on a nematode parasite, Ascaris suum. It increases activation of SLO-1 K+ currents and potentiates effects of emodepside. Our results suggest consideration of the combination of emodepside and diethylcarbamazine for therapy, which is predicted to be synergistic. The mode of action of diethylcarbamazine may involve effects on parasite signaling pathways (including nitric oxide) as well as effects mediated by host inflammatory mediators.
乙胺嗪是一种用于治疗人类和动物丝虫病的药物；它对肠道线虫也有作用，但其作用机制尚不清楚。埃莫昔啶是一种已获批准用于治疗动物肠道寄生线虫的抗耐药驱虫药。埃莫昔啶的新型作用模式和抗耐药特性使其被用于对抗动物的肠道线虫，并作为治疗丝虫寄生虫的候选药物。我们之前已经证明了埃莫昔啶对猪蛔虫SLO-1钾离子样电流的作用。在此，我们证明了曾被认为通过宿主介导作用发挥功效的乙胺嗪对一种线虫寄生虫——猪蛔虫有直接作用。它增加了SLO-1钾离子电流的激活，并增强了埃莫昔啶的作用效果。我们的结果表明，考虑将埃莫昔啶和乙胺嗪联合用于治疗，预计这将具有协同作用。乙胺嗪的作用模式可能涉及对寄生虫信号通路（包括一氧化氮）的影响以及由宿主炎症介质介导的影响。
