In Vivo and In Vitro Sensitivity of Fasciola hepatica to Triclabendazole Combined with Artesunate, Artemether, or OZ78
In Vivo and In Vitro Sensitivity of Fasciola hepatica to Triclabendazole Combined with Artesunate, Artemether, or OZ78
复制标题
DOI：
10.1128/aac.00828-10
复制
发表时间：
2010-11-01
影响因子：
4.9
通讯作者：
Keiser, Jennifer
中科院分区：
文献类型：
--
作者：
Duthaler, Urs;Smith, Thomas A.;Keiser, Jennifer
三氯苯达唑耐药性不断记录从牲畜，因此肝片吸虫感染的新的治疗策略是必要的。我们研究了三氯苯达唑联合青蒿琥酯、蒿甲醚或OZ 78与单药治疗对成年和幼年F。大鼠肝脏三氯苯达唑及其亚砜和砜代谢物的体外实验，每一个与过氧化物的组合，补充了我们的研究。F.感染肝吸虫的大鼠在感染后3至4周（幼年吸虫）和>8周（成年吸虫）接受单一药物或药物组合。采用虫卵计数的负二项回归分析剂量-反应关系以及药物组合的作用是协同还是拮抗。通过基于吸虫运动性的活力量表评价体外测定。青蒿琥酯、蒿甲醚、OZ 78和三氯苯达唑单药治疗的50%有效剂量值分别为113.0、77.7、22.9和2.7 mg/kg体重。肝。三氯苯达唑（2.5mg/kg）与青蒿琥酯或蒿甲醚合用对成虫负荷有协同作用（P < 0.05）。当较低剂量的三氯苯达唑（1.25 mg/kg）与青蒿素联合使用时，观察到对成虫负担和产卵量的拮抗作用。OZ 78和三氯苯达唑组合以及三氯苯达唑效应和其他伴侣药物对蠕虫的效应之间未观察到显著的相互作用（P = 0.07）。我们在体外研究的成年蠕虫同意在体内的结果，而在体外分析的幼虫揭示了更大的相互作用比在体内观察到的。总之，单剂三氯苯达唑表现出比实验药物青蒿琥酯、蒿甲醚和OZ 78更有效的体内和体外杀筋膜活性。当联合使用时，观察到协同作用和拮抗作用，这取决于给药剂量，应在未来的研究中更详细地阐明。
Triclabendazole resistance is continually documented from livestock, and hence new treatment strategies for Fasciola hepatica infections are needed. We investigated the effect of triclabendazole combined with artesunate, artemether, or OZ78 compared to that of monotherapy against adult and juvenile F. hepatica in rats. In vitro experiments with triclabendazole and its sulfoxide and sulfone metabolites, each in combination with the peroxides, complemented our study. F. hepatica-infected rats were subjected to single drugs or drug combinations 3 to 4 weeks (juvenile flukes) and >8 weeks (adult flukes) postinfection. Negative binomial regressions of worm and egg counts were used to analyze dose-response relationships and whether the effects of drug combinations were synergistic or antagonistic. The in vitro assays were evaluated by means of viability scales based on fluke motility. Fifty percent effective dose values of 113.0, 77.7, 22.9, and 2.7 mg/kg of body weight were calculated for monotherapy with artesunate, artemether, OZ78, and triclabendazole, respectively, against adult F. hepatica. Likelihood ratio tests revealed synergistic interactions (P < 0.05) of combinations of triclabendazole (2.5 mg/kg) plus artesunate or artemether on adult worm burden. Antagonistic effects on the adult burden and egg output were observed when a lower triclabendazole dose (1.25 mg/kg) was combined with the artemisinins. No significant interactions (P = 0.07) were observed for OZ78 and triclabendazole combinations and between the triclabendazole effect and the effects of the other partner drugs on juvenile worms. Our in vitro studies of adult worms agreed with the in vivo results, while the in vitro analysis of juvenile worms revealed greater interactions than observed in vivo. In conclusion, single-agent triclabendazole demonstrated a more potent in vivo and in vitro fasciocidal activity than the experimental drugs artesunate, artemether, and OZ78. When combined, synergistic but also antagonistic effects depending on the doses administered were observed, which should be elucidated in more detail in future studies.