Keiser Jennifer, Utzinger Jürg, Tanner Marcel, Dong Yuxiang, Vennerstrom Jonathan L
Swiss Tropical Institute, CH-4002 Basel, Switzerland.
J Antimicrob Chemother. 2006 Dec;58(6):1193-7. doi: 10.1093/jac/dkl408. Epub 2006 Oct 5.
The trematocidal properties of a synthetic peroxide, 1,2,4-trioxolane (OZ78) were determined both in vivo and in vitro.
Two weeks post-infection Echinostoma caproni-infected mice were administered single oral doses of 400-1000 mg/kg OZ78. Fasciola hepatica-infected rats were treated orally with 50-400 mg/kg OZ78 3 and 8-9 weeks post-infection. Worm burden reductions were assessed against untreated control animals. Adult F. hepatica were observed by scanning electron microscopy (SEM) after recovery from the bile duct of a rat 3 days after administration of a single oral dose of 100 mg/kg OZ78 and after in vitro exposure to concentrations of 1, 10 and 100 microg/mL OZ78.
In the E. caproni-mouse model 100% worm burden reductions were achieved with a single oral dose of 1000 mg/kg OZ78. A single dose of 100 mg/kg OZ78 resulted in worm burden reductions of 100% against juvenile and adult F. hepatica. F. hepatica recovered from rats 3 days post-treatment displayed feeble activity and some flukes had died. Typical features revealed by SEM included extensive blebbing and sloughing. Exposure of F. hepatica to 10-100 microg/mL OZ78 in vitro resulted in the death of all trematodes. F. hepatica showed focal blebbing and sloughing of the tegument at all concentrations investigated.
Our data indicate that OZ78 is highly efficacious against F. hepatica and E. caproni and provide a sound platform for identification of a synthetic peroxide drug development candidate against major trematode infections.
测定合成过氧化物1,2,4 - 三氧杂环戊烷（OZ78）的杀吸虫特性，包括体内和体外实验。
对感染卡氏棘口吸虫两周后的小鼠单次口服给予400 - 1000 mg/kg的OZ78。对感染肝片吸虫的大鼠在感染后3周和8 - 9周口服给予50 - 400 mg/kg的OZ78。与未治疗的对照动物相比，评估虫体负荷减少情况。在单次口服给予100 mg/kg OZ78 3天后，从大鼠胆管中回收成虫肝片吸虫，并在体外暴露于1、10和100 μg/mL浓度的OZ78后，通过扫描电子显微镜（SEM）观察。
在卡氏棘口吸虫 - 小鼠模型中，单次口服1000 mg/kg的OZ78可使虫体负荷减少100%。单次给予100 mg/kg的OZ78可使幼年和成年肝片吸虫的虫体负荷减少100%。治疗3天后从大鼠体内回收的肝片吸虫活动减弱，部分吸虫死亡。SEM显示的典型特征包括广泛的起泡和脱落。体外将肝片吸虫暴露于10 - 100 μg/mL的OZ78导致所有吸虫死亡。在所有研究浓度下，肝片吸虫的体表均出现局灶性起泡和脱落。
我们的数据表明，OZ78对肝片吸虫和卡氏棘口吸虫具有高效性，并为鉴定针对主要吸虫感染的合成过氧化物药物开发候选物提供了良好的平台。
