Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
Acta Trop. 2011 Apr;118(1):56-62. doi: 10.1016/j.actatropica.2011.02.003. Epub 2011 Feb 21.
The rapid spread of triclabendazole resistance in veterinary medicine is an important motivation for the discovery and development of novel fasciocidal drugs. The aim of this study was to characterize the fasciocidal properties of 1,2,4,5-tetraoxane (MT04 and MT14) and 1,2,4-trioxane (ST16 and ST28) analogues of the fasciocidal drug candidate OZ78, a 1,2,4-trioxolane. Dose response relationships were determined against juvenile and adult Fasciola hepatica in rats and Echinostoma caproni in mice. The temporal effects of MT04, MT14, ST16, and ST28 compared to OZ78 on the viability of F. hepatica were tested in vitro. The heat flow of OZ78 and MT04 treated flukes was studied with isothermal microcalorimetry. Finally, surface changes to adult flukes were monitored by scanning electron microscopy (SEM) 18, 24, and 48 h post-treatment of rats with 50 mg/kg MT04. Administration of 50-100 mg/kg of the synthetic peroxides resulted in complete elimination of adult F. hepatica from rats. SEM pictures revealed sloughing and blebbing already 18 h post-treatment with MT04. MT04 (100mg/kg) cured infections with juvenile F. hepatica, whereas MT14, ST16, and ST28 showed only low to moderate worm burden reductions. At 300 mg/kg, MT14 was the only compound to completely eliminate worms from E. caproni infected mice. MT14 showed the highest activity against juvenile F. hepatica in vitro. MT04 was very active against adult F. hepatica in vitro, which was confirmed by heat flow measurements. In conclusion, we have identified MT04 as another lead compound with potential against F. hepatica, hence further preclinical studies are necessary to determine if MT04 can be considered a drug development candidate.
三氯苯达唑耐药性在兽医领域的迅速传播是发现和开发新型杀肝片吸虫药物的重要动力。本研究旨在对杀肝片吸虫候选药物 OZ78 的 1,2,4,5-四氧烷（MT04 和 MT14）和 1,2,4-三氧烷（ST16 和 ST28）类似物的杀肝片吸虫特性进行表征。在大鼠和小鼠中，测定了这些化合物对肝片形吸虫幼虫和成虫的剂量反应关系。在体外测试了 MT04、MT14、ST16 和 ST28 与 OZ78 相比对肝片形吸虫活力的时间效应。用等温微量热法研究了 OZ78 和 MT04 处理后肝片形吸虫的热流。最后，用扫描电子显微镜（SEM）监测大鼠经 50mg/kg MT04 处理后 18、24 和 48 小时成虫表面的变化。给予 50-100mg/kg 的合成过氧化物可完全消除大鼠体内的成虫肝片吸虫。SEM 图片显示，MT04 处理 18 小时后即出现脱落和起泡。MT04（100mg/kg）可治愈大鼠感染的肝片形吸虫幼虫，但 MT14、ST16 和 ST28 仅显示低至中度的虫体负荷减少。300mg/kg 时，MT14 是唯一能完全消除感染曼氏血吸虫的小鼠体内蠕虫的化合物。MT14 对体外感染的肝片形吸虫幼虫活性最高。MT04 对体外感染的成虫肝片形吸虫非常活跃，这一点通过热流测量得到了证实。综上所述，我们已将 MT04 确定为另一种具有抗肝片形吸虫潜力的先导化合物，因此需要进一步进行临床前研究，以确定 MT04 是否可被视为药物开发候选物。
