Institute of Parasitology, Vetsuisse Faculty, University of Berne, Langgass-Strasse 122, CH-3012 Berne, Switzerland.
Antimicrob Agents Chemother. 2011 Oct;55(10):4866-72. doi: 10.1128/AAC.00478-11. Epub 2011 Jul 18.
The current chemotherapy of alveolar echinococcosis (AE) is based on benzimidazoles such as albendazole and has been shown to be parasitostatic rather than parasiticidal, requiring lifelong duration. Thus, new and more efficient treatment options are urgently needed. By employing a recently validated assay based on the release of functional phosphoglucose isomerase (PGI) from dying parasites, the activities of 26 dicationic compounds and of the (+)- and (-)-erythro-enantiomers of mefloquine were investigated. Initial screening of compounds was performed at 40 μM, and those compounds exhibiting considerable antiparasitic activities were also assessed at lower concentrations. Of the dicationic drugs, DB1127 (a diguanidino compound) with activities comparable to nitazoxanide was further studied. The activity of DB1127 was dose dependent and led to severe structural alterations, as visualized by electron microscopy. The (+)- and (-)-erythro-enantiomers of mefloquine showed similar dose-dependent effects, although higher concentrations of these compounds than of DB1127 were required for metacestode damage. In conclusion, of the drugs investigated here, the diguanidino compound DB1127 represents the most promising compound for further study in appropriate in vivo models for Echinococcus multilocularis infection.
目前的泡型包虫病（AE）化疗基于苯并咪唑类药物，如阿苯达唑，已被证明是寄生虫生长抑制而不是寄生虫杀灭，需要终身治疗。因此，迫切需要新的、更有效的治疗方法。本研究采用了最近验证的基于功能磷酸葡萄糖异构酶（PGI）从死亡寄生虫释放的测定法，研究了 26 种二价阳离子化合物和甲氟喹的（+）-和（-）-表异构体的活性。在 40 μM 时对化合物进行初步筛选，对具有相当驱虫活性的化合物也在较低浓度下进行评估。在二价阳离子药物中，与硝唑尼特活性相当的 DB1127 进一步研究。DB1127 的活性呈剂量依赖性，并导致严重的结构改变，电镜下可见。甲氟喹的（+）-和（-）-表异构体表现出相似的剂量依赖性作用，尽管这些化合物的浓度比 DB1127 高，才能对包虫蚴造成损害。总之，在所研究的药物中，二胍化合物 DB1127 是在适当的泡型包虫病感染体内模型中进一步研究的最有前途的化合物。
