Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.
PLoS Negl Trop Dis. 2012;6(4):e1612. doi: 10.1371/journal.pntd.0001612. Epub 2012 Apr 10.
The leishmaniases are a complex of neglected tropical diseases caused by more than 20 Leishmania parasite species, for which available therapeutic arsenal is scarce and unsatisfactory. Pentavalent antimonials (SbV) are currently the first-line pharmacologic therapy for leishmaniasis worldwide, but resistance to these compounds is increasingly reported. Alkyl-lysophospoholipid analogs (ALPs) constitute a family of compounds with antileishmanial activity, and one of its members, miltefosine, has been approved as the first oral treatment for visceral and cutaneous leishmaniasis. However, its clinical use can be challenged by less impressive efficiency in patients infected with some Leishmania species, including L. braziliensis and L. mexicana, and by proneness to develop drug resistance in vitro.
METHODOLOGY/PRINCIPAL FINDINGS: We found that ALPs ranked edelfosine>perifosine>miltefosine>erucylphosphocholine for their antileishmanial activity and capacity to promote apoptosis-like parasitic cell death in promastigote and amastigote forms of distinct Leishmania spp., as assessed by proliferation and flow cytometry assays. Effective antileishmanial ALP concentrations were dependent on both the parasite species and their development stage. Edelfosine accumulated in and killed intracellular Leishmania parasites within macrophages. In vivo antileishmanial activity was demonstrated following oral treatment with edelfosine of mice and hamsters infected with L. major, L. panamensis or L. braziliensis, without any significant side-effect. Edelfosine also killed SbV-resistant Leishmania parasites in in vitro and in vivo assays, and required longer incubation times than miltefosine to generate drug resistance.
CONCLUSIONS/SIGNIFICANCE: Our data reveal that edelfosine is the most potent ALP in killing different Leishmania spp., and it is less prone to lead to drug resistance development than miltefosine. Edelfosine is effective in killing Leishmania in culture and within macrophages, as well as in animal models infected with different Leishmania spp. and SbV-resistant parasites. Our results indicate that edelfosine is a promising orally administered antileishmanial drug for clinical evaluation.
利什曼病是一组由 20 多种利什曼原虫引起的被忽视的热带病。目前，五价锑（SbV）是全球治疗利什曼病的一线药物，但对这些化合物的耐药性日益增加。烷基-溶血磷脂类似物（ALPs）是一类具有抗利什曼原虫活性的化合物，其中 miltefosine 已被批准为治疗内脏利什曼病和皮肤利什曼病的第一种口服药物。然而，其临床应用可能受到以下因素的挑战：在感染某些利什曼原虫（包括 L. braziliensis 和 L. mexicana）的患者中，其效率较低；在体外易产生耐药性。
方法/主要发现：我们发现，在评估增殖和流式细胞术测定的不同利什曼原虫种的前鞭毛体和无鞭毛体形式的抗利什曼原虫活性和促进凋亡样寄生虫细胞死亡的能力时，ALPs 按 edelfosine>perifosine>miltefosine>erucylphosphocholine 排序。有效的抗利什曼 ALP 浓度取决于寄生虫种类及其发育阶段。Edelfosine 在巨噬细胞内积累并杀死细胞内的利什曼原虫寄生虫。在感染 L. major、L. panamensis 或 L. braziliensis 的小鼠和仓鼠中，经口服 edelfosine 治疗后，在体内表现出抗利什曼原虫活性，没有任何明显的副作用。Edelfosine 还能杀死 SbV 耐药的利什曼原虫寄生虫，无论是在体外还是体内试验中，并且比 miltefosine 产生耐药性所需的孵育时间更长。
结论/意义：我们的数据表明，edelfosine 是杀灭不同利什曼原虫最有效的 ALP，并且比 miltefosine 不易导致耐药性发展。Edelfosine 在培养物和巨噬细胞内以及感染不同利什曼原虫种和 SbV 耐药寄生虫的动物模型中均能有效杀灭利什曼原虫。我们的结果表明，edelfosine 是一种有前途的口服抗利什曼病药物，值得进一步临床评估。
