In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

Abstract

BackgroundThe 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 FindingsWe 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/SignificanceOur 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.

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

“…Thus, edelfosine has been found to promote apoptosis in activated lymphocytes (Cabaner, et al, 1999), hence suggesting a role for this drug in the treatment of autoimmune diseases (Abramowski, et al, 2014;Mollinedo, 2007). In addition, in vitro and in vivo assays in animal models have shown that edelfosine is a potent anti-inflammatory agent , as well as an effective drug against leishmaniasis Varela, et al, 2012) and schistosomiasis (Yepes, et al, 2014;Yepes, et al, 2015). Additional biomedical applications and patents for…”

C-Geranylated flavonoids fromPaulownia tomentosafruits with antimicrobial potential and synergistic activity with antibiotics

“…The slightly modified method of Varela-M et al (2012) was used for the cultivation and further work with leishmanias. Promastigotes of four species, L. braziliensis (MHOM/CO/88/UA301), L. donovani (MHOM/IN/80/ DD8), L. infantum (MCAN/ES/96/BCN150), and L. panamensis (MHOM/CO/87/UA140), were continually cultured at 27 C by shaking in Schneier's medium (Sigma-Aldrich, Madrid, Spain) supplemented with NaHCO 3 (0.4 g/L), CaCl 2 (0.6 g/L), 10% fetal bovine serum (Sigma-Aldrich, Spain), and penicillin 10 000 U/ mL-streptomycin 10 000 mg/mL (Sigma-Aldrich, Madrid, Spain).…”

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

“…For this reason, in the last decades several drugs, such as amphotericin B and miltefosine (6), paromomycin and pentamidine (7), sitamaquine (8), and edelfosine (9), have been used in the treatment of leishmaniasis. Nevertheless, their high cost and therapeutic complications limit their use.…”