Effect of the lysophospholipid analogues edelfosine, ilmofosine and miltefosine against Leishmania amazonensis

Santa‐Rita, Ricardo M.; Henriques-Pons, Andréa; Barbosa, Helene Santos; Castro, Solange L. de

doi:10.1093/jac/dkh380

Cited by 90 publications

(79 citation statements)

References 25 publications

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“…The reported IC 50 value for the treatment of intracellular amastigotes of Leishmania amazonensis with miltefosine in vitro was 9 mM (3.6 mg ml 21 ) (Santa-Rita et al, 2004), which is higher than the MIC values of 2.5-5 mM (1-2 mg ml 21 ) reported here for the treatment of S. brasiliensis isolates. Therefore, our results indicate that lower miltefosine doses than those used against human leishmaniasis could be effective in the treatment of sporotrichosis.…”

Section: Discussioncontrasting

confidence: 64%

Miltefosine is active against Sporothrix brasiliensis isolates with in vitro low susceptibility to amphotericin B or itraconazole

Borba-Santos

Gagini

Ishida

et al. 2015

Journal of Medical Microbiology

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Sporotrichosis is a common mycosis caused by dimorphic fungi from the Sporothrix schenckii complex. In recent years, sporotrichosis incidence rates have increased in the Brazilian state of Rio de Janeiro, where Sporothrix brasiliensis is the species more frequently isolated from patients. The standard antifungals itraconazole and amphotericin B are recommended as first-line therapy for cutaneous/lymphocutaneous and disseminated sporotrichosis, respectively, although decreased sensitivity to these drugs in vitro was reported for clinical isolates of S. brasiliensis. Here, we evaluated the activity of the phospholipid analogue miltefosine -already in clinical use against leishmaniasis -towards the pathogenic yeast form of S. brasiliensis isolates with low sensitivity to itraconazole or amphotericin B in vitro. Miltefosine had fungicidal activity, with minimum inhibitory concentration (MIC) values of 1-2 mg ml "1 . Miltefosine exposure led to loss of plasma membrane integrity, and transmission electron microscopy (TEM) analysis revealed a decrease in cytoplasmic electron density, alterations in the thickness of cell wall layers and accumulation of an electron-dense material in the cell wall. Flow cytometry analysis using an antimelanin antibody revealed an increase in cell wall melanin in yeasts treated with miltefosine, when compared with control cells. The cytotoxicity of miltefosine was comparable to those of amphotericin B, but miltefosine showed a higher selectivity index towards the fungus. Our results suggest that miltefosine could be an effective alternative for the treatment of S. brasiliensis sporotrichosis, when standard treatment fails. Nevertheless, in vivo studies are required to confirm the antifungal potential of miltefosine for the treatment of sporotrichosis. INTRODUCTIONSporotrichosis is the most frequent subcutaneous mycosis in Latin America, and has high incidence rates in Brazil, especially in the Rio de Janeiro state, where zoonotic transmission prevails (Barros et al., 2010). This disease is caused by dimorphic fungal species from the Sporothrix schenckii complex (Marimon et al., 2007;, including Sporothrix brasiliensis, the most virulent species (ArrillagaMoncrieff et al., 2009;Fernandes et al., 2013) and the most prevalent in the clinical cases from the Rio de Janeiro state (Oliveira et al., 2011;Rodrigues et al., 2013a;Borba-Santos et al., 2014). In zoonotic transmission, sporotrichosis is mainly acquired by scratches, bites or direct contact with lesion secretion from contaminated animals, where yeasts are the infective forms (Rodrigues et al., 2013b).The 'gold standard' treatment for cutaneous and lymphocutaneous forms of sporotrichosis is itraconazole, while amphotericin B is the first-line drug of choice for disseminated forms of the disease (Kauffman et al., 2007). However, recent reports demonstrated that these drugs are less potent against S. brasiliensis isolates, which have high minimum inhibitory concentration (MIC) values in vitro for these antifungals (Ottonelli Stopiglia et a...

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Section: Discussioncontrasting

confidence: 64%

Miltefosine is active against Sporothrix brasiliensis isolates with in vitro low susceptibility to amphotericin B or itraconazole

Borba-Santos

Gagini

Ishida

et al. 2015

Journal of Medical Microbiology

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“…Several studies have demonstrated changes in the mitochondria morphology of some Leishmania spp. previously treated with antileishmanial agents (Delorenzi et al, 2001;Santa-Rita et al, 2004;Ueda-Nakamura et al, 2006;Rodrigues et al, 2007;Santos et al 2008). These studies reported that significant alterations in the mitochondria led to the loss of cell viability and confirmed the importance of this organelle in the viability of L. infantum (Fonseca-Silva et al, 2011).…”

Section: Discussionsupporting

confidence: 53%

Antileishmanial activity and evaluation of the mechanism of action of strychnobiflavone flavonoid isolated from Strychnos pseudoquina against Leishmania infantum

et al. 2015

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The present study aimed to investigate the in vitro antileishmanial activity of strychnobiflavone flavonoid against Leishmania infantum, as well as its mechanism of action, and evaluate the ex vivo biodistribution profile of the flavonoid in naive BALB/c mice. The antileishmanial activity (IC 50 value) of strychnobiflavone against stationary promastigote and amastigote-like stages of the parasites was of 5.4 and 18.9 μM, respectively; with a 50% cytotoxic concentration (CC 50 ) value of 125.0 μM on murine macrophages, resulting in selectivity index (SI) of 23.2 and 6.6, respectively. Amphotericin B, used as a positive control, presented SI values of 7.6 and 3.3 for promastigote and amastigote-like stages of L. infantum, respectively. The strychnobiflavone was also effective in reducing in significant levels the percentage of infected macrophages, as well as the number of amastigotes per macrophage, after the treatment of infected macrophages using the flavonoid. By using different fluorescent probes, we investigated the bioenergetics metabolism of L. infantum promastigotes and demonstrated that the flavonoid caused the depolarization of the mitochondrial membrane potential, without affecting the production of reactive oxygen species. In addition, using SYTOX ® green as a fluorescent probe, the strychnobiflavone demonstrated no interference in plasma membrane permeability. For the ex vivo biodistribution assays, the flavonoid was labeled with technetium99m and studied in a mouse model by intraperitoneal route. After a single dose administration, the scintigraphic images demonstrated a highest uptake by the liver and spleen of the animals within 60 min, resulting in low concentrations after 24 h. The present study therefore demonstrated, for the first time, the antileishmanial activity of the strychnobiflavone against L. infantum, and suggests that the mitochondria of the parasites may be the possible target organelle. The preferential distribution of this compound into the liver and spleen of the animals could warrant its employ in the treatment of visceral leishmaniasis.

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“…Moreover, miltefosine has been successfully used to treat patients with antimony-resistant VL, VL in children and CL in South America (Croft & Engel 2006 (Escobar et al 2002, Santa-Rita et al 2004, CabreraSerra et al 2007). In addition, the induction of apoptosis following miltefosine treatment has already been reported in L. donovani (Paris et al 2004, Verma et al 2007).…”

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confidence: 99%

“…The ultrastructural analysis of edelfosine-treated promastigotes and amastigotes indicated the mitochondrion as the main target. However, plasma membrane alterations and autophagic structures were detected in promastigotes (Santa-Rita et al 2004). The activity of these compounds was evaluated against L. amazonensis using an in vivo mouse model, which showed that perifosine was the most effective compound.…”

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confidence: 99%

Miltefosine induces programmed cell death in Leishmania amazonensis promastigotes

Marinho

Goncalves

Oliveira

et al. 2011

Mem. Inst. Oswaldo Cruz

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In the current study, we evaluated the mechanism of action of miltefosine, which is the first effective and safe oral treatment for visceral leishmaniasis, in Leishmania amazonensis promastigotes. Miltefosine induced a process of programmed cell death, which was determined by the externalization of phosphatidylserine, the incorporation of propidium iodide, cell-cycle arrest at the sub-G0/G1 phase and DNA fragmentation into oligonucleosome-sized fragments. Despite the intrinsic variation that is detected in Leishmania spp, our results indicate that miltefosine causes apoptosis-like death in L. amazonensis promastigote cells using a similar process that is observed in Leishmania donovani

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Effect of the lysophospholipid analogues edelfosine, ilmofosine and miltefosine against Leishmania amazonensis

Abstract: The alkylglycerophosphocholines edelfosine and ilmofosine were more active than the alkylphosphocholine miltefosine against promastigotes and intracellular amastigotes of L. amazonensis, and ultrastructural and flow cytometry data indicate the mitochondrion as a target of edelfosine.

Cited by 90 publications

References 25 publications

Miltefosine is active against Sporothrix brasiliensis isolates with in vitro low susceptibility to amphotericin B or itraconazole

Miltefosine is active against Sporothrix brasiliensis isolates with in vitro low susceptibility to amphotericin B or itraconazole

Antileishmanial activity and evaluation of the mechanism of action of strychnobiflavone flavonoid isolated from Strychnos pseudoquina against Leishmania infantum

Miltefosine induces programmed cell death in Leishmania amazonensis promastigotes

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