The in vitro leishmanicidal activity of hexadecylphosphocholine (miltefosine) against four medically relevant Leishmania species of Brazil

Morais-Teixeira, Eliane de; Damasceno, Quésia Souza; Galuppo, Mariana K.; Romanha, Álvaro J.; Rabello, Ana

doi:10.1590/s0074-02762011000400015

Cited by 38 publications

(31 citation statements)

References 16 publications

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“…In our hands, the CC 50 values obtained for THP-1 and HMØ were 6-to 12-fold lower than those with HePC, which showed cytotoxic levels similar to those described earlier by others (26,43). Compound 1 had the most interesting SI, which was 4-fold higher than that of HePC.…”

Section: Discussionsupporting

confidence: 86%

“…Both of them had no biological effect, implying that the activity is conferred by the furanoside ring. Our IC 50 results using HePC on promastigotes are in coherence with previously published data (26,42), thus allowing reliable comparison of efficacy between our molecules and a reference treatment.…”

Section: Discussionsupporting

confidence: 86%

“…The effects of galactofuranose derivatives on L. donovani promastigote growth were expressed as the reduction percentage of parasite growth obtained for each drug concentration, by comparison to untreated wells, and the 50% inhibitory concentration (IC 50 ) was determined. The selectivity index (SI) was calculated as CC 50 / IC 50 , as described earlier (26). Each experiment was repeated at least thrice.…”

Section: Methodsmentioning

confidence: 99%

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Alkyl Galactofuranosides Strongly Interact with Leishmania donovani Membrane and Provide Antileishmanial Activity

Suleman

Gangneux

Legentil

et al. 2014

Antimicrob Agents Chemother

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fWe investigated the in vitro effects of four alkyl-galactofuranoside derivatives, i.e., octyl-␤-D-galactofuranoside (compound 1), 6-amino-␤-D-galactofuranoside (compound 2), 6-N-acetamido-␤-D-galactofuranoside (compound 3), and 6-azido-␤-D-galactofuranoside (compound 4), on Leishmania donovani. Their mechanism of action was explored using electron paramagnetic resonance spectroscopy (EPR) and nuclear magnetic resonance (NMR), and ultrastructural alterations were analyzed by transmission electron microscopy (TEM). Compound 1 showed the most promising effects by inhibiting promastigote growth at a 50% inhibitory concentration (IC 50 ) of 8.96 ؎ 2.5 M. All compounds exhibit low toxicity toward human macrophages. Compound 1 had a higher selectivity index than the molecule used for comparison, i.e., miltefosine (159.7 versus 37.9, respectively). EPR showed that compound 1 significantly reduced membrane fluidity compared to control promastigotes and to compound 3. The furanose ring was shown to support this effect, since the isomer galactopyranose had no effect on parasite membrane fluidity or growth. NMR showed a direct interaction of all compounds (greatest with compound 1, followed by compounds 2, 3, and 4, in descending order) with the promastigote membrane and with octyl-galactopyranose and octanol, providing evidence that the n-octyl chain was primarily involved in anchoring with the parasite membrane, followed by the putative crucial role of the furanose ring in the antileishmanial activity. A morphological analysis of compound 1-treated promastigotes by TEM revealed profound alterations in the parasite membrane and organelles, but this was not the case with compound 3. Quantification of annexin V binding by flow cytometry confirmed that compound 1 induced apoptosis in >90% of promastigotes. The effect of compound 1 was also assessed on intramacrophagic amastigotes and showed a reduction in amastigote growth associated with an increase of reactive oxygen species (ROS) production, thus validating its promising effect.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

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Alkyl Galactofuranosides Strongly Interact with Leishmania donovani Membrane and Provide Antileishmanial Activity

Suleman

Gangneux

Legentil

et al. 2014

Antimicrob Agents Chemother

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“…Due to this, a different sensitivity of theses parasites to the tested extracts was expected. Previous in vitro studies have also shown differences in sensitivity of Leishmania species to different reference drugs, including pentavalent antimonials, amphotericin B (Minodier and Parola 2007), miltefosine (De Morais-Teixeira et al 2011) and crude or purified plant extracts (Braga et al 2007, Fabri et al 2012a. Among the 17 methanolic extracts tested, 11 showed leishmanicidal activity against at least one promastigote forms of Leishmania species with IC 50 values ranging from 5.0 to 88.3 µg/mL.…”

Section: Resultsmentioning

confidence: 94%

Antileishmanial activity of some Brazilian plants, with particular reference to Casearia sylvestris

Antinarelli

Pinto

Scio

et al. 2015

An. Acad. Bras. Ciênc.

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Leishmaniasis is a complex of diseases caused by Leishmania protozoa which treatment is restricted to a limited number of drugs that exhibit high toxicity, collateral effects and are often costly. There are a variety of tropical plants distributed in Brazil, and for many poor people the therapy for several diseases is based mainly on the use of traditional herbal remedies. In this work, the cytotoxic activity of 17 plant methanol extracts was evaluated on several Leishmania species and murine macrophages. Among them, the extract of Casearia sylvestris, Piptocarpha macropoda, Trembleya parviflora, Samanea tubulosa and Plectranthus neochilus showed a promissing leishmanicidal activity, exhibiting IC 50 values below of 20 µg/mL against at least one species of Leishmania. Casearia sylvestris showed the most expressive activity against all promastigote forms of Leishmania species (IC 50 values of 5.4 µg/mL, 5.0 µg/mL, 8.5 µg/mL and 7.7 µg/ mL for L. amazonensis, L. braziliensis, L. chagasi and L. major, respectively), being more effective than the reference drug miltefosine. In spite of the cytotoxic effect on macrophages (CC 50 value of 5.2 µg/mL), C. sylvestris exhibited a strong inhibition against intracellular amastigotes of L. braziliensis (IC 50 value of 1.3 µg/ mL). Further studies, including bio-guided fractionation will be conducted to identify the active compounds.

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“…Miltefosine, a hexadecylphosphocholine, was initially studied as an anti-tumour agent [5]; more recently, it was described to exhibit both in vitro and in vivo activity against Leishmania parasites [6][7][8][9][10][11]. Oral administration of miltefosine has been used in India to treat visceral leishmaniasis (VL) since 1998.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of miltefosine treatment in Leishmania amazonensis-infected BALB/c mice

Godinho

Simas-Rodrigues

Silva

et al. 2012

International Journal of Antimicrobial Agents

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Leishmaniasis is one of the most serious worldwide diseases caused by protozoan parasites of the Leishmania genus, affecting millions of people around the world. All currently available treatments present severe toxic side effects, require long-term compliance, cause serious side effects and are uncomfortable for patients. Leishmania amazonensis, a species endemic to Brazil, causes severe localised or diffuse skin lesions in humans. Owing to the unsatisfactory nature of the currently available chemotherapies, new approaches have been assessed for improved therapeutic intervention strategies against leishmaniasis. Miltefosine is an alkylphospholipid analogue that exhibits potent activity against the different clinical manifestations of leishmaniasis. Thus, the aim of this study was to investigate the long-term efficacy of miltefosine in BALB/c mice infected with L. amazonensis owing to the lack of a profound study demonstrating its dose-dependent and long-term effects. It was observed that animals treated with 20-50 mg/kg/day of miltefosine exhibited a significant dose-dependent reduction in lesion size; furthermore, in mice receiving higher doses, lesions disappeared after the end of treatment. To confirm a possible parasitological cure, mice up to 250 days after the end of treatment were analysed. No lesions or presence of parasite DNA were found in mice treated with 30, 40 and 50 mg/kg/day of miltefosine. In summary, these results show that miltefosine may be used to treat cutaneous leishmaniasis caused by L. amazonensis, alone or as combination therapy.

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The in vitro leishmanicidal activity of hexadecylphosphocholine (miltefosine) against four medically relevant Leishmania species of Brazil

Cited by 38 publications

References 16 publications

Alkyl Galactofuranosides Strongly Interact with Leishmania donovani Membrane and Provide Antileishmanial Activity

Alkyl Galactofuranosides Strongly Interact with Leishmania donovani Membrane and Provide Antileishmanial Activity

Antileishmanial activity of some Brazilian plants, with particular reference to Casearia sylvestris

Efficacy of miltefosine treatment in Leishmania amazonensis-infected BALB/c mice

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