Aspects of the Cytological Activity of Edelfosine, Miltefosine, and Ilmofosine in Leishmania Donovani

Azzouz, S.; Maache, Mimoun; Santos, Manuel Filipe; Sarciron, Marie‐Elisabeth; Pétavy, A. F.; Osuna, Antonio

doi:10.1645/ge-632r1.1

Cited by 10 publications

(6 citation statements)

References 34 publications

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“…Further, we reported earlier that MFS reduces the size of hepatic granuloma in S . mansoni -infected mice[ 8 ], an effect attributed to the drug accumulation in the liver[ 15 , 48 ] possibly reducing the eggs ability to induce granulomatous responses and/or to immunomodulatory functions reported for MFS[ 49 ]. On the other hand, gastrointestinalstability of LNCs [ 18 ], vesicle-mediated trancytosis of drug transport[ 19 , 50 ] and/or possible gut uptake and translocation as native nanocarriers[ 19 ] might explain the enhanced antischistosomal activity of MFS presented as LNCs.…”

Section: Discussionmentioning

confidence: 99%

Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study

et al. 2015

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Miltefosine (MFS) is an alkylphosphocholine used for the local treatment of cutaneous metastases of breast cancer and oral therapy of visceral leishmaniasis. Recently, the drug was reported in in vitro and preclinical studies to exert significant activity against different developmental stages of schistosomiasis mansoni, a widespread chronic neglected tropical disease (NTD). This justified MFS repurposing as a potential antischistosomal drug. However, five consecutive daily 20 mg/kg doses were needed for the treatment of schistosomiasis mansoni in mice. The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs) as oral nanovectors. MFS was incorporated in LNCs both as membrane-active structural alkylphospholipid component and active antischistosomal agent. MFS-LNC formulations showed high entrapment efficiency (EE%), good colloidal properties, sustained release pattern and physical stability. Further, LNCs generally decreased MFS-induced erythrocyte hemolytic activity used as surrogate indicator of membrane activity. While MFS-free LNCs exerted no antischistosomal effect, statistically significant enhancement was observed with all MFS-LNC formulations. A maximum effect was achieved with MFS-LNCs incorporating CTAB as positive charge imparting agent or oleic acid as membrane permeabilizer. Reduction of worm load, ameliorated liver pathology and extensive damage of the worm tegument provided evidence for formulation-related efficacy enhancement. Non-compartmental analysis of pharmacokinetic data obtained in rats indicated independence of antischistosomal activity on systemic drug exposure, suggesting possible gut uptake of the stable LNCs and targeting of the fluke tegument which was verified by SEM. The study findings put forward MFS-LNCs as unique oral nanovectors combining the bioactivity of MFS and biopharmaceutical advantages of LNCs, allowing targeting via the oral route. From a clinical point of view, data suggest MFS-LNCs as a potential single dose oral nanomedicine for enhanced therapy of schistosomiasis mansoni and possibly other diseases.

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Section: Discussionmentioning

confidence: 99%

Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study

et al. 2015

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“…These compounds possess potent leishmaniacidal activity, although the molecular mechanism of such activity is still controversial. Amongst their various effects in Leishmania parasites, inhibition of membrane lipid synthesis and induction of apoptosis or necrosis have been observed [55–57]. Therefore, understanding the roles of lipid metabolism in Leishmania parasites could have important implications in guiding the development of novel PL analogues that possess anti-protozoan activity.…”

Section: Composition Of Pls and Sls In Leishmaniamentioning

confidence: 99%

Phospholipid and sphingolipid metabolism in Leishmania

Zhang

Beverley

2010

Molecular and Biochemical Parasitology

123

119

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In many eukaryotes, phospholipids (PLs) and sphingolipids (SLs) are abundant membrane components and reservoirs for important signaling molecules. In Leishmania, the composition, metabolism, and function of PLs and SLs differ significantly from those in mammalian cells. Although only a handful of enzymes have been experimentally characterized, available data suggest many steps of PL/SL metabolism are critical for Leishmania viability and/or virulence, and could be a source for new drug targets. Further studies of genes involved in the synthesis (de novo and salvage) and degradation of PLs and SLs will reveal their diverse effects on Leishmania pathogenesis.

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“…A similar process was described for drugs such as miltefosine (43) and curcumin (44), known to act on mitochondria. Even so, we cannot rule out completely the contribution of additional targets for compound 5, as other stimuli allegedly not acting directly on mitochondria (45-47) may also induce this phenotype and inhibition of succinate dehydrogenase was not complete under our assay conditions.…”

Section: Discussionmentioning

confidence: 70%

Mechanisms of Action of Substituted β-Amino Alkanols on Leishmania donovani

Abengózar

Bustos

García-Hernández

et al. 2015

Antimicrob Agents Chemother

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Leishmaniasis is the protozoan disease second in importance for human health, superseded only by malaria; however, the options for chemotherapeutic treatment are increasingly limited due to drug resistance and toxicity. Under this perspective, a quest for new chemical compounds is urgently needed. An N-substituted 2-aminoalkan-1-ol scaffold has been shown to be a versatile scaffold for antiparasitic activity. Knowledge about its mechanism of action is still rather limited. In this work, we endeavored to define the leishmanicidal profile of such ␤-amino alkanol derivatives using a set of 15 N-mono-and disubstituted surrogates, tested on Leishmania donovani promastigotes and intracellular amastigotes. The best compound (compound 5), 2-ethylaminododecan-1-ol, had a 50% effective concentration (EC 50 ) of 0.3 M and a selectivity index of 72 for infected THP-1 cells and was selected for further elucidation of its leishmanicidal mechanism. It induced fast depletion of intracellular ATP content in promastigotes in the absence of vital dye intracellular entry, ruling out plasma membrane permeabilization as its origin. Confocal and transmission electron microscopy analyses showed that compound 5 induced severe mitochondrial swelling and vesiculation. Polarographic analysis using an oxygen electrode demonstrated that complex II of the respiratory chain (succinate reductase) was strongly inhibited by compound 5, identifying this complex as one of the primary targets. Furthermore, for other ␤-amino alkanols whose structures differed subtly from that of compound 5, plasma membrane permeabilization or interference with membrane traffic was also observed. In all, N-substituted ␤-amino alkanols were shown as appealing leishmanicidal candidates deserving further exploration.

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Aspects of the Cytological Activity of Edelfosine, Miltefosine, and Ilmofosine in Leishmania Donovani

Cited by 10 publications

References 34 publications

Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study

Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study

Phospholipid and sphingolipid metabolism in Leishmania

Mechanisms of Action of Substituted β-Amino Alkanols on Leishmania donovani

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