The development of miltefosine for the treatment of visceral and cutaneous Leishmaniasis

Pearson, Richard D.

doi:10.1007/s11908-003-0063-1

Cited by 7 publications

(6 citation statements)

References 8 publications

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“…Miltefosine (hexadecylphosphocholine), an alkylphosphocholine and a membrane-active synthetic ether-lipid analog originally developed for the treatment of cancer [8,9], has proved to be an effective drug for treatment for VL [10][11][12][13]. The antitumor mechanism of Miltefosine relies on apoptosis along with lipid-dependent cell signaling pathways [14].…”

Section: Introductionmentioning

confidence: 99%

Miltefosine triggers a strong proinflammatory cytokine response during visceral leishmaniasis: Role of TLR4 and TLR9

Mukherjee

Gupta

Adhikari

et al. 2012

International Immunopharmacology

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Section: Introductionmentioning

confidence: 99%

Miltefosine triggers a strong proinflammatory cytokine response during visceral leishmaniasis: Role of TLR4 and TLR9

Mukherjee

Gupta

Adhikari

et al. 2012

International Immunopharmacology

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“…Here, we demonstrate that miltefosine induces apoptosis-like death in L. donovani based on observed phenomena such as nuclear DNA condensation, DNA fragmentation with accompanying ladder formation, and in situ labeling of DNA fragments by the terminal deoxyribonucleotidyltransferasemediated dUTP-biotin nick end labeling method. Understanding of miltefosine-mediated death will facilitate the design of new therapeutic strategies against Leishmania parasites.Miltefosine (1-O-hexadecylphosphocholine), an alkylphosphocholine and a membrane-active synthetic ether-lipid analogue originally developed for the treatment of cutaneous metastasis from mammary carcinomas (21, 32), has proved to be an effective treatment for human visceral leishmaniasis (25,38,(52)(53)(54)(55). It has been hailed as potentially the first oral treatment of human leishmaniasis (8,15,16,20,25,31,47,50).…”

mentioning

confidence: 99%

Possible Mechanism of Miltefosine-Mediated Death of Leishmania donovani

Verma

Dey

2004

Antimicrob Agents Chemother

210

132

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Miltefosine causes leishmanial death, but the possible mechanism(s) of action is not known. The mode of action of miltefosine was investigated in vitro in Leishmania donovani promastigotes as well as in extra-and intracellular amastigotes. Here, we demonstrate that miltefosine induces apoptosis-like death in L. donovani based on observed phenomena such as nuclear DNA condensation, DNA fragmentation with accompanying ladder formation, and in situ labeling of DNA fragments by the terminal deoxyribonucleotidyltransferasemediated dUTP-biotin nick end labeling method. Understanding of miltefosine-mediated death will facilitate the design of new therapeutic strategies against Leishmania parasites.Miltefosine (1-O-hexadecylphosphocholine), an alkylphosphocholine and a membrane-active synthetic ether-lipid analogue originally developed for the treatment of cutaneous metastasis from mammary carcinomas (21, 32), has proved to be an effective treatment for human visceral leishmaniasis (25,38,(52)(53)(54)(55). It has been hailed as potentially the first oral treatment of human leishmaniasis (8,15,16,20,25,31,47,50). The leishmaniacidal activities of miltefosine have been associated with perturbation of the alkyl-phospholipid metabolism and the biosynthesis of alkyl-anchored glycolipids and glycoproteins (33,34). Although potential antitumor cell mechanisms of action of miltefosine have been elaborated in mammalian cells (13,44), its exact mode(s) of cytotoxicity has not been determined in Leishmania spp. (9,25,39,46,48,55). It has been known to induce apoptotic death in various cancer cell lines (13,28,32,43,60). However, it is not yet established whether miltefosine can bring about apoptosis-like death in all the forms of Leishmania parasite.There are now increasing numbers of reports regarding unicellular organisms undergoing apoptosis-like death, whose induction is not obligatory but activated under threatening circumstances (1,36,49). Cell death resembling metazoan apoptosis has been reported in several parasitic protozoans (4,10,30,36,49,59,61). Apoptosis greatly affects the host-parasite relationship, since the survival of the parasite inside the vector as well as in the macrophage requires strict control of the population of the parasite (12, 58). Apoptosis could be a useful mechanism to avoid killing of the entire population (36) and thus influence the chemotherapeutic strategies to limit the parasite (11).In the present study we sought to determine the mode of action of miltefosine in Leishmania donovani promastigotes as well as extra-and intracellular amastigotes. We have demonstrated that miltefosine causes apoptosis-like death in L. donovani. Our data set the stage for future development of this class of drug for better treatment of leishmaniasis. MATERIALS AND METHODSReagents. Miltefosine was a kind gift from Zentaris (Frankfurt, Germany). RPMI 1640 culture medium was from Gibco BRL. Fetal calf serum was obtained from Biological Industries (Kibbutz Beit Haemek, Israel). ApoAlert DNA fragmentation assay kit was ...

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“…Phospholipid analogues, such as miltefosine, have been shown to be very effective against parasitic protozoa, especially Leishmania donovani, and are now considered the favorite pharmaceutical treatment for visceral leishmaniasis in India [28]. The association via molecular hybridization combines the pharmacophoric moieties of miltefosine and trifluralin, thereby leading to some compounds that are very active against T.cruzi and L.amazonensis (submitted for publication).…”

Section: Trifluralin Associated With Phospholipid Analoguesmentioning

confidence: 99%

Herbicides as Potential Chemotherapeutic Agents Against Parasitic Protozoa

Souza¹

2013

Herbicides - Advances in Research

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The development of miltefosine for the treatment of visceral and cutaneous Leishmaniasis

Cited by 7 publications

References 8 publications

Miltefosine triggers a strong proinflammatory cytokine response during visceral leishmaniasis: Role of TLR4 and TLR9

Miltefosine triggers a strong proinflammatory cytokine response during visceral leishmaniasis: Role of TLR4 and TLR9

Possible Mechanism of Miltefosine-Mediated Death of Leishmania donovani

Herbicides as Potential Chemotherapeutic Agents Against Parasitic Protozoa

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