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Revision as of 12:38, 24 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 456816569 of page Miltefosine for the Chem/Drugbox validation project (updated: 'CAS_number').  Latest revision as of 12:34, 22 July 2024 edit AnomieBOT (talk | contribs)Bots6,571,142 editsm Substing templates: {{Format ISBN}}. See User:AnomieBOT/docs/TemplateSubster for info. 
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{{short description|Phospholipid drug}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{Drugbox {{Drugbox
| Verifiedfields = changed | Verifiedfields = changed
| verifiedrevid = 415848483 | verifiedrevid = 462252576
| image = Miltefosine structure.svg
| IUPAC_name = 2-(hexadecoxy-oxido-phosphoryl)oxyethyl-trimethyl-azanium
| width = 250
| image = Miltefosine.svg
| image2 = Miltefosine-3D-bs-17.png
| width = 300


<!--Clinical data--> <!--Clinical data-->
| tradename = | tradename = Impavido, Miltex, others
| Drugs.com = {{drugs.com|international|miltefosine}} | Drugs.com = {{drugs.com|monograph|miltefosine}}
| MedlinePlus =
| licence_CA = <!-- Health Canada may use generic or brand name (generic name preferred) -->
| licence_EU = <!-- EMA uses INN (or special INN_EMA) -->
| DailyMedID = Miltefosine
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_category =
| pregnancy_US = <!-- A / B / C / D / X -->
| routes_of_administration = ]
| pregnancy_category =
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --> | class =
| legal_UK = <!-- GSL / P / POM / CD --> | ATCvet =
| ATC_prefix = P01
| legal_US = <!-- OTC / Rx-only -->
| legal_status = | ATC_suffix = CX04
| ATC_supplemental = {{ATCvet|P51|DX07}}
| routes_of_administration = Oral

<!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_AU_comment =
| legal_BR = C1
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=] |language=pt-BR |publication-date=2023-04-04}}</ref>
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment =
| legal_status = Rx-only


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
| bioavailability = High | bioavailability = High
| protein_bound = | protein_bound = ~98%
| metabolism = | metabolism = Slow hepatic (non-]-dependent)
| elimination_half-life = 6 to 8 days and 31 days<ref name=dorlo/>
| elimination_half-life = 6 to 8 days and 31 days <ref name=Dorlo2008>{{cite journal | author = Dorlo TP, van Thiel PP, Huitema AD, Keizer RJ, de Vries HJ, Beijnen JH, de Vries PJ | title = Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients. | journal = Antimicrob Agents Chemother | volume = 52 | issue = 8 | pages = 2855–60 | year = 2008 | pmid = 18519729 | doi = 10.1128/AAC.00014-08 | pmc = 2493105}}</ref>
| excretion = | excretion = Primarily fecal


<!--Identifiers--> <!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = <!-- blanked - oldvalue: 58066-85-6 --> | CAS_number = 58066-85-6
| ATC_prefix = L01
| ATC_suffix = XX09
| PubChem = 3599 | PubChem = 3599
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = | DrugBank = DB09031
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3473 | ChemSpiderID = 3473
| UNII_Ref = {{fdacite|changed|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 53EY29W7EC | UNII = 53EY29W7EC
| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D02494 | KEGG = D02494
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 75283
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 125 | ChEMBL = 125
| NIAID_ChemDB = 130571


<!--Chemical data--> <!-- Chemical and physical data -->
| IUPAC_name = 2-(hexadecoxy-oxido-phosphoryl)oxyethyl-trimethyl-azanium
| C=21 | H=46 | N=1 | O=4 | P=1
| C=21 | H=46 | N=1 | O=4 | P=1
| molecular_weight = 407.568 g/mol
| smiles = P(=O)(OCCCCCCCCCCCCCCCC)OCC(C)(C)C | SMILES = P(=O)(OCCCCCCCCCCCCCCCC)OCC(C)(C)C
| InChI = 1/C21H46NO4P/c1-5-6-7-8-9-10-11-12-13-14-15-16-17-18-20-25-27(23,24)26-21-19-22(2,3)4/h5-21H2,1-4H3
| InChIKey = PQLXHQMOHUQAKB-UHFFFAOYAN
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C21H46NO4P/c1-5-6-7-8-9-10-11-12-13-14-15-16-17-18-20-25-27(23,24)26-21-19-22(2,3)4/h5-21H2,1-4H3 | StdInChI = 1S/C21H46NO4P/c1-5-6-7-8-9-10-11-12-13-14-15-16-17-18-20-25-27(23,24)26-21-19-22(2,3)4/h5-21H2,1-4H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = PQLXHQMOHUQAKB-UHFFFAOYSA-N | StdInChIKey = PQLXHQMOHUQAKB-UHFFFAOYSA-N
| melting_point = 232
| melting_high = 234
}} }}
<!-- Definition and medical uses -->
'''Miltefosine''', sold under the trade name '''Impavido''' among others, is a medication mainly used to treat ] and free-living ] such as '']'' and '']''.<ref name=AHFS2016>{{cite web|author1=American Society of Health-System Pharmacists|title=Miltefosine Monograph for Professionals|url=https://www.drugs.com/monograph/miltefosine.html|website=www.drugs.com|access-date=16 November 2016|date=26 February 2016|url-status=live|archive-url=https://web.archive.org/web/20161117145201/https://www.drugs.com/monograph/miltefosine.html|archive-date=17 November 2016}}</ref> This includes the three forms of leishmaniasis: ], ] and mucosal.<ref name=FDA2014/> It may be used with ] or ].<ref name=WHO2010/> It is taken by mouth.<ref name=FDA2014>{{cite press release|title=FDA approves Impavido to treat tropical disease leishmaniasis|url=https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm389671.htm|work=U.S. ] (FDA)|access-date=30 August 2014|date=19 March 2014|url-status=live|archive-url=https://web.archive.org/web/20140903082843/https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm389671.htm|archive-date=3 September 2014}}</ref>

<!-- Side effects and mechanism -->
Common side effects include ], abdominal pain, ], ], and decreased kidney function.<ref name=AHFS2016/> More severe side effects may include ] or ].<ref name=AHFS2016/> Use during ] appears to cause harm to the baby and use during ] is not recommended.<ref name=AHFS2016/> How it works is not entirely clear.<ref name=AHFS2016/>

<!-- History and culture -->
Miltefosine was first made in the early 1980s and studied as a treatment for ].<ref>{{cite book| vauthors = Greenwood D |title=Antimicrobial Drugs: Chronicle of a Twentieth Century Medical Triumph|date=2008|publisher=OUP Oxford|isbn=978-0-19-953484-5|page=310|url=https://books.google.com/books?id=i4_FZHmzjzwC&pg=PA310|url-status=live|archive-url=https://web.archive.org/web/20170910151716/https://books.google.com/books?id=i4_FZHmzjzwC&pg=PA310|archive-date=2017-09-10}}</ref> A few years later it was found to be useful for leishmaniasis and was approved for this use in 2002 in India.<ref>{{cite book| vauthors = Kumar A |title=Leishmania and Leishmaniasis|date=2013|publisher=Springer Science & Business Media|isbn=978-1-4614-8869-9|page=39|url=https://books.google.com/books?id=5eG5BAAAQBAJ&pg=PA39|url-status=live|archive-url=https://web.archive.org/web/20170910151716/https://books.google.com/books?id=5eG5BAAAQBAJ&pg=PA39|archive-date=2017-09-10}}</ref> It is on the ].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref>

==Medical uses==

===Leishmaniasis===
Miltefosine is primarily used for the treatment of ] and ], and is undergoing ]s for this use in several countries.<ref name=FAPEPI>{{cite news| vauthors = Cristina M, Pedrosa R |title=Hospital de Doenças Tropicais testa droga contra calazar |work=Sapiência |language=pt |publisher=Fundação de Amparo à Pesquisa do Estado do Piauí |date=September 2005 |url=http://www.fapepi.pi.gov.br/sapiencia6/pesquisa3.php |access-date=2006-09-01 |archive-url=https://web.archive.org/web/20060822060527/http://www.fapepi.pi.gov.br/sapiencia6/pesquisa3.php |archive-date=2006-08-22 }}</ref><ref name=Soto>{{cite journal | vauthors = Soto J, Berman J | title = Treatment of New World cutaneous leishmaniasis with miltefosine | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 100 | issue = Suppl 1 | pages = S34–S40 | date = December 2006 | pmid = 16930649 | doi = 10.1016/j.trstmh.2006.02.022 | url = https://zenodo.org/record/1259409 }}</ref> This drug is now listed as a core medication for the treatment of leishmaniasis under the WHO Model List of Essential Medicines.<ref>{{Cite web|url=https://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf|title=19th WHO Model List of Essential Medicines| work = WHO|date=2015|access-date=8 November 2016|url-status=live|archive-url=https://web.archive.org/web/20150513043105/http://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf|archive-date=13 May 2015}}</ref> Several medical agents have some efficacy against visceral or cutaneous leishmaniasis, however, a 2005 survey concluded that miltefosine is the only effective oral treatment for both forms of leishmaniasis.<ref>{{cite journal | vauthors = Berman J | title = Clinical status of agents being developed for leishmaniasis | journal = Expert Opinion on Investigational Drugs | volume = 14 | issue = 11 | pages = 1337–1346 | date = November 2005 | pmid = 16255674 | doi = 10.1517/13543784.14.11.1337 | s2cid = 27189092 | url = https://zenodo.org/record/1236265 }}</ref>

===Amoeba infections===
Miltefosine has been used successfully in some cases of the very rare, but highly lethal, brain infection by the amoeba, '']'', acquired through water entering the nose during a plunge in contaminated water.<ref>{{cite journal | vauthors = Linam WM, Ahmed M, Cope JR, Chu C, Visvesvara GS, da Silva AJ, Qvarnstrom Y, Green J | display-authors = 6 | title = Successful treatment of an adolescent with Naegleria fowleri primary amebic meningoencephalitis | journal = Pediatrics | volume = 135 | issue = 3 | pages = e744–e748 | date = March 2015 | pmid = 25667249 | pmc = 4634363 | doi = 10.1542/peds.2014-2292 }}</ref> It has orphan drug status in the United States for ] and ] (PAM).<ref>{{Cite press release|url= https://www.prnewswire.com/news-releases/profounda-inc-receives-fda-orphan-drug-designation-for-the-treatment-of-primary-amebic-meningoencephalitis-pam-with-miltefosine-300379937.html |title=Profounda Inc. receives FDA orphan-drug designation for the Treatment of Primary Amebic Meningoencephalitis (PAM) with Miltefosine | work = Profounda Inc.| via =www.prnewswire.com|access-date=2017-05-25|url-status=live|archive-url=https://web.archive.org/web/20161222072200/http://www.prnewswire.com/news-releases/profounda-inc-receives-fda-orphan-drug-designation-for-the-treatment-of-primary-amebic-meningoencephalitis-pam-with-miltefosine-300379937.html|archive-date=2016-12-22}}</ref><ref>{{Cite web|url=http://www.prnewswire.com/news-releases/fda-orphan-drug-designation-granted-to-profounda-inc-for-the-treatment-of-acanthamoeba-keratitis-with-miltefosine-300380273.html|title=FDA Orphan Drug Designation Granted to Profounda Inc. for the treatment of Acanthamoeba Keratitis with miltefosine.| work = Profounda Inc.| via = www.prnewswire.com|access-date=2017-05-25|url-status=live|archive-url=https://web.archive.org/web/20161221002837/http://www.prnewswire.com/news-releases/fda-orphan-drug-designation-granted-to-profounda-inc-for-the-treatment-of-acanthamoeba-keratitis-with-miltefosine-300380273.html|archive-date=2016-12-21}}</ref>

=== Pregnancy and breastfeeding ===
Miltefosine is listed as pregnancy category D by the FDA. This means there is evidence-based adverse reaction data from investigational or marketing experience or studies in humans of harm to the human fetus.<ref>{{Cite web|url=https://www.drugs.com/pregnancy-categories.html|title=New FDA Pregnancy Categories Explained | work = Drugs.com |access-date=2016-11-16|url-status=live|archive-url=https://web.archive.org/web/20161116163852/https://www.drugs.com/pregnancy-categories.html|archive-date=2016-11-16}}</ref> Despite this evidence, the potential benefits of miltefosine may warrant use of the drug in pregnant women despite potential risks. A pregnancy test should be done prior to starting treatment. Effective ] should be used while on miltefosine and 5 months after discontinuation of treatment. Its use during breast feeding is most likely unsafe.<ref name="dorlo" />

==Contraindications==
Miltefosine is contraindicated in individuals who have a ] to this medication, pregnant women, and people who have the ].<ref>{{cite web | title=Impavido- miltefosine capsule | website=DailyMed | publisher=Profounda, Inc. | date=5 June 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bcb387ac-2e90-4f5e-94b2-d3635190678e | access-date=26 December 2019}}</ref> It is embryotoxic and fetotoxic in rats and rabbits, and ] in rats but not in rabbits. It is therefore contraindicated for use during pregnancy, and ] is required beyond the end of treatment in women of child-bearing age.<ref>{{cite journal | vauthors = Sindermann H, Engel J | title = Development of miltefosine as an oral treatment for leishmaniasis | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 100 | issue = Suppl 1 | pages = S17–S20 | date = December 2006 | pmid = 16730362 | doi = 10.1016/j.trstmh.2006.02.010 }}</ref>

==Side effects==
Common ]s from miltefosine treatment are ] and ], which occur in 60% of people. Other common side effects are dizziness, headache, and daytime sleepiness.<ref name = "drugs.com">{{Cite web|url=https://www.drugs.com/sfx/miltefosine-side-effects.html|title=Miltefosine Side Effects in Detail | work = Drugs.com |access-date=2016-11-16|url-status=live|archive-url=https://web.archive.org/web/20161117070506/https://www.drugs.com/sfx/miltefosine-side-effects.html|archive-date=2016-11-17}}</ref>

Serious side effects include rash, diarrhea, and arthritis.<ref name = "drugs.com" /> The side effects are more severe in women and young children. The overall effects are quite mild and easily reversed.<ref>{{cite book| vauthors = Seth SD |title=Textbook of Pharmacology|year=2008|publisher=Elsevier India|isbn=978-81-312-1158-8|page=31|url=https://books.google.com/books?id=51ozlZRBvQwC| veditors = Seth SD |chapter=Drug therapy of leishmaniasis|url-status=live|archive-url=https://web.archive.org/web/20170910151716/https://books.google.com/books?id=51ozlZRBvQwC&pg|archive-date=2017-09-10}}</ref>

== Mechanism of action ==
Miltefosine primarily acts on ''Leishmania'' by affecting the species's promastigote and amastigote stages.<ref>{{Cite web|url=http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/1311/impavido-miltefosine|title=Impavido New FDA Drug Approval | work = CenterWatch |access-date=2016-11-09|url-status=live|archive-url=https://web.archive.org/web/20161104192249/http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/1311/impavido-miltefosine|archive-date=2016-11-04}}</ref> Miltefosine exerts its activity by interacting with lipids, inhibiting ] and causing apoptosis-like cell death.<ref>{{Cite web |url= https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM371074.pdf|title=Miltefosine (Impravido) for the Treatment of Visceral, Mucosal and Cutaneous Leishmaniasis| publisher = U.S. Food and Drug Administration |access-date=9 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161024125444/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM371074.pdf|archive-date=2016-10-24}}</ref> This may affect membrane integrity and mitochondrial function of the parasite.{{cn|date=April 2021}}

==History==
===Cancer===
While initially studied as a cancer medication, due to side effects it was never used for this purpose.<ref>{{cite book| vauthors = Cohen J, Powderly WG, Opal SM |title=Infectious Diseases|date=2016|publisher=Elsevier Health Sciences|isbn=978-0-7020-6338-1|page=1367|url=https://books.google.com/books?id=Dhq3DAAAQBAJ&pg=PA1367|url-status=live|archive-url=https://web.archive.org/web/20170910151716/https://books.google.com/books?id=Dhq3DAAAQBAJ&pg=PA1367|archive-date=2017-09-10}}</ref>

] group ] were known since the early 1980s, particularly in terms of their binding affinity with ] venom.<ref>{{cite journal | vauthors = Teshima K, Ikeda K, Hamaguchi K, Hayashi K | title = Bindings of cobra venom phospholipases A2 to micelles of n-hexadecylphosphorylcholine | journal = Journal of Biochemistry | volume = 94 | issue = 1 | pages = 223–232 | date = July 1983 | pmid = 6619110 | doi = 10.1093/oxfordjournals.jbchem.a134333 }}</ref> In 1987 the phospholipids were found to be potent toxins on ].<ref>{{cite journal | vauthors = Fleer EA, Unger C, Kim DJ, Eibl H | title = Metabolism of ether phospholipids and analogs in neoplastic cells | journal = Lipids | volume = 22 | issue = 11 | pages = 856–861 | date = November 1987 | pmid = 3444378 | doi = 10.1007/bf02535544 | s2cid = 4055850 }}</ref> Initial '']'' investigation on the ] activity showed positive result, but then only at high dosage and at high toxicity.<ref>{{cite journal | vauthors = Berger MR, Petru E, Schmähl D | title = Therapeutic ratio of mono or combination bacterial lipopolysaccharide therapy in methylnitrosourea-induced rat mammary carcinoma | journal = Journal of Cancer Research and Clinical Oncology | volume = 113 | issue = 5 | pages = 437–445 | year = 1987 | pmid = 3624299 | doi = 10.1007/bf00390037 | s2cid = 21064546 }}</ref> At the same time in Germany, Hansjörg Eibl, at the ], and Clemens Unger, at the ], demonstrated that the ] of the phospholipid analogue miltefosine (at the time known as hexadecylphosphocholine) was indeed tumour-specific. It was highly effective against ]-induced ], but less so on ] ]s and ] ]-induced ]s, and relatively inactive on Walker 256 ] and autochthonous acetoxymethylmethylnitrosamine-induced ] of rats.<ref>{{cite journal | vauthors = Muschiol C, Berger MR, Schuler B, Scherf HR, Garzon FT, Zeller WJ, Unger C, Eibl HJ, Schmähl D | display-authors = 6 | title = Alkyl phosphocholines: toxicity and anticancer properties | journal = Lipids | volume = 22 | issue = 11 | pages = 930–934 | date = November 1987 | pmid = 3444388 | doi = 10.1007/bf02535558 | s2cid = 24008282 }}</ref><ref>{{cite journal | vauthors = Berger MR, Muschiol C, Schmähl D, Eibl HJ | title = New cytostatics with experimentally different toxic profiles | journal = Cancer Treatment Reviews | volume = 14 | issue = 3–4 | pages = 307–317 | date = December 1987 | pmid = 3440252 | doi = 10.1016/0305-7372(87)90023-5 }}</ref> It was subsequently found that miltefosine was structurally unique among lipids having anticancer property in that it lacks the ] group, is highly selective on cell types and acts through different mechanism.<ref name="Eibl 1990 233–42">{{cite journal | vauthors = Eibl H, Unger C | title = Hexadecylphosphocholine: a new and selective antitumor drug | journal = Cancer Treatment Reviews | volume = 17 | issue = 2–3 | pages = 233–242 | date = September 1990 | pmid = 2272038 | doi = 10.1016/0305-7372(90)90053-i | hdl-access = free | hdl = 11858/00-001M-0000-0013-0D40-8 }}</ref><ref>{{cite journal | vauthors = Hilgard P, Stekar J, Voegeli R, Engel J, Schumacher W, Eibl H, Unger C, Berger MR | display-authors = 6 | title = Characterization of the antitumor activity of hexadecylphosphocholine (D 18506) | journal = European Journal of Cancer & Clinical Oncology | volume = 24 | issue = 9 | pages = 1457–1461 | date = September 1988 | pmid = 3141197 | doi = 10.1016/0277-5379(88)90336-7 }}</ref>

===Leishmaniasis===
In the same year as the discovery of the anticancer property, miltefosine was reported by S. L. Croft and his team at the ] as having antileishmanial effect as well. The compound was effective against '']'' ]s in cultured mouse peritoneal ]s at a dose of 12.8&nbsp;mg/kg/day in a five-day course.<ref>{{cite journal | vauthors = Croft SL, Neal RA, Pendergast W, Chan JH | title = The activity of alkyl phosphorylcholines and related derivatives against Leishmania donovani | journal = Biochemical Pharmacology | volume = 36 | issue = 16 | pages = 2633–2636 | date = August 1987 | pmid = 3606662 | doi = 10.1016/0006-2952(87)90543-0 }}</ref> However, priority was given to the development of the compound for cutaneous ] of ]. In 1992 a new research was reported in which the compound was highly effective in mouse against different ] of different ''Leishmania'' species, and in fact, more potent than the conventional ] therapy by a factor of more than 600.<ref>{{cite journal | vauthors = Kuhlencord A, Maniera T, Eibl H, Unger C | title = Hexadecylphosphocholine: oral treatment of visceral leishmaniasis in mice | journal = Antimicrobial Agents and Chemotherapy | volume = 36 | issue = 8 | pages = 1630–1634 | date = August 1992 | pmid = 1329624 | pmc = 192021 | doi = 10.1128/AAC.36.8.1630 }}</ref> Results of the first clinical trial in humans were reported from Indian patients with chronic leishmaniasis with high degree of success and safety.<ref>{{cite journal | vauthors = Sundar S, Rosenkaimer F, Makharia MK, Goyal AK, Mandal AK, Voss A, Hilgard P, Murray HW | display-authors = 6 | title = Trial of oral miltefosine for visceral leishmaniasis | journal = Lancet | volume = 352 | issue = 9143 | pages = 1821–1823 | date = December 1998 | pmid = 9851383 | doi = 10.1016/S0140-6736(98)04367-0 | s2cid = 33761492 | doi-access = free }}</ref> This promising development promulgated a unique public–private partnership collaboration between ] (later Zentaris GmbH), the ] (WHO) Special Programme for Research and Training in Tropical Diseases, and the ]. Eventually, several successful Phase II and III trials led to the approval of miltefosine in 2002 as the first and only oral drug for leishmaniasis.<ref name=dorlo>{{cite journal | vauthors = Dorlo TP, Balasegaram M, Beijnen JH, de Vries PJ | title = Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis | journal = The Journal of Antimicrobial Chemotherapy | volume = 67 | issue = 11 | pages = 2576–2597 | date = November 2012 | pmid = 22833634 | doi = 10.1093/jac/dks275 | doi-access = free }}</ref>

===''Naegleria fowleri'' and ''Acanthamoeba''===

In 2013, the US ] recommended miltefosine for the treatment of free-living amoeba infections such as ] and ], two fatal protozoal diseases.<ref>{{cite journal | title = Investigational drug available directly from CDC for the treatment of infections with free-living amebae | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 62 | issue = 33 | page = 666 | date = August 2013 | pmid = 23965830 | pmc = 4604798 | url = https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6233a4.htm | url-status = live | archive-url = https://web.archive.org/web/20170711092614/https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6233a4.htm | archive-date = 2017-07-11 | author1 = Centers for Disease Control and Prevention (CDC) }}</ref> Historically, only four survivors have been recorded out of 138 confirmed infections in North America. One American survived the infection in 1978 and one individual from Mexico in 2003. In 2013, two children survived and recovered from primary amoebic meningoencephalitis after treatment with miltefosine.<ref name=cdc>{{cite web |title=Naegleria fowleri - Primary Amebic Meningoencephalitis (PAM)|url=https://www.cdc.gov/parasites/naegleria/treatment.html|publisher=Centers for Disease Control and Prevention|access-date=29 August 2014|year=2014|url-status=live|archive-url=https://web.archive.org/web/20150214042623/http://www.cdc.gov/parasites/naegleria/treatment.html|archive-date=14 February 2015}}</ref><ref>{{cite web| vauthors = Gholipour B |title=Brain-Eating Amoeba: How One Girl Survived|url=http://www.livescience.com/38897-how-to-survive-a-brain-eating-amoeba.html|work=livescience|access-date=29 August 2014|date=14 August 2013|url-status=live|archive-url=https://web.archive.org/web/20141003131011/http://www.livescience.com/38897-how-to-survive-a-brain-eating-amoeba.html|archive-date=3 October 2014}}</ref> In 2016 after treatment that included miltefosine, another child became the fourth person in the United States to survive '']'' infection.<ref>{{cite news| vauthors = Goldschmidt D, Scutti S |title=Rare recovery: Florida teen survives brain-eating amoeba|url=http://www.cnn.com/2016/08/23/health/brain-eating-amoeba-florida-teen-survives/|access-date=23 August 2016|agency=CNN|url-status=live|archive-url=https://web.archive.org/web/20160824145826/http://www.cnn.com/2016/08/23/health/brain-eating-amoeba-florida-teen-survives/|archive-date=24 August 2016}}</ref>

==Society and culture==
===Availability===
Since 2017 Miltefosine is commercially available in the United States through Profounda.<ref>{{Cite press release|url=http://www.prnewswire.com/news-releases/profounda-inc-launches-impavido-miltefosine-the-first-and-only-oral-rx-treatment-for-visceral-mucosal-and-cutaneous-leishmaniasis-in-the-united-states-300238867.html|title=Profounda, Inc. launches Impavido (miltefosine), the first and only oral Rx treatment for visceral, mucosal and cutaneous leishmaniasis, in the United States | work =Profounda Inc. | via = www.prnewswire.com|access-date=2017-05-25|url-status=live|archive-url=https://web.archive.org/web/20170316075853/http://www.prnewswire.com/news-releases/profounda-inc-launches-impavido-miltefosine-the-first-and-only-oral-rx-treatment-for-visceral-mucosal-and-cutaneous-leishmaniasis-in-the-united-states-300238867.html|archive-date=2017-03-16}}</ref> Previously one could only get it from the ] for emergency use under an expanded access ] protocol for treatment of free-living amoeba (FLA) infections: ] caused by '']'' and granulomatous amoebic encephalitis caused by '']'' and '']'' species.<ref name="cdc" /> Miltefosine is almost exclusively produced by Profounda, a private pharmaceutical company.<ref>{{cite web | vauthors = Wessel L | date = 17 September 2016 |url=http://www.businessinsider.com/why-brain-eating-amoeba-miltefosine-medicine-is-hard-to-find-2016-9?amp |title=A life-saving drug that treats a rare infection is almost impossible to find |website=] |access-date=2016-11-01 |url-status=live |archive-url=https://web.archive.org/web/20160919150218/http://www.businessinsider.com/why-brain-eating-amoeba-miltefosine-medicine-is-hard-to-find-2016-9?amp |archive-date=2016-09-19 }}</ref>

=== Economics ===
In the ] a course of treatment costs US$65 to $150.<ref name=WHO2010/> In the ] treatment may be 10 to 50 times greater.<ref name=WHO2010>{{cite book|title=Control of the leishmaniasis: report of a meeting of the WHO Expert Committee on the Control of Leishmaniases|date=March 2010| vauthors = ((World Health Organization)) | author-link = World Health Organization | publisher=World Health Organization|isbn=978-92-4-120949-6|pages=59, 88, 186 | hdl=10665/44412}}</ref>

==Further research==
It is active against some ] and ],<ref name="dorlo" /><ref>{{cite journal | vauthors = Pachioni J, Magalhães JG, Lima EJ, Bueno L, Barbosa JF, de Sá MM, Rangel-Yagui CO | title = Alkylphospholipids - a promising class of chemotherapeutic agents with a broad pharmacological spectrum | journal = Journal of Pharmacy & Pharmaceutical Sciences | volume = 16 | issue = 5 | pages = 742–759 | year = 2013 | pmid = 24393556 | doi = 10.18433/J3CW23 | doi-access = free }}</ref> as well as human ] '']'' and the snail that spreads it '']''.<ref>{{cite journal | vauthors = Eissa MM, El Bardicy S, Tadros M | title = Bioactivity of miltefosine against aquatic stages of Schistosoma mansoni, Schistosoma haematobium and their snail hosts, supported by scanning electron microscopy | journal = Parasites & Vectors | volume = 4 | issue = 1 | page = 73 | date = May 2011 | pmid = 21569375 | pmc = 3114006 | doi = 10.1186/1756-3305-4-73 | doi-access = free }}</ref>

===Antiprotozoal and antifungal activities===
Miltefosine is being investigated by researchers interested in finding treatments for infections which have become resistant to existing drugs. Animal and '']'' studies suggest it may have broad anti-protozoal and anti-fungal properties:
* Animal studies suggest miltefosine may also be effective against '']'', the ] responsible for ].<ref name=Saraiva>{{cite journal | vauthors = Saraiva VB, Gibaldi D, Previato JO, Mendonça-Previato L, Bozza MT, Freire-De-Lima CG, Heise N | title = Proinflammatory and cytotoxic effects of hexadecylphosphocholine (miltefosine) against drug-resistant strains of Trypanosoma cruzi | journal = Antimicrobial Agents and Chemotherapy | volume = 46 | issue = 11 | pages = 3472–3477 | date = November 2002 | pmid = 12384352 | pmc = 128733 | doi = 10.1128/AAC.46.11.3472-3477.2002 }}</ref>
* Several studies have found the drug to be effective against types of fungus: '']'', '']'', '']'' and '']''.<ref name=Widmer>{{cite journal | vauthors = Widmer F, Wright LC, Obando D, Handke R, Ganendren R, Ellis DH, Sorrell TC | title = Hexadecylphosphocholine (miltefosine) has broad-spectrum fungicidal activity and is efficacious in a mouse model of cryptococcosis | journal = Antimicrobial Agents and Chemotherapy | volume = 50 | issue = 2 | pages = 414–421 | date = February 2006 | pmid = 16436691 | pmc = 1366877 | doi = 10.1128/AAC.50.2.414-421.2006 }}</ref>
* A 2006 ''in vitro'' study found that miltefosine is effective against metronidazole-resistant variants of '']'', a sexually transmitted protozoal disease.<ref name=pmid16344287>{{cite journal | vauthors = Blaha C, Duchêne M, Aspöck H, Walochnik J | title = In vitro activity of hexadecylphosphocholine (miltefosine) against metronidazole-resistant and -susceptible strains of Trichomonas vaginalis | journal = The Journal of Antimicrobial Chemotherapy | volume = 57 | issue = 2 | pages = 273–278 | date = February 2006 | pmid = 16344287 | doi = 10.1093/jac/dki417 | doi-access = free }}</ref>
* ], a compound related to miltefosine, was demonstrated in 2007 to exhibit potent ''in vitro'' activity against '']''.<ref name=Choubey2006>{{cite journal | vauthors = Choubey V, Maity P, Guha M, Kumar S, Srivastava K, Puri SK, Bandyopadhyay U | title = Inhibition of Plasmodium falciparum choline kinase by hexadecyltrimethylammonium bromide: a possible antimalarial mechanism | journal = Antimicrobial Agents and Chemotherapy | volume = 51 | issue = 2 | pages = 696–706 | date = February 2007 | pmid = 17145794 | pmc = 1797733 | doi = 10.1128/AAC.00919-06 }}</ref>
* An ''in vitro'' test in 2006 showed that miltefosine is effective against the deadly protozoan pathogens, ''Naegleria fowleri'', ''Balamuthia mandrillaris'', and ''Acanthamoeba''.<ref>{{cite journal | vauthors = Schuster FL, Guglielmo BJ, Visvesvara GS | title = In-vitro activity of miltefosine and voriconazole on clinical isolates of free-living amebas: Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri | journal = The Journal of Eukaryotic Microbiology | volume = 53 | issue = 2 | pages = 121–126 | year = 2006 | pmid = 16579814 | doi = 10.1111/j.1550-7408.2005.00082.x | s2cid = 25517350 }}</ref> However, later ''in vitro'' and animal model experiments showed that it is not as potent as other drugs, such as ]<ref>{{cite journal | vauthors = Kim JH, Jung SY, Lee YJ, Song KJ, Kwon D, Kim K, Park S, Im KI, Shin HJ | display-authors = 6 | title = Effect of therapeutic chemical agents in vitro and on experimental meningoencephalitis due to Naegleria fowleri | journal = Antimicrobial Agents and Chemotherapy | volume = 52 | issue = 11 | pages = 4010–4016 | date = November 2008 | pmid = 18765686 | pmc = 2573150 | doi = 10.1128/AAC.00197-08 }}</ref> and ] (Berenil).<ref>{{cite journal | vauthors = Ahmad AF, Heaselgrave W, Andrew PW, Kilvington S | title = The in vitro efficacy of antimicrobial agents against the pathogenic free-living amoeba Balamuthia mandrillaris | journal = The Journal of Eukaryotic Microbiology | volume = 60 | issue = 5 | pages = 539–543 | year = 2013 | pmid = 23869955 | doi = 10.1111/jeu.12062 | s2cid = 12941376 }}</ref>
* In 2013, there were reports of failure of miltefosine in the treatment of leishmaniasis.<ref>{{cite journal | vauthors = Rijal S, Ostyn B, Uranw S, Rai K, Bhattarai NR, Dorlo TP, Beijnen JH, Vanaerschot M, Decuypere S, Dhakal SS, Das ML, Karki P, Singh R, Boelaert M, Dujardin JC | display-authors = 6 | title = Increasing failure of miltefosine in the treatment of Kala-azar in Nepal and the potential role of parasite drug resistance, reinfection, or noncompliance | journal = Clinical Infectious Diseases | volume = 56 | issue = 11 | pages = 1530–1538 | date = June 2013 | pmid = 23425958 | doi = 10.1093/cid/cit102 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Rai K, Cuypers B, Bhattarai NR, Uranw S, Berg M, Ostyn B, Dujardin JC, Rijal S, Vanaerschot M | display-authors = 6 | title = Relapse after treatment with miltefosine for visceral leishmaniasis is associated with increased infectivity of the infecting Leishmania donovani strain | journal = mBio | volume = 4 | issue = 5 | pages = e00611–e00613 | date = October 2013 | pmid = 24105765 | pmc = 3791894 | doi = 10.1128/mBio.00611-13 }}</ref> Although ] was suspected, studies in 2014 reported that miltefosine is not so effective in children, most probably related to a lack of drug exposure in children.<ref>{{cite journal | vauthors = Dorlo TP, Rijal S, Ostyn B, de Vries PJ, Singh R, Bhattarai N, Uranw S, Dujardin JC, Boelaert M, Beijnen JH, Huitema AD | display-authors = 6 | title = Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure | journal = The Journal of Infectious Diseases | volume = 210 | issue = 1 | pages = 146–153 | date = July 2014 | pmid = 24443541 | doi = 10.1093/infdis/jiu039 | doi-access = free }}</ref> Moverover, males appeared to have a higher probability of relapse as well.<ref>{{cite journal | vauthors = Ostyn B, Hasker E, Dorlo TP, Rijal S, Sundar S, Dujardin JC, Boelaert M | title = Failure of miltefosine treatment for visceral leishmaniasis in children and men in South-East Asia | journal = PLOS ONE | volume = 9 | issue = 6 | pages = e100220 | year = 2014 | pmid = 24941345 | pmc = 4062493 | doi = 10.1371/journal.pone.0100220 | doi-access = free | bibcode = 2014PLoSO...9j0220O }}</ref>
* A 2012 ''in vitro'' study found that miltefosine had promising activity against '']'' ]s.<ref>{{cite journal | vauthors = Vila TV, Ishida K, de Souza W, Prousis K, Calogeropoulou T, Rozental S | title = Effect of alkylphospholipids on Candida albicans biofilm formation and maturation | journal = The Journal of Antimicrobial Chemotherapy | volume = 68 | issue = 1 | pages = 113–125 | date = January 2013 | pmid = 22995097 | doi = 10.1093/jac/dks353 | doi-access = }}</ref>

===Anti-HIV activity===

Miltefosine targets HIV infected ], which play a role ] as long-lived HIV-1 reservoirs. The HIV protein ] activates pro-survival ]/] pathway in primary human macrophages. Miltefosine acts by inhibiting the ], thus removing the infected macrophages from circulation, without affecting healthy cells.<ref name=pmid18237430>{{cite journal | vauthors = Chugh P, Bradel-Tretheway B, Monteiro-Filho CM, Planelles V, Maggirwar SB, Dewhurst S, Kim B | title = Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy | journal = Retrovirology | volume = 5 | issue = 1 | page = 11 | date = January 2008 | pmid = 18237430 | pmc = 2265748 | doi = 10.1186/1742-4690-5-11 | doi-access = free }}</ref><ref name="titleAIDSmeds.com - Top Stories : Parasitic Drug Shows HIV-Fighting Promise">{{cite web |url=http://www.aidsmeds.com/articles/hiv_miltefosine_macrophages_1667_13933.shtml |title=Parasitic Drug Shows HIV-Fighting Promise |access-date=2008-02-02 |date=2008-02-01 |publisher=AIDSmeds.com |archive-url=https://web.archive.org/web/20080212122209/http://www.aidsmeds.com/articles/hiv_miltefosine_macrophages_1667_13933.shtml |archive-date=2008-02-12 }}</ref> It significantly reduces replication of HIV-1 in cocultures of human ]s (DCs) and ]s, which is due to a rapid secretion of soluble factors and is associated with induction of type-I ] (IFN) in the human cells.<ref>{{cite journal | vauthors = Garg R, Tremblay MJ | title = Miltefosine represses HIV-1 replication in human dendritic cell/T-cell cocultures partially by inducing secretion of type-I interferon | journal = Virology | volume = 432 | issue = 2 | pages = 271–276 | date = October 2012 | pmid = 22704066 | doi = 10.1016/j.virol.2012.05.032 | doi-access = free }}</ref>

== References ==
{{Reflist}}

== External links ==
* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/miltefosine | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Miltefosine }}
* {{cite web | title = Miltefosine | url = https://www.drugs.com/international/miltefosine.html | work = Drugs.com }}

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