| 词条 | Miltefosine |
| 释义 |
| Verifiedfields = changed | verifiedrevid = 462252576 | IUPAC_name = 2-(hexadecoxy-oxido-phosphoryl)oxyethyl-trimethyl-azanium | image = Miltefosine structure.svg | width = 250 | tradename = Impavido, Miltex, others | Drugs.com = {{drugs.com|monograph|miltefosine}} | pregnancy_AU = | pregnancy_US = D | pregnancy_US_comment = [1] | pregnancy_category = | legal_AU = | legal_UK = | legal_US = Rx-only | legal_status = ℞-only | routes_of_administration = By mouth | bioavailability = High | protein_bound = ~98% | metabolism = Slow hepatic (non-CYP-dependent) | elimination_half-life = 6 to 8 days and 31 days[2] | excretion = Primarily fecal | CAS_number_Ref = {{cascite|changed|??}} | CAS_number = 58066-85-6 | ATC_prefix = L01 | ATC_suffix = XX09 | PubChem = 3599 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 3473 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 53EY29W7EC | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D02494 | ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI = 75283 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 125 | NIAID_ChemDB = 130571 | C=21 | H=46 | N=1 | O=4 | P=1 | molecular_weight = 407.568 g/mol | smiles = [O-]P(=O)(OCCCCCCCCCCCCCCCC)OCC[N+](C)(C)C | 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 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = PQLXHQMOHUQAKB-UHFFFAOYSA-N }}Miltefosine, sold under the trade name Impavido among others, is a medication mainly used to treat leishmaniasis and free-living amoeba infections such as Naegleria fowleri.[1] This includes leishmaniasis of the cutaneous, visceral, and mucosal types.[4] It may be used together with liposomal amphotericin B or paromomycin.[5] It is taken by mouth.[2] Common side effects include vomiting, abdominal pain, fever, headaches, and decreased kidney function.[1] More severe side effects may include Stevens-Johnson syndrome or low blood platelets.[1] Use during pregnancy appears to cause harm to the baby and use during breastfeeding is not recommended.[1] How it works is not entirely clear.[1] Miltefosine was first made in the early 1980s and studied as a treatment for cancer.[3] A few years later it was found to be useful for leishmaniasis and was approved for this use in 2002 in India.[4] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] In the developing world a course of treatment costs US$65 to $150.[5] In the developed world treatment may be 10 to 50 times greater.[6] Medical usesMiltefosine is primarily used for the treatment of visceral and New World cutaneous leishmaniasis, and is undergoing clinical trials for this use in several countries.[7][8] This drug is now listed as a core medication for the treatment of leishmaniasis under the WHO Model List of Essential Medicines.[9] 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.[10] In addition, it has been used successfully in some cases of the very rare, but highly lethal, brain infection by the amoeba, Naegleria fowleri, acquired through water entering the nose during a plunge in contaminated water.[11] It has orphan drug status in the United States for acanthamoeba keratitis and primary amebic meningoencephalitis (PAM).[12][13] It is active against some bacteria and fungi,[2][14] as well as human trematode Schistosoma mansoni and the snail that spreads it Biomphalaria alexandrina.[15] Pregnancy and breastfeedingMiltefosine 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.[16] 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 birth control should be used while on miltefosine and 5 months after discontinuation of treatment. Its use during breast feeding is most likely unsafe.[2] ContraindicationsMiltefosine is contraindicated in individuals who have a hypersensitivity to this medication, pregnant women, and people who have the Sjögren-Larsson syndrome.[17] It is embryotoxic and fetotoxic in rats and rabbits, and teratogenic in rats but not in rabbits. It is therefore contraindicated for use during pregnancy, and contraception is required beyond the end of treatment in women of child-bearing age.[18] Side effectsCommon side effects from miltefosine treatment are nausea and vomiting, which occur in 60% of people. Other common side effects are dizziness, headache, and daytime sleepiness.[19] Serious side effects include rash, diarrhea, and arthritis.[20] The side effects are more severe in women and young children. The overall effects are quite mild and easily reversed.[21] Mechanism of actionMiltefosine primarily acts on Leishmania by affecting the species's promastigote and amastigote stages.[22] Miltefosine exerts its activity by interacting with lipids, inhibiting cytochrome c oxidase and causing apoptosis-like cell death.[23] This may affect membrane integrity and mitochondrial function of the parasite. HistoryCancerWhile initially studied as a cancer medication, due to side effects it was never used for this purpose.[24] Phospholipid group alkylphosphocholine were known since the early 1980s, particularly in terms of their binding affinity with cobra venom.[25] In 1987 the phospholipids were found to be potent toxins on leukemic cell culture.[26] Initial in vivo investigation on the antineoplastic activity showed positive result, but then only at high dosage and at high toxicity.[27] At the same time in Germany, Hansjörg Eibl, at the Max Planck Institute for Biophysical Chemistry, and Clemens Unger, at the University of Göttingen, demonstrated that the antineoplastic activity of the phospholipid analogue miltefosine (at the time known as hexadecylphosphocholine) was indeed tumour-specific. It was highly effective against methylnitrosourea-induced mammary carcinoma, but less so on transplantable mammary carcinomas and autochthonous benzo(a)pyrene-induced sarcomas, and relatively inactive on Walker 256 carcinosarcoma and autochthonous acetoxymethylmethylnitrosamine-induced colonic tumors of rats.[28][29] It was subsequently found that miltefosine was structurally unique among lipids having anticancer property in that it lacks the glycerol group, is highly selective on cell types and acts through different mechanism.[30][31]LeishmaniasisIn the same year as the discovery of the anticancer property, miltefosine was reported by S. L. Croft and his team at the London School of Hygiene and Tropical Medicine as having antileishmanial effect as well. The compound was effective against Leishmania donovani amastigotes in cultured mouse peritoneal macrophages at a dose of 12.8 mg/kg/day in a five-day course.[32] However, priority was given to the development of the compound for cutaneous metastases of breast cancer. In 1992 a new research was reported in which the compound was highly effective in mouse against different life cycle stages of different Leishmania species, and in fact, more potent than the conventional sodium stibogluconate therapy by a factor of more than 600.[33] Results of the first clinical trial in humans were reported from Indian patients with chronic leishmaniasis with high degree of success and safety.[34] This promising development promulgated a unique public–private partnership collaboration between ASTA Medica (later Zentaris GmbH), the WHO Special Programme for Research and Training in Tropical Diseases, and the Government of India. 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.[35] Naegleria fowleri and acanthamoebaIn 2013, the US Centers for Disease Control and Prevention recommended miltefosine for the treatment of free-living amebae infections such as granulomatous amoebic encephalitis and primary amoebic meningoencephalitis, two fatal protozoal diseases.[36] 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.[37][38] In 2016 after treatment that included miltefosine, another child became the fourth person in the United States to survive Naegleria fowleri infection.[39] Society and cultureAvailabilityMiltefosine is commercially available in the United States through Profounda.[40] Previously one could only get it from the CDC for emergency use under an expanded access IND protocol for treatment of free-living amoeba (FLA) infections): primary amoebic meningoencephalitis caused by Naegleria fowleri and granulomatous amoebic encephalitis caused by Balamuthia mandrillaris, and Acanthamoeba species.[37] Miltefosine is also produced by Profounda, a private pharmaceutical company.[41] Further researchAntiprotozoal and antifungal activitiesMiltefosine is being investigated by researchers interested in finding treatments for infections which have become resistant to existing drugs. Animal and in vitro studies suggest it may have broad anti-protozoal and anti-fungal properties:
Anti-HIV activityMiltefosine targets HIV infected macrophages, which play a role in vivo as long-lived HIV-1 reservoirs. The HIV protein Tat activates pro-survival PI3K/Akt pathway in primary human macrophages. Miltefosine acts by inhibiting the PI3K/Akt pathway, thus removing the infected macrophages from circulation, without affecting healthy cells.[55][56] It significantly reduces replication of HIV-1 in cocultures of human dendritic cells (DCs) and CD4+ T cells, which is due to a rapid secretion of soluble factors and is associated with induction of type-I interferon (IFN) in the human cells.[57] References1. ^1 2 3 4 5 {{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|accessdate=16 November 2016|date=26 February 2016|deadurl=no|archiveurl=https://web.archive.org/web/20161117145201/https://www.drugs.com/monograph/miltefosine.html|archivedate=17 November 2016|df=}} 2. ^1 {{cite web|last1=Yao|first1=Stephanie|title=FDA approves Impavido to treat tropical disease leishmaniasis|url=http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm389671.htm|work=FDA NEWS RELEASE|publisher=U.S. Food and Drug Administration|accessdate=30 August 2014|date=19 March 2014|deadurl=no|archiveurl=https://web.archive.org/web/20140903082843/http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm389671.htm|archivedate=3 September 2014|df=}} 3. ^{{cite book|last1=Greenwood|first1=David|title=Antimicrobial Drugs: Chronicle of a Twentieth Century Medical Triumph|date=2008|publisher=OUP Oxford|isbn=9780199534845|page=310|url=https://books.google.com/books?id=i4_FZHmzjzwC&pg=PA310|language=en|deadurl=no|archiveurl=https://web.archive.org/web/20170910151716/https://books.google.com/books?id=i4_FZHmzjzwC&pg=PA310|archivedate=2017-09-10|df=}} 4. ^{{cite book|last1=Kumar|first1=Awanish|title=Leishmania and Leishmaniasis|date=2013|publisher=Springer Science & Business Media|isbn=9781461488699|page=39|url=https://books.google.com/books?id=5eG5BAAAQBAJ&pg=PA39|language=en|deadurl=no|archiveurl=https://web.archive.org/web/20170910151716/https://books.google.com/books?id=5eG5BAAAQBAJ&pg=PA39|archivedate=2017-09-10|df=}} 5. ^{{cite web|title=WHO Model List of Essential Medicines (19th List)|url=http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1|work=World Health Organization|accessdate=8 December 2016|date=April 2015|deadurl=no|archiveurl=https://web.archive.org/web/20161213052708/http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1|archivedate=13 December 2016|df=}} 6. ^1 2 {{cite book|title=Control of the leishmaniasis: report of a meeting of the WHO Expert Committee on the Control of Leishmaniases|date=March 2010|publisher=World Health Organization|isbn=9789241209496|pages=59, 88, 186|url=http://apps.who.int/iris/bitstream/10665/44412/1/WHO_TRS_949_eng.pdf?ua=1|deadurl=no|archiveurl=https://web.archive.org/web/20160608074251/http://apps.who.int/iris/bitstream/10665/44412/1/WHO_TRS_949_eng.pdf?ua=1|archivedate=2016-06-08|df=}} 7. ^{{cite news|last=Cristina |first=Márcia |author2=Pedrosa, Robert |title=Hospital de Doenças Tropicais testa droga contra calazar |work=Sapiência |language=Portuguese |publisher=Fundação de Amparo à Pesquisa do Estado do Piauí |date=September 2005 |url=http://www.fapepi.pi.gov.br/sapiencia6/pesquisa3.php |accessdate=2006-09-01 |archiveurl=https://web.archive.org/web/20060822060527/http://www.fapepi.pi.gov.br/sapiencia6/pesquisa3.php |archivedate=2006-08-22 |deadurl=yes |df= }} 8. ^{{cite journal |vauthors=Soto J, Berman J |title=Treatment of New World cutaneous leishmaniasis with miltefosine |journal=Trans R Soc Trop Med Hyg |year=2006 |pmid=16930649 |doi=10.1016/j.trstmh.2006.02.022 |volume=100 |pages=S34–40 }} 9. ^{{Cite web|url=http://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf|title=19th WHO Model List of Essential Medicines|last=WHO|first=|date=2015|website=|publisher=|access-date=8 November 2016|deadurl=no|archiveurl=https://web.archive.org/web/20150513043105/http://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf|archivedate=13 May 2015|df=}} 10. ^{{Cite journal | last1 = Berman | first1 = J. | title = Clinical status of agents being developed for leishmaniasis | doi = 10.1517/13543784.14.11.1337 | journal = Expert Opinion on Investigational Drugs | volume = 14 | issue = 11 | pages = 1337–1346 | year = 2005 | pmid = 16255674| pmc = }} 11. ^{{Cite journal|last=Linam|first=W. 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14 : Antiprotozoal agents|Antifungals|Quaternary ammonium compounds|Antiretroviral drugs|Antineoplastic drugs|Zwitterionic surfactants|Protein kinase inhibitors|Embryotoxicants|Fetotoxicants|Drugs acting on the blood and blood forming organs|Antivirals|German inventions|World Health Organization essential medicines|RTT |
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