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Miltefosine
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| Systematic (IUPAC) name |
| 2-(hexadecoxy-oxido-phosphoryl)oxyethyl-trimethyl-azanium |
| Clinical data |
| AHFS/Drugs.com |
International Drug Names |
| Pregnancy cat. |
? |
| Legal status |
? |
| Routes |
Oral |
| Pharmacokinetic data |
| Bioavailability |
High |
| Half-life |
6 to 8 days and 31 days [1] |
| Identifiers |
| CAS number |
58066-85-6 N |
| ATC code |
L01XX09 |
| PubChem |
CID 3599 |
| ChemSpider |
3473 Y |
| UNII |
53EY29W7EC Y |
| KEGG |
D02494 Y |
| ChEMBL |
CHEMBL125 Y |
| NIAID ChemDB |
130571 |
| Chemical data |
| Formula |
C21H46NO4P |
| Mol. mass |
407.568 g/mol |
SMILES
- [O-]P(=O)(OCCCCCCCCCCCCCCCC)OCC[N+](C)(C)C
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InChI
-
InChI=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 Y
Key:PQLXHQMOHUQAKB-UHFFFAOYSA-N Y
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N (what is this?) (verify)
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Miltefosine (INN, trade names Impavido and Miltex) is a phospholipid drug.
Originally developed as an antineoplastic (and licenced for topical use),[2] it is finding use as an antiprotozoal drug. It can be administered orally and topically.
It acts as an Akt inhibitor.
It is also under investigation as a potential therapy against HIV infection.[3][2]
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Contents
- 1 Current antiprotozoal and antifungal applications
- 2 Investigatory antiprotozoal and antifungal usage
- 3 Investigatory usage against HIV infection
- 4 Side effects
- 5 References
- 6 External links
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Current antiprotozoal and antifungal applications
Leishmania: Miltefosine is registered and used by Zentaris GmbH in India, Colombia and Germany for the treatment of visceral and cutaneous leishmaniasis, and is undergoing clinical trials for this use in several other countries, such as Brazil[4] and Guatemala.[5] 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.[6]
Investigatory antiprotozoal and antifungal usage
Miltefosine 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:
- Animal studies suggest miltefosine may also be effective against Trypanosoma cruzi, the parasite responsible for Chagas' disease.[7]
- Several studies have found the drug to be effective against Cryptococcus neoformans, Candida, Aspergillus and Fusarium.[8]
- An in-vitro study found that Miltefosine is effective against metronidazole-resistant variants of Trichomonas vaginalis, a sexually transmitted protozoal disease.[9]
- Hexadecyltrimethylammonium bromide, a compound structurally similar to miltefosine, was recently found to exhibit potent in vitro activity against Plasmodium falciparum.[10]
Investigatory usage against HIV infection
Miltefosine 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.[2]
Side effects
The main side effects reported with miltefosine treatment are nausea and vomiting. Miltefosine has exhibited teratogenicity, and should not be administered to pregnant women.
References
- ^ Dorlo TP, van Thiel PP, Huitema AD, Keizer RJ, de Vries HJ, Beijnen JH, de Vries PJ (2008). "Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients.". Antimicrob Agents Chemother 52 (8): 2855–60. doi:10.1128/AAC.00014-08. PMC 2493105. PMID 18519729. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2493105/.
- ^ a b c Chugh P, Bradel-Tretheway B, Monteiro-Filho CM, et al. (2008). "Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy". Retrovirology 5 (1): 11. doi:10.1186/1742-4690-5-11. PMC 2265748. PMID 18237430. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2265748/.
- ^ "Parasitic Drug Shows HIV-Fighting Promise". AIDSmeds.com. 2008-02-01. http://www.aidsmeds.com/articles/hiv_miltefosine_macrophages_1667_13933.shtml. Retrieved 2008-02-02.
- ^ Cristina, Márcia; Pedrosa, Robert (September 2005). "Hospital de Doenças Tropicais testa droga contra calazar" (in Portuguese). Sapiência (Fundação de Amparo à Pesquisa do Estado do Piauí). Archived from the original on 2006-08-22. http://web.archive.org/web/20060822060527/http://www.fapepi.pi.gov.br/sapiencia6/pesquisa3.php. Retrieved 2006-09-01.
- ^ Soto J, Berman J (2006). "Treatment of New World cutaneous leishmaniasis with miltefosine.". Trans R Soc Trop Med Hyg 100: S34. doi:10.1016/j.trstmh.2006.02.022. PMID 16930649.
- ^ Berman, J. (2005). "Clinical status of agents being developed for leishmaniasis". Expert Opinion on Investigational Drugs 14 (11): 1337–1346. doi:10.1517/13543784.14.11.1337. PMID 16255674.
- ^ Saraiva V, Gibaldi D, Previato J, Mendonça-Previato L, Bozza M, Freire-De-Lima C, Heise N (2002). "Proinflammatory and cytotoxic effects of hexadecylphosphocholine (miltefosine) against drug-resistant strains of Trypanosoma cruzi.". Antimicrob Agents Chemother 46 (11): 3472–7. doi:10.1128/AAC.46.11.3472-3477.2002. PMC 128733. PMID 12384352. //www.ncbi.nlm.nih.gov/pmc/articles/PMC128733/.
- ^ Widmer F, Wright L, Obando D, Handke R, Ganendren R, Ellis D, Sorrell T (2006). "Hexadecylphosphocholine (miltefosine) has broad-spectrum fungicidal activity and is efficacious in a mouse model of cryptococcosis.". Antimicrob Agents Chemother 50 (2): 414–21. doi:10.1128/AAC.50.2.414-421.2006. PMC 1366877. PMID 16436691. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1366877/.
- ^ Blaha C, Duchêne M, Aspöck H, Walochnik J (2006). "In vitro activity of hexadecylphosphocholine (miltefosine) against metronidazole-resistant and -susceptible strains of Trichomonas vaginalis". J. Antimicrob. Chemother. 57 (2): 273–8. doi:10.1093/jac/dki417. PMID 16344287.
- ^ Choubey V, Maity P, Guha M, et al. (February 2007). "Inhibition of Plasmodium falciparum choline kinase by hexadecyltrimethylammonium bromide: a possible antimalarial mechanism". Antimicrob. Agents Chemother. 51 (2): 696–706. doi:10.1128/AAC.00919-06. PMC 1797733. PMID 17145794. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1797733/.
External links
- Eissa M. M., Bardicy S. E., Tadros M. (2011). "Bioactivity of miltefosine against aquatic stages of Schistosoma mansoni, Schistosoma haematobium and their snail hosts, supported by scanning electron microscopy". Parasites & Vectors 4: 73. doi:10.1186/1756-3305-4-73.
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Antiviral drugs: antiretroviral drugs used against HIV (primarily J05)
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Entry/fusion inhibitors
(Discovery & development) |
- gp41 (Enfuvirtide)
- CCR5 (Maraviroc
- Vicriviroc†, Cenicriviroc†, PRO 140†)
- CD4 (Ibalizumab†)
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Reverse-transcriptase
inhibitors (RTIs) |
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Nucleoside &
Nucleotide (NRTI)
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- Nucleoside analogues/NARTIs: Abacavir (ABC)°#
- Emtricitabine (FTC)°#
- Lamivudine (3TC)°#
- Didanosine (ddI)#
- Zidovudine (AZT)#
- Apricitabine†
- Stampidine†
- Elvucitabine†
- Racivir†
- Amdoxovir†
- Stavudine (d4T)#
- Zalcitabine (ddC)◊
- Festinavir†
- Nucleotide analogues/NtRTIs: Tenofovir°#
- GS 7340
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|
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Non-Nucleoside (NNRTI)
(Discovery & development)
|
- (1st generation) Efavirenz°#
- Nevirapine#
- Loviride◊
- Delavirdine◊
(2nd generation) diarylpyrimidines (Etravirine- Rilpivirine)
- Lersivirine†
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|
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| Integrase inhibitors |
- Raltegravir°
- Elvitegravir†
- Dolutegravir†
- Globoidnan A (experimental)
- MK-2048†
- BI 224436†
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| Maturation inhibitors |
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Protease Inhibitors (PI)
(Discovery and development) |
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1st generation
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- Fosamprenavir°
- Lopinavir°#
- Nelfinavir#
- Ritonavir#
- Saquinavir#
- Amprenavir◊
- Indinavir◊#
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2nd generation
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- Atazanavir°
- Darunavir°
- Tipranavir
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| Combined formulations |
- Lamivudine/zidovudine
- Emtricitabine/tenofovir/efavirenz
- Abacavir/lamivudine/zidovudine
- Tenofovir/emtricitabine
- Lopinavir/ritonavir
- Abacavir/lamivudine
- Emtricitabine/rilpivirine/tenofovir
- Elvitegravir/cobicistat/emtricitabine/tenofovir
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| Experimental agents |
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Uncoating inhibitors
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Transcription inhibitors
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Translation inhibitors
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Other
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- Abzyme
- Calanolide A
- Ceragenin
- Cyanovirin-N
- Diarylpyrimidines
- Epigallocatechin gallate (EGCG)
- Foscarnet
- Griffithsin
- Hydroxycarbamide
- Miltefosine
- Portmanteau inhibitors
- Seliciclib†
- Synergistic enhancers
- Tre recombinase
- Zinc finger protein transcription factor
- KP-1461†
- Cobicistat†
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Failed agents
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- Dexelvucitabine
- Capravirine
- Emivirine
- Lodenosine
- Atevirdine
- Brecanavir
- Aplaviroc
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
°DHHS preferred first-line agent. ◊Formerly or rarely used agent.
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cutn/syst (hppv/hiva, infl/zost/zoon)/epon
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drug(dnaa, rnaa, rtva, vacc)
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Antiparasitics – antiprotozoal agents – Excavata antiparasitics (P01)
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| Discicristata |
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Trypanosomiasis
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- African trypanosomiasis: ornithine (Eflornithine#)
- arsenical (Melarsoprol#)
- benzamidine (Pentamidine#)
- naphthalenesulfonate (Suramin#)
Chagas disease: nitroimidazole (Benznidazole#)
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Leishmaniasis
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- macrolide (Amphotericin B#)
Pentavalent antimonials (Meglumine antimoniate#, Sodium stibogluconate)
- benzamidine (Pentamidine#)
- phosphorylcholine (Miltefosine)
- neomycin (Paromomycin)
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PAM
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- macrolide (Amphotericin B)
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| Trichozoa |
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Giardiasis
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- nitroimidazole (Metronidazole#, Tinidazole)
- benzimidazole (Albendazole)
- thiazole (Nitazoxanide)
- nitrofuran (Furazolidone)
- aminoacridine (Quinacrine)
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Trichomoniasis
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- nitroimidazole (Carnidazole, Metronidazole#, Tinidazole)
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Dientamoebiasis
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- nitroimidazole (Metronidazole
- Secnidazole)
- oxyquinoline (Iodoquinol)
- tetracycline (Doxycycline)
- neomycin (Paromomycin)
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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UpToDate Contents
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English Journal
- Repurposing miltefosine for the treatment of immune-mediated disease?
- Verhaar AP1, Wildenberg ME1, Peppelenbosch MP1, Hommes DW1, van den Brink GR2.
- The Journal of pharmacology and experimental therapeutics.J Pharmacol Exp Ther.2014 Aug;350(2):189-95. doi: 10.1124/jpet.113.212654. Epub 2014 May 15.
- Miltefosine is an ether lipid that was initially developed for cancer treatment in the early 1980s. Miltefosine largely failed development for oncology, although it was approved for the topical treatment of breast cancer metastasis. It was subsequently discovered that miltefosine is a highly effecti
- PMID 24833702
- Activity of anti-cancer protein kinase inhibitors against Leishmania spp.
- Sanderson L1, Yardley V2, Croft SL1.
- The Journal of antimicrobial chemotherapy.J Antimicrob Chemother.2014 Jul;69(7):1888-91. doi: 10.1093/jac/dku069. Epub 2014 Mar 25.
- OBJECTIVES: There is an urgent need to develop new and effective treatments for poverty-related neglected diseases. In light of the time required to bring a new drug to market and the cost involved (10-15 years, >1 billion US$), one approach to identifying new treatments for diseases like leishma
- PMID 24668412
- Affinity of alkylphosphocholines to biological membrane of prostate cancer: studies in natural and model systems.
- Wnętrzak A1, Lipiec E, Lątka K, Kwiatek W, Dynarowicz-Łątka P.
- The Journal of membrane biology.J Membr Biol.2014 Jul;247(7):581-9. doi: 10.1007/s00232-014-9674-8. Epub 2014 May 22.
- The effectiveness of two alkylphosphocholines (APCs), hexadecylphosphocholine (miltefosine) and erucylphosphocholine to combat prostate cancer has been studied in vitro with artificial cancerous membrane, modelled with the Langmuir monolayer technique, and on cell line (Du-145). Studies performed wi
- PMID 24848301
Japanese Journal
- 抗感染症ciliatamide誘導体の合成と構造活性相関の検討
- 秋山 将太,中尾 洋一,松本 芳嗣,後藤 康之,三條場 千寿,長田 康孝,梅原 将洋,木村 純二
- 天然有機化合物討論会講演要旨集 55(0), PosterP-46, 2013
- <p>【目的】</p><p>深海の海綿Aapotos ciliataから単離されたciliatamide A～Cは、環状Lys (c-Lysまたはc-Orn)、MePhe、および脂肪酸からなる単純な化合物で、このうちAおよびBは感染症であるリーシュマニア症に対して阻害活性を示すことが報告されている。<sup>1）</sup></p& …
- NAID 130006470693
- Ginsenoside Rh1 Eliminates the Cytoprotective Phenotype of Human Immunodeficiency Virus Type 1-Transduced Human Macrophages by Inhibiting the Phosphorylation of Pyruvate Dehydrogenase Lipoamide Kinase Isozyme 1
- Jeong Jin-Ju,Kim Baek,Kim Dong-Hyun
- Ｂｉｏｌｏｇｉｃａｌ ＆ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｂｕｌｌｅｔｉｎ 36(7), 1088-1094, 2013
- … Ginsenosides Rh1 in the presence of miltefosine (5 µ<span style="font-variant: small-caps;">M</span>) additively increased the anti-cytoprotective activity against HIV-1 Tat-expressing macrophages. …
- NAID 130003361469
- Development and validation of a quantitative assay for the measurement of miltefosine in human plasma by liquid chromatography-tandem mass spectrometry
- DORLO Thomas P. C.,HILLEBRAND Michel J. X.,ROSING Hilde,EGGELTE Teunis A.,DE VRIES Peter J.,BEIJNEN Jos H.
- Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 865(1), 55-62, 2008-04-01
- NAID 10027998434
Related Links
- Miltefosine (INN, trade names Impavido and Miltex) is a phospholipid drug. Chemically it is a derivative of alkylphosphocholine compounds discovered in the early 1980s. It was developed in the late 1980s as an anticancer drug by ...
- Methods For systematic identification of published clinical trials of miltefosine in the treatment of leishmaniasis, the literature database PubMed was searched with the following terms: (miltefosine) AND [(visceral ...
Related Pictures
