Miltefosine

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Miltefosine

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	C₂₁H₄₆N O₄P
Mol. mass	407.568 g/mol
SMILES	eMolecules & PubChem
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
N (what is this?) (verify)

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]

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

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.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2493105.
^ ^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.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2265748.
^ "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.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=128733.
^ 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.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1366877.
^ 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.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1797733.

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.

Antiviral drugs: antiretroviral drugs used against HIV (primarily J05)

Entry/fusion inhibitors
(Discovery & development)

gp41 (Enfuvirtide)
CCR5 (Maraviroc
Vicriviroc^†, Cenicriviroc^†, PRO 140^†)
CD4 (Ibalizumab^†)

Reverse-transcriptase
inhibitors (RTIs)

Nucleoside & Nucleotide (NRTI)	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

Non-Nucleoside (NNRTI) (Discovery & development)	(1^st generation) Efavirenz°^# Nevirapine^# Loviride^◊ Delavirdine^◊ (2^nd generation) diarylpyrimidines (Etravirine Rilpivirine) Lersivirine^†

Integrase inhibitors

Maturation inhibitors

Bevirimat^†
Vivecon^†

Protease Inhibitors (PI)
(Discovery and development)

1^st generation	Fosamprenavir° Lopinavir°^# Nelfinavir^# Ritonavir^# Saquinavir^# Amprenavir^◊ Indinavir^◊^#

2^nd generation	Atazanavir° Darunavir Tipranavir

Combined formulations

Experimental agents

Uncoating inhibitors	TRIM5alpha (gene)

Transcription inhibitors	Tat antagonists

Translation inhibitors	Trichosanthin

Other	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^†

Failed agents	Dexelvucitabine Capravirine Emivirine Lodenosine Atevirdine Brecanavir Aplaviroc

^#WHO-EM
^‡Withdrawn from market
Clinical trials:
- ^†Phase III
- ^§Never to phase III

°DHHS preferred first-line agent. ^◊Formerly or rarely used agent.

M: VIR

virs(prot)/clss

cutn/syst (hppv/hiva, infl/zost/zoon)/epon

drugJ(dnaa, rnaa, rtva, vacc)

Antiparasitics – antiprotozoal agents – Excavata antiparasitics (P01)

Discicristata

Trypanosomiasis	African trypanosomiasis: ornithine (Eflornithine^#) arsenical (Melarsoprol^#) benzamidine (Pentamidine^#) naphthalenesulfonate (Suramin^#) Chagas disease: nitroimidazole (Benznidazole^#) nitrofuran (Nifurtimox^#)

Leishmaniasis	macrolide (Amphotericin B^#) Pentavalent antimonials (Meglumine antimoniate^#, Sodium stibogluconate) benzamidine (Pentamidine^#) phosphorylcholine (Miltefosine) neomycin (Paromomycin)

PAM	macrolide (Amphotericin B)

Trichozoa

Giardiasis	nitroimidazole (Metronidazole^#, Tinidazole) benzimidazole (Albendazole) thiazole (Nitazoxanide) nitrofuran (Furazolidone) aminoacridine (Quinacrine)

Trichomoniasis	nitroimidazole (Carnidazole, Metronidazole^#, Tinidazole)

Dientamoebiasis	nitroimidazole (Metronidazole Secnidazole) oxyquinoline (Iodoquinol) tetracycline (Doxycycline) neomycin (Paromomycin)

^#WHO-EM
^‡Withdrawn from market
Clinical trials:
- ^†Phase III
- ^§Never to phase III

M: PRO

ambz, excv, chrm (strc)

ambz, excv, chrm

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