Miltefosine

Miltefosine

Systematic (IUPAC) name
2-(hexadecoxy-oxido-phosphoryl)oxyethyl-trimethyl-azanium
Clinical data
AHFS/Drugs.com	International Drug Names
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
ChEBI	CHEBI:75283 N
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
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. 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 German scientists Hansjörg Eibl and Clemens Unger.^[2] Simultaneously but independently it was found that the drug could kill Leishmania parasites, and since the mid-1990s successful clinical trials were conducted. The drug became the first (and still the only prescribed) oral drug in the treatment of leishmaniasis. It is now known to be a broad-spectrum antimicrobial drug, active against pathogenic bacteria and fungi,^[1][3] as well as human trematode Schistosoma mansoni and its vector host, the snail Biomphalaria alexandrina.^[4] It can be administered orally and topically.

In the target cell, it acts as an Akt inhibitor. Therefore, it is also under investigation as a potential therapy against HIV infection.^[5][6]

Discovery

Phospholipid group alkylphosphocholine were known since the early 1980s, particularly in terms of their binding affinity with cobra venom.^[7] In 1987 the phosholids were found to potent toxins on leukemic cell culture.^[8] Initial in vivo investigation on the antineoplastic activity showed positive result, but then only at high dosage and at high toxicity.^[9] 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.^[10][11] It was subsequently found that miltefosine was strucrally unique among lipds having anticancer property in that it lacks the glycerol group, is highly selective on cell types and acts through different mechanism.^[12][13]

In the same year as the discovery of the acticancer 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.^[14] 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 fect more potent than the conventional sodium stibogluconate therapy by a factor of more than 600.^[15] Results of the first clinical trial in humans were reported from Indian patients with chronic leishmaniasis with high degree of success and safety.^[16] 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.^[1]

Current antiprotozoal and antifungal applications

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^[17] and Guatemala.^[18] 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.^[19]

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.^[20]

• Several studies have found the drug to be effective against Cryptococcus neoformans, Candida, Aspergillus and Fusarium.^[21]

• An in vitro study found that miltefosine is effective against metronidazole-resistant variants of Trichomonas vaginalis, a sexually transmitted protozoal disease.^[22]

• Hexadecyltrimethylammonium bromide, a compound structurally similar to miltefosine, was recently found to exhibit potent in vitro activity against Plasmodium falciparum.^[23]

• Miltefosine is being made available in the United States through 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 Amebic Encephalitis caused by Balamuthia mandrillaris, and Acanthamoeba species.^[24][25]

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.^[5] 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.^[26]

Dosage

In leishmanisis the recommended dose as oral monotherapy is 2.5 mg/kg/day for a total of 28 days. However, due to frequent commercial shortage of the 10 mg capsule, dosages are often altered. For example, the Indian government recommends 100 mg/day miltefosine for patients with a body weight ≥25 kg (corresponding to ∼1.7–4 mg/kg/day) and 50 mg/day for body weights <25 kg (corresponding to ∼2–5.5 mg/kg/day).^[1] Even up to 150 mg/day for 28 days was found to be quite safe.^[27]

Side effects

The main side effects reported with miltefosine treatment are nausea and vomiting, which occur in 60% of patients. Adverse effect is more severe in women and young children. The overall effects are quite mild and easily reverse.^[28] 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.^[29]

References

External links

• Max Planck Innovation
• FDA Panel Endorses Miltefosine for Leishmaniasis
• Med India
• Drugs.com