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HomeProduct name listMiltefosine

Miltefosine

Synonym(s):Choline hexadecyl phosphate;HePC;HePC, 1-Hexadecylphosphorylcholine;Hexadecyl phosphocholine;Miltefosine - CAS 58066-85-6 - Calbiochem

  • CAS NO.:58066-85-6
  • Empirical Formula: C21H46NO4P
  • Molecular Weight: 407.57
  • MDL number: MFCD00133396
  • EINECS: 622-572-6
  • SAFETY DATA SHEET (SDS)
  • Update Date: 2024-11-19 20:33:22
Miltefosine Structural

What is Miltefosine?

Absorption

After oral administration, miltefosine is slowly absorbed from the gastrointestinal tract with an absolute bioavailability of 82% in rats and 94% in dogs. Absolute bioavailability has not been assessed in humans, however GI absorption rate in a two-compartment model is estimated to be 0.416 hr-1.

Toxicity

Preclinical reproductive toxicity studies in animals showed fetal death and teratogenicity at doses lower than the recommended human dose. Use of miltefosine during pregnancy is therefore strictly contraindicated, and contraceptive use is mandatory for females of child-bearing age during therapy and for 5 months afterwards. Preclinical studies additionally showed impaired female and male fertility in animals. Stevens-Johnson syndrome has been reported, therefore therapy should be discontinued if an exfoliative or bullous rash occurs during treatment.

Description

Miltefosin, representing the prototype of a new phospholipid structure, was introduced for the palliative treatment of skin metastases in patients with breast cancer. It is highly active against the human leukemia tumor cells xenograft in nude mice, leading to growth inhibition and regression of large established tumors. Its mode of antitumor activity is not mediated by the host immune system but by its pharmacological effects at the level of the cancer cell membrane, distinctly different from that of the classical cytostatic drugs which interact with cell proliferation at the level of DNA replication. Protein kinase C inhibition has been suggested as a possible mechanism.

Originator

Asta Medica (Germany)

The Uses of Miltefosine

A phospholipid drug with antineoplastic and antiprotozoal/antifungal properties, also acts as an Akt inhibitor, and under investigation as a potential therapy against HIV infection.

Indications

For the treatment of mucosal (caused by Leishmania braziliensis), cutaneous (caused by L. braziliensis, L. guyanensis, and L. panamensis), and visceral leishmaniasis (caused by L. donovani). In comparing Leishmania drug susceptibility, it has been found that L. donovani is the most susceptible to miltefosine while L. major is the least susceptible. Off-label use includes treatment of free-living amebae (FLA) infections (unlabeled use; CDC, 2013).

Background

Miltefosine is a broad spectrum antimicrobial, anti-leishmanial, phospholipid drug that was originally developed in the 1980s as an anti-cancer agent. It is currently the only recognized oral agent used to treat visceral, cutaneous, and mucosal forms of leishmaniasis, a neglected tropical disease. It can be administered topically or orally and is only indicated in patients aged 12 years or older. The CDC has also recommended it as a first line treatment for free-living amebae (FLA) infections such as primary amebic meningoencephalitis and granulomatous amebic encephalitis.

What are the applications of Application

Miltefosine is a PI 3-kinase and Akt inhibitor that also inhibits anti-IgE induced histamine release

Definition

ChEBI: A phospholipid that is the hexadecyl monoester of phosphocholine.

brand name

Miltex

Antimicrobial activity

Concentrations of 1–5 μm inhibit the promastigotes and amastigotes of Leishmania spp. and the epimastigotes and amastigotes of T. cruzi. Inhibitory concentrations against T. brucei spp. and E. histolytica are closer to 50 μm. Acanthamoeba spp. are variably susceptible, depending on the experimental conditions.

Acquired resistance

There are no reports of clinical resistance in Leishmania so far. Experimental resistance has been induced in vitro against the promastigote stage of Leishmania and two plasma membrane proteins, LdMT and Ld Ros3, are necessary for miltefosine uptake. There is evidence that reduced sensitivity of promastigotes is passed on to intracellular amastigotes.

Pharmaceutical Applications

An alkylphospholipid, originally investigated as an anticancer compound, formulated for oral administration.

Biochem/physiol Actions

Inhibitor of protein kinase C and of phosphatidylcholine synthesis. Used for the treatment of visceral and cutaneous leishmaniasis. Active against metronidazole-resistant and -susceptible strains of Trichomonas vaginalis

Pharmacokinetics

In rodent models the drug is almost completely absorbed after oral administration. About 90% is bound to plasma proteins. It is widely distributed in the body; studies in rats showed highest uptake in kidney, liver and spleen. In rats and dogs bioavailability was 82% and 94%, with maximum values reached after 4–48 h.
In adult human trials repeated oral dosing with 100 mg per day achieved a peak plasma concentration of 70 mg/L after 8–24 h (day 23). The half-life is 6–8 days.

Pharmacokinetics

Little is known about the clinical pharmacodynamics of miltefosine and other antileishmanial drugs.

Clinical Use

Visceral leishmaniasis
Cutaneous leishmaniasis

Side Effects

Mild to moderate gastrointestinal side effects are reported in 40–60% of patients. Moderate to severe nephrotoxicity was seen in 2% and 1% of patients, respectively; increases in creatinine levels were reversible. Miltefosine is contraindicated in pregnancy, based on findings of teratogenicity in rats. It causes hemolysis and cannot be given intravenously.

Metabolism

Miltefosine is metabolized mainly by phospholipase D, releasing choline, choline-containing metabolites, and hexadecanol, which are likely to enter the intermediary metabolism. The metabolites produced by this reaction are all endogenous and are likely used for bio-synthesis of acetylcholine, cell membranes, and long-chain fatty acids.

storage

-20°C

Properties of Miltefosine

Melting point: 232-234° (dec)
storage temp.  room temp
solubility  H2O: soluble10mg/mL, clear, colorless
form  Crystalline solid
color  White to Almost white
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
CAS DataBase Reference 58066-85-6(CAS DataBase Reference)

Safety information for Miltefosine

Signal word Danger
Pictogram(s)
ghs
Skull and Crossbones
Acute Toxicity
GHS06
GHS Hazard Statements H301:Acute toxicity,oral
Precautionary Statement Codes P264:Wash hands thoroughly after handling.
P264:Wash skin thouroughly after handling.
P270:Do not eat, drink or smoke when using this product.
P301+P310:IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P405:Store locked up.
P501:Dispose of contents/container to..…

Computed Descriptors for Miltefosine

InChIKey PQLXHQMOHUQAKB-UHFFFAOYSA-N
SMILES O(CCCCCCCCCCCCCCCC)P([O-])(=O)OCC[N+](C)(C)C

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