Miltefosine Chemical Properties

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

InChIKey

PQLXHQMOHUQAKB-UHFFFAOYSA-N

SMILES

O(CCCCCCCCCCCCCCCC)P([O-])(=O)OCC[N+](C)(C)C

CAS DataBase Reference

58066-85-6(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xn

Risk Statements 

22-43

Safety Statements 

36/37

RIDADR 

UN 2811 6.1 / PGIII

WGK Germany 

3

RTECS 

KH2890000

HS Code 

29239000

Toxicity

LD50 in rats (mg/kg): 246 orally (Muschiol)

Miltefosine Usage And Synthesis

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)

Uses

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.

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.

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.

storage

-20°C

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