Miltefosine Impavido

Structural Formula Ball-and-Stick Model Space-filling Model

^ = Carbon = Hydrogen = Oxygen ; ; = Phosphorous ^ = Nitrogen

Year of discovery: 1990 (H. Eibl, Germany); Year of introduction: 2002 (Zentaris Gmbh); Drug category: Antiprotozoal drug/lysophospholipid analogue; Main uses: For the treatment of visceral and cutaneous leishmaniasis in immunocompetent patients in India but also for immunocompro-mized patients in Germany; Related drugs Pentavalent antimony (Sodium Stibogluconate, SSG), Liposomal amphotericin B.

Miltefosine is an oral drug for the treatment of visceral and cutaneous leishmaniasis, a parasitic infection which causes serious illness in many tropical and poorer regions of the world.1,2

Leishmaniasis is caused by the Leishmania parasite and it is spread by the bite of the female sandfly Lutzomyia longipalpis. There are two main forms of the disease: (1) infection of internal organs (visceral) and (2) infection of the skin (cutaneous). Visceral leishmaniasis affects 500,000 people annually and is usually fatal if left untreated. Each year approximately 1.5 million children and adults develop the two forms of the disease and 70,000 die, mainly from the visceral form.

The disease spreads in a fashion similar to malaria. Female sandflies acquire the amastigote form of the parasite by ingesting blood from infected humans or small mammals. The amastigotes are transformed in the gut of the sandfly to promastigotes, which the sandfly injects into the bloodstream of a human host along with an immunosuppressant. The promastigotes are ingested by white blood cells and revert to amastigotes. In the cutaneous form of the disease the Th1 cells activate phagocytes to destroy the parasite and clear the infection. However, in visceral leishmaniasis, macrophage activation does not occur, and the infection continues.

Phosphatidylcholine is the most abundant phospholipid in animals and plants and the key building block of the lipid bilayer of cell membranes. In the 1980s, the anticancer activity of metabolically stable phosphatidylcholine derivatives was discovered and seve ral potent compounds such as edelfosine, ilmofosine and miltefosine were prepared.

Phosphatidylcholine Lysophosphatidylcholine

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Edelfosine

Ilmofosine

Because these molecules interfere with phospholipid metabolism in cancer cells, phosphatidylcholine analogs were screened against Leishmania. This study showed that miltefosine is efficacious against different stages of the parasitic life cycle. It is believed that in addition to inhibiting parasitic phospholipid metabolism, miltefosine may also interfere with membrane signal transduction.

Miltefosine has been available since 2002 as an oral formulation (Impavido). Standard oral treatment of 100 mg per day (2.5 mg/kg/ day) for 28 days results in a cure rate of 97% for both forms of leishmaniasis. The use of miltefosine has several advantages over other agents (amphotericin B and sodium stibogluconate) currently used for leishmaniasis: (1) oral vs. parenteral administration; (2) fewer side effects and (3) significantly lower cost.

1. Mini-Rev. Med. Chem. 2006, 6, 145-151; 2. Lance! 2005 366, 1561-1577; Refs. p. 179

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