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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. 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, as well as human trematode Schistosoma mansoni and its vector host, the snail Biomphalaria alexandrina. It can be administered orally and topically.
On 19 March 2014, the US Food and Drug Administration approved miltefosine for any form of leishmaniasis, specifically for patients of 12 years of age and older, and became the first approved drug for cutaneous or mucosal leishmaniasis.
In 2013, the US Centers for Disease Control and Prevention recommended miltefosin as the only and first line therapy for granulomatous amoebic encephalitis and primary amoebic meningoencephalitis, two fatal protozoal diseases. Historically, only four survivors have been recorded out of 133 confirmed infections in North America. One American survived the infection in 1978 and one individual from Mexico in 2003. In 2013, two children survived and recovered from primary amoebic meningoencephalitis after treatment with miltefosine.
Miltefosine is used for the treatment of visceral and New World cutaneous leishmaniasis, and is undergoing clinical trials for this use in several countries, such as Brazil, Guatemala. and the United States. 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. It has been used successfully in some cases of the very rare, but highly lethal, brain infection by the amoeba, Naegleria fowleri, acquired through water entering the nose during a plunge in contaminated water.
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 amoebic encephalitis caused by Balamuthia mandrillaris, and Acanthamoeba species.
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 reversed. 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.
Phospholipid group alkylphosphocholine were known since the early 1980s, particularly in terms of their binding affinity with cobra venom. In 1987 the phospholipids were found to be potent toxins on leukemic cell culture. Initial in vivo investigation on the antineoplastic activity showed positive result, but then only at high dosage and at high toxicity. 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. It was subsequently found that miltefosine was structurally unique among lipids having anticancer property in that it lacks the glycerol group, is highly selective on cell types and acts through different mechanism.
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. 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 fact, more potent than the conventional sodium stibogluconate therapy by a factor of more than 600. Results of the first clinical trial in humans were reported from Indian patients with chronic leishmaniasis with high degree of success and safety. 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.
Antiprotozoal and antifungal activities
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.
- Several studies have found the drug to be effective against Cryptococcus neoformans, Candida, Aspergillus and Fusarium.
- A 2006 in vitro study found that miltefosine is effective against metronidazole-resistant variants of Trichomonas vaginalis, a sexually transmitted protozoal disease.
- Hexadecyltrimethylammonium bromide, a compound structurally similar to miltefosine, was demonstrated in 2007 to exhibit potent in vitro activity against Plasmodium falciparum.
- An in vitro test in 2006 showed that miltefosine is effective against amoebic pathogens, Naegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba species. However, later studies showed that it is not as potent as other drugs, such as chlorpromazine and diminazene aceturate (Berenil®). In 2014 it was reported that treatment of Acanthamoeba encephalitis in a 63-year-old male was not cured by miltefosine, or sulfadiazine, fluconazole, flucytosine, and azithromycin.
- In 2013, there were reports of failure of miltefosine in the treatment of leishmaniasis. Although drug resistance was suspected, studies in 2014 reported that miltefosine is not so effective in children, most probably related to a lack of drug exposure in children. Moverover, males appeared to have a higher probability of relapse as well.
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. 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.
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