Miltefosine is primarily used for the treatment ofvisceral andNew World cutaneous leishmaniasis, and is undergoingclinical trials for this use in several countries.[10][11] This drug is now listed as a core medication for the treatment of leishmaniasis under the WHO Model List of Essential Medicines.[12] 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.[13]
Miltefosine 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.[14] It has orphan drug status in the United States foracanthamoeba keratitis andprimary amebic meningoencephalitis (PAM).[15][16]
Miltefosine is listed as pregnancy category D by the FDA. This means there is evidence-based adverse reaction data from investigational or marketing experience or studies in humans of harm to the human fetus.[17] Despite this evidence, the potential benefits of miltefosine may warrant use of the drug in pregnant women despite potential risks. A pregnancy test should be done prior to starting treatment. Effectivebirth control should be used while on miltefosine and 5 months after discontinuation of treatment. Its use during breast feeding is most likely unsafe.[2]
Miltefosine is contraindicated in individuals who have ahypersensitivity to this medication, pregnant women, and people who have theSjögren-Larsson syndrome.[18] It is embryotoxic and fetotoxic in rats and rabbits, andteratogenic in rats but not in rabbits. It is therefore contraindicated for use during pregnancy, andcontraception is required beyond the end of treatment in women of child-bearing age.[19]
Commonside effects from miltefosine treatment arenausea andvomiting, which occur in 60% of people. Other common side effects are dizziness, headache, and daytime sleepiness.[20]
Serious side effects include rash, diarrhea, and arthritis.[20] The side effects are more severe in women and young children. The overall effects are quite mild and easily reversed.[21]
Miltefosine primarily acts onLeishmania by affecting the species's promastigote and amastigote stages.[22] Miltefosine exerts its activity by interacting with lipids, inhibitingcytochrome c oxidase and causing apoptosis-like cell death.[23] This may affect membrane integrity and mitochondrial function of the parasite.[citation needed]
In the same year as the discovery of the anticancer property, miltefosine was reported by S. L. Croft and his team at theLondon School of Hygiene and Tropical Medicine as having antileishmanial effect as well. The compound was effective againstLeishmania donovaniamastigotes in cultured mouse peritonealmacrophages at a dose of 12.8 mg/kg/day in a five-day course.[32] However, priority was given to the development of the compound for cutaneousmetastases ofbreast cancer. In 1992 a new research was reported in which the compound was highly effective in mouse against differentlife cycle stages of differentLeishmania species, and in fact, more potent than the conventionalsodium stibogluconate therapy by a factor of more than 600.[33] Results of the first clinical trial in humans were reported from Indian patients with chronic leishmaniasis with high degree of success and safety.[34] This promising development promulgated a unique public–private partnership collaboration betweenASTA Medica (later Zentaris GmbH), theWorld Health Organization (WHO) Special Programme for Research and Training in Tropical Diseases, and theGovernment 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.[2]
In 2013, the USCenters for Disease Control and Prevention recommended miltefosine for the treatment of free-living amoeba infections such asgranulomatous amoebic encephalitis andprimary amoebic meningoencephalitis, two fatal protozoal diseases.[35] Historically, only four survivors have been recorded out of 138 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.[36][37] In 2016 after treatment that included miltefosine, another child became the fourth person in the United States to surviveNaegleria fowleri infection.[38]
Since 2017 Miltefosine is commercially available in the United States through Profounda.[39] Previously one could only get it from theCDC for emergency use under an expanded accessIND protocol for treatment of free-living amoeba (FLA) infections:primary amoebic meningoencephalitis caused byNaegleria fowleri and granulomatous amoebic encephalitis caused byBalamuthia mandrillaris andAcanthamoeba species.[36] Miltefosine is almost exclusively produced by Profounda, a private pharmaceutical company.[40]
Miltefosine is being investigated by researchers interested in finding treatments for infections which have become resistant to existing drugs. Animal andin vitro studies suggest it may have broad anti-protozoal and anti-fungal properties:
A 2006in vitro study found that miltefosine is effective against metronidazole-resistant variants ofTrichomonas vaginalis, a sexually transmitted protozoal disease.[45]
Anin vitro test in 2006 showed that miltefosine is effective against the deadly protozoan pathogens,Naegleria fowleri,Balamuthia mandrillaris, andAcanthamoeba.[47] However, laterin vitro and animal model experiments showed that it is not as potent as other drugs, such aschlorpromazine (Thorazine)[48] anddiminazene aceturate (Berenil).[49]
In 2013, there were reports of failure of miltefosine in the treatment of leishmaniasis.[50][51] Althoughdrug resistance was suspected, studies in 2014 reported that miltefosine is not very effective in children, most probably related toPKPD issues with this drug.[52] Moverover, males appeared to have a higher probability of relapse as well.[53]
Miltefosine targets HIV infectedmacrophages, which play a rolein vivo as long-lived HIV-1 reservoirs. The HIV proteinTat activates pro-survivalPI3K/Akt pathway in primary human macrophages. Miltefosine acts by inhibiting thePI3K/Akt pathway, thus removing the infected macrophages from circulation, without affecting healthy cells.[55][56] It significantly reduces replication of HIV-1 in cocultures of humandendritic cells (DCs) andCD4+ T cells, which is due to a rapid secretion of soluble factors and is associated with induction of type-Iinterferon (IFN) in the human cells.[57]
^World Health Organization model list of essential medicines: 21st list 2019. Geneva:World Health Organization. 2019.hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Sindermann H, Engel J (December 2006). "Development of miltefosine as an oral treatment for leishmaniasis".Transactions of the Royal Society of Tropical Medicine and Hygiene.100 (Suppl 1):S17–S20.doi:10.1016/j.trstmh.2006.02.010.PMID16730362.
^Fleer EA, Unger C, Kim DJ, Eibl H (November 1987). "Metabolism of ether phospholipids and analogs in neoplastic cells".Lipids.22 (11):856–861.doi:10.1007/bf02535544.PMID3444378.S2CID4055850.
^Hilgard P, Stekar J, Voegeli R, Engel J, Schumacher W, Eibl H, et al. (September 1988). "Characterization of the antitumor activity of hexadecylphosphocholine (D 18506)".European Journal of Cancer & Clinical Oncology.24 (9):1457–1461.doi:10.1016/0277-5379(88)90336-7.PMID3141197.
^Croft SL, Neal RA, Pendergast W, Chan JH (August 1987). "The activity of alkyl phosphorylcholines and related derivatives against Leishmania donovani".Biochemical Pharmacology.36 (16):2633–2636.doi:10.1016/0006-2952(87)90543-0.PMID3606662.
^Ahmad AF, Heaselgrave W, Andrew PW, Kilvington S (2013). "The in vitro efficacy of antimicrobial agents against the pathogenic free-living amoeba Balamuthia mandrillaris".The Journal of Eukaryotic Microbiology.60 (5):539–543.doi:10.1111/jeu.12062.PMID23869955.S2CID12941376.
^Vila TV, Ishida K, de Souza W, Prousis K, Calogeropoulou T, Rozental S (January 2013). "Effect of alkylphospholipids on Candida albicans biofilm formation and maturation".The Journal of Antimicrobial Chemotherapy.68 (1):113–125.doi:10.1093/jac/dks353.PMID22995097.
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