Miltefosine

Last updated
Miltefosine
Miltefosine structure.svg
Miltefosine-3D-bs-17.png
Clinical data
Trade names Impavido, Miltex, others
AHFS/Drugs.com Monograph
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • BR: Class C1 (Other controlled substances) [1]
  • US: WARNING [2] Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability High
Protein binding ~98%
Metabolism Slow hepatic (non-CYP-dependent)
Elimination half-life 6 to 8 days and 31 days [3]
Excretion Primarily fecal
Identifiers
  • 2-(hexadecoxy-oxido-phosphoryl)oxyethyl-trimethyl-azanium
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.151.328 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H46NO4P
Molar mass 407.576 g·mol−1
3D model (JSmol)
Melting point 232 to 234 °C (450 to 453 °F)
  • [O-]P(=O)(OCCCCCCCCCCCCCCCC)OCC[N+](C)(C)C
  • 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 Yes check.svgY
  • Key:PQLXHQMOHUQAKB-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Miltefosine, sold under the trade name Impavido among others, is a medication mainly used to treat leishmaniasis and free-living amoeba infections such as Naegleria fowleri and Balamuthia mandrillaris . [4] This includes the three forms of leishmaniasis: cutaneous, visceral and mucosal. [5] It may be used with liposomal amphotericin B or paromomycin. [6] It is taken by mouth. [5]

Contents

Common side effects include vomiting, abdominal pain, fever, headaches, and decreased kidney function. [4] More severe side effects may include Stevens–Johnson syndrome or low blood platelets. [4] Use during pregnancy appears to cause harm to the baby and use during breastfeeding is not recommended. [4] How it works is not entirely clear. [4]

Miltefosine was first made in the early 1980s and studied as a treatment for cancer. [7] A few years later it was found to be useful for leishmaniasis and was approved for this use in 2002 in India. [8] It is on the World Health Organization's List of Essential Medicines. [9] [10]

Medical uses

Leishmaniasis

Miltefosine is primarily used for the treatment of visceral and New World cutaneous leishmaniasis, and is undergoing clinical trials for this use in several countries. [11] [12] This drug is now listed as a core medication for the treatment of leishmaniasis under the WHO Model List of Essential Medicines. [13] 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. [14]

Amoeba infections

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. [15] It has orphan drug status in the United States for acanthamoeba keratitis and primary amebic meningoencephalitis (PAM). [16] [17]

Pregnancy and breastfeeding

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. [18] 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. Effective birth control should be used while on miltefosine and 5 months after discontinuation of treatment. Its use during breast feeding is most likely unsafe. [3]

Contraindications

Miltefosine is contraindicated in individuals who have a hypersensitivity to this medication, pregnant women, and people who have the Sjögren-Larsson syndrome. [19] 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. [20]

Side effects

Common side effects from miltefosine treatment are nausea and vomiting, which occur in 60% of people. Other common side effects are dizziness, headache, and daytime sleepiness. [21]

Serious side effects include rash, diarrhea, and arthritis. [21] The side effects are more severe in women and young children. The overall effects are quite mild and easily reversed. [22]

Mechanism of action

Miltefosine primarily acts on Leishmania by affecting the species's promastigote and amastigote stages. [23] Miltefosine exerts its activity by interacting with lipids, inhibiting cytochrome c oxidase and causing apoptosis-like cell death. [24] This may affect membrane integrity and mitochondrial function of the parasite.[ citation needed ]

History

Cancer

While initially studied as a cancer medication, due to side effects it was never used for this purpose. [25]

Phospholipid group alkylphosphocholine were known since the early 1980s, particularly in terms of their binding affinity with cobra venom. [26] In 1987 the phospholipids were found to be potent toxins on leukemic cell culture. [27] Initial in vivo investigation on the antineoplastic activity showed positive result, but then only at high dosage and at high toxicity. [28] 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. [29] [30] 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. [31] [32]

Leishmaniasis

In the same year as the discovery of the anticancer 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. [33] 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. [34] Results of the first clinical trial in humans were reported from Indian patients with chronic leishmaniasis with high degree of success and safety. [35] This promising development promulgated a unique public–private partnership collaboration between ASTA Medica (later Zentaris GmbH), the World Health Organization (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. [3]

Naegleria fowleri and Acanthamoeba

In 2013, the US Centers for Disease Control and Prevention recommended miltefosine for the treatment of free-living amoeba infections such as granulomatous amoebic encephalitis and primary amoebic meningoencephalitis, two fatal protozoal diseases. [36] 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. [37] [38] In 2016 after treatment that included miltefosine, another child became the fourth person in the United States to survive Naegleria fowleri infection. [39]

Society and culture

Availability

Since 2017 Miltefosine is commercially available in the United States through Profounda. [40] Previously one could only get it from 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. [37] Miltefosine is almost exclusively produced by Profounda, a private pharmaceutical company. [41]

Economics

In the developing world a course of treatment costs US$65 to $150. [6] In the developed world treatment may be 10 to 50 times greater. [6]

Further research

It is active against some bacteria and fungi, [3] [42] as well as human trematode Schistosoma mansoni and the snail that spreads it Biomphalaria alexandrina . [43]

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:

Anti-HIV activity

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. [56] [57] 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. [58]

Related Research Articles

<span class="mw-page-title-main">Leishmaniasis</span> Disease caused by parasites of the Leishmania type

Leishmaniasis is a wide array of clinical manifestations caused by protozoal parasites of the Trypanosomatida genus Leishmania. It is generally spread through the bite of phlebotomine sandflies, Phlebotomus and Lutzomyia, and occurs most frequently in the tropics and sub-tropics of Africa, Asia, the Americas, and southern Europe. The disease can present in three main ways: cutaneous, mucocutaneous, or visceral. The cutaneous form presents with skin ulcers, while the mucocutaneous form presents with ulcers of the skin, mouth, and nose. The visceral form starts with skin ulcers and later presents with fever, low red blood cell count, and enlarged spleen and liver.

<i>Acanthamoeba</i> Genus of protozoans

Acanthamoeba is a genus of amoebae that are commonly recovered from soil, fresh water, and other habitats. The genus Acanthamoeba has two stages in its life cycle, the metabolically active trophozoite stage and a dormant, stress-resistant cyst stage. In nature, Acanthamoeba species are generally free-living bacterivores. However, they are also opportunistic pathogens able to cause serious and sometimes fatal infections in humans and other animals.

Free-living amoebae are a group of protozoa that are important causes of infectious disease in humans and animals.

<span class="mw-page-title-main">Naegleriasis</span> Rare and usually fatal brain infection by a protist

Naegleriasis, also known as primary amoebic meningoencephalitis (PAM), is an almost invariably fatal infection of the brain by the free-living unicellular eukaryote Naegleria fowleri. Symptoms are meningitis-like and include headache, fever, nausea, vomiting, a stiff neck, confusion, hallucinations and seizures. Symptoms progress rapidly over around five days, and death usually results within one to two weeks of symptoms.

<i>Naegleria</i> Genus of protists

Naegleria is a genus consisting of 47 described species of protozoa often found in warm aquatic environments as well as soil habitats worldwide. It has three life cycle forms: the amoeboid stage, the cyst stage, and the flagellated stage, and has been routinely studied for its ease in change from amoeboid to flagellated stages. The Naegleria genera became famous when Naegleria fowleri, the causative agent of the usually fatal human and animal disease primary amoebic meningoencephalitis (PAM), was discovered in 1965. Most species in the genus, however, are incapable of causing disease.

<span class="mw-page-title-main">Cutaneous leishmaniasis</span> Medical condition

Cutaneous leishmaniasis is the most common form of leishmaniasis affecting humans. It is a skin infection caused by a single-celled parasite that is transmitted by the bite of a phlebotomine sand fly. There are about thirty species of Leishmania that may cause cutaneous leishmaniasis.

<span class="mw-page-title-main">Visceral leishmaniasis</span> Human disease caused by protist parasites

Visceral leishmaniasis (VL), also known as kala-azar or "black fever", is the most severe form of leishmaniasis and, without proper diagnosis and treatment, is associated with high fatality. Leishmaniasis is a disease caused by protozoan parasites of the genus Leishmania.

<span class="mw-page-title-main">Sodium stibogluconate</span> Pharmaceutical drug

Sodium stibogluconate, sold under the brand name Pentostam among others, is a medication used to treat leishmaniasis. This includes leishmaniasis of the cutaneous, visceral, and mucosal types. Some combination of miltefosine, paromomycin and liposomal amphotericin B, however, may be recommended due to issues with resistance. It is given by injection.

<span class="mw-page-title-main">Auranofin</span> Chemical compound

Auranofin is an orally administered gold salt classified by the World Health Organization as an antirheumatic agent. It has the brand name Ridaura. Along with sodium aurothiomalate it is one of only two gold compounds currently employed in modern medicine.

<i>Balamuthia mandrillaris</i> Species of pathogenic Amoebozoa

Balamuthia mandrillaris is a free-living amoeba that causes the rare but deadly neurological condition granulomatous amoebic encephalitis (GAE). B. mandrillaris is a soil-dwelling amoeba and was first discovered in 1986 in the brain of a mandrill that died in the San Diego Wild Animal Park.

<span class="mw-page-title-main">Granulomatous amoebic encephalitis</span> Rare and usually fatal brain infection by certain amoebae

Granulomatous amoebic encephalitis (GAE) is a rare, often fatal, subacute-to-chronic central nervous system disease caused by certain species of free-living amoebae of the genera Acanthamoeba, Balamuthia and Sappinia. The term is most commonly used with Acanthamoeba. In more modern references, the term "balamuthia amoebic encephalitis" (BAE) is commonly used when Balamuthia mandrillaris is the cause. Similarly, Sappinia amoebic encephalitis (SAE) is the name for amoebic encephalitis caused by species of Sappinia.

Antiparasitics are a class of medications which are indicated for the treatment of parasitic diseases, such as those caused by helminths, amoeba, ectoparasites, parasitic fungi, and protozoa, among others. Antiparasitics target the parasitic agents of the infections by destroying them or inhibiting their growth; they are usually effective against a limited number of parasites within a particular class. Antiparasitics are one of the antimicrobial drugs which include antibiotics that target bacteria, and antifungals that target fungi. They may be administered orally, intravenously or topically. Overuse or misuse of antiparasitics can lead to the development of antimicrobial resistance.

<span class="mw-page-title-main">Nitroxoline</span> Antibiotic chemical compound

Nitroxoline is an antibiotic that has been in use in Europe for about fifty years, and has proven to be very effective at combating biofilm infections. Nitroxoline was shown to cause a decrease in the biofilm density of P. aeruginosa infections, which would allow access to the infection by the immune system in vivo. It was shown that nitroxoline functions by chelating Fe2+ and Zn2+ ions from the biofilm matrix; when Fe2+ and Zn2+ were reintroduced into the system, biofilm formation activity was restored. The biofilm degradation ability is comparable to EDTA derivatives, but this drug has a history of human use in clinical settings and therefore has a precedent with which to allow its use against “slimy” biofilm infections.

<span class="mw-page-title-main">Protozoan infection</span> Parasitic disease caused by a protozoan

Protozoan infections are parasitic diseases caused by organisms formerly classified in the kingdom Protozoa. These organisms are now classified in the supergroups Excavata, Amoebozoa, Harosa, and Archaeplastida. They are usually contracted by either an insect vector or by contact with an infected substance or surface.

Sappinia diploidea is a free-living amoeba species.

Cutaneous amoebiasis, refers to a form of amoebiasis that presents primarily in the skin. It can be caused by Acanthamoeba or Entamoeba histolytica. When associated with Acanthamoeba, it is also known as "cutaneous acanthamoebiasis". Balamuthia mandrillaris can also cause cutaneous amoebiasis, but can prove fatal if the amoeba enters the bloodstream It is characterized by ulcers. Diagnosis of amebiasis cutis calls for high degree of clinical suspicion. This needs to be backed with demonstration of trophozoites from lesions. Unless an early diagnosis can be made such patients can develop significant morbidity.

<span class="mw-page-title-main">Dehydroemetine</span> Chemical compound

Dehydroemetine is a synthetically produced antiprotozoal agent similar to emetine in its anti-amoebic properties and structure, but it produces fewer side effects. In the United States, it is manufactured by Roche.

<span class="mw-page-title-main">Post-kala-azar dermal leishmaniasis</span>

Post-kala-azar dermal leishmaniasis (PKDL) is a complication of visceral leishmaniasis (VL); it is characterised by a macular, maculopapular, and nodular rash in a patient who has recovered from VL and who is otherwise well. The rash usually starts around the mouth from where it spreads to other parts of the body depending on severity.

Balamuthia infection is a cutaneous condition resulting from Balamuthia that may result in various skin lesions.

<i>Naegleria fowleri</i> Species of free-living excavate form of protist

Naegleria fowleri, also known as the brain-eating amoeba, is a species of the genus Naegleria. It belongs to the phylum Percolozoa and is classified as an amoeboflagellate excavate, an organism capable of behaving as both an amoeba and a flagellate. This free-living microorganism primarily feeds on bacteria but can become pathogenic in humans, causing an extremely rare, sudden, severe, and almost always fatal brain infection known as naegleriasis or primary amoebic meningoencephalitis (PAM).

References

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