Miltefosine
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Miltefosine, sold under the trade name Impavido among others, is a medication mainly used to treat
leishmaniasis Leishmaniasis is a wide array of clinical manifestations caused by parasites of the trypanosome genus ''Leishmania''. It is generally spread through the bite of phlebotomine sandflies, ''Phlebotomus'' and ''Lutzomyia'', and occurs most freq ...
and free-living amoeba infections such as ''
Naegleria fowleri ''Naegleria fowleri'', colloquially known as a "brain-eating amoeba", is a species of the genus ''Naegleria'', belonging to the phylum Percolozoa, which is technically not classified as true amoeba, but a shapeshifting amoeboflagellate excava ...
'' and ''
Balamuthia mandrillaris ''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 ...
''. This includes the three forms of leishmaniasis:
cutaneous Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different de ...
,
visceral In biology, an organ is a collection of tissues joined in a structural unit to serve a common function. In the hierarchy of life, an organ lies between tissue and an organ system. Tissues are formed from same type cells to act together in a ...
and mucosal. It may be used with
liposomal amphotericin B Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and cryptococcosis. ...
or
paromomycin Paromomycin is an antimicrobial used to treat a number of parasitic infections including amebiasis, giardiasis, leishmaniasis, and tapeworm infection. It is a first-line treatment for amebiasis or giardiasis during pregnancy. Otherwise it is g ...
. It is taken by mouth. Common side effects include
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...
, abdominal pain,
fever Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...
,
headaches Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result of m ...
, and decreased kidney function. More severe side effects may include
Stevens–Johnson syndrome Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN), it forms a spectrum of disease, with SJS being less severe. Erythema ...
or
low blood platelets Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care units, intensive care patients and is seen in a fifth of ...
. Use during
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...
appears to cause harm to the baby and use during
breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...
is not recommended. How it works is not entirely clear. Miltefosine was first made in the early 1980s and studied as a treatment for
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
. A few years later it was found to be useful for leishmaniasis and was approved for this use in 2002 in India. It is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
.


Medical uses


Leishmaniasis

Miltefosine is primarily used for the treatment of
visceral In biology, an organ is a collection of tissues joined in a structural unit to serve a common function. In the hierarchy of life, an organ lies between tissue and an organ system. Tissues are formed from same type cells to act together in a ...
and New World cutaneous leishmaniasis, and is undergoing
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
s for this use in several countries. This drug is now listed as a core medication for the treatment of leishmaniasis under the WHO Model List of Essential Medicines. 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.


Amoeba infections

Miltefosine has been used successfully in some cases of the very rare, but highly lethal, brain infection by the amoeba, ''
Naegleria fowleri ''Naegleria fowleri'', colloquially known as a "brain-eating amoeba", is a species of the genus ''Naegleria'', belonging to the phylum Percolozoa, which is technically not classified as true amoeba, but a shapeshifting amoeboflagellate excava ...
'', acquired through water entering the nose during a plunge in contaminated water. It has orphan drug status in the United States for
acanthamoeba keratitis ''Acanthamoeba'' keratitis (AK) is a rare disease in which amoebae of the genus ''Acanthamoeba'' invade the clear portion of the front (cornea) of the eye. It affects roughly 100 people in the United States each year. ''Acanthamoeba'' are protoz ...
and
primary amebic meningoencephalitis 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 ...
(PAM).


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. 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 Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent unwanted pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth contr ...
should be used while on miltefosine and 5 months after discontinuation of treatment. Its use during breast feeding is most likely unsafe.


Contraindications

Miltefosine is contraindicated in individuals who have a
hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune s ...
to this medication, pregnant women, and people who have the Sjögren-Larsson syndrome. It is embryotoxic and fetotoxic in rats and rabbits, and
teratogenic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related t ...
in rats but not in rabbits. It is therefore contraindicated for use during pregnancy, and
contraception Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent unwanted pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth contr ...
is required beyond the end of treatment in women of child-bearing age.


Side effects

Common
side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s from miltefosine treatment are
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
and
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...
, which occur in 60% of people. Other common side effects are dizziness, headache, and daytime sleepiness. Serious side effects include rash, diarrhea, and arthritis. The side effects are more severe in women and young children. The overall effects are quite mild and easily reversed.


Mechanism of action

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


History


Cancer

While initially studied as a cancer medication, due to side effects it was never used for this purpose.
Phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
group
alkylphosphocholine Alkylphosphocholines are phospholipid-like molecules that have been Chemical synthesis, synthesised, which have remarkable biological and therapeutic activities. They are phosphocholine esters of aliphatic long chain alcohols differing in chain len ...
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 Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'' 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 The Max Planck Institute for Biophysical Chemistry (german: Max-Planck-Institut für biophysikalische Chemie), also known as the Karl-Friedrich Bonhoeffer Institute (german: Karl-Friedrich-Bonhoeffer-Institut), was a research institute of the Ma ...
, and Clemens Unger, at the
University of Göttingen The University of Göttingen, officially the Georg August University of Göttingen, (german: Georg-August-Universität Göttingen, known informally as Georgia Augusta) is a public research university in the city of Göttingen, Germany. Founded ...
, 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 Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...
, but less so on transplantable
mammary carcinoma Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...
s and
autochthonous Autochthon, autochthons or autochthonous may refer to: Fiction * Autochthon (Atlantis), a character in Plato's myth of Atlantis * Autochthons, characters in the novel ''The Divine Invasion'' by Philip K. Dick * Autochthon, a Primordial in the ' ...
benzo(a)pyrene Benzo 'a''yrene (B''a''P or B ) is a polycyclic aromatic hydrocarbon and the result of incomplete combustion of organic matter at temperatures between and . The ubiquitous compound can be found in coal tar, tobacco smoke and many foods, espec ...
-induced
sarcoma A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal (connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sarcom ...
s, and relatively inactive on Walker 256
carcinosarcoma Carcinosarcomas are malignant tumors that consist of a mixture of carcinoma (or epithelial cancer) and sarcoma (or mesenchymal/connective tissue cancer). Carcinosarcomas are rare tumors, and can arise in diverse organs, such as the skin, salivary ...
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 Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...
group, is highly selective on cell types and acts through different mechanism.


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 The London School of Hygiene and Tropical Medicine (LSHTM) is a public research university in Bloomsbury, central London, and a member institution of the University of London that specialises in public health and tropical medicine. The inst ...
as having antileishmanial effect as well. The compound was effective against ''
Leishmania donovani ''Leishmania donovani'' is a species of intracellular parasites belonging to the genus ''Leishmania'', a group of haemoflagellate kinetoplastids that cause the disease leishmaniasis. It is a human blood parasite responsible for visceral leishmani ...
''
amastigote An amastigote is a protist A protist () is any eukaryotic organism (that is, an organism whose cells contain a cell nucleus) that is not an animal, plant, or fungus. While it is likely that protists share a common ancestor (the last eukaryot ...
s in cultured mouse peritoneal
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s 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 Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
of
breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
. 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 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, paramycin and lipo ...
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
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
(WHO) Special Programme for Research and Training in Tropical Diseases, and the
Government of India The Government of India (ISO: ; often abbreviated as GoI), known as the Union Government or Central Government but often simply as the Centre, is the national government of the Republic of India, a federal democracy located in South Asia, c ...
. 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.


''Naegleria fowleri'' and ''Acanthamoeba''

In 2013, the US
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
recommended miltefosine for the treatment of free-living amoeba infections such as
granulomatous amoebic encephalitis Granulomatous amoebic encephalitis (GAE) is a rare, usually 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 m ...
and
primary amoebic meningoencephalitis 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 ...
, two fatal protozoal diseases. 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. In 2016 after treatment that included miltefosine, another child became the fourth person in the United States to survive ''
Naegleria fowleri ''Naegleria fowleri'', colloquially known as a "brain-eating amoeba", is a species of the genus ''Naegleria'', belonging to the phylum Percolozoa, which is technically not classified as true amoeba, but a shapeshifting amoeboflagellate excava ...
'' infection.


Society and culture


Availability

Since 2017 Miltefosine is commercially available in the United States through Profounda. Previously one could only get it from the
CDC The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
for emergency use under an expanded access
IND Ind or IND may refer to: General * Independent (politician), a politician not affiliated to any political party * Independent station, used within television program listings and the television industry for a station that is not affiliated with ...
protocol for treatment of free-living amoeba (FLA) infections:
primary amoebic meningoencephalitis 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 ...
caused by ''
Naegleria fowleri ''Naegleria fowleri'', colloquially known as a "brain-eating amoeba", is a species of the genus ''Naegleria'', belonging to the phylum Percolozoa, which is technically not classified as true amoeba, but a shapeshifting amoeboflagellate excava ...
'' and granulomatous amoebic encephalitis caused by ''
Balamuthia mandrillaris ''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 ...
'' and ''
Acanthamoeba ''Acanthamoeba'' is a genus of amoeboid, amoebae that are commonly recovered from soil, fresh water, and other habitat (ecology), habitats. ''Acanthamoeba'' has two evolutive forms, the metabolically active trophozoite and a dormant, stress-resi ...
'' species. Miltefosine is almost exclusively produced by Profounda, a private pharmaceutical company.


Economics

In the
developing world A developing country is a sovereign state with a lesser developed industrial base and a lower Human Development Index (HDI) relative to other countries. However, this definition is not universally agreed upon. There is also no clear agreem ...
a course of treatment costs US$65 to $150. In the
developed world A developed country (or industrialized country, high-income country, more economically developed country (MEDC), advanced country) is a sovereign state that has a high quality of life, developed economy and advanced technological infrastruct ...
treatment may be 10 to 50 times greater.


Further research

It is active against some
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
and
fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
, as well as human
trematode Trematoda is a class of flatworms known as flukes. They are obligate internal parasites with a complex life cycle requiring at least two hosts. The intermediate host, in which asexual reproduction occurs, is usually a snail. The definitive host ...
''
Schistosoma mansoni A paired couple of ''Schistosoma mansoni''. ''Schistosoma mansoni'' is a water-borne parasite of humans, and belongs to the group of blood flukes (''Schistosoma''). The adult lives in the blood vessels ( mesenteric veins) near the human inte ...
'' and the snail that spreads it ''
Biomphalaria alexandrina ''Biomphalaria alexandrina'' is a species of air-breathing freshwater snail, an aquatic pulmonate gastropod mollusk in the family Planorbidae, the ram's horn snails and their allies. Distribution This species occur in Egypt Habitat ''Bi ...
''.


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 ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' studies suggest it may have broad anti-protozoal and anti-fungal properties: * Animal studies suggest miltefosine may also be effective against ''
Trypanosoma cruzi ''Trypanosoma cruzi'' is a species of parasitic euglenoids. Among the protozoa, the trypanosomes characteristically bore tissue in another organism and feed on blood (primarily) and also lymph. This behaviour causes disease or the likelihood of ...
'', the
parasite Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson has ...
responsible for
Chagas' disease Chagas disease, also known as American trypanosomiasis, is a tropical parasitic disease caused by ''Trypanosoma cruzi''. It is spread mostly by insects in the subfamily ''Triatominae'', known as "kissing bugs". The symptoms change over the cou ...
. * Several studies have found the drug to be effective against types of fungus: ''
Cryptococcus neoformans ''Cryptococcus neoformans'' is an encapsulated yeast belonging to the class Tremellomycetes and an obligate aerobe that can live in both plants and animals. Its teleomorph is a filamentous fungus, formerly referred to ''Filobasidiella neoformans' ...
'', '' Candida'', ''
Aspergillus ' () is a genus consisting of several hundred mold species found in various climates worldwide. ''Aspergillus'' was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli. Viewing the fungi under a microscope, Miche ...
'' and ''
Fusarium ''Fusarium'' is a large genus of filamentous fungi, part of a group often referred to as hyphomycetes, widely distributed in soil and associated with plants. Most species are harmless saprobes, and are relatively abundant members of the soil mi ...
''. * A 2006 ''in vitro'' study found that miltefosine is effective against metronidazole-resistant variants of ''
Trichomonas vaginalis ''Trichomonas vaginalis'' is an anaerobic, flagellated protozoan parasite and the causative agent of a sexually transmitted disease called trichomoniasis. It is the most common pathogenic protozoan that infects humans in industrialized countries ...
'', a sexually transmitted protozoal disease. *
Cetrimonium bromide Cetrimonium bromide ( C16H33)N(CH3)3r; cetyltrimethylammonium bromide; hexadecyltrimethylammonium bromide; CTAB) is a quaternary ammonium surfactant. It is one of the components of the topical antiseptic cetrimide. The cetrimonium (hexadecyltrime ...
, a compound related to miltefosine, was demonstrated in 2007 to exhibit potent ''in vitro'' activity against ''
Plasmodium falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...
''. * An ''in vitro'' test in 2006 showed that miltefosine is effective against the deadly protozoan pathogens, ''Naegleria fowleri'', ''Balamuthia mandrillaris'', and ''Acanthamoeba''. However, later studies showed that it is not as potent as other drugs, such as
chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar dis ...
and
diminazene aceturate Diminazene (INN; also known as diminazen) is an anti-infective medication for animals that is sold under a variety of brand names. It is effective against certain protozoa such as ''Babesia'', ''Trypanosoma'', and '' Cytauxzoon''. The drug may al ...
(Berenil). * In 2013, there were reports of failure of miltefosine in the treatment of leishmaniasis. Although
drug resistance Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, ...
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. * A 2012 ''in vitro'' study found that miltefosine had promising activity against ''
Candida albicans ''Candida albicans'' is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is us ...
''
biofilm A biofilm comprises any syntrophic consortium of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular ...
s.


Anti-HIV activity

Miltefosine targets HIV infected
macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
, which play a role
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
as long-lived HIV-1 reservoirs. The HIV protein Tat activates pro-survival
PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
/
Akt Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...
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 cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...
s (DCs) and CD4+ T cells, which is due to a rapid secretion of soluble factors and is associated with induction of type-I
interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...
(IFN) in the human cells.


References


External links

*
Max Planck Innovation

FDA Panel Endorses Miltefosine for Leishmaniasis




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