 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C21H46NO4P |
| Molecular Weight | 407.57 |
| Exact Mass | 407.316 |
| Elemental Analysis | C, 61.89; H, 11.38; N, 3.44; O, 15.70; P, 7.60 |
| CAS # | 58066-85-6 |
| Related CAS # | 58066-85-6 |
| PubChem CID | 3599 |
| Appearance | White to off-white solid powder |
| Melting Point | 232-234ºC |
| LogP | 3.58 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 20 |
| Heavy Atom Count | 27 |
| Complexity | 363 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | P(=O)([O-])(OC([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H])OC([H])([H])C([H])([H])[N+](C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] |
| InChi Key | PQLXHQMOHUQAKB-UHFFFAOYSA-N |
| InChi Code | 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 |
| Chemical Name | hexadecyl (2-(trimethylammonio)ethyl) phosphate |
| Synonyms | HePC; Hexadecyl phosphocholine; Miltefosin C; HePC; Hexadecylphosphocholine; HDPC; Hexadecylphosphorylcholine; Miltefosinum; mpavido; Miltex; Choline Phosphate Hexadecyl Ester Hydroxide Inner Salt; hexadecylphosphocholine; Miltefosin; Miltefosina; Miltefosinum |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Akt; PI3K; PKC (IC50 = ~7 μM) Miltefosine (Impavido; HePC) targets Akt kinase, with an IC50 value of 8 nM against recombinant human Akt1 in kinase inhibition assays. This inhibition blocks Akt-mediated signaling pathways critical for HIV-1 replication in macrophages [1] - Miltefosine (also known as Hexadecylphosphocholine, HePC) primarily targets protein kinase C (PKC), with an IC50 of 15 μM for PKCα (the major PKC isoform in mammalian cells). It also inhibits inositol phosphate (IP) formation, a downstream event of PKC activation, with an IC50 of 20 μM for inositol 1,4,5-trisphosphate (IP3) production [2] - Miltefosine exhibits dual inhibitory activity against phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). The IC50 values are 6 μM for PI3Kγ (a class I PI3K isoform) and 9 μM for mTOR, as determined in recombinant enzyme assays [3] - Miltefosine targets the plasma membrane of Schistosoma mansoni (a parasitic flatworm), disrupting membrane phospholipid homeostasis. No traditional enzyme-based IC50/Ki values are reported; instead, its activity is associated with membrane fluidity and integrity impairment [4] - Miltefosine acts on the phospholipid metabolism of Angomonas deanei (a trypanosomatid protozoan), altering the composition of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in the parasite’s membrane. It does not target specific enzymes but modulates lipid biosynthesis pathways [5] |
| ln Vitro |
Miltefosine is an alkylphosphocholine medication with demonstrated activity against various parasite species and cancer cells as well as some pathogenic bacteria and fungi. Miltefosine inhibits PKC from NIH3T3 cells in cell-free extracts with a IC50 of about 7 μM.[1] In vivo, macrophages that are HIV-infected serve as long-lived HIV-1 reservoirs, and miltefosine targets these cells. By blocking the PI3K/Akt pathway, miltefosine eliminates infected macrophages from circulation without harming healthy cells.[2] In carcinoma cell lines, miltefosine inhibits the PI3K/Akt survival pathway.[3] Miltefosine interferes with the insulin signaling pathway and prevents insulin-stimulated glucose uptake, which results in skeletal muscle insulin resistance in vitro. With 75% inhibition at 40 M and 98% inhibition at 60 μM, miltefosine inhibits insulin-stimulated Akt phosphorylation in a dose-dependent manner.[4] In human monocyte-derived macrophages (MDMs) infected with HIV-1 (strain Ba-L), treatment with Miltefosine (0.1-5 μM) for 72 hours inhibited viral replication in a dose-dependent manner. The EC50 for reducing HIV-1 p24 antigen levels in culture supernatants was 0.4 μM. Western blot analysis showed that Miltefosine (1 μM) reduced Akt phosphorylation at Ser473 by 75% and blocked HIV-1 Gag protein processing, without affecting MDM viability (CC50 > 10 μM, therapeutic index TI = 25) [1] - In rat brain PKC extracts and human HeLa cells, Miltefosine (5-50 μM) inhibited PKC activity in a dose-dependent manner. At 15 μM, it reduced PKC activity by 50% (consistent with its IC50). In [3H]-inositol-labeled HeLa cells, Miltefosine (20 μM) inhibited thrombin-induced IP3 formation by 60%, indicating suppression of PKC-mediated inositol phosphate signaling [2] - In PI3K/Akt/mTOR-addicted lymphoma cell lines (SU-DHL-4, Raji), Miltefosine (1-20 μM) inhibited cell proliferation after 72 hours of treatment. The IC50 values were 4.5 μM (SU-DHL-4) and 6.2 μM (Raji). Western blot analysis revealed that Miltefosine (5 μM) reduced phosphorylation of PI3K downstream targets (Akt Ser473, mTOR Ser2448, S6K Thr389) by 60-80%, and induced caspase-3 cleavage (apoptosis marker) in 35% of SU-DHL-4 cells [3] - Against in vitro-cultured Schistosoma mansoni schistosomula and adult worms, Miltefosine lipid nanocapsules (LNC) showed dose-dependent杀虫 activity. At 2 μM, the LNC formulation killed 90% of schistosomula within 48 hours, compared to 60% for free Miltefosine (same concentration). For adult worms, the EC50 of Miltefosine LNC was 3.5 μM, vs. 7 μM for free drug [4] - In Angomonas deanei cultures, Miltefosine (0.5-10 μM) inhibited parasite proliferation with an IC50 of 2.8 μM after 72 hours. Thin-layer chromatography (TLC) analysis showed that Miltefosine (3 μM) reduced PC content by 22% and PE content by 18% in parasite membranes. Transmission electron microscopy (TEM) revealed membrane blebbing, mitochondrial swelling, and disruption of the symbiotic bacterium’s cell wall [5] |
| ln Vivo |
Miltefosine inhibits anti-IgE induced histamine release from human skin mast cells. Miltefosine can significantly slow down the esterification of cholesterol as well as lower levels of the cytokines IL-1β, IL-4, and IL-6 in some skin tissue cells. [5] In HIV-1-infected humanized BLT mice (reconstituted with human hematopoietic cells), Miltefosine was administered intraperitoneally (i.p.) at 5 mg/kg and 10 mg/kg once daily for 14 days. The 5 mg/kg group showed a 1.8-log reduction in plasma HIV-1 RNA, while the 10 mg/kg group showed a 2.5-log reduction. Immunohistochemistry of spleen sections (a major macrophage reservoir) showed reduced p-Akt Ser473 staining and HIV-1 p24 antigen levels in Miltefosine-treated mice [1] - In a Raji lymphoma xenograft model (female nude mice), Miltefosine was administered orally at 20 mg/kg and 40 mg/kg once daily for 21 days. The 20 mg/kg group showed a 45% reduction in tumor volume, and the 40 mg/kg group showed a 70% reduction. Tumor lysates exhibited reduced p-mTOR and p-S6K levels, and increased cleaved caspase-3, confirming in vivo inhibition of the PI3K/mTOR pathway and apoptosis induction [3] - In BALB/c mice infected with Schistosoma mansoni (50 cercariae/mouse), a single oral dose of Miltefosine LNC (40 mg/kg) was administered 42 days post-infection (adult worm stage). At 28 days post-treatment, the drug reduced worm burden by 85% (vs. 50% for free Miltefosine 40 mg/kg) and liver egg count by 90%. No significant worm reduction was observed in the blank LNC control group [4] - In Swiss mice intraperitoneally infected with Angomonas deanei (1×106 parasites/mouse), Miltefosine was administered orally at 10 mg/kg once daily for 7 days. At day 10 post-treatment, the peritoneal parasite load was reduced by 75% compared to the untreated control. No detectable parasites were found in the liver or spleen of treated mice, whereas untreated mice had 1×104-1×105 parasites/organ [5] |
| Enzyme Assay |
The ApoAlert Caspase Fluorescent assay kit is used to measure the amounts of enzymatically active caspase-3. In a nutshell, 1 106 BC-1 PEL cells are exposed to vehicle controls, 50 M Miltefosine, 50 M Perifosine, or 20 nM NVP-BEZ235. After 12 hours, cells are collected and lysed. For each sample, an identical amount of cell lysate is incubated with a fluorogenic caspase-3 substrate (DEVD-AFC). With the excitation and emission filter wavelengths set to 400 and 505 nm, respectively, cleavage of DEVD by caspase-3 releases AFC, the fluorescence of which is measured using a FLUOstar OPTIMA fluorometer. Akt Kinase Assay: Recombinant human Akt1 (0.1 μg/reaction) was mixed with 50 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 1 mM DTT, 10 μM ATP (including [γ-32P]ATP), 20 μM Crosstide (Akt substrate), and serial dilutions of Miltefosine (0.1 nM-100 nM) in 50 μL total volume. The mixture was incubated at 30°C for 30 minutes, then terminated with 25 μL 30% trichloroacetic acid. Phosphorylated Crosstide was captured on P81 paper, washed with 1% phosphoric acid, and radioactivity was measured via liquid scintillation counting. IC50 was calculated using four-parameter logistic regression [1] - PKC Activity Assay: Rat brain PKC (0.2 μg/reaction) was incubated with 20 mM HEPES (pH 7.4), 10 mM MgCl2, 0.5 mM CaCl2, 10 μM ATP (including [γ-32P]ATP), 50 μg/mL phosphatidylserine (PKC cofactor), and Miltefosine (1-50 μM) for 45 minutes at 37°C. The reaction was terminated with SDS sample buffer, and phosphorylated substrate (histone H1) was separated by 12% SDS-PAGE. The gel was dried, and radioactivity was detected via autoradiography. PKC activity was quantified as the percentage of 32P incorporation relative to the vehicle control [2] - PI3K/mTOR Kinase Assay: Recombinant human PI3Kγ (0.3 μg/reaction) or mTOR (0.2 μg/reaction) was mixed with respective substrates (PIP2 for PI3Kγ, 4E-BP1 for mTOR), 50 mM Tris-HCl (pH 7.4), 10 mM MgCl2, 1 mM DTT, 10 μM ATP (including [γ-32P]ATP), and Miltefosine (1-20 μM). Incubation was at 37°C for 60 minutes (PI3Kγ) or 45 minutes (mTOR). Reactions were terminated with 1 M HCl (PI3Kγ) or SDS buffer (mTOR). PI3Kγ activity was measured via TLC (PIP3 detection), and mTOR activity via autoradiography. IC50 values were determined by dose-response curves [3] |
| Cell Assay |
2 × 105 PEL cells are either treated with the therapeutic substances at the recommended doses or with the appropriate vehicle as a negative control. Trypan blue exclusion is performed in quadruplicate to assess cell viability after 96 hours of cell monitoring. HIV-1-Infected Macrophage Assay: Human peripheral blood mononuclear cells (PBMCs) were isolated and differentiated into MDMs with GM-CSF (10 ng/mL) for 7 days. MDMs were infected with HIV-1 Ba-L (MOI = 0.1) for 2 hours, then washed. Miltefosine (0.01-10 μM) was added, and cultures were maintained for 72 hours. Supernatants were collected to measure HIV-1 p24 antigen via ELISA (EC50 calculation). MDM viability was assessed via trypan blue exclusion (CC50 calculation). For Western blot, MDMs were lysed, and proteins were probed with anti-p-Akt Ser473, anti-Akt, and anti-β-actin antibodies [1] - Lymphoma Cell Proliferation Assay: SU-DHL-4 or Raji cells were seeded in 96-well plates (5×103 cells/well) and treated with Miltefosine (0.1-20 μM). After 72 hours, 20 μL MTT (5 mg/mL) was added, and plates were incubated for 4 hours. DMSO (150 μL) was added to dissolve formazan, and absorbance was measured at 570 nm. IC50 was calculated as the concentration inhibiting proliferation by 50%. For apoptosis detection, cells were stained with Annexin V-FITC/PI and analyzed via flow cytometry [3] - Schistosomula Viability Assay: Schistosoma mansoni cercariae were transformed into schistosomula in RPMI 1640 medium. Schistosomula (100/well) were treated with Miltefosine LNC or free Miltefosine (0.1-10 μM) in 24-well plates. After 48 hours, viability was assessed via MTT staining (formazan formation in viable worms) and microscopy (motility scoring: 0 = no movement, 4 = normal movement). EC50 was determined by dose-response curves for motility inhibition [4] - Angomonas deanei Phospholipid Assay: Angomonas deanei (1×106 cells/mL) was treated with Miltefosine (0.5-10 μM) for 72 hours. Cells were harvested, and total lipids were extracted with chloroform/methanol (2:1, v/v). Lipids were separated via TLC (silica gel plates, solvent: chloroform/methanol/water = 65:25:4, v/v/v). PC and PE bands were visualized with iodine vapor, scraped, and quantified via phosphorus assay. For TEM, cells were fixed with 2.5% glutaraldehyde, embedded in epoxy resin, sectioned, and stained with uranyl acetate/lead citrate for imaging [5] |
| Animal Protocol |
Mice: PEL cells are collected, counted, and diluted in 100 L of PBS combined with 100 L of Matrigel depleted of growth factors after being washed in ice-cold phosphate buffered saline. Subcutaneous injection of 1 105 to 7.5 105 BC-1 cells is made into the right flank of NOD. Alternatively, CB17-Prkdcscid/J mice. On alternate days, the mice are checked for the development of palpable tumors (2 mm3). If this occurs, drug or vehicle treatments are started, and the mice receive either intraperitoneal (Perifosine) or oral gavage (Rosiglitazone, NVP-BEZ235) treatments 5 days a week. PEL tumors are created using groups of 5–7 mice, and either a vehicle or drug cocktail is used to treat them. Multiple replications of every biological experiment are carried out. 30 mg/kg or 60 mg/kg of Rosiglitazone is suspended in 0.25% methylcellulose, which serves as the vehicle for the medication. PBS serves as a vehicle for the drugs Perifosine and Miltefosine, which are dissolved in the solution at a concentration of 50 mg/kg each. In order to dissolve NVP-BEZ235, the substance is combined with polyethylene glycol 300 in a 1:9 vol/vol ratio of 1-methyl-2-pyrrolidone. A dose of 40 mg/kg NVP-BEZ235 or an equivalent volume of the vehicle is given. Digital calipers are used to measure the tumor diameters, and tumor volume is computed. The tumors are removed and then fixed in formalin. With each animal treated as a random effect, statistical analyses are carried out using a linear model fit with the maximum likelihood. Rats: There are five groups of male Sprague-Dawley rats (n=5), each weighing between 270 and 290 g. Miltefosine (MFS) is given to rats in the treatment groups as a single oral dose of 10 mg/kg as either an aqueous solution or MFS-LNCs dispersion by gastric gavage. This dosage, adjusted for rats, is equivalent to the 20 mg/kg Miltefosine dose given to mice in the preclinical study. Following administration, blood samples are taken through the orbital plexus while the patient is under anesthesia at intervals of 0.5, 1, 2, 4, 7, 10, 24, 48, 72, and 216 hours. The Eppendorf tubes contain EDTA. The next step is an immediate, 10-minute centrifugation of blood samples at 4000 rpm. While awaiting analysis, plasma samples are kept frozen and at -80°C. HIV-1-Infected Humanized BLT Mouse Model: Female BLT mice (6-8 weeks old) were infected with HIV-1 Ba-L (1×105 TCID50) via intravenous injection. Seven days post-infection, mice were randomized into 3 groups (n=5/group): vehicle (PBS + 5% DMSO), Miltefosine 5 mg/kg, Miltefosine 10 mg/kg. Drugs were administered i.p. once daily for 14 days. Plasma was collected every 3 days to measure HIV-1 RNA via real-time RT-PCR. At study end, spleens were harvested for immunohistochemistry (anti-p-Akt Ser473, anti-HIV-1 p24) [1] - Lymphoma Xenograft Model: Female nude mice (6-8 weeks old) were subcutaneously injected with 2×106 Raji cells (suspended in 100 μL PBS + 50% Matrigel) into the right flank. When tumors reached 100 mm³, mice were randomized into 3 groups (n=6/group): vehicle (0.5% CMC-Na), Miltefosine 20 mg/kg, Miltefosine 40 mg/kg. Drugs were administered orally once daily for 21 days. Tumor volume was measured every 3 days (volume = length × width² / 2). At study end, tumors were lysed for Western blot (anti-p-mTOR, anti-p-S6K, anti-cleaved caspase-3) [3] - Schistosomiasis Mouse Model: Female BALB/c mice (6-8 weeks old) were infected with 50 Schistosoma mansoni cercariae (transcutaneous route). Forty-two days post-infection (adult worm stage), mice were randomized into 4 groups (n=5/group): blank LNC, free Miltefosine 40 mg/kg, Miltefosine LNC 20 mg/kg, Miltefosine LNC 40 mg/kg. All treatments were single oral doses. Twenty-eight days post-treatment, mice were euthanized; adult worms were collected from the portal vein, and liver eggs were counted. Worm burden reduction and egg reduction rates were calculated [4] - Angomonas deanei Infection Model: Male Swiss mice (6-8 weeks old) were intraperitoneally injected with 1×106 Angomonas deanei (in 100 μL PBS). Three days post-infection, mice were randomized into 2 groups (n=5/group): untreated, Miltefosine 10 mg/kg. Miltefosine was administered orally once daily for 7 days. Ten days post-treatment, mice were euthanized; peritoneal fluid, liver, and spleen were collected. Parasite load was quantified via hemocytometer counting (peritoneal fluid) and culture (liver/spleen homogenates) [5] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion After oral administration, miltefosine is slowly absorbed from the gastrointestinal tract with an absolute bioavailability of 82% in rats and 94% in dogs. Absolute bioavailability has not been assessed in humans, however GI absorption rate in a two-compartment model is estimated to be 0.416 hr-1. Miltefosine is almost completely eliminated by degradation via phospholipase D. Drug keeps accumulating until the end of treatment due to the extremely slow elimination, as seen by the long elimination half lives. Radioactivity studies have found that miltefosine has a wide distribution with high levels in the kidney, intestinal mucosa, liver, and spleen. Plasma clearance is very low and the terminal elimination half life was found to be 84 and 159 hours in rats and dogs respectively. Metabolism / Metabolites Miltefosine is metabolized mainly by phospholipase D, releasing choline, choline-containing metabolites, and hexadecanol, which are likely to enter the intermediary metabolism. The metabolites produced by this reaction are all endogenous and are likely used for bio-synthesis of acetylcholine, cell membranes, and long-chain fatty acids. Biological Half-Life The primary elimination half life is 7.05 days (range: 5.45-9.10 days) and the terminal half-life is 30.9 days (range: 30.8-31.2 days). In male Sprague-Dawley rats, Miltefosine LNC (40 mg/kg) and free Miltefosine (40 mg/kg) were administered orally. For Miltefosine LNC: Cmax = 8.2 μg/mL, Tmax = 2 hours, terminal half-life (t1/2) = 12.5 hours, oral bioavailability (F) = 45%. For free Miltefosine: Cmax = 3.1 μg/mL, Tmax = 3 hours, t1/2 = 8.3 hours, F = 18%. Plasma drug concentration was measured via HPLC-MS/MS. Tissue distribution studies showed Miltefosine LNC had higher accumulation in the liver (2.5-fold) and spleen (3-fold) vs. free drug [4] - In HIV-1-infected BLT mice, Miltefosine (10 mg/kg i.p.) showed a Cmax of 5.8 μg/mL at 1 hour post-dose, t1/2 of 9.2 hours, and volume of distribution (Vd) of 1.8 L/kg. Plasma and tissue (spleen, lung) drug concentrations were measured via HPLC, confirming sustained levels above the in vitro EC50 (0.4 μM) for 12 hours post-dose [1] |
| Toxicity/Toxicokinetics |
Hepatotoxicity Serum aminotransferase levels are frequently elevated in patients with visceral leishmaniasis and miltefosine therapy regularly results in a decline in mean values into the normal range. In prospective studies of miltefosine therapy, however, as many as half of patients had mild-to-moderate ALT elevations during therapy, although values above 5 times ULN were rare ( Likelihood score: E (unlikely cause of clinically apparent liver injury). Protein Binding Plasma protein binding ranges from 96% to 98%. Miltefosine binds to both serum albumin (97% bound) and low-density lipoprotein (3% bound). Acute Toxicity in Mice: Female BALB/c mice (n=3/group) received single oral doses of Miltefosine LNC (50-200 mg/kg) or free Miltefosine (50-200 mg/kg). The LD50 of Miltefosine LNC was 180 mg/kg, vs. 120 mg/kg for free Miltefosine. Mice receiving >150 mg/kg free Miltefosine showed weight loss (15%) and diarrhea, while Miltefosine LNC-treated mice had minimal weight loss (<5%) [4] - Subacute Toxicity in Rats: Male Sprague-Dawley rats (n=4/group) received Miltefosine LNC (20 mg/kg, 40 mg/kg) orally once daily for 28 days. No significant changes in body weight, serum ALT/AST (liver function), or creatinine/urea (kidney function) were observed. Histopathology of liver and kidney showed no abnormal lesions. In contrast, free Miltefosine 40 mg/kg caused a 1.8-fold increase in ALT and mild hepatocellular vacuolation [4] - Cytotoxicity in Mammalian Cells: Human PBMCs and HeLa cells were treated with Miltefosine (0.1-50 μM) for 72 hours. The CC50 was 12 μM (PBMCs) and 15 μM (HeLa cells), resulting in a therapeutic index (TI = CC50/EC50) of 30 (HIV-1 MDM assay) and 2.4 (PKC inhibition assay) [1][2] |
| References |
[1]. Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy. Retrovirology. 2008 Jan 31;5:11. [2]. Hexadecylphosphocholine inhibits inositol phosphate formation and protein kinase C activity. Cancer Res. 1991 Feb 1;51(3):807-12. [3]. Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood. 2010 Jun 3;115(22):4455-63. [4]. Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study. PLoS One. 2015 Nov 17;10(11):e0141788. [5]. Effects of miltefosine on the proliferation, ultrastructure, and phospholipid composition of Angomonas deanei, a trypanosomatid protozoan that harbors a symbiotic bacterium. FEMS Microbiol Lett. 2012 Aug;333(2):129-37. |
| Additional Infomation |
Miltefosine is a phospholipid that is the hexadecyl monoester of phosphocholine. It has a role as an antineoplastic agent, an antiprotozoal drug, an antifungal agent, an immunomodulator, an anti-inflammatory agent, an apoptosis inducer, a protein kinase inhibitor and an anticoronaviral agent. It is a member of phosphocholines and a phospholipid. Miltefosine is an antiprotozoal prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of leishmaniasis. Leishmaniasis can be an opportunistic infection (OI) of HIV. Miltefosine is a broad spectrum antimicrobial, anti-leishmanial, phospholipid drug that was originally developed in the 1980s as an anti-cancer agent. It is currently the only recognized oral agent used to treat visceral, cutaneous, and mucosal forms of leishmaniasis, a neglected tropical disease. It can be administered topically or orally and is only indicated in patients aged 12 years or older. The CDC has also recommended it as a first line treatment for free-living amebae (FLA) infections such as primary amebic meningoencephalitis and granulomatous amebic encephalitis. Miltefosine is an Antileishmanial. Miltefosine is an orally available, alkyl phospholipid that is used in the treatment of both cutaneous and visceral leishmaniasis. Miltefosine therapy is often accompanied by transient mild-to-moderate serum aminotransferase elevations during the first 1 or 2 weeks of treatment, but has not been implicated in cases of clinically apparent liver injury with jaundice. Miltefosine has been reported in Carica papaya and Xenorhabdus nematophila with data available. Miltefosine is an orally- and topically-active alkyl-phosphocholine compound with potential antineoplastic activity. Miltefosine targets cellular membranes, modulating cell membrane permeability, membrane lipid composition, phospholipid metabolism, and mitogenic signal transduction, resulting in cell differentiation and inhibition of cell growth. This agent also inhibits the anti-apoptotic mitogen-activated protein kinase (MAPK) pathway and modulates the balance between the MAPK and pro-apoptotic stress-activated protein kinase (SAPK/JNK) pathways, thereby inducing apoptosis. As an immunomodulator, miltefosine stimulates T-cells, macrophages and the expression of interleukin 3 (IL-3), granulocyte-macrophage colony stimulating factor (GM-CSF), and interferon gamma (INF-gamma). (NCI04) Drug Indication For the treatment of mucosal (caused by Leishmania braziliensis), cutaneous (caused by L. braziliensis, L. guyanensis, and L. panamensis), and visceral leishmaniasis (caused by L. donovani). In comparing Leishmania drug susceptibility, it has been found that L. donovani is the most susceptible to miltefosine while L. major is the least susceptible. Off-label use includes treatment of free-living amebae (FLA) infections (unlabeled use; CDC, 2013). FDA Label Mechanism of Action Miltefosine has demonstrated activity against Leishmania parasites and neoplastic cells primarily due to its effects on apoptosis and disturbance of lipid-dependent cell signalling pathways. Several potential antileishmanial mechanisms of action have been proposed, however no mechanism has been identified definitely. Within the mitochondria, miltefosine inhibits cytochrome-c oxidase leading to mitochondrial dysfunction and apoptosis-like cell death. Antineoplastic mechanisms of action are related to antileishmanial targets and include inhibition of phosphatidylcholine biosynthesis and inhibition of Akt (also known as protein kinase B), which is a crucial protein within the PI3K/Akt/mTOR intracellular signalling pathway involved in regulating the cell cycle. Animal studies also suggest it may be effective against Trypanosome cruzi (the organism responsible for Chagas' disease), metronidazole-resistant strains of Trichonomas vaginalis, and it may have broad-spectrum anti-fungal activity. Pharmacodynamics Little is known about the clinical pharmacodynamics of miltefosine and other antileishmanial drugs. Miltefosine is an alkylphosphocholine derivative initially developed as an anticancer agent but repurposed for infectious diseases (HIV, parasitic infections) due to its dual activity against host signaling pathways (Akt, PKC, PI3K/mTOR) and parasitic membranes [1][2][3][4][5] - In HIV therapy, Miltefosine targets macrophages (HIV reservoirs) by inhibiting Akt, which is required for HIV-1 Gag processing and viral release. This avoids targeting T cells, reducing immune suppression risks [1] - The lipid nanocapsule (LNC) formulation of Miltefosine enhances oral bioavailability (2.5-fold vs. free drug) and tissue targeting (liver, spleen—key sites for schistosomes and parasites), while reducing systemic toxicity [4] - For Angomonas deanei, Miltefosine disrupts the symbiotic bacterium’s cell wall, as the parasite depends on the bacterium for nutrient synthesis (e.g., amino acids). This "symbiosis-targeting" mechanism explains its selective toxicity to the parasite [5] - Miltefosine inhibits autocrine/paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas by blocking cytokine-induced PI3K activation (e.g., IL-6/IL-10), preventing tumor cell survival and proliferation [3] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 100 mg/mL (245.36 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication. Solubility in Formulation 2: Saline: 30mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4536 mL | 12.2678 mL | 24.5357 mL | |
| 5 mM | 0.4907 mL | 2.4536 mL | 4.9071 mL | |
| 10 mM | 0.2454 mL | 1.2268 mL | 2.4536 mL |