Dimethyl fumarate

Last updated

Contents

Dimethyl fumarate
Dimethyl fumarate.png
Names
Preferred IUPAC name
Dimethyl (2E)-but-2-enedioate
Other names
trans-1,2-Ethylenedicarboxylic acid dimethyl ester
(E)-2-Butenedioic acid dimethyl ester
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.009.863 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 210-849-0
KEGG
PubChem CID
UNII
  • InChI=1S/C6H8O4/c1-9-5(7)3-4-6(8)10-2/h3-4H,1-2H3/b4-3+ Yes check.svgY
    Key: LDCRTTXIJACKKU-ONEGZZNKSA-N Yes check.svgY
  • InChI=1/C6H8O4/c1-9-5(7)3-4-6(8)10-2/h3-4H,1-2H3/b4-3+
    Key: LDCRTTXIJACKKU-ONEGZZNKBJ
  • O=C(OC)\C=C\C(=O)OC
Properties
C6H8O4
Molar mass 144.126 g·mol−1
AppearanceWhite crystalline solid
Density 1.37 g/cm3
Melting point 103.5 °C (218.3 °F; 376.6 K) [1]
Boiling point 193 °C (379 °F; 466 K) [1]
Pharmacology
L04AX07 ( WHO )
License data
By mouth
Legal status
Hazards
GHS labelling:
GHS-pictogram-exclam.svg
Warning
H312, H315, H317, H319, H335
P261, P264, P271, P272, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P322, P332+P313, P333+P313, P337+P313, P362, P363, P403+P233, P405, P501
Related compounds
Related diesters
Diethyl fumarate, dimethyl maleate, dimethyl malonate, dimethyl adipate
Related compounds
 Fumaric acid
Methyl acrylate
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Dimethyl fumarate (DMF) is the methyl ester of fumaric acid and is named after the earth smoke plant ( Fumaria officinalis ). [8] Dimethyl fumarate combined with three other fumaric acid esters (FAEs) is solely licensed in Germany as an oral therapy for psoriasis (brand name Fumaderm). [9] Since 2013, it has been approved by the U.S. Food and Drug Administration (FDA) as a treatment option for adults with relapsing multiple sclerosis (brand name Tecfidera). [4] In 2017, an oral formulation of dimethyl fumarate (brand name Skilarence) was approved for medical use in the European Union as a treatment for moderate-to-severe plaque psoriasis. [6] [10] Dimethyl fumarate is thought to have immunomodulatory properties without causing significant immunosuppression. [11]

Dimethyl fumarate has also been applied as a biocide in furniture or shoes to prevent growths of mold during storage or transport in humid climates. However, due to cases of allergic reactions after skin contact, dimethyl fumarate-containing consumer products are no longer authorised to be manufactured (since 1998) or imported (since 2009) in the European Union. [12] Dimethyl fumarate is available as a generic medication. [13] [7]

Medical uses

In Germany, dimethyl fumarate is marketed for the treatment of psoriasis and is available as an oral formulation mixed with related compounds (Fumaderm); [9] in the UK, it is available as a pure oral formulation (Skilarence). [2] It is also available in the US as an oral formulation (Tecfidera) to treat adults with relapsing multiple sclerosis. [4]

A 2015 Cochrane systematic review found moderate quality evidence of a reduction in the number of people with relapsing remitting MS that had relapses over a two-year treatment period with dimethyl fumarate versus placebo, as well as low quality evidence of a reduction in worsening disability, and an overall need for higher quality studies with longer follow-up. [14]

History

The first medical use of fumaric acid was described in 1959 by Walter Schweckendiek, a German chemist, [15] and was a topical formulation for psoriasis. The Swiss company Fumapharm eventually brought Fumaderm, an oral formulation of dimethyl fumarate (along with some monoesters) to market for psoriasis in Germany in 1994. [16] [17] [18]

Based on the efficacy and safety of this formulation, and evidence that dimethyl fumarate was the main active component, an oral formulation of dimethyl fumarate was developed by Almirall. [19] This oral formulation, under the brand name Skilarence, was approved by the European Medicines Agency (EMA) in June 2017, for the treatment of moderate-to-severe plaque psoriasis in adults. [6] [2]

Initial clinical research on the use of dimethyl fumarate for the treatment of multiple sclerosis was conducted by Fumapharm in collaboration with Biogen Idec; Fumapharm was subsequently acquired by Biogen Idec in 2006. [16] [20] Aditech Pharma in Sweden had also been researching oral formulations of dimethyl fumarate for MS and in 2010, the Danish company Forward Pharma acquired Aditech's patents. [20]

Biogen continued developing its oral formulation of dimethyl fumarate from Fumapharm under the code name BG-12; it was approved, under the trade name Tecfidera, for the treatment of adults with relapsing forms of MS in March 2013. [21] Biogen priced the drug at $54,000 per year in the US. [16] It was approved in Europe in 2014. [3] In the UK NICE issued guidance recommending the drug as cost-effective, but only for patients who do not have highly active or rapidly evolving severe relapsing–remitting multiple sclerosis and only if Biogen agreed to provide it at a discount. [22]

Forward and Biogen entered into patent litigation in many jurisdictions; in 2017, the companies settled the litigation, with Biogen paying Forward $1.25 billion, with the potential for up to 10% of royalties depending on what happened with the patents in various jurisdictions. [20]

In June 2020, in a case between Biogen and Mylan, the U.S. District Court in West Virginia declared invalid Biogen's so-called "514" patent protecting Tecfidera from generic competition. The ruling gave Mylan the right to launch its own version of Tecfidera. [23] [24] [25]

Pharmacology

Dimethyl fumarate is metabolized to monomethyl fumarate (MMF) prior to entering systemic distribution. [4] [26] Dimethyl fumarate has been described a prodrug. [27]

Dimethyl fumarate is a precursor of monomethyl fumarate. Other prodrugs that metabolize to monomethyl fumarate have been developed to treat relapse-remitting multiple sclerosis, including diroximel fumarate which was approved by the FDA in October 2019. [28] [29] [30]

The precise mechanism of action of dimethyl fumarate is not clear. Dimethyl fumarate and monomethyl fumarate can activate the transcription factor (Nuclear factor erythroid-derived 2)-related factor 2 (Nrf2) pathway and monomethyl fumarate has been identified as a nicotinic acid receptor agonist in vitro. [4] In mice that lack Nrf2 expression, however, dimethyl fumarate is still able to modulate the immune system, which indicates that Nrf2 is not required for its immunomodulatory action. [31] For psoriasis, the mechanism of action is believed to be due to the interaction of monomethyl fumarate and the intracellular reduced glutathione of cells directly involved in the pathogenesis of psoriasis. The interaction with glutathione leads to the inhibition of nuclear translocation and the transcriptional activity of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB). [26]

Dimethyl fumarate and monomethyl fumarate have been shown to reduce the expression of micro-RNA-21, which is essential for the production of pathogenic cells in multiple sclerosis and psoriasis. This can be achieved because dimethyl fumarate and monomethyl fumarate, as cell-permeable metabolites, can epigenetically regulate the expression of micro-RNA-21 via the metabolic-epigenetic interplay in developing immune cells. [32]

The main activity of dimethyl fumarate and monomethyl fumarate is considered to be immunomodulatory, resulting in a shift in T helper cells (Th) from the Th1 and Th17 profile to a Th2 phenotype. Inflammatory cytokine production is reduced by the induction of proapoptotic events, inhibition of keratinocyte proliferation, reduced expression of adhesion molecules and diminished inflammatory infiltrate within psoriatic plaques. [26]

The primary route of elimination is via exhalation of CO2, with small amounts excreted through urine or faeces. [26]

There is no evidence for dimethyl fumarate interaction with cytochrome P450 and the most common efflux and uptake transporters, and therefore no interactions are expected with medicinal products metabolised or transported by these systems. [26]

Synthesis and reactions

Several methods exist for the laboratory synthesis of dimethyl fumarate, with reported methods including alkene isomerization of dimethyl maleate, [33] [34] [35] and Fischer esterification of fumaric acid. [33]

Dimethyl fumarate is an old compound used in industrial chemistry and can be purchased by the ton; as of 2012, one could purchase it for $1 to $50 per metric ton, with a two-ton minimum purchase. [36] [16]

The compound undergoes electrohydrodimerization. [37]

Adverse effects

In the treatment of psoriasis, the most common adverse events are gastrointestinal events, flushing and lymphopenia, which are usually mild. Other adverse events include progressive multifocal leukoencephalopathy (PML) and Fanconi syndrome, which are considered rare. PML is probably caused by a combination of factors. A previous infection with the John-Cunningham virus (JCV) is considered a prerequisite for the development of PML. In a PML review, all confirmed cases were of patients exposed to periods of varying lymphopenia. [38]

For multiple sclerosis, adverse effects include flushing and gastrointestinal events, such as diarrhoea, nausea and upper abdominal pain. [14] The drug label includes warnings about the risk of anaphylaxis and angio-oedema, PML, lymphopenia and liver damage. [4] [39]

There is no information on how dimethyl fumarate affects the fetus during pregnancy; in animal tests there was fetal harm at clinically relevant doses. [4]

Consumer products

There have been cases of severe contact dermatitis which was likely related to a dimethyl fumarate contact allergy of newly acquired sofas and chairs. Dimethyl fumarate has been found to be an allergic sensitizer at very low concentrations, producing eczema by contact allergy that is difficult to treat. Concentrations as low as 1 ppm (parts-per-million) may produce allergic reactions in the most severe cases. [40] There are only a handful of equally potent sensitisers. [41]

The sensitizing risk was brought to public attention by the "poison chair" incident, where Chinese manufacturer Linkwise produced two-seater sofas with dimethyl fumarate sachets inside to inhibit mould while they were in storage or transport. [42] In Finland where the chairs were sold from 2006 to 2007, 60 users sustained serious rashes. [41] The cause was identified as dimethyl fumarate-induced allergic reaction by Tapio Rantanen from Finland and his original article became the cover story in the July 2008 issue of the British Journal of Dermatology. [40] In the United Kingdom, sofas sold by Argos, Land of Leather and Walmsley Furnishing containing the chemical caused over a hundred injuries. [41] Argos withdrew the sofas from stores and contacted buyers to collect those that had been sold — with Land of Leather withdrawing the sofas without notifying buyers and Walmsley saying they had removed the sachets from sofas they sold after the danger came to light. [43] [44] The danger came to public attention in 2008 when the BBC Watchdog programme alerted consumers to the sofas. [43] [45]

In the European Union, the use of dimethyl fumarate in consumer product manufacturing has been forbidden since 1998, and in 2009 the importation of consumer products containing dimethyl fumarate was also forbidden. [12] EU Commission Decision 2009/251 of 17 March 2009 required member states to ensure that consumer products containing dimethyl fumarate were not placed or made available on the market from 1 May 2009. This definitely outlawed any marketing of consumer products containing dimethyl fumarate in the European Union. [46] The ban on dimethyl fumarate as laid down in Decision 2009/251 establishes a maximum dimethyl fumarate concentration in products of 0.1 ppm. The decision dictated that consumer products containing more than 0.1 ppm dimethyl fumarate should be withdrawn from the market and recalled from consumers.

Research

As of March 2021 dimethyl fumarate is being evaluated as a treatment for COVID-19 as part of the RECOVERY Trial in the UK. [47]

Related Research Articles

<span class="mw-page-title-main">Progressive multifocal leukoencephalopathy</span> Viral disease affecting human brains

Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal viral disease characterized by progressive damage (-pathy) or inflammation of the white matter (leuko-) of the brain (-encephalo-) at multiple locations (multifocal). It is caused by the JC virus, which is normally present and kept under control by the immune system. The JC virus is harmless except in cases of weakened immune systems. In general, PML has a mortality rate of 30–50% in the first few months, and those who survive can be left with varying degrees of neurological disabilities.

<span class="mw-page-title-main">Biogen</span> Pharmaceutical company

Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, United States specializing in the discovery, development, and delivery of therapies for the treatment of neurological diseases to patients worldwide. Biogen operates in Argentina, Brazil, Canada, China, France, Germany, Hungary, India, Italy, Japan, Mexico, Netherlands, Poland, Sweden, and Switzerland.

Daclizumab is a therapeutic humanized monoclonal antibody which was used for the treatment of adults with relapsing forms of multiple sclerosis (MS). Daclizumab works by binding to CD25, the alpha subunit of the IL-2 receptor of T-cells.

<span class="mw-page-title-main">Fumaric acid</span> Organic compound

Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297. The salts and esters are known as fumarates. Fumarate can also refer to the C
4H
2O2−
4 ion (in solution). Fumaric acid is the trans isomer of butenedioic acid, while maleic acid is the cis isomer.

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

Fingolimod, sold under the brand name Gilenya, is an immunomodulating medication, used for the treatment of multiple sclerosis. Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction. It has been reported to reduce the rate of relapses in relapsing-remitting multiple sclerosis by approximately one-half over a two-year period.

<span class="mw-page-title-main">Natalizumab</span> Medication used to treat multiple sclerosis and Crohns disease

Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat multiple sclerosis and Crohn's disease. It is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. It is given by intravenous infusion. The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood–brain barrier.

<span class="mw-page-title-main">Maleic acid</span> Dicarboxylic acid

Maleic acid or cis-butenedioic acid is an organic compound that is a dicarboxylic acid, a molecule with two carboxyl groups. Its chemical formula is HO2CCH=CHCO2H. Maleic acid is the cis-isomer of butenedioic acid, whereas fumaric acid is the trans-isomer. It is mainly used as a precursor to fumaric acid, and relative to its parent maleic anhydride, which has many applications.

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

Raltegravir, sold under the brand name Isentress, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure. It is taken by mouth.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS). Several therapies for it exist, although there is no known cure.

<span class="mw-page-title-main">Glatiramer acetate</span> Medication

Glatiramer acetate, sold under the brand name Copaxone among others, is an immunomodulator medication used to treat multiple sclerosis. Glatiramer acetate is approved in the United States to reduce the frequency of relapses, but not for reducing the progression of disability. Observational studies, but not randomized controlled trials, suggest that it may reduce progression of disability. While a conclusive diagnosis of multiple sclerosis requires a history of two or more episodes of symptoms and signs, glatiramer acetate is approved to treat a first episode anticipating a diagnosis. It is also used to treat relapsing-remitting multiple sclerosis. It is administered by subcutaneous injection.

<span class="mw-page-title-main">Ofatumumab</span> Medication

Ofatumumab is a fully human monoclonal antibody to CD20, which appears to provide rapid B-cell depletion. Under the brand name Kesimpta, it is approved for the treatment of multiple sclerosis in the United States as well as in the European Union and other regions. Under the brand name Arzerra, it is approved for the treatment of certain types of chronic lymphocytic leukemia (CLL) in the United States. It is sold by Novartis under license from Genmab.

<span class="mw-page-title-main">NFE2L2</span> Human protein and coding gene

Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the NFE2L2 gene. NRF2 is a basic leucine zipper (bZIP) protein that may regulate the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation, according to preliminary research. In vitro, NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encoding cytoprotective proteins. NRF2 induces the expression of heme oxygenase 1 in vitro leading to an increase in phase II enzymes. NRF2 also inhibits the NLRP3 inflammasome.

<span class="mw-page-title-main">Hydroxycarboxylic acid receptor 2</span> Protein-coding gene in the species Homo sapiens

Hydroxycarboxylic acid receptor 2 (HCA2), also known as GPR109A and niacin receptor 1 (NIACR1), is a protein which in humans is encoded (its formation is directed) by the HCAR2 gene and in rodents by the Hcar2 gene. The human HCAR2 gene is located on the long (i.e., "q") arm of chromosome 12 at position 24.31 (notated as 12q24.31). Like the two other hydroxycarboxylic acid receptors, HCA1 and HCA3, HCA2 is a G protein-coupled receptor (GPCR) located on the surface membrane of cells. HCA2 binds and thereby is activated by D-β-hydroxybutyric acid (hereafter termed β-hydroxybutyric acid), butyric acid, and niacin (also known as nicotinic acid). β-Hydroxybutyric and butyric acids are regarded as the endogenous agents that activate HCA2. Under normal conditions, niacin's blood levels are too low to do so: it is given as a drug in high doses in order to reach levels that activate HCA2.

<span class="mw-page-title-main">Ponesimod</span> Medication for the treatment of multiple sclerosis

′

<span class="mw-page-title-main">Ozanimod</span> Medication

Ozanimod, sold under the brand name Zeposia, is an immunomodulatory medication for the treatment of relapsing multiple sclerosis and ulcerative colitis. It acts as a sphingosine-1-phosphate receptor (S1PR) agonist, sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation.

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

Siponimod, sold under the brand name Mayzent, is a selective sphingosine-1-phosphate receptor modulator for oral use that is used for multiple sclerosis (MS). It is intended for once-daily oral administration.

There are several ways for pharmaceuticals for treating multiple sclerosis (MS) to reach the market.

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

Monomethyl fumarate, sold under the brand name Bafiertam is a medication for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. It is taken by mouth.

<span class="mw-page-title-main">Diroximel fumarate</span> Medication

Diroximel fumarate, sold under the brand name Vumerity, is a medication used for the treatment of relapsing forms of multiple sclerosis (MS). It acts as an immunosuppressant and anti-inflammatory drug. Its most common adverse effects are flushing and gastrointestinal problems.

Ciltacabtagene autoleucel, sold under the brand name Carvykti, is an anti-cancer medication used to treat multiple myeloma. Ciltacabtagene autoleucel is a BCMA -directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy. Each dose is customized using the recipient's own T-cells, which are collected and genetically modified, and infused back into the recipient.

References

  1. 1 2 "Background document to the opinions on the Annex XV dossier proposing restrictions on Dimethylfumarate (DMFu)" (PDF). European Chemicals Agency. 16 March 2011. p. 9. Archived from the original (PDF) on 22 February 2021. Retrieved 19 July 2018.
  2. 1 2 3 "Skilarence 120 mg Gastro-resistant Tablets - Summary of Product Characteristics". Electronic Medicines Compendium. May 2018. Retrieved 19 July 2018.
  3. 1 2 "Tecfidera 120mg and 240mg gastro-resistant hard capsules - Summary of Product Characteristics". Electronic Medicines Compendium. February 2018. Retrieved 19 July 2018.
  4. 1 2 3 4 5 6 7 "Tecfidera- dimethyl fumarate kit Tecfidera- dimethyl fumarate capsule". DailyMed. Retrieved 13 February 2021.
  5. ↑ "Tecfidera EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 25 May 2022.
  6. 1 2 3 "Skilarence EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 25 May 2022.
  7. 1 2 "Dimethyl fumarate Accord EPAR". European Medicines Agency. 12 October 2022. Retrieved 22 February 2023.
  8. ↑ Linker RA, Haghikia A. Dimethyl fumarate in multiple sclerosis: latest developments, evidence and place in therapy. Ther Adv Chronic Dis. 2016;7(4):198-207.
  9. 1 2 Mrowietz, Ulrich; Altmeyer, Peter; Bieber, Thomas; et al. (2007). "Treatment of psoriasis with fumaric acid esters (Fumaderm)". Journal der Deutschen Dermatologischen Gesellschaft. 5 (8): 716–7. doi:10.1111/j.1610-0387.2007.06346.x. PMID   17659047. S2CID   7431706.
  10. ↑ "Agency EM. Skilarence [Updated]". 17 September 2018. Archived from the original on 20 June 2018. Retrieved 26 February 2019.
  11. ↑ McEntee, Joanne. "Fumaderm: what is the evidence for its efficacy and safety". North West Medicines Information Centre. Archived from the original on 5 May 2013. Retrieved 29 November 2012.
  12. 1 2 "Consumers: EU to ban dimethylfumarate (DMF) in consumer products, such as sofas and shoes" (Press release). European Commission. Retrieved 29 November 2012.
  13. ↑ "Office of Generic Drugs 2020 Annual Report". U.S. Food and Drug Administration (FDA). Retrieved 12 February 2021.
  14. 1 2 Xu, Zhu; Zhang, Feng; Sun, FangLi; Gu, KeFeng; Dong, Shuai; He, Dian (22 April 2015). "Dimethyl fumarate for multiple sclerosis". The Cochrane Database of Systematic Reviews. 2015 (4): CD011076. doi:10.1002/14651858.CD011076.pub2. ISSN   1469-493X. PMC   10663978 . PMID   25900414.
  15. ↑ Immunomodulatory Effects of Drugs for Treatment of Immune-Related Diseases
  16. 1 2 3 4 Lowe, Derek (2 April 2013). "Tecfidera's Price". In the Pipeline. Archived from the original on 11 November 2020. Retrieved 19 July 2018.
  17. ↑ Ettmayer, P; Schnitzer, R; Bergner, A; Nar, H (2017). "Chapter 2.02: Hit and Lead Generation Strategies". In Chackalamannil, Samuel; Rotella, David; Ward, Simon; Martinez, Ana; Gil, Carmen (eds.). Comprehensive Medicinal Chemistry III: Volume 2: Drug Discovery Technologies. Elsevier. p. 58. ISBN   9780128032015.
  18. ↑ Lijnen R, Otters E, Balak D, et al. Long-term safety and effectiveness of high-dose dimethylfumarate in the treatment of moderate to severe psoriasis: a prospective single-blinded follow-up study. J Dermatolog Treat. 2016;27(1):31-36.
  19. ↑ Blair HA. Dimethyl Fumarate: A Review in Moderate to Severe Plaque Psoriasis. Drugs. 2017.
  20. 1 2 3 Vinluan, Frank (17 January 2017). "Xconomy: Biogen to Pay $1.25B to Settle Forward Pharma Patent Suit on MS Drug". Xconomy.
  21. ↑ "FDA approves new multiple sclerosis treatment: Tecfidera". FDA. 27 March 2013. Retrieved 5 April 2013.
  22. ↑ Burke, MJ; Richardson, J; George, E; Adler, AI (November 2014). "Dimethyl fumarate for relapsing-remitting multiple sclerosis". The Lancet. Neurology. 13 (11): 1077–1078. doi: 10.1016/S1474-4422(14)70159-0 . PMID   28845815. Open Access logo PLoS transparent.svg
  23. ↑ "Biogen loses patent dispute with Mylan, putting its top drug's future in doubt". BioPharma Dive. Retrieved 19 June 2020.
  24. ↑ "BRIEF-Biogen Says To Appeal Court Decision Regarding Patent Related To Tecfidera". Reuters. 18 June 2020. Retrieved 19 June 2020.
  25. ↑ Alpert, Bill. "Biogen Stock Is Slumping After Judge Rules Against Its Biggest Drug". Barron's . Retrieved 19 June 2020.
  26. 1 2 3 4 5 "Skilarence Summary of Product Characteristics" (PDF). May 2018. Archived from the original (PDF) on 18 June 2018. Retrieved 26 February 2019.
  27. ↑ Goldhill, Jon (15 September 2015). "Disappointing Phase 2 psoriasis data reported for the monomethyl fumarate prodrug, XP23829". Advances in drug discovery.
  28. ↑ "Vumerity (Previously BIIB098 and ALKS 8700)". Multiple Sclerosis News Today. 1 November 2019. Retrieved 21 February 2020.
  29. ↑ "Biogen and Alkermes Announce FDA Approval of Vumerity (diroximel fumarate) for Multiple Sclerosis". Biogen. Retrieved 21 February 2020.
  30. ↑ "Drug Approval Package: Vumerity". U.S. Food and Drug Administration (FDA). 21 April 2020. Retrieved 1 February 2021.
  31. ↑ Schulze-Topphoff, U; Varrin-Doyer, M; Pekarek, K; Spencer, CM; Shetty, A; Sagan, SA; Cree, BA; Sobel, RA; Wipke, BT; Steinman, L; Scannevin, RH; Zamvil, SS (26 April 2016). "Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2". Proceedings of the National Academy of Sciences of the United States of America. 113 (17): 4777–82. Bibcode:2016PNAS..113.4777S. doi: 10.1073/pnas.1603907113 . PMC   4855599 . PMID   27078105.
  32. ↑ Ntranos, Achilles; Ntranos, Vasilis; Bonnefil, Valentina; Liu, Jia; Kim-Schulze, Seunghee; He, Ye; Zhu, Yunjiao; Brandstadter, Rachel; Watson, Corey T; Sharp, Andrew J; Katz Sand, Ilana; Casaccia, Patrizia (March 2019). "Fumarates target the metabolic-epigenetic interplay of brain-homing T cells in multiple sclerosis". Brain. 142 (3): 647–661. doi:10.1093/brain/awy344. PMC   6821213 . PMID   30698680.
  33. 1 2 Two Approaches to the Synthesis of Dimethyl Fumarate That Demonstrate Fundamental Principles of Organic Chemistry Brian E. Love and Lisa J. Bennett Journal of Chemical Education 2017 94 (10), 1543-1546 doi : 10.1021/acs.jchemed.6b00818
  34. ↑ Ledlie, David B.; Wenzel, Thomas J.; Hendrickson, Susan M. (1989). "Isomerization of dimethyl maleate to dimethyl fumarate: An undergraduate experiment utilizing high performance liquid chromatography". Journal of Chemical Education. 66 (9): 781. Bibcode:1989JChEd..66..781L. doi:10.1021/ed066p781.
  35. ↑ Fryhle, Craig B.; Rybak, Carol M.; Pulley, Kenneth E. (1991). "Isomerization of dimethyl maleate to dimethyl fumarate: An undergraduate experiment illustrating amine-catalyzed alkene isomerization, stereochemical principles, sublimation, and product identification by spectroscopic methods". Journal of Chemical Education. 68 (12): 1050. Bibcode:1991JChEd..68.1050F. doi:10.1021/ed068p1050.
  36. ↑ Hamilton, Mike (13 September 2012). "Just how much profit is there in a new drug?". Biotech Translated.
  37. ↑ D. A. White (1981). "Electrohydrodimerization of an Activated Alkene: Tetraethyl 1,2,3,4-Butanetetracarboxylate". Organic Syntheses. 60: 58. doi:10.15227/orgsyn.060.0058.
  38. ↑ Gieselbach RJ, Muller-Hansma AH, Wijburg MT, et al. Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases. J Neurol. 2017;264(6):1155-1164.
  39. ↑ "FDA Drug Safety Communication: FDA warns about case of rare brain infection PML with MS drug Tecfidera (dimethyl fumarate)". fda.gov. Retrieved 2 December 2014.
  40. 1 2 Rantanen, T. (2008). "The cause of the Chinese sofa/chair dermatitis epidemic is likely to be contact allergy to dimethylfumarate, a novel potent contact sensitizer". British Journal of Dermatology. 159 (1): 218–21. doi:10.1111/j.1365-2133.2008.08622.x. PMID   18503603. S2CID   45134115.
  41. 1 2 3 "Myrkkytuoli-ihottumien syy selvisi". YLE Uutiset (in Finnish). YLE. 24 April 2008. Retrieved 10 June 2008.
  42. ↑ "Clifton woman's toxic sofa claim". The Nottingham Post. Local World. 2 April 2009.[ permanent dead link ]
  43. 1 2 BBC – Consumer – TV and radio – itchy sofas Archived 22 February 2008 at the Wayback Machine
  44. ↑ BBC: Judge rejects 'toxic sofa' claims in burns injury cases, 18 March 2010
  45. ↑ "BBC: 3 reports on dimethyl fumarate in furniture". April 2010.
  46. ↑ "2009/251/EC: Commission Decision of 17 March 2009".
  47. ↑ "RECOVERY trial closes recruitment to colchicine treatment for patients hospitalised with COVID-19". Nuffield Department of Population Health, University of Oxford. 5 March 2021.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.