Overview

Dimethyl fumarate[DMF] is the methyl ester of fumaric acid^{[1, 2]}. DMF, marketed in Germany under the trade name of Fumaderm, is used for oral therapy of psoriasis in combination with other drugs^[2]. Later it has been used to treat adults with relapsing multiple sclerosis[a chronic inflammatory, demyelinating and neurodegenerative disease of the CNS resulting in neurological disability] since 2013(trade name Tecfidera)^[3]. DMF is thought to have immunomodulatory properties without significant immunosuppression. In preclinical studies, dimethyl fumarate exhibited anti-inflammatory and cytoprotective properties that are generally thought to be mediated via activation of the nuclear factor [erythroid-derived 2]-like 2 transcriptional pathway, which is involved in the cellular response to oxidative stress.
In a non-medical use, DMF has been used as a biocide in furniture or shoes to prevent growths of mold during storage or transport in a humid climate. However, due to incidences of allergic reactions after skin contact the European Union has banned DMF in consumer products since 1998, and since January 2009 the import of products containing DMF has also been banned^[4].

Indication

Dimethyl fumarate[DMF] is mainly indicated for the treatment of the relapsing-remitting Multiple sclerosis(MS), which is a chronic inflammatory, demyelinating and neurodegenerative disease of the CNS, resulting in neurological disability^{[5, 6]}. The disease typically begins in young adults(average age of onset &29 years) and affects twice as many women as men^{[7, 8]}. Initially, most(80–85 %) individuals with MS have a relapsing-remitting[RRMS] disease course with defined clinical exacerbations of neurological symptoms, followed by complete or incomplete remission^{[7, 8]}. Around 50 % of patients develop a secondary progressive MS within 10–15 years of RRMS onset and &89 % of patients develop secondary progressive MS after 25 years[9]. Globally, the estimated median incidence of MS is 2.5 per 100,000 persons and it has a median estimated prevalence of 30 per 100,000 persons^[8].
The pathogenic process of the relapsing-remitting multiple sclerosis involves the migration of auto-reactive T cells across the blood–brain-barrier into the central nervous system where they damage myelin, oligodendrocyte and nerve fibers and lead to further immune cell recruitment^[10]. This inflammatory process causes lesions[predominantly in the cerebellum, brain stem, spinal cord, optic nerves and white matter of brain ventricles] that result in the symptoms typical of MS, including weak/stiff muscles, limb numbness/tingling, balance problems, visual disturbances and cognitive dysfunction^[11]. The lesional inflammatory environment also contributes to MS pathogenesis through the generation of proinflammatory cytokines and oxygen and nitrogen free radicals, establishing a cycle of inflammation and oxidative stress^[12].

Mode of action

In MS, neuronal tissue damage is thought to be caused by aberrant activation and subsequent infiltration of immune cells into the CNS12. Infiltrating cells propagate inflammatory processes within the CNS13, ultimately leading to oligodendrocyte damage that results in demyelination and subsequent axonal transection and neurodegeneration^{[13, 14]}. In addition to pathogenic adaptive autoimmunity processes, the release of free radicals[oxygen and nitrogen] by infiltrating monocytes leads to mounting oxidative stress^[15-17]. As cells of the CNS are highly sensitive to excessive oxidative stress, this further promotes neurodegenerative processes.
Dimethyl fumarate has demonstrated beneficial effects in preclinical models of neuro-inflammation, neuro-degeneration, and toxic oxidative stress but its precise mechanism of action remains unclear^{[18, 19]}. As a second-generation fumarate ester, dimethyl fumarate appears to exert its effects predominantly through activation of the nuclear factor[erythroid-derived 2]-like 2[Nrf2] antioxidant response pathway^[19], which modulates the expression of biomolecules involved in the phase 2 detoxification pathway, and is an important cellular defense mechanism involved in the response to oxidative and xenobiotic stress, and immune homeostasis. The activation of the Nrf2 pathway has a clear role in maintaining immune homeostasis and also appears to have a role in promoting modulation of functional immune responses^[20].

Adverse reactions

Some severe adverse reactions associated with iodomethane may include anaphylaxis and angioedema, progressive multifocal leukoencephalopathy, lymphopenia, liver injury and flushing^[21]. Common side effects may include flushing/warmth, itching, redness, and burning feeling of the skin. Taking this drug with food may reduce flushing. Some other side effects may also include stomach/abdominal pain, heartburn, indigestion, diarrhea, nausea, and vomiting may also occur. These effects usually improve or go away as your body adjusts to the medication. If any of these effects persist or worsen, tell your doctor or pharmacist promptly^{[22, 23]}.

Warning and Risk

Patients who are allergic to dimethyl fumarate should be disabled.
To make sure dimethyl fumarate is safe for administration, the patients should tell your doctor if he/she have: an active infection; or low white blood cell[WBC] counts.
It is not known whether dimethyl fumarate will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using dimethyl fumarate.
If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of dimethyl fumarate on the baby. It is not known whether dimethyl fumarate passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby^[23].

References

1. https://www.drugbank.ca/drugs/DB08908
2. Mrowietz, Ulrich; Altmeyer, Peter; Bieber, Thomas; et al.[2007]. "Treatment of psoriasis with fumaric acid esters[Fumaderm®]". JDDG. 5[8]: 716–7.
3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204063s020lbl.pdf
4. https://chemicalwatch.com/1719/eu-agrees-to-ban-dimethyl-fumarate-dmf-in-consumer-products
5. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372[9648]:1502–17. 
6. Nylander A, Hafler DA. Multiple sclerosis. J Clin Invest. 2012;122(4]:1180–8. 
7. Menge T, Weber MS, Hemmer B, et al. Disease-modifying agents for multiple sclerosis: recent advances and future pros- pects. Drugs. 2008;68(17]:2445–68. 
8. World Health Organization. Atlas: multiple sclerosis resources in the world; 2008. http://www.who.int/mental_health/neurology/ Atlas_MS_WEB.pdf. Accessed 14 Feb 2014. 
9. Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989;112(Pt 1]:133–46. 
10. National Multiple Sclerosis Society. What is MS? 2015. http:// www.nationalmssociety.org. Accessed 3 Dec 2015.
11. National Institute of Neurological Disorders and Stroke. Multiple sclerosis: hope through research. 2015. http://www.ninds.nih.gov/ disorders/multiple_sclerosis/detail_multiple_sclerosis.htm. Accessed 3 Dec 2015.
12. Ortiz GG, Pacheco-Moises FP, Bitzer-Quintero OK, et al. Immunology and oxidative stress in multiple sclerosis: clinical and basic approach. Clin Dev Immunol. 2013;2013:708659.
13. De Stefano N, Narayanan S, Matthews PM, et al. In vivo evidence for axonal dysfunction remote from focal cerebral demyelination of the type seen in multiple sclerosis. Brain 1999;122:1933-9
14. Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120:393-9
15. Silber E, Sharief MK. Axonal degeneration in the pathogenesis of multiple sclerosis. J Neurol Sci 1999;170:11-18
16. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338:278-85
17. Witherick J, Wilkins A, Scolding N, et al. Mechanisms of oxidative damage in multiple sclerosis and a cell therapy approach to treatment. Autoimmune Dis 2011;164608
18. Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert Neuroprotective effects in neuro-inflammation via activation of the Nrf2 antioxidant pathway. Brain 2011;134:678-92
19. Scannevin RH, Chollate S, Jung MY, et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the Nrf2 pathway. J Pharmacol Exp Ther 2012;341:274-84
20. Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 2003;43:233-60
21. https://www.rxlist.com/tecfidera-drug.htm#side_effects_interactions
22. https://www.webmd.com/drugs/2/drug-163864/dimethyl-fumarate-oral/details
23. https://www.drugs.com/sfx/dimethyl-fumarate-side-effects.html

Description

In March 2013, the US FDA approved dimethyl fumarate for the treatment of relapsing forms of multiple sclerosis (MS). Dimethyl fumarate is the newest oral therapeutic for MS. While its mechanism is not completely understood, dimethyl fumarate increases anti-inflammatory cytokines (IL-10, IL-4, and IL-6), decreases proinflammatory cytokines (IL-1β, IL-6, and TNF-α), and activates the Nrf2 pathway to protect neuronal cells. Nrf2 is activated by covalent bond-forming electrophiles such as dimethyl fumarate, a Michael acceptor. Dimethyl fumarate has been used for the treatment of psoriasis in Europe since 1994 and has a favorable long-term safety profile. An exploratory study in patients with relapsing remitting MS showed significant reductions in MS lesions after 18 weeks of treatment with 720 mg/day of dimethyl fumarate. Evaluation of dimethyl fumarate in a mouse experimental autoimmune encephalomyelitis model of MS resulted in reduced spinal cord macrophage inflammation. Dimethyl fumarate is obtained in high purity by esterification of fumaric acid with methanol and catalytic sulfuric acid.

Chemical Properties

fine white crystalline powder

Originator

Biogen Idec (United States)

Uses

Dimethyl fumarate acts as an immunomodulator. It is also used in cycloaddition reactions involving ylides, benzenes and amino acids. It is added to food grains,tobacco,leather and preservation. Clothing

Definition

ChEBI: Dimethyl fumarate is an enoate ester resulting from the formal condensation of both carboxy groups of fumaric acid with methanol. Used for treatment of adults with relapsing forms of multiple sclerosis. It has a role as an immunomodulator and an antipsoriatic. It is an enoate ester, a methyl ester and a diester. It is functionally related to a methanol and a fumaric acid.

brand name

Tecfidera

Synthesis Reference(s)

Synthetic Communications, 21, p. 223, 1991 DOI: 10.1080/00397919108020815
The Journal of Organic Chemistry, 55, p. 329, 1990 DOI: 10.1021/jo00288a056

General Description

Dimethyl fumarate is a novel oral therapeutic agent, which can be used for patients suffering from relapsing-remitting multiple sclerosis. It shows an effective inhibition of mould in bread and can also serve as a potential candidate for the treatment of psoriasis, a chronic autoimmune condition.

Contact allergens

Dimethylfumarate, a strong irritant, is used as an industrial wide spectrum biocide in Asia and mainly in China, for textiles, leather, seeds, food, and cosmetic ingredients. It provoked a worldwide epidemic of severe contact dermatitis, initially from Chinese sofas sold in Finland, Great Britain, and France. It also induced severe burning and contact allergy due to shoes, and to contaminated clothing as well. This chemical, presents as is (white powder) or as tablets contained in little bags disposed in/or around the materials to protect, progressively evaporates and contaminates the environment. It is forbidden in the European Union since 2008

Clinical Use

Treatment of relapsing-remitting multiple sclerosis
Treatment of moderate to severe plaque psoriasis

Drug interactions

Potentially hazardous interactions with other drugs
Aminophylline and theophylline: enhanced effect of aminophylline and theophylline.
Anaesthetics: enhanced hypotensive effect.
Anti-arrhythmics: increased risk of bradycardia, AV block and myocardial depression with amiodarone; increased risk of bradycardia and myocardial depression with dronedarone.
Antibacterials: metabolism increased by rifampicin; metabolism possibly inhibited by clarithromycin, erythromycin and telithromycin.
Antidepressants: enhanced hypotensive effect with MAOIs; concentration of imipramine and possibly other trycyclics increased
Antiepileptics: effect probably reduced by barbiturates, fosphenytoin, phenytoin, and primidone; enhanced effect of carbamazepine; increased levels of fosphenytoin and phenytoin.
Antifungals: negative inotropic effect possibly increased with itraconazole.
Antihypertensives: enhanced hypotensive effect; increased risk of first dose hypotensive effect of postsynaptic alpha-blockers
Antipsychotics: concentration of lurasidone increased.
Antivirals: concentration increased by atazanavir and ritonavir - reduce dose of diltiazem with atazanavir; concentration reduced by efavirenz; use telaprevir with caution.
Avanafil: possibly increases avanafil concentration.
Beta-blockers: risk of bradycardia and AV block if co-prescribed with beta-blockers.
Cardiac glycosides: increased digoxin concentration.
Ciclosporin: increased ciclosporin concentrations.
Cilostazol: increased cilostazol concentration - avoid.
Colchicine: possibly increased risk of colchicine toxicity - suspend or reduce colchicine, avoid concomitant use in renal or hepatic failure.
Cytotoxics: concentration of bosutinib, ibrutinib and olaparib possibly increased - avoid or reduce dose; possibly increased risk of bradycardia with crizotinib.
Fingolimod: increased risk of bradycardia.
Ivabradine: concentration of ivabradine increased - avoid.
Lipid lowering drugs: concentration of lomitapide possibly increased - avoid.
Sirolimus: sirolimus concentration increased.

Metabolism

Diltiazem is almost completely absorbed from the gastrointestinal tract after oral doses, but undergoes extensive first-pass hepatic metabolism resulting in a bioavailability of about 40%. It is extensively metabolised in the liver, mainly by the cytochrome P450 isoenzyme CYP3A4; one of the metabolites, desacetyldiltiazem, has been reported to have 25-50% of the activity of the parent compound.
About 2-4% of a dose is excreted in urine as unchanged diltiazem with the remainder excreted as metabolites in bile and urine.