Showing papers on "Dimethyl fumarate published in 2012"

Fumarates Promote Cytoprotection of Central Nervous System Cells against Oxidative Stress via the Nuclear Factor (Erythroid-Derived 2)-Like 2 Pathway

Abstract: Oxidative stress is central to the pathology of several neurodegenerative diseases, including multiple sclerosis, and therapeutics designed to enhance antioxidant potential could have clinical value. The objective of this study was to characterize the potential direct neuroprotective effects of dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) on cellular resistance to oxidative damage in primary cultures of central nervous system (CNS) cells and further explore the dependence and function of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in this process. Treatment of animals or primary cultures of CNS cells with DMF or MMF resulted in increased nuclear levels of active Nrf2, with subsequent up-regulation of canonical antioxidant target genes. DMF-dependent up-regulation of antioxidant genes in vivo was lost in mice lacking Nrf2 [Nrf2(-/-)]. DMF or MMF treatment increased cellular redox potential, glutathione, ATP levels, and mitochondrial membrane potential in a concentration-dependent manner. Treating astrocytes or neurons with DMF or MMF also significantly improved cell viability after toxic oxidative challenge in a concentration-dependent manner. This effect on viability was lost in cells that had eliminated or reduced Nrf2. These data suggest that DMF and MMF are cytoprotective for neurons and astrocytes against oxidative stress-induced cellular injury and loss, potentially via up-regulation of an Nrf2-dependent antioxidant response. These data also suggest DMF and MMF may function through improving mitochondrial function. The clinical utility of DMF in multiple sclerosis is being explored through phase III trials with BG-12, which is an oral therapeutic containing DMF as the active ingredient.

Effects of dimethyl fumarate on neuroprotection and immunomodulation

Abstract: Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms. We aimed to clarify whether neuroprotective concentrations of dimethyl fumarate have immunomodulatory effects. We determined time- and concentration-dependent effects of dimethyl fumarate and its metabolite monomethyl fumarate on viability in a model of endogenous neuronal oxidative stress and clarified the mechanism of action by quantitating cellular glutathione content and recycling, nuclear translocation of transcription factors, and the expression of antioxidant genes. We compared this with changes in the cytokine profiles released by stimulated splenocytes measured by ELISPOT technology and analyzed the interactions between neuronal and immune cells and neuronal function and viability in cell death assays and multi-electrode arrays. Our observations show that dimethyl fumarate causes short-lived oxidative stress, which leads to increased levels and nuclear localization of the transcription factor nuclear factor erythroid 2-related factor 2 and a subsequent increase in glutathione synthesis and recycling in neuronal cells. Concentrations that were cytoprotective in neuronal cells had no negative effects on viability of splenocytes but suppressed the production of proinflammatory cytokines in cultures from C57BL/6 and SJL mice and had no effects on neuronal activity in multi-electrode arrays. These results suggest that immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity.

Dimethylfumarate Attenuates Renal Fibrosis via NF-E2-Related Factor 2-Mediated Inhibition of Transforming Growth Factor-β/Smad Signaling

Abstract: TGF-β plays a key role in the development of renal fibrosis. Suppressing the TGF-β signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-β signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-β signaling. Results showed that DMF increased nuclear levels of Nrf2, and both DMF and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (α-SMA), fibronectin and type 1 collagen expression in TGF-β-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, DMF and Ad-Nrf2 repressed TGF-β-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of DMF on TGF-β-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of DMF. Finally, DMF suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and α-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, DMF attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-β/Smad3 signaling in an ARE-independent manner, suggesting that DMF could be used to treat renal fibrosis.

Dimethyl fumarate - only an anti-psoriatic medication?

Abstract: Summary Fumaric acid esters have been used successfully in the therapy of psoriasis vulgaris since 1959. In the last 17 years, many of the underlying mechanisms of anti-psoriatic action, such as a Th1/Th2 shift, a suppression of important leukocyte adhesion molecules, the induction of pro-apoptotic pathways in T-cells and recently anti-angiogenic action, have been discovered. Based on the knowledge of these immunomodulatory characteristics, fumaric acid esters have been shown to be effective or potentially effective in a multitude of dermatological as well as non-dermatological diseases. The range of new therapeutic targets reaches from multiple sclerosis to illnesses such as necrobiosis lipoidica, granuloma annulare and sarcoidosis. Experimental approaches offer promising, although preliminary, results on the treatment of cancer, malaria, chronic inflammatory lung diseases, and Huntington disease, to name but a few. This valued and well-known drug mainly prescribed by dermatologists is now experiencing a renaissance far beyond dermatologic applications.

Process for preparing high purity and crystalline dimethyl fumarate

Abstract: The present invention describes a process for the preparation of dimethyl fumarate. The process involves the esterification of fumaric acid and methanol in the presence of sulfuric acid as an acid catalyst. The high purity dimethyl fumarate contains no more than trace amounts of dimethyl sulfate. The present invention also provides a process for the preparation of highly pure dimethyl fumarate with a particle size from 20 to 250μπι.

Controlled release particles comprising dimethyl fumarate

Abstract: The present invention relates to particles of dimethyl fumarate coated by at least one layer of a pH-dependent entero-resistant polymer. The particles are formulated into a pharmaceutical preparation or dosage form for oral administration of dimethyl fumarate for the treatment of autoimmune diseases, in particular multiple sclerosis.

Methods of treating multiple sclerosis and preserving and/or increasing myelin content

Abstract: Methods of treating multiple sclerosis in a subject, including: reducing the frequency of relapse, reducing the annualized relapse rate, reducing the risk of disability progression, reducing the number of new or newly enlarging T2 lesions, reducing the number of gadolinium lesions; and methods of preserving/increasing myelin content in a subject having multiple sclerosis; by daily administering a composition containing a fumarate, such as dimethyl fumarate or monomethyl fumarate, to the subject.

The "poison chair" treatment for multiple sclerosis

Abstract: In the very curious incident of the “poison chair,” hundreds of people in several European cities appeared at clinics with eczematous burns that had no apparent cause. The source was found to be dimethyl fumarate (fumarate), which was used as a fungicide and desiccant in the shipping of sofas. A Finnish physician uncovered the toxin by doggedly pursuing a local outbreak.1 Fumarate and its esters have had a much better safety record as medicinal than as industrial agents. A German biochemist administered fumaric acid to himself in 1959, believing his psoriasis was due to a deficiency of fumarate,2 and a . . .

Combination therapy for treatment of inflammatory demyelinating disease

Abstract: Provided herein include combination therapies for the treatment of neurological inflammatory diseases, such as, for example, demyelinating autoimmune diseases, such as multiple sclerosis and neuromyelitis optica, etc. In various aspects and embodiments, the methods may include administering to a patient an effective dose of an inhibitor of an angiotensin-converting enzyme (ACE) in combination with one or more second compounds, In one aspect, provided is a method of treating a demyelinating autoimmune disease (such as multiple sclerosis) that includes administering to a patient an effective dose of an inhibitor of an angiotensin-converting enzyme (ACE) in combination with one or more compounds selected from the group consisting of a cytokine, a vitamin B, dimethyl fumarate (DMF, also referred to as BG-12) and fingolimod (Gilenya).

sp 2 C–H activation of dimethyl fumarate by a [(Cp*Co)2-μ-(η4 : η4-toluene)] complex

Abstract: The well-defined oxidative addition of the vinylic sp2 C–H bond of dimethyl fumarate is mediated by the cobalt triple decker complex [(Cp*Co)2-μ-(η4 : η4-toluene)] (1) at ambient temperature, affording the dinuclear, bridging cobalt hydride, fumaryl compound (2). The C–H activation product has been characterized by mass spectrometry, NMR spectroscopy, and X-ray crystallography. Computational studies of 2 support asymmetric bonding interactions between the two metal centres and the bridging hydride/fumaryl fragments. Monitoring the reaction of dimethyl fumarate with 1 by 1H NMR spectroscopy allows observation of intermediate [Cp*Co(MeO2CCHCHCO2Me)]n (n = 1 or 2) (3). Addition of 4 equivalents of dimethyl fumarate to 1 results in rapid formation of the bis(ligand) adduct Cp*Co(η2-MeO2CCHCHCO2Me)2 (5). Reversibility of the C–H activation was probed by reaction of additional dimethyl fumarate with 2, suggesting ligand induced reductive elimination is possible under ambient conditions. Reaction between 2 and strong σ or π ligands, such as PMe3 or CO, affords the corresponding Cp*Co(η2-MeO2CCHCHCO2Me)(L) (L = PMe3 (7); L = CO (8)) complexes when heated, demonstrating the ability of 2 to undergo two electron redox processes. Further evidence for reversible C–H activation is provided by the isomerization of dimethyl maleate to the corresponding fumarate using 2, suggesting the complex can serve as a source of Co(I) under the appropriate catalytic conditions.

Method for synthesizing dimethyl fumarate

Abstract: The invention discloses a method for synthesizing dimethyl fumarate. The method includes: adding maleic anhydride and methanol into a four-opening bottle provided with a motor stirrer, a condenser pipe and a thermometer with material quantity ratio as methanol: maleic anhydride=(5-25):1 for stirring, adding (0.4-1.2)g of catalyst stannic chloride into each mol of maleic anhydride, hanging a small silk sealed bag containing MgSO4 powder at the position of each bottle opening, leading temperature to rise to 50-60 DEG C for backflow reaction for 2.5-4.5 h, adding reaction liquor obtained after reaction into cold water for suction filtration to obtain dimethyl formamide (DMF) coarse products, and performing recrystallization by aid of methanol to obtain pure DMF. Compared with the traditional synthetic method of dimethyl fumarate, the method for synthesizing dimethyl fumarate is simple in synthesizing route, and the obtained product dimethyl fumarate is higher in purity.

Preparation method of dimethyl fumarate

Abstract: The invention relates to a preparation method of dimethyl fumarate. According to the preparation method of the dimethyl fumarate, fumaric acid and methanol are taken as raw materials, an acid-functionalized ionic liquid is taken as a catalyst, and an acid-alcohol esterification reaction is carried out under relatively mild conditions so as to synthesize the dimethyl fumarate. The catalyst used in the preparation method is high in activity, low in using amount and easy to separate, recycle and reuse; the defects of difficult catalyst recovery, environment pollution and equipment corrosion in the prior art are overcome; and the preparation method of the dimethyl fumarate has a very good industrial application prospect.

Dimethyl Fumarate Suppresses Inflammation In Vitro Via Both Nrf2-Dependent and Nrf2-Independent Pathways (P02.108)

Abstract: Objective: To investigate if the active ingredient of BG-12 (dimethyl fumarate [DMF]) inhibits macrophage inflammation in vitro via nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent and/or Nrf2-independent pathways. Background BG-12 is in Phase 3 development for relapsing-remitting multiple sclerosis. In DEFINE, BG-12 achieved statistical significance on the primary and secondary endpoints versus placebo. In preclinical studies, DMF reduced CNS inflammation in murine and rat experimental autoimmune encephalomyelitis (EAE). CNS inflammation in EAE and multiple sclerosis is thought to be mediated in part by inflammatory cytokine production by activated macrophages/microglia. The disease-modifying effect of DMF in EAE is associated with activation of the Nrf2 pathway and concurrent suppression of microglial activation. However, it is not known whether this suppression is dependent on Nrf2. Design/Methods: Macrophage cultures derived from the bone marrow of Nrf2+/+ and Nrf2-/- mice were stimulated in vitro for 6 hours by bacterial lipopolysaccharide (LPS). Before LPS stimulation, some cultures were pretreated with DMF. Total RNA was extracted, and transcripts were analysed using real-time reverse transcription polymerase chain reaction. Whole-cell protein extracts were prepared and phosphoproteins were analyzed using Western blots. Results: With LPS stimulation, Nrf2-/- macrophages showed a 3-fold increase in IL1-beta mRNA relative to Nrf2+/+ macrophages. LPS-induced IL-10 mRNA was also increased in Nrf2-/- versus Nrf2+/+ cells. Increased inflammatory capacity of Nrf2-/- macrophages correlated with increased phosphorylation of the proinflammatory p38 MAP kinase. DMF pretreatment suppressed the induction of IL1-beta and IL-10 mRNA in Nrf2+/+ cells but not in Nrf2-/- cells. Interestingly, at higher doses, DMF-mediated suppression of LPS-induced cytokines extended to Nrf2-/- cells. Conclusions: DMF suppresses inflammation in macrophages in vitro via both Nrf2-dependent and Nrf2-independent pathways. Inhibition of macrophage function may contribute to the therapeutic effect of BG-12 as part of its anti-inflammatory and cytoprotective mechanisms of action. Supported by: Biogen Idec Inc. Disclosure: Dr. Bista has received personal compensation for activities with Biogen Idec Inc as an employee. Dr. Zeng has received personal compensation for activities with Biogen Idec as an employee. Ms. Ryan has received personal compensation for activities with Biogen Idec as an employee. Dr. Lukashev has received personal compensation for activities with Biogen Idec as an employee. Dr. Yamamoto has received research support from Chugai Pharmaceutical Company.

Dimethyl fumarate: A fumaric acid ester under investigation for treatment of relapsing-remitting multiple sclerosis

Abstract: Dimethyl fumarate is an investigational drug being studied for the treatment of relapsing-remitting multiple sclerosis (RRMS).

Allergic contact dermatitis from dimethyl fumarate after contact with a Chinese sofa.

Abstract: Background Dimethyl fumarate has been successfully used in the treatment of psoriasis in the past. Despite its clinical use, cutaneous contact with this molecule may cause contact dermatitis. Objective We report a case in which skin exposure to a synthetic fabric sofa containing dimethyl fumarate made by a Chinese furniture manufacturer resulted in a severe, pruritic, papulovesicular, eczematous dermatitis to the sites of contact with the sofa. Methods The patient was patch-tested with serial dilutions of dimethyl fumarate. Results Patch testing results revealed strong positive reactions to dimethyl fumarate at different concentrations. Conclusion Dimethyl fumarate is a potent contact sensitizer and is commonly found in sachets inside furniture and footwear boxes.

Old drug, new price?

Abstract: The immunomodulatory drug dimethyl fumarate blocks GAPDH and aerobic glycolysis in activated immune cells.

Determination of Dimethyl Fumarate in Leather: Purge Assisted Headspace Solid Phase Microextraction Coupled with GC-MS

Abstract: Purge-assisted headspace solid-phase micro-extraction (PA/HS-SPME) was proposed for the determination of dimethyl fumarate (DMF) extracted from finished leather. Samples were extracted from solvent by Accelerated Solvent Extractor (ASE), concentrated and purified with PA/HS-SPME, analyzed by gas chromatography-mass-spectrometry (GC-MS), and quantified against external standards. The parameters of PA/HS-SPME, such as temperature and time, were studied. Under the optimal conditions, the linearity for DMF was over the concentration range of 5-1000ng/ml; the detection limit was 1ng/ml; the relative standard deviation (n=6) was 9.94% at 100ng/ml. The recoveries were in the range of 66.8-91.5%. This eco-friendly method was applied to the determination of DMF in leather samples satisfactorily. The proposed PA/HS-SPME method opens new avenues for the determination of DMF in leather samples.

Another Oral Therapy for Relapsing Multiple Sclerosis: Dimethyl Fumarate (BG-12)

Abstract: Dimethyl fumarate (DMF; BG-12) is an oral compound that, in combination with monoethylfumarate salts, has been licensed in Germany since 1994 as a

Methods of treating multiple sclerosis and preserving and/or increasing myelin content

Abstract: Methods of treating multiple sclerosis in a subject, including: reducing the frequency of relapse, reducing the annualized relapse rate, reducing the risk of disability progression, reducing the number of new or newly enlarging T2 lesions, reducing the number of gadolinium lesions; and methods of preserving/increasing myelin content in a subject having multiple sclerosis; by daily administering a composition containing a fumarate, such as dimethyl fumarate or monomethyl fumarate, to the subject.