fumarates and ethyl-fumarate

Fumarates (fumaric acid esters, FAEs) are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis. In 1994, a proprietary combination of FAEs was licensed for psoriasis by the German Drug Administration for use within Germany. Since then, fumarates have been established as one of the most commonly used treatments for moderate-to-severe psoriasis in Germany and other countries. The licensed FAE formulation contains dimethyl fumarate (DMF), as well as calcium, zinc, and magnesium salts of monoethyl fumarate (MEF). While the clinical efficacy of this FAE mixture is well established, the combination of esters on which it is based, and its dosing regimen, was determined empirically. Since the mid-1990s, the modes of action and contribution of the different FAEs to their overall therapeutic effect in psoriasis, as well as their adverse event profile, have been investigated in more detail. In this article, the available clinical data for DMF are reviewed and compared with data for the other FAEs. The current evidence substantiates that DMF is the main active compound, via its metabolic transformation to monomethyl fumarate (MMF). A recent phase III randomized and placebo-controlled trial including more than 700 patients demonstrated therapeutic equivalence when comparing the licensed FAE combination with DMF alone, in terms of psoriasis clearance according to the Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA). Thus, DMF as monotherapy for the treatment of psoriasis is as efficacious as in combination with MEF, making the addition of such fumarate derivatives unnecessary.

Topics: Dermatologic Agents; Dimethyl Fumarate; Drug Therapy, Combination; Fumarates; Germany; Humans; Psoriasis; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

Necrobiosis lipoidica (NL) is an uncommon granulomatous skin disease with association to diabetes mellitus. To date, no proven effective therapy for NL has been implemented. The standard treatment is topical application of corticosteroids, but numerous agents have been reported for NL, with varying degrees of success. In recent case reports, fumaric acid esters (FAE) have been reported to be effective in granulomatous skin diseases such as granuloma annulare, cutaneous sarcoidosis and NL.. We sought to investigate the efficacy of FAE in a larger number of patients with NL.. Eighteen patients with histopathologically proven NL were consecutively recruited into a prospective noncontrolled study. Dosage of FAE was given according to the standard therapy regimen for psoriasis. FAE were administered for at least 6 months. The treatment outcome was evaluated by means of clinical and histological scoring and 20-MHz ultrasound assessments.. Three patients discontinued therapy with FAE, while the remaining 15 patients finished the study. After a mean +/- SD treatment period of 7.7 +/- 2.9 months, a significant (P < 0.001) decrease in the mean +/- SD clinical score, from 7.4 +/- 1.8 at the beginning to 2.5 +/- 1.3 at the end of therapy, was observed. Significant clinical improvement of NL was accompanied by significant (P = 0.019) increase of dermal density as assessed by means of 20-MHz ultrasound, and significant (P = 0.011) reduction of the histological score. Adverse effects were moderate and consisted mainly of gastrointestinal complaints and flushing. During follow-up of at least 6 months, clinical outcome remained stable in all patients.. The results of this study demonstrate that FAE are beneficial and safe in the treatment of patients with NL.

Topics: Adult; Aged; Aged, 80 and over; Dermatologic Agents; Dimethyl Fumarate; Drug Combinations; Female; Fumarates; Humans; Leg Dermatoses; Male; Middle Aged; Necrobiosis Lipoidica; Prospective Studies; Severity of Illness Index; Skin; Treatment Outcome; Ultrasonography

Systemic treatment of psoriasis with fumaric acid esters (FAE) has been found effective by empirical means. In recent years clinical studies have confirmed the antipsoriatic activity of a defined mixture of different FAE. The aim of the present prospective multicentre study was to investigate further the efficacy and safety of FAE therapy in a large number of patients with severe psoriasis vulgaris. From 101 patients included in the study 70 completed the treatment period of 4 months. Discontinuation was due to adverse events in seven, lack of efficacy in two, and other reasons, such as non-attendance for scheduled visits, in 22 patients. Evaluation of overall efficacy showed a decrease in psoriasis area and severity index of 80% after 4 months of FAE therapy. Laboratory investigations revealed a slight overall decrease of lymphocytes during the treatment period which was more than 50% below baseline in 10 patients. During weeks 4 and 8 mean eosinophil counts were above the normal range. At the end of FAE therapy elevated eosinophil counts had returned to normal values. None of the patients showed changes in renal function parameters throughout the study. Adverse events were reported in 69% of the patients mainly consisting of gastrointestinal complaints (56%) and flushing (31%). In five patients gastrointestinal complaints and in two patients flushing led to withdrawal from the study. Taken together the results of this multicentre study showed in a large number of patients that systemic FAE treatment is effective in severe psoriasis vulgaris. Transient eosinophilia seems to be a characteristic feature of FAE therapy, while lymphocytopenia is usually mild. Adverse effects are dose-related and consist mainly of gastrointestinal complaints and flushing.

Topics: Adult; Aged; Dermatologic Agents; Dimethyl Fumarate; Drug Administration Schedule; Female; Fumarates; Gastrointestinal Diseases; Humans; Male; Middle Aged; Prospective Studies; Psoriasis; Treatment Outcome

The therapeutic effect and the side of effects fumaric acid derivatives used in treatment of psoriasis vulgaris have been subjects of controversy for more than 30 years. A total of 83 patients with severe psoriasis vulgaris were investigated in a single-centre, long-term open (12 months) clinical trial to evaluate the efficacy and safety profile of the fumaric acid ester preparations Fumaderm initial and Fumaderm. The antipsoriatic effect of the fumaric acid derivatives was clear, with a mean reduction of 76% in PASI. Adverse events in were noted in 62% of the patients (mainly flushing and gastrointestinal complaints). These were dose-dependent and decreased in frequency in the course of the study. No severe adverse events occurred. We believe that of fumaric acid derivatives are indicated in cases of severe therapy-resistant psoriasis to and can be used even for long-term application.

Topics: Administration, Oral; Adolescent; Adult; Aged; Dimethyl Fumarate; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Female; Fumarates; Humans; Keratolytic Agents; Long-Term Care; Male; Middle Aged; Psoriasis; Treatment Outcome

Psoriasis vulgaris may benefit from treatment with fumaric acid and/or its derivatives; however, because different preparations have been used, results have been contradictory and difficult to interpret.. The purpose of this clinical trial was to evaluate the therapeutic value of fumaric acid derivatives.. A randomized double-blind study was carried out in patients with psoriasis, comparing a well-characterized formulation of fumaric acid derivatives with placebo.. The results indicated statistically significant superiority of the fumaric acid derivatives over placebo. Adverse events (flush, gastrointestinal disturbances) were initially relatively frequent, but decreased thereafter.. Fumaric acid derivatives were found to be effective and safe in the treatment of psoriasis.

Topics: Abdominal Pain; Adult; Aged; Diarrhea; Dimethyl Fumarate; Double-Blind Method; Drug Combinations; Female; Flushing; Fumarates; Humans; Joints; Male; Middle Aged; Pain; Placebos; Psoriasis; Remission Induction

In 12 healthy volunteers the topical application of monoethyl fumarate caused a spontaneous persistent erythema. Systemic application induced flush. In urticaria pigmentosa the influence was significant higher than in normal skin. This fact suggests a mast cell degranulation caused by monoethyl fumarate.

Topics: Administration, Oral; Adolescent; Adult; Aged; Cell Degranulation; Drug Hypersensitivity; Female; Fumarates; Humans; Male; Mast Cells; Middle Aged; Patch Tests; Randomized Controlled Trials as Topic; Skin Tests

Thirty-nine patients with psoriasis (12 females, 27 males) entered a randomised, double-blind, placebo-controlled study on the efficacy of fumaric acid therapy in an outpatient setting. During 16 weeks the patients were treated with tablets containing a combination of dimethylfumarate and different salts of monoethylfumarate, with octylhydrogen fumarate or with placebo tablets. All patients were treated with identical indifferent topical therapy and followed an elimination diet (avoidance of spices, wine and nuts). Thirty-four patients completed the study. Five patients dropped out because of side effects or aggravation of the skin lesions. The patients treated with the combination of monoethyl- and dimethylfumarate showed a significantly better therapeutic response compared with those who were treated with placebo or octylhydrogen fumarate. Side effects of the fumarate containing tablets were flushing, diarrhoea, a reversible elevation of transaminases, lymphocytopenia and eosinophilia. One patient developed a disturbance of the kidney function which normalised after discontinuation of the therapy.

Topics: Adult; Aged; Double-Blind Method; Female; Fumarates; Humans; Male; Middle Aged; Psoriasis

The activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription function has been implicated in the protection of neurodegenerative diseases. The cytoplasmic protein, Kelch-like ECH-associated protein 1 (Keap1), negatively regulates Nrf2. The Keap1-Nrf2 pathway is a potential therapeutic target for tackling free-radical damage. Dimethyl fumarate (DMF) is currently an approved drug for the treatment of relapsing multiple sclerosis. Recent studies showed that DMF modifies the reactive cysteines in the BTB domain of Keap1 and thus activates Nrf2 transcription function. Intriguingly, our crystal structure studies revealed that DMF also binds to the β-propeller domain (Keap1-DC) of Keap1. The crystal structure of the complex, refined to 1.54 Å resolution, revealed unexpected features: DMF binds (a) to the Nrf2-binding site (bottom region of Keap1-DC, site 1) with moderate interaction, and (b) to the top region of Keap1-DC, near to the blade II (site 2). The specificity of the binding 'site 2' was found to be unique to blade II of the β-propeller domain. The newly identified 'site 2' region in Keap1-DC may have a different functional role to regulate Nrf2. Moreover, the crystal structures of Keap1-DC in complex with the DMF analogs, including monoethyl fumarate, fumarate, and itaconate, also exhibited similar binding modes with Keap1-DC. Binding studies confirmed that DMF binds, in a nanomolar range, to the Keap1-DC region as well as the BTB domain of Keap1. Furthermore, the competitive binding assay in the presence of the Nrf2 peptide affirmed the direct binding of DMF at the Nrf2-binding region of Keap1-DC. Overall, our studies suggest that the drug molecule, DMF, binds at multiple sites of Keap1 and thus potentially activates Nrf2 function through covalent as well as the noncovalent mode of action, to combat oxidative stress. DATABASE: Structural data are available in RCSB-protein data bank database(s) under the accession numbers 6LRZ, 7C60, and 7C5E.

Topics: Amino Acid Sequence; Antioxidant Response Elements; Binding Sites; Cloning, Molecular; Crystallography, X-Ray; Dimethyl Fumarate; Escherichia coli; Fumarates; Gene Expression; Genetic Vectors; Humans; Kelch-Like ECH-Associated Protein 1; Models, Molecular; NF-E2-Related Factor 2; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protein Structure, Tertiary; Recombinant Proteins; Sequence Alignment; Sequence Homology, Amino Acid

To test the hypothesis that dimethyl fumarate (DMF, Tecfidera) elicits different biological changes from DMF combined with monoethyl fumarate (MEF) (Fumaderm, a psoriasis therapy), we investigated DMF and MEF in rodents and cynomolgus monkeys. Possible translatability of findings was explored with lymphocyte counts from a retrospective cohort of patients with MS.. In rodents, we evaluated pharmacokinetic and pharmacodynamic effects induced by DMF and MEF monotherapies or in combination (DMF/MEF). Clinical implications were investigated in a retrospective, observational analysis of patients with MS treated with DMF/MEF (n = 36).. Fumaric acid esters exhibit different biodistribution and may elicit different biological responses; furthermore, pharmacodynamic effects of combinations differ unpredictably from monotherapy. The strong potential to induce lymphopenia in patients with MS may be a result of activation of apoptosis pathways by MEF compared with DMF.

Topics: Animals; Cross-Sectional Studies; Dimethyl Fumarate; Female; Fumarates; Gene Expression Profiling; Humans; Immunosuppressive Agents; Macaca fascicularis; Male; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Rats; Rats, Sprague-Dawley; Retrospective Studies

Delayed-release dimethyl fumarate (also known as gastro-resistant dimethyl fumarate), an oral therapeutic containing dimethyl fumarate (DMF) as the active ingredient, is currently approved for the treatment of relapsing multiple sclerosis. DMF is also a component in a distinct mixture product with 3 different salts of monoethyl fumarate (MEF), which is marketed for the treatment of psoriasis. Previous studies have provided insight into the pharmacologic properties of DMF, including modulation of kelch-like ECH-associated protein 1 (KEAP1), activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway, and glutathione (GSH) modulation; however, those of MEF remain largely unexplored. Therefore, the aim of this study was to evaluate the in vitro effects of DMF and MEF on KEAP1 modification, activation of the NRF2 pathway, and GSH conjugation. Using mass spectrometry, DMF treatment resulted in a robust modification of specific cysteine residues on KEAP1. In comparison, the overall degree of KEAP1 modification following MEF treatment was significantly less or undetectable. Consistent with KEAP1 cysteine modification, DMF treatment resulted in nuclear translocation of NRF2 and a robust transcriptional response in treated cells, as did MEF; however, the responses to MEF were of a lower magnitude or distinct compared to DMF. DMF was also shown to produce an acute concentration-dependent depletion of GSH; however, GSH levels eventually recovered and rose above baseline by 24 hours. In contrast, MEF did not cause acute reductions in GSH, but did produce an increase by 24 hours. Overall, these studies demonstrate that DMF and MEF are both pharmacologically active, but have differing degrees of activity as well as unique actions. These differences would be expected to result in divergent effects on downstream biology.

Topics: Astrocytes; Cell Nucleus; Cysteine; Dimethyl Fumarate; Extracellular Space; Fumarates; Gene Expression Regulation; Glutathione; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Protein Transport

Fumarate-containing pharmaceuticals are potent therapeutic agents that influence multiple cellular pathways. Despite proven clinical efficacy, there is a significant lack of data that directly defines the molecular mechanisms of action of related, yet distinct fumarate compounds. We systematically compared the impact of dimethyl fumarate (DMF), monomethyl fumarate (MMF) and a mixture of monoethyl fumarate salts (Ca(++), Mg(++), Zn(++); MEF) on defined cellular responses. We demonstrate that DMF inhibited NF-κB-driven cytokine production and nuclear translocation of p65 and p52 in an Nrf2-independent manner. Equivalent doses of MMF and MEF did not affect NF-κB signaling. These results highlight a key difference in the biological impact of related, yet distinct fumarate compounds.

Topics: Active Transport, Cell Nucleus; Animals; Bone Neoplasms; Burkitt Lymphoma; Cations; Cell Line, Tumor; Cells, Cultured; Cytokines; Dimethyl Fumarate; Fumarates; Humans; In Vitro Techniques; Lymphocytes; Maleates; Mice; Mice, Knockout; Molecular Structure; Neoplasm Proteins; NF-E2-Related Factor 2; NF-kappa B; NF-kappa B p52 Subunit; Osteosarcoma; Signal Transduction; Spleen; Transcription Factor RelA

Photo-crosslinkable, fumaric acid monoethyl ester-functionalized triblock oligomers are synthesized and copolymerized with N-vinyl-2-pyrrolidone to form biodegradable photo-crosslinked hydrogels. Poly(ethylene glycol) is used as the middle hydrophilic segment and the hydrophobic segments are based on D,L-lactide, trimethylene carbonate or a mixture of these monomers. Two model proteins, lysozyme and albumin, are incorporated in the hydrogels and their release is studied. The composition of the hydrophobic segments could be used to tune degradation behavior and release rates. Careful optimization of photo-polymerization conditions is needed to limit conjugation of proteins to the hydrogels and protein denaturation.

Topics: Animals; Biocompatible Materials; Cattle; Cross-Linking Reagents; Dioxanes; Drug Carriers; Fumarates; Hydrogels; Hydrophobic and Hydrophilic Interactions; Magnetic Resonance Spectroscopy; Muramidase; Photochemical Processes; Polyethylene Glycols; Polymerization; Pyrrolidinones; Serum Albumin, Bovine

Photo-crosslinked networks were prepared from fumaric acid monoethyl ester-functionalized poly(D,L-lactic acid) oligomers and N-vinyl-2-pyrrolidone. Two model proteins, lysozyme and albumin, were incorporated into the network films as solid particles and their release behavior was studied. By varying the NVP content and macromer molecular weight the degradation behavior and protein release profiles of the prepared networks could be tuned. The more hydrophilic and less densely crosslinked networks released albumin and lysozyme at a faster rate. Although active lysozyme was released from the networks over the complete release period, lysozyme release was often incomplete. This was most likely caused by electrostatic and/or hydrophobic interactions between the protein and the degrading polymer network.

Topics: Animals; Cattle; Cross-Linking Reagents; Delayed-Action Preparations; Fumarates; Gels; Glass; Hydrolysis; Lactic Acid; Light; Molecular Weight; Muramidase; Polyesters; Polymers; Pyrrolidinones; Serum Albumin, Bovine; Transition Temperature; Water

Topics: Dimethyl Fumarate; Drug Therapy, Combination; Female; Fumarates; Humans; Middle Aged; Recurrence; Stomatitis, Aphthous

Photo-crosslinkable, fumaric acid monoethyl ester-functionalized poly(trimethylene carbonate) oligomers were synthesized and copolymerized with N-vinyl pyrrolidone (NVP) and vinyl acetate (VAc) to form biodegradable polymer networks. The copolymerization reactions were much faster than homopolymerization of the fumarate end-groups of the macromers. The hydrophilicity of the networks could by varied by mixing NVP and VAc at different ratios. The prepared network extracts were compatible with NIH 3T3 fibroblasts. Release of vitamin B12, used as a model drug, could be tuned by varying network hydrophilicity and macromer molecular weight. A more hydrophilic and less densely crosslinked network resulted in faster release.

Topics: Animals; Biocompatible Materials; Cross-Linking Reagents; Dioxanes; Drug Carriers; Fibroblasts; Fumarates; Hydrophobic and Hydrophilic Interactions; Mice; Molecular Weight; NIH 3T3 Cells; Photochemical Processes; Polymers; Pyrrolidinones; Solubility; Vinyl Compounds; Vitamin B 12

Polymer networks were prepared by photocross-linking fumaric acid monoethyl ester (FAME) functionalized, three-armed poly(D,L-lactide) oligomers using N-vinyl-2-pyrrolidone (NVP) as diluent and comonomer. The use of NVP together with FAME-functionalized oligomers resulted in copolymerization at high rates, and networks with gel contents in excess of 90% were obtained. The hydrophilicity of the poly(D,L-lactide) networks increases with increasing amounts of NVP, networks containing 50 wt % of NVP absorbed 40% of water. As the amount of NVP was increased from 30 to 50 wt %, the Young's modulus after equilibration in water decreased from 0.8 to 0.2 GPa, as opposed to an increase from 1.5 to 2.1 GPa in the dry state. Mouse preosteoblasts readily adhered and spread onto all prepared networks. Using stereolithography, porous structures with a well-defined gyroid architecture were prepared from these novel materials. This allows the preparation of tissue engineering scaffolds with optimized pore architecture and tunable material properties.

Topics: Animals; Cell Adhesion; Fumarates; Mice; Osteoblasts; Porosity; Pyrrolidinones; Resins, Synthetic; Tissue Engineering; Tissue Scaffolds

Biodegradable elastomeric networks were prepared from ethyl fumarate-functionalized poly(trimethylene carbonate) oligomers. Photocrosslinkable macromers were synthesized by reacting three-armed, hydroxyl group-terminated poly(trimethylene carbonate) oligomers with fumaric acid monoethyl ester at room temperature using N,N-dicyclohexylcarbodiimide as a coupling agent and 4-dimethylamino pyridine as a catalyst. Poly(trimethylene carbonate) macromers with molecular weights ranging between 4500 and 13,900 were prepared and crosslinked by ultraviolet-initiated radical polymerization. The gel contents of the resulting transparent networks varied between 74% and 80%. All obtained networks had low glass transition temperatures, which varied between -18 and -13 degrees C. They showed rubber-like behavior and excellent mechanical properties, with tensile strengths and elongations at break of up to 17.5 MPa and 750%, respectively. Moreover, static- and dynamic creep experiments showed that these amorphous networks were highly elastic and resistant to creep. In cyclic tensile testing to 50% strain, the permanent deformation after 20 cycles was 0%, while static creep tests at 35% of the yield stress did not indicate creep or permanent deformation after removal of the load. Porous structures were prepared by photopolymerizing the macromers in the presence of salt particles, and subsequent leaching of the salt. Such networks, built up of non-toxic compounds and designed to release benign degradation products, may find application as tissue engineering scaffolds for dynamic cell culture.

Topics: Cross-Linking Reagents; Dioxanes; Elastomers; Fumarates; Light; Magnetic Resonance Spectroscopy; Materials Testing; Microscopy, Electron, Scanning; Polymers; Porosity; Temperature; Tensile Strength

Biodegradable polymer networks were prepared from fumaric acid derivatives of oligomeric esters. Photo-crosslinkable macromers were prepared by reacting star-shaped hydroxyl-group terminated lactide, epsilon-caprolactone and trimethylene carbonate based oligomers and fumaric acid monoethyl ester in the presence of N,N-dicyclohexylcarbodiimide and 4-dimethylamino pyridine at room temperature. The functionalization method is facile and suited for many hydroxyl-terminated oligomers. The reactivity of the fumarate end groups is such that, upon crosslinking by UV radical polymerization, networks with high gel contents (up to 96%) can be obtained without the addition of reactive diluents. The physical properties of the networks can be tuned by adjusting the composition, architecture and molecular weight of the oligomeric precursors. Such networks, built up of non-toxic compounds and designed to release benign degradation products, may find wide application in tissue engineering and other areas of biomedical research.

Topics: 4-Aminopyridine; Biocompatible Materials; Biodegradation, Environmental; Caproates; Cross-Linking Reagents; Dicyclohexylcarbodiimide; Dioxanes; Free Radicals; Fumarates; Glass; Lactones; Light; Macromolecular Substances; Magnetic Resonance Spectroscopy; Microscopy, Electron, Scanning; Models, Chemical; Polyesters; Polymers; Temperature; Tensile Strength; Tissue Engineering; Ultraviolet Rays

Topics: Dioxanes; Fumarates; Hydrogels; Magnetic Resonance Spectroscopy; Polyethylene Glycols; Ultraviolet Rays

Psoriasis is a chronic inflammatory skin disease that can be successfully treated with a mixture of fumaric acid esters (FAE) formulated as enteric-coated tablets for oral use. These tablets consist of dimethylfumarate (DMF) and salts of monoethylfumarate (MEF) and its main bioactive metabolite is monomethylfumarate (MMF). Little is known about the pharmacokinetics of these FAE. The aim of the present study was to investigate the hydrolysis of DMF to MMF and the stability of MMF, DMF and MEF at in vitro conditions representing different body compartments.. DMF is hydrolyzed to MMF in an alkaline environment (pH 8), but not in an acidic environment (pH 1). In these conditions MMF and MEF remained intact during the period of analysis (6 h). Interestingly, DMF was hardly hydrolyzed to MMF in a buffer of pH 7.4, but was rapidly hydrolyzed in human serum having the same pH. Moreover, in whole blood the half-life of DMF was dramatically reduced as compared to serum. The concentrations of MMF and MEF in serum and whole blood decreased with increasing time. These data indicate that the majority of the FAE in the circulation are metabolized by one or more types of blood cells. Additional experiments with purified blood cell fractions resuspended in phosphate buffered saline (pH 7.4) revealed that at concentrations present in whole blood monocytes/lymphocytes, but not granulocytes and erythrocytes, effectively hydrolyzed DMF to MMF. Furthermore, in agreement with the data obtained with the pure components of the tablet, the enteric-coated tablet remained intact at pH 1, but rapidly dissolved at pH 8.. Together, these in vitro data indicate that hydrolysis of DMF to MMF rapidly occurs at pH 8, resembling that within the small intestines, but not at pH 1 resembling the pH in the stomach. At both pHs MMF and MEF remained intact. These data explain the observation that after oral FAE intake MMF and MEF, but not DMF, can be readily detected in the circulation of human healthy volunteers and psoriasis patients.

Topics: Blood Cells; Buffers; Dermatologic Agents; Dimethyl Fumarate; Drug Stability; Esters; Fumarates; Half-Life; Humans; Hydrogen-Ion Concentration; Hydrolysis; In Vitro Techniques; Intestine, Small; Maleates; Psoriasis; Serum; Stomach

Psoriasis is a chronic inflammatory skin disease. Its treatment is based on the inhibition of proliferation of epidermal cells and interference in the inflammatory process. A new systemic antipsoriasis drug, which consists of dimethylfumarate and ethylhydrogenfumarate in the form of their calcium, magnesium and zinc salts has been introduced in Europe with successful results. In the present study, a homologous series of mono- and diesters of fumaric acid has been studied with respect to the sites and kinetics of presystemic ester degradation using pancreas extract, intestinal perfusate, intestinal homogenate and liver S9 fraction. In addition, intestinal permeability has been determined using isolated intestinal mucosa as well as Caco-2 cell monolayers, in order to obtain estimates of the fraction of the dose absorbed for these compounds. Relationships between the physicochemical properties of the fumaric acid esters and their biological responses were investigated. The uncharged diester dimethylfumarate displayed a high presystemic metabolic lability in all metabolism models. It also showed the highest permeability in the Caco-2 cell model. However, in permeation experiments with intestinal mucosa in Ussing-type chambers, no undegraded DMF was found on the receiver side, indicating complete metabolism in the intestinal tissue. The intestinal permeability of the monoesters methyl hydrogen fumarate, ethyl hydrogen fumarate, n-propylhydrogen fumarate and n-pentyl hydrogen fumarate increased with an increase in their lipophilicity, however, their presystemic metabolism rates likewise increased with increasing ester chain length. It is concluded that for fumarates, an increase in intestinal permeability of the more lipophilic derivatives is counterbalanced by an increase in first-pass extraction.

Topics: Animals; Atenolol; Biological Availability; Caco-2 Cells; Cell Membrane Permeability; Cells, Cultured; Dimethyl Fumarate; Enzyme Inhibitors; Fumarates; Humans; Intestinal Absorption; Intestinal Mucosa; Intestines; Liver Extracts; Microvilli; Pancreatic Extracts; Propranolol; Psoriasis; Swine

Sarcoidosis is a multisystem disease of unknown origin characterized by the formation of noncaseating granulomas, in particular in the lungs, lymph nodes, eyes, and skin. Systemic treatment for cutaneous sarcoidosis can be used for large disfiguring lesions, generalized involvement, or recalcitrant lesions that did not respond to topical therapy.. We report three patients with recalcitrant cutaneous sarcoidosis who were treated with oral fumaric acid esters (FAE). Three female patients presented with cutaneous sarcoidosis that have proved to be refractory to various therapies, including corticosteroids and chloroquine. We treated the patients with FAE in tablet form using two formulations differing in strength (Fumaderm initial, Fumaderm). Dosage of FAE was performed according to the standard therapy regimen for psoriasis patients. After treatment with FAE (4-12 months), a complete clearance of skin lesions was achieved in the three patients. The side effects observed in this trial correspond to the well-known spectrum of adverse effects of FAE (flush, minor gastrointestinal complaints, lymphopenia).. On the basis of our findings FAE therapy seems to be a safe and effective regimen for patients with recalcitrant cutaneous sarcoidosis. Nevertheless further investigations are necessary to confirm our preliminary results.

Topics: Adult; Dimethyl Fumarate; Female; Fumarates; Humans; Sarcoidosis; Skin Diseases

Granuloma annulare is a granulomatous disease of unknown etiology. Various therapies have been tried in disseminated granuloma annulare (DGA), including corticosteroids, several variants of psoralen plus ultraviolet-A radiation, ultraviolet- A1 radiation, systemic retinoids, and dapsone, with variable success. We report a patient with recalcitrant DGA who was treated with fumaric acid esters (FAE).. A 40-year old Caucasian woman presented with a 25-year history of recalcitrant DGA. On both legs and the abdomen there were erythematous annular plaques. She was treated with FAE in tablet form using two formulations differing in strength (low strength tablets: 30 mg dimethylfumarate, 67 mg monoethylfumarate Ca salt, 5 mg monoethylfumarate Mg salt, 3 mg monoethylfumarate Zn salt; high strength tablets: 120 mg dimethylfumarate, 87 mg monoethylfumarate Ca salt, 5 mg monoethylfumarate Mg salt, 3 mg monoethylfumarate Zn salt). After three-month therapy, an almost complete clearance of skin lesions was achieved. With the exception of temporary lymphopenia, no adverse effects were observed. The patient remained in remission during a six-month follow up period.. Our observation has demonstrated that FAE is a potentially beneficial therapeutic option for patients with recalcitrant DGA. However controlled trials are necessary to fully explore the efficacy, optimal dosage, and safety of FAE in the management of DGA.

Topics: Adult; Dermatologic Agents; Female; Fumarates; Granuloma Annulare; Humans

Fumaric acid ester (FAE) therapy has proved to be safe and effective in patients with severe psoriasis vulgaris. This treatment was introduced nearly 30 years ago, but is only now gaining renewed interest among dermatologists. FAE therapy is licensed in Germany and registration is pending in many European countries. Multicentre trials have confirmed the beneficial effect of FAE in psoriasis and have defined the spectrum of its adverse effects. Although the mode of action of FAEs in the treatment of psoriasis is not fully understood, recent experimental data point towards a skewing of the Th1-dominated T-cell response in psoriasis to a Th2-like pattern, and inhibition of proliferation of keratinocytes. This article reviews the experimental and clinical information on FAEs in psoriasis and provides guidelines for the clinical use of FAEs derived from a consensus meeting of leading experts.

Topics: Cytokines; Drug Administration Schedule; Flushing; Fumarates; Humans; Keratinocytes; Liver; Lymphocyte Count; Practice Guidelines as Topic; Psoriasis; T-Lymphocytes

Most studies on the antipsoriatic mode of action of dimethylfumarate focused on its antiproliferative effects in keratinocytes. Because inflammatory skin diseases are associated with an upregulation of endothelial cell adhesion molecules and because the presence of inflammatory cells in dermis and epidermis is considered an important feature in psoriasis, we tested the effect of DMF on cytokine-induced adhesion molecule expression in HUVEC, using in situ ELISA and Northern blotting. Dimethylfumarate inhibited ICAM-1, VCAM-1, and E-selectin expression and reduced adhesion of U937 cells to stimulated HUVEC. Monoethylfumarate and fumaric acid had no effect. Similar inhibitory effects for DMF on VCAM-1 expression were observed after stimulation of HUVEC with LPS, PMA, IL-4, and IL-1 alpha or in combinations with TNF alpha. These data are in agreement with previously reported effects of DMF on intracellular thiol levels and inhibition of NF-kappa B activation. The inhibitory effect on cytokine-induced endothelial adhesion molecule expression may represent another target of dimethylfumarate in psoriasis.

Topics: Blotting, Northern; Cell Adhesion; Cell Adhesion Molecules; Cytokines; Dimethyl Fumarate; E-Selectin; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Fumarates; Gene Expression Regulation; Humans; Intercellular Adhesion Molecule-1; Interleukins; Lipopolysaccharides; Psoriasis; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha; Umbilical Cord; Vascular Cell Adhesion Molecule-1

We show that the spinning side-bands of protonated and non-protonated carbon atoms can be well separated by means of the standard SCP and LCPD experiments at a relatively slow sample spinning rate or at high magnetic field. These experiments offer a promising way of measuring the principal values of chemical shift anisotropies via spinning side-band analysis in a moderately complex system. General spectral editing in 13C cross-polarization magic-angle spinning (CP/MAS) experiments at high field is achieved by incorporating the total side-band suppression (TOSS) pulse sequence into the standard series of spectral editing pulse sequences. It is confirmed that the relative signal intensity for a certain kind of functional group obtained at different polarization, polarization-inversion and depolarization times is about the same as that obtained at low magnetic field, and that the signal intensity distortion introduced by the TOSS sequence for resonances having different chemical shift anisotropies does not interfere with the spectral editing process. However, quantitative results can only be expected in those cases where full restoration of the intensity of the central band can be achieved by the TOSS sequence. This new strategy at high field is demonstrated by using fumaric acid monoethyl ester as a model compound. A typical application to a Chinese resin is presented, where the relative ratio of each functional group in the aliphatic portion to the total number of aliphatic carbon atoms is determined from only three experimental spectra.

Topics: Anisotropy; Carbon Isotopes; Fumarates; Magnetic Resonance Spectroscopy; Magnetics; Molecular Structure

In this study we investigated the histological changes, regression of acanthosis and rate of proliferation, that accompany the healing of psoriatic lesions after fumaric acid esters and dithranol treatment. Biopsies were taken before and during therapy as well as from neighbouring untreated, clinically uninvolved skin and healthy, non-psoriatic volunteers. Specimens were assessed using computer-supported image analysis and immunohistology. The parameters primarily examined were the height of the rete pegs and of the epithelium above the papillary body, the rate of proliferation, the actual number of cells in the two epidermal compartments and the cellular density in the epidermis. Both fumaric acid esters and dithranol reduce the degree of acanthosis; however, the mechanism and the rate of the reduction differ. While under fumaric acid esters the reduction is more rapid at first but subsequently slows down, dithranol leads to a slow but steady decrease of epidermal thickness, so that at the end of our study the degree of acanthosis was less under dithranol. As an underlying mechanism of action, we found that fumaric acid esters reduce the rate of proliferation and thereby decrease the number of cells per rete peg as well as the size of the individual keratinocytes. Dithranol in contrast does not reduce cell renewal. The decrease of the number of cells in the rete pegs might be caused by an increased differentiation time.

Topics: Administration, Topical; Anthralin; Anti-Inflammatory Agents; Cell Count; Cell Division; Cell Size; Dimethyl Fumarate; Fumarates; Humans; Keratinocytes; Psoriasis; Skin

Delayed acquisition of the proton NMR in selected organic molecular solids (L-alanine, durene, ethyl fumarate, and p-hydroxybenzoic acid) is shown to allow the observation of mobile species in the presence of relatively rigid bulk molecules. The mobility is found to be thermally activated. The combination of the thermally activated motion and magic-angle spinning leads to a fraction of these species moving nearly isotropically on the time scale of the inverse of the homonuclear dipolar splitting. In the case of ethyl fumarate and alanine, there exist populations with differing values of T1 and T1 row. This indicates the co-existence of relatively rigid and relatively mobile molecules in the same sample. The intensities under delayed acquisition cannot always be trusted to yield quantitative information. Comparison of spectra taken under delayed acquisition and under the CRAMPS (B.C. Gerstein, R.G. Pembleton, R.C. Wilson and L.M. Ryan, J. Chem. Phys., 66 (1977)361) technique is made.

Topics: Alanine; Benzene Derivatives; Crystallography; Desiccation; Electron Spin Resonance Spectroscopy; Fumarates; Hydrogen; Magnetic Resonance Spectroscopy; Parabens; Protons; Temperature

The 1H magic-angle spinning (MAS) spectrum for a typical powdered solid is composed of a high resolution component and a broadline component. The high resolution component can be well isolated from the broadline component by the Hahn echo sequence with a long echo time. Compared with CRAMPS experiment, which measures the proton system as a whole, the high resolution echo-MAS method measures only a fraction of the solid, which is usually small at room temperature and quite different from the majority of the solid in both molecular motion and chemical environment. It is shown that for a sample of fumaric acid monoethyl ester, the chemical shifts of the high resolution component are apparently distinguishable from the isotropic chemical shifts of the broadline component in the CRAMPS spectrum as the temperature approaches the melting point. In addition, for a sample of malonic acid, the echo-MAS spectrum is sensitive to moisture and temperature, while its corresponding CRAMPS spectrum is not. It is suggested that the molecules which produce the high resolution component are related to the lattice defects in a solid, including the surface disorder of the polycrystallites, while the molecules that generate the broadline component are located on the rigid lattice of the solid.

Topics: Chemical Phenomena; Chemistry, Physical; Crystallization; Crystallography; Fumarates; Hot Temperature; Hydrogen; Magnetic Resonance Spectroscopy; Malonates; Molecular Structure; Protons; Temperature; Water

Topics: Dimethyl Fumarate; Dose-Response Relationship, Drug; Drug Administration Schedule; Fumarates; Humans; Psoriasis; Treatment Outcome

Systemic administration of fumaric acid (FA) derivatives was originally an empirical antipsoriatic treatment, which showed promising clinical results. In the present study, FURA-2-loaded suspensions of cultured normal keratinocytes and SV40-transformed keratinocytes (SVK-14 cells) were used to study the effects of FA derivatives on the intracellular free calcium concentration ([Ca2+]i). Monomethylfumarate (MMF), dimethylfumarate (DMF) and monoethylfumarate (MEF) induced a rapid, transient [Ca2+]i increase in both cell types. This immediate increase reached maximal values of 396 nmol/l 10s after addition of MMF, and fell to basal values within 90-120 s (173 nmol/l for normal keratinocytes and 68 nmol/l for transformed keratinocytes). This increase was not affected by the prior addition of EGTA, indicating that FA derivatives released Ca2+ mainly from intracellular stores into the cytoplasm. Subsequently, dose-dependent inhibitory effects of FA derivatives on keratinocyte proliferation were demonstrated. The results of these experiments revealed that DMF was the most potent, MMF and MEF intermediate, and FA and malonic acid the least potent growth inhibitors. These antiproliferative effects of FA derivatives might be linked to the observed, transient [Ca2+]i elevations.

Topics: Anticarcinogenic Agents; Calcium; Cell Division; Cell Line, Transformed; Cells, Cultured; Depression, Chemical; Dimethyl Fumarate; Dose-Response Relationship, Drug; Fumarates; Humans; Intracellular Fluid; Keratinocytes; L-Lactate Dehydrogenase; Male; Maleates

Oral administration with complex mixtures of fumaric acid derivatives is known to have antipsoriatic efficacy. The present studies aimed to clarify the mode of action and toxicity of the individual compounds. Hyperproliferative HaCaT keratinocytes in monolayer cultures were exposed to fumaric acid, dimethylfumarate, zinc monoethylfumarate, calcium monoethylfumarate and magnesium monoethylfumarate at concentrations between 0.4 microM and 960 microM for 48 h. Cell proliferation was studied by [3H]thymidine incorporation. In addition 14C-labelled amino acid uptake and total protein content were measured. Direct cytotoxicity was determined by the release of cytoplasmic lactate dehydrogenase (LDH) into the culture medium. The corresponding 50% inhibition concentrations (IC50) were calculated for DNA/protein synthesis: 2.3/2.5 microM (dimethylfumarate), 133/145 microM (zinc monoethylfumarate), 215/230 microM (calcium monoethylfumarate), 275/270 microM (magnesium monoethylfumarate), > 960/> 960 microM (fumaric acid). The total protein content was less sensitive. Antiproliferative activity was found for dimethylfumarate and to a lesser degree for calcium monoethylfumarate already at the subtoxic concentrations of 1.3 and 4 microM, respectively. In the case of magnesium monoethylfumarate, zinc monoethylfumarate and fumaric acid there was no such dissociation between their cytotoxic and antiproliferative potential. These data indicate that most of the antipsoriatic potential of fumaric therapies is due to the dimethylfumarate compound.

Topics: Cell Death; Cell Division; Cells, Cultured; Dimethyl Fumarate; DNA; Fumarates; Humans; Keratinocytes; L-Lactate Dehydrogenase; Protein Biosynthesis; Psoriasis

Topics: Adult; Dimethyl Fumarate; Drug Therapy, Combination; Follow-Up Studies; Fumarates; Humans; Psoriasis

We report on two cases of adverse reactions to topical treatment with monoethyl fumarate. One patient suffering from atopic dermatitis reacted with contact dermatitis; the other, suffering from psoriasis, developed a generalized, partly pustulous exanthema as well as signs of systemic involvement, such as tachycardia and dyspnea. As the causative mechanism we suggest non-immunological contact urticaria syndrome.

Topics: Administration, Topical; Adult; Anaphylaxis; Drug Eruptions; Eczema; Female; Fumarates; Humans; Male; Psoriasis

Topics: Dermatologic Agents; Fumarates; Humans; Psoriasis

The nephrotoxic actions of high single oral doses of fumaric acid monoethylester (FA ME) have been investigated in the rat. Fifty mg of this substance produced morphologic lesions of the glomeruli without reducing GFR. Following 100 mg, the lesions were more pronounced and GFR was diminished by about 40%. Despite of hemorrhages in kidney cortex the urines did not contain erythrocytes. Urinary protein was augmented in single cases only. Fifty to 100 mg FA ME induced a marked concentration defect after water deprivation. In parallel FA ME reduced lactate production from glucose by kidney inner medulla in vitro. After in vivo application, however, no morphologic lesions were found in this zone of the kidney. FA ME had no effect on oxygen consumption of kidney slices despite of proximal tubular lesions observed histologically after 100 mg orally. Thus, 100 mg of FA ME have distinct nephrotoxic effects in the rat.

Topics: Animals; Diuresis; Fumarates; Glomerular Filtration Rate; Glycolysis; In Vitro Techniques; Inulin; Kidney; Kidney Diseases; Kidney Medulla; Lactates; Male; Osmolar Concentration; Oxygen Consumption; Rats; Rats, Inbred Strains