ethyl-fumarate and Psoriasis

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

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

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

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

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

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

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

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