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PubMed2004

Fumaric acid esters in the treatment of psoriasis: an Italian experience.

BACKGROUND: Psoriasis is a common, chronic, cell-mediated, inflammatory skin disease. Treatment limitations and a developing understanding of its pathogenesis on a molecular level have encouraged much interest in the field of immunomodulatory therapy. OBJECTIVE: To evaluate the efficacy and safety of fumaric acid esters, in particular dimethylfumarate (DMF), in the treatment of moderate to severe plaque psoriasis intolerant and/or resistant to other conventional systemic therapies. METHODS: A total of 40 patients were enrolled in this study. DMF was orally administered at the daily dose of 30 mg up to 360 mg for a minimum of 6 months treatment. Patients were followed-up with psoriasis area and severity index (PASI) score assessment, and clinical and photographic documentation. RESULTS: A total of 33 (82.5%) patients achieved complete clinical remission with DMF treatment: eight after 3 months and 25 after 6 months. Adverse events, such as intolerable abdominal cramps and incoercible diarrhoea, occurred in four patients who, for this reason, interrupted therapy. CONCLUSION: The findings suggest that DMF is a safe, effective and well-tolerated long-term oral treatment worthy of consideration for selective patients.

Adolescent↗
PubMed2005

Enhanced cytotoxicity of bioreductive antitumor agents with dimethyl fumarate in human glioblastoma cells.

We compared the cytotoxicity of the bioreductive antitumor agents mitomycin C (MMC) and streptonigrin (SN) with or without the DT-diaphorase (DTD) inducer dimethyl fumarate (DMF) in four human glioblastoma cell lines with the conventional chemotherapeutic agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We also examined four other types of cancer cells to compare with glioblastoma cells. Cytotoxicity was measured with the sulforhodamine B (SRB) assay and was represented by 50% inhibition concentration (IC50). Enzymatic activities of DTD, cytochrome b5 reductase and glutathione-S-transferase (GST) in cells were measured spectrophotometrically. IC50 for BCNU was in a range of 28-300 microM in the glioblastoma cell lines. Glioblastoma cells were more sensitive to MMC or SN than to BCNU. Pretreatment with DMF significantly increased cytotoxicity of MMC and SN in glioblastoma cell lines and the NCI-H1299 lung cancer cell line, but had no effect on BCNU cytotoxicity. DMF significantly increased DTD and cytochrome b5 reductase activity, and decreased GST in three of four glioblastoma cell lines. Addition of the DTD inhibitor, dicumarol, significantly inhibited cytotoxicity of MMC and SN, and reversed the increased cytotoxicity seen when DMF was combined with either MMC or SN in all glioblastoma cell lines. Combining inducers of DTD and cytochrome b5 reductase with bioreductive agents may be a potential therapeutic strategy for glioblastoma.

Antineoplastic Agents↗
PubMed1994

Fumaric acid derivatives evoke a transient increase in intracellular free calcium concentration and inhibit the proliferation of human keratinocytes.

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.

Anticarcinogenic Agents↗
PubMed2005

Fumaric acid esters for severe psoriasis: a retrospective review of 58 cases.

BACKGROUND: Fumaric acid esters (FAE) have been used to treat severe psoriasis in northern Europe for over 20 years. A recent systematic review has shown FAE to be an effective systemic treatment for severe psoriasis. However, FAE remain unlicensed in the U.K. OBJECTIVES: To present data relating to the efficacy and tolerability of FAE in severe psoriasis and report our experiences of FAE therapy at one U.K. centre. METHODS: Patients who had received FAE for severe psoriasis at one U.K. regional referral centre between June 1999 and October 2003 were identified from pharmacy records. Their records were analysed retrospectively. RESULTS: Fifty-eight patients (25 women, 33 men) were identified. Fifty-five (95%) of the 58 patients had previously used other systemic antipsoriatic therapies with over 70% previously using two or more agents. Thirty-two patients (55%) showed improvement in their psoriasis with 10 (17%) being rated as 'clear' or 'virtually clear' by the attending physician. No improvement was seen in 28% patients and 16% showed worsening of their disease. Adverse events were common and were reported in 66% patients. These mainly consisted of abdominal pain (61%), diarrhoea (55%), flushing (45%), nausea (21%) and malaise (15%). They led to discontinuation of treatment in 15 patients after a mean period of 4.7 months. Lymphocytopenia developed during treatment in 57% of patients, all of whom had had a baseline value within the normal range. In only one patient was this considered severe enough to warrant withdrawal of treatment. CONCLUSIONS: Our study has shown that FAE are an effective therapy in selected patients with severe psoriasis, even in those who have previously been intolerant of systemic therapy or where it has failed.

Adolescent↗
PubMed2005

Fumaric acid esters in necrobiosis lipoidica: results of a prospective noncontrolled study.

BACKGROUND: 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. OBJECTIVES: We sought to investigate the efficacy of FAE in a larger number of patients with NL. METHODS: 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. RESULTS: 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. CONCLUSIONS: The results of this study demonstrate that FAE are beneficial and safe in the treatment of patients with NL.

Adult↗
PubMed2006

Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study.

An exploratory, prospective, open-label study of fumaric acid esters (FAE, Fumaderm(R)) was conducted in patients with relapsing-remitting multiple sclerosis (RRMS). The study consisted of the following four phases: 6-week baseline, 18-week treatment (target dose of 720 mg/day), 4-week washout, and a second 48-week treatment phase (target dose of 360 mg/day). Ten patients with an Expanded Disability Status Scale (EDSS) score of 2.0-6.0 and at least one gadolinium-enhancing (Gd+) lesion on T1-weighted magnetic resonance imaging (MRI) brain scans participated in the study. Safety was assessed by adverse events (AEs), blood chemistry/hematology, electrocardiogram, and urinalysis. The primary efficacy outcomes were number and volume of Gd+ lesions. Other clinical outcomes included EDSS score, ambulation index (AI), and nine-hole peg test (9-HPT). Effects of FAE on intracellular cytokine profiles, T-cell apoptosis, and soluble adhesion molecules were also assessed. Three patients withdrew during the first 3 weeks of the study because of side effects, non-compliance, and follow-up loss. The most common AEs were gastrointestinal symptoms and flushing; all AEs were reported as mild and reversible. FAE produced significant reductions from baseline in number (P < 0.05) and volume (P < 0.01) of Gd+ lesions after 18 weeks of treatment; this effect persisted during the second treatment phase at half the target dose after the 4-week washout period. EDSS scores, AI, and 9-HPT remained stable or slightly improved from baseline in all patients. Measures of T-cell function demonstrated alterations in cytokines and circulating tumor necrosis factor. The results of this exploratory study suggest that further studies of FAE in patients with MS are warranted.

Administration, Oral↗
PubMed2005

Disseminated granuloma annulare--treatment with fumaric acid esters.

BACKGROUND: The therapy of disseminated granuloma annulare has often limited success. Treatment of granuloma annulare with fumaric acid esters (FAE) has recently been reported to be effective in 2 patients. OBJECTIVES: To assess the efficacy of a systemic therapy with FAE in consecutive patients with disseminated granuloma annulare. METHODS: Eight patients with disseminated granuloma annulare were treated with FAE in tablet form according to the standard therapy regimen used in psoriasis. The colour and the elevation of the skin lesions were assessed by a visual analogue scale before and after therapy. RESULTS: Systemic therapy with FAE induced a significant clinical improvement in elevation and colour of skin lesions, with remission in 3 and partial remission in 4 patients. One patient remained unchanged. Side-effects associated with the therapy were seen in 6 patients. CONCLUSIONS: Systemic therapy with FAE can be effective in patients suffering from disseminated forms of granuloma annulare, but side-effects of FAE have to be taken into consideration.

Administration, Oral↗
PubMed2004

In vitro pharmacokinetics of anti-psoriatic fumaric acid esters.

BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.

Blood Cells↗
PubMed2002

Successful treatment of recalcitrant cutaneous sarcoidosis with fumaric acid esters.

BACKGROUND: 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. CASE PRESENTATIONS: 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). CONCLUSIONS: 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.

Adult↗
PubMed1998

[Determination of antimicrobial preservative dimethyl fumarate by high performance liquid chromatography].

This paper described a HPLC method for determining dimethyl fumarate (DMF), a new antimicrobial preservative. Chromatographic conditions were as follows: Micropak MGH 5 mu cap column, 4.00 mm x 300.0 mm EtOH-H2O (90:10, V/V) eluent, and UV detector at 216 nm. In the range of 0.036-2.96 micrograms, the sample size and peak area showed a linear relationship with regression equation, Y = 3.215 x 10(-6)X - 0.04797 and r = 0.9996. Standard deviation was 3.2 x 10(-4).

Chromatography, High Pressure Liquid↗
PubMed1975

Serum and erythocyte argininosuccinate lyase assay by NADH fluorescence generated from formed fumarate.

Measurement of argininosuccinase (I; EC 4.3.2.1) activity is useful in following the course of disease in hepatitis and in screening for the genetic defect, argininosuccinic aciduria. Methodology is proposed for a novel procedure for the determination of I in serum and erythrocytes. In the procedure, fumarate, generated in the reaction, is assayed by conversion to malate with fumarase, determining the malate enzymatically with malate dehydrogenase, and estimating the NADH formed spectrofluorometrically. By this procedure, the enzyme activity in serum from normal individuals is less than 11 mumol/liter of erthrocytes/per hour. The correlation coefficient between results by this method and by the colorimetric method, which measures the arginine generated in the reaction, is +0.97 for serum and +0.98 for erythrocytes. The proposed procedure has a relatively low initial blank, requires less serum, and is completed faster.

Animals↗
PubMed2006

Treatment of therapy-resistant Alopecia areata with fumaric acid esters.

BACKGROUND: Alopecia areata is a cosmetically very disfiguring clinical picture and can be a great emotional burden to the patient, especially when persisting for a longer period of time. PATIENTS AND METHODS: 10 patients with an alopecia resistant to therapy were treated within the bounds of an open, non-placebo controlled pilot study with fumaric acid esters (FAE's, Fumaderm) for a period of six months and a maximum dose of 120 mg dimethylfumarate per day. The shortest space of time between persistent Alopecia areata and the start of the therapy with FAE was between six months and 17 years. RESULTS: Six patients took benefit from the six months therapy with FAE. In three of them very good results could be observed, presenting an almost entire remission, one patient showed a good success with a focal remission. With two patients a mediocre to moderate outcome was observed with growth of partly diffuse spread or very thin hair. Four patients took no benefit from the FAE therapy at all. CONCLUSIONS: FAE can be useful in the treatment of therapy-resistant Alopecia areata. This therapy approach should be validated in a multi-centre study.

Administration, Topical↗
PubMed1991

Postirradiation sensitization of mammalian cells by the thiol-depleting agent dimethyl fumarate.

Dimethyl fumarate (DMF) depletes intracellular glutathione (GSH) by covalent bond formation in a reaction mediated by GSH-S-transferase. Treatment of hypoxic Chinese hamster V79 cells with 5 mM DMF before irradiation radiosensitizes the cells, resulting in an enhancement ratio (ER) of about 2.7 with minimal toxicity, when the end point is clonogenic cell survival. Under the same conditions aerobic cells are sensitized, and ER of about 1.3 is found, and GSH is reduced to about 3% of control. Very similar results were obtained previously with Chinese hamster ovary (CHO) cells. In addition, new data presented here show that DMF treatment of V79 or CHO cells immediately after irradiation under hypoxic conditions sensitizes the cells, resulting in an ER of about 1.5, DMF treatment after irradiation under aerobic conditions results in an ER of 1.3, and this DMF treatment reduces protein thiols (PSH) to about 70% of control. When induction of DNA damage is measured using the neutral elution assay, treatment of V79 or CHO cells with DMF prior to irradiation under hypoxic conditions results in an ER of 1.9-2.0, but there is no enhancement of DNA damage when DMF is added after irradiation under hypoxic conditions or when cells are treated with DMF before or after irradiation under aerobic conditions. Based on these data we postulate that DMF radiosensitizes killing of hypoxic cells by two actions: depletion of GSH interferes with the chemical competition between damage fixation and repair, and depletion of PSH causes an inhibition of enzymatic repair processes. We also suggest that DMF sensitizes aerobic cells only by inhibition of enzymatic repair processes.

Animals↗
PubMed1989

[The effect of composition and ionic strength of external solution on the aspartate-ammonia lyase and fumarate hydratase activity in Escherichia coli cells].

It was found that the nonspecific effect of ionic strength of the external solution on the enzymatic activity of E. coli cells consists in rapid changes in the permeability of cell membranes interacting with the substrate. This effect depends on the initial substrate concentration, i.e., ionic strength of the external solution, and is maintained for some time as the substrate concentration decreases. Chloramphenicol, a protein synthesis inhibitor, and sodium azide, a respiration inhibitor (300 micrograms/ml and 200 microM, respectively) do not change the enzymatic activity of E. coli cells during the synthesis of L-aspartic and L-malic acids from fumaric acid. The kinetic equations of L-aspartate and L-malate synthesis are described by equations of zero and intermediate (between zero and first) order, respectively.

Ammonia-Lyases↗
PubMed1998

In vivo degradation of a poly(propylene fumarate)/beta-tricalcium phosphate injectable composite scaffold.

This study was designed to investigate the in vivo biodegration and biocompatibility of a poly(propylene fumarate) (PPF)-based orthopedic biomaterial. The effects of varying the PPF to N-vinyl pyrrolidinone ratio and PPF to beta-tricalcium phosphate content were studied. The composite mechanical properties and local tissue interactions were analyzed over 12 weeks. An initial increase in both compressive modulus and strength was seen for composite formulations that incorporated beta-tricalcium phosphate. The samples incorporating a higher PPF to N-vinyl pyrrolidinone ratio reached a maximal compressive strength of 7.7 MPa and a maximal compressive modulus of 191.4 MPa at 3 weeks. The lower PPF to N-vinyl pyrrolidinone ratio samples gained a maximum compressive strength of 7.5 MPa initially and a compressive modulus of 134.0 MPa at 1 week. At 6 weeks, all samples for formulations incorporating beta-tricalcium phosphate crumbled upon removal and were not mechanically tested. Samples that did not incorporate beta-tricalcium phosphate were very weak and insufficient for bone replacement at the 4-day time point and beyond. Tissue interactions resulted in a mild inflammatory response at the initial time points and mature fibrous encapsulation by 12 weeks.

Animals↗
PubMed1999

Crosslinking characteristics of an injectable poly(propylene fumarate)/beta-tricalcium phosphate paste and mechanical properties of the crosslinked composite for use as a biodegradable bone cement.

We investigated the crosslinking characteristics of an injectable composite paste of poly(propylene fumarate) (PPF), N-vinyl pyrrolidinone (N-VP), benzoyl peroxide (BP), sodium chloride (NaCl), and beta-tricalcium phosphate (beta-TCP). We examined the effects of PPF molecular weight, N-VP/PPF ratio, BP/PPF ratio, and NaCl weight percent on the crosslinking temperature, heat release upon crosslinking, gel point, and the composite compressive strength and modulus. The maximum crosslinking temperature did not vary widely among formulations, with the absolute values falling between 38 degrees and 48 degrees C, which was much lower than that of 94 degrees C for poly(methyl methacrylate) bone cement controls tested under the same conditions. The total heat released upon crosslinking was decreased by an increase in PPF molecular weight and a decrease in N-VP/PPF ratio. The gel point was affected strongly by the PPF molecular weight, with a decrease in PPF molecular weight more rapidly leading to a gel point. An increase in initiator concentration had the same effect to a lesser degree. The time frame for curing was varied from 1-121 min, allowing the composite to be tailored to specific applications. The compressive strength and compressive modulus values increased with decreasing N-VP/PPF, increasing NaCl content, and increasing BP/PPF ratio. For all formulations, the compressive strength values fell between 1 and 12 MPa, and the compressive modulus values fell between 23 and 265 MPa. These data suggest that injectable PPF/beta-TCP pastes can be prepared with handling characteristics appropriate for clinical orthopedic applications and that the mechanical properties of the cured composites are suitable for trabecular bone replacement.

Biodegradation, Environmental↗
PubMed2000

Effects of transforming growth factor beta1 released from biodegradable polymer microparticles on marrow stromal osteoblasts cultured on poly(propylene fumarate) substrates.

Recombinant human transforming growth factor beta1 (TGF-beta1) was incorporated into microparticles of blends of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) to create a delivery vehicle for the growth factor. The entrapment efficiency of TGF-beta1 in the microparticles containing 5% PEG was 40.3 +/- 1.2% for a TGF-beta1 loading density of 6.0 ng/1 mg of microparticles. For the same loading, 17.9 +/- 0.6 and 32.1 +/- 2.5% of the loaded TGF-beta1 was released after 1 and 8 days, respectively, followed by a plateau for the remaining 3 weeks. Rat marrow stromal cells showed a dose response to TGF-beta1 released from the microparticles similar to that of added TGF-beta1, indicating the activity of TGF-beta1 was retained during microparticle fabrication and after TGF-beta1 release. An optimal TGF-beta1 dosage of 1.0 ng/mL was determined through a 3-day dose response study for maximal alkaline phosphatase (ALP) activity. The TGF-beta1 released from the microparticles loaded with 6.0 ng TGF-beta1/1 mg of microparticles for the optimal dosage of TGF-beta1 enhanced the proliferation and osteoblastic differentiation of marrow stromal cells cultured on poly(propylene fumarate) substrates. The cells showed significantly increased total cell number, ALP activity, and osteocalcin production with values reaching 138,700 +/- 3300 cells/cm(2), 22.8 +/- 1.5 x 10(-7) micromol/min/cell, and 15.9 +/- 1.5 x 10(-6) ng/cell, respectively, after 21 days as compared to cells cultured under control conditions without TGF-beta1. These results suggest that controlled release of TGF-beta1 from the PLGA/PEG blend microparticles may find applications in modulating cellular response during bone healing at a skeletal defect site.

Animals↗
PubMed2002

Effect of activated charcoal on patulin, fumaric acid and some other properties of apple juice.

In this study, 0, 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 g/l amounts of activated charcoal (AC) were added into apple juice with a patulin content of 62.3 ppb obtained from a well-established manufacturing company. Apple juice samples were then mixed for 0, 5, 10, 20, and 30 min, respectively. Considerable reduction in the patulin and HMF values was found while there is a dramatic improvement in the colour and clearness of apple juice. However, AC did not cause a significant decrease in the fumaric acid level of apple juice. The best result was obtained at 3.0 g/l AC mixed for 5 min. In addition, a negligible reduction in brix and pH values of samples was observed.

Anticarcinogenic Agents↗