fumaric-acid and Multiple-Sclerosis--Relapsing-Remitting

Several lines of evidence have demonstrated the potential biomedical applications of fumaric acid (FA) and its ester derivatives against many human disease conditions. Fumaric acid esters (FAEs) have been licensed for the systemic treatment of the immune-mediated disease psoriasis. Biogen Idec Inc. announced about the safety and efficacy of the formulation FAE (BG-12) for treating RRMS (relapsing-remitting multiple sclerosis). Another FAE formulation DMF (dimethyl fumarate) was found to be capable of reduction in inflammatory cardiac conditions, such as autoimmune myocarditis and ischemia and reperfusion. DMF has also been reported to be effective as a potential neuroprotectant against the HIV-associated neurocognitive disorders (HAND). Many in vivo studies carried out on rat and mice models indicated inhibitory effects of fumaric acid on carcinogenesis of different origins. Moreover, FAEs has emerged as an important matrix ingredient in the fabrication of biodegradable scaffolds for tissue engineering applications. Drug delivery vehicles composed of FAEs have shown promising results in delivering some leading drug molecules. Apart from these specific applications and findings, many more studies on FAEs have revealed new therapeutic potentials with the scope of clinical applications. However, until now, this scattered vital information has not been written into a collective account and analyzed for minute details. The aim of this paper is to review the advancement made in the biomedical application of FA and FAEs and to focus on the clinical investigation and molecular interpretation of the beneficial effects of FA and FAEs.

Topics: Animals; Dimethyl Fumarate; Esters; Fumarates; Humans; Multiple Sclerosis, Relapsing-Remitting; Neuroprotective Agents; Psoriasis

After the approval of fumaric acid in February 2014 another first line agent is now available for the treatment of multiple sclerosis (MS). Along with the various beta interferon preparations, glatiramer acetate, teriflunomide and fumaric acid add to the repertoire of oral therapeutics for the initial treatment of relapsing remitting MS in daily practice. In order to employ these drugs in an individualized and precise medical manner and considering their efficacy and side effects, it seems worthwhile to learn the so far known mode of action and background history. Fumaric acid, as one of the newest drugs approved for MS, reveals the longest history as it was in use for decades as a treatment in psoriasis patients. Furthermore, fumaric acid is a good example for so far not extensively exploited option of drug reposition in medicine in general. The current review summarizes the outcomes of the clinical approval studies of fumaric acid in MS and discusses the dual mode of action, the immunomodulatory and tissue protective effect, as well as the reported adverse events under fumaric acid treatment. This review aims to serve an aid in the daily decision-making practice when choosing the baseline therapy for MS patients.

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Evidence-Based Medicine; Flushing; Fumarates; Gastrointestinal Diseases; Humans; Immunologic Factors; Kidney Diseases; Multiple Sclerosis, Relapsing-Remitting; Neuroprotective Agents; Treatment Outcome

Fumaric acid was originally therapeutically used in psoriasis. Several lines of evidence have demonstrated immunomodulatory but also neuroprotective effects for FAE. Clinical studies in psoriasis showed a reduction of peripheral CD4+ and CD8+ T-lymphocytes due to the ability of FAE to induce apoptosis. In vitro studies with the ester dimethylfumarate (DMF) described an inhibitory effect on nuclear factor kappa B (NF-κB)-dependent transcription of tumor necrosis factor-alpha (TNF-α) induced genes in human endothelial cells. Animal experiments in the mouse model of central nervous system demyelination, MOG-induced experimental autoimmune encephalomyelitis, revealed a clear preservation of myelin and axonal density in the plaque. Molecular studies showed that this is based on the antioxidative mechanism of action via induction of the transcription factor Nrf-2. A phase II clinical trial in relapsing-remitting multiple sclerosis (RRMS) patients with dimethylfumarate showed a significant reduction in the number of gadolinium enhancing lesions after 24weeks.

Topics: Animals; Clinical Trials as Topic; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting