fumarates and Multiple-Sclerosis

Dimethyl fumarate (DMF) is an antioxidative and anti-inflammatory drug approved for treatment of multiple sclerosis and psoriasis; however, beneficial effects of DMF have also been found in other inflammatory diseases and cancers. DMF is a prodrug that is immediately hydrolysed to monomethyl fumarate (MMF) in vivo. Both fumarates activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, and Nrf2 is a key transcription factor of the antioxidant response. The immunosuppressive and anti-inflammatory actions of DMF occur through several mechanisms: via inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and by downregulation of aerobic glycolysis and pyroptosis in activated myeloid and lymphoid cells. MMF is also an agonist of hydroxycarboxylic acid receptor 2 (HCAR2). Differences in the strength of effects and mechanisms of action of both fumarates are discussed. The aim of this review was to analyse and compare the neuroprotective, antioxidative and anti-inflammatory effects of DMF and its active metabolite, MMF, in cellular (in vitro) and animal models of neurodegenerative diseases (NDs), other than multiple sclerosis. There are more than twenty studies that currently represent this field. Most of the studies are concerned with cellular or animal models of Alzheimer's disease (AD) and Parkinson's disease (PD), one utilized a mouse model of Huntington's disease (HD) and one clinical trial was carried out with amyotrophic lateral sclerosis (ALS) patients. The discrepancies in the results of the various studies are discussed, and issues requiring further research have been identified.

Topics: Animals; Dimethyl Fumarate; Fumarates; Humans; Mice; Multiple Sclerosis; Neurodegenerative Diseases; Neuroprotective Agents; NF-E2-Related Factor 2; Signal Transduction

Multiple sclerosis treatment made substantial headway during the last two decades with the implementation of therapeutics with new modes of action and routes of application. We are now in the situation that second-generation molecules, approved since 2018, are on the market, characterized by reduced side effects using a more tailored therapeutic approach. Diroximel fumarate is a second-generation fumarate with reduced gastrointestinal side effects. Moreover, several novel, selective, sphingosine-1-phosphate receptor modulators with reduced off-target effects have been developed; namely siponimod, ozanimod, and ponesimod; all oral formulations. B-cell-targeted therapies such as ocrelizumab, given intravenously, and since 2021 ofatumumab, applied subcutaneously, complement the spectrum of novel therapies. The glycoengineered antibody ublituximab is the next anti-CD20 therapy about to be approved. Within the next years, oral inhibitors of Bruton's tyrosine kinase, currently under investigation in several phase III trials, may be licensed for multiple sclerosis. Those developments currently offer an individualized multiple sclerosis therapy, targeting patient needs with substantial effects on relapses, disability progression, and implications for daily life. In this up-to-date review, we provide a holistic overview about novel developments of the therapeutic landscape and upcoming approaches for multiple sclerosis treatment.

Topics: Antigens, CD20; Fumarates; Humans; Multiple Sclerosis; Recurrence; Sphingosine 1 Phosphate Receptor Modulators

Fumarates are successfully used for the treatment of psoriasis and multiple sclerosis. Their antioxidative, immunomodulatory, and neuroprotective properties make fumarates attractive therapeutic candidates for other pathologies. The exact working mechanisms of fumarates are, however, not fully understood. Further elucidation of the mechanisms is required if these drugs are to be successfully repurposed for other diseases. Towards this, administration route, dosage, and treatment timing, frequency, and duration are important parameters to consider and optimize with clinical paradigms in mind. Here, we summarize the rapidly expanding literature on the pharmacokinetics and pharmacodynamics of fumarates, including a discussion on two recently FDA-approved fumarates Vumerity

Topics: Fumarates; Humans; Immunologic Factors; Multiple Sclerosis

On October 29, 2019, the Food and Drug Administration (FDA) of the United States approved diroximel fumarate (DRF) as an oral fumarate for the treatment of relapsing forms of multiple sclerosis. Another oral fumarate, dimethyl fumarate (DMF), was approved for the same indication on March 27, 2013. Prior to its approval, DRF did not undergo rigorous testing to determine its efficacy, as its active metabolite, monomethyl fumarate, is the same as that of DMF (bioequivalency). The efficacy, safety and tolerability of DMF have previously been demonstrated in a number of clinical trials and real-world studies. For DRF, one phase III study has been completed, and another is in progress to determine its safety, tolerability and efficacy. In this paper, we review the pharmacology, pharmacokinetics, metabolism, clinical studies and drug safety of DRF.

Topics: Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis

The recent approval of several oral disease-modifying drugs (DMDs) for multiple sclerosis (MS) brings promise of improved clinical effectiveness as well as greater drug compliance compared to the existing non-oral DMDs, and substantially increases patient choice and therapeutic options in the effective management of MS. However, for men and women with MS of childbearing age, concerns about the effect of oral DMDs on pregnancy and the fetus may arise. Some limited data from animal reproductive studies of oral DMDs suggest a potential increased risk of early pregnancy loss, impaired growth and birth defects. Although active surveillance mechanisms exist, there is limited data to inform clinical practice. Using existing information from published clinical trials and drug monographs, as well as recent conference proceedings, this review summarizes the mechanism of action (in relation to embryogenesis and pregnancy) and existing animal or human pregnancy-related data for approved (fingolimod, teriflunomide and dimethyl fumarate) and investigational (laquinimod and firategrast) oral DMDs for MS.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Crotonates; Dimethyl Fumarate; Female; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunologic Factors; Multiple Sclerosis; Nitriles; Pregnancy; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Propylene Glycols; Sphingosine; Toluidines

Topics: Administration, Oral; Adult; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Fumarates; Humans; Multiple Sclerosis; Psoriasis; Severity of Illness Index; Treatment Outcome

Multiple sclerosis (MS) as a chronic neuro-inflammatory and neurodegenerative disease of the central nervous system is frequently associated with severe disability and impairment in quality of life. Early disease-modifying treatment options have mainly focused on inflammatory aspects of the disease. Recently, the neurodegenerative features have received more attention in experimental models, paraclinical assessments and the evaluation of drug effects. Fumaric acid esters (FAEs) as orally available immunomodulatory and neuroprotective compounds have thus advanced to a highly interesting MS treatment option. Here, we will review the pharmaceutical history of FAEs, their immunomodulatory and putative neuroprotective mechanisms of action and clinical trial data in relapsing MS.

Topics: Clinical Trials as Topic; Fumarates; Humans; Immunologic Factors; Multiple Sclerosis; Neuroprotective Agents

New oral drugs have considerably enriched the therapeutic armamentarium for the treatment of multiple sclerosis. This review focuses on the molecular pharmacodynamics of fingolimod, dimethyl fumarate (BG-12), laquinimod, and teriflunomide. We specifically comment on the action of these drugs at three levels: 1) the regulation of the immune system; 2) the permeability of the blood-brain barrier; and 3) the central nervous system. Fingolimod phosphate (the active metabolite of fingolimod) has a unique mechanism of action and represents the first ligand of G-protein-coupled receptors (sphingosine-1-phosphate receptors) active in the treatment of multiple sclerosis. Dimethyl fumarate activates the nuclear factor (erythroid-derived 2)-related factor 2 pathway of cell defense as a result of an initial depletion of reduced glutathione. We discuss how this mechanism lies on the border between cell protection and toxicity. Laquinimod has multiple (but less defined) mechanisms of action, which make the drug slightly more effective on disability progression than on annualized relapse rate in clinical studies. Teriflunomide acts as a specific inhibitor of the de novo pyrimidine biosynthesis. We also discuss new unexpected mechanisms of these drugs, such as the induction of brain-derived neurotrophic factor by fingolimod and the possibility that laquinimod and teriflunomide regulate the kynurenine pathway of tryptophan metabolism.

Topics: Administration, Oral; Animals; Blood-Brain Barrier; Crotonates; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immune System; Multiple Sclerosis; NF-E2-Related Factor 2; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines

Topics: Antibodies, Monoclonal; Brain; Crotonates; Dimethyl Fumarate; Fumarates; Guideline Adherence; Humans; Hydroxybutyrates; Immunosuppressive Agents; Interferon-beta; Multiple Sclerosis; Neurologic Examination; Nitriles; Oligodendroglia; Toluidines

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antioxidants; Australia; Clinical Trials, Phase III as Topic; Crotonates; Daclizumab; Dimethyl Fumarate; Disease Management; Disease Progression; Drug Therapy, Combination; Evidence-Based Medicine; Fumarates; Hematopoietic Stem Cell Transplantation; Humans; Hydroxybutyrates; Immunoglobulin G; Immunosuppressive Agents; Interferon-beta; Magnetic Resonance Imaging; Multiple Sclerosis; New Zealand; Nitriles; Quinolones; Randomized Controlled Trials as Topic; Therapies, Investigational; Toluidines; Transplantation, Autologous; Treatment Outcome

Treatments for multiple sclerosis (MS) have changed over the past years as our understanding of immunology and neuroscience has evolved. Experimental autoimmune encephalomyelitis (EAE) continues to remain the major model for MS and has been a major vehicle in the development of new therapeutic targets for MS, including new agents such as natalizumab, fingolimod, and dimethyl fumarate. As progress in the molecular understanding of immunology continues, many observations in EAE are pursued with the ultimate goal of defining the pathophysiology of MS and development of innovative treatments for the disease. Although many consider MS to be a T cell-mediated autoimmune disease directed against myelin antigens, the exact cause of the disease is still unknown. For many years, it was thought that myelin-specific T cells that secreted interferon-γ and were proinflammatory were the major T cell subset that mediated the disease, but recent studies on the cytokine phenotype of pathogenic T cells in EAE and MS have opened debate on this issue. Work over the past several years suggests that the transcription factor T-bet appears to be an important factor in T cell encephalitogenicity; however, recent data suggest that it is also dispensable in certain situations, particularly for Th17 cells. Understanding the molecular mechanisms responsible for T cell encephalitogenicity in MS and other autoimmune diseases will be essential in the development of specific therapies for these inflammatory diseases.

Topics: Animals; Antibodies, Monoclonal, Humanized; Dimethyl Fumarate; Drug Discovery; Encephalomyelitis, Autoimmune, Experimental; Fingolimod Hydrochloride; Fumarates; Humans; Immunotherapy; Molecular Targeted Therapy; Multiple Sclerosis; Natalizumab; Propylene Glycols; Sphingosine; T-Box Domain Proteins; Th17 Cells

The development of new disease-modifying drugs (DMD) in relapsing-remitting multiple sclerosis (RRMS), which share the common denominator of oral administration, considerably improves patient expectations in terms of effectiveness, tolerability and treatment adherence compared with currently available drugs. However, the common route of administration of these drugs does not mean that they are equivalent, since the heading of "oral route" encompasses drugs with distinct indications and mechanisms of action, as well as heterogeneous results in terms of efficacy and safety, allowing treatment to be personalized according to the each patient' s characteristics. Currently, four oral DMD are available or in an advanced stage of clinical development: fingolimod, teriflunomide, dimethyl fumarate and laquinimod. In pivotal trials versus placebo, these molecules reduced the annualized rate of exacerbations versus placebo by 54%, 31%, 53% and 23%, respectively, the risk of progression of disability by 31%, 30%, 38% and 36%, and the number of active lesions showing contrast uptake on magnetic resonance imaging by 82%, 80%, 90% and 37%, respectively. Based on the risk/benefit ratio, fingolimod is indicated in patients with suboptimal response to initial DMD or in severe rapidly progressing RRMS, while the remaining drugs can be used as first-line options. Clinical experience with these treatments will provide new data on safety and effectiveness, which will be determinant when establishing therapeutic algorithms.

Topics: Administration, Oral; Crotonates; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines

Dimethyl fumarate (DMF) has been used as fungicide, but oral DMF activates anti-inflammatory and anti-oxidative pathways that are beneficial in the treatment of psoriasis. BG-12, a specific formulation of DMF, has been approved very recently for the treatment of relapsing-remitting multiple sclerosis (RRMS), which is characterized by both autoimmune lymphocytes leading to inflammation and mitochondrial alterations associated with oxidative stress.. This review describes the pharmacokinetics and the mode of action of DMF, with a focus on molecular and cellular pathways, and discusses clinical results of DMF in RRMS treatment. To identify relevant publications, the author searched the PubMed database by using appropriate keywords and by searching for references cited within the obtained articles.. DMF demonstrated efficacy in several RRMS outcome measures related to disease activity and severity, but results on disability progression have been inconsistent. The overall safety profile might qualify DMF for long-term use, the frequency of side effects such as gastrointestinal complaints and flushing might hamper treatment adherence of MS patients. Since DMF covalently binds to intracellular proteins, the fate of this molecule in the body might need thorough long-term observation during clinical use.

Topics: Animals; Antioxidants; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis; Psoriasis; Treatment Outcome

Dimethyl fumarate (DMF) is an orally administered agent that has been used for over 40 years for the treatment of psoriasis. Recent work demonstrates both DMF immunomodulatory and neuroprotective actions in vitro and in animal models of autoreactive central nervous system inflammation and neurodegeneration. DMF acts through chemical modification of the repressor protein Keap1, allowing stabilization and nuclear translocation of the transcription factor Nrf2, with subsequent downstream activation of a cascade of several cytoprotective and antioxidant pathways. Additionally, suppression of transcription factor NF-κB-mediated proinflammatory signaling results in the inhibition of proinflammatory responses and induction of anti-inflammatory cytokines. BG-12 is an orally administered, enteric-coated microtablet preparation of DMF. In two phase III, relapsing-remitting multiple sclerosis (MS) trials, BG-12 led to a 44 to 53% reduction in annualized relapse rate and a 71 to 85% reduction in new T2 lesions on magnetic resonance imaging. The most common side effects of BG-12 are cutaneous flushing and gastrointestinal symptoms, with the highest incidence in the first month after starting treatment. No serious safety signals were seen during the phase II and III trials, including no increased risk of opportunistic infections or cancer. Altogether, BG-12's novel mechanism of action appears to provide a favorable balance of efficacy, safety, and tolerability for treatment of relapsing MS.

Topics: Animals; Anti-Inflammatory Agents; Central Nervous System; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis; Signal Transduction

Multiple sclerosis (MS) is a chronic, multifactorial disease of the central nervous system (CNS), typified by repetitive relapses and/or progression. The conventional treatment options in MS are limited. However, recently several new drugs have been introduced. Oxidative stress is a crucial factor in MS pathogenesis by ameliorating leukocyte migration, contributing to oligodendrocyte damage and axonal injury. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are created in CNS of MS patients mainly by activated macrophages and microglia structures responsible for demyelinisation and axons disruption. Activated microglia secretes different inflammatory and oxidative stress mediators such as cytokines (TNF and IL- 1b and IL- 6) and chemokines (macrophage inflammatory protein MIP- 1a, monocyte chemoattractant protein, MCP- 1 and interferon (IFN) inducible protein IP- 10). The inflammatory state is promoted by that. MS in chronic stages is dominated by neurogenerative processes involving axon and neuron loss probably resulting from oxidative stress and excitotoxicity. Therefore, consideration of the treatment engaging antioxidants and diet supplementation is needed. The present review describes the antioxidative system in CNS and possible antioxidative therapies in MS. Although some exogenous compounds have been proposed as such approach to MS treatment, there is a strong need for further research in this field. Such investigation is required for better understanding of the potential of protective effects of antioxidants in cellular immunology of MS neurodegeneration. Not only would that increase our knowledge about the disease mechanisms but also could help to establish new goals for innovative treatment methods and provide real therapeutic benefits in MS.

Topics: Antioxidants; Central Nervous System; Cytokines; Fumarates; Glatiramer Acetate; Humans; Multiple Sclerosis; Oxidative Stress; Peptides; Superoxide Dismutase

Dimethyl fumarate is an orally available treatment option for relapsing-remitting multiple sclerosis (MS) in a new formulation with improved gastroenteric coating. The mode of action comprises immunomodulatory effects and an activation of nuclear (erythroid-derived 2) related factor mediated antioxidative response pathways leading to additional cytoprotective effects. In two pivotal phase III trials, dimethyl fumarate, 240 mg twice daily, reduced relapse rates by about 50 % as compared with placebo. In the DEFINE trial, progression of disability was also significantly reduced. Both trials demonstrated a significant reduction of gadolinium-enhanced lesions as well as T2 lesions on cranial MRI. The studies revealed a beneficial safety profile of dimethyl fumarate. The most prevalent side effects were transient flushing and gastrointestinal tract irritation. Dimethyl fumarate has recently been approved in the USA for the treatment of relapsing-remitting MS. The compound is a welcome addition to the immunomodulatory treatment armamentarium for MS patients and physicians alike.

Topics: Animals; Clinical Trials as Topic; Dimethyl Fumarate; Fumarates; Gastrointestinal Diseases; Humans; Immunosuppressive Agents; Multiple Sclerosis; Treatment Outcome

To describe the clinical evidence supporting the safety, efficacy, and clinical utility of oral dimethyl fumarate for the treatment of multiple sclerosis (MS).. A comprehensive PubMed search was conducted in July 2013 using the search terms dimethyl fumarate and Tecfidera. Reference lists of abstracted publications were reviewed to identify relevant works that were not retrieved via the electronic search. Additional information was obtained from the FDA Web site, manufacturer prescribing information, and Clinicaltrials.gov.. Clinical trials and review articles that included the use of dimethyl fumarate in the treatment of MS and were available in English were abstracted for review.. The safety and efficacy of dimethyl fumarate for the treatment of relapsing remitting MS was confirmed in 2 phase III trials, DEFINE and CONFIRM. Relative to placebo, twice-daily dimethyl fumarate was found to reduce the proportion of patients with relapses at 2 years by 34% to 49% and the annualized relapse rate by 44% to 53%. Although the incidence of serious adverse effects did not differ from that of placebo, intolerable flushing and gastrointestinal adverse effects prompted discontinuation in 3% and 4% of patients, respectively.. In March 2013, dimethyl fumarate was approved as a third oral option for patients with relapsing forms of MS. Although no head-to-head trials have been conducted, a comparison of data from phase III trials suggests that the efficacy of dimethyl fumarate is comparable to that of existing oral agents and may offer a preferable safety profile.

Topics: Administration, Oral; Dimethyl Fumarate; Drug Interactions; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis; Treatment Outcome

Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system considered the second cause of disability in young adults. The prognosis of MS has improved significantly since the approval of the first interferon β in 1993 but, compared to other diseases, few new therapeutic products have been commercialized in the last years. However, currently, there are more than 600 ongoing clinical trials and new drugs that aim to improve efficacy and a more convenient schedule of administration, will appear shortly on the market. On the other hand, new safety issues will arise as well as a significant economic impact on the health system. The main efficacy and safety results of these drugs are reviewed in this paper. They can be classified into 2 groups: oral (fingolimod, laquinimod, teriflunomide, BG-12 [dimethyl fumarate], oral cladribine, dalfampridine) and monoclonal antibodies (rituximab, ocrelizumab, ofatumumab, daclizumab, alemtuzumab).

Topics: 4-Aminopyridine; Administration, Oral; Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Cladribine; Clinical Trials as Topic; Crotonates; Daclizumab; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunoglobulin G; Immunosuppressive Agents; Middle Aged; Multicenter Studies as Topic; Multiple Sclerosis; Nitriles; Propylene Glycols; Quinolones; Rituximab; Sphingosine; Toluidines; Young Adult

2012 witnessed important developments for multiple sclerosis, including successful phase III trials of novel oral therapeutics and identification of the potassium channel KIR4.1 as an autoimmune target. Additionally, the lung was highlighted as an important site for immune-cell programming, and the relevance of a TNF receptor variant was clarified.

Topics: Clinical Trials as Topic; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Potassium Channels, Inwardly Rectifying; Quinolones; Receptors, Tumor Necrosis Factor, Type I; T-Lymphocytes

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

Topics: Dermatologic Agents; Dimethyl Fumarate; Fumarates; Granuloma Annulare; HIV Infections; Humans; Immunosuppressive Agents; Multiple Sclerosis; Necrobiosis Lipoidica; Neoplasms; Off-Label Use; Sarcoidosis

Several disease-modifying therapies are approved for the management of multiple sclerosis (MS). While reasonably effective, these therapies require long-term parenteral self-injection, which is inconvenient for some patients and can be associated with injection-related adverse effects. Consequently, there is a need in MS for an oral therapy option. Currently, five oral therapies are in phase III development or have recently been approved for the treatment of relapsing-remitting MS: cladribine (approved in Russia and Australia), fingolimod (approved in the US and Russia), BG-12 (phase III), laquinimod (phase III) and teriflunomide (phase III). While the availability of oral therapies has been much anticipated by physicians and patients, neurologists will need to be cautious in selecting such therapy, which may appear to have efficacy and convenience advantages versus current therapies, but may also carry novel safety and tolerability concerns. The decision to use these new therapies will most likely be based on an overall assessment of efficacy, safety, tolerability and adherence, the potential need for monitoring and cost effectiveness. The objective of this article is to review the currently available data for each of these new oral therapies, which addresses the mechanism of action, efficacy and safety, and to provide a perspective on the potential future role of these therapies within clinical practice. Although better patient compliance is expected with the oral agents compared with the injectables, the safety profiles of these new oral drugs will have to be watched carefully.

Topics: Administration, Oral; Cladribine; Clinical Trials, Phase III as Topic; Crotonates; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Multiple Sclerosis; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system and the most common cause of neurological disability in young adults, along with a considerable clinical and pathological heterogeneity. Since, current therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive phase of this disease, thus novel promising therapeutic strategies might open a light horizon in approaching to an efficient treatment in MS. In this review, we will discuss about relevant patents and novel designed immunosuppressive and anti-inflammatory oral drugs promising for treatment of multiple sclerosis.

Topics: Administration, Oral; Cladribine; Crotonates; Diterpenes; Epoxy Compounds; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Multiple Sclerosis; Nitriles; Patents as Topic; Phenanthrenes; Propylene Glycols; Quinolones; Sphingosine; Toluidines

Multiple sclerosis (MS) is an autoimmune and degenerative disorder. In the past decades, the introduction of parenteral immunomodulatory therapies brought significant progress. These agents increase the number of relapses (shubs) by about 30%, and some of them has been shown to halter the accumulation of neurological symptoms and the development of disability. As first-line agents, interferon beta and glatiramer acetate (consisting of amino acids) can be used. Some new therapeutic strategies have been developed as a result of biotechnological development. The advantage of humanised monoclonal antibodies is that they affect the autoimmune inflammatory process more selectively. Among monoclonal antibodies, natalizumab, which binds to alpha-4-beta-1 integrin receptors and inhibits the migration of T-lymphocytes into the central nervous system, is available from February 2010 in Hungary, recommended as second-line treatment. The efficacy of natalizumab in decreasing relapse rate is > 60%. However, its use is associated with progressive multifocal leukoencephalopathy (PML) in one out of 1000 treated patient. Currently it is recommended as second-line treatment, if the patient has active disease despite immunomodulatory therapy. Among orally administered agents, a preparation containing fingolimod is expected to become available next year, and another pill, cladribin has been also found to be efficient in randomised, controlled phase III trials. Fingolimod acts on sphingosine 1-phosphate receptors-1 (S1P1). Cladribine is a purine nucleotide analogue, and its efficacy is based on long-term reduction of CD4+ and CD8+ lymphocytes. Further promising oral immunomodulatory agents are laquinimod and BG000012 (dimethylfumarate), which are currently being tested in phase III clinical trials in relapsing-remitting MS. The most efficient treatment should be chosen on the basis of the activity, aetiology and the posited pathomechanism of the disease. With the increasing number of therapeutic options, choosing the treatment that is optimal for the patient while also considering side effects might be challenging for both the patients and physicians.

Topics: Administration, Oral; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cladribine; Dimethyl Fumarate; Drug Administration Schedule; Fingolimod Hydrochloride; Fumarates; Glatiramer Acetate; Humans; Immunosuppressive Agents; Interferon-beta; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Peptides; Propylene Glycols; Quinolones; Sphingosine; Treatment Outcome

The current treatments for multiple sclerosis (MS) are, by many measures, not satisfactory. The original interferon-β therapies were not necessarily based on an extensive knowledge of the pathophysiological mechanisms of the disease. As more and more insight has been acquired about the autoimmune mechanisms of MS and, in particular, the molecular targets involved, several treatment approaches have emerged. In this chapter, we highlight both promising preclinical approaches and therapies in late stage clinical trials that have been developed as a result of the improved understanding of the molecular pathophysiology of MS. These clinical stage therapies include oral agents, monoclonal antibodies, and antigen-specific therapies. Particular emphasis is given to the molecular targets when known and any safety concerns that have arisen because, despite the need for improved efficacy, MS remains a disease in which the safety of any agent remains of paramount importance.

Topics: Alemtuzumab; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Cladribine; Crotonates; Daclizumab; Dimethyl Fumarate; Encephalomyelitis, Autoimmune, Experimental; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunoglobulin G; Immunosuppressive Agents; Immunotherapy; Mice; Multiple Sclerosis; Myelin Basic Protein; Nitriles; Peptide Fragments; Propylene Glycols; Quinolones; Rituximab; Sphingosine; Toluidines; Vaccines, DNA

One of the disadvantages of currently available disease-modifying drugs (DMDs) for multiple sclerosis (MS) is their parenteral administration. Moreover, efficacy is only partial. Most patients treated with first-line DMDs do not remain relapse-free. There is a need for new oral drugs that are more effective than currently available compounds. Innovative oral drugs with new mechanisms of action showed promising results in clinical trials. One of these emerging drugs is BG00012 (BG-12), a fumaric acid ester (FAE). Its active agent, dimethyl fumarate had first been included in FAE treatments for psoriasis.. Results that highlight the potential role of BG-12 in MS treatment. We focus on findings of experimental studies and current results of clinical studies with FAE in MS.. An overview of the immunomodulatory and neuroprotective effects of FAE, their effect in animal models of MS and their short-term efficacy and safety profile in a Phase IIb clinical trial.. BG-12 is a promising emerging treatment for relapsing-remitting MS, combining anti-inflammatory and possibly clinically relevant neuroprotective effects with the convenience of oral administration. However, the future role of BG-12 in treatment of MS will have to be determined after the completion of ongoing Phase III studies.

Topics: Animals; Clinical Trials as Topic; Dimethyl Fumarate; Fumarates; Fumaria; Humans; Immunosuppressive Agents; Multiple Sclerosis

Disease-modifying treatments are now available in relapsing-remitting and secondary progressive multiple sclerosis (MS), and their beneficial effects have been shown in several clinical studies. However, as these treatments are only partially effective in halting the MS disease process and are frequently associated with side effects and suboptimal patient adherence, new oral therapeutic approaches are warranted. This review focuses on advances in current and novel oral treatment approaches for MS. Several pivotal reports have provided promising results for new oral therapies evaluating the safety and efficacy of new agents including fingolimod, fumaric acid, cladribine, teriflunomide and laquinimod.

Topics: Cladribine; Clinical Trials, Phase III as Topic; Crotonates; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunosuppressive Agents; Multiple Sclerosis; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines

The US Food and Drug Administration (FDA) has approved several new drugs in the past 2 years. This article provides an overview of some of the newer drugs that are likely to find wider use in the future. The drugs reviewed in this article can be used to treat cardiovascular system problems, diabetes mellitus, multiple sclerosis, hepatitis B infection, hyponatremia, Parkinson's disease, rheumatoid arthritis, pain, constipation, and insomnia. Another drug discussed can be used to help a patient stop smoking. The article also discusses Gardasil, the recombinant vaccine against human papilloma virus (types 6, 11, 16, and 18).

Topics: Abatacept; Acetanilides; Amides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antiparkinson Agents; Antirheumatic Agents; Antiviral Agents; Apomorphine; Benzazepines; Cardiovascular Agents; Fumarates; Hepatitis B; Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18; Humans; Hypoglycemic Agents; Immunoconjugates; Multiple Sclerosis; Natalizumab; Nucleosides; Papillomavirus Vaccines; Pharmacology, Clinical; Piperazines; Pyrazines; Pyrimidinones; Quinoxalines; Ranolazine; Sitagliptin Phosphate; Smoking Cessation; Telbivudine; Thymidine; Triazoles; Varenicline; Viral Vaccines

The recent years have witnessed great efforts in establishing new therapeutic options for multiple sclerosis (MS). There is a clear need for more effective, safe and at the same time orally available treatment options. Here we review the potential of fumaric acid esters (FAE) as a new therapeutic option for MS. FAE have been claimed to possess immunomodulatory properties and are already in clinical use as second-line therapy for severe systemic psoriasis. They also displayed beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model mimicking many aspects of MS. In addition, FAE may also act on the blood-brain barrier and exert neuroprotective properties via activation of anti-oxidative pathways. A first magnetic resonance imaging (MRI) based Phase II study in relapsing-remitting MS (RRMS) revealed a dose-dependent, significant reduction of brain lesion activity for BG-12, a dimethyl FAE compound. Currently, two multicentre, Phase III studies for testing clinical efficacy in RRMS are initiated. In view of their profile, FAE compounds may have the potential to add to our therapeutic options in RRMS in the future.

Topics: Fumarates; Humans; Multiple Sclerosis

Therapy for multiple sclerosis (MS) has changed dramatically over the past decade, yielding significant progress in the treatment of relapsing/remitting and secondary progressive MS. Disease-modifying treatments are now widely available, and their beneficial effects on relapse rates, MRI outcomes and, in some cases, relapse-related disability have been shown in several clinical studies. However, as these treatments are only partially effective in halting the MS disease process and in clinical practice are frequently associated with injection-related side effects and suboptimal patient adherence, new oral therapeutic approaches are warranted.. The aim of the present paper is to present new promising results from emerging oral drugs for multiple sclerosis.. This review focuses on advances in current and novel oral treatment approaches for MS. Nevertheless, most of the data were obtained from Phase I/II clinical trials, we need further confirmation of their safety and efficacy profile from longer Phase III clinical trials.. Several pivotal reports have provided promising results for new oral therapies evaluating the safety and efficacy of new agents including fingolimod, fumaric acid, cladribine, teriflunomide and laquinomid.. It is unknown whether these oral drugs could be used as first-line treatment for MS; this will depend mostly on their safety profile. Alternatively, these drugs could be used as add-on treatment for failed first-line therapy, or as an effective induction agent.

Topics: Administration, Oral; Cladribine; Crotonates; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunosuppressive Agents; Multiple Sclerosis; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines

All licensed disease-modifying drugs for the treatment of relapsing-remitting multiple sclerosis (MS) only display partial efficacy and hitherto require parenteral administration. Thus, there is a high demand for innovative and at the same time orally available MS therapeutics. Fumaric acids and their esters (FAE) may represent such a new class of compounds. FAE display immunomodulatory properties and may also exert neuroprotective effects, as shown in vitro as well as in experimental models of MS. A first Phase II study with the new, modified FAE BG00012/FAG-201 (BG-12) in relapsing-remitting MS revealed significant effects on MRI parameters such as gadolinium-enhancing lesions, T1 hypointense lesions and T2 lesion load after 24 weeks of treatment. The trial also underlined the safety and good tolerability of FAE that are already in clinical use for the systemic treatment of severe psoriasis. Presently, two Phase III studies are ongoing to investigate the clinical long-term efficacy of BG-12. In summary, FAE are potential candidates that may open a new therapeutic option for relapsing-remitting MS in the near future.

Topics: Animals; Clinical Trials as Topic; Esters; Fumarates; Humans; Multiple Sclerosis

In 1993, interferon beta-1b, the first clinically proven disease-modifying agent for multiple sclerosis, was approved, with several comparable agents following close behind. These agents have been beneficial in reducing relapse events and MRI lesions, but all require parenteral administration, leading some otherwise eligible patients to decline such therapies. Oral agents have been studied for decades with mixed results, but a small number of medications currently being tested in phase II/III clinical trials have shown promise in efficacy and tolerability. This review assesses the results of the more thoroughly studied of these agents, some of which may soon be approved for use in multiple sclerosis.

Topics: Administration, Oral; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Cladribine; Clinical Trials as Topic; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Interferon beta-1b; Interferon-beta; Isoxazoles; Leflunomide; Minocycline; Multiple Sclerosis; Mycophenolic Acid; Propylene Glycols; Pyridones; Quinolones; Sphingosine

Fumapharm AG has developed a second-generation fumarate (fumaric acid) derivative, BG 12 [BG 00012, FAG-201, BG 12/Oral Fumarate], for the oral treatment of psoriasis. Biogen Idec is currently evaluating the product in clinical trials as an oral treatment for multiple sclerosis (phase II) and psoriasis (phase III) trials.BG 12 has an immunomodulatory mechanism of action. It seems that this product has been developed to reduce the adverse effects associated with a first-generation product containing fumaric acid esters (mixed dimethylfumarate and monoethylfumarate salts), Fumaderm. Fumaderm was approved in Germany in August 1994 and is currently the leading oral systemic therapy for moderate-to-severe psoriasis in Germany. One of the problems associated with Fumaderm capsules has been its gastrointestinal adverse effects (including diarrhoea and nausea). In September 2003, Biogen (now Biogen Idec) licensed exclusive worldwide rights (excluding Germany) from Fumapharm to develop and market BG 12. Biogen plans to collaborate with Fumapharm to accelerate phase III development for psoriasis and the registration programme worldwide. Financial terms of the agreement were not disclosed. Development plans for BG 12 include other autoimmune and inflammatory disorders, such as multiple sclerosis. In November 2003, Biogen and IDEC Pharmaceuticals merged to form Biogen Idec. Fumapharm completed phase II trials of this second-generation fumarate derivative for psoriasis prior to licensing of the product to Biogen, also with positive results.

Topics: Clinical Trials as Topic; Dimethyl Fumarate; Drugs, Investigational; Fumarates; Humans; Immunologic Factors; Multiple Sclerosis; Psoriasis

We measured changes in brain magnetization transfer ratio (MTR) as a potential indicator of myelin density in brain tissue of patients with relapsing-remitting multiple sclerosis (RRMS) treated with delayed-release dimethyl fumarate (DMF) in the Phase 3 DEFINE study. DEFINE was a randomized, double-blind, placebo-controlled study in which patients with RRMS were randomized 1:1:1 to 2 years of treatment with delayed-release DMF 240 mg twice daily (BID) or three times daily (TID) or placebo. MTR was analyzed in whole brain and normal-appearing brain tissue (NABT) at baseline, week 24, 1 year, and 2 years in a subset of patients. MTR data from 392 patients were analyzed. Mean percentage reduction from baseline to 2 years in median whole brain MTR was -0.386% in the placebo group vs increases of 0.129% (p = 0.0027) and 0.096% (p = 0.0051) in the delayed-release DMF BID and TID groups, respectively. Similarly, mean percentage reduction from baseline in median NABT MTR was -0.392% with placebo vs increases of 0.190% (p = 0.0006) and 0.115% (p = 0.0029) with delayed-release DMF BID and TID, respectively. Post hoc analysis of data from patients with no new or enlarging T2 lesions (n = 147), or who experienced no relapses (n = 238), yielded similar results. In this analysis, increases in MTR in brain tissue most likely reflect increases in myelin density in response to delayed-release DMF. These data in patients with RRMS are consistent with preclinical studies that indicate a potential for cytoprotection and remyelination with delayed-release DMF treatment.

Topics: Adolescent; Adult; Brain; Delayed-Action Preparations; Dimethyl Fumarate; Double-Blind Method; Female; Fumarates; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Placebos; Treatment Outcome; Young Adult

BG-12, an immunomodulatory agent, reduces frequency of new gadolinium-enhancing (Gd+) lesions in relapsing multiple sclerosis (MS). This study reports the effect of 240 mg BG-12 orally three times daily (tid) for 24 weeks on the evolution of new Gd+ lesions to T1-hypointense lesions. Brain magnetic resonance imaging (MRI) scans from patients in placebo and 240 mg BG-12 tid arms of a phase 2b study were examined retrospectively. Included patients had at least one new Gd+ lesion from weeks 4 to 12. Week 24 scans were analyzed for number and proportion of new Gd+ lesions that evolved to T1-hypointense lesions. Eighteen patients receiving BG-12 and 38 patients receiving placebo were included in the analysis. The analysis tracked 147 new Gd+ lesions in patients from the BG-12 group and 221 Gd+ lesions in patients from the placebo group. The percentage of Gd+ lesions that evolved to T1-hypointense lesions was 34% lower with BG-12 treatment versus placebo (29%, BG-12; 44%, placebo; odds ratio 0.51; 95% confidence interval 0.43, 0.61; p < 0.0001). In addition to reducing frequency of new Gd+ lesions, BG-12 significantly reduced probability of their evolution to T1-hypointense lesions in patients with MS compared with placebo.

Topics: Adolescent; Adult; Dimethyl Fumarate; Double-Blind Method; Female; Fumarates; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Retrospective Studies; Young Adult

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.

Topics: Administration, Oral; Adult; Apoptosis; Cytokines; Dimethyl Fumarate; Disability Evaluation; Electroencephalography; Female; Follow-Up Studies; Fumarates; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Pilot Projects; Prospective Studies; Statistics, Nonparametric; T-Lymphocytes; Time Factors

Attenuation in post-vaccination SARS-CoV-2 humoral responses has been demonstrated in people treated with either anti-CD20 therapies or sphingosine-1-phosphate (S1P) receptor modulators. In the setting of disease modifying therapy (DMT) use, humoral response may not correlate with effective immunity, and analysis of vaccine-mediated SARS-CoV-2-specific memory T-cell responses is crucial. While vaccination in patients treated with anti-CD20 agents leads to deficient antibody production, emerging data from live cell assays suggests intact T-cell responses to vaccination. We evaluated post-vaccination SARS-CoV-2 T-cell receptor (TCR) repertoires in DMT-treated patients using the ImmunoSeq. Adults 18-80 years old without prior COVID-19, with neuroimmune conditions, who had been vaccinated with two doses of Pfizer-BioNTech or Moderna mRNA vaccines at least 3 weeks and up to 6 months prior, were recruited. Whole blood was obtained for immunosequencing, and matched serum was obtained for humoral analysis. Immunosequencing of the CDR3 regions of human TCRβ chains was completed using the immunoSEQR Assay (Adaptive Biotechnologies). TCR sequences were mapped across a set of TCR sequences reactive to SARS-CoV-2. Clonal diversity (breadth) and frequency (depth) of TCRs specific to SARS-CoV-2 spike protein were calculated and relationships with clinical variables were assessed.. Forty patients were recruited into the study, aged 25-77, and 27 female. 37 had MS, 2 had neuromyelitis optica spectrum disorder (NMOSD), and 1 had hypophysitis. Subjects treated with anti-CD20 agents and S1P receptor modulators had severely attenuated humoral responses, but SARS-CoV-2-spike-specific TCR clonal depth and breadth were robust across all treatment classes except S1P modulators. No spike-specific or non-spike-specific SARS-CoV-2-associated TCRs were found in those treated with S1P modulators (p = 0.002 for both breadth and depth). Subjects treated with fumarates exhibited somewhat lower spike TCR breadth than subjects treated with other or no DMTs (median 2.27 × 10^-5 for fumarates and 4.96 × 10^-5 for all others, p = 0.008), but no statistically significant difference was demonstrated with spike TCR depth. No other significant associations with DMT type were found. We found no significant correlations between depth or breadth and age, duration of treatment, type of vaccination, or time interval since vaccination.. This is the first study to characterize post-vaccination SARS-CoV-2 TCR repertoires in DMT-treated individuals. We demonstrated a dichotomous response to SARS-CoV-2 vaccination in anti-CD20-treated patients, with severely attenuated humoral response but intact TCR depth and breadth. It is unclear to what degree each arm of the adaptive immune system impacts post-vaccine immunity, both from the standpoint of incidence of post-vaccine infections and that of infection severity, and further clinical studies are necessary. S1P modulator-treated subjects exhibited both severely attenuated humoral responses and absent spike-specific TCR depth and breadth, information which is crucial for counseling of patients on these agents. Our methodology can be used in larger studies to determine the benefit of repeated vaccination doses, including those that are modified to better target modern or seasonal variants, without the use of live cell assays.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Viral; COVID-19; COVID-19 Vaccines; Female; Fumarates; Humans; Middle Aged; Multiple Sclerosis; Receptors, Antigen, T-Cell; SARS-CoV-2; Vaccination; Young Adult

Dimethyl fumarate is an ester from the Krebs cycle intermediate fumarate. This drug is approved and currently used for the treatment of psoriasis and multiple sclerosis, and its anti-angiogenic activity was reported some years ago. Due to the current clinical relevance of this compound and the recently manifested importance of endothelial cell metabolism on the angiogenic switch, we wanted to elucidate whether dimethyl fumarate has an effect on energetic metabolism of endothelial cells. Different experimental approximations were performed in endothelial cells, including proteomics, isotope tracing and metabolomics experimental approaches, in this work we studied the possible role of dimethyl fumarate in endothelial cell energetic metabolism. We demonstrate for the first time that dimethyl fumarate promotes glycolysis and diminishes cell respiration in endothelial cells, which could be a consequence of a down-regulation of serine and glycine synthesis through inhibition of PHGDH activity in these cells. Dimethyl fumarate alters the energetic metabolism of endothelial cells in vitro and in vivo through an unknown mechanism, which could be the cause or the consequence of its pharmacological activity. This new discovery on the targets of this compound could open a new field of study regarding the mechanism of action of dimethyl fumarate.

Topics: Dimethyl Fumarate; Down-Regulation; Endothelial Cells; Fumarates; Humans; Multiple Sclerosis

The NLRP3 inflammasome is a multiprotein complex that regulates caspase-1 activation and subsequent interleukin (IL)-1β and IL-18 release from innate immune cells in response to infection or injury. Derivatives of the metabolites itaconate and fumarate, dimethyl itaconate (DMI), 4-octyl itaconate (4OI) and dimethyl fumarate (DMF) limit both expression and release of IL-1β following NLRP3 inflammasome activation. However, the direct effects of these metabolite derivatives on NLRP3 inflammasome responses require further investigation. Using murine bone marrow-derived macrophages, mixed glia and organotypic hippocampal slice cultures (OHSCs), we demonstrate that DMI, 4OI and DMF pretreatments inhibit pro-inflammatory cytokine production in response to lipopolysaccharide (LPS), as well as inhibit subsequent NLRP3 inflammasome activation induced by nigericin. DMI, 4OI, DMF and monomethyl fumarate (MMF), another fumarate derivative, also directly inhibited biochemical markers of NLRP3 activation in LPS-primed macrophages, mixed glia, OHSCs and human macrophages in response to nigericin and imiquimod, including ASC speck formation, caspase-1 activation, gasdermin D cleavage and IL-1β release. DMF, an approved treatment of multiple sclerosis, as well as DMI, 4OI and MMF, inhibited NLRP3 activation in macrophages in response to lysophosphatidylcholine, which is used to induce demyelination, suggesting a possible mechanism for DMF in multiple sclerosis through NLRP3 inhibition. The derivatives also reduced pro-IL-1α cleavage in response to the calcium ionophore ionomycin. Together, these findings reveal the immunometabolic regulation of both the priming and activation steps of NLRP3 activation in macrophages. Furthermore, we highlight itaconate and fumarate derivatives as potential therapeutic options in NLRP3- and IL-1α-driven diseases, including in the brain.

Topics: Animals; Caspase 1; Caspases; Fumarates; Humans; Inflammasomes; Interleukin-1beta; Lipopolysaccharides; Macrophages; Mice; Multiple Sclerosis; Nigericin; NLR Family, Pyrin Domain-Containing 3 Protein; Succinates

Certain disease modifying therapies may negatively impact the humoral response to SARS-CoV-2 vaccines. Many MS related clinical, demographic, and immunological characteristics can also affect vaccine response but those have not been fully explored. This study aimed to investigate potential correlations between clinical, demographic, and immunological variables in MS patients to post-vaccination spike protein antibody positivity rates and levels.. Patients with MS and related neuroimmunological disorders who requested verification of the immune response to the SARS-COV-2 vaccine were tested for the spike protein antibody from January to October 2021. We performed an exploratory analysis to compare patients with positive versus negative spike protein antibody.. Fifty patients (mean age 53 ±12, 78% females) were included. There were 29 patients with positive post-vaccination spike protein antibody (58%) and 21 with negative antibody (42%). Patients with negative antibody were more likely to have been on B-cell therapy (86% vs 31%, P=.001) while positive patients were more likely to have been on a fumarate (31% vs 4.8%, P=.03). Thirty percent of positive patients on fumarate therapy had mild lymphopenia. No differences existed between groups in gender, age, race, disease phenotype, vaccine brand, and lymphocyte counts. Among patients on B-cell therapy, 33% had a positive spike protein antibody. There was an association between detectable CD19 cells at time of vaccination and positive humoral response to vaccination (P=0.049). There was no relationship between subgroups in terms of vaccine timing relative to B-cell therapy dose. Hypogammaglobulinemia was not associated with seroconversion rates, however it was associated with decreased quantitative spike protein antibody levels (p=0.045).. B-cell therapy is associated with a negative humoral response to SARS-COV-2 vaccines. Patients on B-cell depleting therapy with detectable CD19 counts at the time of vaccination were associated with a positive humoral response. There was no relationship between hypogammaglobinemia and seroconversion rate, however it was associated with decreased spike protein antibody levels. The fumarates are associated with positive humoral response even in the presence of mild lymphopenia.

Topics: Antibodies, Viral; COVID-19; COVID-19 Vaccines; Female; Fumarates; Humans; Lymphocyte Count; Lymphopenia; Male; Multiple Sclerosis; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Vaccination

Prior studies suggest reduced humoral response to COVID-19 vaccination in immunosuppressed populations. Disease modifying therapies (DMTs) for multiple sclerosis (MS) have variable immunomodulatory effects, and limited data are available for all DMTs. We aimed to determine the impact of DMTs on antibody response to COVID-19 vaccination among MS patients.. Patients with documented COVID-19 vaccination dates and anti-spike antibody results post-vaccination were identified between March-August 2021. Clinical data were retrospectively abstracted from chart review. Deidentified data were analyzed to evaluate antibody response, and multivariable logistic regression analyses were used to identify clinical and demographic predictors of antibody response. Data analysis was completed with SAS Studio, v3.8.. A total of 353 individuals had documented COVID-19 vaccine and antibody test dates (58% Pfizer, 38% Moderna, and 4% Johnson & Johnson). Of these 353 patients, 72% developed antibodies, with a mean antibody test interval of 53 days (median 46) post final vaccine dose. 100% of those on no DMT (n = 34), injectables (n = 20), teriflunomide (n = 10), natalizumab (n = 71), and 97.8% of those on fumarates (n = 46/47) had a positive antibody result. One patient on cladribine (n = 1) had a negative antibody result. Of those on sphingosine-1 phosphate (S1P) modulators, 72.4% (n = 21/29) had a positive antibody result. Of those on anti-CD20 therapies, 37.6% (n = 53/141) had a positive antibody result. Multivariate modeling of the total cohort showed anti-CD20 therapy was significantly associated with lower odds of positive antibody response (OR = 0.024, 95% CI 0.01;0.05, p < 0.0001). Among S1P modulators, increased duration of therapy, and not lymphopenia, may be associated with lower odds of positive antibody response. Multivariate modeling of anti-CD20 therapies showed therapy duration < 1 year (OR 8.14, 95% CI 2.896;22.898 p < .0001) and prior COVID-19 infection (OR = 3.95, 95% CI 1.137;13.726, p = .03) were significantly associated with higher odds of a positive antibody response. In patients with recent B-cell data, mean B-cell count was higher in antibody-positive individuals compared to antibody-negative (32.9 vs. 3.9 cells, p = .0056).. MS DMTs had variable impact on antibody response with mRNA and viral vector COVID-19 vaccines. All patients on no DMT, interferons, glatiramer acetate, teriflunomide, natalizumab, and nearly all on fumarates had positive antibody responses post-vaccine. S1P modulators and anti-CD20 therapies attenuated antibody response post-vaccine. For patients on anti-CD20 therapies, shorter duration of therapy and prior COVID-19 infection predicted positive antibody response. Further studies are needed to determine clinical significance of antibody testing, development of cellular mediated immunity, and benefits of booster vaccinations.

Topics: Antibodies, Viral; Antibody Formation; COVID-19; COVID-19 Vaccines; Fumarates; Humans; Immunomodulation; Immunosuppressive Agents; Multiple Sclerosis; Natalizumab; Retrospective Studies

Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS). Clinical and real-world studies of DRF have demonstrated improved gastrointestinal (GI) tolerability and low (< 1%) GI-related treatment discontinuation versus dimethyl fumarate (DMF) and high rates of treatment adherence. Our aim was to conduct a concept elicitation study to identify treatment-related concepts most meaningful to patients and to evaluate how these concepts shape the patient perspective of DRF.. In-depth qualitative interviews were conducted with patients from October to December 2020. US adults who had been prescribed DRF through routine clinical care and had taken DRF for ≥ 3 weeks in the past 6 months were eligible to participate. Semi-structured interviews explored patient perceptions on treatment selection and impact.. Seventeen patients participated in the study. Mean (SD) age was 49.3 (12.0) years. Sixteen patients reported prior disease-modifying therapy, while 10 (58.8%) had prior DMF. DRF treatment duration ranged from ~ 6 weeks to 10 months. Four key concepts emerged: (1) overall wellness and quality of life, (2) ease of administration, (3) minimal and manageable side effects, and (4) patient optimism due to MS treatments. Mode of administration (82.4%), no/mild side effects (70.6%), convenience over injectable/infusion medications (58.8%), and effectiveness (64.7%) were cited as positive aspects of DRF treatment. Frequent dosing (52.9%) and food requirements (41.2%) were cited as negative attributes; however, 94.1% had no dietary changes since starting treatment.. The patient perspective is a key aspect when considering a disease-modifying therapy for MS, given the multitude of options currently available. Overall wellness, ease of administration, and minimal and manageable side effects were DRF-related concepts most meaningful to patients on therapy. Acknowledging these patient perceptions in shared decision-making may lead to greater patient adherence and optimal treatment outcomes.. Multiple sclerosis (MS), an immune-related disease, may present with neurological symptoms that come and go. Diroximel fumarate (DRF) is a next-generation oral treatment for MS, which has been shown in clinical trials to have fewer gastrointestinal side effects compared to dimethyl fumarate (DMF), another oral treatment. Patients’ perspective can shed light on what they value when choosing a treatment, so we interviewed 17 people with MS about how DRF treatment affects their daily life and work. The study participants (49.3 years old on average) received DRF for ~ 6 weeks to 10 months. Around 5 in 10 people had positive feelings about their current health following treatment with DRF. Most felt there was either improvement or no negative change in quality of life since starting DRF treatment; DRF did not affect their work or daily obligations. Treatment characteristics of DRF that were perceived as most important included ease of administration, minimal and manageable side effects, and the facilitation of overall wellness and quality of life. While the oral dosing of DRF was more convenient than injectable or infusion therapy options, about half of the respondents preferred a less frequent treatment regimen than the twice daily dosing of DRF which needs to be taken with food. However, those who switched to DRF from DMF (or other oral medications for MS) expressed that the transition was smooth. Understanding factors that are important to patients can guide treatment choices and help patients stay on treatment longer and have better MS outcomes.

Topics: Adult; Dimethyl Fumarate; Drug-Related Side Effects and Adverse Reactions; Fumarates; Humans; Immunosuppressive Agents; Middle Aged; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Qualitative Research; Quality of Life; Recurrence

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

Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing-remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile.. To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study.. EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory.. As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1-98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%;. Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.

Topics: Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting

Cell-permeable formulations of metabolites, such as fumaric acid esters, have been used as highly effective immunomodulators in patients with multiple sclerosis and yet their mechanism of action remains elusive. Since fumaric acid esters are metabolites, and cell metabolism is highly intertwined with the epigenetic regulation of gene expression, we investigated whether this metabolic-epigenetic interplay could be leveraged for therapeutic purposes. To this end we recruited 47 treatment-naïve and 35 fumaric acid ester-treated patients with multiple sclerosis, as well as 16 glatiramer acetate-treated patients as a non-metabolite treatment control. Here we identify a significant immunomodulatory effect of fumaric acid esters on the expression of the brain-homing chemokine receptor CCR6 in CD4 and CD8 T cells of patients with multiple sclerosis, which include T helper-17 and T cytotoxic-17 cells. We report differences in DNA methylation of CD4 T cells isolated from untreated and treated patients with multiple sclerosis, using the Illumina EPIC 850K BeadChip. We first demonstrate that Krebs cycle intermediates, such as fumaric acid esters, have a significantly higher impact on epigenome-wide DNA methylation changes in CD4 T cells compared to amino-acid polymers such as glatiramer acetate. We then define a fumaric acid ester treatment-specific hypermethylation effect on microRNA MIR-21, which is critical for the differentiation of T helper-17 cells. This hypermethylation effect was attributed to the subpopulation of T helper-17 cells using a decomposition analysis and was further validated in an independent prospective cohort of seven patients before and after treatment with fumaric acid esters. In vitro treatment of CD4 and CD8 T cells with fumaric acid esters supported a direct and dose-dependent effect on DNA methylation at the MIR-21 promoter. Finally, the upregulation of miR-21 transcripts and CCR6 expression was inhibited if CD4 or CD8 T cells stimulated under T helper-17 or T cytotoxic-17 polarizing conditions were treated with fumaric acid esters in vitro. These data collectively define a direct link between fumaric acid ester treatment and hypermethylation of the MIR-21 locus in both CD4 and CD8 T cells and suggest that the immunomodulatory effect of fumaric acid esters in multiple sclerosis is at least in part due to the epigenetic regulation of the brain-homing CCR6+ CD4 and CD8 T cells.

Topics: Adult; Brain; CD4-Positive T-Lymphocytes; DNA Methylation; Epigenesis, Genetic; Female; Fumarates; Gene Expression Regulation; Glatiramer Acetate; Humans; Immunologic Factors; Male; MicroRNAs; Middle Aged; Multiple Sclerosis; Prospective Studies; T-Lymphocytes

Multiple Sclerosis (MS) is an autoimmune-neurodegenerative disorder managed therapeutically by modulating lymphocytes activity which has potential in disease management. Prohibitin 1(PHB) that controls the reactive oxygen species (ROS) and present on the activated lymphocytes have significance in the therapy of MS as esters of fumaric acid that regulates ROS is in phase II/III clinical trials. Thus, we evaluated the expression levels of PHB1 in experimental autoimmune encephalomyelitis (EAE), the animal model of MS and on MS patient's lymphocytes. PHB levels in brain tissue of EAE animals were determined by immunoblotting and on blood lymphocytes from MS relapse, Remission, Optic Neuritis, Neurological controls and Healthy volunteers by FACS using anti-PHB and anti-CD45 antibodies. We observed significant elevation of PHB in EAE brains (91.0 ± 17.59%) vs controls (29.8 ± 12.9%) (p = 0.01) and on lymphocytes of MS patients in acute (73.5 ± 11.20%) or relapsing (69.3 ± 17.33%) phase compared to remission (45.9 ± 8.08%) [p = 0.034 acute vs remission; p = 0.004 relapse vs remission]. Up regulation of PHB in relapsing vs remission MS patients imply the potential use of PHB to clinically evaluate subclinical disease status towards prognosis of an oncoming relapse. Elevated PHB levels in EAE brains signify the role of PHB in regulating ROS and implies PHB's role in oxidative stress.

Topics: Adolescent; Adult; Animals; Brain; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Encephalomyelitis, Autoimmune, Experimental; Female; Fumarates; Humans; Lymphocytes; Male; Mice; Middle Aged; Multiple Sclerosis; Prohibitins; Repressor Proteins; Up-Regulation

Fumaric acid has an important role in the citric acid cycle. Its esters were first used by a German chemist to treat his own psoriasis, hypothesizing that the disease may be related to disturbances in this very cycle. Meanwhile, the mechanisms underlying its anti-inflammatory efficacy are much better understood. A monosubstance derived from the mix of esters used originally is now being authorized for treating multiple sclerosis, and in 2017 dimethylfumaric acid ester became a globally available option to treat psoriasis. This very practical therapeutic will most likely become quite popular amongst patients. Therefore, general practitioners might need to familiarize themselves with the profile of this drug, including its potential risks and some very rare but potentially important adverse effects.. L’acide fumarique joue un rôle important dans le cycle de Krebs. Ses esters ont été utilisés pour la première fois par un chimiste allemand pour traiter son propre psoriasis dans l’hypothèse d’une implication du cycle de Krebs. Depuis, les mécanismes anti-inflammatoires des esters d’acide fumarique ont été mieux décrits. Une mono-substance dérivée du mélange d’esters original est désormais autorisée pour traiter la sclérose en plaques. En 2017, le diméthylfumarate a été ainsi reconnu globalement comme une option thérapeutique pour le psoriasis. Très pratique, ce médicament deviendra probablement très populaire chez les patients. Pour cette raison, les médecins généralistes devraient se familiariser avec son profil pharmacologique, y compris ses risques potentiels et certains effets indésirables rares mais potentiellement dangereux.

Topics: Dietary Supplements; Esters; Fumarates; Humans; Multiple Sclerosis; Psoriasis

Reactive oxygen species play a key role in the pathogenesis of multiple sclerosis as they induce blood-brain barrier disruption and enhance transendothelial leukocyte migration. Thus, therapeutic compounds with antioxidant and anti-inflammatory potential could have clinical value in multiple sclerosis. The aim of the current study was to elucidate the therapeutic effects of monomethyl fumarate on inflammatory-mediated changes in blood-brain barrier function and gain insight into the underlying mechanism.. The effects of monomethyl fumarate on monocyte transendothelial migration across and adhesion to inflamed human brain endothelial cells (hCMEC/D3) were quantified using standardized in vitro migration and adhesion assays. Flow cytometry analysis and qPCR were used to measure the concomitant effects of monomethyl fumarate treatment on protein expression of cell adhesion molecules. Furthermore, the effects of monomethyl fumarate on the expression and nuclear localization of proteins involved in the activation of antioxidant and inflammatory pathways in human brain endothelial cells were elucidated using nuclear fractionation and Western blotting. Statistical analysis was performed using one-way ANOVA followed by the Bonferroni post-hoc test.. Our results show that monomethyl fumarate induced nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 and concomitant production of the antioxidant enzymes heme oxygenase-1 and NADPH:quinone oxidoreductase-1 in brain endothelial cells. Importantly, monomethyl fumarate treatment markedly decreased monocyte transendothelial migration across and adhesion to inflamed human brain endothelial cells. Treatment of brain endothelial cells with monomethyl fumarate resulted in a striking reduction of vascular cell adhesion molecule expression. Surprisingly, monomethyl fumarate did not affect nuclear translocation of nuclear factor-кB suggesting that monomethyl fumarate potentially affects activity of nuclear factor-ĸB downstream of nuclear translocation.. Taken together, we show that monomethyl fumarate, the primary metabolite of dimethyl fumarate, which is currently used in the clinics for the treatment of relapsing-remitting multiple sclerosis, demonstrates beneficial therapeutic effects at the inflamed blood-brain barrier.

Topics: Anti-Inflammatory Agents; Antioxidants; Blood-Brain Barrier; Cell Adhesion; Cell Adhesion Molecules; Cells, Cultured; Coculture Techniques; Cytoprotection; Endothelial Cells; Fumarates; Heme Oxygenase-1; Humans; Leukocytes; Maleates; Multiple Sclerosis; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; NF-kappa B; Transendothelial and Transepithelial Migration

Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a transmembrane glycoprotein that is upregulated on leukocytes in active lesions in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Administration of anti-EMMPRIN Abs reduces the severity of EAE. Minocycline is a tetracycline antibiotic with immune-modulatory properties that decreases the severity of EAE; it was recently found to attenuate the conversion from a first demyelinating event to clinically definite MS in a phase III trial. We investigated whether and how minocycline affects the expression of EMMPRIN on T cells in culture and in mice afflicted with EAE. EMMPRIN expression in cultures of mouse splenocytes or human PBMCs was elevated upon polyclonal T cell activation, and this was reduced by minocycline correspondent with decreased P-Akt levels. An established MS medication, IFN-β, also diminished EMMPRIN levels on human cells whereas this was not readily observed for fingolimod or monomethylfumarate. In EAE-afflicted mice, minocycline treatment significantly reduced EMMPRIN levels on splenic lymphocytes at the presymptomatic (day 7) phase, and prevented the development of disease. Day 7 spleen transcripts from minocycline-treated EAE mice had a significantly lower MMP-9/TIMP-1 ratio, and significantly lower MCT-1 and CD98 levels, factors associated with EMMPRIN function. Day 16 (peak clinical severity) CNS samples from EAE mice had prominent representation of inflammatory perivascular cuffs, inflammatory molecules and EMMPRIN, and these were abrogated by minocycline. Overall, minocycline attenuated the activation-induced elevation of EMMPRIN on T cells in culture and in EAE mice, correspondent with reduced immune function and EAE CNS pathology.

Topics: Animals; Anti-Bacterial Agents; Basigin; Central Nervous System; Clinical Trials, Phase III as Topic; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Fingolimod Hydrochloride; Fumarates; Humans; Interferon-beta; Lymphocyte Activation; Maleates; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Minocycline; Monocytes; Multiple Sclerosis; T-Lymphocytes; Tissue Inhibitor of Metalloproteinase-1

Dimethyl fumarate (DMF), a new drug for multiple sclerosis (MS) treatment, acts against neuroinflammation via mechanisms that are triggered by adduct formation with thiol redox switches. Ethyl pyruvate (EP), an off-the-shelf agent, appears to be a redox analog of DMF, but its immunomodulatory properties have not been put into the context of MS therapy. In this article, we examined and compared the effects of EP and DMF on MS-relevant activity/functions of T cells, macrophages, microglia, and astrocytes. EP efficiently suppressed the release of MS signature cytokines, IFN-γ and IL-17, from human PBMCs. Furthermore, the production of these cytokines was notably decreased in encephalitogenic T cells after in vivo application of EP to rats. Production of two other proinflammatory cytokines, IL-6 and TNF, and NO was suppressed by EP in macrophages and microglia. Reactive oxygen species production in macrophages, microglia activation, and the development of Ag-presenting phenotype in microglia and macrophages were constrained by EP. The release of IL-6 was reduced in astrocytes. Finally, EP inhibited the activation of transcription factor NF-κB in microglia and astrocytes. Most of these effects were also found for DMF, implying that EP and DMF share common targets and mechanisms of action. Importantly, EP had in vivo impact on experimental autoimmune encephalomyelitis, an animal model of MS. Treatment with EP resulted in delay and shortening of the first relapse, and lower clinical scores, whereas the second attack was annihilated. Further studies on the possibility to use EP as an MS therapeutic are warranted.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Cell Survival; Cells, Cultured; Cytokines; Dimethyl Fumarate; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Female; Flow Cytometry; Fumarates; Humans; Immunoblotting; Leukocytes, Mononuclear; Lipopolysaccharides; Lymph Nodes; Macrophages; Microglia; Multiple Sclerosis; NF-kappa B; Pyruvates; Rats; Reactive Oxygen Species; Spinal Cord

Topics: Delayed-Action Preparations; Dimethyl Fumarate; Fatal Outcome; Female; Fumarates; Humans; Immunosuppressive Agents; Leukoencephalopathy, Progressive Multifocal; Lymphocyte Count; Lymphopenia; Middle Aged; Multiple Sclerosis; Opportunistic Infections

Dimethyl fumarate (DMF) is approved for disease-modifying treatment of patients with relapsing-remitting multiple sclerosis. Animal experiments suggested that part of its therapeutic effect is due to a reduction of T-cell infiltration of the central nervous system (CNS) by uncertain mechanisms. Here we evaluated whether DMF and its primary metabolite monomethyl fumarate (MMF) modulate pro-inflammatory intracellular signaling and T-cell adhesiveness of nonimmortalized single donor human brain microvascular endothelial cells at low passages. Neither DMF nor MMF at concentrations of 10 or 50 µM blocked the IL-1β-induced nuclear translocation of NF-κB/p65, whereas the higher concentration of DMF inhibited the nuclear entry of p65 in human umbilical vein endothelium cultured in parallel. DMF and MMF also did not alter the IL-1β-stimulated activation of p38 MAPK in brain endothelium. Furthermore, neither DMF nor MMF reduced the basal or IL-1β-inducible expression of ICAM-1. In accordance, both fumaric acid esters did not reduce the adhesion of activated Jurkat T cells to brain endothelium under basal or inflammatory conditions. Therefore, brain endothelial cells probably do not directly mediate a potential blocking effect of fumaric acid esters on the inflammatory infiltration of the CNS by T cells.

Topics: Active Transport, Cell Nucleus; Brain; Cell Adhesion; Cell Line; Dimethyl Fumarate; Endothelium, Vascular; Fumarates; Human Umbilical Vein Endothelial Cells; Humans; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Interleukin-1beta; Maleates; Microvessels; Multiple Sclerosis; T-Lymphocytes; Transcription Factor RelA

Migration of immunocompetent cells into the central nervous system represents a key event in the immunopathogenesis of multiple sclerosis (MS). Fumaric acid esters have recently been approved for patients with MS. Their mode of action is not fully understood so far. We analyzed the effect of monomethylfumarate (MMF), the immediate metabolite of dimethylfumarate, on migration of lymphocytes and macrophages. Peripheral blood mononuclear cells (PBMCs) were isolated from patients with MS and healthy donors. PBMCs were treated with MMF in vitro and their migratory capacity was studied in a Boyden chamber assay. In addition, expression of matrix metalloproteinases (MMPs), chemokine receptors, adhesion molecules, and molecules of the oxidative stress cascade was assessed. MMF decreased the migratory capacity of T lymphocytes, but not of macrophages. Lymphocytes as well as macrophages responded to MMF by the upregulation of oxidative stress molecules; however, no effect was seen on the expression of MMPs, chemokine receptors, and adhesion molecules. There was no difference in comparison with cells from healthy controls. MMF reduces the migratory activity of lymphocytes most likely by changing their activational state. This points to a potential novel mode of action differentiating this drug from other available immunotherapies.

Topics: Adult; Antigens, CD; Cell Movement; Female; Flow Cytometry; Fumarates; Gene Expression Regulation; Glutamate-Cysteine Ligase; Heme Oxygenase-1; Humans; Leukocytes, Mononuclear; Male; Maleates; Multiple Sclerosis; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Signal Transduction; Statistics, Nonparametric; Time Factors

Topics: Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Leg; Male; Middle Aged; Multiple Sclerosis; Venous Thrombosis

Taken orally, the drug dimethyl fumarate (DMF) has been shown to improve functional outcomes for patients with MS; however, it is unclear how DMF mediates a protective effect. DMF and, more so, its active metabolite, monomethyl fumarate, are known agonists of the hydroxycarboxylic acid receptor 2 (HCA₂), a G protein-coupled membrane receptor. Here, we evaluated the contribution of HCA₂ in mediating the protective effect afforded by DMF in EAE, a mouse model of MS. DMF treatment reduced neurological deficit, immune cell infiltration, and demyelination of the spinal cords in wild-type mice, but not in Hca2⁻/⁻ mice, indicating that HCA₂ is required for the therapeutic effect of DMF. In particular, DMF decreased the number of infiltrating neutrophils in a HCA₂-dependent manner, likely by interfering with neutrophil adhesion to endothelial cells and chemotaxis. Together, our data indicate that HCA₂ mediates the therapeutic effects of DMF in EAE. Furthermore, identification of HCA₂ as a molecular target may help to optimize MS therapy.

Topics: Animals; Cell Adhesion; Dimethyl Fumarate; Encephalomyelitis, Autoimmune, Experimental; Female; Fumarates; Humans; Immunosuppressive Agents; Mice; Mice, Knockout; Multiple Sclerosis; Neutrophil Infiltration; Neutrophils; Receptors, G-Protein-Coupled; Receptors, Nicotinic

Topics: Dimethyl Fumarate; Drug Interactions; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis; Secondary Prevention

Dimethyl fumarate received FDA approval in March 2013 for treatment of multiple sclerosis and has had a rapid uptake in the field due in large part to a favorable safety profile. Side effects of dimethyl fumarate include flushing, gastrointestinal discomfort, and peripheral eosinophilia. We report a case of eosinophilic fasciitis-like disorder occurring in the setting of oral dimethyl fumarate therapy. Eosinophilic fasciitis is rare and may be related to the peripheral eosinophilia known to occur with this medication.. We present a case of a 36-year-old male treated with oral dimethyl fumarate for 16 weeks who developed a bilateral eosinophilic fasciitis-like disorder of the thighs. Magnetic resonance imaging revealed a fluid collection in the fascial plane and histopathologic examination revealed an inflammatory infiltrate with dermal and subcutaneous edema and sclerosis consistent with eosinophilic fasciitis. We discuss studies reporting peripheral eosinophilia with fumaric acid medications as well as the literature exploring possible mechanisms.. With the anticipated widespread use of dimethyl fumarate for multiple sclerosis patients, it is important for practitioners to recognize the symptoms of eosinophilic fasciitis and be aware of a possible association of oral dimethyl fumarate treatment with the development of an eosinophilic fasciitis-like disorder.

Topics: Adult; Dimethyl Fumarate; Eosinophilia; Fasciitis; Fumarates; Humans; Immunosuppressive Agents; Male; Multiple Sclerosis

Topics: Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis

Three FDA-approved oral medications are available for the treatment of relapsing forms of multiple sclerosis: fingolimod, teriflunomide, and dimethyl fumarate. While injection and IV treatments have proven to be beneficial, these newer oral agents also offer positive outcomes for patients. Numerous barriers exist, though, for these oral agents, including the unknown long-term efficacy and safety and potential side effects. Despite possible side effects, oral agents provide convenience, ease of use, and the elimination of injection/IV administration-site pain. To ensure MS patients receive the most appropriate individualized care, clinicians should present all of the available treatment options to both newly diagnosed and established patients.

Topics: Administration, Oral; Crotonates; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunosuppressive Agents; Multiple Sclerosis; Nitriles; Propylene Glycols; Sphingosine; Toluidines

Topics: Administration, Oral; Controlled Clinical Trials as Topic; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis

Topics: Clinical Trials, Phase III as Topic; Dimethyl Fumarate; Fumarates; Glatiramer Acetate; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Peptides

Topics: Administration, Oral; Dimethyl Fumarate; Drug Approval; Drug Industry; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis; United States

Topics: Administration, Oral; Crotonates; Dimethyl Fumarate; Fumarates; Humans; Hydroxybutyrates; Immunologic Factors; Immunomodulation; Immunosuppressive Agents; Multiple Sclerosis; Nitriles; Quinolones; Toluidines

Density functional theory (DFT) calculations at B3LYP/6-31 G (d,p) and B3LYP/6-311+G(d,p) levels for the substituted pyridine-catalyzed isomerization of monomethyl maleate revealed that isomerization proceeds via four steps, with the rate-limiting step being proton transfer from the substituted pyridinium ion to the C=C double bond in INT1. In addition, it was found that the isomerization rate (maleate to fumarate) is solvent dependent. Polar solvents, such as water, tend to accelerate the isomerization rate, whereas apolar solvents, such as chloroform, act to slow down the reaction. A linear correlation was obtained between the isomerization activation energy and the dielectric constant of the solvent. Furthermore, linearity was achieved when the activation energy was plotted against the pKa value of the catalyst. Substituted-pyridine derivatives with high pKa values were able to catalyze isomerization more efficiently than those with low pKa values. The calculated relative rates for prodrugs 1-6 were: 1 (406.7), 2 (7.6×10(6)), 3 (1.0), 4 (20.7), 5 (13.5) and 6 (2.2×10(3)). This result indicates that isomerizations of prodrugs 1 and 3-5 are expected to be slow and that of prodrugs 2 and 6 are expected to be relatively fast. Hence, prodrugs 2 and 3-5 have the potential to be utilized as prodrugs for the slow release of monomethylfumarate in the treatment of psoriasis and multiple sclerosis.

Topics: Catalysis; Computer Simulation; Fumarates; Humans; Isomerism; Kinetics; Maleates; Models, Molecular; Multiple Sclerosis; Prodrugs; Psoriasis; Pyridines; Quantum Theory; Solvents; Thermodynamics

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Crotonates; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Glatiramer Acetate; Humans; Hydroxybutyrates; Immunologic Factors; Interferons; Multiple Sclerosis; Natalizumab; Nitriles; Peptides; Propylene Glycols; Sphingosine; Toluidines

Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Clinical Trials, Phase III as Topic; Dimethyl Fumarate; Drug Approval; Fumarates; Humans; Multiple Sclerosis; Patient Safety

Topics: Alemtuzumab; Animals; Antibodies, Monoclonal, Humanized; Cladribine; Clinical Trials, Phase III as Topic; Crotonates; Dimethyl Fumarate; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Inflammation; Multiple Sclerosis; Natalizumab; Nitriles; Propylene Glycols; Quinolones; Risk Assessment; Sphingosine; Toluidines; United States; United States Food and Drug Administration

Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's as well as Huntington's disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS). Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic-progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Here, fumaric acid esters (FAE) are a new, orally available treatment option which had already been tested in phase II/III MS trials demonstrating beneficial effects on relapse rates and magnetic resonance imaging markers. In vitro, application of dimethylfumarate (DMF) leads to stabilization of Nrf2, activation of Nrf2-dependent transcriptional activity and abundant synthesis of detoxifying proteins. Furthermore, application of FAE involves direct modification of the inhibitor of Nrf2, Kelch-like ECH-associated protein 1. On cellular levels, the application of FAE enhances neuronal survival and protects astrocytes against oxidative stress. Increased levels of Nrf2 are detected in the central nervous system of DMF treated mice suffering from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In EAE, DMF ameliorates the disease course and improves preservation of myelin, axons and neurons. Finally, Nrf2 is also up-regulated in the spinal cord of autopsy specimens from untreated patients with MS, probably as part of a naturally occurring anti-oxidative response. In summary, oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapies like FAE.

Topics: Animals; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Mice; Multiple Sclerosis; Neurodegenerative Diseases; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Transcription, Genetic

Topics: Administration, Oral; Clinical Trials, Phase III as Topic; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis

Inflammation and oxidative stress are thought to promote tissue damage in multiple sclerosis. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for multiple sclerosis treatment. BG00012 is an oral formulation of dimethylfumarate. In a phase II multiple sclerosis trial, BG00012 demonstrated beneficial effects on relapse rate and magnetic resonance imaging markers indicative of inflammation as well as axonal destruction. First we have studied effects of dimethylfumarate on the disease course, central nervous system, tissue integrity and the molecular mechanism of action in an animal model of chronic multiple sclerosis: myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis in C57BL/6 mice. In the chronic phase of experimental autoimmune encephalomyelitis, preventive or therapeutic application of dimethylfumarate ameliorated the disease course and improved preservation of myelin, axons and neurons. In vitro, the application of fumarates increased murine neuronal survival and protected human or rodent astrocytes against oxidative stress. Application of dimethylfumarate led to stabilization of the transcription factor nuclear factor (erythroid-derived 2)-related factor 2, activation of nuclear factor (erythroid-derived 2)-related factor 2-dependent transcriptional activity and accumulation of NADP(H) quinoline oxidoreductase-1 as a prototypical target gene. Furthermore, the immediate metabolite of dimethylfumarate, monomethylfumarate, leads to direct modification of the inhibitor of nuclear factor (erythroid-derived 2)-related factor 2, Kelch-like ECH-associated protein 1, at cysteine residue 151. In turn, increased levels of nuclear factor (erythroid-derived 2)-related factor 2 and reduced protein nitrosylation were detected in the central nervous sytem of dimethylfumarate-treated mice. Nuclear factor (erythroid-derived 2)-related factor 2 was also upregulated in the spinal cord of autopsy specimens from untreated patients with multiple sclerosis. In dimethylfumarate-treated mice suffering from experimental autoimmune encephalomyelitis, increased immunoreactivity for nuclear factor (erythroid-derived 2)-related factor 2 was detected by confocal microscopy in neurons of the motor cortex and the brainstem as well as in oligodendrocytes and astrocytes. In mice deficient for nuclear factor (erythroid-derived 2)-related factor 2 on the same genetic background, the dimethylfumarate mediated ben

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Aldehyde Reductase; Animals; Antigens, Differentiation; Antioxidants; Astrocytes; Axons; CD3 Complex; Cell Proliferation; Cells, Cultured; Chromatography, High Pressure Liquid; Cytokines; Disease Models, Animal; Embryo, Mammalian; Encephalomyelitis, Autoimmune, Experimental; Female; Fumarates; Gene Expression Regulation; Glycoproteins; Green Fluorescent Proteins; Humans; Hydrogen Peroxide; Mass Spectrometry; Mice; Mice, Inbred C57BL; Motor Neurons; Multiple Sclerosis; Myelin Proteins; Myelin-Oligodendrocyte Glycoprotein; NAD(P)H Dehydrogenase (Quinone); Neuroprotective Agents; NF-E2-Related Factor 2; Nogo Proteins; Oxidative Stress; Peptide Fragments; RNA, Small Interfering; Signal Transduction; Sleep; Spinal Cord; Statistics, Nonparametric; Tandem Mass Spectrometry; Time Factors; Transfection

The present study was performed to investigate the effects of dimethylfumarate (DMF) and methylhydrogen fumarate (MHF) on the cytokine pattern of peripheral blood mononuclear cells (PBMCs) of multiple sclerosis (MS) patients. The PBMCs from patients and healthy controls were stimulated with myelin basic protein (MBP) or phytohemagglutinin (PHA) and cultured in the presence of DMF and MHF. The percentage of CD4+IL-4+ and CD4+IFN-γ+ cells was determined by means of intracellular cytokine staining. CD4+IL-4+ cells were significantly increased in the presence of DMF and MHF when PBMCs were stimulated by MBP (P < 0.003). The same significant result was obtained by PHA stimulation (P < 0.049). In terms of CD4+IFN-γ+ cells, the percentage of cells did not significantly differ between the cultures stimulated with MBP or PHA in the presence and absence of the drugs. Results of MBP stimulation in control group also showed a significant increase in CD4+IL-4+ cells in the presence of DMF and MHF. In comparison between patient and control groups, no statistically significant changes were observed. In conclusion, both DMF and MHF effectively increased IL-4 production, whereas they did not significantly change IFN-γ level, indicating the role of these drugs in increasing the production of beneficial cytokines such as IL-4.

Topics: Adolescent; Adult; CD4-Positive T-Lymphocytes; Cell Count; Cell Survival; Cytokines; Dimethyl Fumarate; Female; Fumarates; Humans; Interferon-gamma; Interleukin-4; Leukocytes, Mononuclear; Lymphocyte Activation; Lymphocytes; Male; Maleates; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Phytohemagglutinins; Th1 Cells; Th2 Cells; Young Adult

Topics: Administration, Oral; Clinical Trials, Phase III as Topic; Dimethyl Fumarate; Drug Industry; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis; NF-kappa B

Fumarates improve multiple sclerosis (MS) and psoriasis, two diseases in which both IL-12 and IL-23 promote pathogenic T helper (Th) cell differentiation. However, both diseases show opposing responses to most established therapies. First, we show in humans that fumarate treatment induces IL-4-producing Th2 cells in vivo and generates type II dendritic cells (DCs) that produce IL-10 instead of IL-12 and IL-23. In mice, fumarates also generate type II DCs that induce IL-4-producing Th2 cells in vitro and in vivo and protect mice from experimental autoimmune encephalomyelitis. Type II DCs result from fumarate-induced glutathione (GSH) depletion, followed by increased hemoxygenase-1 (HO-1) expression and impaired STAT1 phosphorylation. Induced HO-1 is cleaved, whereupon the N-terminal fragment of HO-1 translocates into the nucleus and interacts with AP-1 and NF-κB sites of the IL-23p19 promoter. This interaction prevents IL-23p19 transcription without affecting IL-12p35, whereas STAT1 inactivation prevents IL-12p35 transcription without affecting IL-23p19. As a consequence, GSH depletion by small molecules such as fumarates induces type II DCs in mice and in humans that ameliorate inflammatory autoimmune diseases. This therapeutic approach improves Th1- and Th17-mediated autoimmune diseases such as psoriasis and MS by interfering with IL-12 and IL-23 production.

Topics: Animals; Cell Differentiation; Dendritic Cells; Encephalomyelitis, Autoimmune, Experimental; Female; Fumarates; Heme Oxygenase-1; Humans; Interleukin-12; Interleukin-23; Macrophages; Mice; Multiple Sclerosis; NIH 3T3 Cells; Promoter Regions, Genetic; Psoriasis; Reactive Oxygen Species; Signal Transduction; T-Lymphocytes; Transcription Factor RelA

Multiple sclerosis (MS) represents the prototypic inflammatory autoimmune disorder of the central nervous system and the most common cause of neurological disability in young adults, exhibiting considerable clinical, radiological and pathological heterogeneity. A better understanding of the immunopathological processes underlying this disease have recently led to the design of numerous novel therapeutical approaches. Perhaps most importantly, therapy has changed dramatically over the past decade in that all relapsing forms of MS, including early forms of MS are now being treated relatively aggressively. However, there are still unmet needs in the management of this disease, especially since all of the currently available disease-modifying drugs are only partially effective. Most of the clinically relevant therapeutic agents are not yet available as oral formulations. A substantial number of pivotal and preliminary reports provide encouraging new evidence on advances being made in the development of oral therapies for MS. A different strategy is the development of very potent monoclonal antibodies, given intravenously or subcutaneously, many of which are being examined for clinical efficacy. These agents are potentially more effective, but may carry more serious side effects. Finally, drugs with a known good safety profile are being developed further. These advances are critically reviewed and put into perspective.

Topics: Administration, Oral; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Cladribine; Crotonates; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxybutyrates; Immunologic Factors; Injections, Intravenous; Injections, Subcutaneous; Interferon-beta; Multiple Sclerosis; Nitriles; Propylene Glycols; Quinolones; Sphingosine; Toluidines