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Journal of Neurology Mar 2021Dimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing-remitting multiple...
BACKGROUND
Dimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing-remitting multiple sclerosis (RRMS).
OBJECTIVE
To compare the effectiveness of dimethyl fumarate and fingolimod in a real-world setting, where both agents are licensed as a first-line DMT for the treatment of RRMS.
METHODS
We identified patients with RRMS commencing dimethyl fumarate or fingolimod in the Swiss Federation for Common Tasks of Health Insurances (SVK) Registry between August 2014 and July 2019. Propensity score-matching was applied to select subpopulations with comparable baseline characteristics. Relapses and disability outcomes were compared in paired, pairwise-censored analyses.
RESULTS
Of the 2113 included patients, 1922 were matched (dimethyl fumarate, n = 961; fingolimod, n = 961). Relapse rates did not differ between the groups (incident rate ratio 1.0, 95%CI 0.8-1.2, p = 0.86). Moreover, no difference in the hazard of 1-year confirmed disability worsening (hazard ratio [HR] 0.9; 95%CI 0.6-1.6; p = 0.80) or disability improvement (HR 0.9; 95%CI 0.6-1.2; p = 0.40) was detected. These findings were consistent both for treatment-naïve patients and patients switching from another DMT.
CONCLUSION
Dimethyl fumarate and fingolimod have comparable effectiveness regarding reduction of relapses and disability worsening in RRMS.
Topics: Dimethyl Fumarate; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
PubMed: 32974794
DOI: 10.1007/s00415-020-10226-6 -
Aging Jul 2016
Topics: Antineoplastic Agents; Dimethyl Fumarate; Drug Repositioning; Humans; Immunosuppressive Agents; Neoplasms
PubMed: 27429364
DOI: 10.18632/aging.101001 -
Journal of Neuroinflammation Feb 2024Neuroinflammation substantially contributes to the pathology of Alzheimer's disease (AD), the most common form of dementia. Studies have reported that nuclear factor...
BACKGROUND
Neuroinflammation substantially contributes to the pathology of Alzheimer's disease (AD), the most common form of dementia. Studies have reported that nuclear factor erythroid 2-related factor 2 (Nrf2) attenuates neuroinflammation in the mouse models of neurodegenerative diseases, however, the detailed mechanism remains unclear.
METHODS
The effects of dimethyl fumarate (DMF), a clinically used drug to activate the Nrf2 pathway, on neuroinflammation were analyzed in primary astrocytes and App (App-KI) mice. The cognitive function and behavior of DMF-administrated App-KI mice were evaluated. For the gene expression analysis, microglia and astrocytes were directly isolated from the mouse cerebral cortex by magnetic-activated cell sorting, followed by quantitative PCR.
RESULTS
DMF treatment activated some Nrf2 target genes and inhibited the expression of proinflammatory markers in primary astrocytes. Moreover, chronic oral administration of DMF attenuated neuroinflammation, particularly in astrocytes, and reversed cognitive dysfunction presumably by activating the Nrf2-dependent pathway in App-KI mice. Furthermore, DMF administration inhibited the expression of STAT3/C3 and C3 receptor in astrocytes and microglia isolated from App-KI mice, respectively, suggesting that the astrocyte-microglia crosstalk is involved in neuroinflammation in mice with AD.
CONCLUSION
The activation of astrocytic Nrf2 signaling confers neuroprotection in mice with AD by controlling neuroinflammation, particularly by regulating astrocytic C3-STAT3 signaling. Furthermore, our study has implications for the repositioning of DMF as a drug for AD treatment.
Topics: Mice; Animals; Alzheimer Disease; Dimethyl Fumarate; Mice, Transgenic; Neuroinflammatory Diseases; NF-E2-Related Factor 2; Cognitive Dysfunction; Disease Models, Animal
PubMed: 38383481
DOI: 10.1186/s12974-024-03046-2 -
International Journal of Molecular... Oct 2023Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl...
Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl fumarate (DMF) is known to modulate the immune response, activate antioxidative pathways, and improve the blood-brain barrier (BBB) after stroke. However, the specific impact of DMF on immune cells after cerebral ischemia remains unclear. In our study, male mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 min and received oral DMF (15 mg/kg) or a vehicle immediately after tMCAO, followed by twice-daily administrations for 7 days. Infarct volume was assessed on T2-weighted magnetic resonance images on days 1 and 7 after tMCAO. Brain-infiltrating immune cells (lymphocytes, monocytes) and microglia were quantified using fluorescence-activated cell sorting. DMF treatment significantly reduced infarct volumes and brain edema. On day 1 after tMCAO, DMF-treated mice showed reduced lymphocyte infiltration compared to controls, which was not observed on day 7. Monocyte and microglial cell counts did not differ between groups on either day. In the acute phase of stroke, DMF administration attenuated lymphocyte infiltration, probably due to its stabilizing effect on the BBB. This highlights the potential of DMF as a therapeutic candidate for mitigating immune cell-driven damage in stroke.
Topics: Male; Mice; Animals; Dimethyl Fumarate; Stroke; Brain Ischemia; Infarction, Middle Cerebral Artery; Brain; Mice, Inbred C57BL
PubMed: 37958527
DOI: 10.3390/ijms242115540 -
BMC Neurology Jul 2022To compare the effectiveness of dimethyl fumarate (DMF) with subcutaneous interferon beta-1a (IFNβ-1a) in controlling disease activity in patients with...
BACKGROUND
To compare the effectiveness of dimethyl fumarate (DMF) with subcutaneous interferon beta-1a (IFNβ-1a) in controlling disease activity in patients with relapsing-remitting Multiple Sclerosis (MS).
METHODS
Clinical and imaging data from patients treated with either IFNβ-1a or DMF for at least one year were reviewed. The proportion of patients with at least one clinical relapse within 3-15 months after treatment onset, the proportion of patients with new T2 or gadolinium-enhancing lesions, and the proportion of subjects who achieved no evidence of disease activity (NEDA) status were assessed.
RESULTS
Three hundred sixteen (98 on IFNβ-1a, 218 on DMF) subjects were included. Baseline demographics were comparable between groups except for age, disease duration, and the number of previous treatments being higher and relapse rate in the prior year being lower in the DMF-treated group. The proportion of patients having a clinical relapse (24.5% vs. 9.6%; OR = 3.04; P < 0.001) or a new MRI lesion (28.6% vs. 8.7%; OR = 4.19, P < 0.001) at 15 months were higher on IFNβ-1a. 79.9% of the patients achieved NEDA status at 15 months on DMF (vs. 51.1% for IFNβ-1a; OR = 0.26, P < 0.001). Further adjustment for demographics, disease characteristics, treatment and relapse history, and subgroup analyses confirmed these findings.
CONCLUSION
DMF was associated with less clinical and radiological disease activity compared to IFNβ-1a.
Topics: Adjuvants, Immunologic; Antiviral Agents; Dimethyl Fumarate; Humans; Interferon beta-1a; Interferon-beta; Interferons; Recurrence
PubMed: 35820822
DOI: 10.1186/s12883-022-02761-8 -
Translational Stroke Research Dec 2016Oxidative stress plays an important role in cerebral ischemia-reperfusion injury. Dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) are...
Oxidative stress plays an important role in cerebral ischemia-reperfusion injury. Dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) are antioxidant agents that can activate the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and induce the expression of antioxidant proteins. Here, we evaluated the impact of DMF and MMF on ischemia-induced brain injury and whether the Nrf2 pathway mediates the effects provided by DMF and MMF in cerebral ischemia-reperfusion injury. Using a mouse model of transient focal brain ischemia, we show that DMF and MMF significantly reduce neurological deficits, infarct volume, brain edema, and cell death. Further, DMF and MMF suppress glial activation following brain ischemia. Importantly, the protection of DMF and MMF was mostly evident during the subacute stage and was abolished in Nrf2 mice, indicating that the Nrf2 pathway is required for the beneficial effects of DMF and MMF. Together, our data indicate that DMF and MMF have therapeutic potential in cerebral ischemia-reperfusion injury and their protective role is likely mediated by the Nrf2 pathway.
Topics: Animals; Brain Edema; Calcium-Binding Proteins; Dimethyl Fumarate; Disease Models, Animal; Dose-Response Relationship, Drug; Fumarates; Glial Fibrillary Acidic Protein; Glutathione; Immunosuppressive Agents; Infarction, Middle Cerebral Artery; Maleates; Malondialdehyde; Mice; Mice, Inbred C57BL; Microfilament Proteins; NF-E2-Related Factor 2; Neurologic Examination; Neuroprotective Agents; Oxidative Stress; Recovery of Function; Reperfusion Injury; Time Factors
PubMed: 27614618
DOI: 10.1007/s12975-016-0496-0 -
Frontiers in Immunology 2016Several drugs have been approved for treatment of multiple sclerosis (MS). Dimethyl fumarate (DMF) is utilized as an oral drug to treat this disease and is proven to be... (Review)
Review
Several drugs have been approved for treatment of multiple sclerosis (MS). Dimethyl fumarate (DMF) is utilized as an oral drug to treat this disease and is proven to be potent with less side effects than several other drugs. On the other hand, monomethyl fumarate (MMF), a related compound, has not been examined in greater details although it has the potential as a therapeutic drug for MS and other diseases. The mechanism of action of DMF or MMF is related to their ability to enhance the antioxidant pathways and to inhibit reactive oxygen species. However, other mechanisms have also been described, which include effects on monocytes, dendritic cells, T cells, and natural killer cells. It is also reported that DMF might be useful for treating psoriasis, asthma, aggressive breast cancers, hematopoeitic tumors, inflammatory bowel disease, intracerebral hemorrhage, osteoarthritis, chronic pancreatitis, and retinal ischemia. In this article, we will touch on some of these diseases with an emphasis on the effects of DMF and MMF on various immune cells.
PubMed: 27499754
DOI: 10.3389/fimmu.2016.00278 -
Communications Biology Oct 2023Dimethyl 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,...
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: Humans; Dimethyl Fumarate; Endothelial Cells; Fumarates; Multiple Sclerosis; Down-Regulation
PubMed: 37880317
DOI: 10.1038/s42003-023-05443-4 -
Multiple Sclerosis Journal -... 2021For patients with MS, medication switches increase the risk of disease reactivation.
BACKGROUND
For patients with MS, medication switches increase the risk of disease reactivation.
OBJECTIVE
Compare discontinuation rates due to treatment failure or side effects between teriflunomide and dimethyl fumarate, and investigate clinical variables affecting discontinuation rates.
METHODS
All patients who received teriflunomide or dimethyl fumarate at Haukeland University Hospital from 2013 until 2018 were identified. Clinical and demographic variables were extracted from the Norwegian MS Registry. Cause-specific Cox regression models estimated the rate of discontinuation due to treatment failure or side effects.
RESULTS
We included 354 patients treated with either dimethyl fumarate ( = 185) or teriflunomide ( = 169). We found 38% lower risk of discontinuation because of treatment failure for patients using dimethyl fumarate compared to teriflunomide ( < 0.05). In a treatment-naive subgroup ( = 183), we found a 38% reduced risk of discontinuation for any reason among patients using dimethyl fumarate ( < 0.05). There was no significant difference between treatment groups in discontinuation rate due to side effects, although more patients reported side effects when treated with dimethyl fumarate.
CONCLUSION
Our findings suggests that dimethyl fumarate has a lower risk of discontinuation because of treatment failure among both treatment-experienced and treatment-naive patients.
PubMed: 34188949
DOI: 10.1177/20552173211022027 -
Nature Communications Oct 2020Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we...
Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.
Topics: Adult; Anti-Inflammatory Agents; Antioxidants; Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Dimethyl Fumarate; Female; Gene Expression; Gene Knockdown Techniques; Humans; Interferon Type I; Lung; Male; NF-E2-Related Factor 2; Pandemics; Pneumonia, Viral; SARS-CoV-2; Signal Transduction; Succinates; Virus Replication
PubMed: 33009401
DOI: 10.1038/s41467-020-18764-3