-
Therapeutic Advances in Neurological... 2024Teriflunomide is a once-daily oral disease-modifying therapy (DMT) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Only limited information is...
BACKGROUND
Teriflunomide is a once-daily oral disease-modifying therapy (DMT) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Only limited information is available about its real-world use and changes over time.
OBJECTIVES
To collect real-world data on teriflunomide use in clinical routine (and comparison to the previously conducted study TAURUS-MS).
DESIGN
National, open, non-interventional, prospective, multicenter study.
METHODS
TAURUS-MS II was conducted at 220 German sites between July 2017 and March 2022, including RRMS patients treated with teriflunomide. Data on patient demographics, MS history, previous treatment, therapy satisfaction, and safety were collected.
RESULTS
In total, 752 patients were included (65% female) with a mean age (±standard deviation) of 43 ± 11 years. Sixty-six percent had DMT before, and 46% had discontinued their last pretreatment ≤6 months prior to study entry. Among the latter, previous DMTs were interferon (21%), glatiramer acetate (11%), and dimethyl fumarate (9%), and reasons for discontinuation were adverse events (AEs; 55%) and insufficient efficacy (16%). Over 24 months, the mean treatment Satisfaction Questionnaire for Medication scores improved by 6 ± 29 points on effectiveness, 8 ± 20 on convenience, and 12 ± 25 on global satisfaction. The mean number of MS relapses decreased from 0.81 ± 0.81 in the 24 months prior to 0.27 ± 0.57 within 24 months after study entry. Non-serious AEs occurred in 423 patients (56%) and serious AEs in 49 patients (7%). Most reported AEs were alanine aminotransferase increase (11%), hypertension (8%), and alopecia (7%). Compared to TAURUS-MS, patients in TAURUS-MS II were younger, had a higher employment rate, and a higher share of treatment-naïve patients.
CONCLUSION
Mean number of relapses was significantly reduced. Patient satisfaction was significantly improved compared to previous DMT. Tolerability was comparable to previous trials.
TRIAL REGISTRATION
Bundesinstitut für Arzneimittel und Medizinprodukte public database for non-interventional studies, number 7138.
PubMed: 38808094
DOI: 10.1177/17562864241252722 -
Multiple Sclerosis Journal -... 2024The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to...
BACKGROUND
The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to resource limitations.
OBJECTIVE
To use MSBase registry data to compare real-world outcomes in adults with relapsing-remitting MS (RRMS) treated with dimethyl fumarate (DMF) or NSIS (azathioprine, cyclosporine, cyclophosphamide, methotrexate, mitoxantrone or mycophenolate mofetil) between January 1, 2014 and April 1, 2022.
METHODS
Treatment outcomes were compared using inverse probability of treatment weighting (IPTW) Cox regression. Outcomes were annualized relapse rates (ARRs), time to discontinuation, time to first relapse (TTFR) and time to 24-week confirmed disability progression (CDP) or 24-week confirmed disability improvement (CDI; in patients with baseline Expanded Disability Status Scale [EDSS] score ≥2).
RESULTS
After IPTW, ARR was similar for DMF (0.13) and NSIS (0.16; = 0.29). There was no difference in TTFR between cohorts (hazard ratio [HR]: 0.98; = 0.84). The DMF cohort experienced longer times to discontinuation (HR: 0.75; = 0.001) and CDP (HR: 0.53; = 0.001), and shorter time to CDI (HR: 1.99; < 0.008), versus the NSIS cohort.
CONCLUSION
This analysis supports the use of DMF to treat patients with relapsing forms of MS, and may have implications for MS practices in countries where NSIS are commonly used to treat RRMS.
PubMed: 38800132
DOI: 10.1177/20552173241247182 -
FEBS Open Bio May 2024The cellular response to oxidants or xenobiotics comprises two key pathways, resulting in modulation of NRF2 and FOXO transcription factors, respectively. Both mount a...
The cellular response to oxidants or xenobiotics comprises two key pathways, resulting in modulation of NRF2 and FOXO transcription factors, respectively. Both mount a cytoprotective response, and their activation relies on crucial protein thiol moieties. Using fumaric acid esters (FAEs), known thiol-reactive compounds, we tested for activation of NRF2 and FOXO pathways in cultured human hepatoma cells by dimethyl/diethyl as well as monomethyl/monoethyl fumarate. Whereas only the diesters caused acute glutathione depletion and activation of the stress kinase p38, all four FAEs stimulated NRF2 stabilization and upregulation of NRF2 target genes. However, no significant FAE-induced activation of FOXO-dependent target gene expression was observed. Therefore, while both NRF2 and FOXO pathways are responsive to oxidants and xenobiotics, FAEs selectively activate NRF2 signaling.
PubMed: 38794848
DOI: 10.1002/2211-5463.13833 -
BMJ Open May 2024Intracranial aneurysm (IA) is a common cerebrovascular disease. Considering the risks and benefits of surgery, a significant proportion of patients with unruptured IA...
INTRODUCTION
Intracranial aneurysm (IA) is a common cerebrovascular disease. Considering the risks and benefits of surgery, a significant proportion of patients with unruptured IA (UIA) choose conservative observation. Previous studies suggest that inflammation of aneurysm wall is a high-risk factor of rupture. Dimethyl fumarate (DMF) acts as an anti-inflammatory agent by activating nuclear factor erythroid 2-related factor 2 (Nrf2) and other pathways. Animal experiments found DMF reduces the formation and rupture of IAs. In this study, DMF will be evaluated for its ability to reduce inflammation of the aneurysm wall in high-resolution vessel wall imaging.
METHODS AND ANALYSIS
This is a multi-centre, randomised, controlled, double-blind clinical trial. Three hospitals will enrol a total of 60 patients who have UIA with enhanced wall. Participants will be assigned randomly in a 1:1 proportion, taking either 240 mg DMF or placebo orally every day for 6 months. As the main result, aneurysm wall enhancement will be measured by the signal intensity after 6 months of DMF treatment. Secondary endpoints include morphological changes of aneurysms and factors associated with inflammation. This study will provide prospective data on the reduction of UIA wall inflammation by DMF.
ETHICS AND DISSEMINATION
This study has been approved by Medical Ethics Committee of the Beijing Tiantan Hospital, Capital Medical University (approval no: KY2022-064-02). We plan to disseminate our research findings through peer-reviewed journal publication and relevant academic conferences.
TRIAL REGISTRATION NUMBER
NCT05959759.
Topics: Humans; Dimethyl Fumarate; Intracranial Aneurysm; Double-Blind Method; Randomized Controlled Trials as Topic; Adult; Male; Middle Aged; Female; Anti-Inflammatory Agents
PubMed: 38772883
DOI: 10.1136/bmjopen-2023-080333 -
Frontiers in Immunology 2024Dimethyl fumarate (DMF, Tecfidera) is an oral drug utilized to treat relapsing-remitting multiple sclerosis (MS). DMF treatment reduces disease activity in MS....
Dimethyl fumarate (DMF, Tecfidera) is an oral drug utilized to treat relapsing-remitting multiple sclerosis (MS). DMF treatment reduces disease activity in MS. Gastrointestinal discomfort is a common adverse effect of the treatment with DMF. This study aimed to investigate the effect of DMF administration in the gut draining lymph nodes cells of C57BL6/J female mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We have demonstrated that the treatment with DMF (7.5 mg/kg) significantly reduces the severity of EAE. This reduction of the severity is accompanied by the increase of both proinflammatory and anti-inflammatory mechanisms at the beginning of the treatment. As the treatment progressed, we observed an increasing number of regulatory Foxp3 negative CD4 T cells (Tr1), and anti-inflammatory cytokines such as IL-27, as well as the reduction of PGE2 level in the mesenteric lymph nodes of mice with EAE. We provide evidence that DMF induces a gradual anti-inflammatory response in the gut draining lymph nodes, which might contribute to the reduction of both intestinal discomfort and the inflammatory response of EAE. These findings indicate that the gut is the first microenvironment of action of DMF, which may contribute to its effects of reducing disease severity in MS patients.
Topics: Animals; Dimethyl Fumarate; Encephalomyelitis, Autoimmune, Experimental; Lymph Nodes; Mice; Female; T-Lymphocytes, Regulatory; Mice, Inbred C57BL; Mesentery; Cytokines; Immunosuppressive Agents; Disease Models, Animal
PubMed: 38765015
DOI: 10.3389/fimmu.2024.1391949 -
International Journal of Pharmaceutics Jun 2024The nasal administration route has been studied for the delivery of active molecules directed to the Central Nervous System, thanks to the anatomical connection between...
The nasal administration route has been studied for the delivery of active molecules directed to the Central Nervous System, thanks to the anatomical connection between the nasal cavity and the brain. Dimethyl fumarate is used to treat relapsing-remitting multiple sclerosis, with a role as an immunomodulator towards T- T-cells and a cytoprotector towards neurons and glial cells. Its use in therapy is hindered by its low aqueous solubility, and low stability, due to hydrolysis and sublimation at room temperature. To overcome this limitation, in this study we evaluated the feasibility of using two amorphous β-cyclodextrin derivatives, namely hydroxypropyl β-cyclodextrin and methyl β-cyclodextrin, to obtain a nasally administrable powder with a view to nose-to-brain administration. Initially, the interaction product was studied using different analytical methods (differential scanning calorimetry, Fourier transform infrared spectroscopy and powder X-ray diffraction) to detect the occurrence of binary product formation, while phase solubility analysis was used to probe the complexation in solution. The dimethyl fumarate-cyclodextrin binary product showing best solubility and stability properties was subsequently used in the development of a chitosan-based mucoadhesive nasally administrable powder comparing different preparative methods. The best performance in terms of both hydrolytic stability and DMF recovery was achieved by the powder obtained via freeze-drying.
Topics: Dimethyl Fumarate; Chitosan; Powders; Administration, Intranasal; Drug Stability; beta-Cyclodextrins; Solubility; Brain; 2-Hydroxypropyl-beta-cyclodextrin; Spectroscopy, Fourier Transform Infrared; Calorimetry, Differential Scanning; X-Ray Diffraction
PubMed: 38734272
DOI: 10.1016/j.ijpharm.2024.124216 -
Cureus Apr 2024Multiple sclerosis is the most common autoimmune disease affecting the central nervous system (CNS) worldwide. Multiple sclerosis involves inflammatory demyelination of... (Review)
Review
Multiple sclerosis is the most common autoimmune disease affecting the central nervous system (CNS) worldwide. Multiple sclerosis involves inflammatory demyelination of nerve fibers in the CNS, often presenting with recurrent episodes of focal sensory or motor deficits associated with the region of the CNS affected. The prevalence of this disease has increased rapidly over the last decade. Despite the approval of many new pharmaceutical therapies in the past 20 years, there remains a growing need for alternative therapies to manage the course of this disease. Treatments are separated into two main categories: management of acute flare versus long-term prevention of flares via disease-modifying therapy. Primary drug therapies for acute flare include corticosteroids to limit inflammation and symptomatic management, depending on symptoms. Several different drugs have been recently approved for use in modifying the course of the disease, including a group of medications known as fumarates (e.g., dimethyl fumarate, diroximel fumarate, monomethyl fumarate) that have been shown to be efficacious and relatively safe. In the present investigation, we review available evidence focused on monomethyl fumarate, also known as Bafiertam®, along with bioequivalent fumarates for the long-term treatment of relapsing-remitting multiple sclerosis.
PubMed: 38711693
DOI: 10.7759/cureus.57714 -
Frontiers in Immunology 2024Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of...
Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of allergic asthma. Here, we have evaluated the anti-inflammatory impact of dimethyl fumarate (DMF) in allergic asthma with more focus on determining its effect on T cell responses in allergic asthma. By utilizing the ovalbumin (OVA)-induced allergic asthma model, we observed that DMF administration reduced the allergic asthma symptoms and IgE levels in the OVA-induced mice model. Histopathological analysis showed that DMF treatment in an OVA-induced animal model eased the inflammation in the nasal and bronchial tissues, with a particular decrease in the infiltration of immune cells. Additionally, RT-qPCR analysis exhibited that treatment of DMF in an OVA-induced model reduced the expression of inflammatory cytokine (IL4, IL13, and IL17) while augmenting anti-inflammatory IL10 and Foxp3 (forkhead box protein 3). Mechanistically, we found that DMF increased the expression of Foxp3 by exacerbating the expression of nuclear factor E2-related factor 2 (Nrf2), and the in-vitro activation of Foxp3+ Tregs leads to an escalated expression of Nrf2. Notably, CD4-specific Nrf2 deletion intensified the allergic asthma symptoms and reduced the in-vitro iTreg differentiation. Meanwhile, DMF failed to exert protective effects on OVA-induced allergic asthma in CD4-specific Nrf2 knock-out mice. Overall, our study illustrates that DMF enhances Nrf2 signaling in T cells to assist the differentiation of Tregs, which could improve the anti-inflammatory immune response in allergic asthma.
Topics: Animals; Female; Mice; Asthma; Cytokines; Dimethyl Fumarate; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Ovalbumin; Signal Transduction; T-Lymphocytes, Regulatory
PubMed: 38711519
DOI: 10.3389/fimmu.2024.1375340 -
PLoS Genetics May 2024The capacity for bacterial extracellular electron transfer via secreted metabolites is widespread in natural, clinical, and industrial environments. Recently, we...
The capacity for bacterial extracellular electron transfer via secreted metabolites is widespread in natural, clinical, and industrial environments. Recently, we discovered the biological oxidation of phenazine-1-carboxylic acid (PCA), the first example of biological regeneration of a naturally produced extracellular electron shuttle. However, it remained unclear how PCA oxidation was catalyzed. Here, we report the mechanism, which we uncovered by genetically perturbing the branched electron transport chain (ETC) of the soil isolate Citrobacter portucalensis MBL. Biological PCA oxidation is coupled to anaerobic respiration with nitrate, fumarate, dimethyl sulfoxide, or trimethylamine-N-oxide as terminal electron acceptors. Genetically inactivating the catalytic subunits for all redundant complexes for a given terminal electron acceptor abolishes PCA oxidation. In the absence of quinones, PCA can still donate electrons to certain terminal reductases, albeit much less efficiently. In C. portucalensis MBL, PCA oxidation is largely driven by flux through the ETC, which suggests a generalizable mechanism that may be employed by any anaerobically respiring bacterium with an accessible cytoplasmic membrane. This model is supported by analogous genetic experiments during nitrate respiration by Pseudomonas aeruginosa.
Topics: Phenazines; Oxidation-Reduction; Electron Transport; Soil Microbiology; Citrobacter; Anaerobiosis; Bacterial Proteins
PubMed: 38709821
DOI: 10.1371/journal.pgen.1011064