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Human Molecular Genetics Feb 2021Previously we showed that dimethyl fumarate (DMF) dose-dependently increased mitochondrial gene expression and function in cells and might be considered as a therapeutic...
Previously we showed that dimethyl fumarate (DMF) dose-dependently increased mitochondrial gene expression and function in cells and might be considered as a therapeutic for inherited mitochondrial disease, including Friedreich's ataxia (FA). Here we tested DMF's ability to dose-dependently increase mitochondrial function, mitochondrial gene expression (frataxin and cytochrome oxidase protein) and mitochondrial copy number in C57BL6 wild-type mice and the FXNKD mouse model of FA. We first dosed DMF at 0-320 mg/kg in C57BL6 mice and observed significant toxicity above 160 mg/kg orally, defining the maximum tolerated dose. Oral dosing of C57BL6 mice in the range 0-160 mg/kg identified a maximum increase in aconitase activity and mitochondrial gene expression in brain and quadriceps at 110 mg/kg DMF, thus defining the maximum effective dose (MED). The MED of DMF in mice overlaps the currently approved human-equivalent doses of DMF prescribed for multiple sclerosis (480 mg/day) and psoriasis (720 mg/day). In the FXNKD mouse model of FA, which has a doxycycline-induced deficit of frataxin protein, we observed significant decreases of multiple mitochondrial parameters, including deficits in brain mitochondrial Complex 2, Complex 4 and aconitase activity, supporting the idea that frataxin deficiency reduces mitochondrial gene expression, mitochondrial functions and biogenesis. About 110 mg/kg of oral DMF rescued these enzyme activities in brain and rescued frataxin and cytochrome oxidase expression in brain, cerebellum and quadriceps muscle of the FXNKD mouse model. Taken together, these results support the idea of using fumarate-based molecules to treat FA or other mitochondrial diseases.
Topics: Animals; Brain; Dimethyl Fumarate; Dose-Response Relationship, Drug; Friedreich Ataxia; Gene Expression Regulation; Immunosuppressive Agents; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Proteins; Muscles
PubMed: 33432356
DOI: 10.1093/hmg/ddaa282 -
Journal of Medicine and Life Mar 2023The aim of this study was to evaluate the effectiveness of infliximab and dimethyl fumarate (DMF) in reducing renal damage induced by ciprofloxacin. Forty rats were...
The aim of this study was to evaluate the effectiveness of infliximab and dimethyl fumarate (DMF) in reducing renal damage induced by ciprofloxacin. Forty rats were divided into five groups of eight each, with normal saline and CIP 600 mg IP administered to all animals in Groups 1 and 2 for ten days. Groups 3 and 4 were administered infliximab 7 mg/kg and DMF 30 mg/kg 24 hours before the CIP injections. Group 5 received a combination of infliximab/DMF after 24 hours of CIP. The levels of TNF-α, NF-Bp65, and IL-6 were measured, and the results showed that both infliximab and DMF had similar effects. However, the combination of infliximab and DMF had a robust anti-inflammatory and antiapoptotic impact, reducing TNF-α, NF-Bp65, IL-6, and Bcl-2 compared to the renal control group. Bcl-2 immuno-expression was lower in the ciprofloxacin group compared to the control group. DMF and infliximab had no effect on Bcl-2-positive cells, whereas infliximab increased the percentage of Bcl-2-positive cells substantially. CIP induced nephrotoxicity by increasing cytokine release and cell death signaling. Both infliximab and DMF are powerful TNF-α blockers that suppress cytokine release, preventing cell death and apoptosis caused by cytokines. Controlling inflammation and apoptosis can prevent nephrotoxicity.
Topics: Rats; Male; Animals; Dimethyl Fumarate; Infliximab; Tumor Necrosis Factor-alpha; Interleukin-6; Cytokines; Renal Insufficiency; Proto-Oncogene Proteins c-bcl-2
PubMed: 37168296
DOI: 10.25122/jml-2022-0197 -
JAMA Network Open Sep 2022With few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
With few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS).
OBJECTIVE
To compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon β-1a (IFNβ-1a) in POMS.
DESIGN, SETTING, AND PARTICIPANTS
The CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021.
INTERVENTIONS
Patients were randomized to DMF or IFNβ-1a.
MAIN OUTCOMES AND MEASURES
The primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group.
RESULTS
Among 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNβ-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNβ-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNβ-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNβ-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNβ-1a; the rate ratio for DMF vs IFNβ-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNβ-1a.
CONCLUSIONS AND RELEVANCE
This study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon β-1a. DMF was well tolerated.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02283853.
Topics: Adolescent; Child; Dimethyl Fumarate; Female; Humans; Interferon beta-1a; Interferon-beta; Male; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Neoplasm Recurrence, Local
PubMed: 36169959
DOI: 10.1001/jamanetworkopen.2022.30439 -
Journal of Neuroimmunology Dec 2021Dimethyl fumarate is an efficient therapy used widely in patients with relapsing-remitting multiple sclerosis (RRMS). However, lacking effect of treatment has recently... (Comparative Study)
Comparative Study Randomized Controlled Trial
Dimethyl fumarate is an efficient therapy used widely in patients with relapsing-remitting multiple sclerosis (RRMS). However, lacking effect of treatment has recently been reported in patients with primary progressive MS (PPMS) (Højsgaard Chow et al., 2021). In order to further analyze the immunological treatment response we investigated the systemic and intrathecal immunological effects of dimethyl fumarate (DMF) treatment in 50 patients with PPMS who participated in a 48-week randomized controlled trial with dimethyl fumarate vs placebo. We found substantial systemic immunomodulatory effects of DMF treatment comparable with those observed in patients with RRMS. However, intrathecal effects were limited and restricted to CD4 T cells presumably resulting in higher concentrations of intrathecal IL-7.
Topics: Adult; CD4 Lymphocyte Count; Cerebrospinal Fluid; Cytokines; Dimethyl Fumarate; Female; Humans; Immunosuppressive Agents; Injections, Spinal; Interleukin-7; Lymphocyte Subsets; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive
PubMed: 34739914
DOI: 10.1016/j.jneuroim.2021.577756 -
International Journal of Molecular... Dec 2020Air pollution is mainly caused by burning of fossil fuels, such as diesel, and is associated with increased morbidity and mortality due to adverse health effects induced...
Air pollution is mainly caused by burning of fossil fuels, such as diesel, and is associated with increased morbidity and mortality due to adverse health effects induced by inflammation and oxidative stress. Dimethyl fumarate (DMF) is a fumaric acid ester and acts as an antioxidant and anti-inflammatory agent. We investigated the potential therapeutic effects of DMF on pulmonary damage caused by chronic exposure to diesel exhaust particles (DEPs). Mice were challenged with DEPs (30 μg per mice) by intranasal instillation for 60 consecutive days. After the first 30 days, the animals were treated daily with 30 mg/kg of DMF by gavage for the remainder of the experimental period. We demonstrated a reduction in total inflammatory cell number in the bronchoalveolar lavage (BAL) of mice subjected to DEP + DMF as compared to those exposed to DEPs alone. Importantly, DMF treatment was able to reduce lung injury caused by DEP exposure. Intracellular total reactive oxygen species (ROS), peroxynitrite (OONO), and nitric oxide (NO) levels were significantly lower in the DEP + DMF than in the DEP group. In addition, DMF treatment reduced the protein expression of kelch-like ECH-associated protein 1 (Keap-1) in lung lysates from DEP-exposed mice, whereas total nuclear factor κB (NF-κB) p65 expression was decreased below baseline in the DEP + DMF group compared to both the control and DEP groups. Lastly, DMF markedly reduced DEP-induced expression of nitrotyrosine, glutathione peroxidase-1/2 (Gpx-1/2), and catalase in mouse lungs. In summary, DMF treatment effectively reduced lung injury, inflammation, and oxidative and nitrosative stress induced by chronic DEP exposure. Consequently, it may lead to new therapies to diminish lung injury caused by air pollutants.
Topics: Air Pollutants; Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Cytokines; Dimethyl Fumarate; Disease Models, Animal; Inflammation Mediators; Kelch-Like ECH-Associated Protein 1; Mice; NF-kappa B; Oxidation-Reduction; Oxidative Stress; Pneumonia; Reactive Nitrogen Species; Reactive Oxygen Species; Vehicle Emissions
PubMed: 33352854
DOI: 10.3390/ijms21249658 -
Multiple Sclerosis (Houndmills,... May 2018Dimethyl fumarate (DMF) is used to treat relapsing multiple sclerosis and causes lymphopenia in a subpopulation of treated individuals. Much remains to be learned about... (Observational Study)
Observational Study
BACKGROUND
Dimethyl fumarate (DMF) is used to treat relapsing multiple sclerosis and causes lymphopenia in a subpopulation of treated individuals. Much remains to be learned about how the drug affects B- and T-lymphocytes.
OBJECTIVES
To characterize changes in B- and T-cell phenotype and function induced by DMF and to investigate whether low absolute lymphocyte count (ALC) is associated with unique functional changes.
METHODS
Peripheral blood mononuclear cells (PBMCs) were collected from DMF-treated patients, untreated patients, and healthy controls. A subset of DMF-treated patients was lymphopenic (ALC < 800). Multiparametric flow cytometry was used to evaluate cellular phenotypes. Functional response to non-specific and viral peptide stimulation was assessed.
RESULTS
DMF reduced circulating memory B-cells regardless of ALC. Follicular T-helper cells (CD4 CXCR5) and mucosal invariant T-cells (CD8 CD161) were also reduced. DMF reduced T-cell production of pro-inflammatory cytokines in response to polyclonal (PMA/ionomycin) and viral peptide stimulation, regardless of ALC. No differences in activation-induced cell death or circulating progenitors were observed between lymphopenic and non-lymphopenic DMF-treated patients.
CONCLUSION
These data implicate DMF-induced changes in lymphocytes as an important component of the drug's efficacy and expand our understanding of the functional significance of DMF-induced lymphopenia.
Topics: Adult; B-Lymphocytes; Cross-Sectional Studies; Dimethyl Fumarate; Female; Humans; Immunosuppressive Agents; Lymphocyte Count; Lymphopenia; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; T-Lymphocytes
PubMed: 28480794
DOI: 10.1177/1352458517707069 -
Molecular Vision 2019Dimethyl fumarate (DMF) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing-remitting multiple sclerosis (RRMS), a...
PURPOSE
Dimethyl fumarate (DMF) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing-remitting multiple sclerosis (RRMS), a demyelinating autoimmune disease characterized by acute episodes of motor, sensory, and cognitive symptoms. Optic neuritis is an episodic sequela experienced by some patients with RRMS that typically presents as acute, monocular vision loss. Episodes of optic neuritis damage and kill retinal ganglion cells (RGCs), and can culminate in permanent vision loss. The purpose of these studies was to evaluate the capacity of DMF to mitigate optic neuritis. The work presented combines studies of a mouse model of MS and a retrospective chart analysis of files of patients with RRMS treated at the MS Center of Excellence within the Oklahoma Medical Research Foundation.
METHODS
Experimental autoimmune encephalomyelitis (EAE) is a well-established mouse model that recapitulates cardinal features of somatic and visual MS pathologies. EAE was induced in female C57BL/6J mice by inoculation with myelin oligodendrocyte glycoprotein peptide (residues 35-55; MOG). DMF or vehicle was administered twice a day by oral gavage. Visual acuity was measured longitudinally with optokinetic tracking. Post-mortem analyses included quantification of RGCs in retinal flatmounts and quantitative PCR (qPCR) of target genes and regulators of myelin. Retrospective chart analyses were performed using data obtained from deidentified files of patients with RRMS.
RESULTS
In the EAE mouse studies, DMF decreased optic neuritis severity, preserved vision and RGCs, and concomitantly reduced motor deficits when administered by two different treatment regimens (prevention or interventional). DMF was more efficacious when administered as an interventional therapy, and the beneficial effects occurred independently of the induction of target genes. A complementary retrospective chart analysis demonstrated that DMF increased the time to a recurrence of optic neuritis, and protected against subsequent bouts of optic neuritis.
CONCLUSIONS
This work underscores the potential of DMF to mitigate the severity and recurrence of optic neuritis episodes in patients with RRMS.
Topics: Animals; Dimethyl Fumarate; Eye Proteins; Female; Male; Mice, Inbred C57BL; Motor Activity; Optic Neuritis; Retinal Ganglion Cells; Vision, Ocular; Visual Acuity
PubMed: 31523122
DOI: No ID Found -
Clinical Therapeutics Oct 2013Delayed-release dimethyl fumarate (DR-DMF) has cytoprotective and antiinflammatory properties and has recently been approved in the United States as an oral treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Delayed-release dimethyl fumarate (DR-DMF) has cytoprotective and antiinflammatory properties and has recently been approved in the United States as an oral treatment for relapsing forms of multiple sclerosis. The most common adverse events associated with DR-DMF are flushing and gastrointestinal (GI) events, the incidences of which diminish over time.
OBJECTIVE
The purpose of this study was to evaluate the tolerability and pharmacokinetic (PK) profile of DR-DMF with or without concomitant acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor.
METHODS
Healthy volunteers (N = 56) were randomized to receive different dosing regimens of DR-DMF or matching placebo with or without pretreatment with 325 mg aspirin for 4 days. Plasma levels of the active metabolite monomethyl fumarate were assessed on days 1 and 4. Flushing and GI events were assessed using patient-reported scales. Potential flushing mediators were explored.
RESULTS
DR-DMF showed a safety, tolerability, and PK profile consistent with previous clinical experience, with no evidence of accumulation. Pretreatment with aspirin had no effect on the primary PK parameters, AUC0-10h, or Cmax. Flushing severity, assessed by 2 subject-reported rating scales, was generally mild and was rated highest at the start of treatment. Pretreatment with aspirin reduced flushing incidence and intensity without affecting GI events or the PK profile of DR-DMF. In some DR-DMF-treated individuals, plasma concentrations of a prostaglandin D2 (PGD2) metabolite were increased.
CONCLUSIONS
In healthy volunteers, DR-DMF was well tolerated over 4 days of dosing, with a PK profile consistent with that previously reported and no evidence of accumulation. Aspirin pretreatment reduced the incidence and intensity of flushing without affecting GI events or the DR-DMF PK profile. Elevated levels of PGD2 in some DR-DMF-treated individuals suggest that flushing may be, at least in part, prostaglandin mediated. ClinicalTrials.gov identifier: ID: NCT01281111.
Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cyclooxygenase Inhibitors; Delayed-Action Preparations; Digestive System; Dimethyl Fumarate; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Flushing; Fumarates; Healthy Volunteers; Humans; Male; Middle Aged; Treatment Outcome; Young Adult
PubMed: 24139424
DOI: 10.1016/j.clinthera.2013.08.009 -
Iranian Journal of Neurology Jul 2019Glioblastoma multiforme (GBM), the most frequent malignant and aggressive primary brain tumor, is characterized by genetically unstable heterogeneous cells, diffused... (Review)
Review
Glioblastoma multiforme (GBM), the most frequent malignant and aggressive primary brain tumor, is characterized by genetically unstable heterogeneous cells, diffused growth pattern, microvascular proliferation, and resistance to chemotherapy. Extensive investigations are being carried out to identify the molecular origin of resistance to chemo- and radio-therapy in GBM and find novel targets for therapy to improve overall survival rate. Dimethyl fumarate (DMF) has been shown to be a safe drug with limited short and long-term side effects, and fumaric acid esters (FAEs), including DMF, present both anti-oxidative and anti-inflammatory activity in different cell types and tissues. DMF has also anti-tumoral and neuroprotective effects and so it could be repurposed in the treatment of this invasive tumor in the future. Here, we have reviewed DMF pharmacokinetics and different mechanisms by which DMF could have therapeutic effects on GBM.
PubMed: 31749934
DOI: No ID Found -
BMC Research Notes Sep 2016Oral disease-modifying therapies offer equivalent or superior efficacy and greater convenience versus injectable options. (Comparative Study)
Comparative Study Observational Study
BACKGROUND
Oral disease-modifying therapies offer equivalent or superior efficacy and greater convenience versus injectable options.
OBJECTIVES
To compare patient-reported experiences of fingolimod and dimethyl fumarate.
METHODS
Adult relapsing-remitting multiple sclerosis patients treated with fingolimod or dimethyl fumarate were recruited from an online patient community and completed an online survey about treatment side effects, discontinuation, and satisfaction.
RESULTS
281 patients in four groups completed the survey: currently receiving fingolimod (CF, N = 61), currently receiving dimethyl fumarate (CDMF, N = 129), discontinued fingolimod (DF, N = 32) and discontinued dimethyl fumarate (DDMF, N = 59). Reasons for treatment switch were to take oral treatment (CF: 63.3 %, CDMF: 61.8 %), side effects of prior medication (CF: 67.3 %, CDMF: 44.1 %) and lack of effectiveness of prior medication (CF: 38.8 %, CDMF: 31.4 %). Main reasons for discontinuation were side effects (DF: 46.9 %, DDMF: 67.8 %) and lack of effectiveness (DF: 25.0 %, DDMF: 15.3 %). CDMF patients had an increased risk of abdominal pain, flushing, diarrhea, and nausea. Treatment satisfaction was highest among CF patients followed by CDMF, DF, and then DDMF patients.
CONCLUSIONS
Discontinuation was driven by experience of side effects. Patients currently taking dimethyl fumarate were more likely to experience a side effect versus patients currently taking fingolimod. Examination of the relationship between tolerability and adherence/persistence is needed.
Topics: Adult; Aged; Cross-Sectional Studies; Dimethyl Fumarate; Female; Fingolimod Hydrochloride; Health Surveys; Humans; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Patient Satisfaction; Surveys and Questionnaires
PubMed: 27604188
DOI: 10.1186/s13104-016-2243-8