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Genetic Study of Severe Prolonged Lymphopenia in Multiple Sclerosis Patients Treated With Dimethyl Fumarate.

In delayed-release dimethyl fumarate (DMF)-treated patients, absolute lymphocyte count (ALC) often declines in the first year and stabilizes thereafter; early declines have been associated with development of severe prolonged lymphopenia (SPL). Prolonged moderate or severe lymphopenia is a known risk factor for progressive multifocal leukoencephalopathy (PML); DMF-associated PML is very rare. It is unknown whether genetic predictors of SPL secondary to DMF treatment exist. We aimed to identify genetic predictors of reduced white blood cell (WBC) counts in DMF-treated multiple sclerosis (MS) pa…

Persistence with dimethyl fumarate in relapsing-remitting multiple sclerosis: a population-based cohort study.

PurposeTo describe patients initiating dimethyl fumarate (DMF) and measure persistence with DMF, discontinuation, and switching in treatment-naïve DMF patients and patients switching to DMF from other multiple sclerosis disease-modifying treatments (DMTs).MethodsA population-based cohort study of all Stockholm County residents initiating DMF from 9 May 2014 until 31 May 2017. All data were derived from a regional database that collects individual-level data on healthcare and drug utilization of all residents. The study outcomes were persistence with DMF and DMF discontinuation and switching to…

New onset lymphopenia in patients with relapsing multiple sclerosis switching from long-standing dimethyl fumarate treatment to diroximel fumarate: A case series.

Lymphopenia is a known adverse effect in patients with relapsing multiple sclerosis (RMS) treated with fumaric acids. We present a case series of four patients diagnosed with RMS with prolonged lymphocyte stability on dimethyl fumarate for over 1 year who developed significant lymphopenia after transitioning to diroximel fumarate. This case series highlights the need for further research to elucidate the risk of lymphopenia in patients switching between fumaric acids.

Dimethyl [1,4-13C2]Fumarate as a Molecular Sensor for Gluconeogenesis in Renal versus Hepatic Tissues.

The TCA cycle intermediate fumarate is converted to malate by fumarase. Because the fumarate dianion enters intact cells slowly but readily penetrates into necrotic cells with compromised membranes, hyperpolarized (HP) [1,4-13C2]fumarate has been established as a molecular imaging probe for detecting cellular necrosis based on its conversion to [1,4-13C2]malate. To broaden its utility to viable cells, we developed HP-13C-labeled fumarate esters, assuming that esterification would improve membrane permeability and cellular uptake. Since fumarate is metabolized through malate to oxaloacetate, a

Dimethyl fumarate attenuates bile acid retention and liver fibrosis in a mouse model of cholestasis.

Cholestatic liver diseases are characterized by intrahepatic accumulation of bile acids (BAs), exacerbating liver inflammation, and fibrosis. Dimethyl fumarate (DMF) is a clinically approved anti-inflammatory drug that demonstrated protective effects in several experimental models of liver injury. Still, its effect on BA homeostasis and liver fibrosis has not been thoroughly studied. Herein, we hypothesized that DMF could improve BA homeostasis and mitigate the progression of cholestasis-induced liver fibrosis. The DMF was administered to mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DD…

Гибридные нанопчасти на основе гиалюронной кислоты в качестве перспективных перевозчиков Интранасальной администрации диметилФумарата.

ПППОСА: Диметилфумарат (ДМФ) - пероральная терапия с релапсирующим множественным склерозом, быстро метаболизируется в монометилфумарат. Оральное управление DMF вызывает желудочно-кишечный дискомфорт, вызывая вынос лечения. Цель настоящего исследования заключается в разработке новаторской формулировки для управления носовым слоем ДМФ. Гибридные наночастицы (LPN) липидового полимера были разработаны для повышения устойчивости DMF, ограничения побочных эффектов желудочно-кишечного кишечника и увеличения биодоступности головного мозга за счет нацеливания нос на мозг.МЕТОДЫ: С помощью методов магни

Совпадение в аннотации оригинала
PURPOSE: Dimethyl fumarate (DMF), the first-line oral therapy for relapsing-remitting multiple sclerosis, is rapidly metabolized into monomethyl fumarate. The DMF oral administration provokes gastrointestinal discomfort causing treatment withdrawal. The present study aimed to develop an innovative formulation for DMF nasal administration. Lipid-polymer hybri…

Dimethyl Fumarate Used as an Effective Treatment for Granuloma Annulare Disseminatum: An Immunohistochemical Case Study.

This investigation demonstrates the use of dimethyl fumarate (DMF) for the treatment of disseminated granuloma annulare (GAD), a rare and chronic inflammatory skin disease. In this case, progressive GAD was treated with DMF, resulting in significant improvement of skin lesions within 5 weeks and complete healing within 7 months. Clinical response was associated with a reduction in inflammatory cells, including both T cell subsets (CD4+ > CD8+), CD183+/CXCR3+ cells, Langerhans cells (CD1a+), myeloid DCs, M1- and M2-like macrophages and the activation marker HLA-DR in immunohistochemical analysi…

CORRIGENDUM to Progressive multifocal leukoencephalopathy outcomes in patients with multiple sclerosis treated with dimethyl fumarate.

[This corrects the article DOI: 10.1177/20552173221132469.].

Dimethyl Fumarate-Loaded Transethosomes: A Formulative Study and Preliminary Ex Vivo and In Vivo Evaluation.

In this study, transethosomes were investigated as potential delivery systems for dimethyl fumarate. A formulative study was performed investigating the effect of the composition of transethosomes on the morphology and size of vesicles, as well as drug entrapment capacity, using cryogenic transmission electron microscopy, photon correlation spectroscopy, and HPLC. The stability of vesicles was evaluated, both for size increase and capability to control the drug degradation. Drug release kinetics and permeability profiles were evaluated in vitro using Franz cells, associated with different synt…

Thyroid Disorders in Patients Treated with Dimethyl Fumarate for Multiple Sclerosis: A Retrospective Observational Study.

BACKGROUND: Dimethyl fumarate (DMF), a drug used for the treatment of multiple sclerosis (MS) and psoriasis, has been shown to activate the Keap1/Nrf2 antioxidant response. Nrf2 exerts pleiotropic roles in the thyroid gland; among others, single nucleotide polymorphisms (SNPs) in the gene encoding Nrf2 modulate the risk of Hashimoto's thyroiditis (HT), suggesting that pharmacological activation of Nrf2 might also be protective. However, a patient with acute exacerbation of HT after starting DMF for MS was recently reported, raising questions about the thyroidal safety of Nrf2 activators. METH…

Relationship between lymphopenia and disease activity in persons with multiple sclerosis treated with dimethyl fumarate.

BACKGROUND: Dimethyl fumarate (DMF) is a disease-modifying therapy (DMT) used to treat relapsing multiple sclerosis (MS). Its precise mechanism in treating MS involves nuclear factor erythroid-derived 2-related factor-dependent and -independent pathways. Lymphopenia, defined according to NIH Common Terminology for Adverse Events v5.0, is one potential adverse effect. It is unclear whether lymphopenia correlates with disease activity; existing studies have yielded conflicting results. OBJECTIVE: To determine whether lymphopenia in DMF-treated persons with MS (PwMS) correlates with disease acti…

Control of Oxidative Stress and Inflammation in Sickle Cell Disease with the Nrf2 Activator Dimethyl Fumarate.

AIMS: Heme derived from hemolysis is pro-oxidative and proinflammatory and promotes vaso-occlusion in murine models of sickle cell disease (SCD), suggesting that enhanced detoxification of heme may be beneficial. Nuclear factor erythroid-2-related factor-2 (Nrf2) transcription pathway is the principal cellular defense system responding to pro-oxidative and proinflammatory stress. Dimethyl fumarate (DMF), a drug approved for treatment of multiple sclerosis, provides neuroprotection by activating Nrf2-responsive genes. We hypothesized that induction of Nrf2 with DMF would be beneficial in murine…

Tolerability and pharmacokinetics of delayed-release dimethyl fumarate administered with and without aspirin in healthy volunteers.

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…

Bioequivalence of tegomil fumarate gastro-resistant capsules versus dimethyl fumarate gastro-resistant capsules under different fed conditions: two randomized, crossover, phase I studies.

OBJECTIVE: Tegomil fumarate is a newly approved treatment for relapsing-remitting multiple sclerosis. Two phase I studies were performed under different fed conditions to evaluate the bioequivalence and tolerability of tegomil fumarate versus dimethyl fumarate in healthy volunteers. METHODS: These were single-center, open-label, randomized, crossover (full replicate design), phase I studies. In both studies, healthy individuals aged 18-55 years received a single dose of tegomil fumarate (348.4 mg gastro-resistant hard capsule; "test") or an equimolar dose of dimethyl fumarate based on monomet…

Dimethyl Fumarate, But Not Rituximab, Reduces Serum GFAP Levels and PIRMA in Relapsing-Remitting MS.

OBJECTIVE: Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels are believed to reflect mainly acute and chronic disease processes in multiple sclerosis (MS), respectively. In this study, we investigated whether dimethyl fumarate (DMF) and rituximab (RTX) differentially affect these biomarkers. METHODS: RIFUND-MS was a 2-year, rater-blinded, 1:1 randomized controlled multicenter trial comparing DMF and RTX in relapsing-remitting multiple sclerosis (RRMS). Serum samples for analysis of sNFL and sGFAP were collected at baseline and 0, 6, 12 and 24. Log-trans…

The Emerging Role of Dimethyl Fumarate in Alzheimer's Disease-A Systematic Review of Available Preclinical Studies.

Dimethyl fumarate (DMF), a fumaric acid ester, is approved for psoriasis and multiple sclerosis due to its antioxidant and anti-inflammatory properties mediated via Nrf2 activation. Nrf2 regulates genes that protect cells from oxidative stress, a key factor in neurodegenerative diseases such as Alzheimer's disease (AD), which is characterized by amyloid-β and tau accumulation and lipid peroxidation. This systematic review aimed to evaluate preclinical evidence for DMF as a potential therapeutic agent in AD models through Nrf2 activation. A comprehensive literature search of PubMed and Scopus (…

Omaveloxolone, But Not Dimethyl Fumarate, Improves Cardiac Function in Friedreich's Ataxia Mice With Severe Cardiomyopathy.

BACKGROUND: Friedreich's ataxia (FA) is a genetic disorder caused by a severe decrease in FXN (frataxin) protein expression in mitochondria. The clinical manifestation of this disorder is a cerebellar ataxia; however, the common lethal component in FA is cardiomyopathy. METHODS: A conditional Fxnflox/null::MCK-Cre knockout (FXN-cKO) mouse model was used to mimic the late-stage severe cardiomyopathy in FA. Nrf2 (nuclear factor erythroid 2-related factor 2) inducers, omaveloxolone and dimethyl fumarate (DMF), were independently tested in this mouse model to determine the effects on cardiac heal…

Repurposing Dimethyl Fumarate Targeting Nrf2 to Slow Down the Growth of Areas of Geographic Atrophy.

Recently, marketing authorizations were granted by the Federal Drug Administration (FDA) for pegcetacoplan and avacincaptad pegol, which inh … inflammation are two major potential targets to limit the progression of atrophic retinal lesions. Dimethyl fumarate, dimethyl itaconate and other activators of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) display antioxidants and immunomodulatory properties that have shown evidence of efficacy in in vitro and in vivo models of dry A …

Диет модернизирует терапевтическое воздействие диметилфумарата, поддерживаемого иммунометаболическим нейтрофильным рецептором HCAR2.

Монометилфумарат (ММФ) и его пронаркодиметилфумарат (ДМП) в настоящее время являются наиболее широко используемыми агентами для лечения множественных склерозов (МС). Однако не все пациенты получают помощь от ДМФ. Мы предположили, что переменная реакция пациентов может быть связана с их питанием. В поддержку этой гипотезы мыши, подвергшиеся экспериментальному аутоиммунальному энцефаломиэлиту (EAE), являющемуся моделью MS, не пользовались лечением DMF при питании богатой лауричной кислотой диетой. В противоположность этому, мыши на нормальном питании чау (NC) и даже мыши на рационе с высоким сод

Совпадение в аннотации оригинала
Monomethyl fumarate (MMF) and its prodrug dimethyl fumarate (DMF) are currently the most widely used agents for the treatment of multiple sclerosis (MS). However, not all patients benefit from DMF. We hypothesized that the variable response of patients may be due to their diet. In support of this hypothesis, mice subjected to experimental autoimmune encephal…

Effect of smoking on disease activity in multiple sclerosis patients treated with dimethyl fumarate or fingolimod.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), smoking is a known risk factor for disease susceptibility and disability progression. However, its impact on the efficacy of oral disease-modifying drugs (DMDs) is unclear. Therefore, we initiated a single-center, retrospective, observational study to investigate the relationship between smoking and disease activity in RRMS patients under oral DMDs. METHODS: We retrospectively enrolled RRMS patients who initiated oral DMDs (fingolimod or dimethyl fumarate) at our hospital between January 2012 and December 2019. Clinical data and sm…