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1.
Rev Neurol ; 76(s01): S1-S6, 2023 Jan 31.
Artigo em Espanhol | MEDLINE | ID: mdl-36683265

RESUMO

INTRODUCTION: Multiple sclerosis is a chronic neurological disease with numerous disease-modifying treatments available, including dimethyl fumarate (DMF), a first-line therapy for relapsing-remitting multiple sclerosis. Although rates of discontinuation of DMF are generally low in clinical trials, non-adherence to treatment is associated with poorer clinical outcomes. Assessing real-world adherence and predictive factors is critical to be able to improve clinical outcomes for patients. This study evaluated adherence to DMF over 24 months in a cohort of patients treated in a Portuguese healthcare centre. PATIENTS AND METHODS: A prospective, non-interventional, single-centre study with 24 months' follow-up was conducted. The study included adult patients with relapsing-remitting multiple sclerosis treated with DMF in routine clinical practice. Adherence to DMF was calculated and patients were considered to have adhered if the value was above 80%. Clinical and socio-demographic variables were compared between groups. RESULTS: Of the 80 patients included, 74% were women, with a mean age of 39 years and a mean age of 32 years at diagnosis. Twenty-six patients had not received any previous treatment. Adherence varied between 93, 82 and 87.5% at 6, 12 and 24 months, respectively. No differences were found between patients who had not received any prior treatment and those who had been treated. CONCLUSION: This real-world analysis showed significant adherence to DMF treatment by Portuguese patients over a period of two years. However, these results must be interpreted in the light of the substantial changes in outpatient consultations and the various periodic restrictions due to the COVID-19 pandemic, which had an important effect on patient follow-up and data collection.


TITLE: Adhesión real al dimetilfumarato en pacientes con esclerosis múltiple remitente-recurrente.Introducción. La esclerosis múltiple es una enfermedad neurológica crónica con numerosos tratamientos modificadores de la enfermedad disponibles, incluido el dimetilfumarato (DMF), una terapia de primera línea para la esclerosis múltiple remitente-recurrente. Aunque las tasas de discontinuación del DMF suelen ser bajas en los ensayos clínicos, la falta de adhesión al tratamiento se asocia con peores resultados clínicos. Evaluar la adhesión en el mundo real y los factores predictivos es fundamental para mejorar los resultados clínicos de los pacientes. Este estudio evaluó la adhesión al DMF durante 24 meses en una cohorte de pacientes tratados en un centro portugués. Pacientes y métodos. Estudio prospectivo no intervencionista, de un solo centro, con un seguimiento de 24 meses. El estudio incluyó a pacientes adultos con esclerosis múltiple remitente-recurrente tratados con DMF en la práctica clínica habitual. Se calculó la adhesión al DMF y se consideró que los pacientes eran adherentes si el valor estaba por encima del 80%. Se compararon variables clínicas y sociodemográficas entre grupos. Resultados. De los 80 pacientes incluidos, el 74% eran mujeres, con una edad media de 39 años y una edad media en el momento del diagnóstico de 32 años. Veintiséis pacientes no habían recibido tratamiento previo. La adhesión varió entre el 93, el 82 y el 87,5% a los 6, 12 y 24 meses, respectivamente. No se encontraron diferencias entre los pacientes que no habían recibido tratamiento previo y los que sí lo habían recibido. Conclusión. Este análisis en el mundo real mostró una adhesión significativa al tratamiento con DMF durante dos años por parte de los pacientes portugueses. No obstante, estos resultados deben interpretarse considerando los cambios sustanciales en las consultas externas y las diversas restricciones periódicas debidas a la pandemia de COVID-19, que afectaron en gran medida al seguimiento de los pacientes y a la recopilación de datos.


Assuntos
COVID-19 , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Adulto , Humanos , Feminino , Masculino , Fumarato de Dimetilo/uso terapêutico , Fumarato de Dimetilo/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Pandemias , Estudos Prospectivos
2.
Int J Mol Sci ; 24(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36675014

RESUMO

(1) Multiple sclerosis (MS) is a chronic inflammatory disease of autoimmune origin. The Epstein-Barr virus (EBV) is associated with the onset of MS, as almost all patients have high levels of EBV-specific antibodies as a result of a previous infection. We evaluated longitudinally the effects of dimethyl fumarate (DMF), a first-line treatment of MS, on the quantity and quality of EBV-specific IgG in MS patients. (2) Serum samples from 17 MS patients receiving DMF were taken before therapy (T0) and after 1 week (T1) and 1 (T2), 3 (T3) and 6 (T4) months of treatment. Anti-EBV nuclear antigen (EBNA)-1 and capsid antigen (CA) IgG levels and anti-CA IgG avidity were measured in all samples. (3) Serum levels of anti-CA IgG were lower at T1 (p = 0.0341), T2 (p = 0.0034), T3 (p < 0.0001) and T4 (p = 0.0023) than T0. These differences were partially confirmed also in anti-EBNA-1 IgG levels (T3 vs. T0, p = 0.0034). All patients had high-avidity anti-CA IgG at T0, and no changes were observed during therapy. (4): DMF can reduce the amount but not the avidity of the anti-EBV humoral immune response in MS patients from the very early stages of treatment.


Assuntos
Infecções por Vírus Epstein-Barr , Esclerose Múltipla , Humanos , Herpesvirus Humano 4 , Antígenos Virais , Projetos Piloto , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Capsídeo , Formação de Anticorpos , Imunoglobulina G , Anticorpos Antivirais , Proteínas do Capsídeo
3.
J Comp Eff Res ; 12(2): e220193, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36705064

RESUMO

Aim: To analyze the cost-effectiveness of treatment of relapsing remitting multiple sclerosis (RRMS) with cladribine tablets (CladT) and dimethyl fumarate (DMF) from the perspective of the Spanish National Health System (NHS). Methods: A probabilistic Markov model (second-order Monte Carlo simulation) with a 10-year time horizon and annual Markov cycles was performed. Results: CladT was the dominant treatment, with lower costs (-74,741 € [95% CI: -67,247; -85,661 €]) and greater effectiveness (0.1920 [95% CI: -0.1659; 0.2173] QALY) per patient, compared with DMF. CladT had a 95.1% probability of being cost-effective and a 94.1% chance of being dominant compared with DMF. Conclusion: CladT is the dominant treatment (lower costs, with more QALYs) compared with DMF in the treatment of RRMS in Spain.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Fumarato de Dimetilo/uso terapêutico , Cladribina/uso terapêutico , Imunossupressores/uso terapêutico , Análise Custo-Benefício , Espanha
4.
J Med Econ ; 26(1): 139-148, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36546701

RESUMO

BACKGROUND: Several disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis (RRMS) reduce relapse rates and slow disease progression. RRMS DMTs have varying efficacy and administration routes; DMTs prescribed first may not be the most effective on relapses or disease progression. Here, we aimed to quantify the benefit of initiating ofatumumab, a high-efficacy DMT, earlier in the treatment pathway. METHODS: Aggregate data from a real-world cohort of patients with RRMS, who were eligible for dimethyl fumarate (DMF) or ofatumumab treatment within the UK National Health Service (N = 615), were used to produce a simulated patient cohort. The cohort was tracked through a discrete event simulation (DES) model, based on the Expanded Disability Status Scale (EDSS), with a lifetime time horizon. Outcomes assessed were: mean number of relapses, time to wheelchair (EDSS ≥7), and time to death. Two modeling approaches were used. The first compared outcomes between two treatment sequences (base case: ofatumumab to natalizumab versus DMF to ofatumumab). The second incorporated a time-specific delay of 1-5 years for switching from DMF to ofatumumab; the difference in outcomes as a function of increasing delay to ofatumumab are reported. RESULTS: Compared with delayed ofatumumab, fewer relapses and increased time to wheelchair were predicted for earlier ofatumumab in the treatment-sequence approach (mean relapses over the lifetime time horizon: 8.63 versus 9.00; time to wheelchair: 17.55 versus 16.60 years). Time to death was similar for both sequences. At Year 10, a numerically greater proportion of patients receiving earlier ofatumumab had mild disease (EDSS 0-3: 44.12% versus 40.06%). Greater differences, reflecting poorer outcomes, were predicted for relapses and time to wheelchair with increasing delays to ofatumumab treatment. CONCLUSIONS: The DES model provided a means by which the magnitude of benefit associated with earlier ofatumumab initiation could be quantified; fewer relapses and a prolonged time to wheelchair were predicted.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Medicina Estatal , Fumarato de Dimetilo/uso terapêutico , Progressão da Doença , Imunossupressores
5.
Artigo em Inglês | MEDLINE | ID: mdl-36411079

RESUMO

BACKGROUND AND OBJECTIVES: To identify biomarkers associated with treatment response in patients with multiple sclerosis (MS) treated with the oral therapies teriflunomide, dimethyl fumarate (DMF), and fingolimod. METHODS: Serum levels of IL-6, IL-17, TNF-α, granulocyte-macrophage colony-stimulating factor, IL-10, interferon-gamma (IFN-γ) IL-1ß, and chemokine ligand 13 (CXCL13) were measured at baseline and 12 months with single molecule array (Simoa) assays in a cohort of patients with MS treated with teriflunomide (N = 19), DMF (N = 22), and fingolimod (N = 25) and classified into "no evidence of disease activity" (NEDA) and EDA patients after 1 year of treatment. RESULTS: Serum CXCL13 and TNF-α levels were significantly decreased after treatment with teriflunomide in NEDA compared with EDA patients after 1 year of treatment (p = 0.008 for both cytokines). These findings were validated in an independent cohort of patients with MS treated with teriflunomide (N = 36) and serum CXCL13, and TNF-α levels were again significantly reduced in NEDA patients (p < 0.0001 for CXCL13 and p = 0.003 for TNF-α). CXCL13, but not TNF-α, showed good performance to classify NEDA and EDA patients according to a cut-off value of 9.64 pg/mL based on the change in CXCL13 levels between baseline and 12 months, with a sensitivity of 75% and specificity of 82% in the original cohort, and sensitivity of 65.4% and specificity of 60% in the validation cohort. DISCUSSION: Altogether, these results point to CXCL13 as a treatment response biomarker to teriflunomide in relapsing-remitting patients with MS, and the change in CXCL13 levels during the first year of treatment can be used in clinical practice to identify optimal responders to teriflunomide.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Cloridrato de Fingolimode/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Imunossupressores/uso terapêutico , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Quimiocina CXCL13
6.
Free Radic Biol Med ; 194: 284-297, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36528121

RESUMO

Dimethyl fumarate (DMF) is pharmaceutical activator of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates of many cellular antioxidant response pathways, and has been used to treat inflammatory diseases such as multiple sclerosis. However, DMF has been shown to produce adverse effects on offspring in animal studies and as such is not recommended for use during pregnancy. The goal of this work is to better understand how these adverse effects are initiated and the role of DMF-induced Nrf2 activation during three critical windows of development in embryonic zebrafish (Danio rerio): pharyngula, hatching, and protruding-mouth stages. To evaluate Nrf2 activation, wildtype zebrafish, and mutant zebrafish (nrf2afh318/fh318) embryos with a loss of function mutation in Nrf2a, the co-ortholog to human Nrf2, were treated for 6 h with DMF (0-20 µM) beginning at the pharyngula, hatching, or protruding-mouth stage and assessed for survival and morphology. Nrf2a mutant fish had an increase in survival, however, morphology studies demonstrated Nrf2a mutant fish had more severe deformities occurring with exposures during the hatching stage. To verify Nrf2 cellular localization and downstream impacts on protein-S-glutathionylation in situ, a concentration below the LOAEL was chosen (7 µM) for immunohistochemistry and S-glutathionylation. Embryos were imaged via epifluorescence microscopy studies, the Nrf2a protein in the body tissue was decreased with DMF only when exposed at the hatching stage, while total protein S-glutathionylation was modulated by Nrf2a activity and DMF during the pharyngula and protruding-mouth stage. The pancreatic islet and liver were further analyzed via confocal microscopy. Pancreatic islets and liver also had tissue specific differences with Nrf2a protein expression and protein S-glutathionylation. This work demonstrates how critical windows of exposure and Nrf2a activity may influence toxicity of DMF and highlights tissue-specific changes in Nrf2a protein levels and S-glutathionylation in pancreatic islet and liver during embryonic development.


Assuntos
Fumarato de Dimetilo , Peixe-Zebra , Animais , Humanos , Peixe-Zebra/genética , Fumarato de Dimetilo/farmacologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Antioxidantes/farmacologia , Estresse Oxidativo
7.
Redox Biol ; 59: 102560, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36493513

RESUMO

α,ß-Unsaturated carbonyls are a common motif in environmental toxins (e.g. acrolein) as well as therapeutic drugs, including dimethylfumarate (DMFU) and monomethylfumarate (MMFU), which are used to treat multiple sclerosis and psoriasis. These compounds form adducts with protein Cys residues as well as other nucleophiles. The specific targets ('adductome') that give rise to their therapeutic or toxic activities are poorly understood. This is due, at least in part, to the absence of antigens or chromophores/fluorophores in these compounds. We have recently reported click-chemistry probes of DMFU and MMFU (Redox Biol., 2022, 52, 102299) that allow adducted proteins to be visualized and enriched for further characterization. In the current study, we hypothesized that adducted proteins could be 'clicked' to agarose beads and thereby isolated for LC-MS analysis of DMFU/MMFU targets in primary human coronary artery smooth muscle cells. We show that the probes react with thiols with similar rate constants to the parent drugs, and give rise to comparable patterns of gene induction, confirming similar biological actions. LC-MS proteomic analysis identified ∼2970 cellular targets of DMFU, ∼1440 for MMFU, and ∼140 for the control (succinate-probe) treated samples. The most extensively modified proteins were galectin-1, annexin-A2, voltage dependent anion channel-2 and vimentin. Other previously postulated DMFU targets, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), cofilin, p65 (RELA) and Keap1 were also identified as adducted species, though at lower levels with the exception of GAPDH. These data demonstrate the utility of the click-chemistry approach to the identification of cellular protein targets of both exogenous and endogenous compounds.


Assuntos
Fumarato de Dimetilo , Galectina 1 , Humanos , Fumarato de Dimetilo/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch , Proteômica , Fator 2 Relacionado a NF-E2
8.
Mult Scler Relat Disord ; 68: 104371, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36544318

RESUMO

BACKGROUND: It remains unclear how vaccine doses and combinations of vaccination and infection affect the magnitude and quality of immune responses, particularly against novel SARS-CoV-2 variants in subjects with immune-related disorders, such as people with multiple sclerosis (pwMS). Several studies have evaluated the duration of anti-SARS-CoV-2 immune protection in healthy individuals; however clinical data suggest an attenuated short-term humoral response to SARS-CoV-2 vaccines in pwMS receiving disease-modifying therapies (DMTs). METHODS: In this prospective study, we evaluated the humoral response to the third (3rd) BNT162b2 vaccine (booster) dose in a monocentric cohort of pwMS undergoing eight different DMTs, all without previous SARS-CoV-2 infection. Quantitative determination of SARS-CoV-2 IgG Spike titre was carried out by anti-SARS-CoV-2 S assay in 65 pwMS and 9 healthy controls, all without previous SARS-CoV-2 infection. Moreover, these measurements were also compared to their relative levels at 21 days (T1) and ∼6 months (T2) after the second (2nd) vaccination. RESULTS: We observed that the humoral response to the booster dose in Interferon ß-1a-, Dimethyl fumarate- and Teriflunomide-treated pwMS is comparable to healthy controls, while increased in Cladribine-treated pwMS. Additionally, the 3rd dose elicits a seroconversion in the 100% of pwMS under Fingolimod and in the 65% of those under Ocrelizumab. Moreover, multivariate regression analysis showed that treatment with Interferon ß-1a, Dimethyl fumarate and Cladribine positively associates with an increased humoral response. CONCLUSIONS: Taken together this evidence strongly indicates the importance of the booster dose to enhance SARS-CoV-2-specific immunity especially in immunocompromised subjects, such as pwMS under DMTs.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Esclerose Múltipla , Humanos , Anticorpos Antivirais , Vacina BNT162 , Cladribina , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Fumarato de Dimetilo , Interferon beta-1a , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Estudos Prospectivos , SARS-CoV-2 , Vacinação/métodos
9.
Cells ; 11(24)2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-36552824

RESUMO

Dimethyl fumarate (DMF) is a small molecule currently approved and used in the treatment of psoriasis and multiple sclerosis due to its immuno-modulatory, anti-inflammatory, and antioxidant properties. As an Nrf2 activator through Keap1 protein inhibition, DMF unveils a potential therapeutical use that is much broader than expected so far. In this comprehensive review we discuss the state-of-art and future perspectives regarding the potential repositioning of this molecule in the panorama of eye pathologies, including Age-related Macular Degeneration (AMD). The DMF's mechanism of action, an extensive analysis of the in vitro and in vivo evidence of its beneficial effects, together with a search of the current clinical trials, are here reported. Altogether, this evidence gives an overview of the new potential applications of this molecule in the context of ophthalmological diseases characterized by inflammation and oxidative stress, with a special focus on AMD, for which our gene-disease (KEAP1-AMD) database search, followed by a protein-protein interaction analysis, further supports the rationale of DMF use. The necessity to find a topical route of DMF administration to the eye is also discussed. In conclusion, the challenge of DMF repurposing in eye pathologies is feasible and worth scientific attention and well-focused research efforts.


Assuntos
Fumarato de Dimetilo , Fator 2 Relacionado a NF-E2 , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Antioxidantes/metabolismo
10.
Int J Mol Sci ; 23(24)2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36555093

RESUMO

The disorder of adult neurogenesis is considered an important mechanism underlying the learning and memory impairment observed in Alzheimer's disease (AD). The sporadic nonhereditary form of AD (sAD) affects over 95% of AD patients and is related to interactions between genetic and environmental factors. An intracerebroventricular injection of streptozotocin (STZ-ICV) is a representative and well-established method to induce sAD-like pathology. Dimethyl fumarate (DMF) has antioxidant and anti-inflammatory properties and is used for multiple sclerosis treatment. The present study determines whether a 26-day DMF therapy ameliorates the disruption of adult neurogenesis and BDNF-related neuroprotection in the hippocampus and olfactory bulb (OB) in an STZ-ICV rat model of sAD. Considering age as an important risk factor for developing AD, this study was performed using 3-month-old (the young group) and 22-month-old (the aged group) male Wistar rats. Spatial cognitive functions were evaluated with the Morris water maze task. Immunofluorescent labelling was used to assess the parameters of adult neurogenesis and BDNF-related neuroprotection in the hippocampus and OB. Our results showed that the STZ-ICV evoked spatial learning and memory impairment and disturbances in adult neurogenesis and BDNF expression in both examined brain structures. In the aged animals, the deficits were more severe. We found that the DMF treatment significantly alleviated STZ-ICV-induced behavioural and neuronal disorders in both age groups of the rats. Our findings suggest that DMF, due to its beneficial effect on the formation of new neurons and BDNF-related neuroprotection, may be considered as a promising new therapeutic agent in human sAD.


Assuntos
Doença de Alzheimer , Fumarato de Dimetilo , Animais , Humanos , Masculino , Ratos , Doença de Alzheimer/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição , Fumarato de Dimetilo/farmacologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Neurogênese , Bulbo Olfatório/metabolismo , Ratos Wistar , Estreptozocina/efeitos adversos
11.
Sci Rep ; 12(1): 20300, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36434122

RESUMO

The endocannabinoid system (ECS), a signalling network with immunomodulatory properties, is a potential therapeutic target in multiple sclerosis (MS). Dimethyl fumarate (DMF) is an approved drug for MS whose mechanism of action has not been fully elucidated; the possibility exists that its therapeutic effects could imply the ECS. With the aim of studying if DMF can modulate the ECS, the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were determined by liquid chromatography-mass spectrometry in peripheral blood mononuclear cells from 21 healthy donors (HD) and 32 MS patients at baseline and after 12 and 24 months of DMF treatment. MS patients presented lower levels of 2-AG and PEA compared to HD. 2-AG increased at 24 months, reaching HD levels. AEA and PEA remained stable at 12 and 24 months. OEA increased at 12 months and returned to initial levels at 24 months. Patients who achieved no evidence of disease activity (NEDA3) presented the same modulation over time as EDA3 patients. PEA was modulated differentially between females and males. Our results show that the ECS is dysregulated in MS patients. The increase in 2-AG and OEA during DMF treatment suggests a possible role of DMF in ECS modulation.


Assuntos
Endocanabinoides , Esclerose Múltipla , Masculino , Feminino , Humanos , Fumarato de Dimetilo/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Leucócitos Mononucleares
12.
Drug Des Devel Ther ; 16: 3915-3927, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36388086

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disorder of the central nervous system. Disease-modifying drugs (DMDs) and subsequent adherence are crucial for preventing reversible episodes of neurological dysfunction and delayed onset of progressive accumulation of irreversible deficits. Yet, side effects may limit their usage in clinical practice. Gastrointestinal (GI) side effects are a significant limitation of the use of dimethyl fumarate (DMF), the most frequently prescribed oral DMD in MS worldwide. Diroximel fumarate (DRF) is a second-generation oral fumaric acid ester (FAE) that was developed as a formulation with better GI tolerability. The improved tolerability is assumed to be related to a lower synthesis of gut-irritating methanol. Other explanations for DRF's lower extent of GI irritation include a more modest off-target activity due to its chemical structure. The superior GI tolerability of DRF compared to DMF could be proven in clinical trials and lead to approval of DRF for the treatment of relapsing forms of MS/relapsing-remitting MS (United States Food and Drug Administration and European Medicines Agency, respectively). Here, we summarize the mode of action of oral FAE and compare the chemical and physiological characteristics of DMF and DRF. Moreover, we discuss the adverse effects of FAE and introduce the emerging preclinical and trial data leading to the approval of DRF in MS. This article additionally reviews our current understanding of coronavirus disease 2019 (COVID-19) and the efficacy of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination in people treated with FAE.


Assuntos
Fumarato de Dimetilo , Esclerose Múltipla , Humanos , COVID-19 , Fumarato de Dimetilo/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Imunossupressores/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , SARS-CoV-2 , Estados Unidos
13.
Gut Microbes ; 14(1): 2147055, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36398902

RESUMO

Mounting evidence points towards a pivotal role of gut microbiota in multiple sclerosis (MS) pathophysiology. Yet, whether disease-modifying treatments alter microbiota composition and whether microbiota shape treatment response and side-effects remain unclear. In this prospective observational pilot study, we assessed the effect of dimethyl fumarate (DMF) on gut microbiota and on host/microbial metabolomics in a cohort of 20 MS patients. Combining state-of-the-art microbial sequencing, metabolome mass spectrometry, and computational analysis, we identified longitudinal changes in gut microbiota composition under DMF-treatment and an increase in citric acid cycle metabolites. Notably, DMF-induced lymphopenia, a clinically relevant safety concern, was correlated with distinct baseline microbiome signatures in MS patients. We identified gastrointestinal microbiota as a key therapeutic target for metabolic properties of DMF. By characterizing gut microbial composition as a candidate risk factor for DMF-induced lymphopenia, we provide novel insights into the role of microbiota in mediating clinical side-effects.


Assuntos
Microbioma Gastrointestinal , Linfopenia , Esclerose Múltipla , Humanos , Fumarato de Dimetilo/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Estudos Prospectivos , Linfopenia/induzido quimicamente , Fatores de Risco
15.
PLoS One ; 17(11): e0278111, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36441753

RESUMO

Dimethyl fumarate (DMF) is a first-line prodrug for the treatment of relapsing-remitting multiple sclerosis (RRMS) that is completely metabolized to monomethyl fumarate (MMF), the active metabolite, before reaching the systemic circulation. Its metabolism has been proposed to be due to ubiquitous esterases in the intestines and other tissues, but the specific enzymes involved are unknown. We hypothesized based on its structure and extensive presystemic metabolism that DMF would be a carboxylesterase substrate subject to interaction with alcohol. We sought to determine the enzymes(s) responsible for the extensive presystemic metabolism of DMF to MMF and the effect of alcohol on its disposition by conducting metabolic incubation studies in human recombinant carboxylesterase-1 (CES1), carboxylesterase-2 (CES2) and human intestinal microsomes (HIM), and by performing a follow-up study in an in vivo mouse model. The in vitro incubation studies demonstrated that DMF was only metabolized to MMF by CES1. Consistent with the incubation studies, the mouse pharmacokinetic study demonstrated that alcohol decreased the maximum concentration and area-under-the-curve of MMF in the plasma and the brain after dosing with DMF. We conclude that alcohol may markedly decrease exposure to the active MMF metabolite in the plasma and brain potentially decreasing the effectiveness of DMF in the treatment of RRMS.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Animais , Camundongos , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Seguimentos , Etanol , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Doença Crônica , Hidrolases de Éster Carboxílico , Recidiva
16.
Brain Nerve ; 74(10): 1179-1187, 2022 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-36198643

RESUMO

Here, an overview of progressive multifocal leukoencephalopathy (PML) and its drug associations, especially the disease-modifying drug (DMD)-associated PML for multiple sclerosis (MS) were discussed. Additionally, along with presenting the current status of PML in MS caused by natalizumab, fingolimod, and dimethyl fumarate, the possibility of PML onset with siponimod and ofatumumab, the two newly proposed DMDs for MS, was provided. PML treatment in the era of DMD-associated PML, especially PML in MS, is an important issue. With respect to the treatment of PML, to date, there are no specific antiviral drugs against the JC virus; some drugs, that may have therapeutic potential reported recently, were also mentioned.


Assuntos
Vírus JC , Leucoencefalopatia Multifocal Progressiva , Esclerose Múltipla , Antivirais/uso terapêutico , Fumarato de Dimetilo/uso terapêutico , Cloridrato de Fingolimode/uso terapêutico , Humanos , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Natalizumab/efeitos adversos
17.
Front Cell Infect Microbiol ; 12: 957287, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36093181

RESUMO

Tuberculosis (TB) claims nearly 1.5 million lives annually. Current TB treatment requires a combination of several drugs administered for at least 6 months. Mycobacterium tuberculosis (Mtb), the causative agent of TB, can persist in infected humans and animals for decades. Moreover, during infection, Mtb produces differentially culturable bacteria (DCB) that do not grow in standard media but can be resuscitated in liquid media supplemented with sterile Mtb culture filtrates or recombinant resuscitation-promoting factors (Rpfs). Here, we demonstrate that, in an intranasal murine model of TB, Mtb DCB are detectable in the lungs after 4 weeks of infection, and their loads remain largely unchanged during a further 8 weeks. Treatment of the infected mice with dimethyl fumarate (DMF), a known drug with immunomodulatory properties, for 8 weeks eliminates Mtb DCB from the lungs and spleens. Standard TB treatment consisting of rifampicin, isoniazid, and pyrazinamide for 8 weeks reduces Mtb loads by nearly four orders of magnitude but does not eradicate DCB. Nevertheless, no DCB can be detected in the lungs and spleens after 8 weeks of treatment with DMF, rifampicin, isoniazid, and pyrazinamide. Our data suggest that addition of approved anti-inflammatory drugs to standard treatment regimens may improve TB treatment and reduce treatment duration.


Assuntos
Mycobacterium tuberculosis , Tuberculose dos Linfonodos , Animais , Antituberculosos/uso terapêutico , Fumarato de Dimetilo/farmacologia , Modelos Animais de Doenças , Humanos , Isoniazida/farmacologia , Camundongos , Pirazinamida/uso terapêutico , Rifampina/farmacologia
18.
Microsc Res Tech ; 85(12): 3777-3792, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36131631

RESUMO

Oxygen-ozone (O2 -O3 ) therapy is an adjuvant/complementary treatment based on the activation of antioxidant and cytoprotective pathways driven by the nuclear factor erythroid 2-related factor 2 (Nrf2). Many drugs, including dimethyl fumarate (DMF), that are used to reduce inflammation in oxidative-stress-related neurodegenerative diseases, act through the Nrf2-pathway. The scope of the present investigation was to get a deeper insight into the mechanisms responsible for the beneficial result of O2 -O3 treatment in some neurodegenerative diseases. To do this, we used an integrated approach of multimodal microscopy (bright-field and fluorescence microscopy, transmission and scanning electron microscopy) and biomolecular techniques to investigate the effects of the low O3 concentrations currently used in clinical practice in lipopolysaccharide (LPS)-activated microglial cells human microglial clone 3 (HMC3) and in DMF-treated LPS-activated (LPS + DMF) HMC3 cells. The results at light and electron microscopy showed that LPS-activation induced morphological modifications of HMC3 cells from elongated/branched to larger roundish shape, cytoplasmic accumulation of lipid droplets, decreased electron density of the cytoplasm and mitochondria, decreased amount of Nrf2 and increased migration rate, while biomolecular data demonstrated that Heme oxygenase 1 gene expression and the secretion of the pro-inflammatory cytokines, Interleukin-6, and tumor necrosis factor-α augmented. O3 treatment did not affect cell viability, proliferation, and morphological features of both LPS-activated and LPS + DMF cells, whereas the cell motility and the secretion of pro-inflammatory cytokines were significantly decreased. This evidence suggests that modulation of microglia activity may contribute to the beneficial effects of the O2 -O3 therapy in patients with neurodegenerative disorders characterized by chronic inflammation. HIGHLIGHTS: Low-dose ozone (O3 ) does not damage activated microglial cells in vitro Low-dose O3 decreases cell motility and pro-inflammatory cytokine secretion in activated microglial cells in vitro Low-dose O3 potentiates the effect of an anti-inflammatory drug on activated microglial cells.


Assuntos
Doenças Neurodegenerativas , Ozônio , Humanos , Microglia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/farmacologia , Fator 2 Relacionado a NF-E2/uso terapêutico , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/uso terapêutico , Ozônio/farmacologia , Ozônio/metabolismo , Ozônio/uso terapêutico , Microscopia , Inflamação/tratamento farmacológico , Citocinas , Fumarato de Dimetilo/metabolismo , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico
19.
Adv Ther ; 39(11): 5072-5086, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36053450

RESUMO

INTRODUCTION: Current guidelines for relapsing-remitting multiple sclerosis (RRMS) call for treatment with disease-modifying therapies (DMTs) early in the disease to prevent relapses and accumulation of neurologic impairment and disability. However, patients taking certain oral DMTs may experience gastrointestinal (GI)-related adverse events (AEs), particularly at dose titration. We conducted qualitative research with healthcare professionals (HCPs) and patients in Canada to contextualize their experiences with three oral DMTs: dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), and teriflunomide (Aubagio®). The objectives of this study were to (1) gather qualitative data to better understand the patient and HCP experience of GI AEs in oral MS DMT treatment in Canada and (2) determine to what extent two patient-reported outcome (PRO) instruments used in recent oral DMT trials capture what is important to patients regarding GI AEs in oral MS DMT treatment (content validity) and to provide qualitative data to help interpret PRO scores. METHODS: This was a qualitative, non-interventional, descriptive, cross-sectional study comprising HCP and patient interviews conducted in English and French, using a 1:1 semi-structured interview approach. RESULTS: Patients reported 16 unique GI AE concepts related to oral DMTs. The most commonly reported symptoms were diarrhea, indigestion, and nausea. While patients acknowledged the negative impact associated with GI-related AEs, most characterized the treatment experience as positive, focusing on preference for oral administration, perceived efficacy of DMTs in terms of lack of MS relapses, slowed progression of their disease, and improvement in MS symptoms. Results supported the content validity (relevance, comprehension, and comprehensiveness) of the two PROs assessed. HCP feedback reinforced patient perspectives on both GI concepts and the two PRO instruments. CONCLUSION: Outcomes of these research activities include experiential data on the symptom and impact experience of oral DMTs in MS from both patients and HCPs that contribute to the process of determining therapeutic value.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Estudos Transversais , Crotonatos , Fumarato de Dimetilo/efeitos adversos , Cloridrato de Fingolimode/efeitos adversos , Humanos , Hidroxibutiratos , Imunossupressores/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Nitrilas , Pesquisa Qualitativa , Recidiva , Toluidinas
20.
JAMA Netw Open ; 5(9): e2230439, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36169959

RESUMO

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 ß-1a (IFNß-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 IFNß-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 IFNß-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 IFNß-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNß-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNß-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 IFNß-1a; the rate ratio for DMF vs IFNß-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 IFNß-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 ß-1a. DMF was well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT02283853.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Adolescente , Criança , Fumarato de Dimetilo/uso terapêutico , Feminino , Humanos , Interferon beta-1a/uso terapêutico , Interferon beta/efeitos adversos , Interferon beta/uso terapêutico , Masculino , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico
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