RESUMO
Demyelination is generated in several nervous system illnesses. Developing strategies for effective clinical treatments requires the discovery of promyelinating drugs. Increased GABAergic signaling through γ-aminobutyric acid type A receptor (GABAAR) activation in oligodendrocytes has been proposed as a promyelinating condition. GABAAR expressed in oligodendroglia is strongly potentiated by n-butyl-ß-carboline-3-carboxylate (ß-CCB) compared to that in neurons. Here, mice were subjected to 0.3% cuprizone (CPZ) added in the food to induce central nervous system demyelination, a well-known model for multiple sclerosis. Then ß-CCB (1 mg/Kg) was systemically administered to analyze the remyelination status in white and gray matter areas. Myelin content was evaluated using Black-Gold II (BGII) staining, immunofluorescence (IF), and magnetic resonance imaging (MRI). Evidence indicates that ß-CCB treatment of CPZ-demyelinated animals promoted remyelination in several white matter structures, such as the fimbria, corpus callosum, internal capsule, and cerebellar peduncles. Moreover, using IF, it was observed that CPZ intake induced an increase in NG2+ and a decrease in CC1+ cell populations, alterations that were importantly retrieved by ß-CCB treatment. Thus, the promyelinating character of ß-CCB was confirmed in a generalized demyelination model, strengthening the idea that it has clinical potential as a therapeutic drug.
Assuntos
Carbolinas , Cuprizona , Doenças Desmielinizantes , Modelos Animais de Doenças , Remielinização , Animais , Cuprizona/toxicidade , Remielinização/efeitos dos fármacos , Camundongos , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/metabolismo , Carbolinas/farmacologia , Carbolinas/administração & dosagem , Bainha de Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/patologia , Substância Branca/efeitos dos fármacos , Substância Branca/metabolismo , Substância Branca/patologia , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) with inflammation and immune dysfunction. OBJECTIVES: We compared the remyelination and immunomodulation properties of mesenchymal stem cells (MSCs) with their conditioned medium (CM) in the cuprizone model. METHODS: Twenty-four C57BL/ 6 mice were divided into four groups. After cuprizone demyelination, MSCs and their CM were injected into the right lateral ventricle of mice. The expression level of IL-1ß, TNF-α, and BDNF genes was evaluated using the qRT-PCR. APC antibody was used to assess the oligodendrocyte population using the immunofluorescent method. The remyelination and axonal repair were studied by specific staining of the LFB and electron microscopy techniques. RESULTS: Transplantation of MSCs and CM increased the expression of the BDNF gene and decreased the expression of IL-1ß and TNF-α genes compared to the cuprizone group, and these effects in the cell group were more than CM. Furthermore, cell transplantation resulted in a significant improvement in myelination and axonal repair, which was measured by luxol fast blue and transmission electron microscope images. The cell group had a higher number of oligodendrocytes than other groups. CONCLUSIONS: According to the findings, injecting MSCs intraventricularly versus cell-conditioned medium can be a more effective approach to improving chronic demyelination in degenerative diseases like MS.
Assuntos
Cuprizona , Doenças Desmielinizantes , Modelos Animais de Doenças , Inflamação , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Camundongos Endogâmicos C57BL , Animais , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos , Células-Tronco Mesenquimais/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Meios de Cultivo Condicionados/farmacologia , Inflamação/patologia , Inflamação/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Oligodendroglia/metabolismo , Remielinização , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/induzido quimicamente , Fator de Necrose Tumoral alfa/metabolismo , Masculino , Bainha de Mielina/metabolismoRESUMO
BACKGROUND: Current treatments for Multiple Sclerosis (MS) poorly address chronic innate neuroinflammation nor do they offer effective remyelination. The vagus nerve has a strong regulatory role in inflammation and Vagus Nerve Stimulation (VNS) has potential to affect both neuroinflammation and remyelination in MS. OBJECTIVE: This study investigated the effects of VNS on demyelination and innate neuroinflammation in a validated MS rodent model. METHODS: Lysolecithin (LPC) was injected in the corpus callosum (CC) of 46 Lewis rats, inducing a demyelinated lesion. 33/46 rats received continuously-cycled VNS (cVNS) or one-minute per day VNS (1minVNS) or sham VNS from 2 days before LPC-injection until perfusion at 3 days post-injection (dpi) (corresponding with a demyelinated lesion with peak inflammation). 13/46 rats received cVNS or sham from 2 days before LPC-injection until perfusion at 11 dpi (corresponding with a partial remyelinated lesion). Immunohistochemistry and proteomics analyses were performed to investigate the extend of demyelination and inflammation. RESULTS: Immunohistochemistry showed that cVNS significantly reduced microglial and astrocytic activation in the lesion and lesion border, and significantly reduced the Olig2+ cell count at 3 dpi. Furthermore, cVNS significantly improved remyelination with 57.4 % versus sham at 11 dpi. Proteomic gene set enrichment analyses showed increased activation of (glutamatergic) synapse pathways in cVNS versus sham, most pronounced at 3 dpi. CONCLUSION: cVNS improved remyelination of an LPC-induced lesion. Possible mechanisms might include modulation of microglia and astrocyte activity, increased (glutamatergic) synapses and enhanced oligodendrocyte clearance after initial injury.
Assuntos
Doenças Desmielinizantes , Lisofosfatidilcolinas , Ratos Endogâmicos Lew , Remielinização , Estimulação do Nervo Vago , Animais , Ratos , Remielinização/fisiologia , Remielinização/efeitos dos fármacos , Lisofosfatidilcolinas/toxicidade , Doenças Desmielinizantes/terapia , Doenças Desmielinizantes/induzido quimicamente , Estimulação do Nervo Vago/métodos , Masculino , Doenças Neuroinflamatórias/terapia , Doenças Neuroinflamatórias/induzido quimicamente , Doenças Neuroinflamatórias/etiologia , Modelos Animais de Doenças , Esclerose Múltipla/terapia , Esclerose Múltipla/induzido quimicamente , Corpo CalosoRESUMO
Siponimod is a sphingosine 1-phosphate receptor (S1P) modulator used to treat secondary progressive multiple sclerosis (SPMS). We report 3 SPMS patients treated with siponimod who developed new or worsening peripheral oedema soon after commencing treatment. In one case, peripheral oedema resulted in immobility. Siponimod-related peripheral oedema deserves wider recognition due to the potential for morbidity and over-investigation. Clinicians should assess for pre-existing oedema and coexisting conditions that may predispose to developing peripheral oedema prior to commencing siponimod.
Assuntos
Azetidinas , Compostos de Benzil , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Esclerose Múltipla Crônica Progressiva/complicações , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/induzido quimicamente , Esclerose Múltipla/induzido quimicamente , Azetidinas/efeitos adversos , Edema/induzido quimicamenteRESUMO
Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system that injures the myelin sheath, provoking progressive axonal degeneration and functional impairments. No efficient therapy is available at present to combat such insults, and hence, novel safe and effective alternatives for MS therapy are extremely required. Rutin (RUT) is a flavonoid that exhibits antioxidant, anti-inflammatory, and neuroprotective effects in several brain injuries. The present study evaluated the potential beneficial effects of two doses of RUT in a model of pattern-III lesion of MS, in comparison to the conventional standard drug; dimethyl fumarate (DMF). Demyelination was induced in in male adult C57BL/6 mice by dietary 0.2% (w/w) cuprizone (CPZ) feeding for 6 consecutive weeks. Treated groups received either oral RUT (50 or 100 mg/kg) or DMF (15 mg/kg), along with CPZ feeding, for 6 consecutive weeks. Mice were then tested for behavioral changes, followed by biochemical analyses and histological examinations of the corpus callosum (CC). Results revealed that CPZ caused motor dysfunction, demyelination, and glial activation in demyelinated lesions, as well as significant oxidative stress, and proinflammatory cytokine elevation. Six weeks of RUT treatment significantly improved locomotor activity and motor coordination. Moreover, RUT considerably improved remyelination in the CC of CPZ + RUT-treated mice, as revealed by luxol fast blue staining and transmission electron microscopy. Rutin also significantly attenuated CPZ-induced oxidative stress and inflammation in the CC of tested animals. The effect of RUT100 was obviously more marked than either that of DMF, regarding most of the tested parameters, or even its smaller tested dose. In silico docking revealed that RUT binds tightly within NF-κB at the binding site of the protein-DNA complex, with a good negative score of -6.79 kcal/mol. Also, RUT-Kelch-like ECH-associated protein 1 (Keap1) model clarifies the possible inhibition of Keap1-Nrf2 protein-protein interaction. Findings of the current study provide evidence for the protective effect of RUT in CPZ-induced demyelination and behavioral dysfunction in mice, possibly by modulating NF-κB and Nrf2 signaling pathways. The present study may be one of the first to indicate a pro-remyelinating effect for RUT, which might represent a potential additive benefit in treating MS.
Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Masculino , Animais , Camundongos , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Cuprizona/efeitos adversos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , NF-kappa B/metabolismo , Rutina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
BACKGROUND: Multiple sclerosis (MS) is a debilitating inflammatory disease characterized by demyelination, varied remyelination conservation, and partial axonal retention in central nervous system (CNS) lesions. The p38 mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathophysiology of MS. Embelin (EMB), derived from the Embelia ribes plant, possesses diverse biological activities, including anti-inflammatory properties. OBJECTIVE: This study aimed to investigate the neuroprotective effects of EMB in an ethidium bromide (EB)-induced model of MS in Wistar rats. METHODS: Wistar rats were randomly divided into five groups (n = 8). MS-like manifestations were induced by injecting EB (0.1 %/10 µl) into the intracerebropeduncle (ICP) region of the rat brain for seven consecutive days. EMB was administered at doses of 1.25, 2.5, and 5 mg/kg. Behavioral assessments, neuroinflammatory cytokine analysis like tumor necrosis factor-α, interleukin-1-ß, interleukin-6 (TNF-α, IL-1ß, IL-6), oxidative stress marker measurements malondialdehyde, reduced glutathione, superoxide dismutase (MDA, GSH, SOD), and nitrite (NO), Acetylcholinesterase enzyme (AchE), and neurotransmitter level analysis, dopamine, serotonin, and norepinephrine (DA, 5-HT, and NE) were conducted. RESULTS: The study assessed behavioral, neurochemical, biochemical, and neuroinflammatory parameters, along with the modulation of p38 MAPK signaling. EMB administration significantly ameliorated neurological consequences induced by EB, improving motor coordination and gait abnormalities in rats. Furthermore, EMB effectively reduced neuroinflammatory cytokines (TNF-α, IL-1ß, IL-6) and oxidative stress markers (AchE, SOD, MDA, GSH, nitrite). Notably, EMB exhibited a modulatory effect on neurotransmitter levels, increasing GABA, DA, and 5-HT, while reducing glutamate in EB-treated groups. CONCLUSION: This study demonstrates the neuroprotective potential of EMB against the EB-induced model of MS in rats. EMB administration mitigated neurological impairments, attenuated neuroinflammation, alleviated oxidative stress, and restored neurotransmitter balance. These findings highlight the promise of EMB as a therapeutic candidate for MS treatment, providing insights into its potential mechanism of action involving the modulation of p38 MAPK signaling.
Assuntos
Benzoquinonas , Esclerose Múltipla , Fármacos Neuroprotetores , Ratos , Animais , Ratos Wistar , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Etídio/farmacologia , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Acetilcolinesterase/metabolismo , Nitritos , Serotonina/metabolismo , Estresse Oxidativo , Citocinas/metabolismo , Transdução de Sinais , Neurotransmissores/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND: Ocrelizumab is a commonly used anti-CD20 monoclonal antibody with efficacy in the treatment of both relapsing-remitting (RRMS) and primary progressive (PPMS) multiple sclerosis. Real world use of ocrelizumab in MS patients with higher levels of motor disability requiring a walker or a wheelchair is not well characterized as these populations were excluded from initial studies. Higher levels of disability may be a barrier to treatment access. This study aimed to describe the access to, and tolerability and therapeutic outcomes of ocrelizumab in highly disabled MS patients in a real-world setting. METHODS: As part of an ongoing study of ocrelizumab treatment access, barriers, and outcomes in MS patients at the Brigham MS Center, we retrospectively reviewed all patients with an Expanded Disability Status Scale (EDSS) of 6.5 or greater at the time of ocrelizumab initiation. All patients were started on ocrelizumab by their treating providers prior to this study initiation. Patients were excluded for recent rituximab exposure, co-treatment with more than one immunosuppressant, or alternative diagnoses contributing to high EDSS. Data was collected on incidence and severity of side effects while on ocrelizumab, persistence of treatment beyond one year, and MS stabilization versus progression while on this treatment. RESULTS: Of the 1219 patients on ocrelizumab between 2017 and 2021, 113 (9.3 %) had EDSS of 6.5 or greater at the time of ocrelizumab initiation. Of the 113, 51 (45.1 %) were excluded: 6 (5.3 %) because they were duplicates or didn't receive ocrelizumab at our center, 25 (22.1 %) due to rituximab treatment in the previous year, 16 (14.2 %) due to lack of at least 1 year of follow up, and 4 (3.5 %) due to relevant comorbidities/treatment with other immunosuppressants. 62 patients were included in the final analysis. At ocrelizumab start, mean age was 62.1 +/- 8.7 years and median EDSS was 7.0 (range 6.5 to 9.5). Ocrelizumab was started in 26 of the included 62 patients (41.9 %) because of objective clinical disease worsening, in 17 (27.4 %) because of subjective worsening, in 8 (12.9 %) to prevent future progression. 32 patients (51.6 %) continued ocrelizumab throughout the study period, with average length of ocrelizumab use of 36.5 +/- 17.0 months. 29 patients (46.8 %) experienced no side effects during the study period. 29 (46.7 %) patients discontinued treatment, and of those, 9 (31.0 %) cited more than one reason for discontinuation: 17 (58.6 %) cited side effects, 12 (41.4 %) cited progression/lack of benefit, 6 (20.7 %) cited the Covid19 pandemic, and 1 (3.4 %) cited financial issues as a reason for discontinuation. Over the course of the study, 16 (25.8 %) patients had disability worsening by EDSS, 5 (8.1 %) had disability improvement, and 41 (66.1 %) remained stable, with a median end EDSS of 7.0 (range 6.5 to 9.5). Importantly, 18 patients (29.0 %) reported subjective disease stability while on ocrelizumab. CONCLUSIONS: Ocrelizumab may lead to disease stabilization in a subset of highly disabled MS patients, but possible benefits need to be carefully balanced against the incidence of adverse events in this high-risk patient population.
Assuntos
Anticorpos Monoclonais Humanizados , Pessoas com Deficiência , Transtornos Motores , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Pessoa de Meia-Idade , Idoso , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/induzido quimicamente , Rituximab/uso terapêutico , Estudos Retrospectivos , Esclerose Múltipla Crônica Progressiva/complicações , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/induzido quimicamente , Fatores Imunológicos/efeitos adversosRESUMO
Our article "Fingolimod: Assay analysis of US generic capsule products reveals variation in fingolimod content beyond the recommended acceptance criteria" highlighted the variation of active ingredient in generic fingolimod capsule products. This analysis was prompted by reports of clinical adverse events and/or multiple sclerosis relapse in patients following transition from Gilenya® fingolimod capsules (Novartis) to generic fingolimod capsule products. Further assay analysis functioned to both confirm previous out-of-specification findings, and to identify an additional generic product that failed to comply with United States Pharmacopeia (USP) recommendations.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/induzido quimicamenteRESUMO
BACKGROUND: Extended interval dosing (EID) of natalizumab treatment is increasingly used in multiple sclerosis. Besides the clear anti-inflammatory effect, natalizumab is considered to have neuroprotective properties as well. OBJECTIVES: This study aimed to study the longitudinal effects of EID compared to standard interval dosing (SID) and natalizumab drug concentrations on brain atrophy. METHODS: Patients receiving EID or SID of natalizumab with a minimum radiological follow-up of 2 years were included. Changes in brain atrophy measures over time were derived from clinical routine 3D-Fluid Attenuated Inversion Recovery (FLAIR)-weighted magnetic resonance imaging (MRI) scans using SynthSeg. RESULTS: We found no differences between EID (n = 32) and SID (n = 50) for whole brain (-0.21% vs -0.16%, p = 0.42), ventricular (1.84% vs 1.13%, p = 0.24), and thalamic (-0.32% vs -0.32%, p = 0.97) annualized volume change over a median follow-up of 3.2 years. No associations between natalizumab drug concentration and brain atrophy rate were found. CONCLUSION: We found no clear evidence that EID compared to SID or lower natalizumab drug concentrations have a negative impact on the development of brain atrophy over time.
Assuntos
Doenças do Sistema Nervoso Central , Leucoencefalopatia Multifocal Progressiva , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Natalizumab/uso terapêutico , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/induzido quimicamente , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética , Atrofia/patologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Fatores Imunológicos/uso terapêuticoRESUMO
BACKGROUND: Fingolimod (FTY) rebound, a phenomenon of unexpectedly severe disease activity following FTY discontinuation, has been reported to occur in 5-43 % of patients. Only a few larger cohorts have been analyzed. We aimed to determine the frequency and risk factors of FTY rebound in our hospital district in Southern Finland with a population of 1.7 million. METHODS: We searched the Finnish MS-register for patients who were previous or current users of FTY for at least 6 months by November 2020. We assessed medical records and collected basic demographic data for the whole cohort. Criteria for a rebound were: (i) the most severe relapse in patient's history and an increase of at least 2 EDSS points during the relapse occurring within 6 months from FTY cessation, or (ii) more than one relapse within 6 months after FTY discontinuation, this being the highest relapse rate observed during the patient's lifetime. RESULTS: Among 3496 MS patients, we found 331 patients ever starting FTY and 283 of them had used FTY for at least 6 months. Among these 283 patients we discovered a total of 114 discontinuation events in 110 patients. Of the discontinuations, 32 (28 %) were followed by a relapse: 20 (17.5 %) were ordinary relapses not fulfilling rebound criteria, and 12 (10.5 %) were rebounds. The median time to an ordinary relapse and rebound were similar: 8.5 weeks (range 1.3-23) and 9.9 weeks (range 5.9-15.9), respectively. The rebound group was younger at diagnosis (p = 0.034) and had used FTY for a longer time (p = 0.048) before discontinuation compared to the group without a relapse. After discontinuation, rebound group had lower lymphocyte values as compared to both ordinary relapse group (p = 0.027) and no-relapse group (p = 0.006) and neutrophil to lymphocyte ratio (NLR) was increased compared to the no-relapse group (p = 0.019). CONCLUSION: In this study, 10.5 % of patients experienced a rebound, which is similar to the frequencies (10.3-12.5 %) obtained in other larger studies with >100 discontinuations. Relapses of any severity occurred in 28 % of patients discontinuing FTY, and therefore initiation of subsequent disease modifying therapies should occur promptly after discontinuation. Younger age at diagnosis, longer exposure to FTY and lower lymphocyte count as well as higher NLR after discontinuation were identified as risk factors for a rebound. The differences in blood leukocytes indicate that rebound might be a distinct pathophysiological phenomenon compared to an ordinary relapse.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Cloridrato de Fingolimode/efeitos adversos , Imunossupressores/efeitos adversos , Estudos Retrospectivos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/induzido quimicamente , Recidiva , Fatores de Risco , Esclerose Múltipla/induzido quimicamenteRESUMO
INTRODUCTION: During the COVID-19 pandemic, ocrelizumab (OCR) infusions for MS patients were often re-scheduled because of MS center's disruption and concerns regarding immunosuppression. The aim of the present study was to assess changes in OCR schedule during the first wave of pandemic in Italy and to evaluate the effect of delayed infusion on clinical/radiological endpoints. METHODS: Data were extracted from the Italian MS Register database. Standard interval dosing was defined as an infusion interval ≤ 30 weeks, while extended interval dosing was defined as an infusion interval > 30 weeks at the time of the observation period. Clinico-demographics variables were tested as potential predictors for treatment delay. Time to first relapse and time to first MRI event were evaluated. Cumulative hazard curves were reported along their 95% confidence intervals. A final sample of one-thousand two patients with MS from 65 centers was included in the analysis: 599 pwMS were selected to evaluate the modification of OCR infusion intervals, while 717 pwRMS were selected to analyze the effect of infusion delay on clinical/MRI activity. RESULTS: Mean interval between two OCR infusions was 28.1 weeks before pandemic compared to 30.8 weeks during the observation period, with a mean delay of 2.74 weeks (p < 0.001). No clinico-demographic factors emerged as predictors of infusion postponement, except for location of MS centers in the North of Italy. Clinical relapses (4 in SID, 0 in EID) and 17 MRI activity reports (4 in SID, 13 in EID) were recorded during follow-up period. DISCUSSION: Despite the significant extension of OCR infusion interval during the first wave of pandemic in Italy, a very small incidence of clinical/radiological events was observed, thus suggesting durable efficacy of OCR, as well as the absence of rebound after its short-term suspension.
Assuntos
COVID-19 , Esclerose Múltipla , Humanos , Pandemias , Anticorpos Monoclonais Humanizados/uso terapêutico , Imageamento por Ressonância Magnética , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/induzido quimicamente , Fatores Imunológicos/efeitos adversosRESUMO
Information on the pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered cannabis-based medicine (CBM) in capsule formulation in patient populations is sparse. In this exploratory study, we aimed to evaluate the PK and PD in a probable steady state of CBM in neuropathic pain and spasticity in a population of patients with multiple sclerosis (MS). Of 134 patients participating in a randomized, double-blinded, placebo-controlled, trial, 23 patients with MS (17 female) mean age 52 years (range 21-67) were enrolled in this substudy. They received oral capsules containing Δ9 -tetrahydrocannabinol (THC, n = 4), cannabidiol (CBD, n = 6), a combination (THC&CBD, n = 4), or placebo (n = 9). Maximum doses were 22.5 mg (THC) and 45 mg (CBD) a day divided into three administrations. PD parameters were evaluated for pain and spasticity. Blood samples were analyzed using an ultra-high-performance liquid chromatography-tandem mass spectrometer after protein precipitation and phospholipid removal. PK parameters were estimated using computerized modeling. The variation in daily dose and PK between individuals was considerable in a steady state, yet comparable with previous reports from healthy controls. Based on a simulation of the best model, the estimated PK parameters (mean) for THC (5 mg) were Cmax 1.21 ng/mL, Tmax 2.68 h, and half-life 2.75 h, and for CBD (10 mg) were Cmax 2.67 ng/mL, Tmax 0.10 h, and half-life 4.95 h, respectively. No effect was found on the PD parameters, but the placebo response was considerable. More immediate adverse events were registered in the active treatment groups compared with the placebo group.
Assuntos
Canabidiol , Cannabis , Esclerose Múltipla , Neuralgia , Humanos , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Dronabinol/efeitos adversos , Administração Oral , Canabidiol/efeitos adversos , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Neuralgia/tratamento farmacológico , Método Duplo-CegoRESUMO
A 54-year-old woman with multiple sclerosis treated with interferon-ß (IFN-ß)-1b for 15 years presented with sustained hypertension (240/124 mmHg) and retinal bleeding. She had proteinuria, anemia, thrombocytopenia, elevated serum creatinine levels, and haptoglobin depletion. Intravenous nicardipine stabilized her blood pressure, but her renal function and platelet count deteriorated. The initial disintegrin-like metalloprotease with thrombospondin type 1 motifs 13 (ADAMTS13) activity was 28% of normal without its inhibitor. The subsequent peripheral appearance of schistocytes suggested thrombotic microangiopathy (TMA). After IFN-ß-1b cessation, the platelet count increased, and the blood pressure stabilized. The ADAMTS13 activity normalized, although the creatinine level did not. TMA may develop after the long-term use of IFN-ß without adverse events.
Assuntos
Hipertensão , Esclerose Múltipla , Microangiopatias Trombóticas , Feminino , Humanos , Pessoa de Meia-Idade , Interferon beta-1b/efeitos adversos , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/induzido quimicamente , Microangiopatias Trombóticas/induzido quimicamente , Interferon beta/efeitos adversos , Hipertensão/complicaçõesRESUMO
BACKGROUND: Monoamine oxidase (MAO) inhibitors can interact with selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs). There is clinical interest surrounding use of ozanimod with SSRIs/SNRIs because the major metabolites of ozanimod are weak inhibitors of MAO-B in vitro. OBJECTIVE: To evaluate the incidence of treatment-emergent adverse events (TEAEs) potentially related to serotonin accumulation (SA) during concomitant ozanimod and SSRI/SNRI use by performing analyses of data from an open-label, oral ozanimod 0.92 mg trial (DAYBREAK; NCT02576717). METHODS: SA narrow (serotonin syndrome, neuroleptic malignant syndrome, and hyperthermia malignant) and broad (terms potentially associated with SA) MedDRA v24.0 searches were performed using TEAE data from participants with relapsing multiple sclerosis who entered DAYBREAK from phase 3 studies (cutoff February 1, 2022). Incidences of TEAEs matching terms from each search were stratified by SSRI/SNRI use. RESULTS: Of 2257 DAYBREAK participants, 274 (12.1%) used an SSRI/SNRI. No participants had TEAEs matching the SA narrow search terms. There was no significant difference in the percentage of participants with ⩾1 TEAE matching the SA broad search for those on versus off SSRIs/SNRIs (on: 12.4%, n = 34/274; off: 15.6%, n = 310/1982, nominal p = 0.1630). CONCLUSION: MedDRA searches showed no increase in TEAEs potentially associated with SA with concomitant SSRI/SNRI and ozanimod use.
Assuntos
Indanos , Esclerose Múltipla , Oxidiazóis , Inibidores da Recaptação de Serotonina e Norepinefrina , Humanos , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores da Recaptação de Serotonina e Norepinefrina/efeitos adversos , Serotonina , Esclerose Múltipla/induzido quimicamente , Antidepressivos/efeitos adversosRESUMO
Genome-wide association studies identified a single nucleotide polymorphism (SNP) downstream of the transcription factor Sox8, associated with an increased risk of multiple sclerosis (MS). Sox8 is known to influence oligodendrocyte terminal differentiation and is involved in myelin maintenance by mature oligodendrocytes. The possible link of a Sox8 related SNP and MS risk, along with the role of Sox8 in oligodendrocyte physiology prompted us to investigate its relevance during de- and remyelination using the cuprizone model. Sox8-/- mice and wildtype littermates received a cuprizone diet for 5 weeks (wk). Sox8-/- mice showed reduced motor performance and weight compared to wildtype controls. Brains were histologically analysed at the maximum of demyelination (wk 5) and on two time points during remyelination (wk 5.5 and wk 6) for oligodendroglial, astroglial, microglial and myelin markers. We identified reduced proliferation of oligodendrocyte precursor cells at wk 5 as well as reduced numbers of mature oligodendrocytes in Sox8-/- mice at wk 6. Moreover, analysis of myelin markers revealed a delay in remyelination in the Sox8-/- group, demonstrating the potential importance of Sox8 in remyelination processes. Our findings present, for the first time, compelling evidence of a significant role of Sox8 in the context of a disease model.
Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Remielinização , Camundongos , Animais , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Diferenciação Celular , Estudo de Associação Genômica Ampla , Oligodendroglia , Bainha de Mielina/patologia , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Fatores de Transcrição SOXE/genéticaRESUMO
BACKGROUND: Adherence is a prerequisite for the efficacy of any drug, and previous studies have shown that non-adherence is associated with disease activity and increased health care cost in multiple sclerosis (MS). The aim of this study was to investigate rates and reasons for discontinuation of dimethyl fumarate (DMF) among people with MS on a national level and differences between clinics in Denmark. METHODS: This was a nationwide, registry and population study of patients treated with DMF. We calculated standard residuals (SR) demonstrate differences between clinics. For survival analysis regarding discontinuation rates and discontinuation due to specific AEs we used log-rank test Cox-proportional hazards and plotted Kaplan-Meier graphics. RESULTS: We included 2,448 people with MS, treated with DMF from 2013 to 2020. Average treatment duration was 26 months (5,382 treatment years). 49.2 % of patients who initiated treatment with DMF (n = 1205) were continuously treated. Reasons for discontinuation were adverse events (54.5 %, n = 656), active disease (26.1 %, n = 315), pregnancy (9.4 %, n = 113) or other reasons (13.2 %, n = 159). We compared SR to the mean regarding reasons for discontinuation and found significant differences between sites regarding gastrointestinal adverse events, flushing and lymphopenia. Discontinuation due to all adverse events, flushing and lymphopenia were more frequent in female than male patients. CONCLUSION: In this population-based study, we found major differences between the MS clinics in rates and reason for discontinuation of DMF. Our results suggest that management strategies during DMF treatment can reduce discontinuation rates.
Assuntos
Linfopenia , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Masculino , Feminino , Fumarato de Dimetilo/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/induzido quimicamente , Imunossupressores/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Linfopenia/induzido quimicamenteRESUMO
The vaccination with live attenuated vaccines is generally not recommended during natalizumab (NTZ), as it is included among immunosuppressive/immunomodulating therapies. Nevertheless, considering the lack of evidence of a non-Central Nervous System (CNS) immunosuppressive effect of NTZ, after a risk/benefit evaluation, we decided to vaccinate four multiple sclerosis (MS) patients (three with an indication to switch to ocrelizumab for high-risk Progressive Multifocal Leukoencephalopathy (PML) and one for pregnancy planning). No vaccine-related adverse events of any type nor varicella zoster virus (VZV) infections were observed. To the best of our knowledge, these case series represent the first description of the good safety profile of anti-VZV vaccination in MS patients during NTZ treatment.
Assuntos
Leucoencefalopatia Multifocal Progressiva , Esclerose Múltipla , Humanos , Natalizumab/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/induzido quimicamente , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Vacinação/efeitos adversos , Fatores Imunológicos/efeitos adversosRESUMO
Hypogammaglobulinemia is characterized by reduced serum immunoglobulin levels. Secondary hypogammaglobulinemia is of considerable interest to the practicing physician because it is a potential complication of some medications and may predispose patients to serious infections. Patients with multiple sclerosis (MS) treated with B-cell-depleting anti-CD20 therapies are particularly at risk of developing hypogammaglobulinemia. Among these patients, hypogammaglobulinemia has been associated with an increased risk of infections. The mechanism by which hypogammaglobulinemia arises with anti-CD20 therapies (ocrelizumab, ofatumumab, ublituximab, rituximab) remains unclear and does not appear to be simply due to the reduction in circulating B-cell levels. Further, despite the association between anti-CD20 therapies, hypogammaglobulinemia, and infections, there is currently no generally accepted monitoring and treatment approach among clinicians treating patients with MS. Here, we review the literature and discuss possible mechanisms of secondary hypogammaglobulinemia in patients with MS, hypogammaglobulinemia results in MS anti-CD20 therapy clinical trials, the risk of infection for patients with hypogammaglobulinemia, and possible strategies for disease management. We also include a suggested best-practice approach to specifically address secondary hypogammaglobulinemia in patients with MS treated with anti-CD20 therapies.
Assuntos
Agamaglobulinemia , Esclerose Múltipla , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/induzido quimicamente , Antígenos CD20 , Agamaglobulinemia/induzido quimicamente , Agamaglobulinemia/complicações , Rituximab/efeitos adversos , Gerenciamento ClínicoRESUMO
BACKGROUND: While natalizumab (NTZ) is an effective therapy for multiple sclerosis (MS), it is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). After 20 years (2002-2022) of experience with NTZ at our center, we observed no cases of PML. OBJECTIVES: We evaluated the likelihood of experiencing PML in a subset of our treatment cohort, as well as reviewed treatment practices at our center that may mitigate PML risk. METHODS: For this retrospective study, we reviewed patient characteristics, treatment practices, and clinical and MRI findings in patients receiving NTZ from 2006 to 2020. Observation of no PML cases was compared to the global and US PML incidences, and to the expected incidence based on published risk estimates. RESULTS: 766 patients were evaluated. The number of NTZ infusions received ranged from 1 to 126, with a mean of 28. Patients received neurological examination prior to each infusion, which sometimes resulted in a pause in therapy to rule out PML if clinical worsening occurred. Extended interval dosing (EID) was the overall dosing schedule for 31% of patients. EID did not result in higher rates of radiological disease worsening than standard interval dosing (SID) patients. Depending on the analysis conducted, the finding of 0 PML cases in our cohort ranged from slightly unexpected to slightly expected. CONCLUSIONS: The utilization of EID as well as regular clinical monitoring of patients may have lowered PML risk while still maintaining NTZ efficacy.