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1.
Acta Neurol Scand ; 141(1): 77-80, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31657006

RESUMO

OBJECTIVES: Low circulating vitamin D levels are associated with an increased risk of active MRI lesions and relapses in several cohorts with relapsing remitting multiple sclerosis (RRMS). Randomized controlled supplementation trials are, however, negative on their primary endpoints, while secondary MRI endpoints suggest anti-inflammatory effects. Circulating levels of neurofilament light chain (NfL) are a biomarker of disease activity in RRMS. We explored whether 48-week high-dose vitamin D3 supplements were associated with lower circulating NfL levels. MATERIALS & METHODS: Of N = 40 Dutch interferon beta-treated participants with RRMS of the SOLAR trial, plasma samples at baseline and 48-week follow-up were available. Of these participants, N = 24 were supplemented with 14 000 IU/d vitamin D3 and N = 16 with placebo. Twenty-five hydroxyvitamin D3 (25(OH)D3 ) levels were measured with LC-MS/MS, and NfL levels were measured in duplicate with Simoa. RESULTS: Serum 25(OH)D3 levels at 48 weeks were increased in the vitamin D3 when compared to placebo group (median level 281 [IQR 205-330] vs 72 [39-88] nmol/L; P < .01). NfL levels at 48 weeks did not differ between the treatment groups (median level 25.4 [IQR 19.6-32.2] vs 25.3 [17.9-30.1] pg/mL; P = .74). Higher week 48 NfL level showed a trend toward association with a higher risk of combined unique active lesions on the week 48 MRI scan (OR 2.39 [95% CI 0.93-6.12] for each 10 pg/mL increase; P = .07). CONCLUSIONS: Supplementation of high-dose vitamin D3 for 48 weeks was not associated with lower NfL levels. This study does not support an effect of vitamin D3 on this biomarker of neuro-axonal injury.


Assuntos
Colecalciferol/uso terapêutico , Suplementos Nutricionais , Esclerose Múltipla Recidivante-Remitente/sangue , Proteínas de Neurofilamentos/sangue , Vitamina D/sangue , Adjuvantes Imunológicos/uso terapêutico , Adulto , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Humanos , Interferon beta-1a/uso terapêutico , Masculino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico
2.
Neurology ; 93(20): e1906-e1916, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31594857

RESUMO

OBJECTIVE: In the phase II, randomized, double-blind, placebo-controlled Supplementation of Vigantol Oil versus Placebo Add-on in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) Receiving Rebif Treatment (SOLAR) study (NCT01285401), we assessed the efficacy and safety of add-on vitamin D3 in patients with RRMS. METHODS: Eligible patients with RRMS treated with SC interferon-ß-1a (IFN-ß-1a) 44 µg 3 times weekly and serum 25(OH)D levels <150 nmol/L were included. From February 15, 2011, to May 11, 2015, 229 patients were included and randomized 1:1 to receive SC IFN-ß-1a plus placebo (n = 116) or SC IFN-ß-1a plus oral high-dose vitamin D3 14,007 IU/d (n = 113). The revised primary outcome was the proportion of patients with no evidence of disease activity (NEDA-3) at week 48. RESULTS: At 48 weeks, 36.3% of patients who received high-dose vitamin D3 had NEDA-3, without a statistically significant difference in NEDA-3 status between groups (placebo 35.3%; odds ratio 0.93; 95% confidence interval [CI] 0.53-1.63; p = 0.80). Compared with placebo, the high-dose vitamin D3 group had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI 0.52-0.89; p = 0.0045) and change from baseline in total volume of T2 lesions (difference in mean ranks: -0.074; p = 0.035). CONCLUSIONS: SOLAR did not establish a benefit for high-dose vitamin D3 as add-on to IFN-ß-1a, based on the primary outcome of NEDA-3, but findings from exploratory outcomes suggest protective effects on development of new MRI lesions in patients with RRMS. CLINICALTRIALSGOV IDENTIFIER: NCT01285401. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS treated with SC IFN-ß-1a, 48 weeks of cholecalciferol supplementation did not promote NEDA-3 status.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Colecalciferol/administração & dosagem , Interferon beta-1a/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Vitaminas/administração & dosagem , Adulto , Encéfalo/diagnóstico por imagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Resultado do Tratamento , Vitamina D/análogos & derivados , Vitamina D/sangue
3.
Pediatrics ; 144(5)2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31662417

RESUMO

Schilder disease, also termed diffuse myelinoclastic sclerosis, is characterized by a large demyelinating lesion involving 1 or both sides of the centrum semiovale of the cerebral hemispheres. It often presents with tumorlike features and poses a diagnostic challenge. Schilder disease can be monophasic or relapsing, and disease-modifying therapy for the latter scenario is largely empirical. Here, we report a 14-year-old girl with relapsing Schilder disease within 1 year after disease onset. She has been followed-up for nearly 10 years and remains in sustained remission ever since interferon-ß therapy was prescribed after the second attack. In this case study, it is suggested that interferon-ß may induce long-term remission in relapsing Schilder disease and is therefore worth considering in this regard.


Assuntos
Encéfalo/diagnóstico por imagem , Esclerose Cerebral Difusa de Schilder/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Interferon beta-1a/uso terapêutico , Adolescente , Corticosteroides/uso terapêutico , Esclerose Cerebral Difusa de Schilder/diagnóstico por imagem , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética , Metilprednisolona/uso terapêutico , Neuroimagem , Fármacos Neuroprotetores/uso terapêutico , Indução de Remissão , Tomografia Computadorizada por Raios X
4.
Neurology ; 93(19): e1778-e1786, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31484710

RESUMO

OBJECTIVE: To assess the onset of ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS). METHODS: Brain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, ocrelizumab (600 mg), or intramuscular interferon (IFN) ß-1a (30 µg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving ocrelizumab (600 mg) or subcutaneous IFN-ß-1a (44 µg). RESULTS: In patients with RRMS, ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo (p = 0.042) and by week 8 vs intramuscular IFN-ß-1a (p < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-ß-1a (both p < 0.001). In patients with RMS, ocrelizumab significantly reduced ARR (p = 0.005) and the probability of time to first protocol-defined relapse (p = 0.014) vs subcutaneous IFN-ß-1a within the first 8 weeks. CONCLUSION: Epoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with ocrelizumab in patients with RRMS and RMS, respectively. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS and RMS, ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Encéfalo/diagnóstico por imagem , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico , Adulto , Feminino , Humanos , Interferon beta-1a/uso terapêutico , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Recidiva , Fatores de Tempo , Resultado do Tratamento
5.
Eur J Paediatr Neurol ; 23(6): 783-791, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31540711

RESUMO

BACKGROUND: Cognitive impairment (CI) is a critical feature for patients with childhood or juvenile multiple sclerosis (MS). OBJECTIVE: To promote the understanding of CI and to address the impact of different pharmacological treatment strategies on cognitive performance in this patient group. METHODS: A cohort of 19 patients with therapy-naïve or ß-Interferon-treated juvenile MS completed a comprehensive neuropsychological assessment at initial presentation (baseline) and on average 2.5 years later (follow-up). The assessments were complemented with a neuropaediatric examination and conventional cerebral magnetic resonance imaging (MRI). RESULTS: 9 patients (47%) were impaired in at least one test at baseline (z-score <-1.645 compared with age-adjusted normative data), with the highest impairment frequency in the domains processing speed and attention & executive functions. At follow-up a higher impairment frequency was prominent in those patients whose therapy had not been escalated (N = 13, 69% impaired in at least one test), while cognition was preserved or ameliorated in patients whose treatment had been escalated to highly effective drugs (N = 6, 0% impaired) during the observational period. These group differences at follow-up were not attributable to differences regarding demographics, MRI metrics or cognitive performance at baseline. CONCLUSION: Our findings confirm that paediatric MS is associated with considerable CI already in early disease stages. Early administration of highly effective treatment may protect from cognitive decline or alleviate CI in juvenile MS, but larger controlled trials are warranted to confirm these preliminary results.


Assuntos
Disfunção Cognitiva/etiologia , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico , Adolescente , Criança , Disfunção Cognitiva/prevenção & controle , Estudos de Coortes , Função Executiva/efeitos dos fármacos , Feminino , Humanos , Interferon beta-1a/uso terapêutico , Masculino , Testes Neuropsicológicos , Resultado do Tratamento
6.
Complement Ther Med ; 45: 275-279, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31331574

RESUMO

OBJECTIVES: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Several effector mechanisms are involved in the immunopathology of MS and a variety of medications such as beta interferons are applied to treat the disease. This study was conducted to evaluate the anti-inflammatory and immunomodulatory effects of sesame oil in combination with interferon beta-1a in MS treatment. METHODS: Ninety-three MS patients were enrolled in the study. The patients were randomly divided into two groups. The control group (n = 39) received 30 µg/week of interferon beta-1a intra-muscularly. The sesame oil-treated group (n = 54) received interferon beta-1a the same as the control group with the addition of 0.5 ml/kg/day of oral sesame oil for 6 months. RESULTS: After the 6-month study period, the interleukin (IL)-10 concentration in the sesame oil-treated group was significantly greater than that of the control group (p = 0.04). The concentrations of interferon-γ (IFN-γ), nitric oxide (NO), and tumor necrosis factor-α (TNF-α) in the sesame oil group after treatment were significantly less than those of the control group (p = 0.029, p = 0.0001, and p = 0.01, respectively). Lymphocyte proliferation in the sesame oil-treated group was significantly lower at the end of the study than at the beginning (p = 0.001). CONCLUSION: Sesame oil, through a decrease in IFN-γ secretion and anti-inflammatory and anti-oxidant activities, may have beneficial effects for MS patients.


Assuntos
Interferon beta-1a/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Óleo de Gergelim/uso terapêutico , Adolescente , Adulto , Idoso , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Interleucina-10/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Óxido Nítrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
7.
Zh Nevrol Psikhiatr Im S S Korsakova ; 119(2. Vyp. 2): 73-85, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31156245

RESUMO

OBJECTIVES: To evaluate efficacy, safety, and tolerability of the treatment with teberif/interferon ß-1a, to analyze safety, tolerability and dynamics of key efficacy variables after switching from referent drug rebif to biosimilar teberif in patients with remitting multiple sclerosis (RMS). MATERIAL AND METHODS: During the main period of the international multicenter randomized study patients were randomized to receive treatment with teberif for 52 weeks, or rebif for 52 weeks, or placebo for 16 weeks to evaluate efficacy and safety of treatment. After the main study period, patients were group-independently switched to take open-label teberif treatment during the next 48 weeks. RESULTS AND CONCLUSION: The analysis of multiple evaluation parameters of the efficiency during the 1st study period (blinded) and the 2nd study period (open-label) has shown that teberif and rebif demonstrate equivalent efficacy and stable 2-year efficacy of teberif was proven. There were no significant differences between teberif and rebif for all safety, and tolerability parameters. Switching from rebif to teberif didn't influence treatment efficacy. The 2-year study results confirmed a biosimilar teberif's benign tolerability and expected safety profile to other interferons ß-1a in patients with RMS.


Assuntos
Interferon beta-1a , Esclerose Múltipla Recidivante-Remitente , Adjuvantes Imunológicos , Humanos , Interferon beta-1a/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Resultado do Tratamento
8.
J Manag Care Spec Pharm ; 25(4): 490-498, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30917079

RESUMO

BACKGROUND: Cost-effectiveness analyses tend not to take into account the availability of lower-priced generics following loss of exclusivity (LOE) of branded products. By not considering these generics, which are typically adopted quickly, total costs are likely to be overestimated and may be unreflective of real-world payer conditions in the United States. OBJECTIVE: To assess the impact of including future price reductions following LOE on the cost-effectiveness of fingolimod versus intramuscularly administered interferon beta-1a (IM IFNß-1a) as treatments for multiple sclerosis. METHODS: This model was adopted from a previously published Markov model and was conducted from a U.S. payer perspective over a 10-year time horizon. Patients with relapsing-remitting multiple sclerosis entered the model and received either fingolimod (an oral therapy) or IM IFNß-1a (an injectable). These treatments reflect the interventions studied in the TRANSFORMS randomized clinical trial. Clinical, cost, and utility inputs were based on a recent cost-effectiveness review of therapies for multiple sclerosis. To model LOE, price reductions and the proportion of patients switching to generic versions following LOE were based on published estimates. Price reductions varied to reflect the difference in product types (oral vs. large molecule injectable). Assumptions were also made around the proportion of patients switching to generic versions over time following LOE and the projected date of LOE. Outcomes included per-patient total direct costs (medication, administration and monitoring, and disease-related costs including relapses), quality-adjusted life-years, and the incremental cost per quality-adjusted life-year. RESULTS: Assuming no price reductions following LOE, fingolimod was considered cost-effective versus IM IFNß-1a ($118,434 per quality-adjusted life-year), despite having higher total direct costs over 10 years ($475,740 vs. $446,792). When including future price reductions following LOE, total direct costs were reduced with fingolimod and were lower than those accrued with IM IFNß-1a over the model time horizon ($308,570 vs. $442,653). Cost-effectiveness results were sensitive to changes in both clinical parameters and medication costs. Scenario analyses demonstrated that an earlier date of LOE was associated with lower total costs. CONCLUSIONS: Health economic models may predict higher total costs when the price reductions following LOE are not considered. Here, oral fingolimod was seen to be cost-saving versus IM IFNß-1a over the model time horizon when such price reductions were included. The cost implications of not accounting for future price changes may determine whether an intervention is considered cost-effective and as such may influence reimbursement decisions based on cost-effectiveness thresholds. Multiple product types (e.g., oral, injectable, and infused agents) have been approved for use as treatments for multiple sclerosis in the United States, and LOE is likely to have a different effect on each of these therapies. DISCLOSURES: This study was funded by Novartis Pharmaceuticals Corporation. Hua and Hersh report consulting fees from Novartis for work on this study. Hua also reports speaking, advisory board, and consulting fees from Biogen, Genzyme, Teva, EMD Serono, Genentech, TG Therapeutics, and Novartis for activities outside of this study. Hersh also reports speaking and consulting fees from Novartis, Biogen, Genzyme, Genentech, and EMD Serono for activities outside of this study, and research grants from PCORI and Biogen. At the time of this research, Morten and Kusel were paid employees of Costello Medical, which was contracted by Novartis to undertake some of this study's work. Lin, Cave, Herrera, and Ko were paid employees of Novartis at the time of this research. Cave, Herrera, and Ko also report owning stock in Novartis Pharmaceuticals. Varga provided services to Novartis at the time of this research and has nothing further to disclose. This research was presented as a poster at the AMCP Managed Care & Specialty Pharmacy Annual Meeting 2017; March 27-30, 2017; Denver, CO.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Interferon beta-1a/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Administração Oral , Análise Custo-Benefício , Custos de Medicamentos/estatística & dados numéricos , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/economia , Injeções , Interferon beta-1a/administração & dosagem , Interferon beta-1a/economia , Programas de Assistência Gerenciada , Cadeias de Markov , Modelos Econômicos , Esclerose Múltipla Recidivante-Remitente/economia , Anos de Vida Ajustados por Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Mecanismo de Reembolso , Estados Unidos
9.
Neurology ; 92(10): e1007-e1015, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30737333

RESUMO

OBJECTIVE: To assess the value of blood neurofilament light chain (NfL) as a biomarker of recent, ongoing, and future disease activity and tissue damage and its utility to monitor treatment response in relapsing-remitting multiple sclerosis. METHODS: We measured NfL in blood samples from 589 patients with relapsing-remitting multiple sclerosis (from phase 3 studies of fingolimod vs placebo, FREEDOMS and interferon [IFN]-ß-1a, TRANSFORMS) and 35 healthy controls and compared NfL levels with clinical and MRI-related outcomes. RESULTS: At baseline, NfL levels (pg/mL) were higher in patients than in healthy controls (30.5 and 27.0 vs 16.9, p = 0.0001) and correlated with T2 lesion load and number of gadolinium-enhancing T1 lesions (p < 0.0001, both). Baseline NfL levels, treatment, and number of new or enlarging T2 lesions during the studies predicted NfL levels at the end of study (all p < 0.01). High vs low baseline NfL levels were associated (estimate [95% confidence interval]) with an increased number of new or enlarging T2 lesions (ratio of mean: 2.64 [1.51-4.60]; p = 0.0006), relapses (rate ratio: 2.53 [1.67-3.83]; p < 0.0001), brain volume loss (difference in means: -0.78% [-1.02 to -0.54]; p < 0.0001), and risk of confirmed disability worsening (hazard ratio: 1.94 [0.97-3.87]; p = 0.0605). Fingolimod significantly reduced NfL levels already at 6 months (vs placebo 0.73 [0.656-0.813] and IFN 0.789 [0.704-0.884]), which was sustained until the end of the studies (vs placebo 0.628 [0.552-0.714] and IFN 0.794 [0.705-0.894]; p < 0.001, both studies at all assessments). CONCLUSIONS: Blood NfL levels are associated with clinical and MRI-related measures of disease activity and neuroaxonal damage and have prognostic value. Our results support the utility of blood NfL as an easily accessible biomarker of disease evolution and treatment response.


Assuntos
Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/terapia , Proteínas de Neurofilamentos/sangue , Adulto , Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , Avaliação da Deficiência , Feminino , Cloridrato de Fingolimode/uso terapêutico , Humanos , Interferon beta-1a/uso terapêutico , Imagem por Ressonância Magnética , Masculino , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Prognóstico
10.
J Neuroinflammation ; 16(1): 44, 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30777084

RESUMO

BACKGROUND: Aß1-42 peptide abnormal production is associated with the development and maintenance of neuroinflammation and oxidative stress in brains from Alzheimer disease (AD) patients. Suppression of neuroinflammation may then represent a suitable therapeutic target in AD. We evaluated the efficacy of IFNß1a in attenuating cognitive impairment and inflammation in an animal model of AD. METHODS: A rat model of AD was obtained by intra-hippocampal injection of Aß1-42 peptide (23 µg/2 µl). After 6 days, 3.6 µg of IFNß1a was given subcutaneously (s.c.) for 12 days. Using the novel object recognition (NOR) test, we evaluated changes in cognitive function. Measurement of pro-inflammatory or anti-inflammatory cytokines, reactive oxygen species (ROS), and SOD activity levels was performed in the hippocampus. Data were evaluated by one-way ANOVA with Fisher's Protected Least Significant Difference (PLSD) test. RESULTS: We showed that treatment with IFNß1a was able to reverse memory impairment and to counteract microglia activation and upregulation of pro-inflammatory cytokines (IL-6, IL-1ß) in the hippocampus of Aß1-42-injected rats. The anti-inflammatory cytokine IL-10, significantly reduced in the Aß1-42 animals, recovered to control levels following IFNß1a treatment. IFNß1a also reduced ROS and lipids peroxidation and increased SOD1 protein levels in the hippocampus of Aß1-42-injected rats. CONCLUSION: This study shows that IFNß1a is able to reverse the inflammatory and cognitive effects of intra-hippocampal Aß1-42 in the rat. Given the role played by inflammation in AD pathogenesis and the established efficacy of IFNß1a in the treatment of inflammatory diseases of the central nervous system such as multiple sclerosis, its use may be a viable strategy to inhibit the pro-inflammatory cytokine and oxidative stress cascade associated with Aß deposition in the hippocampus of AD patients.


Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Interferon beta-1a/uso terapêutico , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Contagem de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas dos Microfilamentos/metabolismo , Fragmentos de Peptídeos/toxicidade , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/metabolismo , Fatores de Tempo
11.
Immunol Lett ; 207: 46-55, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30684504

RESUMO

Recombinant human interferon beta (rIFN-ß) has long been used as a first-line treatment for multiple sclerosis (MS), and any attempt to develop a long-acting rIFN-ß is desirable since only one pegylated version of long-acting rIFN-ß-1a (Plegridy) is currently available in clinics. Previously, we reported that SL335, a human Fab molecule specific to serum albumin, exhibits an extended serum half-life via utilizing the FcRn recycling mechanism. With the ultimate goal of developing a long-acting rIFN-®, we generated a fusion construct by linking human IFN-ß cDNA to the C-terminus of the SL335 H chain at the DNA level followed by expression of the fusion protein, referred to as SL335-IFN-ß-1a, in Chinese hamster ovary-S (CHO-S) cells. In its N-linked glycosylated form, the resulting fusion protein was easily purified from the culture supernatant via a three-step chromatography process. In vitro functional assays revealed that the fusion protein retained its intrinsic binding capabilities to human serum albumin (HSA) and interferon α/ß receptor (IFNAR) that were almost identical to those of parental SL335 and rIFN-ß-1a (Rebif). In addition, the fusion protein possessed an antiviral potency and anti-proliferation activity comparable to those of Rebif. In pharmacokinetic (PK) analyses using Lewis rats and cynomolgus monkeys, SL335-IFN-ß-1a exhibited at least a two-fold longer serum half-life and a significantly reduced renal clearance rate compared to those of Rebif. Finally, a four-week repeated dose toxicity study revealed no abnormal toxicological signs. In conclusion, our results clearly demonstrated that SL335-IFN-ß-1a is worthy of further development as an alternative long-acting IFN-ß therapeutic.


Assuntos
Fragmentos Fab das Imunoglobulinas/metabolismo , Imunoterapia/métodos , Interferon beta/metabolismo , Esclerose Múltipla/terapia , Proteínas Recombinantes de Fusão/metabolismo , Animais , Células CHO , Cromatografia , Cricetulus , Taxa de Filtração Glomerular , Meia-Vida , Humanos , Fragmentos Fab das Imunoglobulinas/genética , Interferon beta-1a/farmacocinética , Interferon beta-1a/uso terapêutico , Interferon beta/genética , Interferon beta/farmacocinética , Macaca fascicularis , Esclerose Múltipla/imunologia , Ligação Proteica , Estabilidade Proteica , Ratos , Ratos Endogâmicos Lew , Receptor de Interferon alfa e beta/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacocinética , Albumina Sérica/imunologia , Albumina Sérica/metabolismo
12.
Adv Ther ; 36(1): 175-186, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30488338

RESUMO

INTRODUCTION: Patient adherence is a key determinant of treatment success in multiple sclerosis (MS). The RebiSmart® autoinjector facilitates patient self-injection of subcutaneous interferon ß-1a (sc IFN ß-1a) and allows quantitative measurement of adherence via its automated dosing log. We evaluated patient adherence and patient-reported cognitive and health-economic outcomes over 2 years in patients using RebiSmart®. METHODS: In this non-interventional, single-arm study, enrolled patients were 12-65 years of age, had relapsing-remitting MS or a single demyelinating event, and had been prescribed 44 or 22 µg sc IFN ß-1a. Quantitative adherence (proportion of scheduled injections administered) and qualitative adherence (proportion of weeks with treatment schedule correctly followed) were monitored over 2 years. Other end points included self-assessed adherence, patient-reported outcomes (fatigue, depression and quality of life), cognitive outcomes and health-economic outcomes. RESULTS: A total of 368 of 392 (93.9%) enrolled patients were analyzed. Mean quantitative adherence was 85.3% overall (months 1-24), 89.6% for months 1-12 and 83.3% for months 13-24. No major impact on quantitative adherence was observed for sex, age (< 37 years vs. ≥ 37 years), prior medication or participation in the patient support program RebiSTAR®. Mean qualitative adherence was 67.0% overall (months 1-24). Self-assessed adherence was reported as being higher than RebiSmart®-monitored adherence. There was a trend toward more MS-related visits to physicians among patients with high adherence. CONCLUSIONS: Patients using RebiSmart® demonstrated high adherence to treatment that was associated with a slight improvement in information processing speed and working memory and an overall tendency for more intensive self-management. FUNDING: Merck Serono GmbH, Germany, an affiliate of Merck KGaA, Darmstadt, Germany.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Interferon beta-1a/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Cooperação do Paciente/estatística & dados numéricos , Qualidade de Vida , Adolescente , Adulto , Idoso , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Resultado do Tratamento , Adulto Jovem
13.
J Clin Neurosci ; 59: 175-178, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30401571

RESUMO

The objective of our study was to evaluate the relationship of percentage of annualized brain volume loss (aBVL) and no evidence of disease activity (NEDA) in multiple sclerosis (MS) patients under interferon beta 1-a subcutaneous treatment (IFN-beta) during 3 years of follow up. Relapsing remitting MS (RRMS) patients, with less than three years from disease onset, expanded disability status scale (EDSS) ≤3 and in which IFN beta 1-a 44 mcg was indicated, were included. Demographic, clinical and structural parameters from the magnetic resonance (MR) during the 3 years of follow up were analyzed and compared between patients with and without NEDA (defined as the absence of: (a) three-month confirmed disability progression defined as an increase in EDSS score of 1.0; (b) confirmed relapses; and (c) new or enlarged T2 lesions and/or Gd+ lesions). A total of 87 patients, mean age 33 ±â€¯6 years were included. NEDA was reached by 39 patients at year 3. Percentage of aBVL from baseline to months 24 in NEDA patients was -1.1% vs. -1.54% in patients without NEDA (p < 0.001) and from baseline to month 36 it was -1.43% vs. -2.1% (p < 0.001) in patients with and without NEDA, respectively. At 3 years follow up, patients who received IFN beta 1a and were disease-free had lower percentage of aBVL compared to patients with disease activity.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Encéfalo/patologia , Interferon beta-1a/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/patologia , Adulto , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade
14.
Zh Nevrol Psikhiatr Im S S Korsakova ; 119(10. Vyp. 2): 100-109, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31934995

RESUMO

AIM: To evaluate the efficacy and safety of BCD 054 180 µg and 240 µg administered once every 2 weeks for the treatment of remitting multiple sclerosis compared to placebo and low dose interferon beta-1a (LIB) 30 µg administered once weekly. Results of a 20 week blinded interim analysis from a double blind, comparative, randomised, placebo-controlled clinical study are included. MATERIAL AND METHODS: This multinational, multicentre, double blind, comparative, placebo-controlled study enrolled 399 patients with the diagnosis of remitting multiple sclerosis: 114 patients in the sampeginterferon beta 1a and LIB groups each and 57 patients in the placebo group. To ensure the objectivity of data, the study protocol includes a blinded interim analysis to demonstrate the superiority of BCD 054 over placebo based on the number of combined unique active lesions (CUA) on MRI scans after 20 weeks of treatment. RESULTS AND CONCLUSION: An integrated analysis of the efficacy, safety, pharmacokinetics, and pharmacodynamics was performed after 20 weeks of study. Mean CUA per scan was lower in the active treatment groups compared to placebo: 0,986±2,046, 0,619±1,055, 0,665±1,165, 1,673±2,376 (groups 1, 2, 3 and placebo group, respectively). The data for CUA per scan demonstrated the superiority of both BCD 054 180 µg and 240 µg over placebo. Patients receiving active treatment had fewer new and/or enlarging lesions after 20 weeks of treatment. The proportion of patients without new T2-weighted lesions was 74,3%, 86,7%, and 78,1% in groups 1, 2, and 3 compared to 64,9% in the placebo group. Manifestations of flu-like syndrome that is expected for interferon treatment were observed with the same incidence in all the active treatment groups. Its severity, duration or the need for symptomatic treatment did not appear to depend on the type of interferon used.


Assuntos
Interferon beta-1a/química , Interferon beta-1a/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Polietilenoglicóis/química , Método Duplo-Cego , Humanos , Imagem por Ressonância Magnética , Resultado do Tratamento
15.
BMC Neurol ; 18(1): 186, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30400884

RESUMO

BACKGROUND: Little is known about whether tolerability and adherence to treatment can be influenced by weather and temperature conditions. The objective of this study was to assess monthly and seasonal adherence to and safety of sc IFN-ß1a (Rebif®, Merck) in relapsing-remitting multiple sclerosis (RRMS) patients using the RebiSmart® electronic autoinjector. METHODS: A multicentre, prospective observational study in Greece in adult RRMS patients with EDSS < 6, under Rebif®/RebiSmart® treatment for ≤6 weeks before enrollment. The primary endpoint was monthly, seasonal and annual adherence over 12 months (defined in text). Secondary endpoints included number of relapses, disability, adverse events. RESULTS: Sixty four patients enrolled and 47 completed all study visits (Per Protocol Set - PPS). Mean annual adherence was 97.93% ± 5.704 with no significant monthly or seasonal variations. Mean relapses in the pre- and post- treatment 12-months were 1.1 ± 0.47 and 0.2 ± 0.54 (p < 0.0001, PPS). 10 patients (22%) showed 3-month disability progression, 19 (40%) stabilization and 18 (38%) improvement. EDSS was not correlated to pre- (r = 0.024, p = 0.87) or post-treatment relapses (r = 0.022, p = 0.88). CONCLUSION: High adherence with no significant seasonal or weather variation was observed over 12 months. While the efficacy on relapses was consistent with published studies, we could not identify a relationship between relapses and disability. TRIAL REGISTRATION: Greek registry of non-interventional clinical trials ID: 200136 , date of registration: February 18th, 2013.


Assuntos
Interferon beta-1a/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Estações do Ano , Adolescente , Adulto , Idoso , Pessoas com Deficiência , Progressão da Doença , Feminino , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
16.
BMC Neurol ; 18(1): 143, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30217172

RESUMO

BACKGROUND: In the PRISMS study, interferon beta-1a subcutaneously (IFN ß-1a SC) reduced clinical and radiological disease burden at 2 years in patients with relapsing-remitting multiple sclerosis. The study aimed to characterize efficacy of IFN ß-1a SC 44 µg and 22 µg three times weekly (tiw) at Year 1. METHODS: Exploratory endpoints included annualized relapse rate (ARR), 3-month confirmed disability progression (1-point Expanded Disability Status Scale increase if baseline was < 6.0 [0.5-point if baseline was ≥6.0]), active T2 lesions, and no evidence of disease activity (NEDA; defined as no relapses [subanalyzed by relapse severity], 3-month confirmed progression, or active T2 lesions). Effect of IFN ß-1a SC in prespecified patient subgroups was also assessed. RESULTS: Patients were randomized to IFN ß-1a 22 µg (n = 189), 44 µg (n = 184), or placebo (n = 187). At 1 year, IFN ß-1a SC tiw reduced ARR (p < 0.001), risk of disability progression (p ≤ 0.029), and mean number of active T2 lesions per patients per scan (p < 0.001) versus placebo. Clinical and radiological benefits were seen as early as Month 2 and 3. Outcomes in subgroups were consistent with those in the overall population. More patients treated with IFN ß-1a SC tiw achieved NEDA status, versus placebo, regardless of relapse severity (p ≤ 0.006). CONCLUSION: Clinical, radiological, and NEDA outcomes at Year 1 were consistent with Year 2 results. Treatment efficacy was consistent in pre-specified patient subgroups.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Interferon beta-1a/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Progressão da Doença , Feminino , Humanos , Interferon beta/uso terapêutico , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Radiografia , Resultado do Tratamento
17.
Neurol Sci ; 39(12): 2107-2113, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30171370

RESUMO

BACKGROUND AND AIM: Interferon beta is currently the first line treatment of relapsing-remitting multiple sclerosis (RRMS). Different formulations of interferon beta are available. Avonex and CinnoVex are two interferon beta-1a being prescribed by neurologists in Iran. The aim of this study was to compare the four and half year outcome of Avonex and CinnoVex in patients with RRMS. METHODS: A total 186 of patients with definite RRMS diagnosis were followed for four and half years. Patients were randomly assigned to receive either Avonex or CinnoVex. Patients were subsequently visited every 6 months, and MRI was also undertaken prior each visit. The efficacy end points were to compare mean scores of expanded disability status scale (EDSS) and the proportion of patients with MRI and clinical activity in follow-up visits between Avonex and CinnoVex. Safety end point was to compare the percentage of adverse events between two groups. RESULTS: One hundred and eighty-two patients completed the study. The population of study experienced a steady increase in EDSS during follow-up with a mean increase of 1.03. Repeated measures ANOVA revealed no statistically significant difference between Avonex and CinnoVex (p = 0.78). The most common adverse events were headache, myalgia, fatigue, fever, flu symptoms, injection site pain, and depression. Direct comparison of each adverse events revealed no meaningful difference between two groups except for only a few adverse events. There was no statistically significant difference in MRI activity and clinical activity between two groups. CONCLUSION: Avonex and CinnoVex showed similar efficacy and safety outcome in patients with RRMS.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Interferon beta-1a/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adolescente , Adulto , Idoso , Estudos de Coortes , Avaliação da Deficiência , Método Duplo-Cego , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
18.
J Neurosci Nurs ; 50(5): 291-297, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30138155

RESUMO

BACKGROUND: Adherence to medication treatment in patients with multiple sclerosis (MS) is important to increase its effectiveness, reduce patient disability, prevent attacks, and increase the quality of life. AIM: This study investigated factors that influence adherence to disease-modifying therapy in patients with MS. METHODS: This descriptive study was conducted with 198 patients with MS who met the inclusion criteria and agreed to participate between July 2016 and February 2017. Data were collected using an Individual Identification Form that included sociodemographic characteristics, the Multiple Sclerosis Treatment Adherence Questionnaire, the Fatigue Severity Scale, the Self-Efficacy Scale, and the Brief COPE. RESULTS: We found that 59.6% of the patients were adherent to therapy. Patients were significantly more adherent to Avonex than other treatments, and "memory problems" was the most common reason for missing or forgetting medication in nonadherent patients. There was a significant difference between medication adherence and some sociodemographic characteristics and disease characteristics (P < .05). There was no significant difference between coping attitudes, fatigue, and self-efficacy level and medication adherence (P > .05). CONCLUSION: Patients' adherence to medication treatment was low and may be associated with social, physical, and cognitive measures.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Acetato de Glatiramer/uso terapêutico , Interferon beta-1a/uso terapêutico , Adesão à Medicação/psicologia , Esclerose Múltipla/tratamento farmacológico , Adaptação Psicológica , Adulto , Estudos Transversais , Fadiga , Feminino , Humanos , Masculino , Esclerose Múltipla/psicologia , Enfermagem em Neurociência , Qualidade de Vida , Autoeficácia , Inquéritos e Questionários
19.
Int Immunopharmacol ; 62: 109-113, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29990690

RESUMO

INTRODUCTION: Human recombinant interferon beta (IFN-ß) is one of the first line treatments for Relapsing-Remitting Multiple Sclerosis (RRMS). However, the production of neutralizing antibodies (NAb) can impair its function. The aim of this study was to investigate the production of neutralizing antibodies against Rebif® and ReciGen® (two brands of IFN-ß-1a) and to evaluate its correlation with Expanded Disability Status Scale (EDSS). MATERIALS AND METHODS: Serum samples of 71 RRMS patients (34 in ReciGen®, 37 in Rebif® group) were collected. Neutralizing antibody was measured by Myxo-virus resistance protein A (MxA) assay using A549 cell line. The MxA concentration was measured by enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: The median period of treatment with IFN-ß-1a was 18 months in ReciGen® and 24 months in Rebif® arms. The percentage of patients with positive titer of neutralizing antibody (NAb+) had no statistically significant difference between groups (P = 0.6). In both ReciGen® and Rebif® groups, the increase in EDSS score was significantly higher in NAb+ patients compared to NAb- patients (p ≤ 0.05). The duration of using ReciGen® or Rebif® for >24 months was influential in the NAb positivity (OR = 3.78). CONCLUSION: Receiving interferon beta-1a for >24 months is correlated with higher possibility of NAb production. The type of IFN-ß used in the study had no significant impact on NAb positivity. In addition, both groups had comparable EDSS score changes, and NAb status of patients was correlated with their EDSS score.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Anticorpos Neutralizantes/sangue , Medicamentos Biossimilares/uso terapêutico , Pessoas com Deficiência , Interferon beta-1a/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Células A549 , Adjuvantes Imunológicos/administração & dosagem , Adulto , Medicamentos Biossimilares/administração & dosagem , Técnicas de Cultura de Células , Avaliação da Deficiência , Ensaio de Imunoadsorção Enzimática , Humanos , Interferon beta-1a/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/imunologia
20.
Acta Neurol Scand ; 138(5): 447-453, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30033621

RESUMO

OBJECTIVE: Within the last decade, many changes have been made to the management of patients with multiple sclerosis (MS). The aim of our study was to investigate the global impact of all these changes on the disease's course. MATERIALS AND METHODS: This single-centre study was carried out on patients with multiple sclerosis (pwMS) who started treatment with first-line disease-modifying therapies. We have compared three large cohorts of patients with MS diagnosis, for three consecutive periods within July 2001, August 2001-December 2005, and January 2006-September 2011. RESULTS: A total of 1068 relapsing-remitting pwMS cases were included. Patients in the last cohort began treatment earlier (P < 0.0001), started more frequent treatment with high-dose interferon beta or glatiramer acetate (P < 0.0001), and had experienced a more frequent treatment escalation strategy (P = 0.004) than patients in other cohorts. The multivariate analysis adjusted for baseline characteristics showed that pwMS of the last cohort had a high probability of showing no evidence of disease activity (NEDA3) at 4 years (OR 3.22, 95% CIs 1.89-5.47; P < 0.0001). These results were confirmed in a propensity score analysis. CONCLUSIONS: Our study showed an improvement over the last 15 years in the treatment response; this observation can be associated to a paradigm shift in MS treatment strategies.


Assuntos
Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Neurologia/tendências , Adulto , Estudos de Coortes , Progressão da Doença , Feminino , Acetato de Glatiramer/uso terapêutico , Humanos , Interferon beta-1a/uso terapêutico , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Peptídeos/uso terapêutico
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