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1.
PLoS One ; 15(7): e0235449, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32716916

RESUMO

BACKGROUND: Several disease modifying drugs (DMDs) have been approved for the treatment of multiple sclerosis (MS), however, little is known about their differential impact on peripheral blood (PB) B cell subsets. METHODS: We performed a cross sectional study on PB B cells in MS patients treated with interferon-ß (n = 25), glatiramer acetate (n = 19), dimethyl fumarate (n = 15), fingolimod (n = 16) or natalizumab (n = 22), untreated MS patients (n = 20), and in patients with non-inflammatory neurological diseases (n = 12). Besides analyzing routine laboratory data, flow cytometry was performed to analyze naïve B cells (CD19+CD20+CD27-IgD+), non-class switched (CD19+CD20+CD27+IgD+) and class-switched memory B cells (CD19+CD20+CD27+IgD-), double negative B cells (CD19+CD20lowCD27-IgD-) and plasmablasts (CD19+CD20lowCD27+CD38++). RESULTS: Treatment associated changes were found for the overall B cell pool as well as for all B cell subsets. Natalizumab increased absolute numbers and percentage of all B cells mainly by expanding the memory B cell pool. Fingolimod decreased absolute numbers of all B cell subsets and the percentage of total B cells. Fingolimod, dimethyl fumarate and interferon-ß treatments were associated with an increase in the fraction of naïve B cells while class switched and non-class switched memory B cells showed decreased percentages. CONCLUSION: Our results highlight differential effects of DMDs on the PB B cell compartment. Across the examined treatments, a decreased percentage of memory B cells was found in dimethyl fumarate, interferon-ß and fingolimod treated patients which might contribute to the drugs' mode of action in MS. Further studies are necessary to decipher the exact role of B cell subsets during MS pathogenesis.


Assuntos
Subpopulações de Linfócitos B/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/classificação , Antígenos CD/imunologia , Antígenos CD19 , Subpopulações de Linfócitos B/classificação , Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Estudos Transversais , Fumarato de Dimetilo/administração & dosagem , Feminino , Cloridrato de Fingolimode/administração & dosagem , Citometria de Fluxo , Acetato de Glatiramer/administração & dosagem , Humanos , Memória Imunológica/imunologia , Imunofenotipagem , Imunossupressores/administração & dosagem , Imunossupressores/imunologia , Interferon beta/administração & dosagem , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Natalizumab/administração & dosagem , Adulto Jovem
2.
BMC Neurol ; 20(1): 158, 2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32340606

RESUMO

BACKGROUND: Fingolimod (Gilenya®), a first-in-class sphingosine-1-phosphate receptor modulator is approved for the treatment of relapsing-remitting multiple sclerosis. Fingolimod-induced selective immunosuppression leads to an increased risk of opportunistic infections such as cryptococcosis. So far, a total of 8 cases of fingolimod-related cryptococcal meningoencephalitis have been published. CASE PRESENTATION: A 49-year-old female with relapsing-remitting multiple sclerosis presented with cephalgia, fever, confusion and generalized weakness. She had been on fingolimod therapy for the past 5.5 years. Clinical examination suggested meningoencephalitis and laboratory findings showed an IgG2 deficiency. Initially no pathogen could be detected, but after 4 days Cryptococcus neoformans was found in the patient's blood cultures leading to the diagnosis of cryptococcal meningoencephalitis. After antimycotic therapy, her symptoms improved and the patient was discharged. CONCLUSION: MS patients on immunomodulatory  therapy are at constant risk for opportunistic infections. Cephalgia, fever and generalized weakness in combination with fingolimod-induced lymphopenia should be considered a red flag for cryptococcosis.


Assuntos
Criptococose/diagnóstico , Cloridrato de Fingolimode/efeitos adversos , Meningoencefalite/diagnóstico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Feminino , Cloridrato de Fingolimode/administração & dosagem , Humanos , Imunoglobulina G/imunologia , Imunossupressores/uso terapêutico , Linfopenia/induzido quimicamente , Pessoa de Meia-Idade , Infecções Oportunistas/diagnóstico
3.
PLoS One ; 15(3): e0229768, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119696

RESUMO

PURPOSE: In the Brazilian public healthcare system, natalizumab is recommended as fourth-line treatment for relapsing-remitting multiple sclerosis (RRMS). Although natalizumab has already demonstrated higher effectiveness compared with fingolimod in some studies, this real-world study was conducted to evaluate annualized hospitalization rates (AHR) in Brazil for both treatments when switching from platform therapies. As secondary goals, we analyzed RRMS treatment patterns and hospitalization profiles. MATERIAL AND METHODS: We extracted data from the DATASUS database of patients with MS (ICD-10 G35) who initiated treatment from January 2012 to December 2017. Two cohorts were screened for different purposes. Cohort 1 was used to analyze treatment patterns and hospitalization profiles and was defined as individuals who had at least one claim related to MS therapies and had received at least two lines of treatment. The second cohort, which was a subset of the first, was used to compare natalizumab's and fingolimod's AHR reduction from previous treatment lines and included patients switching from platform therapy to one of these two drugs. Cohort 2 adjustment was assessed through two different statistical methods: propensity score (PS) and inverse probability weighting (IPW). RESULTS: Of 29,410 patients screened, 2,876 were included in cohort 1. Three quarters of hospitalizations reported in this cohort were for treatment of MS relapse. Cohort 2 included 1,005 patients, and natalizumab was more commonly used (n = 540) than fingolimod (n = 465). Both PS and IPW analyses showed that patients treated with natalizumab had a statistical significantly reduction in AHR compared with first-line treatment (p<0.01 for both PS and IPW), while fingolimod did not result in significant reduction in AHR (p = 0.20 for PS and p = 0.17 for IPW). CONCLUSION: This study provides real-world evidence of natalizumab's and fingolimod's effectiveness in terms of AHR, with an increased reduction in AHR with natalizumab. The findings of this study also provide information to support disease management and healthcare planning in the Brazilian public healthcare system.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/uso terapêutico , Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Adulto , Idoso , Brasil , Feminino , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/efeitos adversos , Hospitalização/estatística & dados numéricos , Hospitais Públicos/estatística & dados numéricos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Natalizumab/administração & dosagem , Natalizumab/efeitos adversos
4.
J Immunol ; 204(5): 1101-1110, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32034063

RESUMO

Fingolimod is an effective treatment for relapsing-remitting multiple sclerosis. It is well established that fingolimod, a modulator of the sphingosine-1-phosphate pathway, restrains the egress of CCR7+ lymphocytes from lymphatic tissues into the blood, thus resulting in reduced lymphocyte counts in peripheral blood. CXCR5+ T follicular helper (Tfh) cells provide help to B cells, are essential for the generation of potent Ab responses, and have been shown to be critically involved in the pathogenesis of several autoimmune diseases. Besides lymphoid tissue-resident Tfh cells, CXCR5+ circulating Tfh (cTfh) cells have been described in the blood, their numbers correlating with the magnitude of Tfh cells in lymphoid tissues. Although the effect of fingolimod on circulating lymphocyte subsets has been established, its effect on cTfh cells remains poorly understood. In this study, we found that although fingolimod strongly and disproportionally reduced cTfh cell frequencies, frequencies of activated cTfh cells were increased, and the composition of the cTfh cell pool was skewed toward a cTfh1 cell phenotype. The circulating T follicular regulatory cell subset and CXCR5+ CD8+ T cell frequencies were also strongly and disproportionally decreased after fingolimod treatment. In contrast, relative frequencies of CXCR5- memory Th cells as well as regulatory T and B cells were increased. In summary, these data provide new insights into fingolimod-induced compositional changes of lymphocyte populations in the blood, in particular cTfh cells, and thus contribute to a better understanding of the mechanism of action of fingolimod in multiple sclerosis patients.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Cloridrato de Fingolimode/administração & dosagem , Memória Imunológica/efeitos dos fármacos , Esclerose Múltipla/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD8-Positivos/patologia , Feminino , Humanos , Masculino , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Receptores CXCR5/imunologia , Linfócitos T Auxiliares-Indutores/patologia
5.
Eur J Pharm Biopharm ; 148: 1-9, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31917332

RESUMO

Metastatic tumors are the main cause of cancer-related death, as the invading cancer cells disrupt normal functions of distant organs and are nearly impossible to eradicate by traditional cancer therapeutics. This is of special concern when the cancer has created multiple metastases and extensive surgery would be too dangerous to execute. Therefore, combination chemotherapy is often the selected treatment form. However, drug cocktails often have severe adverse effects on healthy cells, whereby the development of targeted drug delivery could minimize side-effects of drugs and increase the efficacy of the combination therapy. In this study, we utilized the folate antagonist methotrexate (MTX) as targeting ligand conjugated onto mesoporous silica nanoparticles (MSNs) for selective eradication of folate receptor-expressing invasive thyroid cancer cells. The MSNs was subsequently loaded with the drug fingolimod (FTY720), which has previously been shown to efficiently inhibit proliferation and invasion of aggressive thyroid cancer cells. To assess the efficiency of our carrier system, comprehensive in vitro methods were employed; including flow cytometry, confocal microscopy, viability assays, invasion assay, and label-free imaging techniques. The in vitro results show that MTX-conjugated and FTY720-loaded MSNs potently attenuated both the proliferation and invasion of the cancerous thyroid cells while keeping the off-target effects in normal thyroid cells reasonably low. For a more physiologically relevant in vivo approach we utilized the chick chorioallantoic membrane (CAM) assay, showing decreased invasive behavior of the thyroid derived xenografts and an increased necrotic phenotype compared to tumors that received the free drug cocktail. Thus, the developed multidrug-loaded MSNs effectively induced apoptosis and immobilization of invasive thyroid cancer cells, and could potentially be used as a carrier system for targeted drug delivery for the treatment of diverse forms of aggressive cancers that expresses folate receptors.


Assuntos
Cloridrato de Fingolimode/administração & dosagem , Metotrexato/administração & dosagem , Nanopartículas , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/patologia , Sistemas de Liberação de Medicamentos , Cloridrato de Fingolimode/farmacologia , Receptores de Folato com Âncoras de GPI/metabolismo , Humanos , Metotrexato/farmacologia , Invasividade Neoplásica/prevenção & controle , Dióxido de Silício/química , Neoplasias da Glândula Tireoide/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancer Lett ; 468: 1-13, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593801

RESUMO

Acute myeloid leukemia (AML) is an aggressive disease associated with very poor prognosis. Most patients are older than 60 years, and in this group only 5-15% of cases survive over 5 years. Therefore, it is urgent to develop more effective targeted therapies. Inactivation of protein phosphatase 2 A (PP2A) is a recurrent event in AML, and overexpression of its endogenous inhibitor SET is detected in ~30% of patients. The PP2A activating drug FTY720 has potent anti-leukemic effects; nevertheless, FTY720 induces cardiotoxicity at the anti-neoplastic dose. Here, we have developed a series of non-phosphorylable FTY720 analogues as a new therapeutic strategy for AML. Our results show that the lead compound CM-1231 re-activates PP2A by targeting SET-PP2A interaction, inhibiting cell proliferation and promoting apoptosis in AML cell lines and primary patient samples. Notably, CM-1231 did not induce cardiac toxicity, unlike FTY720, in zebrafish models, and reduced the invasion and aggressiveness of AML cells more than FTY720 in zebrafish xenograft models. In conclusion, CM-1231 is safer and more effective than FTY720; therefore, this compound could represent a novel and promising approach for treating AML patients with SET overexpression.


Assuntos
Cardiotoxicidade/prevenção & controle , Proteínas de Ligação a DNA/metabolismo , Cloridrato de Fingolimode/administração & dosagem , Chaperonas de Histonas/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Proteína Fosfatase 2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/etiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Cloridrato de Fingolimode/análogos & derivados , Cloridrato de Fingolimode/toxicidade , Frequência Cardíaca/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica/efeitos dos fármacos , Testes de Toxicidade Aguda , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
7.
Int J Mol Sci ; 20(23)2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31795084

RESUMO

A major concern caused by the discontinuation of disease modifying treatment for multiple sclerosis (MS) is a rebound of disease activity. Hypotheses about the underlying mechanism of fingolimod (FTY) induced exaggerated inflammatory responses are diverse. So far, vaccinations as a trigger for rebound activity following FTY suspension have not been described. However, several reports have highlighted the occurrence of neurological and autoimmune side effects after single or combined multi-vaccination procedures. Here, we describe the case of a highly active female MS patient demonstrating recurrent, severe MS relapses accompanied by extensive MRI activity, subsequent to yellow fever vaccination two months following FTY withdrawal. Blood and cerebrospinal fluid immunophenotyping indicated a B cell/plasma cell autoreactivity. Following a therapy with natalizumab the clinical, laboratory, MRI, and disease course improved significantly. This case hints towards a combined immunological mechanism characterized by molecular mimicry, bystander activation, and lymphocyte re-egress, resulting in extensive neurological impairment and shows that natalizumab represents a therapeutic option to counteract B cell mediated autoreactivity. Especially, the diagnostic and therapeutic management of this complex scenario might be instructive for clinical practice.


Assuntos
Cloridrato de Fingolimode/administração & dosagem , Imunossupressores/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/imunologia , Vacina contra Febre Amarela/efeitos adversos , Adulto , Esquema de Medicação , Feminino , Cloridrato de Fingolimode/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Linfócitos/imunologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/uso terapêutico , Vacina contra Febre Amarela/administração & dosagem
8.
Mult Scler Relat Disord ; 36: 101335, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31557679

RESUMO

BACKGROUND: Relapse frequency is often correlated with the prognosis of multiple sclerosis (MS). In patients with relapsing-remitting MS (RRMS), relapses vary in severity and may affect activities of daily living, require steroid intervention, or hospitalization. Incomplete recovery from relapses results in increasing disability. In pivotal phase III studies of fingolimod (FREEDOMS, FREEDOMS II, and TRANSFORMS), the frequency of overall and severe relapses was significantly reduced in patients with RRMS treated with fingolimod compared with placebo or intramuscular interferon ß-1a (IFN ß-1a). The objective of this study was to report the effect of early initiation of fingolimod on relapse severity in patients with RRMS. METHODS: This is a post hoc descriptive analysis of data from the pooled placebo-controlled FREEDOMS/FREEDOMS II studies and from the active-comparator TRANSFORMS study. Patients were analyzed under 2 groups: patients initially randomized to receive fingolimod 0.5 mg during the core phase and continued fingolimod 0.5 mg in the extension phase (immediate fingolimod group), and patients initially randomized to placebo or IFN ß-1a during the core phase and switched to fingolimod during the extension phase (delayed fingolimod group). Annualized relapse rate (ARR) was estimated for severe relapses (defined as Expanded Disability Status Scale increase of >1 point, or >2-point change in 1 or 2 Functional Systems, respectively, or >1-point change in >4 Functional Systems). ARR was also estimated for relapses that affected activities of daily living, required steroid use, or hospitalization. RESULTS: In the pooled FREEDOMS/FREEDOMS II extensions, the immediate fingolimod group showed sustained reductions in the proportion (core: 15.8% and extension: 9.3%) and in ARR over 4 years (0.032 and 0.015) for severe relapses, in relapses requiring steroids (0.149 and 0.123), hospitalization (0.049 and 0.039) and relapses affecting activities of daily living (0.155 and 0.112). In the TRANSFORMS extension, similar reductions were observed in the immedaite group for the proportion of severe relapses (core: 11.8% and extension: 9.8%). ARR remained low over 2 years for severe relapses (0.024 and 0.018), relapses affecting activities of daily living (0.112 and 0.109), relapses requiring steroids (0.156 and 0.161) and hospitalization (0.027 and 0.033). Results in the FREEDOMS/FREEDOMS II and TRANSFORMS extensions for the delayed group were similar. In the TRANSFORMS extension, the proportion of severe relapses were 18.0% (core) and 11.1% (extension); there were significant reductions in ARR for severe relapses (core: 0.079 and extension: 0.029), relapses requiring steroids (0.366 and 0.232), hospitalization (0.092 and 0.055), and relapses affecting activities of daily living (0.285 and 0.144) (all p < 0.0001). Complete recovery was reported for the majority of relapses during the core and extension phases in both the immediate and delayed fingolimod groups (Pooled FREEDOMS/FREEDOMS II: immediate group 59.7%-65.5% and delayed group 64.9%-67.7%; TRANSFORMS: 72.1%-80.0% and 65.4%-70.8%). CONCLUSIONS: In patients with RRMS, the frequency of severe relapses and relapse severity remained low in the immedaite fingolimod group over a period of 4 years. Reductions in the proportion of severe relapses post switch from IFN ß-1a or placebo to fingolimod underscore the clinical benefit and the relevance of an early initiation of fingolimod.


Assuntos
Intervenção Médica Precoce , Cloridrato de Fingolimode/farmacologia , Fatores Imunológicos/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Prevenção Secundária , Adulto , Feminino , Cloridrato de Fingolimode/administração & dosagem , Humanos , Fatores Imunológicos/administração & dosagem , Interferon beta-1a/farmacologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
9.
J Neurol ; 266(12): 3098-3107, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31535270

RESUMO

BACKGROUND: The increase in disease-modifying drugs (DMDs) allows individualization of treatment in relapsing multiple sclerosis (RMS); however, the long-term impact of different treatment sequences is not well established. This is particularly relevant for MS patients who may need to postpone more aggressive DMD strategies. OBJECTIVE: To evaluate different therapeutic strategies and their long-term outcomes, measured as relapses and confirmed disability progression (CDP), in MS 'real-world' settings. METHODS: Multicentre, observational, retrospectively acquired cohort study evaluating the long-term impact of different treatment strategies on disability outcomes in patients with RMS in the Italian MS Register. RESULTS: We evaluated 1152 RMS-naïve patients after propensity-score adjustment. Patients included were receiving: interferon beta-1a (IFN-ß1a) 44 µg switching to fingolimod (FTY; IFN-switchers; n = 97); FTY only (FTY-stayers; n = 157); IFN-ß1a only (IFN-stayers; n = 849). CDP and relapses did not differ between FTY-stayers and IFN-switchers [HR (95% CI) 0.99 (0.48-2.04), p = 0.98 and 0.81 (0.42-1.58), p = 0.55, respectively]. However, IFN-stayers showed increased risk of relapses compared with FTY-stayers [HR (95% CI) 1.46 (1.00-2.12), p = 0.05]. CONCLUSION: The ideal treatment option for MS is becoming increasingly complex, with the need to balance benefit and risks. Our results suggest that starting with FTY affects the long-term disease outcome similarly to escalating from IFN-ß1a to FTY.


Assuntos
Progressão da Doença , Cloridrato de Fingolimode/farmacologia , Fatores Imunológicos/farmacologia , Interferon beta-1a/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Sistema de Registros , Índice de Gravidade de Doença , Adulto , Esquema de Medicação , Feminino , Cloridrato de Fingolimode/administração & dosagem , Humanos , Fatores Imunológicos/administração & dosagem , Interferon beta-1a/administração & dosagem , Itália , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
10.
Mult Scler Relat Disord ; 36: 101376, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31473488

RESUMO

BACKGROUND: Fingolimod and teriflunomide are commonly used in the treatment of relapsing-remitting multiple sclerosis (RRMS). These have not been compared in controlled trials, but only in observational studies, with inconclusive results. Comparison of their effect on relapse and disability in a real-world setting is therefore needed. OBJECTIVES: The objective of this study was to compare the efficacy of fingolimod and teriflunomide in reducing disease activity in RRMS. METHODS: This multicenter, retrospective observational study was carried out with prospectively collected data from 15 centers. All consecutive RRMS patients treated with teriflunomide or fingolimod were included. Data for relapses, Expanded Disability Status Scale (EDSS) scores and brain magnetic resonance imaging (MRI) scans were collected. Patients were matched using propensity scores. Annualized relapse rates (ARR), disability accumulation, percentage of patients with active MRI and treatment discontinuation over a median 2.5-year follow-up period were compared. RESULTS: Propensity score matching retained 349 out of 1388 patients in the fingolimod group and 349 out 678 in the teriflunomide group for final analyses. Mean ARR decreased markedly from baseline after 1 and 2 years of treatment in both the fingolimod (0.58-0.17 after 1 year and 0.11 after 2 years, p < 0.001) and teriflunomide (0.56-0.29 after 1 year and 0.31 after 2 years, p < 0.001) groups. Mean ARR was lower in fingolimod-treated patients than in those treated with teriflunomide at years 1 (p = 0.02) and 2 (p = 0.004). Compared to teriflunomide, the fingolimod group exhibited a higher percentage of relapse-free patients and a lower percentage of MRI-active patients after 2.5-year follow-up. Disability worsening was similar between the two groups. Patients were less likely to discontinue fingolimod than teriflunomide (p < 0.001). CONCLUSION: Fingolimod was associated with a better relapse control and lower discontinuation rate than teriflunomide. The two oral therapies exhibited similar effects on disability outcomes.


Assuntos
Crotonatos/farmacologia , Cloridrato de Fingolimode/farmacologia , Fatores Imunológicos/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Toluidinas/farmacologia , Adulto , Crotonatos/administração & dosagem , Feminino , Cloridrato de Fingolimode/administração & dosagem , Humanos , Fatores Imunológicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Pontuação de Propensão , Estudos Retrospectivos , Prevenção Secundária , Índice de Gravidade de Doença , Toluidinas/administração & dosagem
11.
Artigo em Inglês | MEDLINE | ID: mdl-31454772

RESUMO

OBJECTIVE: To test whether patients with MS on disease-modifying treatments (DMTs) are at a higher risk of acute or chronic hepatitis E virus (HEV) infections or extrahepatic manifestations, we monitored approximately 1,100 persons with MS (pwMS) during 3 years for HEV infection. METHODS: This is an observational case series study. All pwMS were followed in our MS center between January 2016 and December 2018 with at least annual standardized clinical and laboratory assessments. Patients with unexplained liver enzyme elevations were routinely screened for HEV infection. RESULTS: Four cases of acute HEV under DMT (fingolimod [n = 3]; dimethyl fumarate [n = 1]) were identified. Two presented with fulminant icteric hepatitis and one with a HEV-associated neurologic manifestation (neuralgic amyotrophy). No chronic HEV courses were observed. DMT was continued after clearing of HEV or normalization of liver function tests in all cases. CONCLUSION: HEV infection is an important differential diagnosis of drug-induced liver injury in pwMS under DMT. Our data do not suggest an increased incidence of acute HEV infections or chronification in pwMS. However, epidemiologic studies in immunomodulatory-treated patients are needed to further investigate HEV disease courses and extrahepatic manifestations.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doenças Desmielinizantes/diagnóstico , Hepatite E/induzido quimicamente , Hepatite E/diagnóstico , Imunossupressores/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Administração Oral , Adulto , Doenças Desmielinizantes/tratamento farmacológico , Fumarato de Dimetilo/administração & dosagem , Fumarato de Dimetilo/efeitos adversos , Substituição de Medicamentos/efeitos adversos , Feminino , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/efeitos adversos , Acetato de Glatiramer/administração & dosagem , Acetato de Glatiramer/efeitos adversos , Vírus da Hepatite E/isolamento & purificação , Humanos , Imunossupressores/administração & dosagem , Interferon beta-1a/administração & dosagem , Interferon beta-1a/efeitos adversos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto Jovem
12.
J Vet Med Sci ; 81(9): 1249-1258, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31341112

RESUMO

Inflammatory bowel disease (IBD) is a common gastrointestinal disease in dogs. Decreased production of intestinal immunoglobulin A (IgA) has been suggested as a possible pathogenesis in a subset of canine IBD; however, the underlying cause remains unclear. Sphingosine-1-phosphate (S1P) is a lipid mediator that regulates intestinal IgA production by controlling lymphocyte trafficking in mice. The objectives of this study were to clarify the role of S1P in IgA production in dogs and to evaluate the expression of S1P-related molecules in dogs with IBD. First, an S1P receptor antagonist was administrated to five healthy dogs. The S1P receptor antagonist significantly decreased the IgA concentration in sera and feces but did not affect the IgG concentration. Moreover, the immunoreactivity of intestinal IgA was significantly decreased by S1P signal blockade. These results indicate that S1P signaling specifically regulates the intestinal IgA production in dogs. Subsequently, the intestinal S1P concentration and the expression of S1P-related molecules were measured in dogs with IBD and healthy dogs. The intestinal concentration of S1P was significantly lower in dogs with IBD than in healthy dogs. In addition, the gene expression levels of S1P receptor (S1P1) and S1P synthase (SK1) were significantly lower in dogs with IBD than in healthy dogs. Taken together, these observations suggest that decreased S1P production, likely caused by a lower expression of S1P synthetase, leads to attenuation of S1P/S1P1 signaling pathway and the production of intestinal IgA in dogs with IBD.


Assuntos
Doenças do Cão/metabolismo , Imunoglobulina A/metabolismo , Doenças Inflamatórias Intestinais/veterinária , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Animais , Doenças do Cão/patologia , Cães , Fezes/química , Cloridrato de Fingolimode/administração & dosagem , Expressão Gênica , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Intestinos/química , Masculino , Esfingosina/metabolismo , Moduladores do Receptor de Esfingosina 1 Fosfato , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Receptores de Esfingosina-1-Fosfato/genética
13.
Rinsho Shinkeigaku ; 59(8): 536-540, 2019 Aug 29.
Artigo em Japonês | MEDLINE | ID: mdl-31341130

RESUMO

A 42-year-old woman diagnosed with multiple sclerosis (MS) at the age of 37 was initially treated with interferon-ß IM. The frequency of clinical relapses was twice in 4 years. At the age of 41, due to difficulty in administering muscle injections, an oral medication fingolimod was started. However, it was discontinued after a month due to decreased lymphocyte count, following which natalizumab was administered. The number of relapses increased 3 times in eleven months, and the number of T2 lesions on the MRI increased from 12 to 23. Natalizumab was discontinued because the test for the anti-natalizumab antibody was positive. It was suspected that both, the rebound syndrome caused by fingolimod cessation and the drug neutralization by anti-natalizumab antibodies, were associated with the exacerbation of disease activity. Thus, careful attention should be paid to potential occurrence of these events post switching between disease-modifying drugs for treating MS with high activity.


Assuntos
Substituição de Medicamentos/efeitos adversos , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/efeitos adversos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Natalizumab/administração & dosagem , Natalizumab/efeitos adversos , Adulto , Anticorpos , Progressão da Doença , Feminino , Humanos , Injeções Intramusculares , Interferon beta/administração & dosagem , Contagem de Linfócitos , Natalizumab/imunologia , Recidiva
14.
Sci Rep ; 9(1): 10972, 2019 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358793

RESUMO

Lipid metabolism is abnormal in Alzheimer's disease (AD) brain leading to ceramide and sphingosine accumulation and reduced levels of brain sphingosine-1-phosphate (S1P). We hypothesize that changes in S1P signaling are central to the inflammatory and immune-pathogenesis of AD and the therapeutic benefits of fingolimod, a structural analog of sphingosine that is FDA approved for the treatment of multiple sclerosis. We recently reported that the neuroprotective effects of fingolimod in 5xFAD transgenic AD mice treated from 1-3 months of age were greater at 1 mg/kg/day than at 5 mg/kg/day. Here we performed a dose-response study using fingolimod from 0.03 to 1 mg/kg/day in 5xFAD mice treated from 1-8 months of age. At 1 mg/kg/day, fingolimod decreased both peripheral blood lymphocyte counts and brain Aß levels, but at the lowest dose tested (0.03 mg/kg/day), we detected improved memory, decreased activation of brain microglia and astrocytes, and restored hippocampal levels of GABA and glycerophosphocholine with no effect on circulating lymphocyte counts. These findings suggests that, unlike the case in multiple sclerosis, fingolimod may potentially have therapeutic benefits in AD at low doses that do not affect peripheral lymphocyte function.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Encéfalo/efeitos dos fármacos , Reposicionamento de Medicamentos , Cloridrato de Fingolimode/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Cloridrato de Fingolimode/uso terapêutico , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Ácido gama-Aminobutírico/metabolismo
15.
J Neurol ; 266(10): 2512-2517, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31256279

RESUMO

OBJECTIVE: To evaluate the effect of discontinuation of different disease-modifying therapies (DMTs) before pregnancy with respect to the occurrence of relapses and pregnancy outcomes. METHODS: Women with multiple sclerosis who desire to bear children were followed prospectively. Demographic data, clinical characteristics, and the information on the use of DMTs were collected. A multivariate analysis was used to assess the relationship between relapses and the prior use of different DMTs. RESULTS: The present study assessed 75 consecutive pregnancy plans (66 women), 65 of which resulted in pregnancy. The mean age of the participants was 32.1 ± 4.2 years, and the mean disease duration was 6.1 ± 4.2 years. No relapses before pregnancy were reported in the group of women who maintained their DMT until pregnancy confirmation, while 14 relapses were reported in 12/42 women (29%) who discontinued DMT before pregnancy. During pregnancy, patients on natalizumab or fingolimod before pregnancy had a higher rate of relapses. Most women restarted their previous DMT after delivery within the first trimester. The relapse rate in postpartum was 0.07. CONCLUSIONS: Disease-modifying therapies received influences the risk of relapse and disease progression from women who are planning pregnancy. The risk of relapse during pregnancy was significantly higher in the group of women treated with natalizumab or fingolimod compared to the group of women treated with interferon beta or glatiramer acetate. The postpartum risk of relapses was lower than that found in previous reports.


Assuntos
Cloridrato de Fingolimode/administração & dosagem , Acetato de Glatiramer/administração & dosagem , Fatores Imunológicos/administração & dosagem , Interferon beta/administração & dosagem , Esclerose Múltipla/tratamento farmacológico , Natalizumab/administração & dosagem , Complicações na Gravidez/etiologia , Comportamento Reprodutivo , Adulto , Progressão da Doença , Feminino , Seguimentos , Humanos , Gravidez , Transtornos Puerperais/etiologia , Recidiva
17.
J Neurol ; 266(10): 2440-2446, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31209573

RESUMO

BACKGROUND: A high reactivation of multiple sclerosis (MS) was reported in patients treated with alemtuzumab after fingolimod. We aimed to understand whether this shift enhanced the risk for reactivation in a real-life cohort. METHODS: Subjects with relapsing MS, shifting from fingolimod to alemtuzumab were enrolled. We collected the following data: age, sex, disease duration, relapses after fingolimod withdrawal, new T2/gadolinium (Gd)-enhancing lesions in the last magnetic resonance imaging (MRI) during fingolimod and in the first, while on alemtuzumab, lymphocyte counts at alemtuzumab start, and Expanded Disability Status Scale (EDSS) before and after alemtuzumab. RESULTS: We enrolled 77 patients (women 61 (79%); mean age 36.2 years (SD 9.6), and disease duration 12.3 years (SD 6.8) at fingolimod discontinuation; median washout 1.8 months). The annualised relapse rate was 0.89 during fingolimod, 1.32 during washout, and 0.15 after alemtuzumab (p = 0.001). The EDSS changed from a median of 3 (IQR 2-4) at the end of fingolimod to 2.5 after alemtuzumab (IQR 1.5-4) (p = 0.013). The washout length and the lymphocyte count before alemtuzumab were not associated with EDSS change after alemtuzumab (p = 0.59 and p = 0.33, respectively). MRI activity decreased after alemtuzumab compared to that during fingolimod (p = 0.001). At alemtuzumab start, lymphocyte counts were < 0.8 × 103/mL in 21 patients. CONCLUSIONS: In our cohort, alemtuzumab reduced relapse, new T2/Gd-enhancing lesions, and EDSS score, as compared to the previous periods (fingolimod/washout). These results were not related to washout length or lymphocyte counts. Therefore, a rapid initiation of alemtuzumab after fingolimod does not seem to be a risk factor for MS reactivation.


Assuntos
Alemtuzumab/farmacologia , Cloridrato de Fingolimode/farmacologia , Fatores Imunológicos/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Adulto , Alemtuzumab/administração & dosagem , Alemtuzumab/efeitos adversos , Feminino , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/efeitos adversos , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Estudos Retrospectivos , Índice de Gravidade de Doença
18.
PLoS One ; 14(4): e0214469, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30969990

RESUMO

Despite an increase in incidence, treatments for hepatoblastoma remain virtually unchanged for the past 20 years, emphasizing the need for novel therapeutics. FTY720 (fingolimod) is an immunomodulator approved for use in multiple sclerosis in children that has been demonstrated to have anti-cancer properties in multiple cancer types. We have demonstrated that FTY720 activates PP2A in hepatoblastoma, but does not do so via inhibition of the endogenous inhibitors, CIP2A and I2PP2A, as previously observed in other cancers. PP2A activation in hepatoblastoma decreased cell viability, proliferation, and motility and induced apoptosis. In a subcutaneous xenograft model, FTY720 decreased tumor growth. FTY720 in combination with the standard chemotherapeutic, cisplatin, decreased proliferation in a synergistic manner. Finally, animals bearing subcutaneous hepatoblastoma xenografts treated with FTY720 and cisplatin in combination had significantly decreased tumor growth compared to those treated with either drug alone. These findings show that targeting PP2A with FTY70 shows promise in the treatment of hepatoblastoma and that combining FTY720 with cisplatin may be a novel and effective strategy to better treat this devastating pediatric liver tumor.


Assuntos
Cisplatino/administração & dosagem , Hepatoblastoma/patologia , Neoplasias Hepáticas/patologia , Proteína Fosfatase 2/metabolismo , Animais , Apoptose , Autoantígenos/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Proteínas de Ligação a DNA , Feminino , Cloridrato de Fingolimode/administração & dosagem , Hepatoblastoma/tratamento farmacológico , Chaperonas de Histonas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fatores de Transcrição/metabolismo
19.
Pak J Pharm Sci ; 32(1(Special)): 413-419, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30852478

RESUMO

This paper aims to observe and analyze the safety and clinical efficacy of Fingolimod combined with alteplase intravenous thrombolysis in the treatment of acute ischemic stroke. 90 patients with acute ischemic stroke were randomly divided into two groups. 45 patients in the control group were given alteplase intravenous thrombolysis for injection. 45 cases in the trial group were treated with Fingolimod combined with alteplase. There was no significant difference in NIHSS score, mRS score and BI index between the two groups 14 days after treatment, but 90 days after treatment, NIHSS score and mRS score of the experimental group were significantly lower than that of the control group, and BI index was significantly higher (P<0.05). 24 hours after oral administration of Fingolimod (0.5 mg), the circulating blood CD4 + T, CD8 + T, CD19 + B and CD56 + natural killer cells of the patients in the combined treatment group decreased steadily to varying degrees. The results confirm the pharmacological effect of Fingolimod: it changes lymphocyte migration, promotes lymphocyte to enter lymphoid tissue, prevents lymphocyte from leaving lymphoid tissue to enter the peripheral circulation, and thus prevents these immune cells from infiltrating the central nervous system. The results showed that Fingolimod combined with alteplase intravenous thrombolysis is safe for patients with acute ischemic stroke. .


Assuntos
Fibrinolíticos/uso terapêutico , Cloridrato de Fingolimode/uso terapêutico , Reabilitação do Acidente Vascular Cerebral/enfermagem , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico , Administração Oral , Esquema de Medicação , Quimioterapia Combinada , Feminino , Fibrinolíticos/administração & dosagem , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/efeitos adversos , Humanos , Infusões Intravenosas , Linfócitos/citologia , Linfócitos/imunologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/imunologia , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento
20.
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
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