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1.
Neurology ; 96(3): e376-e386, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33328324

RESUMO

OBJECTIVE: To investigate the effects of siponimod on cognitive processing speed in patients with secondary progressive (SP) multiple sclerosis (MS), by means of a predefined exploratory and post hoc analysis of the Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND) study, a randomized controlled trial comparing siponimod and placebo. METHODS: EXPAND was a double-blind, placebo-controlled phase 3 trial involving 1,651 patients with SPMS randomized (2:1) to either siponimod 2 mg/d or placebo. Cognitive function was assessed with the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and Brief Visuospatial Memory Test-Revised (BVMT-R) administered at baseline, 6-month intervals, and end of treatment. RESULTS: Between-group differences in mean change from baseline in SDMT scores were significantly better in siponimod- vs placebo-treated patients at month 12 (difference 1.08 [95% confidence interval 0.23-1.94]; p = 0.0132), month 18 (1.23 [0.25-2.21); p = 0.0135), and month 24 (2.30 [1.11-3.50]; p = 0.0002). Siponimod-treated patients were at significantly lower risk for having a 4-point sustained decrease in SDMT score (hazard ratio [HR] 0.79 [0.65-0.96]; p = 0.0157), while their chance for having a 4-point sustained increase in SDMT score was higher (HR 1.28 [1.05-1.55]; p = 0.0131). PASAT and BVMT-R scores did not differ significantly between the 2 treatment groups (all p > 0.28). CONCLUSION: Siponimod had a significant benefit on SDMT in patients with SPMS. Siponimod-treated patients were at significantly lower risk for having a ≥4-point decrease in SDMT score and had a significantly higher chance for having a ≥4-point increase in SDMT score, a magnitude of change accepted as clinically meaningful. CLINICALTRIALSGOV IDENTIFIER: NCT01665144. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, for patients with SPMS, siponimod had a significant benefit on cognitive processing speed.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Cognição/efeitos dos fármacos , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Adulto , Azetidinas/farmacologia , Compostos de Benzil/farmacologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/psicologia , Testes Neuropsicológicos , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia
2.
Eur Rev Med Pharmacol Sci ; 24(23): 12527-12535, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33336773

RESUMO

Since December 2019, an outbreak of a new coronavirus, COVID-19, infection has been taking place. At present, COVID-19 has spread to most countries worldwide. The latest evidence suggests that cytokine storm syndrome (CSS) is an important cause of the transition from mild to critical pneumonia and critically ill patients' death. The sudden exacerbation of COVID-19 may be related to a cytokine storm. Therefore, early identification and active treatment of CSS may play very important roles in improving the patients' prognosis, and these tasks are given attention in the current treatment of new Coronavirus pneumonia. However, there is still no specific medicine for this purpose. This article reviews cytokine storms and conducts an exploratory review of pharmacotherapy for cytokine storms to provide a reference for clinical treatment.


Assuntos
/imunologia , Síndrome da Liberação de Citocina/imunologia , Miocardite/imunologia , /metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose , Fator Natriurético Atrial/uso terapêutico , Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Glucocorticoides/uso terapêutico , Glicoproteínas/uso terapêutico , Humanos , Hipóxia/metabolismo , Hipóxia/terapia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Isquemia Miocárdica/metabolismo , Miocardite/metabolismo , Miocardite/terapia , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Oxigenoterapia , Respiração Artificial , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Inibidores da Tripsina/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , alfa-Metiltirosina/uso terapêutico
3.
Lancet Gastroenterol Hepatol ; 5(9): 819-828, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32553149

RESUMO

BACKGROUND: Although treatment of Crohn's disease has improved with development of tumour necrosis factor antagonists, fewer than 50% of patients have sustained benefit. Durable maintenance therapy with orally administered alternative treatments remains an unmet need. We aimed to evaluate the effects of ozanimod, an oral agent selectively targeting sphingosine-1-phosphate receptor subtypes 1 and 5, on endoscopic disease activity in Crohn's disease. METHODS: STEPSTONE was a phase 2, uncontrolled, multicentre trial in adults with moderately to severely active Crohn's disease recruited at 28 hospital and community research centres in Canada, the USA, Hungary, Poland, and Ukraine. All patients began treatment with a 7-day dose escalation (4 days on ozanimod 0·25 mg daily followed by 3 days at 0·5 mg daily). Patients then received ozanimod 1·0 mg oral capsule daily for a further 11 weeks, for a 12-week induction period, followed by a 100-week extension. The primary endpoint was change in Simple Endoscopic Score for Crohn's Disease (SES-CD) from baseline to week 12, as determined by a blinded central reader. Data are reported for the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02531113 and EudraCT, number 2015-002025-19, and is completed. FINDINGS: 69 patients were enrolled between Nov 17, 2015, and Aug 18, 2016. At week 12, the mean change from baseline in SES-CD was -2·2 (SD 6·0); 16 (23·2%, 95% CI 13·9-34·9) patients experienced endoscopic response. A reduction from baseline in Crohn's Disease Activity Index (CDAI) score also was observed (mean change -130·4 [SD 103·9]). Clinical remission (CDAI <150 points) was shown in 27 (39·1%, 95% CI 27·6-51·6) patients and response (CDAI decrease from baseline ≥100) in 39 (56·5%, 95% CI 44·0-68·4) of patients. The mean change from baseline in two-item patient-reported outcome (PRO2, stool frequency, abdominal pain scores) score was -66·1 (SD 65·4). Mean change from baseline in Geboes Histology Activity Score (GHAS) was -5·9 (SD 11·0) and in Robart's Histopathology Index (RHI) -10·6 (25·1). Adverse events were most frequently those attributed to Crohn's disease, most commonly Crohn's disease (flare) in 18 (26%) patients. The most commonly reported serious treatment-related adverse events were Crohn's disease (six [9%]) and abdominal abscess (two [3%]). INTERPRETATION: Endoscopic, histological, and clinical improvements were seen within 12 weeks of initiating ozanimod therapy in patients with moderately to severely active Crohn's disease. Phase 3 placebo-controlled trials have been initiated. FUNDING: Celgene Corporation.


Assuntos
Doença de Crohn/tratamento farmacológico , Indanos/uso terapêutico , Quimioterapia de Indução/métodos , Oxidiazóis/uso terapêutico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Abscesso Abdominal/induzido quimicamente , Abscesso Abdominal/epidemiologia , Administração Oral , Adulto , Idoso , Canadá/epidemiologia , Doença de Crohn/diagnóstico por imagem , Doença de Crohn/patologia , Endoscopia/métodos , Endoscopia/estatística & dados numéricos , Feminino , Humanos , Hungria/epidemiologia , Indanos/administração & dosagem , Indanos/efeitos adversos , Análise de Intenção de Tratamento/métodos , Masculino , Pessoa de Meia-Idade , Oxidiazóis/administração & dosagem , Oxidiazóis/efeitos adversos , Medidas de Resultados Relatados pelo Paciente , Polônia/epidemiologia , Estudos Prospectivos , Indução de Remissão , Moduladores do Receptor de Esfingosina 1 Fosfato/administração & dosagem , Moduladores do Receptor de Esfingosina 1 Fosfato/efeitos adversos , Ucrânia/epidemiologia , Estados Unidos/epidemiologia
4.
Drugs Today (Barc) ; 56(1): 37-46, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32055804

RESUMO

Siponimod fumarate (BAF-312) is a synthetic sphingosine 1- phosphate (S1P) receptor modulator, which exerts immunomodulating effects mediated by B- and T-cell sequestration in secondary lymphoid organs. S1P receptor modulators have consistently shown a significant benefit on relapse rate and other measures of disease activity in patients with relapsing multiple sclerosis (MS), compared with both placebo and active comparator. However, most clinical trials of S1P receptor modulators--as well as other therapies for MS--lack evidence of a significant benefit on disability progression. A phase III trial of siponimod for secondary progressive MS showed a significant effect of the active drug compared with placebo on reduction of disability progression. Siponimod exhibits selective affinity for types 1 and 5 S1P receptors, indicating a possible lower risk of bradycardia and vasoconstriction compared with modulators with type 3 S1P receptor affinity. Current evidence supporting siponimod efficacy for secondary progressive MS is reviewed in the present article.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva
5.
J Neurol Neurosurg Psychiatry ; 91(1): 58-66, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31467033

RESUMO

BACKGROUND: In PARADIGMS, a double-blind phase III trial in 215 paediatric patients with multiple sclerosis (MS) (10 to <18 years), fingolimod administered for up to 2 years significantly reduced the annualised relapse rate (ARR) and rate of new/newly enlarged T2 (n/neT2) lesions compared with interferon (IFN) ß-1a. OBJECTIVES: To investigate (1) differences between treatment groups across subpopulations (treatment-naïve, younger/prepubertal patients); (2) disability progression. METHODS: ARRs at 10, 11 and 12 years were estimated based on predefined modelling extrapolations. Changes in Expanded Disability Status Scale (EDSS), and in 3 month (3M) and 6 month (6M) confirmed disability progression (CDP) were evaluated post hoc. RESULTS: In the treatment-naïve subpopulation, fingolimod reduced ARR and n/neT2 lesions by 85.8% and 53.4%, respectively versus INF ß-1a (both p<0.001), compared with 81.9% and 52.6% in the overall population. Model-based ARR reductions in younger patients (≤12 years) were 91.9%-94.6%. Twice as many IFN ß-1a-treated than fingolimod-treated patients had worse EDSS scores at study end (20.6% vs 10.5%, p=0.043). Risk reductions in 3M-CDP and 6M-CDP were 77.2% (p=0.007) and 80.2% (p=0.040), respectively. CONCLUSIONS: Fingolimod in paediatric MS was associated with consistent control of disease activity versus IFN ß-1a (including treatment-naïve and younger patients) and resulted in less disability progression for up to 2 years. TRIAL REGISTRATION NUMBER: NCT01892722.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Interferon beta-1a/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Adolescente , Fatores Etários , Idade de Início , Criança , Avaliação da Deficiência , Progressão da Doença , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Comportamento de Redução do Risco , Resultado do Tratamento
6.
J Neuroimmunol ; 339: 577091, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31739156

RESUMO

Fingolimod is used to treat patients with relapsing-remitting multiple sclerosis; it crosses the blood-brain barrier and modulates sphingosine-1-phosphate receptors (S1PRs). Oligodendrocytes, astrocytes, microglia, and neuronal cells express S1PRs, and fingolimod could potentially improve remyelination and be neuroprotective. We used the cuprizone animal model, histo-, immunohistochemistry, and quantitative proteomics to study the effect of fingolimod on remyelination and axonal damage. Fingolimod was functionally active during remyelination by downregulating S1PR1 brain levels, and fingolimod-treated mice had more oligodendrocytes in the secondary motor cortex after three weeks of remyelination. However, there were no differences in remyelination or axonal damage compared to placebo. Thus, fingolimod does not seem to directly promote remyelination or protect against axonal injury or loss when given after cuprizone-induced demyelination.


Assuntos
Encéfalo/metabolismo , Cuprizona/toxicidade , Cloridrato de Fingolimode/farmacologia , Neuroproteção/fisiologia , Remielinização/fisiologia , Receptores de Esfingosina-1-Fosfato/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Feminino , Cloridrato de Fingolimode/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/metabolismo , Neuroproteção/efeitos dos fármacos , Distribuição Aleatória , Remielinização/efeitos dos fármacos , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores
7.
Am J Gastroenterol ; 115(2): 179-189, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31809296

RESUMO

In recent years, the therapeutic goals in ulcerative colitis (UC) have become increasingly stringent. Histological features seem to be a reliable predictor of disease outcomes after therapy, and histological remission (HR) is the new frontier in the treatment of UC. Here, we first provide a historical perspective before reviewing indexes in the era of biologics; histology as a treatment goal in UC trials; the poor correlation between symptoms, endoscopy, and histology; and the impact of histology on disease outcomes. HR seems to be a promising end point for the treatment of UC because it is typically associated with better outcomes. Two new validated indexes are available to assess histology more accurately in trials, and they may also be applicable to clinical practice. Additional interventional trials are now necessary to establish definitions of HR and its potential for disease modification.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Colo/patologia , Fármacos Gastrointestinais/uso terapêutico , Planejamento de Assistência ao Paciente , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Ácido Aminossalicílico/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Produtos Biológicos , Colite Ulcerativa/patologia , Colite Ulcerativa/fisiopatologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Indanos/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Oxidiazóis/uso terapêutico , Indução de Remissão , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Resultado do Tratamento
8.
Expert Rev Gastroenterol Hepatol ; 14(1): 47-54, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31874053

RESUMO

Introduction: Inflammatory bowel diseases (IBD), which include Crohn's disease and ulcerative colitis, are lifetime chronic inflammatory disorders. Over the past few decades, new therapeutic approaches, including early and more effective intervention with immunomodulators and biological agents, increased the possibility of a favorable modification of the natural history of IBD. Despite this progress, there is still a need to explore new therapeutic options.Area covered: Here, we review the literature about the role of therapeutic sphingolipids in inflammatory bowel disease patients.Expert opinion: Despite the great increase of treatment options in the last 20 years, many patients still do not respond to the induction therapy (primary non-responders) or lose response over time (secondary responders). Small-molecule drugs are a promising group of drugs with low molecular weight, an oral route of administration, and low immunogenicity offering several advantages when compared to biologics such as anti-TNFs and anti-integrins. Sphingosine-1-phosphate (S1P) receptor modulators are some among the new small molecules currently under clinical investigation for the treatment of IBD.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Humanos , Esfingolipídeos/uso terapêutico
9.
Neurodegener Dis Manag ; 9(6): 301-317, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31769344

RESUMO

Identifying the transition of relapsing-remitting multiple sclerosis (MS) to the secondary-progressive MS form remains a clinical challenge due to the gradual nature of the transition, superimposed relapses, the heterogeneous course of disease among patients and the absence of validated biomarkers and diagnostic tools. The uncertainty associated with the transition makes clinical care challenging for both patients and physicians. The emergence of new disease-modifying treatments for progressive MS and the increasing emphasis of nonpharmacological strategies mark a new era in the treatment of progressive MS. This article summarizes challenges in diagnosis and management, discusses novel treatment strategies and highlights the importance of establishing a clear diagnosis and instituting an interdisciplinary management plan in the care of patients with progressive MS.


Assuntos
Gerenciamento Clínico , Progressão da Doença , Imunossupressores/uso terapêutico , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Biomarcadores/sangue , Cuidadores/tendências , Pessoal de Saúde/tendências , Humanos , Imagem por Ressonância Magnética/métodos , Imagem por Ressonância Magnética/tendências , Esclerose Múltipla Crônica Progressiva/sangue , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico
10.
Dermatol Online J ; 25(9)2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31738840

RESUMO

A 55-year-old man with relapsing-remitting multiple sclerosis on fingolimod presented to the dermatology clinic with skin lesions on the left temple and cheek. Histopathology showed a diffuse infiltrate of enlarged, atypical lymphocytes throughout the dermis with an overlying grenz zone and a subpopulation of scattered smaller lymphocytes and plasma cells. Epstein-Barr virus-encoded RNA in situ hybridization stain was positive. Based on the morphologic and immunophenotypic findings, a diagnosis of EBV-positive diffuse large B-cell lymphoma was made. This case aims to raise awareness for the dermatologist that patients on fingolimod may be at increased risk of lymphoproliferative disorders.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Cloridrato de Fingolimode/efeitos adversos , Herpesvirus Humano 4/isolamento & purificação , Linfoma Difuso de Grandes Células B/virologia , Dermatopatias Virais/induzido quimicamente , Moduladores do Receptor de Esfingosina 1 Fosfato/efeitos adversos , Biópsia , Infecções por Vírus Epstein-Barr/induzido quimicamente , Cloridrato de Fingolimode/uso terapêutico , Humanos , Hibridização In Situ , Linfócitos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , RNA Viral/análise , Pele/imunologia , Pele/patologia , Dermatopatias Virais/patologia , Dermatopatias Virais/virologia , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico
11.
Expert Opin Drug Discov ; 14(11): 1199-1212, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31389262

RESUMO

Introduction: Fingolimod, the first oral disease-modifying treatment (DMT) in multiple sclerosis (MS), is a sphingosine 1-phosphate receptor (S1PR) ligand. Approved in 2010, fingolimod has been extensively studied and has been credited with several mechanisms of actions that contribute to its efficacy in MS, among which is the regulation of lymphocyte circulation between the central nervous system and the periphery. Concerns about toxicity, off-target effects, and real-life performance have been raised over time in post-marketing studies of such that next-generation sphingosine-1 phosphate receptor ligands are now being developed. Areas covered: Herein, the authors expand upon previous systematic reviews obtained via PubMed and through their expert opinion on fingolimod use in clinical practice. Long-term data including long-term efficacy, safety, tolerability, and management especially within growing DMT options and pre-treatment constellation in MS patients are discussed, together with the results of an increased understanding of the chemistry underlying the structure-activity relationship. Expert opinion: Despite the limitations illustrated in this article, fingolimod still constitutes a paradigm shift in MS treatment. However, although immunomodulation via S1PRs on lymphocytes has represented a major breakthrough in the clinical management of MS, modifying the evolution of progressive MS will likely require the development of approaches other than merely targeting S1PRs.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Administração Oral , Animais , Desenvolvimento de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Cloridrato de Fingolimode/farmacologia , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Esclerose Múltipla/fisiopatologia , Moduladores do Receptor de Esfingosina 1 Fosfato/efeitos adversos , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Relação Estrutura-Atividade
12.
Stat Med ; 38(23): 4761-4771, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31386219

RESUMO

The treatment effect in subgroups of patients is often of interest in randomized controlled clinical trials, as this may provide useful information on how to treat which patients best. When a specific subgroup is characterized by the absence of certain events that happen postrandomization, a naive analysis on the subset of patients without these events may be misleading. The principal stratification framework allows one to define an appropriate causal estimand in such settings. Statistical inference for the principal stratum estimand hinges on scientifically justified assumptions, which can be included with Bayesian methods through prior distributions. Our motivating example is a large randomized placebo-controlled trial of siponimod in patients with secondary progressive multiple sclerosis. The primary objective of this trial was to demonstrate the efficacy of siponimod relative to placebo in delaying disability progression for the whole study population. However, the treatment effect in the subgroup of patients who would not relapse during the trial is relevant from both a scientific and patient perspective. Assessing this subgroup treatment effect is challenging as there is strong evidence that siponimod reduces relapses. We describe in detail the scientific question of interest, the principal stratum estimand, the corresponding analysis method for binary endpoints, and sensitivity analyses. Although our work is motivated by a randomized clinical trial, the approach has broader appeal and could be adapted for observational studies.


Assuntos
Teorema de Bayes , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Humanos , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Projetos de Pesquisa , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico
13.
FASEB J ; 33(10): 10935-10941, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31284754

RESUMO

Sphingosine-1-phosphate receptor (S1PR) modulators provide protection in preclinical and clinical studies for ischemic stroke, but the influences of S1PR modulation on microvascular thrombosis remain poorly understood. This study investigates the impact of a selective S1PR1 modulator RP101075 on microvascular circulation in a mouse model of laser-induced thrombosis. The flow velocity of cortical arterioles in mice was measured in vivo under 2-photon laser scanning microscopy. Thrombosis was induced in cortical arterioles by laser irritation. At 30 min after laser-induced thrombosis, mice were treated with either RP101075 or vehicle. RP101075 did not alter the flow velocity of cortical arterioles under physiologic conditions. Laser-induced thrombosis led to a pronounced reduction of flow velocity in cortical arterioles that persisted for ≥90 min. The reduction of flow velocity in cortical arterioles following thrombosis was significantly attenuated following RP101075 treatment. RP101075 did not significantly affect coagulation time, bleeding time, heart rate, and blood pressure. In addition, RP101075 treatment reduced thrombus volume, which was accompanied by a reduction of leukocyte content in the thrombus. Our findings demonstrate that the selective S1PR1 modulator RP101075 improves microvascular circulation after thrombosis, implying a component of improved microvascular circulation to the benefit of S1PR modulation in cerebral ischemia.-Li, H., Zhou, X., Li, Y., Ma, X., Gonzales, R. J., Qiu, S., Shi, F.-D., Liu, Q. The selective sphingosine 1-phosphate receptor 1 modulator RP101075 improves microvascular circulation after cerebrovascular thrombosis.


Assuntos
Transtornos Cerebrovasculares/tratamento farmacológico , Indanos/uso terapêutico , Microcirculação , Oxidiazóis/uso terapêutico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Trombose/tratamento farmacológico , Animais , Circulação Cerebrovascular , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
Am J Physiol Cell Physiol ; 317(3): C502-C512, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31241988

RESUMO

Sarcopenia, the age-associated loss of skeletal muscle mass and function, is coupled with declines in physical functioning leading to subsequent higher rates of disability, frailty, morbidity, and mortality. Aging and obesity independently contribute to muscle atrophy that is assumed to be a result of the activation of mutual physiological pathways. Understanding mechanisms contributing to the induction of skeletal muscle atrophy with aging and obesity is important for determining targets that may have pivotal roles in muscle loss in these conditions. We find that aging and obesity equally induce an anabolic resistance to acute skeletal muscle contraction as observed with decreases in anabolic signaling activation after contraction. Furthermore, treatment with the sphingosine-1-phosphate analog FTY720 for 4 wk increased lean mass and strength, and the anabolic signaling response to contraction was improved in obese but not older animals. To determine the role of chronic inflammation and different fatty acids on anabolic resistance in skeletal muscle cells, we overexpressed IKKß with and without exposure to saturated fatty acid (SFA; palmitic acid), polyunsaturated fatty acid (eicosapentaenoic acid), and monounsaturated fatty acid (oleic acid). We found that IKKß overexpression increased inflammation markers in muscle cells, and this chronic inflammation exacerbated anabolic resistance in response to SFA. Pretreatment with FTY720 reversed the inflammatory effects of palmitic acid in the muscle cells. Taken together, these data demonstrate chronic inflammation can induce anabolic resistance, SFA aggravates these effects, and FTY720 can reverse this by decreasing ceramide accumulation in skeletal muscle.


Assuntos
Envelhecimento/efeitos dos fármacos , Cloridrato de Fingolimode/uso terapêutico , Contração Muscular/efeitos dos fármacos , Obesidade/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Envelhecimento/metabolismo , Animais , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Cloridrato de Fingolimode/farmacologia , Lisofosfolipídeos/farmacologia , Lisofosfolipídeos/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular/fisiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Distribuição Aleatória , Sarcopenia/tratamento farmacológico , Sarcopenia/metabolismo , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Esfingosina/uso terapêutico , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia
15.
Drugs ; 79(9): 1009-1015, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31144287

RESUMO

Siponimod (Mayzent®) is an oral selective sphingosine 1-phosphate receptor subtypes 1 and 5 (S1PR1,5) modulator being developed by Novartis Pharmaceuticals for the treatment of multiple sclerosis (MS) and intracerebral haemorrhage. In March 2019, siponimod received its first global approval in the USA, for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease. Siponimod is under regulatory review in the EU and Japan for secondary progressive MS. This article summarizes the milestone in the development of siponimod leading to this first global approval for MS in the USA.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Aprovação de Drogas , Esclerose Múltipla/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , United States Food and Drug Administration/legislação & jurisprudência , Administração Oral , Adulto , União Europeia , Humanos , Japão , Resultado do Tratamento , Estados Unidos
16.
Neuroscience ; 411: 1-10, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31129200

RESUMO

Parkinson's disease (PD) is a progressive aging disorder that affects millions worldwide, thus, disease-modifying-therapies are urgently needed. PD pathology includes α-synuclein (aSyn) accumulation as synucleinopathy. Loss of GM1 gangliosides occurs in PD brain, which is modeled in GM2 synthase transgenic mice. GM2+/- mice have low, not absent GM1 and develop age-onset motor deficits, making them an excellent PD drug testing model. FTY720 (fingolimod) reduces synucleinopathy in A53T aSyn mice and motor dysfunction in 6-OHDA and rotenone PD models, but no one has tested FTY720 in mice that develop age-onset PD-like motor problems. We confirmed that GM2+/-mice had equivalent rotarod, hindlimb reflexes, and adhesive removal functions at 9 mo. From 11 mo, GM2+/- mice received oral FTY720 or vehicle 3x/week to 16 mo. As bladder problems occur in PD, we also assessed GM2+/- bladder function. This allowed us to demonstrate improved motor and bladder function in GM2+/- mice treated with FTY720. By immunoblot, FTY720 reduced levels of proNGF, a biomarker of bladder dysfunction. In humans with PD, arm swing becomes abnormal, and brachial plexus modulates arm swing. Ultrastructure of brachial plexus in wild type and GM2 transgenic mice confirmed abnormal myelination and axons in GM2 transgenics. FTY720 treated GM2+/- brachial plexus sustained myelin associated protein levels and reduced aggregated aSyn and PSer129 aSyn levels. FTY720 increases brain derived neurotrophic factor (BDNF) and we noted increased BDNF in GM2+/- brachial plexus and cerebellum, which contribute to rotarod performance. These findings provide further support for testing low dose FTY720 in patients with PD.


Assuntos
Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Cloridrato de Fingolimode/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , alfa-Sinucleína/metabolismo , Animais , Encéfalo/metabolismo , Cloridrato de Fingolimode/uso terapêutico , Camundongos , Camundongos Transgênicos , Destreza Motora/efeitos dos fármacos , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/metabolismo , Doença de Parkinson Secundária/metabolismo , Teste de Desempenho do Rota-Rod , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico
17.
Stroke ; 50(5): 1224-1231, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31009359

RESUMO

Background and Purpose- The contribution of neuroinflammation and, in particular, the infiltration of the brain by lymphocytes is increasingly recognized as a substantial pathophysiological mechanism after stroke. The interaction of lymphocytes with endothelial cells and platelets, termed thromboinflammation, fosters microvascular dysfunction and secondary infarct growth. Siponimod is an S1PR (sphingosine-1-phosphate receptor) modulator, which blocks the egress of lymphocytes from lymphoid organs and has demonstrated beneficial effects in multiple sclerosis treatment. We investigated the effect of treatment with siponimod on stroke outcome in a mouse model of cerebral ischemia. Methods- Transient middle cerebral artery occlusion was induced in middle-aged wild-type mice. Animals were either treated with siponimod (3 mg/kg; intraperitoneal) or vehicle for 6 days. Stroke outcome was assessed by magnetic resonance imaging (spleen volume: prestroke, day 3, and day 7; infarct volume: days 1, 3, and 7) and behavioral tests (prestroke, day 2, and day 6). Immune cells of the peripheral blood and brain-infiltrating cells ipsilateral and contralateral were analyzed by VETScan and by flow cytometry. Results- Siponimod significantly induced lymphopenia on day 7 after transient middle cerebral artery occlusion and reduced T-lymphocyte accumulation in the central nervous system. No effect was detected for lesion size. Conclusions- For siponimod administered at 3 mg/kg in transient middle cerebral artery occlusion mouse model, our findings do not provide preclinical evidence for the use of S1PR1/5 modulators as neuroprotectant in stroke therapy.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Fatores Etários , Animais , Azetidinas/farmacologia , Compostos de Benzil/farmacologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/metabolismo , Linfócitos T/metabolismo , Resultado do Tratamento
18.
J Neurol Sci ; 399: 6-14, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30738334

RESUMO

Subarachnoid hemorrhage (SAH) results in neurological damage, acute cardiac damage and has a high mortality rate. Immunoresponse in the acute phase after SAH plays a key role in mediating vasospasm, edema, inflammation and neuronal damage. The S1P/S1PR pathway impacts multiple cellular functions, exerts anti-inflammatory and anti-apoptotic effects, promotes remyelination, and improves outcome in several central nervous system (CNS) diseases. RP001 hydrochloride is a novel S1PR agonist, which sequesters lymphocytes within their secondary tissues and prevents infiltration of immune cells into the CNS thereby reducing immune response. In this study, we investigated whether RP001 attenuates neuronal injury after SAH by reducing inflammation. S1PRs, specifically S1PR1, 3 not only exerts anti-inflammatory effects, but also decreases heart rate and induces atrioventricular conduction abnormalities. Therefore, we also tested whether RP001 treatment of SAH regulates cardiac functional outcome. Male adult C57BL/6 mice were subjected to SAH, and neurological function tests, echocardiography, and immunohistochemical analysis were performed. SAH induces neurological deficits and acute cardiac dysfunction compared to sham control mice. Treatment of SAH with a low-dose of RP001 induces better neurological outcome and cardiac function compared to a high-dose of RP001. Low-dose-RP001 treatment significantly decreases apoptosis, white matter damage, blood brain barrier permeability, microglial/astrocyte activation, macrophage chemokine protein-1, matrix metalloproteinase-9 and NADPH oxidase-2 expression in the brain compared to SAH control mice. Our findings indicate that low-dose of RP001 alleviates neurological damage after SAH, in part by decreasing neuroinflammation.


Assuntos
Encéfalo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Receptores de Esfingosina-1-Fosfato/agonistas , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Cloridrato de Fingolimode/análogos & derivados , Frequência Cardíaca/efeitos dos fármacos , Inflamação/tratamento farmacológico , Masculino , Camundongos , Neurônios/metabolismo , Transdução de Sinais/efeitos dos fármacos , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Hemorragia Subaracnóidea/metabolismo
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