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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.
Mult Scler Relat Disord ; 45: 102437, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32763844

RESUMO

We encourage studies on the effectiveness of multiple sclerosis drugs for the treatment of ARDS in COVID-19 infection. These drugs, through the inhibition of the RhoA/actin-dependent expression of virus receptors in the macrophages and macrophage recruitment to the lungs, have the potential to inhibit cytokine storm of lung macrophages, reduce or eliminate ARDS and improve the outcome of COVID-19 infection.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/complicações , Cloridrato de Fingolimode/uso terapêutico , Humanos , Esclerose Múltipla/tratamento farmacológico , Pandemias , Pneumonia Viral/complicações , /virologia
4.
Brain Nerve ; 72(5): 517-523, 2020 May.
Artigo em Japonês | MEDLINE | ID: mdl-32381749

RESUMO

Multiple sclerosis disease modifying drugs (MS-DMD) currently used in Japan are interferon ß-1a, interferon ß-1b and gratiramer acetate, fingolimod, dimethyl furmarate, and natalizumab. Ofatumumab and siponimod will be approved probably in 2021. Ofatumumab is an ant-CD20 human monoclonal antibody. A clinical trial revealed that the efficacy of ofatumumab is clearly superior to teriflunomide that has comparable efficacy to dimethyl fumarate. Siponimod, a selective sphingosine-1-phosphate receptor modulator, exhibited mild, but significant efficacy for secondary progressive form of MS. OCH, a synthetic glycolipid agent, is being tested in phase II clinical trials in Japan. What DMD is to select is challenging since MS prognosis varies and is unexpected. Only very few have truly benign course without treatment. Silent progression should be considered especially in cases with those with interferon ß-1a, interferon ß-1b and gratiramer acetate. Escalation therapy is more widely accepted than initiation of high efficacy therapy in Japan because emphasizing safety. In such strategy three injectables and dimethyl fumarate are regarded as first line therapies. On the other hand, initiation of high efficacy drugs may be reasonable to prevent from disease progression. Even if either is acceptable, early induction of DMD with sufficient efficacy is mandatory for MS treatment.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Fumarato de Dimetilo/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Ensaios Clínicos como Assunto , Cloridrato de Fingolimode/uso terapêutico , Acetato de Glatiramer/uso terapêutico , Humanos , Interferons/uso terapêutico , Japão , Natalizumab/uso terapêutico
6.
Chem Biol Interact ; 323: 109075, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32229109

RESUMO

The use of orchids in herbal medicine has a very long history. Dendrobium species are known to produce a variety of secondary metabolites such as phenanthrens, bibenzyls, fluorenones and sesquiterpenes, and alkaloids and are responsible for their wide variety of medicinal properties. For decades, bibenzyls, which are the main bioactive components derived from Dendrobium species, have been subjected to extensive investigation as likely candidates for cancer treatment. The present study was undertaken to investigate the effect of moscatilin, a bibenzyl derivative from the orchid Dendrobium loddigesii on human melanoma cells. In A375 cells compound moscatilin showed a clear dose-response relationship in the range of 6.25-50 µM concentrations. In addition, we demonstrated an apoptotic response after treatment of cancer cells with this bibenzyl compound at 6.25 and 12.5 µM concentrations that probably involves PTEN activity, inhibition of Hsp70 expression and reactive oxygen species production. Alternatively, the inhibition of the caspase cascade at higher concentrations, 25 and 50 µM, correlated with additional reactive oxygen species increase, probably switched the mode of moscatilin-induced cell death from apoptosis to necrosis.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Benzil/uso terapêutico , Dendrobium/química , Melanoma/tratamento farmacológico , Melanoma/patologia , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Glutationa/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo
7.
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
8.
9.
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
10.
Medicine (Baltimore) ; 98(34): e15415, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441835

RESUMO

BACKGROUND: Multiple sclerosis is the most common demyelinating disease of the central nervous system with serious social and economic burden. Siponimod is a sphingosine-1-phosphate receptor agonist, and clinical trials in the past decade have shown good prospects for the treatment of multiple sclerosis. But there is a lack of comprehensive understanding of the dose-effect relationship and safety in different subtypes of multiple sclerosis at present. METHODS: We will perform a systematic review and meta-analysis of clinical randomized controlled trials to evaluate the efficacy and safety of siponimod in multiple sclerosis. We will search PubMed, EMBASE, Cochrane Library, Clinical Trials, Cochrane Central Register of Controlled Trials (CENTRAL) using a comprehensive strategy. The reference lists of the articles we select for inclusion will be checked to identify additional studies for potential inclusion. Two reviewers will review all literature independently. Upon inclusion of articles, another 2 reviewers will extract available data using a standardized form and assess the potential bias. Review Manager will be used to conduct data synthesis. There is no requirement of ethical approval and informed consent. RESULT: This is the first systematic assessment of siponimod for the treatment of multiple sclerosis. We predict it will provide high-quality synthesis of existing evidence for the efficacy and safety of siponimod for multiple sclerosis and a relatively comprehensive reference for clinical practice and clinical trials about siponimod to be conducted. CONCLUSION: The results of the systematic review and meta-analysis will provide updated evidence for the use of siponimod for multiple sclerosis. REGISTRATION: The systematic review and meta-analysis is registered in the PROSPERO international prospective register of systematic review (PROSPERO#CRD42018112721).


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Compostos de Benzil/administração & dosagem , Compostos de Benzil/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Esclerose Múltipla/classificação , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
13.
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
14.
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
15.
Cells ; 8(1)2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30621015

RESUMO

Multiple sclerosis (MS) is a neuroinflammatory disorder of the central nervous system (CNS), and represents one of the main causes of disability in young adults. On the histopathological level, the disease is characterized by inflammatory demyelination and diffuse neurodegeneration. Although on the surface the development of new inflammatory CNS lesions in MS may appear consistent with a primary recruitment of peripheral immune cells, questions have been raised as to whether lymphocyte and/or monocyte invasion into the brain are really at the root of inflammatory lesion development. In this review article, we discuss a less appreciated inflammation-neurodegeneration interplay, that is: Neurodegeneration can trigger the formation of new, focal inflammatory lesions. We summarize old and recent findings suggesting that new inflammatory lesions develop at sites of focal or diffuse degenerative processes within the CNS. Such a concept is discussed in the context of the EXPAND trial, showing that siponimod exerts anti-inflammatory and neuroprotective activities in secondary progressive MS patients. The verification or rejection of such a concept is vital for the development of new therapeutic strategies for progressive MS.


Assuntos
Anti-Inflamatórios/farmacologia , Azetidinas/farmacologia , Compostos de Benzil/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Adolescente , Adulto , Anti-Inflamatórios/uso terapêutico , Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Sistema Nervoso Central/patologia , Progressão da Doença , Humanos , Pessoa de Meia-Idade , Fármacos Neuroprotetores/uso terapêutico , Adulto Jovem
16.
Cell ; 179(7): 1440, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31951523

RESUMO

Progressive multiple sclerosis (PMS) causes slow accumulation of neurologic disability and has been refractory to treatment with the immunomodulatory medications that effectively control relapsing MS. Siponimod modestly slowed the rate of disability progression among PMS patients who had inflammatory disease activity, evidenced by new or gadolinium-enhancing MRI lesions. To view this Bench to Bedside, open or download the PDF.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Ensaios Clínicos como Assunto , Esclerose Múltipla/tratamento farmacológico , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Compostos de Benzil/administração & dosagem , Compostos de Benzil/efeitos adversos , Humanos , Estados Unidos , United States Food and Drug Administration
17.
Zh Nevrol Psikhiatr Im S S Korsakova ; 119(10. Vyp. 2): 110-119, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31934996

RESUMO

AIM: To study the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis (SPMS) in the Russian population of the EXPAND study. MATERIAL AND METHODS: Ninety-four patients with SPMS from Russia were included in the analysis. Sixty-three patients received siponimod and 31 patients received placebo. The primary endpoint of the study was time to 3-month confirmed disability progression (3m-CDP) events, other clinical and radiological endpoints were also evaluated. RESULTS: The siponimod group showed a 54% reduction in the risk of 3m-CDP compared with the placebo group (p=0.0334). Secondary endpoints also showed the advantage of the drug over placebo. In the siponimod group, mild adverse events associated with impaired liver function, as well as arterial hypertension, were more common. No patient left the study due to an adverse event. CONCLUSION: The use of siponimod in patients with SPMS in the Russian population reduced the risk of disability progression. Siponimod showed a favorable safety profile.


Assuntos
Azetidinas/efeitos adversos , Azetidinas/uso terapêutico , Compostos de Benzil/efeitos adversos , Compostos de Benzil/uso terapêutico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Humanos , Federação Russa
18.
Expert Opin Pharmacother ; 20(2): 143-150, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30517042

RESUMO

INTRODUCTION: Multiple sclerosis (MS) is a chronic central nervous system immune-mediated disease with an important inflammatory component associated with focal demyelination and widespread neurodegeneration. In most cases, the clinical presentation is relapsing-remitting, followed by a secondary progressive phase, characterized by disability accrual unrelated to relapses. In a minority, the phenotype is progressive from the beginning. Major therapeutic achievements have been made concerning the relapsing phase but modifying the evolution of progressive MS remains an unmet need. Areas covered: This review covers siponimod (BAF312), a new sphingosine 1-phosphate receptor modulator, and its role in the treatment of secondary progressive MS. The authors reviewed PubMed English literature using the keywords 'siponimod' or 'BAF312' and 'multiple sclerosis.' They also present the pharmacological profile of siponimod, as well as clinical efficacy and safety, with emphasis on the recently published results of a Phase III trial. Phase II data in relapsing MS are also summarized. Expert opinion: Siponimod may reduce the activity of the disease and has a modest effect on the gradual disability accrual. If approved, it may become one of the few available therapy options for secondary progressive MS.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Animais , Humanos , Recidiva , Resultado do Tratamento
19.
Nat Rev Dis Primers ; 4(1): 43, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30410033

RESUMO

Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults. This disorder is a heterogeneous, multifactorial, immune-mediated disease that is influenced by both genetic and environmental factors. In most patients, reversible episodes of neurological dysfunction lasting several days or weeks characterize the initial stages of the disease (that is, clinically isolated syndrome and relapsing-remitting MS). Over time, irreversible clinical and cognitive deficits develop. A minority of patients have a progressive disease course from the onset. The pathological hallmark of MS is the formation of demyelinating lesions in the brain and spinal cord, which can be associated with neuro-axonal damage. Focal lesions are thought to be caused by the infiltration of immune cells, including T cells, B cells and myeloid cells, into the central nervous system parenchyma, with associated injury. MS is associated with a substantial burden on society owing to the high cost of the available treatments and poorer employment prospects and job retention for patients and their caregivers.


Assuntos
Esclerose Múltipla/diagnóstico , Esclerose Múltipla/terapia , Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Doenças Desmielinizantes/complicações , Humanos , Indanos/uso terapêutico , Imagem por Ressonância Magnética/métodos , Esclerose Múltipla/epidemiologia , Oxidiazóis/uso terapêutico , Fatores de Risco , Tiazóis/uso terapêutico , Tomografia Computadorizada por Raios X/métodos
20.
Cochrane Database Syst Rev ; 10: CD009431, 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30335201

RESUMO

BACKGROUND: Dyspepsia is a common condition associated with gastrointestinal (GI) disease. Prokinetics are the treatment of choice for functional dyspepsia (FD). However, the role of prokinetics in FD treatment is still controversial. OBJECTIVES: We conducted a systematic review and meta-analysis of randomised control trials (RCTs) examining the efficacy of prokinetics in the treatment of FD. The primary outcome was overall absence of or improvement of symptoms and symptom scores at the end of treatment. We also evaluated quality of life (QoL) and adverse events as secondary outcomes. SEARCH METHODS: We performed a systematic search of MEDLINE, Embase, the Cochrane Library, and CINAHL, from 1946 until September 2017. RevMan 5.3 was used to calculate pooled risk ratios (RR) of symptoms persisting or without improved QoL or adverse events, mean difference (MD) or standardised mean difference (SMD) of post-treatment symptoms scores, changes of symptom scores, and QoL, when appropriate with 95% confidence intervals (CI), using a random-effects model. Quality of evidence was evaluated using GRADE methodology. SELECTION CRITERIA: We included studies that were parallel group RCTs comparing one prokinetic with either placebo or another prokinetic of the same or different class for the treatment of FD. Studies involved adults who presented with dyspepsia symptoms and who had negative or insignificant findings on endoscopy as well as no other organic and metabolic disorders. Studies only including participants with primarily reflux or heartburn symptoms were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, study quality and performed data extraction. MAIN RESULTS: From an initial 1388 citations, we identified 43 studies in 40 papers. Of those, 29 studies with 10,044 participants compared six prokinetics with placebo for the outcome of absence of symptoms or symptom improvement. There was a statistically significant effect of prokinetic treatment in reducing global symptoms of FD (RR of remaining dyspeptic = 0.81, 95% CI 0.74 to 0.89; number needed to treat for an additional beneficial outcome (NNTB) =7, very low-quality evidence) with considerable heterogeneity; I2 = 91% (P < 0.00001). After removing cisapride from the analysis, the effect of prokinetics in global symptom improvement still persisted, compared to placebo (RR 0.87, 95% CI 0.80 to 0.94), but was still based on very low-quality evidence. The result showed persistence of significant improvement in subgroups of studies at unclear or at low risk of bias (RR 0.86, 95% CI 0.80-0.92), and in subgroups by molecules of cisapride (RR 0.71, 95% CI 0.54 to 0.93; NNTB = 4), acotiamide (RR 0.94, 95% CI 0.91 to 0.98; NNTB = 20) and tegaserod(RR 0.89, 95% CI 0.82 to 0.96; NNTB = 14).Ten studies compared different types of prokinetics with each other and the most commonly used comparator was domperidone, 10 mg three times a day (eight of the 10 studies). There was a significantly better post-treatment symptom score in other prokinetics, compared to domperidone (SMD -0.19, 95% CI -0.35 to -0.03, very low-quality evidence), but no difference in reducing global symptom (RR 0.94, 95% CI 0.83 to 1.07), and mean difference symptom scores (SMD -0.13, 95% CI -0.31 to 0.05). We found five studies that assessed quality of life, but there was no benefit in improving quality of life with prokinetic treatment (SMD 0.11, 95% CI -0.10 to 0.33; participants = 1774). The adverse events in individual prokinetics was not different from placebo (RR 1.09, 95% CI 0.95 to 1.25; participants = 3811; studies = 17). However, when we looked at the adverse effects by each prokinetic, there were overall greater adverse effects in the active treatment group with cisapride (RR 1.31, 95% CI 1.03 to 1.65; P = 0.03). The most common side effects were diarrhoea, abdominal discomfort and nausea. The funnel plot was asymmetric (Egger's test, P = 0.02) implying reporting bias or other small-study effects may be, in part, driving the benefit of prokinetics compared to placebo in this meta-analysis. The GRADE assessment of the quality of the evidence in each outcome are mostly low or very low due to concerns around risk of bias in study design, unexplained heterogeneity and possible publication bias. AUTHORS' CONCLUSIONS: Due to low, or very low, quality of evidence, we are unable to say whether prokinetics are effective for the treatment of functional dyspepsia . We are uncertain which of the individual prokinetic drugs is the most effective as well as whether prokinetics can improve quality of life. Apart from cisapride, prokinetics are well-tolerated. Good quality RCTs are needed to verify the efficacy of prokinetics.


Assuntos
Dispepsia/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Compostos de Benzil/uso terapêutico , Cisaprida/efeitos adversos , Cisaprida/uso terapêutico , Domperidona/efeitos adversos , Domperidona/uso terapêutico , Eritromicina/análogos & derivados , Eritromicina/uso terapêutico , Fármacos Gastrointestinais/efeitos adversos , Humanos , Indóis/uso terapêutico , Morfolinas/uso terapêutico , Números Necessários para Tratar , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico
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