Abstract:
BACKGROUND:Abnormalities in membrane excitability and Na(+) channel function are characteristic of amyotrophic lateral sclerosis (ALS). We aimed to examine the neuroprotective potential, safety and tolerability of the Na(+) channel blocker and membrane stabiliser flecainide in ALS. METHODS:A double-blind, placebo-controlled, randomised clinical trial of flecainide (200 mg/day) for 32-weeks with a 12-week lead-in phase was conducted in participants with probable or definite ALS recruited from multiple Australian centres (ANZCT Registry number ACTRN12608000338369). Patients were reviewed by a cardiologist to rule out cardiac contraindications. Participants were randomly assigned (1:1) to flecainide or placebo using stratified permuted blocks by a central pharmacy. The primary outcome measure was the slope of decline of the ALS Functional Rating Scale-revised (ALS FRS-r) during the treatment period. FINDINGS:Between March 11, 2008 and July 1, 2010, 67 patients were screened, 54 of whom were randomly assigned to receive flecainide (26 patients) or placebo (28 patients). Four patients in the flecainide group and three patients in the placebo group withdrew from the study. One patient in the flecainide group died during the study, attributed to disease progression. Flecainide was generally well tolerated, with no serious adverse events reported in either group. There was no significant difference in the rate of decline in the primary outcome measure ALS-FRS-r between placebo and flecainide treated patients (Flecainide 0.65 [95% CI 0.49 to 0.98]; Placebo 0.81 [0.49 to 2.12] P = 0.50). However, the rate of decline of the neurophysiological index was significantly reduced in the flecainide group (Flecainide 0.06 [0.01 to 0.11]; Placebo 0.14 [0.09 to 0.19], P = 0.02). Placebo-treated patients demonstrated greater CMAP amplitude reduction during the course of the study in the subset of patients with a reduced baseline CMAP amplitude (Flecainide: - 15 ± 12%; Placebo - 59 ± 12%; P = 0.03). Flecainide-treated patients maintained stabilized peripheral axonal excitability over the study compared to placebo. INTERPRETATION:This pilot study indicated that flecainide was safe and potentially biologically effective in ALS. There was evidence that flecainide stabilized peripheral axonal membrane function in ALS. While the study was not powered to detect evidence of benefit of flecainide on ALS-FRS-r decline, further studies may demonstrate clinical efficacy of flecainide in ALS.
journal_name
EBioMedicinejournal_title
EBioMedicineauthors
Park SB,Vucic S,Cheah BC,Lin CS,Kirby A,Mann KP,Zoing MC,Winhammar J,Kiernan MCdoi
10.1016/j.ebiom.2015.11.022subject
Has Abstractpub_date
2015-12-01 00:00:00pages
1916-22issue
12issn
2352-3964pii
S2352-3964(15)30206-1journal_volume
2pub_type
临床试验,杂志文章,随机对照试验相关文献
EBioMedicine文献大全abstract:BACKGROUND:Impaired fracture healing represents an ongoing clinical challenge, as treatment options remain limited. Calcitonin gene-related peptide (CGRP), a neuropeptide targeted by emerging anti-migraine drugs, is also expressed in sensory nerve fibres innervating bone tissue. METHOD:Bone healing following a femoral...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.102970
更新日期:2020-09-01 00:00:00
abstract:BACKGROUND:Epidemiological, laboratory and clinical studies have established an association between elevated urate and high blood pressure (BP). However, the inference of causality remains controversial. A naturally occurring antioxidant, urate may also be neuroprotective, and urate-elevating treatment with its precurs...
journal_title:EBioMedicine
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.ebiom.2018.10.039
更新日期:2018-11-01 00:00:00
abstract::Dendritic cells (DCs) play an important role in controlling T cell-mediated adaptive immunity in atherogenesis. However, the role of the basic leucine zipper transcription factor, ATF-like 3 (Batf3)-dependent CD8α+ DC subset in atherogenesis remains unclear. Here we show that Batf3-/-Apoe-/- mice, lacking CD8α+ DCs, e...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2017.04.008
更新日期:2017-04-01 00:00:00
abstract::The precise effects of HIV-1 on the gut microbiome are unclear. Initial cross-sectional studies provided contradictory associations between microbial richness and HIV serostatus and suggested shifts from Bacteroides to Prevotella predominance following HIV-1 infection, which have not been found in animal models or in ...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2016.01.032
更新日期:2016-01-28 00:00:00
abstract:BACKGROUND:Acute lung injury (ALI) is a severe life-threatening inflammatory disease. Neutrophil activation is a major pathogenic factor in ALI. Protein kinase B (PKB)/AKT regulates diverse cellular responses, but the significance in neutrophilic inflammation and ALI remains unknown. METHODS:Human neutrophils and neut...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.01.043
更新日期:2019-02-01 00:00:00
abstract:BACKGROUND:Intervertebral disc degeneration (IDD) is a major contributor to lower back pain, however, the molecular and pathogenetic mechanisms underlying IDD are poorly understood. As a high-risk factor for IDD, compression stress was reported to induce apoptosis of nucleus pulposus (NP) cells and extracellular matrix...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.102679
更新日期:2020-03-01 00:00:00
abstract:BACKGROUND:Liver fibrosis is a consequence of chronic inflammation and is associated with protein changes within the hepatocytes structure. In this study, we aimed to investigate if this is reflected by the urinary proteome and can be explored to diagnose liver fibrosis in patients with chronic liver disease. METHODS:...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.103083
更新日期:2020-12-01 00:00:00
abstract::This study aimed to develop and validate a prognostic nomogram for recurrence-free survival (RFS) after surgery in the absence of adjuvant therapy to guide the selection for adjuvant imatinib therapy based on Residual Neural Network (ResNet). The ResNet model was developed based on contrast-enhanced computed tomograph...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2018.12.028
更新日期:2019-01-01 00:00:00
abstract:BACKGROUND:Some interstitial lung disease (ILD) patients develop a progressive fibrosing-ILD phenotype (PF-ILD), with similar persistent lung function decline suggesting common molecular pathways involved. Nintedanib, a tyrosine kinase inhibitor targeting the PDGF, FGF, VEGF and M-CSF pathways, has shown comparable eff...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.10.050
更新日期:2019-12-01 00:00:00
abstract::The emergence and prevalence of antibiotic-resistant bacteria are an increasing cause of death worldwide, resulting in a global 'call to action' to avoid receding into an era lacking effective antibiotics. Despite the urgency, the healthcare industry still relies on a single in vitro bioassay to determine antibiotic e...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2017.05.026
更新日期:2017-06-01 00:00:00
abstract::Inter-individual variability has been a major hurdle to optimize disease management. Precision medicine holds promise for improving health and healthcare via tailor-made therapeutic strategies. Herein, we outline the paradigm of "pharmacometabolomics-aided pharmacogenomics" in autoimmune diseases. We envisage merging ...
journal_title:EBioMedicine
pub_type: 杂志文章,评审
doi:10.1016/j.ebiom.2016.02.001
更新日期:2016-02-02 00:00:00
abstract::Anti-retroviral therapy successfully suppresses HIV-1 infection, but fails to provide a cure. During infection Type 1 IFNs normally play an essential role in viral clearance, but in vivo IFN-α only has a modest impact on HIV-1 infection, suggesting its possible targeting by HIV. Here, we report that the HIV protein, V...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2018.03.006
更新日期:2018-04-01 00:00:00
abstract:BACKGROUND:Neurodegenerative diseases are incurable disorders caused by progressive neuronal cell death. Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in photoreceptor death and progresses to the loss of the entire retinal network. We previously found that proteomic analysis of the adja...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.102636
更新日期:2020-02-01 00:00:00
abstract:BACKGROUND:We developed and validated an artificial intelligence (AI)-assisted prediction of preeclampsia applied to a nationwide health insurance dataset in Indonesia. METHODS:The BPJS Kesehatan dataset have been preprocessed using a nested case-control design into preeclampsia/eclampsia (n = 3318) and normotensive p...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.102710
更新日期:2020-04-01 00:00:00
abstract:BACKGROUND:Atherosclerosis involves a slow process of plaque formation on the walls of arteries, and comprises a leading cause of cardiovascular disease. Long non-coding RNAs (lncRNAs) have been implicated in the pathogenesis of atherosclerosis. In this study, we aim to explore the possible involvement of lncRNA 'cycli...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.102694
更新日期:2020-05-01 00:00:00
abstract:BACKGROUND:Chronic hepatitis B virus (HBV) infections are a global health problem. There is a need for therapeutic strategies blocking continuous infection of liver cells. The grass pollen allergy vaccine BM32 containing the preS domain of the large HBV surface protein (LHBs) as immunogenic carrier induced IgG antibodi...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.102953
更新日期:2020-09-01 00:00:00
abstract:BACKGROUND:Although significant progress has been made in understanding the mechanisms of steatosis and insulin resistance, the physiological functions of the epigenetic regulators in these processes remain largely elusive. METHODS:Hepatocyte-specific Arid1a knockout mice were administrated with high-fat diet (HFD) fo...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.03.021
更新日期:2019-04-01 00:00:00
abstract:BACKGROUND:To improve the early diagnosis of hepatocellular carcinoma (HCC), more effective diagnostic biomarkers are needed. A combination of biomarkers is reported to distinguish individuals with early-stage HCC from at-risk individuals. METHODS:Participants in this study were recruited from six hospitals in China. ...
journal_title:EBioMedicine
pub_type: 杂志文章,多中心研究
doi:10.1016/j.ebiom.2020.102638
更新日期:2020-02-01 00:00:00
abstract:BACKGROUND:Suicide is a major issue for global public health. Suicidality describes a broad spectrum of thoughts and behaviours, some of which are common in the general population. Although suicide results from a complex interaction of multiple social and psychological factors, predisposition to suicidality is at least...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.02.005
更新日期:2019-03-01 00:00:00
abstract:BACKGROUND:Tyrosine kinase inhibitors (TKIs) are clinically effective in non-small cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) oncogene mutations. Genetic factors, other than EGFR sensitive mutations, that allow prognosis of TKI treatment remain undefined. METHODS:We retrospect...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.03.023
更新日期:2019-04-01 00:00:00
abstract::Individual differences in susceptibility to human immunodeficiency virus type 1 (HIV-1) infection have been of interest for decades. We aimed to determine the contribution of large isoform of Mammalian DnaJ (MRJ-L), a HIV-1 Vpr-interacting cellular protein, to this natural variation. Expression of MRJ-L in monocyte-de...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2014.10.002
更新日期:2014-10-07 00:00:00
abstract:PURPOSE:We present a systematic screening for identifying associations between prescribed drugs and cancer risk using the high quality Danish nationwide health registries. METHODS:We identified all patients (cases) with incident cancer in Denmark during 2000-2012 (n=278,485) and matched each case to 10 controls. Compl...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2016.03.018
更新日期:2016-05-01 00:00:00
abstract:BACKGROUND:Acute myeloid leukaemia (AML) is a malignant haematological tumour with high heterogeneity and mortality. A reliable prognostic assessment is critical for treatment strategies. However, the current prognostic evaluation system of AML is insufficient. METHODS:Genome-wide univariate Cox regression analysis wa...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2020.102664
更新日期:2020-02-01 00:00:00
abstract:BACKGROUND:Non-invasive lung adenocarcinoma could benefit from limited resection, nonetheless, there is a lack of method to determine preoperative tumour invasiveness. We aimed to investigate whether folate receptor-positive circulating tumour cells (FR+-CTCs) in combination with maximum tumour diameter (MTD) determine...
journal_title:EBioMedicine
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1016/j.ebiom.2019.02.028
更新日期:2019-03-01 00:00:00
abstract:BACKGROUND:While PARP inhibitors and CDK4/6 inhibitors, the two classes of FDA-approved agents, have shown promising clinical benefits, there is an urgent need to develop new therapeutic strategies to improve clinical response. Meanwhile, extending the utility of these inhibitors beyond their respective molecularly def...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.03.027
更新日期:2019-05-01 00:00:00
abstract:BACKGROUND:Undernutrition is a serious global problem that contributes to increased child morbidity and mortality, impaired neurocognitive development, and decreased educational and economic attainment. Current interventions are only marginally effective, and identification of associated metabolic pathways can offer ne...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.05.043
更新日期:2019-06-01 00:00:00
abstract::Nonalcoholic fatty liver disease is a highly prevalent component of disorders associated with disrupted energy homeostasis. Although dysregulation of the energy sensor AMP-activated protein kinase (AMPK) is viewed as a pathogenic factor in the development of fatty liver its role has not been directly demonstrated. Une...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2018.01.008
更新日期:2018-02-01 00:00:00
abstract:BACKGROUND:Human endogenous retroviruses HERV-W encode a pro-inflammatory protein, named MSRV-Env from its original identification in Multiple Sclerosis. Though not detected in various neurological controls, MSRV-Env was found in patients with chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs). This st...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2016.03.001
更新日期:2016-04-01 00:00:00
abstract:BACKGROUND:Spleen tyrosine kinase (SYK) is frequently upregulated in recurrent ovarian carcinomas, for which effective therapy is urgently needed. SYK phosphorylates several substrates, but their translational implications remain unclear. Here, we show that SYK interacts with EGFR and ERBB2, and directly enhances their...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2019.08.055
更新日期:2019-09-01 00:00:00
abstract::The identification of SYK as a molecular target in B-lineage leukemia/lymphoma cells prompted the development of SYK inhibitors as a new class of anti-cancer drug candidates. Here we report that induction of the SYK gene expression in human cells causes a significant down-regulation of evolutionarily conserved genes a...
journal_title:EBioMedicine
pub_type: 杂志文章
doi:10.1016/j.ebiom.2014.10.019
更新日期:2014-11-01 00:00:00