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Mediators of Inflammation 2022Our previous work has shown that inflammatory processes play a detrimental role in the pathophysiology of acute ischemic stroke (AIS). Neutrophil extracellular traps...
BACKGROUND
Our previous work has shown that inflammatory processes play a detrimental role in the pathophysiology of acute ischemic stroke (AIS). Neutrophil extracellular traps (NETs) have been recognized as a key contributor to the proinflammatory response in AIS and could aggravate blood-brain barrier (BBB) damage. Recently, experimental and clinical researches showed that Edaravone Dexborneol (Eda.B), which is comprised of two active ingredients, Edaravone and (+)-Borneol, was effective in treatment of AIS. However, it is not clear whether the effects of Eda.B against AIS are related to NETs and BBB permeability.
METHODS
Experiment 1 was to detect the effects of Eda.B in AIS patients. Serum samples of volunteers and AIS patients were collected before and 3 days after Edaravone Dexborneol treatment. Markers of NETs and occludin were detected by ELISA kit. Experiment 2 was to explore the effects of Eda.B on experimental stroke mice. Male C57BL/6 mice were subjected to distal middle cerebral artery occlusion (MCAO) and treated with vehicle, Eda.B, or DeoxyribonueleaseI (DNase I). After stroke, the neurobehavioral tests, infarct volume, and cerebral blood flow evaluation were determined. Leakage of Evans blue was to assess the integrity of BBB. Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence were used to examine the expression of NETs and tight junction- (TJ-) associated proteins.
RESULTS
Eda.B significantly improved neurological function and cerebral blood flow but reduced infarct volume after experimental stroke. Eda.B downregulated level of NETs in serum samples of AIS patients and tissue samples of MCAO mouse cortex. Eda.B and DNase I alleviated BBB permeability by upregulating TJ-associated proteins.
CONCLUSION
NETs are related to the early stage of AIS. Eda.B exerted neuroprotective effects and ameliorated BBB permeability after AIS.
Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Deoxyribonuclease I; Edaravone; Extracellular Traps; Humans; Infarction, Middle Cerebral Artery; Ischemic Stroke; Male; Mice; Mice, Inbred C57BL; Permeability; Stroke
PubMed: 36032782
DOI: 10.1155/2022/3855698 -
Stroke and Vascular Neurology Sep 2019Edaravone Dexborneol is a novel neuroprotective agent that comprised edaravone and (+)-borneol, a food additive with an anti-inflammatory effect in animal ischaemic... (Comparative Study)
Comparative Study Randomized Controlled Trial
Safety and efficacy of Edaravone Dexborneol versus edaravone for patients with acute ischaemic stroke: a phase II, multicentre, randomised, double-blind, multiple-dose, active-controlled clinical trial.
BACKGROUND
Edaravone Dexborneol is a novel neuroprotective agent that comprised edaravone and (+)-borneol, a food additive with an anti-inflammatory effect in animal ischaemic stroke models. This study aims to assess the safety and efficacy of Edaravone Dexborneol compared with edaravone in treating patients with acute ischaemic stroke (AIS).
METHODS
In this multicentre, randomised, double-blind, multiple-dose, active-controlled, phase II clinical trial, patients with AIS within 48 hours after stroke onset were randomly assigned (1:1:1:1) to low-dose (12.5 mg), medium-dose (37.5 mg) or high-dose (62.5 mg) Edaravone Dexborneol groups, and an active control group with edaravone (30 mg) by 30 min intravenous infusion every 12 hours, for 14 consecutive days. The primary efficacy outcome was the proportion of modified Rankin Scale (mRS)score ≤1 at 90 days and National Institutes of Health Stroke Scale (NIHSS) score change from baseline to 14 days after randomisation. The safety outcome included any adverse event during 90 days after treatment.
RESULTS
Of 385 patients included in the efficacy analysis, 94 were randomised to low-dose group, 97 to medium-dose group, 98 to high-dose group and 96 to the control group. No significant difference was observed among the four groups on mRS score (mRS ≤1, p=0.4054) at 90 days or NIHSS score change at 14 days (p=0.6799). However, a numerically higher percentage of patients with mRSscore ≤1 at 90 days in the medium-dose (69.39%) and high-dose (65.63%) groups was observed than in the control group (60.64%). No significant difference in severe adverse events was found among the four groups (p=0.3815).
CONCLUSIONS
Compared with edaravone alone, Edaravone Dexborneol was safe and well tolerated at all doses, although no significant improvement in functional outcomes was observed at 90days.
TRIAL REGISTRATION NUMBER
NCT01929096.
Topics: Aged; China; Double-Blind Method; Drug Administration Schedule; Edaravone; Female; Functional Status; Humans; Infusions, Intravenous; Ischemic Stroke; Male; Middle Aged; Neuroprotective Agents; Recovery of Function; Time Factors; Treatment Outcome
PubMed: 31709115
DOI: 10.1136/svn-2018-000221 -
The Medical Letter on Drugs and... Jul 2023
Topics: Humans; Amyotrophic Lateral Sclerosis; Edaravone; Oligonucleotides
PubMed: 37460141
DOI: 10.58347/tml.2023.1681a -
Current Opinion in Neurology Oct 2022The purpose of this review is to discuss the most important recent clinical studies in amyotrophic lateral sclerosis (ALS), including their impact on clinical practice,... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to discuss the most important recent clinical studies in amyotrophic lateral sclerosis (ALS), including their impact on clinical practice, their methodology, and open questions to be addressed in the future.
RECENT FINDINGS
This article focuses on studies, which provided either a positive primary endpoint or positive post hoc analysis, including edaravone, sodium phenylbutyrate-taurursodiol, rasagiline, tofersen, and high-caloric, fat-rich nutrition. It also covers recent developments in the design of clinical ALS studies with regard to inclusion criteria, stratification factors, and outcome parameters.
SUMMARY
Recent clinical studies have indicated various substances to be considered for treatment of ALS. Edaravone has been approved by the US Food and Drug Association (FDA) but not by the European Medicines Agency (EMA), and further studies testing oral formulations are currently conducted. A follow-up study with sodium phenylbutyrate-taurursodiol is ongoing, while follow-up studies for rasagiline and high-caloric, fat-rich nutrition are planned. A phase III study with tofersen was negative but nevertheless yielded promising results. Important developments regarding the design of clinical ALS studies include the implementation of neurofilament light chain (NfL) levels as a standard outcome parameter and the consideration of progression rate for therapeutic response and stratification.
Topics: Amyotrophic Lateral Sclerosis; Edaravone; Follow-Up Studies; Humans; Longitudinal Studies
PubMed: 35942672
DOI: 10.1097/WCO.0000000000001099 -
Expert Review of Neurotherapeutics 2023Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease. While pharmacotherapy options remain limited, the Food and Drug... (Review)
Review
INTRODUCTION
Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease. While pharmacotherapy options remain limited, the Food and Drug Administration (FDA) approved intravenous (IV) and oral edaravone for the treatment of ALS in 2017 and 2022, respectively. With the addition of oral edaravone, patients with ALS may exclusively use oral medications.
AREAS COVERED
The authors performed a review of the published literature using the United States (US) National Library of Medicine's PubMed.gov resource to describe the pharmacokinetics, pharmacodynamics, safety, and efficacy of oral edaravone, as well as pertinent completed and ongoing clinical trials, including the oral edaravone clinical trial development program. The clinical profile of oral edaravone is also discussed.
EXPERT OPINION
Edaravone has been shown to slow the rate of motor function deterioration experienced by patients with ALS. As the oral formulation has been approved, patients with ALS may use it alone or in combination with other approved therapeutics. Additional clinical trials and real-world evidence are ongoing to gain further understanding of the clinical profile of oral edaravone.
Topics: Humans; Edaravone; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Free Radical Scavengers; Administration, Intravenous
PubMed: 37646130
DOI: 10.1080/14737175.2023.2251687 -
Current Opinion in Neurology Oct 2019To review new developments in the field of amyotrophic lateral sclerosis (ALS) clinical trial design and to review the implications of the latest ALS clinical trials. (Review)
Review
PURPOSE OF REVIEW
To review new developments in the field of amyotrophic lateral sclerosis (ALS) clinical trial design and to review the implications of the latest ALS clinical trials.
RECENT FINDINGS
There has been substantial reflection on how clinical trials in ALS are best conducted. The revised Airlie House recommendations are an important milestone and should guide trial design. In addition, innovations using individualized risk-based eligibility criteria, adaptive designs, joint modelling, patient-centred approaches, and remote collection of data show real promise. Edaravone was shown to have benefit on function in a well defined subset of patients with ALS, although there are concerns about the generalizability of the findings. Studies of arimoclomol, inosine, and cellular therapies have demonstrated promising signals in early phase work and are being taken forward into larger studies. Well conducted studies of rasagaline did not show an effect on primary outcome measures.
SUMMARY
For many decades there has been regular disappointment with the results of clinical trials. With the innovations in trial design and advances in our basic understanding of the biology of ALS, the prospects for a step change in treatments for people affected by ALS are strong.
Topics: Amyotrophic Lateral Sclerosis; Clinical Trials as Topic; Edaravone; Humans; Hydroxylamines; Neuroprotective Agents; Research Design; Treatment Outcome
PubMed: 31335338
DOI: 10.1097/WCO.0000000000000731 -
Nature Cell Biology Nov 2020Dystrophin proteomic regulation in muscular dystrophies (MDs) remains unclear. We report that a long noncoding RNA (lncRNA), H19, associates with dystrophin and inhibits...
Dystrophin proteomic regulation in muscular dystrophies (MDs) remains unclear. We report that a long noncoding RNA (lncRNA), H19, associates with dystrophin and inhibits E3-ligase-dependent polyubiquitination at Lys 3584 (referred to as Ub-DMD) and its subsequent protein degradation. In-frame deletions in BMD and a DMD non-silent mutation (C3340Y) resulted in defects in the ability of the protein to interact with H19, which caused elevated Ub-DMD levels and dystrophin degradation. Dmd C3333Y mice exhibited progressive MD, elevated serum creatine kinase, heart dilation, blood vessel irregularity and respiratory failure with concurrently reduced dystrophin and increased Ub-DMD status. H19 RNA oligonucleotides conjugated with agrin (AGR-H19) and nifenazone competed with or inhibited TRIM63. Dmd C3333Y animals, induced-pluripotent-stem-cell-derived skeletal muscle cells from patients with Becker MD and mdx mice subjected to exon skipping exhibited inhibited dystrophin degradation, preserved skeletal and cardiac muscle histology, and improved strength and heart function following AGR-H19 or nifenazone treatment. Our study paves the way for meaningful targeted therapeutics for Becker MD and for certain patients with Duchenne MD.
Topics: Animals; Antipyrine; Cardiomyopathies; Cell Line; Disease Models, Animal; Dystrophin; Enzyme Inhibitors; Female; Half-Life; Humans; Induced Pluripotent Stem Cells; Male; Mice, Inbred C57BL; Mice, Inbred mdx; Mice, Mutant Strains; Muscle Proteins; Muscle Strength; Muscle, Skeletal; Muscular Dystrophies; Mutation; Myocytes, Cardiac; Niacinamide; Oligonucleotides; Protein Stability; Proteolysis; RNA, Long Noncoding; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 33106653
DOI: 10.1038/s41556-020-00595-5