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The Medical Letter on Drugs and... Jul 2023
Topics: Humans; Amyotrophic Lateral Sclerosis; Edaravone; Oligonucleotides
PubMed: 37460141
DOI: 10.58347/tml.2023.1681a -
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 -
Expert Opinion on Investigational Drugs 2023Two established disease-specific therapies for the treatment of amyotrophic lateral sclerosis (ALS) are riluzole and edaravone. Limitations of these medications include... (Review)
Review
INTRODUCTION
Two established disease-specific therapies for the treatment of amyotrophic lateral sclerosis (ALS) are riluzole and edaravone. Limitations of these medications include minimal progression slowing or survival benefit, and effectiveness only in selected populations, particularly for edaravone. AMX0035 and tofersen received US FDA approval in September 2022 and April 2023, respectively. However, phase 3 trials, further examining both medications' efficacy, are ongoing. CNM-Au8 is an efficient catalyst of energy metabolism and is therefore a potential disease-modifying treatment for ALS, a neurodegenerative condition in which there is bioenergetics impairment.
AREAS COVERED
In this review, we provide an overview of the current ALS treatment market, followed by a description of the pharmacodynamics and pharmacokinetics of CNM-Au8. The main preclinical and available early clinical evidence of CNM-Au8 is then described, as well as its potential as an ALS treatment.
EXPERT OPINION
Oral treatment with CNM-Au8 failed to meet primary clinical and electrodiagnostic endpoints in phase 2/3 clinical trials. Despite this failure, a number of exploratory endpoints included in phase 2/3 trials suggest CNM-Au8 has the potential to significantly slow clinical worsening, improve quality of life, and prolong survival in ALS. Further study of CNM-Au8 in a phase 3 clinical trial is currently underway.
Topics: Humans; Amyotrophic Lateral Sclerosis; Edaravone; Neuroprotective Agents; Quality of Life; Drugs, Investigational
PubMed: 37642362
DOI: 10.1080/13543784.2023.2252738 -
Neurological Sciences : Official... Oct 2023The study aims to increase understanding of edaravone's efficacy and safety as an amyotrophic lateral sclerosis (ALS) treatment and provide significant insights... (Meta-Analysis)
Meta-Analysis Review
AIM
The study aims to increase understanding of edaravone's efficacy and safety as an amyotrophic lateral sclerosis (ALS) treatment and provide significant insights regarding this field's future research.
METHODS
We conducted a comprehensive search of the Embase, PubMed, Cochrane Library, Web of Science, and Scopus databases for randomized controlled trials and observational studies up until September 2022. We evaluated the studies' quality using the Cochrane risk of bias tool and the National Institutes of Health tool.
RESULTS
We included 11 studies with 2845 ALS patients. We found that edaravone improved the survival rate at 18, 24, and 30 months (risk ratio (RR) = 1.03, 95% confidence interval (CI) [1.02 to 1.24], P = 0.02), (RR = 1.22, 95% CI [1.06 to 1.41], P = 0.007), and (RR = 1.17, 95% CI [1.01 to 1.34], P = 0.03), respectively. However, the administration of edaravone did not result in any significant difference in adverse effects or efficacy outcomes between the two groups, as indicated by a P value greater than 0.05.
CONCLUSION
Edaravone improves survival rates of ALS patients at 18, 24, and 30 months with no adverse effects. However, edaravone does not affect functional outcomes. In order to ensure the validity of our findings and assess the results in accordance with the disease stage, it is essential to carry out additional prospective, rigorous, and high-quality clinical trials. The current study offers preliminary indications regarding the effectiveness and safety of edaravone. However, further comprehensive research is required to establish the generalizability and sustainability of the findings.
Topics: United States; Humans; Edaravone; Amyotrophic Lateral Sclerosis; Prospective Studies; Quality of Life; Severity of Illness Index
PubMed: 37249667
DOI: 10.1007/s10072-023-06869-8 -
European Journal of Pharmacology Jul 2023DL-3-n-butylphthalide (NBP) and edaravone dexborneol (Eda-Dex) are two promising reagents for stroke treatment. However, the impacts of NBP and Eda-Dex on poststroke...
INTRODUCTION
DL-3-n-butylphthalide (NBP) and edaravone dexborneol (Eda-Dex) are two promising reagents for stroke treatment. However, the impacts of NBP and Eda-Dex on poststroke mental deficits are still poorly understood. In this study, we aimed to investigate and compare the influences of NBP and Eda-Dex on neurological function and cognitive behavior in rats with ischemic stroke.
METHODS
An ischemic stroke model was established by middle cerebral artery occlusion (MCAO). After peritoneal administration of the drugs, the rats were subjected to neurological deficit evaluation, cerebral blood flow (CBF) assays, cerebral infarct area evaluations or behavioral tests. Brain tissues were collected and further analyzed by enzyme-linked immunosorbent assay (ELISA), western blotting or immunohistochemistry.
RESULTS
NBP and Eda-Dex significantly decreased the neurological score, reduced the cerebral infarct area and improved CBF. Behavioral changes as assessed in the sucrose preference test, novel object recognition test, and social interaction test were significantly alleviated by NBP and Eda-Dex in rats with ischemic stroke. Moreover, NBP and Eda-Dex significantly suppressed inflammation by targeting the nuclear factor kappa-B/inducible nitric oxide synthase (NF-κB/iNOS) pathway and significantly inhibited oxidative stress by targeting the kelch-1ike ECH-associated protein l/nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) pathway. In addition, NBP and Eda-Dex distinctly suppressed the activation of microglia and astrocytes and improved neuronal viability in the ischemic brain.
CONCLUSIONS
NBP and Eda-Dex improved neurological function and alleviated cognitive disorders in rats with ischemic stroke by synergistically inhibiting inflammation and oxidative stress.
Topics: Rats; Animals; Edaravone; Neuroprotective Agents; Kelch-Like ECH-Associated Protein 1; Ischemic Stroke; NF-E2-Related Factor 2; Stroke; Infarction, Middle Cerebral Artery; NF-kappa B; Inflammation; Brain Ischemia
PubMed: 37207969
DOI: 10.1016/j.ejphar.2023.175801 -
Clinical Therapeutics Dec 2023Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a...
PURPOSE
Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration.
METHODS
Two single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated.
FINDINGS
After reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported.
IMPLICATIONS
In patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www.
CLINICALTRIALS
gov.
Topics: Humans; Amyotrophic Lateral Sclerosis; Edaravone; Glucuronides; Neuroprotective Agents; Sulfates
PubMed: 37953075
DOI: 10.1016/j.clinthera.2023.09.025 -
Alternative Therapies in Health and... Oct 2023Acute stroke is characterized by rapid progression, high mortality, and disability rates, making it a significant focus in clinical research. Brain-protective agents,... (Review)
Review
BACKGROUND
Acute stroke is characterized by rapid progression, high mortality, and disability rates, making it a significant focus in clinical research. Brain-protective agents, such as butylphthalide and edaravone, have emerged as important therapeutic options for acute stroke.
OBJECTIVE
This study aimed to explore how butylphthalide and edaravone promote healing in acute stroke, drawing on relevant data, literature, clinical experience, and personal concepts.
DESIGN
The study design involves a narrative review, which comprehensively explores the pathogenesis of stroke by referencing relevant data and literature. Clinical experience and personal insights were incorporated to provide a holistic understanding. The primary focus was analyzing the mechanisms through which butylphthalide and edaravone facilitate healing in stroke patients.
RESULTS
The review revealed that butylphthalide exhibited multiple beneficial effects, including the protection of mitochondria, reduction of the inflammatory response, enhancement of microcirculation, decrease in blood-brain barrier permeability, and improving nerve cell function. On the other hand, edaravone demonstrated its efficacy by reducing oxidative stress response, inhibiting inflammatory response, and regulating the metabolism of arachidonic acid and apoptosis. These findings highlight the distinct mechanisms through which butylphthalide and edaravone contribute to the healing process in patients with stroke.
CONCLUSIONS
This study highlights the positive impact of butylphthalide and edaravone on the therapeutic effect and short-term prognosis in acute stroke patients. The findings provide valuable guidance for future research and enhance our understanding of these drugs' mechanisms, offering the potential for improved stroke management and patient outcomes.
Topics: Humans; Edaravone; Sodium Chloride; Antipyrine; Stroke; Treatment Outcome
PubMed: 37499159
DOI: No ID Found -
International Journal of Molecular... Mar 2024The brain is susceptible to oxidative stress, which is associated with various neurological diseases. Edaravone (MCI-186, 3-methyl-1 pheny-2-pyrazolin-5-one), a free... (Review)
Review
The brain is susceptible to oxidative stress, which is associated with various neurological diseases. Edaravone (MCI-186, 3-methyl-1 pheny-2-pyrazolin-5-one), a free radical scavenger, has promising effects by quenching hydroxyl radicals (∙OH) and inhibiting both ∙OH-dependent and ∙OH-independent lipid peroxidation. Edaravone was initially developed in Japan as a neuroprotective agent for acute cerebral infarction and was later applied clinically to treat amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. There is accumulating evidence for the therapeutic effects of edaravone in a wide range of diseases related to oxidative stress, including ischemic stroke, ALS, Alzheimer's disease, and placental ischemia. These neuroprotective effects have expanded the potential applications of edaravone. Data from experimental animal models support its safety for long-term use, implying broader applications in various neurodegenerative diseases. In this review, we explain the unique characteristics of edaravone, summarize recent findings for specific diseases, and discuss its prospects for future therapeutic applications.
Topics: Animals; Female; Pregnancy; Amyotrophic Lateral Sclerosis; Antioxidants; Antipyrine; Edaravone; Free Radical Scavengers; Neurodegenerative Diseases; Neuroprotective Agents; Placenta
PubMed: 38474192
DOI: 10.3390/ijms25052945 -
Molecular Pharmaceutics Oct 2023In vitro intestinal models are used to study biological processes, drug and food absorption, or cytotoxicity, minimizing the use of animals in the laboratory. They...
In vitro intestinal models are used to study biological processes, drug and food absorption, or cytotoxicity, minimizing the use of animals in the laboratory. They usually consist of enterocytes and mucus-producing cells cultured for 3 weeks, e.g., on Transwells, to obtain a fully differentiated cell layer simulating the human epithelium. Other important components are the extracellular matrix (ECM) and strong vascularization. The former serves as structural support for cells and promotes cellular processes such as differentiation, migration, and growth. The latter includes endothelial cells, which coordinate vascularization and immune cell migration and facilitate the transport of ingested substances or drugs to the liver. In most cases, animal-derived hydrogels such as Matrigel or collagen are used as ECM in in vitro intestinal models, and endothelial cells are only partially considered, if at all. However, it is well-known that animal-derived products can lead to altered cell behavior and incorrect results. To circumvent these limitations, synthetic and modifiable hydrogels (Peptigel and Vitrogel) were studied here to mimic xenofree ECM, and the data were compared with Matrigel. Careful rheological characterization was performed, and the effect on cell proliferation was investigated. The results showed that Vitrogel exhibited shear-thinning behavior with an internal structure recovery of 78.9 ± 11.2%, providing the best properties among the gels investigated. Therefore, a coculture of Caco-2 and HT29-MTX cells (ratio 7:3) was grown on Vitrogel, while simultaneously endothelial cells were cultured on the basolateral side by inverse cultivation. The model was characterized in terms of cell proliferation, differentiation, and drug permeability. It was found that the cells cultured on Vitrogel induced a 1.7-fold increase in cell proliferation and facilitated the formation of microvilli and tight junctions after 2 weeks of cultivation. At the same time, the coculture showed full differentiation indicated by high alkaline phosphatase release of Caco-2 cells (95.0 ± 15.9%) and a mucus layer produced by HT29-MTX cells. Drug tests led to ex vivo comparable permeability coefficients () (i.e., ; antipyrine = (33.64 ± 5.13) × 10 cm/s, ; atenolol = (0.59 ± 0.16) × 10 cm/s). These results indicate that the newly developed intestinal model can be used for rapid and efficient assessment of drug permeability, excluding unexpected results due to animal-derived materials.
Topics: Animals; Humans; Caco-2 Cells; Intestinal Mucosa; Endothelial Cells; Intestinal Absorption; Extracellular Matrix; Endothelium; Hydrogels
PubMed: 37677739
DOI: 10.1021/acs.molpharmaceut.3c00532