RESUMO
Background: Edaravone is an anti-stroke medication that may have nitric oxide (NO) modulating properties. This study evaluated the role of NO in the acute and sub-chronic anticonvulsant effects of edaravone in murine models of seizures induced by intraperitoneal (IP) or intravenous (IV) injections of pentylenetetrazole (PTZ) or electroshock (maximal electroshock seizure [MES]). Methods: 132 male albino mice were randomly divided into 22 groups (n=6) and given IP injections of vehicle or edaravone either acutely or for eight days (sub-chronically). The seizure was induced by electroshock or PTZ (IP or IV). The following edaravone doses were used: 7.5, 10, 12.5 (acute); 5, 7.5, 10 (sub-chronic) in IP PTZ model; 5, 7.5, 10 in IV PTZ model; and 5, 10 mg/Kg in the MES. To evaluate NO involvement, 216 mice were randomly divided into 36 groups (n=6) and pretreated with vehicle, edaravone, a non-specific nitric oxide synthase (NOS) inhibitor: N(ω)-nitro-L-arginine methyl ester (L-NAME) (5 mg/Kg), a specific nNOS inhibitor: 7-nitroindazole (7-NI) (60 mg/Kg), or a combination of edaravone plus L-NAME or 7-NI, either acutely or for eight days before seizure induction. Doses of edaravone were as follows: in IP PTZ model: 12.5 (acute) and 10 (sub-chronic); in IV PTZ model: 10; and in the MES: 5 mg/Kg. Data were analyzed using the one-way analysis of variance (ANOVA) followed by Tukey's test (SPSS 18). P≤0.05 was considered statistically significant. Results: In the IP PTZ model, edaravone increased time latencies to seizures (P<0.001), prevented tonic seizures, and death. Edaravone increased the seizure threshold (P<0.001) in the IV PTZ model and shortened the duration of tonic hind-limb extension (THE) in the MES model (P<0.001). In comparison to mice treated with edaravone alone, adding L-NAME or 7-NI reduced seizure time latencies (P<0.001), reduced seizure threshold (P<0.001), and increased THE duration (P<0.001). Conclusion: Edaravone (acute or sub-chronic) could prevent seizures by modulating NO signaling pathways.
Assuntos
Anticonvulsivantes , Pentilenotetrazol , Masculino , Camundongos , Animais , Pentilenotetrazol/efeitos adversos , Anticonvulsivantes/efeitos adversos , Edaravone/efeitos adversos , Óxido Nítrico/efeitos adversos , Óxido Nítrico/metabolismo , NG-Nitroarginina Metil Éster/efeitos adversos , Eletrochoque/efeitos adversos , Convulsões/etiologia , Convulsões/induzido quimicamente , Inibidores Enzimáticos/efeitos adversosRESUMO
Alzheimer's disease (AD), as the main cause of dementia, has a progressive and neurodegenerative pattern with number of cases increasing over the next decades. Therefore, discovering an effective treatment with the ability to invert memory impairment and pathophysiological events of AD seems to be required. The present study performed to investigate the probable effects of Edaravone (EDV) in AD-like disorder induced by intracerebroventricular streptozotocin (ICV-STZ) administration in mice. This study also compares the two different methods of ICV-STZ in the memory impairment induction. NMRI male mice were administrated with 3 mg/kg of STZ for two times during 48 hours span, and after 24 hours, animals were treated with EDV (5 and 10 mg/kg), Donepezil, and Memantine for 14 days. After behavioral tests regarding memory and cognitive function, animals were sacrificed, and the hippocampi were utilized for further analyses. Our results demonstrated that administration of STZ induced memory impairment in the Morris water maze (MWM) test and decreased the discriminative factor in novel object recognition (NOR). The biochemical output shows a significant decrease in ferric reducing antioxidant power (FRAP) and glutathione (GSH) levels followed by increase in malondialdehyde (MDA) and protein carbonylation (PCO) levels. The output showed no difference between the patterns of AD-like disorder induction. Following our treatment groups, administration of EDV (5 and 10 mg/kg), Donepezil, and Memantine significantly improved memory performance and discriminatory behavior. Aforementioned treatments managed to improve FRAP and GSH content of hippocampus, while significantly attenuating MDA, PCO, and nitric oxide overproduction. In addition, no significant difference has been observed between the effect of 5 and 10 mg/kg EDV application. It was supposed that EDV managed to ameliorate memory dysfunction, discriminatory behavior, oxidative stress, and cellular antioxidant power in a dose-independent pattern in mice.
Assuntos
Doença de Alzheimer , Antioxidantes , Ratos , Masculino , Camundongos , Animais , Edaravone/efeitos adversos , Estreptozocina/efeitos adversos , Antioxidantes/farmacologia , Memantina/efeitos adversos , Ratos Wistar , Donepezila/farmacologia , Estresse Oxidativo , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inflamação , Aprendizagem em Labirinto , Modelos Animais de DoençasRESUMO
INTRODUCTION/AIMS: An intravenous (IV) formulation of edaravone has been shown to slow the rate of physical functional decline in amyotrophic lateral sclerosis (ALS). An oral suspension formulation of edaravone was recently approved by the United States Food and Drug Administration for use in patients with ALS. This study assessed the safety and tolerability of oral edaravone. METHODS: This global, open-label, phase 3 study evaluated the long-term safety and tolerability of oral edaravone in adults with ALS who had a baseline forced vital capacity ≥70% of predicted and disease duration ≤3 y. The primary safety analysis was assessed at weeks 24 and 48. Patients received a 105-mg dose of oral edaravone in treatment cycles replicating the dosing of IV edaravone. RESULTS: The study enrolled 185 patients (64.3% male; mean age, 59.9 y; mean disease duration, 1.56 y). The most common treatment-emergent adverse events (TEAEs) at week 48 were fall (22.2%), muscular weakness (21.1%) and constipation (17.8%). Serious TEAEs were reported by 25.9% of patients; the most common were worsening ALS symptoms, dysphagia, dyspnea, and respiratory failure. Twelve TEAEs leading to death were reported. Forty-six (24.9%) patients reported TEAEs that were considered related to study drug; the most common were fatigue, dizziness, headache, and constipation. Sixteen (8.6%) patients discontinued study drug due to TEAEs. No serious TEAEs were related to study drug. DISCUSSION: This study indicated that oral edaravone was well tolerated during 48 wk of treatment, with no new safety concerns identified.
Assuntos
Esclerose Lateral Amiotrófica , Edaravone , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Administração Oral , Esclerose Lateral Amiotrófica/tratamento farmacológico , Constipação Intestinal , Edaravone/administração & dosagem , Edaravone/efeitos adversosRESUMO
BACKGROUND AND OBJECTIVE: The efficacy and safety of edaravone for the treatment of amyotrophic lateral sclerosis (ALS) remain unclear. The aim of this meta-analysis was to provide evidence-based medical guidance and advice for the clinical application of edaravone in the treatment of ALS. METHODS: PubMed, Embase, Chinese Biomedical Literature Database (CBM), Cochrane Library and Web of Science were searched through 09 March 2022 for randomized controlled trials (RCTs) on the safety and efficacy of edaravone versus placebo during follow-up of patients with ALS. A summary of the outcome measures with GRADE was performed. This study was registered on PROSPERO (ID: CRD 42022319997). RESULTS: Five RCTs with a total of 566 participants were included, and there was a significant difference (mean difference [MD] 1.33, 95% confidence interval [CI] 0.33-2.34; p = 0.009) in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score between the treatment and placebo groups. The edaravone group had an increased grip strength (MD 0.26, 95% CI 0.03-0.49; p = 0.03) and modified Norris Scale score (MD 2.81, 95% CI 1.18-4.43; p = 0.0007). However, there were no significant differences between groups for the change in forced vital capacity (FVC)% (MD 0.55, 95% CI - 3.15 to 4.24; p = 0.77), pinch strength (MD 0.05, 95% CI - 0.05 to 0.16; p = 0.33) or Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) score (MD - 4.76, 95% CI - 9.56 to 0.03; p = 0.05). The incidence of adverse events (AEs) (risk ratio [RR] 0.09, 95% CI 0.93-1.05; p = 0.65), serious adverse events (SAEs) (RR 0.72, 95% CI 0.52-1.00; p = 0.05) and the number of deaths (risk difference [RD] 0.00, 95% CI - 0.02 to 0.03; p = 0.83) were not statistically different from the placebo group. The quality of evidence was low only for SAEs, and the remaining outcome measures were of moderate quality. CONCLUSIONS: Compared with placebo, edaravone may provide potential clinical benefits in the treatment of ALS and may not increase the number of AEs and deaths. However, due to the low-quality evidence of the included studies and the small sample size, more high-quality and high-standard research evidence is needed to confirm these results. PROTOCOL REGISTRATION: This study was registered on PROSPERO (ID: CRD 42022319997).
Assuntos
Esclerose Lateral Amiotrófica , Humanos , Edaravone/efeitos adversos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Inquéritos e QuestionáriosRESUMO
Intravenous edaravone is used to treat patients with amyotrophic lateral sclerosis. This randomized, open-label, two-way crossover, single-dose phase 1 study compared the relative bioavailability of a newly developed edaravone oral suspension when administered orally and via a nasogastric tube (NGT) as a model of percutaneous endoscopic gastrostomy tube administration in healthy adult subjects. Thirty-six subjects were randomly assigned to one of two groups, with 18 per group. Blood was collected pre- and post-dose for pharmacokinetic assessments; safety was evaluated. Plasma concentration-time profiles of unchanged edaravone were similar between administration routes. Comparative bioavailability analysis revealed that geometric least squares mean ratios (NGT/oral) for maximum plasma concentration and area under the plasma concentration-time curve from time zero to infinity of unchanged edaravone were 1.052 and 0.981, respectively. No serious adverse events or adverse drug reactions were reported. These results suggest that oral edaravone suspension can be administered directly to the stomach without dose adjustment via feeding tubes; both oral and NGT administration are well tolerated.
Assuntos
Intubação Gastrointestinal , Humanos , Adulto , Edaravone/efeitos adversos , Disponibilidade Biológica , Administração OralRESUMO
Edaravone (EDA), a strong novel free radical scavenger, have been demonstrated to exert neurovascular protective effects clinically. Furthermore, EDA can suppress the lung injury, pulmonary fibrosis and skin fibrosis, while the precise effects and mechanisms of EDA on liver injury and fibrosis remain unclear. The effects of EDA on the Thioacetamide (TAA)-induced liver fibrosis were evaluated by sirius red staining, α-SMA immunohistochemistry. The percentages of immune cell subsets were analyzed by flow cytometry. Immunofluorescence assay was performed to identify the fibrotic properties of hepatic stellate cells (HSCs). Western blot and qPCR were used to detect the levels of liver fibrosis-related molecules and IL-1ß. EDA displayed a hepatic protective role in TAA-induced chronic liver fibrosis via inhibiting monocyte/macrophages recruitment and IL-1ß production of macrophages. Mechanically, EDA inhibited of NF-κB signal pathway and reactive oxygen species (ROS) production in macrophages. Moreover, EDA treatment indirectly suppressed the activation of HSCs by decreasing the IL-1ß secretion of macrophages. Together, EDA protects against TAA-induced liver fibrosis via decreasing the IL-1ß production of macrophages, thereby providing a feasible solution for clinical treatment of liver fibrosis.
Assuntos
Células Estreladas do Fígado , Cirrose Hepática , Humanos , Edaravone/efeitos adversos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/prevenção & controle , Células Estreladas do Fígado/metabolismo , Tioacetamida/toxicidade , Fibrose , Macrófagos/metabolismo , FígadoRESUMO
BACKGROUND: The aim of the study was to define whether edaravone, a free-radical scavenger, influenced angiotensin II (AngII)-induced atherosclerosis and abdominal aortic aneurysms (AAAs) formation. METHODS: Male apolipoprotein E-deficient mice (8-12 weeks old) were fed with a normal diet for 5 weeks. Either edaravone (10 mg/kg/day) or vehicle was injected intraperitoneally for 5 weeks. After 1 week of injections, mice were infused subcutaneously with either AngII (1000 ng/kg/min, n = 16-17 per group) or saline (n = 5 per group) by osmotic minipumps for 4 weeks. RESULTS: AngII increased systolic blood pressure equivalently in mice administered with either edaravone or saline. Edaravone had no effect on plasma total cholesterol concentrations and body weights. AngII infusion significantly increased ex vivo maximal diameters of abdominal aortas and en face atherosclerosis but was significantly attenuated by edaravone administration. Edaravone also reduced the incidence of AngII-induced AAAs. In addition, edaravone diminished AngII-induced aortic MMP-2 activation. Quantitative RT-PCR revealed that edaravone ameliorated mRNA abundance of aortic MCP-1 and IL-1ß. Immunostaining demonstrated that edaravone attenuated oxidative stress and macrophage accumulation in the aorta. Furthermore, edaravone administration suppressed thioglycolate-induced mice peritoneal macrophages (MPMs) accumulation and mRNA abundance of MCP-1 in MPMs in male apolipoprotein E-deficient mice. In vitro, edaravone reduced LPS-induced mRNA abundance of MCP-1 in MPMs. CONCLUSIONS: Edaravone attenuated AngII-induced AAAs and atherosclerosis in male apolipoprotein E-deficient mice via anti-oxidative action and anti-inflammatory effect.
Assuntos
Aneurisma da Aorta Abdominal , Aneurisma Aórtico , Aterosclerose , Angiotensina II/farmacologia , Animais , Aorta Abdominal , Aneurisma Aórtico/complicações , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aterosclerose/complicações , Edaravone/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro , Receptores de LDL/genéticaRESUMO
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with no curative therapies. Edaravone (Radicava®) (Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan), approved in the United States (US) for ALS in adults in 2017, was shown in a clinical trial to slow the rate of physical functional decline in ALS and is administered intravenously. The aim of this paper is to summarize the observed safety profile from real-world patient use during the first 3 years of edaravone availability in the US. METHODS: Edaravone usage data were collected, and adverse events (AEs) were identified from a postmarketing safety database from August 8, 2017 through August 7, 2020 (cutoff date). RESULTS: As of October 3, 2020, 5207 ALS patients had been treated with edaravone. As of August 7, 2020, the most commonly reported AEs included death (not specified), drug ineffective, disease progression, therapeutic response unexpected, fall, asthenia, fatigue, muscular weakness, gait disturbance, and dyspnea. The most commonly reported serious AEs (SAEs) included death (not specified), pneumonia, disease progression, ALS, fall, dyspnea, respiratory failure, device-related infection, hospitalization, and injection-site infection. There were 687 deaths, with 494 reported as death without specifying the cause. Deaths were most commonly attributed to ALS, disease progression, respiratory failure, or pneumonia. Review for administration-site reactions revealed 95 AEs, including 34 site infections, with 22 SAEs (all non-fatal). Five non-fatal SAEs of anaphylaxis were reported. CONCLUSION: In the postmarketing reporting to date, no new safety signals were identified beyond those already known from the edaravone clinical trial program.
Assuntos
Esclerose Lateral Amiotrófica , Edaravone , Adulto , Esclerose Lateral Amiotrófica/tratamento farmacológico , Progressão da Doença , Dispneia/induzido quimicamente , Edaravone/efeitos adversos , Humanos , Insuficiência Respiratória/induzido quimicamente , Estados UnidosRESUMO
Background: Particulate matter (PM) exposure is related to mitochondria dysfunction and airway inflammation. Antioxidant drug edaravone (EDA) is reported to improve the occurrence and development of oxidative stress-related diseases. At present, there is no data on whether EDA can alleviate lung inflammation caused by PM. Methods: The anti-inflammatory effects of EDA were investigated in urban PM-induced human bronchial epithelial cells (HBECs) and C57/BL6J mouse models. In vitro, its effects on the production of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and inflammatory cytokines were assessed by DCFH-DA staining, JC-1 assay, and real-time PCR, respectively. In vivo, the oxidant stress in lung tissues was assessed by dihydroethidium (DHE) staining and malondialdehyde (MDA) activity, and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were assessed by ELISA, respectively. Furthermore, the potential signaling pathways were studied by siRNA transfection and western blot. Results: PM increased the expression of inflammatory cytokines and protein, including IL-6, IL-1α, IL-1ß, and COX-2, while these alternations were significantly alleviated following EDA treatment in a dose-dependent manner. EDA treatment also alleviated the inflammatory responses in lung tissues of PM-exposed mice. We further showed mitochondrial dysfunction in PM-exposed HBECs and mice, which were reversed by EDA treatment. Moreover, the phosphorylation of NF-κB p65 in PM-exposed HBECs and mice was weakened by EDA. Transfection with NF-κB p65 siRNA further inhibited PM-induced inflammation in HBECs. Conclusion: We demonstrated that EDA treatment had a protective role in PM-induced lung inflammation through maintaining mitochondrial balance and regulating the ROS-NF-κB p65 signaling pathway. This provided a new therapeutic method for PM-induced lung inflammation in the future.
Assuntos
NF-kappa B , Pneumonia , Animais , Edaravone/efeitos adversos , Inflamação/tratamento farmacológico , Camundongos , NF-kappa B/metabolismo , Material Particulado/toxicidade , Pneumonia/metabolismo , RNA Interferente Pequeno/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
BACKGROUND AND OBJECTIVE: Aspirin combined with edaravone is more effective than aspirin or edaravone alone in the treatment of ischaemic stroke. Aspirin is defined as a nephrotoxic drug while the renal safety of edaravone is controversial. We aimed to evaluate whether edaravone will increase the nephrotoxicity of aspirin in patients with ischaemic stroke. DESIGN: A propensity score-matched retrospective cohort study. SETTING: A tertiary hospital in China. PARTICIPANTS: Patients with ischaemic stroke were treated with aspirin from February 2007 to May 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: Acute kidney injury (AKI, diagnosed by the Acute Kidney Injury Network), decreased estimated glomerular filtration rate (eGFR,>10%), gastrointestinal bleeding and in-hospital adverse outcomes (defined as dying or giving up treatment in our hospital). RESULTS: We included 3061 patients, and 986 pairs were successfully matched. Of the 986 pairs of patients included, the incidence of AKI between the aspirin group and the combination group showed no significant difference (7.71% vs 6.29%, p=0.217). While the incidence of eGFR decline (24.75% vs 16.94%, p<0.001) was significantly lower in the combination group. The protective effect was significant in patients with baseline eGFR >30 mL/min/1.73 m2, especially in eGFR 60-90 mL/min/1.73 m2. In patients with different complications, the incidence of AKI showed no significant differences in patients with chronic kidney injury, hypertension, anaemia, age above 75 years, except in patients with cardiovascular disease (OR, 2.82; 95% CI 1.50 to 5.29; p<0.001). However, the incidence of gastrointestinal bleeding (1.22% vs 2.84%, p=0.011) and in-hospital adverse outcomes (3.25% vs 7.00%, p<0.001) were significantly higher in the combination group. CONCLUSIONS: Our study indicated that edaravone in patients with ischaemic stroke didn't increase the nephrotoxicity of aspirin, and even had a protective effect on mild renal deterioration. Nevertheless, there is a need to be cautious when patients are in bad pathophysiological conditions and at high risk of bleeding.
Assuntos
Injúria Renal Aguda , Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Idoso , Aspirina/efeitos adversos , Isquemia Encefálica/complicações , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/tratamento farmacológico , Edaravone/efeitos adversos , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/tratamento farmacológico , Humanos , Rim , Masculino , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/etiologiaRESUMO
For investigating an influence on butylphthalide sodium chloride injection combined with edaravone dexborneol on neurological function and serum inflammatory factor levels in sufferers having acute ischemic stroke, 120 sufferers having acute ischemic stroke from September 2020 to September 2021 are chosen for the study subjects. In line with the diverse therapies, they took part in a control group and the study group, with 60 examples in each group. The control group is treated with edaravone dexborneol, and the study group is treated with butylphthalide sodium chloride injection, based on the control group. The posttreatment curative efficacy on the two groups is recorded, and treatment of both the two groups is compared. Before and after neurological function indexes (NIHSS and mRS), inflammatory factor indexes (IL-6, CRP, and TNF-α), life quality index (Barthel index), hemorheological indexes (plasma-specific viscosity), and neurological levels of NSE are logged and contrasted between the two groups of adverse reactions during therapy. Postcure, the overall response rate and Barthel index of the study group obviously overtop those of the control group (p < 0.05). IL-6, CRP, TNF-α, NSE, plasma specific viscosity, and NIHSS and mRS scores obviously hypodown those of the control group (p < 0.05), and untoward effects on the two groups during curing are lower, and the discrepancy is not obvious(p > 0.05). Butylphthalide sodium chloride injection combined with edaravone dexborneol can enhance curative efficacy on sufferers having acute ischemic stroke, improve neurological function, blood rheology, and quality of life, and decrease the secretion of cytokine, having a better effect and high medication safety.
Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Benzofuranos , Edaravone/efeitos adversos , Edaravone/uso terapêutico , Humanos , Interleucina-6/uso terapêutico , Qualidade de Vida , Cloreto de Sódio/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Resultado do Tratamento , Fator de Necrose Tumoral alfa/uso terapêuticoRESUMO
Importance: Intravenous edaravone is approved as a disease-modifying drug for patients with amyotrophic lateral sclerosis (ALS), but evidence for efficacy is limited to short-term beneficial effects shown in the MCI186-ALS19 study in a subpopulation in which efficacy was expected. Objective: To evaluate the long-term safety and effectiveness of intravenous edaravone therapy for patients with ALS in a real-world clinical setting. Design, Setting, and Participants: Multicenter, propensity score-matched cohort study conducted between June 2017 and March 2020 at 12 academic ALS referral centers associated with the German Motor Neuron Disease Network. Of 1440 patients screened, 738 were included in propensity score matching. Final analyses included 324 patients with ALS comprising 194 patients who started intravenous edaravone treatment (141 received ≥4 consecutive treatment cycles; 130 matched) and 130 propensity score-matched patients with ALS receiving standard therapy. All patients had probable or definite ALS according to the El Escorial criteria, with disease onset between December 2012 and April 2019. Subgroups were defined by applying the MCI186-ALS19 study inclusion criteria to evaluate whether patients would have been considered eligible (EFAS) or ineligible (non-EFAS). Exposures: Intravenous edaravone plus riluzole vs riluzole only. Main Outcomes and Measures: Patient characteristics and systematic safety assessment for patients who received at least 1 dose of intravenous edaravone. Effectiveness assessment of edaravone was conducted among patients who received at least 4 treatment cycles compared with propensity score-matched patients with ALS who received only standard therapy. Primary outcome was disease progression measured by decrease in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. Secondary outcomes were survival probability, time to ventilation, and change in disease progression before vs during treatment. To account for the matched design, patients receiving edaravone and their corresponding matched controls were regarded as related samples in disease progression analyses; stratification for propensity score quintiles was used for survival probability and time to ventilation analyses. Results: A total of 194 patients started intravenous edaravone treatment; 125 (64%) were male, and the median age was 57.5 years (IQR, 50.7-63.8 years). Potential adverse effects were observed in 30 cases (16%), most notably infections at infusion sites and allergic reactions. Disease progression among 116 patients treated for a median of 13.9 months (IQR, 8.9-13.9 months) with edaravone did not differ from 116 patients treated for a median of 11.2 months (IQR, 6.4-20.0 months) with standard therapy (ALSFRS-R points/month, -0.91 [95% CI, -0.69 to -1.07] vs -0.85 [95% CI, -0.66 to -0.99]; P = .37). No significant differences were observed in the secondary end points of survival probability, time to ventilation, and change in disease progression. Similarly, outcomes between patients treated with edaravone and matched patients did not differ within the EFAS and non-EFAS subgroups. Conclusions and Relevance: This cohort study using propensity score matching found that, although long-term intravenous edaravone therapy for patients with ALS was feasible and mainly well tolerated, it was not associated with any disease-modifying benefit. Intravenous edaravone may not provide a clinically relevant additional benefit compared with standard therapy alone.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Edaravone/efeitos adversos , Edaravone/uso terapêutico , Administração Intravenosa , Estudos de Coortes , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Satisfação do Paciente , Pontuação de Propensão , Respiração Artificial , Medição de Risco , Resultado do TratamentoRESUMO
OBJECTIVES: To investigate the clinical efficacy and safety of Shenxiong glucose injection combined with edaravone in the treatment of acute large-area cerebral infarction. METHODS: 156 patients with acute large-area cerebral infarction admitted to our hospital from July 2015 to January 2017 were included in the analysis. The patients were randomly divided into experimental (78 cases) and control (78 cases) groups. Patients in the experimental group were given a 30 mg injection of edaravone in 100 ml of 0.9% sodium chloride solution by intravenous drip, twice a day within 30 minutes and a daily 200 ml injection of Shenxiong glucose by intravenous drip. Patients in the control group were given a 30 mg edaravone injection in 100 ml of 0.9% sodium chloride solution by intravenous drip, twice a day, and the drip was completed within 30 minutes. Patients in both groups were treated for 2 weeks. The levels of fibrinogen (FIB), D-dimer, interleukin 6 (IL-6), P-selectin (CD62P), and hypersensitive C-reactive protein (hs-CRP) were evaluated in the two groups of patients. Neurological disability was evaluated using the modified Rankin scale (mRS) and the neurological deficit score (National Institute of Health Stroke Scale, NIHSS). Adverse reactions to the treatments were also recorded. RESULTS: No significant differences in age, gender, medical histories, and blood biochemical indices were observed between the two groups before treatment (P > 0.05). After treatment, the levels of FIB, D-dimer, IL-6, CD62P, and hs-CRP were significantly lower following treatment and compared to the control group (P < 0.05). Also, the mRS and NIHSS scores were significantly lower after treatment and compared with the control group (P < 0.05). The total effective rate of the treatment in the experimental group was significantly higher compared to the control group (P < 0.05). During the treatment period, no obvious adverse reactions were observed in the two groups of patients. CONCLUSIONS: In addition to the routine basic treatment of acute large-area cerebral infarction, the addition of Shenxiong glucose injection combined with edaravone injection can improve platelet aggregation and reduce inflammation by affecting P-selectin, D-dimer, and FIB. This treatment approach promotes the recovery of nerve defect function without obvious adverse reactions in patients with acute large-area cerebral infarction.
Assuntos
Infarto Cerebral/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Edaravone/uso terapêutico , Doença Aguda , Proteína C-Reativa/metabolismo , Infarto Cerebral/sangue , Infarto Cerebral/patologia , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/efeitos adversos , Edaravone/efeitos adversos , Edaravone/farmacologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Selectina-P/sangue , Selectina-P/metabolismo , Resultado do TratamentoRESUMO
ABSTRACT: Edaravone, a free radical-scavenger, was approved in Japan for the treatment of amyotrophic lateral sclerosis (ALS). However, the effect of the drug on renal function in ALS patients remains unclear. This study aimed to investigate renal function in ALS patients on long-term treatment with edaravone by measuring the serum estimated glomerular filtration rate based on cystatin C (eGFR-CysC).In a retrospective study, the data of ALS patients who were treated with over 10 cycles of intravenous edaravone treatment and were evaluated by eGFR-CysC before and after 10 cycles of treatment between July 2015 and June 2018 were analyzed. Then, the results were compared with those of a control ALS group that had never been treated with edaravone.There were 11 patients with ALS who received over 10 cycles of intravenous edaravone treatment. The mean interval between the first and final eGFR-CysC measurements was 18.7â±â7.9âmonths. Three patients (27.3%) had >20âmL/min/1.73âm2 decrease in serum eGFR-CysC. However, no patients discontinued edaravone treatment because of renal dysfunction. The average variation rate of eGFR-CysC was not different between the long-term edaravone group (0.29â±â1.07) and the control group (-0.34â±â0.40).This retrospective, single-center analysis showed no clinical exacerbation of renal function in ALS patients who received long-term treatment with edaravone.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/fisiopatologia , Edaravone/administração & dosagem , Sequestradores de Radicais Livres/administração & dosagem , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/fisiopatologia , Adulto , Idoso , Esclerose Lateral Amiotrófica/sangue , Cistatina C/sangue , Esquema de Medicação , Edaravone/efeitos adversos , Feminino , Sequestradores de Radicais Livres/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
WHAT IS KNOWN AND OBJECTIVE: Edaravone is a new antioxidant and hydroxyl radical scavenger. Although there is evidence that it improves clinical outcomes of patients with acute ischaemic stroke (AIS), it is not yet widely accepted for treatment of AIS in Western countries. We further investigated the efficacy and safety of edaravone through this meta-analysis of randomized controlled clinical trials (RCTs). METHOD: Pubmed, Embase, Web of Science and Cochrane Library were screened up to December 2020 for original articles from SCI journals that published in English. RCTs that compared edaravone versus placebo or no intervention in adult patients and reported the efficacy or safety of edaravone were regarded as eligible. Mortality was regarded as the primary outcome and the improvement of neurological impairment was regarded as the secondary outcome. Safety evaluation was conducted according to the incidence of adverse events. Review Manager 5.3 was employed to perform the assessment of the risk of bias and data synthesis. The Cochrane risk of bias tool for randomized controlled trials was employed to assess the risk of bias. RESULTS AND DISCUSSION: Seven randomized controlled trials with 2069 patients were included. For the incidence of mortality, the pooled RR for studies that evaluated edaravone after three-month follow-up was 0.55 (95% Cl, 0.43-0.7, I2 = 0, P < 0.01). The pooled RR for improvement of neurological impairment at the three months follow-up was 1.54 (95% CI, 1.27-1.87, I2 = 0, P < 0.01) in four RCTs. On subgroup analysis of studies that were conducted in Asia, the RR was 1.56 (95% CI, 1.27-1.90, I2 = 0%; P < 0.01); the pooled RR for studies that conducted in Europe was 1.32 (95% CI, 0.64-2.72; P = 0.45); the pooled RR for studies that used edaravone for two weeks was 1.42 (95% CI, 1.10 to 1.83, I2 = 0%; P < 0.01); the pooled RR for studies that used edaravone for one week was 1.64 (95% CI, 1.24-2.16, I2 = 0%; P < 0.01); the pooled RR for studies that conducted in patients with mean age equal to or over 60 years was 1.52 (95% CI, 1.24-1.87, I2 = 0%; P < 0.01); and the pooled RR for studies that conducted in patients with mean age less than 60 was 1.80 (95% CI, 1.05-3.08, I2 = 0%; P = 0.03). For the incidence of any treatment-related adverse events, the pooled RR for studies that evaluated edaravone during treatment was 0.83 (95% CI, 0.51-1.34, I2 = 0, P = 0.43). The difference of the incidence of any treatment-related adverse events between two groups was not statistically significant. WHAT IS NEW AND CONCLUSION: The limited studies indicate that edaravone can improve neurological impairment with a survival benefit at three-month follow-up, regardless of the mean age and course of treatment. It is worthy of promotion in the clinical treatment of AIS in Asian countries. More well-designed RCTs with larger sample sizes are needed to determine the benefits of edaravone in patients from Western countries.
Assuntos
Edaravone/uso terapêutico , AVC Isquêmico/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Fatores Etários , Edaravone/administração & dosagem , Edaravone/efeitos adversos , Humanos , AVC Isquêmico/mortalidade , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
This randomized, single-blind, 3-way crossover study assessed the effect of edaravone on QT interval, including an exposure-response analysis. Twenty-seven healthy Japanese male volunteers, aged 20 to 49 years, were randomly assigned to receive a single intravenous dose of each treatment in 1 of 3 sequences (n = 9 each): ACB, BAC, and CBA, where A was edaravone 60 mg (therapeutic dose), B was edaravone 300 mg (supratherapeutic dose), and C was normal saline (placebo). Electrocardiographs were collected to assess treatment effects. In an exposure-response analysis, a linear model was determined to be valid and indicated no statistically significant positive slope for the relationship between change from baseline in QTcF (ΔQTcF) and edaravone concentration (0.000155 ms/(ng/mL); P = .1478); upper bounds of 2-sided 90% confidence intervals after placebo adjustment (ΔΔQTcF) were <10 milliseconds at the geometric mean maximum concentration for each edaravone dose. Overall estimated values by time point of ΔΔQTcF ≤0.9 milliseconds, no outlier values, and no morphologic changes suggestive of repolarization abnormalities were observed. Analysis of heart rate, PR interval, and QRS duration also revealed no adverse findings. These data indicate that edaravone, even at supratherapeutic doses, does not produce clinically meaningful QT prolongation and has no clinically relevant cardiac effects.
Assuntos
Edaravone/administração & dosagem , Sequestradores de Radicais Livres/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Adulto , Estudos Cross-Over , Edaravone/efeitos adversos , Edaravone/sangue , Edaravone/farmacocinética , Eletrocardiografia/efeitos dos fármacos , Sequestradores de Radicais Livres/efeitos adversos , Sequestradores de Radicais Livres/sangue , Sequestradores de Radicais Livres/farmacocinética , Voluntários Saudáveis , Humanos , Síndrome do QT Longo , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/sangue , Fármacos Neuroprotetores/farmacocinética , Método Simples-Cego , Adulto JovemRESUMO
PURPOSE: Two studies were conducted to assess the pharmacokinetic (PK) properties and tolerability of edaravone in Japanese subjects with mild to moderate hepatic impairment or normal hepatic functioning (study 1), and in white subjects with severe hepatic impairment compared to subjects with normal hepatic functioning (study 2). METHODS: Studies 1 and 2 were multicenter, open-label, single-dose studies that included subjects aged 18-75 years. In study 1, subjects were stratified into 3 different groups of hepatic functioning according to Child-Pugh score: mild hepatic impairment, score 5 or 6 (n = 8); moderate hepatic impairment, score 7-9 (n = 6); or normal hepatic functioning (n = 8). In study 2, subjects had severe hepatic impairment (Child-Pugh score 10-14; n = 6) or normal hepatic functioning (n = 6). In both studies, all subjects were given edaravone 30 mg IV infused over 60 min on the morning of day 1. Blood samples for use in PK analyses were collected from days 1-3. The PK properties (Cmax, AUC0-last, and AUC0-∞) of edaravone and its sulfate conjugate metabolite were measured. FINDINGS: In study 1, the geometric least-squares mean (GLSM) Cmax and AUC0-∞ of unchanged edaravone were 1.203- and 1.065-fold greater, respectively, in subjects with mild hepatic impairment versus normal hepatic functioning, and were 1.235- and 1.142-fold greater, respectively, in subjects with moderate hepatic impairment versus normal hepatic functioning. In study 2, GLSM Cmax and AUC0-∞ of unchanged edaravone were 1.203- and 1.190-fold greater, respectively, in subjects with severe hepatic impairment versus normal hepatic functioning. In both studies the AUC0-last, AUC0-∞, unbound AUC from time zero to infinity, and Cmax of unchanged edaravone were increased slightly with increases in Child-Pugh classification. No adverse events considered related to edaravone were reported, except for 1 case of sinus bradycardia in a subject with normal hepatic functioning in study 2. The event was moderate in severity, considered as possibly related to edaravone, and resolved during the study. IMPLICATIONS: Mild to moderate and severe hepatic impairment had no apparent clinically significant effects on the PK profile of edaravone in Japanese and white subjects, respectively, relative to individuals with normal hepatic functioning, and there were no notable tolerability concerns. Thus, edaravone dosage adjustments are unlikely to be needed in edaravone-treated patients with mild to moderate and severe hepatic impairment. ClinicalTrials.gov identifiers: NCT03289234 (mild to moderate hepatic impairment) and NCT03664544 (severe hepatic impairment).
Assuntos
Edaravone/farmacocinética , Sequestradores de Radicais Livres/farmacocinética , Hepatopatias/metabolismo , Fármacos Neuroprotetores/farmacocinética , Adolescente , Adulto , Idoso , Área Sob a Curva , Bradicardia/induzido quimicamente , Edaravone/efeitos adversos , Edaravone/sangue , Feminino , Sequestradores de Radicais Livres/efeitos adversos , Sequestradores de Radicais Livres/sangue , Humanos , Hepatopatias/sangue , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/sangue , Adulto JovemRESUMO
The drug edaravone (EDA) is prescribed for the treatment of patients with amyotrophic lateral sclerosis or after an acute cerebral infarction. This synthetic pyrazolone derivative is a potent scavenger of oxygen free radicals and also functions as a modulator of transcription factors, repressing NFκB and activating Nrf2, to regulate oxidative stress. EDA displays complementary anti-oxidative and anti-inflammatory effects. The injectable small molecule is currently investigated for the treatment of several non-neurological diseases. The potential interest of EDA in oncology is reviewed here. EDA is a mild antiproliferative agent but has been found to enhance significantly the anticancer and antimetastatic activities of irinotecan in a colon cancer model. Anticancer derivatives of EDA have been designed but they generally display a limited antiproliferative activity. The antioxidant and anti-inflammatory activity of EDA can be best exploited to protect non-tumor cells from damages induced by chemotherapeutic drugs and radiations. Notably EDA can reduce the renal dysfunction induced by cisplatin, the neurotoxicity of cyclophosphamide and the cardiotoxicity of doxorubicin. Upon treatment with EDA, a significant improvement in neurologic symptoms has been observed in patients with nasopharyngeal carcinoma after radiotherapy. The drug could be used to limit radiation-induced brain injury or oral mucositis. EDA was found to ameliorate autoimmune thyroiditis (Hashimoto thyroiditis), which is a frequent side effect observed after treatment of cancer patients with monoclonal antibodies targeting the immune checkpoint PD-1. Therefore, EDA could also be useful to reduce specific side effects of immuno-therapy. Collectively, the information suggests that the medical use of EDA, a drug with a proven safety after 18â¯years of use in brain-related Human diseases, could be extended to cancer-related conditions.
Assuntos
Edaravone/efeitos adversos , Edaravone/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Sequestradores de Radicais Livres/efeitos adversos , Sequestradores de Radicais Livres/uso terapêutico , Humanos , Inflamação/metabolismo , Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacosRESUMO
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.
Assuntos
Edaravone/administração & dosagem , AVC Isquêmico/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Idoso , China , Método Duplo-Cego , Esquema de Medicação , Edaravone/efeitos adversos , Feminino , Estado Funcional , Humanos , Infusões Intravenosas , AVC Isquêmico/diagnóstico , AVC Isquêmico/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/efeitos adversos , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do TratamentoRESUMO
Background: Radicava® (edaravone), approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2017, may be administered intravenously at clinic sites, infusion centers or at home. Objective: To gain insights into the utilization of Radicava® at 1 year post-launch. Methods: Radicava® usage data were collected, and a survey was conducted among 75 physicians. Adverse events (AEs) were identified from a post-marketing safety database from 8 August 2017 through 3 August 2018 (cutoff date). Results: As of 6 August 2018, 3007 ALS patients were treated with Radicava®. Survey results indicated that 43% of patients received infusions at home, 32% in a clinician's office, and 26% at a referred site. Infusions were administered mainly via implanted port. The most commonly reported AEs were drug ineffective, death (not specified), therapeutic response unexpected, asthenia, fatigue, gait disturbance, disease progression, muscular weakness, fall, and dyspnea. Conclusions: The first year of Radicava® availability to ALS patients in the US provided many key learnings that will help shape strategies for improved patient care.