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Objectives: Edaravone (EDR) is an effective neuroprotective agent in various neurological diseases; however, its use is restricted due to poor oral absorption. Bile salts are known for improving solubility and inhibiting drug crystallization in supersaturated conditions of the gastrointestinal tract (GIT). In our previous work, we prepared coamorphous dispersion (COAM) of EDR with sodium taurocholate (NaTC) using spray drying. The optimized EDR COAM exhibited superior in vitro performance compared to plain EDR. EDR is well absorbed in fasted-over-fed conditions., Methods: The present work, we conducted a pharmacokinetic study for EDR and EDR COAM in fasted and fed conditions to check effect of food on its oral absorption. The LC-MS/MS-based method was developed and validated to determine the amount of EDR in plasma., Results: The results suggested that EDR COAM did not show a significant difference in C max (P=0.3544) and AUC (P=0.1696) of fasted and fed states. On the other hand, plain EDR showed 2-fold and 3-fold reduced C max (P<0.0001) and AUC (P=0.0094) in the fed condition, respectively. The C max and AUC of EDR COAM were improved in fasted (AUC: 2.56-fold) and fed states (AUC: 5.74-fold) than plain EDR, suggesting better oral absorption of COAM than crystalline EDR without having the effect of food., Conclusions: The unique structural attributes of NaTC had the potential to inhibit the recrystallization of EDR in GIT, while concurrently reducing the impact of food on the oral absorption of EDR., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Background: Edaravone has been widely used in amyotrophic lateral sclerosis (ALS) treatment, and a sublingual (SL) tablet has been developed to offer a more convenient alternative for injection. We present a cost-utility analysis to comprehensively evaluate the costs and health outcomes of oral and intravenous edaravone for the treatment of ALS in Chinese medical context., Methods: Cost-utility analysis of SL tablets of edaravone versus intravenous edaravone at home was performed by constructing a 20-year Markov model of ALS stage 1-4 and death. The data were extracted from the literature with model assumptions. Typical sensitivity analysis and scenario analysis for administering SL tablets at home versus intravenous tablets at the hospital were performed., Results: In the base case analysis, with SL tablets and intravenous injections both at home, the model estimated an additional cost of ¥12,670.04 and an additional 0.034 QALYs over 20 years (life time) of modeling analysis, and the ICER was ¥372,648.24 per QALY. However, in the scenario of intravenous administration at the hospital, SL tablet was demonstrated dominance to intravenous injection., Conclusions: Using 3 times the GDP per capita of China in 2023 as the threshold, the SL tablet edaravone was not cost-effective in the context of home treatment for both formulationst, but was dominance to intravenous injection in hospital treatment. The results highlighted the importance of treatment context for health economic analysis., (© 2024. The Author(s).)

Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas., (© 2024. The Author(s).)

Contrast-induced nephropathy (CIN) is a serious complication that occurs subsequent to the administration of contrast media for therapeutic angiographic interventions. As of present, no effective therapy exists to prevent its occurrence. This single-center double-blind randomized controlled trial aimed to evaluate the effect of edaravone, an antioxidant, in a group of high-risk patients undergoing coronary angiography. Ninety eligible patients with chronic kidney disease Stages 3-4 were randomly assigned to either the control group (n = 45) or the intervention group (n = 45). In the intervention group, one dosage of edaravone (60 mg) in 1 L of normal saline was infused via a peripheral vein 1 h prior to femoral artery-directed coronary angiography. Patients in the control group received an equal amount of infusion in their last hour before angiography. Both groups received intravenous hydration with 0.9% sodium 1 mL/kg/h starting 12 h before and continuing for 24 h after angiography. The primary outcome measure was the onset of CIN, defined as a 25% increase in serum creatinine levels 120 h after administration of contrast media. The occurrence of CIN was observed in 5.5% (n = 5) of the studied population: 2.2% of patients in the intervention group (n = 1) and 8.9% of controls (n = 4). However, this difference was not statistically significant. Administration of a single dosage of edaravone 1 h prior to infusion of contrast media led to a reduction in the incidence of CIN. Further investigations, employing larger sample sizes, are warranted to gain a comprehensive understanding of its efficacy., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background: Edaravone dexborneol has been reported as an effective neuroprotective agent in the treatment of acute ischemic stroke (AIS). This study aimed at investigating the impact of edaravone dexborneol on functional outcomes and systematic inflammatory response in AIS patient., Methods: All participants were recruited from the AISRNA study (registered 21/11/2019, NCT04175691 [ClinicalTrials.gov]) between January 2022 and December 2022. The AIS patients were divided into two groups based on whether they received the treatment of edaravone dexborneol (37.5 mg/12 hours, IV) within 48 h after stroke onset. Inflammatory response was determined by detecting levels of cytokines (interleukin-2 [IL-2], IL-4, IL-5, IL-8, IL-6, IL-10, IL-12p70, IL-17, tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], IFN-α, and IL-1β) within 14 days after stroke onset., Results: Eighty-five AIS patients were included from the AISRNA study. Patients treated with edaravone dexborneol showed a significantly higher proportion of modified Rankin Scale score < 2 compared to those who did not receive this treatment (70.7% versus 47.8%; P = 0.031). Furthermore, individuals receiving edaravone dexborneol injection exhibited lower expression levels of interleukin (IL)-1β, IL-6, and IL-17, along with higher levels of IL-4 and IL-10 expression during the acute phase of ischemic stroke (P < 0.05). These trends were not observed for IL-2, IL-5, IL-8, IL-12p70, tumor necrosis factor-α, interferon-γ [IFN-γ], and IFN-α (P > 0.05)., Conclusions: Treatment with edaravone dexborneol resulted in a favorable functional outcome at 90 days post-stroke onset when compared to patients without this intervention; it also suppressed proinflammatory factors expression while increasing anti-inflammatory factors levels., Trial Registration: ClinicalTrials.gov NCT04175691. Registered November 21, 2019, https://www., Clinicaltrials: gov/ct2/show/NCT04175691 ., (© 2024. The Author(s).)

Background: Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone., Mechanism of Action: The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals., Pharmacokinetics: Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5-9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates., Clinical Trials: The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure., Therapeutic Advance: Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The clinical application of EDV, a potent antioxidant drug approved for amyotrophic lateral sclerosis (ALS), is limited by its short biological half-life and poor water solubility necessitating hospitalization during intravenous infusion. Nanotechnology-based drug delivery constitutes a powerful tool through inferring drug stability and targeted drug delivery improving drug bioavailability at the diseased site. Nose-to-brain drug delivery offers direct access to the brain bypassing the blood brain barrier and reducing systemic biodistribution. In this study, we designed EDV-loaded poly(lactic-co-glycolic acid) (PLGA)-based polymeric nanoparticles (NP-EDV) for intranasal administration. NPs were formulated by the nanoprecipitation method. Morphology, EDV loading, physicochemical properties, shelf-life stability, in vitro release and pharmacokinetic assessment in mice were conducted. EDV was efficiently loaded into ∼90 nm NPs, stable up to 30 days of storage, at ∼3% drug loading. NP-EDV reduced H 2 O 2 -induced oxidative stress toxicity in mouse microglial cell line BV-2. Optical imaging and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) showed that intranasal delivery of NP-EDV offered higher and more sustained brain uptake of EDV compared to intravenous administration. This study is the first of its kind to develop an ALS drug in a nanoparticulate formulation for nose-to-brain delivery raising hope to ALS patients where currently treatment options are limited to two clinically approved drugs only., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2022 Mitsubishi Tanabe Pharma America, Inc and The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Since 2015, edaravone is the second drug available for the treatment of Amyotrophic lateral sclerosis (ALS). In this study we analyzed the characteristics and experience of ALS patients treated with this new medication in our country. Sixteen ALS patients were treated with edaravone infusions in three ALS clinics. Most of them were male, had a spinal onset of the disease and a definite diagnosis of ALS. Mean age at first infusion was 53.5 years. Since the diagnosis of ALS, delay in starting treatment with edaravone was five times greater than that of riluzole. Edaravone therapy was usually initiated at a health care facility and was followed by domiciliary cycles. Adverse effects and the need of a special catheter for infusion were rare. Access to edaravone through health insurance was possible in only 43.8% of patients. Altogether, treatment access was limited but feasible and edaravone was well tolerated., (© 2020. Belgian Neurological Society.)

Oxidative stress is a key factor in the pathogenesis of several neurodegenerative disorders and is involved in the accumulation of amyloid beta plaques and Tau inclusions. Edaravone (EDR) is a free radical scavenger that is approved for motor neuron disease and acute ischemic stroke. EDR alleviates pathologies and cognitive impairment of AD via targeting multiple key pathways in transgenic mice. Herein, we aimed to study the effect of EDR on Tau pathology in P301L mice; an animal model of frontotemporal dementia (FTD), at two age time points representing the early and late stages of the disease. A novel EDR formulation was utilized in the study and the drug was delivered orally in drinking water for 3 months. Then, behavioral tests were conducted followed by animal sacrifice and brain dissection. Treatment with EDR improved the reference memory and accuracy in the probe trial as evaluated in Morris water maze, as well as novel object recognition and significantly alleviated motor deficits in these mice. EDR also reduced the levels of 4-hydroxy-2-nonenal and 3-nitrotyrosine adducts. In addition, immunohistochemistry showed that EDR reduced tau phosphorylation and neuroinflammation and partially rescued neurons against oxidative neurotoxicity. Moreover, EDR attenuated downstream pathologies involved in Tau hyperphosphorylation. These results suggest that EDR may be a potential therapeutic agent for the treatment of FTD., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The neuroprotective agent edaravone is an intravenous treatment for amyotrophic lateral sclerosis. As intravenous administration burdens patients, orally administered treatments are needed. This phase 1, open-label, single-dose crossover study in 42 healthy adults evaluated bioequivalence of a 105-mg edaravone oral suspension and intravenous edaravone (60 mg/60 min). The evaluation was whether the 90% confidence intervals (CIs) for the ratio of the maximum plasma concentration (C max ) and area under the plasma concentration-time curve from time 0 to the last quantifiable time point and to infinity of unchanged edaravone were between the bioequivalence limit of 0.80 and 1.25. Metabolic profiles and elimination pathways were also compared between the 2 routes. Geometric mean ratios and 90%CIs of area under the plasma concentration-time curve from time 0 to the last quantifiable time point and to infinity for unchanged edaravone satisfied bioequivalence limits. The geometric mean ratio and its lower limit of 90%CI of C max of the 105-mg oral suspension compared with 60-mg intravenous formulations for unchanged edaravone fell within bioequivalence limits. Both formulations showed triphasic plasma concentration-time profiles of unchanged edaravone after reaching C max . Plasma concentrations of edaravone inactive metabolites after oral administration were higher than with intravenous administration. Edaravone in both routes underwent urinary excretion, mainly as the glucuronide conjugate and, to a lesser extent, as the sulfate conjugate. Urinary excretion of unchanged edaravone was low, and urinary relative composition ratios of unchanged edaravone and metabolites were similar for both formulations. These findings showed equivalent exposure of the 105-mg oral suspension of edaravone to the 60-mg intravenous formulation, supporting further investigation of the oral suspension for treating amyotrophic lateral sclerosis., (© 2021 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Intravenous (IV) edaravone is approved as an amyotrophic lateral sclerosis (ALS) treatment. Because IV administration places a burden on patients, development of orally administered ALS treatments is needed. Therefore, 2 phase 1 studies of oral formulations of edaravone in healthy subjects examined the pharmacokinetics (PK), safety, racial differences, and drug-drug interactions (DDIs) and investigated the dose of the oral formulation considered to be bioequivalent to the approved dose of the IV formulation. Study 1 was a placebo-controlled, randomized, single-blind study of single-ascending-dose oral edaravone with the dose range of 30 to 300 mg (n = 56). Study 2 was conducted in 2 cohorts (n = 84); the first assessed DDIs with multiple-dose edaravone 120 mg/day given over 5 or 8 days (coadministered with single-dose rosuvastatin, sildenafil, or furosemide), and the second evaluated PK and racial (Japanese/White) differences in PK parameters with doses of 100-mg edaravone. The oral formulation of edaravone was well absorbed, and plasma concentrations of unchanged edaravone increased more than dose proportionally within the dose range of 30 to 300 mg. No effect of race on oral edaravone PK and no notable DDI effects possibly caused by orally administered edaravone were observed. The oral edaravone formulations were safe and tolerable under the assessed conditions. Mathematical modeling determined that equivalent exposures in plasma with the approved dose of the IV edaravone formulation, as reported previously, could be achieved when the oral edaravone formulation was administered at a dose of  ≈100 mg, with an absolute bioavailability of ≈60%., (© 2021 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Edaravone is a potent antioxidant and anti-inflammatory agent that is used in the clinic. The aim of the present study was to evaluate the chronic treatment effect of edaravone on penicillin-induced epileptiform activity. Twenty-eight Wistar rats were randomly divided into a total of four groups as penicillin control and edaravone pretreatment groups (1, 10, and 30mg/kg). Firstly, permanent electrodes for electrocorticography (ECoG) recording and canula for penicillin injection were placed as stereotactic under anesthesia. At the end of the recovery period, edaravone pretreatment groups received different doses of edaravone by intraperitoneal injection for 14 days and before 30-min penicillin microinjection. Epileptiform activity was induced by injecting 500 IU penicillin through the intracortical cannula. The effects of edaravone pretreatment on epileptiform activity were evaluated by using both electrophysiological and behavioral parameters. Edaravone pretreatment suppressed epileptiform activity by reducing the mean spike frequency and the behavior scores in ECoG recording. The results of the present study indicated that the use of chronic edaravone had an anticonvulsant effect on penicillin-induced focal onset epileptic activity. Edaravone had an anticonvulsant effect even at low doses., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

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, I 2  = 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, I 2  = 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, I 2  = 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, I 2  = 0%; P < 0.01); the pooled RR for studies that used edaravone for one week was 1.64 (95% CI, 1.24-2.16, I 2  = 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, I 2  = 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, I 2  = 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, I 2  = 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., (© 2021 The Authors. Journal of Clinical Pharmacy and Therapeutics published by John Wiley & Sons Ltd.)

Cisplatin has been widely used as an anticancer agent for a wide range of tumors, but it had nephrotoxicity that was mainly caused by oxidative stress. Edaravone, a free radical scavenger, has reportedly been validated to have a protective effect against renal injury induced by reactive oxygen species. However, most of these reports are against AKI, and few studies have examined the effect of chronic renal injury. In this study, we investigate the effect of edaravone on cisplatin nephropathy in the chronic phase. Twenty-five male Wistar rats were divided into five groups: control, cisplatin, cisplatin + edaravone 1 mg kg -1 , cisplatin + edaravone 10 mg kg -1 , and cisplatin + edaravone 100 mg kg -1 . Edaravone was administrated intraperitoneally every other day for 5 weeks, starting 1 week before cisplatin administration (6 mg kg -1 , i.p.). As a result, proximal tubule injury, interstitial fibrosis, and mononuclear cell infiltration were ameliorated histologically in the group of rats treated with high edaravone dose. In the cisplatin group, the number of α-SMA-, CD68-, and CD3-positive cells increased markedly compared with the Control group, but these numbers were significantly decreased by higher doses of co-administered edaravone. While there was no clear mRNA expression variation in antioxidant enzymes, the apoptosis-promoting factors, caspase8, were markedly reduced in the high-dose edaravone co-administration group compared with the cisplatin group. In conclusion, our results suggested that cisplatin-induced renal injury in the chronic phase was ameliorated by edaravone.

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 18.7 ± 7.9 months. Three patients (27.3%) had >20 mL/min/1.73 m2 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 (0.29 ± 1.07) and the control group (-0.34 ± 0.40).This retrospective, single-center analysis showed no clinical exacerbation of renal function in ALS patients who received long-term treatment with edaravone., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: We aimed to evaluate the protective effect of edaravone on radiation-induced ovarian damage in an experimental rat model., Methods: Thirty-two Wistar albino female rats were randomly divided into four groups. Group 1: control, no treatment, and radiation was applied throughout the study; Group 2: sham, only radiation was applied; Group 3: 45 mg/kg edaravone and radiation were applied; Group 4: 450 mg/kg edaravone and radiation were applied. Edaravone was administered intraperitoneally 30 min before radiotherapy (5 Gy). Two days after radiation exposure, the rats were sacrificed and the ovaries were removed. Histologic changes under light microscopy and immunoreactivity for anti-caspase-3 were noted and compared between the four groups., Results: There was a statistically significant difference in follicle counts, vascular congestion, edema, cytoplasmic vacuolization, hemorrhage, and interstitial cell degeneration between the groups. Radiation causes deterioration in most histopathological parameters. Administration of edaravone at different doses seems to reverse these alterations and alleviate the injury. Antioxidant defense mechanisms appear to be enhanced by edaravone as shown by histopathologically and decreased apoptosis by reducing the expression of anti-caspase-3 activity as demonstrated immunohistochemically., Conclusion: This is the first study evaluating the protective effects of edaravone on radiation-induced ovarian damage. Edaravone decreased the follicular apoptosis and attenuates the radiation-induced ovarian damage in rats.

Background: To investigate the neuroprotective effect of edaravone on excessive-dose propofol-induced neurotoxicity in the hippocampus of newborn rats and HT22 cells., Methods: Cell proliferation was investigated by assessing ki67 expression in the neural stem of the hippocampus of newborn rats and by cell counting kit-8 (CCK8) assay in HT22 cells. Cell apoptosis was assessed in vivo by caspase 3 detection in Western blots and measurement of apoptosis in neurons and glial cells by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Apoptosis was analyzed by flow cytometry in HT22 cells. The Morris water maze was used to evaluate the long-term learning and memory ability of rats. Inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). The expression of mBDNF/TrkB/PI3K pathway-related proteins was detected by Western blot and quantitative reverse transcription-polymerase chain reaction (q-RT PCR)., Results: In neonatal rat hippocampus and HT22 cells, edaravone increased cell proliferation and decreased cell apoptosis after excessive propofol-induced neurotoxicity. In addition, the levels of proinflammatory factors interleukin (IL)-6 and tumor necrosis factor (TNF)-α were reduced by edaravone pretreatment. The use of the tropomyosin receptor kinase B (TrkB) antagonist ANA-12 and TrkB agonist 7,8DHF with propofol groups showed that edaravone mitigated excessive propofol-induced neurotoxicity through the mature brain-derived neurotrophic factor (mBDNF)/TrkB/phosphoinositide 3-kinase (PI3K) pathway. However, the current dose of propofol did not significantly affect long-term learning and memory in rats., Conclusion: Edaravone pretreatment ameliorated propofol-induced proliferation inhibition, neuroapoptosis, and neural inflammation by activating the mBDNF/TrkB/PI3K pathway., Competing Interests: The authors confirm that there are no conflicts of interest in this work., (© 2021 Yang et al.)

Intractable wound healing is the habitual problem of diabetes mellitus. High blood glucose limits wound healing by interrupting inflammatory responses and inhibiting neoangiogenesis. Oxidative stress is commonly thought to be a major pathogenic cause of diabetic complications. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, EDV) is a free radical scavenger which suppress oxidative stress. This study investigates whether EDV can reduce oxidative stress in wound healing HaCaT/human dermal fibroblasts cells (HDFs) in vitro and in vivo animal model. Cell viability and wound healing assays, FACS flow cytometry, and Hoechst 33342 staining were performed to confirm apoptosis and cytotoxicity in H 2 O 2 and EDV-treated HaCaT and HDFs. A streptozotocin-induced hyperglycemic animal model was made in adult C57BL6 mice. Full-thickness skin flap was made on dorsomedial back and re-sutured to evaluate the wound healing process. EDV was delivered slowly in the skin flap with degradable fibrin glue. The flap was monitored and analyzed on postoperative days 1, 3, and 5. CD31/DAPI staining was done to detect newly formed blood vessels. The expression levels of NF-κB, bcl-2, NOX3, and STAT3 proteins in C57BL6 mouse tissues were also examined. The wound healing process in hyper- and normoglycemic mice showed a difference in protein expression, especially in oxidative stress management and angiogenesis. Exogenous H 2 O 2 reduced cell viability in a proportion to the concentration via apoptosis. EDV protected HaCaT cells and HDFs from H 2 O 2 induced reactive oxygen species cell damage and apoptosis. In the mouse model, EDV with fibrin resulted in less necrotic areas and increased angiogenesis on postoperative day 5, compared to sham-treated mice. Our results indicate that EDV could protect H 2 O 2 -induced cellular injury via inhibiting early apoptosis and inflammation and also increasing angiogenesis. EDV might be valuable in the treatment of diabetic wounds that oxidative stress has been implicated.

Background and Purpose: Edaravone dexborneol, comprised of 2 active ingredients, edaravone and (+)-borneol, has been developed as a novel neuroprotective agent with synergistic effects of antioxidant and anti-inflammatory in animal models. The present clinical trial aimed at testing the effects of edaravone dexborneol versus edaravone on 90-day functional outcome in patients with acute ischemic stroke (AIS)., Methods: A multicenter, randomized, double-blind, comparative, phase III clinical trial was conducted at 48 hospitals in China between May 2015 and December 2016. Inclusion criteria included patients diagnosed as AIS, 35 to 80 years of age, National Institutes of Health Stroke Scale Score between 4 and 24, and within 48 hours of AIS onset. AIS patients were randomized in 1:1 ratio into 2 treatment arms: 14-day infusion of edaravone dexborneol or edaravone injection. The primary end point was the proportion of patients with modified Rankin Scale score ≤1 on day 90 after randomization., Results: One thousand one hundred sixty-five AIS patients were randomly allocated to the edaravone dexborneol group (n=585) or the edaravone group (n=580). The edaravone dexborneol group showed significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization, compared with the edaravone group (modified Rankin Scale score ≤1, 67.18% versus 58.97%; odds ratio, 1.42 [95% CI, 1.12-1.81]; P =0.004). The prespecified subgroup analyses indicated that a greater benefit was observed in female patients than their male counterparts (2.26, 1.49-3.43 versus 1.14, 0.85-1.52)., Conclusions: When edaravone dexborneol versus edaravone was administered within 48 hours after AIS, 90-day good functional outcomes favored the edaravone dexborneol group, especially in female patients. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02430350.

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., (© 2020 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Our study aimed to investigate the effect of intravenous thrombolysis with alteplase and edaravone on cerebral hemodynamics and T lymphocyte level in patients harboring acute cerebral infarction.There involved a total of 118 patients with acute cerebral infarction from November 2017 to May 2019 in our hospital were randomly divided into 2 groups: the observation group (59 patients were treated with intravenous thrombolysis with alteplase combined with edaravone) and the control group (59 patients were treated with intravenous thrombolysis of alteplase). The clinical effect, neurological function, cerebral hemodynamic index, T lymphocyte level, oxygen free radical scavenging level and oxidative stress index of the 2 groups were observed and compared.Before the treatment, there were no significant differences in neurological function, cerebral hemodynamic indexes, T-lymphocyte level, oxygen free radical scavenging level and oxidative stress indexes between the 2 groups (P > .05). After the treatment, the neurological function, cerebral hemodynamic indexes, T-lymphocyte level, oxygen free radical scavenging level and oxidative stress indexes of the 2 groups were significantly improved. In addition, the observation group exerted greater beneficial effect in terms of the clinical effect, neurologic function, cerebral hemodynamic index, T lymphocyte level, oxygen free radical scavenging level and oxidative stress index than those of the control group (P < .05).The intravenous thrombolysis with alteplase and edaravone is effective in the treatment of acute cerebral infarction, which also provides better results in terms of improving the clinical efficacy and prognosis of patients and might be an alternative option for clinical practice.

Introduction: Cyclophosphamide (CP) causes redox imbalance and its use is associated with marked cardiotoxicity that limits its clinical applications. The present study investigated the protective effects of acetovanillone (AV) and edaravone (ED) against CP-induced oxidative stress and cardiac damage, emphasizing the role of PI3K/Akt/mTOR and Nrf2 signaling., Materials and Methods: Rats received either AV (100 mg/kg) or ED (20 mg/kg) orally for 10 days and CP (200 mg/kg) on day 7. At day 11, the rats were sacrificed, and samples were collected for analysis., Results: AV and ED ameliorated serum troponin I, CK-MB, LDH, AST and ALP, and prevented cardiac histological alterations in CP-intoxicated rats. Both treatments decreased cardiac lipid peroxidation and enhanced GSH, SOD and cytoglobin in CP-induced rats. AV and ED downregulated Keap1, whereas increased the expression of PI3K, Akt, mTOR and Nrf2 in the heart of rats received CP. Additionally, the binding modes of AV and ED to Keap1 were pinpointed in silico using molecular docking simulations., Conclusion: AV and ED prevent CP cardiotoxicity by attenuating oxidative stress and tissue injury, and modulating cytoglobin, and PI3K/Akt/mTOR and Keap1/Nrf2 signaling. Therefore, AV and ED may represent promising agents that can prevent cardiac injury in patients receiving CP., Competing Interests: The authors declare that there are no potential conflicts of interest., (© 2020 Hassanein et al.)

Surfer's myelopathy is non-traumatic spinal cord injury which develops in beginner surfers. The patient was a 17-year-old female who developed severe paraplegia with bilateral sensory dysfunction below the groin and bladder/rectal dysfunctions after her first surfing lesson. A spinal-cord MRI performed six hours after onset revealed an intramedullary hyperintensity area from T8 to the conus medullaris on the T 2 weighted images. Expansion of this hyperintensity area was observed on Day 3 and showed a reduction on Day 8. After providing intravenous methylpredonisolone, intravenous glycerol and intravenous edaravone, motor function and bladder/rectal functions began to improve after approximately three weeks. In this study, the expansion of the lesion in the early stages of the disease course was observed by sequential spinal MRI. Furthermore, a time lag between improvement according to imaging and improvement in symptoms was also observed.

Purpose: The goal of this study was to compare edaravone pharmacokinetic (PK) variables and tolerability after a single intravenous (IV) infusion of 30 mg over 60 min in subjects with mild renal impairment (estimated glomerular filtration rate 60-89 mL/min/1.73 m 2 ), moderate renal impairment (30-59 mL/min/1.73 m 2 ), or normal renal function (≥90 mL/min/1.73 m 2 )., Methods: This open-label, single-dose study was conducted in Japan. After a screening period of up to 3 weeks, all subjects received a single IV dose of edaravone 30 mg/h on day 1. Blood samples were collected for PK analysis of edaravone and its sulfate conjugate for up to 48 h postdose., Findings: Edaravone was administered to 30 subjects: 11 with mild (Group 1), 8 with moderate (Group 2), and 11 with no (Group 3) renal impairment. Although geometric least-squares mean values for C max and AUC 0-∞ for unchanged edaravone were 1.15- and 1.20-fold greater in Group 1 than in Group 3, and were 1.25- and 1.30-fold greater in Group 2 than in Group 3, no statistically significant differences in exposure (C max and AUC) to edaravone were noted between the 3 groups (P > 0.05). The geometric least-squares mean values for C max and AUC 0-∞ for the sulfate conjugate were 1.41- and 1.50-fold greater in Group 1 than in Group 3, and 1.41- and 1.97-fold greater in Group 2 than in Group 3. Differences in exposure (C max and AUC) to the sulfate conjugate of edaravone were statistically significant between the 3 study groups (P < 0.0001). A total of 5 treatment-emergent adverse events in 3 subjects in Group 1 were considered by the investigator to be reasonably related to edaravone: headache (2 events/2 subjects), vomiting (2 events/1 subjects), and increased blood bilirubin level (n = 1). These treatment-emergent adverse events were mild and recovered without sequelae., Implications: Mild to moderate renal impairment had no clinically significant effects on the PK profile of edaravone in Japanese subjects, relative to individuals with normal renal function, and there were no significant safety concerns. Thus, edaravone dosage adjustments are unlikely to be needed in patients with mild to moderate renal impairment. Clinicaltrials.gov identifier: NCT03289208., Competing Interests: Disclosures All authors are employees of Mitsubishi Tanabe Pharma Corporation. The authors have indicated that they have no other conflicts of interest regarding the content of this article., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Mild hypothermia (MH) and edaravone (EDA) exert neuroprotective effects against cerebral ischemia/reperfusion (I/R) injury through activation of the nuclear factor erythroid 2‑related factor 2 (Nrf2) pathway. However, whether MH and EDA exert synergistic effects against cerebral I/R injury remains unknown. The aim of the present study was to investigate the effects and mechanism of action of MH in combination with EDA in cerebral I/R injury. A rat cerebral I/R injury model was constructed by middle cerebral artery occlusion (MCAO) followed by reperfusion, and the mice were treated by MH, EDA or the inhibitor of the Nrf2 signaling pathway brusatol (Bru). It was observed that mice treated by MCAO had higher neurological deficit scores and oxidative stress levels, and low spatial learning and memory capacity; moreover, the CA1 region of the hippocampi of the mice exhibited reduced neuronal density and viability, and reduced mitochondrial dysfunction. However, MH in combination with EDA reversed the effects of MCAO, which were blocked by Bru injection. The levels of glutathione (GSH), GSH peroxidase, catalase and superoxide dismutase in rat ischemic hemisphere tissues were reduced by Bru. Western blotting demonstrated that the combined treatment with MH and EDA promoted the nuclear localization of Nrf2, and increased the levels of NAD(P)H quinone oxidoreductase and heme oxygenase (HO)‑1. In conclusion, MH combined with EDA exerted synergistic neuroprotective effects against cerebral I/R injury involving changes in the Nrf2/HO‑1 pathway.

Introduction: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease involving both upper and lower motor neurons and resulting in increasing disability and death 3-5 years after onset of symptoms. Over 40 large clinical trials for ALS have been negative, except for Riluzole that offers a modest survival benefit, and Edaravone that modestly reduces disease progression in patients with specific characteristics. Thus, the discovery of efficient disease modifying therapy is an urgent need., Areas Covered: Although the cause of ALS remains unclear, many studies have demonstrated that neuroinflammation, proteinopathies, glutamate-induced excitotoxicity, microglial activation, oxidative stress, and mitochondrial dysfunction may play a key role in the pathogenesis. This review highlights recent discoveries relating to these diverse mechanisms and their implications for the development of therapy. Ongoing phase 2 clinical trials aimed to interfere with these pathophysiological mechanisms are discussed., Expert Opinion: This review describes the challenges that the discovery of an efficient drug therapy faces and how these issues may be addressed. With the continuous advances coming from basic research, we provided possible suggestions that may be considered to improve performance of clinical trials and turn ALS research into a 'fertile ground' for drug development for this devastating disease.

Two high-performance liquid chromatography-tandem mass spectrometry methods were developed and validated for the quantification of edaravone (method A) or taurine (method B) in human plasma. After protein precipitation, separations were achieved on an Ultimate XB-C8 (2.1 × 50 mm, 3.0 µm) column for edaravone and a ZORBAX SB-Aq column (2.1 × 100 mm, 3.5 µm) for taurine, respectively. The detection used electrospray ionization source via multiple reaction monitoring in positive-ion mode for edaravone and negative-ion mode for taurine, respectively. The lower limits of quantification were 10.0 ng/mL for edaravone and 3.00 μg/mL for taurine. The selectivity, accuracy, and precision of the methods were all within acceptable limits. Two methods were successfully applied to a drug-drug interaction study and a pharmacokinetic study of edaravone and taurine in healthy Chinese volunteers after intravenous infusion of single or compound injection. The results showed that co-administration of edaravone with taurine increased the C max and AUC 0-24 of taurine in human plasma while taurine did not affect the systemic exposure of edaravone. Edaravone and taurine have the dose-dependent pharmacokinetic profiles in human., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Edaravone is a free-radical scavenger with relatively favorable properties of brain penetration. It has been approved for the indications of acute ischemic stroke and amyotrophic lateral sclerosis (ALS). This study aimed to establish a pharmacokinetic (PK) model to fit the PK profile of edaravone after a single sublingual (SL) dose of a novel edaravone tablet and single IV infusion of injectable edaravone in healthy Chinese volunteers participating in a bioavailability study. The model is expected to be useful for predicting the concentration-time profiles of edaravone following different dosing regimens in a healthy Chinese population. The purposes were to identify an optimal dose and dosing regimen for the new SL formulation and to support future clinical exploration of this tablet product in its approved indications and other therapeutic fields being developed., Methods: The PK profiles after a single SL dose or IV infusion of edaravone 30 mg can be well described by a 3-compartment linear disposition model, on which a first-order absorption model with a lag time and a parameter for bioavailability was incorporated to fit the absorption phase of the SL dose. Performance of these PK models was evaluated for goodness of fit, residual trends, visual predictive checks, as well as precision of model predictions against external data. The validated models were employed for simulating the PK profiles of edaravone after a single SL dose of 60 mg and IV infusion of 60 mg for 60 min., Findings: The resultant estimates support the possibility and feasibility of demonstrating bioequivalence between an SL administration of edaravone 60 mg and the currently approved dosing regimen for ALS (ie, 60 mg IV over 60 min) once per day. The calculation of sample size suggested that the requirement for subject number was acceptable considering the general capacity of a Phase I study center, and so were the procedures defined in the protocol., Implication: The models can be further applied to simulate favorable concentration-time profiles in diseases with different underlying courses of oxidative stress, and hence facilitate the optimization of current dosing regimens., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Postoperative cognitive dysfunction (POCD) is a common neurological disease affecting the elderly patients after surgery. Unfortunately, no effective treatment for this disease has been discovered. Edaravone, a clinical-used free radical scavenger, at 3 mg/kg has been reported to prevent neuroinflammation induced by the combination of surgery and lipopolysaccharide in adult rodents. However, we found that edaravone at such low concentration could not inhibit POCD in aged mice. Instead, edaravone at 33.2 mg/kg significantly prevented recognition and spatial cognitive dysfunctions in 14 month aged mice after abdominal surgery under general anesthesia with isoflurane. Furthermore, edaravone significantly prevented the increase of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) induced by abdominal surgery in aged mice. Edaravone could also decrease glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) positive areas in the hippocampal regions of surgery mice, suggesting that edaravone might inhibit surgery-induced over-activation of microglia and astrocytes. Moreover, edaravone substantially increased the expression of PSD-95 and pSer9-glycogen synthase kinase-3β (pSer9-GSK3β) as demonstrated by Western blotting assay. Furthermore, the activity of acetylcholinesterase (AChE) is decreased in the mice in edaravone group. All these results suggested that edaravone at high concentrations could inhibit surgery-induced cognitive impairments in aged animals, possibly via the attenuation of neuroinflammation, the increase of synaptic proteins, and the elevation of cholinergic transmission, providing a further support that edaravone might be developed as a treatment of POCD.

Background: This study was conducted to explore whether the effect of edaravone (5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol3-one, EDR) can ameliorate renal warm ischemia-reperfusion injury (IRI) by modulating endoplasmic reticulum stress (ERS) and its downstream effector after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in a rat model., Methods: The rats (n=10) experienced anaesthesia and intubation followed by no CA inducement were defined as the Sham group. Transoesophageal alternating current stimulation was employed to establish 8 min of CA followed by conventional CPR for a resuscitation model. The rats with successful restoration of spontaneous circulation (ROSC) randomly received EDR (3 mg/kg, EDR group, n=10) or equal volume normal saline solution (the NS group, n=10). At 24 hr after ROSC, serum creatinine (SCR), blood urea nitrogen (BUN) levels, and cystatin-C (Cys-C) levels were determined and the protein level of glucose-regulated protein (GRP78), C/EBP homologous protein (CHOP), extracellular signal-regulated kinase (ERK), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), Bax/Bcl-2, and caspase-3 were detected by Western blot method., Results: At 24 hrs after ROSC, SCR, BUN and Cys-C were obviously increased and the proteins expression, including GRP78, CHOP and p-ERK1/2, cleaved-caspase 3 Bax/Bcl-2 ratio, were significantly upregulated in the NS group compared with the Sham group (p<0.05). The remarkable improvement of these adverse outcomes was observed in the EDR group (p<0.05)., Conclusion: In conclusion, we found that EDR ameliorates renal warm IRI by downregulating ERS and its downstream effectors in a rat AKI model evoked by CA/CPR. These data may provide evidence for future therapeutic benefits of EDR against AKI induced by CA/CPR., Competing Interests: Zhao-yin Fu reports grants from National Natural Science Foundation of China and Scientific Research and Technological Development Project of Qinzhou City, during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2020 Fu et al.)

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.

Introduction: Neurosyphilis is a chronic infection of the central nervous system that is commonly found in adult with long latency periods. Neurosyphilis-attributed deaths in young patients have grown exponentially in the past decade, yet there have been few studies on the early stages of neurosyphilis., Patient Concerns: A young male patient with syphilitic cerebral arteritis was evaluated in our clinic for the clinical signs of progressive ischemic stroke., Diagnosis: The progression of syphilitic cerebral arteritis was observed through computed tomography imaging, magnetic resonance imaging, magnetic resonance angiogram, and transcranial color Doppler. The pathological changes and clinical outcomes were reviewed. In this specific case, the development of syphilitic cerebral arteritis was dynamic, continuous, and rapid. The pathogenesis was related to Heubner arteritis, in which the formation of a mural thrombus (MT) causes the severe obstruction of blood flow without complete occlusion, leading to an increased risk of infarction. In this patient, formation of the MT resulted in the infarction of the smaller vessels and narrowing of the larger vessels. The partial dislodgment of the MT from the arterial wall of the larger vessels occluded the smaller vessels, leading to infarction., Interventions: Standard pharmacotherapy for the treatment of the cerebral infarction and a single course of penicillin were applied., Outcomes: Muscle strength was recovered. The Glasgow Coma Scale score was 15, whereas the NIH Stroke Scale score was 0. The increase in blood flow of the right MCA was accompanied by severe stenosis with compensation of the anterior communicating artery. In addition, moderate to severe stenosis of the right vertebral artery and the basilar artery was suspected. There was a possibility that the right posterior communicating artery was recruited for compensation., Conclusion: Progressive stroke was the initial symptom of the neurosyphilis. Disease progression is rapid and difficult to control with a single course of penicillin.

Objective: To observe whether edaravone has a therapeutic and protective effect on retinal injury in diabetic rats through the nuclear factor-κB (NF-κB) pathway., Materials and Methods: The Sprague-Dawley rat model of diabetes was established and divided into diabetes model group (model group) and edaravone treatment group (treatment group). Also, normal control group (control group) was set up. After successful modeling, the blood and retinal tissues of rats were collected. Then, the blood glucose content and serum interleukin-6 (IL-6) were detected. Antioxidant indexes, superoxide dismutase (SOD), and malondialdehyde (MDA), were detected via enzyme-linked immunosorbent assay (ELISA), while the number of corneal nerve fibers was observed microscopically. Moreover, the gene and protein expressions of SOD and NF-κB pathway in tissues were detected via quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) and Western blotting., Results: The level of blood glucose in model group was increased compared with that in control group (p<0.05), indicating the successful modeling. The levels of tumor necrosis factor-α (TNF-α), IL-6, and IL-1 were significantly higher in model group than those in control group. In terms of the antioxidant indexes, the level of MDA in model group was significantly higher than that in other two groups, while the level of SOD in treatment group was significantly increased and close to that in control group. Besides, the number of corneal nerve fibers significantly declined in model group, while it was increased in treatment group but still lower than that in control group. According to the gene detection results, the mRNA expression of NF-κB p65 was markedly higher in model group than that in control group, and it was decreased in treatment group, while the mRNA expression of SOD showed the opposite trend. The protein expression of NF-κB p65 was remarkably higher in model group than in control group, was decreased in treatment group, and was close to that in control group, while the protein expression of SOD showed the opposite trend., Conclusions: Edaravone can affect the oxidation and antioxidation through the NF-κB signaling pathway, thereby exerting a therapeutic and protective effect on retinal injury in diabetic rats.

Background and Purpose- In Japan, nearly half of ischemic stroke patients receive edaravone for acute treatment. The purpose of this study was to assess the effect of edaravone on neurological symptoms in patients with ischemic stroke stratified by stroke subtype. Methods- Study subjects were 61 048 patients aged 18 years or older who were hospitalized ≤14 days after onset of an acute ischemic stroke and were registered in the Japan Stroke Data Bank, a hospital-based multicenter stroke registration database, between June 2001 and July 2013. Patients were stratified according to ischemic stroke subtype (large-artery atherosclerosis, cardioembolism, small-vessel occlusion, and cryptogenic/undetermined) and then divided into 2 groups (edaravone-treated and no edaravone). Neurological symptoms were evaluated using the National Institutes of Health Stroke Scale (NIHSS). The primary outcome was changed in neurological symptoms during the hospital stay (ΔNIHSS=NIHSS score at discharge-NIHSS score at admission). Data were analyzed using multivariate linear regression with inverse probability of treatment weighting after adjusting for the following confounding factors: age, gender, and systolic and diastolic blood pressure at the start of treatment, NIHSS score at admission, time from stroke onset to hospital admission, infarct size, comorbidities, concomitant medication, clinical department, history of smoking, alcohol consumption, and history of stroke. Results- After adjusting for potential confounders, the improvement in NIHSS score from admission to discharge was greater in the edaravone-treated group than in the no edaravone group for all ischemic stroke subtypes (mean [95% CI] difference in ΔNIHSS: -0.46 [-0.75 to -0.16] for large-artery atherosclerosis, -0.64 [-1.09 to -0.2] for cardioembolism, and -0.25 [-0.4 to -0.09] for small-vessel occlusion). Conclusions- For any ischemic stroke subtype, edaravone use (compared with no use) was associated with a greater improvement in neurological symptoms, although the difference was small (<1 point NIHSS) and of limited clinical significance.

Background: Acute ischemic stroke (AIS) is associated with significant morbidity and mortality and has a very narrow window of treatment with fibrinolytics. We investigated the safety and efficacy of combined chlorpromazine and promethazine (C+P) treatment in AIS., Methods: A total of 64 consecutive patients diagnosed with AIS were selected and were randomly (double-blind) assigned into either the control group (standard of care [SOC] treatment) or the treatment group (SOC+C+P [12.5+12.5 mg BID or 25+25 mg BID]) which were treated for 2 weeks. The National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin Scale (mRS) were computed prior to and after treatment to evaluate neurological deficits and daily functional status., Results: In our study, 64 patients (males=81.3%) were divided into either the control (34 patients, 83.3% males, mean age=58.8±11.7 years) or the study group (30 patients, 79.4% males, mean age=62.3±9.1 years). While the NIHSS scores were not different between the control and treatment group at admission (P>0.05), a greater proportion of the cohort in both the groups (control group low NIHSS=79.4%, high NIHSS=20.6%, P<0.01) had a lower NIHSS at admission and (treatment group low NIHSS=83.3%, high NIHSS=16.7%, P<0.01). Interestingly, while both the control and treatment group had lower NIHSS and mRS scores at 90d post treatment compared to those at baseline, there were no significant differences in those scores between the two group (P>0.05) suggesting no improved benefit with C+P. Moreover, using C+P did not lead to any serious adverse effects when compared to the treatment group., Conclusions: While the addition of low dose chlorpromazine and promethazine to standard of care for acute ischemic stroke did not have any significant improvement in functional outcomes, there were no serious adverse effects. Thus, the use of chlorpromazine and promethazine in the acute ischemic stroke setting and future studies using higher doses of C+P are justified.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study was performed to determine the primary factor(s) governing the oral absorption of edaravone, a novel anti-oxidant for the treatment of amyotrophic lateral sclerosis, in rats. While the aqueous solubility of edaravone widely varied depending on the vehicle used, the oral bioavailability of the drug was not low when it was adequately solubilized, as evidenced by the fact that the oral exposure was high (in terms of the absolute bioavailability of 50-90%) at all dose ranges (i.e., 0.5-27 mg/kg) under solubilized conditions in rats. The sum of the in vitro clearance values for edaravone, 12.7 mL/(min × kg), obtained from metabolic stability studies with tissue-homogenates from the rat liver, kidney, intestine, and with the rat plasma, was found to be virtually identical to the systemic clearance of the drug in rats. It was noted that the liver represented over 83.9% of the total elimination with a hepatic extraction ratio of approximately 0.137, indicative of the minor role of hepatic first pass metabolism in the systemic absorption of edaravone after its oral administration. In studies with Ussing chamber with rat intestinal segments and Madin-Darby canine kidney (MDCKII) cells, edaravone was found to be highly permeable (i.e., P app over 10 × 10 -6  cm/s), and appeared to be a substrate for rat P-glycoprotein (P-gp; estimated K m of 421 μM). In contrast, however, the drug did not appear to be a substrate for human P-gp in transport studies with MDCKII-hMDR1 cells. Collectively, these observations suggest that the primary determining factor for the intestinal absorption of edaravone is its solubilization in vehicle/intestinal fluids, rather than permeability, pre-systemic first-pass metabolism, or efflux transport. Considering the fact that the newly approved indication of the drug would require prolonged administration, probably via oral administration, the findings reported herein provide relevant information regarding its use., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Edaravone is a free-radical scavenger. Edaravone 30mg IV has been approved for use in the treatment of acute ischemic stroke in Japan and China, and for amyotrophic lateral sclerosis in Japan and the United States. Considering the inconvenience of IV infusion in clinical practice, an oral tablet formulation of edaravone was developed but failed in 2011 due to poor bioavailability. More recently, a sublingual (SL) tablet formulation of edaravone 30mg was developed by a Good Manufacturing Practices-compliant manufacturer in China. This study explored the bioavailability of the SL tablet of edaravone and aimed to provide evidence to support decision making in future clinical development., Methods: This 2-way crossover study was conducted in 10 healthy male volunteers. Eligible subjects were randomized, in a 1:1 ratio, to 1 of 2 dosing sequences: (1) SL edaravone 30mg, followed by edaravone 30mg IV infusion given over 30 minutes; or (2) edaravone 30mg IV infusion given over 30 minutes, followed by SL edaravone 30mg. The washout period between the 2 dosing periods was at least 24hours. Serial blood samples were collected in each dosing period. The bioavailability of the SL tablet was assessed using bioavailability analysis. Tolerability was evaluated throughout the study., Findings: The plasma concentration-time profile of the SL tablet was similar to that with the IV infusion. Amean (SD) C max of 2030.2 (517.2) ng/mL was reached within a median T max of 0.875hour, which was statistically significantly longer than the median T max with IV administration (0.5 hour). The C max with SL administration corresponded to 83.92% (90% CI, 73.22%-96.18%) of the C max with the start of IV infusion (2354.0 [336.6] ng/mL). The mean AUC 0-t with SL dosing was 5420.07 (1429.75) h · ng/mL, which corresponded to 91.94% (90% CI, 86.81%-97.39%) of the AUC 0-t with IV administration (5824.42 [1338.48] h · ng/mL). Two cases of adverse events were reported during the study; both were considered by the investigator to have been possibly not related to the study treatment., Implications: The bioavailability of the SL tablet of edaravone was 91.94%. Compared with IV administration, C max with SL administration was ∼17% lower and T max was statistically significantly longer. The exposure differences can be addressed by modifying the strength of the SL tablet, and then conducting a second study to demonstrate the pharmacokinetic bioavailability of the sublingually administered new strength versus IV infusion of edaravone., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cerebral vasculature and neuronal networks will be largely destroyed due to the oxidative damage by overproduced reactive oxygen species (ROS) during a stroke, accompanied by the symptoms of ischemic injury and blood-brain barrier (BBB) disruption. Ceria nanoparticles, acting as an effective and recyclable ROS scavenger, have been shown to be highly effective in neuroprotection. However, the brain access of nanoparticles can only be achieved by targeting the damaged area of BBB, leading to the disrupted BBB being unprotected and to turbulence of the microenvironment in the brain. Nevertheless, the integrity of the BBB will cause very limited accumulation of therapeutic nanoparticles in brain lesions. This dilemma is a great challenge in the development of efficient stroke nanotherapeutics. Herein, we have developed an effective stroke treatment agent based on monodisperse ceria nanoparticles, which are loaded with edaravone and modified with Angiopep-2 and poly(ethylene glycol) on their surface (E-A/P-CeO 2 ). The as-designed E-A/P-CeO 2 features highly effective BBB crossing via receptor-mediated transcytosis to access brain tissues and synergistic elimination of ROS by both the loaded edaravone and ceria nanoparticles. As a result, the E-A/P-CeO 2 with low toxicity and excellent hemo/histocompatibility can be used to effectively treat strokes due to great intracephalic uptake enhancement and, in the meantime, effectively protect the BBB, holding great potentials in stroke therapy with much mitigated harmful side effects and sequelae.

Background: Alzheimer's disease (AD) is a devastating neurodegenerative disorder that lacks any disease-modifying drug for the prevention and treatment. Edaravone (EDR), an approved free radical scavenger, has proven to have potential against AD by targeting multiple key pathologies including amyloid-beta (Aβ), tau phosphorylation, oxidative stress, and neuroinflammation. To enable its oral use, novel edaravone formulation (NEF) was previously developed. The aim of the present investigation was to evaluate safety and efficacy of NEF by using in vitro/in vivo disease model., Materials and Methods: In vitro therapeutic potential of NEF over EDR was studied against the cytotoxicity induced by copper metal ion, H 2 O 2 and Aβ42 oligomer, and cellular uptake on SH-SY5Y695 amyloid-β precursor protein (APP) human neuroblastoma cell line. For in vivo safety and efficacy assessment, totally seven groups of APP/PS1 (five treatment groups, one each as a basal and sham control) and one group of C57BL/6 mice as a positive control for behavior tests were used. Three groups were orally treated for 3 months with NEF at an equivalent dose of EDR 46, 138, and 414 µmol/kg, whereas one group was supplied with each Donepezil (5.27 µM/kg) and Soluplus (amount present in NEF of 414 µmol/kg dose of EDR). Behavior tests were conducted to assess motor function (open-field), anxiety-related behavior (open-field), and cognitive function (novel objective recognition test, Y-maze, and Morris water maze). For the safety assessment, general behavior, adverse effects, and mortality were recorded during the treatment period. Moreover, biochemical, hematological, and morphological parameters were determined., Results: Compared to EDR, NEF showed superior cellular uptake and neuroprotective effect in SH-SY5Y695 APP cell line. Furthermore, it showed nontoxicity of NEF up to 414 µM/kg dose of EDR and its potential to reverse AD-like behavior deficits of APP/PS1 mice in a dose-dependent manner., Conclusion: Our results indicate that oral delivery of NEF holds a promise as a safe and effective therapeutic agent for AD., Competing Interests: Disclosure AP, XFZ, and SG are the named inventors of Chinese patent 200610149832.9. The authors report no other conflicts of interest in this work.

Background: Edaravone (EDR) is known for its free radical scavenging, antiapoptotic, antinecrotic, and anticytokine effects in neurological and non-neurological diseases. It is currently available clinically as Radicava ® and Radicut ® , intravenous medications, recently approved for the treatment of amyotrophic lateral sclerosis and cerebral infarction. However, the oral use of EDR is still restricted by its poor oral bioavailability (BA) due to poor aqueous solubility, stability, rapid metabolism, and low permeability. The present study reports the development of novel EDR formulation (NEF) using self-nanomicellizing solid dispersion (SNMSD) strategy with the aim to enable its oral use., Materials and Methods: The selection of a suitable carrier for the development of NEF was performed based on the miscibility study. The optimization of EDR-to-carrier ratio was conducted via kinetic solubility study after preparing SNMSDs using solvent evaporation technique. The drug-polymer carrier interaction and self-nanomicellizing properties of NEF were investigated with advanced characterization studies. In vitro permeation, metabolism, and dissolution study was carried out to examine the effect of the presence of a carrier on physico-chemical properties of EDR. Additionally, the dose-dependent pharmacokinetic study of NEF was conducted and compared with the EDR suspension., Results: Soluplus ® (SOL) as a carrier was selected based on the potential for improving aqueous solubility. The NEF containing EDR and SOL (1:5) resulted in the highest enhancement in aqueous solubility (17.53-fold) due to amorphization, hydrogen bonding interaction, and micellization. Moreover, the NEF demonstrated significant improvement in metabolism, permeability, and dissolution profile of EDR. Furthermore, the oral BA of NEF showed 10.2-, 16.1-, and 14.8-fold enhancement compared to EDR suspension at 46, 138, and 414 µmol/kg doses., Conclusion: The results demonstrated that SNMSD strategy could serve as a promising way to enhance EDR oral BA and NEF could be a potential candidate for the treatment of diseases in which oxidative stress plays a key role in their pathogenesis., Competing Interests: Disclosure AP, X-FZ, and SG are the named inventors of Chinese patent 200610149832.9. Fujian Kangshimei Co, China, owns the intellectual property. The authors report no other conflicts of interest in this work.