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Objective: This network meta-analysis aims to explore the efficacy and safety of neuroprotective agents in patients with ischemic stroke and attempts to identify which drug is the most effective in improving outcomes for patients with acute ischemic stroke (AIS) through a ranking method. Methods: We comprehensively searched the PubMed, Medline, Embase, Web of Science, and Cochrane library databases from their establishment to 30 June 2024. Data were extracted from the studies identified, and their quality was assessed using the Cochrane risk-of-bias tool or the Newcastle–Ottawa Scale (NOS). The outcome measures were for a favorable prognosis, based on the modified Rankin Scale score (mRS) or National Institutes of Health Stroker Scale (NIHSS) score, mortality, and adverse effect with different drug regimens. We utilized Stata version 16.0 and Review Manager (RevMan) version 5.3.0 for statistical analysis. Results: A total of 35 studies were included: 25 randomized control trials, eight retrospective studies, and two prospective studies. The total sample size was 18,423 cases and included nine interventions: citicoline, edaravone (EDV), edaravone dexborneol, cinepazide maleate, cerebrolysin, minocycline, ginkgolide, ginkgo diterpene lactone meglumine (GDLM), and conventional (CON) treatment. Our analysis revealed that, except for edaravone dexborneol, the ginkgolide, EDV, cinepazide maleate, citicoline, cerebrolysin, minocycline, and GDLM treatment schemes reduced the mortality of patients with AIS compared with CON. Each drug regimen significantly improved the neural function of these patients compared with CON, which from highest to lowest was citicoline + vinpocetine, GDLM, citicoline, edaravone dexborneol, cinepazide maleate, ginkgolide, EDV, and CON. Moreover, we also found that, except for citicoline, the ginkgolide, EDV, edaravone dexborneol, GDLM, and cinepazide maleate treatment schemes had a high total treatment effective rate in these patients, the order from highest to lowest being ginkgolide, EDV, edaravone dexborneol, GDLM, cinepazide maleate, CON, and citicoline. In terms of the ineffective rate, we found that, compared with CON, the edaravone dexborneol, EDV, citicoline, GDLM, ginkgolide, and cinepazide maleate treatment schemes all had a lower ineffective rate. Finally, our analysis revealed that, except for cinepazide maleate and ginkgolide, the EDV, minocycline, edaravone dexborneol, GDLM, citicoline, and cerebrolysin schemes all had a higher rate of adverse effect on patients compared to CON. Based on the impact of the adverse effect with different surgical interventions, we further analyzed the effect of these drug treatments by the total treatment effective rate combined with adverse effect, revealing that EDV, ginkgolide, and edaravone dexborneol were the safest and most effective treatments. Conclusion: In patients with AIS, ginkgolide, EDV, cinepazide maleate, citicoline, cerebrolysin, minocycline, and GDLM were associated with a reduction in mortality rate. Moreover, ginkgolide, EDV, edaravone dexborneol, and GDLM treatment schemes revealed not only a high total treatment effective rate but also a low rate of treatment inefficacy. When considering the combination of the total treatment effective rate with adverse effect, EDV, ginkgolide, and edaravone dexborneol were revealed as the safest and most effective. [ABSTRACT FROM AUTHOR]

Background and objective: This study aimed to assess the protective ability of edaravone on testicular torsion–detorsion injury in rats. Methods: Eighteen adult male Sprague–Dawley rats were randomly divided into three groups: Sham group (control, n = 6); testicular torsion/detorsion (T/D group, n = 6) and T/D+edaravone (T/D+E group, n = 6). The spermatic cords of rats of the T/D group and the T/D+E group were rotated 720° in a clockwise direction and maintained for 120 min in this torsion position. Around 90 min after the torsion, edaravone at a dose of 10 mg/kg dissolved in saline was administered IP to the T/D+E group. The testicle was counter‐rotated to its normal position to allow reperfusion for 4 h. Left testes of each animal were excised 240 min after beginning of reperfusion. Oxidative stress markers (TAS, TOS, SOD, and MDA) and apoptotic pathways (Caspase 3, Caspase 8, Caspase 9, Bcl‐2, and Bax,) were assessed by ELISA methods. Also, testicles were subjected to the histopathologic and ultrasound examinations. Results: Ultrasound imaging showed that edaravone reduced the surface area and increased vascularization in testicles with T/D (p < 0.0001, p < 0.05, respectively). Edaravone pretreatment markedly decreased the levels of MDA, TOS, Bcl‐2, Bax, Caspase 3, Caspase 8, and Caspase 9 (p < 0.0001). Also, it increased significantly TAS levels (p < 0.0001) and reduced insignificantly SOD activity. Histopathologic examinations demonstrated that edaravone significantly attenuated the histological damage caused by T/D in testicles. Conclusion: Taken together, the findings indicate that pretreatment of edaravone has protective effect against testicular T/D injury. [ABSTRACT FROM AUTHOR]

Renal fibrosis is the common endpoint of nearly all chronic and progressive nephropathies. Cell death and sterile inflammation are the main characteristics of renal fibrosis, which can lead to end-stage renal failure. The inflammatory reaction triggered by tissue damage is strongly related to necroptosis, a type of caspase-independent, regulated cell death. Using an animal model of unilateral ureteral obstruction (UUO), the anti-fibrotic effects of sorafenib (SOF), a multi-kinase inhibitor, and edaravone (EDV), a potent antioxidant and free radical scavenger, were examined in rats with obstructive nephropathy. Experimentally, animals were divided randomly into five groups: sham; UUO; UUO + SOF (5 mg/kg/day, P.O.); UUO + EDV (20 mg/kg/day, P.O.); and UUO + SOF + EDV groups. The kidney function biomarkers, oxidant/antioxidant status, renal mRNA expressions of TNF-α, collagen-1α, protein expressions of RIPK-1, RIPK-3, MLKL, caspase-8, HYP, MPO, and TNF-α were all significantly modulated by UUO. Administration of either SOF or EDV significantly attenuated cellular and molecular changes induced by UUO. Also, histopathological changes were improved. Moreover, SOF in combination with EDV, significantly improved UUO-induced renal fibrosis compared with each drug alone. Collectively, administration of either SOF or EDV or both of them significantly attenuated the rats with obstructive nephropathy, possibly by blocking the RIPK-3/MLKL necroptotic pathway and suppressing renal oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]

With the severity of chronic kidney disease worldwide, strategies to recover renal function via tissue regeneration provide alternatives to kidney replacement therapy. To exclude side effects from direct cell transplantation, extracellular vesicles (EVs) are great substitutes representing paracrine cell signaling. To build three-dimensional structures for implantation into the 5/6 nephrectomy model by incorporating bioactive materials, including multifunctional EVs (mEVs), porous PMEZE/mEV scaffolds were developed in combination with edaravone (EDV; E) and mEV based on PMEZ scaffolds with PLGA (P), MH-RA (M), ECM (E), ZnO-ALA (Z). The oxygen free radical scavenger EDV was incorporated to induce tubular regeneration. mEVs were engineered to serve regenerative activities with a combination of two EVs from SDF-1α overexpressed tonsil-derived mesenchymal stem cells (sEVs) and intermediate mesoderm (IM) cells during differentiation into kidney progenitor cells (dEVs). mEVs displayed beneficial effects on regeneration by facilitating migration and inducing differentiation of surrounding stem cells, and EDV improved kidney function by regulating the GDNF/RET pathway and their downstream genes. The promotion of MSC recruitment was confirmed with sEV particles number dependently, and the regulation of the GDNF/RET pathway by the effect of EDV and its enhanced effect by mEVs were elucidated using in vitro analysis. The regeneration of tubules was additionally demonstrated through the increased expression of aquaporin-1 (AQP-1) and cadherin-16 (CDH16) for proximal tubules, and calbindin and PAX2 for distal tubules in the renal defect model. With these, structural regeneration and functional recovery were achieved with kidney regeneration in the 5/6 nephrectomy mice model. [ABSTRACT FROM AUTHOR]

Oxidative stress (OS) is the main cause of secondary damage following intracerebral hemorrhage (ICH). The polarity expression of aquaporin-4 (AQP4) has been shown to be important in maintaining the homeostasis of water transport and preventing post-injury brain edema in various neurological disorders. This study primarily aimed to investigate the effect of the oxygen free radical scavenger, edaravone, on AQP4 polarity expression in an ICH mouse model and determine whether it involves in AQP4 polarity expression via the OS/MMP9/β-dystroglycan (β-DG) pathway. The ICH mouse model was established by autologous blood injection into the basal nucleus. Edaravone or the specific inhibitor of matrix metalloproteinase 9 (MMP9), MMP9-IN-1, called MMP9-inh was administered 10 min after ICH via intraperitoneal injection. ELISA detection, neurobehavioral tests, dihydroethidium staining (DHE staining), intracisternal tracer infusion, hematoxylin and eosin (HE) staining, immunofluorescence staining, western blotting, Evans blue (EB) permeability assay, and brain water content test were performed. The results showed that OS was exacerbated, AQP4 polarity was lost, drainage function of brain fluids was damaged, brain injury was aggravated, expression of AQP4, MMP9, and GFAP increased, while the expression of β-DG decreased after ICH. Edaravone reduced OS, restored brain drainage function, reduced brain injury, and downregulated the expression of AQP4, MMP9. Both edaravone and MMP9-inh alleviated brain edema, maintained blood–brain barrier (BBB) integrity, mitigated the loss of AQP4 polarity, downregulated GFAP expression, and upregulated β-DG expression. The current study suggests that edaravone can maintain AQP4 polarity expression by inhibiting the OS /MMP9/β-DG pathway after ICH. [ABSTRACT FROM AUTHOR]

Purpose: To study the impact of edaravone in combination with edaravone and recombinant tissue plasminogen activator (rt-PA) intravenous thrombolysis on serum inflammatory factors in ischemic stroke subjects. Methods: Eighty ischemic stroke patients in the First Affiliated Hospital of Xi'an Medical University, Xi'an, China were randomly assigned to study and control cohorts, each with 40 subjects. Patients in control cohort were administered edaravone and rt-PA intravenous thrombolysis. The study cohort received butylphthalide in combination with edaravone and rt-PA intravenous thrombolysis. Treatment effectiveness/efficacy, neurological function, self-care ability, inflammatory indicator levels, and blood cell levels were compared between the 2 cohorts. Results: Efficacy was significantly better in the study cohort than in the control cohort (p < 0.05). After treatment, NIHSS score was significantly lower in the study cohort than in control cohort, while ADL score was significantly higher in the study cohort (p < 0.05). After medication, CRP level was decreased significantly in both cohorts, but was significantly lower level in the study cohort (p < 0.05). Treatment led to significant reductions in white blood cell count, neutrophil count, and NLR ratio in the study cohort, relative to the control cohort (p < 0.05). Conclusion: The use of butylphthalide in combination with edaravone and rt-PA intravenous thrombolysis produces significant and beneficial effects on ischemic stroke subjects by regulating abnormal levels of inflammatory cells, improving coagulation status and decreasing inflammation. Moreover, it ameliorates neurological defects and improves activities of daily living. There is, however, a need to determine the mechanisms of action of this combination therapy and the influence of other cofounding factors on the activities of the combination therapy. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the inhibitory effect of edaravone (EDR) lotion on chemotherapy-induced alopecia (CIA) to improve the quality of life for patients with cancer. Methods: Wistar rats were intraperitoneally injected with cyclophosphamide (CPA, 75 mg/kg) to induce CIA and divided into six groups: (1) Control; (2) EDR 0%; (3) EDR 0.3%; (4) EDR 3%. The TUNEL-positive area was examined histologically, and mRNA expression levels of the apoptosis-related factors, such as B-cell/CLL lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax), were determined. Results: In the three CPA-treated groups, a decrease in the coverage score (percentage of hairs covered) was observed from days 16 to 18. In addition, coverage scores on day 21, the last day of observation, showed a tendency for the suppression of hair loss to increase, though hair loss was observed in all groups. The coverage scores of the EDR 0.3% and 3% groups after day 17 were significantly higher than those of the EDR 0% group. The TUNEL-positive area of skin tissue on day 16 was extensive in the EDR 0% group and decreased in the EDR 0.3% and 3% groups. The mRNA expression ratio of Bcl-2/Bax on day 21 was maintained at the same level as that of the control group only in the EDR 3% group. Conclusion: This study confirmed the use of EDR lotion to inhibit hair loss, indicating that the clinical application of EDR lotion may improve the quality of life for patients with cancer and their willingness to undergo treatment. [ABSTRACT FROM AUTHOR]

In recent years, the presence of Pharmaceutical Active Compounds (PhACs) in ecosystems has become a serious environmental problem due to their capacity to induce harmful effects at extremely low concentrations in both humans and wildlife. Water treatment plants have not been designed to remove these types of compounds efficiently. Thus, the detection of these pollutants is essential to evaluate their negative impacts and is one of the emerging issues in environmental chemistry. The main objective of this study is to determine the bacterial toxicity of two PhACs (both individually and as a mixture) through the quantification of bioluminescence inhibition in the marine bacteria Aliivibrio fischeri, a commonly used method in short-term toxicity tests. In this work, Acetaminophen and Edaravone, two drugs approved by the Food and Drug Administration, have been studied. The acute toxicity of these PhACs has been tested at two exposure times (5 and 15 min) and different concentrations, by estimation of the median effective concentration (EC50) for each individual compound or in combination at different concentrations. Moreover, the EC50 of the binary mixtures Acetaminophen/Edaravone have been forecast using two traditional predictive models, Concentration Addition and Independent Action. The results show that toxicity decreases with exposure time and depends on the concentration tested. Furthermore, a novel semi-empirical Van Laar-based model has been proposed and validated with the experimental data from this study and literature data, obtaining satisfactory estimations of the EC50 for binary mixtures. Highlights: The bacterial toxicity of Acetaminophen and Edaravone, as well as their binary mixtures, was evaluated using an Aliivibrio fischeri bioluminescence assay. The predictive power of Concentration Addition and Independent Action models was evaluated for combined bacterial toxicity of PhACs. A new semi-empirical Van Laar-based model was developed and validated to predict the bacterial toxicity of binary mixtures of Acetaminophen and Edaravone, providing accurate estimations with limited experimentation. [ABSTRACT FROM AUTHOR]

Abstract 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.

Abstract With the severity of chronic kidney disease worldwide, strategies to recover renal function via tissue regeneration provide alternatives to kidney replacement therapy. To exclude side effects from direct cell transplantation, extracellular vesicles (EVs) are great substitutes representing paracrine cell signaling. To build three-dimensional structures for implantation into the 5/6 nephrectomy model by incorporating bioactive materials, including multifunctional EVs (mEVs), porous PMEZE/mEV scaffolds were developed in combination with edaravone (EDV; E) and mEV based on PMEZ scaffolds with PLGA (P), MH-RA (M), ECM (E), ZnO-ALA (Z). The oxygen free radical scavenger EDV was incorporated to induce tubular regeneration. mEVs were engineered to serve regenerative activities with a combination of two EVs from SDF-1α overexpressed tonsil-derived mesenchymal stem cells (sEVs) and intermediate mesoderm (IM) cells during differentiation into kidney progenitor cells (dEVs). mEVs displayed beneficial effects on regeneration by facilitating migration and inducing differentiation of surrounding stem cells, and EDV improved kidney function by regulating the GDNF/RET pathway and their downstream genes. The promotion of MSC recruitment was confirmed with sEV particles number dependently, and the regulation of the GDNF/RET pathway by the effect of EDV and its enhanced effect by mEVs were elucidated using in vitro analysis. The regeneration of tubules was additionally demonstrated through the increased expression of aquaporin-1 (AQP-1) and cadherin-16 (CDH16) for proximal tubules, and calbindin and PAX2 for distal tubules in the renal defect model. With these, structural regeneration and functional recovery were achieved with kidney regeneration in the 5/6 nephrectomy mice model. Graphical abstract

Ma Huang,1,&ast; Yalan Mo,2,&ast; Haiyun Lei,1,&ast; Miao Chen1 1Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China; 2Centre for Infectious Diseases, General Hospital of Hunan Medical College, Huaihua, Hunan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Miao Chen, Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi City, Gui Zhou, People’s Republic of China, Tel +8613595248166, Email chenmiao64@163.comAbstract: Despite technological advances in science and medicine, acute lung injury (ALI) is still associated with high mortality rates in the ICU. Therefore, finding novel drugs and treatment approaches is crucial to preventing ALI. Drug repurposing is a common practice in clinical research, primarily for drugs that have previously received approval for use in patients, to investigate novel uses of drugs and therapies. One such medication is edaravone, which is a highly effective free-radical scavenger that also has anti-inflammatory, anti-apoptotic, antioxidant, and anti-fibrotic effects. Both basic and clinical studies have shown that edaravone can treat different types of lung injury through its distinct properties. Edaravone exhibits significant protective benefits and holds promising clinical treatment potential for ALI caused by diverse factors, thereby offering a novel approach to treating ALI. This study aims to provide new insights and treatment options for ALI by reviewing both basic and clinical research on the use of edaravone. The focus is on evaluating the effectiveness of edaravone in treating ALI caused by various factors. Keywords: acute lung injury, edaravone, oxidative stress, inflammation, apoptosis, fibrosis

OBJECTIVE: To probe into the role of clinical pharmacists’ intervention in improving the application rationality of edaravone and dexborneol concentrated solution for injection in patients with stroke and its effects on diagnosis-related groups (DRG) payment. METHODS: Related information of patients with stroke who received treatment and were given edaravone and dexborneol concentrated solution for injection in Guangyuan Central Hospital from Sept. 2022 to Jun. 2023 were retrospectively analyzed, 147 patients before intervention (from Sept. 1st, 2022 to Feb. 24th, 2023) and 149 patients after intervention (from Feb. 25th to Jun. 30th, 2023) by clinical pharmacists were enrolled to compare the incidences of irrational medical orders and adverse drug reactions before and after the intervention, as well as the average length of stay, drug costs, hospitalization costs and profit / loss after DRG payment. RESULTS: After intervention, the incidence of irrational medical orders was 19. 46% (29 / 149), lower than that before intervention (80. 95%, 119 / 147). After intervention, 1 patient had adverse drug reactions, less than 5 patients before intervention. After intervention, the average length of stay was 10. 56 d, shorter than 12. 60 d of before intervention. The average drug cost, average hospitalization cost and profit / loss after DRG payment were 7 300. 07 RMB, 28 592. 75 RMB and 3 347. 83 RMB loss, respectively, which were lower than 9 437. 71 RMB, 34 740. 39 RMB and 4 408. 02 RMB loss before intervention, the differences were statistically significant (P < 0. 05). CONCLUSIONS: Clinical pharmacists’ intervention on the application of edaravone and dexborneol concentrated solution for injection in patients with stoke has higher positive effect, which can reduce the occurrence of irrational medical orders and adverse drug reactions, relieve the economic burden of patients to a certain extent, and play a positive role in cost control of hospitals under the DRG payment model. [ABSTRACT FROM AUTHOR]

Edaravone is one of two main drugs for treating motor neurone disease (MND). This review proposes a specific quality target product profile (QTPP) for edaravone following an appraisal of the issues accounting for the poor clinical uptake of the approved IV and oral liquid edaravone formulations. This is followed by a review of the alternative oral formulations of edaravone described in the published patent and journal literature against the QTPP. A total of 14 texts published by six research groups on 18 novel oral formulations of edaravone for the treatment of MND have been reviewed. The alternative oral formulations included liquid and solid formulations developed with cyclodextrins, lipids, surfactants, co-surfactants, alkalising agents, tablet excipients, and co-solvents. Most were intended to deliver edaravone for drug absorption in the lower gastrointestinal tract (GIT); however, there were also four formulations targeting the oral mucosal absorption of edaravone to avoid first-pass metabolism. All the novel formulations improved the aqueous solubility, stability, and oral bioavailability (BA) of edaravone compared to an aqueous suspension of edaravone. A common limitation of the published formulations is the lack of MND-patient-centred data. Except for TW001, no other formulations have been trialled in MND patients. To meet the QTPP of an oral edaravone formulation for MND patients, it is recommended that a tablet of appropriate size and with acceptable taste and stability be designed for the effective sublingual or buccal absorption of edaravone. This tablet should be designed with input from the MND community. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• The combination of edaravone and hyperbaric oxygen therapy can improve the cognitive of patients with delayed encephalopathy after carbon monoxide poisoning compared to hyperbaric oxygen therapy alone. • The combination of edaravone and hyperbaric oxygen therapy can improve activity of daily living of patients with delayed encephalopathy after carbon monoxide poisoning compared to hyperbaric oxygen therapy alone. • The combination of edaravone and hyperbaric oxygen therapy can improve markers of oxidative stress of patients with delayed encephalopathy after carbon monoxide poisoning compared to hyperbaric oxygen therapy alone. The use of both edaravone (EDA) and hyperbaric oxygen therapy (HBOT) is increasingly prevalent in the treatment of delayed encephalopathy after carbon monoxide poisoning (DEACMP). This meta -analysis aims to evaluate the efficacy of using EDA and HBOT in combination with HBOT alone in the treatment of DEACMP. We searched and included all randomized controlled trials (RCTs) published before November 6, 2023, from 12 Chinese and English databases and clinical trial centers in China and the United States. The main outcome indicator was the total effective rate. The secondary outcome indicators included the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI), Hasegawa Dementia Scale (HDS), Fugl-Meyer Assessment (FMA), Superoxide Dismutase (SOD), and Malondialdehyde (MDA). Statistical measures utilized include risk ratios (RR), weighted mean difference (WMD), and 95 % confidence intervals (95 % CI). Thirty studies involving a combined total of 2075 participants were ultimately incorporated. It was observed that the combination of EDA with HBOT for the treatment of DEACMP demonstrated an improvement in the total effective rate (RR: 1.25; 95 % CI: 1.20–1.31; P < 0.01), MMSE (WMD: 3.67; 95 % CI: 2.59–4.76; P < 0.01), MoCA (WMD: 4.38; 95 % CI: 4.00–4.76; P < 0.01), BI (WMD: 10.94; 95 % CI: 5.23–16.66; P < 0.01), HDS (WMD: 6.80; 95 % CI: 4.05–9.55; P < 0.01), FMA (WMD: 8.91; 95 % CI: 7.22–10.60; P < 0.01), SOD (WMD: 18.45; 95 % CI: 16.93–19.98; P < 0.01); and a reduction in NIHSS (WMD: −4.12; 95 % CI: −4.93 to –3.30; P < 0.01) and MDA (WMD: −3.05; 95 % CI: −3.43 to –2.68; P < 0.01). Low-quality evidence suggests that for DEACMP, compared to using HBOT alone, the combined use of EDA and HBOT may be associated with better cognition and activity of daily living. In the future, conducting more meticulously designed multicenter and large-sample RCTs to substantiate our conclusions is essential. [ABSTRACT FROM AUTHOR]

Three new prenylated dihydroflavones, moralbaflavones A–C (1–3), together with four known ones (4a/4b, 5, and 6) were isolated from the root barks of Morus alba L. Their structures including the absolute configurations were determined by the analysis of HRMS, NMR, and ECD data. The neuroprotective properties of these prenylated dihydroflavones were screened at the concentration of 10 µM in the sodium nitroprusside-induced rat pheochromocytoma PC-12 cells, and the results showed moralbaflavone C (3) possessed significant neuroprotective activity, being more potent than the positive control edaravone. [ABSTRACT FROM AUTHOR]

Cardiotoxicity is a significant adverse effect of cisplatin (CIS) that necessitates extensive medical care. The current study examines the cardioprotective effects of edaravone (EDV), obeticholic acid (OCA), and their combinations on CIS-induced cardiac damage. Rats were allocated into five groups: the normal control group, the remaining four groups received CIS (7.5 mg/kg, i.p.) as a single dose on the fifth day and were assigned to CIS, OCA (10 mg/kg/day) + CIS, EDV (20 mg/kg/day) + CIS, and the (EDV + OCA) + CIS group. Compared to the CIS-treated group, co-treating rats with EDV, OCA, or their combinations significantly decreased ALP, AST, LDH, CK-MB, and troponin-I serum levels and alleviated histopathological heart abnormalities. Biochemically, EDV, OCA, and EDV plus OCA administration mitigated cardiac oxidative stress as indicated by a marked decrease in heart MDA content with a rise in cardiac antioxidants SOD and GSH associated with upregulating Nrf2, PPARγ, and SIRT1 expression. Besides, it dampened inflammation by decreasing cardiac levels of TNF-α, IL-1β, and IL-6, mediated by suppressing NF-κB, JAK1/STAT3, and TLR4/p38MAPK signal activation. Notably, rats co-administered with EDV plus OCA showed noticeable protection that exceeded that of EDV and OCA alone. In conclusion, our study provided that EDV, OCA, and their combinations effectively attenuated CIS-induced cardiac intoxication by activating Nrf2, PPARγ, and SIRT1 signals and downregulating NF-κB, JAK1/STAT3, and TLR4/p38MAPK signals. Outlined diagram summarized the possible protective mechanisms of OCA and/or EDV against cisplatin-induced cardiac injury [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Subarachnoid hemorrhage (SAH) serves as a disease characterized by high incidence rate, which is exceedingly prevalent and severe. Presently, there is no unambiguous or efficacious intervention for the neurological impairment following SAH. Administering multi-targeted neuroprotective agents to reduce oxidative stress (OS) and neuroinflammation caused by early brain injury (EBI) has been demonstrated to improve neurological function and prognosis following SAH. Edaravone dexborneol (EDB), a novel multi targeted neuroprotective medication, combines four parts edaravone (EDA) with 1 part (+)-borneol in proportion. Clinical trials conducted in China have revealed during 2 days of acute ischemic stroke (AIS), early administration of EDB leads to improved therapeutic outcomes compared to treatment in EDA monotherapy. Currently, there is no clear evidence that EDB can effectively treat SAH, therefore, our study aims to investigate its potential therapeutic effects and mechanisms on EBI after SAH. Method: We used the intravascular threading method to establish a mouse model of SAH to explore whether EDA and EDB could produce anti-OS and antiapoptosis effects. Behavioral assessment of mice was conducted using the balance beam experiment and the modified Garcia scoring system. Neuronal damage due to OS and Keap1/Nrf2 signaling pathway were detected through techniques of immunofluorescence, Western blotting, spectrophotometry. The group of EDA and EDB were injected intraperitoneally for 72 h after SAH. Results: The experiment results indicated that EDB lead to remarkably positive results by significantly enhancing neurological function, reducing blood-brain barrier (BBB) injury, and effectively inhibiting neuronal apoptosis after SAH. Further examination indicated EDB significantly reduced the expression of Keap1 and increased the expression of Nrf2, and it inhibited MDA, and enhanced SOD activity after SAH. These outcomes surpassed the effectiveness observed in EDA monotherapy. However, the application of ML385 reversed the anti-OS effects of EDB and EDA. Conclusion: Our experimental findings indicated that EDB could activate Keap1/Nrf2 signaling pathway to reduce OS damage, thereby protecting neurological function and enhancing behavioral abilities after SAH. These outcomes could facilitate the creation of new approaches for the clinical management of SAH. [ABSTRACT FROM AUTHOR]

Objective To explore the efficacy of probucol combined with edaravone in patients with cerebral ischemic stroke ( CIS), and the influence on their hemodynamics and neurological function. Methods We retrospectively selected 82 CIS patients as research subjects; they were divided into control group and observation group according to different therapeutic regimens, each with 41 cases. The control group was treated with edaravone while the observation group was treated with edaravone plus probucol. Patients of the two groups were continuously reated for 14 days. The clinical efficacy, National Institute of Health stroke scale (NIHSS) score, modified Barthel index (mBI), mini-mental state examination (MMSE) score, the average velocity (Vm), difference in symmetry of peak flow velocity (DVp), difference in symmetry of average flow velocity (DVm) and peak flow rate (Vp) of the middle cerebral artery, serum Occludin, high sensitivity C reactive protein (hs-CRP), matrix metalloproteinase (MMP)-9 and omentin-1, and the occurrence of adverse reactions were compared between the two groups. Results The total effective rate of the observation group was higher than that of the control group after treatment (92. 68% vs. 75. 61%,P<0. 05). The mBI and MMSE scores of the observation group were higher than those of the control group after treatment while NIHSS score was lower ( P < 0. 01); the Vm and Vp of the middle cerebral artery, and omentin-1 level were all higher than those of the control group while DVp, DVm, and serum Occludin, hs-CRP and MMP-9 levels were all lower than those of the control group (P<0. 05). The incidence of adverse reactions did not vary significantly between the two groups ( P > 0. 05). Conclusion Probucol combined with edaravone shows definite efficacy on CIS, which improves patients􀆳 cerebral hemodynamics, inhibits inflammatory reaction, and relieves neural dysfunction with high safety. [ABSTRACT FROM AUTHOR]

ObjectiveThis network meta-analysis aims to explore the efficacy and safety of neuroprotective agents in patients with ischemic stroke and attempts to identify which drug is the most effective in improving outcomes for patients with acute ischemic stroke (AIS) through a ranking method.MethodsWe comprehensively searched the PubMed, Medline, Embase, Web of Science, and Cochrane library databases from their establishment to 30 June 2024. Data were extracted from the studies identified, and their quality was assessed using the Cochrane risk-of-bias tool or the Newcastle–Ottawa Scale (NOS). The outcome measures were for a favorable prognosis, based on the modified Rankin Scale score (mRS) or National Institutes of Health Stroker Scale (NIHSS) score, mortality, and adverse effect with different drug regimens. We utilized Stata version 16.0 and Review Manager (RevMan) version 5.3.0 for statistical analysis.ResultsA total of 35 studies were included: 25 randomized control trials, eight retrospective studies, and two prospective studies. The total sample size was 18,423 cases and included nine interventions: citicoline, edaravone (EDV), edaravone dexborneol, cinepazide maleate, cerebrolysin, minocycline, ginkgolide, ginkgo diterpene lactone meglumine (GDLM), and conventional (CON) treatment. Our analysis revealed that, except for edaravone dexborneol, the ginkgolide, EDV, cinepazide maleate, citicoline, cerebrolysin, minocycline, and GDLM treatment schemes reduced the mortality of patients with AIS compared with CON. Each drug regimen significantly improved the neural function of these patients compared with CON, which from highest to lowest was citicoline + vinpocetine, GDLM, citicoline, edaravone dexborneol, cinepazide maleate, ginkgolide, EDV, and CON. Moreover, we also found that, except for citicoline, the ginkgolide, EDV, edaravone dexborneol, GDLM, and cinepazide maleate treatment schemes had a high total treatment effective rate in these patients, the order from highest to lowest being ginkgolide, EDV, edaravone dexborneol, GDLM, cinepazide maleate, CON, and citicoline. In terms of the ineffective rate, we found that, compared with CON, the edaravone dexborneol, EDV, citicoline, GDLM, ginkgolide, and cinepazide maleate treatment schemes all had a lower ineffective rate. Finally, our analysis revealed that, except for cinepazide maleate and ginkgolide, the EDV, minocycline, edaravone dexborneol, GDLM, citicoline, and cerebrolysin schemes all had a higher rate of adverse effect on patients compared to CON. Based on the impact of the adverse effect with different surgical interventions, we further analyzed the effect of these drug treatments by the total treatment effective rate combined with adverse effect, revealing that EDV, ginkgolide, and edaravone dexborneol were the safest and most effective treatments.ConclusionIn patients with AIS, ginkgolide, EDV, cinepazide maleate, citicoline, cerebrolysin, minocycline, and GDLM were associated with a reduction in mortality rate. Moreover, ginkgolide, EDV, edaravone dexborneol, and GDLM treatment schemes revealed not only a high total treatment effective rate but also a low rate of treatment inefficacy. When considering the combination of the total treatment effective rate with adverse effect, EDV, ginkgolide, and edaravone dexborneol were revealed as the safest and most effective.

Background and Aim: Edaravone is known for its efficacy in inhibiting free radical formation, activating microglia, and promoting neurogenesis and neuroprotection following acute ischemic stroke. This clinical trial aimed to investigate the effects of Edaravone on clinical symptoms and oxidative stress factors in patients with acute ischemic stroke. Methods: In this clinical trial, fifty-two patients diagnosed with acute ischemic stroke were randomly assigned to receive either Edaravone (120 mg daily up to 3 doses intravenously) or a placebo in addition to standard treatment. Stroke severity was assessed using the NIH Stroke Scale (NIHSS) and Modified Rankin Scale (MRS) at hospitalization and three months post-stroke. Antioxidant capacity, protein oxidation, and lipid peroxidation levels were measured during hospitalization and three days later. Results: Twenty-six patients were included in each group and were matched in terms of risk factors, neurological symptom severity, antioxidant capacity, protein oxidation, and lipid peroxidation at hospitalization. At the three-month follow-up, both groups showed a decrease in neurological symptom severity, with a slightly higher reduction observed in the Edaravone group, though not statistically significant (P=0.256). A similar proportion of patients achieved an MRS score of ≤2 within three months post-stroke in both groups (23.1% in the placebo group vs. 30.8% in the Edaravone group, P=0.755). All eight deaths within the first three months occurred in the placebo group. The most common side effect was intracerebral hemorrhage (13.5%), predominantly in the placebo group. Despite higher mean antioxidant capacities in the intervention group, no significant difference was observed post-intervention. Conclusion: The study suggests that adding Edaravone to standard treatment for acute ischemic stroke may lead to improved patient outcomes. However, further research with larger sample sizes is needed to establish the efficacy of this medication.

DISCLOSURES: Funding for this summary was contributed by Blue Cross Blue Shield of MA, California Healthcare Foundation, The Patrick and Catherine Weldon Donaghue Medical Research Foundation, Arnold Ventures, and Kaiser Foundation Health Plan Inc., to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, AbbVie, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy Solutions, Express Scripts, Genentech/ Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health First, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer. Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, Sun Life Financial, uniQure, and United Healthcare. Mr Nikitin, Ms McKenna, Ms Richardson, and Drs Rind and Pearson are employed by ICER. Through their affiliated institutions, Drs Makam, Carlson, and Suh received funding from ICER for the work described in this summary.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegeneration involving motor neurons. The 3-5 years that patients have to live is marked by day-to-day loss of motor and sometimes cognitive abilities. Enormous amounts of healthcare services and resources are necessary to support patients and their caregivers during this relatively short but burdensome journey. Organization and management of these resources need to best meet patients' expectations and health system efficiency mandates. This can only occur in the setting of multidisciplinary ALS clinics which are known as the gold standard of ALS care worldwide. To introduce this standard to the care of Iranian ALS patients, which is an inevitable quality milestone, a national ALS clinical practice guideline is the necessary first step. The National ALS guideline will serve as the knowledge base for the development of local clinical pathways to guide patient journeys in multidisciplinary ALS clinics. To this end, we gathered a team of national neuromuscular experts as well as experts in related specialties necessary for delivering multidisciplinary care to ALS patients to develop the Iranian ALS clinical practice guideline. Clinical questions were prepared in the Patient, Intervention, Comparison, and Outcome (PICO) format to serve as a guide for the literature search. Considering the lack of adequate national/local studies at this time, a consensus-based approach was taken to evaluate the quality of the retrieved evidence and summarize recommendations.

Objective: This study aimed to evaluate the efficacy of combining diterpene ginkgolide meglumine injection (DGMI) with edaravone for the treatment of acute ischemic stroke. This is particularly relevant because Western drugs, excluding intravenous thrombolysis, have shown limited success. Methods: A comprehensive search was conducted using multiple databases, including PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure WanFang, VIP, and Chinese Biomedical Database (CBM) until June 2023. The data were analyzed using fixed-effects and random-effects models in Review Manager. The mean difference with 95% confidence interval was calculated for each outcome. Results: Eighteen studies involving 1,636 participants were included in the analysis. The DGMI group showed significant reductions in the National Institutes of Health Stroke Scale (NIHSS) score, modified Rankin Scale (mRS) score, and C-reactive protein (CRP) level, compared to the control group. Furthermore, the DGMI group showed a significant improvement in superoxide dismutase (SOD) levels and a reduction in malondialdehyde (MDA) levels. The combination of DGMI and edaravone was more effective in reducing neuron-specific enolase (NSE) levels following brain tissue injury than edaravone alone. Additionally, DGMI complemented edaravone in reducing rheological parameters associated with ischemic stroke, including hematocrit, plasma viscosity, platelet adhesion rate, and erythrocyte deformation index. Conclusion: The combination of DGMI and edaravone significantly improved the therapeutic efficacy in patients with acute ischemic stroke. However, more extensive and high-quality clinical trials are required to validate these underlying mechanisms. [ABSTRACT FROM AUTHOR]

Ferroptosis has recently been recognized as a mechanism of cerebral ischemia-reperfusion (I/R) injury, attributed to blood-brain barrier (BBB) disruption. Edaravone dexboneol (Eda.B) is a novel neuroprotective agent widely employed in ischemic stroke, which is composed of edaravone (Eda) and dexborneol. This study aimed to investigate the protective effects of Eda.B on the BBB in cerebral I/R and explore its potential mechanisms. Transient middle cerebral artery occlusion (tMCAO) Sprague-Dawley-rats model was used. Rats were randomly assigned to sham-operated group (sham, n = 20), model group (tMCAO, n = 20), Eda.B group (Eda.B, n = 20), Eda group (Eda, n = 20) and dexborneol group (dexborneol, n = 20), and Eda.B + Zinc protoporphyria group (Eda.B + ZnPP, n = 5). Infarct area, cellular apoptosis and neurofunctional recovery were accessed through TTC staining, TUNEL staining, and modified Garcia scoring system, respectively. BBB integrity was evaluated via Evans blue staining. Nuclear factor E2 related factor 2 (Nrf-2)/heme oxygenase 1 (HO-1)/glutathione peroxidase 4 (GPX4) signaling were qualified by Western blot. Transmission electron microscopy (TEM) revealed alterations in ipsilateral brain tissue among groups. Glutathione (GSH) and malondialdehyde (MDA) levels, and Fe2+ tissue content determination were detected. Eda.B effectively improved neurological deficits, diminished infarct area and cellular apoptosis, as well as ameliorated BBB integrity in tMCAO rats. Further, Eda.B significantly inhibited ferroptosis, as evidenced by ameliorated pathological features of mitochondria, down-regulated of MDA and Fe2+ levels and up-regulated GSH content. Mechanistically, Eda.B attenuated BBB disruption via Nrf-2-mediated ferroptosis, promoting nuclear translocation of Nrf-2, increasing HO-1, GPX4 expression, alleviating the loss of zonula occludens 1 (ZO-1) and occludin as well as decreasing 4-hydroxynonenal (4-HNE) level. This study revealed for the first time that Eda.B safeguarded the BBB from cerebral I/R injury by inhibiting ferroptosis through the activation of the Nrf-2/HO-1/GPX4 axis, providing a novel insight into the neuroprotective effect of Eda.B in cerebral I/R. [Display omitted] • This study aimed to investigate the protective effects of Eda.B on the BBB in cerebral I/R and explore its potential mechanisms. • Eda.B safeguarded the BBB from cerebral I/R injury by inhibiting ferroptosis through the activation of the Nrf-2/HO-1/GPX4 axis. • These findings provided novel prospects for Eda.B as a potential therapeutic strategy for cerebral I/R injury. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which the death of motor neurons leads to loss of muscle function. Additionally, cognitive and circadian disruptions are common in ALS patients, contributing to disease progression and burden. Most ALS cases are sporadic, and environmental exposures contribute to their aetiology. However, animal models of these sporadic ALS cases are scarce. The small vertebrate zebrafish is a leading organism to model neurodegenerative diseases; previous studies have proposed bisphenol A (BPA) or β-methylamino- l -alanine (BMAA) exposure to model sporadic ALS in zebrafish, damaging motor neurons and altering motor responses. Here we characterise the face and predictive validity of sporadic ALS models, showing their potential for the mechanistic study of ALS drugs. We phenotypically characterise the BPA and BMAA-induced models, going beyond motor activity and motor axon morphology, to include circadian, redox, proteostasis, and metabolomic phenotypes, and assessing their predictive validity for ALS modelling. BPA or BMAA exposure induced concentration-dependent activity impairments. Also, exposure to BPA but not BMAA induced motor axonopathy and circadian alterations in zebrafish larvae. Our further study of the BPA model revealed loss of habituation to repetitive startles, increased oxidative damage, endoplasmic reticulum (ER) stress, and metabolome abnormalities. The BPA-induced model shows predictive validity, since the approved ALS drug edaravone counteracted BPA-induced motor phenotypes, ER stress, and metabolic disruptions. Overall, BPA exposure is a promising model of ALS-related redox and ER imbalances, contributing to fulfil an unmet need for validated sporadic ALS models. [Display omitted] • We characterise face and predictive validity of zebrafish models of sporadic ALS (sALS). • Phenotypes of sALS models include behavioural impairments and axonopathy. • BPA-induced sALS model shows altered metabolism and increased ER/redox stress. • ALS drug edaravone counteracts sALS phenotypes, modulating ER stress and metabolism. [ABSTRACT FROM AUTHOR]