Clinical Efficacy and Short-Term Prognosis of Butylphthalide and Sodium Chloride Injection Compared to Edaravone in the Treatment of Patients with Acute Stroke.

Background: Acute stroke is characterized by rapid progression, high mortality, and disability rates, making it a significant focus in clinical research. Brain-protective agents, such as butylphthalide and edaravone, have emerged as important therapeutic options for acute stroke. Objective: This study aimed to explore how butylphthalide and edaravone promote healing in acute stroke, drawing on relevant data, literature, clinical experience, and personal concepts. Design: The study design involves a narrative review, which comprehensively explores the pathogenesis of stroke by referencing relevant data and literature. Clinical experience and personal insights were incorporated to provide a holistic understanding. The primary focus was analyzing the mechanisms through which butylphthalide and edaravone facilitate healing in stroke patients. Results: The review revealed that butylphthalide exhibited multiple beneficial effects, including the protection of mitochondria, reduction of the inflammatory response, enhancement of microcirculation, decrease in blood-brain barrier permeability, and improving nerve cell function. On the other hand, edaravone demonstrated its efficacy by reducing oxidative stress response, inhibiting inflammatory response, and regulating the metabolism of arachidonic acid and apoptosis. These findings highlight the distinct mechanisms through which butylphthalide and edaravone contribute to the healing process in patients with stroke. Conclusions: This study highlights the positive impact of butylphthalide and edaravone on the therapeutic effect and short-term prognosis in acute stroke patients. The findings provide valuable guidance for future research and enhance our understanding of these drugs' mechanisms, offering the potential for improved stroke management and patient outcomes.

Interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery.

BACKGROUND: Brain radionecrosis (tissue death caused by radiation) can occur following high-dose radiotherapy to brain tissue and can have a significant impact on a person's quality of life (QoL) and function. The underlying pathophysiological mechanism remains unclear for this condition, which makes establishing effective treatments challenging. OBJECTIVES: To assess the effectiveness of interventions used for the treatment of brain radionecrosis in adults over 18 years old. SEARCH METHODS: In October 2017, we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, Embase and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) for eligible studies. We also searched unpublished data through Physicians Data Query, www.controlled-trials.com/rct, www.clinicaltrials.gov, and www.cancer.gov/clinicaltrials for ongoing trials and handsearched relevant conference material. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of any intervention directed to treat brain radionecrosis in adults over 18 years old previously treated with radiation therapy to the brain. We anticipated a limited number of RCTs, so we also planned to include all comparative prospective intervention trials and quasi-randomised trials of interventions for brain radionecrosis in adults as long as these studies had a comparison group that reflects the standard of care (i.e. placebo or corticosteroids). Selection bias was likely to be an issue in all the included non-randomised studies therefore results are interpreted with caution. DATA COLLECTION AND ANALYSIS: Two review authors (CC, PB) independently extracted data from selected studies and completed a 'Risk of bias' assessment. For dichotomous outcomes, the odds ratio (OR) for the outcome of interest was reported. For continuous outcomes, treatment effect was reported as mean difference (MD) between treatment arms with 95% confidence intervals (CIs). MAIN RESULTS: Two RCTs and one prospective non-randomised study evaluating pharmacological interventions met the inclusion criteria for this review. As each study evaluated a different drug or intervention using different endpoints, a meta-analysis was not possible. There were no trials of non-pharmacological interventions that met the inclusion criteria.A very small randomised, double-blind, placebo-controlled trial of bevacizumab versus placebo reported that 100% (7/7) of participants on bevacizumab had reduction in brain oedema by at least 25% and reduction in post-gadolinium enhancement, whereas all those receiving placebo had clinical or radiological worsening or both. This was an encouraging finding but due to the small sample size we did not report a relative effect. The authors also failed to provide adequate details regarding the randomisation and blinding procedures Therefore, the certainty of this evidence is low and a larger RCT adhering to reporting standards is needed.An open-label RCT demonstrated a greater reduction in brain oedema (T2 hyperintensity) in the edaravone plus corticosteroid group than in the corticosteroid alone group (MD was 3.03 (95% CI 0.14 to 5.92; low-certainty evidence due to high risk of bias and imprecision); although the result approached borderline significance, there was no evidence of any important difference in the reduction in post-gadolinium enhancement between arms (MD = 0.47, 95% CI - 0.80 to 1.74; low-certainty evidence due to high risk of bias and imprecision).In the RCT of bevacizumab versus placebo, all seven participants receiving bevacizumab were reported to have neurological improvement, whereas five of seven participants on placebo had neurological worsening (very low-certainty evidence due to small sample size and concerns over validity of analyses). While no adverse events were noted with placebo, three severe adverse events were noted with bevacizumab, which included aspiration pneumonia, pulmonary embolus and superior sagittal sinus thrombosis. In the RCT of corticosteroids with or without edaravone, the participants who received the combination treatment were noted to have significantly greater clinical improvement than corticosteroids alone based on LENT/SOMA scale (OR = 2.51, 95% CI 1.26 to 5.01; low-certainty evidence due to open-label design). No differences in treatment toxicities were observed between arms.One included prospective non-randomised study of alpha-tocopherol (vitamin E) versus no active treatment was found but it did not include any radiological assessment. As only one included study was a double-blinded randomised controlled trial, the other studies were prone to selection and detection biases.None of the included studies reported quality of life outcomes or adequately reported details about corticosteroid requirements.A limited number of prospective studies were identified but subsequently excluded as these studies had a limited number of participants evaluating different pharmacological interventions using variable endpoints. AUTHORS' CONCLUSIONS: There is a lack of good certainty evidence to help quantify the risks and benefits of interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery. In an RCT of 14 patients, bevacizumab showed radiological response which was associated with minimal improvement in cognition or symptom severity. Although it was a randomised trial by design, the small sample size limits the quality of data. A trial of edaravone plus corticosteroids versus corticosteroids alone reported greater reduction in the surrounding oedema with combination treatment but no effect on the enhancing radionecrosis lesion. Due to the open-label design and wide confidence intervals in the results, the quality of this data was also low. There was no evidence to support any non-pharmacological interventions for the treatment of radionecrosis. Further prospective randomised studies of pharmacological and non-pharmacological interventions are needed to generate stronger evidence. Two ongoing RCTs, one evaluating bevacizumab and one evaluating hyperbaric oxygen therapy were identified.

Ear drops for the removal of ear wax.

BACKGROUND: Ear wax (cerumen) is a normal bodily secretion that can become a problem when it obstructs the ear canal. Symptoms attributed to wax (such as deafness and pain) are among the commonest reasons for patients to present to primary care with ear trouble.Wax is part of the ear's self-cleaning mechanism and is usually naturally expelled from the ear canal without causing problems. When this mechanism fails, wax is retained in the canal and may become impacted; interventions to encourage its removal may then be needed. Application of ear drops is one of these methods. Liquids used to remove and soften wax are of several kinds: oil-based compounds (e.g. olive or almond oil); water-based compounds (e.g. sodium bicarbonate or water itself); a combination of the above or non-water, non-oil-based solutions, such as carbamide peroxide (a hydrogen peroxide-urea compound) and glycerol. OBJECTIVES: To assess the effects of ear drops (or sprays) to remove or aid the removal of ear wax in adults and children. SEARCH METHODS: We searched the Cochrane ENT Trials Register; Cochrane Register of Studies; PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 23 March 2018. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which a 'cerumenolytic' was compared with no treatment, water or saline, an alternative liquid treatment (oil or almond oil) or another 'cerumenolytic' in adults or children with obstructing or impacted ear wax. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. The primary outcomes were 1) the proportion of patients (or ears) with complete clearance of ear wax and 2) adverse effects (discomfort, irritation or pain). Secondary outcomes were: extent of wax clearance; proportion of people (or ears) with relief of symptoms due to wax; proportion of people (or ears) requiring further intervention to remove wax; success of mechanical removal of residual wax following treatment; any other adverse effects recorded and cost. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. MAIN RESULTS: We included 10 studies, with 623 participants (900 ears). Interventions included: oil-based treatments (triethanolamine polypeptide, almond oil, benzocaine, chlorobutanol), water-based treatments (docusate sodium, carbamide peroxide, phenazone, choline salicylate, urea peroxide, potassium carbonate), other active comparators (e.g. saline or water alone) and no treatment. Nine of the studies were more than 15 years old.The overall risk of bias across the 10 included studies was low or unclear. PRIMARY OUTCOME: proportion of patients (or ears) with complete clearance of ear waxSix studies (360 participants; 491 ears) contributed quantitative data and were included in our meta-analyses.Active treatment versus no treatmentOnly one study addressed this comparison. The proportion of ears with complete clearance of ear wax was higher in the active treatment group (22%) compared with the no treatment group (5%) after five days of treatment (risk ratio (RR) 4.09, 95% confidence interval (CI) 1.00 to 16.80); one study; 117 ears; NNTB = 8) (low-quality evidence).Active treatment versus water or salineWe found no evidence of a difference in the proportion of patients (or ears) with complete clearance of ear wax when the active treatment group was compared to the water or saline group (RR 1.47, 95% CI 0.79 to 2.75; three studies; 213 participants; 257 ears) (low-quality evidence). Two studies applied drops for five days, but one study only applied the drops for 15 minutes. When we excluded this study in a sensitivity analysis it did not change the result.Water or saline versus no treatmentThis comparison was only addressed in the single study cited above (active versus no treatment) and there was no evidence of a difference in the proportion of ears with complete wax clearance when comparing water or saline with no treatment after five days of treatment (RR 4.00, 95% CI 0.91 to 17.62; one study; 76 ears) (low-quality evidence).Active treatment A versus active treatment BSeveral single studies evaluated 'head-to-head' comparisons between two active treatments. We found no evidence to show that one was superior to any other.Subgroup analysis of oil-based active treatments versus non-oil based active treatmentsWe found no evidence of a difference in this outcome when oil-based treatments were compared with non-oil-based active treatments. PRIMARY OUTCOME: adverse effects: discomfort, irritation or painOnly seven studies planned to measure and did report this outcome. Only two (141 participants;176 ears) provided useable data. There was no evidence of a significant difference in the number of adverse effects between the types of ear drops in these two studies. We summarised the remaining five studies narratively. All events were mild and reported in fewer than 30 participants across the seven studies (low-quality evidence).Secondary outcomesThree studies reported 'other' adverse effects (how many studies planned to report these is unclear). The available information was limited and included occasional reports of dizziness, unpleasant smell, tinnitus and hearing loss. No significant differences between groups were reported. There were no emergencies or serious adverse effects reported in any of the 10 studies.There was very limited or no information available on our remaining secondary outcomes. AUTHORS' CONCLUSIONS: Although a number of studies aimed to evaluate whether or not one type of cerumenolytic is more effective than another, there is no high-quality evidence to allow a firm conclusion to be drawn and the answer remains uncertain.A single study suggests that applying ear drops for five days may result in a greater likelihood of complete wax clearance than no treatment at all. However, we cannot conclude whether one type of active treatment is more effective than another and there was no evidence of a difference in efficacy between oil-based and water-based active treatments.There is no evidence to show that using saline or water alone is better or worse than commercially produced cerumenolytics. Equally, there is also no evidence to show that using saline or water alone is better than no treatment.

Edaravone Improves Septic Cardiac Function by Inducing an HIF-1α/HO-1 Pathway.

Septic myocardial dysfunction remains prevalent and raises mortality rate in patients with sepsis. During sepsis, tissues undergo tremendous oxidative stress which contributes critically to organ dysfunction. Edaravone, a potent radical scavenger, has been proved beneficial in ischemic injuries involving hypoxia-inducible factor- (HIF-) 1, a key regulator of a prominent antioxidative protein heme oxygenase- (HO-) 1. However, its effect in septic myocardial dysfunction remains unclarified. We hypothesized that edaravone may prevent septic myocardial dysfunction by inducing the HIF-1/HO-1 pathway. Rats were subjected to cecal ligation and puncture (CLP) with or without edaravone infusion at three doses (50, 100, or 200 mg/kg, resp.) before CLP and intraperitoneal injection of the HIF-1α antagonist, ME (15 mg/kg), after CLP. After CLP, rats had cardiac dysfunction, which was associated with deformed myocardium, augmented lipid peroxidation, and increased myocardial apoptosis and inflammation, along with decreased activities of catalase, HIF-1α, and HO-1 in the myocardium. Edaravone pretreatment dose-dependently reversed the changes, of which high dose most effectively improved cardiac function and survival rate of septic rats. However, inhibition of HIF-1α by ME demolished the beneficial effects of edaravone at high dose, reducing the survival rate of the septic rats without treatments. Taken together, edaravone, by inducing the HIF-1α/HO-1 pathway, suppressed oxidative stress and protected the heart against septic myocardial injury and dysfunction.

Drugs in clinical development for the treatment of amyotrophic lateral sclerosis.

INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron progressive disorder for which no treatment exists to date. However, there are other investigational drugs and therapies currently under clinical development may offer hope in the near future. Areas covered: We have reviewed all the ALS ongoing clinical trials (until November 2016) and collected in Clinicaltrials.gov or EudraCT. We have described them in a comprehensive way and have grouped them in the following sections: biomarkers, biological therapies, cell therapy, drug repurposing and new drugs. Expert opinion: Despite multiple obstacles that explain the absence of effective drugs for the treatment of ALS, joint efforts among patient's associations, public and private sectors have fueled innovative research in this field, resulting in several compounds that are in the late stages of clinical trials. Drug repositioning is also playing an important role, having achieved the approval of some orphan drug applications, in late phases of clinical development. Endaravone has been recently approved in Japan and is pending in USA.

Edaravone attenuates intracerebroventricular streptozotocin-induced cognitive impairment in rats.

Alzheimer's disease is a major cause of dementia worldwide. Edaravone, a potent free radical scavenger, is reported to be neuroprotective. The present study was designed to investigate the effect of chronic edaravone administration on intracerebroventricular-streptozotocin (ICV-STZ) induced cognitive impairment in male Wistar rats. Cognitive impairment was developed by single ICV-STZ (3 mg/kg) injection bilaterally on day 1. Edaravone (1, 3 and 10 mg/kg, orally, once daily) was administered for 28 days. Morris water maze and passive avoidance tests were used to assess cognitive functions at baseline and on days 14 and 28. ICV-STZ caused cognitive impairment as evidenced by increased escape latency and decreased time spent in target quadrant in the Morris water maze test and reduced retention latency in the passive avoidance test. STZ caused increase in oxidative stress, cholinesterases, inflammatory cytokines and protein expression of ROCK-II and decrease in protein expression of ChAT. Edaravone ameliorated the STZ-induced cognitive impairment. STZ-induced increase in oxidative stress and increased levels of pro-inflammatory cytokines (TNF-α, IL-1ß) were mitigated by edaravone. Edaravone also prevented STZ-induced increased protein expression of ROCK-II. Moreover, edaravone significantly prevented STZ-induced increased activity of cholinesterases in the cortex and hippocampus. The decreased expression of ChAT caused by STZ was brought towards normal by edaravone in the hippocampus. The results thus show that edaravone is protective against STZ-induced cognitive impairment, oxidative stress, cholinergic dysfunction and altered protein expressions. This study thus suggests the potential of edaravone as an adjuvant in the treatment of Alzheimer's disease.

Effect of free radical scavenger, edaravone, for patients with carbon monoxide poisoning.

OBJECTIVE: Chronic neurological symptoms after carbon monoxide (CO) poisoning are caused by various biological processes in the damaged brain, with free radicals playing roles as mediators in establishing pathological processes leading to chronic neurological symptoms under CO poisoning. This study aimed to clarify the effects of a free radical scavenger, edaravone, in patients with CO poisoning. METHODS: We retrospectively compared two groups comprising patients treated with hyperbaric oxygenation alone (Group A, n=25) or edaravone in addition to hyperbaric oxygenation (Group B, n=25). Edaravone was administrated intravenously at 30 mg every 12h for 7 days. Patient characteristics, general conditions on admission, and frequency of chronic neurological symptoms were compared between groups. Among patients showing chronic neurological symptoms, cognitive function and daily activity were also compared between groups. RESULTS: No significant differences in characteristics or general conditions on admission were identified between groups. In Group B, no patients presented with marked complications caused by edaravone. Although chronic persisting symptoms were less frequent in Group B (n=1, 0.04%) than in Group A (n=5, 20%), this difference was not significant. In the 11 patients showing chronic symptoms, scores for cognitive function and daily activity in the chronic phase were better in Group B than in Group A, but no significant differences were apparent. CONCLUSIONS: The present results suggest that edaravone represents a tolerable and feasible treatment for CO-poisoned patients. Further studies are needed to clarify whether edaravone can favorably influence chronic neurological symptoms caused by CO poisoning.

The edaravone and 3-n-butylphthalide ring-opening derivative 10b effectively attenuates cerebral ischemia injury in rats.

AIM: Compound 10b is a hybrid molecule of edaravone and a ring-opening derivative of 3-n-butylphthalide (NBP). The aim of this study was to examine the effects of compound 10b on brain damage in rats after focal cerebral ischemia. METHODS: SD rats were subjected to 2-h-middle cerebral artery occlusion (MCAO). At the onset of reperfusion, the rats were orally treated with NBP (60 mg/kg), edaravone (3 mg/kg), NBP (60 mg/kg)+edaravone (3 mg/kg), or compound 10b (70, 140 mg/kg). The infarct volume, motor behavior deficits, brain water content, histopathological alterations, and activity of GSH, SOD, and MDA were analyzed 24 h after reperfusion. The levels of relevant proteins in the ipsilateral striatum were examined using immunoblotting. RESULTS: Administration of compound 10b (70 or 140 mg/kg) significantly reduced the infarct volume and neurological deficits in MCAO rats. The neuroprotective effects of compound 10b were more pronounced compared to NBP, edaravone or NBP+edaravone. Furthermore, compound 10b significantly upregulated the protein levels of the cytoprotective molecules Bcl-2, HO-1, Nrf2, Trx, P-NF-κB p65, and IκB-α, while decreasing the expression of Bax, caspase 3, caspase 9, Txnip, NF-κB p65, and P-IκB-α. CONCLUSION: Oral administration of compound 10b effectively attenuates rat cerebral ischemia injury.

Edaravone prevents lung injury induced by hepatic ischemia-reperfusion.

BACKGROUND: Lung injury is a major clinical concern after hepatic ischemia-reperfusion (I/R), due to the production of reactive oxygen species in the reperfused liver. We investigated the efficacy of edaravone, a potent free-radical scavenger, for attenuating lung injury after hepatic I/R. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were assigned to sham + normal saline (NS), I/R + NS, or I/R + edaravone group. Rats in the I/R groups were subjected to 90 min of partial hepatic I/R. Five minutes before reperfusion, 3 mg/kg edaravone was administered to the I/R + edaravone group. After 6 h of reperfusion, we evaluated lung histopathology and wet-to-dry ratio. We also measured malondialdehyde (MDA), an indicator of oxidative stress, in the liver and the lung, as well as cytokine messenger RNA expressions in the reperfused liver and plasma cytokine concentrations. RESULTS: Histopathology revealed lung damages after 6 h reperfusion of partial ischemic liver. Moreover, a significant increase in lung wet-to-dry ratio was observed. MDA concentration increased in the reperfused liver, but not in the lungs. Edaravone administration attenuated the lung injury and the increase of MDA in the reperfused liver. Edaravone also suppressed the reperfusion-induced increase of interleukin-6 messenger RNA expressions in the liver and plasma interleukin-6 concentrations. CONCLUSIONS: Edaravone administration before reperfusion of the ischemic liver attenuates oxidative stress in the reperfused liver and the subsequent lung injury. Edaravone may be beneficial for preventing lung injury induced by hepatic I/R.

Montelukast, a cysteinyl leukotriene receptor-1 antagonist, attenuates chronic brain injury after focal cerebral ischaemia in mice and rats.

OBJECTIVES: Previously we demonstrated the neuroprotective effect of montelukast, a cysteinyl leukotriene receptor-1 (CysLT(1) ) antagonist, on acute brain injury after focal cerebral ischaemia in mice. In this study, we have determined its effect on chronic brain injury after focal cerebral ischaemia in mice and rats. METHODS: After transient focal cerebral ischaemia was induced by middle cerebral artery occlusion, montelukast was intraperitoneally injected in mice or orally administered to rats for five days. Behavioural dysfunction, brain infarct volume, brain atrophy and neuron loss were determined to evaluate brain lesions. KEY FINDINGS: Montelukast (0.1 mg/kg) attenuated behavioural dysfunction, brain infarct volume, brain atrophy and neuron loss in mice, which was similar to pranlukast, another CysLT(1) receptor antagonist. Oral montelukast (0.5 mg/kg) was effective in rats and was more effective than edaravone, a free radical scavenger. CONCLUSION: Montelukast protected mice and rats against chronic brain injury after focal cerebral ischaemia, supporting the therapeutic potential of CysLT(1) receptor antagonists.

The antioxidant edaravone attenuates ER-stress-mediated cardiac apoptosis and dysfunction in rats with autoimmune myocarditis.

Experimental autoimmune myocarditis (EAM) is mediated by myocardial infiltration by myosin-specific T-cells secreting inflammatory cytokines. In this study, rat models of EAM were prepared by injection with porcine cardiac myosin. One week after immunization, edaravone was administered intraperitoneally at 3 or 10 mg/kg/day to rats for 2 weeks. Cardiac function was measured by haemodynamic and echocardiographic studies and TUNEL assay was performed. Left ventricular (LV) expression of NADPH oxidase sub-units (p47(phox) and p67(phox)), pro-inflammatory cytokines (TNF-alpha), endoplasmic reticulum (ER) stress signalling proteins (GRP78, caspase-12 and GADD153) and mitogen-activated protein kinase (MAPK) family proteins (phospho-p38 MAPK and phospho-JNK) were measured by western blotting. Edaravone improved LV function in a dose-dependent manner. Central venous pressure was significantly low and LV ejection fraction and fractional shortening was significantly high in edaravone groups compared with those in the vehicle group. In addition, edaravone treatment down-regulated LV expressions of p47(phox), TNF-alpha, GADD153, phospho-p38 MAPK and phospho-JNK. Furthermore, the LV expressions of p67(phox), GRP78, caspase-12 and TUNEL-positive cells of rats with EAM treated with edaravone were significantly low compared with those of the vehicle group. These findings suggest that edaravone ameliorated the progression of EAM by inhibiting oxidative and ER stress and, subsequently, cardiac apoptosis.

A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy?

IMPORTANCE OF THE FIELD: Edaravone (Radicut) is a free radical scavenger marketed in Japan by Mitsubishi Tanabe Pharma Corp. to treat acute ischemic stroke (AIS) patients presenting within 24 h of the attack. Injectable edaravone ampoules (30 mg b.i.d., i.v., 14 days) were first approved on 23 May 2001. On 19 January 2010, as a new innovation, the Radicut BAG (Intravenous BAG) was approved by the Japanese Ministry of Health and Welfare. Efficacy of edaravone ranges from large significant clinical improvements to only modest improvements in clinical function measured using standard stroke scales when administered 6-72 h following an ischemic stroke. With almost 17 years of edaravone clinical experience, a few adverse events--including acute renal failure--have been noted. WHAT THE READER WILL GAIN: This is the only article to date to critically review available clinical efficacy and toxicology data published in the literature to ascertain whether edaravone should be further pursued as a candidate for development worldwide. AREAS COVERED IN THIS REVIEW: This review covers clinical studies carried out over the period 1993-2008. TAKE HOME MESSAGE: Edaravone may be a useful neuroprotective agent to treat the > 15 million victims worldwide who are devastated by stroke annually. Additional clinical studies are necessary to verify the efficacy of edaravone.

Edaravone, a free radical scavenger, in the treatment of idiopathic sudden sensorineural hearing loss with profound hearing loss.

OBJECTIVE: Edaravone, a free radical scavenger, is a clinical drug that is widely used to reduce neuronal damage after acute cerebral infarction in Japan since 2001. The aim of this study was to investigate whether edaravone could improve treatment result in idiopathic sudden sensorineural hearing loss (ISSHL) patients with severe hearing loss. METHODS: Between 2004 and 2006, 14 patients of ISSHL with the mean hearing levels equal or over 90dB at the initial visit were treated with edaravone. 14 counterpart control patients were selected from 45 patients who had similar prognostic factors and were treated with hyperbaric oxygenation therapy (HBO) in the past decade. RESULTS: There were no significant differences between edaravone group and the control group in hearing recovery. CONCLUSION: We considered that edaravone was not able to bring remarkable effect compared with conventional treatment regimen for ISSHL.

Retinal artery embolization during carotid angioplasty and carotid artery stenting: case report.

A 69-year-old man presented with a rare case of retinal artery embolization, which occurred as a complication of carotid angioplasty and carotid artery stenting performed for recurrent cerebral infarction. Magnetic resonance imaging and angiography showed right internal carotid artery stenosis with ulceration. Carotid angioplasty and carotid artery stenting were performed using the distal protection system with the PercuSurge GuardWire. However, just after dilation, the patient complained of ocular pain and blurred vision on the right, which was subsequently diagnosed as retinal artery embolization. Heparin was given for 15 hours after stenting, and aspirin and ticlopidine medication were continued. The patient received hyperbaric oxygen therapy for 1 week. The patient's blurred vision gradually improved, but visual field defect remained. Debris was probably flushed into the external carotid artery, and passed through an anastomosis into the ophthalmic artery, resulting in retinal artery embolization.

Edaravone (MCI-186) scavenges reactive oxygen species and ameliorates tissue damage in the murine spinal cord injury model.

The present study evaluated the effect of the free radical scavenger edaravone on lesion volume and neurological dysfunction after spinal cord injury (SCI) in mice, and investigated its protective effects on superoxide generation. Female C57BL/6 mice were subjected to SCI using a pneumatic impact device and were treated with 3 mg/kg of edaravone or vehicle 30 minutes before the insult. Motor functions were quantitatively evaluated. Lesion volume was assessed by Dohrmann's two-cone method after one week. In situ detection of superoxide in the injured cord was carried out using the superoxide-sensitive dye dihydroethidium (DHE) staining technique. Pretreatment with edaravone significantly improved motor dysfunction and reduced the lesion volume to about 63% of the control (p < 0.05). Semi-quantitative measurements of red fluorescence emitted from DHE revealed that the superoxide concentration increased in the lesion periphery at 1 and 3 hours after the insult, and that pretreatment with edaravone significantly inhibited the increase of superoxide concentration in the lesion periphery at both time points (p < 0.0001). Double staining with DHE and monoclonal antibody against MAP2 showed that most cells positive for DHE were also positive for MAP2. These findings suggest that edaravone ameliorates tissue damage by scavenging reactive oxygen species, especially in the neurons, after SCI.

Combination drug therapy using edaravone and Daio-Orengedoku-to after transient focal ischemia in rats.

In this study, we investigated the effect of Daio-Orengedoku-to (DOT) on ischemic brain damage in a rat model of focal ischemia-reperfusion and attempted to identify synergistic effects for the combination of edaravone and DOT against ischemic insult. Ischemia was induced by intraluminal occlusion of the right middle cerebral artery for 2 h and reperfusion followed for 22 h. To determine the neuroprotective effect of DOT, it was administered orally just before reperfusion and then 2 h after reperfusion. To examine the effects of combination therapy on survival, rats were divided into groups treated with edaravone, DOT, and edaravone and DOT. Microglial activation, neutrophil infiltration and brain-derived neurotrophic factor (BDNF) expression were examined in surviving animals. Infarct volume was significantly reduced by DOT (100, 200 and 400 mg/kg; P < 0.05), and edaravone plus DOT markedly improved the survival rate after transient ischemia (P = 0.0133). Microglial activation was reduced by edaravone and DOT and their combination (P < 0.05), and neutrophil infiltration was lowered in these groups (P < 0.05). BDNF-positive cells were increased in the combination edaravone and DOT group (P < 0.05). It appears that the neuroprotective mechanisms of combined therapy involve inhibition of microglial activation, reduction of invading neutrophils and enhancement of BDNF expression.

Combination effects of normobaric hyperoxia and edaravone on focal cerebral ischemia-induced neuronal damage in mice.

We evaluated the potential neuroprotective effects of combination treatment with normobaric hyperoxia (NBO) and edaravone, a potent scavenger of hydroxyl radicals, on acute brain injuries after stroke. Mice subjected to 2-h filamental middle cerebral artery occlusion were treated with NBO (95% O2, during the ischemia) alone, with edaravone (1.5 mg/kg, intravenously after the ischemia) alone, with both of these treatments (combination), or with vehicle. The histological and neurological score were assessed at 22-h after reperfusion. Infarct volume was significantly reduced in the combination group [36.3+/-6.7 mm3 (n=10) vs. vehicle: 65.5+/-5.9 mm3 (n=14) P<0.05], but not in the two monotherapy-groups [NBO: 50.5+/-5.8 mm3 (n=14) and edaravone: 56.7+/-5.8 mm3 (n=10)]. The combination therapy reduced TUNEL-positive cells in the ischemic boundary zone both in cortex [6.0+/-1.4 x 10(2)/mm2 (n=5) vs. vehicle: 18.9+/-2.4 x 10(2)/mm2 (n=5), P<0.01] and subcortex [11.6+/-1.5 x 10(2)/mm2 (n=5) vs. vehicle: 22.5+/-2.1 x 10(2)/mm2 (n=5), P<0.01]. NBO and combination groups exhibited significantly reduced neurological deficit scores at 22-h after reperfusion (vs. vehicle, P<0.05). Combination therapy with NBO plus edaravone prevented the neuronal damage after focal cerebral ischemia and reperfusion in mice, compared with monotherapy of NBO or edaravone.

The novel antioxidant edaravone: from bench to bedside.

Over the last decade, important advances have been made to support the fact that reactive oxygen species (ROS) are generated and play a harmful role during the acute and late stages of cerebral ischemia. Several drugs, such as radical scavengers and antioxidants, have been evaluated in preclinical and clinical studies. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; Radicut, Mitsubishi Tanabe Pharma Corporation) is a novel antioxidant that is currently used in Japan for the treatment of patients in the acute stage of cerebral infarction. Edaravone scavenges ROS and inhibits proinflammatory responses after brain ischemia in animals and humans. In particular, postischemic inflammation, leading to brain edema and infarction due to neuronal damage and endothelial cell death, can be ameliorated by edaravone. In addition to these antistroke effects, edaravone has also been shown to prevent oxidative damage to various extracerebral organs. Therefore, in addition to its usefulness in the treatment of stroke, edaravone is expected to play an integral role in the treatment of many oxidative stress-related diseases.

[From willow bark to the coxibs. Development of antiphlogistic analgesics]. / Von der Weidenrinde zu den Coxiben. Entwicklung der antiphlogistischen Analgetika.

Antiphlogistic analgesics comprise the most widely used class of drugs worldwide. These compounds derive more or less directly from three prototypes which were discovered about 130 years ago in Central Europe: acetylsalicylic acid (aspirin), acetanilide (the forerunner of acetaminophen), and phenazone. All of them are still available. Attempts to improve their effect/side effect spectrum and enhance their analgesic activity led to the development of animal models of inflammatory pain which allowed for the screening and discovery of the so-called aspirin-like drugs, also termed nonsteroidal antiinflammatory drugs (NSAIDs) or cyclooxygenase inhibitors. This group presently dominates the market despite the fact that all these compounds imply the risk of unwanted drug effects, including gastrointestinal ulcers, renal dysfunction, inhibition of blood coagulation, pseudoallergic reactions, and possibly also accelerated development of atherosclerosis. Attempts to reduce these unwanted drug effects on the basis of molecular pharmacological insights resulted in the development of the so-called selective cyclooxygenase-2 inhibitors which are presently discussed ambiguously. These compounds appear to go along with less gastrointestinal toxicity, they do not inhibit blood coagulation, and have a reduced propensity for causing pseudoallergic asthmatic attacks. They may, on the other hand, cause more unwanted cardiovascular effects than the traditional NSAIDs. Hope for further reduction of unwanted drug effects comes from the recently discovered role of glycinergic spinal pain control. It is hoped that new classes of analgesic compounds may result from these new glycinergic mechanisms.

Hyperbaric oxygen combined with intravenous edaravone for treatment of acute embolic stroke: a pilot clinical trial.

The efficacy of hyperbaric oxygen (HBO) therapy combined with intravenous edaravone (free radical scavenger) administration was prospectively investigated in patients with acute embolic stroke involving the anterior cerebral circulation. Patients with acute embolic stroke in the anterior cerebral circulation admitted within 48 hours of onset from August 2001 to March 2002 with National Institutes of Health Stroke Scale (NIHSS) scores on admission of 5 or more were assigned randomly to HBO and control groups. The HBO group underwent HBO therapy combined with intravenous edaravone administration for 7 days, whereas the control group received only conventional treatment. The primary endpoint was the modified Rankin Scale score at 90 days (favorable outcome, score 0 or 1). The secondary endpoint was the NIHSS score at 7 days. Analysis was carried out by intention to treat. Six of the 19 patients in the HBO group, but only one of the 19 patients in the control group, had favorable outcomes at 90 days (p < 0.05), although NIHSS score at 7 days did not differ significantly between the two groups. HBO therapy combined with intravenous edaravone administration appears to be effective for the treatment of patients with acute embolic stroke in the anterior cerebral circulation.