Background and Objective: Stroke patients with severe leg paralysis are often bedridden in the acute and subacute phase, which increases the risk of disuse muscle atrophy in the chronic phase. The evidence to date indicates that oxidative stress plays an important role in the mechanism of disuse muscle atrophy. Therefore, the aim of this study was to determine if long-term radical scavenger treatment with edaravone following an acute stroke prevents the progression of disuse muscle atrophy and improves leg locomotor function in the chronic phase.
Methods: This randomized controlled pilot study was conducted at 19 acute stroke and rehabilitation centers across Japan. Forty-seven ischemic stroke patients with at least leg motor weakness admitted within 24 hours of onset were randomly assigned to receive continuous intravenous infusions of edaravone 30mg twice daily for 3 days (short-term group) or 10–14 days (long-term group).
The primary endpoints of the study included the degree of leg disuse muscle atrophy, as measured by the percentage change from baseline in femoral muscle circumference 15 cm above the knee, and the improvement in leg locomotor function, as assessed by the maximum walking speed over 10 m, 3 months after the onset of stroke.
Results: Three-month follow-up was completed by a total of 41 patients (21 in the short-term group and 20 in the long-term group). On admission, there was no significant difference in the severity of stroke or the grade of leg paresis between the two treatment groups. The grade of disuse muscle atrophy and incidence of gait impairment 3 weeks after stroke onset were also similar between the short- and long-term groups.
However, disuse muscle atrophy of the paretic and non-paretic legs was significantly less severe in the long-term versus the short-term treatment group (3.6 – 5.9% and 1.5 – 6.0% vs 8.3 – 5.2% and 5.7 – 6.4%; p< 0.01 and p < 0.05) 3 months after stroke onset. Additionally, the maximum walking speed over a distance of 10m was significantly greater in the long-term group (98 – 67 vs 54 – 55 cm/sec; p < 0.05).
Conclusion: Edaravone treatment for up to 14 days suppresses the progression of disuse muscle atrophy and improves leg locomotor function to a greater extent than shorter-term treatment in acute stroke patients. This suggests that the management of stroke may be improved with long-term edaravone therapy by providing myoprotective effects that ameliorate functional outcome in the chronic phase.
- Donnan GA, Fisher M, Macleod M, et al. Stroke. Lancet 2008 May 10; 371 (9624): 1612-23
- Schneider R, Gautier JC. Leg weakness due to stroke: site of lesions, weakness patterns and causes. Brain 1994 Apr; 117 (Pt 2): 347-54
- Kortebein P, Ferrando A, Lombeida J, et al. Effect of 10 days of bed rest on skeletal muscle in healthy older adults. JAMA 2007 Apr 25; 297 (16): 1772-4
- Kondo K, Ota T. Changes with time in cross-sectional areas of leg muscles in early stroke rehabilitation patients: disuse muscle atrophy and its recovery. Jpn J Rehabil Med 1997; 34: 124-33
- Odajima N, Ishiai S, Okiyama R, et al. CT findings of leg muscles in the hemiplegics due to cerebrovascular accidents: correlation to disuse atrophy. Rinsho Shinkeigaku 1987 Sep; 27 (9): 1154-62
- Kondo H. Oxidative stress in skeletal muscle atrophy induced by immobilization. In: Reznick AZ, editor. Oxidative stress in skeletal muscle. Basel: Birkhauser, 1998: 197-13
- Kondo H. Oxidative stress in muscular atrophy. In: Sen CK, Hanninen O, editors. Handbook of oxidants and antioxidants in exercise. Amsterdam: Elsevier, 2000: 631-53
- Kondo H, Itokawa Y. Oxidative stress in muscular atrophy. In: Sen CK, Packer L, Hanninen O, editors. Exercise and oxygen toxicity. Amsterdam: Elsevier, 1994: 319-42
- Powers SK, Kavazis AN, DeRuisseau KC. Mechanisms of disuse muscle atrophy: role of oxidative stress. Am J Physiol Regul Integr Comp Physiol 2005 Feb; 288 (2): R337-44
- Powers SK, Kavazis AN, McClung JM. Oxidative stress and disuse muscle atrophy. J Appl Physiol 2007 Jun; 102 (6): 2389-97
- Edaravone Acute Infarction Study Group. Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction: randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis 2003; 15 (3): 222-9
- Unno Y, Katayama M, Shimizu H. Does functional outcome in acute ischaemic stroke patients correlate with the amount of free-radical scavenger treatment? A retrospective study of edaravone therapy. Clin Drug Investig 2010; 30 (3): 143-55
- Lapchak PA. A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy? Expert Opin Pharmacother 2010; 11 (10): 1753-63
- Yamamoto Y, Kuwahara T, Watanabe K. Antioxidant activity of 3-methyl-1-phenyl-2-pyrazolin-5-one. Redox Rep 1996; 2: 333-8
- Lee BJ, Egi Y, van Leyen K, et al. Edaravone, a free radical scavenger, protects components of the neurovascular unit against oxidative stress in vitro. Brain Res 2010 Jan 11; 1307: 22-7
- Ueno Y, Zhang N, Miyamoto N, et al. Edaravone attenuates white matter lesions through endothelial protection in a rat chronic hypoperfusion model. Neuroscience 2009 Aug 18; 162 (2): 317-27
- Yamamoto T, Yuki S, Watanabe T, et al. Delayed neuronal death prevented by inhibition of increased hydroxyl radical formation in a transient cerebral ischemia. Brain Res 1997 Jul 11; 762 (1-2): 240-2
- Мицубиси Танабе Фарма Корпорейшн Radicut (edaravone) [Japanese prescribing information]. Osaka: Mitsubishi Tanabe Pharma Corporation, 2009
- Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia: the ischemic penumbra. Stroke 1981 Nov-Dec; 12 (6): 723-5
- Heiss WD. Experimental evidence of ischemic thresholds and functional recovery. Stroke 1992 Nov; 23 (11): 1668-72
- Brunnstrom S. Motor testing procedures in hemiplegia: based on sequential recovery stages. Phys Ther 1966 Apr; 46 (4): 357-75
- Dorman PJ, Counsell CE, Sanderrock PAG. Recently developed neuroprotective therapies for acute stroke: a qualitative systematic review of clinical trials. CNS Drugs 1996; 5 (6): 457-74
- Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 2008 Sep; 55 (3): 363-89
- O’Collins VE, Macleod MR, Donnan GA, et al. 1,026 experimental treatments in acute stroke. Ann Neurol 2006 Mar; 59 (3): 467-77
- Shuaib A, Lees KR, Lyden P, et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 2007 Aug 9; 357 (6): 562-71
- Kondo H, Miura M, Kodama J, et al. Role of iron in oxidative stress in skeletal muscle atrophied by immobilization. Pflugers Arch 1992 Jun; 421 (2-3): 295-7
- Kondo H, Kodama J, Kishibe T, et al. Oxidative stress during recovery from muscle atrophy. FEBS Lett 1993 Jul 12; 326 (1-3): 189-91
- Yamamoto Y, Yanagisawa M, Tak NW, et al. Repeated edaravone treatment reduces oxidative cell damage in rat brain induced by middle cerebral artery occlusion. Redox Rep 2009; 14 (6): 251-8
- Houkin K, Ueno K, Tada M, et al. Arterial recanalization in an acute stage of cerebral infarction. Neurol Med Chir (Tokyo) 1987 Apr; 27 (4): 295-301
Abstract. Ischemic stroke remains a pressing problem today. Its pathogenesis consists of a sequential cascade of reactions in the brain, which, in addition to ischemia, are responsible for further damage to brain tissue and slow down the development of compensatory and regenerative mechanisms. Attempts to break the pathological cascade have been going on for decades.
The first promising molecule that demonstrated the potential of a scavenger (cleaner, absorber) of excessive aggressive peroxides in preclinical studies was MCI-186, which is used in clinical practice under the name edaravone. The aim of the study the results of which are presented in this paper was to establish the clinical effects of edaravone (Xavron) as a concomitant therapy of acute ischemic stroke (СТІКс) in real clinical practice.
Effects on the damaging mechanisms of active oxygen radicals in the hyperacute period of stroke (including cases of recanalization therapy) may increase the potential for recovery in the future.
Assess the impact of radical scavenger use on the long-term effects of stroke in routine clinical practice.
Material and methods
The open case-control study covered 53 stroke departments in Ukraine. 570 patients with ischemic stroke received additional therapy with “Xavron” (edaravone, Yuria-Pharm, Ukraine) – 30 mg twice daily, by infusion, during the hospitalization staying, starting 1 hour after admission (active treatment group, ATG).
430 patients corresponding by age and sex received conventional treatment (control group, CG). The average length of hospital stay was 9.690.19 days. The average score on NIHSS in the ATG was 11.670.26 and 10.930.29 in CG. The number of thrombolysis procedures was 25 (4.4%) in ATG and 30 (6.98%) in CG.
Results. At the time of discharge, the NIHSS score was 6.340,22 in ATG versus 7.460.27 in CG, p=0,001. The mean mRS score was almost the same at discharge (2.660.06 in ATG and 2.770.22 in CG). But after 3 months, the average score of mRS in ATG was significantly lower – 1.871.36 against 2.561.49, p <0.01. Dichotomous comparison of mRS 0-1 vs. 2-6: 42.47% in ATG vs. 32.74% in CG, p = 0.0018.
For mRS 0-2 / 3-6: 65.4% in ATG and 56.1% in CG, p = 0.0029. Positive dynamics of mRS “-1 point” for 90 days was observed in 62.6% of ATG patients against 34.8% in CG: OR = 2.42 (95% CI – 2.42 – 4.17). Hemorrhagic transformation of stroke was observed in 9 (1.84%) ATG patients and 22 (5.67%) CG patients, p = 0.0012. Hospital mortality was 0.7% in ATG and 2% in CG, p = 0.0713.
Additional therapy with free radical scavengers is perspective approach to strengthening the restorative potential after stroke.
- Московко С.П., Кириченко О.В., Руденко Г.С. Протокол відкритого багатоцентрового дослідження «випадок — контроль» щодо безпеки та ефективності використання едаравону (Ксаврон®) у гострому періоді ішемічного інсульту в умовах реальної клінічної практики. Здоров’я України. Спецвипуск «Інсульт». 2020. 1(52). С. 15-16.
- Ganesh A., Luengo-Fernandes R., Wharton R.M., Rothwell P.M. Ordinal vs dichotomous analysis of modified Rankin Scale, 5-year outcome, and cost of stroke. Neurology. 2018. 91. e1951-e1960. Doi: 10.1212/WNL.00000000006554.
- Chen C., Li M., Lin L., Chen S., Chen Y., Hong L. Clinical effects and safety of edaravone in treatment of acute ischaemic stroke: A meta-analysis of randomized controlled trials. J. Clin. Pharm. Ther. 2021 Feb 27. doi: 10.1111/jcpt.13392.
- Московко С.П., Кириченко О.В., Руденко Г.С. Проміжні результати дослідження СТІКс (Супутня Терапія Інсульту Ксавроном) — відкритого багатоцентрового дослідження «випадок — контроль». Журнал неврології ім. Б.М. Маньковського. 2021. Т. 9. № 1.
- Watanabe K. How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis? Journal of Clinical Biochemistry and Nutrition. 2018. Vol. 62. Issue 1. P. 20-8. https://doi.org/10.3164/ jcbn.17-622.
Edaravone is a neuroprotective agent, and several studies have suggested that it may be beneficial in acute ischaemic stroke.
Objectives. To assess the efficacy and safety of edaravone for acute ischaemic stroke.
Main results. Authors included three trials. All three included trials were of edaravone plus another treatment compared with the other treatment alone. The dose of edaravone injections in the three trials was the same at 60 mg per day. The course of treatment in all three trials is 14 days. All three trials reported adverse events; there were no differences between the treatment group and the control group. Overall, edaravone appeared to increase the proportion of participants with marked neurological improvement compared with the control group, and the difference was significant (risk ratio (RR) 1.99, 95% confidence interval (CI) 1.60 to 2.49).