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Publications

First experience of using Xavron, a free radical scavenger, in patients with acute ischemic stroke

Abstract. Background. In acute ischemic stroke (AIS), more than 1,000 substances with known neuroprotective effects have been studied, but their effectiveness is considered insufficiently convincing. In 2018, Ukraine launched the release of a new free radical scavenger Xavron (active ingredient — edaravone), which since 2001 has been successfully prescribed in Japan for the treatment of AIS and is a part of the Japanese national guidelines for the treatment of AIS. The purpose of this work is to study the effectiveness of a new neuroprotective drug Xavron (edaravone) in the comprehensive therapy of patients with AIS. Materials and methods. A prospective, integrated clinical, neurological and laboratory examination was conducted in 28 patients (13 women and 15 men) with AIS. The patients were divided into two groups that did not differ in terms of main characteristics and treatment. However, patients in the first group (n = 18) received Xavron (30 mg edaravone) twice daily intravenously. In the control group (n = 10), the drugs with neuroprotective effect were not used. Results. The analysis of Glasgow Coma Scale scores showed a positive dynamics in the majority of patients in both groups without significant statistical difference (p > 0.05). However, the analysis of FOUR (Full Outline of UnResponsiveness) scores showed that in the group where Xavron was used for neuroprotection, since day 5 the level of consciousness was restored more quickly than in the control group. The difference between group 1 and controls became significant within 9–10 days of treatment (p< 0.05). On day 3 in the control group, the level of neuron-specific enolase (NSE) increased by 10 times (from 9.2 to 96.4 ng/ml). Subsequently, there was a rapid decrease in the NSE level, which in the main group of patients was normalized until day 10 of treatment, and in the control group, the NSE level did not reach the reference values within 10 days of therapy (p < 0.05). Conclusions. The use of Xavron (edaravone) in patients with AIS was significantly effective in terms of neurological status (level of consciousness on the FOUR scale) and the dynamics of neurological markers (NSE). Further research is needed to clarify the role of Xavron (edaravone) in the intensive care of AIS patients.

Authors: Emergency medicine № 3 (98), 2019
Posted: Emergency medicine № 3 (98), 2019
Effect of a Novel Free Radical Scavenger, Edaravone (MCI-186), on Acute Brain Infarction

Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke.

We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation.

A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382).

Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.

Authors: Eiichi Otomo
Posted: Cerebrovasc Dis 2003
Acute ischemic stroke: revealing the maximum possibilities of pharmacotherapy

Materials of the XXI International Scientific and Practical Conference “Interdisciplinary Issues in Modern Neurology”, April 22-24, Truskavets, Ukraine.

Much attention was paid during the event to the problematic aspects of managing patients with acute ischemic stroke. Within the framework of intensive therapy in cardioneurology a separate scientific symposium discussed the possibilities of modern pharmacotherapy for acute stroke, which are available to doctors today and allow to improve the results of treatment and reduce the disability of patients with stroke.

Authors: Chemer N.M., Darii V.I., Oros M.M.
Posted: Medical newspaper "Health of Ukraine", № 12 (457), 2019
Acute Kidney Injury and Edaravone in Acute Ischemic Stroke: The Fukuoka Stroke Registry

Background: A free radical scavenger, edaravone, which has been used for the treatment of ischemic stroke, was reported to cause acute kidney injury (AKI) as a fatal adverse event. The aim of the present study was to clarify whether edaravone is associated with AKI in patients with acute ischemic stroke. Methods: From the Fukuoka Stroke Registry database, 5689 consecutive patients with acute ischemic stroke who were hospitalized within 24 hours of the onset of symptoms were included in this study. A logistic regression analysis for the Fukuoka Stroke Registry cohort was done to identify the predictors for AKI. A propensity score–matched nested case–control study was also performed to elucidate any association between AKI and edaravone. Results: Acute kidney injury occurred in 128 of 5689 patients (2.2%) with acute ischemic stroke. A multivariate analysis revealed that the stroke subtype, the basal serum creatinine level, and the presence of infectious complications on admission were each predictors of developing AKI. In contrast, a free radical scavenger, edaravone, reduced the risk of developing AKI (multivariate-adjusted odds ratio [OR] .45, 95% confidence interval [CI] .30-.67). Propensity score–matched case–control study confirmed that edaravone use was negatively associated with AKI (propensity score–adjusted OR .46, 95% CI .29-.74). Conclusions: Although AKI has a significant impact on the clinical outcome of hospital inpatients, edaravone has a protective effect against the development of AKI in patients with acute ischemic stroke.

Authors: Masahiro Kamouchi et al.
Posted: International Neurological Journal, №3 (105), 2019
The search for new methods and drugs to struggle with cerebral stroke and its complications

The scientific-practical conference “Opportunities and Achievements of Modern Pharmacotherapy in the Practice of a Neurologist” held in Kharkov on March 14-15, 2019. It was organized by Association of Neurologists, Psychiatrists and Narcologists of Ukraine, Institute of Neurology, Psychiatry and Narcology of the National Academy of Medical Sciences of Ukraine, Kharkiv National University named after V.N. Karazin.

The event was devoted to innovative methods of diagnosis, treatment and prevention of pathologies of central nervous system. Stroke remains a major central nervous system disease due to high prevalence, disability and mortality. You will find an overview of some of the reports voiced at the conference.

Authors: V.M. Mishchenko, V.I. Darii, I.V. Khubetova, T.S. Mishchenko
Posted: Health of Ukraine. Thematic issue "Neurology, Psychiatry, Psychotherapy" No. 2, 2019.
How is edaravone effective against acute ischemic stroke and amyotrophic lateral  sclerosis?

Abstract. Edaravone isa low-molecular-weight antioxidant drug targeting peroxyl radicals among many types of reactive oxygen species. Because of its amphiphilicity, it scavenges both lipid- and water-soluble peroxyl radicals by donating an electron to the radical. Thus, it inhibits the oxidation of lipids by scavenging chain-initiating water-soluble peroxyl radicals and chain-carrying lipid peroxyl radicals. In 2001, it was approved in Japan as a drug to treat acute-phase cerebral infarction, and then in 2015 it was approved for amyotrophic lateral sclerosis (ALS). In 2017, the U.S. Food and Drug Administration also approved edaravone for treatment of patients with ALS. Its mechanism of action was inferred to be scavenging of peroxynitrite. In this review, we focus on the radical-scavenging characteristics of edaravone in comparison with some other antioxidants that have been studied in clinical trials, and we summarize its pharmacological action and clinical efficacy in patients with acute cerebral infarction and ALS.

Authors: Kazutoshi Watanabe, Masahiko Tanaka, Satoshi Yuki, Manabu Hirai, Yorihiro Yamamoto
Posted: J. Clin. Biochem. Nutr. January 2018. Vol. 62, № 1. Р. 20-38
Ukrainian legislation on the prevention and treatment of rare (orphan) diseases

From 01 January 2015, amendments to the Fundamentals of Legislation of Ukraine on Health Care implemented by the Law of Ukraine No. 1213-VII dated 15 April 2014, have become effective. According to the implemented amendments to the legislation, patients with rare (orphan) diseases shall be provided, on a continuous and free basis, with medicinal products for the treatment of these diseases and appropriate food products for special dietary consumption in accordance with their list and volumes approved by the central executive body responsible for the formation of the national health care policy, in accordance with the procedure established by the Cabinet of Ministers of Ukraine.

At the same time, on 15 April 2015, the CMU Resolution No. 160 of 31 March 2015 “On approval of the procedure for providing citizens suffering from rare (orphan) diseases with medicines and appropriate food products for special dietary consumption” became effective. According to the specified Procedure, provision of the citizens suffering from rare (orphan) diseases with medicines and food products is performed by respective healthcare institutions according to the place of residence or treatment of such citizens.

References to laws:

Authors: Верховна Рада України; Кабінет міністрів України.
Posted: Відомості Верховної Ради (ВВР), 2014, № 26; Постанова Кабінету міністрів України №160 від 31.03.2015 р.
Extended revised ALS Scale (ALSFRS-R)

Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) is a tool for monitoring the progression of disability in patients with amyotrophic lateral sclerosis (ALS). The disadvantage of ALSFRS is that its rating of the bulbar functions and limb functionality is overweighted compared to the rating of respiratory dysfunction.

A revised ALS functional rating scale (ALSFRS-R) retains the properties of the original scale, while demonstrating a valid structure and internal weighting.

The revised ALS functional rating scale (ALSFRS-R) is useful for physicians and scientists to diagnose patients, track disease progression, study and compare the results of different ALS treatment regimens in clinical trials.

ALSFRS-R includes 12 questions scored from 0 to 4. 0 means no function, whereas 4 means full functionality.

Authors: ALS Functional Rating Scale Revised (ALS-FRS-R).
Posted: version of May 2015.
Safety and efficacy of edarowon in patients with amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled study

This randomized double-blind parallel trial (Phase III) was attended by patients aged 20-75 years with grade 1 or 2 ALS from 31 hospitals in Japan. Patients had a score of at least 2 for each of all 12 points of ALSFRS-R, a forced vital lung capacity of ≥ 80% and an established or suspected ALS according to the revised El Escorial criteria. Patients with duration of the disease not exceeding 2 years were subject to inclusion.

Between 28 November 2011 and 03 September 2014, 213 patients were examined and 192 potential participants were selected. Of these, 137 patients completed the full period of follow-up: 69 were randomized to receive edaravone, 68 were randomized to receive placebo. 68 patients who were administered edaravone and 66 who received placebo were included in the primary analysis of efficacy. As a result, the change in ALSFRS-R was -5.01±0.64 in the edaravon group and -7.50±0.66 in the placebo group. The difference between the groups was -2.49 (p=0.0013) in favor of edaravone. 58 (84%) patients treated with edaravone and 57 (84%) patients on placebo reported treatment-related side effects. 11 (16%) patients receiving edaravone and 16 (24%) receiving placebo had serious side effects; 1 (1%) patient receiving edaravone and 4 (6%) patients receiving placebo had adverse events (one case of dysphagia in the edaravone group versus one case of dyspnoea, two cases of respiratory disorders and one case of rash in the placebo group), which resulted in withdrawal of these patients from the study.

Therefore, edaravone has proven its effectiveness in patients with amyotrophic lateral sclerosis (ALS) who met the inclusion criteria, demonstrating a significantly lower rate of reduction in the assessment of ALS progression according to ALSFRS-R versus placebo.

Authors: The Writing Group on behalf of the Edaravone (MCI-186) ALS 19 Study Group.
Posted: сайт thelancet.com/neurology, 15 травня 2017.
In 2017, the FDA approved a new drug for the treatment of lateral amyotrophic sclerosis (press release, in English)

On 05 May 2017, US Food and Drug Administration (FDA) approved edaravone as an officially recommended drug product for the treatment of patients with amyotrophic lateral sclerosis (ALS).

The U.S. Food and Drug Administration today approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease.

“After learning about the use of edaravone to treat ALS in Japan, we rapidly engaged with the drug developer about filing a marketing application in the United States,” said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This is the first new treatment approved by the FDA for ALS in many years, and we are pleased that people with ALS will now have an additional option.”

ALS is a rare disease that attacks and kills the nerve cells that control voluntary muscles. Voluntary muscles produce movements such as chewing, walking, breathing and talking. The nerves lose the ability to activate specific muscles, which causes the muscles to become weak and leads to paralysis. ALS is progressive, meaning it gets worse over time. The Centers for Disease Control and Prevention estimates that approximately 12,000-15,000 Americans have ALS. Most people with ALS die from respiratory failure, usually within three to five years from when the symptoms first appear. 

Radicava is an intravenous infusion given by a health care professional. It is administered with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period. Subsequent treatment cycles consist of dosing on 10 of 14 days, followed by 14 days drug-free.

The efficacy of edaravone for the treatment of ALS was demonstrated in a six-month clinical trial conducted in Japan. In the trial, 137 participants were randomized to receive edaravone or placebo. At Week 24, individuals receiving edaravone declined less on a clinical assessment of daily functioning compared to those receiving a placebo.

The most common adverse reactions reported by clinical trial participants receiving edaravone were bruising (contusion) and gait disturbance.

Radicava is also associated with serious risks that require immediate medical care, such as hives, swelling, or shortness of breath, and allergic reactions to sodium bisulfite, an ingredient in the drug. Sodium bisulfite may cause anaphylactic symptoms that can be life-threatening in people with sulfite sensitivity.

The FDA granted this drug orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Radicava to Mitsubishi Tanabe Pharma America, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency is also responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Authors: The U.S. Food and Drug Administration.
Posted: офіційний сайт FDA, травень 2017.