Vascular inflammation underlies the development of atherothrombotic stroke


Pirogov Russian National Research Medical University, Moscow, Russia

Atherothrombotic stroke is the one of the most common subtypes of ischemic cerebral circulatory disorders, the cause of which is atherosclerosis of the major arteries of the brain or their branches. The results of recent studies have shown that the atherosclerotic process is based on an inflammatory process in the vascular wall that leads to the initiation of atherosclerosis, endothelial dysfunction, oxidative stress, and the redistribution of various protein components in the blood-brain barrier. As a result, the progression of the described conditions leads to the manifestation of clinical symptoms and the formation of an acute vascular event. Understanding of the molecular components underlying functional disorders and damages of the cerebral vessels gives the key to modern therapy strategies. It is forming the foundation for the adequate, pathogenetically reasonable drug correction. For such patients, it should be aimed at the normalization of cerebral and central hemodynamics and incorporate the mechanisms of neuroplasticity. The drug 2-ethyl-6-methyl-3-oxypyridine-succinate (mexidol) can be considered as one of the pathogenetically justified agents in complex drug therapy of brain ischemia. Keywords: ischemic stroke, atherosclerosis, vascular inflammation, oxidative stress, endothelial dysfunction, ethylmethylhydroxypyridine succinate.

Efficacy and safety of ethylmethylhydroxypyridine succinate in patients with ischemic stroke


1Research Centre for Examination of Medical Devices, Moscow, Russia;
2Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia;
3Pirogov Russian National Research Medical University, Moscow, Russia;
4Federal Scientific Center — All-Russian Scientific Research Institute of Experimental Veterinary Medicine named after K.I. Skryabin and Ya.R. Kovalenko, Moscow, Russia

Stroke is still the most significant problem of the modern medicine and the leading cause of mortality and morbidity. There is the great experience of neuroprotection in patients with stroke in the Russian Federation. In clinical practice it’s important to follow conditions, where neuroprotection will have maximum safety and effectiveness. The clinical trials of ethylmethylhydroxypyridine succinate (mexidol) in patients with acute ischemic stroke are described in the present review. Early management (in the first 6 hours) with mexidol significantly improve recovery dynamic and stroke outcome. Therapy with mexidol increases neurological recovery, improves vital activity and quality of life of patients with stroke. Furthermore, mexidol demonstrates high safety profile. Keywords: ischemic stroke, thrombolytic therapy, clinical trial, disability, antioxidant system, ethylmethylhydroxypyridine succinate, Mexidol.

The trial of the efficacy and safety of sequential therapy with mexidol forte 250 in acute and early recovery stages of hemispheric ischemic stroke



Magnitogorsk Irong&Steel Clinical Hospital, Magnitogorsk, Russia

Objective. To evaluate the efficacy and safety of sequential therapy with mexidol (solution for intravenous and intramuscular injections) and mexidol forte 250 (coated tablets) in acute and early recovery stages of hemispheric ischemic stroke. Material and methods. The changes in scores on the modified Rankin Scale (mRs) (primary endpoint), the National Institute of Health Stroke Scale (NIHSS), the Bartel Index (BI), the Montreal Cognitive Assessment (MoCa), the Beck Depression Inventory (BDI), the EuroQol Quality of Lifes Scale ( EQ–5D) were assessed in the end of treatment (secondary endpoint). Results and Conclusion. Prolonged and sequential therapy with mexidol at the dose 500 mg daily during 14 days (saturation phase) and mexidol forte 250 at the dose of 250 mg three times a day during 60 days (maximum therapeutic effect) provides additional opportunities for a more complete recovery in acute and early recovery stages of hemispheric ischemic stroke (increases quality of life, improves movement and cognitive functions). Keywords: hemispheric ischemic stroke, mexidol forte 250, acute and early recovery stages, quality of life.

Efficacy and safety of Mexidol across age groups in the acute and early recovery stages of hemispheric ischemic stroke (results of additional sub-analysis of a randomized double blind multicenter placebo-controlled study, in parallel groups trial EPICA)



1Pirogov Russian National Research Medical University, Moscow, Russia;
2Russian Clinical and Research Center of Gerontology of Pirogov Russian National Research Medical University, Moscow, Russia;
3Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical (Sechenov University),
Moscow, Russia;
4Russian Medical Academy of Continuous Professional Education, Moscow, Russia

Aim. To evaluate the efficacy and safety of prolonged sequential therapy with mexidol in the acute and early recovery stages of hemispheric ischemic stroke (IS) across age groups according to the World Health Organization classification. Material and methods. The study is an additional analysis across age groups among patients participated in the randomized double blind multicenter placebo-controlled, in parallel groups trial EPICA. All subjects (62 men and 88 women) were subdivided into age groups: younger than 60 years, 60—65 years, 76—90 years. Additionally, all participants were divided into 2 populations: ITT (Intent to treat population, patients who received at least one treatment/placebo dose) and PP (Per protocol population, patients who received treatment per study protocol). Results of Modified Rankin scale (mRs) at the end of treatment period, Barthel index, Beck depression inventory, European Quality of Life Questionnaire were assessed. Results. The efficacy of mexidol assessed with all the scales did not differ depending on the age group. By the end of treatment, the mean mRS score was lower in the 76-90 years subgroup (in both populations), compared to placebo (p<0,001). The decrease in mean mRS score (Visit 1—5) was more prominent in patients aged 60—65 years (p=0,025), including patients with diabetes mellitus (DM). Patients aged 76—90 years and patients with DM, compared to placebo, had a decrease of the severity of cognitive-affective depression symptoms (p=0,049 and p=0,02) and an increase in patients without problems with everyday activities (p=0,007 and p=0,02). Patients with DM, compared to placebo, also had the higher levels of everyday activity (p=0,023) and quality of life (p=0,045). There were no statistically significant differences in the frequency of side-effects in patients of all groups. Conclusion. It is recommended to include mexidol in therapy of patients with IS in the acute and early rehabilitation stages in all age groups, including patients with DM. Keywords: ischemic stroke, mexidol, ethylmethylhydroxypyridine succinate, efficacy and safety, ischemic stroke, acute period, acute rehabilitation period, EPICA.

Results of a Randomized, Double-Blind, Multicenter, Placebo-Controlled, Parallel-Group Study of the Efficacy and Safety of Mexidol in Prolonged Sequential Therapy of Patients in the Acute and Early Recovery Stages of Hemispheric Stroke (the EPICA study)

L. V. Stakhovskaya1, N. A. Shamalov1, D. R. Khasanova2, E. V. Mel’nikova3, A. S. Agaf’ina4, K. V. Golikov5, E. I. Bogdanov6, A. A. Yakupova6, L. V. Roshkovskaya7, L. V. Lukinykh8, T. M. Lokshtanova9, I. E. Poverennova10, and L. A. Shchepankevich11

1 Research Institute of Cerebrovascular Pathology and Stroke, Pirogov Russian National Research Medical University, Russian Ministry of Health, Moscow, Russia; e-mail:

2 Interregional Clinical Diagnostic Center, Kazan, Russia.

3 St. Petersburg City Clinical Hospital No. 26, St. Petersburg, Russia.

4 St. Petersburg City Clinical Hospital No. 40 of the Resort Administrative District, St. Petersburg, Russia.

5 St. Petersburg City General Hospital No. 2, St. Petersburg, Russia.

6 Kazan Sate Medical University, Russian Ministry of Health, Kazan, Russia.

7 Nikolaevskaya Hospital, St. Petersburg, Russia.

8 Vsevolzhsk Clinical Interregional Hospital, Leningradskaya Oblast, Russia.

9 Pirogov City Clinical Hospital No. 1, Samara, Russia.

10 Seredavin Samara Regional Clinical Hospital, Samara, Russia.

11 Research Institute of Experimental and Clinical Medicine, Novosibirsk, Russia.

Objectives. To assess the effi cacy and safety of prolonged sequential therapy with Mexidol in patients with hemispheric ischemic stroke (IS) in the acute and early recovery phases. Materials and methods. A randomized, double-blind, multicenter, placebo-controlled, parallel-group study included 151 patients (62 men and 89 women) was performed in which 150 patients (62 men and 88 women) aged 40–79 years were randomized. Simple randomization was used to defi ne two groups: patients of group 1 received Mexidol therapy at a dose of 500 mg/day by intravenous infusion for 10 days followed by oral doses of 1 tablet (125 mg) three times a day for eight weeks. Patients of group 2 received placebo by the same protocol. The duration of involvement in the trial was 67–71 days. Results. At the end of treatment, mean scores on the modified Rankin scale (mRS) were lower in group 1 than group 2 (p = 0.04). Decreases in mean mRS scores (at visits 1–5) were more marked in group 1 (p = 0.023). The proportion of patients achieving recovery corresponding to 0–2 points on the mRS (at visit 5) was signifi cantly greater in group 1 (p = 0.039). Testing on the National Institutes of Health Stroke Scale at visit 5 gave a signifi cantly lower score in group 1 (p = 0.035). Decreases in scores on the National Institutes of Health Stroke Scale at the end of treatment relative to the baseline level in patients with diabetes mellitus were more marked in group 1 (p = 0.038). In group 1, the total population and the subpopulation of patients with diabetes mellitus showed more marked improvements in quality of life, which was apparent by visit 2. The proportion of patients without diffi culty mobilizing was signifi cantly greater in group 1 (p = 0.022). There were no signifi cant differences in the frequencies of adverse events in patients of the two groups. Conclusions. Use of Mexidol in the acute and early recovery phases of IS is recommended. Keywords: acute cerebrovascular accident, Mexidol, ethylmethylhydroxypyridine succinate, effi cacy and safety, ischemic stroke, acute phase, early recovery phase, EPICA.

The efficacy of ethylmethylhydroxypyridine in the rehabilitation treatment of poststroke patients


1 Research center for examination of medical devices, Moscow, Russia

2 Sechenov First Moscow state medical University (Sechenov University), Moscow, Russia

The analysis of the clinical efficacy and safety of ethylmethylhydroxypyridine succinate (mexidol) in the complex of rehabilitation measures in patients after ischemic stroke (IS) shows that course treatment with mexidol improves the recovery of neurological functions, decreases neurological deficit, cognitive disorders, including memory impairment, and manifestations of asthenic syndrome, increases the level of social adaptation and improves the psycho-emotional state of patients, reduces spasticity, increases motor and speech activity, praxis, reliably eliminates the ignoring syndrome. There is a decrease in the level of total cholesterol and low-density b-lipoproteins in the blood, and decrease in the severity of hypercoagulation. The results of the studies have convincingly shown the efficacy of mexidol at all stages of rehabilitation treatment of patients with IS.
Keywords: ethylmethylhydroxypyridine succinate, mexidol, rehabilitation, recovery, stroke.

Efficacy and safety of the drug Mexidol forte 250 as part of long-term sequential therapy in patients with carotid stroke


1 Samara Regional Clinical Hospital named after V.D. Seredavina, Samara, Russia;

2 Samara State Medical University, Samara, Russia

Objective. To evaluate an effect of long-term sequential therapy with mexidol and mexidol forte on the functional outcome of patients with carotid ischemic stroke. Material and methods. The study included 50 patients with newly developed carotid stroke, hospitalized in the stroke unit on the first day from the onset of the disease. Patients of the main group (n=25) received mexidol in a dose of 500 mg intravenously once a day for 14 days, then mexidol forte 250 in tabs 250 mg 3 times a day for 60 days. Patients of the comparison group (n=25) received standard basic therapy. The significance of intergroup differences was assessed using the Mann—Whitney test, Fisher’s exact test, and relative risk (OR) calculation. Differences were considered significant at a level of p<0,05. Results. After 14 days of therapy, both groups of patients showed a positive trend compared to baseline. At the same time, patients of the mexidol group had a higher MoCA score (U=173,5, p=0,006), a lower score when performing tasks on dynamic praxis (U=214,0, p=0,028) and optical spatial disturbances (U=170,5, p=0,003), better memorization strength (181,5, p = 0,006) and better performance on abstraction MOCA subtest (U=200,5, p=0,014). By the 74th day, the absence of moderate cognitive impairment (MoCA> 26 points) was diagnosed in 17 patients (68%) of the main group and 14 patients (56%) of the comparison group. No significant differences were found. Moreover, patients of the main group had a significantly lower NIHSS score (U=124,0, p<0,001) and a lower degree of disability: a total mRS score 0—2 was achieved in 19 (76%) patients of the main group and only in 12 (48%) patients of the comparison group (OR=3,34, F=0,07, p<0,05). Also, patients receiving long-term sequential therapy with mexidol and mexidol forte 250 had milder spatial disorders than patients of the comparison group. Conclusion. Consecutive treatment with mexidol and mexidol forte 250 in the acute and early recovery periods of ischemic stroke positively affects the regression of local neurological symptoms, increases the likelihood of achieving independence in everyday life by 3,34 times, and reduces the severity of optical-spatial, neurodynamic and memory impairments.
Keywords: ischemic stroke, mexidol, mexidol forte 250, cognitive impairment, functional outcome.

Review of clinical guidelines for the treatment and prevention of ischemic stroke


Pirogov Russian National Research Medical University, Russian Ministry of Health, Moscow, Russia

One of the leading causes of death, disability and severe maladaptation of patients is ischemic stroke, which accounts for about 80% of all types of acute cerebrovascular accidents. At the same time, approximately 2/3 of the patients show residual effects of cerebral circulation disorders of varying severity. Currently, the problem of ischemic stroke attracts great attention and international and domestic recommendations developed for the prevention, treatment and rehabilitation of stroke patients are one of the aspects of work in this area. The article provides an overview of the latest clinical guidelines for the early management of patients with acute ischemic stroke of the American Heart Association and the American Stroke Association, as well as features of stroke therapy and prevention in Russia, Europe and USA. Keywords: ischemic stroke, clinical guidelines, therapy of ischemic stroke.

Pharmacoeconomic analysis of the neuroprotective medicines in the treatment of ischemic stroke


1Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia;
2Pirogov Russian National Research Medical University N.I.Pirogov Russian National Research Medical University of the Ministry of Health
of Russia, Moscow, Russia

Objective. To perform a pharmacoeconomic analysis of the most frequently prescribed neuroprotective medicines for treating patients with mild ischemic stroke in the acute and early rehabilitation periods in the Russian Federation. Material and methods. Three medical technologies were compared: ethylmethylhydroxypyridine succinate (mexidol), inosine + nicotinamide + riboflavin + succinic acid (cytoflavin) and a deproteinized hemoderivate of the blood of calves (actovegin). Cost minimization analysis, budget impact analysis and sensitivity analysis were performed based on the indirect comparison results. Results. Efficacy analysis shows that mentioned above medicines have the same efficacy: mean difference mexidol is 0,2 (CI min 0,25; max 0,65), cytoflavin — 0,61 (CI min 0,23; max 0,99), actovegin 0,2 (CI min 0,18; max 0,22). The cost minimization analysis for the Russian Federation shows that mexidol therapy is associated with the lowest costs, while savings are observed both in the evaluation of total costs and separate components: intravenous ampoules and tablet forms. The savings in comparison with cytoflavin and actovegin are 231 RUB and 12,872 RUB, respectively. These savings will be enough to treat five patients with ischemic stroke (IS) with mexidol. Moreover, oral mexidol therapy is cheaper than the same dosage forms of cytoflavin and actovegin by 481 RUB and 3,164 RUB, respectively. This is an advantage for the treatment of population at the outpatient stage. Budget impact analysis has shown that the budget for the medicines for treating IS at the current distribution between treatment regimens, is estimated at 1.99 BN RUB. The increase in the proportion of patients receiving mexidol by 10% reduces total costs to 1.75 BN RUB, which is 240 M RUB less than current costs. With these savings 85 thousand patients with IS could be treated. The sensitivity analysis reveals that the result of the cost minimization analysis and the budget impact analysis remain stable when both the amount of the population and the cost of 1 mg of mexidol vary from –10% to + 10%. Conclusions. Mexidol has the same efficacy as alternatives. However mexidol is superior to cytoflavin and actovegin in terms of cost minimization analysis. The savings from one course of alternatives will cover costs of treatment of five patients with IS using mexidol. The increase in the proportion of patients receiving mexidol is associated with savings, which allows us to consider mexidol therapy of mild IS as budget-saving in the Russian Federation. Keywords: pharmacoeconomics, indirect comparison, cost minimization analysis, budget impact analysis, neuroprotectors, ischemic stroke.

Evaluation of blood rheology by patients with acute ischemic stroke with Mexidol administration


1 Department of Neurology and Neurosurgery, Siberian State Medical University, Tomsk, Russia;
2 Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia

Objective. To study rheological properties of blood in patients with acute ischemic stroke treated with mexidol. Material and methods. Sixty patients with acute stroke, including 32 patients who received mexidol (500 mg/IV/20 days) and 28 people who received magnesium sulfate (2000 mg/IV/20 days) were examined. The control group included 20 people without a cardiovascular pathology. Blood rheology (viscosity of whole blood, plasma viscosity, hematocrit, aggregation and deformability of erythrocytes, fibrinogen level) was evaluated in patients three times: for the first 12 hours, 3—5 days and 18—20 days after hospitalization. Results. Hyperviscosity syndrome was observed in all patients with stroke. A significant decrease in blood viscosity was found in patients treated with mexidol: in the 3–5th day at low shear rates and in the 18—20th day at 3—100 s–1 shear rates. Significant differences in hematocrit (p=0.026) and fibrinogen levels (p=0.017) in patients treated with different drugs were found in the 18—20th day of the disease. Higher erythrocyte deformability index was recorded in patients treated with mexidol in the 3—5th day at shear rates of 90 and 890 s–1, in the 18—20th day at shear rates of 90—360 s–1. Conclusion. The study confirms the impact of mexidol on the fluidity of blood during the acute cerebral ischemia and shows its efficacy in reducing blood viscosity, decreasing the level of hematocrit and fibrinogen, increasing the deformability of erythrocytes.
Keywords: acute ischemic stroke, rheological parameters of blood, blood viscosity, erythrocytes deformability, mexidol (ethylmethylhydroxypyridine succinate), treatment of stroke.