WO2019088881A1 - Edaravone combinations for treating ischemic brain damage - Google Patents

Abstract

The present invention relates to a combination of edaravone with at least one substance selected from the group consisting of ebselen, resveratrol, uric acid, dehydroascorbic acid and disufenton sodium for the treatment of acute cerebrovascular accident (ACVA) (ischemic stroke) with the aim of decreasing neurological symptoms and decreasing impairment of the patient's performance of everyday activities, as well as decreasing the CNS function impairment associated with stroke; amyotrophic lateral sclerosis (ALS), with the aim of slowing the progression of CNS functional impairments; transitory ischemic attack (TIA), in the acute period and after the attack has occurred; chronic cerebral ischemia; and cognitive and behavioral disorders in the case of cerebrovascular diseases.

Description

 EDARAVON COMBINATIONS FOR TREATMENT OF ISCHEMIC

 BRAIN DAMAGE

The present invention relates to the combination of Edaravone with at least one substance selected from the group including ebselen, resveratrol, uric acid, dehydroascorbic acid and disufentone.

 This combination is used to treat:

 - acute cerebrovascular accident (ONMK) - a stroke of the ischemic type in order to reduce neurological symptoms, disorders in the performance of the patient’s daily actions, as well as functional disorders of the central nervous system associated with stroke,

 - amyotrophic lateral sclerosis (ALS) in order to slow the progression of CNS functional disorders,

 - transient ischemic attack (TIA) in the acute period and after the attack suffered,

 - chronic brain ischemia,

 - cognitive and behavioral disorders in vascular diseases of the brain,

 - neurodegenerative diseases.

Every year in the Russian Federation, all forms of stroke are recorded in more than 500,000 people. Cerebral infarctions or ischemic strokes account for 65-75%, transient ischemic attacks (TIA) - 10-15%, hemorrhagic strokes - 15-20% of all forms of stroke.

 The frequency of cerebral strokes among persons over 50-55 years old increases in 1, 8-

2 times in each subsequent decade of life.

 Fatalities in the acute period of stroke occur in 34.6%, and in the first year after the end of the acute period - in 13.4%; severe disability with the need for permanent care is present in 20.0% of stroke patients. 56.0% of people have disabilities, and only 8.0% return to their previous work activities.

Disability due to stroke ranks first among all causes of primary disability and is 3.2 per 10,000 population. Thus, increasing the effectiveness of medicines aimed at treating various forms of stroke is one of the acute problems of modern medicine, the solution of which is essential for improving public health.

 Edaravone

 Edaravone (Edarovone, MCI- 186) is a synthetic antioxidant used in the form of a solution for intravenous administration (30 mg / 20 ml, ampoules), with a neuroprotective effect proven in randomized clinical studies (RCT) during an acute and reducing period in ischemic stroke, which manifests itself in the form of improving the functional state of the central nervous system (motor function, the intellectual, sensitive and emotional sphere), as well as reducing the degree of disability (the ability to self-service and the implementation of daily activities).

 Chemical name: 5-methyl-2-phenyl-2,4-dihydro-ZN-pyrazolid-3-one. Structural formula:

Edaravone is a colorless or pale yellowish crystals or crystalline powder. It is freely soluble in ethanol (99.5) and in acetic acid (100) and slightly soluble in water.

 Edaravone was developed in the late 1980s as a free radical scavenger as a treatment for stroke. The treatment method using Edaravona, introduced by Koji Abe at Okayama University Hospital in Japan, was aimed at preventing brain swelling that can occur after a stroke.

Edaravon has been marketed in Japan by Mitsubishi Pharma for the treatment of stroke since 2001 and is currently a generic drug. Currently, Edaravon, sold under the Radicava and Radicut brands, is an intravenous medication used to recover from a stroke and treat amyotrophic lateral sclerosis (ALS).

 The exact mechanism of its action is unknown. It is known that the drug is an antioxidant, and, as expected, oxidative stress is part of the process that leads to the death of neurons in patients with ALS.

 It is known that free radicals, such as hydroxyl radical (OH), play a major causal role in the development of cerebral vascular disorder caused by ischemia. With ischemia or ischemic reperfusion, hyperactivity of the arachidonic acid metabolic system increases the formation of free radicals. These free radicals oxidize unsaturated fatty acids of cell membrane lipids, which leads to damage to the cell membrane and, ultimately, to cerebral dysfunction.

 Although the etiology of the development and progression of ALS is unknown, the possible involvement of oxidative stress caused by free radicals in the pathogenesis of this disease is assumed. Edaravone removes free radicals and inhibits lipid peroxidation and thus is supposed to prevent oxidative damage to brain cells (vascular endothelial cells / nerve cells).

 Indications for use of Edaravona include:

 1. improvement of neurological symptoms, relief of the disturbance of the activity of everyday life and functional disorders associated with acute ischemic stroke;

 2. inhibition of the progression of functional disorder in patients with ALS.

 Ebselen

Ebselen (also called PZ 51, DR3305 and SPI-1005) is a free radical scavenger, a synthetic drug molecule with anti-inflammatory, antioxidant and cytoprotective activity. It acts as an analogue of glutathione peroxidase and can also react with peroxynitrite. Chemical name: 2-phenyl-1,2-benzizoselenazol-3 (2H) - it. Structural formula:

 Ebselen is being investigated as a possible remedy for the treatment of reperfusion brain damage and stroke, hearing loss and tinnitus, as well as bipolar disorder.

 In addition, Ebselen can be effective against infections caused by Clostridium difficile.

 Ebselen is a powerful absorber of hydrogen peroxide, as well as hydroperoxides, including membrane-bound hydroperoxides of phospholipids and cholesterol esters. It has been shown that several ebselen analogs remove hydrogen peroxide in the presence of thiols.

 Resveratrol

 Resveratrol is a strong antioxidant, a neuroprotector. The first mention of resveratrol was published in a Japanese article in 1939 by Michio Takaoka Michio Takaoka, who isolated it from a plant of the family Veratrum, a species of grandiflorum, and later, in 1963, from the roots of the Japanese spoon.

 Chemical name: 3,5,4'-trihydroxy-trans-stilbene. Structural formula:

It is a stilbenoid, a type of natural phenol and phytoalexin produced by some plants in response to damage, or when the plant is exposed to pathogens such as bacteria or fungi. The sources of resveratrol in food are the skin of grapes, blueberries and raspberries. Although resveratrol is used as a dietary supplement, there is no clear evidence that resveratrol consumption affects human longevity or health.

 Resveratrol derivatives are known, such as trans-3,5,4'-trihydroxy-stilbene; 3,4 ', 5-stilbentriol; trans resveratrol.

 In 201 1, a systematic review of existing studies of resveratrol showed that by this time there is insufficient evidence of its effect on the life expectancy or illness in humans, and there are no recommendations for its consumption beyond the amount usually obtained from food, which is estimated to be less than 4 mg / day. Most of the studies showing the positive effects of resveratrol have been carried out on animals, and at the same time there are not enough clinical studies on humans. In this regard, currently resveratrol is being actively studied in animals and humans.

 Resveratrol is being studied as a possible drug to reduce complications from ischemic stroke or acute brain injury.

 Uric acid

 Uric acid can act as an antioxidant, a physiological absorber of peroxynitrite. It is a colorless crystals, poorly soluble in water, ethanol, diethyl ether, soluble in alkali solutions, hot sulfuric acid and glycerin.

Uric acid is a well-known natural antioxidant present in fluids and tissues throughout the body. It is believed that oxygen free radicals and cellular calcium overload contribute to the damage and death of neurons that occur after cerebral ischemia in stroke victims. Uric acid protects rat hippocampal cultured neurons from death caused by damage associated with the pathogenesis of cerebral ischemia, including the effects of glutamate - a stimulating amino acid, and cyanide - a metabolic poison.

 Uric acid inhibits the accumulation of reactive oxygen species (hydrogen peroxide and peroxynitrite) and lipid peroxidation associated with various types of stroke. Mitochondrial function, impaired by excitotoxic and metabolic strokes, is retained in neurons treated with uric acid.

 Uric acid has a neuroprotective effect, which includes suppressing the accumulation of oxygen free radicals, stabilizing calcium homeostasis and preserving mitochondrial function, indicating a potential therapeutic use of uric acid in ischemic stroke and related neurodegenerative conditions.

 Dehydroascorbic acid

 Dehydroascorbic acid is an oxidized derivative of ascorbic acid. The chemical composition of ascorbic acid is 2,3-dienol-gulonic acid lactone. Ascorbic acid — an oxidized derivative of sorbitan hexatomic alcohol — is characterized by the presence of a diene group, which determines the ability of vitamin C to easily undergo oxidation with the simultaneous reduction of other compounds.

 Ascorbic acid is a colorless crystals, easily soluble in water, strongly acidic taste. Insoluble in benzene, chloroform, diethyl ether, fats. Aqueous solutions of ascorbic acid are acidic. Ascorbic acid is easily oxidized, forming dehydroascorbic acid, which retains its vitamin value.

Dehydroascorbic acid is a very unstable compound and, when reduced, is converted back to ascorbic acid. This property of vitamin C determines its active participation in redox processes. Ascorbic and dehydroascorbic acids are active components of electron transfer processes. At pH 7 (and above), dehydroascorbic acid is irreversibly oxidized to L-diketogulonic acid, which no longer has the properties of vitamin C. Vitamin C is involved in many enzymatic reactions, as an activator or inhibitor of a number of enzymatic systems. The oxidation of ascorbic acid easily occurs in a neutral and alkaline environment; it is catalyzed by heavy metal ions (copper, iron, silver). In an acidic environment, the reducing properties of ascorbic acid are much less pronounced.

 The daily human need for vitamin C depends on the age, physiological state and severity of the work and amounts to 70–120 mg for adults and 30–70 mg for children.

 Ascorbic acid Dehydroascorbic acid (reduced form) (oxidized form) WO 2001089520 discloses that dehydroascorbic acid, being a transport form of vitamin C, passes the blood-brain barrier and provides reliable neuroprotection after a stroke in mice.

 It is also known that the toxicity of dehydroascorbic acid is unexpectedly and significantly reduced when administered as a buffer composition. And buffered preparations of dehydroascorbic acid reduce the effects of ischemia in the mouse model of stroke, even with the introduction of a few hours after the induction of ischemia.

It was also shown (Huang J. et al., PNAS, 2001) that, in contrast to exogenous ascorbic acid, which did not affect infarct volume, mortality and complications of stroke, dehydroascorbic acid creates dose-dependent neuroprotection in vivo in reperfused and non-reperfusion cerebral ischemia. . Thus, as a natural form of ascorbic acid, which is able to pass the blood-brain barrier, dehydroascorbic acid is a promising pharmacological agent for stroke therapy.

 Sodium disufenton

 Sodium disufenton (NXY-059, the commercial name of the drug is Cerovive) is a free radical scavenger that is a disulphonyl derivative of the neuroprotective spin-trap phenylbutylnitron (PBN).

 AstraZeneca is currently conducting clinical trials of the drug. The first series of clinical trials showed that sodium disufenton has a neuroprotective effect in the treatment of stroke, but problems have arisen with the reproducibility of the results. Currently, studies of sodium disufenton as one of the potential potent neuroprotectors continue.

 The relevance of the present invention

 According to the Federal Clinical Recommendations (2013), based on the recommendations of the European Union (ESO, 2008) and the United States (AHA / ASA) (2008, 2015), the goals of the treatment of stroke include:

 (1) reducing the risk of early neurological complications,

 (2) improved functional outcome; (3) reduced risk of cardiovascular complications.

 Drug therapy for stroke (existing treatment technologies) includes the following approaches.

(1) Drug-induced thrombolysis (the goal is to restore perfusion): all patients with stroke after 4.5 hours from the beginning of the development of the disorder are candidates for intravenous thrombolytic therapy. Patients who received intravenous tissue plasminogen activator (Alteplaza) for 4.5 hours from the beginning of the development of symptoms, after 3 months. characterized by 30% lower level of neurological deficit / lack of it compared with placebo (class I, grade A).

 (2) Antiplatelet drugs (the goal is to reduce the risk of recurrent blood clots): acetylsalicylic acid (ASA) at a dose of 100-325 mg / day is shown for 48 hours after the onset of stroke, ASA should not be considered as an alternative to intravenous thrombolysis. ASA is not prescribed when planning thrombolytic therapy.

 (3) Anticoagulants (the goal is to reduce the risk of recurrent blood clots): the effectiveness of subcutaneous administration of unfractionated heparin in low and medium doses, low molecular weight heparins when administered in the first 24 to 48 hours from developing a stroke has not been proven. Subcutaneous administration of heparin or low molecular weight heparins is indicated in patients with a high risk of venous thrombosis and pulmonary embolism (obesity, diabetes, prolonged immobilization).

 (4) Neuroprotection (the goal is to ensure the survival of neurons in conditions of hypoperfusion and stabilization of the penumbra zone). The use of nootropics, antioxidants, metabolic drugs.

 Currently, the only drug used in ischemic stroke, which allows to quickly restore the patency of cerebral vessels and thereby reduce the number of dead neurons, is recombinant tissue plasminogen activator. According to open sources, about 2% -5% of patients with ischemic stroke have a medical thrombolysis (the main reason is limited access to CT, thrombolysis is effective only in a strictly limited period of time).

 Neuroprotection is the only alternative method for the treatment of stroke, thus, the introduction of neuroprotectors with a proven clinical effect in the practice of the treatment of stroke is an important task.

At the moment, the development of combinations of Edaravona with other substances is a promising direction in the treatment of all types of stroke. The closest analogue of the combination proposed in this application is the combination of Edaravone with borneol, which by itself, without any action, can increase the effectiveness of the drug with which it is used together, speaking in as an adjuvant (WO 2009109132 Al, JIANGSU SIMCERE PHARMACEUTICAL, September 11, 2009). The disadvantage of this solution is a slight increase in the effectiveness of Edaravone, and therefore the further development of drugs with increased antioxidant activity remains relevant.

 The present invention is the creation of new highly effective drugs for the treatment of ONMK, BAS, TIA, chronic brain ischemia, cognitive and behavioral disorders in vascular brain diseases, neurodegenerative diseases. Edaravone

 Technical results:

 - an increase in the antioxidant effect, which consists in the ability to absorb free radicals, due to the synergistic effect of the combination of Edaravone with ebselenom, resveratrol, uric acid, dehydroascorbic acid and / or disufentone;

 - Improving the effectiveness of treatment of acute cerebral circulatory disorders (ONMK), amyotrophic lateral sclerosis (ALS), transient ischemic attack (TIA) in the acute period and after an attack, chronic brain ischemia, cognitive and behavioral disorders in vascular diseases of the brain;

 - expansion of the arsenal of drugs for the treatment (complex therapy) of stroke,

ALS, TIA, chronic cerebral ischemia, cognitive and behavioral disorders in vascular diseases of the brain, neurodegenerative diseases.

The task is solved, and the technical result is achieved by creating a combination for the treatment of acute cerebral circulatory disorders (ONMK), amyotrophic lateral sclerosis (ALS), transient ischemic attack (TIA) in the acute period and after the previous attack, chronic brain ischemia, cognitive and behavioral disorders in vascular diseases of the brain, neurodegenerative diseases containing in effective amounts (a) Edaravon and (b) at least one, two, three, four or five substances selected s of the group consisting of Ebselen, resveratrol, uric acid, and dehydroascorbic acid disufentona. According to preferred embodiments, the specified technical result is also achieved by the fact that:

 - the combination is in the form of a solution for injection;

 - the combination is in liposomal form;

 - the above-mentioned combination of active ingredients are in the following daily dosages:

 Edaravone 30 - 700 mg / day;

 Ebselen 200 - 3,600 mg / day;

 Resveratrol 2 - 5 000 mg / day;

 Uric acid 250 to 2000 mg / day;

 Dehydroascorbic acid 7 000 - 35 000 mg / day;

 Sodium disufenton 500 - 6 000 mg / day.

 - active substances in the above-mentioned combination are in the following preferred mass ratios:

 Edaravone: Ebselen from 1: 120 to 3.5: 1,

 Edaravone: resveratrol from 1: 166.6 to 350: 1,

 Edaravone: uric acid from 1: 66.6 to 2.8: 1,

 Edaravone: dehydroascorbic acid from 1: 1 166.6 to 1:10,

 Edaravone: sodium disufenton from 1: 200 to 1.4: 1.

 - said combination further comprises substances selected from the group consisting stilbazulenilnitron, oksiresveratrol, Ν-tert butilfenilnitron, skutellarin, choline alphosceratus, citicoline sodium, piracetam, lipoic acid, Ν-acetylcysteine, ascorbic acid, succinic acid, taurine, inosine, caffeine , sodium (E) -3- [4- (1H-imidazol-1 -ylmethyl) phenyl] -2-propenoate and other inhibitors of thromboxane synthase, argatroban and other inhibitors of thrombin, glutathione monoethyl ether, puerarin, butylphthalide and palmitoyl ethanolamide.

The problem is solved, and the claimed technical result is also achieved with a pharmaceutical composition for treating stroke, BAS, TIA in the acute period and after suffering an attack, chronic brain ischemia, cognitive and behavioral disorders in vascular diseases of the brain, containing a combination of (a) Edaravone and (b ) at least one substance selected from the group consisting of ebselen, resveratrol, uric acid, dehydroascorbic acid and disufenton in effective amounts, as well as at least one excipient and / or at least one pharmaceutically acceptable carrier.

 According to preferred embodiments, the specified technical result is also achieved by the fact that:

 - the above composition is in the form of a solution for injection;

 - the said composition is in liposomal form;

 - in the above-mentioned composition, the active ingredients are in the following preferred daily dosages:

 Edaravone 30 - 700 mg / day;

 Ebselen 200 - 3,600 mg / day;

 Resveratrol 2 - 5 000 mg / day;

 Uric acid 250 to 2000 mg / day;

 Dehydroascorbic acid 7 000 - 35 000 mg / day;

 Sodium disufenton 500 - 6 000 mg / day.

 - in the above-mentioned composition, the active substances are contained in preferred weight ratios:

 Edaravone: Ebselen from 1: 120 to 3.5: 1,

 Edaravone: resveratrol from 1: 166.6 to 350: 1,

 Edaravone: uric acid from 1: 66.6 to 2.8: 1,

 Edaravone: dehydroascorbic acid from 1: 1 166.6 to 1:10,

 Edaravone: sodium disufenton from 1: 200 to 1, 4: 1;

 - said composition further comprises substances selected from the group consisting stilbazulenilnitron, oksiresveratrol, Ν-tert butilfenilnitron, skutellarin, choline alphosceratus, citicoline sodium, piracetam, lipoic acid, Ν-acetylcysteine, ascorbic acid, succinic acid, taurine, inosine, caffeine sodium (E) -3- [4- (1H-imidazol-1-ylmethyl) phenyl] -2-propenoate and other thromboxane synthase inhibitors, argatroban and other thrombin inhibitors, glutathione monoethyl ether, puerarin, butylphthalide and palmitoyl ethanolamide.

The problem is solved, and the claimed technical result is also achieved in a set for the treatment of stroke, BAS, TIA in the acute period and after an attack, chronic cerebral ischemia, cognitive and behavioral disorders in vascular diseases of the brain, containing instructions for use and effective amounts of a combination of (a) Edaravona and (b) at least one substance selected from the group consisting of ebselen, resveratrol, uric acid, dehydroascorbic acid and disufenton, and optionally, at least one pharmaceutically acceptable excipient.

 According to preferred embodiments, the specified technical result is also achieved by the fact that:

 - in the above kit, the active ingredients are in the following preferred daily dosages:

 Edaravone 30 - 700 mg / day;

 Ebselen 200 - 3,600 mg / day;

 Resveratrol 2 - 5 000 mg / day;

 Uric acid 250 to 2000 mg / day;

 Dehydroascorbic acid 7 000 - 35 000 mg / day;

 Sodium disufenton 500 - 6 000 mg / day.

 - the above-mentioned set, in which the active substances are contained in the preferred mass ratios:

 Edaravone: Ebselen from 1: 120 to 3.5: 1,

 Edaravone: resveratrol from 1: 166.6 to 350: 1,

 Edaravone: uric acid from 1: 66.6 to 2.8: 1,

 Edaravone: dehydroascorbic acid from 1: 1 166.6 to 1:10,

 Edaravone: sodium disufenton from 1: 200 to 1, 4: 1;

 - the above-mentioned set additionally contains substances selected from the group including stilbasulenilnitron, oxyresveratrol, α-tert-butyl phenyl nitrone, scutellarine, choline alphoscerate, citicoline sodium, piracetam, lipoic acid, α-acetylcysteine, ascorbic acid, succinic acid, tauru-trans-citrate, tauronic acid, tauronic acid, toluene acid, ascorbic acid, succinic acid, lipoic acid, β-acetylcysteine, ascorbic acid, succinic acid , caffeine, sodium (E) -3- [4- (1H-imidazol-1-methylmethyl) phenyl] -2-propenoate and other thromboxane synthase inhibitors, argatroban and other thrombin inhibitors, glutathione monoethyl ether, puerarin, butylphthalide and palmitoyl ethanol amide;

The problem is solved, and the claimed technical result is also achieved by applying the specified combination, composition or kit for treatment of ONMK, ALS, TIA in the acute period and after an attack suffered, chronic cerebral ischemia, cognitive and behavioral disorders in vascular diseases of the brain.

 In another preferred embodiment, the invention relates to the above use, wherein the stroke is a stroke of the ischemic type, as well as functional disorders of the CNS associated with the stroke.

 The problem is solved, and the claimed technical result is also achieved in the method of combined treatment of stroke, ALS, TIA in the acute period and after the attack, chronic cerebral ischemia, cognitive and behavioral disorders in vascular diseases of the brain, where effective amounts are used as neuroprotective drugs the above combination, composition or set.

 According to the preferred embodiments, the said technical result is also achieved by the fact that the stroke is a stroke of the ischemic type, as well as functional disorders of the CNS associated with the stroke.

 The problem is solved, and the claimed technical result is also achieved by the method of combined treatment of stroke, BAS, TIA in the acute period and after an attack, chronic cerebral ischemia, cognitive and behavioral disorders in vascular diseases of the brain, where the mentioned neuroprotective drugs are used in effective amounts combination, said composition, or said set.

 According to preferred embodiments, said technical result is also achieved in that:

 - Onmk is a stroke of the ischemic type, as well as functional disorders of the central nervous system associated with stroke;

 - the introduction of the above-mentioned combination, the said composition or the above-mentioned set is carried out by injection;

 - the active ingredients of the above-mentioned combination are administered in the following preferred daily dosages:

Edaravone 30 - 700 mg / day; Ebselen 200 - 3,600 mg / day;

 Resveratrol 2 - 5 000 mg / day;

 Uric acid 250 to 2000 mg / day;

 Dehydroascorbic acid 7 000 - 35 000 mg / day;

 Sodium disufenton 500 - 6 000 mg / day;

 - active ingredients of the above combination are in preferred mass ratios:

 Edaravone: Ebselen from 1: 120 to 3.5: 1,

 Edaravone: resveratrol from 1: 166.6 to 350: 1,

 Edaravone: uric acid from 1: 66.6 to 2.8: 1,

 Edaravone: dehydroascorbic acid from 1: 1 166.6 to 1:10,

Edaravone: sodium disufenton from 1: 200 to 1, 4: 1;

 - mentioned composition is administered in the following preferred daily dosages:

 Edaravone 30 - 700 mg / day;

 Ebselen 200 - 3,600 mg / day;

 Resveratrol 2 - 5 000 mg / day;

 Uric acid 250 to 2000 mg / day;

 Dehydroascorbic acid 7 000 - 35 000 mg / day;

 Sodium disufenton 500 - 6 000 mg / day.

A dosage form containing (a) Edaravone and (b) at least one, two, three, four or five substances selected from the group consisting of ebselen, resveratrol, uric acid, dehydroascorbic acid and disufentone, in effective amounts, as well as Optionally, excipients may be a dosage form for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ophthalmic, aural, local, buccal, nasal and m a natural introduction.

The dosage form may be selected from the group consisting of liquid dispersions, solutions, emulsions, gels, aerosols, ointments, creams, lyophilized preparations, tablets, capsules, controlled preparations release, sustained-release preparations, sustained-release preparations, pulsed-release preparations, and mixed rapid release and controlled release preparations.

 Edaravone and at least one, two, three, four or five substances selected from the group consisting of Ebselen, resveratrol, uric acid, dehydroascorbic acid and disufentone are prepared as one or more pharmaceutical compositions by mixing them with pharmaceutically acceptable excipients. Then from the resulting pharmaceutical compositions receive one or more individual dosage forms.

 The selection of specific excipients is carried out depending on the intended route of administration and dosage form, as known to a person skilled in the art. Suitable pharmaceutical carriers, excipients and their compositions are described, for example, in Remington: The Science and Practice of Pharmacy 1995, edited by E.W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania.

Pharmaceutically acceptable excipients can be selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary and dispensing agents, delivery vehicles, such as preservatives, stabilizers, fillers, dispersants, humectants, emulsifiers, suspending agents. , thickeners, sweeteners, fragrances, flavors, antibacterial agents, fungicides, lubricants, prolonged delivery regulators, choice the ratio of which depends on the nature of the active ingredients, mode of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, such as parabens, chlorobutanol, sorbic acid, and similar compounds. The composition may also include isotonic agents, for example, sugars, sodium chloride and them similar ones. Prolonged action of the composition can be achieved with the help of agents that slow down the absorption of the active principle, for example, aluminum monostearate, cellulose derivatives and gelatin. Examples of suitable carriers, solvents, diluents, and delivery vehicles are water, ethanol, polyalcohols, and mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, and the like. Examples of dispersing agents and dispensing agents are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, as a mixture with traditional pharmaceutical carriers. Suitable standard forms of administration include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and transbukkalnye forms of administration, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

Compositions suitable for parenteral injection may contain physiologically acceptable, sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution in sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or fillers include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by using a coating such like lecithin, by maintaining the required particle size in the case of dispersions and by the use of surfactants.

 Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is mixed with at least one of the following: (a) one or more inert excipients (or carriers), such as disubstituted calcium phosphate; (B) fillers or diluents, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (d) humectants, such as glycerin; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato, corn or tapioca starch, alginic acid, some complex silicates and sodium carbonate; (f) solution retarders, such as paraffin wax; (g) absorption accelerators, such as quaternary ammonium compounds; (h) wetting agents such as cetyl alcohol and glyceryl monostearate; (i) adsorbents, such as kaolin and bentonite; and (j) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets and pills, dosage forms may also contain buffering agents.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, such as cottonseed oil, groundnut oil, wheat germ oil, olive oil, castor oil and sesame oil, glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols, sorbitol esters of fatty acids, or mixtures of these substances, and the like. In addition to such inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and flavoring agents.

 The preferred dosage form of Edaravone and at least one, two, three, four or five substances selected from the group consisting of ebselen, resveratrol, uric acid, dehydroascorbic acid and disufenton according to the invention is a liquid dosage form for intravenous injection, preferably , solution in ampoules, both as a solution containing the active substances together, and as separate solutions containing the active substances separately, with ampoules containing Edaravone and amp ly containing at least one, two, three, four or five substances selected from the group consisting of ebselen, resveratrol, uric acid, dehydroascorbic acid and disufenton are packaged together as a set, although any pharmaceutically acceptable drug can be used form.

 In one embodiment, the implementation of Edaravone is administered by injection or by any other method and at least one, two, three, four or five substances selected from the group consisting of Ebselen, resveratrol, uric acid, dehydroascorbic acid and disufenton are also injected or in any other way.

 In one embodiment, the implementation of Edaravone is contained in a tablet and at least one, two, three, four or five substances selected from the group consisting of ebselen, resveratrol, uric acid, dehydroascorbic acid and disufenton are also contained in the tablet tablets containing Edaravone and tablets containing at least one, two, three, four or five substances selected from the group consisting of ebselen, resveratrol, uric acid, dehydroascorbic acid and disufenton are packaged together as a set.

 Preferably, the kit contains instructions for use and is packaged in a carton box.

Optionally, any of the considered combinations, compositions or kits may contain additional substances useful for the treatment ischemic brain injury, selected from the group: stilbazulenilnitron, oksiresveratrol, Ν-tert-butilfenilnitron, skutellarin, choline alphosceratus, sodium, citicoline, piracetam, lipoic acid, Ν-acetylcysteine, ascorbic acid, succinic acid, taurine, inosine, caffeine, sodium (E ) -3- [4- (1H-imidazol-1-ylmethyl) phenyl] -2-propenoate or other inhibitors of thromboxane synthase, argatroban or other inhibitors of thrombin, glutathione monoethyl ether, puerarin, butylphthalide and palmitoylethanolamide.

 Edaravone and at least one, two, three, four or five substances selected from the group consisting of ebselen, resveratrol, uric acid, dehydroascorbic acid and disufentone can be used as part of combinations, pharmaceutical compositions, dosage forms and kits according to the present invention in the form of free bases or free acids, prodrugs, conjugates, pharmaceutically acceptable salts, solvates, clathrates, polymorphic forms, Ν-oxides and co-crystals.

 The term "treatment" means any treatment of a disease or condition in a subject, including 1) suppressing the development of a disease or condition, which means stopping or suppressing the development of clinical symptoms, and / or 2) reducing the intensity of symptoms of a disease or condition, which means regression of clinical symptoms.

 The term "therapeutically effective amount" means an amount of a compound of the present invention or any derivative thereof that (1) treats or prevents a particular disease, condition or disorder, (2) alleviates, improves or eliminates one or more of the symptoms of a particular disease, condition or disorder, or (3) prevents or delays the onset of one or more of the symptoms of a particular disease, condition or disorder described in this specification.

The term "pharmaceutically acceptable" means that the substance or composition to which this term is used must be chemically and / or toxicologically compatible with the other ingredients of the preparation and are safe for whoever is being treated with this substance or composition. The terms "comprising", "comprising" means that the indicated combinations, compositions, and kits include the listed components, but do not exclude the inclusion of other components.

 The terms "Edaravone", "Ebselen", "Resveratrol", "Uric acid", "Dehydroascorbic acid" and "disufenton" include any of the above, such as, for example, free bases, prodrugs, conjugates, pharmaceutically acceptable salts, solvates, clathrates, polymorphic forms,-oxides and co-crystals.

The term "pharmaceutically acceptable salts" includes salts of the active compounds, which are prepared using relatively non-toxic acids or bases, depending on the particular substituents selected in the composition of certain therapeutic agents described in the present invention. If the therapeutic agents described in the present invention contain relatively acidic functional groups, basic addition salts are formed when the neutral form of these compounds reacts with a sufficient amount of the required base, both in solvent-free medium and in a suitable inert solvent. Examples of salts of pharmaceutically acceptable inorganic bases include salts of aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (And), potassium, sodium, zinc, etc. . Salts of pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, natural amines, and the like, such as arginine, betaine, caffeine, choline, S-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol , 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, ip-iplpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl glucamine, morpholine, piperazine, piperidine, polyamine resins, pethylamine, morpholine, piperazine, piperidine, polyamine resins, pethylamine, morpholine, piperazine, piperidine, polyamine resins, pethylamine, morpholine, piperazine, piperidine, polyamine resins, pethylamine, morpholine, piperazine, piperidine, polyamine resins, pethylamine, morpholine, piperazine, piperidine, polyamine resins, pethylamine, morpholine, piperazine, piperidine, polyamine resins , Tripropylamine, tromethamine and the like If the therapeutic agents described in the present invention contain relatively basic functional groups, acid addition salts form when the neutral form of these compounds reacts with a sufficient amount of the desired acid in both solvent-free and natural inert solvent. Examples of such salts are salts with inorganic acids, such as hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, or organic acids, such as acetic acid, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, p-toluene sulfonic acid, benzenesulfonic acid, methanesulfonic acid, lactic acid, ascorbic acid, etc. These salts can be obtained from neutral compounds by known methods. Examples of pharmaceutically acceptable base addition salts include inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, magnesium, aluminum salts, and the like. First of all, preferred are salts of potassium and sodium, (see, for example, Berge SM et al., "Pharmaceutical Salts", J. of Pharmaceutical Science, 1977, 66, p. 1-19); Bundgaard H., Ed. Design of Prodrugs (Elsevier Science Publishers, Amsterdam), 1985).

"Neurodegenerative diseases" means specific conditions and diseases characterized by damage and primary death of nerve cell populations in certain areas of the central nervous system. Neurodegenerative diseases include, but are not limited to, Alzheimer's and Parkinson's;Huntington's disease (chorea); multiple sclerosis; cerebellar degeneration; amyotrophic lateral sclerosis; dementia with calves levi; spinal muscular atrophy; peripheral neuropathy; spongiform encephalitis (“mad cow disease”, Kreitsfeldt-Jakob disease); AIDS-related dementia; multi-infarction dementia; fronto-temporal dementia; leukoencephalopathy (a disease of disappearing white matter); chronic neurodegenerative diseases; stroke; ischemic, reperfusion and hypoxic brain damage; epilepsy; cerebral ischemia; glaucoma; traumatic brain injury; Down syndrome; encephalomyelitis; meningitis; encephalitis; neuroblastoma; schizophrenia; depression. In addition, neurodegenerative diseases include pathological states and disorders that develop during hypoxia, abuse of addictive substances, when exposed to neurotoxins, infectious and oncological diseases of the brain, as well as neuronal damage, associated with autoimmune and endocrine diseases; and other neurodegenerative processes.

 The daily dose of a combination or composition varies depending on various factors, for example, the particular combination chosen, the condition of the particular patient in need of treatment, his body weight and the particular disease he was diagnosed with, and the severity of the development of this disease. Thus, the selection of doses is carried out individually, taking into account the views of the attending physician. However, usually good results are obtained with the administration of Edaravon 30 mg x 2 times a day (morning and evening) intravenously, for 14 days. Next, you should take a break in the application of 14 days, after which it is possible to conduct a second cycle of intravenous infusions of 30 mg x 2 times a day, in a course of 14 days.

 Although the invention described above has been described in some detail to illustrate and exemplify for purposes of clarity and understanding, the description and examples should not be construed as limiting the scope of the invention.

Example 1. Model of ischemic stroke.

In the experiment, Spreg-Dowley rats (9-10 weeks, 250-270 g) were used, 8 animals per experimental group. Focal cerebral ischemia was induced by intraluminal occlusion of the middle cerebral artery (MCAO) in rats, as described in (Zhou et al., 2010). When using chloral hydrate anesthesia (350 mg / kg), a 4/0 surgical nylon monofilament with a rounded tip was inserted into the left internal carotid artery, moving 20-21 mm from the bifurcation of the carotid artery until slight resistance was felt. At this point, the intraluminal thread blocked the middle cerebral artery and covered all sources of blood flow from the internal carotid artery, the anterior cerebral artery and the posterior cerebral artery. Throughout the procedure, the body temperature of the rats was maintained at 37 ± 0.5 ^° C. Regional cerebral blood flow was measured using a flexible probe and laser Doppler flowmetry (Moor Instruments, Axminster, Devon, UK) (criteria for animal inclusion in the experiment: regional cerebral blood flow decreased on 85- 95%). The thread was left in place for 120 minutes and then removed for reperfusion. In the control animals, the occlusive thread was inserted only 7 mm above the carotid bifurcation.

 The combination of the present invention, a placebo (carrier) and the active substances separately administered intravenously immediately after the manipulation in doses, in terms of man, mg / day:

 Edaravone - 30, 300, 700 mg / day;

 Ebselen - 200, 1500, 3600 mg / day;

 resveratrol, 2, 2000, 5000 mg / day;

 uric acid, 250, 1000, 2000 mg / day;

 dehydroascorbic acid, 7000, 15000, 35000 mg / day;

 sodium disufenton, 500, 3000, 6000 mg / day;

Edaravone, 30 mg / day + ebselen, 3600 mg / day;

 Edaravone, 300 mg / day + ebselen, 1500 mg / day;

 Edaravone, 700 mg / day + ebselen, 200 mg / day;

Edaravone, 30 mg / day + resveratrol, 2 mg / day;

 Edaravone, 300 mg / day + resveratrol, 2000 mg / day;

 Edaravone, 700 mg / day + resveratrol, 5000 mg / day;

Edaravone, 30 mg / day + uric acid, 250 mg / day;

 Edaravone, 300 mg / day + uric acid, 1000 mg / day;

 Edaravone, 700 mg / day + uric acid, 2000 mg / day;

Edaravone, 30 mg / day + dehydroascorbic acid, 7000 mg / day;

 Edaravone, 300 mg / day + dehydroascorbic acid, 15000 mg / day;

 Edaravone, 700 mg / day + dehydroascorbic acid, 35000 mg / day; Edaravone, 30 mg / day + sodium disufenton, 500 mg / day;

 Edaravone, 300 mg / day + sodium disufenton, 3000 mg / day;

 Edaravone, 700 mg / day + sodium disufenton, 6000 mg / day.

The effect of the injected substances was assessed by the volume of the stroke area (anatomical criterion) and the measurement of the neurological index (functional criterion).

Measurement of the volume of the infarction region (the area of the brain affected by ischemia) was performed 24 hours after MCAO. The brain was quickly removed and frozen at –20 ° C for 5 min. Coronal sections were made at a distance of 1-2 mm from the end of the frontal lobes, and the sections were immersed in 2% TTC at 37 ° C for 20 minutes. The infarction volume was expressed as a percentage of the area of the coronal section in stroke affected hemisphere. The results of the assessment of the volume of the infarction with the administration of placebo, the active substances separately, as well as their combinations are summarized in Tables 1-5.

Table 1. The effect of Edaravon and Ebselen, applied separately or in combination, on the volume of the region of the region after the MSAO.

 * - difference from the expected (calculated) additive effect of the combination

Edaravone + Ebselen (significance level p <0.05).

Table 2. Effect of Edaravone and Resveratrol, used individually or in combination, on the amount of ins to k after MCAO.

 difference from the expected (calculated) additive effect of the combination

Edaravone + resveratrol (significance level p <0.05).

Table 3. The effect of Edaravone and uric acid, used alone or in combination, on the stroke volume in rats after MCAO.

 Drug The scope of infarction,

 %

 Placebo 85.0 ± 1, 5

Edaravone, 30 mg / day 55.0 ± 1, 5 Edaravone, 300 mg / day 45.2 ± 1, 5

 Edaravone, 700 mg / day 40.0 ± 1, 5

 Uric acid, 250 mg / day 47.8 ± 1.5

 Uric acid, 1000 mg / day 44.3 ± 1, 5

 Uric acid, 2000 mg / day 42.1 ± 1.5

 Edaravone, 700 mg / day + uric acid, 2000 mg / day 12.8 ± 1.5 *

Edaravone, 30 mg / day + uric acid, 250 mg / day 17.6 ± 1, ^$ 5

Edaravone, 300 mg / day + uric acid, 1000 mg / day 14.0 ± 1, ^$ 5

 difference from the expected (calculated) additive effect of the combination

Edaravone + uric acid (significance level p <0.05).

Table 4. Effect of Edaravone and Dehydroascorbic Acid (DHA), used individually or in combination, on the stroke volume in rats after

MCAO.

 l - difference from the expected (calculated) additive effect of the combination

Edaravone + dehydroascorbic acid (significance level p <0.05). Table 5. The effect of Edaravone and sodium disufenton, used separately or in combination, on the stroke volume in rats after MCAO.

 Drug Volume of infarction,%

Placebo 85.0 ± 1, 5

 Edaravone, 30 mg / day 55.0 ± 1.5

 Edaravone, 300 mg / day 45.2 ± 1.5

 Edaravone, 700 mg / day 40.0 ± 1, 5

 Sodium disufenton, 500 mg / day 55.1 ± 1, 5

 Sodium disufenton, 3000 mg / day 49, 1 ± 1, 5

 Sodium disufenton, 6000 mg / day 46.5 ± 1, 5

 Edaravone, 700 mg / day + sodium disufenton, 6000 19.1 ± 1, 5 ** mg / day

Edaravone, 30 mg / day + sodium disufenton, 500 12.5 ± 1, 5 ** mg / day

 Edaravone, 300 mg / day + sodium disufenton, 3000 16.5 ± 1, 5 ** mg / day

 ** - difference from the expected (calculated) additive effect of the combination Edaravon + sodium disufenton (significance level p <0.05).

The neurological index is a combination of motor, sensory, reflex and balance tests (Chen et al., 2001). This assessment includes an assessment of animals for hemiparesis (response to raising rats by the tail or placing rats on a flat surface), abnormal movements (immobility, tremors, convulsions), sensory deficiency (test for determining the reaction of limbs to tactile and proprioceptive stimulation) and missing reflexes auricle, cornea, fright). The neurological index was rated on a scale from 0 to 18 (normal score 0, mild injury 1-6, moderate injury 7-12, severe injury 13-18) on the 15th day after reperfusion and daily therapy with the combinations of the present invention.

 Table 6. Effect of Edaravone and Ebselen, used individually or in combination, on the neurological index in rats after MCAO.

 Combination Neurological index, average

 Placebo 14.0 ± 0.5

 Edaravone, 30 mg / day 8.8 ± 0.5

 Edaravone, 300 mg / day 8.0 ± 0.5

 Edaravone, 700 mg / day 7.5 ± 0.5

 Ebselen, 200 mg / day 10.1 ± 0.5

 Ebselen, 1500 mg / day 9.5 ± 0.5

 Ebselen, 3600 mg / day 8.9 ± 0.5

 Edaravone, 700 mg / day + ebselen, 3600 mg / day 3.8 ± 0.5 *

 Edaravone, 30 mg / day + ebselen, 200 mg / day 5.0 ± 0.5 *

 Edaravone, 300 mg / day + ebselen, 1500 mg / day 4.0 ± 0.5 *

 * - difference from the expected (calculated) additive effect of the combination Edaravon + Ebselen (significance level p <0.05)

Table 7. Effect of Edaravone and Resveratrol, used alone or in combination, on the neurological index in rats after MCAO.

 Combination Neurological index, average

 Placebo 14.0 ± 0.5

 Edaravone, 30 mg / day 8.8 ± 0.5

 Edaravone, 300 mg / day 8.0 ± 0.5

Edaravone, 700 mg / day 7.5 ± 0.5 Resveratrol, 2 mg / day 9.4 ± 0.5

Resveratrol, 2000 mg / day 8.4 ± 0.5

 Resveratrol, 5000 mg / day 7.6 ± 0.5

 Edaravone, 700 mg / day + resveratrol, 5000 mg / day 2.2 ± 0.5

Edaravone, 30 mg / day + resveratrol, 2 mg / day 4.6 ± 0.5 ^#

 Edaravone, 300 mg / day + resveratrol, 2000 mg / day 2.7 ± 0.5 "

 # - difference from the expected (calculated) additive effect of the combination Edaravon + resveratrol (significance level p <0.05).

Table 8. The effect of Edaravone and uric acid, used separately or in combination, on the neurological index in rats after MCAO.

 Combination Neurological index, average

 Placebo 14.0 ± 0.5

 Edaravone, 30 mg / day 8.8 ± 0.5

 Edaravone, 300 mg / day 8.0 ± 0.5

 Edaravone, 700 mg / day 7.5 ± 0.5

 Uric acid, 250 mg / day 8.7 ± 0.5

 Uric acid, 1000 mg / day 8.1 ± 0.5

 Uric acid, 2000 mg / day 7.5 ± 0.5

 Edaravone, 700 mg / day + uric acid, 2000 2.5 ± 0.5 *

mg / day

Edaravone, 30 mg / day + uric acid, 250 4.9 ± 0.5 ^$

mg / day

 Edaravone, 300 mg / day + uric acid, 1000 3.0 ± 0.5 *

mg / day

 $ - difference from the expected (calculated) additive effect of the combination Edaravone + uric acid (significance level p <0.05).

 Table 9. The effect of Edaravone and dehydroascorbic acid (DHA), used separately or in combination, on the neurological index in rats after MCAO.

 Combination Neurological index, average

 Placebo 14.0 ± 0.5

 Edaravone, 30 mg / day 8.8 ± 0.5

 Edaravone, 300 mg / day 8.0 ± 0.5

 Edaravone, 700 mg / day 7.5 ± 0.5

 Dehydroascorbic acid, 7000 mg / day 9.3 ± 0.5

 DHA, 15,000 mg / day 8.2 ± 0.5

 DHA, 35,000 mg / day 7.8 ± 0.5

Edaravone, 700 mg / day + DHA, 35000 mg / day 3.3 ± 0.5 ^Λ

Edaravone, 30 mg / day + DHA, 7000 mg / day 4.6 ± 0.5 ^Λ Edaravone, 300 mg / day + DHA, 15000 mg / day 3.9 ± 0.5 l - difference from the expected (calculated) additive effect of the combination Edaravone + dehydroascorbic acid (significance level p <0.05).

Table 10. Effect of Edaravone and Sodium Disufenton Used

 ** - difference from the expected (calculated) additive effect of the combination Edaravon + sodium disufenton (significance level p <0.05).

Statistical processing of the safety parameters and the design of the results of the study comparing the use of the combinations of the present invention in combined use and monotherapy with these drugs was performed using the statistical package SPSS Statistics 19.0.

To compare the effectiveness of using the combinations of the present invention in a combined use with the expected (calculated) additive effect of these drugs in appropriate dosages for monotherapy of the effects of stroke with these drugs, the addition of changes in averages used the known statistical rules for the addition of mean value and root-mean-square errors. At the same time, there is an obvious sharp statistically significant (significance level p <0.05) increase in the effectiveness of using the combinations of the present invention in combined use as compared with stroke monotherapy with these drugs, which may indicate an unexpected synergistic effect of joint use, since the combination effect with combined application statistically higher additive effect, expected, based on data of monotherapy in appropriate doses.

Example 2. Training of rats in the Morris water maze to assess their spatial cognitive abilities after an experimental stroke.

 To assess the effect of the combinations of the present invention on the long-term effects of a stroke, training of experimental stroke rats was carried out in the Morris water maze. The stroke was modeled as described in Example 1 above. Training was conducted at 36-40 days after a stroke.

 Rats were subjected to MCAO for 120 minutes and were treated with Edaravone, ebselenom, resveratrol, uric acid, dehydroascorbic acid, sodium disuffenton alone or in combination in the doses indicated in Example 1, intravenously. For treatment, the drugs were injected immediately after reperfusion and then for 14 days.

 A round pool was used, which was filled with water at a temperature of 20-22 ° C. A 14 cm high circular ceramic platform was placed in the pool. The behavior of the animals was recorded using an automated computer video system in combination with the Any-maze movement analysis program (Stoelting Co., USA).

 Prior to the experiments, we selected animals suitable for training. For this, the platform was placed 1 cm above the water level. The animal was placed on the platform for 20 seconds. Then it was lowered into the water on the opposite side of the pool and allowed to find the platform and climb it for 60 seconds, where it was left for 20 seconds. After that, the animal was re-immersed in the water on the opposite side of the pool and allowed to look for a platform. If it could not independently find the platform within 60 seconds, the experimenter helped him to move to the platform and climb it. If the animals could not independently find the platform in two attempts in a row, then they were excluded from the experience.

During the next 2 days, the platform was located 0.5 cm below the water level. Every day, animals were given 4 attempts to find a platform in for 60 seconds. The interval between attempts was 20 seconds, during which they were on the platform. Every day, before the first attempt, the animal was placed on the platform for 20 seconds. Recorded the time elapsed from the moment of launching the animal into the water before climbing on the platform. Animals were immersed in water at 3 different points on the half of the pool opposite to the platform.

 On the 3rd day, the platform was absent, and the animals were once placed in the pool for 60 seconds. The time during which the animal was in the square, where the platform had been located on previous days, was recorded, which served as an indicator of the effectiveness of the training that was conducted in the previous 2 days. The experiment was carried out in the daytime in an isolated laboratory room using “white noise” with an intensity of about 70 dB above the human hearing threshold. The experiments used automated motion recognition using a video system and the Any-maze program.

 Tables 1-1-15 present the test results using the combinations of the present invention, respectively, indicating a reduction in memory impairment in mice caused by stroke. This demonstrates the therapeutic effect of the combinations of the present invention in neurodegenerative diseases and cognitive disorders.

Table 1 1. The effect of Edaravon and Ebselen, used alone or in combination, on the long-term effects of a stroke.

 Combination Duration of stay in the area of the site after 2 days

 learning with

 Rats that did not suffer a stroke + 22.0 ± 0.2

placebo

 Placebo + stroke 6.5 ± 0.2

 Edaravone, 30 mg / day + stroke 15.1 ± 0.2

 Edaravone, 300 mg / day + stroke 15.5 ± 0.2

 Edaravone, 700 mg / day + stroke 15.9 ± 0.2

 Ebselen, 200 mg / day + stroke 15.0 ± 0.2

 Ebselen, 1500 mg / day + stroke 15.0 ± 0.2

 Ebselen, 3600 mg / day + stroke 15.4 ± 0.2

 Edaravone, 700 mg / day + ebselen, 3600 19.5 ± 0.2 *

mg / day + stroke

Edaravone, 30 mg / day + ebselen, 200 mg / day 18.3 ± 0.2 * + stroke

 Edaravone, 300 mg / day + ebselen, 1500 18.9 ± 0.2 *

 mg / day + stroke

 * - difference from the expected (calculated) additive effect of the combination Edaravon + Ebselen (significance level p <0.05).

 Table 12. Effect of Edaravone and Resveratrol, used alone or in combination, on the long-term effects of the injection.

 # - difference from the expected (calculated) additive effect of the combination

Edaravone + resveratrol (significance level p <0.05).

Table 13. Effect of Edaravone and Uric Acid, used individually or in combination, on the long-term effects of a stroke.

 Combination Duration of stay in the area of the site after 2 days of training, with

 Rats that did not suffer a stroke + 22.0 ± 0.2

 placebo

 Placebo + stroke 6.5 ± 0.2

 Edaravone, 30 mg / day + stroke 15.1 ± 0.2

 Edaravone, 300 mg / day + stroke 15.5 ± 0.2

 Edaravone, 700 mg / day + stroke 15.9 ± 0.2

 Uric acid, 250 mg / day + stroke 14.8 ± 0.2

 Uric acid, 1000 mg / day + stroke 15.1 ± 0.2

 Uric acid, 2000 mg / day + stroke 15.9 ± 0.2

Edaravone, 700 mg / day + uric acid, 19.8 ± 0.2 * 2000 mg / day + stroke

 Edaravone, 30 mg / day + uric acid, 18.7 ± 0.2 *

 250 mg / day + stroke

 Edaravone, 300 mg / day + uric acid, 19.2 ± 0.2 *

 1000 mg / day + stroke

 $ - difference from the expected (calculated) additive effect of the combination Edaravone + uric acid (significance level p <0.05).

Table 14. Effect of Edaravone and Dehydroascorbic Acid (DHA), used alone or in combination, on the long-term effects of a stroke.

^{And the} difference from the expected (calculated) additive effect of the combination Edaravone + dehydroascorbic acid (significance level p <0.05).

Table 15. Effect of Edaravone and Sodium Disufenton Used by

Combination Duration of stay in the area of the site after 2 days of training, with

Rats that did not suffer a stroke + 22.0 ± 0.2

 placebo

 Placebo + stroke 6.5 ± 0.2

 Edaravon, 30 mg / day + stroke 15, 1 ± 0.2

 Edaravone, 300 mg / day + stroke 15.5 ± 0.2

Edaravone, 700 mg / day + stroke 15.9 ± 0.2 Sodium disufenton, 500 mg / day + 13.6 ± 0.2

stroke

 Sodium disufenton, 3000 mg / day + 14.0 ± 0.2

stroke

 Sodium disufenton, 6000 mg / day + 14.9 ± 0.2

stroke

 Edaravone, 700 mg / day + disufenton 19.3 ± 0.2 **

sodium, 6000 mg / day + stroke

 Edaravone, 30 mg / day + disufenton 18.2 ± 0.2 **

sodium, 500 mg / day + stroke

 Edaravone, 300 mg / day + disufenton 18.8 ± 0.2 **

sodium, 3000 mg / day + stroke

 - difference from the expected (calculated) additive effect of the combination

Edaravone + sodium disufenton (significance level p <0.05).

Example 3. Evaluation of the effect of combinations according to the invention on free radicals.

 The combinations of the present invention in concentrations (mm):

 Edaravone from 0.17 to 4.76,

 Ebselen from 0.73 to 13.14,

 resveratrol from 0.01 to 21, 93,

 uric acid from 1, 49 to 1 1.90,

 dehydroascorbic acid from 0.17 to 210.75,

 sodium disufenton from 1, 31 to 15.75;

 which corresponds to the mass ratios of combinations:

 Edaravone: Ebselen from 1: 120 to 3.5: 1,

 Edaravone: resveratrol from 1: 166.6 to 350: 1,

 Edaravone: uric acid from 1: 66.6 to 2.8: 1,

 Edaravone: dehydroascorbic acid from 1: 1 166.6 to 1:10,

 Edaravone: sodium disufenton from 1: 200 to 1, 4: 1;

 dissolved in acetonitrile and their quenching activity in generation systems

• OH, 0 ₂ ·, and ΝΟ · were determined by electron paramagnetic resonance (EPR). Measurements were performed using a Bruker ESR spectrometer operating in the X-band.

To detect radicals · ΟΗ 50 μl of a 40 μM solution of FeS0 ₄ , 50 μl of a combination according to the present invention or carrier (acetonitrile), 50 μl of a 200 mM 5,5-dimethylpyrroline M-oxide spin trap (DMPO) are mixed in a test tube. Then add 50 μl of 400 μM H ₂ 0 ₂ to the tube. Amount formed the reaction product DMPO-OH is evaluated exactly 30 seconds after the addition of H ₂ O ₂ . The signal intensity is estimated from the relative magnitude of the peak of the second specific signal of the quartet of the spin adduct DMPO-OH. Magnetic field, sweep width, microwave frequency, power, modulation frequency, modulation amplitude, temperature, gain and sweep time are 348 mT, 20 mT, X-band, 20 mW, 100 kHz, 0.2 mT, 25 ° C, 5 10 ⁴ and 84 s, respectively.

To detect radical anions 0 ₂ · - 50 μl 0.4 units / ml xanthine oxidase, 50 μl 1.44 mm xanthine, 50 μl 40 mm spin trap 5- (diethoxyphosphoryl) -5-methyl-1-pyrrolin-K- oxide (DEPMPO) and 50 μl of the combination according to the present invention; superoxide dismutase or carrier (acetonitrile) is mixed at room temperature. The amount of DEPMPO-UN spin adduct formed is measured 5 minutes after the addition of xanthine. Magnetic field, sweep width, microwave frequency, power, modulation frequency, modulation amplitude, temperature, gain and sweep time are 347 mTl, 20 mTl, X-band, 20 mW, 100 kHz, 0.1 mT, 25 ⁰ С, 5 ^χ 10 ⁴ and 84 s, respectively.

 Table 16. Antioxidant activity of the studied combinations.

 Combination, concentration Free radical scavenging

 (•HE), %

 Solvent (acetonitrile) 1.0 ± 1.5

 Edaravon, 1, 7 mM 65.0 ± 1, 5

 Ebselen, 5.47 mM 60.1 ± 1, 5

 Resveratrol, 8.77 mM 64.3 ± 1.5

 Uric acid, 5.95 mM 64.2 ± 1.5

 Dehydroascorbic acid, 86.21 mM 63.8 ± 1, 5

 Sodium disufenton, 7.87 mM 62.5 ± 1, 5

 Edaravone, 1.7 mM + ebselen, 5.47 mM 82.0 ± 1, 5 *

 Edaravone, 1.7 mM + resveratrol, 8.77 85.0 ± 1, 5 *

mM

Edaravone, 1, 7 mM + uric acid, 84.5 ± 1, ^$ 5

 5.95 mM

Edaravon, 1, 7 mM + 84.2 ± 1.5 ^Λ

dehydroascorbic acid, 86.21 mM

 Edaravone, 1, 7 mM + sodium disufenton, 83.8 ± 1.5 **

7.87 mM * - difference from the expected (calculated) additive effect of the combination Edaravon + Ebselen (significance level p <0.05);

 # - difference from the expected (calculated) additive effect of the combination Edaravon + resveratrol (significance level p <0.05);

 $ - difference from the expected (calculated) additive effect of the combination

Edaravone + uric acid (significance level p <0.05);

^{And the} difference from the expected (calculated) additive effect of the combination Edaravone + dehydroascorbic acid (significance level p <0.05);

 ** - difference from the expected (calculated) additive effect of the combination Edaravon + sodium disufenton (significance level p <0.05).

Free radical oxidation is one of the leading mechanisms of brain substance damage in acute and chronic ischemia. The results of experimental and clinical studies indicate a link between the activation of free radical formation processes and the severity of ischemic stroke (A.V. Chugunov, P.R. Kamchatnov, N.A. Mikhailova "Correction of free radical oxidation - pathogenetic approach to the treatment of acute ischemic stroke" / / Journal of Neurology and Psychiatry, 2009, N ° 10, Issue 2).

 In this case, it is assumed that free radical oxidation (oxidative stress) contributes to the progression of amyotrophic lateral sclerosis (ALS) as well (SC Barber, RJ Mead, PJ Shaw. "Oxidative stress in ALS: A mechanism of neurodegeneration and a therapeutic target" // Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2006, vol. 1762 (1 1-12), pp. 1051-1067), and the main role belongs to the change in the properties of superoxide dismutase-1, an enzyme that protects the body's cells from destruction under the influence oxygen radicals, i.e. performs the antioxidant function (D.Liu "The role of free radicals in amyotrophic lateral sclerosis" // J. Mol. Neurosci. 1996, vol.7 (3), pp.159-67).

Thus, the ability of the compositions of the present invention to effectively bind free radicals can be considered as their ability to treat neurodegenerative diseases, acute cerebral circulatory disorders (ACVA), amyotrophic lateral sclerosis (ALS), transient ischemic attack (TIA) in the acute period and after suffering an attack , chronic cerebral ischemia, cognitive and behavioral disorders in vascular diseases of the brain. The invention can be used in medicine, pharmacology.

Literature

 I. WO 2009109132 Al (JIANGSU SIMCERE PHARMACEUTICAL), April 1, 2009.

2. Parnham Μ ,, Sies H., "Ebselen: prospective therapy for cerebral ischaemia", Expert Opin. Investig. Drugs., 2000, v.9, is.3, p .: 607-619. PMID 1 1060699. doi: 10.1517 / 13543784.9.3.607.

3. Yamaguchi, T., Sano K., et al., "Ebselen's ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group", Stroke, 1998, v.29, is.1, p : 12-17. 4. Terlinden, R., Feige, M., Romer, A., et al., Determination of high-performance liquid chromatography, J. Chromatogr., 1988, v.430, is2, p: 438-442.

5. Ogawa A. et al., Ebselen acute middle cerebral artery occlusion: a placebo-controlled, double-blind clinical trial. Cerebrovasc. Dis., 1999, v.9, is.2, p: 1 12-1 18.

6. Parnham M.J. et al., The pharmacology of ebselen, Agents Actions, 1991, v.32, is.1-2, p: 4-9.

 7. Schewe, T., Molecular actions of ebselen - an antiinflammatory antioxidant, Gen.

 Pharmacol., 1995, v.26, is.6, p: l 153-1 169.

 8. Sies H., Ebselen, a selenoorganic compound as glutathione peroxidase mimic, Free Radic. Biol. Med., 1993, v.14, is.3, p: 313-323.

 9. Lopez M.S., Dempsey R.J., Vemuganti R., Resveratrol neuroprotection in CNS injury, Neurochem. Int., 2015, v.89, p: 75-82.

 10. US 6515020 Bl (SIGMA TAU HEALTHSCIENCE SPA), 04.02.2003 - Combination of carnitines and resveratrol for the prevention or treatment of cerebral and senile disorders (the combination of carnitines and resveratrol).

 I i. Yu, Z.F., Bruce-Keller, A.J., Goodman, Y., Mattson, M.P., Uric acid protects people in vivo, J. Neurosci. Res., 1998, v.53, is.5, p: 613-625.

 12. WO 2001089520 A2 (PROGENICS PHARM INC), 29.1 1.2001

 13. Huang J. et al., Dehydroascorbic acid, a blood-borne barrier barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke, PNAS, 2001, v.98, is.20, p: l 1720-1 1724.

Claims

CLAIM  1. Combination for the treatment of acute cerebral circulatory disorders (ONMK), amyotrophic lateral sclerosis (ALS), transient ischemic attack (TIA) in the acute period and after an attack, chronic cerebral ischemia, cognitive and behavioral disorders in vascular diseases of the brain, neurodegenerative diseases , characterized in that the said combination contains in effective amounts  (a) edaravone and  (b) at least one substance selected from the group consisting of ebselen, resveratrol, uric acid, dehydroascorbic acid and disufenton.  2. The combination according to claim 1, characterized in that said combination is in the form of an injection solution.  3. The combination according to claim 1, characterized in that said combination is in liposomal form.  4. The combination according to claim 1, characterized in that in the above-mentioned combination of active ingredients are in daily dosages:  Edaravone 30 - 700 mg / day;  Ebselen 200 - 3,600 mg / day;  Resveratrol 2 - 5 000 mg / day;  Uric acid 250 to 2000 mg / day;  Dehydroascorbic acid 7 000 - 35 000 mg / day;  Sodium disufenton 500 - 6 000 mg / day.  5. The combination according to claim 1, characterized in that in the above-mentioned combination of the active substances are in the preferred mass ratios:  Edaravone: Ebselen from 1: 120 to 3.5: 1,  Edaravone: resveratrol from 1: 166.6 to 350: 1,  Edaravone: uric acid from 1: 66.6 to 2.8: 1,  Edaravone: dehydroascorbic acid from 1: 1 166.6 to 1:10, Edaravon: disulfentone sodium from 1: 200 to 1, 4: 1. 6. The combination according to claim 1, characterized in that the said combination further comprises substances selected from the group including Stilbazulelennitron, oxyresveratrol, Ν-tert-butylphenylnitron, skutellarin, choline alfoscerate, citicoline sodium, piracetam, lipoic acid, N-acetylcysteine, ascorbic acid, succinic acid, taurine, inosine, caffeine, sodium (E) -3-ros, acid, succinic acid, taurine, inosine, caffeine, sodium (E) -3-ros, acid, succinic acid, taurine, inosine, caffeine, sodium (E) -3. 1H-imidazol-1-ylmethyl) phenyl] -2-propenoate and other thromboxane synthase inhibitors, argatroban and other thrombin inhibitors, glutathione monoethyl ester, puerarin, butylphthalide and palmitoyl ethanolamide.  7. Pharmaceutical composition for the treatment of stroke, ALS, TIA in the acute period and after an attack, chronic cerebral ischemia, cognitive and behavioral disorders in vascular diseases of the brain, characterized in that the said composition contains in effective amounts a combination  (a) edaravona and  (b) at least one substance selected from the group consisting of ebselen, resveratrol, uric acid, dehydroascorbic acid and disufentone, as well as at least one excipient and / or at least one pharmaceutically acceptable carrier.  8. The composition according to claim 7, characterized in that said composition is in the form of an injection solution.  9. The composition according to claim 7, characterized in that said composition is in liposomal form.  10. The composition according to claim 7, characterized in that in the above-mentioned composition, the active ingredients are in the following preferred daily dosages:  Edaravone 30 - 700 mg / day;  Ebselen 200 - 3,600 mg / day;  Resveratrol 2 - 5 000 mg / day;  Uric acid 250 to 2000 mg / day;  Dehydroascorbic acid 7 000 - 35 000 mg / day;  Sodium disufenton 500 - 6 000 mg / day. 11. The composition according to p. 7, characterized in that in the above-mentioned composition, the active ingredients are contained in the preferred mass ratios: Edaravone: Ebselen from 1: 120 to 3.5: 1,  Edaravone: resveratrol from 1: 166.6 to 350: 1,  Edaravone: uric acid from 1: 66.6 to 2.8: 1,  Edaravone: dehydroascorbic acid from 1: 1 166.6 to 1:10,  Edaravone: sodium disufenton from 1: 200 to 1, 4: 1.  12. The composition according to claim 7, characterized in that said composition additionally contains substances selected from the group including stilbazulenyl nitrone, oxyresveratrol, α-tert-butylphenylnitron, scutellarine, choline alphoscerate, citicoline sodium, piracetam, lipoic acid, N-acetylcysteine , ascorbic acid, succinic acid, taurine, inosine, caffeine, sodium (E) -3- [4- (1H-imidazol-1 -ylmethyl) phenyl] -2-propenoate and other thromboxane synthase inhibitors, argatroban and other thrombin inhibitors, monoethyl Glutathione ester, puerarin, butylphthalide and p lmitoiletanolamid.  13. A kit for the treatment of ONMK, ALS, TIA in the acute period and after a postponed attack, chronic brain ischemia, cognitive and behavioral disorders in vascular diseases of the brain, characterized in that the said kit contains in effective quantities  (a) edaravone and  (b) at least one substance selected from the group consisting of Ebselen, resveratrol, uric acid, dehydroascorbic acid and disufenton, as well as instructions for use and optionally at least one pharmaceutically acceptable excipient.  14. The kit according to claim 13, characterized in that in said kit the active substances are in the following preferred daily dosages:  Edaravone 30 - 700 mg / day;  Ebselen 200 - 3,600 mg / day;  Resveratrol 2 - 5 000 mg / day;  Uric acid 250 to 2000 mg / day;  Dehydroascorbic acid 7 000 - 35 000 mg / day; Sodium disufenton 500 - 6 000 mg / day. 15. The kit according to claim 13, characterized in that in said kit the active substances are contained in preferred weight ratios:  Edaravone: Ebselen from 1: 120 to 3.5: 1,  Edaravone: resveratrol from 1: 166.6 to 350: 1,  Edaravone: uric acid from 1: 66.6 to 2.8: 1,  Edaravone: dehydroascorbic acid from 1: 1 166.6 to 1:10,  Edaravone: sodium disufenton from 1: 200 to 1, 4: 1.  16. The kit according to claim 13, wherein said kit further comprises substances selected from the group including stilbazulelennitron, oxyresveratrol, α-tert-butylphenylnitron, scutellarine, choline alphoscerate, citicoline sodium, piracetam, lipoic acid, α-acetylcysteine, ascorbic acid, succinic acid, taurine, inosine, caffeine, sodium (E) -3- [4- (1H-imidazol-1-ylmethyl) phenyl] -2-propenoate and other thromboxane synthase inhibitors, argatroban and other thrombin inhibitors, monoethyl ether glutathione, puerarin, butylphthalide and palmitoyl tanolamide.  17. The use of a combination according to claim 1, the composition according to claim 7 or the kit according to claim 13 for the treatment of stroke, allopathy, TIA in the acute period and after an attack, chronic cerebral ischemia, cognitive and behavioral disorders in vascular diseases of the brain.  18. The use according to claim 17, wherein the stroke is a stroke of the ischemic type, as well as functional disorders of the CNS associated with stroke.  19. The method of combined treatment of stroke, ALS, TIA in the acute period and after an attack, chronic cerebral ischemia, cognitive and behavioral disorders in vascular diseases of the brain, characterized in that the combination according to claim 1 is used as neuroprotective drugs, the composition according to claim 7 or the kit according to item 13.  20. The method according to p. 19, characterized in that the stroke is a stroke of the ischemic type, as well as functional disorders of the CNS associated with stroke. 21. The method according to p. 19, characterized in that the introduction of the combination according to claim 1, the composition according to claim 7 or the kit according to item 13 is injection. 22. The method according to p. 19, characterized in that the active ingredients of the combination according to claim 1 is administered in preferred daily dosages:  Edaravone 30 - 700 mg / day;  Ebselen 200 - 3,600 mg / day;  Resveratrol 2 - 5 000 mg / day;  Uric acid 250 to 2000 mg / day;  Dehydroascorbic acid 7 000 - 35 000 mg / day;  Sodium disufenton 500 - 6 000 mg / day.  23. The method according to p. 19, characterized in that the active ingredients of the combination according to claim 1 are in the preferred mass ratios:  Edaravone: Ebselen from 1: 120 to 3.5: 1,  Edaravone: resveratrol from 1: 166.6 to 350: 1,  Edaravone: uric acid from 1: 66.6 to 2.8: 1,  Edaravone: dehydroascorbic acid from 1: 1 166.6 to 1:10, Edaravone: sodium disufenton from 1: 200 to 1, 4: 1.  24. The method according to p. 19, characterized in that the composition of claim 8 is administered in the preferred daily dosages:  Edaravone 30 - 700 mg / day;  Ebselen 200 - 3,600 mg / day;  Resveratrol 2 - 5 000 mg / day;  Uric acid 250 to 2000 mg / day;  Dehydroascorbic acid 7 000 - 35 000 mg / day;  Sodium disufenton 500 - 6 000 mg / day.