RU2465002C1 - Agent possessing neuroprotective, antiamnestic, antihypoxic, antioxidant and antiischemic activity, and method for preventing and treating acute and chronic disturbed cerebral circulation - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine. What is offered is a pharmaceutical composition in the solid dosage form possessing neuroprotective, antiamnestic, antihypoxic, antioxidant and antiischemic activity in a combination with antiemetic activity, containing methionyl-glutamyl-histidyl-phenylalanine-prolyl-glycyl-proline and ethylmethylhydroxypyridine succinate as active ingredients in certain proportions. What is presented is using said composition for making an agent for preventing and treating acute and chronic disturbed cerebral circulation. There are presented agent and method for preventing and treating acute and chronic disturbed cerebral circulation.

EFFECT: presented group of inventions provides effective agents aiming at preventing and treating acute and chronic disturbed cerebral circulation with minimal side effects and antiemetic activity.

8 cl, 7 tbl, 11 ex

Description

The invention relates to medicine, in particular to pharmacology, and in particular to agents with neuroprotective, antiamnestic, antihypoxic-antioxidant and anti-ischemic activity, intended, in particular, for the treatment of acute and chronic cerebrovascular disorders, including cerebral stroke and its consequences.

One of the urgent problems of modern neurology is the development of means to protect the central nervous system by activating various metabolic processes of the brain. The relevance of the development of new drugs with neuroprotective activity is determined by the high mortality from stroke.

Known drug ethylmethylhydroxypyridine succinate with neuroprotective activity [2].

Known heptapeptide methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline, which has a similar activity [1].

Currently, ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline are widely used in various fields of medicine. For example, both drugs are used in neurology for acute and chronic cerebrovascular insufficiency and related diseases, including cerebral stroke and its consequences [1-4]. However, in the clinic, these drugs are not always effective, they have side effects.

The technical result of the invention is the expansion of the arsenal of drugs and the creation of a new drug with, along with high neuroprotective, antiamnestic, antihypoxic, antioxidant and antiischemic activity and antiemetic activity, and a method for the prevention or treatment of acute and chronic cerebrovascular disorders with minimal side effects. The joint use of drugs allows you to reduce the amount of the drug taken for prevention and treatment, since when used together, a higher activity of the drug is shown, which is not characteristic and higher than that of individual substances.

The specified technical result is achieved due to the fact that the pharmaceutical composition in solid dosage form, with neuroprotective, antiamnestic, antihypoxic, antioxidant and antiischemic activity in combination with antiemetic activity, includes methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-as active components proline and ethylmethyl-hydroxypyridine succinate, in wt.%:

methionyl-glutamyl-histidyl-phenylalanyl-

prolyl-glycyl-proline 0.02-2.00 ethyl methyl hydroxypyridine succinate 98.00-99.98

The technical result is also achieved by the use of the specified pharmaceutical composition for the manufacture of agents with neuroprotective, antiamnestic, antihypoxic, antioxidant and antiischemic activity in combination with antiemetic activity for the prevention or treatment of acute and chronic cerebrovascular disorders.

The technical result is also achieved by means with neuroprotective, antiamnestic, antihypoxic, antioxidant and antiischemic activity in combination with antiemetic activity for the prevention or treatment of acute and chronic cerebrovascular disorders containing the specified pharmaceutical composition.

In addition, the tool can be made in a form suitable for oral administration.

In addition, the tool can be made in the form of tablets.

In addition, the tool can be made in the form of capsules. The technical result is also achieved in a method for the prevention or treatment of acute and chronic cerebrovascular disorders, which comprises administering to a patient a pharmaceutically effective amount of an agent containing said pharmaceutical composition.

In addition, the patient is orally administered an agent containing the specified pharmaceutical composition in a dose of 100-210 mg 1-2 times a day with a gradual increase in dose until a therapeutic effect is obtained within 2-5 weeks.

The invention is illustrated by the following examples.

Example 1

8 l of water for injection is poured into a reactor equipped with an anchor stirrer. Then the valve is opened to supply sterile nitrogen to the reactor and water is bubbled for 5 minutes. After that, 4 g of the substance of ethylmethyl-hydroxypyridine succinate and 5 mg of the substance methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline are continuously loaded into the reactor with constant stirring and bubbling the solution with nitrogen. Mixing lead to complete dissolution. Then, the pH of the solution was adjusted to a value of 4.5-5.5 by the addition of a 1 M solution of acetic acid. The resulting solution was adjusted to a volume of 10 l with water for injection and passed through a sterilizing filter. Under aseptic conditions, bottling in ampoules with a capacity of 2 ml, 1 ml per ampoule, is carried out. Cartridges with ampoules are placed in a sublimation chamber, where they are frozen to a temperature of minus 40 ° С with a freezing rate of 10 ° С / h, and then subjected to drying by vacuum. Ampoules with the obtained dry lyophilized form of the drug are sealed under nitrogen.

Example 2

6 g of the substance and 40 mg of the substance methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline are dissolved with stirring and bubbling with nitrogen in 8 l of water for injection, in which 0.71 g of ammonium acetate is previously dissolved, the pH of the resulting solution is adjusted to a value 4.5-5.0 using a 1 M solution of acetic acid and add water for injection to a total volume of 10 l. Sterilized filtration of the resulting solution is carried out and under aseptic conditions, it is bottled under nitrogen in ampoules with a capacity of 2 ml of 1 ml in an ampoule. Filled ampoules are sealed under nitrogen.

The pharmacological activity of the described pharmaceutical composition was studied experimentally by known methods / 5 /.

Example 3

Antihypoxic effect of the composition containing ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline as active components on the model of acute normobaric hypoxic hypoxia with hypercapnia (in a pressure chamber) (Table 1)

The studies were performed on white nonlinear male mice with an average weight of 22 ± 1 g according to a known method [5].

Acute normobaric hypoxic hypoxia with hypercapnia was reproduced by placing mice (individually) in a pressure chamber: animals were placed in glass jars of the same volume (250 cm ³ ), which were hermetically sealed. As oxygen was consumed, its concentration in the air of the vessel and in the body decreased, and the amount of carbon dioxide, on the contrary, increased. As a result, animals developed acute hypoxic hypoxia with hypercapnia. The life expectancy of mice was recorded with a stopwatch (until breathing stopped) in a pressure chamber in minutes (with an accuracy of 0.1 minutes), and the effectiveness of the tested pharmacological substances was judged by its increase. The test substances and isotonic sodium chloride solution (control) were administered intraperitoneally before the animals were placed in the chamber.

The results are presented in table 1.

It was found that ethylmethylhydroxypyridine succinate at doses of 30 and 50 mg / kg did not significantly affect, and at a dose of 100 mg / kg significantly (p <0.05) increased the life expectancy of animals in acute normobaric hypoxia with hypercapnia by 27%. Methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline at doses of 0.025 and 0.2 mg / kg practically did not change the life expectancy of mice in a pressure chamber. When using a composition with ethyl methylhydroxypyridine succinate and methionyl glutamyl histidyl phenylalanyl prolyl glycyl proline, they caused a tendency in three cases (ethyl methyl hydroxypyridine succinate 30 mg / kg + methionyl glutamyl histidyl prolyl 25 mg kg, ethylmethylhydroxypyridine succinate 30 mg / kg + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline 0.2 mg / kg and ethylmethylhydroxypyridine succinate 50 mg / kg + methionyl-glutamyl-histidyl-phenylanyl-prol mg / kg) or in other tested doses Beginningly (p <0.05), the animal lifespan increased by 22% (ethyl methyl hydroxypyridine succinate 50 mg / kg + methionyl glutamyl histidyl phenylalanyl prolyl glycyl proline 0.2 mg / kg) and 33% (ethyl methyl hydroxypyridine succinate 50 mg / kg + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.025 mg / kg).

From table 1 it is seen that the use of a composition containing ethyl methylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline in its composition leads to an increase in life expectancy, more significant than with separate use of these drugs in the same doses. A sharp increase in the effectiveness of the effect of the composition with the combined use of ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline as active components does not occur due to an increase in the dosages of these active components with a minimal negative effect of these drugs.

Example 4

Anti-ischemic effect of a composition containing ethyl methyl ethyl hydroxypyridine succinate and methionyl glutamyl histidyl phenylalanyl prolyl glycyl proline as active components in a model of circulatory hypoxia of the brain (Table 2)

The studies were performed on white non-linear male mice weighing 31-38 g (age 11-13 months).

Circulatory hypoxia of the brain (cerebral ischemia) was reproduced by simultaneous ligation (under ether anesthesia) of both common carotid arteries. In false-operated animals (control group), the operation was limited to the stage of access to the common carotid arteries. Animals after surgery were observed for several weeks. The studied substances (ethylmethylhydroxypyridine succinate, methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline) and isotonic sodium chloride solution (control) were administered intraperitoneally for 7 days: on the first day after ligation and 3 hours after surgery, the rest 6 days - 1 time per day.

After bilateral ligation of the common carotid arteries, mice died during the first 6 days.

From table 2 it is seen that the survival rate of animals in the control group after 6 days after bilateral ligation of the common carotid arteries was 78% (of 117 killed 26 mice). Ethyl methyl hydroxypyridine succinate at a dose of 100 mg / kg significantly (p <0.05) increased the number of surviving mice to 97%, i.e. had an almost complete protective effect. Ethyl methylhydroxypyridine succinate at a dose of 30 mg / kg and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.025 and 0.2 mg / kg) did not significantly change the survival of animals. However, when using a composition with active components (ethylmethylhydroxypyridine succinate + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline) in the indicated doses, they significantly (p <0.05) increased the number of surviving mice to 96-97% (Table 2 )

Example 5

Anti-amnestic effect of the composition containing ethyl methyl ethyl hydroxypyridine succinate and methionyl glutamyl histidyl phenylalanyl prolyl glycyl proline as active components in the model of amnesia caused by electroconvulsive shock (Table 3)

The effect of the composition of ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline on the learning and memory processes was studied on white nonlinear male mice (weighing 20-24 g) using a conditional passive avoidance reaction (passive avoidance reaction) of electrocutaneous irritation [6 ]. At present, the passive avoidance reaction test is a basic model for assessing the effect of substances on the formation and reproduction of a commemorative footprint under normal conditions and under conditions of its disruption (amnesia), as well as the most informative methods for assessing the effectiveness of substances with nootropic activity [5]. The installation for mice was a black experimental chamber measuring 30 × 40 × 30 cm with an electrode floor and a white plastic platform (7.5 × 7.5 × 0.5 cm), which was placed on the floor in the center of the chamber. Mice (alone) were placed on a plastic platform. Usually, animals descended (or jumped) from the platform onto the electrode floor, where they received a “punishment” - an electric shock (at this time a constant electric current of 0.8 mA was applied to the chamber floor). Electric current was turned on only when the mouse touched the floor with all four limbs. The usual reaction of animals was to return to a safe platform. After 5 minutes of training, passive avoidance reaction was developed in mice — they remained on the platform. Testing for the safety of passive avoidance reaction was carried out 24 hours after the amnesiac effect. Moreover, if the animal left the platform within 1 minute, he observed retrograde amnesia of the passive avoidance skill.

An electroconvulsive shock (electric current parameters: 50 Hz, 50 mA, 0.3 s), which was applied to mice using clip-type electrodes fixed on the auricles (transpineally) immediately after learning of passive avoidance reaction, was used as an amnesic effect [5]. In the animals of the control group, a pseudo-electroconvulsive shock was caused: pinneal electrodes were applied for application by electroconvulsive shock without applying an electric current. Pharmacological substances were administered intraperitoneally during the period of generalized seizures caused by electroconvulsive shock, i.e. immediately after electroconvulsive shock. Testing mice for the preservation of passive avoidance reaction was performed 24 hours after electroconvulsive shock.

It was found that electroconvulsive shock in most mice caused retrograde amnesia of passive avoidance skill: in 82% of the animals (p <0.001), passive avoidance depression was observed after 24 hours. Ethylmethylhydroxypyridine succinate at a dose of 30 mg / kg and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline at a dose of 0.2 mg / kg did not significantly change the amnestic effect. However, when using the composition (with the active components ethyl ethyl methyl hydroxypyridine succinate + methionyl glutamyl histidyl phenylalanyl prolyl glycyl proline) they significantly weakened the indicated doses (p <0.05) by 2 times (Table 3).

From table 3 it is seen that the use of a composition containing as active components ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline leads to a decrease in the amnestic effect, more significant than with separate use of these drugs in the same doses. A sharp increase in the effectiveness of the effect when combined in the composition of the composition of ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline does not occur due to an increase in the dosages of these active components with minimal negative impact of these drugs.

Example 6

Antiamnestic effect of a composition containing ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline as active components in the model of amnesia caused by swimming mice in cold water while the wheel rotates to exhaustion (Table 4)

The studies were performed on white nonlinear male mice weighing 20-24 g using the development of passive avoidance reaction in animals (described in example 5).

Animals (individually) were placed in a plastic box filled with water 17 × 9 × 19 cm in size with a rotating ribbed wheel. Swimming mice in cold water with the simultaneous rotation of the wheel to exhaustion (PMHV) was used immediately after learning passive avoidance reaction. The safety of passive avoidance reaction was checked 24 hours after the end of PMHV. In this case, the most pronounced mnestic disturbances were observed in mice when they swam in water (on average 10.6 min), which had a temperature of 12-14 ° C, and the room temperature was 16-20 ° C. The animals were placed in wet cold sawdust as a false PMHV.

It was found that PMHV caused retrograde amnesia of the passive avoidance skill in most mice: in 62% of the animals (p <0.001), passive avoidance amnesia was observed after 24 hours. Ethyl methyl hydroxypyridine succinate at a dose of 10 mg / kg and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline at a dose of 0.025 mg / kg did not significantly affect amnesia of passive avoidance reaction. However, when using the composition (with the active components ethyl ethyl methyl hydroxypyridine succinate + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline) they significantly (p <0.05) weakened the amnestic effect 2.1 times (Table 4) (Table 4). )

From table 4 it is seen that the use of a composition containing as active components ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline leads to a weakening of the amnestic effect, more significant than with separate use of these drugs in the same doses. A sharp increase in the effectiveness of the effect when using ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline as active components in the composition does not occur due to an increase in the dosages of the individual active components with minimal negative impact of these drugs.

Example 7

Anti-amnestic effect of the composition with the active components of ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline on the model of amnesia caused by swimming mice with bandaged common carotid arteries in cold water with simultaneous rotation of the wheel to exhaustion (table 5)

On the model of amnesia caused by PMHV, the efficacy of drugs in mice with bandaged common carotid arteries was evaluated (see Example 4). After 6-10 days after the operation, the surviving animals practically did not differ from the control (falsely operated, n = 20) according to the orientational research reaction and emotional status (open field test). In this regard, they were used in the passive avoidance reaction test (described in Example 5). Testing for the safety of passive avoidance reaction was carried out 24 hours after amnesic exposure (PMHV). The test substances and isotonic sodium chloride solution (control) were administered intraperitoneally (see above; the last time methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline was administered 10 minutes, ethylmethylhydroxypyridine succinate 60 minutes before training mice).

It was found that PMHV caused retrograde amnesia of passive avoidance skill in most mice with bandaged common carotid arteries: passive avoidance amnesia was observed in 65% of animals (p <0.001) after 24 hours. Methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.025 mg / kg) and ethylmethylhydroxypyridine succinate (30 mg / kg) had a slight effect on passive avoidance reaction. However, when used together (ethylmethylhydroxypyridine succinate + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline), they significantly (p <0.05) had a clear antiamnestic effect, reducing the severity of amnesia by 1.8 times (Table 5) .

From table 5 it is seen that the use of a composition containing as active components ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline, leads to an increase in antiamnestic effects, more significant than with separate use of these components in the same doses. A sharp increase in the effectiveness of the effect when combined in the composition of the composition of ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline does not occur due to an increase in the dosages of the individual components with minimal negative impact of these drugs.

Example 8

Anti-amnestic effect of the composition on the model of amnesia caused by acute normobaric hypoxic hypoxia with hypercapnia (in a pressure chamber) (Table 6)

The studies were performed on white nonlinear male mice weighing 20-24 g using the development of passive avoidance reaction in animals (described in example 5).

The model of acute normobaric hypoxic hypoxia with hypercapnia described in Example 3 was also used to induce passive avoidance skill in animals with retrograde amnesia. For this, mice immediately after training passive avoidance reaction were placed (individually) in a pressure chamber for 16-18 minutes, depending on the severity of the symptoms of oxygen deficiency and weight (the more weight, the usually less time spent in the pressure chamber). In the control group, animals were subjected to false hypoxia - mice were placed in glass jars of the same volume, which were not covered. The preservation of passive avoidance reaction was performed 24 hours after the end of exposure to hypoxia with hypercapnia. Substances were administered orally through a probe (ethylmethylhydroxypyridine succinate 60 minutes, methionyl-glutamyl-histidyl-phenylalanil-prolyl-glycyl-proline 10 minutes) before training the mice.

It was found that 24 hours after a 16-18-minute stay of mice in a pressure chamber, most of them had retrograde amnesia: in 64% of animals (p <0.001). Ethylmethylhydroxypyridine succinate at a dose of 30 mg / kg and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline at doses of 0.025 and 0.2 mg / kg did not significantly affect amnesia of passive avoidance reaction. However, when used together (ethylmethylhydroxypyridine succinate + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline) they significantly (p <0.05) had a distinct antiamnestic effect, reducing the severity of amnesia by 1.7-2.1 times ( table 6).

From table 6 it is seen that the use of a composition containing ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline as active components leads to an increase in anti-amnestic effect, more significant than with separate use of these drugs in the same doses . A sharp increase in the effectiveness of the effect when combined in the composition of the composition of ethylmethylhydroxypyridine and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline does not occur due to an increase in the dosages of these components with minimal negative impact of these drugs.

Table 1 The effect of the composition of ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline on the life span of mice in a pressure chamber (M ± m) Substance (dose, mg / kg) The number of mice Life span, minutes Isotonic sodium chloride solution (control) 16 28.1 ± 1.0 Ethyl Methyl Hydroxypyridine Succinate (30) 10 29.0 ± 1.5 Ethyl Methyl Hydroxypyridine Succinate (50) 10 30.9 ± 1.6 Ethyl Methyl Hydroxypyridine Succinate (100) 16 35.6 ± 3.1 * Methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.025) 10 28.9 ± 1.1 Methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.2) 10 29.8 ± 1.2 Ethylmethylhydroxypyridine succinate (30) + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0,025) 12 31.7 ± 2.1 Ethylmethylhydroxypyridine succinate (30) + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.2) 10 32.9 ± 2.4 Ethylmethylhydroxypyridine succinate (50) + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0,025) 12 33.1 ± 2.3 Ethylmethylhydroxypyridine succinate (50) + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.2) fourteen 34.2 ± 2.0 * Ethylmethylhydroxypyridine (100) succinate + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.025) fourteen 37.3 ± 3.2 * Note. * - p <0.05 - differences are statistically significant compared with the control (student criterion).

table 2 The effect of the composition of ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline on the survival of mice 6 days after bilateral ligation of the common carotid arteries Substance (dose, mg / kg) The number of mice The number of surviving mice (%) Isotonic sodium chloride solution (control) 117 91 (78) Ethyl Methyl Hydroxypyridine Succinate (100) 29th 28 (97) * Ethyl Methyl Hydroxypyridine Succinate (30) twenty 18 (90) Methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.025) 23 20 (87) Methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.2) 25 23 (92) Ethylmethylhydroxypyridine succinate (30) + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0,025) 28 27 (96) * Ethylmethylhydroxypyridine succinate (30) + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.2) 31 30 (97) * Note. * - p <0.05 - significance of differences compared with control (Fisher's exact method).

Table 3 The effect of the composition ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline on amnesia in mice caused by electroconvulsive shock (ESH) Test conditions and substance (dose, mg / kg) Total number of mice The number of mice trained passive avoidance reaction (%) The number of mice with amnesia passive avoidance reaction after 24 hours after amnesic exposure (%) Isotonic sodium chloride solution + pseudo-ESH (control 1) thirty 27 (90) 5 (19) Isotonic sodium chloride solution + ESH (control 2) thirty 28 (93) 23 (82) °°° Ethylmethylhydroxypyridine succinate (30) + ESH eleven 10 (91) 5 (50) Methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.2) + ESH eleven 10 (91) 7 (70) Ethylmethylhydroxypyridine succinate (30) + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.2) + ESH 24 22 (92) 9 (41) * Note. The differences are statistically significant compared with control 1 and control 2, respectively (Fisher's exact method): ° or * - p <0.05, ° °° or *** - p <0.001.

Table 4 The effect of the composition of ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline on the amnestic effect caused by swimming mice in cold water while spinning the wheel to exhaustion (PMHV) Test conditions and substance (dose, mg / kg) Total number of mice The number of mice trained passive avoidance reaction (%) The number of mice with amnesia of passive avoidance reaction 24 hours after PMHV (%) Isotonic sodium chloride solution + false PMHV (control 1) 52 48 (92) 8 (17) Isotonic solution of sodium chloride + PMHV (control 2) 55 52 (94) 32 (62) °°° Ethylmethylhydroxypyridine succinate (10) + PMCV 19 17 (89) 8 (47) ° Methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.025) + PMCV 22 20 (91) 8 (40) Ethylmethylhydroxypyridine succinate (10) + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.025) + PMCV 22 21 (95) 6 (29) * Note. The differences are statistically significant compared to control 1 and control 2, respectively (Fisher's exact method): ° - or * - p <0.05, ° °° or *** - p <0.001.

Table 5 The effect of the composition of ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline on the amnestic effect caused in mice with bandaged common carotid arteries by swimming in cold water while spinning the wheel until exhaustion (PMXV) Test conditions and substance (dose, mg / kg) Total number of mice The number of mice trained passive avoidance reaction (%) The number of mice with amnesia of passive avoidance reaction 24 hours after PMHV (%) Isotonic sodium chloride solution + false PMHV (control 1) 34 29 (85) 6 (21) Isotonic solution of sodium chloride + PMHV (control 2) 47 40 (85) 26 (65) °°° Ethylmethylhydroxypyridine succinate (30) + PMHV 19 17 (89) 8 (47) Methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.025) + PMCV fifteen 13 (87) 7 (54) Ethylmethylhydroxypyridine succinate (30) + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.025) + PMCV 24 22 (92) 8 (36) * Note. The differences are statistically significant compared with control 1 and control 2, respectively (Fisher's exact method): ° or * - p <0.05, ° °° or *** - p <0.001.

Table 6 The effect of the composition of ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline on amnesia in mice caused by acute normobaric hypoxic hypoxia with hypercapnia Test conditions and substance (dose, mg / kg) Total number of mice The number of mice trained passive avoidance reaction (%) The number of mice with amnesia passive avoidance reaction after 24 hours after amnesic exposure (%) Isotonic sodium chloride solution + false hypoxia (control 1) thirty 28 (93) 5 (18) Isotonic sodium chloride solution + hypoxia (control 2) 48 44 (92) 28 (64) °°° Ethylmethylhydroxypyridine succinate (30) + hypoxia 12 11 (92) 5 (45) Methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.025) + hypoxia eleven 10 (91) 6 (60) Methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.2) + hypoxia eleven 10 (91) 5 (50) Ethylmethylhydroxypyridine succinate (30) + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0,025) + hypoxia 26 24 (92) 9 (38) * Ethylmethylhydroxypyridine succinate (30) + methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline (0.2) + hypoxia 21 20 (95) 6 (30) * Note. The differences are statistically significant compared to control 1 and control 2, respectively (Fisher's exact method): ° or * - p <0.05, °° or ** - p <0.01, ° °° or *** - p < 0.001.

Example 9

Antiemetic effect of the composition (table 7)

The studies were performed on 13 male cats weighing 3.1-4.2 kg, which were in free behavior. Xylazine, which is traditionally used to induce vomiting in cats, was used as an emetic agent [7]. Xylazine was administered to animals intramuscularly (IM) at a dose of 0.66 mg / kg [7]. The latent period (PL) of the emetic reaction and the number of emetic acts were recorded within 1 hour after the intramuscular administration of xylazine (since animals usually experienced repeated vomiting). Ethylmethylhydroxypyridine succinate, methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline, their composition and isotonic sodium chloride solution (control) were administered (twice) to the animals subcutaneously 4 hours and 45 minutes before the administration of xylazine.

In a series of experiments conducted on 6 male cats, it was found that individually neither methyl methyl hydroxypyridine succinate at a dose of 100 mg / kg (2 times 50 mg / kg) nor methionyl glutamyl histidyl phenylalanyl prolyl glycyl proline at a dose of 0.4 mg / kg (2 times 0.2 mg / kg) do not have antiemetic activity (Table 7).

In the II series of experiments conducted on 7 animals, it was found that the composition with ethyl methylhydroxypyridine succinate and methionyl glutamyl histidide phenylalanyl prolyl glycyl proline (2 times 50 and 0.2 mg / kg, respectively) compared with the control significantly (p <0.05) increases by 2 times the LP of the emetic reaction and reduces the number of emetic acts by 43% (Table 7). Therefore, this composition, in contrast to its active components, has antiemetic activity.

As a result of the studies, it was found that the proposed composition has a pronounced high neuroprotective, antiamnestic, antihypoxic, antioxidant and antiischemic activity in combination with antiemetic activity and can be used to create new drugs for the treatment of pathologies of the central nervous system. In this case, there is a synergistic effect manifested when ethylmethylhydroxypyridine succinate and methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline are used as active components in the composition, which is significantly higher than the efficiency of separate use of these components.

Drug Examples

Example 1

Capsules were obtained by a well-known method (Chueshov V.I. et al. Industrial technology of drugs, T.2, MTK - Book; Publishing House of NFAU, 2002, pp. 400-413).

To prepare the capsules, the ingredients are mixed based on the composition of one capsule: ethylmethylhydroxypyridine 100 mg; methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline 0.5 mg; lactose 83.3 mg; pre-gelatin starch 18.9 mg; Aerosil 2.5 mg; magnesium stearate 2.6 mg; sodium lauryl sulfate 2.3 mg

The composition of the hard gelatin capsule: gelatin, titanium dioxide, water, dye.

Example 2

Tablets were prepared in a well-known manner (ibid., Pp. 353-368).

To prepare the tablets, the ingredients are mixed based on the composition of one tablet: ethylmethylhydroxypyridine 100 mg; methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline 0.5 mg; lactose monohydrate 122 mg; sodium carboxymethyl cellulose (sodium carmellose) 25 mg, magnesium stearate 2.6 mg; shell - polyvinyl alcohol, talc, titanium dioxide.

The composition of the shell for tablets: Opadry II white, macrogol (polyethylene glycol), polyvinyl alcohol, talc, titanium dioxide.

A method for the prevention or treatment of acute and chronic cerebrovascular disorders involves administering to the patient a pharmaceutically effective amount of the drug - the patient is orally administered the drug at a dose of 100-210 mg 1-2 times a day with a gradual increase in dose until a therapeutic effect is obtained within 2-5 weeks. The maximum daily dose is 1260 mg.

The invention will expand the arsenal of drugs and create new drugs with, along with high neuroprotective, antiamnestic, antihypoxic, antioxidant and antiischemic activity and antiemetic activity, intended for the prevention and treatment of acute and chronic cerebrovascular disorders with minimal side effects, reduce the amount of medication taken due to its high efficiency.

Literature

1. RF patent №2251429 (2005).

2. The register of medicines of Russia. Encyclopedia of medicines - 14 vol. - M., radar - 2006 - p. 488-489.

3. Gusev E.I., Skvortsova V.I. Cerebral ischemia. - M .: Medicine, 2001.

4. Fedin A.I., Rumyantseva S.A., Mironova O.P., Evseev V.P. The use of the antioxidant Mexidol in patients with acute cerebrovascular accident. Guidelines. - M., 2002 .-- 16 p.

5. Voronina T.A., Ostrovskaya R.U. Guidelines for the study of the nootropic activity of pharmacological substances // Guide to the experimental (preclinical) study of new pharmacological substances. / Ed. Fisenko V.P. - M., 2000. - P.153-158.

6. Buresh Y., Bureshova O., Houston P.D. Methods and basic experiments to study the brain and behavior. - M., Higher school., 1991 .-- 399 p.

7. But C.M., But S.T., Wang J.J. et al. Effects of dexamethasone on emesis in cats sedated with xylazine hydrochloride // Am J Vet Res. - 2001. - Vol.62, N 8. - P.1218-1221.

Claims (8)

1. The pharmaceutical composition in solid dosage form, which has neuroprotective, antiamnestic, antihypoxic, antioxidant and antiischemic activity in combination with antiemetic activity, including methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline, ethylmethyrnylhydroxyhydroxy as active components the ratio of components, wt.%:
methionyl-glutamyl-histidyl-phenylalanyl- prolyl-glycyl-proline 0.02-2.00 ethyl methyl hydroxypyridine succinate 98.00-99.98 2. The use of the pharmaceutical composition according to claim 1 for the manufacture of agents with neuroprotective, antiamnestic, antihypoxic, antioxidant and antiischemic activity in combination with antiemetic activity for the prevention or treatment of acute and chronic cerebrovascular disorders. 3. An agent having neuroprotective, antiamnestic, antihypoxic, antioxidant and antiischemic activity in combination with antiemetic activity for the prevention or treatment of acute and chronic cerebrovascular disorders, containing the pharmaceutical composition according to claim 1. 4. The tool according to claim 3, characterized in that it is made in a form acceptable for oral use. 5. The tool according to claim 4, characterized in that it is made in the form of tablets. 6. The tool according to claim 4, characterized in that it is made in the form of capsules. 7. A method for the prevention or treatment of acute and chronic disorders of cerebral circulation, characterized in that it comprises administering to the patient a pharmaceutically effective amount of an agent according to claim 3. 8. The method according to claim 7, characterized in that the patient is orally administered the drug according to claim 3 at a dose of 100-210 mg 1-2 times a day with a gradual increase in dose until a therapeutic effect is obtained within 2-5 weeks.