EA020948B1 - Pharmaceutical composition with antihypoxic, neuroprotective and antiamnesic action and with ability to improve physical efficiency - Google Patents

Abstract

The invention relates to medicine, in particular, to a pharmaceutical composition which has an antihypoxic, neuroprotective and antiamnesic action and an ability to improve physical efficiency and which is also used to treat acute and chronic cerebral-circulation disorders, including ischemic stroke and other diseases and conditions accompanied by a lower cognitive function. This pharmaceutical composition contains semax and choline alfoscerate as active ingredients at a ratio between 1:50 and 1:8,000 (w/w), respectively, as well as pharmaceutically acceptable excipients. The invention solves a problem of a product range extension for simple-composition drug products with a strong neuroprotective action accompanied by an antihypoxic and antiamnesic action and by an ability to improve physical efficiency.

Description

The invention relates to medicine, specifically to a pharmaceutical composition having antihypoxic, neuroprotective and antiamnestic activity and the ability to increase physical performance, intended, in particular, for the treatment of acute and chronic cerebrovascular disorders, including ischemic stroke and other diseases and conditions accompanied by a decrease cognitive functions.

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

Known heptapeptide - methionyl-glutamyl-histidyl-phenylalanil-prolyl-glycyl-proline (hereinafter Semax), which has high neuroprotective activity [1].

Known drug choline alfoscerate, which has similar activity [6, 11].

Currently, semax and choline alfoscerate 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 [3, 7, 8, 12, 13]. However, in the clinic, semax and choline alfoscerates are not always effective [3, 9, 12].

Also known is a pharmaceutical neuroprotective, antioxidant, antihypoxant, antiapoptotic and membrane protective composition containing 100-250 mg of 3-hydroxypyridine and 100-400 mg of choline alfoscerate, additionally containing a pharmaceutically acceptable magnesium derivative, 1-pyridoxine, nicotinamide, idebenone, ubenimon . a pharmaceutically acceptable zinc derivative and pharmaceutically acceptable excipients [14]. This composition contains a large number of active components, which is not always appropriate and effective.

The objective of the invention is to expand the arsenal of drugs of simple composition with pronounced neuroprotective activity in combination with antihypoxic and antiamnestic activity and the ability to increase physical performance.

The goal is achieved by the described pharmaceutical composition having neuroprotective, antihypoxic and antiamnestic activity and increasing physical performance, containing as active components semax and choline alfoscerates taken in a weight ratio of 1:50 to 1: 8000, respectively, and pharmaceutically acceptable excipients.

The invention is illustrated by the following examples.

Example 1

100 mg of Semax and 10 g of choline alceferate (weight ratio 1: 100) are mixed with 100 ml of pyrogen-free water. To the resulting mixture, 10 g of mannitane are added with stirring. The solution is frozen and lyophilized. The result is a lyophilisate, which is then used in the study of the pharmacological activity of the resulting composition.

Similarly prepare compositions containing semax and choline alceferate in a weight ratio of from 1:50 to 1: 8000.

The pharmacological activity of the compositions indicated in Example 1 was studied experimentally by known methods [4].

Example 2

Antihypoxic effect of the composition of semax and choline alfoscerate on a model of acute normobaric hypoxic hypoxia with hypercapnia (in a pressure chamber) (Table 1).

Studies were performed on white nonlinear male mice weighing 20-25 g by a known method [4].

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 heat chamber in minutes (with an accuracy of 0.1 min), and the pharmacological substances tested were evaluated by its increase. The studied substances and isotonic sodium chloride solution (control) were administered intraperitoneally (a composition containing semax and choline alfoscerate - for 3 hours, one semax - for 3 hours, one choline alfoscerate - 3 hours) before the animals were placed in a pressure chamber.

The results are presented in table. 1. It was found that semax (alone) at doses of 0.025 and 0.2 mg / kg and one choline alfoscerate at a dose of 200 mg / kg did not significantly change the life expectancy of mice in a pressure chamber. However, a composition containing semax and choline alfoscerate significantly (p <0.05) increased the life expectancy of animals by 27% (semax composition 0.2 mg / kg and

- 1,020,948 choline alfoscerate 200 mg / kg) and 29% (composition of semax 0.025 mg / kg and choline alfoscerate 200 mg / kg). Moreover, the composition was significantly (p <0.05) superior to semax (1.2 times) and choline alfoscerate (1.2-1.3 times) separately in terms of severity of action.

Example 3

The neuroprotective effect of the composition of semax and choline alfoscerate (table. 2).

The studies were performed on white non-linear male rats weighing 220-280 g, contained in vivaric conditions, in which ischemic stroke was simulated.

The neuroprotective effect of the composition of semax and choline alfoscerate was studied in rats with experimental cerebral ischemia. Brain ischemia in rats was reproduced by simultaneous ligation (under ether anesthesia) of both common carotid arteries. In false-operated animals (control group No. 1), the operation was limited to the stage of access to the common carotid arteries. In control group No. 2 rats received only isotonic sodium chloride solution. In the experimental groups, animals were injected intraperitoneally with various substances (semax and choline alfoscerate separately and a composition containing them) 1 time per day for 7 days; on the first day - 1 and 3 hours after surgery. Animals after surgery were observed for 2 weeks, taking into account the survival of rats. Neurological deficit in animals was determined (by a blind method) according to the McCga scale \ in c1 a1. [10] (in points) every hour for 24 hours, and then 1 time per day. The severity of the condition was determined by the sum of the corresponding points. False-operated animals had no neurological deficit.

The results of the study of the neuroprotective effect of the composition of semax and choline alfoscerate and other substances are presented in table. 2. It can be seen from it that in rats of the control group No. 2, the neurological deficit was most pronounced (8.9 ± 0.1 points) 2 and 3 days after bilateral dressing of the common carotid arteries; however, 24% (18 rats out of 75) animals died in the control.

It was found that semax (one) at a dose of 0.5 mg / kg / day and choline alfoscerate (one) at a dose of 100 mg / kg / day equally reduced the mortality of rats from 24% (control) to 14% (p> 0, 05). A composition containing semax and choline alfoscerate significantly (p <0.05) increased the number of surviving rats to 100% (i.e., the rats did not die). Moreover, in relation to mortality, the composition significantly (p <0.05) exceeded both semax (by 14%) and choline alfoscerate (by 14%). In addition, the neurological deficit was significantly reduced, and in terms of the severity of the effect on the neurological deficit, the composition significantly (p <0.05) exceeded both semax (1.1 times) and choline alfoscerate (1.1-4.2 times) (tab. 2).

Example 4

Antiamnestic effect of the composition of semax and choline alfoscerate on the model of amnesia caused by electroconvulsive shock (table. 3).

The effect of the composition of semax and choline alfoscerate on the learning and memory processes was studied on white nonlinear male mice (weighing 20-24 g) using the conditional passive avoidance reaction (passive avoidance reaction) of electric skin irritation [2]. 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 used today to evaluate the effectiveness of substances with nootropic activity [4]. The installation for mice was a black experimental chamber 30x40x30 cm in size with an electrode floor and a white plastic platform (7.5x7.5x0.5 cm), which was placed on the floor in the center of the chamber. Mice (alone) were placed on a plastic platform. Usually, animals came down (or jumped) from the platform to the electrode floor, where they received a punishment - an electric shock (at this time a constant electric current of 0.5 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 min, he had retrograde amnesia of passive avoidance skill.

An electroconvulsive shock (ESH; electric current parameters: 50 Hz, 50 mA, 0.3 s), which was applied to mice with the help of clips in the form of clips fixed on the auricles (transpineally), immediately after the passive avoidance reaction was used as an amnesic effect [5 ]. In animals of the control group, a pseudoelectroconvulsive shock was caused: pinneal electrodes were applied to apply ESH without applying an electric current. Semax (one), choline alfos-cerate (one), a composition containing them, and isotonic sodium chloride solution (control) were administered intraperitoneally during generalized seizures caused by ESH, i.e. immediately after the ECS. Testing of mice for the preservation of passive avoidance reaction was performed 24 hours after ES.

It was established that ESH caused retrograde amnesia of passive avoidance skill in most mice: in 82% of animals (p <0.001), passive avoidance reaction was observed after 24 hours. Semax at a dose of 0.2 mg / kg and choline alfoscerate at a dose of 200 mg / kg did not significantly change the amnestic effect. However, the composition containing semax and choline alfoscerate significantly (p <0.05) weakened the amnestic effect in

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2.3 times (table. 3). Moreover, in terms of its severity of action, the composition significantly (p <0.05) exceeded both semax (2.1 times) and choline alfoscerate (1.8 times) separately.

Example 5

Antiamnestic effect of the composition of semax and choline alfoscerate on the model of amnesia caused by swimming of mice in cold water with the simultaneous rotation of the wheel 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).

The animals (individually) were placed in a 17x9x19 cm plastic box filled with water with a rotating ribbed wheel. Swimming mice in cold water (temperature 12-14 ° C) 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. The animals were placed in wet cold sawdust as a false PMHV.

It was found that PMHV caused retrograde amnesia of passive avoidance skill in most mice: in 62% of animals (p <0.001), passive avoidance reaction was observed after 24 hours. Semax at a dose of 0.025 mg / kg and choline alfoscerate at a dose of 200 mg / kg did not significantly affect amnesia of passive avoidance reaction. However, the composition containing semax and choline alfoscerate significantly (p <0.05) attenuated the amnestic effect 2.7 times (Table 4). Moreover, in terms of the severity of action, the composition significantly (p <0.05) exceeded both semax (by 27%) and choline alfoscerate (by 27%).

Example 6

Antiamnestic effect of the composition of semax and choline alfoscerate on the amnesia model caused by scopolamine (Table 5).

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).

To reproduce the scopolamine amnesia model, an m-anticholinergic blocker was administered to mice intraperitoneally at a dose of 1 mg / kg immediately after learning of passive avoidance reaction [4]. Animals of the control group received an isotonic sodium chloride solution intraperitoneally in the same volume. Semax (one), choline alfoscerate (one) and a composition containing them were administered intraperitoneally 3 hours before the training of mice. The passive avoidance reaction was tested 24 hours after intraperitoneal injection.

It was found that scopolamine caused retrograde amnesia of the passive avoidance skill in most mice: 72% of the animals (p <0.001) had passive avoidance amnesia after 24 hours. Semax at a dose of 0.025 mg / kg and choline alfoscerate at a dose of 100 mg / kg did not significantly affect amnesia of passive avoidance reaction. However, the composition containing semax and choline alfoscerate significantly (p <0.05) weakened the amnestic effect by 2 times (Table 5). Moreover, in terms of the severity of action, the composition significantly (p <0.05) exceeded both semax (32%) and choline alfoscerate (28%).

Example 7

Antiamnestic effect of the composition of semax and choline alfoscerate on the model of amnesia caused by acute normobaric hypoxic hypoxia with hypercapnia (in a heat 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 larger the mass, 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. Semax (one), choline alfoscerate (one), the composition containing them, and isotonic sodium chloride solution (control) were administered intraperitoneally (composition - 3 hours, semax - 3 hours, choline alfoscerate - 3 hours) before training mice.

It was found that 24 hours after a 16-18-minute stay of mice in a heat chamber, most of them had retrograde amnesia: in 64% of animals (p <0.001). Semax at a dose of 0.025 mg / kg and choline alfoscerate at a dose of 200 mg / kg did not significantly affect amnesia of passive avoidance reaction. However, the composition containing semax and choline alfoscerate significantly (p <0.05) had a clear antiamnestic effect, reducing the severity of amnesia by 2 times (Table 6). Moreover, in terms of the severity of action, the composition significantly (p <0.05) exceeded semax (by 27%) and choline alfoscerate (by 25%) separately.

Example 8

The effect of the composition of semax and choline alfoscerate on the physical performance of mice (table. 7).

Studies were performed on white nonlinear male mice weighing 20-22 g.

The physical performance of mice was evaluated by running test in a six-track treadmill [5].

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One animal was placed on each treadmill of the conveyor belt. The speed of the tape was 32 m / min. The mice ran to exhaustion, the criterion of which was the absence of a reaction to electric shock when they were on the electric table. The running time of the animals in minutes (with an accuracy of 0.1 min) was taken into account. Semax (one), choline alfoscerate (one), the composition containing them, and isotonic sodium chloride solution (control) was administered intraperitoneally (composition - 3 hours, semax - 3 hours, choline alfoscerate - 3 hours) before running in a treadmill .

It was found that semax at a dose of 0.01 mg / kg and choline alfoscerate at a dose of 0.5 mg / kg did not significantly change the physical performance of mice by running test in a treadmill. However, a composition containing semax and choline alfoscerate significantly (p <0.05) increased the physical performance of mice by 26% (Table 7). Moreover, in terms of the severity of action, the composition significantly (p <0.05) exceeded both semax (by 29%) and choline alfoscerate (by 23%).

As a result of the studies, it was found that the proposed pharmaceutical composition has a pronounced neuroprotective, antihypoxic and antiamnestic activity, can also increase physical performance and can be used to create new drugs for the treatment of various pathologies of the central nervous system.

Table 1

The effect of the composition of semax and choline alfoscerate on the life expectancy of mice in a pressure chamber (M ± t)

Substance (dose, mg / kg) The number of mice Life span, minutes Isotonic sodium chloride solution (control) sixteen 26.8 * 0.7 Salmon (0.025) 14 28.1 * 0.8 Semax (0.2) 14 28.7 + 0.8 Choline Alfoscerate (200) 14 27.3 + 0.9 The composition of semax (0,025) and choline alfoscerate (200) sixteen 34.7 * 2.4 * “* Composition of semax (OD) and choline alfoscerate (200) sixteen 34.1 + 2.0 * ° “

* p <0.05 - significance of differences compared with control;

О p <0.05 - significance of differences compared with semax;

# p <0.05 - significance of differences compared with choline alfoscerate (Student's test).

table 2

Change in neurological deficit (in points, M ± t) in rats after bilateral ligation of the common carotid arteries under the influence of the composition of semax and choline alfoscerate

Substance (dose, mg / kg / day) Duration after surgery (hours / h /, day / day /) 12 h 24 h 2 days 3 days 5 days 7 days 10 days 14 days Isotonic sodium chloride solution (control) / p = 75 / 8.6 + 0.1 8.8 * 0.1 8D ± 0.1 8.9 * 0.1 8.8 * 0.1 8.7 * 0.1 8.6 * 0.1 8.6 * 0.1 Semax (0.5) / p = 36 / 5.3 ± 0.1 5.6 ± 0.1 5,810,1 5.8 * 0.1 5.7 * 0.1 5.4 * 0.1 5.2 * 0.1 5.1 * 0.1 Choline alfoscerate (100) / n = 28 / 5.3 ± 0.1 • 5.8 + 0.1 6.3 * 0.1 63 * 0.1 6D + 0.1 * 5.9 + 0.1 " 5.8 * 0.1 5.7 * 0.1 ♦ The composition of semax (0.5) and choline alfos- cerate (100) / p-30 / 4.8 + 0.1 4.9 ± 0.1 •about" 5D ± 0D ♦ n # 5.2 * 0.1 ♦ s ” 5, (iodine * o 4,9Sh ♦ about 4.8 * 0.1 ”about # 4.7 + OL *about

* p <0.05 - significance of differences compared with control;

□ p <0.05 - significance of differences compared with semax;

# p <0.05 - significance of differences compared with choline alfoscerate (Student's test).

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Table 3

The effect of the composition of semax and choline alfoscerate on amnesia in mice caused by electroconvulsive shock (ESH)

Test conditions and substance (dose, mg / kg) General number mice The number of mice trained passive avoidance reaction (%) The number of mice with amnesia of passive avoidance reaction 24 hours after an amnesic dose. actions (%) 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) °°° Semake (0.2) + ESH 22 20 (91) 15 (75) ° Choline alfoscerate (200) + ESH thirty 28 (93) The composition of semax (0.2) and choline alfoscerate (200) + ESH thirty 28 (93) 10 (36)

The differences are statistically significant compared with control 1 and control 2, respectively:

° or * p <0.05; p <0.001;

o p <0.05 - significance of differences compared with semax;

# p <0.05 - significance of differences compared to choline alfoscerate (Fisher's exact method).

Table 4

The effect of the composition of semax and choline alfoscerate on the amnestic effect caused by swimming mice in cold water with the simultaneous rotation of the wheel to exhaustion (PMHV)

In experiments 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) °°° Semake (0.025) + PMHV thirty 28 (93) 14 (50) ° Choline alfoscerate (200) + PMHV 26 24 (92) 12 (50) ° The composition of semax (0,025) and choline alfoscerate (200) + PMHV 28 26 (93) 6 (23) ’“

The differences are statistically significant compared with control 1 and control 2, respectively:

° or * p <0.05;

°°° p <0.001;

О p <0.05 - significance of differences compared with semax;

# p <0.05 - significance of differences compared to choline alfoscerate (Fisher's exact method).

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Table 5

The effect of the composition of semax and choline alfoscerate on amnesia in mice caused by scopolamine

Test conditions and material test (dose, mg / kg) General number mice The number of mice trained passive avoidance reaction (%) The number of mice with amnesia passive avoidance reaction after 24 hours after amnesiruklego exposure (%) Isotonic sodium chloride solution + isotonic sodium chloride solution (control 1) 31 29 (94) 5 (17) Isotonic sodium chloride solution + scopolamine (control 2) 32 29 (91) 21 (72) ⁰⁴⁰ Semake (0.025) + scopolamine 31 28 (90) 19 (68) ° Choline alfoscerate (100) + scopolamine thirty 28 (93) 18 (64) ° The composition of semax (0,025) and choline alfoscerate (100) g scopolamia thirty 28 (93) 10 (36) *

The differences are statistically significant compared with control 1 and control 2, respectively:

° or * p <0.05;

°°° p <0.001;

□ p <0.05 - significance of differences compared with semax;

# p <0.05 - significance of differences compared to choline alfoscerate (Fisher's exact method).

Table 6

The effect of the composition of semax and choline alfoscerate on amnesia in mice caused by acute normobaric hypoxic hypoxia with hypercapnia

Test conditions and substance (dose, mg / kg) General number mice The number of mice trained passive avoidance reaction (%) The number of mice with amnesia of passive avoidance reaction 24 hours after amyzedi 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) °°° Semake (0.025) + hypoxia 24 22 (92) 13 (59) ° Holiva alfoscerat (200) + hypoxia '32 30 (94) 17 (57) ° The composition of semax (0,025) and choline alfoscerate (200) + hypoxia thirty 28 (93) 9 (32) *

The differences are statistically significant compared with control 1 and control 2, respectively:

° or * p <0.05; p <0.001;

□ p <0.05 - significance of differences compared with semax;

# p <0.05 - the significance of the differences compared with cholyl alfoscerate (Fisher's exact method).

Table 7

The effect of the composition of semax and choline alfoscerate on the physical performance of mice by running test in a treadmill (M ± t)

Substance (dose, mg / kg) The number of mice Running time, minutes Isotonic sodium chloride solution (control) 14 6.8 ± 0.1 Semake (0.01) 14 6.6 ± 0.1 Choline Alfoscerate (0.5) 14 7.0 + 0.1 Composition of semax (0.01) and choline alfoscerate (0.5) 14 8.6 ± 0D *

* p <0.05 - significance of differences compared with control;

О p <0.05 - significance of differences compared with semax;

# p <0.05 - significance of differences compared with choline alfoscerate (Student's test).

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From the above tables it follows that with a weight ratio of semax and choline alfoscerate below 1:50 and above 1: 8000, the effectiveness of the combined composition does not change.

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Claims (1)

CLAIM A pharmaceutical composition with neuroprotective, antihypoxic and antiamnestic activity and increasing physical performance, containing as active components semax and choline alfoscerates, taken in a weight ratio of 1:50 to 1: 8000, respectively, and pharmaceutically acceptable excipients.