Ergogenic pharmaceutical composition exhibiting antihpoxic, neuroprotective and antiamnestic activity

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns creation of a pharmaceutical composition with a wide spectrum of pharmacological activity, namely exhibiting antihypoxic, neuroprotective and antiamnestic activity, and also showing an ergogenic nature. The declared pharmaceutical composition contains semax and choline. The outcome of experiments proves that the offered pharmaceutical composition containing semax and choline, mutually intensifies an effect of each of them.

EFFECT: composition can find application in creation of the new drug preparations exhibiting neuroprotective activity in a combination with antihypoxic and antiamnestic activity and the ergogenic nature and used for treatment of various pathologies of the central nervous system.

12 tbl, 4 dwg

 

The invention relates to the creation of a pharmaceutical composition with a wide spectrum of pharmacological activity, namely having antihypoxic, neuroprotective and antiamnesic activity, but can also increase physical performance.

One of the urgent problems of modern medicine is the development of effective means of protection of the Central nervous system through activation of various metabolic processes of the brain. The urgency of developing new medicines, with pronounced neuroprotective activity is determined, in particular, the high mortality in stroke.

Famous original domestic drug Semax (heptapeptide methionyl-glutamyl-histidyl-i.e. phenylalanyl-prolyl-glycyl-Proline), highly neuroprotective activity (Ipharmacy et al., 2005; Aguchi et al. /edit/, 2008).

Known drug alfostserat (nootrop with holinomimeticski properties, which contains 40.5% of the total metabolic protected choline; provides for the synthesis of acetylcholine and phosphatidylcholine in the membrane of neurons, improves synaptic transmission, plasticity, and function of receptors, cerebral blood flow and enhances the metabolic processes in the brain, activates the reticular formats the Yu brain stem), which has similar activity (Asa, AVL, 2007; Aguchi et al. /edit/, 2008; Onishchenko et al., 2008).

Currently Semax and alfostserat widely used in neurology in acute and chronic insufficiency of cerebral circulation and related diseases, including stroke and its consequences (Eyisi, Whiskerton, 2001; Aguchi et al. /edit/, 2008; Di Perri et al., 1991; Pametti et al., 2001). However, in the clinic of Semax and alfostserat not always effective (Eyisi, Whiskerton, 2001; Parnetti et al., 2001; Mandat et al., 2003).

In connection with the foregoing objective of the present invention is to expand the Arsenal of drugs with pronounced neuroprotective activity in combination with antihypoxic and antiamnesic activity and ability to improve physical performance.

This goal is achieved by creating a pharmaceutical composition which contains as active ingredients Semax and alfostserat with the following content of components in mg/kg:

Semax0,025-0,3
alfostserat800,0

Antihypoxic action of the composition of Semax and Hainaulters on the model of acute normobaric hypoxic hypoxia with hypercapnia (thermocamera) investigated on nonlinear white mice-males weighing 20-25 g by well-known methods, described in the "Manual on experimental (preclinical) study of new pharmacological substances" (2000).

Acute normobaric hypoxic hypoxia with hypercapnia reproduced by placing mice (alone) in thermocamera: animals were placed in glass jars of the same size (250 cm3), which is hermetically closed. As the oxygen concentration in the air of the vessel and in the body is decreased and the amount of carbon dioxide, on the contrary, increased. As a result, the animals developed acute hypoxic hypoxia with hypercapnia. Recorded using a stopwatch the lifespan of mice (until you stop breathing) in thermocamera in minutes (accurate to 0.1 minutes /min/) and to increase judged on the effectiveness of proven pharmacological substances. Analyte and isotonic sodium chloride solution (control) was administered intraperitoneally //b/ (a composition containing the peptide and alfostserat, for 3 hours (h), one peptide for 3 h, one alfostserat - 3 h) prior to placing animals in thermocamera.

Acute gemicescuu hypoxia was produced by subcutaneous (s/C) administration to mice of methemoglobinaemia sodium nitrite (NaNO2) at a dose of 300 mg/kg As is known, NaNO2translates the oxyhemoglobin to methemoglobin causes methemoglobinemia and 100%death of animals in the dose. Analyte and isotonic sodium chloride solution (control) was administered in a/b (a composition containing the peptide and alfostserat, 3 h, one peptide for 3 h, one alfostserat - 3 h) prior to the introduction of NaNO2. Recorded using a stopwatch the lifespan of mice (until you stop breathing) in minutes (with an accuracy of 0.1 min) in acute himicheskoi hypoxia.

Acute histotoxic hypoxia was modeled by s/C injection mice sodium nitroprusside dose of 20 mg/kg. He is able to completely inhibit (by group CN-) cytochrome oxidase and the dose to cause 100% mortality of mice. Analyte and isotonic sodium chloride solution (control) was administered in a/b (a composition containing the peptide and alfostserat, 3 h, one peptide for 3 h, one alfostserat - 3 h) prior to the introduction of sodium nitroprusside. Recorded using a stopwatch the lifespan of mice (until you stop breathing) in minutes (with an accuracy of 0.1 min) in gistologicheskoe hypoxia.

Acute hypobaric hypoxia was modeled in mice in a flow-exhaust chamber; animals raised with a speed of 50 m/s to the "height" of 11000 m (Methodical recommendations for a pilot study of drugs proposed for clinical studies as antihypoxic tools / Under the editorship of the.Dolukhanova, 1990). Recorded survival rate and life expectancy of animals. Analyte and isotonic sodium chloride solution (control) was administered in a/b (a composition containing the peptide and alfostserat, 3 h, one peptide for 3 h, one alfostserat - 3 h) prior to placing the animals in the chamber.

Neuroprotective composition of Semax and choline alfoscerate was evaluated in animals with experimental cerebral ischemia - on model of ischemic stroke. Studies performed on nonlinear white rats-males weighing 220-280 g contained in pivarnik conditions, which simulated ischemic stroke.

Cerebral ischemia in rats was produced by simultaneous ligation (under ether anesthesia) of both common carotid arteries. Lonaprisan animals (control group No. 1), the operation was limited to the stage of access to the common carotid arteries. In the control group No. 2 rats received only isotonic sodium chloride solution. In the experimental groups the animals were injected in b/W various substances (Semax and alfostserat separately and composition containing it) 1 times a day for 7 days; on the first day - after 1 and 3 h after surgery. Animals after surgery was observed within 2 weeks of taking into account the survival rate of rats. Neurological deficits in animals were identified (blind IU the Odom) on a scale McGraw et al. (1976) (in points) every hour for 24 h, and then 1 time per day. The severity of the condition was determined by the sum of the respective points. Lonaprisan animal neurological deficit was absent.

The influence of the composition of Semax and choline alfoscerate on the processes of learning and memory were investigated on nonlinear white mice-males (weighing 20-24 g)using conditional response of passive avoidance (passive avoidance reaction) skin irritation (Abares et al., 1991; Kemzyme et al., 1995). Currently, the test passive avoidance reaction is a basic model to assess the impact of substances on the formation and reproduction memorable track in normal conditions and in conditions of its disorders (amnesia), as well as the most informative of the current methods of evaluating the effectiveness of substances with neuroprotective activity ("Guidance on experimental (preclinical) study of new pharmacological substances", 2000). The production of passive avoidance reaction in mice produced on the basis of skin reinforcement method Cumin et al. (1982) taking into account the recommendations Mondadori et al. (1990). Installation for mice was an experimental camera black size 30×40×30 cm from the electrode floors and white plastic platform (7,5×7,5×0.5 cm), which were placed on the floor in the center of the camera. Mice (alone) was placed on a plastic platform. Usually animals down (or jump) from platforms the electrode on the floor, where do they get the "punishment" - electric shock (this time on the floor of the chamber filed a constant electric current of 0.5 mA). The electric current was turned on only when mouse touch the ground with all four limbs. The usual response of the animals was the return on a safe platform. After 5 min of training in mice was developed passive avoidance reaction - they remained on the platform. Testing the integrity of the passive avoidance reaction was performed at 24 h after amazonvideo impact. If the animal left the platform within 1 min, it was noted retrograde amnesia skill passive avoidance.

As amazonvideo effects used electroconvulsive shock (ECS; the parameters of the electric current: 50 Hz, 50 mA, 0.3 s), which was applied to mice with electrodes in the form of clips recorded on the ears (transpennine), immediately after learning of passive avoidance reaction ("Guidance on experimental (preclinical) study of new pharmacological substances", 2000). Animals of the control group was caused pseudoalteromonas shock: put pineline electrodes for applying ESS without supply of electric current. Semax (one), alfostserat (one), composition containing them, and isotonic sodium chloride solution (control) was administered in a/b during generalized seizures caused ESS, i.e. directly the NGOs after ESS. Testing mice for the preservation of the passive avoidance reaction produced within 24 hours after ESS.

Antiamnesic effect of Semax and choline alfoscerate on the model of amnesia induced by scopolamine, researched nonlinear white mice-males weighing 20-24 g with the use of animals passive avoidance reaction (described above). To play model scopolamine amnesia m-cholinergic antagonist was administered to mice in a/b at a dose of 1 mg/kg immediately after learning of passive avoidance reaction ("Guidance on experimental (preclinical) study of new pharmacological substances", 2000). Analyte and isotonic sodium chloride solution (control) was administered in a/b (a composition containing the peptide and alfostserat, 3 h, one peptide for 3 h, one alfostserat for 3 h) was administered once in b/W to training mice. Testing mice for the preservation of the passive avoidance reaction produced after 24 h after injection of scopolamine.

Antiamnesic effect of Semax and choline alfoscerate on the model of amnesia caused by swimming mice in cold water with simultaneous rotation of the wheel to the point of exhaustion, researched nonlinear white mice-males weighing 20-24 g with the use of animals passive avoidance reaction (described above). Animals (alone) were placed in water-filled plastic box size 17×9×19 cm with a rotating ribbed wheel. Swimming mice in cold water with simultaneous rotation the m wheels to exhaustion (PMHW) was applied immediately after learning of passive avoidance reaction. Safety passive avoidance reaction was checked after 24 h after PMHW. As false PMHW used the shelter animals in cold wet sawdust. Analyte and isotonic sodium chloride solution (control) was administered in a/b (a composition containing the peptide and alfostserat, 3 h, one peptide for 3 h, one alfostserat for 3 h) was administered once in b/W before learning of mice.

Antiamnesic effect of Semax and choline alfoscerate on the model of amnesia caused by acute normobaric hypoxic hypoxia with hypercapnia (thermocamera), were investigated on nonlinear white mice-males weighing 20-24 g with the use of animals passive avoidance reaction (described above). The above model of acute normobaric hypoxic hypoxia with hypercapnia also used for summoning animals retrograde amnesia skill passive avoidance. For this purpose, mice immediately after learning of passive avoidance reaction was placed (separately) in thermocamera for 16-18 minutes, depending on the severity of the symptoms of oxygen deficiency and weight (the more mass, the more typically less than the time of their stay in thermocamera). In the control group of animals was subjected to false hypoxia - planted mice in glass jars of the same size, which is not closed. Check save passive avoidance reaction was performed at 24 h after exposure to hypoxia with hyperk what PNIA. Analyte and isotonic sodium chloride solution (control) was administered in a/b (a composition containing the peptide and alfostserat, 3 h, one peptide for 3 h, one alfostserat - 3 hours) once before learning of mice.

Investigation of the influence of the composition of Semax and choline alfoscerate on physical work capacity in mice. Studies performed on nonlinear white mice-males weighing 20-22, Physical performance of mice was evaluated by test runs in shestigolosie the treadmill (Col et al., 2002). Each treadmill belt was placed animal. The belt speed was 32 m/min Mouse ran to full exhaustion, the criterion of which was the lack of response to stimulation by electric current when exposed to electric table". Take into account the duration of animals running in minutes with an accuracy of 0.1 minutes Semax (one), alfostserat (one), composition containing them, and isotonic sodium chloride solution (control) was administered intraperitoneally (song for 3 h, the peptide for 3 h, alfostserat for 3 h) to running in the treadmill.

To decipher the mechanism of action of the composition of Semax and choline alfoscerate conducted electrophysiological studies on experiencing cross sections of the hippocampus of rats (VGUI et al., 2000; N.V.Kalashnicova et al., 2005). Summary the Yu electrical activity was recorded in the pyramidal layer of the CA1 field using a single glass microelectrodes, filled with 0.15 M sodium chloride. Ortho - and antitumour electrical stimulation was carried out through bipolar platinum electrodes (rectangular pulses of 0.1 MS, the amplitude of 3-8 In, single or paired), which were placed in the field Shaffer collaterals and alveus respectively. Registered single or paired ortho - and antikamnia population responses. Investigated the effect of Semax and choline alfoscerate, and their composites with different concentrations of the answers to these questions. This has allowed, in particular, to assess their effect on synaptic transmission in the system of collaterals Shaffer - the pyramid fields CA1.

Polarographic study of the respiration of isolated mitochondria of brain cells in rats. Mitochondria were isolated from brain tissue nonlinear white rats-males (weighing 210-260 g) by differential centrifugation according to the method Brustovetsky, Dubinsky (2000). Determination of protein content in isolated mitochondria was performed by the method of Bradford (1976). The oxygen consumption of isolated mitochondria was detected polarographically using standard electrode Clark in 1 ml of incubation medium (mannitol - 215 mm, sucrose - 75 mm MgCl22 mm, KH2PO4- 10 mm, bovine serum albumin and 0.1%, EGTA - 1 mm, HEPES 20 mm, pH 7,4) with constant stirring. Speed needs the help of oxygen (O 2) expressed in nanomolar (nm) O2per 1 min per 1 mg of protein of the mitochondria. Investigated the effect of Semax and choline alfoscerate, as well as their composition in different concentrations on respiration of isolated mitochondria of brain cells in rats. Numeric data processed by methods of variation statistics.

Antihypoxic action of the composition of Semax and choline alfoscerate 4 models of acute hypoxia. In a model of acute normobaric hypoxic hypoxia with hypercapnia (thermocamera) it was found that the peptide at doses of 0.025 and 0.2 mg/kg did not significantly change the lifespan of mice in thermocamera, and in doses of 0.05 and 0.3 mg/kg significantly (p<0,01) increased this ratio by 23% and 24%, respectively (table 1). Alfostserat in doses of 100, 200, 400 and 800 mg/kg did not change considerably the life expectancy of animals.

However, compositions containing the peptide and alfostserat, significantly increased the lifespan of animals in thermocamera: composition of Semax 0.025 mg/kg and choline alfoscerate 200 mg/kg, as well as the composition of Semax 0.05 mg/kg and choline alfoscerate 100 mg/kg by 29% (p<0.01), and the composition of the peptide 0.2 mg/kg and choline alfoscerate 200 mg/kg by 27% (p<0.01), and the composition of the peptide 0.3 mg/kg and choline alfoscerate 200 mg/kg - 31% (p<0.01), and the composition of the peptide 0.3 mg/kg and choline alfoscerate 100 mg/kg by 30% (p<0.01), and comp is the position of Semax 0.05 mg/kg and choline alfoscerate 400 mg/kg 20% (p<0.05), and the composition of the peptide 0.3 mg/kg and choline alfoscerate 400 mg/kg and 21% (p<0.05), and the composition of the peptide 0.05 mg/kg and choline alfoscerate 800 mg/kg to 68% (p<0.01), and the composition of the peptide 0.3 mg/kg and choline alfoscerate 800 mg/kg by 73% (p<0,001).

Thus, the expression of the action of the composition of Semax 0.025 mg/kg and choline alfoscerate 200 mg/kg, Semax 0.2 mg/kg and choline alfoscerate 200 mg/kg, Semax 0.05 mg/kg and choline alfoscerate 800 mg/kg, and Semax 0.3 mg/kg and choline alfoscerate 800 mg/kg significantly (p<0,05) exceeded Semax (1.2-3.0 times) and alfostserat (1.2-1.5 times) separately. Composition of Semax 0.05 mg/kg and choline alfoscerate 100 mg/kg, and Semax 0.3 mg/kg and choline alfoscerate 100 mg/kg significantly (p<0,05) was surpassed only alfostserat (1.2 times). Composition of Semax 0.05 mg/kg and choline alfoscerate 400 mg/kg, and Semax 0.3 mg/kg and choline alfoscerate 400 mg/kg on the severity of the actions was not significantly superior to the peptide and alfostserat separately.

In a model of acute himicheskoi hypoxia was found that the peptide at doses of 0.025, 0.05 and 0.3 mg/kg, alfostserat dose of 800 mg/kg, as well as the composition of Semax 0.025 mg/kg and choline alfoscerate 800 mg/kg did not significantly change the lifespan of mice (table 2).

However, compositions containing the peptide and alfostserat significantly (p<0,05) increased prod littelest life of animals: the composition of Semax 0.05 mg/kg and choline alfoscerate 800 mg/kg 25% and the composition of Semax 0.3 mg/kg and choline alfoscerate 800 mg/kg (27%).

In a model of acute gistologicheskoe hypoxia revealed that the peptide at doses of 0.025, 0.05 and 0.3 mg/kg, alfostserat dose of 800 mg/kg, as well as the composition of Semax 0.025 mg/kg and choline alfoscerate 800 mg/kg did not significantly change the lifespan of mice (table 3). However, compositions containing the peptide and alfostserat significantly (p<0,05) increased the life expectancy of animals: the composition of Semax 0.05 mg/kg and choline alfoscerate 800 mg/kg by 23% and the composition of the peptide 0.3 mg/kg and choline alfoscerate 800 mg/kg of 25%. However, only the composition of the peptide 0.3 mg/kg and choline alfoscerate 800 mg/kg on severity of action significantly (p<0,05) exceeded Semax 1.2 times.

In a model of acute hypobaric hypoxia was found that the peptide at a dose of 0.025 did not change considerably the life expectancy of mice in thermocamera, and in doses of 0.05 and 0.3 mg/kg significantly (p<0,01) increased this ratio to 55% and 58%, respectively (table 4). Alfostserat dose of 800 mg/kg significantly (p<0,05) increased this ratio to 35%. However, compositions containing the peptide and alfostserat, significantly increased the life expectancy of animals: the composition of Semax 0.025 mg/kg and choline alfoscerate 800 mg/kg 87% (p<0.01), and the composition of the peptide 0.05 mg/kg and choline alfoscerate 800 mg/kg by 13% (p< 0.001) and the composition of the peptide 0.3 mg/kg and choline alfoscerate 800 mg/kg - 113% (p<0,001).

At the same time, the severity of the actions specified composition significantly (p<0,05) exceeded Semax (1.3-1.8 times) and alfostserat (1.4-2.1 times) separately.

It should be noted that the composition of Semax 0.3 mg/kg and choline alfoscerate 800 mg/kg significantly (p<0,05) increased the survival of mice with 0% (control) to 33%.

So, in different models of acute hypoxia composition of Semax and choline alfoscerate able to provide antihypoxic action, surpassing each of the ingredients, especially in the hermetic and the chamber.

Neuroprotective composition of Semax and choline alfoscerate model of ischemic stroke.

The results of the study neuroprotective action of the composition of Semax and choline alfoscerate and other substances are presented in table 5. It showed that, in rats of the control group No. 2 neurological deficit was most pronounced (8,9±0,1 points) after 2 and 3 days after bilateral ligation of the common carotid arteries; in the control died 24% (18 rats from 75) animals.

It was found that the peptide (one) at a dose of 0.5 mg/kg/day and alfostserat (one) at a dose of 100 mg/kg/day equally reduced mortality in rats with 24% (control) to 14% (p>0,05). Alfostserat (one) at a dose of 50 mg/kg/day reduced the mortality of rats to 18% (p>0.05) and at doses of 200 and 400 mg/kg/day - up to 6% and 3%, respectively (p<0,05). Therefore, choline alfoscerate characteristic is nearly linear dependence of the effect of the dose. The composition comprising the peptide of 0.5 mg/kg/day and alfostserat 50 mg/kg/day, reduced the mortality of rats to 8% (p<0,05). The composition containing the peptide of 0.5 mg/kg/day and alfostserat in doses of 100, 200 and 400 mg/kg/day significantly (p<0,05) increased the number of surviving rats to 100% (i.e., rats were killed). In terms of mortality, the composition comprising the peptide of 0.5 mg/kg/day and alfostserat 100 mg/kg/day significantly (p<0,05) was superior and Semax (14%) and alfostserat (14%). The composition containing the peptide of 0.5 mg/kg/day and alfostserat in doses of 200 and 400 mg/kg/day, in terms of mortality significantly (p<0,05) was surpassed only Semax (14%). In addition, significantly decreased neurological deficit, and on the severity of the action on neurological deficit compositions containing the peptide of 0.5 mg/kg/day and alfostserat in doses of 100, 200 and 400 mg/kg/day significantly (p<0,05) excelled as Semax (1.1-1.2 times)and alfostserat (1.1-1.2 times) (table 5). The composition comprising the peptide of 0.5 mg/kg/day and alfostserat 50 mg/kg/day, this index significantly (p<0,05) was surpassed only alfostserat (1.1-1.2 times).

So, on the model of ischemic stroke, the composition comprising the peptide and the oline alfoscerate, has a marked neuroprotective effect, as a rule, surpassing in intensity of action of each ingredient.

Antiamnesic effect of the composition of Semax and choline alfoscerate on different models of amnesia.

It is established that ASS caused most mice retrograde amnesia skill passive avoidance: in 82% of the animals (p<0,001) after 24 h was observed amnesia passive avoidance reaction. The peptide at a dose of 0.2 mg/kg and alfostserat at a dose of 200 mg/kg did not change considerably amnestic action, and alfostserat at a dose of 400 mg/kg significantly (p<0,05) weakened the amnestic effect of 1.6 times (table 6).

The composition comprising the peptide of 0.2 mg/kg and alfostserat 200 mg/kg significantly (p<0,05) weakened the amnestic effect of 2.3 times, and a composition comprising the peptide of 0.2 mg/kg and alfostserat 400 mg/kg, 3.3 times (p<0,001). While the expression of the action of the composition significantly (p<0,05) was superior and Semax (2.1-3.0 times), and alfostserat (1.8-2.1 times) separately.

Found that scopolamine caused mostly mice retrograde amnesia skill passive avoidance: 72% of the animals (p<0,001) after 24 h was observed amnesia passive avoidance reaction. The peptide at a dose of 0.025 mg/kg and alfostserat in doses of 100 and 200 mg/kg did not significantly affect the amnesia passive avoidance reaction, and alfostserat at a dose of 400 mg/kg significantly (p<0,01) weakened amnestic effect 2.1 the Aza (table 7).

The composition comprising the peptide of 0.025 mg/kg and alfostserat 100 mg/kg, significantly weakened the amnestic effect 2-fold (p<0.05), and a composition comprising the peptide of 0.025 mg/kg and alfostserat 200 mg/kg to 2.9-fold (p<0,001). The composition comprising the peptide of 0.025 mg/kg and alfostserat 400 mg/kg completely prevented the development of CPAR amnesia. At the same time, the intensity of the action of a composition comprising the peptide of 0.025 mg/kg and alfostserat 100 mg/kg, and a composition comprising the peptide of 0.025 mg/kg and alfostserat 200 mg/kg significantly (p<0,05) was superior and Semax (1.9-2.7 times), and alfostserat (1.8-2.0 times). The composition comprising the peptide of 0.025 mg/kg and alfostserat 400 mg/kg significantly (p<0,05) was surpassed only Semax (4 times).

It was found that 24 h after 16-18 minute stay of mice in thermocamera most of them were observed retrograde amnesia: 64% of the animals (p<0,001). The peptide at a dose of 0.025 mg/kg and alfostserat at a dose of 200 mg/kg did not significantly affect the amnesia passive avoidance reaction, and alfostserat at a dose of 400 mg/kg significantly (p<0,05) weakened the amnestic effect of 1.8 times (table 8).

The composition comprising the peptide of 0.025 mg/kg and alfostserat 200 mg/kg significantly (p<0,05) had a distinct antiamnesic effect, reducing the severity of amnesia 2 times. The composition comprising the peptide of 0.025 mg/kg and choline Altos erat 400 mg/kg, completely prevented the development of CPAR amnesia. At the same time, the intensity of the action of a composition comprising the peptide of 0.025 mg/kg and alfostserat 200 mg/kg significantly (p<0,05) was superior and Semax, and alfostserat (1.8 times). The composition comprising the peptide of 0.025 mg/kg and alfostserat 400 mg/kg significantly (p<0,05) was surpassed only Semax (3.5 times).

It is established that PMHW caused mostly mice retrograde amnesia skill passive avoidance: in 62% of the animals (p<0,001) after 24 h was observed amnesia passive avoidance reaction. The peptide at a dose of 0.025 mg/kg and alfostserat at a dose of 200 mg/kg did not significantly affect the amnesia passive avoidance reaction, and alfostserat at a dose of 400 mg/kg significantly (p<0,05) weakened the amnestic effect of 1.9 times (table).

The composition comprising the peptide of 0.025 mg/kg and alfostserat 200 mg/kg significantly (p<0,05) weakened the amnestic effect of 2.7 times. The composition comprising the peptide of 0.025 mg/kg and alfostserat 400 mg/kg completely prevented the development of CPAR amnesia. At the same time, the intensity of the action of a composition comprising the peptide of 0.025 mg/kg and alfostserat 200 mg/kg significantly (p<0,05) was superior and Semax, and alfostserat (2.2 times). The composition comprising the peptide of 0.025 mg/kg and alfostserat 400 mg/kg significantly (p<0,05) was surpassed only Semax (2.9 times).

Now, on different models of amnesia composition of Semax and choline is alfoscerate has expressed antiamnesic action surpassing each ingredient.

The influence of the composition of Semax and choline alfoscerate on physical work capacity in mice.

It was found that the peptide in a dose of 0.01 mg/kg and alfostserat at a dose of 0.5 mg/kg did not significantly change the physical performance of mice on the test run in the treadmill. However, a composition comprising the peptide and alfostserat significantly (p<0,05) increased the physical capacity of mice by 26% (table). While the expression of the action of the composition significantly (p<0,05) was superior and Semax (29%), and alfostserat (23%).

It was also found that the peptide at a dose of 0.3 mg/kg and alfostserat at doses of 1, 10, 200 and 800 mg/kg, and their composition was not significantly changed physical performance mice (TBLB).

It was found that the peptide at a dose of 0.05 mg/kg significantly (p<0.001) reduced physical capacity of mice by 29%. Alfostserat at a dose of 100 mg/kg also significantly (p<0,01) reduced this figure by 30%. Although their composition and unreliable increased physical performance compared with the control group (9%), however, it significantly stimulated physical performance compared with each of the ingredients: peptide - 38% (p<0.001) and choline by alfoscerate by 39% (p<0,01), i.e. the negative impact of each of the drugs was neutralized.

Thus, the composition of the peptide in a dose of 0.1 mg/kg and choline alfoscerate at a dose of 0.5 mg/kg in contrast to its ingredients can increase physical performance of mice on the test run in the treadmill.

Polarographic study of the influence of the composition of Semax and choline alfoscerate on respiration of isolated mitochondria of brain cells of rats.

Polarographic study of respiration in preparations of isolated mitochondria of brain cells in rats showed that the initial rate of oxygen consumption by mitochondria is averaging 5.3±0.1 nm O2/min·mg protein of mitochondria (n=110).

On sections of the hippocampus of rats, it was shown that the peptide (at concentrations of 10, 100 and 500 µm) inhibits orthodrome population responses in the CA1 field (figure 1), which indicates its ability to inhibit synaptic transmission in the system of collaterals Shaffer - pyramidal neurons in the CA1 field of the hippocampus.

Population responses after application of choline alfoscerate in various concentrations was not significantly changed its value from peak to peak, but changed its shape, i.e. an additional epileptiform component, which increased depending on the concentration (500 μm - 5 mm) (figure 2).

Alfostserat did not significantly enhance the effect of the peptide (at concentrations of 100 and 500 µm). The peptide also did not affect epileptiform component that appears after application of choline alfoscerate (figure 3).

The experimental results prove that the proposed pharmaceutical composition comprising the peptide and the hall is on alfoscerate, mutually enhances the effect of each of them.

The claimed composition may find use in the development of new drugs with neuroprotective activity in combination with antihypoxic and antiamnesic activity and ability to improve physical performance and used for treatment of various pathologies of the Central nervous system.

Pharmaceutical composition having antihypoxic, neuroprotective and antiamnesic activity and improve physical performance

Isotonic solution of sodium chloride (control)
Table 1
The influence of the composition of Semax and choline alfoscerate on the lifespan of mice in thermocamera (M±m)
Substance (dose, mg/kg)The number of miceLife expectancy minutes
Isotonic solution of sodium chloride (control)1626,8±0,7
Semax (0,025)1428,1±0,8
Semax (0,2)1428,7±0,8
Semax (0,3)1433,2±1,9**
Alfostserat (200)1427,3±0,9
The composition of the peptide (0,025) and choline alfoscerate (200)1634,7±2,4**☐#
The composition of the peptide (0.2) and choline alfoscerate (200)1634,1±2,0**☐#
The composition of the peptide (0.3) and choline alfoscerate (200)1435,1±2,7**#
Isotonic solution of sodium chloride (control)1225,6±1,0
Semax (0,05)1431,5±1,4**
Alfostserat (100)1228,3±1,1
The composition of the peptide (0.05) and choline alfoscerate (100)1233,1±1,9**#
The composition of the peptide (0.3) and choline alfoscerate (100)1233,4±2,0**#
1027,9±1,2
Alfostserat (400)1030,1±1,6
The composition of the peptide (0.05) and choline alfoscerate (400)1033,6±2,1*
The composition of the peptide (0.3) and choline alfoscerate (400)1033,8±2,2*
Isotonic solution of sodium chloride(control)1026,6±1,1
Alfostserat (800)1030,6±1,8
The composition of the peptide (0.05) and choline alfoscerate (800)1044,8±4,6**☐#
The composition of the peptide (0.3) and choline alfoscerate (800)1046,0±4,8***☐#
Note. * - p<0,05, ** p<0,01, *** p<0,001 - the significance of the differences compared with control;- p<0.05 is the significance of the differences compared with Semax;#- p<0,05,##- p<0,01 - the significance of the difference is s compared to choline by alfoscerate (student test).

Pharmaceutical composition having antihypoxic, neuroprotective and antiamnesic activity and improve physical performance

Table 2
The influence of the composition of Semax and choline alfoscerate on the lifespan of mice with acute himicheskoi hypoxia (M+m)
Substance (dose, mg/kg)The number of miceLife expectancy minutes
0.9% NaCl solution (control)162L2±1,1
Semax (0,025)1019,6±2,7
Semax (0,05)1222,3±1,8
Semax (0,3)1222,6+1,8
Alfostserat (800)1222,1±1,7
The composition of the peptide (0,025) and choline alfoscerate (800)1223,8±1,8
To notice Semax (0.05) and choline alfoscerate (800) 1426,6±1,9*
The composition of the peptide (0.3) and choline alfoscerate (800)1426,9±2,0*
Note. The differences are statistically significant compared to control (student test): * p<0,05.

Pharmaceutical composition having antihypoxic, neuroprotective and antiamnesic activity and improve physical performance

Table 3
The influence of the composition of Semax and choline alfoscerate on the lifespan of mice with acute gistologicheskoe hypoxia (M±m)
Substance (dose, mg/kg)The number of miceLife expectancy minutes
0.9% NaCl solution (control)1615,9±0,4
Semax (0,025)1015,6+0,5
Semax (0,05)1216,7±0,6
Semax 0,3) 1216,9±0,7
Alfostserat (800)1217,8±0,8
The composition of the peptide (0,025) and choline alfoscerate (800)1217,9±0,9
The composition of the peptide (0.05) and choline alfoscerate (800)1419,5±1,0*
The composition of the peptide (0.3) and choline alfoscerate (800)1419,8+1,0*
Note. The differences are statistically significant compared to control (student test): * p<0,05;- p<0.05 is the significance of the differences compared with Semax.

Pharmaceutical composition having antihypoxic, neuroprotective and antiamnesic activity and improve physical performance

Table 4
The influence of the composition of Semax and choline alfoscerate on life expectancy and survival rate of mice after acute hypobaric hypoxia (M±m)
In the society (dose, mg/kg)The number of miceLife expectancy minutesThe number of surviving mice (%)
0.9% NaCl solution (control)143,1+0,30 (0)
Alfostserat (800)124,2±0,4*0 (0)
Semax (0,025)123,3+0,30 (0)
Semax (0.05)144,8±0,4**0 (0)
Semax (0,3)144,9+0,4**0 (0)
The composition of the peptide (0,025) yolina of alfoscerate (800)125,8±0,5**☐#1 (8)
The composition of the peptide (0.05) of Yalina of alfoscerate (800)126,3+0,6***☐#2 (17)
The composition of the peptide (0,3) and Hainaulters (800) 156,6+0,7***☐#5 (33)*
Note. The differences are statistically significant compared with control: * p<0,05, ** - p<0,01, *** p<0,001;- p<0.05 is the significance of the differences compared with Semax;#- p<0.05 is the significance of the differences compared to choline by alfoscerate (student test, Fisher's exact method).

Pharmaceutical composition having antihypoxic, neuroprotective and antiamnesic activity and improve physical performance

Pharmaceutical composition having antihypoxic, neuroprotective and antiamnesic activity and improve physical performance

Table 6
The influence of the composition of the peptide and holiya of alfoscerate at amnesia in mice caused by electroconvulsive shock (ECS)
Conditions of the experiments and the substance (dose, mg/kg)The total number of miceThe number of mice trained passive avoidance reaction (%)The number of mice with amnesia passive avoidance reaction after 24 hours amazonvideo impact (%)
Isotonic solution of sodium chloride + pseudois (control 1)3027 (90)5 (19)
Isotonic solution of sodium chloride + ASS (control 2)3028 (93)23 (82)°°°
Semax (0,2) + ESS2220(91)15 (75)°
Alfostserat (200) + ESS3028 (93)18 (64)°
Alfostserat (400) + ESS3027 (90)14 (52)*
The composition of the peptide (0.2) and choline alfoscerate (200) + ESS3028 (93)10 (36)*☐#
The composition of the peptide (0.2) and choline alfoscerate (400) + ESS3028 (93)7 (25)***☐#
Note. The differences are statistically significant compared to control 1 and control 2, respectively: ° or * - R<0,05, °°° - p<0,001;- p<0.05 is the significance of the differences compared with Semax;#- p<0.05 is the significance of the differences compared to choline by alfoscerate (Fisher's exact method).

Pharmaceutical composition having antihypoxic, neuroprotective and antiamnesic activity and improve physical performance

Table 7
The influence of the composition of Semax and choline alfoscerate at amnesia in mice induced by scopolamine
Conditions of the experiments and the substance (dose, mg/kg)The total number of miceThe number of mice trained passive avoidance reaction (%)The number of mice with amnesia passive avoidance reaction after 24 hours amazonvideo impact (%)
Isotonic solution of sodium chloride + isotonic solution of sodium chloride (control 1)3129 (94)5 (17)
Isotonic solution of sodium chloride + scopolamine (control 2)3229 (91)21 (72)°°°
Semax (0,025) + scopolamin the 3128 (90)19 (68)°
Alfostserat (100) + scopolamine3028 (93)18 (64)°
Alfostserat (200) + scopolamine2928 (96)14 (50)
Alfostserat (400) + scopolamine3029 (97)10 (34)**
The composition of the peptide (0,025) and choline alfoscerate (100) + scopolamine3028 (93)10 (36)*☐#
The composition of the peptide (0,025) and choline alfoscerate (200) + scopolamine2928 (96)7 (25)***☐#
The composition of the peptide (0,025) and choline alfoscerate (400) + scopolamine3029 (97)5 (17)***
Note. The differences are statistically significant compared to control 1 and control 2, respectively: ° or * - p<0,05, the°° - p<0,001;- p<0.05 is the significance of the differences compared with Semax;#- p<0.05 is the significance of the differences compared to choline by alfoscerate (Fisher's exact method).

Pharmaceutical composition having antihypoxic, neuroprotective and antiamnesic activity and improve physical performance

Table 8
The influence of the composition of Semax and choline alfoscerate at amnesia in mice, caused by acute normobaric hypoxic hypoxia with hypercapnia
Conditions of the experiments and the substance (dose, mg/kg)The total number of miceThe number of mice trained passive avoidance reaction (%)The number of mice with amnesia passive avoidance reaction after 24 hours amazonvideo impact(%)
Isotonic solution of sodium chloride + false hypoxia (control 1)3028 (93)5 (18)
Isotonic solution of sodium chloride + hypoxia (control 2)4844 (92)28 (64)°°°
With the max (0,025) + hypoxia 2422 (92)13 (59)°
Alfostserat (200) + hypoxia3230 (94)17 (57)°
Alfostserat (400) + hypoxia2928 (96)10 (36)*
The composition of the peptide (0,025) and choline alfoscerate (200) + hypoxia3028 (93)9 (32)*☐#
The composition of the peptide (0,025) and choline alfoscerate (400) + hypoxia3029 (97)5 (17)***
Note. The differences are statistically significant compared to control 1 and control 2, respectively: ° or * - p<0,05, °°° p<0,001;- p<0.05 is the significance of the differences compared with Semax;#- p<0.05 is the significance of the differences compared to choline by alfoscerate (Fisher's exact method).

Pharmaceutical composition having antihypoxic, neuroprotective and antiamnesic activity and improve physical performance

Table 9
The influence of the composition of Semax and choline alfoscerate on the amnestic effects of swimming mice in cold water with simultaneous rotation of the wheel to exhaustion (PMHW)
Conditions of the experiments and the substance (dose, mg/kg)The total number of miceThe number of mice trained passive avoidance reaction (%)The number of mice with amnesia passive avoidance reaction after 24 hours PMHW (%)
Isotonic solution of sodium chloride + false PMHW (control 1)5248 (92)8 (17)
Isotonic solution of sodium chloride + PMHF (control 2)5552 (94)32 (62)°°°
Semax (0,025) + PMHF3028 (93)14 (50)°
Alfostserat (200) + PMHF2624 (92)12 (50)°
Alfostserat (400) + PMHF2928 (96) 9 (32)*
The composition of the peptide (0,025) and choline alfoscerate (200) + PMHF2826 (93)6 (23)*☐#
The composition of the peptide (0,025) and choline alfoscerate (400) + PMHF3029 (97)5 (17)***
Note. The differences are statistically significant compared to control 1 and control 2, respectively: ° or * - p<0,05, °°° p<0,001;- p<0.05 is the significance of the differences compared with Semax;#- p<0.05 is the significance of the differences compared to choline by alfoscerate (Fisher's exact method).

Pharmaceutical composition having antihypoxic, neuroprotective and antiamnesic activity and improve physical performance

Table 10A
The influence of the composition of Semax and choline alfoscerate on physical performance of mice on the test run in the treadmill (M±m)
Substance (dose, mg/kg)The number of miceDuration of run, minutes
Isotonic solution of sodium chloride (control)146,8±0,1
Semax (0,01)146,6±0,1
Alfostserat (0,5)147,0±0.1
The composition of the peptide (0.01) and choline alfoscerate (0,5)148,6±0,2*☐#
Note. * - p<0.05 is the significance of the differences compared with control;- p<0.05 is the significance of the differences compared with Semax;#- p<0.05 is the significance of the differences compared to choline by alfoscerate (student test).

Pharmaceutical composition having antihypoxic, neuroprotective and antiamnesic activity and improve physical performance

Table 10B
The influence of the composition of Semax and choline alfoscerate on physical performance of mice on the test run in the treadmill (M±m)
SubstanceDose, mg/kgThe number of mice Duration of run, minutes
Control (isotonic sodium chloride solution)85,8±0,4
Semax +0,0186,9±0,7
Alfostserat5
Control86,0±0,4
Semax0,0185,7±0,5
Control86,3±0,3
Alfostserat1087,0±0,5
Control86,1±0,3
Alfostserat186,7±0,3
Control 85,8±0,3
Semax +0,0186,0±0,7
Alfostserat10
Control85,8±0,3
Semax +0,0186,6±0,4
Alfostserat1
Control169,6±0,6
Semax0,0586,8±0,3***
Control167,4±0,3
Semax0,386,2±0,8
Control 1613,2±0,6
Alfostserat10089,2±0,9**
Control167,5±0,3
Alfostserat20086,6±1,2
Control89,8±0,8
Alfostserat80088,6±0,8
Control108,1±0,4
Semax +0,05108,8±0,9
Alfostserat100
Control109,2±0,9
Semax +0,05 108,5±0,9
Alfostserat200
Control109,0±0,6
Semax +0,05107,1±0,9
Alfostserat800
Control109,8±0,9
Semax +0,3107,8±0,9
Alfostserat100
Control108,4±0,6
Semax +0,3107,9±0,8
Alfostserat200
Control108,5±0,8
Semax +0,3108,2±0,6
Alfostserat800
Note. The differences are statistically significant compared to control (student test): ** p<0,01, *** p<0,001.

Pharmaceutical composition having neuroprotective, antihypoxic, antiamnesic activity and increasing physical activity, characterized in that it comprises the peptide and alfostserat the next component content, mg/kg:

Semax0,025-0,3
alfostserat800,0



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to a therapeutic and diagnostic agent used in treatment or diagnostics of a cerebral disease caused by a mitochondrial dysfunction, or in a method for prevention within a surgical intervention and an intravascular surgery, and also to a diagnostic technique for cerebral diseases. The therapeutic agent contains an iron compound and δ-aminolevulinic acid or its salt by formula R2R1NCH2COCH2CH2COR3 (1) where each R1 and R2 independently represents hydrogen atom, and R3 represents a hydroxyl group or C1-24 alkoxy group. The diagnostic agent contains 8-aminolevulinic acid or its salt by formula specified above. The diagnostic technique for the cerebral disease caused by mitochondrial dysfunction, involves a stage of introduction of the specified diagnostic agent followed by a stage of exposure of a diagnosed brain region to light, capable to excite protoporphyrin IX, accompanied by emission of red light, and a stage of diagnostics of the involved brain by the detected emission of red light.

EFFECT: higher diagnostic efficiency.

7 cl, 4 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular, to pharmacy. As medical substance composition contains therapeutically effective quantity of trimetazidine dihydrochloride, as prolonging agent - interpolymer complex of polyacrylic acid and polyethylenglucol. As additional substances composition includes: bibasic calcium phosphate, monocrystalline cellulose, basic calcium carbonate, group of sliding substances - stearic acid and/or its salts. Composition can be made in form of pills, covered with coating, contains optimal quantity of additional substances, makes it possible to sufficiently release medical substance and ensures its high bio-availability.

EFFECT: obtaining prolonged pharmaceutical composition, which has antianginal action.

16 cl, 6 tbl, 6 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to field of pharmaceutics and medicine and pharmaceutical composition for treatment of reperfusion disorders, which contains inert auxiliary substances and as active component compounds of general formula I-Iva.

EFFECT: obtaining pharmaceutical composition for treatment of reperfusion disorders.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel flavonoid compounds of formula 1 where R1-R5 assume values given in the description. The invention also relates to a pharmaceutical composition based on said compounds and a treatment and prevention method. Such compounds and corresponding pharmaceutically acceptable derivatives and/or salts are used in pharmaceutical, veterinary and nutraceutical fields.

EFFECT: compounds and compositions have antioxidant properties and are especially effective in treating ischemic and reperfusion injury.

39 cl, 19 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns an injection dosage form for treating an acute ischemic stroke and a craniocereberal injury characterised by the fact that as an active ingredient, it contains a therapeutically effective amount of heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro, and at least one substance chosen from a group of antioxidants.

EFFECT: invention provides high neuroprotective effect in acute severe CNS affections associating various models of the stroke and the craniocereberal injury, as well as high stability and prolonged use.

12 cl, 13 ex, 2 dwg, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an ester presented by formula [2] where R1' represents 1) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, or 2) -CO-C1-C6 alkoxy; R2' represents 1) hydrogen or 2) C1-C6 alkyl, R3', R4' and R5' are identical or different, and each represents 1) hydrogen, 2) halogen, 3) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, 4) C1-C6 alkoxy, 5) -COR13' where R13' represents (a) hydroxy, (b) C1-C6 alkyl, (c) C1-C6 alkoxy which is optionally substituted by one or more identical or different substitutes selected from (1) hydroxy, (2) C1-C6 alkoxy which is optionally substituted by phenyl, (3) -NR11'CO-C1-C6 alkyl where R11' represents hydrogen, (4) -CONR8'R9' where R8' and R9' are identical or different, and each represents C1-C6 alkyl, (5) -CO- C1-C6 alkoxy optionally substituted by phenyl, (6) phenyl optionally substituted by one or more identical or different substitutes selected from halogen, C1-C6 alkoxy and -CO-C1-C6 alkoxy, and (7) a heterocycle selected from pyridyl, thienyl and which all can be substituted by one or more identical or different C1-C6 alkyl groups, or (d) -OR19' where R19' represents a group or a group or piperidyl which is optionally substituted by -CO-C1-C6alkyl, 6) a heterocycle selected from oxadiazolyl and tetrazolyl, and said heterocycle is optionally substituted by C1-C6 alkyl optionally substituted by one or more identical or different substitutes selected from -CONR8'R9' (R8' and R9' have the same values as defined above) and -CO-aralkyloxy, or 7) nitrile; R6' and R7' are identical or different, and each represents 1) C1-C6 alkyl or 2) a nitrogen-containing 5 or 6-members saturated heterocycle containing a monocycle formed when R6', R7' and a neighbouring nitrogen atom are taken together, and optionally including oxygen as a heteroatom; Y1, Y2, Y3 are identical or different, and represent, 1) all carbon atoms, or 2) one of Y1, Y2, Y3 represent a nitrogen atom, and the others are carbon atoms; Y4 represent a carbon or nitrogen atom ;-X- represents 1) -(CH2)1 where 1 represents an integer 1 to 3, 2) -CH2-NR18'-CH2- where R18' represents C1-C6 alkyl, or 3) or to its pharmaceutically acceptable salt.

EFFECT: compounds presented by formula are effective as agents for treatment or prevention hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes and hypertension or similar diseases since they are withdrawn very quickly and exhibit excellent MTP inhibitory activity.

23 cl, 32 tbl, 137 ex

FIELD: chemistry.

SUBSTANCE: invention relates to aminophosphate derivatives of general formula (1a), pharmaceutically acceptable salts or hydrates thereof, which can be used in medicine as S1P (sphingosine-1-phosphate) receptor modulators,

where R3 is a straight alkyl group containing 1-3 carbon atoms; X is an oxygen or sulphur atom and n equals 2 or 3.

EFFECT: obtaining novel biologically active compounds with high S1P receptor modulating action.

9 cl, 59 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

, where R and R1 independently denote a link selected from: i) hydrogen; ii) substituted or unsubstituted phenyl and iii) substituted or unsubstituted 5- or 6-member heteroaryl in which heteroatoms are selected from nitrogen, oxygen, sulphur or combinations thereof; said substitutes are selected from: i) C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; ii) C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkoxy; iii) C1-C4 linear, C3-C4 branched or C3-C4 cyclic halogenalkyl; iv) halogen; v) -CN; vi) -NHC(O)R4 vii) -C(O)NR5aR5b; viii) 5- or 6-member heteroaryl in which heteroatoms are selected from nitrogen, oxygen, sulphur or combinations thereof; or ix) two substitutes may be taken together to form a condensed ring containing 5-7 atoms; R4 is C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; R5a and R5b each independently denotes: 1) hydrogen; ii) C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; or iii) R5a and R5b can be taken together to form a ring containing 3-7 atoms; R2 is selected from: i) -OR6; or ii) -NR7aR7b; R6 is hydrogen or C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; R7a and R7b each independently denotes: i) hydrogen; ii) C1-C4 linear, C3-C4 branched or C3-C4 cyclic alkyl; or iii) R7a and R7b may be taken together to form a ring containing 3-7 atoms; R3 is hydrogen, methyl or ethyl; L is a binding link of formula -[C(R8aR8b)]n -R8a and R8b each independently denotes hydrogen, methyl or ethyl; n ranges from 1 to 3; R9 is hydrogen or methyl; or pharmaceutically acceptable salt thereof; provided that R and R1 both denote hydrogen. The invention also relates to compositions based on the described compounds for treating anaemia or assisting wound healing and use of said compounds to prepare a composition for treating anaemia or wounds.

EFFECT: novel compounds which are HIF-16 prolyl hydroxylase inhibitors are obtained.

14 cl, 18 ex, 15 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: for treatment of patients with ischemic heart disease in addition to basic therapy introduced is cudesan in dose 25 drops simultaneously with preductal MB 35 mg 2 times per day during meal for 3 months, with further parenteral introduction of essentiale H in dose 0.5-1 g for 10 days, after that, enterally in dose 1 capsule 3 times per day for 20 days. Course of treatment is repeated 3 times per year.

EFFECT: expressed anti-ischemic effect and normalisation of processes of lipid peroxidation, including in patients with severe affection of coronary channel and expressed diastolic dysfunction of left ventricle.

2 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to a therapeutic and diagnostic agent used in treatment or diagnostics of a cerebral disease caused by a mitochondrial dysfunction, or in a method for prevention within a surgical intervention and an intravascular surgery, and also to a diagnostic technique for cerebral diseases. The therapeutic agent contains an iron compound and δ-aminolevulinic acid or its salt by formula R2R1NCH2COCH2CH2COR3 (1) where each R1 and R2 independently represents hydrogen atom, and R3 represents a hydroxyl group or C1-24 alkoxy group. The diagnostic agent contains 8-aminolevulinic acid or its salt by formula specified above. The diagnostic technique for the cerebral disease caused by mitochondrial dysfunction, involves a stage of introduction of the specified diagnostic agent followed by a stage of exposure of a diagnosed brain region to light, capable to excite protoporphyrin IX, accompanied by emission of red light, and a stage of diagnostics of the involved brain by the detected emission of red light.

EFFECT: higher diagnostic efficiency.

7 cl, 4 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to medicine. Described is composition for transcutaneous absorption of denepezil or its hydrochloride. Composition for transcutaneous absorption includes 2-[(1-benzyl-4-pyperidinyl)methyl]-5,6-dimethoxyindan-1-on and/or its hydrochloride and chloride of metal in layer of adhering under pressure glue preparation, which was subjected to linking.

EFFECT: composition is stable and resistant to loss of cohesive ability of layer adhering with pressure on glue preparation, when applied, and is resistant to adhesive transfer resulting from cohesive destruction during removal by exfoliation.

10 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydroquinoline derivatives of formula (I), where values of C3-C4, R2, R3, R4, R5, L1, L2, Y and X are given in claim 1, as muscarinic receptor agonists; compositions containing said compounds; methods of inhibiting muscarinic receptor activity using said compounds; methods of treating diseased conditions associated with the muscarinic receptor using said compounds, and methods of identifying a subject suitable for treatment using said compounds.

EFFECT: improved properties of compounds.

22 cl, 1 tbl, 3 ex, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 5-amino-3-(2-nitroxipropyl)-1,2,4-thiadiazoles of general formula , where R1, R2 can be similar or different and independently represent hydrogen, substituted or non-substituted aryl or heteroaryl or aralkyl, alkyl, cycloalkyl, and R1 + R2 can represent heteroaryl (optionally substituted piperasin and piperidin).

EFFECT: obtained are novel compounds, which can be applied in medicine for treatment of neurodegenerative diseases.

1 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed group of inventions relates to medicine, namely to neurosurgery and biotechnology, and can be used for cultivation of nerve stem cells of mammal, excluding embryonic human cells, and for treatment of spasticity, rigidity, spinal cord or amniotrophic state in subject, requiring such treatment. For cultivation of said cells preliminarily incubated in culture vessel is solution, which contains poly-D-lysine in concentration from 0.1 mkg/ml to 1 mg/ml during from 5 minutes to 3 hours. After that, culture vessel is rinsed and dried. Nerve stem cells are inoculated into said culture vessel without serum. After that, solution of fibronectin and, at least, one mitogen is added into culture vessel and nerve stem cells are cultivated without serum. Then, cultivated nerve stem cells are passed until fusion. For treatment of said states nerve stem cells, cultivated be claimed method, are concentrated. Therapeutically efficient amount of said concentrated nerve stem cells is introduced into region of patient's central nervous system tissue with decreased level of GABA-producing or glycin-producing neurons.

EFFECT: group of inventions ensures efficient method of cultivating mammalian nerve stem cells, excluding embryonic human cells, which makes it possible to achieve in vitro higher degree of neuronal differentiation to the level sufficient for treatment of said states and improvement of survival in vivo of such cells, as well as efficient treatment of spasticity, rigidity or amniotrophic state in subject due to introduction into their central nervous system tissues with lower level of GABA-producing or glycin-producing neurons of cells, able to differentiate into sufficient number of GABA-producing or glycin-producing neurons in said tissue.

10 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), in which X denotes N or CR3, M denotes (CH2)m; m equals 0 or 1, R1 denotes H or lower alkyl which can be substituted with a group selected from a group consisting of mono- or di-lower alkylamino and -O-lower alkyl, R2 denotes H or lower alkyl, R3 denotes H or lower alkyl substituted with a group selected from a group consisting of halogen, mono- or di-lower alkylamino and cyclic amino, R41 denotes H or pyridine which can be substituted with a cyano group, R42 denotes a bridged polycyclic hydrocarbon or a bridged azacyclic hydrocarbon, each of which can be substituted, R5 denotes a group selected from a group consisting of halogen, cyano, lower alkyl-carbonyl, lower alkyl-oxycarbonyl, hydroxycarbonyl, formyl, amidinooxycarbonyl, guanidinooxycarbonyl, guanidino, carbamoyl, -C(=O)-5- or -6-member heterocycloalkyl, -C(=O)-5- or -6-member heteroaryl, lower alkyl, lower alkenyl, -O-lower alkyl, 5- or 6-member heterocycloalkyl and 5-member heteroaryl, each of which can be substituted, provided that when R5 denotes a 5-member heteroaryl, X denotes -CR3; or R41 and R15 can be bonded through a defined functional group to form divalent groups shown below: (I-A) (I-B) or (I-C), in which RA denotes H or acyl, which can be substituted, provided that the term "substituted" with respect to R4 and/or R5 denotes substitution with one or more substitutes selected from a group comprising the following substitutes: (a). halogen; (b) -OH, -O-R2, -O-phenyl, -OCO-RZ-OCONH-RZ oxo (=O); (c) -SH, -S-R2, -S-phenyl, -S-heteroaryl, -SO-R2, -SO-phenyl, -SO-heteroaryl, -SO3H, -SO2-RZ, -SO2-phenyl, - SO2-heteroaryl, sulphamoyl, which can be substituted with one or two RZ groups; (d) amino, which can be substituted with one or two RZ groups, -NHCO-RZ, -NHCO-phenyl, -NHCO2-RZ, -NHCONH2, -NHCONH-RZ, -NHSO2-R0, -NHSO2-phenyl, -NHSO2NH2, -NO2, =N-O-RZ; (e) -CHO, -CO-RZ, -CO2H, -CO2-RZ, carbamoyl, which can be substituted with one or two RZ groups, -CO-cyclic amino, -COCO-RZ, cyano; (f) RZ; (g) phenyl, which can be substituted with one or more groups selected from substitutes described above in paragraphs from (a) to (f), a 5- or 6-member heterocycloalkyl, a 5- or 6-member heteroaryl, a 5- or 6-member heterocycloaryl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing compounds of formula II, a pharmaceutical composition based on said compounds which is a Janus kinase 3 inhibitor, a method of treating and/or preventing different immunopathological diseases, including autoimmune diseases, inflammatory diseases and allergic diseases.

EFFECT: novel compounds are obtained and described, which can be used as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission or diseases caused by pathological cytokine signal transmission.

14 cl, 579 ex, 72 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel pyrimidine derivatives or their pharmaceutically acceptable salts, possessing inhibiting activity with respect to glycogensintase kinase-3 (GSK3). In compound of formula I: R1 is selected from hydrogen, cyano, C1-3alogenoalkinyl, SO2NRbRc, C0-2alkyl(O)NRbRc, C1-4alkylNBbRc, SO2Ri, C(O)ORa, CH(OH)Rj and C(O)Rj; R2 and R4 are independently selected from hydrogen, halogeno, cyano, NO2, C1-4alkyl, C1-3ahalogenoalkyl, ORa, C(O)NRbRc, SO2Ri, and C(O)ORa; or R1 and R2 together with atoms, to which they are bound, are bound with formation of 5- or 6-member heterocyclic ring, which contains one S, any of the hydrogen atoms of group CH2 in said heterocyclic ring can be substituted by oxo, hydroxy, and sulphur atom in said heterocyclic ring is probably oxydised to -SO2-; R3 and R5 represent hydrogen; R6 represents tetrahydropyran; R7 is selected from hydrogen, C1-3alkyl, cyano and C1-3halogenoalkyl; R8 represents hydrogen; Ra is selected from C1-3alkyl and C1-3halogenoakryl. Other radicals are given in formula of invention.

EFFECT: compounds can be applied in manufacturing medication for prevention and/or treatment of predemential states, moderate cognitive failure and type II diabetes, Alzheimer's disease and Parkinson disease, as well as bone-associated malfunctions.

40 cl, 3 dwg, 1 tbl, 122 ex

FIELD: medicine.

SUBSTANCE: what is offered is a monoclonal antibody which binds with Aβ Globulomer containing CDRs of a heavy and light chain. There are described: composition for diagnosing Alzheimer's disease, and also a composition and an antibody-based vaccine for preventing or treating Alzheimer's disease. What is disclosed is application of the antibody for preparing a drug for the intended application stated above. There are described: versions of a diagnostic technique for Alzheimer's disease, an antibody-based diagnostic kit for Alzheimer's disease.

EFFECT: use of the invention provides new Aβ Globulomer antibodies which are detected more selectively than common antibodies.

16 cl, 10 dwg, 5 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to application of neramexane or its pharmaceutically acceptable salt in a combination with a glutamate release inhibitor for treating neurodegenerative disorders, and also emotional instability and pseudobulbar affect associated with neurodegenerative disorders. The glutamate release inhibitor is selected from riluzole and its pharmaceutically acceptable salts. The neurodegenerative disorder represents a motor neuron disease.

EFFECT: therapy with the combined neramexane and riluzole provides relieved progression of the neurodegenerative disease which surpasses a relief effect induced by therapy with riluzole only.

35 cl, 4 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclohexylamine derivatives of formula (I), having inhibiting properties towards at least one monoamine transporter, such as serotonin transporter, dopamine transporter or norepinephrine transporter, or a combination of two or more transporters. The compounds can be used to treat and/or prevent central nervous system disorders such as pain, depression, anxiety, schizophrenia, sleep disorder etc. In formula (I) , n equals 0 or 1; s equals 1, 2 or 3, m equals a whole number from 0 to 12; Ar is

or where Y and Z are (i) both halogen; or (ii) one of Y and Z is CF3 or OCF3 and the other is hydrogen; Y1, Z1, Y2 and Z2 each independently denotes H or a halogen; each X independently denotes H, halogen, CF3, OR5, (C1-C4)alkyl, optionally substituted with halogen or OH, or NR6R7; each R1 and R2 independently denotes H or (C1-C6)alkyl; and each R3 and R4 independently denotes H or (C1-C9)alkyl optionally substituted with OH; where each R5 independently denotes H, (C1-C4)alkyl or phenyl; and each R6 and R7 independently denotes H or (C1-C4)alkyl; where at least two of R1, R2, R3, R4 and X together with atoms to which they are bonded are optionally bonded to form a 5-6-member ring, where the 5-6-member ring is selected from: a) R3 and R4 together with a nitrogen atom to which they are bonded optionally form a pyrrolidine, piperidine, piperazine or morpholine ring, which is optionally substituted with (C1-C4)alkyl; b) when R3 is H or lower alkyl, X and R4 together with atoms to which they are bonded optionally form a 1,3-oxazine ring; c) two X substitutes together with a carbon atom to which they are bonded optionally form a 1,3-dioxolane ring; and d) when R1 and R3 denote hydrogen, R2 and R4 together with atoms to which they are bonded optionally form a 5- or 6-member saturated heterocyclic ring containing one nitrogen atom.

EFFECT: high efficiency of using the compounds.

29 cl, 36 dwg, 11 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: claimed is preparation for overcoming multidrug resistance, which presents hexapeptide of structural formula: lisyl-histidyl-glycyl-lisyl-histidyl-glycine. On the basis of claimed substance it is possible to create medications, possessing higher efficiency of overcoming multidrug resistance, enhanced by specificity of action with respect to transport proteins of multidrug resistance (MRP), enhanced harmlessness and not causing toxic reactions.

EFFECT: medications can be used for prevention and therapy of patients with phenomena of multidrug resistance.

4 cl, 7 dwg, 8 ex

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