Medication for treatment of cardiovascular diseases

FIELD: medicine.

SUBSTANCE: invention represents a mixture of two structural isomers: 2,6-di(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-4-methylphenol and its diastereomers, and 2-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-6-(2,2,1-trimethylbicyclo[2.2.1]hept-5-yl)-4-methylphenol, and their diastereomers with the ratio of the first and second structural isomer isomers from 60:40 wt % to 95:5 wt %.

EFFECT: extension of the arsenal of means, possessing simultaneously haemorheological, anti-aggregate, anti-thrombogenic, retinoprotecting, endothelium-protecting, neuroprotecting, anti-arrhythmia and anti-ischemic activity, enhancing the cerebral blood flow.

4 dwg, 20 tbl, 6 ex

 

The agent for treating cardiovascular disease

The invention relates to medicine, specifically to pharmacology, and relates to funds with hemorheologic, antiaggregatory, antithrombogenic, renoprotective, endotheliocytes, neuroprotective, antiarrhythmic and anti-ischaemic activity, increasing cerebral blood flow.

It is known tool that has antiradical, hemorheological, antiplatelet and anti-platelet activity [Patent No. 2347561, A61K 31/05, 2008].

Known agent exhibiting anti-ischemic properties [Patent No. 2499593, A61K 31/05, 2013].

Known agent exhibiting antiarrhythmic activity [p. P. Shchetinin Antiarrhythmic activity of Gibernau in the model of acute ischemia / reperfusion / Bulletin of Siberian medicine, 2003, volume 12, No. 3, p. 153-156].

Known remedy possessing a neuroprotective activity [Patent No. 2406488, A61K 31/05, 2010].

It is known tool that has renoprotective activity [Patent No. 2406487, A61K 31/05, 2010].

Known agent exhibiting endothelization properties [I. S. Ivanov Neuroprotective and anti-platelet activity 4-methyl-2,6-diisobornylphenol is separated / abstract of thesis of candidate of biological Sciences, Tomsk, 2009, 24].

Known agent capable of increasing brain to�the peripheral circulatory problems [Patent No. 2351321, A61K 31/05, 2009].

These funds represent 4-methyl-2,6-diisobornylphenol is separated.

It is known that such compounds is a mixture of structural isomers [Patent No. 2502719, SS 39/17, 2013], but it is not known about the ratio of these isomers in the mixture, and the influence of the ratio to be shown by their pharmacological activity.

The object of the invention is to expand the Arsenal of tools that has both hemorheological, antiaggregatory, antithrombogenic, renoprotective, endotheliocytes, neuroprotective, antiarrhythmic and anti-ischaemic activity, increasing cerebral blood flow. Also the task of the invention is to identify pharmacological activity of the specified means of showing specified properties.

The task is achieved by using a mixture of structural isomers of 2,6-di(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-4-METHYLPHENOL (isomer 1) and 2-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl), 6-(2,2,1-trimethylbicyclo[2.2.1]hept-5-yl)-4-METHYLPHENOL (isomer 2) as drugs having hemorheological, antiagregatini, antithrombogenic, renoprotective, endothelization, neuroprotective, anti-arrhythmic and anti-ischemic properties increases brain blood flow with a high degree of activity in the following ratio of�Mer:

from 60 to 95 wt.% for the first isomer and 40 to 5 wt.% for the second isomer.

In the literature there is no information on the use of a mixture of structural isomers of 2,6-di(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-4-METHYLPHENOL and 2-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl), 6-(2,2,1-trimethylbicyclo[2.2.1]hept-5-yl)-4-METHYLPHENOL with the specified ratio of isomers as hemorheological, antiaggregative, antithrombogenic, renoprotective, endothelization, neuroprotective, anti-arrhythmic, anti-ischemic, increasing cerebral blood flow remedies in diseases of the cardiovascular system. The literature describes the use of only one isomer is 2,6-di(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-4-METHYLPHENOL, however, the allocation in its pure form leads to large losses in output and higher prices for the drug.

New in the present invention is that as a hemorheologic, antiaggregative, antithrombogenic, renoprotective, endothelization, neuroprotective, anti-arrhythmic, anti-ischemic, increasing cerebral blood flow means uses a mixture of these diastereomers diastereomers of 2,6-di(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-4-METHYLPHENOL and 2-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl), 6-(2,2,1-trimethylbicyclo[2.2.1]hept-5-yl)-4-METHYLPHENOL with the ratio of isomers 60:40 wt.% + 95:5 m�S.%, which can be used to treat cardiovascular diseases. This mixture is obtained by selection of the conditions of the alkylation reaction Friedel-Crafts para-cresol by camphene and does not require expensive purification methods. The ratio of isomers was calculated from the NMR spectra (Fig. 1) and the ratio of areas of peaks on HPLC (Fig. 2 - 95:5 and Fig. 3 - 60:40). For the analysis used a liquid chromatograph "SURVEYOR LC", equipped with a UV detector with photodiode array (firm Thermo, USA).

The separation of the mixture of diastereomers was performed on a Hypercarb column, 100×2.1 mm, particle size 5 µm (Thermo, USA). Mobile phase - acetonitrile + 0.1% formic acid, the elution is isocratic, flow rate of 600 μl/min (Fig. 2) or eluent acetonitrile + N2O + 0.1% formic acid, the elution gradient, the flow rate of 300 ál/min (Fig. 3). The structure of 2,6-di(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-4-METHYLPHENOL was confirmed rentgenostrukturnyi analysis (Fig. 4).

For the specialist, these properties are not explicitly follow from the prior art.

Thus the subject of the study were the following compounds.

The compound 1 - 4-methyl-2,6-diisobornylphenol is separated.

Compound 2 is a mixture of structural isomers and their diastereomers: 2,6-di(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-4-METHYLPHENOL and 2-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl), 6-(2,2,1-trim�tibetica[2.2.1]hept-5-yl)-4-METHYLPHENOL with the ratio of isomers from 60% to 95 wt.% for the first isomer and 40% to 5 wt.% for the second isomer.

The effectiveness of compound 2 compared to the control and compound 1 was demonstrated in model experiments on Wistar rats after intragastric administration at a dose of 100 mg/kg.

In all examples, the statistical processing of the results was carried out using the software "BioStat" for Windows using t-student criterion and criterion χ2. To assess the reliability of differences when comparing the average values used nonparametric Mann-Whitney test.

The invention is illustrated by examples of specific performance.

Example 1. Experiments conducted on 90 female rats Wistar weighing 190-210 g. Rats were divided into 3 groups of 30 animals each. The total model of transient cerebral ischemia by the method of W. A. Pulsinelli, J. B. Brierley [1979] evaluated the neuroprotective effects. To do this 1 day before the simulation of ischemia in anesthetized rats (thiopental sodium 60 mg/kg, intraperitoneally) at the level of the first cervical vertebra was performed thermocoagulation of both vertebral arteries. After 24 hours under ether anesthesia on both carotid artery occluders overlap by 30 minutes. the Consistency of the model was evaluated by pallor of the visible part of the choroid, the dilated pupils, the development of hyperventilation. Reperfusion was performed by withdrawal of the occluders. Rats control�Noah group were administered intragastrically 1 ml of 1% starch gel, animals of experimental groups of compounds 1 and 2 at a dose of 100 mg/kg in 1 ml of starch gel once a day for 7 days. The first injection was performed 1 hour after the creation of the model of ischemia, the latest introduction - 1 hour before blood sampling. In the first 2-5 h after playing a total model of transient cerebral ischemia in rats was observed the most severe symptoms of damage to the Central nervous system in the form areflection, seizures, spastic paralysis of the limbs, tonic tension of the muscles of the trunk, lateral position. Assessment of the functional state of the higher nervous activity on the 1st, 4th, 5th and 7th day after the creation of the total model of transient cerebral ischemia was performed according to the scale Stroke-index [McGraw CP., 1977] in the following indicators: spontaneous motor activity (normal, increased or reduced, no), gait disorders (stiffness, shakiness, slowness of movement, impaired orientation), the reflex withdrawal of the tail, both front and rear paws, the reaction to the sound, tremors, convulsions, muscle tone of the trunk and extremities (normal, increased, no), the signs of ptosis (none, unilateral, bilateral). Each indicator was evaluated in points: points - norm; 1 point - mild changes; 2 points - pronounced changes. Neurological deficit belly�CSOs was estimated by the sum of scores for all indicators. In addition, in each group of rats was determined by the proportion of animals with severe neurological disorders (6 points or more), with disorders of moderate severity (3-5 points) and with minor changes (up to 2 points). The survival of animals was recorded on the 1st, 4th and, 5th and 7th day after total transient cerebral ischemia. Upon completion of the experiments were carried out euthanasia of animals.

The research results show that in the control during the first days after total transient cerebral ischemia killed 30% of the rats. At the same time, we treated animals with compounds 1 and 2, on the first day, respectively, killed 15 and 11% of the rats that was approximately 2 times lower than the benchmark (table. 1). Despite the fact that the average score of neurological deficit at WYSIWYG rats of all groups was not significantly different (tab. 2) show a distinct tendency to decrease under the influence of compounds 1 and 2 the number of animals with severe neurological impairment and a corresponding significant increase in the number of animals with an average degree of neurological deficit (table. 2). In the treatment of compound 2 showed a significant decline in the death rate of rats and neurological disorders as compared with the control and administration of the compound 1.

In the control mortality of rats to the fourth day after total �tranzitornoe cerebral ischemia was greatest (45%), during the subsequent observation period, mortality was not increased. In the experimental groups the animals by that time was much lower and did not change to 5-7 days (tab. 1). The severity of neurological disorders was similar in surviving animals treated with compound 1 and control for 4 days. In rats treated with compound 2, was shown to improve neurologic disorders (table. 2). Starting with 4 days in the control group, there was a decrease in the severity of neurological symptoms. However, the recovery of neurological status in rats treated with compounds 1 and 2, occurred at a higher rate. So, for 5 days the average score of neurological deficit in the groups treated with compounds 1 and 2 was, respectively, 1.6 and 2 times less control, and by day 7 there was a continuing trend towards full restoration of function of the Central nervous system.

Thus, the use of compound 2 in the treatment of ischemic brain damage in the largest extent compared to compound 1 reduces the death of animals and accelerates the recovery of neurological status in WYSIWYG animals.

Example 2. The study endothelization activity of compounds 1 and 2 were conducted on models of pathological conditions (n�complete cerebral ischemia and diabetes mellitus).

The model of incomplete cerebral ischemia in anesthetized (ether narcosis) female rats Wistar were reproduced by complete occlusion of the left carotid artery and restricting blood flow through the right carotid artery 50% of the source under the control of the electromagnetic flowmeter. I lonaprisan animals was carried out similar surgery, but without ligation of vessels. Wounds were treated with antiseptics and stitches.

To assess the endothelial dysfunction was studied endothelium-dependent and endothelialization reaction vessels in rats. To do this, anesthetized animals were continuously recorded systemic arterial pressure (SBP). To measure the GARDEN animals in the right carotid artery with an implanted catheter, filled with a mixture of saline and heparin. Endothelium-dependent vasodilation was recorded during bolus intravenous administration of acetylcholine (5 µg/kg), endothelialization vasodilation - when bolus intravenous administration of sodium nitroprusside (30 µg/kg). Acetylcholine and sodium nitroprusside was injected into the femoral vein. Endothelial function was assessed using the coefficient of endothelial dysfunction (CED), calculated as the ratio of the areas under the curves of blood pressure in response to intravenous� introduction of sodium nitroprusside and in response to intravenous acetylcholine [Tyurenkov I. Y., Voronov A.V., 2008].

Experiments with the reproduction of the model of incomplete cerebral ischemia was conducted on female rats of Wistar weighing 260-280 g Were formed 5 groups of 10 animals each. Groups of rats: intact control, loneprimavera and treated with compound 1 and compound 2. Animal control, lonaprisan and intact groups were administered intragastrically 1 ml of starch gels. Rats treated with compounds 1 and 2 drugs were administered in a dose of 100 mg/kg. Starch gel and suspension of compounds 1 and 2 in the starch gel was injected to animals once a day for 5 days. The first injection was performed 1 hour after the creation of the model of incomplete cerebral ischemia. 5 days 1 hours after the last administration of compounds 1 and 2 or starch gels rats were anesthetized (thiopental sodium 60 mg/kg, intraperitoneally) and the evaluation of endothelial function.

The results suggest that in the group lonaprisan rats changes endothelialization and endothelium-dependent vasodilation compared with intact animals have not been identified, the CED was 2,1±0,2 (PL. 3). Consequently, all observed changes in the control and the groups treated with compounds 1 and 2 are not related to the effects of surgery. In ischemic rats of the control group CED comp�fork 3,4±0,4, which is 60% higher than the value in the group lonaprisan rats (tab. 3). Thus, incomplete cerebral ischemia in rats was accompanied by endothelial dysfunction. Describes the changes of endothelial function with primary violation of endothelium-dependent vasodilation are consistent with the data on the formation of endothelial dysfunction in ischemic and reperfusion injury of the brain tissue of rats. In the group of rats with cerebral ischemia treated with compound 2 QED amounted to 1.9±0,2, which was significantly different from the control and the group treated with compound 1 and was similar lineameriloan animals.

Thus, in course of intragastric administration of compound 2 compared to compound 1 exhibits a greater endothelization activity in the model of incomplete cerebral ischemia in rats.

To create a model of diabetes in rats-females Wistar once intraperitoneally administered streptozotocin at a dose of 60 mg/kg in citrate buffer. In the experiment, the animals were selected with the level of glucose in the blood from 19 to 26 mmol/l glucose Level in whole blood was measured using a glucometer (guidance on the preclinical testing of medicines. Part one. - M. Cole, 2012. - 944 (C).

Assessment of endothelial dysfun�tion conducted in accordance with the methodology outlined in the previous section.

Experiments with the reproduction of the model of diabetes mellitus was conducted in rats female Wistar weighing 240-260 g 30 animals were reproduced model of diabetes mellitus and 1 month after injection of streptozotocin were selected rats in the group treated with compound 1, compound 2 and control with a similar level of glucose in the blood, which is in the range from 19 to 26 mmol/l during the following month daily intragastrically to animals of the control and intact groups were injected starch gel, rats experimental groups - compounds 1 and 2 at a dose of 100 mg/kg in starch gel. After 1 h after the last administration of compounds 1 and 2 rats were anesthetized (thiopental sodium 60 mg/kg, intraperitoneally) and the evaluation of endothelial function.

The results showed that in rats of the control group was identified endothelial dysfunction. This was evidenced by a significant increase in QED 1.5 times in comparison with intact animals. Describes the changes in the control group of animals are consistent with the data on the availability of endothelial dysfunction in diabetic patients and animal models of this disease. In animals treated with compound 2, CED was significantly significantly 1.6 and 1.2, respectively, lower than in the control and in the application of compound 1 in the treatment Saharna� diabetes.

Thus, in course of intragastric administration of compound 2 compared to compound 1 exhibits a greater endothelization activity in diabetes mellitus in rats.

Example 3. On the model of diabetic retinopathy was assessed renoprotective effects of compounds 1 and 2. The experiments were performed on 40 female rats Wistar weighing 220-250 g. the Model of diabetic retinopathy in rats was reproduced by a single intraperitoneal injection of streptozotocin at a dose of 60 mg/kg of body weight. The level of hyperglycemia (over 18 mmol/l), loss of body weight, the severity of polyuria and polydipsia was the criteria of severity of diabetes. Within 30 days after the administration of streptozotocin, the rats were divided into 3 groups. Rats of experimental groups with glucose concentration of 21.8±2,5 (compound 1) and 22.0±1,9 (compound 2) mmol/l daily for 30 days were administered intragastrically compounds 1 and 2 at a dose of 100 mg/kg of body weight, in the form of suspension in 1 ml of starch gels. Animals of the control group with a glucose concentration of 22.3±2.2 mmol/l was injected the same amount of starch gels according to the same scheme. The group of intact animals that were in similar conditions. The Central sections of retinas of rats were material studies that had been prepared (after 60 days after you started� injection of streptozotocin) immediately after euthanasia with ether narcosis of animals. Central portion of the rear wall of the eyes were fixed in 2.5% glutaraldehyde in 0.2 M cacodylate buffer (pH 7.4), after fixed in 2% solution of osmium tetroxide and embedded in a mixture of EPON resins-araldit. Semi-thin sections were stained by toluidine blue, ultrathin contractionary with uranyl acetate and analyzed by lead citrate, and viewed and photographed in the electron microscope. On semi-thin sections derived counting neurosensory cells with pyknosis nuclei per 1000 cells on each retina, and hyperchromic piknomorfnyh associative neurons and radial gliocytes, ganglionic neurons with a total focal chromatolysis and piknomorfnyh 200 cells on each retina. Using a measuring ocular grid Avtandilov were calculated numerical density of nuclei in the outer nuclear layer in the area of 900 μm2specific area of vessels with stasis, sludge and thrombosis, glioneuronal index.

The results of these studies show that after the development of streptozotocin diabetes in the retinas of animals marked morphological signs of degeneration of all the structural components of the retina. Destructive changes neurosensory cells are expressed in the appearance of perikaryon different size, deformation of nuclei, between which grow the hypertrophied scleral�e processes of radial glia. Shifting single cores neurosensory cells in photostory and outer mesh layers. Quantitative analysis showed a three-fold increase in the percentage of neurosensory cells pyknosis kernel characterized by increase osmiofilii of nucleus and cytoplasm, and decreased to 1.56 times the density distribution of nuclei neurosensory cells in the outer nuclear layer compared to intact control (table. 5). The changes of associative neurons are reactive in nature. When streptozotocin diabetes in rats of the control group was observed an increase in the percentage of hyperchromic neurons compared with intact control (table. 6). Degeneration multipolar neurons with long-term hyperglycemia on the background of streptozotocin-induced diabetes is characterized mainly different severity chromatolysis. In the control panel first noted chromaticities changes ganglionic neurons (table. 7): increasing the level of neurons with focal and total chromatolysis 6-7 times compared to intact controls, while the number of piknomorfnyh neurons increases 3.8 times. During prolonged hyperglycemia in rats of control group were identified destructive processes in the radial glorith, which was reflected by the increase of the electron density of cytoplasm and nucleus. The number piknomorfnyh HL radial�acetow relative values of intact control increases, accompanied by a decline glioneuronal index (tab. 8). In the control group was noted severe disturbance of microvascularization, characterized by the reliable increase compared with intact control specific area of choroidal vessels with sludge and stasis of formed elements (tab. 9).

Treatment with compound 2 is more effective for preventing destruction of the neurosensory cells, resulting in a decrease in the percentage of piknotičnyh nuclei of neurons to the values of intact control and increase the number of rows of kernels relative to the control group and the group of rats treated with compound 1 (table. 5). However, the density distribution of nuclei neurosensory cells in the outer nuclear layer is reduced, which is likely due proliferative one-progressive reaction of radial glia in the form of proliferation and hypertrophy scleral spikes. The introduction of compound 2 in contrast to compounds 1 contributed fully intact neurons of the inner nuclear layer from the damaging effect of stand for a long period of hyperglycemia, which was reflected in the lack of significant differences in all indicators of degradation of associative neurons of rats treated with compound 2 and intact groups (tab. 6). Intragastric administration of compound 2 OK�had a positive impact on the ganglionic neurons of the retina, moreover, the percentage of neurons with total and focal chromatolysis was decreased relative to the values of the control group and the group of animals treated with compound 1, while remaining still significantly higher values of intact control (table. 7). Also when administered to rats of compound 2 showed full recovery of all indicators of degradation radial glycidol (PL. 8). So, the percentage piknomorfnyh radial gliocytes decreased with glioneuronal index increased relative to the control values and the values of the group of rats treated with compound 1. When administered to animals of compound 2 showed a significant improvement in hemodynamics, which was reflected in a significant decrease in the specific area of vessels with stasis, sludge and thrombosis in comparison with similar indicators of control rats and treated with compound 1 (table. 9).

Thus, term treatment with compound 2 at a dose of 100 mg/kg compared with compound 1 for 30 days to rats with diabetic retinopathy, developed on the background of streptozotocin-induced diabetes, have had a more pronounced renoprotective effect, resulting in a reduction in the severity of destruction of all structural components of the retina. Compound 2 in contrast to compound 1 has a significantly higher renoprotective activity.

Example 4. The effect of compounds 1 and 2 in a single parenteral and three-time intragastric administration to rats on the cerebral blood flow was studied by means of registration in the carotid artery velocity of blood flow using electromagnetic flow meter.

Experiments to study the effects of a single parenteral administration of compounds 1 and 2 on the dynamics of cerebral blood flow (MC) and systemic blood pressure (SBP) held on 26 rats male Wistar weighing 340-360 g Were divided into 3 groups of animals. Animals of the control group (n=8) was introduced subcutaneously 1 ml of cremophor. Rats experimental groups (n=18) were injected subcutaneously compounds 1 and 2 at a dose of 100 mg/kg as a solution in 1 ml of cremophor.

In anesthetized rats (thiopental sodium 60 mg/kg, intraperitoneally) were prepared through the right femoral artery and implanted catheter for measurement of systemic blood pressure. Left common carotid artery was prepared and tied the external carotid artery. On the common carotid artery was imposed cuff sensor and detecting the magnitude of cerebral blood flow using an electromagnetic blood flow meter.

The experiments to study the influence of three-time intragastric administration of compounds 1 and 2 on the cerebral blood flow was conducted on 18 rats male Wistar weighing 250-280 g Were divided into 3 groups of animals. Rats in the control group (n=6) were administered intragastrically once daily for 3 days equivolume amount of starch gels. Animals of the experimental group intragastrically once daily for 3 days was introduc�s of compound 1 (n=6) and 2 (n=6) at a dose of 100 mg/kg in starch gel. On the 3rd day of the experiment after 1 h after the last injection were carried out to measure cerebral blood flow in rats.

The results of these studies indicate that in the control after a single parenteral (subcutaneous) administration of cremator rats the level of MC for 1 h was stable, in the next 30 min measurement revealed a slight tendency of decrease in cerebral blood flow. While there was a trend to lower GARDEN during the measurement, which is obviously linked to the experimental conditions (presence of surgical trauma and the use of anesthesia) (PL. 10). During a three-day intragastric introduction of the starch gel in the control group, the value of cerebral blood flow was estimated at 5.9±0.5 ml/min (table. 11).

Subcutaneous injection of an oil solution of compounds 1 and 2 rats contributed, starting with 5 min of measurement to the end of the observation significant increased MK. In the period from 45 to 90 min of the experiment the values of MK in rats treated with compound 2, were significantly higher values of this index in the control groups and treated with compound 1. In this case, the level of the GARDEN during the whole observation period, no significant differences between groups of animals have been detected (tab. 10).

In exchange intragastric administration to rats of compound 2 at a dose of 100 mg/kg the value of cerebral blood flow was 8.9±0.4 ml/min, Thu�, respectively, 47 and 22% higher than the rate in the control group and animals treated with compound 1 (table. 11).

Thus, subcutaneous injection of an oil solution of compound 2 at a dose of 100 mg/kg increased more significantly compared with controls and animals treated with compound 1 cerebral blood flow without causing a decrease in systemic blood pressure. Three-time intragastric administration of compound 2 at a dose of 100 mg/kg causes a significant increase of cerebral blood flow and the severity of the effect is superior to compound 1. The present invention expands the Arsenal of tools that can increase cerebral blood flow.

Example 5. The study of hemorheological, antitrombozitarnae and anti-platelet activities of compounds 1 and 2 were conducted on models of hyperviscosity blood ex vivo, intravascular thrombosis in rats.

Experiments to study the hemorheological properties of compounds 1 and 2 were conducted on 20 rats male Wistar weighing 270-290 g. Rats were randomized into 4 groups of 5 animals each. The rats in the control group were administered starch gel, animals of the experimental group - pentoxifylline (400 mg/kg) or compound 1 and 2 (100 mg/kg). Drugs and equivolume amount of starch gels (2 ml) was administered intragastrically by gavage one hour before blood collection.

Value� blood viscosity and aggregation of erythrocytes was assessed in blood samples immediately after capture and after 1 h after incubation of the blood at a temperature of 20.0±0,4°C. Blood was taken from the common carotid artery under ether anesthesia. As anticoagulant was used in 3.8% sodium citrate solution in a ratio of blood 1:9. Blood viscosity was measured on a rotational viscometer in the range of shear rates from 5 to 300-1before and after incubation of the samples at a temperature of 20.0±0,4°C for 60 min.

In the same series of experiments the spontaneous aggregation of erythrocytes was studied using electrometrical method. Criterion aggregation activity of erythrocytes was the halftime aggregation T1/2- the time at which the value of the photometric signal is reduced in two times.

The initial values of blood viscosity animals of the control group at shear rates from 5 to 300-1ranged from 8.3±0.1 to 4.5±0.1 MPa C. Incubation data blood samples for 60 minutes at a temperature of 20.0±0,4°C resulted in significant (16-31%) increase in the viscosity of blood. Pentoxifylline caused a significant compared to control lowering of blood viscosity at low shear rates to the incubation. After incubation, the observed increase in blood viscosity in all the investigated range of shear rates, however, the values of this index were significantly lower compared with values in the control group. Therefore, intragastric administration of pentoxifylline rats ul�Chalo source hemorheological indicators at low speeds of saiga and slowed the development of hyperviscosity" blood in vitro. Compound 2 compared to the control and compound 1 exerted a pronounced effect on the viscosity of the blood. In animals treated with compound 2 compared to the control group of animals with the introduction of compound 1, immediately after blood sampling revealed a significant decrease in the viscosity of blood at low shear rates, and after incubation at high shear rates (tab. 12).

The original values of the aggregation of red blood cells between the groups did not differ significantly. Incubation of the blood of rats in the control groups led to increased aggregation of red blood cells by 37%. The introduction of pentoxifylline prevented the acceleration of the aggregation of erythrocytes during incubation. Intragastric administration to rats of compound 2 slowed the aggregation of erythrocytes during incubation of blood, which resulted in significant increase of half aggregation of erythrocytes compared to the control and compound 1 at 55% and 22% respectively (table. 13).

Thus, compound 2 is able to limit the development of hyperviscosity blood and increased aggregation of red blood cells ex vivo. The effect of compound 2 by a degree higher than the effect of compound 1 and comparable with pentoxifylline.

Experiments on the study of antiplatelet activity of compounds 1 and 2 were conducted on 20 rats male Wistar weighing 300-320 g,�which Rats were divided into 4 groups (5 animals each). One hour before blood sampling the animals of experimental groups were administered pentoxifylline (400 mg/kg) or compound 1 and 2 (100 mg/kg). The rats in the control group were administered equivolume amount of starch gels. Blood was taken from the common carotid artery under ether anesthesia. As anticoagulant was used in 3.8% sodium citrate solution in a ratio of blood 1:9. Platelet aggregation was determined by nephelometric method. According to the standard method were obtained rich (TC) and poor (Betp) platelet plasma and counted the number of platelets. After determining the number of platelets in TC was carried out to standardize the number of platelets, for which TC was diluted with the necessary quantity of Betp to 400±27 thousand of platelets in 1 mm3in the sample. To assess the antiplatelet effect of the vascular wall were used TC and Betp intact rats donor. Platelet aggregation was assessed in a standardized plasma on the device, agregatogramme were recorded using a chart recorder. After adding inducer of aggregation were recorded changes in the level of optical density TC. As a criterion for aggregation activity of platelets was used an indicator of the degree of aggregation ( % ), characterized by varying the optical density of the TC after adding the cell aggregation inducer. In this case, for 100% of the accepted value of�optical density Betp, and 0% to the optical density TC. As inducer of aggregation used ADP at a final concentration of 4·10-6M.

The results of these studies showed that in the control group, the amplitude of platelet aggregation induced by ADP at a final concentration of 4·10-6M, was 29±2%. The amplitude of the ADP-induced platelet aggregation after administration of pentoxifylline was significantly lower than in the control group. After administration of compound 2, the amplitude of platelet aggregation was also significantly significantly lower than in the control group and the group with the introduction of compound 1 (table. 14).

Thus, compound 2 compared to compound 1 has a pronounced effect on vascular-platelet hemostasis. Anti-platelet activity of compound 2 may be due to antiplatelet and endothelization properties.

Experiments to study anti-platelet activity of compounds 1 and 2 were performed on 24 rats male Wistar weighing 260-280 g Were formed 4 groups of 6 animals each. Animals of the control group was injected starch gel. Rats of experimental groups were respectively administered pentoxifylline (400 mg/kg), compounds 1 and 2 (100 mg/kg). Soy�of inane and equivolume amount of starch gels (2 ml) was administered intragastrically by gavage 1 time a day for 5 days. On the 5th day of the experiment, after 1 h after the last injection the animals were anesthetized (thiopental sodium at a dose of 60 mg/kg, intraperitoneally), isolated left common carotid artery and the reproduced model of intravascular thrombosis. On prepared carotid artery were imposed cuff sensors and detecting the amount of blood flow through the vessel by means of an electromagnetic blood flow meter. Further, under the carotid artery was underlaid with a strip of filter paper and plastic film. On that artery superimposed on top of a strip of filter paper, which was applied 1 drop of 10% solution of FeCl2. Measure blood flow in the artery was conducted from the moment of application of ferric chloride on the left carotid artery to stop blood flow in it (the formation of thrombus). Calculation of reduction of blood flow relative to the initial value of the blood flow was expressed as a percentage. The weight of the thrombus was evaluated by the gravimetric method.

In animals of the control group after exposure of the vascular wall with a solution of FeCl2there is a complete cessation of blood flow through the vessel. The average time a complete stop of blood flow to zero was 22±1 min. Weight of thrombus, defined through a day after application of ferric chloride, amounted to 1.40±0.1 mg (tab. 15). In exchange intragastric administration to rats pins�oxyphylla registered a decrease of blood flow by 28% from the original value to the 90th min of the experiment. The following day, in the lumen of the carotid arteries in rats of this group of thrombus was not detected. The use of pentoxifylline reduces blood clots in the area of stenosis. Coursework intragastric administration to animals of compound 2 prevented the cessation of blood flow after application of the solution of FeCl2. To the 90th min of the experiment in rats treated with compound 2, there was a reduction of blood flow by 9%. The introduction of compound 2 completely prevented thrombus formation in the carotid artery on the next day after application with a solution of FeCl2. In antithrombogenic activity of compound 2 were significantly superior to compound 1.

Thus, compound 2 compared to compound 1 possesses pronounced anti-platelet activity.

Example 6. The study of the antiischemic and antiarrhythmic activity of compounds 1 and 2 are made according to the guidelines for conducting pre-clinical trials of medicinal products (Part one. - M. Cole, 2012. - 944 p) on the model of ischemia and reperfusion in rats, which is recommended for playback of ischemia and ventricular arrhythmias of the type.

The experiments were carried out on 66 rats male Wistar weighing 260-280 g. the Rats were randomized into 3 groups. Rats of experimental groups were respectively administered compounds 1 and 2 at a dose of 100 mg/kg in the form suspension 1% starch gel (2 ml) intragastrically by gavage 1 time a day for 3 days before and 3 days after creating the model. Animals of the control group was injected equivolume amount of starch gel according to the same scheme.

Compounds 1 and 2 were investigated using electrocardiographic (ECG) and morphological techniques. To reproduce the model animals were anesthetized by thiopental sodium (60 mg/kg, intraperitoneally), intubated and connected to a ventilator. After the thoraco - and pericardiotomy underwent occlusion of the left coronary artery at the level of the lower edge auricula sinistra without disturbing the topography of the heart in the chest by the method of Cohen [Cohen A. H. Surgical simulation method coronacion of heart attack and cardiac aneurysm in rats // Pathological physiology and experimental therapy. 1979. No. 3. S. 79-81]. The duration of occlusion of the left coronary artery was 20 min, after which the ligature was untied and carried out postischemic reperfusion. During the period of ischemia and 10 min reperfusion was performed ECG monitoring in the II standard lead with the help of computer electrocardiography. Verification of correctness of ligating and the adequacy of the model was monitored based on changes in the height of the ST segment on the ECG. I lonaprisan animals was carried out similar surgery without overlapping ligation of the left coronary and�the matter.

At 3 days after reperfusion, the rats were re-anesthetized with thiopental sodium (60 mg/kg, intraperitoneally), intubated and connected to a ventilator and imposed ligature. To determine the zone of hypoperfusion bolus into the femoral vein was injected with 0.2 ml of a 5% solution of the dye patent blue violet, and in the next 20-30 extracted with heart. Areas of the myocardium with preserved perfusion was painted in green, reperfusion remained unpainted.

Sections of the hearts were prepared on a freezing microtome. Part of the slices were left in native form to assess areas of hypoperfusion, while Other sections were stained nitroblue tetrazolium (nst) to identify in tissue dehydrogenase activity. The slices were concluded in glycerol-gelatin gel and scanned. The size of zones of hypoperfusion and changes in dehydrogenase activity was estimated with the use of Adobe Photoshop. For the area of the infarct zone was taken with a sharp decline in dehydrogenase activity. For this purpose, the slices of the myocardium allocated sites, the total intensity of which was reduced 2.5 times or more relatively intact areas of the myocardium, reflecting the topography of the reduction to the same extent dehydrogenase activity [Kogan A. H. Surgical simulation method coronacion heart attack and an�Prisma of the heart in rats // Pathological physiology and experimental therapy. 1979. No. 3. S. 79-81].

The results show that in the control group during the first hours after restoration of blood supply to the myocardium of the left ventricle killed 11 animals out of 22 (50%). In animals treated with compound 2, in the period of reperfusion of the 22 animals were killed 1. Mortality in the group of rats treated with compound 2 was 4%, which was significantly different from the level in the control group of animals received intragastrically compound 1 (table. 16).

In rats of the control group to the first day and for the next 3 days after resuming perfusion of the myocardium of the left ventricle on ECG was observed the appearance of pathological Q evidencing the presence of necrotic changes in the myocardium, and decrease in the amplitude of the T wave relative to the original values. After restoration of blood supply to the myocardium during the reperfusion period in rats of the control group remained significant decrease in the amplitude of R-wave relative to the original values characterizing the violation of the process of depolarization of the ventricles due to the shutdown of part of the myocardium of the processes of excitation. In the group of rats with the introduction of compound 2 compared to the control group of animals treated with compound 1 within 1-3 days after reperfusion showed a significant decrease in the amplitude of Q on ECG after the episode �Chemie/reperfusion. During the reperfusion period to the third day in a group of rats, treated with compound 2 was identified distinct significant increase waves amplitudes R and T relative to control and the group of animals with the introduction of compound 1 (table. 17).

As can be seen from table 19 to the size of hypoperfusion of the total area of cross sections of the myocardium of the studied groups did not differ significantly. In animals treated with compound 2, compared with the control group of rats with the introduction of compound 1 showed a significant reduction zone is sharply reduced dehydrogenase activity of the total area of the myocardium and the area of the zone of hypoperfusion. Therefore, treatment-and-prophylactic administration of compound 2 at a dose of 100 mg/kg reduces the mortality of animals after an episode of ischemia/reperfusion and significantly reduced the infarcted area from the total area of the myocardium and the area of hypoperfusion compared with the same indicators in the control group and the group of animals treated with compound 1 (table. 18).

In animals of control and experimental groups in the ischemic and reperfusion periods in different proportions mentioned all kinds of ventricular arrhythmias high grades in Lown: polytopia ventricular premature beats, ventricular tachycardia, ventricular fibrillation. In control rats velemichsky the period basic share in the cardiac rhythm disturbance amounted to ventricular fibrillation (50%) and ventricular tachycardia (27%) (table. 20). Mortality in the control group of rats was 50% (table. 16). The main cause of death was fatal arrhythmias, in particular atrial left ventricle with subsequent cardiac arrest.

In animals of the experimental groups prophylactic administration of compounds 1 and 2 during the ischemic episode were not significantly changed the structure of heart rate in comparison with the frequency and nature of arrhythmias in animals of the control (tab. 19). Significant differences in the number and severity of arrhythmias in rats studied groups were identified in reperfusion period. In the group of animals treated with compound 2, compared with the control and the group with the introduction of compound 1 significantly (6-fold and 1.7-fold, respectively) increased the number of animals without ventricular arrhythmias and significantly decreased the number of rats with fatal ventricular atrial (PL. 20). The decrease in pathological changes in heart rhythm and reduce the number of rats with the most severe form of arrhythmia called ventricular atrial - manifested itself in a reduction of mortality of animals protected by compound 2 in perifusion period.

Compound 2 at a dose of 100 mg/kg of body weight, in contrast to the control and compound 1 when health care introduction in the model of ischemia and reperfusion significantly reduced the incidence and severity of arrhythmias, decreased with�Artest animals due to fatal arrhythmias.

Thus, a significant area reduction of myocardial infarction, reducing the frequency and severity of arrhythmia and mortality of animals protected by compound 2, due to its anti-ischemic and antiarrhythmic actions.

The present invention expands the Arsenal of tools that has both hemorheological, antiaggregatory, antithrombogenic, renoprotective, endotheliocytes, neuroprotective, antiarrhythmic and anti-ischaemic activity, increasing cerebral blood flow.

The agent for treating cardiovascular disease comprising a mixture of 2,6-di(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-4-METHYLPHENOL and its diastereomers, and 2-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-6-(2,2,1-trimethylbicyclo[2.2.1]hept-5-yl)-4-METHYLPHENOL and its diastereoisomers with a ratio of 2,6-di(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-4-METHYLPHENOL and 2-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-6-(2,2,1-trimethylbicyclo[2.2.1]hept-5-yl)-4-METHYLPHENOL from 60 to 95 wt.% for the first isomer and 40 to 5 wt.% for the second isomer.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to synthetic biologically active heterocyclic substances having antagonist activity on purinoreceptors and which are products of modifying pyridoxin, particularly n-(1,5-dihydro-3-R-8-methyl-9-hydroxy-[1,3]dioxepino[5,6-c]pyridinyl-6-azo)phenyl sulphonic acid and salt forms thereof of general formula I , where is selected from: a hydrogen atom, ethyl, heptyl or octyl.

EFFECT: compounds of the given formula have high antagonist activity on purinoreceptors and can be used in medicine and veterinary.

2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of synthetic biologically active heterocyclic substances as purinoreceptor antagonists, said substances having antagonist activity on purinoreceptors and being a product of modifying pyridoxin, particularly n-(1,5-dihydro-3-R1-3-R2-8-methyl-9-hydroxy-[1,3]dioxepino[5,6-c]pyridinyl-6-azo)phenyl sulphonic acid and salt forms thereof of general formula I , where R1 is a hydrogen atom or methyl, R2 is methyl, isopropyl.

EFFECT: compounds of the given formula have high antagonist activity on purinoreceptors and can be used in medicine and veterinary.

2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

possessing properties of binding with delta opioid receptors. In formula I R1 is selected from the group, consisting of phenyl, pyridinyl and thiazolyl, with R1 being optionally substituted with one or two substituents, independently selected from the group, consisting of C1-4alkoxy, fluorine atom, chlorine atom, bromine atom and cyanogroup; in addition, R1 is optionally substituted with di(C1-4alkyl)aminocarbonyl; Y represents O, S, H3, vinyl, ethinyl or S(O); R2 represents a substituent, selected from the group, consisting of hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, fluorine atom, chlorine atom, bromine atom and hydroxy; Ra represents hydrogen or methyl; R3 is selected from the group, consisting of pyrrolidin-2-ylmethyl; pyrrolidin-3-ylmethyl; piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperidin-2-ylethyl, piperidin-3-ylethyl, piperidin-4-ylethyl, pyridine-4-yl-(C1-2)alkyl, azetidin-3-ylmethyl; morpholin-2-ylmethyl, morpholin-3-ylmethyl, imidazolylmethyl, thiazolylmethyl, (amino)-C3-6cycloalkyl, 3-hydroxy-2-aminopropyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[2.2.2]octanyl, guanidinylethyl, 4-(imidazol-1-yl)phenylmethyl, 2-(methylamino)ethyl, 2-diethylaminoethyl, 4-diethylaminobut-2-yl, piperidin-3-yl, piperidin-4-yl and pyrrolidin-3-yl; with piperidin-3-yl being optionally substituted on a carbon atom with phenyl; with pyrrolidin-2-yl in pyrrolidin-2-yl-methyl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl being optionally substituted on a nitrogen atom with methyl, phenylmethyl, phenethyl or methylcarbonyl.

EFFECT: compounds can be used in the treatment of pain, induced by diseases or conditions, such as osteoarthritis, rheumatoid arthritis, migraine, burn, fibromyalgia, cystitis, rhinitis, neuropathic pain, idiopathic neuralgia, toothache, etc.

24 cl, 3 tbl, 19 ex

Hypotensive means // 2554815

FIELD: medicine.

SUBSTANCE: invention represents a hypotensive means, which contains felodipinum as an active component, as well as target additional components: mesoporous silicon dioxide, lactose, hypromeloza. Realisation of the invention ensures the high technological efficiency of the claimed medical means production with the provision of a prolonged release of an active substance with the application of available components. Felodipinum is included into spherical particles with a highly developed mesoporous structure of silicon oxide.

EFFECT: increase of stability in storage and protection from unfavorable environmental factors.

4 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of structural formula I

which can be used for protecting cardiomyocytes or for preventing or treating a disease or a disorder related to cardiomyocyte apoptosis. In formula I A represents =S, -SR4 or =O, X represents F, Cl, Br or I, R1 represents phenyl, R2 and R3 are connected to form morpholine, and R4 represents C1-C6-alkyl.

EFFECT: invention refers to using the compound for producing the therapeutic agent for protecting cardiomyocytes or for preventing or treating a disease or a disorder related to cardiomyocyte apoptosis, and to the method for producing the above compounds.

8 cl, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I, possessing ability of binding with delta-opioid receptors. In formula R1 is selected from the group, consisting of i) phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxyl, di(C1-4alkyl), aminocarbonyl, chlorine and fluorine, in such a way that only one di(C1-4alkyl)aminocarbonyl is present; ii) naphthyl; iii) pyridinyl, optionally substituted with one substituent, selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; iv) pyrimidin-5-yl; v) furanyl; vi) thienyl; vii) 5-oxo-4,5-dihydro-[1,2,4]oxodiazol-3-yl; and viii) di(C1-2alkyl)aminocarbonyl; Y represents ethyl, vinyl or bond; or Y represents O, when R1 represents optionally substituted phenyl, where substituent represents C1-4alcoxy; R2 represents phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, fluorine, chlorine and cyano, trifluoromethoxy and hydroxy; or R2 represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alcoxycarbonyl or carboxysubstituent; R3 is selected from the group, consisting of i) 3-aminocyclohexyl; ii) 4-aminocyclohexyl; iii) piperidin-3-yl; iv) piperidin-4-yl; v) pyrrolodin-2-yl-methyl, in which pyrrolodin-2-yl is optionally substituted by 3-rd or 4-th position with one or two fluorine-substituents; vi) azetidin-3-yl; vii) 2-(N-methylamino)ethyl; viii) 3-hydroxy-2-aminopropyl; ix) piperidin-3-yl-methyl; x) 1-azabicyclo[2.2.2]octan-3-yl; and xi) 8-azabicyclo[3.2.1]octan-3-yl; or R3 together with Ra and nitrogen atom, which they both are bound to, form piperazinyl, optionally substituted with 4-C1-4alkyl; Ra represents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted with azetidin-3-yl.

EFFECT: compounds can be used in treatment of pain in the range from medium to strong, caused by diseases or conditions, such as osteoarthritis, migraine, burn, fibromyalgia, cystitis, rhenite, neuropathic pain, idiopathic neuralgia, toothache, etc.

21 cl, 4 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 3-phenylpropionic acid derivatives of formula

wherein R1A represents hydrogen, methyl, ethyl, cyclopropyl or cyclobutyl, R1B is hydrogen or methyl, R2A represents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl, R2B is hydrogen or methyl or R1A and R2A are combined together, and in a combination to carbon atoms to which they are attached, form a cyclopropyl ring of formula

wherein R1B and R2B have the values as specified above, or R2A and R2B are combined together, and in a combination to a carbon atom, to which they are attached, form a cyclic group of formula or

wherein n means a number 1 or 2, R3 is hydrogen, fluorine or methyl, R4 represents hydrogen, fluorine, chlorine or a cyanogroup, R5A represents methyl, R5B is trifluoromethyl or R5A and R5B are combined together, and in a combination to a carbon atom, to which they are attached, form a difluorosubstituted cycloalkyl ring of formula or

R6 represents chlorine, alkyl with 1-4 carbon atoms, alkenyl with 2-4 carbon atoms, cyclopropyl or cyclobutyl; alkyl with 1-4 carbon atoms and alkenyl with 2-4 carbon atoms can contain up to three fluorine atoms, cyclopropyl and cyclobutyl up to three fluorine atoms as substitutes, and R7 represents hydrogen, fluorine, chlorine, methyl or a methoxy group. The invention also refers to a therapeutic agent containing the above compounds and to a method for producing the compounds of formula (I).

EFFECT: compounds of formula (I) activate the form of soluble haem-free guanylate cyclase and are applicable in the method of treating and/or preventing cardiac failure, angina, hypertension, pulmonary hypertension, ischemia, vascular diseases, disturbed microcirculation, thromboembolic diseases and arterial sclerosis.

6 cl, 4 tbl, 113 ex

FIELD: food industry.

SUBSTANCE: invention relates to a polyphenol grape extract, a compound for oral administration, a food product, beverage, a taste additive, a nutraceutical product, a revitalising composition and therapeutic remedy including the said grape extract. According to the invention, the grape extract contains nearly 5-15 wt % of monomers, nearly 5-20 wt % of dimers, nearly 3-10 wt % of trimers, nearly 2-10 wt % of tetramers and nearly 2-10 wt % of pentamers.

EFFECT: grape extract reduces blood pressure with patients suffering from prehypertonic condition or metabolic syndrome.

27 cl, 4 dwg, 8 tbl, 7 ex

Vasopressor agent // 2552529

FIELD: chemistry.

SUBSTANCE: invention refers to N, S-substituted isothiourea derivatives of the general formula (1) in the form of salts with pharmacologically acceptable acids as a NOS-inhibitory and vasopressor agent wherein: n=1, 3, i.e. an acyl substitute represents cyclobutanoyl or cyclohexanoyl; R represents an alkyl group: C2H5, i-C3H7; HX represents a pharmacologically acceptable inorganic or organic acid: HCl, HBr, HI, hydrogen methyl sulphate, oxalic, succinic acids, etc.

EFFECT: extending the range of products of the vasopressor action.

6 cl, 7 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, namely to implanted medical devices. A device for drug delivery includes an implanted intra-lumen framework, which has a luminal surface and abluminal surface; a multitude of through hollows in the intra-lumen framework, where each of the multiple through holes contains a composition, selected from the following groups. Compositions of a mTOR inhibitor and base structure, which has the configuration, which will make it possible for the mTOR inhibitor in the composition of the mTOR inhibitor to elute, mainly in the abluminal direction for seven (7) to one hundred and twenty (120) days, with the composition of the mTOR inhibitor containing a polymer in a combination with the mTOR inhibitor and the base structure containing a multitude of polymer layers with the absence of mTOR inhibitors; compositions of a phosphodiesterase III inhibitor and an upper covering structure, which has the configuration, making it possible for the phosphodiesterase III inhibitor in the composition of the phosphodiesterase III inhibitor to elute, mainly in the luminal direction for five (5) to sixty-one (61) day, with the composition of the phosphodiesterase III inhibitor containing the polymer in a combination with the phosphodiesterase III inhibitor, and the upper covering structure containing a multitude of polymer layers in the absence of the phosphodiesterase III inhibitor.

EFFECT: invention makes it possible to provide independent on each other rates of sirolimus and cistazol release, simultaneously providing the targeted delivery of each of the medications.

6 cl, 30 dwg, 7 tbl

FIELD: medicine.

SUBSTANCE: before operation analysis of patient's haemostasis by means of thrombodynamics is carried out, and 12 hours before beginning operation anticoagulant prophylaxis with enoxaparin in dose 40 mg s/c 1 time per day performed. Analysis of thrombodynamics and coagulogram are repeated one day after operation, In case of detection of hypercoagulation (increase of one or some indices of thrombodynamics - initial speed of clot growth, stationary speed of clot growth, clot density, appearance of spontaneous clots) dose of enoxaparin is increased to 60 mg one time per day, and in case of detection of hypocoagulation (reduction of one or several indices of thrombodynamics - initial speed of clot growth, stationary speed of clot growth, clot density, delay of clot growth) dose of anticoagulant is reduced twice - 20 mg of enoxaparin per day.

EFFECT: method makes it possible to prevent development of post-operative venous thromboembolic complications in patients with colorectal cancer; said regimen of enoxaparin introduction provides prevention of both thromboembolic and hemorrhagic complications in said group of patients.

2 ex

FIELD: chemistry.

SUBSTANCE: thrombocyte aggregation-inhibiting heteromeric peptides based on imidazo[4,5-e]benzo[1,2-c;3,4-c']difuroxane are disclosed: , where R=Phe-Ile-Ala-Asp-Thr; Arg-Tyr-Gly-Asp-Arg; Lys-Ile-Ala-Asp-Asp; His-Ile-Gly-Asp-Asp.

EFFECT: improved properties.

1 dwg, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-carb(arginyl)oxymethylimidazo[4,5-e]benzo[1,2-c; 3,4-c']difuroxane of formula .

EFFECT: improved properties of the compound.

1 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of pharmaceutics and represents a medication, possessing venomotor and anticoagulant action, which includes a dry extract of vine leaves, a base, preservatives, solvents, and is characterised by the fact that it additionally contains heparin in the form of a pharmaceutically acceptable salt, as the base it contains a hydrophilic gel-generating agent, as the solvents it contains purified water, propyleneglycol, ethyl alcohol rectified 95%, as the preservatives it contains nipagin, nipasol, with the following component ratio, wt %: dry extract of vine leaves with the content of the sum of flavonoides counter per rutin no less than 8% - 0.1-30.0; heparin in the form of a pharmaceutically acceptable salt - 100-1000 Units, hydrophilic gel-generating agent - 0.2-20.0; nipagin - 0.01-0.2; nipasol - 0.01-0.2, propyleneglycol - 3.0-70.0; ethyl alcohol rectified 95% - 3.0-70.0; purified water - the remaining part.

EFFECT: invention provides the creation of the medication in the form of a gel with good absorption, fast soaking, storage stability and acceptable organoleptic properties.

4 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a citrate of a compound described by formula (II) below, and a pharmaceutical composition containing said citrate.

EFFECT: experimental results of the present inventions prove that said citrate can inhibit activity of phosphodiesterase type 5 and can be used for treating erectile dysfunction, for inhibiting thrombocyte aggregation and treating thrombosis, for reducing pulmonary hypertension and treating cardiovascular diseases, asthma and diabetic gastroparesis.

2 cl

FIELD: medicine.

SUBSTANCE: invention concerns preparing systemic and topical solid and soft dosage forms for external application in the form of a 1.5% hydrophilic gel and rectal capsules containing a 7.5% hydrophilic gel 1.9 g (in terms of the amount of the active substance of 0.14 g/capsule), for preventing and treating chronic venous insufficiency possessing anticoagulant, antithrombotic, anti-inflammatory, antiexudative and antitranssudative, capillary protective activities and improving haemorheology. An active pharmacologically active substance is presented by a substance of a potassium salt of sulphated arabinogalactan; a hydrophilic base is Aerosil, glycerol and pure water; the ingredients of the agent are taken in certain proportions, wt %.

EFFECT: invention provides the effective prevention and treatment of chronic venous insufficiency, has a broad spectrum of therapeutic action, improves haemorheology, tones the vessels and can be used in particular for treating varicose veins, thrombosis and posttraumatic oedema.

5 cl, 7 ex, 8 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmaceutical industry, and describes a dosage form of Clopidogrel presented in the form of a solid gelatine capsule. The dosage form contains Clopidogrel hydrogen sulphate, lactose anhydride, microcrystalline cellulose, sodium croscarmellose, colloidal silicon dioxide and magnesium stearate.

EFFECT: according to the invention, the dosage form of Clopidogrel contains a high amount of the active ingredient; it is prepared without the use of a wet granulation technique, and provides the more accurate dosage of the ingredients and the stability of the substances used.

9 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of immunology and biotechnology. Claimed is monoclonal antibody or its functional fragment, where said antibody and fragment bind with activated protein C and inhibit anticoagulant activity, but do not bind and do not inhibit activation of inactivated protein C, where said antibody is obtained by immunisation of mammal by APC and screening of binding ability of said antibody with APC, but not with protein C. Also described is pharmaceutical composition for treating diseases associated with anticoagulation activity of APC, including said antibody in effective amount and pharmaceutically acceptable carrier. Claimed are: method of inhibiting anticoagulation activity of activated protein C in subject, method of inhibiting amidolytic activity of activated protein C in subject, method of treating subject, requiring blood coagulation; method of treating subject with haemophilia; method of modulating haemostasis in subject; as well as method of modulating thrombogenesis in subject, which include introduction of effective quality of said antibody to subject. In addition, described is method of treating subject with sepsis, including introduction of effective quality of said antibody and activated protein C.

EFFECT: invention makes it possible to obtain monoclonal antibody or its functional fragment, where said antibody and fragment bind with activated protein C and inhibit anticoagulation activity, but do not bind and do not inhibit activation of inactivated protein C.

17 cl, 11 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine. What is described is a system of the transdermal delivery of a drug containing an effective dose of an antithrombotic agent, such as tirofiban, or its pharmaceutically acceptable salt. A dose of the delivered drug is proportional to an applied plaster size and reaches 60-85% of thrombocyte inhibition. The system enables providing the individualised treatment of patients. There are presented methods of treating various disorders, when the thrombocyte inhibition is required.

EFFECT: transdermal delivery system can deliver the drug to the patient for the prolonged period of time.

25 cl, 12 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and can be used for treating trophic ulcers and purulonecrotic involvements of lower extremities in diabetic patients. That requires a baseline therapy and a regional fibrinolytic therapy. Conducting the regional fibrinolytic therapy following applying a rubber bandage on the lower one-third of the shin is accompanied by administering Urokinase medac in a dose of 100 thousand units into the heel bone once a day within 5 days.

EFFECT: in the setting of reducing the total dosage of the preparation, the invention enables providing the high concentration of Urokinase medac in a pathological centre, improving microcirculation and metabolic processes in the involved tissues, accelerating the wound healing and reducing the length of hospital admission of the patients suffering from diabetic foot syndrome.

2 ex

FIELD: medicine.

SUBSTANCE: what is presented is using Histochrom (same as echinochrome A or pentahydroxyethyl naphthoquinone) as an agent able to prevent pulmonary fibrosis developed under cytostatic agents. The invention can be used for the pharmacological prevention and correction of the pulmonary tissue disorders caused by administering the cytostatic agents.

EFFECT: preventing hypertrophy of interalveolar connective tissue in the lungs associated with administering bleomycin.

4 dwg, 1 tbl

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