Method for preventing and treating diabetes mellitus complications associated with developing degenerative processes in nerve tissue, pharmaceutical composition for neuroprotective therapy of such complications, and method for preparing it

FIELD: medicine, pharmaceutics.

SUBSTANCE: presented group of inventions refers to medicine. What is presented is a method for preventing and treating the diabetes mellitus complications associated with the developing degenerative processes of the nervous tissue, comprising administering a medicine containing a peptide of general formula Pro-Gly-Pro, or a pharmaceutically acceptable salt thereof in effective amounts. There are presented pharmaceutical composition comprising said peptide for the neuroprotective therapy of the complications of diabetes mellitus and the method for preparing it.

EFFECT: group of inventions enables the more effective prevention and treatment of the diabetes mellitus complications associated with the developing degenerative processes of the nervous tissue by the use of the peptide Pro-Gly-Pro, or a pharmaceutically acceptable salt thereof.

9 cl, 2 dwg, 4 tbl, 7 ex

 

The invention relates to medicine and concerns the methods and drugs used for the prevention and treatment of complications of diabetes associated with the development of degenerative processes in the nervous tissue.

Diabetes mellitus is accompanied by the development of a number of complications, including those related to impairment of function of the Central and peripheral nervous systems. One of the most common complications of diabetes and a major cause of vision loss in persons of middle age - diabetic retinopathy (DR). It is characterised by a specific lesion of the vessels and the neuronal layers of the retina. Another complication of diabetes, is associated with the functioning of the nervous system, is diabetic encephalopathy (TE). It manifests itself in the development of impaired memory and learning ability and is especially common in the elderly. Despite some significant differences in pathogenetic mechanisms of its origin and course, both of these complications are equally characteristic of insulin-dependent and insulin-independent diabetes. Currently, the main way to prevent OTHERS is to maintain a long and most stable of diabetes. Other known therapeutic agent to prevent the Oia or slow the development of OTHERS in its early stages were not effective. In the later stages of the OTHERS recognized as the most effective method is laser photocoagulation, but its use carries a risk of hemorrhage in the retina and the vitreous body. Methods of prevention and treatment of TE in currently undeveloped and are not widely used in the treatment of diabetes.

In the literature there are reports of positive influence on the course of such complications of diabetes like diabetic polyneuropathy (DP), preparations on the basis of the b vitamins, in particular neuroactivity (RF patent No. 2262928 to the invention). It is also known the use of antioxidant emoxipin (3-hydroxy-6-methyl-2-ethyl-pyridine hydrochloride) in the treatment of diabetic retinopathy (Kozlov S.A. and others, 2003). However, emoxipin has a number of undesirable side effects, inherent to the group of antioxidants.

The task given to the establishment of the claimed group of inventions is to develop effective ways and means of prevention and treatment of complications of diabetes associated with the development of degenerative processes in the nervous tissue, such as diabetic retinopathy (DR), diabetic encephalopathy (TE) and diabetic neuropathy (DN). The result achieved when the solution of the problem consists in the possibility of carrying out preventive and curative not roprotective therapy, aimed at preventing or slowing the neurodegenerative processes in the retina and brain at all stages of development of complications of diabetes associated with the development of degenerative processes in the nervous tissue, such as diabetic retinopathy (DR), diabetic encephalopathy (TE) and diabetic polineuropathy (DP).

To achieve this result we propose a method for the prevention and treatment of complications of diabetes associated with the development of degenerative processes in the nervous tissue, including reception of medicines containing peptide with neuroprotective effect, as active substance, in which the peptide used in the peptide of General formula Pro-Gly-Pro or its pharmaceutically acceptable salt in an effective amount.

For the achievement of the proposed pharmaceutical composition for neuroprotective therapy of complications of diabetes, including peptides with neuroprotective effect as an active substance and a pharmaceutically acceptable excipient, in which the peptide used in the peptide of General formula Pro-Gly-Pro or its pharmaceutically acceptable salt. The content of the peptide or its pharmaceutically acceptable salt can be selected in the range from 0.01 to 80 wt.%; to notice can be made acceptable for oral administration, for example in the form of tablets or capsules or suspension or solution, in the case of execution in the form of tablets do it in the form of tablets weighing 150 mg, of the following composition: peptide or its pharmaceutically acceptable salt, 10 mg, colloidal silicon dioxide 6 mg, corn starch - 54 mg, microcrystalline cellulose - 80 mgpharmacy composition can also contain a peptide of General formula Pro-Gly-Pro in the form of acetate or hydrochloric salt, or a mixture of the peptide of General formula Pro-Gly-Pro and these salts.

To achieve this result it is also proposed a method of obtaining a pharmaceutical composition for neuroprotective therapy of complications of diabetes, including mixing the active substances and excipients, in which the active substances are used in the peptide of General formula Pro-Gly-Pro or its pharmaceutically acceptable salt. The content of the peptide or its pharmaceutically acceptable salt can be selected in the range from 0.01 to 80 wt.%: the composition can be obtained in an acceptable form for oral administration, for example in the form of tablets weighing 150 mg, of the following composition: peptide or its pharmaceutically acceptable salt, 10 mg, colloidal silicon dioxide 6 mg, corn starch -54 mg, microcrystalline cellulose - 80 mg

The invention is illustrated in Fig.1, katarantaduhan the results of the analysis of glial fibrillar acidic protein (GFCB) using immunoblotting in soluble and insoluble fractions of protein extracts from the retina healthy (V) and diabetic rats without treatment (I), and after an 11-week intragastric administration of the peptide Pro-Gly-Pro at a dose of 7 mg/kg (III), and 2 with the results of the sample analysis of the content of various forms GFCB in the soluble fraction of the extract from the prefrontal cortex of diabetic rats by the method of Western blot turns.

The peptide Pro-Gly-Pro (shed-glycyl-Proline) consists of natural amino acids, has a gross formula C12H19N3O4and the molecular weight 269,3. Natural peptide Pro-Gly-Pro present in trace quantities in the blood and tissues as a product of degradation of collagen and collagen-like proteins in the digestive tract and tissues of the body (Samonina et al., 2002). The peptide Pro-Gly-Pro also formed in the body as one of the degradation products of peptides included in the composition of medicinal products of the peptide (Met-Glu-His-Phe-Pro-Gly-Pro) and selenka (Thr-Lys-Pro-Arg-Pro-Gly-Pro) (Zolotarev and others, 2006). The data obtained show a good absorption of the peptide through the gastrointestinal tract, its high bioavailability, low rate of excretion from the body and a high resistance to the action of proteases.

It is known that the peptide Pro-Gly-Pro protects cells of the pancreas that produce insulin, from the toxic effects of alloxan in experimental insulin-dependent diabetes in animals (Ashmarin and others, 2005; Ashmarin and others, 2008). However, it was not known what but is there such a peptide direct antidiabetic effect, i.e. the ability to reduce the concentration of glucose in the blood, on the background of already developed insulin-dependent diabetes. Also do not describe the use of peptide Pro-Gly-Pro as a means of prevention and treatment of diabetic retinopathy (DR) and diabetic encephalopathy (DE).

In the framework of this application, the term "pharmaceutically acceptable salts" means salts that are pharmaceutically acceptable, i.e. they are safe, non-toxic, and which possess pharmacological activity inherent in the original connection. Pharmaceutically acceptable salts according to this invention receives through communication between a source compound of General formula Pro-Gly-Pro and pharmaceutically acceptable acid, with the formation of salt accession acid, or a pharmaceutically acceptable base, with the formation of salt accession of the substrate, using methods well known in chemistry. Pharmaceutically acceptable acids, which form the ammonium salt with the free amino groups of peptides and functional equivalents include organic acids such as acetic, lactic, malic, ascorbic, succinic, benzoic, citric, methansulfonate or toluensulfonate acid, or inorganic acids, such as chlorite is Todorova, Hydrobromic, uudistoodetena, sulfuric or phosphoric acid. Pharmaceutically acceptable bases, which form a carboxylate salt with the free carboxyl groups of peptides and functional equivalents include methylamine, ethylamine, dimethylamine, triethylamine, Isopropylamine, Diisopropylamine and other mono-, di - and trialkylamines and arylamine. It should also be understood that all references to pharmaceutically acceptable salts include pharmaceutically acceptable solvate, complexes or compounds of joining, such as hydrates or aturity.

In the framework of this application, in experiments on Mature white rats (190-230) conducted a study of acute and chronic toxicity and local irritation of the pharmaceutical composition (FC) - based peptide Pro-Gly-Pro. In acute experiments, it was shown that after intragastric dose of FC, which causes the death of animals was greater than 5000 mg/kg In chronic experiment daily intragastric administration of FC within 30 days of white rats at doses of 120 mg/kg and 480 mg/kg, exceeding the given conversion on the surface of the body 3 and 12 times the dose equivalent to the preferred daily therapeutic dose for humans (30 mg), not had any unwanted toxic effects. When microsco the practical and the histopathological study of the tissues of the gastrointestinal tract in animals after 30-day course of introduction of the FC-based peptide Pro-Gly-Pro in the dose found no signs of local irritation.

Studies were conducted on Mature Wistar rats weighing 250-300g. The animals were kept with free access to food and water under a 12-hour light mode lighting. Insulin-dependent diabetes mellitus was induced by single intraperitoneal introduction of the solution streptozotocin (STZ) in citrate buffer at a dose of 60 mg/kg In the experiment were selected only those animals that have six days after STZ injection, the concentration of glucose in the blood exceed the value of 15 mmol/l Peptide Pro-Gly-Pro in the form of aqueous solutions of a given concentration in drinking brackish water was administered by intragastric catheter once a day for 11 weeks.

It is known that chronic hyperglycemia caused by introduction of streptozotocin, leads to the development of several complications, including AL and TE. Specific neuroprotective effect of peptide Pro-Gly-Pro was assessed by its ability to normalize the content of glial fibrillar acidic protein (GFCB) in the retina and in the prefrontal areas of the cortex. GFCB is a measure of the reactivity of glia and recognized marker of neurodegeneration (Rungger-Brändle et al., 2000; Zeng et al., 2009). The number GFCB in the sample was determined by the method of Western blot turns into soluble (cytosolic) and insoluble (intermediate filaments; extraction 4M urea) fractions, normalized to the content of the sample l is mine - nuclear constitutive protein and resulted in the contents of the main forms GFCB with a molecular mass of CA in the soluble fraction of the extract.

All taken in the experiment the animals were divided into five groups: I - animals with STZ-induced diabetes, which for 11 weeks was administered intragastrically drinking water (n=7); II-IV - animals with STZ-induced diabetes, which during the 11 weeks was administered intragastrically solutions peptide study drug Pro-Gli-Pro in doses of 3; 7 and 15 mg/kg/day (n=5, 4, 7); V - control animals without diabetes, who for 11 weeks was administered intragastrically drinking water (n=9). After 72 h after STZ injection, the concentration of glucose in the blood of most rats exceeded the value of 20 mmol/l and remained almost unchanged throughout the experiment. Induced by STZ induced hyperglycemia caused also a number of other characteristic of diabetes changes of physiological and biochemical parameters in rats after 12 weeks of hyperglycemia (table 1).

Table 1
IndexExperimental group
V (Norm + H2O)I (Diabetes + H2Oh)
Blood glucose, mmol/l7,8±0,526,0±3,4***
Glycosylated hemoglobin (HbA1c), %4,8±0,410,2±0,7***
Mass, g347±19530±43***
Daily water consumption, ml160-20035-50
*** p<0,001 compared with a group of healthy rats (t-test t-test). All numerical data are presented as mean ± error of the mean.

Long-term administration of Pro-Gly-Pro (7 mg/kg/day) resulted in a significant decrease in both soluble and insoluble forms GFCB in the retina (figure 1, table 2). Study of dose-response relationships showed that the most effective reduction GFCB was achieved by the application of Pro-Gly-Pro in doses of 7 and 15 mg/kg/day (table 3). At these doses the content as the primary (49 kDa)and optional forms (<49 kDa) GFCB in the retina was reduced almost to levels observed in healthy rats.

Chronic STZ-induced hyperglycemia caused a significant increase in the content GFCB in the retina (figure 1). Quantitative assessment GFCB in soluble and insoluble fractions of the retina IU is one of Western blot turns showed the content GFCB in diabetic rats was increased 2-3 fold (p<0.05) as compared with the control animals (table 2). This, along with a significant increase in the content of the main form GFCB with a molecular mass of 49 kDa observed the accumulation of additional forms, characterized by a lower molecular weight (figure 1). Both these facts testify to intensive cytoskeletal rearrangement in astrocytes and Millerovskij cells, characteristic pathological activation of glia.

Table 2
GroupInsoluble fractionSoluble fractionThe total fraction
(Diabetes + H2Oh)1,67±0,251,70±0,30*3,43±0,42*
(Diabetes + Pro-Gli-Pro; 7 mg/ml)1,21±0,210,68±0,261,48±0,26#
(Norm + H2Oh)0,88±0,220,67±0,131,06±0,15
* p<0,05 compared with a group of healthy rats;#p=0.07 compared with a group of diabetic rats without treatment (U-test Mann-Whitney). All numerical data are presented as mean ± error of the mean.

Table 3
GroupGFCB (49 kDa)GFCB (<49 kDa)The total content of GFCB
(Diabetes + H2Oh)3,37±0,51*3,50±0,61***6,87±0,99***
(Diabetes + Pro-Gli-Pro; 3 mg/ml)2,65±0,411,51±0,19##4,16±0,55
(Diabetes + Pro-Gli-Pro; 7 mg/ml)1,88±0,421,08±0,16##2,96±0,56#
(Diabetes + Pro-Gli-Pro; 15 mg/ml)1,65±0,18##1,15±0,24##2,80±0,30###
(Norm + H2O)1,55±0,290,56±0,112,12±0,31
* p<0,05, *** p<0,001 compared with a group of healthy rats; # p<0,05, ## p<0,01, ### p<0,001 compared to diabetic group of rats cured without the I (U-Mann-Whitney test). All numerical data are presented as mean ± error of the mean.

As shown by the results of quantitative analysis using Western blot turns in the prefrontal areas of the cortex, chronic STZ-induced hyperglycemia practically no influence on the content of GFCB in the insoluble fraction, but caused a significant increase GFCB in the soluble fraction (figure 2). In this case, as in the case of the retina, in addition to the main form GFCB (49 kDa) observed the appearance of additional forms GFCB characterized by a lower molecular weight. Quantitative analysis using Western blot turns showed that the total content of GFCB in the soluble fraction of the prefrontal areas of the cortex of diabetic rats is approximately 2 times higher than in healthy rats (table 4). When 11-week intragastric administration to rats peptide Pro-Gly-Pro significant reduction in the content of the main form GFCB (49 kDa) in the soluble fraction was observed only when using doses of 15 mg/kg/day (table 4). The content of the main form GFCB reached values observed in healthy rats. From each experimental group was selected sample with the most typical content GFCB.

Table 4
GroupGFCB (49 kDa)
(Diabetes + H2O)1,6±0,07***
(Diabetes + Pro-Gli-Pro; 3 mg/ml)1,34±0,21
III. (Diabetes + Pro-Gli-Pro; 7 mg/ml)1,56±0,24
IV. (Diabetes + Pro-Gli-Pro; 15 mg/ml)0,75±0,09###
V. (Norm + H2Oh)1,00±0,03
***p<0,001 compared with a group of healthy rats; ### p<0,001 compared with a group of diabetic rats without treatment (U-test Mann-Whitney). All numerical data are presented as mean ± error of the mean.

Thus, the obtained in these studies suggest a neuroprotective effect of long-term systematic introduction of the peptide Pro-Gly-Pro on retina and brain of rats with experimentally induced PD and TE. The protective effect of the peptide was expressed as a decrease in the content marker protein - GFCB. Set that to prevent/slow down the progression of neurodegenerative processes in the retina and brain of rats with STZ-induced diabetes clean the Dimo daily intragastric application of the peptide in doses of from 7 to 15 mg/kg

The following additional examples illustrate the possibility of using Pro-Gly-Pro as neuroprotective drugs for the treatment of complications of diabetes.

Example 1

Rat male with a body weight of 216 g, which previously caused streptozotocin-induced diabetes, administered for 11 weeks intragastric tube 0.9 ml of a solution of the peptide Pro-Gly-Pro in drinking water at a dose of 7 mg/kg/day. Then 3 days after the last injection of peptide rat make euthanasia and method of protein Western blot turns determined in the retina and prefrontal areas of the cortex of the rat brain content marker protein neurodegeneration - GFCB. The measured value of the content of the main form GFCB (49 kDa) in the retina was $ 1,65 oted that in 2.0 times lower than the average diabetic rats untreated peptide (see table 3). In the prefrontal areas of the cortex (the soluble fraction of the extract) the contents of the main form GFCB (49 kDa) was 1,36 ated, which is 1.2 times lower than the average diabetic rats untreated peptide (see table 4). Experimental evidence suggests that long-term administration of peptide Pro-Gly-Pro at a dose of 7 mg/kg/day leads to the suppression of neurodegenerative processes caused by chronic hyperglycemia, set ATCA and to a lesser extent, in the cortex of the brain.

Example 2

Rat male with a body weight of 215 g, which previously caused streptozotocin-induced diabetes, administered for 11 weeks intragastric tube 0.9 ml of a solution of the acetate salt of the peptide Pro-Gly-Pro in drinking water at a dose of 7 mg/kg/day. Then 3 days after the last injection of peptide rat make euthanasia and method of protein Western blot turns determined in the retina and prefrontal areas of the cortex of the rat brain content marker protein neurodegeneration - GFCB. The measured value of the content of the main form GFCB (49 kDa) in the retina was $ 1,57 ated, which is 2.1 times lower than the average diabetic rats untreated peptide (see table 3). In the prefrontal areas of the cortex (the soluble fraction of the extract) the contents of the main form GFCB (49 kDa) was 1.51 oted that 1.1 times lower than the average diabetic rats untreated peptide (see table 4). Experimental evidence suggests that long-term administration of acetate salts Pro-Gly-Pro at a dose of 7 mg/kg/day leads to the suppression of neurodegenerative processes caused by chronic hyperglycemia in the retina and, to a lesser extent, in the cortex of the brain.

Example 3

Rat male with weight t is La 233 g, which previously caused streptozotocin-induced diabetes, administered for 11 weeks intragastric tube 0.9 ml of a solution of the acetate salt of the peptide Pro-Gly-Pro in drinking water at a dose of 15 mg/kg/day. Then 3 days after the last injection of peptide rat make euthanasia and method of protein Western blot turns determined in the retina and prefrontal areas of the cortex of the rat brain content GFCB. The measured value of the content of the main form GFCB (49 kDa) in the retina was $ 1,50 ated, which is 2.3 times lower than the average diabetic rats untreated peptide (see table 3)and did not differ from performance in healthy rats. In the prefrontal areas of the cortex (the soluble fraction of the extract) the contents of the main form GFCB (49 kDa) was 0.59 ated, which is 2.7 times lower than the average diabetic rats untreated peptide (see table 4), and 1.7 times lower than in healthy rats. Experimental evidence suggests that long-term administration of acetate salts Pro-Gly-Pro in the dose of 15 mg/kg/day leads to a strong suppression of neurodegenerative processes caused by chronic hyperglycemia in the retina and the cortex.

Example 4

In the control experiment, the rat-male with a body weight of 240 g, whose prewar the tion caused streptozotocin-induced diabetes, administered for 11 weeks intragastric tube 0.9 ml of drinking water. Then 3 days after the last injection of peptide rat make euthanasia and method of protein immunoblotting determine in the retina and prefrontal areas of the cortex of the rat brain content GFCB. The measured value of the total content GFCB was $ 4,24 ated, which is 2.7 times higher than the average in healthy rats (see table 3). In the prefrontal areas of the cortex (the soluble fraction of the extract) the contents of the main form GFCB (49 kDa) amounted to 1.48 ated, which is 1.5 times higher than the average in healthy rats (see table 4). Experimental evidence suggests that in the absence of treatment with the peptide of General formula Pro-Gly-Pro or its pharmaceutically acceptable salt is observed the development of neurodegenerative processes in the retina and cerebral cortex of rats caused by prolonged hyperglycemia.

Example 5

Was prepared in a pharmaceutical composition for treatment of diabetes and its complications, made in the form of tablets of the following composition (in milligrams):

the peptide Pro-Gly-Pro - 10 mg;

- colloidal silicon dioxide 6 mg;

- corn starch - 54 mg;

- microcrystalline cellulose - 80 mg

In the technological capacity of the mixer-homogenizer consistently contributed peptide Pro-Gly-Pro, silicon on the oxide colloid, the microcrystalline cellulose and corn starch, periodically subjecting the mixture is stirred until a homogeneous mass. Then to the mixture gradually, with constant stirring, was added a 10% starch paste. The resulting paste is rubbed through a sieve, dried under vacuum and were crushed to granules of a size not more than 1 mm is Obtained after treatment with magnesium stearate and starch mass was pressed into tablets weighing 150 mg using the appropriate stamp.

Example 6

Was prepared in a pharmaceutical composition for treatment of diabetes and its complications, made in the form of tablets of the following composition (in milligrams):

acetate salt of the peptide Pro-Gly-Pro - 10 mg;

- colloidal silicon dioxide 6 mg;

- corn starch - 54 mg;

- microcrystalline cellulose - 80 mg

In the technological capacity of the mixer-homogenizer consistently contributed acetate salt of the peptide Pro-Gly-Pro, colloidal silicon dioxide, microcrystalline cellulose and corn starch, periodically subjecting the mixture is stirred until a homogeneous mass. Then to the mixture gradually, with constant stirring, was added a 10% starch paste. The resulting paste is rubbed through a sieve, dried under vacuum and were crushed to granules of a size not more than 1 mm By the scientists after treatment with magnesium stearate and starch mass was pressed into tablets weighing 150 mg using the appropriate stamp.

Example 7

Was prepared in a pharmaceutical composition for treatment of diabetes and its complications, made in the form of tablets of the following composition (in milligrams):

- hydrochloric salt of the peptide Pro-Gly-Pro - 10 mg;

- colloidal silicon dioxide 6 mg;

- corn starch - 54 mg;

- microcrystalline cellulose - 80 mg

In the technological capacity of the mixer-homogenizer consistently contributed hydrochloric salt of the peptide Pro-Gly-Pro, colloidal silicon dioxide, microcrystalline cellulose and corn starch, periodically subjecting the mixture is stirred until a homogeneous mass. Then to the mixture gradually, with constant stirring, was added a 10% starch paste. The resulting paste is rubbed through a sieve, dried under vacuum and were crushed to granules of a size not more than 1 mm is Obtained after treatment with magnesium stearate and starch mass was pressed into tablets weighing 150 mg using the appropriate stamp.

1. Method for the prevention and treatment of complications of diabetes associated with the development of degenerative processes in the nervous tissue, including reception of medicines containing peptide with neuroprotective effect, as active substance, characterized in that the peptide used in the peptide of General formula Pr-Gly-Pro or its pharmaceutically acceptable salt in an effective amount.

2. Pharmaceutical composition for neuroprotective therapy of complications of diabetes, including peptides with neuroprotective effect as an active substance and a pharmaceutically acceptable excipient, characterized in that the peptide used in the peptide of General formula Pro-Gly-Pro or its pharmaceutically acceptable salt.

3. The composition according to claim 2, characterized in that the content of the peptide or its pharmaceutically acceptable salt is 0.01-80 wt.%.

4. The composition according to claim 2 or 3, characterized in that it is made acceptable for oral administration, for example in the form of a tablet or capsule, or suspension, or solution.

5. The composition according to claim 4, characterized in that it is made in the form of tablets weighing 150 mg, of the following composition: peptide or its pharmaceutically acceptable salt, 10 mg, colloidal silicon dioxide 6 mg, corn starch - 54 mg, microcrystalline cellulose - 80 mg

6. A method of obtaining a pharmaceutical composition for neuroprotective therapy of complications of diabetes, including mixing the active substances and excipients, characterized in that the active substance used in the peptide of General formula Pro-Gly-Pro or its pharmaceutically acceptable salt.

7. The method according to claim 6, characterized in that the content of the peptide or pharmaceutically pickup is integral salt is 0.01-80 wt.%.

8. The method according to claim 6 or 7, characterized in that the composition is obtained in the form acceptable for oral administration.

9. The method according to claim 8, characterized in that the composition is obtained in the form tablets weighing 150 mg, of the following composition: peptide or its pharmaceutically acceptable salt, 10 mg, colloidal silicon dioxide 6 mg, corn starch - 54 mg, microcrystalline cellulose - 80 mg



 

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4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine, namely to pharmaceutical compositions for topical application. What is described is a pharmaceutical composition for topical application, containing insulin and liposomes bound thereto containing hydrated lecithines in a combination with cholesterol in the form of a plaste having rapid cutaneous penetration, and an ability to reduce blood glucose.

EFFECT: usability and ease of dosing.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition in form of solid dosage form for treatment or prevention of diabetes, which contains therapeutically efficient quantity of metformin, polyvinylpyrrolodone, stearic acid and/or its salt, starch, silicon dioxide, characterised by the fact that as polyvinylpyrrolidone it contains polyvinylpirrolidone with molecular weight from 1000000 to 1500000 and additionally glycerol and/or basic finely dispersed magnesium carbonate.

EFFECT: pharmaceutical composition possesses high strength and ensures high degree of active substance release.

10 cl, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to tetrahydroimidazo[1,5-a]pyrazine derivatives of formula I or to their pharmaceutically acceptable salts (I), wherein: Ar represents phenyl, wherein phenyl is additionally substituted by 1-3 substitutes independently specified in halogen; R1 represents trifluoromethyl; R2 is specified in a group consisting of hydrohyl, alkyl having 1 to 4 carbon atoms, alkoxyl having having 1 to 4 carbon atoms, cycloalkyl representing a 5-6-member monocyclic ring group consisting of carbon completely, and -NR4R5, wherein each alkoxyl is optionally substituted by one group specified in a group consisting of phenyl and -OC(O)OR8; R3 is specified in a group consisting of a hydrogen atom and alkyl having 1 to 4 carbon atoms; each of R4 and R5 is independently specified is a group consisting of a hydrogen atom, alkyl having 1 to 4 carbon atoms, cycloalkyl representing a 3-8-member monocyclic ring group consisting of carbon completely, phenyl and pyridinyl, wherein each alkyl or phenyl is optionally substituted by one or more group specified in a group consisting of halogen, a cyano group, -SO2R7, -NR4R5 and -C(=O)OCH3; or R4 and R5 together with an atom, whereto attached form a 5-6-member heterocycle wherein the 5-6-member heterocycle optionally contains one or more N, O or S atom, and each 5-6-member heterocycle is optionally substituted by one or more groups consisting of halogen, hydroxyl, an amino group, alkyl having 1 to 4 carbon atoms, hydroxyalkyl 1 to 4 carbon atoms, -SO2R7, -C(O)NR4R5, -C(O)R7, =O; R7 represents alkyl 1 to 4 carbon atoms; and R8 is specified in a group consisting of alkyl 1 to 4 carbon atoms, and cycloalkyl representing a 5-6-member monocyclic ring group consisting of carbon completely. The invention also refers to methods for preparing them, a pharmaceutical composition having dipeptidyl peptidase IV inhibitory activity and containing said derivatives.

EFFECT: there are produced new compounds and composition on their basis which can find application in medicine for treating type 2 diabetes mellitus or hyperglycemia.

17 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical composition and medicine, and represents a hypoglycemic, hypocholesteremic, hypolipidemic and (or) antioxidant combination of bis-(γ-L-glutamyl)-L-cysteinyl-glycine in the form of disodium salt and lipoic acid in the form of sodium salt, and coordination compounds formed by palladium, copper and γ-L-glutamyl-L-cysteinyl-glycine wherein the molar ratio of bis-(γ-L-glutamyl)-L-cysteinyl-glycine of disodium salt : sodium lipoate : palladium : copper found within the range of 100-10000:100-10000:1-10:1-10.

EFFECT: invention provides higher therapeutic effectiveness.

7 cl, 4 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely, to antidiabetic composition. Method of obtaining antidiabetic pharmaceutical composition includes preparation of trituracio mixture of active substance repaglinide, taken in therapeutically efficient quantity, with complex-forming substance, solubiliser and colloid silicon dioxide, further addition of filling agent, disintegrant and lubricant, and tabletting by method of direct pressing.

EFFECT: pharmaceutical composition in form of tablet, obtained by claimed method, is characterised by high degree of active substance release, satisfactory strength and has storage term longer than 2 years.

10 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention provides a novel form of of 3-(3-{4-[3-(b-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)-2,2-dimethylpropionamide (chem. 1) with improved storage stability. Since bis[3-(3-{4-[3-(b-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)-2,2-dimethylpropionamide]monosebacate has extremely excellent storage stability, it can be used as a medicinal substance. Furthermore, it shows extremely good crystalline properties and can be purified by a conventional method, and therefore is suitable for the industrial preparation.

EFFECT: high storage stability.

9 cl, 2 ex, 5 tbl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a novel compound of structural formula I representing low molecular galactomannan having molecular weight about 702 Daltons and molecular formula C24H46O23. The compound is prepared of parts of the plant Trigonella foenum graecum selected from the group consisting of roots, shoots, leaves, seeds; preferentially seeds. What is also declared is a composition comprising an effective amount of a compound, optionally together with the adjuvants, for improving the body composition, increasing strength and positive effect on the factors associated with pre-diabetic and diabetic conditions.

EFFECT: invention refers to a method for preparing the compound of formula I, as well as to a method of treating pre-diabetic and diabetic diseased conditions in an individual in need thereof.

23 cl, 7 ex, 2 tbl, 8 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I), wherein A represents a pyrrole group or a pyrazole group, and X represents a carbon atom or a nitrogen atom; R1 represents a carboxy group; R2 independently represents a group specified in a substitute group α; R3 independently represents phenyl(C1-C6alkyl)group substituted by, phenyl(C1-C6alkyl)group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α); m is equal to 0, 1, 2 or 3, n is equal to 0 or 1; each of R4, R5, R6 and R7 independently represents a hydrogen atom, C1-C6alkyl group or a halogen atom; B represents a substituted naphthyl group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α), or the group represented by formula (II), wherein B1, B2 and α are those as specified in the patent claim. Also, the invention refers to a pharmaceutical composition possessing lipolysis inhibiting activity, to the use of the compounds of formula (I) in preparing a drug preparation for treating hyperlipidemia, dislipidemia, abnormal lipid metabolism, arteriosclerosis or type II diabetes mellitus and to a method of treating or preventing the mentioned diseases.

EFFECT: preparing the compounds of formula (I) possessing lipolysis inhibiting activity.

36 cl, 1 dwg, 1 tbl, 69 ex

FIELD: food industry.

SUBSTANCE: present invention relates to food industry. One proposes application of an agent masking taste for improvement of one or several characteristics chosen from mouthfeel, taste, aftertaste and odour of a liquid water nutritional composition containing the following nucleoside(s): uridine, cytidine and/or their derivative(s), and/or their nucleotide(s) as well as an unpleasant tasting edible oil. The agent masking taste is chosen from the group consisting of cellulose; starch; xanthum gum; gellan gum; alginate; galactomannans such as galactomannans of fenugreek seeds, guar gum, tara gum, locust gum and cassia gum; karaya gum; tragacanth gum; carrageenan and their mixture. Additionally, one proposes a liquid composition containing fish oil (i), uridine (ii), cytidine and/or their nucleotides and an agent masking taste (iii). The liquid composition is applied for prevention and/or treatment of neurodegenerative disorders.

EFFECT: invention allows to produce a composition containing an unpleasant tasting oil and nucleotides/nucleosides with improved mouthfeel, taste, aftertaste and odour.

20 cl, 4 dwg, 2 tbl

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