Method for modification of polyphenol-containing herbal materials and use of modified polyphenol-containing herbal materials in medicine

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to a product containing an insulin response. A method for producing the product containing the insulin response involving mixing at least one polyphenol-containing herbal material specified in a group consisting of fruit, vegetables, tea, green tea, coffee, cocoa, chocolate and bark, and at least aqueous edible solvent for making the mixture; heating said mixture; adding at least one lactic acid bacilli strain specified in Lactobacillus plantarum, and optionally at least one protein source specified in a group including peptones, tryptones, yeast extracts and their combinations to said heated mixture for making the fermented mixture; and exposing said fermented mixture to the conditions suitable for fermentation for making the product reducing the insulin response, and optionally eliminating the Lactobacillus plantarum strain. The use of the product reducing the insulin response for preparing a composition for preventing or treating diabetes, metabolic syndrome, obesity and cardiovascular diseases.

EFFECT: product prepared by the method described above effectively reduces the insulin response.

15 cl, 7 dwg, 11 tbl

 

The technical field to which the invention relates

This invention relates to method modification politieacademie vegetable material(s) and to new applications in medicine different politieacademie vegetable material(s).

The level of technology

The world Health Organization (WHO) predicts that 300 million people (~5% of the population) will have type 2 diabetes in 2025. This means that a significant number of the population will suffer from a variety of metabolic disorders such as metabolic syndrome. The term "metabolic syndrome" was discussed as in clinical diagnostics, as well as definitions. He still refers to causing concern a group of metabolic risk factors, which identifies subjects with high risk of developing type 2 diabetes and cardiovascular diseases.

Currently, there are three main criteria that are generally accepted by the International Diabetes Federation (IDF) and the world Health Organization (WHO), which are obesity, dyslipidemia and insulin resistance. Each of these risk factors is a good prognostic factor (indicator) cardiovascular disease. However, insulin resistance is a key component of this is metabolicheskogo syndrome, because it predicts as type 2 diabetes and cardiovascular disease. The secretion of insulin is necessary not only to maintain glucose metabolism, but also for the regulation of lipid metabolism and vascular tone. Insulin resistance leads to inaccurate regulation of beta-cells to maintain euglycemia (normoglycemia), leading to hyperinsulinemia, which, in turn, exacerbates insulin resistance in major metabolic tissues and organs, such as muscle, adipose tissue and liver, and develops pathological range between insulin resistance and hyperinsulinemia. The cause of insulin resistance is not fully elucidated, and there are several genetic disposition (genetic inheritance, polymorphism), molecular factors, such as oxidative stress and various markers of inflammation, which can interfere with the signal transmission of the insulin.

Last but not least, is a big influence of an intense modifications in life style, which, as was found in studies with adjustment, delay or prevent type 2 diabetes 40-58%. Diet in these studies with adjustment aimed at reducing weight by reducing the absorption of energy from fat, primarily saturated fat (partially C is replaceable monounsaturated fat), was, moreover, rich in fiber, whole grains, vegetables and fruits. These diet restrictions were accompanied by 30 minutes of physical activity a day. Physiological benefits with the use of intensive life-style changes are reduced body weight and reduced blood pressure and improved insulin sensitivity and lipid content of the blood. This will affect the whole range of risk components and, as it was found to delay or prevent the development of diseases associated with metabolic syndrome.

In view of the above, it is not surprising that a huge amount of effort was involved in the investigation of the mechanism underlying the above-mentioned diseases, as well as in finding new ways to prevent, mitigate or treat these diseases.

Foods that cause a decrease in insulin response are considered auspicious because high levels of insulin (hyperinsulinemia) after eating are risk factors for disease development, in the amount of metabolic syndrome (cardiovascular diseases, type 2 diabetes and obesity). Thus, foods that cause lower levels of insulin in the body, may be preferred for people in the industrialized part of the world, where the increase of problems a heart condition what about the disease, such as type 2 diabetes, obesity and metabolic syndrome.

In accordance with this invention have been found new ways of treatment and prevention of such diseases.

The invention

In one aspect, the invention provides a method of modifying politieacademie vegetable material(s), where the method includes:

a) mixing at least one politieacademie material and at least one solvent to provide a mixture;

b) heating the mixture to eliminate present bacterial species to provide a heated mixture;

c) adding at least one modifying polyphenol strain of lactic acid bacteria and optionally at least one source of protein, in any order or simultaneously, to this heated mixture to provide a fermentation mixture; and

(d) placing a fermentation mixture to conditions suitable for fermentation of this fermentation mixture to provide a mixture of the modified politieacademie vegetable material(s) and

e) optional removal of the modifying polyphenol strain of lactic acid bacteria to provide a mixture of the modified politieacademie vegetable material(s), not containing live lactic acid bacteria.

In the optional aspect of the invention provides the use of a mixture of modified politieacademie vegetable material(s), containing live lactic acid bacteria, or a mixture of the modified politieacademie vegetable material(s), not containing live lactic acid bacteria for the manufacture of a composition for prevention or treatment of diabetes, metabolic syndrome and cardiovascular diseases.

Brief description of figures

Figure 1 shows curves of plasma glucose after a meal obtained after ingestion of different drinks from blueberries tested individuals, regarding the comparative drink containing glucose.

Figure 2 shows the insulin response of serum after intake of different foods from blueberries subjected to various processes/additives, in comparison with comparative drink containing glucose.

Figure 3 shows insulin response after ingestion of different foods from blueberries subjected to various processes/additives, in comparison with the untreated control (untreated). After 30 minutes, this In-fermented produces a significantly lower insulin response compared to control (untreated) (P<0.05, the criterion Dunnet with B-raw option as a control).

Figure 4 shows curves of plasma glucose after a meal obtained after ingestion of fermented beverage made from blueberries with live B. what Karimi and fermented drink, in which these bacteria are then destroyed by pasteurization.

Figure 5 shows the insulin response after ingestion of fermented beverage made from blueberries with live bacteria, where these bacteria are then destroyed by pasteurization.

6 shows the content of catechin, epicatechin, aglycone of proanthocyanidin dimer, aglycone of proanthocyanidin trimer aglycone proanthocyanidin tetramer, 3,4-dihydroxyphenylpropionic acid, 3-phenylmalonic acid, protocatechuic acid and cyanidin-3-galactoside/cyanidin-3-glucoside in a puree of berries, rose hips, bilberry, blueberry peel and peel cranberries, before and after fermentation.

Fig.7 shows the content of catechin, epicatechin, procyanidin B2, aglycone of proanthocyanidin trimer, aglycone proanthocyanidin tetramer, 3,4-dihydroxyphenylpropionic acid, L-(-)-3-phenylmalonic acid, protocatechuic acid and cyanidin-3-galactoside/cyanidin-3-glucoside in blueberries before fermentation and after fermentation with Lactobacillus plantarum HEAL 19, Lactobacillus plantarum 299v or Pediococcus acidilactici.

Detailed description of embodiments of the invention

In one embodiment, the method of the invention a mixture of at least one politieacademie plant material and at least one solvent obtained by homogenization. This solvent is predpochtite the flax water, tap water or distilled water, but may be another water suitable for food solvent, such as mineral water, juices, such as fruit and vegetable juices, milk and other beverages.

To eliminate any bacterial species, such as bacteria and/or microorganisms present in the prepared mixture of at least one politieacademie material and at least one solvent, to prevent any growth, heated in stage b) takes place at a temperature of 60°C-100°C, preferably 80°C to 100°C, more preferably 90°C-100°C, i.e. at a temperature sufficient to destroy bacteria and microorganisms, such as pasteurization at 94°C for 2 seconds or by using a conventional autoclave for destruction of bacteria present. Fermentation provided in stage d), should only take place for a specific strain of lactic acid bacteria added to this mixture. Thus, it is necessary to eliminate any bacteria that may be present in the stage of heating (b)before fermentation. The decision about the temperature of heating and the duration of heating are accepted in accordance with the desired result, i.e. to kill any present bacteria and microorganisms.

After stage heating (b) the pH of the heated mixture can bitdamaged to a pH in the range of about 4.5 to 9, preferably 5-7, for example, the addition of KOH, as polyphenoloxidase material can be acidic. This is because the added strain of lactic acid bacteria will grow well in this range of pH. This at least one modifying polyphenol strain type in the amount of approximately 105-109CFU/ml of the mixture. Preferably, the fermentation takes place in the presence of at least one protein source, such as a source of amino acids, and the specified protein source selected, but is not limited to, from the group consisting of peptone, tryptone (milk broth), yeast extracts and their combinations. Another example is meat broth or broth oatmeal, which also contain the necessary components for these bacteria. Fermentation can take place without added protein source, i.e. in the presence of only components added politieacademie plant material (added politieacademie plant materials), i.e. the present proteins and carbohydrates in these plant materials. This at least one protein is added to or is present in amounts of 0.0001-0.1 wt.% the total mixture.

In one embodiment of this invention indicated at least one modifying polyphenol strain of lactic acid bacteria using the EN group, consisting of Lactobacillus, Pediococcus, Streptococcus, Weissella, Leuconostoc, Oenococcus, Lactococcus and phylogenetically related genera. In another embodiment of this invention indicated at least one modifying polyphenol Lactobacillus selected from the group consisting of Lactobacillus plantarum, Lactobacillus paraplantarum, Lactobacillus pentosus and Lactobacillus argentoratensis.

Preferably Lactobacillus plantarum selected from the group of strains consisting of Lactoabacillus plantarum 299, DSM 6595, which was deposited on 2 July 1991 in the German Collection of microorganisms and cell cultures GmbH, Lactobacillus plantarum 299v, DSM 9843, which was deposited on March 16, 1995 in the German Collection of microorganisms and cell cultures GmbH, Lactobacillus plantarum HEAL 9, DSM 15312, Lactobacillus plantarum HEAL 19, DSM in 15,313 and Lactobacillus plantarum HEAL 99, DSM 15316, which were deposited on November 27, 2002 in the German Collection of microorganisms and cell cultures GmbH, and then got rooms access, above.

After adding the particular strain of lactic acid bacteria fermentation conditions are: a temperature of approximately 30°C-50°C, preferably approximately 35°C-45°C, particularly preferably approximately 37°C-40°C, in liquid medium at atmospheric pressure. Fermentation usually takes place, has not yet achieved a pH<5, preferably <4. If fermented yoghurt fermentation continues until pH<4,6-4,7. Fermentation takes place within approximately 10-30 hours, preferably about 15-25 hours, for example about 20-24 hours. The duration of the fermentation should be sufficient to provide a useful modified politieacademie plant material (useful modified politieacademie plant materials).

After completion of the fermentation takes place optional step f) removing the modifying polyphenol strain of lactic acid bacteria by heating, ultraviolet radiation, gamma radiation, pressure, electric current, electric discharge, pulsed electric fields, electric shock or sterile filtration. Through the elimination of this strain of lactic acid bacteria can be used the mixture of the modified politieacademie vegetable mixture that does not contain lactic acid bacteria, in any composition, which can be taken inside the individual.

Politieacademie plant material(s)that are modified by fermentation of a strain of lactic acid bacteria selected, for example, from the group consisting of fruits, vegetables, berries, tea, grains, green tea, coffee, cocoa, chocolate and crust. Fruits and berries selected, for example, from the group consisting of blueberry, bilberry, cranberry, apples, banana, black currant, strawberry, raspberry, rose hips, is inograd, citrus, black mountain ash, Japanese quince, blackthorn, dog rose and elder, olives, caper berries and other fruits rich in polyphenols. The bark is usually the bark of the cinnamon tree. Vegetables, for example, selected from varieties of beans. This invention is not limited to the above specific examples. An important aspect in relation to the selected politieacademie vegetable material(s) is that used politieacademie plant material must be able to ferentiates strain of lactic acid bacteria and to provide a modified politieacademie plant material.

In this context, the phrase "modification politieacademie plant material" means that the fermentation of the added strain of lactic acid bacteria occurred in the presence of polyphenoloxidase plant material. This fermentation takes place and affects the present polyphenolic groups with the formation of the modified politieacademie vegetable material(s). In this context, the term "modified politieacademie plant material(s)" refers to the product (products)obtained after fermentation politieacademie plant material in the presence of lactic acid bacteria strain under these conditions. In the experimental part, t is stireman politieacademie plant material is blueberries, cranberries and rose, and it was shown that only the test product contained in fermented blueberries, cranberries, and wild rose, causing a significant effect on lower insulin response that indicates the highest likelihood that the fermentation politieacademie materials causes a lower insulin response. Thus, according to this invention, the term "modified politieacademie plant material(s)" means those substances which are obtained after fermentation politieacademie plant materials. Such "modified politieacademie plant material should provide the desired effect of reducing the insulin response in people after taking them inside in comparison with ingestion politieacademie plant material that has not been fermented by lactic acid bacteria strain. Reducing the level of insulin administered modified politieacademie plant material in any suitable form should occur in the range of about 1-50%, preferably about 5-40%, more preferably about 10-30%, even more preferably about 15-25%, for example approximately 25%.

This invention relates also to the use of mixtures of modified politieacademie rastitel the th material(s), containing live lactic acid bacteria, or a mixture of the modified politieacademie vegetable material(s), not containing live lactic acid bacteria for the preparation of compositions for the prevention or treatment of diabetes, metabolic syndrome, obesity and cardiovascular diseases.

This composition is preferably a pharmaceutical composition or food composition. This food composition is, for example, a food product or nutritional Supplement.

This food product may be selected from the group consisting of varieties of bread, cheeses, yoghurts, juices, diet drinks, diet cakes, pasta, biscuits (cookies) and Breakfast cereals. Convenient is the inclusion of a mixture of modified politieacademie plant material(s) or a mixture of the modified politieacademie vegetable material(s), not containing live lactic acid bacteria in the food composition as the composition is easily used by an individual to maintain health and to prevent the above-mentioned cardiovascular diseases.

Method and material

Test products

To demonstrate the effects of the present invention was tested to assess potential differences in glucose and insulin response after a meal, after the pickup is inside various compositions based politieacademie vegetable material(s), such as blueberries and sucrose, depending on 1) the type and extent of processing by heating the composition of blueberries, 2) the presence of producing lactic acid bacteria (Lactobacillus plantarum 299v and Lactobacillus plantarum HEAL 19, respectively) in this composition, and (3) fermentation composition blueberries with L. plantarum HEAL 19.

In this study consisted of five different test drinks drink and reference (Ref.). These test drinks consisted of a single raw unfermented drink from bilberry (B-monot.), one drink on the basis of non-fermented with blueberries which have pasteurizable (B-pastes.), two drinks, which were pasteurizable and did not fermentatively with the addition of Lactobacillus plantarum 299v and HEAL 19, respectively (B-299v and B-HEAL), and one drink, which was pasteurizable and fermentatively (B-farms.) L. plantarum HEAL 19. Reference the drink consisted of glucose dissolved in water. Berries blueberries (Vaccinium myrtillus) was mixed up mashed potatoes before storage at -20°C. After thawing, the blueberry was diluted with water (1:1) and homogenized for 5 minutes using a home mixer. After that blueberries were diluted a second time (1:1) to obtain a 25% solution of blueberries. Then this solution blueberries homogenized at 25000 rpm high-performance disperser (Ultra Turrax T25, Janke &Kunkel IKA Werke GmbH & Co.KG, Staufen, Germany). Took samples of unfermented drink from bilberry (B-raw) and Zam is rajawali at -20°C until used in the study with the meal. The remaining solution blueberries were pasteurizable (94°C, 2 (C) and kept at -20°C (B-pasteurized).

Two drinks with separate addition of Lactobacillus plantarum 299v (B-299v and Lactobacillus plantarum HEAL 19 (B-HEAL 19) were prepared by thawing B-pasteurized drink for one day before the study and added the appropriate strain of Lactobacillus and after that this drink was allowed to stand overnight in the refrigerator (+4°C) before submission.

Approximately one week before serving 600 ml of pasteurized solution blueberries were fermentatively in the vessel, was added KOH to obtain a pH of 5. After this, the solution blueberries were inoculable using Lactobacillus plantarum HEAL 19 (1×107colony forming units (CFU)/ml). One gram autoclaved flowers feed (horse) beans was added as a nitrogen source. The solution blueberries gave to ermentrout for 20 hours until they received the final CFU 1×109/ml (pH 3,8) (B-fermented). After fermentation solution blueberries were stored at 4°C. the Fermentation was carried out with the use of Probi AB (Lund, Sweden). Glucose drink was used as the reference drink containing 30 g of D-glucose (VWR international Ltd. Poole, England) and 300 ml of water. All drinks containing 30 g of carbohydrates. Baton white wheat bread (WWB, Dollar Storfranska, Lockarp, Sweden) was given to each of the test subjects at the beginning of this study. Individually wybran the number of slices should be eaten in the evening before each event.

Table 1 shows the different composition of the test beverages drink and reference.

Before serving in each drink of blueberries added 72,8 ascorbic acid, 320,1 mg trecomex (modified potato starch), 291 mg CNK (carrageenan E407) and 26,18 g of sucrose. In addition to In-fermented drink was added 1.18 g of glucose to compensate for loss of carbohydrates during fermentation. Finally, all drinks from blueberries complement of 32.0 g of water, so that received 300 g of drinks from blueberries, containing 20% blueberries and 30 g of carbohydrates.

Studies of test-drinks

All drinks were served as Breakfast and were given randomly, with an interval of at least five days. All subjects received written informed consent. Subjects were aware that they can withdraw from this study at any time without further explanation. This study was approved by the ethics Committee of the faculty of medicine Lund University.

Test subjects

Fifteen healthy non-Smoking volunteers, 7 women and 8 men, participated in this study emergency reception drink. The average age was 25±2,4 (mean ± SD) years and the average body mass index was in the normal range (22,4±2.0 kg/m2; mean±SD). These subjects did not receive any drug treatment. They were asked in order to avoid taking alcohol, physical activity and lunch, rich in fiber, a day before performing the test. The subjects ate individually selected number of WWB (wheat white bread) between 9 and 10 hours in the evening before each event. It is individually selected number of slices should be the same throughout the study. Subjects were asked not to eat anything more after ingestion of WWB before arrival in the laboratory. But was allowed, if you want to drink a small amount of water after 10 o'clock in the afternoon. Each subject participated in four cases at intervals of at least one week.

Study design and drawing blood

These subjects came to the laboratory in the morning in 07,45, and they inserted the catheter into the vein, leading from the elbow. In each case, all participants filled out a questionnaire concerning their physical condition during this day, including feelings of stress or anxiety. Drink drank continuously for 10 minutes. Capillary blood was collected for analysis of serum insulin and for analysis of plasma glucose fasting blood and 15, 30, 60, 90, 120, 180, 240 minutes after drinking the drink.

Analysis glucose

Blood glucose was determined in B-Glucose Analyser (Hemocue 201 +, Hemocue AB, Angelholm, Sweden).

Analysis of insulin

Samples of serum insulin was stored at -20°C. This is the analysis performed on the integrated analyzer for immunoassay (CODA Open Microplate System; Bio-Rad Laboratories, Hercules, CA) using a kit enzyme immunoassay (Mercodia Insulin Elisa; Mercodia AB, Uppsala, Sweden).

Calculations and statistical analysis

For each participant and each test drink incremental area under the curve (AUC) when 0-45 minutes and 0-120 minutes for blood glucose and serum insulin was calculated using the program GraphPad PRISM (version 3.02; GraphPad Software Inc, San Diego). All areas below the line of the background were excluded from these calculations. At each time point, blood glucose and serum insulin were statistically analyzed. These statistical calculations were performed using the statistical program MINITAB Statistical Software (release 13.1 for windows). Significance was determined using the General linear model (ANOVA), followed by the criterion of multiple comparisons Tukey or criterion Dunnet. Differences resulting in P<0.05 are considered significant.

Plasma glucose

As a very early (0-45 min)and late (0-90 min) area under curve of glucose was significantly lower after taking the drink from blueberries in comparison with glucose reference drink. The GI values for drinks of blueberries was going well in the range of 58-64 and were significantly lower than for the reference glucose (GI=100). This reaction plasma glucose is shown in figure 1.

Table 2
Plasma glucose after the reference glucose drink and drink from blueberries that have been pasteurized, fermented, and/or supplemented by bacteria
DrinksnThe value of fasting (mmol/l)The magnitude of the peak (Delta) at 30 min (mmol/l)The area under the curve 0-45 min (mmol min/l)GI (0-90 min)
Glucose155,2±0,14,1±0,3a115,6±8,2a100±0,0a
In-naobr.145,2±0,13,0±0,2b80,8±7,2b58±4,6b
In-paste.135,2±0,13,0±0,3b82,4±7,1D64±5,5b
In the farm.155,2±0,12,8±0,3b76,±8,0 b61±6,9b
B-299V145,3±0,13,2±0,2b81,1±6,9b60±4,7b
B-HEAL19145,2±0,12,9±0,2ban 80.2±5,3b63±4,4b
These figures show mean values ± SD, n=number of test subjects. Mean values in the same column with different letters are significantly different (P<0,05).

Serum insulin

Insulin response after ingestion of different drinks from blueberries and reference of the drinks shown in figure 2. In the range of 30-60 minutes all drinks from blueberries caused a significantly lower insulin response than glucose reference drink. After 15 minutes, the level of insulin after administration of In-fermented beverage was significantly lower in comparison with glucose reference drink. In the early phase after intake (expressed as 0-45 min AUC) In fermented drink caused a lower insulin response than B-HEAL 19.

To study the importance of pasteurization, fermentati is (with L. plantarum HEAL 19) or adding Lactobacillus plantarum to the raw material cranberries insulin response B-pastes., B-farms., B-299v and B-HEAL 19 compared with untreated control drink (B-naobr.). At 30 min after intake of B-farms. was significantly lower in comparison with untreated. At 120 min, B-299v and B-HEAL 19 was found to lower insulin response compared to In-raw option. Comparison of early insulin response (0-45 min AUC) showed that farm. gave a significantly lower insulin response (25%) in comparison with untreated drink from blueberries (P<0,05, table 4). No pasteurization, no adding Lactobacillus plantarum 299v or Lactobacillus plantarum HEAL 19, respectively, were not significantly influenced by the area of insulin after administration of relatively unprocessed drink from blueberries.

Table 3
Insulin response in the serum of healthy test subjects after ingestion of a glucose drink and drinks on the basis of raw material blueberries subjected to pasteurization, fermentation, and/or supplemented by bacteria
DrinksnThe value of fasting (mmol/l)The magnitude of the peak (Delta) at 30 min (mmol/the) The area under the curve 0-45 min (mmol min/l)GI (0-90 min)
Glucose1543,3±22ab243±30,3a6,8±0,8a100±0,0a
In-naobr.1433,8±6,2b166±18,9bc4,4±0,4bc63±6,6b
In-paste.1347,2±67ab141±21,6bc3,9±0,5bc56±3,2b
In the farm.1550,0+5,6a119±17,8b3,3±0,4D46+3,7b
B-299v1449,3±7,8a188±25,9c4,9±0,8c61±5,8b
B-HEAL1914 45,0±5ab153±18,8bc4,4±0,6bc64±6,0b
These figures show mean values ± SD, n=number of test subjects. Mean values in the same column with different letters are significantly different (P<0,05).

Fermentation of blueberries using Lactobacillus plantarum HEAL19 is, apparently, a key factor for reduced insulin response. These results suggest that the fermentation process improves the economy of insulin.

Table 4
Comparison of insulin response pasteurized and fermented beverage made from blueberries with raw drink from blueberries as control
DrinksThe area under the curve 0-45 min (nmol min/l)The difference in insulin response relative to the In-camera raw drink (%)
In-naobr.4,4±0,4_
In-paste.3,9±0,5-11
In the farm.3,3±0,4-25
*indicates significant difference compared to the control beverage, raw (P<0.05, the criterion Dunnet with In-raw drink as a control drink.

This is 25% lower insulin response after ingestion of fermented drink blueberries with Lactobacillus plantarum HEAL 19 is not accompanied by a similar decrease in plasma glucose, because of the reaction of plasma glucose after ingestion of the drink was on the same level. However, fermentation of blueberries using Lactobacillus plantarum HEAL19 is, apparently, a key factor in reduced insulin response observed with drinks containing fermented blueberries. This effect was not observed when adding the same bacteria Lactobacillus plantarum HEAL 19 to drink from blueberries just before receiving. Thus, it is not the presence of the bacteria per se leads to reduced insulin response, but rather is important in itself fermentation. An active mechanism that causes this interest effect could be due to the components produced or modified by fermentation, i.e. modified polyphenolic components available in blueberries after fermentation.

In General, you can make the substance of the conclusion, fermented drink blueberries reduced insulin response by 25% compared to non-fermented drink blueberries. In the future, products designed for people with metabolic disorders, represent an additional way of warning and may also reduce the development of type 2 diabetes and endothelial disorders. Considering the "epidemic disease with metabolic disorders" in the larger perspective, preferably by integrating all aspects of this problem, i.e. not only nutrition-related clinical, but also social, cultural and economic, you can get the possibility of introducing a General healthy lifestyle in the West and in developing countries. It is hoped that a more thorough understanding of these aspects of all consumers will force the industry to comply with the desires of the market.

Test that compares the effects for drinks with live bacteria with effects for drinks with eliminated bacteria

In this study consisted of two different test drink for assessment does the drink, in which the culture of L. plantarum HEAL 19 pasteurized after fermentation, the same low insulin response, and drink, in which the culture of L. plantarum HEAL 19 left alive after fermentation.

The test drinks consisted of a single drink pasteurized and fermention the frame L. plantarum HEAL 19, and one drink, which was pasteurizable and fermentatively L. plantarum HEAL 19 and then pasteurizable after this fermentation. Berries blueberries (Vaccinium myrtillus) was mixed up mashed potatoes before storage at -20°C. After thawing, the blueberry was diluted with water (1:1) and homogenized for 5 minutes using a home mixer. After that blueberries were diluted a second time (1:1) to obtain a 25% solution of blueberries. Then this solution blueberries homogenized at 25000 rpm high-performance disperser (Ultra Turrax T25, Janke &Kunkel IKA Werke GmbH & Co.KG, Staufen, Germany). Took samples of unfermented drink from bilberry (B-raw) and frozen at -20°C until used in the study by ingestion. The remaining solution blueberries were pasteurizable (94°C, 2 (C) and kept at -20°C (B-pasteurized).

Approximately one week before serving 600 ml of pasteurized solution blueberries were fermentatively in the vessel, was added KOH to obtain a pH of 5. After this, the solution blueberries were inoculable using Lactobacillus plantarum HEAL 19 (1×107colony forming units (CFU)/ml). One gram autoclaved flowers feed (horse) beans was added as a nitrogen source. The solution blueberries gave to ermentrout for 20 hours until they received the final CFU 1×109/ml (pH 3,8) (B-fermented). After fermentation solution cher the IKI kept at 4°C or, again, was pasteurizable. Fermentation was carried out with the use of Probi AB (Lund, Sweden).

Table 5 shows the different composition of these test drinks.

Before serving in each drink of blueberries added 72,8 ascorbic acid, 320,1 mg trecomex (modified potato starch), 291 mg CNK (carrageenan E407) and 26,18 g of sucrose. In addition to In-fermented drink was added 1.18 g of glucose to compensate for loss of carbohydrates during fermentation. Finally, all drinks from blueberries complement of 32.0 g of water, so that received 300 g of drinks from blueberries, containing 20% blueberries and 30 g of carbohydrates.

Studies of test-drinks

All drinks were served as Breakfast and were given randomly, with an interval of at least five days. All subjects received written informed consent. Subjects were aware that they can withdraw from this study at any time without further explanation. This study was approved by the ethics Committee of the faculty of medicine Lund University.

Test subjects

Fifteen healthy non-Smoking volunteers, 7 women and 8 men, participated in this study emergency reception drink. The average age was 25,5±1,34 (mean±SD) years and the average body mass index was in the normal range (20,8±0.24 kg/m2; mean ± SD). One of these subjects Stra is al from gastric flu in the days before one test case, and hence, was excluded from this study. These subjects did not receive any drug treatment. They were asked to avoid alcohol intake, physical activity and lunch, rich in fiber, a day before performing the test. The subjects ate individually selected number of WWB (wheat white bread) between 9 and 10 hours in the evening before each event. It is individually selected number of slices should be the same throughout the study. Subjects were asked not to eat anything more after ingestion of WWB before arrival in the laboratory. But was allowed, if you want to drink a small amount of water after 10 o'clock in the afternoon. Each subject participated in four cases at intervals of at least one week.

Study design and drawing blood

These subjects came to the laboratory in the morning in 07,45, and they inserted the catheter into the vein, leading from the elbow. In each case, all participants filled out a questionnaire concerning their physical condition during this day, including feelings of stress or anxiety. Drink drank continuously for 10 minutes. Capillary blood was collected for analysis of serum insulin and for analysis of plasma glucose fasting blood and 15, 30, 60, 90, 120, 180, 240 minutes after drinking the drink.

Analysis glucose

<> Blood glucose was determined in B-Glucose Analyser (model no. 120401, Hemocue AB, Angelholm, Sweden).

Analysis of insulin

Samples of serum insulin was stored at -20°C. This analysis was performed on the integrated analyzer for immunoassay (CODA Open Microplate System; Bio-Rad Laboratories, Hercules, CA) using the set for firmenlogo immunoassay (Mercodia Insulin Elisa; Mercodia AB, Uppsala, Sweden).

Calculations and statistical analysis

For each participant and each test drink incremental area under the curve (AUC) when 0-45 minutes and 0-120 minutes for blood glucose and serum insulin was calculated using the program GraphPad PRISM (version 3.02; GraphPad Software Inc, San Diego). All areas below the line of the background were excluded from these calculations. At each time point, blood glucose and serum insulin were statistically analyzed. These statistical calculations were performed using the statistical program MINITAB Statistical Software (release 13.1 for windows). Significance was determined using the General linear model (ANOVA), followed by the criterion of multiple comparisons Tukey or criterion Dunnet. Differences resulting in P<0.05 are considered significant.

Plasma glucose

As a very early (0-45 min)and late (0-120 min) area under curve of glucose were slightly lower after ingestion of the test drink, which was pasteurized after fermentation, in comparison with the test drink with live bacteria, to which it can be seen in figure 4. The profile curve of glucose was analyzed by dividing the period during which blood glucose remains above the value measured on an empty stomach, maximum increase in blood glucose from the values measured on an empty stomach. This quotient is called the quota (share) duration/peak (min/Δ mm). High value of quota duration/peak glucose indicates that the curve of glucose is long and low, while a low value indicates an unfavorable profile curve with short and tall shape of the curve. The GI value could not be determined, because this test was not included reference to the drink.

Table 6
AUC 120 min (plasma glucose) for fermented drink with live bacteria and fermented and pasteurized drink
DrinksAUC 120 minSEM (n=12)
In-farms. live bacteria85,868,13
In-fermented and pasteurized81,439,10
These figures show mean values ± SD, n=number of t is St-subjects.

Table 7
AUC 45 min (plasma glucose) and quota duration/peak glucose for fermented drink with live bacteria and pasteurized drink
DrinksAUC 45 minSEM (n=12)Neg AUC 30-120 minSEM (n=12)Quota duration/peak glucoseSEM (n=12)
In-farms. live bacteria69,906,1122,65is 4.9326,363,21
In-fermented and pasteurized62,28to 5.9316,664,5029,213,21
These figures show mean values ± SD, n=number of test subjects.

Serum insulin

Insulin response after oral administration of two drinks of blueberries shown in figure 5. AUC who was b lower after ingestion of the test drink, which was pasteurized after fermentation, in comparison with the test drink with live bacteria. The GI value could not be determined, because this test was not included reference to the drink.

Table 8
AUC 120 min (response of serum insulin) for fermented drink with live bacteria and fermented and pasteurized drink
DrinksAUC 120 minSEM (n=12)
In-farms. live bacteria6,651,06
In-fermented and pasteurizedof 5.750,51
These values were transformed using Box-Cox Transformation before analysis.

Discussion

Both drinks were given approximately the same response to glucose. The drink, which was pasteurizable, i.e. bacteria were killed, showed the best results on insulin response than drink with live bacteria. In an earlier study observed no effect from one of pasteurization on insulin response, i.e. pasteurized berries cher the IKI gave the same result, as raw blueberries. However, this invention indicates that the degree of processing by heating after fermentation to a considerable extent may affect insulin response.

The mechanism of this effect requires further evaluation. One theory is that the more powerful processing by heating, through actions on polyphenols and other bioactive components in blueberries, has the effect of reducing insulin, which illustrates a drink with destroyed by heating the bacteria due to additional stages of processing by heating.

Analysis of phenolic compounds

To provide evidence that modification politieacademie plant material takes place, were compared to the contents of catechin, epicatechin, aglycone of proanthocyanidin dimer, aglycone of proanthocyanidin trimer aglycone proanthocyanidin tetramer, 3,4-dihydroxyphenylpropionic acid, L-(-)-3-phenylmalonic acid, protocatechuic acid and cyanidin-3-galactoside/cyanidin-3-glucoside in mashed berries and seeds) rose hips, bilberry, blueberry peel and peel cranberries before and after fermentation.

All factions of the fruit was pasteurizable before fermentation in order to avoid that other organisms will affect the fermentation.

For the analysis of phenolic compounds in the samples were weighed and obavljale solution for extraction (concentration in this sample: 50% ethanol, 0,05M phosphoric acid, alternative 50% methanol and 0.5%). After that, these samples were extracted for 10 minutes in an ultrasonic bath and then centrifuged, then the supernatant was transferred into vials and analyzed using VIH-MS analysis. VIH-MS analysis was performed as described by Salminen et al. Characterization of proanthocyanidin aglycones and glycosides from rose hips by high performancce liquid chromatography-mass spectrometry, and their rapid quantification together with Vitamin C. J Chrom A, 2005; 1077:170-180, and Salminen et al. Characterization of hydrolysable tannins from leaves of Betula pubescens by high-performance liquid chromatography-mass spectrometry. J Chrom A, 1999; 864: 283-291 using ion spray API 150 EX Turbo.

This device was installed in the negative mode, i.e. analyzed negatively charged ions. System WICH consisted of a pump WICH type PerkinElmer LC-200 Micro Pump and sampler PerkinEImer 200 Auto sampler. The injection volume of the samples was equal to 8 μl.

Scanning was performed during the mass numbers 90-1000V m/z. Specific mass number, used to detect:

Catechin, m/z 289 (M-H)

Epicatechin, m/z 289 (M-H)

Procyanidin B2, m/z 577 (M-H)

The aglycone of proanthocyanidin dimer, m/z 577 (M-H)

The aglycone of proanthocyanidin trimer aglycone, m/z 865 (M-H)

The aglycone of proanthocyanidin tetramer, m/z 1153 (M-H)

3,4-dihydroxyphenylpropionic acid, m/z 181 (M-H)

L-(-)-3-phenylmalonate acid, m/z 165 (M-H)

Protocatechuic acid, m/z 153 (M-H)

The cyanidin-3-galactoside, qi is nidin-3-glucoside, m/z 447 (M-H)

Figure 6 you can see the results of this study indicate that the modification politieacademie plant material takes place as in blueberries and berries cranberry and rosehip berries.

In a study on rats it was shown that concentrations of selected phenolic compounds in the caecum were different ingestion of berries, rose hips plus Lactobacillus plantarum 299v or Lactobacillus plantarum HEAL 19 in comparison with the consumption of only the berries of the wild rose (table 10). This indicates that these polyphenolic components were modified during fermentation in the caecum.

Table 10
Selected phenolic compounds content in the caecum. Peak 1 = µg catechin/g wet weight, peak 2, 3, 4, and 6 = mg of catechin equivalents/g fresh weight (fw), peak 5 = µg quartzetine-rhamnoside/g fresh weight (fw)
Peak 1 catechin Rt of 13.8 min, m/z 289Peak 2 Rt at 16.1 min, m/z 291Peak 3 Rt 17,1 min, m/z 385Peak 4 Rt of 18.6 min, m/z 291Peak 5 Rt 23,1 min, m/z 447Peak 6 Rt of 29.3 min, m/z 289
Colitis control1,65,301,70,69,3
Lp299v0,95,803,31,08,2
HEAL 191,2of 5.402,20,82,4
Rose hip29,9the 122.7100,812,20,28,6
Rose hip + Lp299v38,7119,851,511,30,218,2
Rose hip + HEAL 19of 40.9134,228,217,10,264,4

Test that compares the fermentation with Lactbacillus plantarum HEAL 19, Lactobacillus plantarum 299v or Pediococcus acidilactici

To provide evidence that modification politieacademie plant material takes place during the fermentation with other bacteria, were compared to the contents of catechin, epicatechin, aglycone of proanthocyanidin dimer, aglycone of proanthocyanidin trimer aglycone proanthocyanidin tetramer, 3,4-dihydroxyphenylpropionic acid, L-(-)-3-phenylmalonic acid, protocatechuic acid and cyanidin-3-galactoside/cyanidin-3-glucoside in blueberries before and after fermentation Lactobacillus plantarum HEAL 19, Lactobacillus plantarum 299v or Pediococcus acidilactici.

The results of this study can be seen in Fig.7, showing that modification politieacademie plant material takes place after fermentation with all the tested bacteria, i.e. Lactobacillus plantarum HEAL 19, Lactobacillus plantarum 299v or Pediococcus acidilactici.

1. A method of obtaining a product that lowers insulin response, including:
a) mixing at least one politieacademie plant material selected from the group consisting of fruits, vegetables, berries, tea, green tea, coffee, cocoa, chocolate bark and at least one water fit for food of the solvent to provide a mixture;
b) heating the mixture to eliminate present bacterial species to obtain agreei mixture;
c) adding at least one strain of lactic acid bacteria selected from Lactobacillus plantarum, and optionally at least one protein source selected from the group consisting of gelatin, tryptone, yeast extracts and their combination, in any order or simultaneously, to this heated mixture to provide a fermentation mixture; and
d) the exposure of this fermentation mixture to conditions suitable for fermentation of this fermentation mixture to provide a product that lowers insulin response; and
e) optional elimination of Lactobacillus plantarum for providing a product that lowers insulin response, not containing live lactic acid bacteria.

2. The method according to claim 1, where the at least one strain of Lactobacillus plantarum add in the amount of approximately 105-109CFU/ml of the mixture.

3. The method according to any one of claims 1 or 2, in which the at least one protein is added in amounts of 0.0001-0.1 wt.% by weight of the mixture.

4. The method according to any one of claims 1 or 2, in which Lactobacillus plantarum selected from the group consisting of Lactobacillus plantarum 299, DSM 6595, Lactobacillus plantarum 299v, DSM 9843, Lactobacillus plantarum HEAL 9, DSM 15312, Lactobacillus plantarum HEAL 19, DSM in 15,313 and Lactobacillus plantarum HEAL 99, DSM 15316.

5. The method according to any one of claims 1 or 2, where the fermentation conditions are fermentation at a temperature of 30-50°C, in liquid medium at atmospheric pressure.

6. The method according to any of the claim 1 or 2, where the fermentation proceeds, so far not reached a pH<5, preferably <4.

7. The method according to any one of claims 1 or 2, where the elimination of Lactobacillus plantarum occurs by heating, ultraviolet radiation, gamma radiation, pressure, electric current, electric discharge, pulsed electric fields, sterile filtration or electric shock.

8. The method according to claim 1, where fruits and berries selected from the group consisting of blueberry, bilberry, cranberry, apples, banana, black currant, strawberry, raspberry, rose hips, grape, citrus, Aronia, Japanese quince, blackthorn, dog rose and elder, caper berries, olives or other fruits rich in polyphenols.

9. The method according to claim 1, where the bark is the bark of the cinnamon tree.

10. The application reduces insulin response product according to any one of claims 1 to 9, for the manufacture of a composition for the prevention or treatment of diabetes, metabolic syndrome, obesity and cardiovascular diseases.

11. The use of claim 10, where this composition is a pharmaceutical composition or food composition.

12. The application of claim 11, where the food composition is a food product or nutritional Supplement.

13. The application indicated in paragraph 12, where the specified food product selected from the group consisting of breads, cheeses, yogurts, juices, diet drinks, que the practical briquettes, pastes, biscuits and cereal products.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmacy and represents microsphere with controlled release, which has covering layer and contains core, which contains exendin as active ingredient and biodegradable polymer, and covering layer, which covers core with covering material, exendin being exendin-4 (SEQ ID NO:2), biodegradable polymer represents polymer, selected from group, consisting of polylactide (PLA), polyglycolide (PGA), lactide and glycolide copolymer (PLGA), polyorthoester, polyanhydride, polyhydroxybutyric acid, polycaprolactone and polyalkylcarbonate; copolymer or simple mixture of two or more polymers, selected from said group of polymers; copolymer of said polymer and polyethylene glycol (PEG); or polymer-sugar complex, in which sugar is bound with said polymer or said copolymer, covering material is selected from group, consisting of essential amino acids, polypeptides and organic nitrogenous compounds, essential amino acid being one or more, selected from group, consisting of arginine, lysine and histidine; polypeptide represents L-Lys-L-Thr-L-Thr-L-Lys-L-Ser; and organic nitrogenous compound is selected from group, consisting of creatine, creatinine and urea, content of covering layer constitutes from 0.01 to 5 wt fractions in terms per 100 wt fractions of microsphere.

EFFECT: invention ensures increase of bioaccessability and reduction of initial peak of exendin for prevention of such side effects as vomiting, nausea, headache.

10 cl, 7 ex, 5 tbl, 7 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to protein tyrosine phosphatase 1B inhibitors of the given formula which are suitable for treating diabetes type 2 and cancer, or pharmaceutically acceptable salts thereof, in which X is selected from CH and N; R1 is selected from C1-3alkyl, optionally substituted with 1-3 halogens or one -OH, -CN, -C(=O)H, -C(=O)C1-3alkyl group, -HC=NOH, -(CH3)C=NOH, -HC=NOC1-3alkyl, -(CH3)C=NOC1-3alkyl, -C(=O)OC1-3alkyl, -C(=O)NHR6, -CH=CH-phenyl, in which phenyl is substituted with -C(=O)OH; R3 is a halogen; R6 is selected from H, C1-3alkyl, phenyl, and CH2-phenyl, where phenyl in both cases is optionally substituted with a halogen.

EFFECT: obtaining novel biologically active compounds for treating diabetes type 2 and cancer, as well as pharmaceutical compositions based thereon.

10 cl, 2 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely therapy and endocrinology, and may be applicable as a lipid, carbohydrate and protein normalising drug in treating type II diabetes mellitus, atherosclerosis and metabolic syndrome. That is ensured by adding the integrating therapy with the drug Uglanex.

EFFECT: invention provides effective treatment of said pathological conditions ensured by reducing a cholesterol level, an atherogenicity index, blood sugar, insulin resistance and albuminuria.

3 tbl

FIELD: food industry.

SUBSTANCE: invention relates to alimentation field. The infant food set for prevention of children adiposity contains at least three separate nutritional compositions where each of them represents a separate meal for 6-36 months old children. The nutritional compositions include macronutrients content whereof gradually changes in an essentially rectilinear way from the composition containing nearly 40-50% of fat energy and nearly 40-49% of carbohydrate energy for 6 months old babies to the composition containing 30-35% of fat energy and nearly 50-55% of carbohydrate energy for 36 months old children. Additionally one proposes a method for reduction of 6-36 months old children adiposity risk and a dietary regime for such children; these method and dietary regime envisage usage of the said infant food set.

EFFECT: invention allows to prevent adiposity with children during their subsequent life.

22 cl, 6 dwg, 19(32) tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compounds of general formula where Ar is part of quinoline or isoquinoline, which is substituted or unsubstituted; B is -O-; R1 is hydrogen or S(O)2R4; R2 is S(O)2R4, C(O)OR5 or C(O)(CH2)n-C(O)OR6; R3 is halogen; R4 is an aryl which is unsubstituted or optionally has up to five identical or different substitutes selected from a group consisting of halogen, alkyl, fluoroalkyl, hydroxyl, alkoxy, trifluoromethoxy, cyano, amide, CH3CONH-, acyl and carboxyl; R5 is phenyl; R6 is hydrogen; n is an integer from 1 to 3; and a pharmaceutically acceptable salt or solvate. Also described is a method of producing compounds of formula (I) and pharmaceutical compositions containing said compounds, and also a method of treating metabolic disorders associated with resistance to insulin and hyperglycaemia and use of compounds of formula (I) to prepare a medicinal agent for treating metabolic disorders.

EFFECT: novel compounds which are suitable for treating metabolic disorders associated with resistance to insulin or hyperglycaemia are obtained and described.

28 cl, 54 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely peptides which can find application for metabolic syndrome correction.

EFFECT: what is presented is an agent for metabolic syndrome correction representing the tripeptide L-lysyl-L- glutamyl -L-tryptophane.

3 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, veterinary science, herbal medicine, food and pharmaceutical industry, and may be used in preparing herbal drugs, namely herbal extracts and microelements. The agent contains dry extracts of goat's-rue, Garsinia, linseeds, young shoots of bilberry, bean shell, Gymnema Sylvestre, hill-growing saltwort, rhizomes of a wheat grass and microelements - chromium picolinate, magnesium oxide and vanadium sulphate.

EFFECT: agent provides tissue and cell metabolic change expressed in lower blood glucose level.

7 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely therapy and endocrinology, and concerns correction of lipoperoxidation accompanying hypolipidemic therapy of the patients with metabolic syndrome. That is ensured by the combined introduction of statins and coenzyme Q10 scheduled as follows: atorvastatin 20 mg a day in the evening, cudesan equivalent to the content of coenzyme Q10 30 mg a day in the morning daily for 8 weeks with a pause of 8 weeks and renewed introduction; the therapeutic course is 1 year.

EFFECT: such regiment and empirically prescribed drug doses provide intensified antioxidant protection and reduced free-radical lipid oxidation that in turn enables the prolonged introduction of statines that ensures a maximum hypolipidemic effect with no side effects of these preparations.

4 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to versions of applying an antisecretory protein which corresponds the amino acid sequence SEQ ID NO:6, its homologue, and/or a fragment containing the amino acid sequence SEQ ID NO:4 showing equivalent activity, and/or its pharmaceutically active salt for preparing a pharmaceutical composition and/or nutritional care for treatment and/or prevention a dysfunction, e.g. a pathological function, lipid raft, receptor and/or small pit hypo- or hyperfunction. The lipid raft, receptor and/or small pit dysfunction can be induced by or cause a number of the other conditions, such as vascular and pulmonary dysfunctions and/or endocrine disorders, e.g. diabetes and related disorders.

EFFECT: group of inventions enables controlling intracellular transport and cell product release, as well as normalising tissue component distribution in various diseases.

13 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: compounds activate glucokinase and can be used to prepare medicine for treating of metabolic disorders, for lowering blood glucose level, for treating hyperglycemia, for treating IGT, for treating Syndrome X, for treating impaired fasting glucose (IFG), for treating type 2 diabetes, for treating type 1 diabetes, for delaying the progression of impaired glucose tolerance (IGT) to type 2 diabetes, for delaying the progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes, for treating dyslipidemia, for treating hyperlipidemia, for treating hypertension, for lowering food intake, for appetite regulation, for for treating obesity, for regulating feeding behaviour, or for enhancing the secretion of enteroincretins. In compounds of formula , A denotes , R3 is selected from a group consisting of phenoxy and benzyloxy, each possibly substituted with one or more substitutes independently selected from R12; R12 is F, CI, Br, -CF3, -CN methyl, ethyl, isopropyl, tert-butyl, methoxy, methylthio, ethoxy, cyclopropyl-methoxy, -NHC(O)CH3 or -S(O)2-CH3; R30 is methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, benzyloxy or cyclopropyl-methoxy, each possibly substituted with one or more substitutes independently selected from R12; R8 is methylthio, isopropylthio, ethylthio or 2-methylpropylthio, each substituted with one or more substitutes independently selected from R34; R34 is carboxy.

EFFECT: improved properties of the compound.

13 cl, 1 tbl, 242 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to oxadiazolidinone compounds presented by following formula (I), or to their pharmaceutically acceptable salts, (symbols in the presented formula represent the following values, R1: -H, R0: lower alkyl, Rz: the same or different from each other, and each represents -H or lower alkyl, L: *-CH2-O- or *-CH2-NH-, where the symbol * in L represents binding with the ring A and a substitution position in the group L in the ring B represents the 4-position, the ring A: benzole, the ring B: benzole or pyridine, R2; the same or different respectively, and each represents -halogen or -R0, n: 0 or 1, R3: phenyl which can be substituted by a group selected from the group G3, The group G3: halogen, -R0, halogen-lower alkyl, -ORz, -CON(Rz)2, -CON(Rz)-heteroring group, -O-S(O)2-R0, -O-lower alkylene-ORz, -O-lower alkylene-O-COR2, -O-lower alkylene-N(RZ)2, -O-lower alkylene-N(Rz)CO-Rz, -O-lower alkylene-CO2Rz, -O-lower alkylene-CON(Rz)2, -O-lower alkylene-CON(Rz)-(lower alkyl substituted by the group-ORz), -O-lower alkylene-SR0, -O-lower alkylene-cycloalkyl, -O-lower alkylene-CON(Rz)-cycloalkyl, -O-lower alkylene-heteroring group and -O-lower alkylene-CON(Rz)-heteroring group, where lower alkylene in the group G3 can be substituted by halogen or -ORz, and cycloalkyl and the heteroring group in the group G3 can be substituted by the group selected by the group G1, The group G1: halogen, cyano, -R0, -ORz, -N(RZ)2, -S-R0, -SO2-R0, -SO2N(Rz)2, -CO-R2, -CON(Rz)2, -CON(Rz)-lower alkylene-OR2, -N(Rz)CO-Rz, oxo, -(lower alkylene which can be substituted by the group -ORz)-aryl, heteroring group and lower alkylene-heteroring group where aryl and the heteroring group in the group G1 can be substituted by the group selected from the following group G2, the group G2: halogen, cyano where the heteroring group means a group containing a ring selected from i) a monocyclic 5-7-members, saturated or unsaturated heteroring containing 1 to 3 heteroatoms selected from O, S and N, ii) a bicyclic heteroring in which the heterorings selected in i) mentioned above are ring-condensed where the condensed rings can be the same or different, and iii) the bicyclic heteroring in which the heteroring selected in i) mentioned above is condensed with a benzoic ring or 5-7-members cycloalkane, R4: -H. The invention refers to a pharmaceutical composition, to application of the compounds under cl.1, as well as to a method for preventing and/or treating diabetes.

EFFECT: making new biologically active compounds representing GPR40 agonist, an agent stimulating insulin secretion and/or an agent for preventing and/or treating diabetes.

9 cl, 27 ex, 138 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to endocrinology and can be used for reduction of hypoglycemia acute exacerbation or severe hypoglycemia exacerbation in patients with type II diabetes after treatment with insulin. For this purpose vildagliptin or its salt is introduces to patient in combination with insulin.

EFFECT: invention ensures reduction of risk of hypoglycemia development, as well as necessity to apply several antihyperglycemic medications.

12 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where X is C(R8R9), NR10, O, S; R1 is phenyl which is substituted with 1-3 substitutes selected from a group which includes halogen, hydroxy group, lower alkyl, hydroxy-lower alkyl and CN; R2 is hydrogenor lower alkyl; R3 and R4 are hydrogen; R5 and R6 are hydrogen; R7 is oxadiazolyl or triazolyl, where oxadiazolyl or triazolyl is substituted with R11; R8 and R9 denote hydrogen; R10 denotes hydrogen, lower alkyl, lower alkyl-carbonyl or lower alkyl-sulfonyl, R11 denotes aryl or hetearyl, selected from a group comprising pyridinyl, pyrazinyl, pyrimidinyl, pyridinyl-2-one, oxadiazolyl, indazolyl, 1,3-dihydrobenzimidazol-2-one, 1,3-dihydroindol-2-one, benzotriazolyl, imidazopyridinyl, triazolepyridinyl, tetrazolepyridinyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H-indol-5-yl, pyrimidin-4-one, furanyl, thiadiazolyl, pyrazolyl, isoxazolyl, pyrimidin-2,4-one, benzoxazin-3-one, 1,4-dihydrobenzoxazin-2-one, indolyl, thiophenyl, oxazolyl, benzooxazin-2-one; 3,4-dihydroquinazolin-2-one, pyridazinyl, quinoxalinyl, benzothiazolyl, benzothiadiazolyl, naphthyridinyl, cinnolinyl, 1,4-dihydroquinoxalin-2,3-dione and 1,2-dihydroindazol-3-one, where the aryl or heteroaryl is optionally substituted with 1-3 substitutes selected from a group which includes lower alkyl, hydroxy group, B(OH)2, carboxy-lower alkoxy group, carbamoyl-lower alkoxy group, cyano group, hydroxy-lower alkyl, fluoro-lower alkyl, lower alkoxy group, halogen, S(O2)R13, C(O)R14, NO2, NR15R16, phenyl-lower alkoxy group, [1,3,4]oxadiazol-2-one, oxadiazolyl, triazolyl and isoxazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyrrolyl, where imidazolyl is optionally substituted with lower alkyl, and where isoxazolyl is substituted with lower alkyl; R12 denotes hydrogen or lower alkyl; R13 denotes lower alkyl, NR17R18 or fluoro-lower alkyl; R14 denotes NR19 R20, lower alkoxy group, lower alkenyl-oxy group or lower alkyl; R15 and R16 independently denote hydrogen, lower alkyl, lower alkyl-carbonyl, lower alkyl-SO2, lower alkenyl-oxycarbonyl and lower alkyl-NH-carbonyl; or NR15R16 denotes heterocyclyl selected from a group which includes morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, piperidin-2-one, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, pyrrolidinyl, 1,1-dioxoisothiazolidinyl, pyrrolidin-2-one, imidazolidine-1,4-dione, 2,4-dihydro[1.2.4]triazol-3-one, pyrrolidine-2,5-dione, azetidin-2-one and 1,3-dihydroimidazol-2-one, where the heterocycle is optionally substituted with hydroxy-lower alkyl or lower alkyl-carbonyl; R17 and R18 independently denote hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl; or NR17 R18 denotes morpholinyl; R19 and R20 independently denote hydrogen, lower alkyl, cycloalkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl or cyano-lower alkyl; or NR19 R20 denotes heterocyclyl selected from a group which includes morpholinyl, pyrrolidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, piperazin-2-one, thiazolidinyl, thiomorpholinyl, 1,3,8-triaza-spiro[4.5]decane-2,4-dione and spiro(1- phthalan)piperidin-4-yl, where the heterocyclyl is optionally substituted with a hydroxy group, lower alkyl-(SO2), lower alkyl, lower alkyl-carbonyl or lower alkoxy group, carboxyl group, carbamoyl, cyano group and phenyl; and to their pharmaceutically acceptable salts. Invention also pertains to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which inhibit hepatic carnitine palmitoyltransferase 1 (L-CPT1).

35 cl, 565 ex, 10 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to pharmaceutical industry and concerns a composition for glucose delivery through an oral mucosa for increasing of glucose (sugar) blood level of an individual. The composition contains: a. effective amount of glucose, b. effective amount of sodium glycocholate, c. effective amount of a pharmaceutically acceptable carrier; the composition it is free from additional active pharmaceutical agents.

EFFECT: development of the effective method for increasing glucose (sugar) blood level.

13 cl, 9 ex, 4 tbl, 7 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) which are protein tyrosine kinase 1B(PTP-1B) inhibitors and can be used in medicinal preparations for treating and preventing diseases related to high concentration of glucose in blood, for example diabetes and obesity. In formula (I) X is a X-1 group or X-2: , where R1 and R2 are each independently selected from a group consisting of hydrogen, lower alkyl, alkoxy-lower alkyl and hydroxyl-lower alkyl, under the condition that, R1 and R2 both represent hydrogen; R3, R4, R6 and R7 are each independently selected from a group consisting of hydrogen, lower alkyl; lower alkyl substituted with halogen or hydroxy; lower alkoxy; lower alkoxy substituted with halogen, hydroxy or lower alkoxy; hydroxyl, halogen, lower alkylthio, lower alkylsufanyl, lower alkylsufanyl, aminosufonyl, cyano, nitro, carbamoyl, lower mono- or dialkylcarbamoyl, lower alkanoyl, benzoyl, phenyl, phenyl substituted with halogen, phenyloxy, lower mono- or dialkylamino, hydroxy-substituted lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, heterocycloalkyl, hydroxy-substituted heterocycloalkyl, heterocyclyloxy, heterocyclylcarbonyl; where each heterocycloalkyl in the said values represents a 5-6-membr ring containing 1-2 heteroatoms selected from nitrogen and oxygen, and which can be substituted with lower alkyl or phenyl-lower alkyl; carboxyl, lower alkoxycarbonyl and a substitute of formula: ; R8 is selected from a group consisting of hydrogen, lower alkylthio, halogen, alkoxy-lower alkoxy, lower alkoxy, halogen-lower alkyl, hydroxy-lower alkyl; represents a 5-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of hydrogen, sulphur and nitrogen; R8 and R9 each independently represents hydrogen or lower alkyl.

EFFECT: novel compounds have useful biological properties.

31 cl, 7 dwg, 152 ex

FIELD: medicine.

SUBSTANCE: present invention concerns new, selectable hybrid polypeptides expressing at least two hormonal activities containing a first biologically active module of a peptide hormone covalently bonded with at least one additional biologically active module of the peptide hormone.

EFFECT: polypeptides can be used as agents for treatment and prevention of metabolic diseases and disorders associated with overweight.

19 cl, 6 dwg, 6 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new 2-alkylsufanyl-3-arylsufonyl-cycloalkano[e]pyrazolol[1,5-a]pyrimidines of general formula 1 or 2-alkylsufanyl-3-arylsufonyl-cycloalkano[d]pyrazolo[1,5-a]pyrimidines of general formula 2, which are antagonist of 5-HT6 receptors. In compounds of formula 1

and 2 ,

R1 is a hydrogen atom or C1-C3 alkyl; R2 is C1-C3 alkyl; R3 is a hydrogen atom, one or two optionally identical halogen atoms, C1-C3 alkyl or hydroxyl, optionally substituted with C1-C3 alkyl; n is an integer equal to 1, 2 or 3.

EFFECT: compounds can be used in preventing and treating diseases of the central nervous system, anxiolytics and as compounds with nootropic effect and suitable for enhancing memory.

12 cl, 1 dwg, 4 tbl, 9 ex

Diabetes treatment // 2363465

FIELD: medicine.

SUBSTANCE: present group of inventions relates to medicine, particularly to endocrinology. For this purpose sufficient amounts of a compound which inhibits HIF hydroxylase activity are introduced.

EFFECT: design of a method of treating diabetes and other conditions, related to glucose pathometabolism, through stabilisation of HIFα.

8 cl, 12 dwg

FIELD: medicine.

SUBSTANCE: invention refers to pharmacology. The method for improving amino acid absorption in a vertebrate, including a mammal and a bird, includes introduction to a vertebrate of AKG (alpha-ketoglutaric acid), mono- and dimetallic AKG salts, chitosan-AKG or their mixtures in amount and/or at rate sufficient to maintain the desired effect. The method for decreasing plasma glucose absorption in a vertebrate, including a mammal and a bird, involves introduction to a vertebrate, including a mammal and a bird, of AKG, mono- and dimetallic AKG salts, chitosan-AKG or their mixtures in amount and/or at rate sufficient to maintain the desired effect of glucose absorption. The method of prevention, inhibition or relief of the condition with high-glucose plasma level in a vertebrate, including a mammal and a bird includes introduction to a vertebrate, including a mammal and a bird, of AKG, mono- and dimetallic AKG salts, chitosan-AKG or their mixtures in amount and/or at rate sufficient to maintain the desired effect on the specified condition.

EFFECT: application of AKG, mono- and dimetallic AKG salts, chitosan-AKG or their mixtures in therapeutically effective amount for making the composition used to prevent, relieve and treat the condition with high-glucose plasma level, application of AKG, mono- and dimetallic AKG salts, chitosan-AKG or their mixtures for making the composition used to improve absorption, changed absorption, deteriorated absorption and disordered absorption of amino acids and/or peptides.

19 cl, 3 tbl, 3 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to an antimicrobial composition. The prolonged release pharmaceutical antimicrobial composition containing fir oil, myramistine, deproteinised dialysate of healthy veal blood, retinol acetate, aminocaproic acid, lidocaine hydrochloride and a film-forming mixture of polyvinyl alcohol, edible potato starch and glycerol in physiologic saline in certain proportions.

EFFECT: composition shows effective antimicrobial activity, hemostatic, anaesthetic and wound-healing activity.

4 tbl

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