New application of therapeutically effective peptides

FIELD: medicine.

SUBSTANCE: tripeptides Ile-Pro-Pro (IPP) and/or Val-Pro-Pro (VPP) are applicable for preparing a product removing arterial stiffness and for preparing a product improving vascular elasticity. They are made of casein or casein-containing starting material by fermentation with the strain Lactobacillus helveticus DSM 13137 or Lactobacillus helveticus DSM 17754 and recovery by concentration and nanofiltration. The product contains a ferment composition containing the casein-recovered peptides Ile-Pro-Pro and/or Val-Pro-Pro, and living lactic acid bacteria. For the purpose of removing arterial stiffness, the product containing Ile-Pro-Pro and/or Val-Pro-Pro is introduced into an individual. For the purpose of improving vascular elasticity, the product containing Ile-Pro-Pro and/or Val-Pro-Pro is introduced into an individual with using said biologically active peptides.

EFFECT: invention promotes prevention and normalisation of endothelial dysfunction, improves vascular elasticity and removes arterial stiffness.

12 cl, 3 tbl, 5 ex

 

The technical field to which the invention relates

The invention relates to the prevention and treatment of endothelial dysfunction with biologically active peptides and their containing products. It was found that a product having a high content of short-chain peptides, particularly effective for use in accordance with the present invention.

The product is used in accordance with the present invention, can be manufactured, for example, as food for a healthy lifestyle or pharmaceutical product. It contains low molecular weight peptides, such as the tripeptides Ile-Pro-Pro (IPP), Val-Pro-Pro (VPP) or containing mixtures or concentrates, and operates by improving epithelial function and cure of diseases associated with her. The specific objective of this invention is to reduce stiffness and, thus, increase the elasticity of blood vessels with the use of low molecular weight peptides, such as the tripeptides Ile-Pro-Pro (IPP), Val-Pro-Pro (VPP) or mixtures, concentrates and other products that contain them.

The level of technology

Vascular endothelium locally regulates vascular tone through the release of vasodilator substances, such as endothelial relaxing factor (EDRF), nitric oxide, prostacyclin and endothelial hyperpolarising factor (EDHF),and vasoconstrictor substances, such as thromboxane A2free radicals and endothelin. In several clinical studies have shown the importance of nitric oxide in basal and induced control of vascular tone in large epicardial coronary arteries and coronary microcirculation (see review work Vapaatalo H, Mervaala E. Clinically important factors influencing endothelial function. Med Sci Monit 2001; 7(5): 1075-1085. Drexler H, Hornig B. Endothelial dysfunction: a novel therapeutic target. J Mol Cell Cardiol 1999; 31: 51-60). The above relaxation factors of endothelial origin corrects endothelial dysfunction, for example, in atherosclerosis. The endothelium is associated with the regulation of vascular tone by modulation of blood coagulation, promote and prevent the growth of blood vessels, modulation of inflammation and act as object effects and unwanted effects of drugs. The release of EDRF is stimulated by an increase in vascular flow, for example, bradykinin, thrombin, acetylcholine and serotonin.

The endothelium controls the tone of the underlying smooth muscle in response to certain pharmacological and physiological stimuli. Functionally, the endothelium is involved in vascular growth, adhesion of lymphocytes and immune regulation, the metabolism of circulating amines, the metabolism of lipoproteins and integration and transfer of hematopoietic signals.

E. docilely dysfunction is characterized by decreased secretion of vasodilatory mediators, increased production of vasoconstrictor substances, increased sensitivity to vasoconstrictor substances and/or stability of smooth muscles of blood vessels by endothelial vasodilator substances.

Dysfunction is a consequence of imbalance between relaxing and reducing factors or agents that stimulate and any abscopal growth. Inflammation, oxidation of lipoproteins or other reactions of oxidative stress are factors that affect the development and maintenance of endothelial dysfunction. Theoretically, the most clear and direct indicators of endothelial dysfunction are nitric oxide and its metabolites, as well as cyclic GMP.

Endothelial dysfunction can be both a cause and a consequence of several clinical conditions such as hypertension, atherosclerosis, coronary heart disease, heart failure, diabetes, and high cholesterol in the blood. The most direct evidence of endothelial dysfunction are violations of the balance between reduced production or functioning of the receptors to vasodilator factors, such as nitric oxide, prostacyclin, endothelial hyperpolarising factor (EDHF), and natriuretic peptides; or higher education or sensitivity to vasoconstrictor agents such as endothelin-1, angiotensin II, endoperoxide and thromboxane A2.

Treatment of endothelial dysfunction can be accomplished in several known drugs, the most important of which are inhibitors of angiotensin-converting enzyme (ACE)inhibitor angiotensin II receptor, drugs nitrates and drugs lowering cholesterol. The effect of ACE inhibitors is based mainly on their ability to improve the action of bradykinin, which increases the synthesis of nitric oxide in the endothelium. Induced and/or enhanced production of nitric oxide or adding nitrates can balance insufficient domestic production of nitric oxide. Drugs and nitrates act as exogenous EDRF and expand blood vessels, in addition, they are active as anti-thrombotic compound into the damaged veins.

In WO 02/34767 A1, Selwood, etc. described peptides which are fragments of factor a vascular endothelial growth (VEGF) and is suitable for suppression of angiogenesis. In accordance with the invention, the peptides contain from three to eight amino acids, and a key feature of the amino acid sequence is the presence and location of basic residues, particularly residues arginine (Arg) or lysine (Lys). The document includes a description of several peptides containing from six to sixteen amino acids. None of sod is RIT sequence Isoleucine-Proline-Proline (IPP) or Valine-Proline-Proline (VPP). According to the publication, the peptides may be useful in diseases where angiogenesis plays in the pathology of a significant role. Such diseases may include diabetic retinopathy, age-related degeneration yellow spots (ARDS), cancer, endometriosis, psoriasis and rheumatoid arthritis.

In WO 99/45941, Sandberg and others, described composition is used to improve the plasticity, elasticity, or the appearance of the fabric. The composition is made up of peptides that belong to any of the 41 petidomo fragment, obtained by thermolytic cleavage of elastin. Preferably, the composition comprises a polypeptide having the formula R1-felling-felling-prolyl-glutamine-R2, where R1 is the amino-terminal part of the peptide, and R2 is a carboxy-terminal part of the peptide. The composition is preferably applied to the skin in cosmetic compositions. In accordance with the document, the composition may also be useful in the treatment of hypertension, ischemic heart disease, arteriosclerosis, angina pectoris, thrombosis, coronary artery disease, chronic obstructive pulmonary disease and restenosis after angioplasticheskih operations.

WO 01/91700 A2 and U.S. patent 6962904 B1, Mitts and other, partially based on the same research that WO 99/45941, Sandberg and other Documents describe the composition to increase the elasticity of the tissue, and these compositions are made from pepti is s, corresponding to sequences found in elastin, in particular, sequences-Valine-Valine-Proline - Valine-Valine-Proline-Asparagine-. These compositions are useful for improving the production of elastin in the tissues. According to the literature, the main practical application is the use in cosmetic products, but also indicates that the composition can be useful in the treatment of, for example, hypertension, coronary heart disease, arteriosclerosis, angina, thrombosis, coronary artery disease, chronic obstructive lung disease and restenosis after angioplasticheskih operations.

Described peptide fragments of elastin contain large amounts of residues are glycine and/or Proline compared to other amino acid sequences. The fragments do not include sequence Isoleucine-Proline-Proline (IPP) and/or Valine-Proline-Proline (VPP).

Production of biologically active peptides fermentation is well studied and described in the prior art, with a special interest peptides isolated from milk. It was shown that they possess, for example, the ability to bind opioid receptor, the activity of ACE inhibitor and antimicrobial properties. Conducted some research in connection with, for example, hypertension, but the effects on the R peptides on endothelial function have not been described. In particular, the effects of tripeptides Valine-Proline-Proline (VPP) and Isoleucine-Proline-Proline (IPP) and products containing them, on endothelial function have not been described in the prior art.

The tripeptides VPP and IPP are known compounds which have been described as inhibitors of ACE with antihypertensive (blood pressure-lowering). For example, in the work of J Dairy Sci 78 (1995) 777-783, Nakamura and others describe the application of starter culture containingLactobacillus helveticusandSaccharomyces cerevisiaeto obtain the two ACE inhibitors. Both compounds were identified as tripeptides, Val-Pro-Pro and Ile-Pro-Pro. Although this publication does not describe antihypertensive effect of tripeptidesin vivoprovided that this is the next objective of the research.

In U.S. patent 5449661, Nakamura and others, disclosed the receipt of a peptide containing the sequence Tripeptide Val-Pro-Pro and its application to reduce high blood pressure. The peptide obtained by the fermentation of skim milk powder by using strain JCM-1004Lactobacillus helveticusafter which the peptide is purified chromatographically and liabilitiesa.

In WO 99/16862, Yamamoto and others, describe the strain CM4, FERM BP-6060Lactobacillus helveticusthat is capable of producing tripeptides Val-Pro-Pro and/or Ile-Pro-Pro in large quantities.

In WO 01/32905, Valio, describes the product with antihypertensive properties, and receive the Product produced by fermentation casinadirosa feedstock using lactic acid bacteria, and holding nanofiltration received fermentation product containing peptide. Antihypertensive properties of the product are manifested, in particular, due to the content of tripeptides IPP and VPP. In WO 03/070267, Valio, described the use of IPP and VPP, as well as product described in WO 01/32905, in obtaining the product, increase the availability of minerals. This product can be used, for example, to enhance osteogenesis (bone formation), strengthening of the skeletal system and the treatment or prevention of osteoporosis.

Blood vessels are involved in the diseases associated with elastic properties, including hypertension, arteriosclerosis, angina, angiogenesis, myocardial infarction, thrombosis, coronary artery disease, restenosis after angioplasticheskih operations and chronic obstructive pulmonary disease. Cardiovascular diseases are among the most widespread diseases in the world, and they are in the list of the five most life-threatening diseases in many countries. Unfortunately, with rising standards of living also increases the risk of these diseases, and therefore, they will have even greater value in the future. Currently, in addition to conventional medicines, the consumer is offered an attractive alternative in the form of functional foods.

Functional foods, Ulu is superior to the elasticity of blood vessels and improves and normalizes endothelial function, will, therefore, be welcomed as part of the regular diet. Also worthy of consideration introduction as a medical or pharmaceutical product peptides with useful properties in terms of stiffness of the arteries.

BRIEF description of the INVENTION

Thus, the aim of the present invention is the provision of a product that, as part of a regular diet or drugs and pharmaceutical product, improves or normalizes endothelial function and, therefore, can prevent, alleviate or cure disorders and diseases associated with endothelial dysfunction. Endothelial dysfunction plays a significant role in determining the stiffness or elasticity of the blood vessels that, in turn, is very important for many severe diseases, e.g. coronary heart disease, arteriosclerosis, angina pectoris, thrombosis, coronary artery disease, chronic obstructive pulmonary disease and restenosis after angioplasticheskih operations. Therefore, the ability to increase the elasticity of blood vessels is a particularly important feature of the present invention.

The product that will be used according to the invention, consists of or contains peptides that improve endothelial function.

The next objective of this izopet the tion is the provision of a product as such, as agent, improves endothelial function, or for use for the manufacture of a functional food or medicine, intended for consumption.

Another objective of the present invention is the provision of a method of prevention, mitigation or treatment of endothelial dysfunction, and disorders and diseases associated with her, by assigning the individual in need of such treatment, peptides, improves endothelial function, or product thereof sufficient to achieve the desired effect of the number.

Another objective of the present invention is the provision of a method of prevention, mitigation or treatment of endothelial dysfunction, as well as disorders and diseases associated with her, by introducing individual product with a high content of low molecular weight peptides derived from casein and obtained by fermentation casinadirosa feedstock using strain CMF-16H, DSM 13137Lactobacillus helveticusor strain LB 1936, DSM 17754Lactobacillus helveticusand, optionally, partial or full removal of the casein and other milk proteins and/or lactose, sufficient to achieve the desired amount. In a preferred embodiment, the fermentation product is also subject to nanofil the walkie-talkie.

DETAILED description of the INVENTION

In accordance with the present invention, surprisingly, it was found that the above objectives are achieved with the use of low molecular weight peptides, in particular, tripeptides Ile-Pro-Pro (IPP), Val-Pro-Pro (VPP). Now it is proved that these peptides are able to normalize endothelial function, improving the elasticity of blood vessels and to counteract the stiffness of the arteries.

The peptides used in accordance with the present invention are biologically active peptides, corresponding to those obtained by the hydrolysis of casein or casinadirosa raw materials such as milk. As considered suitable short-chain peptides di-, tri - and tetrapeptide and mixtures thereof. In particular, the peptides are the tripeptides IPP and VPP, a mixture of peptides, including IPP and VPP, and the products and compositions containing them.

The preferred implementation provides a great opportunity for the normalization of endothelial dysfunction and is associated with endothelial disorders.

Thus, the invention relates to the use of low molecular weight isolated from casein peptides for the manufacture of the product, improves endothelial function.

Further, the invention relates to the use of a product containing a low molecular weight, selected from CA who Eina peptides, for the manufacture of the product, improves endothelial function.

Preferably, low molecular weight isolated from casein peptides include di-, tri - and tetrapeptide and mixtures thereof. Most preferably the high content of IPP and VPP.

Further, the invention relates to the use of a product with a high content of low molecular weight, derived from casein peptides, which were obtained by the fermentation casinadirosa feedstock using lactic acid bacteria, and possibly nanofiltration received peptidases fermentation in the manufacture of the final product, improving endothelial function.

As a preferred variant implementation of the invention relates to the use of a composition of the leaven, which contains peptides isolated from casein, minerals and live lactic acid bacteria for the manufacture of the product, improves endothelial function.

The invention also relates to a method of normalization of endothelial function and endothelium-dependent violations by assigning the individual peptides, which normalizes endothelial function and endothelium-dependent disorders, or product thereof in a quantity sufficient to achieve the desired effect.

First of all, the individual is people. Positive effects of products is impressive according to the invention, of course, also useful for animals, especially Pets and farm animals. Examples thereof include dogs, cats, rabbits, horses, cows, pigs, goats, sheep and birds.

The tripeptides VPP and IPP can be obtained synthetically or by hydrolysis of the raw material containing the specified sequence. In a preferred embodiment, the peptides derived from casein or casehistories of raw materials by fermentation. Particularly preferred is the use of the method described in WO 01/32905 where a product containing biologically active peptides obtained by fermentation with subsequent concentration and nanofiltration. This is the preferred method of implementation provides wonderful opportunities for the use of raw materials of various types and modifications of the composition of the final product according to the requirements, as described in detail in WO 01/32905 hereby entered in this text by reference.

When biologically active peptides for use in accordance with the present invention are obtained by fermentation feedstock can be any product that contains sequences required for biologically active peptides as part of its own peptide or protein sequence. Milk proteins, especially casein, prefer the Yong for use as such or in the form of various drugs. Suitable feedstocks include various dairy products contain casein, such as skim milk or milk with various fat contents as such or in the form of a corresponding dry milk and milk products such as sour milk, buttermilk, yogurt, sour, unripe cheese, etc.

Fermentation can be carried out using any of lactic acid bacteria, which are able to produce the desired peptides from the feedstock. Suitable lactic acid bacteria can be detected among the species belonging to the genera, for example,Lactobacillus, Lactococcus, Leuconostoc, StreptococcusandBifidobacterium. The most pronounced among lactic acid bacteria proteolytic properties ofLactobacillus helveticus, and is therefore considered as the most suitable for this purpose. The preferred strain ofLactobacillus helveticusisL.helveticusCMF-16H, DSM 13137, which is described in patent publication WO 01/32836. Especially preferred is aLactobacillus helveticusLB 1936, DSM 17754, which is described in detail in patent publication FI20065054.

Lactic acid bacteria can be used as pure cultures or mixed cultures, separately or in conjunction with commonly used and commercially available starter cultures. Lactic acid bacteria can also be used in conjunction with other the microorganisms.

The fermentation conditions are selected so as to satisfy the requirements of the applied strain for the formation of a sufficient number of biologically active peptides to obtain the desired effect. The selection of the suitable conditions, such as temperature, pH and aeration, is part of the practical knowledge of a specialist in this field. Typically, fermentation is conducted at a temperature of from about 30 to 45°C. the Fermentation is carried out until, until it forms the desired amount of biologically active peptides. Usually the process takes about 20 to 30 hours. During fermentation is formed a mixture of different peptides. In the case of a sufficiently long fermentation mainly obtained relatively short di - and tripeptides, such as Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP). Preferably, the incubation time of from about 22 to 24 hours.

The obtained cell suspensions can be used as such, or the peptides can be separated and purified using standard techniques. The preferred treatment is the concentration, for example, evaporation or partial or complete drying of cell suspension by distributing the slurry over the surface of the plate, drying, and finally grinding the well-conserved dry powder.

Additional processing cell suspension is ay nanofiltration is an excellent way facilitate the production of peptides (active against endothelial functions, such as the stiffness of the arteries), together with the necessary minerals in the same product. By selecting the type of membrane for nanofiltration and the process conditions it is possible to influence the composition of the obtained product.

Nanofiltration spend up to achieve the required spacing of the dry matter content, which may range from about 20 to 40%, or up to the approximate ratio of the volume concentrations from 5 to 20. By nanofiltration content of peptides in the product increases. The composition of the final products naturally depends on the fermentation conditions, an optional treatment by nanofiltration and other possible preliminary and additional processing.

Unexpectedly, it has been shown that in accordance with the present invention, the tripeptides IPP and VPP and products containing them, reduce arterial stiffness and, thus, useful in arterial dysfunction. During the period of exposure in ten weeks outpatient stiffness index arteries (AASI), a measure of arterial stiffness, has improved significantly in the group treated with a product containing the tripeptides IPP and VPP, compared with the control group; even in the first unoptimized test index fell by about n is 9% compared with the control group. Average AASI at the end of the period of treatment was 0,31±0,15 inLactobacillus helveticusand 0.34±0,17 in the control group.

The products described above may be used as such to achieve the desired effect. Products can also be dried and used in powder form or liofilizirovannogo of the drug. The products are preferably also used to produce functional food or other products. Use as a medicinal or pharmaceutical products is also possible.

The concept of "food" has a wide meaning in the present invention include all consumable products, which can be in solid, gel or liquid form, and covering both the finished products and products, as an additive or part of the product during consumption of added biologically active peptides or products that contain them. Food can, for example, be a product of the dairy industry or the beverage industry. Typical products include dairy products such as yogurt, buttermilk, cottage cheese, sour milk, sour milk, buttermilk, and other dairy products, immature and Mature cheeses cheeses, toppings for snacks, etc. Another important group includes drinks such as beverage from whey, fruit drinks and aerovane drinks.

In accordance with the invention, biologically active peptides or products containing it, applied in sufficient to achieve the desired amount. In the case of the product obtained by the two-stage method described above, the amount to use depends largely on the degree of concentration of the serum and is, for example, from 0.1 to 30%, preferably approximately from 5 to 15%, when calculating the relative weight of the final product.

Biologically active peptides or products containing them, can be added into the food during its manufacture or to the finished food product. Consider food products, thus, include the desired peptides or product containing, in addition to other components contained in the relevant food products, and is fully consistent with the taste and characteristics of these conventional products.

The invention will be described in detail by the subsequent examples. These examples are only to illustrate the invention and should not be construed as limiting in any way the scope of protection. Presented examples demonstrate favorable, beneficial and therapeutic effect of IPP and VPP as such or in combination, on arterial stiffness by enhancing endothelial function, as well as site is citicoline end products for reception of biologically active peptides.

EXAMPLE 1

Influence of biologically active product on blood

stiffness

Arterial stiffness can be measured using ultrasonic equipment or applanation tonometry, or with the use of ambulatory index rigidity of the arteries (AASI). AASI was defined as 1 minus the cosine of an angle of inclination to the axis x of diastolic or systolic pressure during 24-hour ambulatory monitoring, and is a reliable indicator of arterial stiffness (Li Y, Wang JG, Dolan E, Gao PJ, Guo HF, T. Nawrot Ambulatory arterial stiffness index derived from 24-hour ambulatory blood pressure monitoring. Hypertension 2006; 47(3):359-64).

In a randomized study where the control group was also a placebo, 94 patients with hypertension not receiving any drugs, took either milk fermented with strains ofLactobacillus helveticusCMF-16H in accordance with Example 2, or a control product within ten weeks after a four-week preparatory period. Twenty-four-hour ambulatory blood pressure measurement was performed at the beginning and at the end of the experimental period. Mean values of baseline systolic and diastolic blood pressure was to 132.6±9,9/83,0±8.0 mm Hg in the treated group,Lactobacillus helveticusand 130,3±9,6/an 80.2±7.0 mm Hg in the control group is.

At the end of the ten-week experimental period, systolic and diastolic blood pressure to a greater extent decreased in the treated group, the productLactobacillus helveticuscompared with the control group. The treatment effect on SBP (systolic blood pressure) was -4,1 (95% Cl: -6,6 to-1.8, p<0,001). The treatment effect on DBP (diastolic blood pressure) amounted to - $ 1.8 (95% Cl: was 3.7 to -0,0, p=0,048).

Index AASI was defined using the values of ambulatory blood pressure and their analysis by the method proposed by Li et al., ibid. Index AASI grows linearly with age in both men and women. Low index values AASI more favorable than high values, and therefore, if the value decreases, it improves arterial stiffness index. The average values of the baseline AASI was 0.36±0.15 inLactobacillus helveticusand 0.36±0,17 in the control group. At the end of the experimental period the mean values AASI was 0,31±0,14 inLactobacillus helveticusand 0.34±0.15 in the control group.

Within ten weeks of the experimental period, the index AASI has improved statistically significantly in the tested groups (p=0,043), but not statistically significant in the control group (p=0,47) (table 1).

Table 1
Index change AASI after a 10-week experimental period
The importance of
(2-sided)
The difference in the mean
The test groupIndex change AASI0,043-0,0427
The control groupIndex change AASI0,474-0,0195

EXAMPLE 2

Getting products that are suitable in the present invention

The strain ofLactobacillus helveticusCMF 16-H, DSM 13137, were grown in medium MRS at 37°C for 24 hours and sown in reconstituted milk (10%) for the formation of the leaven. Two growth cycle of yeast (15%) were made in the environment of the fermenter made of 9-10% skimmed milk powder and sterilized at 110°C for 10 minutes. Fermentation was carried out at 37°C for 22 to 24 hours with continuous vigorous stirring. Product (a) can be used as such, in dry and/or ground form, or the desired peptides can be separated from the product using known methods.

The procedure was repeated with the use ofLactobacillus helveticusLB 1936, DSM 17754, and whole milk or buttermilk, with the responsibility instead of skimmed milk powder, in order to produce relevant products b and c.

EXAMPLE 3

The final product is suitable in the present invention

Peptide concentrate

Sour milk containing peptides, active in the correction of endothelial dysfunction, was obtained by adding about 1% of the peptide to concentrate commercially available sour milk. The composition of the product are shown in Table 2, which for comparison also shows the composition of commercially available sour milk sour milk AB produced by Valio Ltd.

To obtain the peptide concentrate Evolus® fermentation was performed as described in Example 2. The cell suspension was separated using a centrifuge to clarify. Thus, pre-treated serum was subjected to nanofiltration through the membrane Nanomax-50 at 40°C and a pressure of 30 bar. Serum was filtered as long as the ratio of volume concentration was not reached 9.

Table 2
The composition of the product Evolus and commercial lactic acid
product (sour milk AB, Valio Ltd)
Information about the nutritional value
product/100 g (p is the resource center 200 g)
EvolusSour milk AB
Calories260 kJ/
61 kcal
220 kJ/
53 kcal
Proteins3.0 g3.2 g
Carbohydrates12 g4.4 g
Of which lactose1.0 g*
Fiber0 g0 g
Fats0.1 g2.5 g
Calcium150 mg**120 mg
Potassium233 mg170 mg
Magnesium13 mg11 mg
Sodium24 mg39 mg
The tripeptidesIle-pro-pro1.1 mg0
Val-pro-pro1.3 mg0
* Over 80% of the lactose enzyme destroyed
** 25% of the recommended daily intake

EXAMPLE 4

The final product is suitable in the present invention

The fermented beverage Evolus Tehojuoma

To get a daily dose of fermented milk drink Evolus® Tehojuoma fermentation was performed as described in Example 2. Next to the dairy product was added 1% peptide concentrate Evolus®, prepared as described in Example 3. The product containing the required daily dose of the active ingredient as such, is intended for use.

Information about the nutritional value of the product are shown in Table 3. Other ingredients that contain milk drink is pasteurized skim milk, milk protein concentrate, thickeners, calcium seaweed, acidity regulator, starter, flavouring, vitamins (folic acid, B6, B12) and dye.

Table 3
the song lactic acid drink Evolus® Tehojuoma
Information about the nutritional value of the product/100 g (per 100 ml)Evolus
Calories260 kJ/
61 kcal
Proteins3.5 g
Carbohydrates11 g
Of which lactose1.0 g*
Fiber0 g
Fats0.1 g
Calcium200 mg**
Potassium410 mg
Magnesium15,5 mg
Sodium38 mg
Folic acid66 mcg***
Vitamin B60,66 mg***
Vitamin B120,33 mg***
* Over 80% of the lactose enzyme destroyed
** 25% of the recommended daily intake
*** 33% of the recommended daily intake

EXAMPLE 5

The final product is suitable in the present invention

Soft cheese

Soft cheese, such as fresh cheese, processed cheese and cheese (fresh cheese) was obtained according to the conventional production technologies. For example, processed cheese Evolus® was obtained by mixing cottage cheese, cream or butter, and other ingredients were subjected to heat treatment and Packed. Peptide concentrate Evolus®, prepared as described in Example 3, was added to the enriched cream cheese mixture. The product containing the required daily dose of the active ingredient as such is intended for use.

1. The use of Ile-Pro-Pro and/or Val-Pro-Pro to obtain the product reduces arterial stiffness.

2. The use of Ile-Pro-Pro and/or Val-Pro-Pro to obtain a product which improves the elasticity of blood vessels.

3. The use according to claim 1 or 2, characterized in that Ile-Pro-Pro and/or Val-Pro-Pro presents in the form of the food product.

4. The use according to claim 3, characterized in that the food product has a high content selected from low molecular weight casein peptides, and which is obtained by fermentation casinadirosa feedstock with lactic acid bacteria.

5. The use according to claim 4, characterized in that the food product has a high content selected from low molecular weight casein peptide is in, and which is obtained by fermentation casinadirosa feedstock with Lactobacillus helveticus CMF-16H, DSM 13137, or with Lactobacillus helveticus LB 1936, DSM 17754, optionally with partial or complete removal of the casein and other milk proteins and/or lactose and nanofiltration obtained containing fermented protein product.

6. The use according to claim 4, characterized in that the product comprises a composition of the starter culture containing isolated from casein low molecular weight peptides Ile-Pro-Pro and/or Val-Pro-Pro, and live lactic acid bacteria.

7. The use according to claim 3, characterized in that the food product is a product of the dairy industry, beverage industry, industry processed food, industry ready meats, bakery industry or the confectionery industry.

8. The use according to claim 7, characterized in that the product is a fermented milk product.

9. The use according to claim 7, characterized in that the product is a beverage, preferably a beverage from whey, fruit drink or beer.

10. The use according to claim 1 or 2, characterized in that the product is a pharmaceutical product.

11. The way to reduce arterial stiffness, including the introduction of individual product containing Ile-Pro-Pro and/or Val-Pro-Pro defined in claim 1.

12. Method for improving Elasti the particular blood vessels, includes introduction to the individual product containing Ile-Pro-Pro and/or Val-Pro-Pro defined in claim 2.



 

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31 cl, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to a new chemical compound, a 3-(2,2,2-trimethylhydrazinium)propionate-5-nicotinate hydroxide 3-(2,2,2-trimethylhydrazinium)potassium propionate derivative, (CH3)3N+HCH2CH2COOKRCOO- wherein exhibiting antiischemic activity.

EFFECT: what is produced and described is the new compound which may be effective as an agent showing antiischemic activity.

1 cl, 1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to medicine, specifically a novel chemical compound - a 3-(2,2,2-trimethylhydrazinium) propionate derivative - potassium glycinate 3-(2,2,2-trimethylhydrazinium) propionate (CH3)3N+NHCH2CH2COOKRCOO-, where , having antiischemic activity.

EFFECT: obtaining a compound with antiischemic activity.

1 cl, 1 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics. A pharmaceutical granule is spherical or spheroidal and has volume density 0.6-1.3 g/ml and disintegration 0.5-5 minutes. Active pharmaceutical ingredients are preparations of Traditional Chinese Medicine, herbal preparations or their extracts with a nucleus made of an extract of Traditional Chinese Medicine or herbal preparations, and a pharmaceutically acceptable carrier. The content of the pharmaceutically acceptable carrier with respect to total granule weight makes 10-60 wt %. The granule diameter can be equal to 700-1500 mcm. The granule nucleus diameter can be equal to 200-750 mcm. The granule can be also coated with a layer of 2-5 wt % with respect of total granule weight. A method for making the granules consists in introducing initial granules into a layer of a fluidised material as an excipient; the active pharmaceutical ingredients are prepared in the form of a suspension or a solution of the viscosity controlled within 6.0-9.8 MPa·s with using a viscosity-control agent; then they are sprayed over a surface of the initial granule for making a finished granule.

EFFECT: granules possess fast disintegration, contain a small amount of the carrier and contain a low single dose.

12 cl, 5 ex

FIELD: medicine.

SUBSTANCE: method implies introducing into a laboratory animal a phytococktail which contains mixed 70% alcoholate of snowdone rose, common licorice, eleuterococcus, horseheal taken in proportions 2:2:1:1, and dissolved in distilled water in proportions 1:50. The phytococktail is introduced in rats through probes in amount 1 ml per 150-200 g of animal's weight from 16.00 to 18.00 o'clock for 15 days.

EFFECT: higher vascular thromboresistance ensured by higher endothelial aggregation ability mediated by activation of antioxidant and anti-inflammatory effects of the vascular epithelium.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula 1, or their pharmaceutically acceptable salts showing the properties of incretin secretagogues, preferentially the properties of a bile acid receptor TGR5 agonist. The compounds are applicable for treating metabolic diseases associated with glucose metabolism, such as diabetes, obesity, metabolic syndrome, etc. In formula 1 R1, R2 and R3 independently represent a cyclic system substitute specified in: hydrogen, C1-C3alkyl, halogen, a trifluoromethyl group, C1-C3alkoxy, a cyano group, a trifluoromethoxy group; an amino group substituted by C1-C3alkyl; or two radicals R3, found at carbon neighbours in a benzene ring, together with the benzene ring bound therewith form 3,4-methylene dioxyphenyl; R4 represents hydrogen, C1-C5alkyl, a carboxyl group, C1-C3alkoxycarbonyl or an amide group CONHR5; R5 is an optionally substituted by C1-C3alkyl, C5-C6cycloalkyl optionally substituted by phenyl, benzyl, pyridyl; X and Y represent two hydrogen atoms or an oxygen atom, provided Y=O, then X=2H, provided Y=2H, then X=O or X=Y=2H; the sign (N) shows the possibility of bioisosteric substitution of the benzene ring by the pyridine, pyrimidine, pyridazine, triazine or pyrazine ones.

EFFECT: preparing the pharmaceutical composition and the combined drugs with the use of the compounds of formula 1 or the based pharmaceutical composition and a protein kinase DPP-IV inhibitor specified in Vildagliptin or Sitagliptin, and/or an endogenous bile acid or mied bile acid secretagogues.

53 cl, 7 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I, as well as to their physiologically acceptable salts wherein: X means NH; R1 means (C1-C6)-alkyl; R2 means OH; R2' means H; R5' means (C1-C6)-alkylene-O-S(O)2-R6; R3, R3', R4, R4' and R5 independently mean H, OH, (C1-C6)-alkylene-O-S(O)p-R6, O-(CH2)m-phenyl; at least one of the radicals R3, R3', R4, R4' and R5 has the value -O-(CH2)m-phenyl; R6 means OH; m=1; p=2.

EFFECT: compounds can find application in medicine, eg as lipid-lowering agents.

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present patent claim discloses sulphonyl-substituted compounds of formula QUIN which are used for the purpose of a method for producing a macrocyclic compound of formula (I)

EFFECT: compounds of formula (I) are effective active agents for treating Hepatitis C viral (HCV) infection.

8 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition showing stress-protective action which contains peptide R1-Lys1-Arg2-Pro3-R2 [SEQ ID NO:1] or R1-Lys1-Arg2-Arg3-Pro4-R2 [SEQ ID NO:2] wherein R1=NH2 or CH3CO and R2=OH or NH2 and a method for prevention and/or treatment functional or stress-induced disorders caused by extreme factors.

EFFECT: producing the pharmaceutical composition exhibiting stress-protective action.

3 cl, 9 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to peptide-based compounds containing three-member rings containing a heteroatom, which efficiently and selectively inhibit specific activity of N-terminal nucleophilic (Ntn) hydrolase, bonded with a proteasome. The peptide-based compounds contain epoxide and are functionalised at the N-end.

EFFECT: peptide-based compounds exhibit anti-inflammatory properties and cell proliferation inhibition, oral administration of said peptide-based proteasome inhibitors is possible owing to bioavailability thereof.

23 cl, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely dermatology and may be used for stimulating skin wound healing. That is ensured by parenteral introduction of a combination of Gly-His-Lys peptides and thymogen in equimolar single doses 0.5 mcg/kg of body weight once a day for ten days.

EFFECT: method provides reduced length of healing ensured by improved wound healing ability of skin and functional activity of neutrophils.

1 tbl, 2 ex

Iap inhibitors // 2451025

FIELD: chemistry.

SUBSTANCE: invention relates to novel IAP inhibitors of general formula , where Q, X1, X2, Y, Z1, Z2, Z3, Z4, R1, R2, R3, R3', R4, R4', R5, R6, and R6', and n assume values given in the description.

EFFECT: compounds can be used as therapeutic agents for treating malignant growths.

15 cl, 33 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound having the structure of formula (I), or its pharmaceutically acceptable salt, wherein specified radicals are presented in the description, and also concerns a compound representing or its pharmaceutically acceptable salt. The present invention declares a pharmaceutical composition possessing inhibitory activity in the relation to 20S proteasome containing a pharmaceutically acceptable carrier or a diluent and a therapeutically effective amount of the compound, and also the invention refers to methods of treating the immune diseases, such as inflammatory intestinal disease, to treating cancer, to treating infection, to treating proliferative diseases, to treating neurodegenerative disease or asthma.

EFFECT: higher clinical effectiveness.

34 cl, 21 ex, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a drug for gastroduodenal diseases caused by Helicobacter pylori, and to a method of treating these diseases by inhibiting apoptosis in gastric epitheliocytes, administering the drug containing an amount of a peptide of formula H-Glu-Asp-Gly-OH effective with respect to Helicobacter pylori. The invention also concerns a pharmaceutical composition and applying it.

EFFECT: group of inventions provides producing a new group of the preparations containing biologically active compounds on the basis of peptides, exhibiting specific activity with respect to Helicobacter pylori.

9 cl, 4 ex, 1 tbl, 17 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: in claim described are organic compounds of formula I where radicals are given in description, which are applicable for elimination, prevention or alleviation of one or more symptoms, associated with HCV disorders.

EFFECT: obtaining pharmaceutical composition which possesses inhibiting activity with respect to NS3-4 HCV serinprotease, including formula I compound and pharmaceutically acceptable carrier.

30 cl, 25 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to auristatin peptides, including MeVal-Val-Dil-Dap-norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), and these peptides were attached to ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting "ligand-drug" conjugates are active in vitro and in vivo.

EFFECT: high activity of the compounds.

118 cl, 19 dwg, 12 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds act specifically through antagonistic inhibition of the LHRH receptor. The invention also relates to medicinal agents containing at least one novel compound as an active component. The medicinal agents are suitable particularly for use as measured peroral drug formulations for mammals, particularly humans.

EFFECT: novel tetrahydrocarbazole derivatives have improved properties and can be used as GPCR receptor inhibitors.

23 cl, 11 dwg, 9 tbl, 15 ex

FIELD: food industry.

SUBSTANCE: invention relates to a carbohydrate gel for sport alimentation; the gel contains at least water in an amount of 20-60 g/100 g of the gel, glucose and fructose at a ratio of values within the range of 3:1 - 1:1. The gel represents a semi-solid material with a consistence relatively soft and viscous during chewing. The gel is applied in an amount corresponding to consumption of at least 30 g of CHO (carbohydrates) per hour, preferably - at least 50 g of CHO per hour, more preferably -at least 65 g of CHO per hour and most preferably - between 80 g of CHO per hour and 110 g of CHO per hour.

EFFECT: carbohydrate gel may be applied for minimisation of digestive tract related problems in the process of training, for maintaining a higher level of sugar in blood and intensified oxidation of exogenic carbohydrates as well as for preparation of a food product intended to ensure enhanced effectiveness in the process of training and to simultaneously ensure improved digestive acceptability and/or for therapy or prevention of digestive tract related problems.

17 cl, 5 dwg, 2 tbl, 5 ex

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