Method for improving signal transfer in islets of langerhans in diabetes mellitus and in its prophylaxis

FIELD: medicine, endocrinology.

SUBSTANCE: invention relates to treatment of diabetes mellitus in mammals. Invention proposes applying inhibitors of enzyme dipeptidyl peptidase IV as an active component in manufacturing a medicinal agent, and in a method for treatment of diabetes mellitus. Invention provides enhancing the functional activity of insulin-producing cells in animal and differentiation of epithelial cells of the pancreas.

EFFECT: improved method for insulin producing and diabetes treatment.

20 cl, 5 dwg, 2 tbl, 2 ex

 

Prerequisites

Part of the pancreas consists of two glandular tissue, one is a collection of cells that perform the exocrine function of the pancreas, by means of which these exocrine cells synthesize and release digestive enzymes into the intestine; other fabric performs endocrine function of the pancreas, synthesizing and releasing hormones into the bloodstream. The most important value in the endocrine functions of the pancreas are β-cells. These cells synthesize and secrete the hormone insulin. The hormone insulin plays a vital role in maintaining normal physiological levels of glucose in the blood. There are molecules, which are the effectors of the endocrine cells of the pancreas. Incretin is an example of such molecules. Incretin stimulate induced glucose insulin secretion of the pancreas.

It was shown that incretin, such as amide and the like peptide-1 (7-36) ("GLP-1"; or lizard similar Asendin-4) and gastric inhibitory polypeptide ("GIP"), are insulinotropic, i.e. their presence or stability can provide rapid suppression of blood glucose effects, stimulating insulin secretion. (Demuth, H.U., et al., DE 196 16 486:1-6, 1996; Pauly, R.P. et al., Regul. Pept. 64(1-3): 148, 1996, the contents of which are shown here in Kacha is TBE reference in full). In addition, it was shown that GLP-1 acts as a growth hormone Islands, stimulating proliferation β-cells, thus increasing cell mass and translating undifferentiated cells of the pancreas in specialized cells of the islets of Langerhans. These cells exhibit enhanced insulin secretion and glucagon (Yaekura, K. et al., IN: VIP, RACER, and Related Peptides, W. G. Forssmann, and S. I. Said (eds.). New York: New York Academy of Sciences, 1998, p. 445-450; Buteau, J. et al., Diabetologia 42 (7): 856-864, 1999, the contents of which are hereby incorporated by reference in full).

Previously it was proposed to use exogenous bioactive GLP-1 or its analogs or to stimulate the regeneration of cells of the islets in vivo, or for producing cells of the pancreas in patients with diabetes mellitus and treatment of such cells ex vivo in tissue culture using bioactive GLP-1. It was believed that this treatment ex vivo promotes regeneration and/or differentiation of cells of the islets, which are then able to synthesize and secrete insulin or glucagon (Zhou, J. et al., Diabetes, 48 (12): 2358-2366, 1999; Xu, G. et al., Diabetes, 48 (12): 2270-2276, 1999, the contents of which are hereby incorporated by reference in full).

However, this treatment requires enteral or parenteral administration to patients bioactive GLP-1, including the possibility of surgical intervention. One aspect is the elimination of the neobhodimosti surgical treatment, enteral or parenteral application of bioactive GLP-1.

The invention

The present invention relates to a new method that allows to reduce the activity of the enzyme dipeptidyl peptidases (DP IV or CD 26) or activity of DP IV-like enzyme in the blood of mammals induced by effectors of this enzyme, resulting in reduced degradation of gastrointestinal polypeptide amide-1 like peptide-1 7-36 (GLP-17-36) (or group of structurally related functional analogues of this peptide, such as GLP-17-36, or truncated but biologically active fragments of GLP-17-36) under the action of DP IV and DP IV-like enzymes. This treatment will reduce or delay the decrease in the concentration of functionally active (including GLP-1 derivatives) circulating peptide hormone GLP-1 or its analogues.

The result is increased stability of the circulating endogenous peptides GLP-1 (including derivatives of GLP-1), caused by inhibition of the activity of DP IV activity of GLP-1 is extended, providing a functionally active hormones, representing circulating peptides GLP-1 (including derivatives of GLP-1), reinforcing somatostatinomas stimulation of pancreatic cells so that these cells have proliferated to the functionally active cells acute is vcov of Langerhans. In addition, insensitive cells of the pancreas or damaged pancreatic cells can be transformed into functionally active cells of the islets of Langerhans under the action of GLP-1.

It was expected that the transformation of the insensitive cells of the pancreas or destroyed pancreatic cells into functionally active cells of the islets of Langerhans resulting in increased insulin secretion and increase in the concentration of insulin in plasma. Oddly enough, according to research healthy people, volunteers and obese diabetic Zucker rats, insulin decreased after treatment with the inhibitor of DP IV isaaciantidentifying (R/98) (see examples 1 and 2, respectively). However, the resulting regeneration of the islets of Langerhans modifies the action of endogenous insulin and other hormones of the islets, such as glucagon, so that the treated mammal is stimulation of carbohydrate metabolism. As a result, the level of glucose in the blood falls below the glucose concentration, characteristic of hyperglycemia, as shown in examples 1 and 2. The mechanism that triggers such effects have not been studied in detail. However, the resulting regeneration of cells of the islets in the future is valid for metabolic disorders, including glycosuria, hyperlipidemia, as well as the severe metabolic acidosis and diabetes preventing or facilitating their complications.

In contrast to other proposed methods known in this field, as, for example, transplantation of cells or tissue of pancreas or treatment of pancreatic cells ex vivo GLP-1 or accendino-4 followed by re-implantation of the treated cells, the present invention does not call and does not require complicated and expensive surgery and provides available oral therapy. The present invention represents a new approach to reducing the high concentration of glucose in the blood. This method is commercially viable and is particularly suitable for use in the treatment of human diseases, many of which are caused by long-term increase of glucose levels in the blood.

Brief description of drawings

The present invention will be further considered with reference to the drawings, where

figure 1 graphically presents the time dependence of the circulation of bioactive GLP-1 in humans (n=36) from the oral administration of an inhibitor of DP IV in the form of a composition R/98;

figure 2 graphically presents the dependence of the AUC circulating bioactive GLP-1 in humans (n=36) from the oral administration of an inhibitor of DP IV in the form of a composition R/98;

figure 3 graphically presents the improvement of the morning of glucose in the blood (UGC) after pedestr the th monotherapeutic treatment composition R/98 in the amount of 8.7 mg/kg/day fat diabetic rats fa/fa;

on figa graphically presents the improvement in the regulation of glucose due to treatment with an inhibitor of DP IV after a 16-day treatment of obese diabetic rats;

on FIGU graphically presents the reduction of insulin secretion following treatment with an inhibitor of DP IV after 16, day treatment of obese diabetic rats;

on figa graphically presents the content of glucose in the blood as a function of time while maintaining or improving glycemic status after 21 days subacute treatment of obese diabetic rats fa/fa included in the composition of the inhibitor of DP IV R/98;

on FIGU graphically presents the content of insulin in the plasma as a function of time while maintaining superior glycemic status after 21 days subacute treatment of obese diabetic rats fa/fa included in the composition of the inhibitor of DP IV R/98.

Detailed description

The present invention relates to a new method of differentiation and/or restoration of the structure of the cells of the pancreas. As a consequence, regeneration of cells of the islets of Langerhans will have a favorable effect on the synthesis and release of endogenous insulin and other hormones of the islets, such as glucagon, thus stimulating carbohydrate metabolism.

Induced glucose secretion of insulin is regulated by many hormones, neurotransmit the development. Of particular interest are two intestinal hormone, like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), each of which is insulinotropic agent. Insulinotropic agents have the ability to stimulate or cause the stimulation of the synthesis or expression of the hormone insulin.

GLP-1 is a strong intestinal insulinotropic agent that increases insulin secretion and reduces glucose levels, including levels that occur in diabetes type I and II. GLP-1 alternative is the result of tissue-specific cleavage in the L-cells of the intestinal L-cells of the endocrine part of the pancreas and neurons in the brain. GIP is synthesized and released the duodenum and the proximal part of the jejunum after a meal. Release depends on several factors, including the nature of power and the previous state of health. It was originally discovered and named in connection with any abscopal effect against gastric secretion. However, as the promotion of the study of this hormone have explained it more relevant physiological functions. More specifically, GIP is insulinotropic agent with a stimulating effect on the synthesis and release of insulin.

DP IV is a farm is t, which ectopeptidases, which selectively cleaves peptides at the penultimate N-terminal residues of Proline and alanine. Endogenous substrates of this enzyme include incretin, such as glucosidase insulinotropic polypeptides, as GIP and GLP-1. In the presence of DP IV these hormones enzyme is restored to the inactive form. The inactive form of GIP and GLP cannot induce the secretion of insulin, so the glucose levels in the blood increase, especially in hyperglycemic condition. Elevated glucose levels are associated with various pathological conditions, including diabetes mellitus (Type 1 and 2) and complications associated with diabetes.

It was also discovered that DP IV plays a role in mediated T-cell immune response, for example, in transplantation. It was shown that inhibition of DP IV prolongs the life time of heart transplants. In addition, inhibition of DP IV contributed to the suppression of rheumatoid arthritis. DP IV was also assigned a role in the penetration of HIV in T cells (T-helper cells).

Were developed agents, such as N-(N'-substituted glycyl)-2-cyanopyrrolidines, L-threo-solicitation (R/98), L-ALLO-solicitation, L-threo-isolatin1encoding, and L-ALLO-isolatin1encoding, which inhibit the enzymatic activity of DP IV and described in the publications US 600115, WO 99/61431, WO 99/67278, WO 99/67279, DE 19834591, WO 97/40832, DE 19616486 C2, WO 98/19998, WO 00/07617, WO 99/38501 and WO 99/46272, the contents of which are hereby incorporated by reference in full. The purpose of these agents is the inhibition of DP IV and thereby reducing the levels of glucose in the blood, making the treatment of hyperglycemia and related diseases associated with elevated levels of glucose in the blood becomes effective. The authors of this invention have unexpectedly discovered that such agents can be advantageously used in different therapeutic purposes, already known to specialists in this field.

Diseases, which are characterized by the manifestation of hyperglycemia include diseases such as diabetes type I and II. Diabetes in General can be characterized as a failure of the release of the hormone β-cells of the pancreas. Normally, these cells synthesize and secrete the hormone insulin. In diabetes mellitus type I : this failure occurs due to the destruction of beta cells in the autoimmune process. Diabetes mellitus type II occurs mainly due to a combination of beta-cell failure and peripheral resistance to insulin. In patients with diabetes the beta cells is reduced, and the problem is not only the ability of beta cells to synthesize and release physio is agicheskii insulin, but a critical mass of these insulin-producing cells of the pancreas. It is known that in diabetes there is a loss of beta cells. With the loss of the insulin producing cells of the endocrine function of the pancreas is experiencing stress, for example, for the production of insulin. By reducing the release of insulin due to hyperglycemia may worsen pathological processes.

GLP-1 acts as a growth hormone Islands, stimulating proliferation β-cells, thus increasing cell mass and translating undifferentiated cells of the pancreas in specialized cells of the islets of Langerhans. Thus, under the action of GLP-1 cells of the pancreas carry out enhanced secretion of insulin and glucagon (Yaekura, K. et al., IN: VIP, PACAP, and Related Peptides, W.G. Forssmann and S.I. Said (eds.). New York: New York Academy of Sciences, 1998, p. 445-450; Buteau, J. et al., Diabetologia 42 (7): 856-864, 1999). The inventors have found that it is desirable to increase the half-life of GLP-1, thereby restoring the structure of the beta cells of the pancreas. The inventors have also discovered the means by which may be impaired catabolism of GLP-1 to improve the recovery patterns of the cells of the pancreas.

The method according to the present invention for the treatment of hyperglycemia in mammals, including humans, but not limited to, include all the I increase in the availability of GLP-1 by inhibition of DP IV or activity of related enzymes with the use of an inhibitor of this enzyme. Oral administration of an inhibitor of DP IV may be preferable in most cases. However, the present invention presents other route of administration. When the inhibition of the enzymatic activity of DP IV half-life of the active form of GLP-1 will be significantly extended and maintained under physiological conditions. The extension of the presence of active GLP-1, in particular, in the tissue of the pancreas will contribute to the differentiation of epithelial cells of the pancreas to effector cells of the pancreas, such as insulin-producing P-cells. Moreover, the extension of the presence of physiologically active GLP-1 in pancreatic tissue will contribute to the regeneration of those βcells that already exist, but need to be restored. Oddly enough, this effect is noticeable only when re-dosing (see example 2). After discontinuation of the medicinal product restores metabolic status, which was before treatment, subacute or chronic introduction of certain doses of effector DP IV is necessary to maintain the achieved improved glucose in the blood. These restored insulin-producing cells can then effectively participate in the correction and maintenance of normal physiological glucose levels.

In the present invention is endogenous GLP-1 Sint is Seretse and released normal physiological pathways. Eating can stimulate the release of GLP-1. On the other hand, glucose or its analogs can be administered orally in the form of a pharmaceutically acceptable carrier (e.g., "sugar pills") to stimulate release of endogenous GLP-1. So glucose can be taken before, concurrently or after administration of inhibitors of DP IV.

This invention relates also to pharmaceutical compositions. Such compositions comprise a therapeutically (or prophylactically) effective amount of the inhibitor (and/or sugar pills, accompanying the introduction of an inhibitor of DP IV) and a pharmaceutically acceptable carrier or excipient. Media and composition recommended in the laboratory and sterile. The production technology in the ideal case is chosen accordingly to the method of administration in accordance with conventional methods.

Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions (e.g., NaCl), alcohols, gum, vegetable oil, bezinovye alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, viscous paraffin, fatty acid esters, hydroxymethylcellulose, perfume oil, polyvinylpyrrolidone, etc. Pharmaceutical preparations can be sterilized and, if desired, mixed the auxiliary agents for example, lubricating agents, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic and similar substances that do not interact adversely with the active components, but which improve stability, manufacturability, and/or aesthetic appeal.

The composition, if desired, can also contain small amounts of moisturizer or emulsifying agents, or agents that hold the pH. In addition, the composition may be a liquid solution, suspension, emulsion, tablet, dragee, capsule, forms, delayed release or powder. In addition, the composition may be in the form of a suppository, with a traditional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinylpyrolidone, saccharin sodium, cellulose, magnesium carbonate, etc.

Further, the composition can be manufactured in accordance with methods well known in the field of pharmaceutical compositions suitable for intravenous administration to man. Typically, compositions for intravenous administration are sterile isotonic aqueous buffer is Astor. When necessary, the composition may also include dissolving agent and a local anaesthetic for the relief of pain at the injection site. Usually the ingredients are served either alone or in mixture with each other in a standard dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active compound. When the composition is administered infusion, it can be placed in an infusion bottle containing pharmaceutically acceptable sterile water, saline or dextrose solution/water. When the composition is administered by injection, an ampoule of sterile water for injection or saline can be set so that the ingredients can be mixed immediately prior to administration.

Finally, the compositions according to the invention can be manufactured in neutral form or as a salt.

Pharmaceutically acceptable salts include salts that are formed with free amino groups, as, for example, derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and derived from sodium, potassium, ammonium, calcium, iron hydroxides, Isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine and other salt forms, which are known by the s in this field.

The amount of composition according to the invention, which will be effective in the treatment of specific disorders or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, optional can be conducted in vitro and/or in vivo to determine the optimal spacing of doses. The exact dose to be used in the composition will also depend on the route of administration and the severity of the disease or disorder. The dose should be determined physician for each individual patient.

A qualified specialist in this field will be obvious that can be done numerous modifications of the examples and instructions, including the receipt of other inhibitors of DP IV and other therapeutic compositions without departure from the essence and not going beyond the scope of the present invention. The following examples, as described, are not intended to limit the scope of the present invention.

EXAMPLES

Example 1

DP IV-inhibitor R/98 actively transported through the intestinal carrier peptides Rest. Quick and active transport R/98 through the intestinal mucosa explains the rapid onset of action, tmaxis a necessary condition for effective action dipeptidylpeptidase IV (DP IV). Oral pickup is R/98 leads to the maximum directed inhibition from 15 to 20 min and from 30 to 40 min after food intake in rats and humans, respectively. Therefore, the DP IV-inhibitor should be introduced for 10-20 min before the glucose or food.

In the first study R/98 human pharmacodynamic parameters, such as the insulin concentration and the concentration of GLP-1 in plasma and the concentration of glucose in the blood, were studied in 36 healthy male volunteers.

Oral input dose R/98 was 7.5 mg, 15 mg, 30 mg, 60 mg, 120 mg and 240 mg of the Results of the above pharmacodynamic parameters is shown below in Table 1.

36 healthy males were divided into 3 individual groups of 12 people each. In each individual group of 9 people received active drug R/98 and 3 received placebo. Persons receiving the active drug, the dose was administered twice at different periods and with different content of active substances. Obtained groups dose R/98 were as follows: group I received 7.5 mg and 60 mg; group II received 15 mg and 120 mg; and group III received 30 mg and 240 mg of Persons in all groups treated with placebo received placebo at both doses.

A preliminary study of persons who participated in the study, conducted within 3-14 days before the examination. The second part of the study included an experimental phase and the subsequent six receptions single doses of ascending concentrations R/98 (periods from to 6; Table 2), which was completed subsequent assessment. All persons who participated in the preliminary study and the experimental phase were separated by a phase out at least 5 days. Further research was conducted at least 7 days after the last injection of study drug. Research methodology in six periods was identical, except for the studied doses.

Methods

Oral test glucose tolerance ("PTG"):

The subjects were fasting for at least 12 hours and 3 days to observe carbohydrate diet before each PTG. In each test, glucose tolerance examinee received 300 ml mono/disaccharide glycosides of solution, equivalent to 75 g of glucose (Dextro® O.G.-T, Boehringer Mannheim, FRG). Blood samples (1.2 ml tubes containing sodium fluoride) were taken immediately prior to consumption of glucose and after 30, 60, 90 and 120 min thereafter. Any concentration of glucose above 126 mg/DL (7.0 mmol/l) 0 min and 120 min was considered as a pathological state of glucose tolerance.

Long pttg conducted on day 1 of each period of drug administration. Subjects received 300 ml mono/disaccharide glycosides of solution, equivalent to 75 g of glucose. Blood samples (1.2 ml) were taken at the following intervals: 1)for 5 minutes prior to the consumption of glucose; 2) through 5, 15, 30, 45, 60, 75, 90, 120, 150 and 180 min after the use of glucose; 3) 4, 12, and 24 and 48 hours after the consumption of glucose.

In addition, there have been additional pharmacodynamic parameters, are well known in this field

Insulin: 4,7 ml of blood was collected in tubes containing 4.9 ml EDTA. Samples were centrifuged (1500 g, 10 min) and stored frozen at -70°until laboratory analysis.

Glucose: 1.2 ml of blood was collected in tubes containing 1.2 ml of sodium fluoride. Plasma samples were centrifuged at 1500 g for 10 min and kept frozen at -70°until laboratory analysis.

GLP-1: 2,7 ml of blood was collected in tubes with EDTA and placed on ice or frozen and thereto was added inhibitor dipeptidylpeptidase IV. Inhibitor researchers have prepared in advance. Blood was collected in tubes and immediately centrifuged at 1000 g for 10 min in a refrigerated centrifuge and blood was placed on ice and centrifuged within 1 hour, and poured into equal samples. Blood was stored in appropriate quantities at -70°With (to avoid multiple cycles of freezing/thawing) until laboratory analysis.

Results

The concentration of active GLP-1 was shown to dose-dependent effect R/98 compared with placebo. Limit individual concentration varied between 2-68 pmol/L. the mean values in the group prior dose was between of 3.77±2,62 pmol/l and 6.67ଙ,43 pmol/l and increased to 4,22 and 7,66 pmol/l after placebo, but 11.6 pmol/l (15 mg) and 15,99 pmol/l (240 mg R/98) after application of the inhibitor. If the relative average increase was determined from the absolute concentrations, the concentration of active GLP-1 was increased by approximately 200% - 300% after treatment with placebo, but approximately 300-400% after treatment R/98. The absolute increase in average after applying 15-240 mg R/98 was 2-3 times higher compared to placebo and a dose of 7.5 mg (see Table 1) and mainly shows the dose-response. The increase above the prior dose was approximately up to 3-4 hours on a dose R/98.

Insulin concentrations showed a General unit interval values between 3,40 and 155, 1mm, mkme/ml Average values (±CO) concentrations prior doses ranged between of 7.96±1,92 mkme/ml (30 mg) and 11,93+2,91 mkme/ml (60 mg R/98). After consumption of 75 g of glucose after 10 min of dose R/98/placebo average concentrations of insulin were increased by 30,12 mkme/ml (120 mg R/98)-56,92 mkme/ml (30 mg) for 40-55 minutes there were No obvious differences between placebo and groups who were prescribed R/98, and, in addition, there is no evidence of dose-dependent effect R/98. Interestingly, the absolute increase in the concentration of insulin was lowest in the two groups receiving the highest dose R/98 (see Table 1). The concentration of insulin was increased in accordance with the s 3-4 hours in all groups, including the placebo group.

Glucose concentration was changed in the limiting interval from 2,47 to 11.7 mmol/l at fasting during OGGT or after a meal among all the studied persons Average concentrations prior dose between 4,55±0,41 (15 mg) and a 4.83±0.30 mmol/l (7.5 mg R/98) came close to each other and showed a small difference. The average maximum concentration was achieved 40-55 min after consumption of the dose, i.e. 30-45 min after ingestion of 75 g glucose. Absolute average concentrations were highest in the two placebo groups and in the group that received a dose of 7.5 mg R/98. The lowest absolute average values were observed in the groups receiving a dose of 15 mg, 60 mg and 240 mg of the average change in the interval between 3,44 and is 4.21 mmol/l and 1.71 and to 3.41 mmol/l, respectively, and close to the average values given in Table 1. Although strict dependence on dose was not observed, these results show a weaker increase in the concentrations of glucose with increasing doses from 15-240 mg R/98 compared with placebo.

td align="center"> 30 mg
Table 1:

Maximum changes in pharmacodynamic parameters (0-12 h, average)
Placebo7.5 mg15 mgPlacebo60 mg120 mg240 mg
(1-3)R/98R/98R/98(4.6)R/98R/98R/98
GLP-1,3,904,1010,00or 10.60and 5.3012,2011,1014,50
active0:25 h1:10 am0:25 h0:40 h0:40 h0:25 h0:25 h0:25 h
[pmol/l]
Insulin46,2941,8629.67 per59,8442,9043,3528,6333,36
[McKie/ml]0:55 h0:55 h0:55 h0:40 h0:40 h0:40 h0:40 h0:40 h
Glucose3,43of 4.662,433,385,332,922,391,73
[mmol/l]0:55 h0:55 h 0:55 h0:40 h0:55 h0:40 h0:40 h0:40 h

Table 2:

Adjusted Cmaxand AUC glucose concentration through 0-3 h after PTH
AUC0→in[MMOL*MIN/L]Cmax[MMOL]
Average ±SDScore95%-ClAverage ±80Score95%-Cl
Periods 1.3
Placebo223,9±br143.34,16±1,10
7.5 mg R/98to 299.7±byr111.475,8-48,1-199,74,94±1,580,78-0,40 is 1.96
15 mg R/98130,9±125,2-93,0-216,9-30,92,92±1,10-1,24*-2,43-0,06
30 mg R/98116,1±134,0-107,7-231,6 of 16.23,26±1,07-0,90-2,08-0,28
Periods 4-6
Placebo252,9±103,34,91±1,14
60 mg R/98to 151.8±, and 99.2-101,1-204,8-2,63,50±1,66-1,41*-2,66-0,17
120 mg R/98a 126.7±147,3-126-1*-229,8-22,43,09±1,47-1,82**-3,07-0,58
240 mg R/9824,7±66,6-228,2***-331,8-124-51,99±0,69-2,92***-4,16-1,68
1The results of the ANOVA comparing the data from placebo

*p<0,05; **p<0,01; ***p<0,001

Adjusted in relation to the control average maximum value (Cmaxconcentration of glucose was greater than 4.0 mmol/l in only two groups: placebo and 7.5 mg R/98.

These values were also below 3.0 mmol/l groups treated with 15 mg and 240 mg R/98. A statistically significant difference with the introduction of the placebo was in the groups receiving doses of 15 mg, 60 mg, 120 mg and 240 mg R/98, but not in the groups receiving a dose of 7.5 mg and 30 mg Corrected in comparison with the control, the average value is of AUC were > 200 mmol*min/l after placebo and 7.5 mg R/98, but certainly below 200 mmol*min/l after doses of 15 mg and 240 mg R/98. The decrease in the total content of glucose after pttg was statistically significant in the groups receiving doses of 15 mg, 60 mg, 120 mg and 240 mg R/98, but not in the groups receiving a dose of 7.5 mg and 30 mg (see Table 2). To estimate adjusted relative to control, was similar to the values obtained for the unadjusted data. Thus, the data suggested a decidedly more low glucose after PTH in healthy subjects, who R/98, which is approximately, but not exactly, which was dose dependent.

Conclusions

The results of this study allow the following pharmacodynamic conclusions:

Active GLP-1 was increased by approximately 300-400% after the introduction of R/98 for 10 min to ptth, for a dose of 7.5 mg was not seen noticeable results with the introduction of placebo (see figure 1 and 2). The concentration of insulin was decreased at doses of 120-240 mg after stimulation of 75 g glucose. For PTH in healthy subjects, concentrations of glucose testified significantly weaker increase after the introduction of R/98 (15-240 mg) compared with placebo, administered in a similar R/98 dosage.

Example 2

In obese Zucker rats, P32/98 initial secretion of insulin depends on nutrition. However, during the subacute l the treatment P32/98 reduces the total daily secretion of insulin. Compared with the control glibenclamide, which increases the release of insulin by 27%, P32/98 causes the saving of insulin, saving 45% compared to control.

Testing was performed in order to determine whether P32/98 the first candidate that affect glucose tolerance in vivo, increasing the half-life of circulating incretins GIP and GLP-1.

Comparative studies were performed with glibenclamide (Maninile® Berlin-Chemie, Berlin, Germany) as a reference substance. Glibenclamide is one of the most effective drugs for reducing blood glucose in patients with diabetes mellitus type 2 and one of the most commonly prescribed sulfonylurea drugs.

Male rats Zucker fa/fa, with abnormalities of glucose metabolism, but also represents a model of diabetes mellitus type 2 on animals investigated in the following way:

P32/98 and glibenclamide was given once daily before meals for 21 days. Monitored parameters were the contents of the morning blood glucose and plasma insulin. Profile day and night concentrations monitored glucose and blood insulin from 16 to 17 days. To assess changes in glucose tolerance was performed pttg finally on the 21st day, tracking the kinetics of blood glucose and plasma insulin. Glibenclamide (DAB 1996; R011150/33372) was p who Daren Berlin-Chemie (Berlin, Germany). Male Zucker rats (fa/fa) weighing about 300 g were purchased from Charles River (Sulzfeld, Germany).

Methods

Conditions: Animals were kept individually in normal conditions with controlled temperature (22±2° (C) when a 12/12-hour cycle of light/dark (lighting at 06:00 and. m.).

Standard litter (ssniff®, Soest, Germany) and tap water, acidified with HCl, was provided ad libitum.

Catheterization of the carotid artery: after one week of adaptation, the rats were implanted carotid caterer under General anesthesia (injection of 0.25 ml/kg administered intraperitoneally Rompun® [2%], Bayer, Germany) and 0.5 ml/kg administered intraperitoneally Velonarkon® (Arzneimittelwerk Dresden, Germany). Animals were left for one week to recover. The catheter was rinsed with a saline solution with heparin (100 IU/ml) three times a week.

Re-introduction: 30 males neadiabaticheskikh of Wistar rats and 30 males diabetic Zucker rats were randomly selected for KB (reference Substance: glibenclamide)-, TV (Test Substance: R/98) and KO (Control) groups (N=10 per group). After that nediabeticescoy Wistar rats once daily administered orally KB (5 mg/kg body weight) or TV (21,61 mg/kg body weight) and Zucker diabetic rats once daily administered orally KB (1 mg/kg body weight) or TV (21,61 mg/kg body weight) for 21 days at 0500 the day (before the usual food consumption in Ternovoy phase). is completed, the animals were injected orally with 1% solution of cellulose (5 ml/kg). Every morning at 07.30 in the morning from the tail veins take blood samples to measure blood glucose and plasma insulin. The last blood samples this part of the program to measure blood glucose and plasma insulin were taken on the 15th day at 07.30 in the morning. Oral drug therapy was continued for one week. Profile information of daytime and nighttime concentrations of blood glucose (Δt=3 h) and plasma insulin (Δt=3-6 h) at the above treatment was tracked 16th day (beginning at 0500 days) on the 17th day (ending at 02.00 days).

Pttg: Final pttg was performed on day 21 with blood samples from the tail vein. Blood samples were taken from the tail vein in 12 hours (the night before the 21st day), at 0 min (immediately before pttg)10, 20, 30, 40, 50, 60, 80, 100 and 120 min blood Samples were collected in glass capillaries 20 ál for measurement of blood glucose and in Eppendorf tubes (100 μl). The Eppendorf tubes and immediately centrifuged and the plasma fraction was stored at -20°for analysis of insulin.

The glucose content in blood glucose was measured using glucose oxydase method. (Super G GlukosemeBigerät; Dr. Müller Gerätebau, Freital, Germany).

Insulin plasma: Quantitative analysis of the concentration of insulin or antibody-based test conducted by RIA method (LINCO Research, Inc. St. Charles, Mo., USA.

Results

Profile day and night concentrations of glucose in the blood (SMPhU): the Average concentration of glucose in the blood in the KO group on day 16 was 7,78± 0,83 mmol/l before administration of a medicinal product at 0500 days. After oral administration of placebo and eating in Ternovoy phase of glucose in the blood was increased to maximum values 12,18±of 1.34 mmol/l at 11.00 day. After that, the content of glucose in the blood very slowly fell to the lowest values 7,27±0.61 mmol/l in 11 hours. in the morning, with a subsequent increase to 8.90±0,92 mmol/l 02.00 day the next day. In the HF group was observed a similar pattern of glucose in the blood. However, comparable with respect to the control animals averages of 7.96±1.13 mmol/l at 0500 the day was observed stronger increase to 14.80±of 1.46 mmol/l (11.00 hours) and subsequent reduction to 7,66±1,22 mmol/l (11.00 am) and a further slight decrease to 7.34±0.77 mmol/l 02.00 day the next day, respectively. In the TV group Zucker rats had normal average blood glucose of 5.25±0.16 mmol/l at 0500 the day, and a single value was in the range of from 4,34 to 6,07 mmol/l glucose in the blood was increased approximately 3 mmol/l to 8.34±0.47 mmol/l at 11.00 day. This was accompanied by a permanent reduction to the basic values achieved at 08.00 am(5,64±0,23), which was maintained at 11.00 a.m. (5,33±0.14 mmol/l) and 02.00 day the next day (5,51±0,19 mmol/l), respectively.

Profile day and night of the content of insulin in the blood: (the m figv): rats Zucker KO and KB was strong hyperinsulinemia. The mean values of insulin were volatile at 0500 days in KO group (47,0±to 8.7 ng/ml), 08.00 day (45,5±and 7.7 ng/ml), 05.00 am (54,2±of 5.7 ng/ml) and 02.00 day the next day (61,0±to 10.2 ng/ml; NS), which had no relation to the fluctuations of glucose in the blood. In KB group in Ternovoy phase day from 06.00 06.00 in the morning was a significant increase in the values of plasma insulin with a maximum at 5.00 am. This parameter was increased by high values of hyperinsulinemia 50,0±to 8.2 ng/ml (05.00 day) through 57,3±to 8.2 ng/ml (08.00 days) to 76.3±to 8.6 ng/ml (05.00 in the morning; p<0,01 compared to the initial value), which was accompanied by a decrease to 58.3±and 7.3 ng/ml (02.00 day the next day). In this KB group, insulin was strongly shifted in phase with respect to the fluctuations of glucose in the blood. In rats, Zucker group TV was also hyperinsulinemia. Insulin plasma at 0500 days was significantly lower than in the KB group (p<0.05 compared with group KB). Accordingly, the increase in blood glucose (Figa, C) increased rate of insulin plasma at 08.00 day (41,9±8.5 ng/ml). The maximum value of insulin were measured at 05.00 in the morning (57,1±to 8.6 ng/ml; p<0,01 compared to the initial value). The concentration of insulin in plasma were decreased, reaching the initial concentration (24,3±to 3.7 ng/ml) to about 2.00 the next day, which was a mn is considerably lower than in groups TO or KB (p<0,01 compared to groups or TO TV).

Pttg after 21 days of treatment, the curve of blood glucose (see Figa): Last admission medication at 0500 the day and fasting during the night on day 21 was accompanied by a significant decrease of glucose in the blood in the group TO with 8,68±of 1.26 mmol/l (05.00 day) up to 5.08±0.24 mmol/l (p<0,05)in group KB 8,81±to 1.21 mmol/l to 4,91±and 0.37 mmol/l (p<0,01 and in the group TV with 5,75±0.23 mmol/l to 4,88±0.13 mmol/l (p<0,01). For this reason, oral glucose load was obtained from comparable basic level of glucose concentration in all three experimental groups determined in the morning (07.30 a.m.).

In the group TO the glucose content in the blood increased after oral administration of glucose to the maximum values 14,64±to 1.42 mmol/l per 40 minutes Later, there was a significant gradual decrease to 9.75±0.46 mmol/l by the end of the test (120 min). In the KB group, there was a sharp increase in blood glucose to a higher value 16,33±0.98 and 16,24±1,09 mmol/l in 50 min and 80 min, respectively. High glucose concentration was maintained until the end of the study, 120 min (100 min: 15,13±0,76 mmol/l, 120 min: 14,81±0.66 mmol/l; NS from the previous maximum values). Were found similar to the average values of the curve of blood glucose in the TV and the group TO. The content of glucose in the blood increased to 4.54± of 0.65 mmol/l in 50 min and significantly decreased to values 10,67 ± of 0.62 mmol/l (120 min; NS from KOH).

The area under the curve of glucose concentration (G-AUC0-120min) in groups TO and the TV was 823±41 and 895±50 mmol·min/l, respectively (NS). In the KB group this parameter was 1096±76 mmol·min/l, and this value was significantly higher than in group CO (p<0,01) or TV (p<0,05).

Pttg after 21 days of treatment, the plasma insulin (see figv): Fasting during the night Zucker rats leads to decreased concentrations of insulin in plasma of animals of the group TO (14,6±to 3.7 ng/ml), in the group to 11.8 KB±1.5 ng/ml and in group TV to 9.3±1.5 ng/ml, respectively. No significant differences between experimental groups. After stimulation with glucose level insulin plasma for the most part remained unchanged in groups TO, KB and TV. Slightly higher values were found in 120 min only in the group TO, making 21,3±3.0 ng/ml, which was significantly higher than in the TV (p<0,05).

I-AUC0-inin General was low. In the TV group this parameter was lower than in groups TO or KB (NS).

Conclusions

Morning glucose content in blood of Control animals receiving placebo, had a high content of glucose in the blood (about 7.5 mmol/l).

The average concentration did not change during the study. Treatment of KB has increased the level of glucose the blood by about 1.5 mmol/l within two days. The glucose content in the blood was high. Introduction TV reduced the level of blood glucose to normal levels within 5 days. The content of glucose in the blood remained within the normal range until the end of the study.

Insulin plasma from control rats Zucker was hyperinsulinemia and further shows a slight increase of insulin within 14 days of observation. In Zucker rats treated with KB, shows an increase of insulin to much higher concentrations than in control animals. The use of TV was slightly reduced the concentration of insulin within 14 days compared to control animals.

Pttg after 21 days of treatment, maintenance of blood glucose: Fasting during the night reduced the level of blood glucose to normal values in the experimental groups. In animals receiving placebo, shows an increase of glucose in the blood by about 9 mmol/l for 40 min after glucose load and then a gradual decline. In Zucker rats treated with KB, elevated blood glucose after glucose load about 11 mmol/l without reducing during the test. The average values of the curve of glucose in the blood of animals treated with the TV did not differ from control. Introduction KB increased G-AUC, the TV reception was not increased G-AUC compared with placebo.

Pttg after 21 days of treatment, insulin plasma: control the Rys Zucker fasting was observed the highest of the three experimental groups of insulin, approximately 15 ng/ml After glucose load insulin was significantly increased only by the end of the test (120 min). In rats treated with KB, fasting insulin was slightly lower, is 12.5 ng/ml at the beginning of pttg and earlier increase in 40 min without reduction by the end of the test. In rats fed the TV, had the lowest content of insulin on an empty stomach ˜9 ng/ml at the beginning of pttg, early moderate increase in 20 minutes in relation to the content of glucose in the blood, increasing and decreasing concentrations between 40 min and 100 min I-AUC was slightly lower in rats fed the TV.

Conclusion

Inhibitor of DP IV R/98 (TR), administered once daily, normalized to the level of the morning blood glucose, reduced hyperinsulinemia, kept the concentration of glucose in the blood profile of day and night concentrations below the critical 8.3 mmol/l (patients with diabetes). A positive effect on the metabolism remained limited time after stopping treatment.

1. The use of at least one inhibitor of the activity of the enzyme dipeptidylpeptidase IV as an active ingredient in the manufacture of a medicinal product for re-introduction to improve the functional activity of the insulin-producing cells from the animal with the failure of the insulin-producing capacity.

2. The use according to claim 1, where the specified functionally increase the activity of insulin-producing cells includes ensuring more efficient production of insulin by the cells the endogenous source of insulin.

3. The use according to any one of the preceding paragraphs, where the aforementioned increase of the functional activity of the insulin-producing cells includes ensuring differentiation of epithelial cells of the pancreas into insulin-producing cells.

4. The use according to any one of the preceding paragraphs, where the specified inhibitor activity of the enzyme dipeptidylpeptidase IV selected from the group consisting of N-(N'-substituted glycyl)-2-cyanopyrrolidines, N-aminoethylethanolamine, N-AMINOETHYLPIPERAZINE, such as L-threo-solicitation, L-ALLO-solicitation, L-threo-isolatin1encoding and L-ALLO-isolatin1encoding, and their pharmaceutical salts.

5. The use according to any one of the preceding paragraphs, where the specified medicinal product adapted for oral administration.

6. The use according to any one of claims 1 to 4, where the specified drug adapted for intravenous or intramuscular injection.

7. The use according to any one of claims 1 to 5, where the specified drug is fit for long-term oral administration.

8. The use according to any one of claims 1 to 4, where the specified drug is fit for long-term administration by intravenous or intramuscular injection.

9. The use according to any one of the preceding paragraphs,where the specified drug adapted for introduction before the introduction of glucose or food consumption.

10. The use according to any one of the preceding paragraphs, where the medicinal product contains a therapeutically effective amount of at least one inhibitor of the activity of the enzyme dipeptidylpeptidase IV.

11. The way to increase the functional activity of the insulin-producing cells from the animal with the failure of the insulin-producing ability, which includes the re-introduction of specified animal a therapeutically effective amount of at least one inhibitor of the activity of the enzyme dipeptidylpeptidase IV.

12. The method according to claim 11, where the aforementioned increase of the functional activity of the insulin-producing cells includes ensuring more efficient production of insulin by the cells of endogenous producers of insulin.

13. The method according to claim 11 or 12, where the aforementioned increase of the functional activity of the insulin-producing cells is provided by the differentiation of the epithelial cells of the pancreas into insulin-producing cells.

14. The method according to any of § § 11-13, where the specified inhibitor activity of the enzyme dipeptidylpeptidase IV selected from the group consisting of N-(N'-substituted glycyl)-2-cyanopyrrolidines, N-aminoethylethanolamine, N-AMINOETHYLPIPERAZINE, such as L-threo-solicitation, L-allisonallison, L-threo-isolatin1encoding and L-ALLO-izolacija the one, and their pharmaceutically acceptable salts.

15. The method according to any of § § 11-14, where the aforementioned introduction includes oral administration.

16. The method according to any of § § 11-14, where the aforementioned introduction includes intravenous or intramuscular injection.

17. The method according to any of § § 11-14, where the aforementioned introduction includes long-term oral administration.

18. The method according to any of § § 11-14, where the aforementioned introduction includes a long introduction by intravenous or intramuscular injection.

19. The method according to any of § § 11-18, where the glucose or meal carried out before, during or after administration of the inhibitor activity of the enzyme dipeptidylpeptidase IV.

20. The method according to claim 19, where the aforementioned introduction of the indicated inhibitor activity of the enzyme dipeptidylpeptidase IV occurs before the specified injection of glucose or a meal.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of norbornylamine with exo-configuration of nitrogen atom and endo-anellated 5-6-membered cycles of the formula (I) and with exo-configuration of nitrogen atom and exo-anellated 5-6-membered cycles of the formula (Ia) , and their pharmaceutically acceptable salts or trifluoroacetates also. In compounds of the formula (I) or (Ia) A means (C1-C4)-alkylene; S1 means optionally (C1-C4)-alkyl; S2 means (C1-C4)-alkyl or hydrogen atom (H) being if S1 and S2 mean alkyl then X in the group [-N+(S1S2)-X-] corresponds to pharmacologically acceptable anion or trifluoroacetate; B means saturated or unsaturated carbon 5- or 6-membered cycle; R1, R2, R3, R4 and R5 have values given in the description. Also, invention relates to a method for preparing these compounds and to a medicinal agent. These compounds can be used for preparing medicinal agents useful for treatment or prophylaxis in breathing impulse disturbance, in particular, in breathing disturbance caused by sleep, transient breathing stop during sleep, snore, for treatment or prophylaxis of acute and chronic renal diseases, in particular, acute and chronic renal insufficiency and, disturbance in intestine, gallbladder, ischemic states of peripheral and central nervous system disturbances, severe attacks and others symptoms. Compounds are inhibitors of sodium-proton exchange, show effect on serum lipoprotein and therefore they can be used in prophylaxis and regression of atherosclerotic alterations.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

21 cl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of glucopyranosyloxybenzylbenzene represented by the formula (I): wherein R1 represents hydrogen atom or hydroxy(lower)alkyl; R2 represents lower alkyl group, lower alkoxy-group and lower alkylthio-group being each group is substituted optionally with hydroxy- or (lower)alkoxy-group, or to its pharmaceutically acceptable salts. Also, invention relates to pharmaceutical composition eliciting hypoglycemic activity and to a method for treatment and prophylaxis of hyperglycemia-associated diseases, such as diabetes mellitus, obesity and others, and to their intermediate compounds. Invention provides preparing new derivatives of glucopyranosyloxybenzylbenzene that elicit the excellent inhibitory activity with respect to human SGLT2.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 tbl, 2 ex

FIELD: pharmaceutical industry, in particular high quality insulin drug of durable action.

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EFFECT: effective and economical method for insulin production with increased yield and purity; insulin of durable action and low immunological properties.

12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: it is suggested to apply Pro-Gly-Pro tripeptide known as anticoagulant to keep stable norglycemia and stable normoinsulinemia in circulation at no side effects because the above-mentioned tripepetide is being natural human and animal metabolite.

EFFECT: higher efficiency of application.

3 cl, 5 ex, 2 tbl

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to human insulin drug of durable action. Drug contains human insulin substance of high purity, protamine sulfate, zinc chloride, glycerol, m-cresol, phenol, sodium dihydrogenphosphate dihydrate or disodium hydrogenphosphate heptahydrate, sodium chloride, and water and has residual proteolysis activity not more than 0.005 adsorption units.

EFFECT: human insulin drug of durable action with increased physiological activity and physical and chemical storage stability.

4 ex, 1 tbl

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to human insulin drug with activity of 100 IU/ml, including cartridge forms. Drug contains active ingredient, glycerol as isotonic agent, conserving agent and water, wherein it contains human insulin substance of high purity with residual proteolysis activity not more than 0.005 adsorption units, sodium chloride as additional isotonic agent, m-cresol as conserving agent, and additionally sodium dihydrogenphosphate dihydrate or disodium hydrogenphosphate heptahydrate as substance with buffer capacity and pH 6.9-7.8.

EFFECT: human insulin drug of short action with increased physiological activity and physical and chemical storage stability.

6 ex, 1 tbl

FIELD: organic chemistry, pharmacology.

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EFFECT: new anorexia pharmaceuticals.

5 cl, 4 ex, 2 tbl

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new aromatic diketone derivatives of formula I

(R4, R5, R6, and R7 are independently H, OH, X-alkyl, wherein X represents oxygen; K is group of formula II

or III

;

L is group of formula IV

;

or K and L together form group of formula VI ,

wherein R1 and R3 are independently H or alkyl; R2 is H or alkyl; X1-X7 are independently O, NH; and ring "cyclus" together with carbon atom labeled with letters c and d represents anthraquinone, hydroquinone or phenyl, optionally substituted with one or more hydroxyl, alkoxyl, or alkyl groups), as well as pharmaceutically accepts salts thereof, ethers, esters, tautomers, stereomers and mixtures in any ratio. Derivatives of present invention are glucose-6-phosphatetranslocase inhibitors. Also disclosed are method for production of derivatives, pharmaceutical composition containing the same, and uses thereof as drugs, in particular for treatment of diabetes mellitus.

EFFECT: new compounds and pharmaceutical composition for treatment of diabetes mellitus.

20 cl, 4 tbl, 6 ex

FIELD: medicine, oncology, immunology, tumor biology.

SUBSTANCE: invention relates, in particular, to methods for enhancing cytotoxicity based on applying anti-CD38-immune toxins. Method involves carrying out the treatment of patient with pathophysiological state taken among the group including myelomas and leukosis and involves the following stages: a) administration to the indicated patient the pharmacologically effective dose of retinoid that enhances expression of antigen CD38; and b) administration to the indicated patient the pharmacologically effective dose of immune toxin acting against effectively expressing antigen CD38. Method provides enhancing the cytotoxicity with respect to above said diseases in their resistance to anti-tumor medicinal agents.

EFFECT: enhanced and valuable method for treatment.

6 cl, 1 tbl, 9 dwg, 10 ex

FIELD: chemistry of peptides, medicine.

SUBSTANCE: invention relates to compound of the structure: N-methyl-(D-Leu-D-Val-D-Phe-D-Phe-D-leu)-NH2 designated for using as an active component in manufacturing a medicinal agent used for inhibition of natural β-amyloid peptides aggregation in patients suffering with disorder associated with β-amyloidosis and in treatment of Alzheimer's disease. Also, invention relates to a pharmaceutical composition, a method for inhibition of natural β-amyloid peptides, a method for detection of natural β-amyloid, a method for detection for the presence or absence of natural β-amyloid peptides in biological sample and to a method for treatment of patient with disorder associated with β-amyloidosis.

EFFECT: improved method for detecting, valuable medicinal properties of agent.

14 cl, 5 tbl, 5 dwg, 9 ex

FIELD: medicine, peptides.

SUBSTANCE: invention relates to biologically active peptides able to inhibit motility of cells stimulated by the chemokine MCP-1. Invention proposes peptide of the formula: H-DHLDKQTQTPKT-OH and its pharmaceutically acceptable salts. The claimed peptide can be used in cardiology for covering stents in angioplasty in aims for prophylaxis of restenosis.

EFFECT: valuable medicinal properties of peptide.

1 sch, 2 ex

Oligopeptides // 2260597

FIELD: organic chemistry, peptides, biochemistry.

SUBSTANCE: invention describes oligopeptide or its salt taken among the group consisting of oligopeptide (1) and (2): Lys-Ser-Ile-Glu-Gln-Ser-Cys-Asp-Gln-Asp-Glu (I), Ser-Ile-Glu-Gln-Ser-Cys-Asp-Gln-Asp-Glu (II); Ser-Ile-Glu-Gln-Ser-Cys-Asp-Gln-Asp (III); Ser-Ile-Glu-Gln-Ser-Cys-Asp-Gln (IV); Ser-Ile-Glu-Gln-Ser-Cys-Asp (V); Ser-Ile-Glu-Gln-Ser-Cys (VI); Ile-Glu-Gln-Ser-Cys-Asp-Gln-Asp-Glu (VII); Glu-Gln-Ser-Cys-Asp-Gln-Asp-Glu (VIII); Gln-Ser-Cys-Asp-Gln-Asp-Glu (IX); 2) oligopeptide with amino acid sequence obtained by deleting by C- or N-end of one or some amino acids in any amino acid sequence (I)-(IX), and the modified oligopeptide representing oligopeptide biotinylated or dimerized by sulfhydryl group of cysteine residue based on oligopeptide determined in (1) or (2). Oligopeptides elicit activity with respect to hair growth stimulation.

EFFECT: valuable properties of oligopeptides.

11 cl, 6 dwg, 4 ex

FIELD: medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to agents used in treatment of ulcerous-erosion injures in gastroduodenal region. Method involves diluting 100 mcg of dry lyophilized powder of immunomodulating agent "Superlimf" in 3-5 ml of 0.9% isotonic solution and irrigation of ulcer or erosion with this solution 1 time per a day by the endoscopy method. The treatment course is 3-4 procedures with break for 4-5 days. Method provides alteration of cytokine pattern of tissues, induction of influx of mononuclear phagocytes to the injure focus that results to localization of inflammation and the complete epithelization of ulcers and erosions.

EFFECT: improved and effective method for treatment.

1 ex

FIELD: medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to agents used in treatment of ulcerous-erosion injures in gastroduodenal region. Method involves diluting 100 mcg of dry lyophilized powder of immunomodulating agent "Superlimf" in 3-5 ml of 0.9% isotonic solution and irrigation of ulcer or erosion with this solution 1 time per a day by the endoscopy method. The treatment course is 3-4 procedures with break for 4-5 days. Method provides alteration of cytokine pattern of tissues, induction of influx of mononuclear phagocytes to the injure focus that results to localization of inflammation and the complete epithelization of ulcers and erosions.

EFFECT: improved and effective method for treatment.

1 ex

FIELD: medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to agents used in treatment of ulcerous-erosion injures in gastroduodenal region. Method involves diluting 100 mcg of dry lyophilized powder of immunomodulating agent "Superlimf" in 3-5 ml of 0.9% isotonic solution and irrigation of ulcer or erosion with this solution 1 time per a day by the endoscopy method. The treatment course is 3-4 procedures with break for 4-5 days. Method provides alteration of cytokine pattern of tissues, induction of influx of mononuclear phagocytes to the injure focus that results to localization of inflammation and the complete epithelization of ulcers and erosions.

EFFECT: improved and effective method for treatment.

1 ex

FIELD: medicine, chemistry of peptides.

SUBSTANCE: invention proposes a new anti-arrhythmic agent that represents a peptide ligand of opioid receptors deltorphine D - compound of the formula (I): Tyr-D-Leu-Phe-Ala-Asp-Val-Ala-Ser-Thr-Ile-Gly-Asp-Phe-His-Ser-Ile-NH2 (I). The effect of this agent is associated with stimulation of opioid receptors and results to reducing frequency in arising multiple ventricular extrasystoles and episodes of ventricular tachycardia.

EFFECT: valuable medicinal properties of agent.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: vaccine is high molecular weight protein conjugate with angiotensine II taken in high molecular weight protein : angiotensine II proportion of 1:12-55 in % by weight. The conjugate is modified with equilibrium quantity of immunocompetent polyelectrolyte like polyoxydonium.

EFFECT: stable physiological response within prolonged period of 6-12 months.

3 tbl

FIELD: bioorganic chemistry.

SUBSTANCE: invention provides somatostatin agonists of general formula: A1-cyclo{Cys-A2-D-Trp-A3-A4-Cys}-A5-Y1 (I), wherein A1 represents aromatic D- or L-α-amino acid selected from Phe, D-Phe, Tyr, D-Tyr, β-Nal, D-β-Nal, Cha, or D-Cha; A2 aromatic α-amino acid selected from Phe, Tyr, β-Nal, and Cha; A3 Lys or Orn; A4 β-hydroxyvaline, Ser, hSer, or Thr; A5 β-hydroxyvaline, Ser, hSer, or Thr; and Y1 represents NH2; amide nitrogen atoms of peptide groups and amine group of A1 in compound I are optionally substituted by methyl group, provided that at least one methyl group is available and that compound I cannot have following formula: D-Phe-cyclo{Cys-Phe-D-Trp-Lys-(N-Me-Thr)-Cys}-Thr-NH-2. pharmaceutically acceptable salts of compound I are also claimed.

EFFECT: expanded synthetic possibilities in peptide synthesis.

24 cl, 2 tbl, 18 ex

FIELD: medicine, therapy, gastroenterology.

SUBSTANCE: method involves preliminary assay of the disorder type in gallbladder motor contraction and bile-excretion ways followed by prescribing thermal low-mineralized hydrocarbonate-sodium-sulfate-calcium-magnesium mineral water in the dose by 200-300 ml, 3 times per a day, 1 h before eating, tubages № 3 with mineral water, bathes and shower with mineral water every day for 10-14 days. In the hypotonic type of motor activity method involves mineral water at temperature 25-30°C, and in the hypertonic type - at temperature 38-40°C. Method provides accelerating in scars formation of ulcers and epithelization of erosions in gastroduodenal system, to prevent frequent exacerbations and to reduce activity of Chelicobacter-induced inflammation.

EFFECT: improved therapy method.

4 tbl, 2 ex

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