Method for preventing and treating ulcers of gastro-intestinal tract

FIELD: medicine.

SUBSTANCE: peptide of the following formula: X-Pro-Gly-P, where X = Thr-Lys-Pro-Arg-; Lys-pro-Arg-; pro-Arg-; Arg-, being of untiulcerous activity. They should be applied at intraperitoneal injection at the dosage of 0.58-3.20 mcM g/kg for preventing and treating ulcers of gastro-intestinal tract.

EFFECT: higher efficiency and prophylaxis.

4 dwg, 5 ex

 

The invention relates to medicine, for the prevention and treatment of ulcers of the gastrointestinal tract.

Known substance peptide - heptapeptide which received the name “slank”, the formula Thr-Lys-Pro-Arg-Pro-Gly-Pro with anti-anxiety action (Seredenin S.B., M. Kozlovskaya, Blednov Y.A. and other Study of anti-anxiety actions analogue of endogenous peptide of tuftsin on inbred mice with different phenotype emotional stress response. Journal of higher nervous activity. 1998, C. issue 1, c.153-160) [1]. However, antiulcer activity of selenka and method of prevention and treatment of ulcers of the gastrointestinal tract with its use is not described.

Izvestno substance peptide is a Tripeptide Pro-Gly-Pro with antiulcer activity (Shamonina Mrs x and drgorila blood flow to the stomach as one of the possible mechanisms of the anti-ulcer effects of short prolinsoderzhashchikh peptides. Russian physiological journal. Sechenov, 2001, 87, No. 11, s-1492) [2]. However, the techniques of the method for the prevention and treatment of ulcers of the gastrointestinal tract with the use of this known peptide is not described.

Known peptides of the General formula:

X-Pro-Gly-Pro, where X is Lys-Pro-Arg-Pro-Arg -, - Arg-as psychostimulants (Dr. M.M. and other Comparative study of the impact of fragments of tuftsin on the performance of conditional Rea is the passive avoidance. Chemical-pharmaceutical journal, 2001, 35(3), p.3-5) [3].

However, antiulcer activity data of known peptides and method of prevention and treatment of ulcers of the gastrointestinal tract using them is not described. The known method of prevention and treatment of ulcers of the gastrointestinal tract by injecting drug peptide. (Patent RU №2191593, class a 61 K 38/08, a 61 P 1/04, publ. 27.10.02 [4] - the prototype. As a drug peptide in this known method uses heptapeptide which received the name “Semax”, formula Met-Glu-His-Phe-Pro-Gly-Pro.

However, the modern Russian market dictates the need for expansion of the funds used for the prevention and treatment of ulcers of the gastrointestinal tract. In addition, the effectiveness of medicines used in the known method [4]not so high, and the range of doses to which it is used, not wide enough.

The technical result achieved by the present invention, is expanding the range antiulcer means having high efficiency in a wide range of doses, increasing the efficiency of treatment of ulcers of the gastrointestinal tract with the use of these funds.

This technical result is achieved by the fact that the method of prevention and treatment I had in the gastrointestinal tract by injecting drug peptide distinctive ability is as drug use peptide of General formula:

X-Pro-Gly-Pro, where X=Thr-Lys-Pro-Arg; Lys-Pro-Arg-; Pro-Arg; Arg-who injected intraperitoneally at a dose of 0.58-3,30 µmol/kg body weight.

Figure 1 presents a diagram describing the effect of the peptide Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro, Arg-Pro-Gly-Pro on ethanol damage to the mucosa of the stomach.

Figure 2 presents a diagram describing the effect of the peptide Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg - Pro-Gly-Pro-Pro-Arg - Pro-Gly-Pro, Arg - Pro-Gly-Pro for stress ulceration.

Figure 3 presents a diagram describing the effect of the peptide Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro, Arg - Pro-Gly-Pro on the development acetate ulcers.

4 shows a diagram describing the effect of the peptide Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro, Arg-Pro-Gly-Pro regeneration acetate ulcers.

Below are examples of the invention's implementation:

Example 1.

Peptides injected white outbred rats or Wistar rats intraperitoneally at a dose of 0.58-3,30 µmol/kg body weight in saline solution (0.5 ml per 200 g weight of the animal) for 1 h before oral ethanol or induction of ulcer formation by immersing the animals in the water. To call ulcerative lesions of the mucous membrane of the stomach orally administered 1 ml 96° ethanol or immobilized in the supine position the animal in an upright position is placed in water the temperature of 16° C. In case of multiple introduction of drugs administered after the ulcerogenic action of factor - appliques on the serous membrane of the stomach glacial acetic acid. With this purpose in anesthetized with ether animals reveal the abdomen, bare stomach and on the serosal surface of the gastric fundus (closer to the greater curvature) on 15 impose a cotton swab (area 0.5 mm2)soaked in glacial acetic acid. The surface of serous membranes are dried, cut and sew within 1-7 days the animals get food and water without restrictions. Every day in 1-3-day immediately after exposure to the factor that causes the plague, i.e. on the background of the development of ulcers, or for 4-6 days on the background of already developed ulcers animals, animals receive an intraperitoneal injection of one of the drugs. Control animals received intraperitoneally at the same time injected the same volume of saline. After 1-2 h after injection of ethanol or 3 hours of rats in the water, or on 4 or 7 days after application of acetic acid are slaughtered and under binocular loupe determine the size of the lesions of the gastric mucosa. Antiulcer effect of the drug is calculated as % reduction of area damage experimental animals to the area of damage control animals.

These materials illustrate the achievement of the goal. Thus, figure 1 shows that the horse ulcerative lesions after 1 h after oral administration of ethanol on the background of the introduction of most drugs significantly significantly decreased compared to control rats. Control animals is 72.4 mm2that is significantly larger than the area of damage in rats, which for 1 h prior to the introduction of ethanol received a 0.60 µmol/kg - Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro, Arg-Pro-Gly-Pro. The damaged area was 48, 25, 47, 36, 59 and 46%, respectively. Thus, these drugs display a pronounced anti-ulcer protective effect, equal to 52% for Thr-Lys-Pro-Arg-Pro-Gly-Pro, 75% for - Lys-Pro-Arg-Pro-Gly-Pro, 53% for - Pro-Arg-Pro-Gly-Pro, 64% for - Arg-Pro-Gly-Pro.

A three-hour immersion in water is accompanied by damage of the gastric mucosa considered in the literature as stress ulcers, the area in which the control average 0,834 mm2. Immersion in water, performed after 1 h after intraperitoneal administration of 0.58 µmol/kg peptides resulted in a much smaller area of damage. The damaged area was equal to 11, 14, 45, 85, 50, 98 and 30% (compared to control) in the preliminary introduction Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro, Arg-Pro-Gly-Pro, respectively (figure 2). Thus, all drugs are distinct reliable anti-ulcer protective effect, equal to 89% for Thr-Lys-Pro-Arg-Pro-Gly-Pro, 86% Lys-Pro-Arg-Pro-Gly-Pro, 55% for - Pro-Arg-Pro-Gly-Pro, 15% for - Arg-Pro-Gly-Pro.

Size of the ulcers at 4 days after application of glacial acetic acid on the serous membrane of the stomach of animals from the control was the average of 44.9 mm 2. The area of the ulcers in animals, which in the course of three days, were injected intraperitoneally one of the study drug Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro, Arg-Pro-Gly-Pro in the dose of 0.62 mmol/kg, was calculated in % of the areas ulcers in the control. It turned out that the area of the ulcer was reduced to 53,44; 22,64; 55,79; 48,98 with the introduction respectively Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro, Arg-Pro-Gly-Pro (figure 3). Thus Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro, Arg-Pro-Gly-Pro are reliable protective antiulcer effect on acetate model of ulcer formation, equal 46,56; 77,36; 44;21; 51,02; accordingly, for Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro, Arg-Pro-Gly-Pro.

Introduction peptide Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro, Arg-Pro-Gly-Pro at a dose of 0.58 µmol/kg for 4-6 days after application of the acid, i.e. on the background of already developed ulcers also accompanied by a significant decrease in the area of ulcers compared with control, which is shown in Fig 4. The area of ulceration on day 7 was reduced to 51,59; 41,03; 43,94; 42,85% with the introduction of respectively Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro (figure 4). Arg-Pro-Gly-Pro reduced area ulcers to 84.61%. Thus, Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro, except Arg-Pro-Gly-Pro show reliable medical antiulcer effect on acetate model of ulcer formation, equal 48,41; 58,97; 56,06% respectively for Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pr. Only Arg-Pro-l-RHS showed a tendency to decrease development acetate ulcers. The results of this series of experiments indicate that therapeutic antiulcer effect of Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro, Arg-Pro-Gly-Pro.

Thus, the obtained data demonstrate that Thr-Lys-Pro-Arg-Pro-Gly-Pro, Lys-Pro-Arg-Pro-Gly-Pro-Pro-Arg-Pro-Gly-Pro, Arg-Pro-Gly-Pro show as the tread (ethanol, stress and acetate model)and treatment (acetate model) antiulcer properties in the experiment on animals.

Example 2

Take the drug Thr-Lys-Pro-Arg-Pro-Gly-Pro, 1.0 mg, dissolved in 5 ml of physiological NaCl solution and injected intraperitoneally 5 laboratory rats that within 24 h had no food, no water and were kept in cages with mesh bottom to prevent coprophagia, 0.5 ml per 200 g of body weight (500 μg/kg to 0.6 µmol/kg). The control animals in the same way enter a 0.85% NaCl solution at a dose of 0.5 ml per 200 g of body weight. After 1 h perorally injected 1 ml 96° ethanol. After 1 h after injection of ethanol are slaughtered by air, open the abdominal cavity, cut the stomach, cut on the lesser curvature and washed under running water. Then, the inner surface of the stomach are examined under a binocular magnifier with an eyepiece micrometer and calculate the area of damage in each stomach and then the average size of the lesions in the control and experience of the Oh groups. The damaged area is in the stomachs of the rats of the control group: 14,4; 44,75; 30,75; 38,5; 64,8 mm2. On average 38,58 mm2. The area of damage in rats that received Thr-Lys-Pro-Arg-Pro-Gly-Pro: 21,0; 13,6; 12,5; 1,5; 5,0 mm2; the average area of damage of 10.72 mm2. Protective antiulcer effect is 72%.

Example 3

Take the drug Lys-Pro-Arg-Pro-Cly-Pro -1,167 mg, dissolved in 7.5 ml of saline. The Wistar rats, which for 24 h had no food, no water and were kept in cages with mesh bottom to prevent coprophagia, intraperitoneally injected with 0.5 ml per 200 g of body weight (389 mg/kg-0.6 µmol/kg). Control rats of Wistar line in the same way enter a 0.85% NaCI solution at a dose of 0.5 ml per 200 g of body weight. After 1 h, rats immobilizes in the supine position and in a vertical position is placed in water with a temperature of 16°C. After 3 hours the rats score ether. Then do as described in example 2.

In the calculation of the square of all point of damage in the mucosa of the rats, known in the literature as stress ulcers, it turned out that the experimental rats the size of ulcers is significantly less than the control. The damaged area is in the stomachs of the rats of the control group: 1,36; 1,34; 1,13; 0,95; 0,33 mm2. An average of 1.02 mm2. The area of damage in rats that received Lys-Pro-Arg-Pro-Cly-RHS: 0,01; 0,01;.0,76; 0,24, 0,2 mm2; the average area of damage of the measuring - 0,24% mm 2. Protective antiulcer effect equal 76,47%.

Example 4

Take 10 rats weighing 180-200 g, which for 24 h had no food or water and were kept in cages with wire mesh bottoms in order to avoid coprophagia. Under ether anesthesia to expose the abdominal cavity, exposing the stomach and on the serosal surface of the gastric fundus (closer to the greater curvature) on 15 impose a cotton swab (area 0.5 mm2)soaked in glacial acetic acid. The surface of serous membranes dried, the incision is sutured. Take the drug Arg-Pro-Cly-RHS - 1,104 mg Every day 368 µg dissolved at 3.33 ml of physiological NaCl solution and daily for 1, 2 and 3 days after 24 h injected intraperitoneally 5 experimental rats on of 0.53 ml per 200 g of body weight (292,85 ág/kg - 0.64 µmol/kg). The control animals in the same way enter a 0.85% NaCI solution at a dose of 0.5 ml per 200 g of body weight. On the 4th day rats score ether. Then proceed as described in example 2. Size of the ulcers in the control animals at 4 days after application of acetic acid 48,0; 48,0; 32,0; 35,78; 67.5 mm2. The average size of the ulcer - 46,26 mm2. In rats treated for three days Arg-Pro-Cly-Pro, the area of damage was 10.8:0:22.75; 41.5:0. The average size of the ulcers equal 15,01 mm2. Protective antiulcer effect equal 67,55%.

Example 5

Take 10 rats weighing 180-200 g, which for 24 h did not receive food. neither the odes and were kept in cages with wire mesh bottoms in order to avoid coprophagia. Under ether anesthesia to expose the abdominal cavity, exposing the stomach and on the serosal surface of the gastric fundus (closer to the greater curvature) on 15 impose a cotton swab (area 0.5 mm2)soaked in glacial acetic acid. The surface of serous membranes dried, the incision is sutured. Take the drug Pro-Arg-Pro-Cl-RHS - 1,248 mg Every day 416 µg dissolved at 3.33 ml of physiological NaCl solution and daily for 4, 5 and 6 days (on the background of already formed ulcers) after 24 h injected intraperitoneally 5 experimental rats according to 0.48 ml per 200 g of body weight (299,5 µg/kg of 0.58 µmol/kg). The control animals in the same way enter a 0.85% NaCI solution at a dose of 0.5 ml per 200 g of body weight. On day 7, rats score ether. Then proceed as described in example 2. Size of the ulcers in the control animals on day 7 after application of acetic acid 18,04; 40,0; 45,6; 42,0; 20.0 mm2. The average size of the ulcers in this experiment, control rats 33,13 mm2. In rats treated for three days Pro-Arg-Pro-Gly-Pro, the area of damage was 24,0; 8,75; 0; 9,0; 40,0 mm2. The average size of the ulcers equal 16,35 mm2. Protective antiulcer effect equal 53,67%.

Thus, the peptides of the formula

X-Pro-Gly-Pro, where X=Thr-Lys-Pro-Arg; Lys-Pro-Arg-; Pro-Arg; Arg-used by the method according to the invention, have a high antiulcer activity in a wide range of doses. Spaceballs the invention, providing use as a medicinal product of any of these substances peptide in a wide range of doses, provides high efficiency for the prevention and treatment of ulcers of the gastrointestinal tract.

Method for the prevention and treatment of ulcers of the gastrointestinal tract by injecting drug peptide, characterized in that as a drug used in the peptide of General formula:

X-Pro-Gly-Pro, where

X=Thr-Lys-Pro-Arg-;

Lys-Pro-Arg-;

Pro-Arg-;

Arg, that is administered intraperitoneally at a dose of 0.58-3,30 µmol/kg body weight.



 

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