Method for decreasing body weight in experiment in animals

FIELD: medicine, experimental medicine.

SUBSTANCE: one should introduce tripeptide Pro-Gly-Pro for laboratory animals as injections at the quantity of 0.09-1.0 mg/kg body weight, and, also, gelatin as fodder additive. The method suggested enables to suppress appetite, decrease the quantity of fodder intake that leads to decreased body weight as a result.

EFFECT: higher efficiency.

2 cl, 5 dwg, 5 ex

 

The invention relates to pharmacology, biochemistry, and can be used to suppress appetite, reduce food intake and reduce body weight in animals and is based on the use of the simplest prolinsoderzhashchikh peptides, which are derivatives of the well-known endogenous peptides and food proteins.

Currently overweight and obesity is one of the main factors contributing to the occurrence of cardiovascular diseases in the adult population. Numerous studies conducted and published recently, showed that, among other things, the risk of mortality in cardiovascular diseases and other pathologies increases in direct proportion to the increase in weight (metric BMI). Treatment for excess weight requires significant costs and often leads to disability. It is therefore extremely important from the point of view of health, well-being, aesthetic appeal and try to fix and remove excess weight. It has been shown that weight reduction of 15% can cause positive changes in health status.

The strategy is to bring the body to a normal or acceptable weight should decrease calories and increase physical activity, but to implement it in practice is quite complex is without the use of additional, medical or other assistance.

A known method for correcting the weight of the person by psychotherapeutic installation to reduce appetite using simultaneously nutritious diet nutrition and increased control over food intake. Said treatment is recommended only in the hospital, which is not always acceptable to the individual (RF application No. 99114939, And 61 M 21/00, 1999.07.07, publ. 2001.05.10).

In the application of the Russian Federation No. 94039527 (A 61 N 5/06, 1994.10.20, publ. 1997.02.27) notes that weight reduction can be quite simple and in a short time by exposure to red and green for Central vision and the orange - on peripheral, developing combinatorial creation of visual images, positively acting on the human homeostasis, reducing the appetite.

Widely used for weight loss fasting in different variations regarding diet and fluid intake, but it is recommended only in the hospital (RF patent No. 2005491, a 61 K 35/78, 1991.06.14, publ. 1994.01.15).

Feelings of hunger and satiety are regulated by centers in the brain, primarily the centers of the hypothalamic region. In some pathological conditions involving obesity, overweight, should be used in complex therapy medicinal product, Ogre is ichigaya appetite (anorectics).

At the present time are used as anorectics some synthetic compounds non-hormonal nature, such as amphetamine. The last treatment is performed in combination with low-calorie diet, if necessary, with fasting days. Assign inwards in the form of tablets (25 mg) 2-3 times a day. Treatment is 1.5-2.5 months. If necessary, designate a refresher course after 3 months (Medmaravis. Medicines, M.: Medicine, 1994, t.ii, str).

Known also use for the treatment of obesity and conditions associated with them, derivatives of 1,5-benzodiazepine, as well as their salts and solvate, by introducing a therapeutically effective amount, which results in anorectics effect, is the regulation of appetite, invoked a feeling of fullness (WO 94/24149, GB, publ. 27.10.94, RF patent 2135486, C 07 D 243/12, publ. 27.08.99).

In the published 1999.07.20 the application of the Russian Federation No. 97113700, a 61 K 31/40 (DK No. 96/00011, 10.01.96, publ. 1999.07.20 describes the use of 3,4-diphenylpropane in compositions with pharmaceutically acceptable carrier for the treatment and prevention of obesity.

However, the chemicals usually cause side reactions of the body, such as the appearance of irritability, insomnia, dry mouth, nausea, allergies, fluid retention in the body, etc. When prescribing drugs to people with Soboleva who eat the cardiovascular system and when gipertireoze caution. Paranal, in particular, has a stimulant effect on the Central nervous system, which is not always positive for the person. In addition, this treatment still requires a complex therapy in combination with a low calorie diet and/or fasting days.

Given the disadvantages of the use of chemical drugs for weight loss and appetite suppressant, in recent years, a search for similar funds among the compounds of endogenous nature, in particular proteins.

High molecular weight proteins against obesity proposed in the patents of the Russian Federation No. 97121100, a 61 K 38/16, publ. 1999.08.27 and No. 97114945, a 61 K 38/00, publ. 1999, 07, 20 (country priority - US).

A peptide comprising an analogue of carboxykinase sequence of growth hormone, where carboxykinase sequence contains residues 177-191 human growth hormone:

Leu-Arg-Iie-VaI-Gin-Cys-Arg-Ser-VaI-GIy-GIy-Ser-Cys-Giy-Phe, or a sequence of growth hormone, non-human mammal, in combination with a pharmaceutically acceptable excipient and/or diluent, is proposed for the treatment of obesity in humans (WO 99/12969 (AU), publ. 1999.18.03, the Russian Federation No. 2000109265, From 07 To 14/61, publ. 2002.03.10).

According to the patent of Russian Federation №96109211 (07 K 14/47, publ. 1998.10.27) (country priority - US) proposed a homogeneous or recombinant biologically active human or murine protein of obesity, the content is of ASCII sequence: SEQ ID NO:6 or SEQ ID NO:3 or a fragment, with activity for a specified protein, or conjugates of polyethylene glycol and/or polypropyleneglycol associated with the specified protein with an average molecular weight of 15 kDa to 60 kDa, to reduce food intake in mammals and lower speed adding their weight, treatment, prevention and management of obesity and related diseases.

In the patent of Russian Federation №2197261, a 61 K 38/16, 2003, 27.01 (PCT/DC 97/00086, 1997, 27.02., PCT/WO 97/31943, 1997, 04.09), taken as a prototype, the use of pharmaceutical compositions containing the peptide, for the suppression of appetite or induction of satiety in an individual, but also for the prevention and treatment of diseases or disorders associated with impaired regulation of appetite. As mentioned peptide using glucagon-like peptide, called GLP-2 is secreted from intestinal L-cells, with the following amino acid sequence:

HADGSFSDEMNTILDNLAARDFINWLIQTKITD (GLP-2-person)

HADGSFSDEMNTILDNLATRDFINWLIQTKITD (GLP-2-rat)

HADGSFSDEMNTVLDNLATRDFINWLLHTKITD (GLP-2-hog)

The peptide GLP-2 or its homolog, you can get a technique recombinantly DNA in accordance with methods well-known in this field, in particular a DNA sequence encoding the peptide GLP-2, you can select or synthesize based on the published DNA sequence preproglucagon person.

The method of suppressing appetite Khujand who are by injection of a solution of the pharmaceutical composition on the basis of the indicated peptide in the amount of 5-10 µg/kg body weight. The drug inhibited the consumption of food at 24-32%.

The disadvantages of using these peptides and compositions on their basis are:

- the difficulty of obtaining, separation, purification of the used peptides, since, as a rule, required or osmotic separation, or high-performance liquid chromatography, gel filtration, etc.,

- the risk of side effects, including hormonal, given the relationship of these peptides with hormones.

The present invention is the provision of opportunities to reduce food intake with simultaneous elimination of side reactions in the process of suppression of appetite and weight loss.

This object is achieved in that in the method of reducing body weight in an experiment in experimental animals, including the introduction of the last effective amount of a substance based on the peptide, as indicated substance use gliproliny peptide representing the Tripeptide Pro-Gly-Pro or globalinstanceid food protein, which is gelatine.

It is preferable to use the Tripeptide Pro-Gly-Pro injection in the amount of 0.09-1.0 mg/kg of body weight, and globalinstanceid food protein in the form of food supplements at a dose of 8-10:1 (parts by weight), respectively.

The method is as follows on the example of gipr lanovogo peptide, representing the Tripeptide Pro-Gly-Pro, without restricting the use of other globalnav - Pro-Gly and Gly-Pro, and globalinstanceid food protein, representing gelatine in the experiment on the experimental animals.

Certain number of pipeline Pro-Gly-Pro always present in a living organism, forming as a result of degradation of a number of larger peptides and proteins, which suggests that this peptide as an endogenous compound that does not have serious negative side effects. It is known that globalin Pro-Gly-Pro possesses antiulcer and anti-thrombotic agents properties.

Globalin Pro-Gly-Pro or food protein - gelatin containing a large number of piperalin Pro-Gly-Pro and its metabolites Pro-Gly and Gly-Pro, enter white outbred rats daily for 4-14 days. Gelatin is used as a food Supplement. Rats in the control group get softened in water dry feed and water without restrictions, and the animals of the experimental rats, the same food additive in the form of gelatin in a ratio of 9:1 and water, without limitation, piperalin Pro-Gly-Pro, dissolved in saline, intraperitoneally administered daily at a dose of 0.09-1.0 mg/kg of body weight. Control animals received intraperitoneally at the same time injected the same volume of saline. At the end of the experiment determine the change of body weight per 10 g per day or the amount of food consumed.

In this work, we used globalin Pro-Gly-Pro, synthesized in the laboratory of regulatory peptides of the Institute of Molecular genetics RAS (Moscow) classical methods of synthesis in solution using mixed anhydrides.

As a food Supplement used gelatin company ICN Biomedical Inc. (Ohio, USA), or the Russian gelatin which 86-90% protein.

The research results are processed by the application program Statistica 5.0 for Windows when using LSD test. Differences were considered significant at P<0.05.

Figure 1 shows the impact of pipeline Pro-Gly-Pro on the change in body weight of rats fed globalin Pro-Gly-Pro (1 mg/kg) daily for 5 days.

Figure 1 shows that in control animals the increase of body weight per 100 g weight per day for 6-th day amounted to 1.88 g, and in animals treated with intraperitoneal administration of pipeline Pro-Gly-Pro in the dose of 1 mg/kg daily for 5 days - 0.99, This distinction reliably. Rats treated with globalin Pro-Gly-Pro was added in average daily 0.89 g less per 100 g mass.

Similar results were obtained when fed to rats gelatin as a food Supplement enriched with Pro-Gly-Pro and its metabolites.

Figure 2 illustrates that the control animals increased body weight per 100 g weight per day for 6 days was 2.5 g, and in animals treated with the additive of 4.5 g for 6 days.

Even more is the difference detected for longer receiving food Supplement in the amount of 4 g in 10 days.

Figure 3 presents the results of experiments with 10-day feeding supplements. The rats of this group were added to 3.5 g/100 g weight/day, rats received food Supplement added considerably less 1,95 g/100 g weight/day, i.e. experimental rats were increased at day 1.5 g less than the control.

Figure 4 illustrates the change is an increase in body weight of control and experimental rats after 14-day experiment. The weight gain in the control rats averaged 2,31 g/100 g/day. Rats receiving food Supplement for 14 days to 3.75 g, has gained weight 1.06 g/100 g weight/day, i.e. increase their weight was less than 1.25 g/100 g/day.

Reducing the increase of body weight of the rats when getting nutritional supplements may be due to several reasons, among which may be anorexia, i.e. less consumption of food. It turned out that a 5-day intraperitoneal administration of pipeline Pro-Gly-Pro in the dose of 1 mg/kg / day resulted in decreased food intake in these rats compared with the control, which received intraperitoneal injection of saline. Rats not receiving globalin Pro-Gly-Pro, average daily absorbed 13.9 g/100 g of body weight. Animals receiving globalin Pro-Gly-Pro for 5 days, ate an average of only 9.2 g/100 g of body weight (figure 5).

Example 1

Take 8 outbred rats weighing 195-210 g and dividing them into two groups: control and experimental. The control group of rats daily for 5 days intraperitoneally injected with 1 ml of physiological solution, and the experimental - 1 mg/kg mass globalin Pro-Gly-Pro, dissolved in 1 ml of physiological solution. On day 6, rats were weighed and counted the change in weight in grams per 100 g of body weight per day. Find that weight change, g/100 g weight/day in the control rats is: 2,5; 2,38; 2,25; 2,16 (average 2,32); experimental 1,57; 0,97; 1,0; 1,36 (average of 1.23), representing 53% of the control, i.e. the effect of reducing the addition of body weight of the Tripeptide is 47%.

Example 2

Take 20 outbred rats weighing 130-160 g and divide them into two groups: control and experimental. Experienced rats daily for 5 days has been dissolved in warm water gelatine (4 g). Gelatine used as an additive to conventional stern. Rats in the control group received softened in water dry feed and water without restrictions, and the animals of the experimental group, the same food additive in the form of dry gelatin in a ratio of 9:1 (parts by weight) and water without restrictions. On day 6, rats were weighed and counted the change in weight in grams per 100 g of body weight per day. Find that weight change, g/100 g weight/day in the control rats is: 4,83; 2,22; 1,92; 11,13; 3,4; 3,62; 4,27; 1,29; 2,77; -0,41 (on average 3,52); experienced- -0,54; 0,43; 2,19; 1,2; 0,54; -0,18; 0,27; -1,02; 0,27; 0,54 (on average 0,37), representing 10.5% of the control, i.e. the effect of reduction in which Alenia body weight used as a nutritional Supplement is equal to 89.5%.

Example 3

Take 20 outbred rats weighing 218-256 g and divide them into two groups: control and experimental. Experienced rats daily for 9 days had been dissolved in warm water gelatine. Gelatine used pipeline Pro-Gly-Pro as an additive to conventional stern. Rats in the control group received softened in water dry feed and water without restrictions, and the animals of the experimental group, the same food additive in the form of dry gelatin in a ratio of 9:1 (parts by weight) and water without restrictions. On day 10, rats were weighed and counted the change in weight in grams per 100 g of body weight per day. Find that weight change, g/100 g weight/day in the control rats is: 2,05; 2,47; 4,55; 2,58; 3,01; 2,33; 3,07; 6,72; 2,17; 2,3 (on average, 3,13); in rats fed dietary Supplement, -1,20; 0,75; 1,97; 2,17; 2,19; 2,44; 1,22; 2,48; 1,23; 2,40 (on average 1,81)that is 57,76% of control, i.e. the effect of reducing the addition of body weight when used as a nutritional Supplement for 9 days is 42,25%.

Example 4

Take 10 outbred rats weighing 200-225 g and divide them into two groups: control and experimental. Experienced rats daily for 14 days has been dissolved in warm water gelatine. Gelatine used as an additive to conventional stern. Rats in the control group received softened in water dry feed and water without restrictions, and the animals of the experimental group, the same food with the addition of a VI is e gelatin in a ratio of 9:1 (parts by weight) and water without restrictions. On day 15, rats were weighed and counted the change in weight in grams per 100 g of body weight per day. Find that weight change, g/100 g weight/day in the control rats is: 3,30; 6,71; 2,29; 5,01; 3,19 (on average, 4,10); in rats that received food Supplement, - 0,20; 1,78; 1,62; 0,43; 0,47 (on average 0,90), which is 21,95% of control, i.e. the effect of reducing the addition of body weight when using nutritional supplements within 14 days is 78,05%.

Example 5

Take 8 outbred rats weighing 195-210 g and divide them into two groups: control and experimental. The control group of rats daily for 5 days intraperitoneally injected with 1 ml of physiological solution, and the experimental - 1 mg/kg mass globalin Pro-Gly-Pro, dissolved in 1 ml of physiological solution. Every day in a cage animal control or experimental rats were placed a certain amount of feed (at the rate of 40 g per 200 g of body weight) and the next day was weighing the remaining food and to calculate the amount of eaten food. On day 6 was determined by the total number of intake control or experimental rats. The amount of food eaten was calculated in grams per 100 g of body weight of rats in the day. Find that the amount of intake, g/100 g body weight/day, in control rats is: 22,5; 16,3; 12,70; 11,7 (average 15,80); experienced - a 9.09; 6,10; 8,90; 9,1 (average 8,30), representing 53.5% of the control, i.e. rats on the background is diprolene Pro-Gly-Pro absorb food 46,50% less than the control.

The given examples show that the proposed a fundamentally new physiological drug globalin Pro-Gly-Pro and food Supplement containing it is very effective. Based on experimental data, we can say that the same pipeline Pro-Gly-Pro gliprolinov peptides will have a similar effect of reducing food intake and reduce body weight. The effect of reducing the addition of body weight is 47,0% 5 days prior 78,0% 14 days of receiving pipeline. The advantage of these drugs, containing globalin Pro-Gly-Pro food supplements before many other well-known means of reducing weight also is notorious physiology of their composition and origin, excluding adverse reactions.

1. The way to reduce body weight in experiment on experimental animals, including the introduction of the last effective amount of a substance based on a peptide, characterized in that, as specified substance use gliproliny peptide representing the Tripeptide Pro-Gly-Pro or globalinstanceid food protein, which is gelatine.

2. The way to reduce body weight in experiment on experimental animals according to claim 1, wherein the Tripeptide Pro-Gly-Pro use by injection in the amount of 0.09-1.0 mg/kg of body weight.

3. The way to reduce body weight is xperimenta on experimental animals according to claim 1, characterized in that globalinstanceid food protein used in the form of food supplements at a dose of 8-10:1 parts by weight, respectively.



 

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SUBSTANCE: invention relates to polycyclic dihydrothiazoles and their physiologically acceptable salts and physiologically functional derivatives. Invention describes compounds of the formula (I): wherein r1 and R1' mean independently of one another atoms H, F, Cl, Br and J; R2 means hydrogen atom (H); R3 means chlorine (Cl), bromine (Br) atom; R4 means phenyl, and a method for their preparing. Compounds can be used, for example, as anorectics for prophylaxis or obesity treatment.

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5 cl, 4 ex, 2 tbl

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is prescribed, or its pharmaceutically acceptable salt, ester, amide or a precursor. Also, invention relates to a method for manufacturing the medicinal preparation used for prophylaxis or treatment of states wherein inhibition of activity of enzyme is required wherein indicated enzyme catalyzes hydrolysis of ester functional groups. In the formula (1) A means a 6-membered aromatic or heteroaromatic ring; R1 means a branched or unbranched alkyl (its carbon chain can be broken by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or their substituted derivative wherein a substitute is taken independently among the following group: halogen atom, alkyl, alkyl substituted with halogen atom, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy-, cyano-, nitro-group, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5)R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCX1X2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7, -C(O)NHNR6R7, -C(O)N(OR5)R6 or lipid, or steroid (natural or synthetic) under condition that any substituting heteroatom in R1 or R2 must be separated from exocyclic nitrogen atom by at least two carbon atoms (preferably, saturated atoms), and wherein R4 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl, OR6, NHCX1X2CO2R6 or NR6R7; R5 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl; R6 and R7 are taken independently among hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl, reduced heteroarylalkyl or -(CH2)n(OR5)m wherein n = from 1 to 12, preferably, from 2 to 10; m = from 1 to 3; R5 means preferably (C2-C10)-alkyl; X1 and X2 represent independently hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl or reduced heteroarylalkyl. Also, invention describes compound of formulae (II), (IIa) and (IIb) given in the description and a method for preparing compound of formulae (II), (IIa) and (IIb), pharmaceutical composition used for prophylaxis or treatment of obesity and/or accompanying disorder, nutrition product, a method for prophylaxis or treatment of obesity or accompanying disorders, a method for inhibition of activity of enzymes, a method for reducing fat content in animals, a cosmetic method for maintaining this weight and a new intermediate compound of the formula (IV) indicated in the description. Invention discloses the possibility for prophylaxis or treatment of obesity or accompanying disorders.

EFFECT: valuable medicinal properties of compounds.

33 cl, 1 dwg, 2 tbl, 5 ex

FIELD: peptides, pharmacy.

SUBSTANCE: invention relates to low-molecular derivatives of peptides that are able to act as inhibitors in interaction between laminine and nidogen (interactions laminine/nidogen). Also, invention relates to a method for their preparing, pharmaceutical composition prepared on thereof and their using for preparing pharmaceutical agents, and for identification of inhibitors in interaction laminine/nidogen.

EFFECT: valuable properties of peptides.

5 cl, 12 dwg

FIELD: medicine, traumatology.

SUBSTANCE: osseous defect after filling with collapan and usage of metallofixative should be covered with absorbable collagen film that provides orientation of osseous regenerate's organization.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine.

SUBSTANCE: the suggested multi-purpose heterogeneous collagen matrix for implantation is being flexible-elastic mass obtained out of two collagen sources, moreover, one source is a tissue of vertebrates of one and the same class, and another source - that of an animal of another class, moreover, collagen sources are animal tissues of, for example, mammalian class and avian class, matrix consists of two phases: solid phase - as microspheres out of mammalian tissue collagen, and liquid phase - out of denaturated avian tissue collagen at the ratio of phases being (1-10) : (1-10), at microspheres size being 100-300 mcm, as for final products of biodegradation they are represented by CO2 and H2O. Matrix, additionally, contains components of physiological culture media, and, also, additives that favor the growth and differentiation of cells and tissues, antibacterial and/or antiviral components, and, also, antiaggregation preparations in their efficient quantity, for example, additionally, it contains embryonic cells of nervous tissue. Another aspect of the present innovation deals with the method to obtain the matrix due to preparing mammalian collagen solution (MCS) and denaturated avian collagen solution (ACS), moreover, it is necessary to apply 0.3 M acetic acid, at final concentration for MCS being approximately 0.5-1.5%, and for ACS - approximately 3.0-5.0%, then MCS should be treated with γ -irradiation at the dosage of 1.0 Mrad to be further homogenized to obtain microspheres. Then both MCS and ACS should be washed off with distilled water up to pH of not less than 6.0 and with phosphate buffer solution to mix washed off mammalian collagen and avian collagen at 1:1 ratio at obtaining matrix. The matrix obtained should be additionally supplemented with antibacterial and/or antiviral components, and, also, stimulating agents for tissue regeneration and antiaggregation preparations. The matrix obtained should be sterilized due to γ -irradiation at the dosage of 0.5 Mrad/1 ml. The present innovation enables to obtain new heterogeneous collagen matrix which is considered to be a multi-purpose one applied for transplantology and substitution surgery of different tissues and organs in alive body in case of tissue lesions. Moreover, it is distinguished by controlled terms of biodegradation.

EFFECT: higher efficiency of application.

13 cl, 16 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: method involves applying surgical intervention and antitumor therapy. After having removed a part or the whole lung, mediastinum is opened by cutting out horseshoe-shaped or rectangular flap of mediastinal pleura and carrying out lymphodissection. Then, hemostatic sponge is placed in mediastinum. The sponge is impregnated with antitumor chemotherapeutical preparations in intraoperative mode. Pleura is sutured above the sponge. Another hemostatic sponge impregnated with cytostatic preparations in intraoperative mode is attached to visceral pleura of interlobular sulcus.

EFFECT: prolonged chemotherapeutical preparations delivery to malignant neoplasm foci or subclinical metastases.

The invention relates to medical and cosmetic industry

The invention relates to medicine, namely dentistry
The invention relates to medicine, dental surgery, and in particular to methods of treatment of a wound after tooth extraction and implant
The invention relates to the pharmacy, and in particular to methods of obtaining hemostatic drugs
The invention relates to medicine, namely to neurosurgery, and can be used to improve the clinical results of treatment of patients with occlusive hydrocephalus

FIELD: pharmaceutics.

SUBSTANCE: the set of components is suggested containing: (a) pharmaceutical preparation including low-molecular thrombin inhibitor or its pharmaceutically acceptable derivative in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier; and (b) pharmaceutical preparation including pre-medicine of low-molecular thrombin inhibitor or pharmaceutically acceptable derivative of this pre-medicine in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier, where components (a) and (b), each of them, should be taken in the form suitable to be introduced together; it is, also, suggested to apply this set of components for treating the state at which it is necessary or preferably to inhibit thrombin. The innovation enables to treat thrombotic states such as thrombosis of deep veins and pulmonary embolism.

EFFECT: higher efficiency of application.

30 cl, 1 tbl

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