The agent with immunomodulatory activity

 

(57) Abstract:

The invention relates to pharmaceutical industry. It is proposed to use the dipeptide L-lysyl-L - glutamic acid as a means possessing immunomodulatory activity. 10 table.

The invention relates to pharmaceutical industry and relates to the application of known dipeptide L-lysyl-L-glutamic acid (L-Lys-Glu) as a means possessing immunomodulatory activity.

Known compounds having immunomodulatory activity, these include preparations of thymus derived from animal products, such as: thymosin [1] the adjuvant [2] taktivin [3] and others. These drugs consist of complex substances polypeptide of nature, which are capable of handling different stages of proliferation and differentiation of T-lymphocytes. Their use as immunomodulating agents is difficult due to the complexity of the methods of preparation, low output active substances, considerable variability in their physical and chemical properties, and also because of the possibility of patients adverse reactions due to the presence of natural preparations of thymus ballast components.

the method of high performance liquid chromatography immune-active fractions, representing the dipeptide L-Glu-L - Trp. The optimal dose of the drug timogen for intramuscular injection of 100 μg of 1 times a day for 5-10 days.

However, the effectiveness of thymogen as immune-modulating means is reduced due to the complexity of chemical synthesis, instability of the drug in solution, as well as the unwarranted use of large doses of the drug.

Known dipeptide L-Lys-L-Glu [5] currently used as a component for peptide synthesis.

The problem to which the invention is directed, is the application of known dipeptide L-Lys-L-Glu as an immunomodulating tools.

The synthesis of the dipeptide was performed by the classical method in the solution.

Example of synthesis of the dipeptide:

1. NN-dimensionstability--benzyl-glutamic acid [I]

0,154 g (of 0.65 mmol) g-benzylguanine acid suspension in 3 ml of dimethylformamide, with stirring 0,091 ml of 0.65 mmol) of triethylamine, then 0,300 g (0.59 mmol) of N-oxysuccinimide ether NaNe-dibenzyloxybenzene. The reaction mixture was stirred for 12 h at room temperature. Then dissolve the product with ethyl acetate (h). The organic layer was washed with 1 n H2SO4, water until neutral, dried over PA2SO4. The solvent is distilled off in vacuum at 40oWith, the residue is dissolved in 1-2 ml of ethyl acetate and planted the product with hexane. Recrystallization in the system ethyl acetate/ hexane. The product is filtered and dried in vacuum over P2ABOUT5. Output 0,330 g (88%). Rg 0,81 (benzene:acetone 1:1, Silufol).

2. L-Lysyl-L-glutamic acid.

Protected dipeptide [1] 0,330 g dissolved in 10 ml of methanol, add 3 ml of water and hydronaut over palladium on coal. Monitoring by TLC. Upon completion of the hydrogenation the catalyst is filtered off, the residue is dissolved in a minimum amount of water and planted with methanol. The product is filtered, washed with ethanol, dried in vacuum over P2ABOUT5. Output 0,110 g (85%). So pl. 194-196oC. []2020,0oC (C=3,0; N20) Rg 0,54 (acetonitrile:water 1:3, "Magk"). Electrophoresis: EGly1,96; FHis0,98 (1400 volts, 45 min, 2% acetic acid, "Watmann 3MM").

In experimental study of the specific activity of the claimed substances, carried out in comparison with timagenes identify new, unknown dipeptide L-Lys-L-Glu immunoactive properties, swiatlowski examples.

The effect of the dipeptide L-Lys-L-Glu on the expression of E-receptors of thymocytes.

"Tripsinova" model.

Assess the impact of the dipeptide L-Lys-L-Glu on the expression of E-receptors treated with trypsin lymphoid cells in the thymus of intact Guinea pigs (males) weighing 180-200, the Principle of the method is that after the treatment of thymocytes proteolytic enzyme trypsin, is the destruction of much of the E-receptors on the surface of cells to rabbit erythrocytes, resulting in a decreased percentage of T-lymphocytes detected in the reaction of rosethorne. Previously established that the addition of thymogen to treated with trypsin to thymocytes leads to the restoration of the destroyed part of E-receptors, resulting in the increase in the number of rosette cells (T-lymphocytes).

To assess the biological activity of the dipeptide L-Lys-L-Glu was used 48 Guinea pigs. With the aim of obtaining suspensions of lymphocytes in the thymus of animals homogenized in medium 199. In suspensions of thymocytes was determined by the percentage of "active" T-lymphocytes (EA-ROCK) method rosethorne with rabbit erythrocytes[6]

The dipeptide L-Lys-L-Glu and timogen was dissolved in 0.9% NaCl solution and was made in chevolet to reduce more than 2 times the number of lymphocytes, having on the surface of E-receptors. The addition of the dipeptide L-Lys-L-Glu at concentrations of 10-41 µg/ml and thymogen at concentrations of 10-21 µg/ml resulted in restoration of the number of E-receptors in T-lymphocytes of the thymus (table.1).

Thus, the dipeptide L-Lys-L-Glu in a large range of concentrations enhances the expression of E-receptors of T lymphocytes, which might be due to the direct ligand-receptor interaction. Similar action has timogen at a dose 100 times higher than the dose of the dipeptide L-Lys-L-Glu, which indicates a higher biological activity of a new synthetic dipeptide.

2. The model of "old dogs".

Assess the impact of the dipeptide L-Lys-L-Glu on the expression of E-receptors of thymocytes old Guinea pigs (males weighing 700-800,

The principle of the method is that in animals with age-related involution of the thymus on the surface of lymphocytes decreases the number of E-receptors to rabbit erythrocytes, resulting in decreasing the percentage of rosette T-lymphocytes.

With the purpose of comparative evaluation immunostimulating action of the dipeptide L-Lys-L-Glu and thymogen used thymocytes 42 intact marine stnoe the content of T-lymphocytes (E-ROCK) method rosethorne with rabbit erythrocytes [7]

Studied dipeptide and timogen was dissolved in 0.9% NaCI solution and added into the cell culture at concentrations of 1,10-2, 10-4µg/ml.

The results of the experiment found that in Guinea pigs with age-related involution of the thymus reduced the number of T-lymphocytes, detected in the reaction of rosethorne. Timogen contributed to significant increase in rosette T-lymphocytes only at a concentration of 1 μg/ml, whereas the dipeptide L-Lys-L-Glu had a stimulating effect on the expression of E-receptors of T lymphocytes in all the tested concentrations (table.2).

Thus, the stimulatory effect of L-Lys-L-Glu is manifested in concentrations in 100-10000 times smaller than the concentration of thymogen.

The effect of the dipeptide L-Lys-L-Glu on subpopulations of T-lymphocytes in human peripheral blood.

Assess the validity of the dipeptide L-Lys-L-Glu on lymphocyte subpopulations, using the reaction of an indirect immunofluorescence assay with monoclonal antibodies raised to differentsirovannym antigens to the cell surface.

Lymphocytes were isolated from heparinized (25 u/ml) peripheral blood of 18 patients with purulent-inflammatory diseases of the lung and chronic gnante density ficoll-eurotrust. Selected cells were incubated with the dipeptide L-Lys-L-Glu in concentrations of 1, 10-2, 10-4μg/ml and timagenes in concentrations of 1, 10-2, 10-4μg/ml for 45 min at 37oC.

In a control sample was added medium 199. Then in cultures of lymphocytes using the method of indirect immunofluorescence reaction with mouse monoclonal antibodies OKT and OCT ("Ortho",USA), received by differentsirovannym the surface antigens of lymphocytes [8] determined the percentage of T-helper cells (OKT+), T-suppressor (OCT+) and calculated the coefficient of differentiation OCT+/OCT+.

It is established that the effect of the dipeptide L-Lys-L-Glu in all concentrations increased initially decreased the number of T-helper cells (PL.3). Timogen restored the content of T-helper cells at concentrations of 1, 10-2µg/ml of Both drugs significant change in the number of T-suppressors in this category of patients in studies in vitro did not cause.

The results of the experiment indicate pronounced immunobiological activity of the dipeptide L-Lys-L-Glu, manifested in the increased expression of receptor of T-helper cells. Timogen has a similar effect in the end is mmunicate healthy animals.

The work is performed on a healthy Guinea pigs male weighing 250-300 g In each experimental and control group consisted of 10 animals. The study drugs were administered to the animals once daily intramuscularly for 5 days at doses of: dipeptide L-Lys-L-Glu 0,01 µg/kg, timogen 1 µg/kg to the Animals of the control group on a similar scheme was injected with saline.

Analysis was performed on 10 days from the beginning of injection. In the blood, thymus, lymph nodes, spleen and red bone marrow was evaluated by the number of T-lymphocytes, "active" T-lymphocytes in the reaction spontaneous rosethorne with rabbit erythrocytes, lymphocytes method rosethorne with sheep erythrocytes treated with antibodies and complement [9]

It is established that 10 days from the beginning of injection, the animals treated with the new dipeptide and timogen, there has been an increase in the number of T-lymphocytes in the peripheral blood, thymus, spleen and bone marrow (table.4). Along with this, timogen contributed to the increase in the number of b-lymphocytes in the peripheral blood, and the dipeptide L-Lys-L-Glu in the spleen.

The findings suggest that the study of dipeptide provides similar to those 100 times smaller than timogen.

The effect of the dipeptide L-Lys-L-Glu on the indices of nonspecific protection and the immune system of mice.

The study used 80 mice male CBA weighing 18-20 g, which once daily intraperitoneally for 6 days was administered investigational drugs: timogen in doses of 1 mg/kg and 0.01 mg/kg and the dipeptide L-Lys-L-Glu in the dose of 0.01 μg/kg of the Control animals were injected with pyrogen-free saline. All animals were divided into two parts, 40 mice, each of which was 4 groups of 10 animals. In the first part of the animals are not subjected to any additional impact, in the second received intraperitoneal injection of peptone.

In the first part of the experiment, animals were scored by the method of cervical dislocation and investigated the thymus, spleen and neindutsirovannom cells of peritoneal exudate. Thymus and spleen were weighed.

The homogenized spleen, two spleens were prepared cell suspension and determined the percentage of T - and Limfotsitov in the indirect method of immunosenescence [10] to identify on their surface Thy-1 antigen and immunoglobulin receptors. The immune serum to Thy-1 antigen was obtained by immunization of rabbits with a total fraction of mouse IgG, selected precipitation with ammonium sulfate.

Using fasovannogo devices fluorescent microscope was determined by the total number of splenocytes in the field of view and cells, giving the luminescence membrane type.

Cells of peritoneal exudate was pulirula, were counting their total number and determined the percentage of macrophages in smears stained by Romanovsky. Then they were centrifuged at 150 g for 10 min, resuspendable in medium 199 and determined the ability of cells to recover nitro-blue tetrazolium (nst) [12] as an inductor used zymosan. opsonizing complement Guinea pigs according to standard methods [13] the Results were taken into account in the multi-channel spectrophotometer at a wavelength of 620 nm.

To assess the absorption capacity of macrophages used the reaction with neutral red [14] the Results were taken into account in the multi-channel spectrophotometer at a wavelength of 540 nm.

The other part of the animal (40 mice, 10 animals per group) for 2.5 h before the end of the experiment received intraperitoneal injection of 10% sterile peptone to obtain maximum yield of neutrophils (95-98%). The concentration of cells in the peritoneal bhakta absorption served daily culture of Staphylococcus aureus at a final concentration of 250 million/ml.

In smears stained by Romanovsky-the Institute has identified the phagocytic index (the percentage of neutrophils involved in phagocytosis and phagocytic index (number of microbes captured one neutrophil) [15]

When studying the action of drugs on the weight of the thymus and spleen (table.5) it was found that the introduction of the dipeptide L-Lys-L-Glu in the dose of 0.01 mg/kg had no effect on the weight of the thymus, but caused an increase in the weight of the spleen.

Introduction thymogen in comparable dose of 0.01 μg/kg caused a different effect reducing weight of thymus and spleen.

Timogen in a large dose of 1 mcg/kg, approaching the dosage used in the clinic, caused a significant reduction in the weight of thymus, while not affecting the weight of the spleen.

Reducing the weight of lymphoid organs, observed under the action of thymogen at a dose of 0.01 μg/kg, was also caused by the decrease in the number of cells of peritoneal exudate (0.9 million/ml compared with control 1.9 million/ml). Another dose of thymogen, and the dipeptide L-Lys-L-Glu on the contents of the cells of peritoneal exudate had no effect (1.9 million/ml and 1.8 million/ml, respectively). The percentage of macrophages among cells of peritoneal exudate in the groups did not change and remained within the normal range was Avalos (PL.6) In other groups the content of any T-, no b-lymphocytes did not change.

When studying the effect of drugs on resident peritoneal macrophages (table. 7 and 8) had a stimulatory effect of the dipeptide L-Lys-L-Glu and thymogen in doses of 0.01 mg/kg were noted equally for both groups of animals the strengthening of both spontaneous and induced the ability of macrophages to restore the PCT, and the ability to absorb neutral red dipeptide L-Lys-L-Glu were 1.3 times more active than timogen.

Timogen at a dose of 1 mg/kg had no effect on the studied characteristics of macrophages.

To study the effect of drugs on the functional activity induced by peptone neutrophils showed that the dipeptide L-Lys-L-Glu possessed the ability to enhance chemotactic (PL. 9) activity and phagocytosis of staphylococci (table.10).

Timogen in comparable dose of 0.01 μg/kg did not possess the ability to stimulate neutrophils. However, in a large dosage of 1 mg/kg of body weight timogen also stimulated phagocytosis and chemotaxis of neutrophils.

Thus, both of the investigated drug had the potential to cause significant redistribution of lymphoid cells in the body, and to provide a stimulating dascalescu can stimulate macrophages, and neutrophils, while timogen in a large dose (1 mg/kg) stimulated only neutrophils, and to a lesser dose (0,01 mg/kg) stimulated only macrophages.

The results of experimental study of the proposed drug attest to its high immunological activity New dipeptide has a strong immunostimulatory effects on indices of cellular and humoral immunity in doses example, 100-1000 times smaller than timogen. The dipeptide L-Lys-L-Glu has a broader spectrum of action on the indices of nonspecific resistance of the organism, increasing the functional activity of phagocytes and neutrophils in a dose 100 times smaller than timogen.

Thus, the known prior to the filing of an invention application properties of the dipeptide L-Lys-L-Glu does not suggest obvious use as immunomodulating funds, which means the application of the above dipeptide for a new purpose.

Sources of information

1. Gldstein A. L. on A. Zatz M. M. et. al. Purification and bioligcal activity of thymosin, a hormone of the thymus gland // Proc. Nat. Acad. USA.

1972. Vol. 69, No. 7. P. 1800-1803.

2. Mashkovsky M. D. Medicines. M. Medicine, 1988. so 2, 9 main, C. 168-175.

3. Arion C. J. Taktivin (T-AK the tx2">

4. Yakovlev, M. Khavinson C. H. frost Century, and other Comparative study of the biological activity of thymalin and synthetic peptide thymus // proc.Dokl.scient.Conf."Biochemistry medicine" L. 1988, C. 217-218.

5. SERVA Catalog. Heidelberg, 1987/88.-PE 1 PE 40.

6. Nekam K, Fudenberg, H. H. Strelkanskas A. J. Identification of "activ" T-lymphocytes among effector cells in guinea pigs // Immunopharmacol.-1982. -Vol.5, N 1.-P. 85-94.

7. Stadecker, M. J. Bishop, G. H. H. Wortis Rosette formation by guinea pig thymocytes and thymus derived lymphocytes with rabbit red blood cells // J. Immunol.-1973. Vol.111, N 6.-P. 1834-1837.

8. Reinherz, E. L. Kung, P. C. Goldstein G. S. F. Schlossman Separation of functional subsets of human T-cells by a monoclonal antibody // Proc. Nat. Acad. Sci. USA 1979. Vol.76, N 8.-P. 4061-4065.

9. Bianco C. Patrick R. Nussenzwieg V. A population of lymphocytes bearing a membrane receptor for antigen-antibody complement complexes. I. Separation and characterization // J. Exp. Med. 1970. Vol.132, N 4.-P. 702-720.

10. Storch Century Emmrich Th. Determination of cellular markers using membrane immunofluorescence assay // Immunological methods. M. Medicine, 1987.- S. 254-268.

11. Jolub E. S. Brain-associated O antigen: reactivity rabbit anti-mouse brain nith mouse lymphoid cells // Cell. Immunol.-1971.-Vol.2.-P. 353-361.

12. Rook, J. A. W. et al.//J. Immun.Meth.-1985.-Vol.82-P. 161-167.

13. Guidelines for the evaluation of the immunological properties of pharmacological agents. M. 1992.

14. Methods study faguoqitirute cells in the evaluation of the immune status of the person. L. 1986.


 

Same patents:

The invention relates to the synthesis of biologically active compounds, in particular to new derivatives of N-phenylglycinate formula

< / BR>
the way they are received and to farbkomposition based on them

The invention relates to new biologically active compounds derived boron-containing peptides and pharmaceutical composition having inhibitory activity to trypsinogen serine proteases, which can find application in biology and medicine

The invention relates to new derivatives of dipeptides with pharmacological activity, and the way they are received, and may find application in medicine

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to applying compounds of the formula (I) for preparing an antibacterial composition and veterinary composition eliciting with the enhanced activity.

EFFECT: valuable properties of agents.

4 cl, 3 tbl, 78 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to macrocyclic peptides of the general formula (I): wherein W means nitrogen atom (N); R21 means hydrogen atom (H), (C1-C6)-alkoxy-, hydroxy-group or N-(C1-C6-alkyl)2; R22 means hydrogen atom (H), (C1-C6)-alkyl, CF3, (C1-C6)-alkoxy-group, (C2-C7)-alkoxyalkyl, C6-aryl or Het wherein het means five- or six-membered saturated or unsaturated heterocycle comprising two heteroatoms taken among nitrogen, oxygen or sulfur atom and wherein indicated Het is substituted with radical R24 wherein R23 means hydrogen atom (H), -NH-C(O)-R26, OR26, -NHC(O)-NH-R26, -NHC(O)-OR26 wherein R26 means hydrogen atom, (C1-C6)-alkyl; R3 means hydroxy-group or group of the formula -NH-R31 wherein R31 means -C(O)-R32, -C(O)-NHR32 or -C(O)-OR32 wherein R32 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; D means a saturated or unsaturated alkylene chain comprising of 5-10 carbon atoms and comprising optionally one-three heteroatoms taken independently of one another among oxygen (O), sulfur (S) atom, or N-R41 wherein R41 means hydrogen atom (H), -C(O)-R42 wherein R42 means (C1-C6)-alkyl, C6-aryl; R4 means hydrogen atom (H) or one-three substitutes at any carbon atom in chain D wherein substitutes are taken independently of one another from group comprising (C1-C6)-alkyl, hydroxyl; A means carboxylic acid or its alkyl esters or their derivatives. Invention relates to pharmaceutical compositions containing indicated compounds and eliciting activity with respect to hepatitis C virus and these peptides inhibit activity of NS3-protease specifically but don't elicit significant inhibitory activity with respect to other serine proteases.

EFFECT: valuable biochemical and medicinal properties of peptides.

106 cl, 9 tbl, 61 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: organic chemistry and drugs.

SUBSTANCE: New class of compounds of general formula 1, where R has formula 2 or 3; other residues are as described in claim of invention is disclosed. Said compounds are interleikyn-1β converting enzyme (ICE) inhibitors and have specific structural and physicochemical properties. Invention also relates to pharmaceutical composition containing said compounds. Compounds and composition of present invention are particularly useful in ICE activity inhibition and thereby can be used as drug for treating of diseases mediated by IL-1, apoptosis, IGIF and IFN-γ, as well as inflammations, autoimmune diseases, bone-destructive disorder, infections, disorder associated with cell proliferation, degenerative and necrotic disorders. Uses of claimed compounds and compositions as well as methods for production of N-acylamino compounds also are disclosed.

EFFECT: effective interleikyn-1beta converting enzyme inhibitors.

64 cl, 35 ex, 35 tbl, 21 dwg

FIELD: medicine, gastroenterology.

SUBSTANCE: traditional eradication therapy should be supplemented with licopid at the dosage of 10 mg per os once daily before breakfast for 10 d. The present innovation prevents transfer of microorganisms into inactive form, accelerates restoration of mucosal epithelial layer in gastroduodenal area, provides complete eradication of microorganisms, that in its turn, favors to prevent disease exacerbation and restoration of gastroduodenal functions.

EFFECT: higher efficiency of therapy.

3 dwg, 2 ex

FIELD: biotechnology, biochemistry.

SUBSTANCE: invention relates to producing the biologically active complex eliciting antioxidant and immunomodulating activity and used in medicine, cosmetics, veterinary science and food industry. The biologically active complex preparing by enzymatic hydrolysis of muscle tissue represents complex of biologically active compounds involving carnosine and anserine in the amount 85-97 wt.-% of the native content of these components in poultry muscle tissue, 1-7 weight parts of amino acids, 0.5-12 weight parts of oligopeptides of molecular mass 10 kDa, not above, and 0.1-15 weight parts of cyclic and polycyclic phenolic compounds as measured for 1 weight part of carnosine and anserine in the complex. This complex is prepared by enzymatic hydrolysis of milled and homogenized water muscle tissue in preferable dilution homogenate with water in the range 0.2-0.6 and with using proteolytic enzymes in the amount 2-5 wt.-% of the protein content and working at pH 4.5-8.5 and at enhanced temperature being preferably at 45-65°C. Product is isolated as extract or powder prepared in drying the extract. Invention provides enhancing effectiveness of the claimed complex.

EFFECT: improved method for preparing, valuable properties of complex.

7 cl, 6 tbl, 6 ex

FIELD: medicine, cardiology, gastroenterology.

SUBSTANCE: invention relates to a method for treatment of ulcer-erosion injures in gastroduodenal region in patients with arterial hypertension. Method involves detection of immune disturbances and carrying out the combined immunomodulating therapy and hypotensive therapy. Immunocorrecting complex consists of licopide, cortexinum, vetoronum TK in arterial hypertension of I-II degree and comprises superlymph additionally in arterial hypertension of III degree. Method provides attaining optimal results in treatment for relatively short time due to adequate immunocorrection in such patients.

EFFECT: improved method for treatment.

5 cl, 6 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new inhibitors of thrombin of the formula (I)

,

method for their preparing, intermediate compounds used for their preparing of the formula (II)

and a pharmaceutical composition comprising compounds of the formula (I). Invention provides enhancing effectiveness in inhibition of thrombin.

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

23 cl, 61 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a combined medicinal agent used in treatment of arterial hypertension. The proposed agent comprises the combination of enalapril maleate and hydrochlorothiazide as an active component, and also sodium hydrocarbonate, starch, lactose, iron oxide and stearate as accessory substances. The proposed agent is stable in storage and releases the active component easily.

EFFECT: improved and valuable properties of agent.

8 cl, 1 tbl, 5 ex

FIELD: veterinary science, pharmacy.

SUBSTANCE: invention proposes a composition for antioxidant protection of cells, tissues and a whole body against hyperproduction of free radicals in acute inflammation, chemical thermal and radiation damages. The composition comprises peroxyredoxin Prx VI and, additionally, lipoic acid and pharmaceutically acceptable additives. The composition comprises peroxyredoxin Prx VI and dihydrolipoic acid taken in the effective amount in the ratio peroxyredoxin Prx VI to dihydrolipoic acid in the range (w/w) from 1:1 to 50:1 wherein peroxyredoxin Prx VI can represents human recombinant peroxyredoxin Prx VI. Also, invention relates to a method for enhancing antioxidant protection of mammals involving delivery of indicated pharmaceutical composition is carried out into intercellular space of tissue, organ or a whole body of mammal. The delivery can be carried out by passive or active diffusion in application or spraying, by parenteral or endolumbal administration by injection, by parenteral administration, infusion, inhalation, drainage, by sublingual, vaginal or rectal administration, by nasal or ophthalmic drops. Except for, the delivery can be carried out with using other therapeutic agent, in particular, interferon simultaneously. Invention provides prophylaxis of secondary alternative damages, recovery of epithelial tissue, protection of biomacromolecules against effect of irradiation.

EFFECT: valuable medicinal properties of composition.

6 cl, 9 tbl, 11 dwg, 45 ex

Up!