Cyclophilin a as granulocytopoiesis stimulant, radioprotector and immune stimulant

FIELD: medicine.

SUBSTANCE: invention concerns medicine, particularly granulocytopoiesis stimulants, radioprotectors and immune stimulants. Under cytostatics effect Cyclophilin A amplifies granulocyte precursor removal from marrowbone and stimulates granulocytopoiesis.

EFFECT: in case of sublethal radiation, cyclophilin A stimulates migration of marrowbone stem elements and participates in recovery of blood cells and immune system, and shows redioprotection properties.

4 dwg, 2 tbl


The invention relates to medicine, namely to funds with granulocytopoiesis, radioprotective and immunostimulatory properties.

It is known that in Oncology uses a number of medicines, promoting the recovery of hematopoiesis after application of radio - and chemotherapy, such as macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (g-CSF) (Richards D. Prevention of oral mucositis in cancer patients treated with chemotherapy or radiotherapy. Evid Based Dent. 2006; 7 (4): 106; Peoples GE, Holmes JP, Hueman MT, Mittendorf EA, Amin A, Khoo S, Dehqanzada ZA, Gurney JM, Woll MM, Ryan GB, Storrer CE, Craig D, Ioannides CG, Ponniah S. Combined clinical trial results of a HER2/neu (E75) vaccine for the prevention of recurrence in high-risk breast cancer patients: the U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Clin Cancer Res. 2008 Feb 1; 14 (3): 797-803).

The closest in purpose to the claimed tool (prototype) is a granulocyte colony-stimulating factor (g-CSF) (Xiao BG, Lu CZ, Link H. Cell biology and clinical promise of G-CSF: immunomodulation and neuroprotection. J Cell Mol Med. 2007; 11 (6): 1272-90). It is known that g-CSF induces the differentiation of stem elements of bone marrow neutrophils (granulocytes), mobilizes their release into the peripheral blood, increasing their production. G-CSF polarizes T-cell differentiation from T-helper 1 type to the helpers of the 2nd type (Pan L, Delmonte JJ, Jalonen CK, Ferrara JL. Prereatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. Blood 1995; 86: 4422-9). The use of g-CSF promotes the generation of suppressor T cells (CD4+25+) and suppressor of cytokine (IL-10, TGF-β) (Morris ES, MacDonald KP, Rowe V, Johnson DH, Banovic T, Clouston AD, Hill GR. Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance. Blood 2004; 103 3573-81). In addition, g-CSF is a radioprotector (Bertho JM, Frick J, Prat M, Demarquay C, Dudoignon N, Trompier F, Gorin NC, Thierry D, Gourmelon P. Comparison of autologous cell therapy and granulocyte-colony stimulating factor (G-CSF) injection vs. G-CSF injection alone for the treatment of acute radiation syndrome in a non-human primate model. Int J Radiat Oncol Biol Phys. 2005 Mar 1; 63 (3): 911-20., Streeter PR, Dudley LZ, Fleming WH. Activation of the G-CSF and Flt-3 receptors protects hematopoietic stem cells from lethal irradiation. Exp. Hematol. 2003 Nov; 31 (11): 1119-25).

Object of the invention is the expansion of the range of funds

with stimulating granoulozitopoez, radioprotective and immunostimuliruyushhim action.

Cyclophilin A - protein with a molecular mass of 18 KD with catransition activity (G. Fischer, H. Bang, C. Mech S. Determination of enzymatic catalysis for the cis-trans-isomerization of peptide binding in proline-containing peptides. Biomed. Biochim. Acta. 43. 1984. P.1101-11). Cyclophilin a is a ligand for binding of cyclosporine A, and this is due to the immunosuppressive effect of the latter (D.A.Fruman, S.J.Burakoff, B.E.Bierer. Immunophilins in protein folding and immunosuppression. FASEB J. 8. 1994. 391-400). Cyclophilin And is actively involved in autoimmune diseases, causing inflammation in the periphery (P.Zhu, J.Ding, J.Zhou, Expresion of CD147 on monocytes/macrophages in rheumatoid arthritis: its potential role in monocyte accumulation and matrix metalloproteinase production. Arthritis Research & Therapy. 7. 2005. P.1023-33, A.Billich, G.Winkler, H.Aschauer, A.Rot, P.Peichl. J Exp Med. 185. 1997. P.975-80). Activated macrophages can secrete cyclophilin And the external environment (B.Sherry, N.Yarlett, A.Strupp. Identification of cyclophilin A as A proinflammatory secretory product of lipopolysaccharide-activated macrophages. Proc.Natl. Acad. Aci. 89 (1992) 3511-15). Cyclophilin a has a chemotactic effect, regulating the migration of Mature monocytes, neutrophils, eosinophils and T-lymphocytes, thus forming a zone of inflammation (Q.Xu, M.C.Leiva, SA.Fischkoff, R.E.Handschumacher, C.R.Lyttle. Leukocyte chemotactic activity of cyclophilin. J Biol.Chem. 267.1992. P.1168-71). Cyclophilin And is not used as a drug. The main efforts of the researchers focused on the search for substances antagonists (various forms of cyclosporine A), the neutralizing effect of cyclophilin And in inflammatory and other processes (Shuai Chen, Xuemei Zhao, Jinzhi Tan, Structure-based identification of small molecule compounds targeting cell cyclophilin A with anti-HIV-1 activity. European Journal of Pharmacology, 565. 2007. P.54-59).

To accomplish the task assessed the impact of cyclophilin And migration of stem cells from bone marrow in vivo in sublethal irradiated mice according to the method Till J.E., McCullough E.A (J.E.Till, ..McCullough. A direct measurment of the radiation sensitivity of normal mouse bone marrow cells. Rad Res. 14 (1961) 213-22). Native cyclophilin And were obtained from the culture fluid of cells murine thymoma EL-4 by biochemical purification to final protein purity not less than 95%. For irradiation use the built 35-50 adult mice females (C57BL/6x CBA) F1 at the age of 12-14 weeks weighing 20-22 g, which were divided into five groups of 7-10 animals in each group. Mice were irradiated With60gamma - ray therapeutic apparatus "Agat-R (Russia) with an initial capacity of 1.9×1014Bq dose of 4.5 Gy. The experiment was repeated three times.

Cyclophilin And were injected to the mice tail vein at a dose of 30 μg/mouse 24 hours after irradiation. As a control were injected buffer used when cleaning cyclophilin A. within seven days after irradiation, the mice were scored by the method of cervical dislocation. The spleen was removed and placed in fixative liquid, consisting of glacial acetic acid and absolute alcohol in a ratio of 1:3. Visual counting of endogenous colonies in each spleen was performed after 4 hours.

It was revealed that the number of colonies of stem cells produced in the spleen studied mice was increased 2-3 times compared to control animals.

Next was an in-depth analysis of the target cells of cyclophilin And in the bone marrow. Bone marrow cells were obtained by washing the culture medium RPMI 1640 femur and tibia bones of the mouse. Cell suspension was obtained by skipping through a needle of the syringe, and precipitated in a centrifuge. Erythrocytes were removed 0,85% solution of NH4Cl, then washed with a solution of Earl. Then the cells were diluted with RPMI medium 1640 and used at a concentration of ×10 6%.

When evaluating surface markers migrated bone marrow cells used transwell with the size of the pores are 5 micron (Costar). The buffer containing cyclophilin A, was placed on the bottom of 24-hole tablet in the amount of 600 ál. The bone marrow cells of mice (5×106/ml) were placed over the membrane in a volume of 100 μl and were cultured for 90 minutes at 37°C and 5% CO2. In the control buffer (the eluate from the column) and a buffer containing cyclophilin A, and bone marrow cells were added to bovine serum albumin to a final concentration of 0.5%. After a time the cultivation of the membrane were removed and the number of migrated cells in the bottom wells were counted under a microscope.

To determine the cellular phenotype was used the method of flow cytofluorometry (FaxCalibur, Beckon Dickenson Cell Quest program). Identification of cellular markers was performed using fluorescencebased monoclonal antibodies (Pharmingene), using antibodies to molecules: CD31 (PE), Gr-l(CD97) (FITC), SCA-1 (FITC),CD3 (FITC), B220 (PE), CD19 (FITC),.CDllb(PE), CDllc (FITC). Dead cells was determined by adding propecia iodide and were excluded from the study.

For detection of targets that are sensitive to the presence of cyclophilin And analyzed the phenotype of bone marrow cells that migrated in vitro under his influence.

SCA-1 marker characterizes the population of immature GE is poeticheskih stem cells in the bone marrow. The influence of cyclophilin And migration of stem SCA+cells presented on Figa, thus there is a slight increase in the number of cells carrying the marker. The influence of cyclophilin And susceptible cells later differentiation, lost a molecule of SCA-1 on its surface.

GR molecule-1 (CD97) is a marker of granulocytes different levels of differentiation and Mature neutrophils. The adhesion molecule CD31 is present on immature granulocytes (GR-1+cells) and its amount is reduced in the process of cell maturation (A.Solowiej, P.Biswas, D.Graesser, J.A.Madri. Lack of platelet endothelial cell adhesion molecule-1 attenuates foreign body inflammation because of decreased angiogenesis. American J. of Pathology. V.162. 2003. P.953-62). Immature precursors of granulocytes GR-1+CD31+carrying both of the analyzed molecules on their surface, show a pronounced ability to migrate under the influence of cyclophilin A. Influence of cyclophilin And migration of the precursors of granulocytes shown in Figv. Also, there was an increase of migration of immature CD31+not related to the granulocyte precursors.

CD3+- marker T-cell population. In the bone marrow are the T-cells of various degrees of differentiation. The influence of cyclophilin And migration of T-cells in the bone marrow presented on Figs. The analysis showed that T-cells are highly sensitive to resultview of cyclophilin A. The number of cells migrated in the presence of cyclophilin And increased more than 10-fold compared to control.

In the analysis of B220+CD19+markers shown that precursor cells are also susceptible chemoattractive action cyclophilin And that reflected on Fig.1D. Cyclophilin And influence the migration of precursor cells of different degrees of differentiation (less Mature - B220+and more Mature B220+CD19+).

Cyclophilin And also stimulates the migration of precursors of dendritic cells with the phenotype of CDllb+CDllc+and CDllc+presented at Five. At the same time, the precursors of macrophages with phenotype CDllb+CDllc-not sensitive to the presence of cyclophilin And that distinguishes them from Mature monocytes.

Evaluation of biological activities of recombinant cyclophilin And man. Because of the almost complete gomologichnosti (a difference of one amino acid) cyclophilin And mouse and human species shows nonspecific activity. The effect of recombinant human cyclophilin And those obtained from the transfected gene cyclophilin And human cells E-coli, education splenic colonies of stem cells in sublethal irradiated mice are presented in table 1 and in figure 2 (a, B). On Figa presents the spleen of a mouse treated with buffer, figure 2 is - the spleen of a mouse treated with 50 μg of cyclophilin A. As can be seen, cyclophilin And significantly increases the migration of stem cells that form colonies in the spleen.

To assess the ability of cyclophilin And to restore hematopoiesis conducted a comparative analysis of its activity with g-CSF on the model for determining the activity of g-CSF (Morrison SJ, Wright DE, Weissman IL. Cyclophosphamide/granulocyte colony-stimulating factor dosage of hematopoietic stem cells to proliferate prior to mobilization. Proc. Natl. Acad. Sci. USA Vol.94, pp.1908-1913, 1997). Mice CBA (H-2to) was treated with cyclophosphamide, which was administered intraperitoneally at a dose of 150 mg/kg of body weight. A day later the mice were injected subcutaneously cyclophilin A (25, 50 and 100 µg/mouse) or g-CSF (2 μg/mouse). As a control were injected buffer used when cleaning cyclophilin A. the Injection was carried out during four days, after which the blood of animals examined on the contents of the number of leukocytes, lymphocytes, granulocytes and monocytes.

Blood sampling was carried out from a cut tail vein in a volume of 5 microliters and bred her in 95 Microlitre 3% acetic acid. Blood smears were prepared on glass, dried, and treated with 96% ethanol for 1-2 s, re-dried and treated with paint Azur-eosin according to Romanovsky within 30-45 minutes, the slides were washed in water, dried and perform microscopic examination.

The obtained results revealed comparable in Sodeistvie of cyclophilin and g-CSF on the recovery of the number of leucocytes in peripheral blood of mice treated with cyclophosphamide (103on microliter of blood) (Figure 3 and Table 1). Cyclophilin as well as g-CSF is a means of promoting the differentiation of stem cells of bone marrow, granulocytes, and mobilizes them into the bloodstream (Figure 4, Table 2).

The technical result of the invention:

- Cyclophilin And enhances the migration of stem elements from the bone marrow to the periphery of sublethal irradiated animals.

- Stimulates the formation of precursors of granulocytes and their exit from the bone marrow into the bloodstream when applied chemotherapy.

- Stimulates migration of dendritic cells and precursors of T - and b-lymphocytes.

Cyclophilin And can be used as a stimulator granulocytopoiesis, radioprotector and immunostimulant.

Table 1
Dose cyclophilin And in µg/mouse01102550
The number of colonies in the spleen7,48,26,815,720,0

Table 2
Morphological groupControlcyclophilin AndG-CSF
Granulocytes7+-0,571,0+is 12.571,3+-5,8
Lymphocytes89+-027,0+is 12.525,6+-4,9

Cyclophilin A - stimulator granulocytopoiesis, radioprotector and immunostimulant.


Same patents:

FIELD: medicine.

SUBSTANCE: invention concerns medicine and Fc-erythropoietin fused protein with improved pharmacokinetics. Invention claims novel sialylated Fc-EPO fused proteins preferably including modification pair in Fc part, as well as in EPO part, showing improved pharmacokinetics. Particularly, Fc-EPO proteins have longer half-life in blood serum and higher efficiency in vivo. Fc-EPO fused proteins synthesised in BHK cells show much longer half-life in blood serum and higher efficiency in vivo than similar Fc-EPO fused proteins obtained in other cell lines, such as NS/0 cells.

EFFECT: improved pharmacokinetic properties of erythropoietin.

23 cl, 14 ex, 6 tbl, 11 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to crystalline forms of 1,2-pyrrolidinedicarboxamide, N1-(4-chlorophenyl)-N2-[2-fluoro-4-(2-oxo-1(2H)-pyridinyl)phenyl]-4-methoxy-, (2R,4R)-(9CI), as well as to methods of obtaining said crystalline forms and to their pharmaceutical compositions, which have inhibitory activity towards Xa factor.

EFFECT: high stability of new crystalline forms.

19 cl, 9 ex, 7 dwg, 5 tbl

FIELD: medicine .

SUBSTANCE: invention refers to medicine and namely to pharmacology and deals with remedies influencing free-radical processes, hemorheology, thrombocyte aggregation and intravascular thrombosis. It has been proposed to use (3,5-dimethyl-4- hydroxy)benzyl thiododecane which is known for its antioxidant activity as antiaggregant remedy decreasing blood hyperviscosity, and antithrombogenic remedy.

EFFECT: there has been shown the stated effectiveness of the remedy by means of blood hyperviscosity pattern and increase of blood flow under conditions of its complete stop when there are no thrombs in arteria the next day.

4 tbl, 14 ex

FIELD: medicine .

SUBSTANCE: invention refers to medicine and namely to pharmacology and deals with remedies influencing free-radical processes, hemorheology, thrombocyte aggregation and intravascular thrombosis. It has been proposed to use (3,5-dimethyl-4- hydroxy)benzyl thiododecane which is known for its antioxidant activity as antiaggregant remedy decreasing blood hyperviscosity, and antithrombogenic remedy.

EFFECT: there has been shown the stated effectiveness of the remedy by means of blood hyperviscosity pattern and increase of blood flow under conditions of its complete stop when there are no thrombs in arteria the next day.

4 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: invention relates to group of the new compounds presented by structural formulas A-K ,

and their pharmaceutically acceptable isomers, salts, salvates and to polymorphous forms.

EFFECT: inhibitory action with respect to thrombin receptors.

20 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: to prevent severe pregnancy complications in thrombopillic patients, 1-2 months prior to planned pregnancy, preparation VESSEL DUE F is introduced in a dose 1000 units/day - 2 tablets twice a day to ensure decrease in lupus anticoagulant (LA) activity by at least 0.8. Then onset of pregnancy follows. During the first pregnancy trimester, VESSEL DUE F is substituted for Clexane injected in abdomen subcutaneously in a dose 0.4 ml/day daily. Starting from thirteenth week of pregnancy, VESSEL DUE F therapy is recommenced in a previous dose - 2 tablets twice a day until delivery. Introduction of VESSEL DUE F is prolonged continue within the first postpartum month.

EFFECT: integrated effect on all the links of haemostasis system, prolonged intake of tableted formulation without side effects on a foetus during pregnancy and lactation.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical compound to improve renal function that contains KW-3902 30 mg or its pharmaceutically acceptable salt, ester, amide, and furosemide. Also there are disclosed method to induce diuretic effect, method to improve renal function, method to support renal function and method to recover renal function in a patient.

EFFECT: effective recovery of renal function in patients with congestive heart failure.

13 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the chemical pharmaceutical industry and relates to the composition, method of obtaining and application of the means based on the perfluorinated emulsions intended for usage as blood substitutes and other medicinal preparations. The essence of the method lies in the development of the method and composition consisting of two promptly excreting (C8-C10) and/or slowly excreting (C11-C12) perfluorcarbons in the ratio from 1/1 to 10/10, or mixture of three perfluorocarbons: two promptly excreting (C8-C10) and one slowly excreting (C11-C12), or one promptly excreting (C8-C10) and two slowly excreting (C11-C12) in the ratio 1/1/1 to 10/10/10, or mixture of four perfluorocarbons: two promptly excreting (C8-C10) and two slowly excreting (C11-C12) in the ratio 1/1/1/1 to 10/10/10/10. The perfluorocarbon mixture has the concentration in the range from 1% (0.5% vol.) to 100% (50% vol.) with average particle size in the range 30-80 nm, it is emulgated with proxanol-268 taken in amount from 0.2% to 20% with molecular mass 6000-12000.

EFFECT: compound contains acceptable electrolyte solution or other acceptable media.

17 cl, 12 ex, 1 tbl, 1 dwg

FIELD: medicine.

SUBSTANCE: intraperitoneal introduction to laboratory animals of hyaluronidase preparation in a dose of 1000 SU/kg once a day within 2 days is combined with subcutaneous introduction of granulocytic colony-stimulating factor (G-CSF) in a dose 125 mkg/kg once a day within 5 days.

EFFECT: effective myelopoiesis stimulation.

2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemically and physically stable compositions containing VII factor or polypeptide, related to VII factor, so such compositions can be stored, available and applicable at room temperature. The composition contains effective amount of VII factor polypeptide, and sucrose and polyol combination with humidity about 3% or less. The invention also concerns the method for preparing stable VII factor polypeptide as involving stages of introduction of said VII factor polypeptide in a solution containing sucrose and polyol combination as a stabiliser, and processing of said solution to produce a solid composition. In addition to sucrose and polyol combination, an antioxidant that is, e.g. homocysteine, cysteine, cystathionine, methionine or glutathione, can be added. Polyol represents, e.g. mannitol, sorbite or xylite. There is also disclosed method for treatment of reactive syndrome of VII factor that involves introduction of VII factor combined with sucrose and polyol. There is also offered application of VII factor polypeptide to prepare a medical product used for treatment of reactive syndrome of VII factor. The invention is related to stable compositions of VII factor polypeptide that does not contain degradation products and does not show decreasing activity of VII factor polypeptides if stored in natural conditions within at least 6 months.

EFFECT: improved stability of the composition.

48 cl, 12 ex, 7 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, radiology and ophthalmology, and can be used for reducing the risk of radiation cataract genesis at chronic effect of low doses of ionisation radiation. For that purpose water with decreased content of deuterium is injected to the organism. At that, deuterium concentration can be 1 ppm to 140 ppm. Potable water with decreased deuterium concentration can be injected to the organism orally, parenterally or by installing into the eye independently or as the solvent for physiologically active substances and pharmacological preparations. Potable water with decreased deuterium concentration can be injected to the organism till chronic influence of low doses of ionisation radiation takes place, as well as during the effect of ionisation radiation and after it.

EFFECT: method allows restraining formation of phacoscotasmus, having excluded such side effects as surface keratitis, blepharitis, and pruritus.

4 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the chemical and pharmaceutical industry. Schizandra seeds are extracted using 70-90% ethyl alcohol first at room temperature and then while heating at temperature between 65-70°C.

EFFECT: invention increases output of active substances.

2 ex, 1 tbl, 1 dwg

FIELD: medicine.

SUBSTANCE: for preventing and treating of inflammatory processes in an animal's organism, the animal's body lesion is coated with a water-vegetative preparation, also to be introduced in a vaginal, uterine or intestinal cavity. Said preparation is made as follows. Powdered dry drug plants are placed in a dark glass bottle in a certain weight ratio. The plant mixture is covered with a vegetable oil 2500.0 g and kept at room temperature in continuous stirring for 30 days. Then a liquid component is separated to produce an oil-vegetative preparation. The water-vegetative preparation is made by covering the raw material with 2500.0 g of hot, but no more than 50°C, 0.9% sodium chloride brine, and kept in stirring for 30 days at a room temperature. Then formalin is added at 0.6 g per 100.0 g of water-vegetative infusion.

EFFECT: more effective prevention and treatment.

FIELD: medicine.

SUBSTANCE: invention relates to pharmacy. The method for making storage-stable multicomponent water/oil/water emulsions which contain one or more biologically active substances includes the stage a) that involves a biologically active substance added in an aqueous phase, the stage b) that involves the aqueous phase emulsified by addition to an oil phase through a loose membrane, and the stage c) that involves phase inversion in the emulsion from the stage b) by cooling the mixture at low rate 0.3 K/min. An emulsifier is added to the aqueous phase at the stage a) and/or to the oil phase at a stage b).

EFFECT: invention provides the identical external and internal aqueous phases containing the same amount of the active substance, with immediate release of the active substance from the external phase and slow release thereof from the internal phase.

12 cl, 1 tbl, 4 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: method is implemented by resection craniotomy, removals of intracranial haemorrhages and introduction of hyperosmolar preparations and saluretic agents. Then a catheter is installed in common carotid artery, and dexamethasone is introduced up to 8 mg a day during to 5 days.

EFFECT: reduced time of treatments, directional and prolonged effect on cerebrum, ensured maximum concentration of the introduced preparation in cerebrum in shorter time, and reduced risk of hemorrhagic and embolic complications.

4 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention concerns making a preparation of hive products used for treatment of various diseases. Said method consists in mechanical mixing of natural honey with comb capping and propolis, or natural honey mix with comb capping, propolis and dead beers, or honey is mixed with homogenate of bee-moth larvae, or honey is mixed with bee-bread and drone homogenate. The technology is simple and accessible.

EFFECT: preparations made by provided technology possess a broad spectrum of pharmacological action.

4 cl, 4 ex, 1 tbl

FIELD: medicine; gynaecology.

SUBSTANCE: prevention of postoperative complications involving embolised uterine arteries in uterus myomas is ensured by pre-measuring the diametre of contrasted uterine arteries in a proximal part. Regular volume of polyvinyl alcohol PVA, PVA-particles is divided into 4 parts. Number of portions of PVA-particles required for emoblisation is calculated by formula: n=(d+1.5 mm)/3, where n is a number of portions, d is an arterial diametre (mm). Estimated number of embolisate portions is introduced consistently.

EFFECT: effective emoblisation of uterine arteries with smaller amount of embolisate and reduction of side complications.

2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 represents 3-10-member non-aromatic heterocyclic group, where group is limited by group containing nitrogen as ring-constituting atom, and nitrogen, having additional bond, or group represented by formula -NR11aR11b, where R11a and R11b can be similar or differ from each other, and each represents hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10-member heteroaryl or 4-10-member non-aromatic heterocyclic group, and R11a and R11b can be substituted with substituent selected from group of substituents A or group of substituents B, and R1 can be substituted with substituent selected from group of substituents A or group of substituents B; R2 and R3 represent hydrogen; R4, R5, R6 and R7 can be similar or differ from each other, and each represents hydrogen, halogen, C1-6 alkyl; R8 represents hydrogen or C1-6 alkyl; R9 represents 3-10-member non-aromatic heterocyclic group, where group is limited by group containing nitrogen as ring-constituting atom, and nitrogen, having additional bond, or group represented by formula -NR11aR11b, where R11a and R11b have the same values as described above; n represents integer 1 or 2; and X represents group, represented by formula -C(R10)=, or nitrogen, where R10 represents hydrogen; where group of substituents A consists of halogen, hydroxyl and oxogroup; where group of constituents B consists of C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10-member heteroaryl, 3-10-member non-aromatic heterocyclic group, C1-6 alkoxy, 5-10-member heteroaryloxy, 4-10-member non-aromatic heterocyclic oxygroup and group represented by formula -T1-T2-T3, and each group in group of substitutes B can be substituted with substituent selected from group of substituents C, where T1 represents direct bond or C1-6 alkylene, T2 represents group represented by formula -NRT1-, T3 represents hydrogen or C1-6 alkyl, and RT1 represents hydrogen or C1-6 alkyl; and where group of substutuents C consists of hydroxyl, C1-6 alkyl, 3-10-member non-aromatic heterocyclic group and di-C1-6 alkylaminogroup, to pharmaceutical composition possessing anti-tumor activity, to inhibitors of: hepatocyte growth factor receptor, angiogenesis and cancer dissemination, as well as to anti-tumor medication.

EFFECT: obtaining novel compounds which demonstrate anti-tumor activity.

31 cl, 111 ex, 18 tbl

FIELD: medicine.

SUBSTANCE: for depression of concentration of ammonia in blood by means of the enzyme introduced in erythrocytes of glutamin synthetase, it is incapsulated in erythrocytes using the dialysis method. The obtained ammocytes are entered intravenously to the animals with experimental acute hyperammoniemia.

EFFECT: invention dilates an arsenal of the agents reducing concentration of ammonia at the expense of creation of an agent, possessing high efficiency and not causing immunologic rejection throughout several days.

1 tbl

FIELD: medicine; pharmaceutics.

SUBSTANCE: preparation includs methylnaltrexone or its salt and a chelating agent. The preparation represents a solution which has pH from 2 to 6. The chelating agent is ethylenediaminetetraacetic acid or its derivative.

EFFECT: decomposing prevention of methylnaltrexone or its salts and stability of a methylnaltrexone preparation in the form of a solution after storage within 12 months.

10 cl, 3 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: medicinal agent contains alpha and/or beta and/or gamma human recombinant interferon, tocopherol acetate or other tocopherol derivatives, ascorbic acid and/or its salts, pantothenic acid or calcium pantothenate, or dexapanthenol, riboflavin or levocarnitine, and orotic acid and/or ornithine or its derivative - citrulline malate, or Glutoxim, antibacterial, antimycotic agents, additives: emulsifiers, stabilisers, preservatives, antioxidants and base. The formulation is suppositories in certain component ratio.

EFFECT: efficiency for severe infectious diseases and mixed infections.

9 cl, 18 ex