Application of bradykinin-b2 receptors antagonists for osteoarthrosis treatment
SUBSTANCE: invention refers to application of peptides of antagonistic action in the relation bradykinin, suitable for medical products for prevention and treatment of diseases influenced by increased activity of matrix metalloproteinase. They are degenerative arthropathies, e.g., osteoarthrosis, spondylosis, as well as cartilage atrophy caused by joit injury or prolonged joint immovability following meniscus or patella damage or ligamentous rupture.
EFFECT: invention provides more effective brake of matrix splitting in comparison with only MMP inhibition of already released or formed tissues.
3 cl, 1 tbl
The invention relates to the use of peptides with antagonistic activity against bradykinin to obtain drugs for the treatment of degenerative joint disease.
In degenerative joint diseases such as osteoarthritis, slow growing destruction of the joint, which is caused, in particular, proteolytic cleavage of collagen by collagenases. Collagenase belong to the superfamily of metalloproteinases (MP) or matrix metalloproteinases (MMP). MMP is able to cleave fibrillar and defibrillatory collagen and proteoglycans, all of which are important components of the cartilage matrix. MMP-3 is involved in the biological degradation of the extracellular matrix and is found in increased amounts in patients with osteoarthritis, therefore, MMP-3 is of special significance in the breakdown of the articular matrix in osteoarthritis (Manicourt et al. (1994), Arthritis and Rheumatism, 37: 1774-83).
Bradykinin is a natural nonapeptide, which exhibits a pharmacological effect, leading to inflammation and pain. Peptides with an antagonistic effect to bradykinin already described in the European patent 0370453 B1. In addition, it is known that peptides with an antagonistic effect to bradykinin can be used in the treatment of osteoarthritis or rheumatoi the aqueous arthritis (AU 638 350). Osteoarthritis and rheumatoid arthritis are diseases of the joints with acute inflammatory phase in the course of the disease. In the work Lerner'and others (Arthritis and Rheumatism (1987), 30, 530-540) reported that although in the course of rheumatoid arthritis bradykinin may increase bone resorption, however, does not stimulate the decomposition of the cartilage matrix.
When searching for active compounds for the treatment of degenerative diseases of the joints, it was found that the peptides used according to the invention, prevent the provision of such MSEs as MMP-3 (as well as MMP-1 and MMP-13). Due to this splitting of the matrix can be slowed down more effectively, compared with the inhibition of both MMP, already released or formed in the tissue.
Therefore, the invention relates to the use of compounds of formula I
to obtain drugs for the treatment of degenerative diseases of the joints, which means:
A A1) hydrogen atom, (C1-C8)-alkyl, (C1-C8-alkanoyl, (C1-C8-alkoxycarbonyl or (C1-C8)-alkylsulfonyl, in which 1, 2 or 3 hydrogen atoms may optionally be substituted respectively 1, 2 or 3 identical or different residues from the series of carboxy, amino, (C1-C4)-alkyl, (C1-C4)-alkylamino, hydroxy, (C1-C 3)-alkoxy, halogen, di(C1-C4)-alkylamino, carbarnoyl, sulfamoyl, (C1-C4-alkoxycarbonyl, (C6-C12)-aryl and (C6-C12)-aryl-(C1-C5)-alkyl,
or 1 respectively a hydrogen atom optionally substituted by a residue of a number (C3-C8-cycloalkyl, (C1-C4)-alkylsulfonyl, (C1-C4-alkylsulfonyl, (C6-C12)-aryl-(C1-C4)-alkylsulfonyl, (C6-C12)-aryl-(C1-C4-alkylsulfonyl, (C6-C12)-aryloxy, (C3-C9-heteroaryl and (C3-C9)-heteroalkyl,
and 1 or 2 hydrogen atoms replaced by one or two identical or different residues from the series of carboxy, amino, (C1-C4)-alkylamino, hydroxy, (C1-C4)-alkoxy, halogen, di(C1-C4)-alkylamino, carbarnoyl, sulfamoyl, (C1-C4-alkoxycarbonyl, (C6-C12)-aryl and (C6-C12)-aryl-(C1-C5)-alkyl;
a2) (C1-C8-cycloalkyl, carbarnoyl,
which may optionally be substituted at the nitrogen (C1-C6)-alkyl or (C6-C12)-aryl,
(C6-C12)-aryl, (C6-C12-ariail, (C6-C12)-arylsulfonyl or (C3-C9-heteroaryl, or (C3-C9-heteroaryl, and in the residues, is definitely the to in paragraphs (a 1and a2), respectively heteroaryl, ariail, arylsulfonyl and heteroaryl optionally substituted by 1, 2, 3 or 4 different residues from the series of carboxy, amino, nitro, hydroxy, cyano, (C1-C4)-alkylamino, (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, di(C1-C4)-alkylamino, carbarnoyl, sulfamoyl and (C1-C4-alkoxycarbonyl, or
a3) residue of formula II
R(1) is defined as A in paragraphs (a1or a2),
R(2) means a hydrogen atom or methyl,
R(3) means a hydrogen atom or a (C1-C6)-alkyl, and alkyl unsubstituted or once substituted amino, substituted amino, hydroxy, carbamoyl, guanidino, substituted guanidino, ureido, mercapto, methylmercapto, phenyl, 4-chlorophenyl, 4-florfenicol, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, phthalimido, 4-imidazolyl, 3-indolium, 2-tanila, 3-tanila, 2-pyridium, 3-pyridium or cyclohexyl,
moreover, substituted amino in place of residue-NH-A-, and substituted guanidino is instead residue-NH-C(NH)-NH-A, where A is defined as in paragraph (a1or a2);
B Arg, Lys, Orn, 2,4-diaminobutyric or a residue of L-homoarginine,
and accordingly amino - or guanidinium side chain may be substituted by A, as described in paragraph (a1) is whether and 2);
X compound of the formula IIIa or IIIb
where G' independently of one another denotes a residue of formula IV
in which R(4) and R(5) together with bearing their atoms form a heterocyclic mono-, bi - or tricyclic system with 2 to 15 C atoms, and n is from 2 to 8;
E means the residue of phenylalanine,
which is optionally substituted with halogen in the 2-nd, 3-rd or 4-th position of the cycle, or
tyrosine, O-methyltyrosine, 2-titillans, 2-pyridylamine or nafcillin;
F independently of each other means the residue of a neutral, acidic or basic, aliphatic or aromatic amino acid,
which may be substituted in the side chain,
or means covalent bond;
(D)-Tic residue of the formula V
G means G' or a covalent bond;
F' means the balance of the basic amino acids Arg or Lys in the L - or D-form or a covalent bond,
moreover, the guanidine group or the amino group of the side chain may be substituted by A, as defined in paragraphs (a1or a2),
or a residue-NH-(CH2)nwith n equal to 2-8,
or a covalent bond;
K residue-NH-(CH2)x-CO with x equal to 1 to 4, or a covalent bond;
M is defined as F,
and their physiologically p is ielemia salt.
The next object of the invention is also the use according to the invention the compounds of formula I, in which the means:
B Arg, Orn or Lys,
moreover, the guanidine group or the amino group of the side chain unsubstituted or may be substituted (C1-C8-alkanoyl, (C7-C13-eilola, (C3-C9-heteroallyl, (C1-C8-alkylsulfonyl or (C6-C12-arylsulfonyl, and aryl, heteroaryl, abilily, arylsulfonyl and heteroarylboronic residues, as described above in paragraph (a2), may optionally be substituted by 1, 2, 3 or 4 identical or different residues;
E phenylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 2-forfinally, 3-forfinally, 4-forfinally, tyrosine, O-methyltyrosine or β-(2-thienyl)-alanine;
K is a covalent bond, and
M is a covalent bond.
Further, the invention relates to the use according to the invention the compounds of formula I, in which the means:
A hydrogen atom, (D)- or (L)-H-Arg, (D)- or (L)-H-Lys or (D)- or (L)-H-Orn;
B Arg, Orn or Lys,
moreover, the guanidine group or the amino group of the side chain may be substituted by hydrogen atom, (C1-C8-alkanoyl, (C6-C12-eilola, (C3-C9-heteroallyl, (C1-C8-alkylsulfonyl or (C6-C12arils what Hanila, moreover, aryl, heteroaryl, abilily, arylsulfonyl and heteroarylboronic residues optionally may be substituted by 1, 2, 3 or 4 identical or different residues from the series methyl, methoxy and halogen;
C Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly;
E Phe or Thia;
F Ser, Hser, Lys, Leu, Val, Nle, Ile or Thr;
K covalent bond
M covalent bond
G residue of the heterocyclic system of the formula IV selected from the remnants of the heterocycles of pyrrolidine (A), piperidine (B), tetrahydroisoquinoline (C)CISorTRANS-decahydroquinoline (D)CIS-endo - octahedrons (E),CIS-Exo-octahedrons (E),TRANS-octahedrons (E),CIS-endo-,CIS-Exo-,TRANS-octahydrocyclopenta[b]pyrrole (F) or hydroxyproline (V);
The invention relates also to the use according to the invention the compounds of formula I, wherein it is selected from the group:
The invention relates also to the use according to the invention D-arginyl-L-arginyl-L-prolyl-L-polyglycol-3-(2-thienyl)-L-alanyl-L-seryl-(3R)-1,2,3,4-tetrahydro-3-athinaikon-(2S,3aS,7aS)-octahydro-1H-indole-2-carbonyl-L-arginine, which is also known as HOE140.
The term "(C1-C8)-alkyl" is understood hydrocarbon residues, carbon chain which is linear or branched and contain the t 1 to 8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, 2,3-dimethylbutyl, heptyl, neohexyl or octyl.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "(C3-C8-cycloalkyl" refers to residues that are produced from 3-8-tier of monociclo as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
The term "(C6-C12)-aryl" refers to aromatic carbon residues with 6-14 carbon atoms in the cycle. (C6-C12)-aryl residues are, for example, phenyl, naphthyl, for example 1-naphthyl, 2-naphthyl, biphenylyl, for example, 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, antrel or fluorenyl. Biphenylene residues, raftiline residues and especially phenyl residues are preferred aryl residues.
The term "(C3-C9-heteroaryl" refers to these residues, as acridines, azetidine, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzothiazole, benzotriazole, asterisell, benzisoxazole, benzisothiazole, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolines, bromanil, bromanil, cinnoline, decahydroquinoline, 2H,6H-1,5,2-detainer, dihydrofuro[2,3-b]-tetrahydrofuran, furanyl, furutani, imidazolidinyl, imidazolyl, they are azolyl, 1H-indazole, indoline, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isopropanol, isoindolyl, isoindolines, isoindolyl, ethenolysis (benzimidazolyl), isothiazolin, isoxazolyl, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, phenanthridines, phenanthrolines, phenazines, phenothiazines, phenoxathiin, phenoxazines, phthalazine, piperazinil, piperidinyl, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, paradoxicaly, predominately, peridotitic peridotites, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, 2H-pyrrolyl, pyrrolyl, hintline, chinoline, 4H-hemolysins, honokalani, hinokitiol, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, 6H-1,2,5-thiadiazine, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrene, thiazolyl, thienyl, theNational, cyanoacetyl, tenomodulin, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xantinol.
Preferred pyridyl, 2-pyridyl, 3-pyridyl or 4-pyridyl; pyrrolyl as 2-pyrrolyl and 3-pyrrolyl; furyl, 2-furyl and 3-furyl; thiophenyl; thienyl as 2-thienyl and 3-thienyl; imidazolyl, pyrazolyl, oxazolyl, isoxazole is, thiazolyl, isothiazolin, tetrazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzothiophene, 1,3-benzodioxolyl, indazoles, benzimidazoles, benzoxazoles, benzothiazoles, chinoline, ethenolysis, bromanil, isopropanol, cinnoline, hintline, honokalani, phthalazine, predominately, pyridopyrimidines, pyridopyrimidines, purines and pteridines.
Used according to the invention, the peptides are given as described in the patent EP 0370453 B1.
Due to their pharmacological properties, the compounds according to the invention is suitable for selective prevention and treatment of degenerative joint diseases such as osteoarthritis, spondylosis or atrophy of cartilage after joint injuries or prolonged immobility of the joint after damage to the meniscus or kneecap or torn ligaments.
The term "osteoarthritis" refers to a disease that occurs mostly when there is a mismatch between the voltage and permissible load individual parts of the joint and the articular tissue, which is connected with the growing destruction of cartilage and is not primarily inflammatory. In the foreground pathology are damaged articular cartilage, as razvlechenie, the emergence of a zone of demarcation or hyalinization, with subsequent reactive changes in the subchondral bone, and is also changing the capsule.
The term "spondylosis" refers to osteoarthritis of the vertebral body, which is characterized by non-inflammatory atrophy of the cartilage of the vertebral body and intervertebral cartilages.
The use of the drug according to the invention may be by inhalation or transdermal application, or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Preferably intra-articular or topical application.
Suitable solid or galenovye ready compositions are, for example, suspensions, emulsions or suitable for injection solutions and drugs with slow release of the active substance, upon receipt of which used conventional auxiliary means.
Preferably the pharmaceutical drugs and get injected in dosage units, each unit dose contains as an active ingredient a specific dose of a compound according to formula I according to the invention. In the case of injection solutions in vials of this dose can be up to about 300 mg, but preferably from about 10 to 100 mg, and in the case of solutions for injection for intra-articular injection to about 300 micrograms, preferably up to 100 micrograms.
For the treatment of adult patients in accordance with the effectiveness of the compounds according to formula I recommend what I daily dose from about 0.01 mg/kg to 10 mg/kg of active ingredient when used systematically, the application of solutions for injection are recommended daily dose of 0.001 mg/kg to 0.005 mg/kg of the active substance, and for topical or Inhalative application of the recommended daily dose of from 0.01 mg/kg to 5 mg/kg of the active substance. Under some circumstances may, however, be set higher or lower daily doses. The introduction of the daily dose can be performed by a single dose in the form of a separate element dose or several smaller items dosing, as well as by repeated administration of divided doses at regular intervals.
Hereinafter the invention is explained more examples.
Abbreviations used for amino acids, correspond to the conventional in the chemistry of peptides three-letter code, as described in Europ. J. Biochem. 138,9 (1984).
Other abbreviations used below.
HOE140 obtained as described in patent EP 0370453 B1.
The drugs examples
For analysis of modifying the disease course of action HOE140 belonging to the cartilage model of the cell culture was analyzed expression of MM is -3 in cell lines chondrosarcoma SW1353 (ATCC: HTB 94). For the experiment were cultivated SW1353 cells under standard conditions (37°C, 5% CO2) in DMEM-glutamax with 10%serum fetal calf (FKS) in plastic vials for growing crops. After removal of trypsin from the cells, 50,000 cells were seeded in wells in 96-well flat-bottomed plate in a environment without FKS and pre-incubated in incubator connection with HOE140. After an hour spent stimulating the cells by adding IL1-β man (0.1 ng/ml, Roche) in a total volume of 300 μl.
After 24 hours of incubation under standard conditions was collected supernatant of cell culture, 5 minutes, centrifuged and frozen at -20°C for further analysis.
Analysis of the expression of MMP-3 in the supernatant of cell culture was performed then using a commercial test system MMP-3 ELISA kit (Amersham) according to the manufacturer. Parallel to this, the remaining cells was WST-test for cytotoxicity. Here we used the existing commercial system testing firm Roche, and the measurements were carried out according to the Protocol of the manufacturer.
The results are shown in the following table 1.
Bradykinin increases the release of MMP-3 by more than 30%. This increased release of MMP-3 inhibited with HOE140, depending on the dose.
|Table 1< / br>The release of MMP-3 cells SW|
|Option incentive||The release of MMP-3||Relative values, based on the original value|
|MW (OD 450 nm)||SD|
|IL1α (0.05 ng/ml)||328||17||100|
|IL1α + bradykinin (0.1 ám)||433||32||132,0|
|IL1α + bradykinin (0.1 ám) +0.05 microns HOE140||458||50||139,6|
|IL1α + bradykinin (0.1 ám) +0.1 ám HOE140||371||8||113,1|
|IL1α + bradykinin (0.1 ám) +0.5 µm HOE140||309||18||a 94.2|
|IL1α + bradykinin (0.1 ám) +1 μm HOE140||306||27||93,3|
1. The use of the compounds of formula I
selected from the group:
to obtain the medicine the funds for the prevention and treatment of osteoarthritis, spondylosis or atrophy of cartilage after joint injuries or prolonged immobility of the joint after damage to the meniscus or kneecap or torn ligaments.
2. The use according to claim 1, wherein the applied compound D-arginyl-L-arginyl-L-prolyl-L-polyglycol-3-(2-thienyl)-L-alanyl-L-seryl-(3R)-1,2,3,4-tetrahydro-3-athinaikon-(2S,3S,7S)-octahydro-1H-indole-2-carbonyl-L-arginine.
3. The use of the compounds of formula I according to claim 1 or 2, characterized in that the introduction is performed by subcutaneous, intra-articular, intraperitoneal injection or intravenous injection or by transdermal injection.
SUBSTANCE: can be used as method of treatment of osteomyelitis and septic arthritis, caused by bacterial agents, including with plural medicinal resistance. For this purpose mammal is introduced with pharmacologically effective amount of tigecycline separately or in combination with ryphampycine antibiotic. This agent is also offered also for manufacturing of medical products for treatment of given diseases.
EFFECT: invention provides increased efficiency of bone, marrow and joints infection treatment to preferential tigecycline distribution through bone tissue, marrow and synovial fluid.
48 cl, 5 dwg, 11 tbl, 3 ex
SUBSTANCE: invention relates to the compound with the formula (1): where R1 is C1-C12 alkyl group, which can have the substitute, or C2-C12 alkenyl group, which can have the substitute represented with the C6-C14 aryl group, which can be substituted with the halogen atoms; each of R2 and R3 represent the hydrogen atom, alkyl group, hydroxyalkyl group, dihydroxyalkyl group, or R2 and R3 form with the adjacent nitrogen atoms the 5-membered, 6-membered, or 7-membered nitrogen-containing saturated heterocyclic group, which can be substituted with the alkyl group; (the dotted line means the possible double bind), or its salt, as well as to the pharmaceutical composition containing the said compound, and to its application as a pharmaceuticals and to the treatment method.
EFFECT: invented compound demonstrates inhibiting activity against the tumor necrosis factor production (TNF-α) and improved absorbability after oral administration.
16 cl, 1 tbl, 18 dwg, 1 ex
SUBSTANCE: invention refers to new pyridazine -3 (2H) derivatives, the chemical formula of which corresponds to the general formula , in which R1, R2, R3, R4 and R5 have values indicated in the formula of the invention. The compounds of the formula (I) are effective and selective inhibitors of phosphodiesterase 4. The invention also refers to the method of their preparation, pharmaceutical composition which includes these compounds, and to the application for medicine preparation for treatment of disease state or disease which medicable by meance of phosphodiesterase 4 inhibition. Besides, the object of the invention is the method of disease state and disease treatment by means of phosphodiesterase 4 inhibition.
EFFECT: new compounds have effective biological properties.
19 cl, 25 tbl, 278 ex
FIELD: medicine; rheumatology.
SUBSTANCE: invention can be used for treatment of steroid-dependant rheumatoid arthritis. For this purpose basic and anti-inflammatory therapy is performed including agents of calcium and native vitamin D. Additionally agent of active vitamin D - alpha-calcydol is prescribed. At that agent dose from minimum (0.5 mcg) to maximum (1.5 mcg), therapy duration and multiplicity are prescribed on the basis of dose and duration of prescribed corticosteroids in terms of prednisolone.
EFFECT: invention enables to increase remission period due to individual optimal selection of therapy.
4 cl, 2 ex
FIELD: medicine; physiotherapy.
SUBSTANCE: patient is prescribed with balneo-, EHF-, pelotherapy within period from November to January, and in July. If patient is treated from February to June, and from August to October, treatment also includes phytotherapy. Phytotherapy includes application of leuzeae tincture and phytotea containing: pure licorice root - 1 portion, garden violet herb - 1 portion, rosehip - 2 portions, common birch leaves - 2 portions, lingonberry leaves - 2 portions, trifid beggars-ticks herb - 2 portions. leuzeae tincture is taken in dose 15-20 drops 30-40 minutes after eating, twice a day, within first half of day. Phytotea is taken in dose 40-50 ml 20-30 minutes before eating, 3 times a day.
EFFECT: reduces treatment time; increases treatment efficiency.
2 ex, 3 tbl
SUBSTANCE: invention refers to medicine and can be applied for treatment of dystrophic diseases of musculoskeletal system: deforming osteoarthrosis or osteohondrosis. Electrophoresis is applied with saline sediment of mineral water "Amurskaya-2" within 15 to 30 minutes, for 10-15 procedures. For deforming osteoarthrosis treatment current intensity is 20 - 30 mA, and for osteohondrosis treatment - 15-20 mA. Method ensures reduced treatment duration and improved quality of life for patients with musculoskeletal system diseases.
EFFECT: reduced treatment duration and improved quality of life for patients with musculoskeletal system diseases.
SUBSTANCE: invention relates to the formula I compounds or its pharmaceutically acceptable salt or hydrate where Z means N; X1 means O or S, R1 means alkyl containing one to six carbon atoms; R2 designates hydrogen or alkyl containing one to six carbon atoms; and R3 designates hydrogen or alkyl containing one to six carbon atoms substituted with the -ORa group where Ra means alkyl containing one to six carbon atoms; saturated nonaromatic cyclic radical containing 3 to 8 atoms in a cycle where one atom in a cycle is a heteroatom selected from N or O, whereas the rest of the atoms in the cycle are carbon atoms, one or two of these carbon atoms being not necessarily substituted by nitrogen atom with the groups -C(O)(C1-C6alcoxy) or -SO2-C1C6alkyl. Invention also relates to pharmaceutical composition.
EFFECT: compounds possess inhibiting activity.
13 cl, 1 tbl, 8 ex
FIELD: medicine; pharmacology.
SUBSTANCE: invention relates to the novel compounds with formula (I) and their pharmaceutically acceptable salts. The compounds of this invention has the properties of the NPY receptor antagonists and can be used fortreatment of such diseases as arthritis, diabetes, malnutrition, obesity. In general formula (I) , R1 means phenyl or 6-term nitrogen-containing heteroaryl, where in at least one of two meta-positions each phenyl group or 6-term nitrogen-containing heteroaryl group is substituted by group R5; R2 means hydrogen; R3 means C3-C6cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, where in at least one of two ortho-positions each group of C3-C6 cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, substituted by group R6; R4 means hydrogen, C1-C6alkyl; R5 means hydrogen, cyano, trifluoromethyl, C1-C6alkyl-SO2-, amino-SO2-, halogen, C1-C6alcoxy, C1-C6alkylcarbonil or aminocarbonil; R6 means hydrogen, halogen, cyano, nitro, trifluoromethyl, C1-C6 alkyl, C1-C6 alcoxy or hydroxy, provided, one R5 group, and R6 doesn't mean hydrogen.
EFFECT: described compounds and based on them pharmaceutical agents are efficient in treatment and prevention of above listed diseases.
19 cl, 2 tbl, 2 dwg, 130 ex
FIELD: medicine; pharmacology.
SUBSTANCE: invention relates to the method of treatment of diseases caused by abnormality of cartilaginous and/or bone tissue; the method includes the treatment course of applications of hydrolysed collagen and cosmetic clay to the painful area, when the KollAmin-80 or Epydermat-0 are rubbed into the painful area, and then the diluted cosmetic clay is applied, the area is covered with the polyethylene film or compressor paper and warmth-keeping for 30-40 min once daily, with course of 30-60 days 3-6 times annually.
EFFECT: high therapeutic efficiency is achieved.
2 cl, 9 ex
SUBSTANCE: preparation has mixture of collagen I and collagen II taken approximately in 1:19 to 19:1 proportion, respectively. The matrix is usable as supporting implant for restructuring cartilage of vertebral column or meniscus.
EFFECT: stimulated injured cartilage recovery.
19 cl, 2 dwg, 1 tbl
SUBSTANCE: 2 blood samples are taken with interval 3 days against complex medicinal supplement under the following scheme. Therapy of the first exfusion day is characterized with single introduction of phetabolyl 0.4 mg/kg intramuscularly, 5% vitamin B1 - 50 mg intravenously, vitamin B12 - 500γ st. units intramuscularly, 5%vitamin C - 150 mg intravenously and 10 % aminoplasmal E - 250 ml intravenously drop-by-drop. The same day and the next two days imply intramuscular injection of ferrum lek 100 mg once, sorbypher 325 mg twice a day, folic acid - 5 mg 3 times a day. For the second day exfusion is accompanying with single subcutaneous introduction of epocryne in dosage 4 thausand UNITS. Then for the third day control inspection is carried out. The second day of exfusion implies single introduction of 5% vitamin B6 - 50 mg intravenously, 5% vitamin C - 150 mg intravenously, vitamin B12 - 500γ st.units intramuscularly and 10% aminoplasmal E - 250 ml intravenously drop-by-drop. This day and in the subsequent two - three days imply intramuscular introduction of ferrum lek 100 mg once, sorbypher 325 mg twice a day, folic acid - 5 mg 3 times a day. For the second day exfusion is accompanying with single subcutaneous introduction of epocryne in dosage 4 thausand UNITS. Then for the third day control inspection is carried out again. Since the first exfusion and before autoblood preparation nutritive supplement is carried out using module protein added to mix "Berlamine Modular" 50 g twice a day daily. After exfusion autoblood is divided on erythrocyte mass and fresh frozen plasma.
EFFECT: prevention of dangerous erythropoiesis and metabolic disorders.
1 ex, 3 cl
SUBSTANCE: disclosed are peptides derived from proenzyme forms of matrix proteinases which represent inhibitors of matrix proteinases. Amino acid sequence is disclosed in description. Described are composition for stimulation of healthy skin formation, containing therapeutically effective amount of peptides. Also disclosed are dressing for wounds, method for stimulation of healthy skin formation and wound healing. Disclosed is using of composition in production of drug for wound healing.
EFFECT: new anti-aging and wound-healing agents.
15 cl, 28 dwg, 6 tbl, 7 ex
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention proposes a pharmaceutical composition used in treatment of patients suffering from cerebrospinal sclerosis. The composition comprises as an active component inhibitor of dipeptidyl peptidase IV (DPIV) of the general formula (I): wherein A means a residue of amino acid comprising at least one functional group in by-side chain; B means oligopeptide comprising up to 20 amino acids in its chain length, or polyethylene glycol of molecular mass up to 20000 g/mole, or optionally substituted organic amine, amide, alcohol, acid or aromatic compound comprising from 8 to 50 carbon atoms representing substituted or optionally substituted phenyl, benzyl, naphthyl, biphenyl and wherein a substitute can mean replacing with one or some groups of alkyl, alkenyl, alkynyl, mono- or multivalent acyl, alkanoyl, alkoxyalkanoyl or alkoxyalkyl as by-side groups; C means group of thiazolidine, pyrrolidine, cyanopyrrolidine, hydroxyproline, dehydroproline or piperidine bound by amide bond with the group A. In animal model study administration of inhibitor DPIV as isoleucylthiazolidine fumarate in the dose 1 mg/kg resulted to the absence of clinical symptoms of disease. In other experiments this inhibitor caused accelerating recovery and shoed anti-inflammatory effect also.
EFFECT: valuable medicinal and biochemical properties of inhibitors.
4 cl, 8 dwg, 14 ex
FIELD: medicine, ophthalmology.
SUBSTANCE: the present innovation deals with applying a composition that contains antagonists of integrin αvβ3 and/or αvβ5 receptors for manufacturing the medicinal preparation indicated for treating angioproliferative ocular diseases. The compositions mentioned could be presented as nanoparticles. Application of the declared compositions provides the chance for intravitreous introduction.
EFFECT: higher efficiency of therapy.
46 cl, 1 ex, 1 tbl
FIELD: medicine, pharmaceuticals.
SUBSTANCE: disclosed is application of dipeptidyl peptidase inhibitors (DPIV-inhibitors) particularly isoleucyl-tiazolidine as active ingredient of pharmaceutical hypotensive composition for mammalian suffering from diabetes. Disclosed is stabilizing of systolic blood pressure in diabetic fats and lowering levels thereof from 170 mmHg (control animals without isoleucyl-tiazolidine) to 150 mmHg.
EFFECT: new dipeptidyl peptidase inhibitors useful in pharmaceutical hypotensive composition.
9 cl, 9 dwg, 11 tbl, 20 ex
FIELD: biotechnology, medicine, oncology.
SUBSTANCE: invention proposes peptide of the structure Tyr-Ser-Leu and a pharmaceutical composition based on thereof that is used for stimulating antitumor immune response. Also, invention proposes methods for treatment of mammal and for modulation of the immune response. Proposed inventions expand assortment of agents used in treatment of cancer diseases.
EFFECT: valuable medicinal properties of peptide and pharmaceutical composition.
20 cl, 48 tbl
FIELD: chemistry of peptides, medicine, pharmacology.
SUBSTANCE: invention relates to using the combination of bioactive regions SYSMEHFRWGKPV and YGGFM in pro-opiomelanocortine in manufacturing a medicine used in treatment of inflammatory, degenerative and autoimmune diseases, traumas, infections and burns. Also, invention relates to using polypeptide chosen from group: YGGFMSYSMEHFRWGKPVYGGEM, YGGFMSYSMEHFRWGKPV, SYSMEHFRWGKPVYGGFM and compositions eliciting cytoprotective properties. Invention provides enhancing in peptides effect.
EFFECT: valuable medicinal properties of peptides.
9 cl, 1 tbl, 1 dwg
FIELD: medicine, gynecology.
SUBSTANCE: before operation it is necessary to sample patient's blood to divide it into plasma and blood cells. Blood plasma should be divided into three parts and frozen. After operation one should intravenously reinfuse by drops erythrocytic mass incubated for 30 min at 37° C with 2 g lendacyn followed by further lendacyn injection per 1g intramuscularly during the next 6 d. Blood plasma should be portionally defrosted, incubated at 37° C with: 10000 U trasilol, 0.15 g lisozyme, 0.02 g novocain, after incubation it is necessary to add 100 ml gelatinol to be reinfused for a patient on the 2nd, 4th and 6th d against the onset of therapy course through microirrigator withdrawn out of posterior arch during operation. The innovation provides combined impact of antibiotics upon pathological focus biotransformed with erythrocytic mass and local immunomodulating and resolving effect and, thus, decreased formation of adhesions, fistulas and cicatrices.
EFFECT: higher efficiency of therapy.
SUBSTANCE: invention proposes different compositions able to induce production of antibodies against Tat HIV-1 that can inhibit multiplication of HIV-1. Also, invention proposes a method for induction of antibodies raised against Tat HIV-1, in vitro method for assay of the presence of antibodies and their titer values, a method for reducing HIV-1 virus levels, sequence of synthetic nucleic acid and synthetic molecule. Proposed group of inventions can be used for inhibition of multiplication of HIV-1 in infected patients and for attenuation of HIV-1 multiplication after the primary infection in early infected persons.
EFFECT: valuable methods and compositions.
39 cl, 7 dwg, 9 tbl, 5 ex
FIELD: medicine, biochemistry, pharmacy.
SUBSTANCE: invention relates to new compounds that represent inhibitors of caspases, in particular, inhibitors of interleukin-1β-converting enzyme and their pharmaceutical compositions. Proposed compounds can be used successfully as agents directed against diseases mediated by interleukin-1, apoptosis and factor inducing interferon-γ or by interferon-γ.
EFFECT: valuable medicinal and biochemical inhibitors.
FIELD: biotechnology, medicine, oncology, peptides.
SUBSTANCE: invention relates to a method based on phage display for preparing peptides interacting specifically with mammary Ehrlich tumor and can be used in therapy and diagnosis of malignant neoplasm. Peptides are prepared by affinity selection from phage peptide libraries comprising ten millions of different peptides of size 15 amino acid residues, the group of nine peptides wherein each peptide shows ability for accumulation in Ehrlich tumor. For practice using mimetic-peptides selected by such manner can be prepared by chemical synthesis and to use for preparing conjugates on their basis with the known cytotoxic preparations, radioactive isotopes and they can be incorporated in the composition of liposomal preparations for visualization of tumor neoplasm also.
EFFECT: valuable medicinal properties of peptides.
2 dwg, 2 ex