Application of bradykinin-b2 receptors antagonists for osteoarthrosis treatment

FIELD: medicine.

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

and

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;

I-OH,-NH2or NHC2H5;

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);

F' Arg;

I OH.

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.

Oicoctahydro-1H-indole-2-carbonyl
Thia2-thienylene
Tic1,2,3,4-tetrahydroisoquinoline-3-ylcarbonyl

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 incentiveThe release of MMP-3Relative values, based on the original value
MW (OD 450 nm)SD
restimulating9320
IL1α (0.05 ng/ml)32817100
IL1α + bradykinin (0.1 ám)43332132,0
IL1α + bradykinin (0.1 ám) +0.05 microns HOE14045850139,6
IL1α + bradykinin (0.1 ám) +0.1 ám HOE1403718113,1
IL1α + bradykinin (0.1 ám) +0.5 µm HOE14030918a 94.2
IL1α + bradykinin (0.1 ám) +1 μm HOE1403062793,3

1. The use of the compounds of formula I

selected from the group:

H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH,

H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH,

H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH,

H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH and

H-(D)-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH,

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.



 

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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.

1 ex

FIELD: virology.

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

Caspase inhibitors // 2274642

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.

35 cl

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

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