Inhibitor of matrix metalloproteinases

FIELD: biotechnology.

SUBSTANCE: invention relates to inhibitor of matrix metalloproteinases representing extract from fungus Canoderma atrum obtained by using of water and/or lower alcohols as extractant. Also disclosed are pharmaceutical agent for inhibition of tumor metastasis containing of 0.03-10 wt.% of abovementioned extract and foodstuff containing claimed extract.

EFFECT: improved inhibitor of matrix proteinases.

3 cl, 18 ex, 4 tbl

 

The scope to which the invention relates.

The present invention relates to an inhibitor of matrix metalloproteinases (MMP). More specifically, the invention relates to an inhibitor of MMP, with a high degree of safety and are believed to affect the prevention, suppression and reduce the symptoms of various MMP-activated disorders and diseases, such as metastatic cancer, ulcers, rheumatoid arthritis, osteoporosis, periodontal diseases and skin aging.

Background of invention

Cancer is one of the leading causes of death in most developed countries. In Japan in 30% of cases, cancer is the cause of death. The progress observed in the surgical treatment and radiation therapy often allows you to remove the primary cancer. Still a high prevalence of the disease is attributed to a metastatic properties of cancer. Currently cancer with multiple metastases are extremely difficult to treat. Thus, one of the major problems in the treatment of cancer, in addition to conventional therapy primary focus is to create a method of suppressing metastasis. In this case, the mechanism of metastasis in cancer it gradually becomes clear at the molecular level. As one of the metastatic processes observed decomposition system of extracellular matrices.

Metastases RA is and represent this state, in which cancer cells released from the primary site, with blood spread throughout the body, delivered live to another body and begin to multiply in the tissues of the body. Typically, the tumor tissue is surrounded by a dense extracellular matrix. Enzymatic decomposition (animals) extracellular matrix is required for proliferation of cancer cells from the primary site. The extracellular matrix consists of a variety of macromolecules, including collagen, elastin, fibronectin, laminin and proteoglycan. MMD is a group of primary enzymes involved in Animalize extracellular matrices. MMP is activated and observed increased expression of enzymes in the process of vascularization in a cancer tissue or cancer metastasis, as described in the quote below, the link 1. Therefore, it is expected that the reduction in the expression of enzymes and inhibition of enzyme activity was inhibited invasion of cancer cells (tumor spreading and, thus, the metastasis of the cancer.

Link 1

"Retinoid-Mediated Suppression of Tumor Invasion and Matrix Metalloproteinase Synthesis", Shoenermark M.P. et al., Annals New York Academy of Sciences, Vol.878, pp.466-486, 1999.

In the process of invasion of cancer cells in the macromolecule collagenosis is a particularly important stage. The degradation of type IV collagen, which is present on the basilar membrane of the blood vessel, neo is absolutely essential for to cancer cells into the blood vessel or stand out from the blood vessel. Liotta et al. [reference 2] found that the effect of type IV collagenolytic enzyme secreted by cancer cells is an important factor in determining the metastatic ability of cancer. Gelatinase, part of the MMP, is an enzyme produced by fibroblasts, endothelial cells and cancer cells, demoralizing matrices of type IV collagen, gelatin, and elastin. I believe that the substance exhibiting inhibitory activity, for example, in relation to gelatinase, inhibits vascularization in tumor tissues and in cancer metastasis and is effectivnes tool for the prevention and treatment of various cancers and carcinomas.

Link 2

"Metastatic potential correlates with enzymatic degradation of basement membrane collagen", Liotta L.A. et al. Nature, Vol.284, pp. 67-68, 1980.

In the quote below, the link 3 is reported that MMP plays an important role in degradation of extracellular matrix in viral diseases, including various cancers, ulcers, rheumatoid arthritis, osteoporosis and periodontitis. Activated MMP under the action of external stimuli, such as ultraviolet radiation destroys important for maintaining skin structure components. As was recently noted, MMD is a factor that accelerates aging, UV-activated-and what lay.

Link 3

"Matrix metalloproteinases as tissue destructive proteinases", Mitsutoshi Nakata, Yasunori Okada., KOKYU (Respiratory) Vol 18, No. 4, pp 365-371, 1999.

Thus, believed that MMP inhibitors have an effect on the treatment and symptomatic relief caused by DFID disorders and diseases, and they are actively studied for the purpose of screening. Such inhibitors are described in the following links:

JAPANESE PATENT LAID - OPEN GAZETTE No. 9-40552

JAPANESE PATENT LAID - OPEN GAZETTE No. 11-147833

PATENT LAID - OPEN GAZETTE No. 2000-226311

The aim of the present invention is the creation of a MMP inhibitor having inhibitory activity against activation of MMP produced by strains of highly metastatic cancer cells, and effectively preventing and relieving the symptoms caused by activated MMP disorders and diseases, such as cancer metastasis.

The invention

The authors of the present invention as the target used in the highest degree of safe plant extracts and organized the screening of plant extracts on MMP-inhibitory activity. As a result of intensive research, the applicants have discovered that extracts (solvent) Ganoderma mushrooms have exceptional MMP-inhibitory effect and significantly inhibit the metastasis of cancer in animal models of metastasis of cancer in the lungs.

Earlier in CN 1291511, 2001 description is of use to prevent and kill cancer cells extract of the mushroom Ganoderma lucidum.

In the present invention discloses the use as an inhibitor of matrix metalloproteinases, drugs to suppress metastasis and cosmetics extract of the mushroom Ganoderma atrum obtained using as the extracting solvent of water and/or lower alcohols.

It is also proposed the introduction of this extract in food products.

Examples of carrying out the invention

Are discussed further embodiments of the present invention. Mushrooms Ganoderma class Basidiomycetes used in the present invention, are used for herbal medicines "Reishi" are related to polyporus fungi Ganoderma, Ganodermataceae. Mushrooms include Ganoderma Ganoderma lucidum (Reishi, Reishi), Ganoderma atrui-n and Ganoderma sinense (in accordance with the nomenclature in the cited reference, Acta Microbiologica Sinica, 19(3), 265-279, 1979), although this classification is not the only possible (limiting). Mushrooms Ganoderma used in the present invention are fungi Ganoderma atrum.

As extractants of the invention use water or a lower monohydroxy alcohols (e.g. methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and 2-butanol). As extractant may be a single solvent or a mixture of two, or a mixture of both solvents.

The content of the extract of the mushroom Ganoderma especially in medicines is the interval 0.03-10.0 wt.% - the weight of the dry product of the total weight of drugs, and the dry extract content of less than 0.03 wt.% does not guarantee a sufficient effect of the present invention. On the other hand, the dry extract content of more than 10 wt.% no increases efficiency and, therefore, not economical. In food this content is not specifically limited.

Mushroom extract Ganoderma can be used in the form of a solution extracted substances (extracts) without any additional processing or with the necessary processing, such as concentration, dilution, filtration or bleaching and deodorization using activated carbon or the like Extracted solution (hood) was evaporated to dryness, dried, depending on requirements, by using spray drying or freeze drying.

The MMP inhibitor according to this invention can be incorporated into different types of medicines used for the prevention, suppression or symptomatic relief of disorders and diseases caused by activated MMP. The MMP inhibitor may contain various additives, which are components usually added in medicines, pharmaceutical and food products in specific quantitative interval, not having a harmful effect on the action of e is stricta. Additives include fillers, stabilizers, preservatives, binders, substances that contribute to crushing, hydrocarbons, fatty acids, alcohols, esters, surfactants, Soaps, pH regulators, antiseptics, substances imparting taste and odor, substances that retain moisture, poroshkoobraznymi agents, UV absorbers, thickeners, dyes, antioxidants, brighteners, chelating agents, oils, fats and waxes.

Possible examples of dosage forms according to this invention include powders, pills, tablets, injectable solutions, suppositories, emulsions, capsules, granules, liquids (including tinctures, liquid extracts, alcoholic tinctures, suspensions and soft drinks and other foods with mushroom extract can also be of different types.

Some examples of compositions according to this invention are discussed below. These examples are not limiting, but only illustrative. In the compositions in the respective examples, unless otherwise indicated, the term "part" means "weight part.

The drug 1: Aqueous extract of Ganoderma atrum, obtained by extraction with hot water

To 20 g of dry Ganoderma atrum add 400 ml of purified water, extracted at a temperature of 95-100°C for 2 hours and filtered solution of the extract. The filtrate is evaporated and lyophilizers, obtain 1.4 g of dry water ex is rakta Ganoderma atrum.

Drug 2: 50% ethanol extract of Ganoderma atrum (obtained by extraction with 50%ethanol)

To 100 g of dry Ganoderma atrum add 900 ml of 50%ethanol, extracted at room temperature for 7 days and then filter the solution with the extract. The filtrate is evaporated to dryness, to obtain 1.9 g of the extract of Ganoderma atrum, obtained by extraction of 50%ethanolism solution.

Drug 3: Ethanol extract of Ganoderma atrum

To 100 g of dry Ganoderma atrum add 900 ml of ethanol, extracted at room temperature for 7 days and then filter the solution with the extract. The filtrate is evaporated to dryness, to obtain 1.5 g of dry ethanol extract of Ganoderma atrum.

Preparation 4: Aqueous extract of Ganoderma lucidum (Reishi), obtained by extraction with hot water

To 20 g of dry Ganoderma lucidum add 400 ml of purified water, extracted at a temperature of 95-100°C for 2 hours and filtered solution of the extract. The filtrate is evaporated and lyophilizers, obtain 2.0 g of dry aqueous extract of Ganoderma lucidum (Reishi).

Preparation 5: Extract of Ganoderma lucidum (Reishi), obtained by extraction with 50%ethanol

To 100 g of dry Ganoderma lucidum (Reishi) add 900 ml of 50%ethanol, extracted at room temperature for 7 days and then filter the solution with the extract. The filtrate is evaporated to dryness, to obtain 3.1 g of an extract of Ganoderma lucidum (Reishi), obtained by extraction with 50%ethanol concrete is.

Preparation 6: Ethanol extract of Ganoderma lucidum (Reishi)

To 100 g of dry Ganoderma lucidum (Reishi) add 900 ml of ethanol, extracted at room temperature for 7 days and then filter the solution with the extract. The filtrate is evaporated to dryness, to obtain 2.5 g of an ethanol extract of Ganoderma lucidum (Reishi).

Example 1: Powder 1

RecipeContent
1. Aqueous extract of Ganoderma atrum (Drug 1)2 pieces
2. Dry maize starch38.0
3. Microcrystalline cellulose60.0

[Get]

Mix components 1-3, receiving powder 1.

Example 2: Powder 2

Powder 2 receive, replacing the aqueous extract of Ganoderma atrum in Example 1 to extract Ganoderma atrum 50%ethanol (Preparation 2).

Example 3: Powder 3

Powder 3 receive, replacing the aqueous extract of Ganoderma atrum in Example 1 by an aqueous extract of Ganoderma lucidum (Reishi) (Preparation 4).

Example 4: Powder 4

Powder 4 receive, replacing the aqueous extract of Ganoderma atrum in Example 1, an equal amount of a mixture of an aqueous extract of Ganoderma atrum (Drug 1) and aqueous extract of Ganoderma lucidum (Reishi) (Preparation 4).

Comparative example 1: Powder And powder without the extract of the mushroom Ganoderma). Powder And is prepared by replacing the aqueous extract of Ganoderma atrum in Example 1 on a dry corn is wet starch.

Example 5: Tablets

RecipeContent
1. Ethanol extract of Ganoderma atrum
(Preparation 3)5.0 parts
2. Dry maize starch25.0
3. Calcium carboxymethylcellulose20.0
4. Microcrystalline cellulose40.0
5. Polyvinylpyrrolidone7.0
6. Talc3.0

[Cooking]

Mix components 1-4 and as a binder for the formation of granules to the mixture an aqueous solution of the component 5. Then the granules add the component 6 and formed into tablets. The weight of each tablet is 0.52,

Example 6: Food pills

RecipeContent
1. 50.0% Ethanolic extract (Preparation 3)5.0 parts
2. Dry maize starch50.0
3. Erythritol20.0
4. Citric acid40.0
5. Ester of fatty acid and of sucrose7.0
6. FlavorAn adequate amount
7. WaterAn adequate amount

[Cooking]

Mix components 1-4 and 7 and receive granules. Then the beads add components 5 and 6 and is formed into tablets. The weight of each tablet is 1.0,

Example 7: Drink

RecipeContent
1. Ethanol extract of Ganoderma lucidum
(Preparation 6)1.0
2. Peconic Kapiolani0.05
3. Malic acid5.0
4. Corrigent0.1
5. Water to total amount100 pieces

[Cooking]

Dissolve the components 2 and 3 in a little water and mix components 1, 4 and 5 with a solution.

Next, we describe experimental studies were undertaken detailed discussion of the present invention.

Experiment 1: Test for inhibition of MMP.

Mushroom Ganoderma is subjected to testing for inhibition of gelatinase activity method demografie with gelatin. Prepare a 10% SDS-PAGE gel (1 mm thick)containing 0.6 mg/ml gelatin, and get 0.014 ml of the culture supernatant of cells In 16 mouse melanoma cells subjected to gel electrophoresis in neustanovivshiesya. Then to remove SDS gel for 30 minutes and successively washed twice with 2.5% solution of Triton X-100 (Triton X-100, Sigma Chemical Co.) at room temperature and washed the gel incubated in 30 mm buffer solution tris-HCl (pH 7.6)containing 200 ml of sodium chloride, 5 mm calcium chloride and 0.01% brij-35 (Sigma Chemical Co.) at 37°C for 24 hours. To the buffer solution which is impregnated gel, add each of the following extracts: aqueous extract of Ganoderma atrum (Drug 1), an aqueous extract of Ganoderma lucidum (Reishi) (Preparation 4) and a mixture of equal amounts of aqueous extract of Ganoderma atrum and aqueous extract of Ganoderma lucidum (Reishi). Upon completion of the reaction, the gel is stained with a 0.2% solution of Kumasi brilliant blue R and discolor solution of 5% methanol, 7.5% acetic acid. Gelatinase activity is defined as the unpainted strip painted in blue color gel using a densitometer (Atto Densitograph AE-6905, Atto Co.) and calculate the rate of inhibition. The rate of inhibition (%) calculated by the following equation (1), based on the testimony of the densitometer. The results are shown in Table 1. Extracts of Ganoderma mushrooms inhibit gelatinase produced by cells of the murine melanoma b 16, depending on concentration.

A: the Value indicated by the densitometer, adding extract of the mushroom Ganoderma.

In: the Value displayed den what icomera, without the addition of extract of the mushroom Ganoderma.

Table 1
SamplesThe final concentration of reaction solution [%]The rate of inhibition [%]
S10.2538
0.5064
1.099
S20.259
0.5049
1.096
S30.2526
0.5058
1.098
S1: Aqueous extract of Ganoderma atrum (Drug 1)

S2: Aqueous extract of Ganoderma lucidum (Reishi) (Preparation 4)

S3: a Mixture of equal amounts of aqueous extract of Ganoderma atrum and aqueous extract of Ganoderma lucidum (Reishi)

Experiment 2: Test for inhibition of MMP.

50% Ethanol extract of Ganoderma lucidum (Reishi) (Preparation 5), ethanol extract of Ganoderma lucidum (Reishi) (Preparation 6), 50% ethanol extract of Ganoderma atrum (Preparation 5) and ethanol extract of Ganoderma atrum (Preparation 3) is also subjected to the above test. The results are shown in Table 2. The final concentrations of these che is ireh extracts in the respective reaction solutions in all cases were very low, namely 0.03%. However, the ethanol extracts of Ganoderma mushrooms at this low concentration more effectively inhibit gelatinase produced by cells In 16 murine melanoma, compared to their aqueous extracts.

Table 2
SamplesThe final concentration of reaction solution [%]The rate of inhibition [%]
T1

T2

T3

T4
0.03

0.03

0.03

0.03
67

78

85

96
T1: 50% Ethanol extract of Ganoderma lucidum (Reishi) (Preparation 5)

T2: Ethanol extract of Ganoderma lucidum (Reishi) (Preparation 6)

T3: 50% Ethanol extract of Ganoderma atrum (Drug 2)

T4: Ethanol extract of Ganoderma atrum (Preparation 3)

Experiment 3: Test for suppression (suppression) cancer metastasis

Each of the following extracts: aqueous extract of Ganoderma atrum (Drug 1), an aqueous extract of Ganoderma lucidum (Reishi) (Preparation 4) and a mixture of equal amounts of aqueous extract of Ganoderma atrum and aqueous extract of Ganoderma lucidum (Reishi) in the amount of 100 mg/kg injected into the abdominal cavity, one group of C57BL/6 mice once a day for 1 week. The control group in the abdominal cavity injected with saline. In this example, each group included 8 mice. Then into the tail vein of each of the mice injected cells In 16 murine melanoma with density 1× 105cells in the mouse. After injection continue the re-introduction of each sample. 3 weeks after inoculation of cancer cells from each mouse extract light and fixed in 10%formalin solution. Fixed in formalin light is divided into 5 shares and consider the number of nests of metastatic cells on the surface of the shares. The results are shown in Table 3. Introduction extract of the mushroom Ganoderma largely suppresses the formation of nests of metastatic cells compared with the control group. Therefore, the extract of the mushroom Ganoderma possesses sufficient resistance to metastasis.

Table 3
SamplesThe average number of nests of metastatic cells
U149
U28
U325
U414
U1: saline

U2: an Aqueous extract of Ganoderma atrum (Drug 1)

U3: Aqueous extract of Ganoderma lucidum (Reishi) (Preparation 4)

U4: a Mixture of equal amounts of aqueous extract of Ganoderma atrum and aqueous extract of Ganoderma lucidum (Reishi)

According to the above results, an aqueous extract of Ganoderma atrum (Drug 1), an aqueous extract of Ganoderma lucidum (Reishi) (Preparation 4) and a mixture of equal number of the qualities of an aqueous extract of Ganoderma atrum and aqueous extract of Ganoderma lucidum (Reishi) in severely inhibit MMP and inhibit the metastasis of the cancer. 50% Ethanolic extracts and ethanol extracts of Ganoderma atrum and Ganoderma lucidum (Reishi) (Drugs 2, 3, 5 and 6) are also subjected to the above test suppression. The results show that 50% ethanolic extracts and ethanol extracts of these fungi Ganoderma also very much inhibit MMP and inhibit the metastasis of the cancer.

Experiment 4: Test for suppression (suppression) cancer metastasis

Nutritious food (food) for the experiment is prepared by adding each of the powders 1-4 (Examples 1-4) of the present invention, which contain, respectively, an aqueous extract of Ganoderma atrum (Drug 1), 50% ethanol extract of Ganoderma atrum (Preparation 2), an aqueous extract of Ganoderma lucidum (Reishi) (Preparation 4) and a mixture of equal amounts of aqueous extract of Ganoderma atrum and aqueous extract of Ganoderma lucidum (Reishi) with a concentration of 5.0%, in sales of nutritional food (MF feeding mice and rats: Oriental Yeast Co., Ltd.). A group of mice eating without restrictions appropriate food (food). Another group of mice eating without limitation of the experimental feed containing 5.0% powder (Comparative example 1) without adding any extract of the mushroom Ganoderma (control group). In this example, each group of 8 mice. As in Experiment 2, in this example, cancer cells inoculant 2 weeks after the start of feeding nutritious food additive since the Cabinet. Consider the number of nests of metastatic cells. The results are shown in Table 4. Add in nutritious food each powder containing the extract of the mushroom Ganoderma, significantly suppresses the formation of nests of metastatic cells compared with the control group (Comparative example). That is, the mushroom Ganoderma effectively inhibit the metastasis of the cancer.

Table 4
SamplesThe average number of nests of metastatic cells
V162
V235
V333
V447
V541
V1: Comparative example

V2: Powder 1 (Example 1)

V3: Powder 2 (Example 2)

V4: Powder 3 (Example 3)

V5: Powder 4 (Example 4)

All the tablets from Example 5 and pelletized feed of Example 6 grind to a powder in a mortar. The powders of the samples subjected to the above test suppression for powders. As for the drink of Example 7, then 0.3 ml of sample administered orally to each mouse once a day via a stomach tube, and study the effect of the sample on the metastasis of the cancer. Samples from Examples 5-7 also effectively inhibit the metastasis of the cancer.

Prom the industrial applicability

As described above, extracts of Ganoderma mushrooms inhibit the activation of MMP produced by cancer cells, and inhibit metastasis of cancer associated with activated MMP. The MMP inhibitor according to this invention, preferably, applied to prevent, suppress and symptomatic relief of various disorders and diseases caused by activated MMP, such as metastasis of cancer, ulcers, rheumatoid arthritis, osteoporosis, periodontal diseases and skin aging.

1. Inhibitor of matrix metalloproteinase-containing extract of the mushroom Ganoderma atrum obtained using as the extracting solvent of water and/or lower alcohols.

2. Drug for suppression of metastasis, containing from 0.03 to 10 wt.% extract of the mushroom Ganoderma atrum obtained using as the extracting solvent of water and/or lower alcohols.

3. A food product containing an extract of the mushroom Ganoderma atrum obtained using as the extracting solvent of water and/or lower alcohols.



 

Same patents:

FIELD: organic chemistry, medicine, gerontology.

SUBSTANCE: invention relates to using hydrogenated pyrido[4,3-b]indoles of the formula (1) and the formula (2) as an agent for prophylaxis of premature aging. Also, invention relates to a pharmacological agent based on thereof possessing with the geroprotective activity and to a method for prophylaxis of premature aging.

EFFECT: valuable medicinal properties of agents.

20 cl, 6 dwg, 5 tbl, 2 ex

FIELD: medicine, surgery.

SUBSTANCE: the present innovation deals with visualization of biliary excretion during laparoscopic cholecystectomy. For this purpose, one should introduce 10 ml 0.4%-indigo carmine blue solution intravenously, after cholecystectomy one should treat cholecyst bed with 3%-aqueous hydrogen peroxide solution diluted in 500 ml isotonic solution. Moreover, small open ducts should be stained into light-blue color, and additional ducts - into more intensive light-blue color. If necessary, the procedure mentioned should be repeated. The innovation provides the chance for qualitative implementation of electrocoagulation of biliary ducts and cholecyst bed and, thus, prophylaxis of biliary excretion in postoperational period.

EFFECT: higher efficiency.

1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes using one or some unsubstituted or substituted fumaric acid monoalkyl and dialkyl esters as a specific inhibitor of transcription NF-kappa B-dependent gene as a component of pharmaceutical composition used in treatment of NF-kappa B-mediated diseases. Diseases are chosen from the group consisting of diffuse systemic scleroderma, syphilitic osteochondrotis (Veger's disease), Cutis marmorata, (Livedo Reticularis), Behcet's disease, panartheriitis, nonspecific ulcerous colitis, vasculitis, osteoarthritis, gout, arteriosclerosis, Reiter's syndrome, broncho-pulmonary granulomatosis, encephalitis types, endotoxic shock (septic-toxic shock), sepsis, pneumonia, encephalomyelitis, nervous-psychic anorexia, Rennert's T-lymphomatosis, mesangial nephritis, post-angioplasty restenosis, cytomegalovirus retinopathy, adenoviral diseases, such as adenoviral cold diseases, adenoviral pharyngo-conjunctival fever and adenoviral ophthalmia, AIDS, Guillain-Barr syndrome, post-herpetic neuralgia or neuralgia after shingles, inflammatory demyelinizing polyneuropathy, multiple mononeuropathy, mucoviscidosis, Bekhterev's disease, Berret's esophagus ulcer, infection with Epstein-Barr virus (EBV), cardiac re-modeling, interstitial cystitis, diabetes mellitus type II, radio-sensitized malignant tumors, partial resistance of malignant cells to chemotherapeutic agents (resistance to many medicinal agents used in chemotherapy), ring-shaped granulomas and oncological diseases, such as breast cancer, colon cancer, melanoma, primary carcinoma of liver cells, adenocarcinoma, Kaposi's sarcoma, prostate cancer, leukosis, such as acute myeloid leukosis, multiple myeloma (plasmocytoma), Burkitt's lymphoma and Kastleman's tumor. The selective inhibition of indicated receptors provides carrying out the suppression of inflammation in treatment of above enumerated diseases.

EFFECT: valuable medicinal properties of substances.

10 cl, 2 tbl, 7 ex

FIELD: medicine, cosmetics.

SUBSTANCE: invention relates to a composition used for enhancing the growth and/or hardening breast tissue, and/or for inhibition of growth of benign callosities in breast tissue, and/or for promoting in their treatment. The claimed composition comprises hop, L-ornithine, rye, buckwheat, malt and barley taken in the following ratio, wt.-%: hop, 25-40; fennel, 1-10; buckwheat, 5-15; rye, 1-10; barley, 20-35; malt, 5-15, and L-ornithine, 5-15. The composition can be made as a suitable tabletted formulation and it is prepared from natural components. Also, invention relates to a method for preparing a solution of suspension used for enhancing the growth and/or hardening breast tissue, and/or inhibition of the growth of benign callosities in breast tissue, and/or for promoting in their treatment wherein the claimed composition as a tabletted formulation is mixed with water.

EFFECT: valuable medicinal and cosmetic properties of composition.

5 cl, 3 tbl, 9 ex

FIELD: biology, embryology.

SUBSTANCE: invention relates to a method for controlling oocytes quality and a composition for addition in medium for culturing oocytes. Method for controlling the oocytes quality involves placing at least one oocyte in cultural medium and carrying out culturing. The cultural medium comprises at least one anti-sense oligonucleotide of length 17-30 nucleotides wherein each of them is complementary to mRNA of at least one of the following genes: gene-inductors of apoptosis, such as HRK, FAS, FASL, BAX, Caspase-3, genes of growth factors, such as IGF1, gene-receptors of growth factors, such as IGF1R, genes regulating the dividing embryos rate, such as HLA-E, HLA-F, HLA-G, genes of cellular stress, such as HSF1 and HSF2. The composition added in cultural medium comprises one or more an anti-sense oligonucleotide describes above and acceptable solvent. The advantage of invention involves enhancing the quality and viability of oocytes and enhancing the therapeutic effectiveness in treatment of sterility.

EFFECT: improved controlling method, improved properties of composition.

15 cl, 2 dwg, 10 ex

FIELD: medicine, gastroenterology, pharmacology.

SUBSTANCE: invention relates to compositions comprising a substance possessing regulating activity, for example, inhibition of proliferation of cells expressing AILIM, for suppression of onset of intestine inflammatory diseases, in particular Crohn's disease, and colitis. Invention provides enhancing the therapeutic effect.

EFFECT: valuable medicinal properties of agents.

10 cl, 12 dwg, 2 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: the present innovation deals with treating acute anterior and posterior ischemic optic neuropathy due to introducing vasodilators and anticoagulants as caffeine, halidor, dicinon in complex therapy in hospital for 10 d. Moreover, it is necessary to perform parabulbar introduction of 0.3 ml dexasone, 0.2 ml caffeine, 0.3 ml emoxipin successively, fractionally every 20 min once daily in combination with daily intramuscular injections once daily of 2.0 ml dicinon and 1.0 ml halidor and intravenous injection of haemodesum by drops per 200.0 ml on the 1st, 3d and 5th d of therapy. Also, it is necessary to carry out 5 seances of hirudotherapy for temple area every other day under coagulogram control. Then one should introduce milgamma, dicinon and nootropil at age-dependent dosages for 1 mo ambulatorily. The innovation provides complex improvement of microcirculation and metabolicocular and cerebral processes, regeneration of nervous tissue and reconstruction of optic nerve's conductivity at decreased frequency of therapeutic side effects.

EFFECT: higher efficiency of therapy.

2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: method involves administering pyrimidine nucleotide precursors at a daily dose of 0.05-0.3 g/kg of body weight. The method is applicable under condition that cytotoxic chemotherapy agent does not belong to pyrimidine nucleoside analogs.

EFFECT: enhanced effectiveness in eliminating mitochondrial respiration chain dysfunction.

2 cl

Adaptogen // 2279877

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention proposes using acizol representing bis-(1-vinylimidazol-N) zinc diacetate as an adaptogen. Acizol is known early as antidote. Acizol exceeds plant Eleutherecoccus senticosus by activity with respect to indices of functional state of the body adaptation systems due to providing the higher intensity of tissue respiration, improvement of energetic metabolism and regenerative processes.

EFFECT: enhanced effectiveness and valuable medicinal and biochemical properties of adaptogen.

1 dwg, 8 tbl

FIELD: medicine, anesthesiology, resuscitation.

SUBSTANCE: one should correct hemostasis disorders intra-operationally due to introducing fraxiparine about 40-80 min against the onset of operation along with intravenous injection of mexidol, by drops at the dosage of about 5-6 mg/kg patient's body weight dissolved in 400 ml 0.9%-NaCl solution at the rate of 60 drops/min. The present innovation enables to create the peak of fraxiparine and mexidol concentrations at traumatic stage of operation that enables to correct hemostasiological disorders during operative interference and at early post-operational period due to combined action of preparations onto different links of hemostasis.

EFFECT: higher efficiency and accuracy of correction.

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions used for inhibition of metastasis or prophylaxis of malignant tumor relapse after the topical therapy. As an active component, compositions contain derivative of polysaccharide comprising polysaccharide with carboxyl group bound with an active substance possessing anti-tumor activity through amino acid or peptide consisting of from 2 to 8 amino acids that are similar or different, or its salt wherein this active anti-tumor substance is represented by derivative of camptothecin of the formula (I) by claim 1 or compound of the formula (II) by claim 1 given in the invention description. The topical therapy involves surgery, radiation therapy, thermotherapy, cryotherapy or laser-burning therapy. Proposed compositions allow providing the high concentration of active substance in tumor metastasis region and prophylaxis of relapses of malignant tumor after carrying out the topical therapy.

EFFECT: valuable medicinal properties of pharmaceutical compositions, improved method of treatment.

9 cl, 1 dwg, 4 tbl, 6 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new sulfonamide derivatives possessing anti-tumor activity, namely to compounds of the formula (I): wherein R6 means hydroxyl; R7 means methyl, isopropyl, isobutyl, benzyl or indole-3-ylmethyl; R8 means hydrogen atom; R9 means phenylene; R10 means thienyl, furyl or pyridyl optionally substituted with lower alkyl or halogen atom. Also, invention relates to their derivatives or pharmaceutically acceptable salts or solvates. Invention describes medicinal agents used in treatment or prophylaxis of cancer and for prophylaxis of metastasis. Also, invention describes a case for treatment of cancer in mammal.

EFFECT: improved treatment method, valuable medicinal properties of agent.

5 cl, 17 tbl, 112 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: medicine, in particular angiogenesis prophylaxis and treatment.

SUBSTANCE: invention relates to 2-cyclooxygenase inhibitors selected from group containing 4-[5-(4-chlorophenyl)-3-phenyl-1H-pyrazole-1-yl] benzenesulfonamide; 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl] benzenesulfonamide; 4-[5-methyl-3-phenyloxazole-4-yl] benzenesulfonamide or pharmaceutically acceptable salts thereof and pharmaceutical composition containing the same in therapeutically effective amount. Said composition are useful in treatment and/or prophylaxis of angiogenesis disorders such as metastasis, eye angiogenesis, diabetic retinopathy, etc. in subjects are needed in such treatment and/or prophylaxis.

EFFECT: new pharmaceuticals for angiogenesis treatment and/or prophylaxis.

5 cl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

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

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: oncology.

SUBSTANCE: invention is directed, in particular, to treatment of patients with Ewing's sarcoma and osteogenic sarcoma at different stages of malignant process. Method comprises chemotherapy and beam therapy. Samples of venous blood are taken from children in age of 5 to 12 years in amounts not larger than 5% of the total volume of circulating blood per 1 introduced dose of chemical preparation and, from adolescents and young persons, in amount of 200 ml. Then 4 courses of polychemotherapy are fulfilled with autoblood according to standard treatment schemes for given diseases, taking into account stages of disease, in recommended doses. Between 2nd and 3rd chemotherapy courses, radiotherapy is fulfilled on metastatic focuses in lungs. After 4 courses of induction autohemo-chemotherapy, local therapy on the primary focus (radiotherapy and/or surgical treatment) is fulfilled and also radiotherapy on metastatic focuses in other bones, after which follows consolidation involving chemical preparation of the second line.

EFFECT: improved remote results of treatment , suppressed metastatic focuses, reduced tumor dimensions, and weakened toxic manifestations of therapy.

2 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: medicine.

SUBSTANCE: invention proposes applying bis-phosphonic acids (bis-phosphonates) for the embolic treatment of angiogenesis and corresponding methods for prophylaxis or treatment of angiogenesis by embolization. Invention provides suppression of growth, invasion or metastasis of tumors, treatment of angiogenesis in myocardium ischemia, rheumatic arthritis, osteoarthritis by embolization of newly formed vessels in intra-arterial route of administration of bis-phosphonate (for example, pamidronic acid or zoledronate).

EFFECT: valuable medicinal properties of medicine agents.

10 cl, 3 dwg, 7 ex

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for treatment of patients with disseminated forms of prostate cancer. Method involves administration of navelbine in the dose 30 mg/m2 on the background of anti-androgenic therapy. The course time in navelbine administration is 4 weeks and from 7-th day after the last injection of navelbine method involves administration of strontium-89 chloride in the dose 4 mKi (150 MBk), once time per 3 months, two injections. For patients with the amount of osseous metastases above 6 the dose of strontium-89 chloride is 8 mKi per one administration (300 MBk). In further courses of systemic therapy are repeated in 3 months, not early. Method shows the optimal regimen set in administration of preparations and provides the maximal effect of navelbine on osseous metastases followed by damaging effect of strontium-89 chloride on blood vessels of tumor and its cells and the absence of the potentiation toxicity on the hemopoiesis system.

EFFECT: improved and enhanced effectiveness of treatment.

3 dwg, 2 ex

FIELD: medical engineering.

SUBSTANCE: method involves exposing an intraocular neoplasm after vitrectomy and retinotomy, smoothening retina with perfluororganic compound later substituted with silicon oil. After having removed the neoplasm, intravenous 10% Perfluorane emulsion transfusion is carried out at a rate of 60 drops per 1 min in the amount of 80-100 ml. Next to it, photosensitizer is intravenously drop-by-drop introduced into cubital vein of the same arm. Laser irradiation of blood is carried out with power of 20-50 mW through laser light guide set in advance into cubital vein of the other arm in 5-15 min after starting introducing Perfluorane. When applying 0.1-1% water solution of Khlorine as photosensitizer at a dose of 0.2-0.5 mg/kg, irradiation is carried out at wavelength of 630-633 nm during 10-45 min. The treatment is administered twice with 5 days long pause.

EFFECT: enhanced effectiveness of treatment; reduced risk of tumor cells dissemination and metastases formation.

3 cl

FIELD: pharmacy.

SUBSTANCE: invention proposes a medicinal agent for oral administration possessing an anti-inflammatory effect. Medicinal agent is made as a solid dosed formulation for oral administration that comprises meloxicam as an active substance, stearic acid or stearate as a slipping substance, maltodextrin as a binding agent, croscarmellose sodium salt as a disintegrating agent and dextrin as a filling agent taken in the definite ratio of components. Invention provides enhancing the biological availability of agent and improving its consumption properties. Invention can be used in the development of a medicinal agent made as a solid dosed formulation for oral administration possessing an anti-inflammatory effect.

EFFECT: improved and valuable pharmaceutical properties of agent.

10 cl, 11 tbl, 32 ex

Up!