Extract of fraxinus excelsior seeds and its therapeutic application
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to the field of pharmaceutics. An extract of Fraxinus excelsior seeds, capable of activating PPAR-alpha, which contains nuzhenide GI3, oleoside methyl ester, excelside B, GI5, salidroside, in effective quantities. An application of the extract of Fraxinus excelsior seeds to obtain a medication for treating a state, in which the PPAR-alpha activation is useful, is described. Also described is a method of treating a subject with the state, in which the PPAR-alpha activation is useful. A method of obtaining the extract of Fraxinus excelsior seeds is disclosed.
EFFECT: application of the claimed extract makes it possible to treat states, in which the PPAR-alpha activation is useful in an efficient way.
14 cl, 11 dwg, 2 tbl, 13 ex
Background of invention
Diabetes mellitus type 2 (DM-2) is a common worldwide disease characterized by a deficiency of insulin and insensitivity to insulin. DM-2 is heavy, which creates a problem for the health of a disease associated with high morbidity and mortality, and is the sixth leading cause of death in the USA [Minino et al, 2007, National Vital statistics Report, 55]. It is expected that by 2025 the number of patients with diabetes may increase to 300 million [King et al, 1998, Diabetes Care, 21, 1414-31]. In the United States by 7 percent of the population of 20.8 million children and adults have diabetes [French, 2007, Inside, 12, 46-7], and expenses in connection with medical costs and lost productivity in the United States are evaluated as $132 billion in 2002 [Hogan et al, 2003, Diabetes Care, 26, 917-32]. Treatment DM-2 include the use of insulin, insulin analogs or modified insulin, increased release of insulin and action of insulin, inhibition of glucose production in the liver, and the inhibition of seizure of glucose [Moller, 2001, Nature, 414, 821-27]. In addition to this therapeutic effect is also used worldwide for the treatment of DM-2 use traditional medicine. For the treatment of symptoms of DM-2 ethnopharmacologically or experimentally used more than 1200 species of organisms [Maries and Farnsworth, 1996, Protocol J. Botanical Med., 1, 85-137].
It is generally accepted that fast is the increasing prevalence of obesity is a serious public health problem in the United States. In accordance with the data from the 1999-2000 National Health and Nutrition Examination Survey (NHANES), approximately two-thirds (64.5 per cent) of U.S. adults are overweight, compared with 55.9 percent, as reported in the study of NHANES III, conducted between 1988 and 1994. The prevalence of obesity has also dramatically increased from 22.9% to 30.5 per cent during the same period. An increasing number of people with obesity are likely to have a high risk of development of various obesity-related diseases, including diabetes [Flegal et al, 2002, JAMA. 288, 1723-1727 and Kuczmarski et al 1994, JAMA. 272, 205-221].
Fraxinus excelsior L., a plant of the familyOleaceaewidely known as "ash" or "ash high in the countries of Central Asia and Europe [Gilman and Watson, 1993, Fact Sheet ST-264, November]. This plant is also widely distributed in Tafilalet, the South-Eastern region of Morocco, and is known there as "l ssane l ousfour". The Tafilalet region among the regions of Morocco is considered the area where the development of the art of herbal medicine [Eddouks et al, 2002, J. Ethnopharmacol. 82, 97-103]. In recent studies it was shown thatF. excelsior(FE) has antibacterial and antioxidant activity. Extract FE in methanol showed the highest antioxidant activity with RC50component of 1.35×10-2in quantitative analysis with α,α-diphenyl-β-picrylhydrazyl (DPPH). Extract FE in n-hexane and dichloromethane is also active against eight p is testirovanie species of gram-positive and gram-negative pathogenic bacteria, including methicillin-resistantStaphylococcus aureuswith the values of minimum inhibitory concentration (MIC) in the range of 1.25×10-1mg/ml [Middleton et al, 2005, Indian J. Pharma. Res., 2, 81-6]. Described the hypotensive effect of FE on normotensive and spontaneously hypertensive rats. Oral administration once a day aqueous extract of the seeds of FE resulted in a significant increase in systolic blood pressure and a significant increase urination in rats of both types [Eddouks et al, 2005, J. Ethnopharmacol., 99, 49-54]. Aqueous extracts of seeds of FE showed a strong hypoglycemic and antihyperglycemic activity in normal and induced streptozotocin (STZ) rats without affecting baseline concentration of insulin in plasma [Maghrani et. al, 2004, J. Ethnopharmacol., 91, 309-16]. One of the mechanisms of hypoglycemic effect of FE may be phlorizin-like effect of inhibiting the reabsorption of glucose in the kidney [Eddouks et al, 2004, J. Ethnopharmacol., 94, 149-54].
It has been described that FE mainly contains coumarins, secoiridoid and fenretinide. [Kostova and Iossifova, 2007, Fitoterapia 78, 85-106]. Secoiridoid found in FE, are formed from Olesia. These types of secoiridoids exist only in plants of the family Oleaceae [Egan et al, 2004, Biochem. Sys. Ecol., 32, 1069-71].
The present invention relates to new secoiridoids, which were isolated from the extract of the seeds ofFraxinus excelsior(the General name ash). It was identified two compounds as (1) 3-ethylidene-2-[(6-O-β-D-glyukopiranozil-β-D-glyukopiranozil)oxy]-3,4-dihydro-5-(methoxycarbonyl)methyl ester of (2S,3E,4S)-2H-Piran-4-acetic acid, called exiled A, having the chemical formula C22H32O16(Fig.1-1); and (2) 3-ethylidene-2-[(6-O-β-D-glyukopiranozil-β-D-glyukopiranozil)oxy]-3,4-dihydro-5-(methoxycarbonyl)2-(4-hydroxyphenyl)ethyl ester of (2S,3E,4S)-2H-Piran-4-acetic acid, called exiled B, having the formula C30H40O17(Fig.1-2). Both compounds are secoiridoid type Olesia characterized ekzoticheskoy 8,9-olefin functional group.
Also the present invention relates to a method of obtaining the selected compositions formed from FE. The composition can be a unique method of extraction and selection. The seeds are crushed into granules with a particle size in the range from 0.1 mm to 30 mm to increase the surface area for contact with the solvent and to improve the efficiency of extraction. In one embodiment of the method, the temperature of extraction is in the range from 20°C to 100°C. In a preferred embodiment, the temperature of extraction is in the range from 50°C to 70°C. the Ratio of plant material to the mixture of solvents used in the extraction process varies from 1:1 on the 1:10 per gram per milliliter. In one embodiment of the method ratio is from 1:3 to 1:8. The period of incubation, during which the plant material is in contact with the mixture of solvents is from about 2 h to about 24 h the Solvent extraction may be water, a mixture of water-alcohol (1% to 99% alcohol in water and alcohol. The preferred alcohols are ethanol (EtOH) and methanol (MeOH). After incubation of plant material and solvent, the solvent is separated from the rest of the plant material and extraction composition to concentrate until the solid components of the composition will not contain, in total approximately 1%-35% of secoiridoidsF. excelsior. Secoiridoid include two new glycoside type olesinov, exiled A and exiled B, dimeric secoiridoid, Nugent (nuzhenide) (3) (Fig.1-3), GI3 (4) (Fig.1-4) and GI5 (5) (Fig.1-5), and ligstroside, dimethyl ether complex of Olesia (6) (Fig.1-6) and complex oleosin-11 methyl ether. Other components include phenolic compounds, salidroside, coumarins and flavonoids. After graduation extract secoiridoid emit. Secoiridoid can be distinguished from the extract FE chromatography.
Secoiridoid extracted from dry powder extract FE. The powder is dissolved in alcohol and powder secoiridoid extracted with alcohol. Then the alcohol is evaporated and the OS is asisa residue, including secoiridoid, placed in a chromatographic column filled with resin C-18 reversed-phase. Several fractions containing different compounds elute in a series of systems of water and 10% MeOH/90% water and MeOH. Fractions are compared in the analysis of high-performance liquid chromatography (HPLC) and eluent with similar types of HPLC, pooled. Combined fractions divide column chromatography normal phase silica gel and elute with chloroform (CHCl3), a mixture of CHCl3-methanol, ranging from 90%, 80% CHCl3up to 100% MeOH, obtaining several sub-fractions. Subtractio compare HPLC and the fractions that contain exiled A and exiled B, unite, respectively. Combined fractions are then cleaned by a combination of column chromatography through resin C-18, MCI GEL CHP-20P and/or Sephadex LH-20, with getting clean aixelsyd A and aixelsyd B.
Using spectroscopic methods, including nuclear magnetic resonance (NMR), ultraviolet (UV), infrared (IR) and mass spectroscopy (MS), revealed new chemical structure aixelsyd A and aixelsyd B, and determines their physical properties. Known chemical structure of secoiridoids identified by direct comparison of the NMR spectra with spectra found in the literature. IR spectra were recorded on a spectrophotometer Prkin-Elmer 1600 FTIR using KBr plates. NMR spectra were obtained on Varian INOVA 400 with deuterated methanol (CD3OD) as solvent. All 2D correlation spectra were obtained using a standard gradient pulse sequences software Varian NMR. Correlation spectra include COSY (correlation spectroscopy), TCOSY (total correlation spectroscopy), HMQC (heteronuclear multiple quantum coherence), HMBC (heteronuclear correlation with multiple links) and ROESY (enhanced spectroscopy Noe with rotating bezel). The HPLC analysis was performed using a HPLC system Agilent model 1100, equipped with a Quaternary pump, automatic probabilism, four-channel online degasser, a detector with a photodiode matrix and software Agilent Chemstation. Molecular weight was determined using LC/MS ESI/APCI mass spectrometry ion trap Finnigan LCQ. UV spectra were obtained on a Schimadzu spectrophotometer, UV-1700 UV-Visible.
Also the present invention relates to the inhibitory effect of dimeric secoiridoids, GI5 (5) and Noranda (3), undifferentiated cells 3T3-L1. The main component of the increase in body mass is the deposition of adipose tissue in the body in the process of adipogenesis. Adipokines characterized by an increase in the number and RA is the measure of fat cells. Inhibition of adipogenesis by inhibiting the synthesis of fat in the cells to reduce the number and size of fat cells provides control over body weight.
The present invention relates to the activation of PPAR-alpha byFraxinus excelsior(FE) and dedicated secoiridoids of the FE complex of dimethyl ether Olesia (6), aixelsyd A (1) and GI3 (4). Activated proliferation peroxisome receptor (PPAR) are nuclear receptors that control many cellular and metabolic processes. PPAR-alpha is expressed mainly in the liver, where it plays an important role in the control of fatty acid oxidation [Reddy and Hashimoto, 2001, Annu Rev Nutr., 21, 193-230]. Induction of fatty acid oxidation through activation of PPAR-alpha improves lipid profiles in plasma. In different mouse models agonists of PPAR-alpha reduces the level of triglycerides in plasma, reduce obesity and reduce steatosis of the liver and muscles, resulting in increasing insulin sensitivity and reducing the level of glucose in the blood [Guerre-Millo et al, 2000, J. Biol. Chem., 275, 16638-42 and Kim et al, 2003, Diabetes 52, 1770-8].
Also the present invention relates to the aforementioned composition, which is suitable for the treatment of metabolic syndrome to reduce the level of glucose in blood of a subject with DM-2, to facilitate weight loss and to balance the insulin levels in order to prevent GI is insulinemia, symptom of resistance to insulin in patients with DM-2. When male mice C57BL/6J fed a diet high in fat, they develop obesity, hyperglycemia and hyperinsulinemia. Introduction effective amount of FE can significantly reduce the glucose level in mice to reduce their body weight and fat level in the body and reduce insulin levels in plasma.
In clinical trials in humans, 16 healthy volunteers were given on an empty stomach 50 grams of glucose for induction occur after ingestion of glucose and injected FE or placebo (wheat bran). In the extract group FE decreased growing, emerging after a meal, the glucose concentration in plasma compared with placebo. It was statistically significant (P=0.02) reduced the area under the curve of glucose level in blood (AUC), characterizing glycemia. The seed extract FE also meaningful level induced (P=0.002) insulin secretion after 90 min after administration of glucose.
Brief description of figures
Additional characteristics, advantages and features of the present invention will be apparent to the person skilled in the art in the light of the following detailed discussion of preferred embodiments of the present invention, given with reference to the accompanying drawings, in which:
In Fig.(1-1)to(1-6) illustrates the molecular structure of e is sellside A, aixelsyd B, Noranda, GI3, GI5 and complex dimethyl ether of Olesia, respectively.
Figure 2 illustrates the activity of the seizure of glucose (inmin) for compounds GI5 (5) and Noranda (3) for 1, without processing, 2, insulin, 3, insulin and MeOH, 4 nagenda at concentrations of 0.004%, 0,02%, 0.05% and 0.1%; 5, GI5 at concentrations of 0.004%, 0,02%, 0.05% and 0.1%.
Figure 3 illustrates the relative activation of the slit receptor GAL4/PPARα seed extractFraxinus excelsior L.and 100 microns by phenobarbital (positive control) compared with the effect of DMSO (control condition) (values are average values±SD (n=4). *P<0,05, **P<0,01; ***P<0,001. t-student test).
Figure 4 illustrates the results of fasting glucose (mg/DL) for mice in the diet with a low fat diet (LF), high fat (HF) and Fraxinus (HF+extract FE) after feeding for 16 weeks.
Figure 5 illustrates the results for average body weight (g) in mice with diet low in fat (LF), high fat (HF) and Fraxinus (HF+extract FE) after feeding for different numbers of weeks.
Figure 6 illustrates the potential relative activation of PPARα (%) in reporter cell lines using concentrations in the range 10-5M-10-9M for selective synthetic PPARα activator WY14.643, and dedicated connections to concentrate the radio 10 -4M and water solution of 1:10 extract of the seeds of FE, with the designation of the connections marked as: FE19028 (Nugent, 3), FE20015 (GI3, 4), FE20031 (dimethyl ether complex of Olesia, 6), FE21008 (aixelsyd A, 1) and FE21023 (GI5, 5).
Figure 7 illustrates the mass (g) omental fat individual mice from groups LF (n=10), HF (n=10) and seed extract FE, respectively.
On Fig illustrated mass (g) retroperitoneal fat individual mice from groups LF (n=10), HF (n=10) and seed extract FE, respectively.
Figure 9 illustrates the levels of insulin in fasting plasma (ng/ml) from individual mice from groups LF (n=10), HF (n=10) and seed extract FE, respectively.
On figa and 10B, respectively, are illustrated comparison (mmol/l from time to time) between seed extractFraxinus excelsior L(FE) (1.0 g) and matching placebo in the form of wheat bran (1.0 g) on glycemia in healthy volunteers, which were introduced 50 g of glucose, for (A) increasing glycemia in separate moments of time, and (B) the area under the curve of glucose level in blood (AUC), where the values are the average±SEM. *P=0.02, paired t-test (n=16).
On figa and 11B, respectively, are illustrated comparison (IU/l against time) between seed extractFraxinus excelsior L(1.0 g) and the corresponding placebo in the form of wheat bran (1.0 g) in insulin levels in healthy volunteers, which were introduced 50 g of glucose, for (A) nerastas is insulinemia in separate moments of time, and (B) area under the curve (AUC), describing insulinemia where the values are average values±SEM. **P=0.002, t-student test (n=16).
Detailed description of the invention
Relative to the drawings and the following examples, the following describes preferred embodiments of the present invention to extract seedsFranxinus excelsior.
Extraction of secoiridoids fromFraxinus excelsiorwater
In General 2.5 kg seedsF. excelsiorwas air-dried and then crushed in a large powder with a particle size of approximately 1-2 mm Coarse powder was immersed in water in percolator at 80-90°C for 5 hours and the water extract was decanted from percolator. The extraction process was repeated three times. All aqueous extracts were combined and concentrated on a vacuum rotary evaporator. After evaporation of the water received in total 550 grams of dry powdered extract. The HPLC analysis indicates that the obtained powder extract contained two main secoiridoid, 11,4% (wt./mass.) mugenda and 6.2% GI3. Also the composition contained 0,19% complex oleosin-11-methyl ester, 0,41% aixelsyd B, 0,63% GI5, 0,2% salidrosides, together with some trivial secoiridoids, including ligstroside, dimethyl ether complex of Olesia and exiled A.
Extraction of secoiridoids fromFraxinus excelsiorwater, mixture of water-EtOH and EtOH
To prepare samples, and each sample contained 5 g of seeds ofF. excelsior. Each sample was crushed into powder and subjected to extraction with a solvent of 200 ml of water, a mixture of 25% EtOH/75% water, a mixture of 50% EtOH/50% water, a mixture of 75% EtOH/25% water and EtOH, respectively. After extraction for 24 hours at room temperature (22-24°C), the solvent evaporated and the residual solids were analyzed by HPLC. The content of secoiridoids and salidroside are shown in table 1.
The main content of secoiridoids and salidroside using different solvents (results expressed as percentage by weight)
|Connection||Eton||75% Eton||50% Eton||25% Eton||water|
|Complex on the methyl ester of Olesia||0,57||0,91||0,78||0,74||0,96|
The selection of secoiridoids fromF. excelsior
3.5 liters of methanol was added to 500 grams of powder extract obtained by the method described in example 1, and was stirred for 3 hours at room temperature. A solution of methanol was separated from the powder by filtration. The same process was repeated once, two extracts in methanol were combined and concentrated under reduced pressure, obtaining in total 54 grams of dry extract in methanol. The extract in methanol was re-dissolved in water and filtered to remove insoluble substances. Then the filtrate was subjected times is to bookmark chromatography with reversed phase resin (C-18, washed with water and a gradient solvent system MeOH-water, 10% MeOH in water to 100% MeOH. Gathered in total 7 fractions. Each faction elyuirovaniya with a column, evaporated in vacuum and combined in the analysis of HPLC. Fractions 2, 3 and 7 was placed on a chromatographic column filled silikagelevye resin, and suirable from the system chloroform-methanol, from CHCl3, 10% MeOH/CHCl3, 20% MeOH/CHCl3up to 100% MeOH. Fractions collected from the column with silica gel, was compared by HPLC analysis, and each separated eluent was re-subjected to column chromatography on resins MCI GEL CHP-20P and/or Sephadex LH-20 and suirable system water-methanol to obtain the pure compounds. It was discovered two new compounds, exiled A and exiled B, in addition to several known compounds: Noranda, GI3, GI5, ligstroside, dimethyl ether complex of Olesia, complex oleosin-11-methyl ester and salidroside. All chemical structures were established by spectroscopic methods.
Establishing patterns aixelsyd A and aixelsyd B
Exiled A (1) was obtained as amorphous powder. Its molecular formula C22H32O16was determined on the basis of his MC, and confirmed by1H and13C NMR (table 2). UV-spectrum showed a specific absorption at 232 (sh) nm, formed by a system of simple ARITHIGNORE nologo ether, conjugated with carbonyl group. The IR spectrum showed the functional hydroxyl groups at vmax3401, complex ether in 1734, 1717, and α,β-unsaturated complex ester at 1626 cm-1. A detailed analysis of1H,13C-NMR and 2D correlation spectra indicated exiled A bearing group secoiridoid glucoside type Olesia, which was confirmed by proton signals at δH7,51 (s, H-3), to 5.93 (s, H-1), between 6.08 (arcs, J=7,2, 0.8 Hz, H-8), 1,72 (d, J=7,6 Hz, H3-10) and 4,80 (d, J=8.0 Hz, H-1'), with the corresponding signals of the carbon-13 if δc155, 2mm (C-3), or 94.8 (C-1), of 124.7 (C-8), of 13.6 (C-10) and 100.5 (C-1'F). Two tone methoxyl when δH3,62 (OCH3, δc51,9) and 3.70 (OCH3, δc52,3) showed correlation with C-7 (δc173,7) and C-11 (δc168,6) in the gHMBC spectrum, respectively, indicating exiled A, having an element of complex dimethyl ether 7,11-Olesia [Boros and Stermitz, 1991, J. Nat. Prod., 54, 1173-246]. In addition, the occurrence of the additional NMR signals due to β-glucopyranosyloxy group (δc100,6, 77,6, 77,8, 71,6, 75,3 and 70,1), confirmed exiled as A complex of dimethyl ether 7,11-Olesia carrying another glucosyl. Position glucosyl was defined as attached to C-6' group Olesia, because there was a shift towards weak fields, amounting to 7.5 ppm signal at C-6', and the shift towards a strong field component of 0.5 and 2.6 MDA C-3' and C-5', accordingly, when compared with exelsior A with the same position 7,11-dimethylalanine. This conclusion was further confirmed by the correlation gHMBC spectrum, in which the observed cross-peaks between H-1"' if δH4,35 and C-6' at δc70,1 ppm, and between H-6' (δH4,15 and of 3.84 ppm) and C-1"' (δcto 105.3 ppm). A methyl group was located in the E-configuration of the 8,9-olefin communication and was confirmed by ROESY spectrum, where they observed a strong correlation between H-10 (δH1,72) and H-5 (δH3,96). In the same range correlation between H-1 (δH5,93) and H-6 (δcof 2.51) confirmed glycosyl in C-1, the receiving β-configuration. Thus, it was determined that the structure aixelsyd A represents a 3-ethylidene-2-[(6-O-β-D-glyukopiranozil-β-D-glyukopiranozil)oxy]-3,4-dihydro-5-(methoxycarbonyl)methyl ester of (2S,3E,4S)-2H-Piran-4-acetic acid, called exiled A. Complete data1H and13C NMR are shown in table 2.
Aixelsyd B (2) was isolated as a colorless amorphous powder. Its molecular formula was determined as C30H40O17when MC and confirmed by NMR. In the UV spectrum, in addition to typical absorption at 230 nm simple ARITHIGNORE enol ether conjugated with a carbonyl group, an additional absorption at 275 and 283 nm indicated the existence of phenol. IR parasalicil at v max3400, α,β-unsaturated ester in 1701, 1636, and the aromatic ring at 1518 cm-1. Spectra1H and13C NMR aixelsyd B showed typical signals due oleoides groups: the olefinic signals at δH7,50 (s, H-3), δWith155, 2mm (C-3), actulally when δH5,94 (s, H-1), δWithto 94.7 (C-1), anomeric signal from glucosyl when δH4,82 (d, H-1'), δWithto 100.3 (C-1'), olefinic proton of the group of ethylidene when δH6,05 (d, H-8), δWithof 124.8 (C-8) and methyl of ethylidene when δHto 1.61 (d, H3-10), δWith13,6 (C-10). The observed signals phenylethanoids, as well as spin system AA'BB' in the aromatic ring at δHof 6.71 (2H, DD, J=6,8, 2,8 Hz) and δH7,02 (2H, DD, J=6,8, 2,8 Hz), confirmed the configuration of para-substituted fenilalanina. Far correlation1H13C, identified in the gHMBC between H-1 when δH4.26% and C-7 at δWith67,0 ppm, confirmed that in position C-7 was attached phenylethanol that combines structure aixelsyd B ligstroside, complex pair-hydroxyphenylethylamine air metrologia [Takenaka et al, 2000, Phytochemistry, 55, 275-84]. Similarly exercitu A, it was suggested that the observed additional β-glucopyranosyl element in exercide B attached to C-6'. This was confirmed by the shift towards a weak field, the components of 7.3 ppm, signal C-13 C-6' aixelsyd B, and the shift towards forces the aqueous fields, components of 0.7 and 2.9 ppm, C-3' and C-5', respectively, when compared with ligstroside. Further evidence of such Association was observed in the gHMBC spectrum, where there was a strong correlation between the anomeric signal from glucosyl when δHor 4.31 (H-1"' and when δWithto 70.1 (C-6'). The position of the methyl group was assigned to C-11 due to the observed far cross-peak signals at δH3,69 (OCH3and δWith168,7 (C-11) in the gHMBC spectrum. Thus, the connection aixelsyd B was identified as 3-ethylidene-2-[(6-O-β-D-glyukopiranozil-β-D-glyukopiranozil)oxy]-3,4-dihydro-5-(methoxycarbonyl)2-(4-hydroxyphenyl)ethyl ester of (2S,3E,4S)-2H-Piran-4-acetic acid, called exiled B. Providing data1H and13C NMR are shown in table 2.
Data1H13C NMR and HMBC for connections aixelsyd A (1) and aixelsyd B (2) (CD3OD)
|No||δH||δc||HMBC (H-C)||δH||δc||HMBC (H-C)|
|1||to 5.93||94,8 d||8,1'||5,94||94,7 d||8, 1'|
|3||7,51||155, 2mm l||1, 4, 5, 11||7,50||155, 2mm l||1, 4, 5, 11|
|5||3,96 DD (9,0, 4,3)||31,9 d||1, 3, 4, 6, 7, 8, 9, 11||3,95 DD (9,6, 4,0)||32,0 d||7, 11|
|6||was 2.76 DD (14,4, 4,4)||41,1 t||4, 5, 7, 9||2,72 DD (14,0, 4,0)||41,3 t||7|
|of 2.51 DD (14,0, 10,0)||4, 5, 7, 9||2,50 DD (14,0, 9,6)||7||7||173,7||173,4C|
|8||between 6.08 DQC (7,2, 0,8)||of 124.7 d||1, 5, 10||6,05 d (6,8)||124,8E||1, 5, 9, 10|
|10||1,72 d (7,6)||13,7 kV||8,9||1,61 d (7,2)||13,6 kV||8,9|
|OCH3||3,70||52,3 kV||11||3,69||51,9 kV||11||OCH3||3,62||51,9 kV||7|
|1'||4,80 d (8,0)||100,6 d||1||4,82 d (7,6)||100,4 d||1, 2'|
|2'||3,24-3,68 m||77,6 d||3,12-3,55 m||77,5 d|
|3'||3,24-3,68 m||77,8 d||3,12-3,55 m||77,8 d|
|4'||3,24-3,68 m||71,6 d||3,12-3,55 m||71,5 d|
|5'||3,24-3,68 m||75,3 d||3,12-3,55 m||75,1 d|
|6'||4,15 DD (12,0, 1,6)||70,1 t||1'"||4,15 d (10,4)||70,1T||5', 1'"|
|3,84 of user. d (12,0)||3,81 DD (11,6, 2,4)|
|1"||4.26 m||67,0 t||7, 2", 3"|
|4,06 m||7, 2", 3"|
|2"||2,80 t (6,8)||35,2 t|
|4"||7,02 DD (6,8, 2,8)||RB 131.1 d||2", 3", 6"|
|5"||of 6.71 DD (6,8, 2,8)||116,4 d||3", 4", 6"|
|7"||of 6.71 DD(6,8, 2,8)||116,4 d|
|8"||7,02 DD (6,8, 2,8)||RB 131.1 d|
|1'"||4,35 d (8,0)||105,2 d||6'||or 4.31 d (8,0)||105,2 d||2'"||3,24-3,68 m||74,7 d||3,12-3,55 m||74,7 d|
|3'"||3,24-3,68 m||77,7 d||3,12-3,55 m||77,6 d|
|4'"||3,24-3,68 m||71,5 d||3,12-3,55 m||71,4 d|
|5"'||3,24-3,68 m||77,8 d||3,12-3,55 m||77,6 d|
|6'"||3,98 DD (9,6, 4,4)||62,7 t||3,74 DD (12,0, 6,8)||62,6 t|
|3,75 DD (12,0, 6,8)||3,62 DD (12,0, 6,8)|
Chemical shifts δ are expressed in ppm (ppm) against tetramethylsilane (TMS) as a standard for comparison; a plurality of signal represented as singlet (s), doublet (d), triplet (t), Quartet (q), doublet of doublet (DD), doublet of Quartet (DQC), and multiple (m); the coupling constant in brackets are expressed in Hz; used solvent to obtain NMR spectra is CD3OD.
Inhibitory effect GI5 (5) and Noranda (3) on undifferentiated cells 3T3-L1
The main component of the increase in body mass is the deposition of adipose tissue in the body through a process of adipogenesis. Adipokines characterized by an increase in the size and number of fat cells. Secoiridoid, GI5 and Nugent isolated fromF. excelsiorshowed a significant and mild inhibitory activity against adipogenesis, respectively, by blocking the cascade nedifferencirovannaja cells 3T3-L1 in differentiated adipocyte to achieve the effect of weight control and reduction of obesity in the body. Differentiation preadipocytes 3T3-L1 induced hormonal cocktail of methylisobutylxanthine, dexamethasone, and insulin (MDI) in the presence or absence of compounds. Ten days after induction of differentiation, the treated cells were analyzed in relation to their relevant act is vnesti capture glucose, what is an indirect indicator of differentiation (adipogenesis), because preadipocyte incapable induced insulin seizure of glucose, mediated by vector glucose-4 (GLUT4), whereas fully differentiated adipocytes capable of such seizure. Connection, GI5 and Nugent used in four different concentrations: 0,004%, 0,02%, 0.05% and 0.1%. As a negative control was used untreated (undifferentiated) cells, and as a positive control was used insulin. As control was used methanol (MeOH), a solvent for the compounds. The results showed that GI5 and Nugent isolated fromF. Excelsior,have a meaningful and soft inhibitory activity against adipogenesis, respectively, blocking the cascade from undifferentiated cells 3T3-L1 in differentiated adipocytes to achieve the effect of weight control and reduction of obesity in the body (see figure 2).
Activation of PPAR-alpha byFraxinus excelsior
Activated proliferation peroxisome receptor (PPAR) are nuclear receptors that control many cellular and metabolic processes. PPAR-alpha is expressed mainly in the liver, where it plays an important role in the control of fatty acid oxidation (Reddy and Hashimoto, 2001, Annu Rev Nutr., 21, 193-230). In ukcia of fatty acid oxidation through activation of PPAR-alpha improves lipid profiles in plasma. In different mouse models agonists of PPAR-alpha reduces the level of triglycerides in plasma, reduce obesity and reduce steatosis in the liver and muscles, increasing, thus, insulin sensitivity and reducing the level of glucose in the blood [Guerre-Millo et al, 2000, J. Biol. Chem., 275, 16638-42 and Kim et al, 2003, Diabetes, 52, 1770-8].
It was shown that the extract of the seeds ofFraxinus excelsiorobtained using as solvent water, as described in example 2 (extract FE), activates PPAR-alpha. The relative activation of PPAR-alpha extract FE and phenobarbital (positive control) compared with DMSO (control conditions) was calculated as the fluorescence signal luciferase (reporter gene)obtained from active compounds after incubation with transfitsirovannykh GAL4/receptor PPAR-alpha cells. First, cells COS-7 (cultured in DMEM+10% FCS) was temporarily transfusional fused protein GAL4/PPAR-alpha and design DNA carrying the luciferase. For transfection, first received plasmid pGAL5-TK-pGL3 by embedding five copies of binding sites for GAL4 DNA (transcription factor of yeast) before promoter timedancing plasmid pTK-pGL3. Then designed a plasmid pGAL4-hPPAR alpha by amplification using PCR DEF domains hPPAR alpha (AK 180-464). The resulting PCR products were cloned into pBD-GAL4 (Stratagene, La Jolla, USA), and then the Chimera was subcloned into the vector pKDNA3. After transfection with the notches of COS-7 were incubated for 24 h with 0 μg/ml (reference conditions), 1 µg/ml, 3 μg/ml, 10 μg/ml, 30 μg/ml, 100 μg/ml, 300 μg/ml and 1000 μg/ml of extract FE or 100 μm fenofibrate (positive control). As a solvent used DMSO. After incubation, the cells were collected and conducted analysis of luciferase. Activation of PPAR-alpha extract FE and phenobarbital led to the expression of luciferase and the subsequent increase in fluorescent signal, which was measured using spectrophotometer Tecan Ultra (Tecan, Austria). The results were expressed as the relative activation of the GAL4/PPAR-alpha, is proportional to the fluorescent signal emitted by extract FE and phenobarbital compared to the fluorescent activity of the control (DMSO). The results are presented as mean values±SD for four experiments for each test (figure 3). Differences between groups were calculated using t-student criterion (XLSTAT 2008, AddinsoftTM, USA). Results activation of PPAR-alpha extract FE are presented in figure 3. Activation of PPAR-alpha extract FE reached 18% at 1000 µg/ml the Results are expressed as the percentage of fenofibrate, activator of PPAR-alpha is used as a compound for comparison.
The ability to extract FE activate PPAR-alpha can be explained, in part, the effect of decreasing blood glucose levels observed in animal studies.
The hypoglycemic activity of the extract E in male mice C57BL/6J
Male mice C57BL/6J were divided into three groups: 1) negative control group, where 20 male mice were kept on a diet with a low fat diet (LF) with an intake of approximately 10 kcal per day; 2) positive control group, where 20 mice fed a diet high in fat (HF) and consumption approximately 60 kcal per day, and due to feeding with a high fat content, in this group of mice developed obesity, hyperglycemia and hyperinsulinemia; 3) the group of 0.5% extract FE, where 10 male mice were fed a diet with high content fats, like males in group 2, but the diet was mixed with 0.5% extract FE. Consumption of food and fluids, and body weight was measured once a week. Carried out monitoring of the symptoms and possible toxicity. From the tail vein were collected blood samples and carried out monitoring of fasting glucose levels with the use of the device for measuring the level of glucose in the blood. Before the experiment was determined by the initial data. No statistical differences among these three groups.
After the introduction in the course of 16 weeks, a group of mice who were given the extract FE, showed significantly lower levels of blood glucose compared with the control group with high fat content (p<0,001), which indicates a strong hypoglycemic effect of the extract FE (figure 4).
Akti is the ability of the extract FE in reducing body weight in male mice C57BL/6J
We measured the body weight of each mouse from the same groups as in example 7. Between the three groups were not significant differences in initial body weight. After feeding for 16 weeks, all mice in groups on a diet high in fat (group 2 and 3) was significantly higher weight gain than the group that was fed a diet low in fat. However, the degree of increase in body mass in the FE group was significantly lower compared to the positive control group, indicating that the activity of the extract FE in the control of body weight (figure 5).
Activity against PPAR-alpha aixelsyd A (1), GI3 (4) and dimethyl ether complex of Olesia (6)
Five individual compounds isolated from an aqueous extract of the seeds ofFraxinus excelsior(FE), were tested in relation to the activity of PPAR-alpha. In this analysis of synthetic and selective activator of PPAR-alpha WY 14.643 served as positive control and DMSO used to dissolve these compounds served as a negative control. Five clean secoiridoids were partially active in concentratie 10M. Connection aixelsyd A complex of dimethyl ether Olesia and GI3 showed good activity (6).
Reducing obesity via seed extractFraxinus excelsior(FE) in male mice C57BL/6J
is the end of the experiment (from example 7), after feeding for 16 weeks, mice from all four groups were subjected to anesthesia and were killed. Gland and zabroshenny fat from individual mice was collected and weighed. The results showed that the extract of the seeds of FE reduced the increase Salnikova fat 18.3% and increased retroperitoneal fat 17.8%, respectively (Fig.7 and 8).
Reduced levels of insulin in the fasting plasma using seed extract ofFraxinus excelsior(FE) in male mice C57BL/6J
At the end of the experiment (from example 7), we determined the levels of insulin in the fasting plasma using an Elisa kit for mice. Mice who were given the extract of the seeds ofFraxinus,had significantly lower levels of insulin in plasma compared with levels in the control group when the diet is high in fat (P<0,05) (Fig.9).
The activity of the extract of seeds ofFraxinus excelsior(FE) in lowering blood sugar levels
To evaluate the effect of the compositions of the present invention in humans, conducted a randomized, double-blind, placebo-controlled and cross-sectional study in humans. In General, it was attracted sixteen healthy individuals (11 men and 5 women) from India. It was required that the age of the subjects ranged from 25 to 55 years, body mass index was 26±2.2 kg/m2and fasting glucose was 4.4±0.09 mmol/l For group introduction the Oia used seed extract FE, and for the placebo group used the powder wheat bran. The daily dosage for humans in this study was 1 g of seed extract FE. Subjects were instructed to take either two capsules of the extract of the seeds of FE (500 mg each) or two placebo capsules (500 mg of wheat bran in each) orally as a single dose before glucose load (50 g in 100 ml water) for the evaluation of glycemic response. After the breeding season, within one week, the two groups changed with each other. In the course of the study, obtained blood samples from the index finger through 0, 15, 30, 45, 60, 90 and 120 minutes. The tested extract/placebo was given with 100 ml of water immediately after taking the blood sample on an empty stomach at time 0 minutes the subject Then he swallowed the drink with glucose for 5-8 minutes (50 g in 100 ml of water, D-glucose, Qualigens Co., Glaxo India). During this time included a timer. Additional blood samples of the index finger were taken after 15, 30, 45, 60, 90 and 120 min after the initial reception drink with glucose. Glucose concentration was determined in whole blood in capillaries using the Bayer glucometer and Essentia glucotrip. To calculate the positive incremental area under the curve (AUC) of the concentration of glucose in the blood for the placebo group and group introduction FE, through different periods of time. Significant differences between groups were calculated with what ispolzovaniem two-sided paired t-test t-test. Analyses were conducted using the software XLSTAT 2008 (AddinsoftTM, USA). Statistical significance was set at P<0,05. All data are presented as mean±SEM.
On the chart the rise of blood glucose after pairwise comparison presents the reduction of glucose levels using seed extract FE after a meal, in the course of the experiment 15 (2,0±0.26 mmol/l vs. 1.7±0.21 mmol/l), 30 (4,0±0.41 mmol/l compared with 3.7±0.33 mmol/l), 45 (4,2±0.41 mmol/l compared with 3.7±0.47 mmol/l), 60 (3,4±0.46 mmol/l vs 3,4±0,41), 90 (1,8±0,38 mmol/l 1.6±0.31 mmol/l) and 120 (0,58±0.29 mmol/l vs 0,21±0.27 mmol/l) minutes compared with the corresponding placebo from wheat bran (figa). Paired t-student test showed that the differences (299,8±28,8 min mmol/l vs 273,2±25,2 min mmol/l) in the effect of the introduction (FE vs. placebo) on average AUC was statistically significant (P=0.02). The results are presented on figv.
Acute insulinotropic effect of seed extract ofFraxinus excelsior(FE) the person
Insulinotropic effect of the composition was evaluated as an additional goal of the clinical trial described in example 12. Samples of venous blood (7-8 ml) were taken after 0, 30, 60, 90 and 120 min in subjects who took the test FE/placebo separator tubes for serum. Blood was allowed to clot for 15 mi the ut, and then it was centrifuged at 1500×g for 10 minutes. Then the resulting serum was analyzed in relation to insulin using immunological analysis of electrochemiluminescence (ECLIA). As for the group to placebo, and group the introduction of FE was calculated positive area under the curve (AUC), describing growing insulinemia, for levels of insulin at different points in time. Significant differences between groups were calculated using two-sided paired t-test t-test. Analyses were conducted using the software XLSTAT 2008 (AddinsoftTM, USA). Statistical differences were set at P<0,05. All data are presented as mean±SEM. FE (55,5±4,6 IU/l) induced significantly different (P=0.002) insulin secretion after 90 minutes compared with placebo (43,5±5,0 IU/l) (figa). Found no significant differences in the mean values of AUC for insulinemia (0-120 minutes) in the group the introduction of FE (6041,6±340,5 min IU/l) compared with placebo (5996,3±594,58 min IU/l) (pigv).
Stimulation of insulin secretion after 90 min, apparently, is the direct influence of FE on the cells of the pancreatic islets, which returned to normal at the end of the study (after 120 minutes). This may reduce insulin resistance and improve insulin sensitivity in these cases. In addition, since the absence of Tvout significant differences in the mean values of AUC for insulinemia between treatment groups and placebo application of the extract is safe, without causing eventually the hyperinsulinemia in the subsequent hours after injection.
It should be understood that the effective amount of the extract FE can vary depending on the weight of the animal or person who performed the introduction, as it is known to specialists in this field. In addition, the extract FE can be delivered to any common environment, shaped in the form of liquid, powder or granules, in the form of capsules, tablets or capsules, or other conventional dosage forms, together with fillers, additives, binders, excipients, flavors and the like, as are commonly used in nonprescription pharmaceuticals and dietary supplements for products.
The person skilled in the art will understand that the present invention may be protected by implementation options other than the described embodiments of and numerical values and ranges are provided for purposes of illustration, but not limitation.
1. Extract of seeds of Fraxinus excelsior, is able to activate PPAR-alpha containing:
from 1% to 15% by weight Noranda,
from 1% to 17% by weight GI3,
from 0.5% to 1% by weight of complex methyl ester Olesia,
from 0.03% to 0.12% by weight aixelsyd In,
from 0.1% to 1.7% by weight GI5
and from 0.08% to 0.7% by weight of salidroside
where the extract is an aqueous, aqueous-alcoholic or alcoholic.
2. The use of the extract of seeds of Fraxinus excelsior according to claim 1 to obtain a treatment for the condition in which useful activation of PPAR-alpha.
3. The use according to claim 2, where the treatment is carried out by blocking the synthesis of fats and/or hypoglycemic activity, and/or reducing body weight and/or reduce obesity, and/or control levels of insulin in the fasting plasma directed against hyperinsulinemia, and/or stimulation of insulin sensitivity and provide a useful quick insulinotropic effect.
4. The use according to claim 2, where the treatment includes treatment of the metabolic syndrome and/or treatment of diabetes mellitus type 2 and/or preventing hyperinsulinemia.
5. The method of treatment of a subject, which is a condition in which useful activation of PPAR-alpha, where the method includes administration of the extract of seeds of Fraxinus excelsior according to claim 1.
6. The method according to claim 5, where the treatment is carried out by blocking the synthesis of fats, and/or hypoglycemic activity, and/or reducing body weight and/or reduce obesity, and/or control levels of insulin in the fasting plasma directed against hyperinsulinemia, and/or stimulation of insulin sensitivity and provide a useful quick insulinotropic effect.
7 the Method according to claim 5, where the treatment involves the treatment of the metabolic syndrome and/or treatment of diabetes mellitus type 2 and/or preventing hyperinsulinemia.
8. The method according to any of pp.5-7, where the subject is the man.
9. The method of obtaining the extract of the seeds of Fraxinus excelsior according to claim 1, including extraction and selection of songs from the seeds of Fraxinus excelsior with a process that includes:
grinding the seeds of Fraxinus excelsior in particle;
contacting the crushed particles with a mixture of solvents;
Department of crushed particles from the mixture of solvents;
powder dissolves in alcohol
and evaporation of the alcohol,
where the temperature of extraction is between 50°C to 70°C,
the ratio of plant material to solvent mixture is from 1:1 to 1:10 per gram per milliliter, and
the mixture of solvents is water, a mixture of water-alcohol or alcohol.
10. The method according to claim 9, where the crushed particles have a diameter from 0.1 mm to 30 mm
11. The method according to claim 9, where the ratio of the crushed particles to the solvent mixture is from 1 gram to 1 ml to 1 gram to 10 ml, preferably from 1 gram to 3 ounces to 1 ounce to 8 ounces.
12. The method according to claim 9, where the crushed particles are in contact with the mixture of solvents in the course of from 2 hours to 24 hours.
13. The method according to claim 9, where the mixture of solvents containing ethanol.
14. The method according to claim 9, where the mixture is solvent contains methanol.
SUBSTANCE: halogenated hydrocarbonate chloride sodium, alkaline, boron, high-magnesium, iodine and fluorine natural mineral water 'Lazarevskaya Tselebnaya' No. 84-E of the Volkonskoye deposit in Sochi is taken according to the following procedure: 18-20 minutes before meals in small sips, 6 times a day daily in a dose of 180-200 ml at t=24-25°C for 40 days every 3-5 days with taking the above natural halogenated mineral water in the same amounts for the following 45 days. The therapeutic course makes 3 years and repeats every 3 months.
EFFECT: method enables reducing metabolic disorders by a systemic insulin-producing effect in a combination with a hypolipidemic and diuretic component.
3 cl, 4 tbl, 2 ex
SUBSTANCE: invention refers to medicine, namely to gastroenterology and endocrinology, and concerns treating patients suffering from dyspepsia syndrome in a combination with overweight. That is ensured by therapy with preparations improving metabolism, promoting weight loss and fat absorption, as well as antidepressants. The therapy is differentiated taking into account an anxiety level (HARS) and a depression level (HDRS) according to Hamilton rating scales, nutritional status assessed by bioimpedancemetry, a degree of manifestation of sleep disorders, eating behaviour typing, eating regimen and daily rhythm determination , level evaluation of glucose, immunoreactive insulin, cholesterol, high-density lipoprotein (HDLP), triglyceride in venous blood, blood glucose tolerance, gustation, life quality assessment.
EFFECT: differentiated approach provides an effective treatment of dyspepsia in a combination with weight loss, correction of eating behaviour and metabolic processes.
2 ex, 2 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to the pharmaceutical industry, namely to an agent with an antidyslipidemic and analgesic effect. The method for preparing the phytocomplex with the antidyslipidemic and analgesic effect, involving: a) grinding peeled bergamot fruit to prepare an undegraded mixture, b) introducing pectinolytic enzymes into the mixture; c) reducing pulp content; d) inactivating the above enzymes added at the stage b), to prepare a degraded mixture; e) performing ultrafiltration of the degraded mixture through membranes isolating the substances having a molecular weight of over 30,000 Da, to prepare a transparent solution; f) introducing the transparent solution on a polyphenol absorption column; g) washing the polyphenol absorption column with water and increasing pH to prepare an aqueous polyphenol fraction; h) transmitting the aqueous polyphenol fraction to cationic resin to recover the phytocomplex in an aqueous phase; i) drying the phytocomplex in the aqueous phase. The phytocomplex in the aqueous phase with the antidyslipidemic and analgesic effect. The phytocomplex with the antidyslipidemic and analgesic effect. A pharmaceutical composition with the antidyslipidemic effect containing the phytocomplex, and pharmaceutically acceptable additives. A pharmaceutical composition with the analgesic effect containing the phytocomplex, and pharmaceutically acceptable additives.
EFFECT: phytocomplex described above possesses the evident antidyslipidemic and analgesic effect.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.
EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.
22 cl, 27 dwg, 1 tbl, 756 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to the chemical-pharmaceutical industry, and represents using a biologically active agent for preparing a drug for metabolic disorders specified in a group consisting of insulin resistance syndrome and diabetes mellitus, including type I diabetes mellitus and type II diabetes mellitus, and obesity, wherein the agent represents a compound of formula
wherein n=1 or 2; m=0, 1, 2, 4 or 5; q=0; t=0 or 1; R3 represents hydrogen; A is phenyl, unsubstituted or substituted by 1 or 2 alkyls having 1 or 2 carbon atoms; and R1 is hydrogen or alkyl having 1 or 2 carbon atoms; or when R1 represents hydrogen - a pharmaceutically acceptable salt of the compound.
EFFECT: preparing the drug for metabolic disorders.
18 cl, 6 ex, 22 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to pharmaceutical industry and represents a pharmaceutical composition for prevention and treatment of the metabolic syndrome and diabetic nephropathy, which contains the following active substances: taurine, a dry extract of motherwort herb, a dry extract of hawthorn fruit and accessory substances, with components present in the composition in a specified ratio in wt %.
EFFECT: invention provides extension of the arsenal of means for prevention and treatment of the metabolic syndrome and diabetic nephropathy.
10 cl, 13 ex, 19 tbl
SUBSTANCE: present group of inventions refers to medicine, namely to therapy and cardiology, and concerns lowering triglycerides without increasing LDL cholesterol in an individual receiving a concomitant statin therapy with initial fasting triglycerides 200 mg/dl to 500 mg/dl. That is ensured by administering ethyl eicosapentaenoate 4 g a day additionally.
EFFECT: invention provides lowering both total triglycerides, and low-density lipoproteins.
30 cl, 6 tbl
SUBSTANCE: compound has formula I: |Chemical formula 1| where A is O, NR, S, S(=O), S(=O)2 or Sc; B is hydrogen or ; R1 is hydrogen, C1-C8 alkyl or halogen; R2 is hydrogen, C1-C8 alkyl, or ; Xa and Xb is independently CR or N; R is hydrogen or C1-C8 alkyl; R3 is hydrogen, C1-C8 alkyl; R4 and R5 are independently hydrogen, halogen or C1-C8 alkyl; R6, is hydrogen. C1-C8 alkyl, or a pharmaceutically acceptable organic salt; R21, R22 and R23 are independently hydrogen, halogen, NO2, C1-C7 alkyl, unsubstituted or substituted with halogen, C3-C12 heteroaryl, containing one or more heteroatoms selected from N, O and S; m equals an integer from 1 to 4; p equals an integer from 1 to 5; s equals an integer from 1 to 5; u equals an integer from 1 to 3; w equals an integer from 1 to 4; and alkyl in R1, R3, R4, R5 and R6 can further be substituted with one or more halogens, C3-C7 cycloalkyl or C1-C5 alkylamine. Also disclosed are methods of producing selenazole derivatives, a pharmaceutical composition, a functional feed additive composition, a functional beverage, a food additive, animal feed, a functional cosmetic composition, a peroxisome proliferator-activated receptor (PPAR) activator composition.
EFFECT: invention enables to obtain a selenazole derivative which activates a peroxisome proliferator-activated receptor.
15 cl, 1 dwg, 6 tbl, 298 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine, more specifically to an agent that can be used for treating the lipid storage disease. A pharmaceutical composition contains calcium rosuvastatin in the therapeutically effective amount, lactose as an excipient containing 94.7-98.3 wt % of lactose monohydrate and povidone, cross povidone as a desintegrant, colloidal silicone dioxide as a glidant, stearate as a lubricant, with the composition containing an inorganic salt with a polyvalent cation. The pharmaceutical composition according to the invention is characterised by the substantial reduction of calcium rosuvastatin storage destruction, fast disintegration, high release rate of the active agent, high breaking and abrasive strength, and has a shelf life of more than 2 years.
EFFECT: preparing the agent that can be used for treating the lipid storage disease.
5 cl, 2 tbl
SUBSTANCE: pharmaceutical composition in a dose of 4 g a day containing at least 90 wt % of ethyl eicosapentaenoate is administered into an individual having initial fasting triglycerides within the approximate range of 500 mg/dl to 2000 mg/dl for a period of time effective to reduce fasting triglycerides by at least 15% as compared to initial fasting triglycerides before the first administration of the pharmaceutical composition. The second version involves administering approximately 4 g a day of the pharmaceutical composition containing at least 96 wt % ethyl eicosapentaenoate into an individual with initial fasting triglycerides from approximately 500 mg/dl to approximately 2000 mg/dl receiving neither any pharmaceutical composition, nor a concomitant statin therapy, for a period of time effective to reduce fasting triglycerides by at least 25% as compared to another similar individual. The third version provides reducing triglycerides and apoliprotein B in an individual having initial fasting triglycerides from approximately 500 mg/dl to approximately 2000 mg/dl and receiving no concomitant therapy changing the lipid profile, and involves administering approximately 4 g a day of the pharmaceutical composition containing at least 96 wt % of ethyl eicosapentaenoate for a 12-week period. The individual shows the fasting triglycerides reduction by at least 25% and the fasting apoliprotein B reduction as compared to the reference having initial triglycerides within the range from 500 mg/dl to approximately 2000 mg/dl and receiving neither any pharmaceutical composition, nor a concomitant therapy changing the lipid profile.
EFFECT: method improvement.
4 cl, 1 ex
SUBSTANCE: viral hepatitis in simulated in laboratory animals (rats) with D-galactosamine. Hepatitis is treated by single oral administration of immobilised hyaluronidase 25 unit/kg. Administration either precedes simulation, or is combined with the beginning of stimulation.
EFFECT: method enables reducing a severity of metabolic and morphological hepatic disorders effectively in stimulating hepatitis identical to viral hepatitis in a human with underlying reduced xenobiotic load on the body.
1 ex, 3 tbl
SUBSTANCE: invention relates to a compound of formula II, methods of producing a compound of formula I
and formula II
a pharmaceutical composition and versions of use for treating inflammation and/or liver damage. In the compound of formula II, R1 is H; R2 is a linear or branched C1-C18alkoxy; C-18 is in an α-configuration.
EFFECT: high efficiency of the method.
18 cl, 7 tbl, 8 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to the pharmaceutical industry, namely to a method of obtaining a preparation, possessing a hepatoprotective action. The method of obtaining the preparation, possessing the hepatoprotective action consists in extraction of crushed corn styles with stigmas with ethyl alcohol by a method of multi-step countercurrent extraction with completed cycle in a battery of 5 diffusers, a waste raw material is additionally extracted in 4 and 5 diffusers with an applied extractant, after which it is poured out and passed through 5 diffuser, and kept for a specified time; then, the waste raw material is pressed, the combined extract is settled, the purified extract is condensed under vacuum, dried in a vacuum oven until the dry extract is obtained and crushed under specified conditions.
EFFECT: method is effective for obtaining a stable preparation with the expressed hepatoprotective action.
FIELD: veterinary medicine.
SUBSTANCE: method comprises administering to the animals in the supine position, in addition to the general course of treatment during 5-7 days of 0.5% novocaine solution, depending on the age at a dose of 1.0-2.0 ml per kg of live body weight with adding 1.0 g of cefazolin in the region of the round ligament of the liver, the administration of novocaine solution with cefazolin. The injections are carried out in a cat in the supine position, at the point at 4.8-5.2 cm cranial to the umbilicus along the sagittal line of the abdomen in the dorsal direction. The puncture is made with the needle to the depth of 0.9-1.1 cm to the feeling of characteristic falling of the needle under the aponeurosis of the rectus abdominis muscle. The preparation solution is administered under pressure.
EFFECT: method is simple to use and highly effective for the treatment of acute hepatosis in cats.
2 tbl, 1 ex
SUBSTANCE: invention may be used for prevention of intrahepatic portal hypertension (IPH) in residual tissue of liver in patiens after hepatectomy (HE) of the different volume. That is ensured by an ultrasonography to determine a spleen area to be taken as an original size with underlying standard postoperative therapy in the first postoperative hours. Serotonine adipinate is administered intravenously drop-by-drop in a dose of 5-10 mg an hour with a spleen size monitored periodically. Administering the preparation is terminated if observing a decrease of the spleen area by not less than 10% of the original size.
EFFECT: improved blood circulation in the residual tissue of the liver, prevented IPH decreasing thereby a mortality of the given group of patients.
2 ex, 1 tbl
SUBSTANCE: method involves a dietary therapy, taking mineral water in an amount of 100-150 ml, 3 times a day and exposure to a physical factor. What is used is the Pevzner's diet No. 5. Karachinskaya chloride-hydrocarbonate sodium gas-free mineral water of total mineralisation up to 3 g/dm3, at a temperature of 38-40°C is taken 30-40 minutes before a meal. The physical factor represents a magnetic laser therapy and an EHF therapy. The contact magnetic laser therapy covers three zones sequentially at a frequency of 5 Hz: an epigastric zone and the right and left upper hypochondria along the midclavicular lines, for 4 minutes for each zone within the course of 10 procedures. The EHF therapy involves combined exposure on two projection zones: in the right hypochondrium and on the sternum generated by a broadband noise emitter at an emission frequency of 40-63 GHz, for 20 minutes, every day within the course of 10 procedures.
EFFECT: method provides more effective rehabilitation treatment following endoscopic cholecystectomy ensured by the early integrated therapeutic exposure.
2 ex, 4 tbl
SUBSTANCE: invention refers to medicine, namely gastroenterology, and may be used for treating the patients with the first stage cholelithiasis. That is ensured by administering the preparation Mucofalc 1 sachet 3 times a day for 22-24 weeks.
EFFECT: method enables extending the range of drug preparations having litholytic action in the first stage cholelithiasis with no side effects.
2 tbl, 2 ex
SUBSTANCE: composition, which has antiviral activity, includes ammonium glycyrrhizinate, β-cyclodextrin, emulsifier, preservative, lysozyme, polymeric carrier, pH regulator, demineralised water, with specified component ratio. Composition, which has antiviral activity, includes betulinic acid, β-cyclodextrin, emulsifier, preservative, sanguiritrinum, polymeric carrier, suppository base, pH regulator, demineralised water, with specified component ratio.
EFFECT: claimed compositions have expressed antiviral action.
2 cl, 1 tbl, 7 ex
FIELD: food industry.
SUBSTANCE: composition with hepato-protective and immunostimulating properties contains oxygenated dextran with molecular weight equal to 40-70 kDa and a vegetal raw material component chosen from the following group: dry Saint-Mary-thistle fruits extract, dry hill-growing saltwort extract, dry purple echinacea herb extract as well as microcrystalline cellulose as a physiologically acceptable filler, taken in a specified quantity.
EFFECT: hepato-protective and immunostimulating properties enhancement.
1 tbl, 8 ex
SUBSTANCE: invention refers to medicine and cell technologies. What is presented is a cell product containing a population of sub-mandibular salivary duct stem cells described by the phenotype CD49f+/EpCAM+ and changing an expression profile for 1AAT+/PEPCK+/G6P+/TDO+/CYP P4503A13+ after the treatment with valproic acid in the concentration of 0.1-40 mM and cultivation in collagen gel, as well as gaining the capacity to synthetise urea and albumin.
EFFECT: invention allows providing the effective recovery of the insufficient synthetic and detoxification hepatic function accompanying acute and chronic hepatic failure when used both in artificial liver apparatuses, and in the direct transplantation into the affected liver, and can be used for a cell replacement therapy of a wide spectrum of acute and chronic hepatic pathologies, including treating cirrhosis, acute and chronic hepatic failure, as well as for the recovery of the synthetic and detoxification hepatic functions when used as an active cell component in extracorporeal liver apparatuses.
2 tbl, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions relates to a composition for teeth cleaning and a method of its obtaining. The claimed composition for teeth cleaning contains in one phase an orally acceptable carrier; a source of fluorine ions; a source of bivalent tin ions; a source of zinc ions and, at least, one polyphosphate salt, selected from a group, which consists of inorganic polyphosphates, which have 3 or fewer atoms of phosphorus; and the general content of water in the composition for teeth cleaning constitutes less than approximately 10% of the composition mass. The method of obtaining the claimed composition includes mixing the source of bivalent tin ions with a water buffer system, adapted for chelation of bivalent tin ions in a premix, formed in this way; and combining the premix with the active components and the orally acceptable carrier.
EFFECT: combination of sources of bivalent tin, fluorine, zinc and the upper mentioned polyphosphate with a low content of water makes it possible to obtain the composition for teeth cleaning in the form of a one-phase system, which provides a possibility of an effective delivery of unstable in water active ingredients, which begin a reaction with each other in one phase.
28 cl, 2 dwg, 3 tbl, 5 ex