Naringin and naringenin as a means for the prevention or treatment of liver diseases

 

(57) Abstract:

A new active ingredient of the pharmaceutical composition, a food composition or beverage for prevention or treatment of lipodystrophy liver or cirrhosis of the liver in mammals, including man. As such ingredients are known flavonoids naringin or naringenin. The invention expands the Arsenal of the declared destination. 8 C.p. f-crystals, 6 tab., 6 Il.

The scope of the invention

The present invention relates to the use of naringin or naringenin for inhibiting the activity of acyl COA-cholesterol-o-acyltransferase (AST), inhibiting the accumulation of complexes of macrophage-lipid on the endothelium of arteries and for the prevention or treatment of liver diseases in mammals.

Background of the invention

In recent years, coronary cardio-circulatory diseases, such as atherosclerosis and hypercholesterolemia, are increasingly becoming a major cause of mortality. It was reported that elevated levels of cholesterol in the plasma cause the deposition of fat, macrophages and foam cells in the walls of blood vessels and that these deposits lead to the formation of plaques, and then to atherosclerosis reduce the absorption of cholesterol and lipids. Another way is the inhibition of cholesterol absorption by inhibiting enzymes involved.

Acyl COA-cholesterol-o-acyltransferase (ACAT) promotiom the formation of esters of cholesterol in the blood. Foam cells are formed as a result of AST and contain a large number of ester cholesterol, which carry low-density lipoprotein (LDL). The formation of foam cells in the artery walls increases with the increase of AST activity, and accordingly, the ACAT inhibitor may also serve as a means for the prevention of atherosclerosis. It was further reported that the level of blood LDL-cholesterol can be lowered by inhibiting ACAT activity (Witiak, D. T. and D. R. Feller (eds. ), Anti-Lipidemic Drugs: Medicinal, Chemical and Biochemical Aspects, Elsevier, pp. 159-195, 1991).

On the other hand, the deterioration of the liver may be due to excessive consumption of alcohol or food with a high content of lipids, or as a result of infection with hepatitis b or C, and it can develop in hepatitis can lead to cirrhosis or liver cancer. In particular, excessive consumption of food high in fat and alcohol causes fatty liver, when a large number of lipid otat-pyruvate transaminase) and GTP (-glutamyl of transpeptidase) (So Banciu et al., Med. In-terne., 20, 69-71, 1982; and Par A. et al., Acta. Med. Acad. Sci. Hung., 33, 309-319, 1976).

There have been many attempts to develop drugs that inhibit ACAT activity; and the result is reported that the selection of multiple compounds from cultures of different microorganisms. Examples of such compounds include peripherary isolated from the culture of Aspergillus fumigatus (S. Omura et al., J. Antibiotics, 46, 1168-1169, (993) and Ekaterin isolated from Pseudomonas sp. (S. Nagamura et al., J. Antibiotics, 45, 1216-1221, 1992).

Further, as means for treatment of hypercholesterolemia was developed inhibitor of HMG-CoA reductase, called lovastatin (Lovastatin), which is marketed by Merck Co., U. S. A.

However, it is known that this medicine causes harmful side effect - increases the content of creatine kinase in the liver.

Accordingly continues to exist a need to create non-toxic inhibitors of ACAT and inhibitors accumulation of complexes of macrophage-lipid on the epithelium of the arteries and means for the prevention or treatment of liver diseases.

The authors of the present invention have attempted to develop new and effective ACAT inhibitor, an inhibitor of accumulation of the complexes microfilmed and medium spans ingin or naringenin have the potential ACAT inhibitory activity, inhibiting the accumulation of complexes of macrophage-lipid, and activity in the prevention or treatment of liver diseases.

Naringin (C27H32ABOUT14, M. C. : 580,53) and the aglycone naringin, which naringenin (C15H12O5, M. C. : 272,25) are flavonoids found in lemons, grapefruits, tangerines, dei Cedri and oranges (Citrus sinensis) (Horowitz, Gentili, Tetrahedron, 19, 773, 1963).

It was reported that naringin or naringenin have anti-cancer, antiviral activity, and activity in lowering cholesterol levels (Monforte, M. T., et al., Farmaco., 50 (9), 595-599, 1995, Sep.; JP 95-86929; JP 95-86930; Felica, V., et al., J. Med. Virol., 15, 71-79, 1985; EP 0352147 A2, 1990.1.24 and Martin M. J., et al., Pharmacal., 49, 144-150, 1994).

Next naringin was used as giving the bitterness agent, a sweetener or as the basis of chewing gum.

However, still do not report about ACAT inhibitory activity, neither of inhibitory activity against the accumulation of complex macrophage-lipid or preventive or therapeutic activity naringin or naringenin.

Summary of the invention.

Accordingly, the main purpose of the present invention is a new applied the present invention is a new use naringin or naringenin to inhibit the accumulation of complexes of macrophage-lipid on the endothelial lining of the arteries in mammals.

The next objective of the present invention is a new use naringin or naringenin for the prevention or treatment of liver diseases in mammals.

A brief description of the drawings.

The above and other objectives and features of the present invention will become clearer from the following description of the invention together with the attached drawings, where:

in Fig.1A, 1B and 1C presents artery of rabbits, which were administered with 1% cholesterol; 1% cholesterol plus 1 mg/kg Lovastatinand 1% cholesterol plus 0.1% of naringin respectively, and

at PFH. 2A, 2B and 2C presents the microscopic features of the disease of rabbits that were administered with 1% cholesterol; 1% cholesterol plus 1 mg/kg Lovastatinand 1% cholesterol plus 0.1% of naringin respectively.

Detailed description of the invention

In accordance with one aspect of the present invention proposed the use of naringin or naringenin for inhibiting the activity of acyl COA-cholesterol-o-acyltransferase (AST) in mammals.

In accordance with another aspect of the present invention proposed the use of naringin or naringenin to inhibit the accumulation of complexes of macrophage-lipid on endothelial slozano application naringin or naringenin for the prevention or treatment of liver diseases in mammals.

Naringin or naringenin can be extracted from the peel of citrus fruit or to synthesize the way, opened Zemplen, Bognar, Ber., 75, 1043, 1943, and Seka, Prosche, Monatsh., 69, 284, 1936. Next naringenin can be obtained by hydrolysis naringin.

Naringin or naringenin demonstrate inhibitory effect on AST activity and inhibiting the accumulation of complexes of macrophage-lipid on the endothelial lining of the arteries, as well as preventive or therapeutic effect against diseases of the liver at doses of 0.1 mg/kg/day or more, and the inhibitory effect increases with increasing dose.

Moreover, despite the potential efficiency naringin or naringenin, they demonstrate low toxicity or mitogenome in tests on mice. More specifically, naringin or naringenin generally non-toxic when administered orally to mice at a dose of 1000 mg/kg, which corresponds to the dose at a dose of 50 to 100 g/kg of body weight naringin or naringenin for patients weighing 50 kg in Addition, naringin and naringenin have no harmful effects on the liver.

The present invention also proposed a pharmaceutical composition for the inhibition of ACAT activity and ingibirovannihmi liver, which includes naringin or naringenin as an active ingredient and pharmaceutically acceptable excipients, carriers, or diluents.

The pharmaceutical composition can be prepared in accordance with any of the usual procedures. In the preparation of the composition the active ingredient is preferably mixed with a carrier, or diluted by a carrier, or enclosed in a carrier, which may be in the form of a capsule, cachet, or any other container. When the carrier serves as a diluent, it may be solid, semi-solid or liquid material and functions as a carrier, excipient or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, powders, sterile packaging, etc.

Examples of suitable carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxy which contain fillers, antiglycation agents, lubricating agents, wetting agents, flavoring agents, emulsifiers, preservatives, etc. of the Composition of the present invention can be prepared so as to provide quick, slow or delay the release of active ingredient after their introduction mammals, using any well-known specialists of the way.

The pharmaceutical compositions of the present invention can be administered in a number of ways, including oral, percutaneous, subcutaneous, intravenous and intramuscular introduction. For men the typical daily dose naringin or naringenin may be in the range of from about 0.1 to 100 mg/kg body weight, preferably from 3 to 10 mg/kg of body weight, and can be entered as a single dose or in divided doses.

However, it should be understood that the amount of active ingredient that is administered in reality, should be determined taking into account various factors, including the subject to the treatment condition, the chosen route of administration, age, sex and weight of the patient, and the severity of the symptoms; and therefore, the above dose in no way should limit the scope of the invention.

Moreover, naringin or naringenin can be included in products or apidianaki macrophage-lipid on the endothelial lining of the arteries and/or for the prevention or treatment of liver diseases. Food or drinks may include various meats; juices, such as vegetable juices (for example, carrot juice and tomato juice) and fruit juices (such as orange juice, grape juice, pineapple juice, Apple juice and banana juice); chocolates; snacks; candy; pizza; products made from grain flour, such as bread, muffins, crackers, cookies, biscuits, noodles and so on ; chewing gum; dairy products such as milk, cheese, yogurt and ice cream; soups; bouillons; pastes, ketchups and sauces; tea; alcoholic beverages; soft drinks such as Coca-Cola and Pepsi-Cola; complexes of vitamins and a variety of healthy foods.

In this case, the content naringin or naringenin in food or beverages may be in the range of from 0.01 to 5 wt.%. In particular, the beverage in accordance with this invention can contain from 200 to 10000 mg naringin or naringenin in 1000 ml of drink.

As mentioned above, naringin or naringenin can be used as an effective non-toxic pharmaceutical agent for inhibition of ACAT activity, inhibiting the accumulation of complexes of macrophage-lipid on the endothelium of arteries and/or for the prevention or treatment of diseases of the five without limiting its scope.

Next following interest for solid mixtures in solid, liquid in liquid and solid in a liquid is given based on the weight/weight, volume/volume and weight/volume, respectively; and all reactions carried out at room temperature, unless otherwise indicated.

Example 1. Extraction naringin from the peel of citrus.

Peel tangerines (Cheju Island, Korea), dei Cedri (Jeollanamdo, Korea), and oranges, grapefruits and lemons (California, CA, U. S. A.), dried at room temperature and pulverized into a powder with a particle size of from 100 to 200 μm. 50 ml of methanol is added to 500 mg of each powder citrus peel and extracted in a water bath at 50oC for 6 h thus Obtained extract was cooled and filtered, and then methanol is added to the filtrate to a volume of 50 ml.

To determine the content naringin in the obtained extracts, 5,0 ál of the obtained extract is processed using high-performance liquid chromatography (HPLC) using a column Lichrosorb RP-8 (5 ám, h mm), which is pre-balance 37% methanol and support at a temperature of 30oC. Extract elute 37% methanol at a flow rate of 1.0 ml/min Standard solutions prepared by dissolving naringin (Sigma Chemical Co. U. S. A.) in Meath who were above. Eluate detected at 280 nm with a spectrophotometer operating in the UV-visible range, and the content naringin calculated by comparing the area under the curves HPLC of extracts of citrus peel and a standard solution. Content (%) naringin in various citrus peel extracts are presented in table. I.

Example 2. Toxicity oral introduction naringin or naringenin.

7-8 week without specific pathogenic ICR female mice (6 pieces), each weighing from about 25 to 29 g, and male mice (6 pieces), each weighing from about 34 to 38 g, grown under conditions of temperature 221oC, humidity 555% and photoperiod of 12 h light/12 h darkness. Food (Cheiljedang Co., food for mice and rats) and sterilized water and allow mice.

Naringin and naringenin dissolved in 0.5% tween 80 to a concentration of 100 mg/ml, and this solution was administered orally to mice in an amount of 0.2 ml per 20 g of the bodies of mice. The solution is injected once, and the mice are observed for 10 days for signs of harmful effects or death in accordance with the following scheme: 1, 4, 8 and 12 h after injection and every 12 h thereafter. Weight change of mice register every day to determine the effect of naringin or naringenin. Next 10 on origin or naringenin has shown no toxicity at a dose of 1000 mg/kg The autopsy showed that mice did not develop any pathological deviations, and within 10 days of the test period there was no loss of weight. Accordingly, it was concluded that naringin or naringenin is nontoxic when administered orally to animals.

Example 3. Introduction naringin or naringenin animals.

30 four-week rat strain Sprague-Dawley (Tainan laboratory animal center, Korea), weighing from 90 to 110 g uniformly randomly divided into three dietary groups. Rats in the three groups give three different foods with high cholesterol content, that is, AIN-76 laboratory animal feed (ICN, Biochemicals, Cleveland, HE, U. S. A.) containing 1% cholesterol (control group), and 1% cholesterol plus 0.1% of naringin or naringenin, respectively. The composition of the feed, which gave the three groups are presented in table. II.

Rats were fed on request special food together with water for 6 weeks, absorbed amount was recorded daily, and the rats were weighed every 7 days, and then analyzed the results. All rats showed a normal growth rate and there are no noticeable differences between the three groups from the point of view of the amount of feed consumed and weight gain is not on pidof in plasma.

The impact of the introduction of rats naringin or naringenin on the plasma cholesterol and neutral lipids is determined as follows.

Blood samples taken from rats of three different dietary groups, and perhaps fractions of plasma HDL using HDL-cholesterol reagent (Sigma Chemical Co., Cat. 352-3) containing dextran-sulfate. The levels are full of cholesterol and HDL-cholesterol determined using Sigma Diagnostic Kit Cat. 352-100 (Sigma Chemical Co., U. S. A.) (Allain et al., Clin. Chem., 20, 470-475, 1974). The content of neutral lipids determined using Sigma Diagnostic Kit Cat. 339-50 (Bucolo G. and David H. , Clin. Chem., 19, 476-482, 1973). The results obtained are presented in table. III, where the levels of total plasma cholesterol in rats, the stern of which was naringin or naringenin reduced by 32% and 18% respectively compared with the control group.

Example 5. Activity naringin and naringenin in relation to inhibition of ACAT.

(Stage 1) preparation of microsomes.

To determine the effect on rats feed with naringin or naringenin on the activity of AST microsome assay isolated from the tissues to the liver to be used as a source of enzymes.

Initially, the rats of the three groups obtained in example 3, medium (0.1 M KN2RHO4, pH 7.4, 0.1 mm EDTA and 10 mm-mercaptoethanol). The homogenate was centrifuged at 3000 g for 10 min at 4oWith the thus obtained supernatant cetrifugation at 15000 g for 15 min at 4oC to obtain the supernatant. This supernatant is placed in ultracentrifuging vials (Beckman) and centrifuged at 100000 g for 1 h at 4oWith getting the precipitate of microsomes, which is then suspended in 3 ml of homogenization medium, and centrifuged at 100000 g for 1 h at 4oC. the thus Obtained residue is suspended in 1 ml of the homogenization medium. The concentration of protein in the resulting suspension is determined by the Lowry method, and then adjusted to a value of from 4 to 8 mg/ml of the Obtained suspension stored at very low temperature (Biofreezer, Forma Scientific Inc.).

(Stage 2) AST analysis.

to 6.67 μl of 1 mg/ml cholesterol in acetone mixed with 6 μl of 10% Triton WR-1339 (Sigma Co.) in acetone, and then the acetone is removed from the mixture by evaporation using nitrogen gas. To the resulting mixture add distilled water in such a quantity to bring the cholesterol concentration up to 30 mg/ml

To 10 μl of the resulting aqueous solution of cholesterol add 10 ál of 1 M KNoC for 30 minutes

10 μl of the solution (l14C) oleoyl-COA (0.05-mccoury, final concentration: 10 μm) are added to a pre-incubated mixture, and the mixture was incubated in a water bath at 37oC for 30 minutes To this mixture is added 500 μl of a mixture of isopropanol: heptane (4:1 (vol./vol.), 300 μl of heptane and 200 μl of 0.1 M KN2RHO4(pH 7.4), and the mixture was intensively stirred using a centrifuge, and then left to stand at room temperature for 2 minutes

200 μl of the obtained supernatant is placed in scintillation vials, and to this add 4 ml of scintillation fluid (Lumac). The resulting mixture was analyzed for radioactivity using a scintillation counter 1450 Microbeta (Wallacoy, Finland). AST activity is calculated as picomole of cholesterolaemia synthesized per minute per mg protein (pmol/min/mg protein). The results obtained are presented in table. IV.

As can be seen from the data table. IV, ASAT activity observed for the groups of rats in the feed which was added naringin or naringenin, lower than for the control group by 20.2% lipid, in animals, food which added naringin or naringenin.

(Stage 1). Introduction animals naringin or naringenin.

24 three-month new Zealand white rabbit (Yeonam Horticulture and Animal Husbandry College, Korea), each weighing from about 2.5 to 2.6 kg, grown in conditions 202oC and relative humidity 555%, and photoperiod of 12 h light/12 h darkness. Rabbits are divided into groups of 6 rabbits, and rabbits four groups fed four different composition of feed, i.e. RC4 feed (Oriental Yeast Co., Japan) containing 1% cholesterol (control group); 1% cholesterol plus 1 mg/kg Lovastatin(Merck, U. S. A.) (comparative group); 1% cholesterol plus 0.1% of naringin and 1% cholesterol plus 0.1% of naringenin, respectively. Food RC4 contains 7.6 percent moisture, 22/8% crude protein, 2.8% of crude fat, 8,8% crude ash, to 14.4% crude cellulose and 43.6% of the soluble compounds that do not contain nitrogen. Rabbits fed this way for 6 weeks with free access to food and water.

(Stage 2). Analysis of strips of fat into the main artery.

Rabbits fed scheme stage 1, kill and cut chest. It cut the main artery of approximately 5 cm in the forward direction from a point located 1 cm above the valve AOP is up in the Cup. Main artery of the photograph, and then produce staining strips of fat by way Esper, E., et al., (J. Lab. Clin. Med., 121, pp. 103 -- 110, 1993) as follows.

Part isecheno main artery washed three times for 2 min anhydrous propylene glycol and stained for 30 min with saturated solution of Oil Red O (ORO, Sigma Co.) in the propylene glycol. After this artery washed twice for 3 min in 85% propylene glycol to remove residual dye solution, and then washed with saline solution. Artery photographed, and the photograph explore. The area of the colored section (section with strips of fat) is determined using the image analyzer (LEICA Q-600, Germany) and calculate its proportion (%) of the total area of the artery.

On the other hand, another part of the main artery of the paint in accordance with the method hematoxylin-eosin (H& E) and the method of three-Masson staining and observed under a microscope to confirm the fact that complexes of macrophage-lipid accumulate in the inner membrane, In-ternus, an elastic membrane and the environment.

Next in rabbits take blood samples to determine the levels full of cholesterol and triglycerides by the method of example 4.

The results of predsedatelei arteries significantly reduced for groups with 1 mg/kg Lovastatin, 0,1% naringin and 0.1% of naringenin in comparison with the control group. Accordingly, it was confirmed that naringin and naringenin inhibit the accumulation of complexes of macrophage-lipid on the endothelium of the arteries. In particular, it is noteworthy that the activity naringin or naringenin in respect of inhibiting the accumulation of complexes of macrophage-lipid occurs when cholesterol levels in the blood more than 1100 mg/DL, which is much higher than in healthy rabbits, i.e., about 50 mg/DL. This result suggests the possibility of a new mechanism to prevent the onset of atherosclerosis, which is different from blocking the synthesis of cholesterol due to an inhibitor of HMG-CoA reductase, blocking the absorption of cholesterol by ACAT inhibitor or block transfer of cholesterol due to SETR inhibitor.

In Fig. 1A, 1B and 1C presents artery of rabbits, which were administered with 1% cholesterol (control group); 1% cholesterol plus 1 mg/kg Lovastatinecomparative group); 1% cholesterol plus 0.1% of naringin respectively. As can be seen in Fig.1A, 1B and 1C, there is a thick layer of complex macrophage-lipid on the endothelium of the arteries of the rabbits that were administered with 1% cholesterol, whereas very thin layers or even the plus 1 mg/kg Lovastatineand 1% cholesterol plus 0.1% of naringin respectively.

Accordingly, it was concluded that naringin or naringenin strongly inhibit the accumulation of complexes of macrophage-lipid on the endothelium of the arteries.

Example 7. Prevention of liver diseases using naringin.

(Stage 1). The rat naringin.

20 four-week rat strain Sprague-Dawley (Taihan laboratory animal center, Korea), weighing from 90 to 110 g uniformly randomly divided into two dietary groups. Rats in these two groups give two different foods with high cholesterol content, i.e., AIN-76 laboratory animal feed (ICN, Biochemicals, Cleveland, HE, U. S. A.) containing 1% cholesterol (control group), and 1% cholesterol plus 0.02% of naringin respectively. The composition of the feed, which gave these two groups are presented in table. VI.

Rats were fed on request special food together with water for 6 weeks, absorbed amount was recorded daily, and the rats were weighed every 7 days, and then analyzed the results. All rats showed a normal growth rate, and there are no noticeable differences between the two groups from the point of view of the amount of feed consumed and weight gain no noble rats naringin on liver function are examined as follows.

Blood samples taken from rats of the two diet groups, and determine the levels of serum GOT (glutamate-oxaloacetate transaminase levels) and GPT (glutamate-pyruvate transaminase levels) according to the method of Reitman and Frankel (Reitman, S. and J. S. Frankel, Am.J. Clin. Pathol., 28, 56, 1956). GOT and GPT are synthesized in the liver and heart, and secreted into the blood stream if the damage these organs. Accordingly, the GOT and GPT are representative markers of liver function, and high levels of GOT and GPT in serum indicate serious liver damage.

The results show that the GOT and GPT levels for a group naringin were below the levels for the control group by about 30 and 10%, respectively.

(Stage 3). Experiment on rabbits.

Repeat the procedure stage 1, except that instead of rats use 30 three-month new Zealand white rabbits (Yeonam Horticulture and Animal Husbandry College, Korea), each weighing from about 2.5 to 2.6 kg, and in rabbits fed for six weeks in three different composition of feed, i.e. RC4 feed containing 1% cholesterol (control group); 1% cholesterol plus 1 mg/kg Lovastatine(comparative group) and 1% cholesterol plus 0.1% of naringin respectively.

After that in rabbits irout intramuscular injection of ketamine (75 mg/kg) and cut the abdominal cavity. The color and degree of sclerosing liver is determined on the eyes, and the livers removed from the rabbit, fixed in 10% neutral bateriafina formalin for more than 24 hours Otfiksirovat the liver was washed with a sufficient amount of water, gradually dehydrated 70, 80, 90 and 100% ethanol, and then conclude in paraffin. Enclosed in paraffin-embedded liver is cut into layers with a thickness of 4 μm by using a microtome and stained with hematoxylin and eosin. Painted samples of the liver make transparent xylene, placed with permount and observe under a microscope to confirm the presence of lesions.

In Fig. 2A, 2B and 2C presents the microscopic features of the disease of rabbits that were administered with 1% cholesterol (control group); 1% cholesterol plus 1 mg/kg Lovastatine(comparative group) and 1% cholesterol plus 0.1% of naringin respectively. As can be seen in Fig.2A and 2B, the liver cells of control group and comparative group irregular and enlarged, and has accumulated a large amount of fat. On the contrary, as seen in Fig.2C, the liver cells naringinase group remained normal, and there is no fat storage. This result shows that naringin strongly inhibits fatty liver without any harmful near the t 55-year-old man in a daily dose of 10 µg/kg over 68 days and determine the levels of GOT, GPT and GTP directly before administration (day 0) and after 45 and 68 days after injection (days 45 and 68, respectively. The levels GOT in the serum of 45 and 68 day decreased by 17%, respectively, compared to day 0. The levels of GPT in the serum of 45 and 68 day decreased by 15 and 19%, respectively, compared to day 0. Further, the GTP levels in the serum of 45 and 68 day decreased by 25% and 51%, respectively, compared to day 0. Unexpectedly, the reduction of the GTP level in serum was more than 50%, and this result suggests that naringin or naringenin has a high protecting the liver activity, and preventive activity against liver diseases such as hepatitis, fatty liver and alcoholic fatty liver.

In another case, naringin oral introduced a 56-year-old man who constantly consumed alcoholic beverages in quantities of 100 cm3a day in the daily dose of 6 mg/kg for 30 days, and the GTP level in serum was determined immediately before introduction (day 0) and after 30 days of injection (day 30). Accordingly, the initial GTP level in serum at day 0 was 129 international. u/l, whereas the 30 day he decreased to 69 international. u/l, which corresponds to the normal value. This result until the and and hepatocirrhosis.

Example 9. Products containing naringin or naringenin.

Products containing naringin or naringenin, prepared as follows.

(1). Preparation of tomato ketchup and sauce.

Naringin or naringenin add to tomato ketchup or sauce in a quantity in the range of from 0.01 to 5 wt.% to obtain a health-improving tomato ketchup or sauce.

(2). Cooking products from wheat flour.

Naringin or naringenin added to wheat flour in an amount in the range of from 0.01 to 5 wt.%, and prepare bread, muffins, cookies, crackers and noodles using this mixture to obtain a health-improving products.

(3). Cooking soups and gravies.

Naringin or naringenin add to soups and gravies in amount in the range of from 0.01 to 5 weight. % to get a health-boosting soups and gravies.

(4). Cooking beef.

Naringin or naringenin add to the minced beef in a quantity in the range of from 0.01 to 5 wt.% to obtain a health-improving beef.

(5). Preparation of dairy products.

Naringin or naringenin add to milk in the number Voennoe.

However, in the preparation of cheeses naringin or naringenin added to the coagulated milk protein; and in the case of making yogurt, naringin or naringenin added to the coagulated milk protein after fermentation.

Example 10. Drinks containing naringin or naringenin.

(1). Preparation of vegetable juice.

From 200 to 10000 mg naringin or naringenin add to 1000 ml of tomato or carrot juice to obtain health-improving vegetable juices.

(2). Preparation of fruit juice.

From 200 to 10000 mg naringin or naringenin added to 1,000 ml of Apple or grape juice to obtain health-improving fruit juices.

(3). Preparation of carbonated beverages.

From 200 to 10000 mg naringin or naringenin add to 1000 ml of Coca-Cola or Pepsi-Cola to obtain health-improving carbonated drinks.

Although the present invention has been described in relation to the above examples, it should be understood that the specialists can make various modifications and changes of the invention that fall within the scope of the invention and are defined by the attached claims.

1. Skin is distrofia liver or cirrhosis of the liver in mammals.

2. Application under item 1 where the mammal is man.

3. Application under item 1, where naringin or naringenin is administered to the mammal in the form of a composition containing naringin or naringenin, and the specified composition selected from the group consisting of pharmaceutical compositions, food compositions and drink.

4. Application under item 3, where the effective amount naringin or naringenin contained in the pharmaceutical composition is in the range from 0.1 to 100 mg/kg body weight/day.

5. Application under item 3, where the content naringin or naringenin in the food composition is 0.01-5 weight. %.

6. Application under item 3, where the food composition is meat, chocolate, snacks, candy, pizza, foods prepared from flour of cereals, chewing gum, dairy products, soups, broths, pastes, ketchups, sauces, vitamins or health products.

7. Application under item 6, where the products are prepared from flour of cereals, are bread, muffins, crackers, cookies, biscuits or noodles.

8. Application under item 3, where the composition of the drinks are milk products, vegetable juices, fruit juices, teas, alcoholic drinks or carbonated drinks.


 

Same patents:

The invention relates to medicine and can be used for the treatment of dysfunctions of the hepatobiliary system of different origin

The invention relates to medicine

The invention relates to medicine, in particular to a gastroenterologist, and for the treatment of hypertonic-hyperkinetic forms of biliary dyskinesia in young people

The invention relates to medicine, specifically to the use of Ximena as hepatoprotective and detoxification remedies for the treatment and prevention of purulent-septic diseases

The invention relates to medicine, therapy, can be used for the treatment of chronic viral hepatitis

The invention relates to medicine, mainly for abdominal surgery

The invention relates to medicine, Hepatology, to methods of treatment of primary biliary cirrhosis using georeferential

The invention relates to pharmaceutical industry
The invention relates to the pharmaceutical industry, specifically to medicines used for the prevention, mitigation or treatment of pathological conditions by destroying parasitic organisms through chemical effects on their physiology

The invention relates to the field of medicine and is suitable for treatment of infections of the upper and lower respiratory tract infections, septic conditions, mastitis, osteomyelitis, peritonitis other suppurative-inflammatory processes

The invention relates to pharmaceutical industry and relates to a suppository having antifungal activity

The invention relates to a derivative of benzopyran-2-it formula I, where R1denotes a hydrogen atom, a hydroxyl radical, optionally substituted alkyl radical, optionally interrupted by oxygen atom, sulfur or nitrogen, CNS radical or a radical NRcRdX denotes an oxygen atom or a radical N-N(CH3)2or radical NOalc2where alc2denotes optionally substituted alkyl radical, optionally interrupted by oxygen atom, sulfur or nitrogen,2denotes a hydrogen atom or halogen atom, R3denotes a hydrogen atom, an alkyl radical or a halogen atom, R4denotes a radical NRgRh, optionally substituted aryl or heteroaryl radical, R5denotes a hydrogen atom or O-alkyl, R6denotes alkyl or CH2-O-alkyl, R7denotes a hydrogen atom or alkyl

The invention relates to a derivative of erythromycin General formula (II), (III), (IV) and (V), where R is a substituted C1-C10-alkyl, C3alkenyl,3-quinil, etc
The invention relates to the production of antibiotics, namely the technology of water-soluble salts of erythromycin, erythromycin phosphate
The invention relates to medicine, to Institute, to methods of treatment of tuberculosis of the respiratory organs with severe exudative reaction in children

The invention relates to the field of pharmacology and applies ointment antifungal activity
Up!