Preparation to reduce insulin resistance

FIELD: medicine.

SUBSTANCE: present invention presents a preparation to reduce insulin resistance. The preparation contains 3-O-v-D-glucopyranosyl-4-methylergost-7-ene-3-ole, or an extract made with using an organic solvent, or an extract made with using hot water, or a drained liquid of a plant of Liliaceae family, or fraction thereof which contains this compound as an active component.

EFFECT: production of the preparation which is suitable for inhibition of adipocytokine production, particularly adipocytokine which cause insulin resistance, and for prevention of pathological conditions caused by insulin resistance, or simplification of clinical course of said pathological conditions.

9 cl, 3 ex

 

Description

The technical field to which the invention relates

The present invention relates to means for lowering insulin resistance, which contains 3-O-β-D-glyukopiranozil-4-metalurgist-7-EN-3-ol as an active ingredient, and food and drink containing it. In particular, the present invention relates to means for lowering insulin resistance, which has the effect of regulating the production of adipocytokines representing the factors involved in the beginning and the exacerbation of the pathological condition in which insulin resistance plays a role, such as free fatty acid, factor tumor necrosis, chemoattractant of monocytes protein-1 and resistin, and refers to a food or drink containing it.

Description of the prior art

Insulin is a hormone produced by beta cells in the islets of Langerhans of the pancreas, and plays an important role in maintaining homeostasis of a living organism by influencing lipid metabolism and protein metabolism, and the metabolism of sugars through the insulin receptors, which are present in the target tissues of insulin, such as skeletal muscle, liver and adipose tissue. Examples of the effects of insulin in relevant target tissues including the up promoting the absorption of glucose from the blood into muscle cells and adipocytes, promoting the production of glycogen in liver and muscle tissues, inhibition of gluconeogenesis in the liver, promoting the consumption of glucose and fatty acid synthesis in adipocytes, and inhibition of the destruction of lipids. Insulin resistance is a condition in which cells, organs or individuals require large amounts of insulin than the number normally required to obtain the appropriate effects of insulin, that is, the condition disorders the effects of insulin, which reduced insulin sensitivity. As the results of previous epidemiological studies, hypertension, diabetes, hyperlipidemia (hypertriglyceridemia, Hypo-HDL-cholesterolemia), obesity and the like status are considered pathological conditions, based on insulin resistance. Insulin resistance causes the lack of effects of insulin during the metabolism of sugars leads to compensatory hyperinsulinemia to maintain blood sugar levels, whereby occurs hyperglycemia and glucose intolerance, and diabetes contributes to the depletion of β-cells of the pancreas. In addition, hyperinsulinemia enhances the activation of the sympathetic nerves and promotes the absorption of sodium in the kidneys, causing hypertension, and also causes hyperlipidemia and hyperuricemia after a meal, is liczenie level of inhibitor-1 plasminogen activator (PAI-1) and similar effects.

However, insulin resistance causes abnormal lipid metabolism, caused by the effects of insulin, and the level of free fatty acids (FFA)released from adipocytes, increases in the liver to facilitate the synthesis of triglycerides (TG), resulting in hypertriglyceridemia. Furthermore, the activity of lipoprotein lipase (LPL)which generally have high insulin sensitivity, decreases resistant to insulin condition, thereby reducing the destruction of TG, and is further compounded by hypertriglyceridemia. In addition, an exacerbation of diabetes complications such as retinopathy, nephropathy and gangrene caused by angiopathy, and are aggravated by such arteriosclerotic diseases as myocardial infarction and cerebral infarction, and hypertension exacerbates cardiovascular disease. As described above, it is believed that insulin resistance plays a significant role in the aggravation of pathological complications (non-patent document 1).

In recent years, according to the analysis of specific bodies of gene expression were identified that are secreted from the fatty tissue of various physiologically active substances and thus adipose tissue has been recognized as not only fabrics of energy storage, but also the largest endocrine organ in a living organism. Endocrine factors derived from adipose tissue, have the generic name adipocytokine and play an important role in maintaining homeostasis during metabolism. However, it is believed that in the case of obesity, there is a condition in which fat accumulates, is produced and secreted excessive or too small number of adipocytokines and disrupted the balance of adipocytokines, leading to insulin resistance.

Adipocytokine are divided into two groups: one that increases sensitivity to insulin, and one that causes insulin resistance; representative examples of the first group include adiponectin, leptin, AMRS (AMP-dependent protein kinase) and the like. In particular, it was reported that adiponectin has the effect of eliminating the insulin resistance and the effect of inhibiting gluconeogenesis in the liver (non-patent document 2).

Meanwhile, examples of adipocytokines that cause insulin resistance, in addition to the above FFA and PAI-1, include factor-α tumor necrosis (TNF-α), a chemoattractant of monocytes protein-1, which is a type of inflammatory chemokine, and resistin. In particular, it was reported that TNF-α has the effect of inducing insulin resistance by inhibition of tyrosine phosphorylation of insulin receptor and IRS1 (substrate 1 insulin receptor in the mechanism of transmission of the insulin signal, so that oclasses the effect of insulin. In addition, it was reported that under the condition of insulin resistance, the level of MCP-1 in vivo is increased, and the levels of GLUT4 mRNA (Transporter-4 glucose), which is a transporting glucose media, PPARγ (receptor γ-activated proliferation peroxisomes), which is an intranuclear receptor, β3AR (β3-adrenergic receptor), which is a type of catecholamine receptor type β adipocyte, and ar (fatty acid binding protein 2 adipocyte), which is a protein, fatty acid binding, reduced. Therefore, MCP-1 is the etiological agent of the reduction in insulin sensitivity (non-patent documents 3, 4 and 5).

As a means to reduce insulin resistance have been developed biguanide tools that inhibit gluconeogenesis, mainly in the liver, and derivatives of thiazolidine that increase sensitivity to insulin in muscle and adipose tissue. These funds have already been approved as drugs for the treatment of diabetes, and has also been used to treat arteriosclerosis. It is believed that each of the derivatives of thiazolidine submitted by troglitazone and pioglitazone, acts as a ligand for receptor-activated proliferation peroxisomes (PPAR), which is the first transcription factor type intranuclear receptor, to facilitate the differentiation of adipocytes, thereby reducing insulin resistance.

In addition, as means for reducing insulin resistance have been disclosed: a means to reduce insulin resistance, containing adiponectin or its genes as an active ingredient (patent document 1), a preventive and/or therapeutic agent used about diseases caused by insulin resistance, which contains a substance having affinity for subtype 3 receptor bombezin (BRS-3), as an active ingredient (patent document 2), a means for reducing the level of free fatty acids (FFA)containing a derivative of pyrrole as an active ingredient (patent document 3) and the like. In addition, as a means of containing the substance obtained from food or drink, as the active ingredient were disclosed composition for reducing insulin resistance, containing acetic acid and its ion or salt as an active ingredient (patent document 4), medicine to lower insulin resistance, including containing fatty oil specific diglyceride and/or monoglyceride (patent document 5) and the like.

It was known that such plant sterols as β-sitosterol, campesterol and stigmasterol, Okaz who provide the effect of reducing the level of cholesterol in the blood by inhibiting the absorption of cholesterol, and attempts of its practical application by adding them as fat composition in edible oil. In addition, there were disclosed a tool against obesity and means of improving lipid metabolism, containing cholestenone compound as an active ingredient, which is synthesized by the use of plant sterols, such as β-sitosterol and campesterol as source material (patent documents 6-8 and non-patent document 6).

In addition, have been disclosed: a stimulator of secretion of adiponectin, containing an extract of at least one of rice bran, mushroom shimeji, chrysanthemums, rye, downy birch and Spanish Jasmine (Alpinia zerumbet), and triterpen type cycloartane or cycloartenol and/or (24S)-24,25-dihydroxyacetone, which are derived triterpene type cycloartane (patent document 9).

The aloe genus, belonging to the liliaceae plant, is a group of plants, including Aloe vera (Aloe barbadenisis Miller), Aloe arborescens (Aloe arborescens Miller var. Natalensis Berger) and the like, and empirically it is known that they have different efficiency. For example, discloses a means of reducing immunosuppression containing botanology fraction of aloe extract or aloin (patent document 10), means associated with reduced levels of glucose in the blood (patent documents 11 to 14), the tool is La prevention and treatment of obesity (patent document 15), and the like, but nothing was reported about the effect of reducing insulin resistance provided by the plants belonging to the genus Aloe.

Disclosure of invention

When using biguanides funds, which is a common drug to reduce the insulin resistance that can lead to dysfunction of the gastrointestinal tract or rarely lactic acidosis. In addition, derived thiazolidine, which is a similar tool, can sometimes cause serious side effects such as fluid retention, weight gain and liver dysfunction, therefore its use requires additional attention. Next on the insulin resistance in conditions other than diabetes or hyperglycemia, it is practically difficult to use antidiabetics. In such conditions was desirable to develop tools, which has high safety, which can daily be entered into and which can effectively reduce the resistance to insulin at the minimum possible pain.

In connection with the above problems, the authors of the present invention have studied the mechanisms associated with lifestyle diseases caused by insulin resistance,such as hypertension, diabetes, hyperlipidemia (hypertriglyceridemia, Hypo-HDL-cholesterolemia) and obesity, and has studied the means associated with the prevention, improvement, etc. for diseases associated with lifestyle, that is, the means for decreasing insulin resistance. They drew attention to adipocytokine, which are the factors involved in the start and worsening of insulin resistance, and carefully researched new effective substance that can reduce insulin resistance by controlling the above factors. As a result, they found that 3-O-β-D-glyukopiranozil-4-metalurgist-7-EN-3-ol has the effect of regulating the production of adipocytokines, such as free fatty acid, TNF-α and MCP-1, in particular a pronounced effect of reducing the production of adipocytokines that cause insulin resistance, thereby decreasing insulin resistance.

In relation to the above effects of the present invention in the patent document 9 describes only a preventive effect of plant extract on differentiation of cultured adipocytes and stimulating effect of ergosterol on the secretion of adiponectin. In addition, it cannot be described and will not be disclosed for reducing insulin resistance effect of the active ingredient of the present invention.

The AOC is e, the authors of the present invention have found that 3-O-β-D-glyukopiranozil-4-metalurgist-7-EN-3-ol directly reduces insulin resistance without interfering with the property of insulin secretion or by such studies using test tolerability of insulin (insulin test stress) in addition to the method of fixation of the glucose level, the method steady state plasma glucose (SSPG) and the method of minimal models, which are conventional methods of assessment of insulin resistance.

Such a test of endurance insulin is not disclosed in the above patent documents 1-5. The authors of the present invention have found a more advantageous effect of reducing insulin resistance than the usual effects of lowering insulin resistance, which is not associated with insulin secretion, and accomplished the present invention.

The present invention is the provision of means for reducing insulin resistance, which contains 3-O-β-D-glyukopiranozil-4-metalurgist-7-EN-3-ol as an active ingredient. In addition, another objective of the present invention is the provision of a physiologically functional food or drink containing medicine to lower insulin resistance, such as a food product for use on certain m the medical indications.

The first invention of the present application to solve the above problems is a means to reduce insulin resistance, containing the compound represented by the following structural formula (1), as the active ingredient.

The second invention of the present application to solve the above problems is a means to reduce insulin resistance, which contains the extract obtained using an organic solvent, the extract obtained with the use of hot water, or wrung liquid containing the compound represented by the following structural formula (1), or his faction, as the active ingredient, where the extract obtained using an organic solvent, the extract obtained with the use of hot water, or by extraction of the liquid of the plant or its fractions, contains at least about 0.001% of the compound represented by the following structural formula (1) in terms of dry weight. In addition, preferably, if the above plant is a plant of the Liliaceae.

The third invention of the present application to solve the above problems is a food product or a beverage containing means for reducing the resistance to the insulin, in accordance with the first or second invention, preferably, to a food product or beverage contained 0,0001% or more compounds represented by the above structural formula (1) in terms of dry weight.

The fourth invention of the present application to solve the above problems is the use of compounds represented by the above structural formula (1), or extract obtained using an organic solvent, the extract obtained with the use of hot water, or a spin liquid plants, containing, calculated on the dry weight of at least about 0.001% of the compound, or its fractions, upon receiving means to reduce insulin resistance. In addition, it is preferable that the above plant was a plant of the Liliaceae.

The fifth invention of the present application to solve the above problems is a method of reducing insulin resistance, which includes the introduction of compounds represented by the above structural formula (1), or extract obtained using an organic solvent, the extract obtained with the use of hot water, or the extraction of fluid from a plant containing, calculated on the dry weight of at least about 0.001% of the compound, or its fractions, subject, to the showing should reduce insulin resistance. In addition, it is preferable that the above plant was a plant of the Liliaceae.

Medicine to lower insulin resistance of the present invention and the food and drink that contains it, you can safely vvodit or ingest, and it has a preventive effect on associated with lifestyle diseases, which was thought to have been caused by insulin resistance. In addition, the active ingredient means for reducing the insulin resistance of the present invention can be easily obtained from plants of the family Liliaceae, such as Aloe vera (Aloe barbadensis Miller), which can safely be ingested from the point of view of the experience of using the food product and which is quite affordable.

Brief description of drawings

The drawing is a graph showing the change of blood glucose level in the test of resistance to insulin.

The best way of carrying out the invention

Next will be explained in detail preferred embodiments of the present invention. However, the present invention is not limited to the following preferred options for implementation and it can be freely modified within the scope of the present invention. In addition, no other definitions used here is the percentage indicates the mass.

p> In the present invention the effect of reducing insulin resistance (the effect of increasing insulin sensitivity) means the effect of preventing or reducing various adverse effects on health caused by a reduction in insulin sensitivity, such as in diseases associated with lifestyle. In particular, the tool of the present invention effectively inhibits the increase in the level or production of adipocytokines that cause insulin resistance, such as the inhibitor of plasminogen activator (PAI-1), free fatty acid (FFA), the factor of tumor necrosis (TNF-α), MCP-1 and resistin, which provide preventive and improving effects on pathological state involved in insulin resistance, and effect on risk reduction, prevention, improvement or treatment of diseases associated with insulin resistance, such as hyperinsulinemia, hyperlipidemia, abnormal glucose tolerance, diabetes, hypertension, obesity, arteriosclerosis and the like. Thus, the means for decreasing insulin resistance of the present invention can be defined as a means to improve insulin sensitivity or means for regulating the production of adipocytokines, in particular the means for regulating the production of adipocytokines, is the quiet cause insulin resistance.

There are ways of assessment of insulin resistance, such as the method of fixing the glucose level, the method steady state plasma glucose (SSPG) and method of minimal models, the method of assessment of insulin resistance calculation assessment of insulin resistance by the homeostasis model (HOMA-IR) according to the level of glucose in blood and the concentration of insulin in fasting blood test and insulin resistance. Any of the above methods can be used to assess insulin resistance, however, in the present invention, it is preferable to use test glucose tolerance test (insulin stress) with the use of animals, because the test is not affected by the property insulin secretion or similar factors, thus, it is possible to directly investigate the sensitivity to insulin.

The compound having a structure represented by the above formula (1), has the effect of increasing the sensitivity to insulin and thus can prevent or reduce a pathological condition caused by insulin resistance. Therefore, the connection can be used as an active ingredient a means to reduce insulin resistance or a food or drink containing it. In addition, insulin sensitivity can also be assessed by measuring the reduction level CH the goats blood after injection of insulin.

The compound used as the active ingredient a means to reduce resistenti to insulin (also referred to as "the tool of the present invention") of the present invention, is a compound having a structure represented by the above chemical formula (1), i.e. 3-O-β-D-glyukopiranozil-4-metalurgist-7-EN-3-ol. The compound of the present invention has a structure formed by dehydration condensation of hydroxyl compounds at position 3 4-metalurgist-7-EN-3-ol, and a hydroxyl group in position 1 is D-glucose.

Most preferably, the purity of the compounds of the present invention, used as an active ingredient means for reducing the insulin resistance of the present invention, was 100%. However, the purity can be appropriately set within the range in which the tool has the effect of reducing insulin resistance.

In addition, the composition is used as an active ingredient means for reducing the insulin resistance of the present invention (also referred to as "the composition of the present invention"), is an extract of a plant of the family Liliaceae or a fraction containing at least about 0.001%, calculated on dry weight, preferably 0.01% in re the couple on a dry weight or more preferably of 0.1%, calculated on the dry weight of the above compounds of the present invention. The upper limit of the content of the compounds of the present invention is not specifically limited and may be, for example, preferably 10% of the mass. or 50 wt. -%, 70% of the mass. or 90% of the mass.

In the present invention dry weight means the weight measured after drying the connection method of drying, a certain "Test losses during drying", which is a common method of testing described in the 14th revised edition of the Japanese Pharmacopoeia (March 30, 2001, Notice No. 111 Ministry of health, labour and welfare). For example, weight of compounds of the present invention can be determined as follows: measure approximately 1 g of the compound of the present invention and dried at 105°C for 4 h; and the resulting material is cooled in a drying Cabinet; and the mass of compound is weighed on the scales.

The compound of the present invention or its containing composition can be obtained, for example, extragere fraction containing the compound of the present invention, from a plant belonging to the family Liliaceae, and containing the compound of the present invention, part or product of its destruction, the use of an organic solvent or hot water and the concentration of the fraction.

Examples of the above plants, belonging to the family Liliaceae, include plants belonging to the genus Aloe, or Allium. Examples of RA the plants of the genus Aloe include Aloe barbadensis Miller, Aloe feroxMiller, Aloe africanaMiller, Aloe arborescen Miller var. natalensis Berger, Aloe spicata Baker etc. Although when the connection of the present invention or its containing compositions can be used whole the specified connection, it is preferable to use his mesophyll (part, which is a transparent gel). Such plant or part thereof ruin preferably using a homogenizer or similar devices, by means of this szhizhajut and the connection of the present invention or its containing composition is extracted from the destroyed product using an organic solvent or hot water. Examples of the organic solvent include alcohols such as methanol, ethanol and butanol, and so on; esters such as methyl acetate, ethyl acetate, propyl and butyl acetate and so on; ketones such as acetone and methyl isobutyl ketone and so on; ethers, such as simple diethyl ether and simple petroleum ether and so on; hydrocarbons such as hexane, cyclohexane, toluene and benzene, and so on; halogenated hydrocarbons such as carbon tetrachloride, dichloromethane and chloroform, etc.; heterocyclic compounds such as pyridine, etc.; glycols such as ethylene glycol, etc.; polyhydric alcohols such as polyethylene glycol and so on; nitrile solvents such as acetonitrile, etc., mixtures of these solvents is her etc. In addition, these solvents may be anhydrous or aqueous. Among these solvents, particularly preferred mixture of ethyl acetate/butanol (3:1) and a mixture of chloroform/methanol (2:1).

As extraction method : you can use the method used for conventional extraction of plant components. Typically used, for example, a method of heating in a vessel with reflux condenser 1-300 parts by weight of an organic solvent with 1 part by weight of fresh plant or dried plants when heated at a temperature below the boiling point of the solvent and stirring or shaking, or the way to perform the extraction by sonication at room temperature. By separating insoluble solids from the extraction fluid, using a suitable method such as filtration or centrifugation, it is possible to obtain the crude extract.

The crude extract can be cleaned by various types of chromatography, such as chromatography on a column of silicagel in normal or reversed phase. When the gradient of a mixture of chloroform/methanol is used as a solution for elution in chromatography on a column of silicagel in the normal phase, the connection of the present invention eluted when the mixing ratio of chloroform:methanol = about 5:1. In addition, when g is giant mixture of chloroform/methanol is used as a solution for elution in chromatography on a column of silicagel in reversed phase, the connection of the present invention eluted with methanol at a concentration of about 95%. The resulting fraction can be further cleaned HPLC or similar method.

Whether or not the compound or the composition containing it is obtained as described above, contains a compound of the present invention, can be confirmed by measuring the preventive effect of the products of adipocytokines that cause resistance to insulin, as an indicator by using, for example, methods shown in the following examples. That is, if a compound glycoside associated with glucose at aglionby part, or does Aglyamova part 4-metalurgist-7-EN-3-ol, can be confirmed, for example,13C-NMR or similar method.

The compound of the present invention can also be obtained by condensation of D-glucose and 4-metalurgist-7-EN-3-ol. 4-metalurgist-7-EN-3-ol can be obtained by extraction from plants and clean. D-glucose and 4-metalurgist-7-EN-3-ol can be condensing, for example, a combination of the methods described in Jikken Called Koza (Lecture of Experimental Chemistry), 4th edition, vol. 26, 1992 (described in p.272, p.297 and p.342). That is, D-glucose is completely azetilirovanna, and then anomeric position is transformed into α-bromide. Then 4-metalurgist-7-EN-3-ol interacts with α-bromide in simple diethyl ether for achievement of the β-glycosylation. Then acetyl group is hydrolyzed in a mixture of sodium methoxide/methanol to obtain the target compound.

The compound of the present invention can be used as an active ingredient means for reducing the insulin resistance of the present invention and a food or drink containing it in its pure form. In addition, the extract obtained with an organic solvent, the extract obtained by hot water, or wrung from the plant liquid containing the compound of the present invention, or its fraction (hereinafter referred to as "extract, etc. can also be used as an active ingredient a means to reduce insulin resistance, and containing a food product or beverage.

In the present invention wrung liquid can be obtained by processing homogenate plants compressor collecting untreated or wrung liquid plants, and filtration the crude material to remove insoluble fraction (impurities) filter or filter material. For example, when Aloe vera is used as a plant of the family Liliaceae, then wrung liquid Aloe vera can be obtained by processing the gel part of the mesophyll, obtained by crushing a leaf Aloe vera machine for grinding, compression wrung fluid to collect raw Aloe vera and filtering neoch the seal material Aloe vera to remove impurities filter or filter material. In this case, it is preferable that the total content of aloin and aloe-emodina, which are contained in large quantities in the skin of the leaves of Aloe vera, was 5 ppm or less.

The above extract, etc. that must be contained in the means for decreasing resistenti to insulin, preferably contains at least about 0.001%, calculated on dry weight, preferably from 0.01 to 1% based on dry weight, particularly preferably from 0.05 to 1%, calculated on the dry weight of the compounds of the present invention. In addition, the above extract, etc. that must be contained in the food product or beverage, preferably contains at least 0.0001% in terms of dry weight, preferably from 0.001 to 1% in terms of dry weight, particularly preferably 0.005 to 1%, calculated on the dry weight of the compounds of the present invention. In addition, the above extract, etc. may be a solution or it can also be lyophilized or spray dried in the usual manner and stored or used in powder form.

As a means to reduce the insulin resistance of the present invention the connection of the present invention or a composition containing it as an extract, etc. or in combination with a pharmaceutically acceptable carrier, can be Perera is Ino or parenteral enter the mammal, including humans. In the preparation of the present invention, the compound of the present invention can be a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include metal salts (inorganic salts)and organic salts, including, for example, salts listed in the guide Remington''s Pharmaceutical Sciences,” 17th edition, p.1418, 1985. Their specific examples include without limitation, salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate and Hydrobromic, and salts of organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluensulfonate, pamoate, salicylate and stearate. In addition, the salt may be a salt with a metal such as sodium, potassium, calcium, magnesium and aluminum, or a salt with amino acid such as lysine. In addition, a solvate, such as the hydrates of the above compounds, or their pharmaceutically acceptable salts also fall under the scope of the present invention.

Dosage form means for reducing the insulin resistance of the present invention is definitely not limited and may be appropriately selected depending on therapeutic purpose. Specific forms include tablet, pill, powder, solution, suspension, emulsion, granule, capsule, syrup, suppository, solution d is I injection ointment, transdermal system, eye drops, nasal drops, etc. To receive them, you can use additives generally used in conventional medicine to lower insulin resistance as pharmaceutical carriers, such as excipients, binding agents, disintegrating agents, lubricating agents, stabilizers, flavoring agents, diluents, surfactants and solvents for injection solutions, etc. in Addition, yet reduces the effect of the present invention, the compound of the present invention or its containing extract, etc. can be used in combination with other agents, has the effect of reducing insulin resistance.

Although the number of compounds of the present invention or its extract, etc. contained in the means for decreasing insulin resistance of the present invention, is not specifically limited and can appropriately select, this quantity may be, for example, at least about 0.001 wt. -%, preferably from 0.01 to 1 wt. -%, particularly preferably from 0.05 to 1% of the mass. translated into a number of compounds of the present invention.

Medicine to lower insulin resistance of the present invention can prevent, alleviate or cure various diseases, complications and podobn is e, caused by resistance to insulin, and can reduce the risks of these diseases, complications and the like. In addition, the means for decreasing insulin resistance of the present invention can preferably be applied in a patient, resistantanti to insulin which is lower than insulin resistance in healthy individuals. In addition, insulin resistance generally means a condition in which the level of insulin in the plasma of fasting is from 10 to 15 mked/ml or more, and the index of NOMA is 1.73 or more.

Examples of various diseases caused by insulin resistance include hypertension, hyperlipidemia, diabetes, and arteriosclerosis. Examples of the complications caused by these diseases include (a) cerebral stroke, nephrosclerosis and renal failure caused by hypertension, (b) arteriosclerosis and pancreatitis caused by hyperlipidemia, (C) diabetic retinopathy, nephropathy, neuropathy and diabetic gangrene caused by diabetes, and (d) cerebral stroke, cerebral infarction, cardiovascular diseases such as angina and myocardial infarction, nephropathy, such as uremia, nephrosclerosis and renal failure caused by arteriosclerosis. In addition, the authors of the present invention have found that the compound of the present invention has the effect of reducing the level, the Alc in hemoglobin and reduce hyperlipidemia (WO 2006/035525). Preferably, the diseases in which it is applied medicine to lower insulin resistance, was not a disease, with higher levels in hemoglobin Alc, than those in healthy persons.

In addition, it is expected that the tool of the present invention, which has the effect of reducing insulin resistance, has the effect of inhibiting the production and increase of adipocytokines that cause insulin resistance, such as TNF-α, MCP-1 and FF. Therefore, the tool of the present invention has the effect of preventing and/or facilitate the flow of diseases caused by increased levels of the above adipocytokines, which include autoimmune diseases such as rheumatoid arthritis, Crohn's disease, inflammatory diseases of various organs, such as jade, pancreatic, hepatitis, and pneumonitis, angiopathy, sepsis, cancer cachexia. Thus, the means for decreasing insulin resistance of the present invention can preferably be used in a patient, which increased the production of adipocytokines, in particular a patient who increased production of adipocytokines that cause insulin resistance.

The introduction means according to the present invention is not specifically limited and may be going the way they are selected in accordance with the method of treatment of a particular disease. In addition, the route of administration is preferably determined depending on the dosage form, age, gender, and other characteristics of the patients, the severity of symptoms in patients etc. Dose means the present invention can appropriately be selected depending on the scheme of administration, age, sex, disease severity, and other characteristics of the patients and so the Number of compounds according to the present invention as the active ingredient is usually selected from the range of preferably from 0.001 to 50 mg/kg/d, preferably from 0.01 to 1 mg/kg/d as a test dose. In addition, when you use the extract etc. containing the compound of the present invention, the dry weight of the extract, etc. is selected from the range preferably from 0.1 to 1000 mg/kg/d, preferably from 1 to 100 mg/kg/d as a trial number. In any case, the dose can be taken inside or several times a day as fractional portions.

The compound of the present invention or its containing composition can be added to food or drink (drink or food) for food or drink, has the effect of reducing insulin resistance. The shape and property of the food or beverage is not specifically limited, while not broken, the effect of the active ingredient, and a food product or apidoc can be taken orally and can be obtained in the usual manner by the use of raw materials, usually used for food or drink, except that is added above the active ingredient. In addition, a number of compounds of the present invention or its containing extract, etc. contained in the food product or beverage of the present invention, is not specifically limited and can be selected appropriately. For example, the compound of the present invention or its containing extract, etc. contained in the food product or beverage in an amount of at least 0.0001% per mass., preferably from 0.001 to 1 wt. -%, preferably 0.005 to 1 wt%. translated into a number of compounds of the present invention.

Food or drink of the present invention can be used in various indications for which is used the effect of reducing insulin resistance. For example, the tool of the present invention can be used as a food product or beverage, is used to reduce or eliminate risk factors associated with lifestyle diseases caused by insulin resistance. In addition, food product or beverage of the present invention can prevent diseases caused by insulin resistance, such as hypertension, hyperlipidemia, diabetes and the like, and can reduce the risks of these diseases is the second. In addition, food product or beverage of the present invention can prevent various complications caused by sites for Dr to insulin, such as cerebral stroke, nephrosclerosis and renal failure caused by hypertension, atherosclerosis, pancreatitis and similar diseases caused by hyperlipidemia, diabetic retinopathy, nephropathy, neuropathy and diabetic gangrene caused by diabetes, cerebral stroke, cerebral infarction, cardiovascular diseases such as angina and myocardial infarction, nephropathy, such as uremia, nephrosclerosis and renal failure caused by arteriosclerosis, and can reduce the risks of these diseases.

In addition, it is expected that the food product or beverage of the present invention has the effect of inhibiting the production and increase of adipocytokines that cause insulin resistance, such as TNF-α, MCP-1 and FFA. Therefore, the tool of the present invention has the effect of diseases and reduce the risk of these diseases, caused by increased levels of the above adipocytokines, which include autoimmune diseases such as rheumatoid arthritis, Crohn's disease, inflammatory diseases of various organs, such as nephritis, pancreatitis, hepatitis, and pneumonitis, angiopathy, sepsis, cancer, cachexy is. Thus, a food product or beverage of the present invention can preferably inside the patient, which increased the production of the above adipocytokines, in particular a patient who increased production of adipocytokines that cause insulin resistance.

Food or drink of the present invention is preferably supplied in the form of food or drink supplied with an indication that the food or drink is used to reduce insulin resistance, such as "food or drink containing a compound that has the effect of reducing insulin resistance, characterized as "To reduce insulin resistance", "food or drink containing plant extract, described as "To reduce insulin resistance", or "food or drink containing an extract of Aloe vera, described as "To reduce insulin resistance", and the like. In addition, since the compound of the present invention and containing composition has the effect of reducing insulin resistance, thus it is considered that the indication of the reduction of insulin resistance is set to increase insulin sensitivity". Therefore, food or drink on astasia invention can be described as designed To increase insulin sensitivity". In other words, the stated purpose "To reduce insulin resistance" can be replaced with a stated purpose "To improve insulin sensitivity".

The edition used for the above indications, should not necessarily be limited to the expression "To reduce insulin resistance or To increase insulin sensitivity, and any other wording that expresses the effect of increasing insulin sensitivity, or effect the prevention and reduction of insulin resistance, of course, included in the scope of the present invention. In this edition, it is also possible, for example, specifying, based on the different applications, enabling consumers to recognize the effect of reducing insulin resistance or the effect of increasing insulin sensitivity. Examples will include the indication "Suitable for those who have a tendency to insulin resistance and is Used to reduce or eliminate the factor (s) the risk of diseases associated with lifestyle.

Above, the term "instruction" includes all steps to inform consumers on the above application and any instructions, or resembling conductive analogy with the above apply, enter the amount of "instructions" of the present invention, regardless of the destination, content, concrete objects, environments, etc. instructions. However, the indication is preferably done using an expression that allows users to immediately understand the above application. Specific examples include the actions as instructed above apply to the goods or packages of goods related to food product or beverage of the present invention, the action definition, delivery, performance definitions assignment or delivery, or importation of such goods, or packaging of the goods supplied, indicating the above-mentioned application, presentation, or dissemination of advertising information, price lists or business information relating to the goods, indicating the above-mentioned applications, or providing information, including information about the content indicating the above-mentioned application of electromagnetic means (the Internet, etc) and so the Indication is preferably an indication approved by the administration and so on (for example, an indication in the form, based on the approved sample, which qualifies on the basis of any of a variety of legal systems provided by the administration), and especially preferably an indication of the promotional materials in ongoing forms, such as packaging, containers, catalogs, brochures and details rationae sheets, other documents etc.

Examples of instructions also include instructions as a food product for health, functional food, nutritional product for enteral feeding, food for special dietary use, a food product with claims on nutritional function, quasi-drug, etc. as well as instructions, approved by the Ministry of health, labour and welfare, for example instructions, approved on the basis of the food product for certain hygienic applications and similar systems. Examples of the latter include instructions as food for certain hygienic applications from qualified hygienic claims, indications about the impact on the structure and function of the body, the claim of reducing the risk of diseases and so on, but rather typical examples include guidance on the food to be certain hygienic applications (in particular, guidance on applying for health), are presented in the supplementary instructions of the Law on the promotion of health (Decree No. 86 of the Ministry of health, labour and welfare of Japan from April 30, 2003) and similar instructions.

The present invention will be specifically explained with reference to the following examples. However, the amount this is the total of the invention is not limited to the following examples.

First of all, examples of obtaining explained that the compound or composition of the present invention can be obtained from plants belonging to the family Liliaceae.

Example 1 obtaining

As examples of the preparation of the plants belonging to the family Liliaceae. Below will be described examples of the preparation of 3-O-β-D-glyukopiranozil-4-metalurgist-7-EN-3-ol from Aloe vera.

3-O-β-D-glyukopiranozil-4-metalurgist-7-EN-3-ol were extracted from Aloe vera and purified as described below.

The mesophyll (the part in the form of a transparent gel) in an amount of 100 kg was sigali using a homogenizer, to it was added 100 l of a mixture of ethyl acetate/butanol (3:1) and stirred. The mixture was left overnight for separating a mixture of ethyl acetate/butanol and aqueous layer was extracted mixture of ethyl acetate/butanol. The extract from this mixture of ethyl acetate/butanol obtained by concentration of the mixture ethyl acetate/butanol under reduced pressure, had a lot of 13.5, the Effect of reducing insulin resistance was evaluated for the above water layer test tolerability of insulin and extract from a mixture of ethyl acetate/butanol described below in example 3, and the effect was observed for the extract from a mixture of ethyl acetate/butanol. Therefore, attempts were made separation and purification of components in the extract.

First, the above extract was investigated thin layer of chromatographie is (Merck Ltd., silica gel 60F254 and RP-18F2543). As a result, the allocation method on the basis of chromatography in normal phase on a column of silica gel using mixtures of ethyl acetate/butanol was appropriate. Accordingly, a solution of 13 g of the above extract, dissolved in 1 ml of a mixture of chloroform/methanol (1:1)was loaded on a column Packed with 400 g of silica gel 60 (Merck Ltd.) to achieve the adsorption of the components on the column, then the components were suirable mixture method stepwise gradient of chloroform/methanol, in which the concentration of methanol stepwise increased (the ratio of mixing of chloroform:methanol= 100:1, 25:1, 10:1, 5:1 1:1), and the eluate was fractionally for each relation mixing a mixture of chloroform/methanol. Outputs raw cleaning products obtained from fractions after removal of the solvent, respectively 1,44, 3,0, 1.17 and 2,27, the above reduction assessment of insulin resistance was confirmed that among these factions active component existed in the faction, elyuirovaniya mixture of chloroform:methanol = 5:1 (raw product cleaning).

In addition, for isolation and purification of the active component from the above raw material of the cleaning product And the raw product purification And investigated using thin-layer chromatography (Merck Ltd., silica gel 60F254 and RP-18F2543). As a result, the allocation method n is the basis of chromatography in reversed phase column with silica gel was suitable. Accordingly, the above raw product purification And dissolved in 1 ml of a mixture of chloroform/methanol (1:1) and loaded on a column filled with 180 g COSMOSIL 140 (Nacalai Tesque, Inc.) to achieve the adsorption of the components on the column. Then elution was performed consistent application of 600 ml of an 85% solution of methanol, 600 ml of 95% solution of methanol and 100 ml of 100% methanol. 3-O-β-D-glyukopiranozil-4-metalurgist-7-EN-3-ol was concentrated and allocated in the faction, elyuirovaniya 95% methanol, and its mass after removal of the solvent was 370 mg. Then this product is called the connection 1.

Due to the fact that the compound 1 showed the Rf value, very close to that of the glucoside of β-sitosterol in the study, based on thin-layer chromatography, it was expected that he is a glycoside in which 1 molecule of sugar is associated with aglionby part. In addition, to study the sugar composition of compound 1 compound 1 was subjected to methanolysis, and then turned in TMS derivative (trimethylsilyl) and was subjected to measurement of GC-MS (gas chromatography - mass spectrometry). As a result, when the measurement is derived TMS for the sugar connection parts 1, it showed major peaks at values of the retention time of 14.28, 14,61 and 16,34 min, which is essentially consistent with the values of the retention time of the major peak of the sample of glucose (Nacalai Tasque, nc.), 14,27, 14,60 and 16,33 minutes in Addition, no peaks were observed, corresponding to the main peaks of the sample galactose (Kishida Chemical Co., Ltd.) and sample xylose (Kishida Chemical Co., Ltd.). Thus, it was confirmed that the type of sugar contained in the compound 1 represented glucose.

On the basis of the above evaluation results, it was found that compound 1 was a glycoside in which 1 molecule of glucose linked to aglionby part. However, when compound 1 was analyzed13C-NMR (125 MHz, CDCl3), was confirmed by the existence of impurities. Therefore, it was considered that to determine its structure requires additional cleaning. Accordingly, compound 1 was madanolsavam and then azetilirovanna, and then were confirmed structure aglionby part, and the binding site aglionby parts and sugar. The following paragraphs will describe his method.

Connection 1 in the amount of 50 mg was dissolved in methanol (50 ml)containing 5% hydrochloric acid. And the solution is boiled in a vessel under reflux for 6 h to methanolysis and dried to obtain the remainder (about 30 mg). This residue was purified by chromatography on a column of silica gel (hexane:chloroform = 9:1) to obtain compound 2 (10 mg). this compound 2 (5 mg) is added acetic anhydride and pyridine (2 drops of each) and heated at 70°C in ECENA 30 min for acetylation, and then, the solvent of the reaction mixture is evaporated to obtain compound 3. The analysis of compound 3 was performed GC-MS and13C-NMR (125 MHz, CDCl3).

The results of the analysis of this compound 3 GC-MS and13C-NMR (125 MHz, CDCl3) is shown below.

3-Acetoxy-4-metalurgist-7-ene used as reference substance, was obtained by extraction of aloe Vera gel, purification of the extract, confirming the structure of the pure product13C-NMR and its acetylation.

13C-NMR spectrum (magnitude d in CDCl3); C-l:36,8, C-2:27,3, C-3:78,7, C-4:37,0, C-5:46,9, C-6:26,8, With-7:117,4, C-8:139,4, C-9:49,7, C-10:34,9, C-ll:21,6, C-12:39,7, C-13:43,6, With-14:55,1, C-15:23,1, C-16:28,2, C-17:56,3, C-18:12,0, C-19:14,2, C-20:36,5, C-21:19,0, C-22:33,9, C-23:30,6, C-24:39,1, C-25:32,6, C-26:20.4, THE C-27:18,4, C-28:15,6, C-29:15,3.

GC-MS

Apparatus: GC-17A/GCMS5050A (SHIMADZU)

GC column: NEUTRA BOND-5 (GL Sciences)

The column temperature: 100°C (2 min) → 10°C./min → 300°C/28 min.)

Temperature of injection: 250°C

Carrier gas: Not (1.3 ml/min)

Temperature boundary: 300°C

Type MS: EI

Ionization energy: 70 eV

Results

Reference substance: 3-acetoxy-4-metalurgist-7-ene: tR (retention time in min) = 39,4; m/z 456 [M]+, 441 [M-CH3]+, 396 [M-AcOH]+, 381 [M-CH3-Asón]+

Connection 3: tR (min) = 39,2; m/z 456 [M]+, 441 [M-CH3]+, 396 [M-AcOH]+, 381 [M-CH3-Asón]+

The results of NMR measurement of the compound 3 was consistent with the values of 3-acetoxy-4-metile the GOST-7-ene, presented in the literature (Yukagaku (Oil Chemistry), Vol. 36, No. 5, pp. 301-319, 1987). These results revealed that compound 2 was a 4-metalurgist-7-EN-3-ol. In addition, the measurement result is FAB-MS (fluorescent antibody - mass spectrometry), it was found that the molecular mass of compound 1 was 576. When compound 2 (Aglyamova part) and glucose was condensed, the molecular weight of the obtained compound was 414 (compound 2)+180 (glucose)-18 (water)=576, which is consistent with the molecular mass of compound 1. The above results revealed that compound 1 had the structure of 3-O-β-D-glyukopiranozil-4-metalurgist-7-EN-3-ol.

Molecular formula, molecular weight and chemical formula of the compounds shown below.

Connection 1

Molecular formula: C35H60About6

Molecular weight: 576

Chemical formula: compound 1 has the following chemical formula (1)

Connection 2

Molecular formula: C29H50About

Molecular weight: 414

Chemical formula: compound 2 has the following chemical formula (2)

Connection 3

Molecular formula: C31H52About2

Molecular weight: 456

Chemical formula: compound 3 has the following chemical formula (3)

Example of getting 2

The mesophyll (the part in the form of a transparent gel) Aloe vera dried by heating to 0.3 g of crushed dried Aloe vera powder was added 60 ml of 60, 80 or 100% ethanol, and the mixture was heated in a vessel under reflux at 60°C for 1 h, the Extract was centrifuged at 1500 rpm for 20 min, and the supernatant liquid was concentrated under reduced pressure to remove ethanol and thereby obtain the crude extract. Dry weight of the crude extracts obtained by extraction using 60, 80 or 100% ethanol were respectively 65, 42 and 18 mg. Thin-layer chromatography, it was confirmed that these crude extracts contained 3-O-β-D-glyukopiranozil-4-metalurgist-7-EN-3-ol.

Example of getting 3

The mesophyll (the part in the form of a transparent gel) Aloe vera dried by heating to 0.3 g of crushed dried Aloe vera powder was added 60 ml of water, and the mixture was heated in a vessel under reflux at 95°C for 5 h, the Extract was centrifuged at 1500 rpm for 20 min, and the supernatant liofilizirovanny to obtain 75 mg of the crude extract. Thin-layer chromatography, it was confirmed that the crude extract contained 3-O-β-D-glyukopiranozil-4-metalurgist-7-EN-3-ol.

Example 4

The mesophyll (the part in the form of a transparent gel) Aloe vera dried load the cation, crushed and dried, to 21 kg of the thus obtained powder Aloe vera added 90 l of a mixture of chloroform/methanol (2:1), then immersed overnight in this mixture at room temperature and was collected by filtration, and to the residue obtained by the filtration was again added 90 l of a mixture of chloroform/methanol (2:1). This procedure was repeated a total of 4 times. The obtained filtrate (350 l) was concentrated at 28°C for final receipt 784 g of the crude extract. To this crude extract in the amount of 780 g) was added to 2 l of a mixture of chloroform/methanol (2:1), was stirred for 1 h and filtered to extract the layer (A) mixture of chloroform/methanol. To the residue obtained by filtration, successively added to 2.5 l of water and 2 l of ethyl acetate and stirred for 1 h and extracted ethyl acetate layer (B). In the remaining aqueous layer was again added to 5 l of chloroform and stirred for 1 h and extracted chloroform layer (S).

Extracted with an organic solvent extracts a, b and C were mixed, concentrated at 23°C and loaded on a column Packed with silica gel glass column 52 mm × 350 mm, packing material IR-63/210-W (Daiso Co., Ltd.). In the subsequent monitoring of the eluate thin-layer chromatography 10 l of a mixture of hexane/chloroform (1:1), 10 l of chloroform, 20 l of a mixture of chloroform/methanol (10:1) and 20 l of a mixture of chloroform/methanol (5:1) was passed through the column at al is m order and extract fraction 1 (approximately 1 l), fraction 2 (about 1.5 l), fraction 3 (approximately 1.5 l) and fraction 4 (about 1.5 l) was used for elution solvents.

Thin-layer chromatography, it was confirmed that the fraction 3 contained the target glycoside, and then the solvent fraction 3 was removed to obtain humidity 131.6 g of the crude extract. This crude extract in the amount of 130 g was again loaded onto a column Packed with silica gel glass column 70 mm × 500 mm, packing material SP-60-40/60 (Daiso Co., Ltd.) and consistently suirable 10 l of a mixture of chloroform/methanol (30:1), 50 l of a mixture of chloroform/methanol (20:1), 10 l of a mixture of chloroform/methanol (10:1) and 10 l of a mixture of chloroform/methanol (1:1) in the form of solutions for elution in the conditions of a pressure of 10 kgf·cm-2and flow rate 40 ml/min Eluate was fractionally as fractions of 100 ml by using the collector fractions for collection of fractions 1 through 8.

The collected fractions were examined by thin-layer chromatography and as a result it was found that the target glycoside and impurities existed in fraction 7. Therefore, this fraction was concentrated, and was again loaded onto a column Packed with silica gel glass column 70 mm × 500 mm, packing material SP-60-40/60 (Daiso Co., Ltd.) and consistently suirable 10 l of a mixture of chloroform/methanol (20:1) and 10 l of a mixture of chloroform/methanol (10:1) in the form of solutions for elution in unloveable 10 kgf·cm -2and flow rate of 40 ml/min. as a result received to 25.3 g of 3-O-β-D-glyukopiranozil-4-metalurgist-7-EN-3-ol, which was a target glycoside contained in the faction, elyuirovaniya mixture of chloroform/methanol (10:1).

Example 1

This example is performed to assess changes in the level of free fatty acids (FFA) in serum caused by the use of the present invention to reduce insulin resistance using rats, ZDF (Zucker Diabetic Fatty)that represent animal models of diabetes with obesity, accompanied by insulin resistance.

(1) get sample

3-O-β-D-glyukopiranozil-4-metalurgist-7-EN-3-ol obtained in example obtain 1, was dissolved in DMSO (dimethyl sulfoxide), and the concentration was brought to 15 μg/ml of distilled water to obtain thus the test specimen. In this case, the final concentration of DMSO was brought up to 0.2%. In addition, received the solution without the test sample as a negative sample.

(2) Method of test

ZDF rats aged 6 weeks. (purchased from Charles River Laboratories, Inc., USA) previously fed diet with high fat content (Research Diet, Inc.) within 1 month. These rats were divided into groups consisting of 6 rats each. Each group of rats with oral probe was administered 1 ml of 400 g of body weight (37,5 mg/kg of mass of the body) of the test specimen or negative sample 1 time/day. On the 45th day from the beginning of introduction of samples, blood samples of rats were taken on an empty stomach, and the level of free fatty acids in serum were measured using the NEFA C-test Wako (Wako Pure Chemical Industries, Ltd.).

(3) the Results (the level of free fatty acids in the blood)

In table 1 shows the levels of free fatty acids in the serum of rats on the 45th day from the beginning of the introduction. Compared with the group that was administered a negative sample, it was observed that the group that was administered the test sample, the levels of free fatty acid in serum was decreased to 53%. During the period of introduction, according to autopsy studies, side effects were not observed. In addition, the values of R in the tables indicate the likelihood of statistical significance of the differences on the criterion of Tukey-Kramer.

Table 1
SampleFree fatty acid (mEq/l)The value p
The test sample1,948±0,648*0,0073
Negative sample3,700±0,892-
* indicates that there were statistically significant the initial inhibitory effect on the production of free fatty acids.

Example 2

This example was made to assess the effect of the means for reducing the insulin resistance of the present invention on the number of produced TNF-α and MCP-1 in each cell of adipose tissue using rats, ZDF (Zucker Diabetic Fatty)that represent animal models of diabetes with obesity, accompanied by insulin resistance.

(1) get sample

Example 2 used the same test sample and a negative sample, as those which were obtained in example 1.

(2) Method of test

ZDF rats aged 6 weeks. (purchased from Charles River Laboratories, Inc., USA) previously fed diet with high fat content (Research Diet, Inc.) within 1 month. These rats were divided into groups consisting of 6 rats each. Each group of rats with oral probe was administered 1 ml of 400 g of body weight (37,5 mg/kg body weight) of the test specimen or negative sample 1 time/on daily basis. On the 45th day from the beginning of introduction of samples in rats took adipose tissue of the epididymis in conditions of starvation and 1 g of each sample of adipose tissue was added to 1.5 ml of medium D-MEM/F12 containing 0.5% albumin bovine serum, followed by cultivation at 37°C. After 1 h of cultivation supernatant of the culture was collected and ELISA assay (Biosource) in the supernatant fluids of the cultures was measured concentrate the radio TNF-α and MCP-1.

(3) the Results (the number of the produced TNF-α and MCP-1

Table 2 shows the number of the produced TNF-α in adipose tissue. Table 3 shows the number of the produced MCP-1 in adipose tissue.

As is evident from the presented results, in the group that was administered the test sample was observed significant inhibiting effects on production and TNF-α, and MCP-1 compared with group, which has introduced a negative sample. The results of this example it was found that the introduction of means for reducing the insulin resistance of the present invention reduces the production of adipocytokines that cause insulin resistance in adipose tissue, which exacerbate insulin resistance, and prevents the development of insulin resistance. In addition, the values of R in the tables indicate the likelihood of statistical significance of the differences on the criterion of Tukey-Kramer.

Table 2
SampleTNF-α (PCG/ml)The value p
The test sample117,4±47,9*0,0298
Negative sample353,1±192,8 -
* indicates that there was a statistically significant inhibitory effect on the production of TNF-α

Table 3
SampleMCP-1 (PCG/ml)The value p
The test sample23,3±3,6*0,0302
Negative sample38,8±14,3-
* indicates that there was a statistically significant inhibitory effect on the production of MCP-1.

Example 3

This example is performed to assess the reinforcing effect of the means according to the present invention in reducing insulin resistance and increase insulin sensitivity by performing a test of endurance insulin using rats, ZDF (Zucker Diabetic Fatty)that represent animal models of diabetes with obesity, accompanied by insulin resistance.

(1) get sample

Example 3 used the same test sample and a negative sample, as those which were obtained in examples 1 and 2.

(2) the manual testing

ZDF rats aged 6 weeks. (purchased from Charles River Laboratories, Inc., USA) previously fed diet with high fat content (Research Diet, Inc.) within 1 month. These rats were divided into groups consisting of 6 rats each. Each group of rats with oral probe was administered 1 ml of 400 g of body weight (37,5 mg/kg body weight) of the test specimen or negative sample 1 time/day. On the 35th day from the start of injection of the samples was performed test tolerability of insulin. In this example, the test tolerability of insulin was performed in such a way that: rats were starved for 4 h and then were injected intraperitoneally 10 IU/kg body weight of human insulin (Eli Lilly and Company); and changes over time, the level of glucose in the blood was measured from the beginning of the introduction of insulin to 60 min after injection.

(3) the Results (Test tolerability of insulin)

The results of this example were as shown in the drawing. The drawing shows the results of the test tolerability of insulin. As is evident from the drawing, the group that was administered the test sample, showed lower levels of blood glucose levels than the group that was administered a negative sample at any point in time from 15 min to 60 min after the start of insulin administration. The results of this example it was found that the introduction of means for reducing the insulin resistance of the present invention p is increases sensitivity to insulin.

Industrial applicability

The present invention can provide a means to reduce insulin resistance, which is safe, no side effects and can improve insulin sensitivity and to provide a physiologically functional food or drink, such as food products, for use in certain medical conditions, containing means for decreasing insulin resistance. Medicine to lower insulin resistance and physiologically functional food or drink containing medicine to lower insulin resistance, has a therapeutic or prophylactic effect on diseases, complications and the like condition caused by a reduced sensitivity to insulin, such as those associated with lifestyle diseases such as hypertension, diabetes, hyperlipidemia and arteriosclerosis, and have effects that reduce the risk of these diseases, complications and the like conditions.

1. Medicine to lower insulin resistance, containing the compound represented by the following structural formula (1)as an active ingredient

2. Medicine to lower insulin resistance, which contains the extract obtained with the use of the organic solvent, the extract obtained with the use of hot water and wrung fluid or a fraction containing the compound represented by the following structural formula (1), as the active ingredient, where the extract obtained using an organic solvent, the extract obtained with the use of hot water, or spin liquids plants or their fractions, contains, calculated on the dry weight of at least about 0.001% of the compound represented by the following structural formula (1)

3. Medicine to lower insulin resistance according to claim 2, in which the above plant is a plant of the family Liliaceae.

4. Food or drink containing medicine to lower insulin resistance according to any one of claims 1 to 3.

5. Food or drink according to claim 4, which contains of 0.0001 wt.% or more compounds represented by the above structural formula (1).

6. The use of compounds represented by the following structural formula (1), or extract obtained using an organic solvent, the extract obtained with the use of hot water, or spin liquids plants or their fractions, containing, calculated on the dry weight of at least about 0.001% of the compound, upon receiving means to reduce insulin resistance

7. The use according to claim 6, where the above plant is a plant of the family Liliaceae.

8. The way to reduce insulin resistance, which includes the introduction of compounds represented by the following structural formula (1), or extract obtained using an organic solvent, the extract obtained with the use of hot water, or the extraction of fluid from plants, which contain in terms of dry weight, at least about 0.001% connection

9. The method of claim 8, where the above plant is a plant of the family Liliaceae.



 

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2 cl, 3 ex

FIELD: organic chemistry, chemistry of steroids.

SUBSTANCE: invention relates to a new method for synthesis of 6β-formyl-B-norcholestane-3β,5β-diol of the formula (I): by constricting six-membered B-ring of cholesterol. Method involves photooxidation of cholesterol with air oxygen at irradiation by visible light in the presence of porphyrine photosensibilizing agent immobilized on low-molecular fraction of copolymer of tetrafluoroethylene and perfluoro-3,6-dioxo-5-methyl-6-sulfonylfluoride octene-1 in the mass ratio porphyrine photosensibilizing agent : cholesterol = 1:(12-15). As porphyrine photosensibilizing agent 5,10,15,20-tetraphenylporphyrine can be used. Method shows technological simplicity, it doesn't require rigid conditions and provides the high yield of the end product.

EFFECT: improved preparing method.

2 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention represents new derivatives of 17,20-dihydrofusidic acid of the formula (Ia)

wherein Q1 and Q2 are similar or different and mean -CO-, -CHOH-, -CHRO- wherein R means (C1-C4)-alkyl; Q3 means -CH2-; Y means hydrogen atom (H); A means -O- or -S-; R1 means (C1-C4)-alkyl, (C2-C4)-olefin, (C1-C6)-acyl, (C3-C7)-cycloalkylcarbonyl, benzoyl. These derivatives are used in pharmaceutical compositions for treatment of infectious diseases, in particular, in composition for topical applying for treatment of infectious diseases of skin and eyes.

EFFECT: valuable medicinal properties of compounds.

22 cl, 7 tbl, 41 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):

wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

38 cl, 1 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology and endocrinology, and concerns normalisation of thromboplastin formation in patients suffering from arterial hypertension with impaired glucose tolerance. That is ensured by integrated treatment including graduated static and dynamic physical exercises, and also introduction of pioglitazone in a dose 30 mg once in the morning and a lisinopril in a dose 10 mg once a day in the morning during 1.5 months.

EFFECT: complex of specific medical agents and physical activity combined with empirically specified duration of treatment provides normalisation of thromboplastin formation that in turn reduces risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology and endocrinology, and concerns correction of blood microvesicle level in arterial hypertension with impaired glucose tolerance. That is ensured by integrated treatment including graduated physical exercises, and introduction of Fosinopril in a dose 10 mg once in the morning and pioglitazone in a dose 30 mg once in the morning. Therapeutic course is at least 7 weeks.

EFFECT: complex of drug-free modalities and specific pharmacological preparations combined with empirically specified time of treatment provides maintained optimum microvesicle level that in turn allows considerably reducing risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely haematology, cardiology and endocrinology and concerns correction of blood microvesicle level in arterial hypertension (AH) and pancreatic diabetes type II (PD II). That is ensured by integrated therapy involving graduated physical exercises, as well as introduction of lisinopril in a dose 10 mg once in the morning, amlodipine in a dose 5 mg once in the morning and pioglitazone in a dose 30 mg once in the morning for therapeutic course at least 7 weeks.

EFFECT: complex of specific medical preparations and physical exercises combined with empirically specified duration of treatment provides effective correction of blood microvesicle level and, thereby, reduced risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely haematology and endocrinology, and concerns normalisation of thrombocyte sensitivity to aggregation inducers in patients suffering from arterial hypertension with impaired glucose tolerance. That is ensured by integrated therapy including graduated physical exercises, and introduction of lisinopril in a dose 10 mg once a day in the morning and pioglitazone in a dose 30 mg once a day in the morning. Therapeutic course lasts for at least 6 weeks. The method enables complete normalisation of thrombocyte sensitivity to aggregation inducers owing to potentiation of therapeutic effect of certain components of integrated therapy.

EFFECT: that in turn allows reducing risk of thrombotic complications in given group of patients.

1 ex, 3 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely haematology, cardiology and endocrinology, and covers correction of thrombocyte intravascular activity in patients suffering from arterial hypertension with impaired glucose tolerance. It is ensured by integrated treatment including graduated static and dynamic loading, and introduction of pioglitazone in a dose 30 mg once a day in the morning and lisinopril in a dose 10 mg once a day in the morning.

EFFECT: such complex of specific medical agents and physical activity provides short-term - within 1,5 months - normalisation of thrombocyte intravascular activity that in turn reduces risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology and endocrinology, and concerns normalisation of lipid content in thrombocyte membranes in arterial hypertension and impaired glucose tolerance. That is ensured by integrated treatment including graduated physical exercise, and introduction of pioglitazone in a dose 30 mg once a day in the morning and lisinopril in a dose 10 mg once a day in the morning during 1.5 months.

EFFECT: such complex of specific medical agents and physical activity combined with empirically selected duration of treatment provides effective correction of lipid composition of thrombocyte membranes and thereby reduced risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology and endocrinology, and concerns normalisation of thrombocyte aggregation in patients suffering from arterial hypertension with impaired glucose tolerance. It is ensured by integrated treatment including graduated physical exercise, and introduction of pioglitazone in a dose 30 mg once a day in the morning and lisinopril in a dose 10 mg once a day in the morning during not less than 1.5 months.

EFFECT: such complex of specific medical products and physical exercise combined with empirically selected duration of treatment provides effective correction of thrombocyte aggregation and, thereby reduced risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely haematology, and covers thrombocyte normalisation of ADP and ATP secretion in patients with arterial hypertension and impaired glucose tolerance. It is ensured by integrated treatment including graduated physical exercise, introduction of pioglitazone in a dose 30 mg once a day in the morning and lisinopril in a dose 10 mg once a day in the morning.

EFFECT: such complex of specific pharmacological preparations and drug-free modalities provide complete thrombocyte normalisation of ADP and ATP secretion within 1,5 months that in turn allows normalising thrombocyte function in this group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology and endocrinology, and concerns normalisation of antiplasmin alpha-2 level in arterial hypertension (AH) with impaired glucose tolerance. That is ensured by complex treatment involving graduated physical activities, and introduction of pioglitazone in a dose 30 mg once a day in the morning and lisinopril in a dose 10 mg once a day in the morning within 1.5 months.

EFFECT: such complex of specific pharmacological preparations combined with drug-free modalities, as well as fitted duration of treatment provide reduced risk of thrombotic complications that is ensured by normalisation and correction of antiplasmin alpha-2 level, thereby fibrinolytic systems in the given group of patients.

3 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology and endocrinology, and concerns normalising endotheliocytemia in arterial hypertension with impaired glucose tolerance. It is ensured by complex therapy that involves graduated physical activities, as well as introduction of pioglitazone in a dose 30 mg once a day in the morning and lisinopril in a dose 10 mg once a day in the morning during 1.5 months.

EFFECT: invention provides effective correction of endotheliocytemia owing to potentiation of therapeutic effect of certain components of the complex therapy; than in turn allows reducing risk of thrombotic complications in the given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry and concerns pharmaceutical composition for prevention and treatment of diseases and disease states connected with metabolic pathways of cycloxygenase-2 (CG-2) and 5-lipooxygenase (5-LO), which contains mixture of extract obtained from Scutellariae and enriched with flavonoids with free B-ring, which include baicalein, and extract obtained from Acacia and enriched with flavans, which include catechine and epicatechine. Claimed invention also relates to method of body weight loss and control over glucose level in blood. Methods by claimed invention include introduction to person, who needs it, of efficient amount of composition by claimed invention together with pharmaceutically acceptable carrier. Claimed invention mainly relates to prevention and treatment of diseases and states connected with metabolic pathways of cycloxygenase-2 (CG-2) and 5-lipooxygenase (5-LO), including, but not confining to it, stopping discomfort and pain in joints, induced by such states as osteoarthritis, rheumatoid arthritis and other injuries caused by overload.

EFFECT: composition possesses high efficiency.

35 cl, 22 ex, 15 tbl

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