The use of alpha-ketoglutaric acid for the treatment of failure of nutrition or state with a high level of glucose plasma. Α-ketoglutar acid alpha ketoglutaric acid formula

Glutaric acid (pentantic acid) - two-axis limit carboxylic acid. It has a sufficiently high solubility in water, compared with adipic acid. Used in the production of polymers, such as polyester and polyamides. The keto-derivative of glutar acid is α-ketoglutaric acid, one of two ketone-producing hydrochloric acid. The name "Ketoglutaric acid" without additional designations usually means alpha form. β-ketoglutaric acid differs only by the position-beanoneal function, it is much less common.

Anion-ketoglutaric acid, α-ketoglutarat (also called oxoglutate) is an important biological connection. This is a ketokisloid that is formed by the administration of incorporate. Alfa-Ketoglutarat is one of the compounds formed by the Krebs VTsikle.

Biological significance

Crebs cycle

The α-ketoglutarat is a key product of Krebs, it is formed as a result of the decarboxylation of isocatrate, the alpha-ketoglutarate of the dehydrogenase complex is converted as a result of a dehydrogenase complex. Anarterotic reactions to replenish the cycle at this stage by the synthesis of α-ketoglutarata transmination of glutamate, or the agglutamatetdeehydrogenase glutamate.

Synthesis amino acids

Glutaminsitezed is ruling with the help of the enzyme of glutaminesyntetase, which at the first stage forms glutamyl phosphate, using the ATP phosphate as the phosphate donor; The glutamine is formed as a result of the nucleophilic replacement of phosphate cation of ammonium in glutamaly phosphate, the reaction products are glutamine and inorganic phosphate.

Transport Ammonia

Another function of alpha-ketoglutar acid is the transport of ammonia distinguished as a result of amino acid catabolism.

α-ketoglutarat is one of the most important ammonia carriers in metabolic paths. Amino-acid amino groups are attached to the α-ketoglutarata in the transministration reaction are transferred to the liver, falling urea.

§ 6. Amber Acid

succinic acid (Buttanic acid, ethane-1,2-dicarboxylic acid) is a two-axis limit carboxylic acid. Colorless crystals soluble in water and alcohol. Contained in small quantities in many plants, amber. Stimulates growth and increases the crop of plants, accelerates developmentacks. In industry, succinic acid is obtained mainly hydrogenation of maleyan anhydride. First received in the XVII century distillation of amber. Salts and amber acid esters are called succinates (lat.sucincinum - amber).

Properties

Melting point 183 degrees. Above 235-TI Celsius, H 2 O and is moving into amber anhydride. Amber Acid is easily removed at 130-140 ° C. The solubility in water is as follows (grams in 100 g. Water): 6.8 (at 20 ° C), 121 (at 100 ° C). Also dissolved in ethyl alcohol: 9.9 (5 ° C); in diethyl ether - 1.2 (at 15 ° C). Insoluble acid of binzole, gasoline, chloroform. The dissociation constants are as follows: to A1 \u003d 7.4 * 10 -5, to A2 \u003d 4.5 * 10 -6.

Chemical properties

Methylene succinic acid groups have a high reactivity, which is associated with the influence of carboxyl groups. When brominating, amber acid gives a dibromyantic acid Hooc- (CHBR) 2 -COOH. Amber Acid dieters are condensed with ketones (Condensation of Stobbe) and Saldehydes. Summacomyamineanic acid forming a suuccinimidi of its N-substituted analogs (R-H, alkylIliaryl group). Mono- and diaminidic acids obtained with aromatic iglorocyclicamines are used for the synthesis of some dyes, insecticidal medicinal substances.

Amber Acid and its anhydride easily react Friedel-Kraftsas as aromatic compounds (so-called succinocylation), forming derivatives of 4-aryl-4-ketomaslic acid.

Biochemical role

Amber Acid is involved in the process of cellular respirationShydrogen-breeding organisms.

Lethal doses (LD 50): orally - 2.26 g / kg (rats), intravenously - 1.4 g / kg (mice). PDKV water of water bodies 0.01 mg / l

Application

Amberic acid is used to obtain plastics, resins, drugs (in particular, quinolithin), for synthetic purposes, as well as vanalitical chemistry. The extensive industry is used in the wandering supplement E363. The medical acid is used, in particular, as one of the means to combat hanging syndrome. Amberic acid is also used as fertilizer. It accelerates the ripening of fruits, increases yield, increases the content of blood sugar in fruits. Increases cold resistance, droughness and resistance to diseases.

Alpha Ketoglutaric acidplays an important role in metabolism. It participates in the Krebs cycle, which is part of the energy generation mechanism in the cell.

Alpha Ketoglutaric acid from Kirkman does not cause increased acidity, since this is a buffered version (alpha-ketoglutaric acid is mixed with its salts of calcium and magnesium)

Exactly Crebs cycle It produces energy for us in sufficient quantity so that we can live and work. Thanks to the Krebs cycle, the cells provide energy to all the processes occurring in our organism. That is why it is vital that this metabolic mechanism functions without failures.

Here are some of the signs of the cycle of Krebs. If the failure occurs in the brain, then the person will experience such symptoms as a decrease in the concentration of attention, excessive emotional reactions; Mental diseases may occur. In the muscles, the closed Crex cycle is manifested as fibromyalgia; In the liver, the processes of cleansing the body from toxic products of its livelihoods can be disturbed; If this happens with lymphatic cloth, immunity decreases; If with skin - infections, eczema or psoriasis occur.

Through the formation of alpha ketoglutaric acid in the energy exchange, arginine, glutamine, glutamine k-ta, proline and histidine are included.

Another important function of alpha ketoglutaric acid is ammonia transport (Ammonia neutralization). In the human body, there is a decay of about 70 grams of amino acids per day: while released a large number of Ammonia, which is a highly toxic compound. Amino-acid amino acids are attached to alpha ketoglutar acid and transferred to the liver, falling into the removal cycle through urea.

Alpha Qetoglutaric acid:

1. Reduces the high level of glucose in blood plasma (oxidizing carbohydrates)

2. EliminateGipoxia ( hypoxia ― oxygen starvation)

3. Reduces the symptoms of chronic heart failure ( heart failure causes hypoxia organs and tissues that ketoglutaric acid can eliminate)

4. Accelerates metabolism

5. Improves work immune systemin the period of severe stress

6. Participates in the restoration of metabolism

7. Used to treat liver encephalopathy

8. Need to those who are on a protein diet (connects ammonia and forms non-toxic connections)

Alpha ketoglutaric acidyou can take with or without food. Hypoallergenic capsules can be swallowed or open, and mix powder with fruit juice or food. It has a pleasant taste resembling citrus.

Does not contain: sugar, starch, soy, wheat, casein, gluten, milk, preservatives, yeast, gelatin, flavors, dyes, fish, peanuts or nuts.

Composition 1 capsules:
Alpha-ketoglutaric acid - 300 mg

Α-ketoglutaric acid
General
Systematic name	2-oxopentic acid
Traditional names	α-ketoglutaric acid 2-oxoglutaric acid
Chem. formula	C 5 H 6 O 5
Physical properties
condition	solid
Molar mass	146,0981 ± 0,0059 g / mol
Thermal properties
T. Plave.	112-116 ° C.
T. Kip.	160 ° C.
Chemical properties
Solubility in water	10 g / 100 ml
Classification
Reg. Cas	328-50-7
Pubchem.	51
Reg. EinecS number	206-330-3
Smiles.
Chebi.	30915
Safety
Toxicity	the caustic substance is very annoying the skin, is an irritant.
Data is given for standard conditions (25 ° C, 100 kPa), unless otherwise indicated.

α-ketoglutarova (alpha-Ketoglutarova) acid - One of the two ketone derivatives of glutar acid. The name "Ketoglutaric acid" without additional designations usually means alpha form. β-ketoglutaric acid It differs only by the position of the ketone functional group and is much less common.

Biological significance

Crebs cycle

The α-ketoglutarat is a key product of Krebs, is formed as a result of decarboxylation of isocatrate and is converted to succinyl-COA in the alpha-ketoglutarat dehydrogenase complex. Anaplerotic reactions can replenish the cycle at this stage by the synthesis of the α-ketoglutaratus transmination of glutamate, or the action of glutamatedehydehydrogenase on glutamate.

Synthesis amino acids

Transport Ammonia

Another function of alpha-ketoglutar acid is the transport of ammonia distinguished as a result of amino acid catabolism.

α-ketoglutarat is one of the most important ammonia carriers in the metabolic paths. Amino acid amino groups are attached to the α-ketoglutarata in the transministration reaction and transferred to the liver, falling into the urea cycle.

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Notes

Excerpt characterizing α-ketoglutaric acid

"Ah, Chere, Je Ne Vous Reconnaissais Pas, [ah, honey, I didn't recognize you," Anna Mikhailovna said with a happily smile, easily by signing to the nephew of the graph. - Je viens d "Arriver et Je Suis a vous Pour Vous Aider a SOIGNER MON OnCLE. J`imagine, Combien Vous Avez Souffert, [I came to help you walk for the uncle. Imagine how you were crawling,] - she added, with participation Obtaining eyes.
Princess did not answer anything, did not even smiled and immediately came out. Anna Mikhailovna removed gloves and in the conquered position was located on the chair, inviting Prince Vasilla to sit beside himself.
- Boris! She said to her son and smiled, "I'll go to the count, to the uncle, and you look at Pierre, MON AMI, shake, do not forget to give him an invitation from Rostov. They call him lunch. I think he will not go? She turned to the prince.
"On the contrary," said the prince, apparently not in the spirit. - Je Serais Tres Content Si Vous Me Debarrassez De CE Jeune Homme ... [I would be very happy if you walked me from this young man ...] Sits here. The graph never asked about him.
He shrugged. The waiter led a young man down and up another staircase to Peter Kirillovich.

Pierre never managed to choose their careers in St. Petersburg and, indeed, was expelled to Moscow for a rue. The story that Graf Rostov was told was fair. Pierre participated in the binding of a quarter with a bear. He arrived a few days ago and stopped, as always, in his father's house. Although he assumed that his story is already known in Moscow, and that the ladies surrounding his father, always unfavorable to him, will take advantage of this case to irritate the graph, he all went on the day of arrival at half pasta. Entering the living room, the usual location was printed, he greeted the ladies who were sitting on the chains and for the book, which one of them read out loud. There were three of them. Senior, clean, with a long waist, a strict girl, the very one that went to Anna Mikhailovna, read; Younger, both rosy and pretty, distinguished from each other just that one had a mole above the lip, very beautiful her, sewed in the chambers. Pierre was encountered as a dead man or worried. The eldest princess interrupted reading and silently looked at him with frightened eyes; The youngest, without a mole, took exactly the same expression; The smaller, with a moles, a fun and ridiculous nature, bent to the backslands to hide a smile caused, probably the upcoming scene, the fun of which she foresaw. She pulled down the wool and bent, as if disassembling patterns and barely holding back from laughter.
"Bonjour, Ma Cousine," said Pierre. - Vous Ne Me Geesnnaissez Pas? [Hello, Kuzina. You will not recognize me?]
- I recognize you too well, too good.
- How is the health of the graph? Can I see him? - asked Pierre awkward, as always, but not embarrassed.
- The graph suffers and physically and morally, and it seems you made sure to cause him more moral suffering.

The invention relates to the field of pharmacology. The method of improving the absorption of amino acids in the spine, including a mammal and a bird, includes the introduction of AKG (alpha-ketoglutaric acid), mono- and dimetallic salts of AKG, chitosan-akg, or mixtures thereof in quantity and / or with a frequency sufficient to ensure the desired Effect. A method for reducing the absorption of plasma glucose in a spine, including a mammal and a bird, in which a spinal animal, including a mammal and a bird, is introduced AKG, mono- and dimetallic salts AKG, chitosan-akg or mixtures thereof in quantity and / or with a frequency sufficient for ensuring the desired effect on the absorption of glucose. Method of preventing, inhibition or facilitating a condition with a high level of glucose plasma in a spinal animal, including a mammal and a bird, in which a vertebral animal, including a mammal and a bird, is introduced AKG, mono- and dimetallic salts of AKG, chitosan-akg or mixtures thereof and / or with a frequency sufficient to ensure the desired effect on the specified state. The use of AKG, mono- and dimetallic AKG salts, chitosan-akg or mixtures thereof, in a therapeutically effective quantity for the manufacture of a composition for preventing, facilitating or treating a state with a high level of glucose plasma. The use of AKG, mono- and dimetallic salts of AKG, chitosan-akg or their mixtures for the manufacture of a composition for improving suction, altered suction, deteriorating suction and impaired absorption of amino acids and / or peptides. 5 n and 14 zp F-ls, 3 tab., 1 yl.

Pictures to Patent Patent 2360671

FIELD OF THE INVENTION

This invention relates to a method for improving the absorption of amino acids, as well as a method for reducing glucose absorption in a spinal animal, including a mammal and a bird. It is also considered to manufacture a composition for improving the absorption of amino acids in the specified vertebral.

Prior art

Sugar diabetes is a serious metabolic disease, which is characterized by the presence of constantly increased levels Plasma glucose. The classic symptoms of diabetes in adults are polyuria, polydipsia, acetionalura, fast mass loss in combination with elevated glucose levels in plasma.

Normal glucose concentrations in the plasma on an empty stomach are less than 115 milligrams for decylitr. In patients with diabetes, the glucose concentrations in an empty stomach plasma are above 140 milligrams for decylitr. As a rule, diabetes is developing in response to damage to the beta cells of the pancreas. This damage can be caused by primary diabetes mellitus, in which beta cells are destroyed by an autoimmune system, or a secondary diabetic response to other primary diseases, such as pancreatic disease, hormonal disorders, except for the absence of insulin, medicinal or chemical induction, insulin receptor anomalies , genetic syndromes or others.

Primary diabetes can be classified as type I diabetes (also called insulin-dependent diabetes mellitus or IDDM) or type II diabetes (also called insulin-dependent diabetes or NIDDM).

Type I diabetes, youthful or insulin-dependent diabetes, is a well-known hormone-deficient state, in which the beta cells of the pancreas are destroyed by means of their own mechanisms of immune protection of the body. In patients with type I diabetes, the ability to secure endogenous insulin is weak or absent. These patients develop strong hyperglycemia. Type I diabetes was deadly before introducing approximately 70 years ago with insulin replacement therapy - first using insulins from animal sources, and quite recently using human insulin obtained using recombinant DNA technology. Currently it is clear that the destruction of beta cells with type I diabetes leads to the combined failure of two hormones, insulin and amylin. When the pancreas cells are destroyed, the ability to secrete insulin and amine is lost.

The nature of damage to the beta cells of the pancreas in diabetes type II is unclear. In contrast to the beta cells of the pancreas of type I diabetics, type II diabetic beta cells retain the ability to synthesize and secrete insulin and amylin. Type II diabetes is characterized by insulin resistance, that is, the insufficiency of the normal metabolic response of peripheral tissues for insulin. In other words, insulin resistance is a state in which the circulating insulin generates an insufficient biological response. In clinical terms, insulin resistance is present when normal or elevated plasma glucose levels are preserved against the background of normal or elevated insulin levels. Hyperglycemia associated with type II diabetes can sometimes be reversed or weakened with a diet or a weight loss sufficient to restore the sensitivity of peripheral tissues to insulin. In reality, type II diabetes is often characterized by hyperglycemia in the presence of elevated, compared with normal, insulin levels in plasma. The progression of type II diabetes is associated with elevated plasma glucose concentrations and is associated with a relative decrease in glucose secretion speed induced. For example, insulin may present in the late stage of type II diabetes mellitus.

Famous treatment and prevention of diabetes

The priority target in the treatment of all forms of diabetes is the same, namely: a decrease in plasma glucose concentrations to values \u200b\u200bas far as possible close to normal, and due to this minimization of both short-term and long complications of this disease (Tchobroutsky, Diabetologia 15: 143-152 (1978)).

The relationship between the degree of hyperglycemia in diabetes and the resulting long complications was further confirmed in a newly completed clinical test for diabetes control and its complications (DCCT, Diabetes Control and Complications Trial), undertaken National institutions Healthcare (The Diabetes Control and Complications Trial Research Group, N. ENG. J. MED. 329: 977 (1993)). DCCT was performed during a 10-year period in 29 clinical centers throughout the United States and Canada and showed that the decrease in the average plasma glucose concentrations during type I diabetes reduced receptor complications. Retinopathy development decreased by 76%, the progression of retinopathy by 54%, also decreased signs of renal disease (proteinuria, albuminuria). Also reduced the development of significant neuropathic changes.

The treatment of type I diabetes is inevitably involved in the introduction of substitution doses of insulin administered by the parenteral route. In combination with proper diet and independent glucose monitoring in plasma, most type I diabetics can achieve a certain level of glucose control in plasma.

In contrast to type I diabetes, treatment of type II diabetes often does not require insulin. A system of therapeutic treatment with type II diabetes usually includes dietherapy and lifestyle change, first usually for 6-12 weeks.

Features of a diabetic diet include adequate, but not excessive total consumption of calories, regular meals, restriction of saturated fat content, concomitant increase in polyunsaturated content fatty acids and increased consumption of food fiber.

Changes in lifestyle include maintaining regular physical activity, which contributes both to the regulation of mass and to reduce the degree of resistance to insulin.

If, after an adequate diet and lifestyle changes, hyperglycemia on an empty stomach is preserved, then a diagnosis of "primary nutritional disorders" can be diagnosed, and then for the regulation of glucose in the plasma and through this minimization of the disease, either oral hypoglycemic therapy will be necessary, or the insulin-therapy system directly. Type II diabetes, which does not react to a diet and a decrease in mass, can react to therapy by oral hypoglycemic agents, such as sulfonylurea or biguenides. Insulin therapy, however, is used to treat other patients with type II diabetes, especially those who have failed during the primary diet and does not suffer from obesity, or those who have failed both in the primary diet and in secondary oral hypoglycemic therapy.

The use of amylin agonists in the treatment of diabetes mellitus is described in US patents No. 5124314 and 5175145. Excess of amiline action imitates the main signs of type II diabetes, and the amylin blockade is proposed as a new therapeutic strategy.

Famous therapeutic agents are, for example, diabetic pills, based, for example, on sulfonylurea, which help the pancreas produce more insulin and help the body better use insulin. Possible side effects: hypoglycemia, stomach disorder, skin rash or itching and weight gain.

Other pills are based on biguenides that limit the production of glucose liver, as well as reduce the amount of insulin in the body, improve the indicators of fat and cholesterol in the blood. Possible side effects are painful state in combination with alcohol, deterioration of existing kidney problems, weakness, dizziness, difficulty breathing, nausea and diarrhea.

Other pills are based on alpha-glucosidase inhibitors and block enzymes that split starch. Possible side effects are problems with the stomach.

Other pills are based on thiazolidinediones that help cells become more sensitive to insulin. Possible side effects are that they should not be used in the concomitant liver disease (regular checks), hypoglycemia and use only in combination with different therapy, as well as the less effective effect of contraceptive pill, adding mass, risk of anemia, swelling (edema).

Other pills are based on meglitinides that help the pancreas producing more insulin after eating. Possible side effects are hypoglycemia and weight gain.

In addition, there is a combination of oral drugs, based, for example, on gliburide (sulfonylurase) and metformines (Biguanide), called, for example, "Glucovance". Possible side effects are hypoglycemia, the impossibility of use in the disease of the kidneys and the undesirability of applications in combination with alcohol.

US Pat. No. 5,23,4906 discloses compositions containing glucagon and amylin agonist, and their use for regulation or treatment of hyperglycemic states.

In WO 93/10146, amylin agonists and their use for the treatment or prevention of hyperglycemic states, including insulin-dependent states, such as diabetes mellitus are disclosed.

Renal failure and failure

Renal failure or kidney dysfunction is a state in which the kidneys are not able to purify blood from waste. Renal failure causes the accumulation of toxic waste in the blood. The kidneys normally have an excessive cleansing ability, and the kidney function can be 50% of the normal, before symptoms appear. Symptoms are itching, fatigue, nausea, vomiting, loss of appetite, leading to malnutrition. Renal failure is often associated with diabetes and high blood pressure. The symptoms mentioned above, that is, vomiting and loss of appetite, lead to failure of nutrition in a subject suffering from renal failure.

The dialysis procedure reduces the impact of the waste on the kidneys. However, this procedure takes a lot of time, and the patient may need her holding several times a week. The patient passing a dialysis procedure needs medical supervision, and this procedure is both expensive and time and time.

Oxidation of glutamata

Thanks to research in situ on the rats Windmueller and Spaethh (1), it is known that glutamate and glutamine are an important metabolic fuel for the small intestine. Windmueller and Spaethh were the first to inform the significant partial metabolism of glutamate (95%) and glutamine (70%) by the gastrointestinal tract in the suction process. These results have since been confirmed in vivo both on piglets (2) and in humans (3).

In the process of the oxidation of glutamate of the first stage, transamination is any number of enzymes, deamination of glutamatedehydrogenases (GDH), many of which are expressed in the gastrointestinal tract (4, 5). Disamination by GDH leads to the formation of AKG (alpha-ketoglutaric acid) and free ammonia. In the process of transministration of aminotransferase branched chains (VSM), glutamate transmits an amino group to branched-containers, forming AKG and the corresponding branched amino acid.

Alpha ketoglutaric acid

Glutamine and its derivatives, such as alpha-ketoglutaric acid (AKG), are molecules that play a central role in systemic and intestinal metabolism by the Krebs cycle. However, the mechanisms are still not fully understood (Pierzynowski, SG and SJÖDIN, A. (1998) J. Anim. A. Feed Sci. 7: 79-91; and Pierzynowski, SG et al. EDS: KBK Knutsen and Je Lindberg, Uppsala 19-21 June, 2001).

AKG (2-oxo-pentandionic acid, 2-oxoglutaric acid, alpha-oxoglutaric acid, alpha-oxopentandionic acid, 2-ketoglutaric acid, 2-oxo-1,5-pentandionic acid, 2-oxopentandionic acid, 2-oxoglutane acid) Theoretically, it can be a product of glutamine decay, glutamate, glutamic acid in the process of metabolism in the body. It can also serve as a predecessor not only for glutamine and arginine, but also for some other amino acids, and therefore it is considered as a catabolic protein protector. Olin et al., 1992, showed that when AKG was added to fish food, urine release was decreased. Similarly, people when AKG is added to solutions for general parenteral nutrition (TPN) in a mixture with other amino acids, there is a good protection against loss of nitrogen after surgery (Pierzynowski, SG and SJÖDIN, A. (1998) J. Anim. A. Feed SCI . 7: 79-91). In the case of people, AKG is likely to combine with the collapse of muscle proteins to serve as an intestinal tract during the so-called postoperative stress, such as catabolism, starvation, etc.

In Riedel E. et al., NEPHRON 1996, 74: 261-265, which is the closest analogue of the present invention, it is shown that the introduction of the Calcium carbonate-carbonate effectively improves the metabolism of amino acids in hemodialysis patients.

The needs for metabolites belonging to the glutamine family for the intestinal function, reeds et al. (1996, AM. J. Of Physiol. - Endocrinology and Metabolism 270: 413-418), which reported almost 100% utilization of glutamate / glutamine at the first pass through the small intestine piglets.

AKG can be an important energy donor by several paths of conversion, for example, through ornithine and Pretrad to GABA (gamma-aminox kilot) or succinate. Theoretically, AKG can also act as an ammonium ion acceptor, it is possible through the transformation into glutamate / glutamine.

Therefore, in the light of the aforementioned problems in high degree It is desirable to develop means and methods for treating and preventing hyperglycemic conditions, such as diabetes mellitus, as well as malnutrition, often associated with diabetes and, for example, renal failure, in mammals, such as cats, dogs or people in which problems could be avoided or side effects associated with means and methods from the prior art. There is also a need for improving well-being in addition to the state of food in both renal and diabetic patients. In this regard, the present invention is directed to these needs and interests.

Summary of the essence of the invention

From the point of view of the above deficiencies, known in the field of prevention, treatment and / or facilitating diabetes, as well as other related hyperglycemic diseases, and the high cost of medical care, as well as for correction of power failure associated, for example, with diabetes and renal failure, The present invention provides new and improved methods and compositions for preventing, treating and / or facilitating diabetes and power failure.

The object of the present invention is the proposal of the method of improving the absorption of amino acids in the spine, including a mammal and a bird. This method includes the introduction of a vertebral animal, including a mammal and bird, AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof in an amount and / or frequency sufficient to ensure the desired effect on the absorption of amino acids.

In one embodiment of this method AKG, derivatives or metabolites AKG, analogs of AKG or mixtures thereof are selected from the group consisting of alpha-ketoglutaric acid (AKG), Ornithine-AKG, Arginine-AKG, glutamine-akg, glutamate-akg, leucine-AKG , chitosan-akg and other AKG salts with amino acids and amino acid derivatives; Mono- and dimetallic salts of AKG, such as CAAKG, CA (AKG) 2 and Naakg.

In yet another embodiment, the vertebrate animal is a rodent, such as a mouse, rat, guinea pig or rabbit; bird, such as turkey, chicken, chicken or other broilers; farm animals such as a cow, horse, pig, piglery or other freely moving agricultural animals; Or a pet, such as a dog or a cat.

In yet another embodiment, the vertebrate animal is a person.

In another embodiment, the amino acid is any essential amino acid.

In the following embodiment, the essential amino acid is isoleucine, leucine, lysine and proline.

In addition, the invention includes a method for reducing the absorption of glucose in a spinal animal, including a mammal and a bird. This method includes introducing a vertebrate, including mammal and bird, AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof in an amount and / or with a frequency sufficient to ensure the desired effect on glucose suction.

In addition, the invention includes a method of preventing, inhibiting or facilitating a condition with a high level of glucose in a spinal animal, including a mammal and a bird. This method includes the introduction of a vertebral animal, including a mammal and bird, AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof in an amount and / or frequency sufficient to ensure the desired effect on the specified state.

In one embodiment, a high level of glucose is diabetes mellitus of type I or type II.

In addition, the invention includes the use of AKG, derivatives or AKG metabolites, analogs of AKG or their mixtures for the manufacture of a composition for preventing, facilitating or treating a state with a high level of glucose.

In one embodiment, a high level of glucose in plasma is diabetes mellitus I or type II.

The invention also relates to the use of AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof for the manufacture of a composition for preventing, facilitating or treating malnutrition.

In one embodiment, the composition is a pharmaceutical composition, possibly with a pharmaceutically acceptable carrier and / or additives.

In another embodiment, the composition is a food or food additive.

In yet another embodiment of food or dietary supplement is a dietary additive and / or component in the form of solid food and / or beverage.

In yet another embodiment of AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof in the manufactured composition are in a therapeutically effective quantity.

In yet another embodiment, the therapeutically effective amount is 0.01-0.2 g / kg body weight per daily dose.

Brief description of graphic materials

The drawing shows the kinetics of leucine as a whole in the body at control and infusted AKG pigs. Values \u200b\u200bare mean ± SEM (RMS error); n \u003d 9, each pig has received both control and AKG. The values \u200b\u200bfor AKG did not differ from control when using dispersion analysis (ANOVA). AKG - - -Choglutarat; NOLD - non-oxidative removal of leucine; Ra is the rate of appearance of leucine; Balance - Ra, deducted from NOLD, is a protein residue in the organism of leucine.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

In the context of this application and the invention, the following definitions are used.

The term "pharmaceutical composition", when used here, refers to the therapeutically effective composition according to the invention.

The term "therapeutically effective quantity", or "effective amount" or "therapeutically efficient", when used herein, refers to such a quantity that provides the therapeutic effect for this state and administration mode. This is a predetermined number. active substancecalculated so as to produce the desired therapeutic effect in combination with the necessary additive and diluent, that is, a carrier or solvent for administration. In addition, this term is designed to designate a quantity sufficient to reduce, and most preferably warnings, a clinically significant deficit of activity, function and owner response. Alternatively, the therapeutically effective amount is sufficient to cause an improvement in the clinically significant state of the owner. It is obvious to those skilled in the art that the amount of compound may vary depending on its specific activity. Suitable dosages may contain a predetermined amount of the active composition calculated in such a way as to produce the desired therapeutic effect in combination with the necessary diluent, that is, the carrier or additive. In methods and use for the manufacture of compositions according to the invention, a therapeutically effective amount of the active component is provided. The therapeutically effective amount can be determined by a medical or veterinary employee of secondary qualifications on the basis of patient features such as age, mass, floor, condition, complications, other diseases, etc., as well known in the art.

The term "derivative" in this specification is intended for designation chemical substanceobtained from the starting material either directly or by modifying or partial substitution.

The term "analog" in this specification is intended to designate compounds that are structurally similar to others, but are not necessarily isomers. Analogues have similar function (s), but differ in structure or evolutionary origin.

When used in this specification, the term "treatment" refers to treatment for the purpose of curable, which can be a complete / final or partial curing of state or states.

The term "facilitate" in this specification is intended to designate not only a decrease in the intensity of the state or symptom, but also a delayed start of a state or symptom.

The term "warn" This specification is designed to refer to the guarantee that any event does not happen, for example, a condition or symptom relating to the underdeveloped Git (gastrointestinal tract) will not arise. As a result of the warning of a certain state or symptom, the beginning of such a state or symptom is delayed.

The term "increased absorption of amino acids" in this specification is intended to indicate the change in the overall absorption of amino acids in the spinal animal compared with the vertebral animals that do not receive treatment or administration of the invention. Changes are considered as an increase, if the general absorption is quantitatively higher in the specified vertebral animal compared to the spinal the same species that does not receive the specified treatment.

The term "kinetics" in this specification is designed to designate a permanent or frequent monitoring or measurement of the absorption of amino acids, as well as glucose in the spinal animal to determine the speed of their suction.

The term "sodium-AKG", when used here, use interchangeably with the terms "AKG-NA", "Na-Akg", "Na-salt AKG", "AKG (Na-salt)".

The term "chitosan-akg", when used here, use interchangeably with the terms "AKG-Chitosan", "AKG (Sol Chitosan)".

Diagnostics of type I and type II diabetes

The diagnosis of patients affected by diabetes type I and type II is within the framework of the qualifications of those skilled in the art. For example, individuals over the age of 35 years old with symptoms of polydipsy, polyuria, polyphagia (with weight loss or without loss of mass) in combination with increased concentrations of glucose in plasma and without ketoacidosis in history are usually considered within the diagnosis of type II diabetes mellitus. The presence of obesity, positive family history in relation to type II diabetes and normal or elevated concentrations of insulin and C-peptide in an empty stomach plasma is the additional characteristics of most patients with type II diabetes. Under the "Therapeutically effective quantity" means the amount that either in one-time or in multiple doses favorably reduces the plasma glucose concentration in a subject affected by type II diabetes mellitus.

Now the inventors have unexpectedly found that the infusion site has an impact on the absorption of AKG. After a duodenal infusion AKG, an increased absorption of amino acids and reduced absorption of glucose was unexpectedly observed.

Consequently, the present invention can be used to reduce glucose in plasma in a subject with insulin-dependent type II diabetes.

Diagnostics of power failure

Diagnosis of patients with malnutrition, that is, with poor or insufficient nutrition or hypotrophy, is within the framework of the skills of a person skilled in the art. Usually, evaluation is evaluated to assess general status Health individual.

Diagnosis of renal failure

Diagnosis of patients affected by renal failure is within the framework of the skills of a person skilled in the art.

There are two forms of renal failure, acute and chronic renal failure (ACF and CRF). Ostly renal failure can usually be reversed, while chronic renal failure usually progresses. CRF treatment is divided into predialism and active uremium treatment using, for example, dialysis or transplantation. There is no accurate definition of predialism as an initial point, but usually predialism is determined as a period of time between the diagnosis of renal failure and the beginning of active treatment. Dialysis and transplantation are treated as active treatment.

The method of improving the absorption of amino acids

According to the invention, a method for improving the absorption of amino acids in a spine, including a mammal and a bird, is disclosed. This method includes the introduction of a vertebral animal, including a mammal and bird, AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof in an amount and / or frequency sufficient to ensure the desired effect on the absorption of amino acids.

The absorption of amino acids is considered to be improved when compared with the absorption of amino acids in the spine, including a mammal and a bird that does not receive these AKG, derivatives or Metabolites AKG, analogs of AKG or mixtures thereof.

In the following embodiments of this method AKG, derivatives or Metabolites AKG, analogs of AKG or mixtures thereof are selected from the group consisting of alpha ketoglutaric acid (AKG), Ornithine-AKG, Arginine-AKG, glutamine-akg, glutamate-akg, leucine-akg , chitosan-akg and other AKG salts with amino acids and amino acid derivatives; Mono- and dimetallic salts of AKG, such as CAAKG, CA (AKG) 2 and Naakg.

In the following embodiments, the vertebrate animal is a rodent, such as a mouse, rat, guinea pig or rabbit; bird, such as turkey, chicken, chicken or other broilers; farm animals such as a cow, horse, pig, piglery or other freely moving agricultural animals; Or a pet, such as a dog or a cat.

In the following embodiment, the vertebrate animal is a person. A person can be a patient in need of treatment of malfunction due to, for example, renal failure, diabetes, sports, age (children and elderly people), pregnancy, nervous anorexia, nervous bulimia, bing nutrition, compulsive overeating or other non-specific nutritional disorders ( EDNOS).

The vertebral animal, such as a specified person, in the following embodiments may be any vertebrate, in need of increasing the availability and disposal of amino acids, such as essential amino acids or conditionally essential amino acids, in particular isoleucine, leucine, lysine and proline.

Examples of essential amino acids are alpha-amino acids, such as isoleucine (IIE), leucine (LEU), lysine (LYS), methionine (MET), phenylalanine (PHE), threonine (THR), tryptophan (Try) and Valin (VAL) of people. Essential amino acids differ between the species. Two other amino acids are needed rats, namely Arginine (ARG) and GISTIDIN (HIS).

The following embodiments are those where the amino acid is any amino acid, such as alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, threonine, cysteine, tyrosine, glutamine, histidine, lysine, arginine, aspartate, asparagin, glutamate, Glutamine, glycine and serine.

The following embodiments are those where the amino acid is any essential or conditionally essential amino acid. Examples of essential or conditionally essential amino acids are shown in Table 2.

In the following embodiment, essential or conditionally essential amino acids are chosen from the group consisting of isoleucine, leucine, lysine and proline.

The method of reduced glucose suction and method of preventing, inhibition or facilitating glucose in plasma

Plasma glucose level is the amount of glucose (sugar) in the blood. It is also known as level of glucose in blood serum. The amount of glucose in the blood is expressed in milly salm per liter (mmol / l) or mg / for.

Normally, glucose levels in a plasma in humans remain within a narrow limits, from about 4 to 8 mmol / l. Plasma glucose levels are higher after meals and usually the lowest in the morning. The levels of glucose on an empty stomach are approximately 70-110 mg / dL (3.9-6.1 mmol / l), and 2 hours after eating, the levels normally are about 80-140 mg / dL (4.4-7, 8 mmol / l). Plasma glucose level\u003e 180 mg / dl (\u003e 10.0 mmol / l) 2 hours after meals usually consider high meaning Plasma glucose. It is also true in the case of a glucose value in plasma\u003e 140 mg / for an empty stomach.

If a person has, for example, diabetes, its plasma glucose level is sometimes shifted beyond these limits. The main disadvantage of all patients with diabetes is the reduced insulin ability to induce the removal of glucose molecules (sugar) by the cells of the body from the blood. Regardless of whether this reduced insulin activity is a consequence of a reduced amount of insulin produced (for example, type i diabetes) or the insensitivity of cells to a normal amount of insulin, the result is the same, that is, too high levels of glucose plasma. This is called "hyperglycemia", which means "High blood glucose concentration". Typically, hyperglycemia is diagnosed when glucose plasma is more than 240 mg / dl (\u003e 13.4 mmol / l).

According to the invention, a method for reducing the absorption of glucose in a plasma of a spine, including a mammal and a bird. This method includes introducing a vertebrate, including mammals and bird, AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof in an amount and / or with a frequency sufficient to ensure the desired effect on glucose suction.

Reducing the absorption of glucose after the introduction of AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof may be 5-50%, for example 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50% of the initial value of glucose in plasma.

In the following embodiment, the reduction in suction is 20-40% of the initial value of glucose in the plasma.

In the following embodiment, the decrease is 30% of the initial glucose value in the plasma.

In addition, the method of preventing, inhibition or facilitating the state with a high concentration of glucose in plasma has a spinal animal, including a mammal and a bird. This method includes the introduction of a vertebrate, including a mammal and bird, AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof in an amount and / or with a frequency sufficient to ensure the desired effect on the specified state with a high glucose concentration in plasma.

In the following embodiment, the condition with a high concentration of glucose in the plasma is a hyperglycemic state.

These methods relating to states with a high plasma glucose concentration or hyperglycemic states include the following embodiments, where AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof are selected from the group consisting of alpha-ketoglutaric acid (AKG), ornithine AKG, arginine-AKG, glutamine-akg, glutamate-akg, leucine-akg, chitosan-akg and other AKG salts with amino acids and amino acid derivatives; Mono- and dimetallic salts of AKG, such as CAAKG, CA (AKG) 2 and Naakg.

In addition, the following embodiments are those where the vertebral animal is a rodent, such as a mouse, rat, guinea pig or rabbit; bird, such as turkey, chicken, chicken or other broilers; farm animals such as a cow, horse, pig, piglery or other freely moving agricultural animals; Or a pet, such as a dog or a cat.

In addition, the following embodiments are those where the vertebral animal is a person.

In addition, in the following embodiments, these conditions with a high concentration of glucose plasma are a consequence, for example, acromegali, Cushing syndrome, hyperthyroidism, pancreatic cancer, pancreatitis, peochromocytomes, insufficient insulin or excessive meal.

In addition, in the following embodiments, these states with a high concentration of glucose plasma are a consequence of type I or type II diabetes.

AKG application for diabetes and to treat malnutrition

According to the invention, the use of AKG, derivatives or AKG metabolites, analogs of AKG or their mixtures for the manufacture of a composition for preventing, relieving or treating a state with a high glucose concentration in plasma are discovered.

Examples of states with a high concentration of glucose in plasma and hyperglycemic states are shown in the previous paragraph.

The following embodiments include those in which a hyperglycemic state is a diabetes mellitus of type I or II.

According to the invention, the use of AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof for the manufacture of a composition for preventing, facilitating or treating power failure are discovered.

In the following embodiments of the specified applications, said composition is a pharmaceutical composition with a pharmaceutically acceptable carrier and / or additives.

In the following embodiments, the composition is a food or food additive.

In the following embodiments, food or dietary supplement is a dietary additive and / or component in the form of solid food and / or beverage.

In the following embodiments of AKG, derivatives or Metabolites AKG, analogues of AKG or mixtures thereof in the manufactured composition are in therapeutically effective quantity.

In the following embodiments, the therapeutically effective amount is 0.01-0.2 g / kg body weight per daily dose.

Introduction AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof

According to methods disclosed above, AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof are injected with a vertebral animal, including a mammal and a bird; rodent, such as a mouse, rat, guinea pig or rabbit; Bird, such as turkey, chicken, chicken or other broilers; agricultural animals, such as a cow, horse, pig, piglery or other freely moving agricultural animals; or a pet, such as a dog or a cat.

Introduction can be carried out by different paths depending on which type of vertebral is subject to treatment, on the state of the vertebral animal in need of such methods, and on a specific testimony for treatment.

In one embodiment, the introduction is carried out in the form of food or dietary supplement, such as a dietary additive and / or component in the form of solid food and / or beverage. The following embodiments may be in the form of suspensions or solutions, such as a drink described below.

Also, dosage forms may include capsules or tablets, such as chewing or soluble, such as hiding tablets, as well as powder and other dry forms, known to a person skilled in the art, such as pills, such as micropyluli, granules and grains.

Introduction can occur in the form of parenteral, rectal or oral power or food additive, as shown above.

Parenteral carriers include sodium chloride solution, ringer dextrose, dextrose and sodium chloride, ringer solution with lactate or fatty oils.

Food and dietary supplement can also be emulsified. The active therapeutic ingredient can then be mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerin, ethanol or the like and combinations thereof. In addition, if desired, the composition may contain small amounts of auxiliary substances, such as moisturizers or emulsifying agents, PH-, buffer agents that enhance the effectiveness of the active ingredient.

You can offer various forms of parenteral food or food additives, such as solid food, liquid or lyophilic or dried by other drugs. They may include diluents from various buffers (for example, Tris-HCl, acetate, phosphate), for pH and ion power, additives, such as albumin or gelatin, to prevent absorption on surfaces, detergents (for example, Twin 20, Twin 80, Pluronic F68, bile acid salts), solubilizing agents (for example, glycerin, polyethylene glycerol), antioxidants (for example, ascorbic acid, sodium metabisulphite), preservatives (for example, thimerosal, benzyl alcohol, parabens), volumetric substances or tonicity modifies (for example, lactose, Mannitol), covalent addition of polymers, such as polyethylene glycol, to composition, complexation with metal ions or inclusion of a substance inside or to the surface of granulated polymer compound preparations, such as polyacrylic acid, polyglycolic acid, hydrogels, etc. Or on liposomes, microemulsions, micelles, single-layer or multi-layer vesicles, erythrocyte shadows or spheroplasts.

In one embodiment, food or food additive is introduced in the form of a beverage or its dry composition by any of the methods of the invention.

The drink contains an effective amount of AKG, derivatives or AKG metabolites, analogs of AKG or mixtures thereof, together with a water-soluble carrier suitable for nutrition, such as minerals, vitamins, carbohydrates, fat and proteins. Examples of AKG, derivatives or AKG metabolites, analogs of AKG or mixtures there are alpha ketogluaric acid (AKG), Ornithine-AKG, Arginine-AKG, glutamine-akg, glutamate-akg, leucine-akg, chitosan-akg and other AKG salts with amino acids and derivatives of amino acids; Mono- and dimetallic salts of AKG, such as CAAKG, CA (AKG) 2 and Naakg.

All these components are supplied in a dry form if the drink is supplied in a dry form. The drink supplied in the ready-to-use form further comprises water. The finished beverage solution may also have adjustable tonicity and acidity, for example, as a buffer solution according to the general proposals in the above paragraph.

the pH is preferably in the range of approximately 2-5 and, in particular, about 2-4, to prevent the growth of bacteria and mushrooms. You can also use a sterilized drink with a pH of about 6-8.

Drink can be supplied separately or in combination with one or more therapeutically effective compositions.

Application of AKG, derivatives or Metabolites AKG, analogs of AKG or mixtures thereof

According to the invention, AKG, derivatives or AKG metabolites, analogs of AKG or their mixtures for the manufacture of a composition for preventing, facilitating or treating hyperglycemic conditions, such as type I type I and type II diabetes, as well as for the treatment of malnutrition of nutrition, are disclosed.

The following embodiments of the invention include the application where the composition is a pharmaceutical composition. This pharmaceutical composition can be together with a pharmaceutically acceptable carrier and / or additives, such as diluents, preservatives, solubilizing agents, emulsifying agents, adjuvants and / or carriers useful in methods and in the application disclosed in the present invention.

In addition, when used here, "pharmaceutically acceptable carriers" are well known to those skilled in the art and may include 0.01-0.05 m phosphate buffer or 0.8% saline solution, but are not limited to them. In addition, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic ethers, such as ethyloleate. Aqueous carriers include water, alcohol / aqueous solutions, emulsion or suspension, including salt and buffer medium. Parenteral carriers include sodium chloride solution, ringer dextrose, dextrose and sodium chloride, ringer solution with lactate or fatty oils. Preservatives and other additives may also be present, such as, for example, antimicrobial agents, antioxidants, chelating agents, inert gases, and the like.

The following embodiments of the invention include the use where the composition is a dietary additive and / or component in the form of solid food and / or beverage.

Such a manufactured composition, such as a pharmaceutical composition, or food, or a dietary supplement, contains a composition according to the invention and may additionally contain a carrier and / or a number of second or additional active ingredient affecting any hyperglycemic state, such as diabetes type I and II, as well as power failure.

Dose of the introduced pharmaceutical composition

According to the invention, the use of AKG, derivatives or AKG metabolites, analogues of AKG or their mixtures for the manufacture of the composition according to the invention involves the introduction of a therapeutically effective amount of a spinal animal, such as a bird or a mammal in need of this. Such a therapeutically effective amount is approximately 0.01-0.2 g / kg body weight per daily dose.

AKG, derivatives or Metabolites AKG, analogs of AKG or mixtures thereof

According to the invention, AKG are included, derivatives or AKG metabolites, analogs of AKG or mixtures thereof. Examples of AKG, derivatives or Metabolites AKG, analogs of AKG or mixtures there are alpha ketoglutaric acid (AKG), Ornithine-AKG, Arginine-AKG, glutamine-akg, glutamate-akg, leucine-akg, chitosan-akg and other AKG salts with amino acids and derivatives of amino acids; Mono- and dimetallic salts of AKG, such as CAAKG, CA (AKG) 2 and Naakg.

Targets for administration

How can a specialist in the art, methods and pharmaceutical compositions of the present invention can be easily understood for introducing any vertebral animal in need, such as a bird, including turkey, chicken or chicken and other broilers, but not limited to, and freely Movement animals, or mammals, including pets, such as feline or pince representatives, but not limited to, farm animals, such as representatives of cows, horses, goats, sheep and pigs, but not limited to, wild animals, or in nature, either in the zoological garden, experimental animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., that is, for veterinary applications.

People are also included as a target for introducing in the treatment of any high levels Plasma glucose or hyperglycemic state, such as type I and type II diabetes, as well as any state associated with malnutrition, after, for example, renal failure, type I and type II diabetes.

In addition, any vertebrate animals, such as those mentioned above, need to increase the availability and disposal of amino acids, such as essential amino acids or conditionally essential amino acids, in particular isoleucine, leucine, lysine and proline, may also be targeted. A person may also be a patient in need of treatment of nutritional failure or in increasing the availability and disposal of amino acids due to, for example, renal failure, surgical interventions, such as pancreaectomy or transplantation, geriatric conditions, diabetes, sports, sports, age (children and elderly people), pregnancy, nervous anorexia, nervous bulimia, bing nutrition disorders, compulsive overeating, nutrition disorders, metabolic disorders, or other non-specific nutritional disorders (EDNOS), breakingles, lack of an appetite for an appetite or due to exhausting disease.

1. Windmueller, H. G., & Spaeth, A. E. (1975) Intestinal Metabolism of Glutamine and Glutamate from the Lumen As Compared to Glutamine from Blood, Arch. Biochem. Biophys. 171: 662-672.

2. STOLL V., BUN-IN, D. G., HENRY, J, HUNG, Y, JAHOOR, F, & REEDS, P. J. (1999) Substrate Oxidation by The Portal Drained Viscera of Fed Piglets. Am. J. Physiol. 277: E168-E175.

3. Matthews, D. E., Marano, M. A., & Campbell, R. G. (1993) Splanchnic Bed Utilization of Glutamine and Glutamic Acid in Humans. Am. J. Physiol. 264: E848-E854.

4. Madej, M., Lundh, T., & Lindberg J. E. (1999) Activities of Enzymes Involved In Glutamine Metabolism In Connection with Energy Production In The Gastrointestinal Tract Epithelium of Newborn, Suckling and Weaned Piglets. Biol. NEONATE 75: 250-258.

5. SURYAWAN, A., HAWES, J. W., HARDS, R.A., SHIMOMURA, Y., JENKINS, A. E., & HUTSUN, S. M. (1998) A Molecular Model of Human Branched-Chain Amino Acid Metabolism. Am. J. Clin. NUTR. 68: 72-81.

6. Lambert, V. D., Stoll, V., Niinikoski, H., Pierzynowski, S., & Bun-in, D.g. (2002) Net Portal Absorption of Enterally Fed Alpha-Ketoglutarate Is Limited in Young Pigs. J. Nutr. 132: 3383-3386.

7. Kristensen, N. V., Jungvid, H., Femandez, J. A., & Pierzynowski, S. G. (2002) ABSORPTION AND METABOLISM OF A-KETOGLUTAATE IN GROWING PIGS. J. Anim. Physiol. Anim. NUTR. 86: 239-245.

8. Bergmeyer, H. U., & BEMT, E. (1974) 2-oxoglutarate. UV Spectrophotometric Determination. In: Methods of Enzymatic Analysis, 2nd ED. (Bergmeyer, H. U., ED.). Academic Press, New York, NY.

9. Pajor, A. M. (1999) Sodium-Coupled Transporters for Krebs Cycle Intermediates. Annu. Rev. Physiol. 61: 663-682.

10. Murphy, J. M., Murch, J. M., And Ball, R. O. (1996) Proline Is Synthesized from Glutamate During Intragastric Infusion But Not During Intravenous Infusion In Neonatal Piglets. J. Nutr. 126: 878-886.

Below the invention is illustrated by a number of non-limiting examples.

Although the invention is described in respect of specific disclosed embodiments, the person skilled in the art may foresee other embodiments, options or combinations that are specifically mentioned, but, nevertheless, are included in the scope of the appended claims.

Section materials and methods for examples 1-2

Design research

The piglets of females (n \u003d 9) were purchased in Texas Department of Criminal Justice, Huntsville, TX.

The piglets (age 14) were brought to the Children "S Nutrition Research Center and during the 7-day adaptation period contained on a dieting from a liquid milk substitute (Life Life, Merrick, Middleton, Wi) with a norm of 50 g / (kg · day).

The composition of the milk substitute (per kg of dry matter) was 500 g lactose, 100 g of fat and 250 g of protein.

After 7 days during the night, the piglets were left without food and prepared them to operation, as described earlier (2).

Describing briefly, under the isofluran anesthesia under aseptic conditions, the pins were implanted with a polyethylene catheter (outer diameter of 1.27 mm, BECTON DICKINSON, SPARKS, MD) into the general portal vein and silaty catheters (outer diameter of 1.78 mm) into the jugular outer vein and carotid artery .

Ultrasonic flow sensor (inner diameter from 8 to 10 mm, Transonic, IFhaca, NY) placed around a portal vein.

Silicone catheter (outer diameter 2.17 mm, Baxter Healthcare, McGaw Park, IL) implanted into the lumen of the duodenum. Catheters were filled with a sterile physiological solution containing heparin (2.5 × 10 4 Ер / l), and turned out to be out either on the left side (vessels of the duct and duodenal catheter, the flow sensor), or between the blades (the jugular catheter and the carotid artery catheter).

Immediately before the operation, animals were obtained intramuscular injection of an antibiotic (20 mg / kg Enrofloxacin, Bayer, Shawnee Mission, KS) and intramuscular analgesic injection (0.1 mg / mg of beotorofenol Tartrate. Fort Dodge Labs, Fort Dodge, IA).

Before the renewal of enteric food after operation, piglets were kept on a fully parenteral diet for 24 hours at a rate of 5 ml · kg -1 · h -1. The piglets were given 7 days per recovery after the operation. In all piglets, the absorption of food and the rate of adding mass returned to the preoperative levels.

Preparation of samples

Blood samples immediately placed on ice and centrifuged.

The plasma was collected, immediately frozen in liquid N 2 and stored at -80 ° C before analysis.

Amino acid analysis

For amino acid analysis of plasma 0.2 ml, plasma aliquots were mixed with an equal volume aquatic solution Metionin sulfone (4 mmol / l) and centrifuged at 10000 × g for 120 minutes after 10 kDa cutting filter.

The aliquot of the filtrate of 50 μl of dried and amino acids was analyzed by HPLC on the reversed phase of their pico tag, Waters, Wobum, MA).

The plasma AKG was determined by the Bergmeyer and BemT (8) method with minor modifications.

Describing briefly, the analysis was carried out in 0.5 ml of the working solution consisting of 100 mmol / l of phosphate buffer (pH 7.6), 4 mmol / l ammonium chloride and 50 μmol / l Nadh.

An appropriate plasma amount containing 1-10 AKG nmol was added to the working solution.

The indication of the initial absorption was obtained at 340 nm.

After recording the initial absorption in each tube, ~ 6 units (in the amount of 10 μl) of bovine GDH (G2501; Sigma-Aldrich, St. Louis, MO) was added.

After a 10-minute incubation, the second absorption testimony was removed at 340 nm.

The amount of AKG in the sample is directly proportional to the absorption reduction between the first and second indication.

The concentration of AKG was calculated by using a standard curve.

Definition of ammonia plasma

Ammonia in plasma was determined using a set for spectrophotometric analysis (171-C, Sigma-Aldrich, St. Louis, MO).

Definition of glucose plasma

Plasma glucose was determined using a set for spectrophotometric analysis (315-100; Sigma-Aldrich, St. Louis, MO).

Blood Bicarbonate Determination

To estimate the blood enrichment by bicarbonate aliquot of whole blood (1.0 ml) was placed in 10 ml Vacutainer (Becton Dickinson, Franklin Lakes, NJ) and 0.5 ml of perchloric acid was added (10% w / w.).

Room air (10 ml), profiled through a sodasorb; Grace Container Products, Lexington, MA), was injected into Vacutainer, chose to a gas-tight syringe and transferred to the second Vacutainer.

The isotopic enrichment of carbon dioxide in the gas sample was measured on a continuous flow mass spectrometer to determine the ratio of isotopes (ANCA; EUROPA INSTRUMENTS, CREWE, U.K.).

Definition of ketoisocapronic acid in plasma

Plasma ketoisocapron acid (KIC) was isolated by cation exchange chromatography (AG-50V, BIO-RAD resin).

The eluents were treated with sodium hydroxide (100 μl; 10 n.) And HCl hydroxylamine (200 μl; 0.36 m) and heated (60 ° C; 30 min). After cooling the pH of the samples were adjusted to the value<2.

Ketocislotes were extracted in 5 ml of ethyl acetate and dried in a nitrogen atmosphere at room temperature.

The preparation of KIC derivatives was carried out by adding 50 μl of a mixture of N-methyl-n-tert-butyl-dimethylsilyl-triftoracetamide + 1% tert-butyl dimethylchlorosilane.

The isotopic enrichment of KIC was determined by EL GC-MS (gas chromatography - mass spectrometry with electron impact ionization (GC mass spectrometer Hewlett Packard 5970 with Hewlett Packard 5890 Series II GC) by monitoring ions at 316 m / z and 317 m / z .

Determination of isotopic enrichment of plasma urea

Isotopic enrichment of plasma urea was determined by EL GC-MC analysis. The proteins were deposited from 50 μl of plasma with 200 μl of ice acetone.

After shaking, the protein was separated by centrifugation, and the supernatant was selected and dried in a nitrogen atmosphere.

250 μl bis (dimethyl acetale) of Malon aldehyde in dilution 1:20 and concentrated HCl (30% by weight) were added to the drowning supernatant, the sample was incubated at room temperature for 2 hours, and then evaporated to dryness (Speedvac, Savant Instruments, Forma Scientific , Marietta, Oh).

Urea derivatives were obtained using 50 μl of a mixture of N-methyl-N-tert-butyl-dimethylsilyl-trifluoroacetamide + 1% tert-butyl dimethylchlorosilane, and isotopic plasma enrichment was determined using EL GS-MS analysis by monitoring ions with M / Z 153-155.

Calculations

The pure residue of metabolites in the portal vein [μmol / (kg · h)] was calculated as follows:

where CONC. It is a blood concentration (μmol / l), Port and Art belong to the blood of portal veins and arterial blood, and PBF is the blood flow of the portal vein [l / (kg · h)].

The flow of leucine as a whole was calculated as follows:

where R is the rate of infusion of a labeled atom [μmol / (kg · h)] and

IE Infusate and IE Plasma are isotopic enrichments (expressed in mol.%) Of the infusted labeled atom and kic plasma, respectively.

CO 2 production in the body was calculated as follows:

where IE Infusate is the enrichment of H 13 CO 3 - in the infusion (overweight percentage), IE ARTERIAL BICARBONATE is an enrichment of arterial blood (overweight percentage) and the infusion rate of the labeled atom [μmol / (kg · h)] during intravenous Bicarbonate infusions that continued in each processing period. All equation was divided by 0.82 to correct the reimbursement of infusted labeled carbon in Bicarbonate.

The oxidation of leucine as a whole [μmol / (kg · h)] was calculated as follows:

where is the isotopic enrichment of bicarbonate during the infusion of 1-s 13-licin and IE LEU is an isotopic enrichment of 1-C 13 -KIC during a 1-° C infusion.

The non-oxidative removal of leucine as a whole (NOLD) is an assessment of the inclusion of leucine into the muscles. NOLD [μmol / (kg · h)] were calculated using the following equation:

The rate of appearance of leucine as a whole organism (Ra) [μmol / (kg · h)] is an assessment of protein catabolism, and it was calculated as:

The flow of urea as a whole organism was calculated as follows:

where IE is an enrichment of infusation, PE is a plasma enrichment in a stable condition during urea and Ir infusion is the infusion rate.

Statistical analysis

For all statistical criteria, it was believed that the value of P \u003d 0.05 represents statistical significance.

In Example 1, the effect of AKG on kinetics, appearance in the arteries, in a portal vein and a clean appearance of individual amino acids, AKG, glucose, ammonia and leucine, using a general linear model method (Minitab. Inc., State College, PA). INC., STATE COLLEGE, PA). This model included the effects of adding AKG and a pig. Pig included as a random variable. The average for testing conditions was calculated on the computer using the LSMEANS function. The unilateral T-criterion of Student was used to check whether the pure AKG residue was significantly higher than zero during control treatments.

Example 1 - measurements of AKG, glucose, ammonia in plasma, blood flow and urea flow as a whole organism

The purpose of this example is to assess the influence of AKG infusion on AKG, glucose, ammonia in plasma, blood flow and the flow of urea as a whole.

Experiments on animals

The piglets were deprived of food for 15 hours before the start of the experiment.

Per day of the experiment, at the time of time 1 h, with a primary dose (7.75 ml / kg; 25% w / w. Aqueous solution; orally) a continuous duodenal infusion of a milk substitute was prepared as 25% (wt. / wt.) aqueous solution, which provided ~ 920 kJ and 12.5 g of protein / (kg · day).

Or saline (control; 930 mmol / l NaCl), or sodium-akg (Na-AKG), 930 mmol / l, from Sigma-Aldrich, St. Louis, MO was dissolved in a milk substitute.

The AKG level was chosen on the basis of previous data (6) from the laboratory, when to observe the detected AKG residue in the portal vein, more than 2.5% of the dry matter of food was required.

The piglets were also obtained intravenous (200 μmol / kg) continuous 6-hour infusion 15 N 2-windows (98%; Cambridge Isotope Laboratories).

At the time of time, 0 hours began with a primary dose (15 μmol / kg) continuous 2-hour infusion NAH 13 CO 2 (15 μmol / (kg · h); 99%; Cambridge Isotope Laboratories, Andover, MA).

Arterial samples were obtained through 0, 90, 105 and 120 minutes after the start of the infusion of NAH 13 CO 2 to determine the production of CO 2 as a whole.

At the time of time 2 h, the infusion of NAH 13 CO 2 was stopped and started with the primary dose (40 μmol / kg) a continuous 4-hour infusion of 1-1 13 C-leucine (40 μmol / (kg · h); 99%; Cambridge Isotope Laboratories) .

Arterial samples and samples from the portal vein were obtained at the time of time 4, 5 and 6 hours to determine the kinetics of leucine and urea, as well as the mass residue of ammonia, AKG, glucose and amino acids.

All pigs were treated with both control and AKG on a fully randomized diagram with gaps of at least 24 hours between processing periods.

results

AKG, glucose, ammonia in plasma, blood flow and urea flow as a whole, the body is presented in Table 1.

Table 1. Effect of AKG infusion on the concentration of metabolites, pure residue in a portal vein and kinetics 1- 13 C-leucine and 15 n 2-windows in general organism.
	AKG 1 (% Food dry matter)
0	3,75	R
Infusion rate AKG μmol / (kg · h)	0	930	-
Bloodflow in a gathering vein, l / (kg · h)	3,21 ± 0.28 2	3.36 ± 0.27	0,34
Arterial AKG, μmol / l	13.8 ± 1.7	27.4 ± 3.6	<0,01
AKG in a portal vein, μmol / l	22.0 ± 1,4.	64.6 ± 5.9	<0,001
Pure AKG residue in a portal vein, μmol / (kg · h)	19.7 ± 2.8	95.2 ± 12.	<0,001
Clean residue AKG portal veins,% of infusted	-	10.23 ± 0.57.	-
Clean glucose residue in a gala vein, μmol / (kg · h)	303.1 ± 61.	203.9 ± 69.	<0,05
Clean residue ammonia in a portal vein, μmol / (kg · h)	520.1 ± 66.	561.1 ± 53.	0,91
Urea flow as a whole organism, μmol / (kg · h)	398.3 ± 35.	377.8 ± 39.	0,56
1 AKG, -Chiglutarat; 2 SEM (RMS Error)

AKG infusion raised (p<0,01) концентрацию AKG в артериях и воротной вене и чистый остаток AKG в воротной вене. Даже когда AKG не инфузировали в двенадцатиперстную кишку, чистое всасывание AKG в воротной вене было значимо выше 0. Однако чистое всасывание AKG в воротной вене было повышено (Р<0,001) при обработке AKG по сравнению с контролем. Чистый остаток AKG в воротной вене составлял 95 мкмоль/(кг·ч), что составляет только 10,23% от инфузированного количества.

Clean residue in a portal vein 10.23% in reality is some reassessment of the absorption of infusted AKG, since when only saline is infusing, statistically significant absorption AKG occurred. If you make a correction to the absorption of AKG from control food, the share of infusted AKG appears in the drainage vein drainage decreases to 8.12%.

Interestingly, the pure glucose residue in the portal vein was lowered (p<0,05) при обработке AKG. Обработка AKG не оказывала влияния на кровоток в воротной вене, чистый остаток аммиака в воротной вене и поток мочевины в целом организме.

Proline concentrations both in the arteries and in the portal vein were elevated (p<0,05), а лейцин в воротной вене имел тенденцию (Р<0,01) к повышению при обработке AKG (данные не представлены). Массовый остаток аминокислот в воротной вене представлен в таблице 2. Обработка AKG повышала (Р<0,05) массовый остаток лейцина, лизина и пролина в воротной вене и имела тенденцию к повышению массового остатка изолейцина (Р<0,10).

Table 2. Clean residues of amino acids in a carrier vein in pigs receiving duodenal infusion 0 or 930 μmol / (kg · h) AKG (n \u003d 5).
Amino acid	Control	AKG 1.
Palace Vienna		Palace Vienna
μmol / (kg · h)	% of arrival	μmol / (kg · h)	% of arrival
Essential amino acids
Isoleucine	164.5 ± 26.	100,1	230.2 B ± 28	140,0
Leucine	294.9 ± 44.	76,3	438.6 A ± 50	113,4
Phenylalanine	80.4 ± 11.	83,3	95.2 ± 11.	98,7
Valin	218.5 ± 33.	85,2	279.3 ± 32.	108,9
GISTIDIN.	27.7 ± 11.	43,1	45.9 ± 3.8.	71,4
Thronin	185.0 ± 40.	66,4	210.9 ± 18.	75,7
Lysine	237.7 ± 35.	72,3	324.5 A ± 37	98,8
Tryptophan	38.6 ± 6.4	-	47.2 ± 4.3.	-
Conditionally essential amino acids
Arginine	95.2 ± 24.	85,8	109.0 ± 19.	98,3
Proline	216.4 ± 25.	69,9	354.5 A ± 32	114,5
Tyrosine	85.7 ± 12.	100,6	115.8 ± 17.	135,9
Neassential amino acids
Alanine	539.6 ± 61.	182,9	557.8 ± 48.	189,0
Aspartate	28.2 ± 4.6	9,2	29.7 ± 6.0	9,6
Asparagin	169.9 ± 23.	-	185.6 ± 18.	-
Glutamate	64.2 ± 23.	14,9	80.1 ± 17.	18,6
Glutamine	17.2 ± 12.	-	25.5 ± 45.	-
Glycine	167.0 ± 27.	109,4	177.2 ± 20.	116,0
Serine	213.3 ± 89.	94,4	244.7 ± 64.	108,3
and differs from control (P 0.05); B differs from control (p<0,10)
1 AKG, -Chiglutarat; 2 mean ± SEM

The kinetics of leucine as a whole body is shown in the drawing. AKG processing did not affect the flow as a whole body, NOLD, RA and oxidation.

Example 2 - Measurement of the average AKG disappearance in the list

The purpose of this example is the assessment of the average disappearance of the infusted Bolus AKG in the Sail.

Experiments on animals

Pigs (n \u003d 7) were carried out by duodenal bolus infusion (7.75 ml / kg; 25% (w / w) aqueous solution) of a liquid milk substitute (Litter Life, Merrick) containing 25 mg / ml sodium-akg (1040 μmol / kg BW).

After 1 hour, pigs were killed.

The small intestine was carefully clamped in the proximal part of the duodenum and the distal part of the ileum, removed and washed with a jet of 2 × 50 ml of physiological solution to rinse the intestine.

The washes were collected, combined, and the aliquot of 15 ml was instantly frozen in liquid N 2 and stored at -80 ° C for the subsequent AKG analysis.

results

Infusing AKG Bolus 1040 μmol / kg. The average disappearance in the lumen was 663 ± 38 μmol / kg in one hour. This value is 63.8 of 1040 μmol / kg infusted AKG.

Discussion and general conclusion from experiment 1 and 2

In example 1, AKG was continuously infusing in a duodenum, and only 10% of the infusted AKG appeared in the drainage vein.

Observation that only 10% of the infusted AKG appeared in the plasma of the portal vein, increases the likelihood of some options for the fate of the AKG in the lumen. One of the possible explanations of the small appearance of AKG in the portal vein is that the AKG transport is limited. Sodium / dicarboxylate co-conveyors capable of transporting AKG exist on the pussy chamber of the pig (9), therefore it seems unlikely that AKG will not be captured by enterocytes. To check this, the authors of the invention infusted one duodenal bolus 1040 μmol / kg and found that more than 660 μmol / kg disappears from the small intestine of piglets for 1 h (example 2). Thus, approximately 64% of the AKG bolus disappeared from the lumen of the duodenum only in 1 hour.

AKG infusion did not affect the pure disappearance of glutamate and glutamine in the portal vein, as previously observed (6). If the absorbed AKG turned into glutamate, it should have been either released into the blood of the carrier vein, or to turn into other amino acids.

However, it would be possible to expect that the release of glutamate and glutamine will not increase through AKG, even if there is a significant transformation into these amino acids, given that very little food glutamate or glutamine is released by PDV (Portal Drain Viscera, the inner part of the drainage vein) In normal nutrition (references 1, 2). Showing (10) that proline can be synthesized from intestinal glutamate bowel fabric. Considering that the increase in the pure PROLIN residue in the portal vein was 138.1 μmol / (kg · h) in pigs treated with AKG, and that more than 800 μmol / (kg · h) AKG was not taken into account in the residue in the portal vein, possibly that the increase in the pure balance of the Proline in a portal vein can be fully the result of the transformation from AKG. However, such a significant transformation of AKG in the Proline in enterocyte should lead to a decrease in ammonia residue in a portal vein, but the residue of ammonia in the portal vein remained unchanged. The lack of effect on the ammonia residue in the portal vein was also reflected in similar urea synthesis speeds in two groups.

Transaminase of branched amino acids (ACA) catalyzes the interaction between AKG and branched amino acids (leucine, isoleucine and valine). ACA transumens, forming glutamate from AKG and the corresponding ketokislot from each VSA. Additional AKG can lead to a decrease in the net release of ACA from PDV by stimulating ACA transamination to the formation of glutamate. However, the release of leucine in the portal vein was increased by AKG, although it did not affect Leucine's kinetics as a whole. The pure Lisin residue in the Master Vienna also increased by AKG. Due to the fact that the net residue of many amino acids in the carrier vein was about 100% for many amino acids during the treatment of AKG, it was unclear whether AKG has saved amino acids or increased the release of amino acids due to proteolysis in the inner part of the drainage veins.

In addition, the probable fate of AKG inside the enterocyte is oxidation through the cycle of tricarboxylic acids (TSA). If the entire carbon is infused in the form of AKG, oxidized to CO 2, should be expected to increase CO 2 output from PDV, whereas the production of CO 2 as a whole with an AKG infusion. Interestingly, the pure glucose residue in the portal vein decreased when processing AKG.

Due to the fact that significant amounts of AKG disappeared from the lumen of the small intestine, but this cannot be explained by the drainage Vienna drainage neither in relation to AKG, nor with respect to the net residue of the AKG metabolism, the fate of AKG during enteral nutrition remains unclear. However, when AKG is infusing into a duodenum, only 10% of the feed in the lumen appeared in the drainage of the portal vein, although this amount of AKG was enough to increase the residue in the portal vein and the concentration of this compound in the blood circulation. Thus, despite the uncertainty regarding the accurate metabolic fate of AKG in the lumen, these results indicate that the availability of food AKG from the intestine is limited.

The resulting increase of AKG in blood circulation did not have an effect regarding the pure appearance of glutamate, glutamine, ammonia, ACA, in the portal vein.

In addition, an increased systemic AKG did not have an effect on leucine kinetics in PDV or as a whole by the body or a stream of urea. These results are consistent with previous data, when AKG delivered intragery.

Example 3 - Comparative influence of Na-AKG and chitosan-AKG, entertainly entered, on the resorption of amino acids and ketok acids in enterocytes and blood plasma and their metabolism

The purpose of this example is to compare the effect of Na-AKG (or Na-salt AKG) and chitosan-AKG introduced by enterically, to the resorption of amino acids and ketok acids in enterocytes and blood plasma and their metabolism. Also measured the effect of Na-AKG and chitosan-akg on the conversion of ketok acids in amino acids by monitoring the levels of amino acids in the blood plasma. This study is an inspection of the hypothesis from the fact that AKG affects the conversion of ketok acids in the amino acids in the intestine and improves protein synthesis.

Experiments on animals

In this experiment, only three pigs were used; These pigs had a body weight about 20 kg. The pigs were divided into cashes and fed standard food for 4-5 days to adapt to new fixtures. Then the pigs are surgically implanted catheters and intestinal cannula and gave 3-7 days to restore.

The surgical procedures used were the procedures commonly used in the art and famous technicians in the art.

After the operation, in this case, a 3-day recovery period was provided, and the pigs were fed once a day (at the time of 10.00) with standard feed (3% of body weight). After the reduction period, the level of amino acids in the blood plasma was measured under the conditions of administration of Na-AKG (see experiment (2)), the administration of chitosan-AKG (experiment (3)) and without the introduction of AKG (Experiment (1); Check Experiment), Additional Details which are shown below.

The conditions for introducing AKG.

Experiment (1).

Ketocislots or amino acids (amines) (total volume 50 ml) infusted intteno-modenal (I.D.) in a dose of * "Equivalent of the morning power" for 1 hour.

10 servings were given in 1 h (50 ml of dose +50 ml of saline).

This experiment was a control experiment

(* The "Equivalent of Morning Power" means that animals received about the same amount of amino acids, which is usually present in the stern corresponding to the morning power).

Blood samples were taken (on the source ** level, 0 h) and after 1, 2, 4 hours.

(** The initial level is determined as a sample at time 0 to amino acid infusions / ketok acids.)

(Processing may include the use of 5 drops of EDTA + tracilol, centrifugation and freezing of plasma at -20 ° C.)

Experiment (2).

Ketocislotes or amino acids (amines) mixed with Na-AKG (in total 50 ml), infusted intteno-modenal (I.D) at a dose of * "Equivalent of the morning power" for 1 hour (10 servings were given in 1 hour, 50 ml Doses, possibly with saline).

Blood samples (5 ml of solid blood for amino acid analysis from the artery, portal, hepatic vein) were collected in ethylenediaminetetraacetic acid (EDTA) with aprotinine to stop coagulation and proteinase activity.

Experiment (3).

Ketocislotes or amino acids (amines) mixed with chitosan-akg (in total 50 ml), infusted intteno-modenal (I.D.) in a dose of * "Equivalent of the morning power" for 1 hour (10 servings were given for 1 hour, 50 ml Doses, possibly with saline).

Blood samples were taken (at the initial level, 0 h) and after 1, 2, 4 hours.

Blood samples (5 ml of solid blood for amino acid analysis from the artery, portal, hepatic vein) were collected in ethylenediaminetetraacetic acid (EDTA) with aprotinine to stop coagulation and proteinase activity.

results

The following Table 3 shows the results of this study.

I is a salt Na-AKG

II is a salt of chitosan-akg

Increment in time \u003d (amino acids in import 0 - amino acid level after 1, 1.5 and 2.5 h)

The differing small or capital letters shown with the results describe the statistical differences when p<0,05.

Discussion and general conclusions for example 3

This example shows that chitosan-akg salt improves the absorption of essential amino acids. This improvement is greater than achieved using Na-AKG. This observation is important and essential for better recycling of food amino acids to improve the absorption of amino acids in the disturbed tissue of the intestine, detected, for example, in diabetic patients or the elderly.

Examples of food (dietary) additives and / or component

AKG, AKG mono and dimetallic salts or chitosan-AKG can be used as an active agent.

The composition of the beverage (per 1000 liters):

Drink is prepared using a standard method. Ingredients, with the exception of citric acid, ascorbic acid and carbon dioxide, are mixed in a suitable tank equipped with a mechanical stirrer. Then add citric acid and ascorbic acid and are thoroughly stirred for 15-20 minutes. Add remaining water. The resulting mixture is saturated with carbon dioxide and poured into suitable containers.

Pet food

The composition of the feed:

The specified composition is prepared by simply mixing these components in accordance with traditional technologies and packaged in standard packaging by weight of 0.25, 0.5 and 1 kg.

CLAIM

1. A method for improving the absorption of amino acids in a spine, including a mammal and a bird, in which a vertebral animal, including a mammal and a bird, is introduced AKG (alpha-ketoglutoic acid), mono- and dimetallic salts of AKG, chitosan-akg or mixtures thereof in quantity and / or with a frequency sufficient to ensure the desired effect on the absorption of amino acids.

2. The method according to claim 1, where the mono- and dimetallic salts of AKG are selected from the group consisting of CAAKG, CA (AKG) 2 and Naakg.

3. The method according to claim 1, where the vertebral animal is a rodent, such as a mouse, rat, guinea pig or rabbit; bird, such as turkey, chicken, chicken or other broilers; farm animals such as a cow, horse, pig, piglery or other freely moving agricultural animals; Or pet, such as a dog or a cat.

4. The method according to claim 1, where the vertebral animal is a person.

5. The method according to any one of claims 1 to 4, where the amino acid is any essential amino acid.

6. The method according to claim 5, where the essential amino acid is isoleucine, leucine, lysine and proline.

7. A method for reducing the absorption of plasma glucose in a spine, including a mammal and a bird, in which a vertebral animal, including a mammal and a bird, is introduced AKG, mono- and dimetallic salts of AKG, chitosan-akg or mixtures thereof in quantity and / or frequency, Sufficient to ensure the desired effect on glucose suction.

8. Method of preventing, inhibition or facilitating a state with a high level of glucose plasma in a spine, including a mammal and a bird, in which a vertebral animal, including a mammal and a bird, is introduced AKG, mono- and dimetallic salts AKG, chitosan-akg or mixtures thereof In quantity and / or with frequency sufficient to ensure the desired effect on the specified state.

9. The method according to any one of claims 7 and 8, where the mono and dimetallic salts of AKG are selected from the group consisting of CAAKG, CA (AKG) 2 and Naakg.

10. The method according to any one of claims 7 and 8, where the vertebral animal is a rodent, such as a mouse, rat, guinea pig or rabbit; bird, such as turkey, chicken, chicken or other broilers; farm animals such as a cow, horse, pig, piglery or other freely moving agricultural animals; Or a pet, such as a dog or a cat.

11. The method according to any one of claims 7 and 8, where the vertebral animal is a person.

12. The method according to claim 8, where the condition with a high level of glucose plasma is a diabetes mellitus of type I or type II.

13. The use of AKG, mono- and dimetallic salts of AKG, chitosan-akg or mixtures thereof, in a therapeutically effective amount for the manufacture of a composition for preventing, facilitating or treating a high level of glucose in plasma.

14. The application according to claim 13, wherein the condition with a high level of glucose plasma is a diabetes mellitus of type I or type II.

15. The use of AKG, mono- and dimetallic AKG salts, chitosan-akg or mixtures thereof in a therapeutically effective amount for the manufacture of a composition for improving suction, altered suction, deteriorating suction and impaired absorption of amino acids and / or peptides.

16. Application according to any one of claims 13 and 15, where the composition is a pharmaceutical composition with a pharmaceutically acceptable carrier and / or additives.

17. Application according to any one of claims 13 and 15, where the composition is food or food additive.

18. The application according to claim 17, where food or food additive is a dietary additive and / or component in the form of solid food and / or beverage.

19. Application according to any one of claims 13 and 15, where the therapeutically effective amount is 0.01-0.2 g / kg body weight per daily dose.

α-ketoglutar acid in, α-ketoglutaric acid geourone
α-ketoglutarova (alpha-Ketoglutarova) acid - One of the two ketone derivatives of glutar acid. The name "Ketoglutaric acid" without additional designations usually means alpha form. β-ketoglutaric acid differs only by the position of the ketone functional group and is much less common.

Anion α-ketoglutar acid, α-ketoglutarat (also called oxoglutarat) - an important biological connection. This is a ketokisloid that is formed during the deamination of glutamate. Alpha Ketoglutarat is one of the compounds formed in the Krebs cycle.

• 1 Biological significance
  • 1.1 Crec cycle
  • 1.2 Synthesis of amino acids
  • 1.3 Transport Ammonia
• 2 Notes

Biological significance

Crebs cycle

The α-ketoglutarat is a key product of Krebs, is formed as a result of decarboxylation of isocatrate and is converted to succinyl-COA in the alpha-ketoglutarat dehydrogenase complex. Anaplerotic reactions can replenish the cycle at this stage by the synthesis of the α-ketoglutaratus transmination of glutamate, or the action of glutamatedehydehydrogenase on glutamate.

Synthesis amino acids

Glutamine is synthesized from glutamate with the enzyme of glutaminsyntetase, which in the first stage forms glutamyl phosphate, using ATP phosphate as a donor; The glutamine is formed as a result of the nucleophilic replacement of phosphate cation of ammonium in glutamaly phosphate, the reaction products are glutamine and inorganic phosphate.

Transport Ammonia

Another function of alpha-ketoglutar acid is the transport of ammonia distinguished as a result of amino acid catabolism.

α-ketoglutarat is one of the most important ammonia carriers in the metabolic paths. Amino acid amino groups are attached to the α-ketoglutarata in the transministration reaction and transferred to the liver, falling into the urea cycle.

Notes

1. 1 2 Biochemistry. A short course with exercises and tasks / ed. E. S. Severin and A. Ya. Nikolaev. - M.: Goeotar-Honey, 2001. - 448 p., Il.
2. 1 2 3 4 Filippovich Yu. B. Basics of biochemistry: studies. For chemical. and biol. specialist. Ped. Un-Tov and In-Tov / Yu. B. Filippovich. - 4th ed., Pererab. and add. - M.: "Agar", 1999. - 512 p., Il.
3. Berezov T. T. Biological chemistry: Tutorial / T. T. Berezov, B. F. Korowkin. - 3rd ed., Pererab. and add. - M.: Medicine, 1998. - 704 p., Il.

α-ketoglutar acid ascorbic, α-ketoglutaric acid, α-ketoglutaric acid geourone, α-ketoglutaric acid folic acid