RU2177321C1 - Selenium-containing carotene-protein organic substance for regulation of metabolic processes (its variants) - Google Patents

Abstract

FIELD: biochemical pharmacology, clinical medicine. SUBSTANCE: invention proposes selenium-containing carotene-protein organic substances eliciting regulating effect on tissue metabolism and including protein, selenium, phospholipid, β-carotene, vitamins C and E, inulin, flavonoids and different inorganic ions - zinc, manganese and copper cations. Invention can be used for treatment of patients with diseases accompanying with disorders of tissue metabolism, in part, protein, lipid and carbohydrate metabolism and for activation of effect of vitamins A, C, E as regulators of metabolic and antioxidant processes in human body. EFFECT: activated metabolism, relative normalization of biochemical indices, recovery of functions of vascular and endocrine systems. 8 cl, 14 dwg, 9 ex

Description

 The invention relates to the field of pharmacology and pharmacodynamics, biochemical medicine, cellular and molecular biology, immunopharmacology of trace elements, pharmacology of substances that regulate metabolic processes and can be used in clinical medicine for the treatment of various diseases accompanied by disorders of tissue metabolism, in particular protein, fat and carbohydrate, as well as activation of the action of vitamins A, C and E as regulators of metabolic and antioxidant processes in the human body.

 Despite the production of numerous drugs used as regulators of metabolic processes, the problem of activation and correction of metabolism in the body has not yet been resolved. For the most part, various drugs of selective and targeted action are used to correct certain biochemical processes.

 For example, selenium, which is a part of various medicinal substances, is used to regulate redox reactions in the body: Centrum - 25 μg, Cevitam - 25 μg, Vitomax - 50 μg, Triovid - 50 μg. However, in these preparations, selenium is located as an additional trace element supplement to other active substances. It is known that numerous selenoproteins of plasma and tissues (brain, liver, heart, testicles, pancreas, etc.) play an important antioxidant role by eliminating free radicals. Since glutathione peroxidase is the main depot of selenium in the cell, the activity of this enzyme sharply decreases with a deficiency of this microelement. Despite numerous pharmacological and biochemical studies on selenium, an organic selenoprotein preparation has not yet been obtained.

 Of the antioxidant pharmacological agents, substances are widely used containing vitamins A, C and E and trace elements selenium, zinc, copper, manganese. For example, the drug Tera-Min (a biologically active food supplement) contains a variety of vitamins in combination with trace elements such as manganese, copper, zinc. The medicinal substance "Super Antioxidant" consists of vitamins A, C, E, selenium and various types of plants. Stress with Zinc as a medicine is also a dietary supplement and contains a complex of various vitamins and minerals - copper and zinc. The drug Tsinkuprin (Tsinkuprin-forte) contains trace elements of zinc and copper together with organic matter. The feasibility of combining copper with zinc is confirmed by the fact of the activation of enzymes that eliminate free radicals and affect the biosynthesis and functional activity of connective tissue.

 In this regard, the new class of created drugs in their structure and mechanism of action must stereochemically, i.e., biologically and chemically, correspond to those substances of the human body that directly carry out metabolic processes in the human body.

 To solve this problem, medicinal substances are proposed that have a regulatory effect on tissue metabolism. They include a low molecular weight component - a protein obtained by extraction from protein-containing plant materials with organic solvents; selenium, phospholipid, β-carotene, vitamins C and E, inulin, flavones and various inorganic ions introduced by aqueous solutions - cations of zinc, copper, manganese.

 The various substances we obtained are called selenium carotenoprotein organic substances.

 The invention is illustrated attached to the description of FIG. 1-14.

 Obtaining selenocarotinoprotein (SeKP).

Protein-containing plants, for example cereals and legumes, as well as protein-rich corn leaves, are used as starting products. The green mass is pre-dried and ground. By extraction with ether, alcohol or dimexide, protein-organic complexes are recovered from the resulting feed. The resulting extract was evaporated and freeze drying was carried out. The prepared powder is dissolved in 60 - 90% ethanol, selenium is introduced (after thermolysis of selenourea) at a rate of 6-12 μg per 1 ml of solution, then β-carotene obtained by extraction with organic solvents from plants containing this substance (leaves and fruits) is added mountain ash, rose hip, hawthorn, etc.). The molar ratio of β-carotene and selenoprotein is 8: 1. Substances are placed in an electromagnetic (power 5 • 10 ^-3 W / cm ² ) sinusoidal high-frequency field of 20-30 MHz for 5 minutes. The specified field can be created, for example, in SQUID magnetometers, which are used for magnetoencephalography. The substance thus produced is placed in vials and sealed.

 1. Substance selenocarotinoprotein SeKP.

 The Selenocarotinoprotein (SeKP) molecule is two protein polypeptide α and β chains connected by a disulfide bridge at cysteine residues (the α chain consists of 20 amino acid residues, 29 amino acid β). Selenium enters the lateral alkyl radicals of amino acid residues, connecting some links of the α and / or β chains of one or neighboring protein molecules (Fig. 2).

At all physiological pH values, selenocarotinoprotein is ionized. Charged are the C- and N-terminal groups and the side chains bonded to the α-carbon atoms containing a carboxylic acid (- COO ^- ) or an amino group (-NH ₃ ⁺ ) (Fig. 2).

 β-carotene, related to photosynthetic pigments, like chlorophyll under the influence of sunlight or another type of radiation (in particular high-frequency electromagnetic exposure) is excited and with the loss of an electron turns into a positively charged particle. Electrons can reduce positively charged amino groups, and β-carotene (+) binds to negatively charged carboxyl groups of the terminal carbon and / or glutamic acid residues (Fig. 1, 2).

 The molar ratio of β-carotene: selenoprotein is 8: 1.

 2. Substance selenophospholipocarotinoprotein (SeFLKP).

 The substance includes a molecule of selenocarotinoprotein (Fig. 2), to which phosphoglycerol is attached through the C-terminal carboxyl groups and / or carboxyl groups of the side chains linked to α-carbon atoms (glutamic acid and / or proline residues) (Fig. 3).

 3. Substance L-ascorbate-selenocarotinoprotein.

 The substance includes a molecule of selenocarotinoprotein (Fig. 2), to which L-ascorbic acid is attached via residues of serine and / or tyrosine (like sugars) (Fig. 4, 5).

IL-ascorbic acid (γ-lactone-2,3-dehydrogulonic acid)
II - dehydro-L-ascorbic acid (γ-lactone-2,3-diketogulonic acid) The molar ratio of vitamin C and selenocarotinoprotein is 5: 1.

 4. Substance α-tocopherol-selenocarotinoprotein.

 The substance includes a molecule of selenocarotinoprotein (Fig. 2), to which α-tocopherol (via an ester bond) can be attached via the C-terminal carboxyl groups and / or carboxyl groups of the glutamic acid residues (Fig. 6, 7).

 The molar ratio of vitamin E and selenocarotinoprotein is 5: 1.

 5. Substance inulin-selenocarotinoprotein. The substance includes a molecule of selenocarotinoprotein (Fig. 1), to which (possibly) through the residues of serine and / or tyrosine (via O-glycosidic bonds) an inulin polysaccharide is attached (Fig. 8, 9).

 The molar ratio of inulin: SeKP 5: 1.

 6. The substance flavono-selenocarotinoprotein (Fig. 11).

 The substance includes a molecule of selenocarotinoprotein (Fig. 2), to which flavonols (a group of flavonoids) (Fig. 10), for example rutin (3-ramnoglucoside quercetin), catechin (R, R ') are attached via carboxyl groups of glutamic acid and / or terminal carbon = OH) and other biologically active flavonoids (vitamin P).

 The molar ratio of flavonoid: SeKP 5: 1.

7. The substance is zinc-selenophospholipocarotinoprotein (Zn ²⁺ -SeFLKP).

The substance includes a molecule of selenophospholipocarotinoprotein (Fig. 3), to which zinc cations (Zn ²⁺ ) are attached via carboxyl groups (-COO ^- ) of glutamic acid residues (Fig. 12).

The molar ratios of Zn ²⁺ : SeFLKP 2: 1.

8. The substance is manganese-selenophospholipocarotinoprotein (Mn ²⁺ -SeFLKP).

The substance includes a molecule of selenophospholipocarotinoprotein (Fig. 3), to which manganese cations (Mn ²⁺ ) are attached via carboxyl groups (-COO ^- ) of glutamic acid residues (Fig. 13).

The molar ratios of Mn ²⁺ : SeFLKP 2: 1.

9. The substance is copper-selenophospholipocarotinoprotein (Cu ²⁺ -SeFLKP).

The substance includes a molecule of selenophospholipocarotinoprotein (Fig. 3), to which copper (Cu) cations are attached via carboxyl groups (-COO ^- ) of glutamic acid residues (Fig. 14).

The molar ratio of Cu ²⁺ : SeFLKP 2: 1.

 Se-KPOVs include an asymmetric protein molecule with an alpha helix and a beta structure. The hydrophobic end of the Se-KPOV molecule passes into an alpha helix, the beta structure of the Se-KPOV molecule is crimped accordingly, and on the outside of the amino acid chain, as well as on the inside, there are both selenide and disulfide bonds that provide spatial stability and at the same time the flexibility of this molecule.

 The entire Se-KPOV molecule contains 15 amino acids. Accordingly, the above technology can be obtained molecules of a variety of selenium carotenoprotein organic substances with different numbers of amino acids and relatively low molecular weight.

 The acute toxicity of the drug was studied with intraperitoneal administration of Se-KPOV at a dose of 250 mg / kg to mice (age 6 weeks, weight 28-30 g). The LD value was 700 mg / kg.

 In the study of general toxicity, mice were injected with Se-KPOV at a dose of 100 mg / kg per day intraperitoneally continuously for 10 days. No weight loss or any other abnormalities were observed, and subsequently, when these mice were observed for three months, no abnormalities were detected.

 As a result of the studies, it was found that Se-KPOVs are organic low-molecular compounds, have regulatory metabolic effects, are non-toxic, completely soluble in water and biological fluids - blood, lymph and cerebrospinal fluid. Depending on the amount of amino acids in the ligand, 1 ml of Se-KPOV contains from 20 to 30 mg of substance and 6-12 μg of selenium.

 The dose of the drug administered depends on the clinical condition of the patient, his age, weight, as well as the route of administration. An effective therapeutic daily dose for a patient is from 6 mg to 150 mg of the active substance, which is administered simultaneously or fractionally.

 The method of activation and regulation of metabolic processes is as follows.

 The resulting preparation Se-KPOV is a solution of the active substance in 60 - 90% ethanol, 1 ml of which contains 20-30 mg of the drug substance. Se-KPOV is administered orally, intramuscularly, intravenously, intraarterially, and also externally as a suspension in an oil solution or as an ointment with an oil-alcohol filler.

When administered orally, the required dose is calculated as follows:
20 drops of the solution contain 20-30 mg of the drug substance;
10 drops (1/2 ml) contain 10-15 mg of the drug;
5 drops (1/4 ml) contain 5-7.5 mg of the drug;
3 drops (1/7 ml) contain 3.3 mg of the drug.

 With intramuscular, intravenous or intraarterial administration, the drug is dissolved in physiological saline for better dissociation in a ratio of 1:10 when using 60% alcohol or 1:15 with 90% alcohol.

For example: for children under 6 years of age with a moderate clinical pathology, the drug is administered once as an injection from 0.1 ml to 0.5 ml per day, with a severe degree of pathology, the specified dose is administered twice a day. When conducting intensive therapy, the drug is administered intramuscularly or intravenously (intraarterially) in 1.0-2.0 ml, respectively, with the addition of 10 or 20 ml of physiological saline. In the case of oral administration, depending on the age, weight and degree of damage, from 0.5 ml to 3.0 ml, moreover, the drug is dissolved in 1/3 cup boiled slightly warm water (36-38 ^o C).

 The duration of treatment can vary from 1 to 3 months, in case of a severe course of pathology, the treatment is repeated with an interval of 1-2 months until a pronounced clinical effect. During the treatment, the immunological status of the patient is monitored according to the detailed clinical formula and immunogram.

 When selenium carotenoprotein organic substances are used, metabolic activation, carbohydrate, protein and fat, is observed, which is manifested by an improvement in the patients' clinical well-being, relative normalization of biochemical parameters, and restoration of the functions of the vascular and endocrine systems.

Claims (8)

1. Selenoprotein preparation for regulating metabolic processes based on proteoselen, characterized in that it contains selenoprotein, which is two polypeptide α and β chains of a protein of plant origin, selenium introduced into the lateral alkyl radicals, polypeptide chains are also connected by a disulfide bridge at cysteine residues moreover, the α-chain consists of residues of 20 amino acids, the β-chain of 29 amino acids, while selenoprotein is connected to β-carotene at the terminal carbon groups and / or glutamine residues to slots in a molar ratio to the protein of 8: 1 (. Figure 2) and obtained by the action of the sinusoidal electromagnetic field with a power flux density of 5 • 10 ^-3 W / cm ² at a frequency of 20-30 MHz.  2. Selenoprotein preparation for regulating metabolic processes based on selenoprotein, characterized in that the preparation contains selenocarotinoprotein, characterized in claim 1, to which through the C-terminal carboxyl groups and / or carboxyl groups of the side chains linked to the α-carbon atoms at the remainder glutamic acid, and possibly proline attached phosphoglycerol (figure 3).  3. Selenoprotein preparation for regulating metabolic processes based on selenoprotein, characterized in that the preparation contains selenocarotinoprotein, characterized in claim 1, to which L-ascorbic acid (Fig. 5) in the molar ratio of acid is attached via the remainder of serine and / or tyrosine (figure 5): protein - 5: 1.  4. Selenoprotein preparation for regulating metabolic processes based on selenoprotein, characterized in that the preparation contains selenocarotinoprotein described in claim 1, to which α-tocopherol is attached via the C-terminal carboxyl group and / or carboxyl groups of the glutamic acid residues (Fig. 7 ) through an ester bond in a molar ratio of tocopherol: protein - 5: 1.  5. Selenoprotein preparation for regulating metabolic processes based on selenoprotein, characterized in that the preparation contains selenocarotinoprotein, as described in claim 1, to which the inulin polysaccharide (Fig. 9) is attached via O-glycosidic bonds in the molar ratio of inulin: protein = 5: 1.  6. Selenoprotein preparation for regulating metabolic processes based on selenoprotein, characterized in that the preparation contains selenocarotinoprotein, characterized in claim 1, to which a biologically active flavonoid (11) in a molar ratio is attached through the carboxyl groups of glutamic acid and / or terminal carbon flavonoid: protein = 5: 1.  7. Selenoprotein preparation according to claim 6, characterized in that the flavonoid is rutin, catechin or vitamin P. 8. Selenoprotein preparation for regulating metabolic processes based on selenoprotein, characterized in that the preparation contains selenophospholipocarotinoprotein described in claim 2, to which zinc cations (Fig. 12), manganese (Fig. 13) are attached through carboxyl groups of glutamic acid residues or copper (Fig. 14), with a molar ratio of cation Me ²⁺ : protein = 2: 1.

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