Selenium glycoprotein organometallic substance, having an immunostimulating action (and its variants)

 

(57) Abstract:

The invention relates to medicine, pharmacology, trace elements and molecular biology and can be used for the treatment of diseases associated with the inhibition of the production of CD4-helper cells, reduction killing and phagocytic activity. The invention consists in obtaining selenium glycoprotein of Organoelement compounds with immunostimulating properties. Substances include low molecular weight component, protein, selenium, balance of carbohydrate and various inorganic ions, injected saline aqueous solutions: cations calcium, strontium, magnesium, iron, anions - cyanide, phosphate, dihydroartemisinin, iodide. The technical result is to obtain medicinal substances, for which there is an increase in the production of CD4 T-helper cells, the increase in killing and phagocytic activity 4 C. p. F.-ly, 8 ill.

The invention relates to the field of chemical pharmacology and pharmacodynamics, biochemical medicine, cellular and molecular biology, immunopharmacology trace elements and can be used in clinical medicine for the treatment of various diseases, accompanied by the helpers, reduction killing and phagocytic activity.

Currently in clinical pharmacology for immunostimulation using both synthetic and organic matter of natural origin. It is, as a rule, preparations of extracts of thymus, lymph nodes, connective tissue and spleen. Such drugs are well known in clinical practice substances, for example timogen, T-activin, mielopid, timoptic etc. (Mashkovsky, M. D. "Drugs, corrective processes of immunity" in kN. "Medicinal product", Kharkov, Torching", 1997, so 2, S. 199-207).

In recent years the attention of many researchers attracted selenium and its compounds, as it is proved that the cellular and humoral immune processes, particularly the stimulation of the cellular immune reactions are carried out with the help of this trace element. (Kudrin, A. C., Rocky A. C., lark A. A., Rock, M. G., Gromova, O. A. in the book. "Immunopharmacology trace elements", ed. KMK, M., 2000, S. 222-223, 354-357).

In this regard, to maintain an active immune system selenium as a trace element is introduced into the complexes of vitamin preparations, such as Centrum (Reference VIDAL "Lekarstvennye based on the biomass of algae (patent GB 2203043, 1988 or patent RU 2096037), which has a tonic effect, which is associated with the direct effect of selenium compounds on the immune system. However, these medicinal substances are not sufficiently high content of organic selenium, and technology of obtaining them is complex and requires a long time.

In the patent (RU 2138271 S1, 1999) proposed a tool UCS (proteogenomic complex), production technology which is to some extent allowed the previous difficulties, however, the identification of the structure of this selenium organic matter produced was not.

The data presented suggests that the modern technology of selenium preparations of a new class implementing immunostimulirutuyu activity should be based on the structure and topology present in the body active, associated with selenium biomolecules - especially glycoproteins, stereochemical respective receptors lymphocytic immune system. (J. Plater "Visual immunology, M. Medicine, 1999, S. 34 and 35).

In this regard, create medicines new class in its structure and mechanism of action should stereochemically stimulating the function of the immune system.

To solve this task offers medicinal substance having an immunostimulating action. They include low-molecular weight component - protein, obtained by extraction of the protein-containing vegetable raw materials with organic solvents; selenium, balance of carbohydrates (e.g. sucrose) and various inorganic ions, injected saline aqueous solutions: cations calcium, strontium, magnesium, iron, anions - cyanide, phosphate, dihydroartemisinin, iodide.

We received a variety of substances are salt forms of selenoproteome.

The invention is illustrated attached to the description of the drawings (see Fig. 1 - 8).

Getting selenoproteome (Se)

As the original products use green mass of protein-enriched plants, such as cereals, legumes, leaves of corn. Extraction from plant tissue extract protein. The extraction was carried out with ether, ethyl alcohol, Dimexidum. The extract obtained is evaporated and produce lyophilic drying. The powder is dissolved in 60-90% ethanol solution. The solution is injected selenium obtained by thermolysis of Selenomethionine (6-12 μg per 1 ml of solution). Salesaccutane field (capacity 510-3W/cm, the frequency of 20-30 MHz). Field can be created, for example, in squidmaster used in magnetoencephalography.

Molecule selenopyran - Se (Fig. 1) represents two polypeptide alpha - and beta-chain protein, connected by a disulfide bridge at cysteine residues (alpha chain consists of 20 amino acids residues, beta of 29 amino acids). Selenium is obtained by thermolysis of Selenomethionine, included in the side alkyl radicals of amino acids, connecting some links of alpha and/or beta-chains of one or two neighboring protein molecules, thereby further "stitching" them. To selenoprotein through basic residues of the amino acids serine and/or tyrosine joins sucrose via O-glycosidic linkages. Molecular weight Se - 6835. The molar ratio of protein, selenium, carbon, 1:4:5.

When all physiological pH values, selenopyran ionized. Charged are C - and N-terminal group and the associated carbon atoms of the side chain containing a carboxyl or amino group (-COO-, -NH3+) (Fig. 1).

In the interaction of selenoproteome with aqueous solutions of salts occur salt of communication between opposite Sarajevo calcium dihydroartemisinin-selenopyran (CaH2SiO4-Se).

The substance includes ionized selenopyran (Fig. 1), to which carboxyl groups (-COO-) glutamic acid (and possibly Proline) and C-terminal groups attached cations calcium (Ca2+), amino groups (-NH3+) histidine, arginine and N-terminal group joined dihydroartemisinin anions (H2SiO42-to - and/or-circuits of the same molecule or an adjacent molecule selenoproteome (Fig.2). The molecular mass of CaH2SiO4-Se - 7531, molar ratio Se:Ca2+:H2SiO42-- 1:8:4.

2. Substance calcium cyanide-selenopyran (Ca(CN)2-Se).

The substance includes ionized selenopyran (Fig. 1), to which carboxyl groups (-COO-) glutamic acid (and possibly Proline) and C-terminal groups attached cations calcium, amino groups (-NH3-) histidine, arginine and N-terminal group joined the cyanide anion (CN-to - and/or-circuits of selenoproteome (Fig. 3). The molecular mass of Ca(CN)2-Se - 7363, the molar ratio Se:Ca2+CN-- 1:8:8.

3. Substance calcium phosphate-selenopyran (CaHPO4-Se).

4. Substance calcium iodide-selenopyran (CaI2-Se).

The substance includes ionized selenopyran (Fig. 1), to which carboxyl groups (-COO-) glutamic acid (and possibly Proline) and leaf carbon attached cations of calcium; amino groups (-NH3-) histidine, arginine and N-terminal group joined the iodide anions (I-to - and/or-circuit (Fig. 5). Molecular weight (CaI2-Se) - 7409. The molar ratio Se:Ca2+:I-- 1:8:8.

5. Substance strontium dihydroartemisinin-selenopyran (SrH2SiO4-Se).

The substance includes ionized selenopyran (Fig. 1), to which carboxyl groups (-COO-) glutamic acid (and possibly Proline) and leaf carbon to recognize the PE attached dihydroartemisinin anions (H2SiO42-to and/or chain of one molecule or an adjacent molecule selenoproteome (Fig. 6). Molecular weight SrH2SiO4-Se - 7915. The molar ratio Se: Sr2+:H2SiO42-- 1:8:4.

6. Substance magnesium phosphate-selenopyran (MgHPO4- Se).

The substance includes ionized selenopyran (Fig. 1), to which carboxyl groups (-COO-) glutamic acid and C-terminal groups attached to magnesium cations (Mg2+); the amino group of histidine, arginine and N-terminal group attached to the phosphate anions (HPO42-to the alpha and/or beta chain of the same molecule or an adjacent molecule selenoproteome (Fig.7). Molecular weight MgHPO4-Se - 7411. The molar ratio Se:Mg2+:HPO42-- 1:8:4.

7. Substance ferric phosphate-selenopyran (FeHPO4-Se).

The substance includes ionized selenopyran (Fig. 1), to which carboxyl groups (-COO-) glutamic acid and C-terminal groups attached cations of iron (II) (Fe2+); the amino group of histidine, arginine and N-terminal group attached to the phosphate anions to the alpha and/or beta chain of one molestia Se:Fe2+:HPO42-- 1:8:4.

Examples of obtaining selenium glycoprotein of Organoelement compounds - Se-GPAUL (salt form)

Example 1. The method of obtaining calcium dihydroartemisinin-selenoproteome (CaH2SiO4-Se).

To selenoproteome add the required amount of an aqueous solution of orthosilicate calcium, previously subjected to electrolysis and hydrolysis. The mixture was kept in the high-frequency electromagnetic field (capacity 510-3W/cm2the frequency of 20-30 MHz).

Example 2. The method of obtaining calcium cyanide-selenoproteome (Ca(CN)2-Se).

To selenoproteome add the required amount of an aqueous solution of calcium cyanide, previously subjected to electrolysis. The mixture was kept in the high-frequency electromagnetic field (capacity 510-3W/cm2the frequency of 20-30 MHz).

Example 3. The method of producing calcium phosphate-selenoproteome (CaHPO4-Se).

To selenoproteome add the required amount of calcium hydrogen phosphate, previously subjected to electrolysis. The mixture was kept in the high-frequency electromagnetic field (capacity 510-3W/cm, frequency 20-alinaparasey add a certain amount of an aqueous solution of iodide of calcium previously subjected to electrolysis. This mixture is kept in a high-frequency electromagnetic field (capacity 510-3W/cm2the frequency of 20-30 MHz).

Example 5. The method of producing strontium dihydroartemisinin - selenoproteome (SrH2SiO4-Se).

To selenoproteome add a certain amount of an aqueous solution of orthosilicate strontium, previously subjected to electrolysis and hydrolysis. The mixture was kept in the high-frequency electromagnetic field (capacity 510-3W/cm2the frequency of 20-30 MHz).

Example 6. The method of obtaining magnesium phosphate-selenopyran (MgHPO4-Se).

To selenoproteome add the required amount of magnesium ions, obtained by electrolysis of glycerol magnesium and the required number of phosphate anions obtained by electrolysis of calcium hydrogen phosphate. The mixture was kept in the high-frequency electromagnetic field (capacity 5102W/cm2the frequency of 20-30 MHz).

Example 7. The method of obtaining iron phosphate-selenoproteome (FeHPO4-Se).

To selenoproteome add the required amount of iron ions, obtained by electrolysis of acetate tetrahydrate iron, and if necessary the magnetic field (capacity 510-3W/cm2the frequency of 20-30 MHz).

Se-GPAUL include asymmetric protein molecule with alpha-helix and beta-structure. The hydrophobic end of the molecule Se-GPAUL goes into alpha-helix, beta-structure molecules Se-GPAUL tortuous accordingly and on the outer side of the amino acid chain, as well as on the inside, there are simultaneously selenide and disulfide bond, providing spatial stability and at the same time, the flexibility of this molecule.

In the structure of the whole molecule Se-GPAUL is 15 amino acids. Accordingly, the above technology can be derived molecules varied selenium glycoprotein of Organoelement compounds with different numbers of amino acids and a relatively low molecular weight.

Acute toxicity of the preparation was studied intraperitoneal injection Se-GPAUL at a dose of 250 mg/kg to mice (age 6 weeks, weight 28-30 g). The value of LD was 700 mg/kg

In the study the overall toxicity mice were injected Se-GPAUL at a dose of 100 mg/kg / day intraperitoneally continuously for 10 days. Weight loss and any other violations were not observed, in the future, under the observation of these mice for three months, declined the Xia organic compounds have immunostimulating properties, non-toxic, completely soluble in water and biological fluids - blood, lymph and cerebrospinal fluid. In 1 ml of Se-GPAUL contains, depending on the number of amino acids in the ligand from 20 to 30 mg of the substance and 6 mcg of selenium.

The dose of an administered drug depends on the clinical condition of the patient, his age, weight, and method of administration. Effective therapeutic daily dose for the patient is from 6 to 150 mg of active substance that is administered simultaneously or fractionally.

The method of activation and stimulation of the immune system is as follows.

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

When oral administration is necessary, the dose is calculated as follows:

20 drops of solution containing 20-30 mg of the drug substance;

10 drops (1/2 ml) contains 10-15 mg drug;

5 drops (1/4 ml) contains 5-7,5 is whether intra-arterial administration of drug dissolved in physiological solution for best of dissociation in the ratio of 1:10 using the 60% alcohol or 1:15 with 90% alcohol.

For example: children up to 6 years in clinical pathology moderate the drug is administered once in the form of injections from 0.1 to 0.5 ml / day, severe pathology of the specified dose is administered twice a day. In the intensive therapy the drug is administered intramuscularly or intravenously (intraarterially) at 1.0-2.0 ml, respectively, with the addition of 10 or 20 ml of physiological solution. In the case of oral administration, depending on the age, weight and extent of injury from 0.5 to 3.0 ml, and the drug is dissolved in 1/3 Cup boiled lukewarm water (36-38oC). The duration of treatment can vary from 1 to 3 months, in the case of a seriously leaking pathology, repeat the treatment at intervals of 1-2 months prior to the expressed clinical effect. During treatment control immunological status of the patient for extended clinical formula and the immunological.

When using immunostimulatory selenium glycoprotein of Organoelement compounds (salt form) is the active stimulation of the immune system, manifested by improvement in clinical condition of patients and normalization of the immune system by increasing production of CD4 cells T-helper cells, as well as Voprosi action based protosiren, characterized in that it contains selenoprotein which consists of two polypeptide - and-chain protein in lateral alkyl radicals which entered selenium, connecting some of the links - and-chains of one or two adjacent molecules of the protein, polypeptide chain also connected by a disulfide bridge at cysteine residues (chain consists of 20 amino acids residues, is a chain of 29 amino acids), with selenoprotein connected with sucrose by means of O-glycosidic linkages through the remainder of the amino acids serine and/or tyrosine in a molar ratio of protein : selenium : carbohydrate = 1 : 4 : 5 (Fig.1) and obtained under the action of a sinusoidal electromagnetic field with flux density 5 10-3W/cm2at a frequency of 20-30 MHz.

2. Selenoproteins preparation with immunostimuliruyushhim action on the basis of selenoprotein, characterized in that the preparation contains selenopyran described in paragraph 1, to which carboxyl groups (-COO-) glutamic acid and C-terminal groups attached cations calcium (CA2+) or strontium (Sr2+), amino groups (NH3+) histidine, arginine and N-terminal group joined dihydroartemisinin anions (H2SiOthe Oia or strontium : H2SiO42-- 1 : 8 : 4 (Fig.2 and 6).

3. Selenoproteins drug, possess immunostimulating action on the basis of selenoprotein, characterized in that the preparation contains selenopyran described in paragraph 1, to which carboxyl groups (-COO-) glutamic acid and C-terminal groups attached cations calcium (CA2+), amino groups (NH3+) histidine, arginine and N-terminal group joined the cyanide anion (CN-or iodide anions (J-to or chain selenoproteome at a molar ratio of protein : CA2+CN-or J-1 : 8 : 8 (Fig.3 and 5).

4. Selenoproteins drug, possess immunostimulating action on the basis of selenoprotein, characterized in that the preparation contains selenopyran described in paragraph 1, to which carboxyl groups (-COO-) glutamic acid and C-terminal groups attached cations calcium (CA2+), or magnesium (Mg2+), or iron (Fe2+), amino groups (NH3+) histidine, arginine and N-terminal group attached to the phosphate anions (NRA42-to - and/or-circuits of selenoproteome when the molar ratio is

 

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