The remedy for the prevention and treatment of infectious diseases and correction of pathological conditions of the living body

 

(57) Abstract:

The invention relates to medicine. Agent for the prevention, treatment and elimination of consequences of viral, bacterial, cancer, liver diseases, gastrointestinal tract, urinary system, immune system, wounds, burns, stress, used in medicine and veterinary medicine, contains a pyrophosphate polyprenol General formula: H-[-CH2-C(CH3)= CH-CH2-]a-X, where X is the anion pyrophosphoric acid, and not less than 7. The proposed tool is more active because it has a multifunctional activity at the cellular level. 5 table.

The invention relates to a means for prevention, treatment and elimination of consequences of viral, bacterial, cancer, liver diseases, gastrointestinal tract, urinary system, immune system, wounds, burns, stress, used in medicine and veterinary medicine.

Known antiviral agent, in the form of monophosphate of polyprenol General formula H-[-CH2- (CH3)= SN-SN2-]and-X (polyprenylated), where a is the number of isoprene units, X is the anion of phosphoric acid (RU, patent 2005475 And 61 To 31/21, 1991). Using known which of the proposed use of biologically active substances is to improve the efficiency of its antiviral action.

This technical result is achieved by using pyrophosphate polyprenol [1, 2] the General formula H-[-CH2- (CH3)= SN-SN2-]and-X, where X is the anion pyrophosphoric acid, and not less than 7, as a means for the prevention and treatment of infectious diseases and correction of pathological conditions of the living organism.

The proposed biologically active substance has a multifunctional activity at the cellular level and at the level of the organism as a whole.

At the cellular level it is embedded in the cell membrane, increasing their conductivity, normalizes and stimulates the biosynthesis of glycoproteins on the cell surface, normalizes the reproduction of cells, intercellular and, as a consequence, interstitial interaction.

In the body as a whole - normalizes the functioning of the immune system, promotes tissue regeneration, improves the functioning of individual organs, enhances hematopoietic function.

Describes the properties of the proposed biologically active substances allow it to be used for prevention, treatment and elimination of consequences of viral, bacterial, cancer, diseases of pecanpie funds can be illustrated by the following examples.

Example 1. Antiviral activity of pyrophosphate polyprenol.

The experiments were conducted on mice SV infected intranasally with influenza virus type A (H1N1) strain WSN in a dose of 5 LD50.

Simultaneously with the virus once introduced monophosphate of polyprenol or pyrophosphate polyprenol (solution of 0.4% at a dose of 5 μg per mouse).

The average life expectancy of animals, which were injected monophosphate of polyprenol, was 6.6 days, the animals, which were introduced pyrophosphate polyprenol - 8.1 days.

The example indicates that more effective action pyrophosphate polyprenol compared with monophosphates of polyprenol.

Example 2. Preventive protective effect of pyrophosphate polyprenol in mice treated with endotoxin of gram-negative bacteria.

In the experiment white mice weighing 20 g Animal-1 day before injection of endotoxin injected intraperitoneally pyrophosphate of polyprenol at the rate of 100 mg per 1 kg of body weight. Then the animals injected intraperitoneally 7 mg of glycolipid chemotype Re obtained from Salmonella Minnesota R595 by extraction with chloroform, and methanol. The death of animals into account within 3 days. Each group should have at least 20 belly is anything from the deaths of 6 of the 20 animals. Differences between groups significant at p<0,01.

Tests conducted on 3 volunteers with dysbiosis. Volunteers were orally administered 3 ml of a 0.4% solution of pyrophosphate polyprenol morning and evening for 3 days and 1 time on the fourth laziness. Before the first admission and 6 hours after the last dose of the analysis of blood and feces. In the blood determine the content of IgG-antibodies to endotoxin of gram-negative bacteria (glycolipid of chemotype Re), the total number of leukocytes and leukocyte numbers, svyazyvaysya endotoxin in the bloodstream or are able to bind endotoxin in vitro (blood smears). The antibody is determined using enzyme-linked immunosorbent assay (ELISA) using protein a labeled with horseradish peroxidase. As an indicator of the standards used pooled blood sera of 40 healthy volunteers. Leukocytes, bound endotoxin in vivo were detected using ELISA in blood smears using antibodies to Re-glycolipid, labeled with horseradish peroxidase. For the detection of leukocytes, are able to bind endotoxin in vitro, the strokes first treated with a Re-glycolipid, and then conjugate is sevov on various nutrient media. Research results are reflected in table 1.

After povtornogo drug recovery has been observed in all the studied indices to normal.

Example 4. Correction of pathological conditions. Correction stressinducing immunodeficiency

For the induction of stress, experimental mice were kept in conditions of limited movements (muscle deprivation). Within 10 days, the mice were placed one each in plastic chambers 8,54,02,0 cm to 7 hours each day. Control mice were kept in standard cages for 10 individuals (the size of a standard cell 421411 cm). On the 10th day stress experimental and control animals were injected with the test antigen-sheep red blood cells, after which the animals were kept under normal conditions [2] . To determine the level of stress used local hemolysis in gel [1] . The mice were injected intraperitoneally a sheep erythrocytes (EB) 5108in the order of 0.5 mil To 5 days after immunization in mice took spleen and obtained a suspension of erythrocytes. Test cells (106in 0.1 ml) were introduced into the molten agarose (0.7 percent), with swietlicki 20%-tion sheep red blood cells, after which the resulting mixture was layered on the surface of plastic cups is 1 ml of complement Guinea pigs, and incubated additionally for 1 h at 37oWith, then the complement decanted and count the zones of hemolysis. The calculation of the number of antibody productive cells (ATOC) produced 1 million viable splenocytes.

Investigated the following groups of mice (10 animals per group):

1. Control - treated EB (5%) intraperitoneally in 0.5 ml.

2. Subjected to stress - receiving unit on the 7th day stress.

3. Mouse, in which 1-day stress was introduced pyrophosphate polyprenol, and on the 7th day DL.

The results presented in table 2, show that the stress-induced hypokinesia, induces in mice a significant suppression of the primary immune response unit (204 up to 70 atok 1 million splenocytes). A single injection of the drug increases the number of ATOC to normal, completely preventing the development of stressinducing immunodeficiency.

Example 5. Correction of pathological conditions. The study of the production of interferon.

The experiments were conducted on mice SW, surviving after infection with influenza virus type A (H1N1) strain WSN.

The mice SW (weight of mice 12-14 g) was injected intraperitoneally pyrophosphate of polyprenol. After 24 h in the experimental and control the Intesa interferon in the serum. 2. The level of interferon synthesis induced by Newcastle disease virus (virus-induced interferon, VBN, 108TCD50/02 ml). 3. The level of interferon synthesis induced by staphylococcal enterotoxin A (mitogen-induced interferon, sea, 1 μg/ml). The interferon titration is carried out in cell cultures of L-929. As a test virus use 100 TCD50virus encephalomyocarditis mice. Per unit of interferon take the last dilution of the sample, providing 50% protection of the cells in complete destruction of the monolayer in the control.

In the experiment used the following groups of mice: 1) control (C), 2) control treated with pyrophosphate polyprenol (CPR), 3) control of the survivors of a viral infection (KB), 4) the survivors of a viral infection and treated with pyrophosphate polyprenol (WFP).

Set (PL. 3) that the pyrophosphate polyprenol restores the rate of interferon status of mice surviving after viral infection, while not affecting the interferon status of mice without interferon deficiency.

Example 6. Correction of pathological conditions. The profile of cytokine mRNA.

Used cell line MG-63 (osteogen the th livestock (cattle). When the cells of a solid monolayer growth medium was changed for a supportive and experienced the culture was treated with pyrophosphate polyprenol. After 2, 24 and 48 h the cells were removed with trypsin solution and versene, washed with saline and perform the allocation of total RNA (used sets for selecting RNA Rneasy Total RNA System - Qiagen, Santa Clarita, CA) followed by cDNA synthesis using oligo dT primers and AMV-reverse transcriptase (New England Biolabs, Bedford, MA). cDNA was used as template in the reaction RT-PCR with pairs of primers for the following cytokines - IFN-, IFN-, IL-lb, IL-2, IL-4, IL-6, IL-10, TNF- (Yamamura et al. , 1991; Gelder et al. , 1995; Lin et al. , 1998). Reaction conditions - 94oWith 2 min; 35 cycles at 94o1 min - 55o2 min - 72oWith 2 min; 72o5 min --> SHUT-OFF. The reaction product was detected by electrophoresis in 3% agarose gel.

It has been shown that in cells MG-63 pyrophosphate polyprenol induced biosynthesis of mRNA for IL-1 and IL-2. Induction was clearly observed at 24 h after treatment; the reaction product was not detected after 2 h after treatment; trace amounts of PCR product was detected after 48 h after treatment. It should be noted that in cells MG-63 constitutive were presented mRNA for IFN - and TNF-.

Prima is adenilatcyclase (2-5A synthetase), while in complex with dsRNA, polimerizuet ATP in oligoadenylate that activate ribonuclease, RNase L. system Activation of the enzymes of the 2-5A synthetase/RNase L leads to increased decay of mRNA in the cell and, as consequence, to decrease in the rate of cell reproduction, suppression of viral infection and others Used transplantable line of human cells J-96, obtained from the blood of men, patient subacute monocytic leukemia, and transplantable line of mouse fibroblasts L-929. Cells were cultured in medium 199 with 10% serum of cattle embryo. On the 2nd day of cultivation when the cells of an incomplete monolayer growth medium was replaced with supports (with 2% serum of cattle embryo) and were treated with pyrophosphate polyprenol. After 24 h the cells were removed from the glass with a solution of Versene, besieged by centrifugation at 2000g for 5 min, suspended in the buffer and frozen at -70oC. After thawing cells was appropriate processing and determination of the activity of 2-5A synthetase according to A. N. Narovlya et al. (1988). Activity of 2-5A synthetase was expressed in moles AMR included in the dimer 2-5A for 14 h incubation per 1 mg protein in the cell lysate. As can be seen from table 4, when processing cells J-96 and L is I, exceeding its original 5.7 times for cell culture J-96 and 2.9 times for the culture of cells L-929.

Example 8. Correction of pathological conditions. Effect on camp-dependent protein kinase.

Used transplantable line of human cells J-96, obtained from the blood of men, patient subacute monocytic leukemia. Cells were cultured in medium 199 with 10% serum of cattle embryo. On the 2nd day of cultivation when the cells of an incomplete monolayer growth medium was replaced with supports (with 2% serum of cattle embryo) and were treated with pyrophosphate polyprenol. After 24 h the cells were removed from the glass with a solution of Versene, besieged by centrifugation at 2000g for 5 min, suspended in the buffer and frozen at -70oC. After thawing cells was appropriate processing and determination of the activity of camp-dependent protein kinase according to A. N. Narovlya et al. (1988). The activity of protein kinase expressed in pulses per 1 min per 1 mg of protein in the cell lysate.

Presented in the table 5 data allow us to compare the activity of this enzyme in cell culture J-96 with and without treatment with pyrophosphate polyprenol. It is shown that the activity of camp-dependent is iterator

1. Rip J. W. et al. , Distribution, metabolism and function of dolichol and polyprenols. //Prog. Lipid Res. - 1985. - v. 24. - 6. -p. 269-309.

2. Shibaev V. N. , Danilov L. L. New developments in the synthesis of phosphopolyprenols and their glycosyl esters. // Biochem. Cell. Biol. - 1992. - v, 70. - 6. - R. 429-437.

The use of pyrophosphate polyprenol General formula

N-[-CH2-C(CH3)= CH-CH2-]a-X

where X is the anion pyrophosphoric acid,

a - not less than 7,

as a means for the prevention and treatment of infectious diseases and correction of pathological conditions of the body.

 

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