Medication possessing immunostimulating and hemostimulating action

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of immobilised oligonucleotides as immunostimulating and hemostimulating medication for peroral introduction. Immobilised on polyethylene oxide oligonucleotides of DNA of salmon soft roes demonstrate immuno- and hemostimulating activity in conditions in vivo in case of peroral introduction in experimental animals and in vitro, which is manifested in stimulation of phagocytic reactions in vivo and in vitro, increase of IFN-γ in vitro, increase of cytotoxic activity of natural killers, increase of spontaneous proliferative activity of lymphoid cells of experimental animals and index of B-lymphocyte stimulation, increase of nitrogen oxide production, as well as in enchancement of hemopoiesis regeneration in early terms after cytostatic impact.

EFFECT: immobilised by physical method oligonucleotides are protected from destruction in gastrointestinal tract, which facilitates their permeability through intestine wall and increases bioavailability.

11 tbl

 

The invention relates to medicine, specifically to pharmacology, and relates to agents that affect the immune and hematopoietic systems.

To maintain immunity in acute inflammatory diseases (e.g. pneumonia) load only on the bone marrow increases hundreds of times. And the most intense, prolonged and costly time in maintaining the number and activity of immune cells is the synthesis of nucleic acids: DNA and RNA. Deficiency of oligonucleotide fragments of nucleic acids, leading to a chronic course of various diseases, low immunity and reduce the body's ability to self-regulation and the repair of damaged structures, which significantly reduces the quality of life. When conducting radiation or cytotoxic therapy is affected primarily functions quickly regenerating cellular structures, which include the bone marrow. It is in the bone marrow leads to the formation of the key cells responsible for immunity and protection of the internal environment - lymphocytes, neutrophils, macrophages. Therefore, suppression of bone marrow function, depletion of its reserves affects the whole body. therapeutic use of stimulants of the immune and hematopoietic systems is largely limited due to their side effects [1, 2]. In addition, a number of drugs is with the battle protein and therefore, they are used exclusively parenteral (by injection), that also has its negative consequences.

The closest analogue to the proposed remedy for the achieved result is the sodium salt of deoxyribonucleic acid (desoxyn), derived from the ROE of sturgeon and partially depolimerizovannogo using ultrasound to the molecular weight of 2.7 to 4.0×105Daltons. According to the literature desoxyn has a therapeutic effect in acute radiation sickness II-III severity and with Hypo - and aplastic conditions of the blood system, caused by radiotherapy or chemotherapy [3]. It is assumed that due to the receipt of detoxicate damaged by drugs or ionizing radiation hematopoietic tissue amplification of nucleic acid synthesis, which leads to an increase in the rate of division of hematopoietic precursor cells and, consequently, accelerated recovery cellularity germ blood.

The use of the drug is limited due to the complications inherent in the parenteral route of administration. When using detoxicate marked tenderness at the injection site, patients can increase body temperature, possible allergic and anaphylactic reactions [3, 4].

The objective of the invention is to expand the Arsenal of immuno - and haemostimulating funds.

The task is solved by when what emeniem immobilized oligonucleotides as immunostimulating and haemostimulating tools for oral administration.

Preparation of immobilized oligonucleotides is a short DNA fragments purified proteolytic enzymes, molecular weight in the range of 500-700 kDa, obtained from raw materials - "salmon ROE Extract - deoxyribonucleic acid of low molecular weight". Immobilization of oligonucleotides is carried out by irradiation of a 10% aqueous solution of polyethylene oxide (PEO) with a molecular weight of 1.5 kDa stream of accelerated electrons at a dose of 1.5 Mrad and entering in the irradiated solution of DNA oligonucleotides salmon ROE fish to a final concentration of 10 mg in 1 ml, the mixture is stirred for 10 minutes to obtain opalescense solution. Pre-irradiated polyethylene oxide forms a micelle containing condensed DNA that helps to protect the DNA from degradation in the gastrointestinal tract and facilitates the permeability of molecules through the intestinal wall. Increased bioavailability of this drug suggests the possibility of its application by ingestion.

New in the present invention is that immobilized on PEO oligonucleotides (- AN) was first proposed for use as immuno - and haemostimulating tools for oral administration.

Therefore, the drug that we offer for oral administration may be a drug you the ora in patients with contraindications for the use of other drugs and does not have adequate analogues. The advantages of this drug are obvious. First, the use of nanotechnology radiation synthesis and gamma radiation for immobilization of molecules of the drug on the native low molecular weight prevents them from degradation in the gastrointestinal digestive tract and creates conditions for transport across the cells of the intestinal mucosa into the bloodstream. Secondly, the unique technology allows you to create water-soluble conjugates of polymers and protein drugs drugs sizes of 20-100 nm with enhanced bioavailability when enteral intake and saved pharmacological activity and therapeutic efficacy [5].

Application immobilized on PEO oligonucleotides became possible thanks to the discovery they have immunostimulatory properties, namely stimulation of the phagocytic reaction in vivo and in vitro, increasing the production of interferon-gamma (IFN-γ) in vitro, enhancing the cytotoxic activity of natural killer cells (EC), the increase of spontaneous proliferative activity of lymphoid cells in experimental animals and stimulation index of lymphocytes, increase nitric oxide production, as well as gemostimuliruyuschee properties when introduced per os.

Application immobilized on PEO oligonucleotides for oral administration as and is mono - and haemostimulating means are not described in literature. This property is not explicitly derived for the expert from the prior art. Immobilized oligonucleotides can be used in patients with immune deficiency associated with acute and chronic infectious diseases, Hypo - and aplastic conditions of the blood system against the background of radiation therapy and treatment with cytostatics.

Thus, this solution meets the criteria of the invention: "novelty", "inventive step", "industrial applicability".

Immunostimulatory properties immobilized on PEO oligonucleotides have been found through experimental research.

To establish immunostimulating activity immobilized on PEO oligonucleotides been studied for their effect on phagocytosis of neutrophils in vivo and in vitro production of IFN-γ in vitro, the activity of the EC, the proliferative activity of lymphoid cells in oral method of use of the investigational product, the production of nitric oxide peritoneal macrophages laboratory animals when adding them-AN in vitro.

Study of the immunotropic activity immobilized on PEO oligonucleotides was carried out according to the "guidance for the study of immunotropic activity of pharmacological substances" [6].

In the study were used 175 of male mice Lin and CBA/CaLac and 22 mouse-male line BALB/C mice weighing 18-20 g at the age of 1.5-2 months, obtained from the nursery of the Institute of pharmacology WITH the RAMS. Mouse strain BALB/C were used as a source of peritoneal macrophages. Animals were conventional 1-St category (certificate of SE Research center of biomedical technologies RAMS No. 188-05). Content, nutrition, care of animals and removing them from the experiment was carried out in accordance with the requirements of the rules of work with the use of experimental animals" (Annex to order of the USSR Ministry of health from 12.08.1977, No. 755).

Mice immobilized oligonucleotides administered orally rate for 10 or 14 days once daily at a dose of 10 mg/kg, 100 mg/kg and 250 mg/kg in a volume of 0.2 ml sterile saline control animals received equivalent volume of solvent (saline). As the background used intact animals matched for age and gender.

In experiments in vitro them-DIVISION was added in the culture of neutrophils and mononuclear cells of healthy donors (40 people aged 24-38 years) at doses of 0.07 μg/ml, and 0.7 μg/ml and 7 mg/ml, and the culture of peritoneal macrophages of mice at doses on the order distinguished from 0,00034 μg/ml to 33,775 µg/ml.

Cytostatic myelosuppression simulated single intraperitoneal introduction of animal solution ftorpirimidinov of the antimetabolite 5-fluorouracil in 1/3 Mack the distribution panel is minimal tolerated dose (MTD) (76 mg/kg).

Scored animals by decapitation under ether anesthesia, or by an overdose of chloroform.

The phagocytic activity of peritoneal neutrophils was assessed 24 h after the end of the 14-day course of introduction of immobilized oligonucleotides on the ability of phagocytes to absorb the daily culture of Staph. aureus, strain 209. On smears the contents of the peritoneal cavity was taken into account the percentage of neutrophils across the microbes (phagocytic index - PHI) and the average number of staphylococci, absorbed one cell phagocytic number FC) [6].

To assess the impact of the drug on phagocytosis in vitro took blood from healthy donors from the cubital vein into a test tube with heparin at the rate of 25 UNITS per 1 ml of the investigated blood was mixed with 0.8 ml of 3% solution of gelatin prepared with medium 199. Prepared cell suspension containing 2 million neutrophils in 1 ml of Simultaneously preparing a suspension Staph. aureus, strain 209 at a concentration of 20 million/ml In the formulation of the reaction were mixed in 96-well round-bottom tablets 90 ál of cell suspension and 90 μl of Staphylococcus (ratio 1:10) and the plates were incubated at 37°C for 30 min To study the effect of them is AN on phagocytosis to the mixture was added to 20 µl sample of the drug at concentrations of 0.07 μg/ml, and 0.7 μg/ml and 7 mg/ml After incubation the plates were centrifuged for 10 min at 1000 rpm, the precipitate was prepared m the conditions on a slide, were fixed with ethanol for 30 min and stained with azure II-eosin for 30-40 minutes On smears were taken into account, the percentage of neutrophils across the microbes (phagocytic index - PHI) and the average number of staphylococci, absorbed one cell phagocytic number FC) [6].

Assessing the impact of the drug on the production of IFN-γ was performed on the culture of mononuclear cells (MNCs) in the peripheral blood of healthy donors [6]. To do this, the study drug was added to the culture of the mononuclear cells at concentrations of 0.07 μg/ml, and 0.7 μg/ml and 7 mg/ml in a volume of 50 μl. IFN-γ in daily supernatant cultures of mononuclear cells was determined using the ELISA method, using the corresponding set of the production company "Vector-best" (Novosibirsk).

Study of the effect of exchange rate 14-day introduction to them-SO on the functional activity of the EC was determined in the cytotoxic response by their ability to lyse cells myeloblastosis line K-562, using a colorimetric method [7].

To assess the impact of exchange rate 14-day introduction to them-SO on the proliferative activity of T - and b-lymphocytes in experimental animals used reaction besttransport, which to some extent is an integral method to determine their functional activity [6]. This method is based on the ability of some lectins to induce polyclonal activation and proliferationrelated, which was estimated colorimetrically [8]. For activation of T-lymphocytes used phytohemagglutinin (PHA); to activate b-lymphocytes - lipopolysaccharide (LPS). As a source of lymphoid cells used splenocytes experimental animals.

To determine the effect of study drug on the production of nitric oxide peritoneal macrophages intact mice im-DIVISION was added in the culture of macrophages in doses on the order distinguished from 0,00034 μg/ml to 33,775 µg/ml Macrophages were cultured in flat-bottomed 96-well tablets at a concentration of 2×105cells per well 48 h, and then collected from the wells adosados and measured it the amount of nitrite using reagent Grace by using a spectrophotometer "Titertek Multis-can MCC" ("Titertek", Finland) at a wavelength of 540 nm [9].

As the ligand of TLR-9 used CpG-oligonucleotide ODN1826 ("InvivoGen, USA). As a blocker TLR-9 used inhibitory oligonucleotide ODN2088 ("InvivoGen, USA).

Gemostimuliruyuschee properties to them-AN was studied on the model of the cytotoxic myelosuppresive caused by the introduction of 5-fluorouracil (5-FU). Preparation of immobilized oligonucleotides were administered to mice per os daily from 1st to 10th day of the study at a dose of 250 mg/kg

3, 5, 7, 9, 11 and day 13 of the experiment in mice using an automated Hematology analyzer ABACUS (Diatron, ABC is Riya) in veterinary regime assesses the condition of the peripheral part of the system of Eritrea (hemoglobin, the number of erythrocytes, hematocrit, mean corpuscular concentration of hemoglobin). Further, conventional methods studied the content of reticulocytes, different forms of leukocytes in the peripheral blood [10]. After killing method craniocervical dislocation under ether anesthesia were assessed total number of myelokaryocytes and absolute content of cellular elements of individual shoots of haematopoiesis in the bone marrow [11].

Statistical processing of the results was carried out using the statistical software package Statistica for Windows (version 5.0) with a preliminary estimate of the normal distribution and the t-student test, rejecting the variational series from a normal distribution was applied the method of nonparametric statistics Wilcoxon-on-Mann-Whitney.

Results confirming immunostimulatory properties immobilized on PEO oligonucleotides in oral usage.

Example 1. The study of the phagocytic activity of peritoneal neutrophils was assessed 24 h after the end of the 14-day course of introduction of immobilized oligonucleotides at a dose of 10 mg/kg (group 3), at a dose of 100 mg/kg (group 4) or solvent (group 2) by the ability of phagocytes to absorb the daily culture of Staph. aureus, strain 209. Course introduction to them-SO in a dose of 10 mg/kg resulted in dostov momu increase the relative amount faguoqitirute of neutrophils in experimental animals as compared with the control group, and with the background, and with the group of mice treated with the study drug at a dose of 100 mg/kg (table 1). The number of absorbed bacteria (FC) in the group of animals using them-SO in a dose of 10 mg/kg was statistically significantly higher compared to the values of the control group. Course introduction to them-SO in a dose of 100 mg/kg did not lead to significant changes in the phagocytic index and phagocytic number of neutrophils in experimental animals compared

Table 1
Assessment of the impact of the course introduction of immobilized oligonucleotides on the phagocytic activity of peritoneal neutrophils of mice CBA/CaLac
The studied parametersGroups of experimental animals
Group 1
Background
(n=7)
Group 2
Control
(n=7)
Group 3
im AN
(10 mg/kg)
(n=7)
Group 4
im AN
(100 mg/kg)
(n=7)
FI %12,0±0,3614,0±0,73*24,14±2.06 to*
2-3P<0,001
16,57±1,41*
3-4P<0,05
FC2,97±0,142,60±0,163,69±0,31
2-3P<0,01
2,96±0,15
Note: * - the differences between the experimental groups and background, between the control group and the background significant (p<0.05), and n is the number of animals in the group.

with the control group, only the background there was a statistically significant increase in the relative number faguoqitirute neutrophils.

Example 2. Evaluation of the effect of immobilized oligonucleotides on the phagocytosis of neutrophils in vitro. Adding them to AN neutrophils peripheral blood of healthy donors in various concentrations (of 0.07 μg/ml, and 0.7 μg/ml and 7 mg/ml) was observed a significant increase in phagocytic number relative to the value of the control group during introduction to the culture of neutrophils dose of immobilized oligonucleotides of 0.7 ág/ml (table 2). It should also be noted that when adding them to AN neutrophils in different doses indicators phagocytic activity above the control values, although statistically insignificant, with increasing concentrations of added them AN phagocytic index was down and phagocytic number is increased.

Table 2
Evaluation of the effect of immobilized oligonucleotides at doses of 0.07 μg/ml, and 0.7 μg/ml and 7 mg/ml when added in vitro phagocytosis of neutrophils in the peripheral blood of donors
The studied parametersThe experimental group
Group 1 Control
(n=10)
Group 2
im AN
(of 0.07 µg/ml)
(n=10)
Group 3
im AN
(0,7 µg/ml)
(n=10)
Group 4
im AN (7 µg/ml)
(n=10)
FI %26,90±2,6535,50±3,5333,80±3,3432,10±3,06
FC3,86±0,36to 4.73±0,414,91±0,26
1-3P<0,05
5,09±0,50
Note: n is the number of donors in the group.

Example 3. Evaluation of the effect of immobilized oligonucleotides on the synthesis of IFN-γ by peripheral blood mononuclear cells. Adding them is AN a statistically significant increased production of IFN-γ was observed at the dose of insertion of the preparation of 0.7 ág/ml (table 3). Spontaneous generation studies the target cytokine in this group was significantly higher as compared to the

Table 3
Evaluation of the effect of immobilized oligonucleotides at doses of 0.07 μg/ml, and 0.7 μg/ml and 7 mg/ml when added in vitro culture of mononuclear cells in the synthesis of IFN-γ
The experimental groupThe concentration of cytokines (PG/ml)
Group 1 Control (without addition of drugs) (n=10)for 9.64±1,17
Group 2 them-AN (0,07 mg/ml) (n=10)10,31±1,14
Group 3 im AN (0,7 µg/ml) (n=10)21,29±to 5.21
1-3P<0,05
2-3P<0,05
Group 4 them-AN (7 μg/ml) (n=10)9,52±1,46
Note: n is the number of donors in the group.

control, or with a group, which is AN added dose of 0.07 mg/ml

Example 4. Study of the effect of immobilized oligonucleotides on the functional activity of natural killer cells of mice. After a 14-day course introducing them-SO in a dose of 10 mg/kg functional activity of natural killer cells in mice were increased as compared with the background, and with the control group, the ri of all the studied ratios of target to the effectors but statistically insignificant (table 4). In this application of them-DIVISION course in a dose of 100 mg/kg was significantly increased

Table 4
Assessment of the impact of the course introduction of immobilized oligonucleotides in doses of 10 mg/kg and 100 mg/kg on natural killer activity (ESA) mice of CBA/CaLac
The studied parametersThe experimental group
Group 1
Background (n=7)
Group 2 Control (n=7)Group 3
im AN
(10 mg/kg) (n=7)
Group 4
im AN
(100 mg/kg) (n=7)
ESA (%) ratio of target: effector 1:1035.70 barm±2,6632,67±1,4438,90±3,3238,86±2,43
2-4p<0,05
ESA (%) ratio of target: effector 1:2535,24±2.26 and34,20±1,2339,61±2,5439,36±1,55
2-4p<0,05
ESA (%) ratio of target: effector 1:5037,49±1,50 37,60±1,4242,68±2,7849,32±4,47
1-4p<0,05
2-4p<0,05
Note: n - number of animals in the group.

cytotoxic activity of EC experimental animals compared with control at all tested ratios of target to the effectors, and the ratio of target-to-effector 1:50 functional activity of natural killer cells was statistically significantly increased compared to the background.

Example 5. Study of effect of immobilized oligonucleotides on the proliferative activity of lymphocytes. After a 14-day course introducing them-SO in a dose of 10 mg/kg there was a significant increase of spontaneous proliferative activity of lymphoid cells in experimental animals as compared with the background, and with the control group (table 5). When the stimulation index (IP) of T-lymphocytes statistically

Table 5
Assessment of the impact of the course introduction of immobilized oligonucleotides in doses of 10 mg/kg and 100 mg/kg on the proliferative activity of lymphocytes of mice CBA/CaLac
The studied parametersGroup exp the pilot animals
Group 1
Background (n=7)
Group 2 Control (n=7)Group 3
im AN
(10 mg/kg) (n=7)
Group 4
im AN
(100 mg/kg) (n=7)
Spontaneous proliferation (eduppu.)0,196±0,0160,217±0,0050,238±0,007
1-3p<0,05
2-3p<0,05
0,206±0,006
3-4p<0,01
IP (PHA)1,11±0,081,06±0,021,12±0,031,23±0,16
IP (LPS)1,94±0,221,53±0,152,09±0,07
2-3p<0,01
1,99±0,14
2-4p<0,05
Note: n - number of animals in the group.

were not significantly changed in the group using them-SO in a dose of 10 mg/kg and 100 mg/kg, However, the stimulation index of lymphocytes in both experimental groups with the course introduction to them-SO in a dose of 10 mg/kg and 100 mg/kg was significantly higher than the corresponding figure in the control group.

Example 6. Study of effect of immobilized oligonucleotides on products : the Yu of nitric oxide in the culture of peritoneal macrophages in vitro. The study drug (table 6) dose-dependently stimulated the production of nitric oxide in concentrations 3,3775 and 33,775 µg/ml.

Table 6
The effect of immobilized oligonucleotides on the production of nitric oxide peritoneal macrophages
Concentration
im AN (µg/ml)
NO (nitrite, µm)
the control(without addition of drug)19,0±1,0
0,0003421,4±1,9
0,0033819,9±1,3
0,0337819,7±1,5
0,3377518,9±1,7
3,3775027,0±2,5*
33,775049,5±3,2*
Note: * - significant differences from controls (p<0,05).

To elucidate the role of receptor TLR-9 stimulation of nitric oxide drug were used commercial ligand of TLR-9 (CpG-oligonucleotide ODN1826) and blocker TLR-9 (inhibitory oligonucleotide ODN2088). The results of the study are presented in table the CE 7. Stimulatory effect of CpG-oligonucleotide dose-dependently reversed by blocking the receptor TLR-9. The effect of the study drug were also abolished the inhibitory oligonucleotide ODN2088.

Thus, the study drug has a stimulating effect on macrophages. This action is mediated by macrophage receptor TLR-9.

Table 7
The role of TLR-9 stimulation of nitric oxide production by peritoneal macrophages immobilizerturning oligonucleotide
Conditions of cultivationProduction of nitric oxide in the presence of:
control-12.5 μm of the ligand of TLR-93,3775 μg/ml to them-AN33,775 μg/ml to them-AN
control-2014,3±0,5*6,7±1,0*10,4±0,6*
+ blocker TLR-9 1,25 µm07,8±0,6*#0#4,0±0,5*#
+ blocker TLR-9 2.5 μm 00#0#0#
Notes: * - significant differences with control-1 (p<0,05);
# - significant differences with control-2 (p<0,05).

Example 7. Study of the effect of immobilized oligonucleotides on the restoration of blood, suppressed by introduction of 5-fluorouracil. The introduction of them-DIVISION contributed to a significant increase in the absolute number of leukocytes in the peripheral blood during petticoating recovery of hemopoiesis (9th, 11th, 13th day) (table 8). Found in the experience of leukocytosis was a consequence of the accumulation of the number of lymphocytes and neutrophils within a specified time. Course introduction the study drug at a dose of 250 mg/kg increased the content of immature (on the 3rd and 5th days) and Mature (7 days) forms of neutrophilic granulocytes in comparison with the same parameters cytotoxic control (table). Course introduction to them-DIVISION contributed to the increase in the number of reticulocytes (13 days) and platelets (9th and 13th day) in the peripheral blood after administration of 5-FU (table 10, 11).

The table is 10
Influence of the preparation of immobilized oligonucleotides at a dose of 250 mg/kg on the dynamics of the content of reticulocytes in the peripheral blood of mice of CBA/CaLac treated with 5-fluorouracil (‰)
The timeframe of the study dayThe experimental group
5-fluorouracilImmobilized oligonucleotides
Intact control30,17±1,9230,17±1,92
316,29±1,38*13,57±1,19*
515,5±3,06*14,78±3,10*
711,78±1,25*14,20±1,40*
917,56±1,23*18,16±1,36*
1122,85±2,73*18,65±2,07*
P<0,02
1317,93±5,58*31,59±3,45
P<0,02

Thus, the use of the proposed method physical Immo is waste utilization technologies of DNA oligonucleotides salmon ROE of fish polyethylene oxide, mass of 1.5 kDa, allows to obtain a preparation for oral administration, which shows significant immunostimulirutuyu activity, which is expressed in the stimulation of the phagocytic reaction in vivo and in vitro, the increased production of IFN-γ in vitro, enhancing the cytotoxic activity of natural killer cells, the increase of spontaneous proliferative activity of lymphoid cells in experimental animals and stimulation index of lymphocytes, increase nitric oxide production, as well as gemostimuliruyuschee properties when introduced per os.

References

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4. Rykov EJ, Laktionov P.P., Vlasov V.V. Activating effect of DNA on the immune system // Successes of modern biology. - 2001. No. 121. - P.160-171.

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11. Goldberg ED, Digi A.M., Shah V.P. Methods of tissue culture in Hematology. - Tomsk: Publishing house of Tomsk state University, 1992. - 272 S.

The use of immobilized oligonucleotides, which are pieces of DNA molecular weight of 500-700 kDa purified proteolytic enzymes derived from an extract of salmon ROE, immobilized on polyethylene oxide by irradiation of a 10%aqueous solution of polyethylene oxide with a molecular weight of 1.5 kDa stream of accelerated electrons at a dose of 1.5 Mrad and entering in the irradiated solution of DNA oligonucleotides salmon ROE fish to a final concentration of 10 mg in 1 ml, as immunostimulating and haemostimulating tools for oral administration.



 

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6 dwg, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an aqueous composition for coating outer, inner, front and roof surfaces, having bactericidal action. The water paint composition contains elementary silver and at least one additional component selected from a group comprising a silver salt, chitosan and/or chitosan derivatives. The water paint composition contains at least one organic or inorganic binder, and can additionally contain ZnO nanoparticles with average size of 500 nm. The invention also relates to use of silver nanoparticles combined with at least one additional component selected from a silver salt, chitosan, chitosan derivatives and optionally ZnO nanoparticles as a bactericidal agent in aqueous compositions for painting inner, front, roof and outer surfaces. The method of applying the coating on inner, outer, front and roof surfaces of a building involves depositing the water paint composition.

EFFECT: obtaining a composition having highly efficient bactericidal action and does not have allergenic and toxic effect on the human body.

17 cl, 2 dwg, 1 ex

Nanobinder // 2412919

FIELD: chemistry.

SUBSTANCE: invention relates to production of binder for concrete and mortars used in construction, as well as for making articles based on binder, filler and/or aggregates and reinforcement and used in different engineering fields. The nanobinder includes a fractionated composition which can form liquid-tempering cured systems of the type of mono-structural rock or a strong mono-component aggregate which contains filler. More than half of the fractional composition contains particles with defining dimensions, which are traditional during cement production, formed by grinding the initial sintered cement clinker. The remaining part is in form of particles which are finer compared to those during production of conventional cement and include two nanofractions. The defining dimensions of the particles of the first nanofraction are not more than 0.14 times the least defining dimension of the particles of traditional cement grinding with weight percentage content in the binder equal to 1.2-35 wt %. The defining dimensions of the particles of the second nanofraction in the nanobinder are not more than 0.14 times the average statistical value of the corresponding parametres of the particles of the first of the said nanofractions with weight percentage content of 0.6-35% of the weight of the particles of the first of the said nanofractions.

EFFECT: good strength and main operational characteristics - frost resistance, longevity and water resistance of concrete and mortar.

1 ex

FIELD: process engineering.

SUBSTANCE: invention relates to electron-beam production of ultra dispersed materials. Proposed method comprises heating the substance by relativistic electron beam at atmospheric pressure to vapor-phase state, condensing vapors by cooling them in gas flow and separating the formed two-phase system. Two single-elements substances are subjected to heating to form a homogeneous melt the vapors of which form the particles of solid composite nanopowders of the core-shell type. Note here that condensation temperature of one substance is lower than that of the second substance and higher than condensation temperature of both substances. Note also that heating is carried out stage-by-stage, first, to produce homogeneous melt, and, second, to reach vapor-phase state on increasing electron beam power.

EFFECT: nanoparticles coated by thin shell from different substance, reduced sintering.

1 tbl, 7 dwg, 1 ex

FIELD: information technology.

SUBSTANCE: optical differentiating nanodevice consists of two constant optical signal sources, two input optical nanofibre Y-splitters, two optical nanofibre couplers, an optical nanofibre N-output splitter, an optical N-input nanofibre coupler, nanofibre and two extension nanotubes.

EFFECT: high-speed differentiation of coherent and incoherent optical signals, potentially possible for optical processor circuits, and nanodevice design.

1 dwg

FIELD: medicine.

SUBSTANCE: claimed group of inventions relates to medicine, namely to therapy and hematology, and concerns application of stabilisers of HIF-alpha for intensification of erythropoeisis. For this purpose introduced is inhibitor of HIF-prolylhydroxilase, which represents structural mimetic of 2-oxoglutarate, in efficient quantity.

EFFECT: invention ensures treatment and prevention of nemia of different genesis, including, refractive to exogenous introduction of erythropoietin (EPO), due to suppression of anti-inflammatory cytokines, inhibiting EPO synthesis in organism, as well as increase of expression of gene, coding proteins, taking part in synthesis of hemoglobin in vivo.

78 cl, 27 dwg, 5 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics, in particular deals with composition with prolonged release of active substance, representing iron source, containing at least one coated granule, said coated granule consisting of particle, which contains said active substance, covered with at least two coats, containing combination of excipients, as well as to method of obtaining it. Claimed compositions can be used for obtaining medication, intended for treatment and/or prevention of iron deficiency and anemia, induced by iron deficiency.

EFFECT: invention provides composition with prolonged release of active substance, possessing high stability and ensuring protection of active substance from oxidation.

30 cl, 2 ex, 3 dwg

FIELD: medicine.

SUBSTANCE: invention refers to veterinary science. A method involves feeding of 0.01% Phosphopag solution in a single dose 300.0 ml and Ecoe suspension in a single dose 250 mg/kg of body weight to newborn calves.

EFFECT: method allows recovering digestive system functioning, normalising blood rheology, normalising calves' growth and development.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is disclosed an application of complex iron (III) compounds with poly-maltha, hydrogenated dextrins or maltodextrin oxidation products for reparing an oral drug for iron deficiencies in patients suffering a chronic inflammatory intestinal disease, particularly Crohn's disease and nonspecific ulcerative colitis. When having been administered, the declared drugs have not invoked oxidative stress in contrast to iron sulphate therapy.

EFFECT: declared compounds are well tolerable, provide high compliance.

8 cl, 1 dwg, 3 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing a microelement drug on the basis of an iron-dextrin complex. The method includes the following stages: mixed water-soluble iron (III) salt and one or more water-soluble salts containing other microelements, e.g., cobalt, copper, zinc, manganese and selenite, and low-molecular dextrin are neutralised before sedimentation of iron (III) hydroxide, alkalised to pH 9-11, heated up to complete resolution and neutralised with an acid. Then, membrane ultrafiltration procedure is used to purify the prepared colloidal iron-dextrin complex with microelement atoms deposited in a polymeric covalent lattice of iron (III) oxide, and to concentrate it.

EFFECT: method allows preparing high-effective high iron fixation polymicroelement drug ensuring the best effect in treating iron-deficient conditions and promoting immune system resistance.

3 cl, 2 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to neurology, neurosurgery and resuscitation, and concerns treating hypertension-hydrocephalic syndrome. That is ensured by the prescription of iron preparations only in patients with low peripheral blood haemoglobin regardless of sex and age, before the administration of a common pharmacotherapy.

EFFECT: method provides effectively treating hypertension-hydrocephalic syndrome ensured by reduced hypoxia and related hydrophilism of cerebral tissues.

7 tbl

FIELD: medicine, veterinary science.

SUBSTANCE: invention refers to veterinary science. The method involves three intramuscular introduction of ferroglucin 75 mg (1 ml) every 5 days, three intramuscular introduction of phosprenyl by different syringes in different points simultaneously with an iron preparation, 0.12 ml/kg for the first injection, 0.10 ml/kg for the second injection, 0.08 ml/kg for the third injection, and the intramuscular injections of gamavit 0.018 ml/kg once a day for eight days starting with the first injection of ferroglucin.

EFFECT: method allows to prevent vascular complications in newborn calves with anaemia, to optimise microcirculation and tissue trophism, to hasten the growth, to improve a herd, to produce greater amount of meat production, to produce an expected healthy posterity from these animals.

1 ex

FIELD: medicine, veterinary science.

SUBSTANCE: invention refers to veterinary science. The method involves prescription of two intramuscular injection of ferroglucin 150 mg (2 ml) every 10 day, three intramuscular injections of phosprenyl in different syringes into different points, 0.12 ml/kg for the first time together with an iron agent, 0.10 ml/kg five days after the first injection of ferroglucin, 0.07 ml/kg for the third time together with the second injection of ferroglucin and intramuscular injections of gamavit 0.020 ml/kg once a day for eight days starting with the first injection of ferroglucin.

EFFECT: method allows to normalise spontaneous erythrocyte aggregation in suckling calves with anaemia, to provide higher additional weights, to reduce mortality and to produce an expected healthy posterity from these animals.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazopyrazines of formula where Q1 and R1 have the values specified in the patent claim, and to their pharmaceutically acceptable salts showing IGF-1R enzyme inhibiting activity and applicable for treatment and/or prevention of various diseases and conditions which are sensitive to tyrosine kinase inhibition.

EFFECT: preparation of the compounds showing IGF-1R enzyme inhibiting activity.

27 cl, 294 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns application of at least one Lactobacillus plantarum strain specified from the group containing Lactobacillus plantarum 299, DSM 6595, Lactobacillus plantarum 299v, DSM 9843, Lactobacillus plantarum HEAL 9, DSM 15312, Lactobacillus plantarum HEAL 19, DSM 15313, Lactobacillus plantarum HEAL 99, DSM 15316 for preparing a composition improving adsorption iron or its ions by a mammal, preferentially a human. The composition contains a material carrier which is fermented by one or more strains specified from said group of lactic acid bacilli. To ensure better adsorption of iron or its ions, this composition is introduced in a mammal, preferentially a human. Said lactic acid bacilli are applied for preparing a pharmaceutical composition for treating anaemia.

EFFECT: invention provides better adsorption of iron or its ions, improves the general health and individual health due to better body adsorption of iron.

17 cl, 2 tbl

FIELD: medicine, veterinary science.

SUBSTANCE: method for preparing an immunostimulating drug for animals consists in the fact that stevioside is dissolved in 0.9 % physiologic saline, the prepared solution is added to pre-grinded lecithin, then olive oil heated to 35-40°C is introduced gradually in the prepared composition and mixed; further the prepared solution is filtered and autoclaved at temperature 115-120°C for 15-20 minutes, then the produced sterile drug is bottled and corked up. The immunostimulating drug for animals contains stevioside, 0.9 % physiologic saline, olive oil, lecithin in a certain ratio.

EFFECT: higher viability and productivity of animals by correcting body immune responsiveness.

2 cl, 4 tbl, 8 ex

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