Synthetic immunogen for protection against toxic action of narcotic and psychoactive substances

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to immunology, and can be used for treating drug abuse, industrial and domestic poisonings, and in man-induced disasters, etc. The invention represents a synthetic immunogen for the protection against toxic action of narcotic and psychoactive substances. The immunogen is presented in the form of a conjugate of a macromolecular carrier specified in: natural or artificial protein, oligo- and polypeptide, carbohydrate, lipid or nucleotide, and haptene - a narcotic or psychotropic compound, and additionally contains poly(4-nitrophenyl)acrylate covalently bond to the conjugate within the range of ratios 2 to 7 moles of the conjugate per one mole of poly(4-nitrophenyl)acrylate with the ratio of haptene and the macromolecular carrier in the conjugate makes 2-17 moles of haptene per 1 mole of the carrier.

EFFECT: using this invention leads to eliciting a stable immune response for a long period of time and providing the body protection against toxic action of the narcotic and psychotropic substances by produced specific haptene antibodies.

3 cl, 4 tbl, 29 ex

 

The invention relates to medicine, in particular to immunology, and can be used in the toxic action of various forms of drugs, poisoning with various poisons in industry and everyday life, when man-made disasters and the like, for the treatment and prevention of the abuse of narcotic and psychoactive substances.

Known synthetic immunogen for the treatment and prevention of the misuse of drugs (in particular, opiate dependence), which represents the conjugate as a carrier is a natural or artificial protein and hapten - narcotic or psychotropic compounds. And as the media it contains bovine serum albumin or synthetic polypeptides and glycoproteins, and the hapten - morphine, or codeine, or heroin, or methadone, or the like ([see Kovalev IE, Field O.Y "the Biochemical basis of immunity to low molecular weight chemical compounds". M.: Nauka, 1985).

However, this immunogen carrier impurities, reducing its therapeutic (immunostimulirutuyu) the activity requires the use of large doses (up to 20 mg/kg), additionally, the length of immunization reaches 6 months, and achievement of stable and/or prolonged immunity is not always possible.

Famous adopted for the prototype synthetic immunogen for the treatment and p is opractice abuse of narcotic and psychoactive substances, represents the complex conjugate as macromolecular carrier is a natural or synthetic protein (egg albumin, or human gamma globulin, or microbial toxins) and hapten - narcotic or psychotropic compounds of the following groups of low molecular weight compounds: aromatic propanamine, or isoquinolines, or diphenylmethane, or indolamine, or derivatives of barbituric acid, or derivatives substituted piperidinol with the polymer matrix, which take immunocompetent polyelectrolyte polyoxidonium. Ratio, wt.%: conjugate polyoxidonium is 1:1,5-5,0. This immunogen has a high immunological activity at lower doses and duration of treatment up to 12 months (RF patent No. 2236257, IPC7A61K 39/385, A61K 39/39, published. 20.09.2004).

However, the duration of immunization (resistance humoral immunity), provided by the use of this immunogen is insufficient.

The present invention is the creation of immunogen, which for a long time allows you to keep the body stable immune response and reduces the toxic effect of drugs and psychoactive substances due to persistent high titers of specific antibodies.

The problem is solved in that in the known synthetic immunogen d the I protection against the toxic effects of narcotic and psychoactive substances, representing the conjugated macromolecular carrier selected from the range: natural or synthetic protein, oligo - and polypeptide, carbohydrate, lipid or nucleotide, and hapten - narcotic or psychotropic compounds, it is new that it further comprises poly(4-nitrophenyl)acrylate, which is covalently linked to conjugate in the range of ratios of from 2 to 7 moles of conjugate per mole of poly(4-nitrophenyl)acrylate, the ratio of hapten and macromolecular carrier in the conjugate is 2-17 of moles of hapten per 1 mol of the media.

As a macromolecular carrier selected from the group of natural proteins, it contains a compound selected from the range: ovalbumin, human gamma globulin, albumin, lysozyme, microbial toxins, proteins of the blood serum.

As a hapten, it can contain narcotic or psychotropic compound selected from a number of opiates, such as morphine, heroin, codeine, cannabinoids such as Delta-9-tetrahydrocannabinol, amphetamine, such as methamphetamine, ecstasy, cocaine, such as benzoylecgonine, barbiturates, such as barbanel, phenobarbital, benzodiazepines, such as gydesen, methadone, phencyclidine, tricyclic antidepressants, cotinine and their derivatives and metabolites.

The ratio of hapten and macromolecular carrier in conjugate with the element 2-17 of moles of hapten per 1 mol of the carrier, is optimal to obtain the immunization of more than affine and specific antibodies to this class of haptens. If the ratio is less than 2:1, the antibodies are not produced if more than 17:1, that produces low-affinity nonspecific antibodies that give cross-reactions with other classes of substances.

The inventive synthetic immunogen provides an effective immune response due to the covalent bond of the conjugate with poly(4-nitrophenyl)acrylate, which in standard conditions allows to reproduce the structure of the immunogen in a predetermined range of ratios, achieving increasing the duration of persistent humoral immunity to 18 months.

The range of ratios of from 2 to 7 moles of conjugate per mole of poly(4-nitrophenyl)acrylate provides standardization and control of pharmacological effect in predetermined proportions in the formation and consolidation of the structure of the immunogen. Our studies have shown that when the ratio of 1:1 complex is formed small in size, not able to induce persistent humoral response and to ensure the production of antibodies, and the use ratio of the conjugate and poly(4-nitrophenylacetate) more than 1:7 does not allow to form stable covalent bonds. The ratio of 1:7 gives the maximum possible stable and reproducible replacement of the polymer m is tricy conjugate with the hapten.

Using the proposed synthetic immunogen specific media and haptens protects the human body from a wide range of toxic substances (including drugs, industrial poisons, various carcinogens).

Analysis of the known technical solutions allows us to conclude that the invention is not known from the level of the investigated technique that demonstrates its compliance with the criterion of "novelty".

The essence of the present invention for professionals not obvious from the prior art, which allows to make a conclusion about its compliance with the criterion of "inventive step".

The possibility of preparation of synthetic immunogen of the available industrially produced components on conventional equipment using known methods to achieve the objectives demonstrates compliance invention, the criterion of “industrial applicability”.

Table 1 presents summary data for the study of the specificity of the antibodies obtained by immunization of rabbits with synthetic immunogenum.

Table 2 presents data on the specificity of antibodies, isolated by affinity chromatography from serum of patients with opium addiction, where * is the specificity is less than 0.001.

Table 3 presents data on the definition of scanty affinity (Ka) for antibodies to morphine, isolated from the serum of blood donors and patients with opium addiction.

Table 4 presents the formulations of synthetic immunogen known and taken for the prototype, as well as their pharmacological action.

In the present invention, the term inhibitor refers to a substance that is used in the procedure of the competitive ELISA to assess the specificity and affinity of antibodies. As inhibitors used compounds structurally related to the hapten, which is part of the declared immunogen, as well as drugs and number of psychotropic medicines other chemical nature. This methadone, pseudoephedrine, norephedrine, barbanel, cannabinol, morphine, heroin, codeine and other

These examples suggest, but do not limit the claimed invention.

Synthesis of conjugates of macromolecular carriers with haptens.

The introduction of carboxyl-containing derivatives, contributing to the reaction of binding of the hapten with a macromolecular carrier, for opiates, cocaine, barbiturates, benzodiazepines was carried out by their interaction with chlorinated acetic and succinic acids in absolute solvent.

Synthesis of carboxyl derivatives of cannabinoids, amphetamine, methadone, phencyclidine, tricyclic antidepressants, cotinine conducted what about the reaction of diazotization with p-aminobenzoic acid.

On the basis of modified narkotikatidskrift and psychotropic substances prepared conjugates, in which these substances are covalently linked to macromolecular carriers.

The condensation reaction carboxyl-containing derivatives of haptens with macromolecular carrier was carried out by the method of activated esters or by using water-soluble carbodiimide, glutaraldehyde, or isobutylphthalate. Macromolecular carriers contained above haptens in the range of ratios of from 2:1 to 17:1 of moles of hapten per mole of the macromolecular carrier. Method of purification of the synthesized conjugates was used column gel chromatography (Sephadex G-25).

The number of moles of hapten by contacting macromolecular protein carrier, was determined using the comparative spectral analysis in the ultraviolet and visible regions.

Example 1. Synthesis of conjugate of morphine with ovalbumin

A solution of 50 mg (0.001 mmol) of ovalbumin in 5.0 ml of distilled water was mixed with 2.0 ml dimetilformamida (DMF)containing 15,0 mg (0,039 mmol) 6-(3-(aminohexanoate)-propionate)morphine and cooling was added dropwise a solution of 15 mg (by 0.055 mmol) of water-soluble carbodiimide in 3 ml of distilled water. The reaction mixture was incubated for 5 h at 4°C. the resulting conjugate vyd the Lyali gel-chromatography on a column of Sephadex G-25 and freeze-dried.

Received 25 mg of morphine conjugate with ovalbumin (M-OVA)containing 5 moles of morphine per mole of protein.

Example 2. Synthesis of conjugates of amphetamine with ovalbumin

Derived d 1-1-phenyl-2-aminopropane (5 mg; 0,112 mmol) and (10 mg; 0,00022 mmol) of ovalbumin was dissolved in 3.0 ml of 0.1 M phosphate buffer. Dropwise with stirring to the reaction mixture was added 70 μl (0.3 mmol) of a solution of glutaraldehyde at room temperature. Gradually the reaction mixture was acquired characteristic yellow color, indicating the end of the reaction. To stop the reaction, to the mixture was added 40 μl of 1M solution of lysine and incubated for 1 hour. The resulting conjugates were dialyzed against phosphate buffer overnight at 4°C. the Selection of the conjugate was performed by gel-chromatography on a column of Sephadex G-25 and freeze-dried. Received 5 mg of the conjugate, containing 12 moles of amphetamine per mole of protein.

Example 3. Synthesis of conjugate of cocaine with ovalbumin

Conjugate of cocaine with ovalbumin (Kok-OVA) was obtained according to the method of example 1 from 50 mg (0.001 mmol) of ovalbumin and 2.0 mg (0.005 mmol) benzoylecgonine.

Received 29 mg of the conjugate Kok-OVA containing 14 mol of cocaine per mole of protein.

Example 4. Synthesis of conjugate tetrahydrocannabinol with ovalbumin

To a solution of 15 mg (3,3×10-3mmol) of ovalbumin in 3 ml distilled the ode was added a solution of 7.4 mg (0.02 mmol) of the substance Delta-9-tetrahydrocannabinol, modified by reaction Asociatia with p-aminobenzoic acid in 1 ml DMF, cooled the reaction mixture to 0°C and under stirring was added 5 mg of water soluble carbodiimide. The reaction mixture was stirred for 12 hours in the refrigerator, the precipitation of urea and highlighted the obtained conjugate by gel-chromatography on Sephadex G-25.

Received 10 mg of conjugate tetrahydrocannabinol with ovalbumin (Δ9TGK-OVA), containing 15 moles of hapten per mole of protein.

Example 5. Receiving morphine conjugate to lysozyme

To a solution of 50 mg (3,57×10-3mmol) of lysozyme in 2.5 ml of 0.3 M solution of NaHCO3added upon cooling, 0.3 ml of a solution of the mixed anhydride of 6-succinylamino obtained from 19,2 mg (0.05 mmol) of 6-succinylamino and 6.0 μl of isobutylacetate. The reaction mixture is incubated for 18 hours. At 4°C produced morphine conjugate to lysozyme was isolated by gel-filtration on a column of Sephadex G-25 and freeze-dried.

Received 30 mg of morphine conjugate to lysozyme (M-Liz).

The number of attached morphine was calculated according to the UV-spectra of the original protein and the conjugate according to the change of the absorption at 280 nm. According to the UV spectra obtained in the conjugate contained 12 moles of morphine per mole of protein.

Example 6. Obtaining conjugates of morphine with polylysine (M-Polylith)

A solution of 50 mg (0.001 mmol) polylysine (polystructure peptides) in 5.0 ml of distilled water was mixed with 2.0 ml of DMF, containing 15,0 mg (0,039 mmol) of 6-succinylamino, and cooling was added dropwise a solution of 15 mg (by 0.055 mmol) of water-soluble carbodiimide in 3 ml of distilled water. The reaction mixture was incubated for 5 h at 4°C. the resulting conjugate was isolated by gel chromatography on a column of Sephadex G-25 and freeze-dried.

Received 25 mg of morphine conjugate with polylysine (M-Polylith)containing 10 moles of morphine per mole of protein.

Example 7. Obtaining conjugates of morphine with polylysine (M-Polylith)

A solution of 27 mg (0,0006 mmol) polylysine in 30 ml of 0.25 M solution of NaHCO3was added to a solution of the mixed anhydride of 3-O-carboxymethylation. The mixture was stirred at 0°C during the night. The selection of the conjugate was performed by gel-filtration on a column of Sephadex G-25 and freeze-dried.

Received 20 mg of morphine conjugate with polylysine (M-Polylith)containing 2 mol of morphine per mole of protein.

Example 8. Getting conjugate Δ9-tetrahydrocannabinol with gamma-globulin (Δ9TGK-gamma-globulin)

To a solution of 15 mg (3,3×10-3mmol) of gamma globulin in 3 ml of distilled water was added a solution of 7.4 mg (0.02 mmol) substances derived 4-carboxyphenyl-azo Δ9-tetrahydrocannabinol (cannabinoid) in 1 ml DMF, cooled the reaction mixture to 0°C and under stirring was added 5 mg of water soluble carbodiimide. actionnow the mixture was stirred for 12 hours in the fridge the precipitation of urea and highlighted the obtained conjugate by gel-chromatography on Sephadex G-25.

Received 12 mg of conjugate Δ9-tetrahydrocannabinol with gamma-globulin (Δ9TGK-gamma-globulin)containing 5 moles Δ9-tetrahydrocannabinol per mole of protein.

Example 9. Synthesis of conjugated antigens of amphetamine with diphtheria tocina (A-Dt)

In the same way as in example 2, was used derivative d 1-1-phenyl-2-aminopropane (2 mg; 0.06 mmol) and 10 mg (0,00022 mmol) protein of diphtheria toxin, which was dissolved in 2.0 ml of 0.1 M phosphate buffer. Next carried out the operations described in example 2. Received 7 mg of the conjugate, containing 6 moles of amphetamine per mole of protein.

Example 10. Obtaining a conjugate of Barbara with gamma-globulin (G-gamma-globulin)

In the same way as in example 8, using a solution of 15 mg (3,3×10-3mmol) of gamma globulin in 3 ml of distilled water to which was added while cooling and stirring, a solution of 1 ml of DMF containing 5.2 mg (0.03 mmol) of Barbara, derivative of barbituric acid and 5 mg of water soluble carbodiimide. Then he has followed the procedure as in example 8.

Received 10 mg of the conjugate of Barbara with gamma-globulin (G-gamma-globulin), containing 6 moles of Barbara per mole of protein.

Obtaining synthetic immunogen complex, consisting of a macromolecular conjugate but what of Italia in the form of natural or artificial protein and hapten - narcotic or psychotropic compounds covalently associated with a polymeric matrix in the form of poly(4-nitrophenyl)acrylate.

Preparation of synthetic immunogens carried out by known conventional methods, by keeping the ratio of hapten and macromolecular carrier in accordance with the proposed invention

The reaction was performed using poly(4-nitrophenyl)acrylate. The conjugate contained above macromolecular carriers and haptens in ratios from 2:1 to 17:1 of moles of hapten per mole of the macromolecular carrier (Examples 1-10).

Control over the degree of covalent binding of poly(4-nitrophenyl)acrylate with a macromolecular conjugate of a carrier in the form of natural or artificial protein and hapten - narcotic or psychotropic compounds were carried out spectrophotometrically by the number formed in the reaction of p-NITROPHENOL.

Example 11. Getting immunogen consisting of a conjugate of ovalbumin with morphine (M-OVA), covalently linked to poly(4-nitrophenyl)acrylate with a ratio of 7 moles of conjugate per mole of poly(4-nitrophenyl)acrylate

To a solution of 6 mg of poly(4-nitrophenyl)acrylate (mV 40000) in 1.5 ml of dimethyl sulfoxide (DMS) add 3.8 mg M-OVA obtained in example No. 1, containing as hapten 6-(3-(aminohexanoate)-propionate)morphine videris the Ute, the reaction mixture during the day at 20°C, and then add 200 ál of 25% ammonia. The solvent is evaporated in vacuum. The remaining oil is washed repeatedly with ether.

Get complex with 7:1 substitution of the polymer matrix conjugate of morphine with a spacer on the 6th position of the morphine molecule.

Example 12. Getting immunogen consisting of ovalbumin conjugate (M-OVA) with morphine, covalently linked to poly(4-nitrophenyl)acrylate at a ratio of 5 moles of conjugate per mole of poly(4-nitrophenyl)acrylate.

Same as in example 11, only as a source of connection take 3.5 mg of poly-(4-nitrophenyl)acrylate in 1 ml LCA and 2 mg M-OVA obtained in example No. 1, containing as hapten (6-(3-(aminohexanoate)-propionate)of morphine.

The resulting complex has a 5:1 substitution of the polymer matrix conjugate with a derivative of morphine with a spacer on the 6th position of the morphine molecule.

Example 13. Getting immunogen consisting of a conjugate polylysin (M-Polylith) with morphine, covalently linked to poly(4-nitrophenyl)acrylate with a ratio of 3 moles of conjugate per mole of poly(4-nitrophenyl)acrylate.

Same as in example 11, only as a source of connection take 5 mg of poly(4-nitrophenyl)acrylate in 2 ml of DMF and 3 mg of the conjugate M-Polylith obtained in example No. 7.

The resulting complex has a 3:1 replacement polymer matrix conjugate polylysine with Spey the leader (3-O-carboxymethylamino) at the 3rd position of the morphine molecule.

Example 14. Getting immunogen consisting of a conjugate gamma globulin with Δ9-tetrahydrocannabinol (Δ9TGK-gamma-globulin), covalently linked to poly(4-nitrophenyl)acrylate with a ratio of 2 moles of conjugate per mole of poly(4-nitrophenyl)acrylate.

Same as in example 11, only as a source of connection take 3.5 mg of poly(4-nitrophenyl)acrylate in 1 ml LCA and 2 mg of conjugate Δ9TGK-gamma-globulin, obtained in example 8.

The resulting complex has a 2:1 replacement polymer matrix conjugate Δ9TGK-gamma-globulin.

Example 15. Getting immunogen consisting of a diphtheria toxin conjugate of amphetamine, covalently linked to poly(4-nitrophenyl)acrylate with a ratio of 4 moles of conjugate per mole of poly(4-nitrophenyl)acrylate.

Same as in example 11, only as a source of connection take 3.5 mg of poly(4-nitrophenyl)acrylate in 1 ml LCA and 2.5 mg of conjugate amphetamine-diphtheria toxin obtained in example No. 9.

The resulting complex has a 4:1 replacement of a polymeric matrix of poly(4-nitrophenyl)acrylate conjugate amphetamine-diphtheria toxin.

Example 16. Getting immunogen consisting of a conjugate gamma globulin with barbarian, covalently linked to poly(4-nitrophenyl)acrylate with a ratio of 2 mol of conjugate per mole of poly(4-nitrophenyl)acrylate.

What primere 11, just as the initial connection charge 3.5 mg of poly(4-nitrophenyl)acrylate in 1 ml LCA and 3 mg of the conjugate barbanel-gamma-globulin, obtained in example No. 10.

The resulting complex has a 6:1 substitution of the polymer matrix conjugate barbanel-gamma-globulin.

Pharmacological action of synthetic immunogens with a variety of the above macromolecular carriers and haptens is characterized by the synthesis of antibodies specific for each of the hapten. These results are based on repeated tests carried out on mice, rabbits, and volunteer groups (in accordance with article 124 of the criminal code, St of the fundamentals of legislation on health protection of citizens, and article 21, part 2 of the Constitution). For these purposes, used formulations of synthetic immunogen presented in examples 11-16 with various macromolecular carriers and haptens and ratios (conjugate poly(4-nitrophenyl)acrylate) in the claimed limits

Synthetic immunogen was administered to patients in the form of a solution subcutaneously in the amount of 0.5 ml After two weeks, the procedure was repeated and then continued introduction of the immunogen 1 time per week for six weeks. The rise time of an active immune response was determined by standard methods enzyme-linked immunosorbent assay (ELISA). Patients were under regular observation of change is the group of health for 3 years.

To obtain serum containing specific antibodies, used 6 rabbits (males) weight 2.5 kg Immunization was performed by introduction of synthetic immunogen consisting of a conjugate of the hapten with a macromolecular carrier covalently linked to poly(4-nitrophenyl)acrylate in a predetermined ratio, at the rate of 1 mg per rabbit. During the month, with an interval of 7 days was performed injections of 0.2 ml in 4 point near the spine at the shoulders and rump. Immunization of rabbits drug on the scheme resulted in the serum of high titers of antibody to the immunogen. The results were evaluated by ELISA. In response to the direct ELISA found that the resulting antibodies have a titer from 1:6000 to 1:12000. In the competitive ELISA is the binding of the hapten. The titer of antibodies to immunocomplex decreased to 1:400 using the concentration of the hapten of 0.001 mol, which indicates the presence of antibodies to this connection.

Preclinical studies

In animal experiments it was shown that the obtained synthetic immunogen able to induce immune responses with the appearance of antibodies that specifically interacts with the hapten and neutralizing their activity in the body. In a series of experiments investigated the possibility of neutralizing the toxic effects of morphine in animals.

Example 17. Group the e control animals, consisting of six unimmunized rabbits, and the experimental group, which includes six rabbits pre-immunized with a synthetic immunogen morphine-ovalbumin-poly(4-nitrophenyl)acrylate, according to the above scheme, was intravenously injected absolutely lethal dose of morphine 100 mg/kg (LD100). It was found that all six rabbits of the control group died from a specified lethal dose.

Among the immunized rabbits death is not registered in any of the six cases, i.e. there has been a clear immunological protection formed during immunization with specific antibodies.

Example 18. Similar to the above Example 17 was conducted studies in two groups of six adult mongrel rats of both sexes. One group was immunized with a synthetic immunogen amphetamine-diphtheria toxin-poly(4-nitrophenyl)acrylate based 30 mg/kg was administered the lethal dose of psychoactive substances meth animals first and second groups. It is established that the animals died in the control group who did not receive the immunogen.

Among immunized rats death is not registered in any of the six cases, i.e. there has been a clear immunological protection formed during immunization with specific antibodies.

Example 19. Similar to the above Example 17 six Polo is zrelyh outbred rats of both sexes were immunized with a synthetic immunogen barbanel-gamma-globulin-poly(4-nitrophenyl)acrylate (hapten from the group of derivatives of barbituric acid at the rate of 30 mg/kg Was administered a lethal dose of sleeping pills - barbiturate. The animals died in the control group who did not receive the immunogen.

Among immunized rats death is not registered in any of the six cases, i.e. there has been a clear immunological protection formed during immunization with specific antibodies.

Research on the above scheme, made for haptens that are included in the claimed composition immunogen showed similar results. Thus, the synthesized immunocomplex specifically binds the hapten not only in vitro, but also in the whole organism.

Example 20. Determination of the specificity of the antibodies generated by immunization with a synthetic immunogen, the composition of which is presented in table 1.

The next step was to evaluate the immunochemical properties of the antibodies generated in the process of immunization. Specificity was studied in the test competitive ELISA. To do this, in solid-phase ELISA as inhibitors used compounds structurally related to the hapten, which is part of the declared immunogen, as well as drugs and number of psychotropic medicines other chemical nature.

For each of these compounds was determined by the concentration at which 50% inhibition of the interaction antiJapanese antibodies to the antigen on TV is rdeu phase. Specificity was calculated as the percentage ratio of molar concentrations of the analyte and the original hapten. The results of the study of the specificity of the antibodies shown in table 1.

According to table 1 shows that only immune rabbit antibodies to haptens, forming part of the claimed immunogen, did not give cross-reactions with compounds of other classes and to a lesser extent react with structurally related substances, and interacted only with haptens, included in the complex conjugate with a macromolecular carrier. So, for immunogen consisting of a conjugate of ovalbumin with morphine (M-OVA), covalently linked to poly(4-nitrophenyl)acrylate with a ratio of 7 moles of conjugate per mole of poly(4-nitrophenyl)acrylate (example 11)produce antibodies specifically reactive with morphine, heroin and, to a lesser extent with codeine. Cross-reaction of no with methadone, amphetamine, cannabinoids, cocaine and other substances not belonging to the class of opiates. Similar results were obtained for immunogen consisting of a conjugate polylysin (M-Polylith) with morphine, covalently linked to poly(4-nitrophenyl)acrylate with a ratio of 3 moles of conjugate per mole of poly(4-nitrophenyl)acrylate (example 13). For immunogen consisting of a conjugate gamma globulin with Δsup> 9-tetrahydrocannabinol (Δ9-THC), covalently linked to poly(4-nitrophenyl)acrylate with a ratio of 2 moles of conjugate per mole of poly(4-nitrophenyl)acrylate, specific reaction of antibodies is observed only for cannabinoids (example 14). For immunogen consisting of a diphtheria toxin conjugate of amphetamine, covalently linked to poly(4-nitrophenyl)acrylate, with a ratio of 4 moles of conjugate per mole of poly(4-nitrophenyl)acrylate antibodies react with amphetamine and to a lesser extent with methamphetamine in the absence of reaction with the structures of ephedrine, as well as compounds of other classes (example 15). For immunogen consisting of a conjugate gamma globulin with barbarian, covalently linked to poly(4-nitrophenyl)acrylate with a ratio of 2 mol of conjugate per mole of poly(4-nitrophenyl)acrylate obtained antibodies interact with barbarian and to a lesser extent with phenobarbital, preventing cross-reactions with compounds of other classes (example 16).

Calculation of affinity constant (Ka) for specific antibodies in the immune serum. Based on the curves of the competitive ELISA, using as an inhibitor of the hapten from the immunogen, Ka was determined as the reciprocal of the concentration of free inhibitor required for 50% inhibition of antibody (I5o), contacting immobilienbank the m on the tablet antigen. Ka=I/I50.

Ka antibodies from the serum of rabbits was 108-1010M-1.

Clinical studies.

Similar studies specificity were carried out with antibodies, isolated by affinity chromatography from serum of volunteers - addicts immunized with a synthetic immunogen is the complex conjugate of ovalbumin-morphine-poly(4-nitrophenyl)acrylate.

The immunogen was injected 10 volunteers suffering from opium addiction, age: 20-30 years. Duration of drug use: 2-10 years. The immunogen was injected subcutaneously in the upper third of the right shoulder and left hand alternately, once a week, 8-10 injections per course.

The effect of immunogen begins to develop after a latent period, which occurs from the moment the first injection and lasts for 2-3 weeks. The formation of cellular and humoral immune responses needed to neutralize drugs occurs by the end of 8-10 weeks from the beginning of immunization. This results in intense ripening clone of immune cells, causing the production of high-affinity, specific antibodies are stimulated under the influence of processes responsive cells of the immune system, resulting in the interaction of T - and B-lymphocytes, the functioning of macrophages, induced the formation of mononuclear cells. the human body accumulates antibodies able to bind doses of drugs or other toxic substances, and many times (8-12 times) exceeding lethal. Thus, immunization of the patient offered by the drug leads to the development of long-lasting tolerance to specific substances in the absence of any negative effects.

From the original 10 sera addicts antipathie antibodies selected in all samples. According to ELISA in the sera contained antibodies of IgG - and IgM-class against morphine, heroin and codeine, responsive to each of the metabolites. Generalized data on the specificity antimorphine antibodies isolated from the serum of patients with opium addiction, presented in table 2.

As can be seen from the table, all isolated from serum antibodies have their individual specificity and do not give cross-reactions with the studied inhibitors, substances of other classes: methadone, pseudoephedrine, norephedrine, barbanel, cannabinol - the percentage of cross-linking, indicating specific interaction, less than 0,001. Connection of the opium group, morphine, heroin show 100% binding to selected patients antibodies.

Calculation of affinity constant (Ka) (table 3) was carried out on the basis of the curves inhibitory ELISA, using as an inhibitor of morphine. CA was defined as the reciprocal of the end of the ation of the free inhibitor, required for 50% inhibition of antibody (I5o)contacting immobilized on the plate with antigen. Ka=I/I50.

As in the case of immune rabbit antibodies, antipathie antibodies isolated from the serum of the blood of drug addicts, practically do not interact with drugs of a different class. Antibodies isolated from the serum of patients with addiction compared to antibodies from rabbit immune sera have a lower affinity constant and a broader spectrum of specificity.

Thus, antibodies obtained by immunization of animals or human artificial synthetic immunogenum, can be used to neutralize the harmful effects of psychoactive substances, which in turn can be used to protect against the toxic effects in case of abuse of narcotic and psychoactive substances.

To confirm the data given in the table "Composition of synthetic immunogens and their pharmacological action," provides more information.

Formulations of synthetic immunogen known and taken for the prototype, as well as their pharmacological action, confirmed in examples 21-27, summarized in table 4.

Example 21

The patient is 20 years old, 4 years old opium addiction.

Initial laboratory data: 1 the l of blood plasma contains 2000 pmol germinomatous antibodies defined inhibitory ELISA.

Patients were immunized with a synthetic immunogen: the complex conjugate of ovalbumin:morphine:poly(4-nitrophenyl)acrylate (7:1)obtained in example 11.

Laboratory data (6 weeks from start of treatment with immunogen): ELISA 1 ml 80000 pmol germinomatous antibodies. After 9 weeks of Mature T-lymphocytes and stimulates the formation of antibodies that cause the maturation of b-lymphocytes, occurs lifelong cellular immunity; allergic reactions are absent.

Control and laboratory data (after 14 months of starting treatment with immunogen): ELISA 1 ml to 50,000 pmol. The amount of specific antibodies in 25 times greater than the original data, indicating a persistent immunity.

For a specified period of time (14 months) recurrence of the disease was not observed.

The data documented in the patient records.

Example 22

The patient is 30 years old, 3 years opium addiction.

Initial laboratory data: 1 ml blood plasma contains 2100 pmol germinomatous antibodies, detectable inhibitory ELISA.

Patients were immunized with a synthetic immunogen: the complex conjugate of ovalbumin:morphine:poly(4-nitrophenyl)acrylate (5:1)obtained in example 12.

Laboratory data (6 weeks from start of treatment with immunogen): ELISA 1 ml - 70000 pmol germinomatous the antibodies. After 9 weeks of Mature T-lymphocytes and stimulates the formation of antibodies that cause the maturation of b-lymphocytes, occurs lifelong cellular immunity; allergic reactions are absent.

Control and laboratory data (after 13 months of starting treatment with immunogen): ELISA 1 ml 60000 pmol. The amount of specific antibodies is approximately 30 times greater than the original data, indicating a persistent immunity.

For a specified period of time (13 months) recurrence of the disease was not observed.

The data documented in the patient records.

Example 23

The patient is 25 years old, 4 years opium addiction.

Initial laboratory data: ELISA 1 ml - 1600 pmol; the patient at the time of admission to the clinic determined the competitive ELISA intoxication and the presence of drug group opiates and cannabinoids.

Patients were immunized with a synthetic immunogen: the complex conjugate polylysin:morphine:poly(4-nitrophenyl)acrylate (3:1)obtained in example 13,

Laboratory data (6 weeks after the beginning of immunization): ELISA 1 ml - 75000 pmol of specific antibodies; determining the competitive ELISA content of opiates, cannabinoids - negative, i.e. enhanced sorption of metabolites and xenobiotics. After 9 weeks of Mature T-lymphocytes and stimulates the formation of antibodies that cause with revenue b-lymphocytes, occurs lifelong cellular immunity; allergic reactions are absent.

Control and laboratory data (after 16 months of starting treatment with immunogen): ELISA 1 ml 60000 pmol. The amount of specific antibodies in more than 35 times greater than the original data, indicating a persistent immunity.

For a specified period of time (16 months) recurrence of the disease was not observed.

The data documented in the patient records.

Example 24

The patient 32 years, 10 years galerna drug addiction.

Initial laboratory data: the IFA has determined that 1 ml contains 1500 pmol antibodies.

Patients were immunized with a synthetic immunogen: the complex conjugate gamma globulin with Δ9-tetrahydrocannabinol: poly(4-nitrophenyl)acrylate (2:1)obtained in example 14.

Laboratory data: IF ml - 91000 pmol (after 6 weeks from the start of the immunization strengthening the detoxification function of the body is installed in the test competitive ELISA. Increased production of antibodies; resistance humoral immunity; the absence of allergic reactions; life cell-mediated immunity.

Control and laboratory data (18 months from start of treatment with immunogen): ELISA 1 ml to 50,000 pmol (increase of specific antibodies more than 30 times, and save them in the body).

For a specified period of time (1 month) no disease recurrence was observed.

The data documented in the patient records.

Example 25

The patient is a 27 years, 5 years - the abuse of psychostimulants amphetamine.

Initial laboratory data: the IFA has determined that 1 ml contains 1500 pmol antibodies.

Patients were immunized with a synthetic immunogen complex conjugate diphtheria toxin:amphetamine and poly(4-nitrophenyl)acrylate obtained in example 15.

Laboratory data: ELISA 1 ml - 91000 pmol of specific antibodies (after 6 weeks from the start of the immunization), increases the production of antibodies. After 8 weeks of Mature T-lymphocytes and stimulates the formation of antibodies that cause the maturation of b-lymphocytes, occurs lifelong cellular immunity; resistance humoral immunity; the absence of allergic reactions;

Control laboratory data: (after 15 months of starting treatment with immunogen) ELISA 1 ml - 52000 pmol antibodies (increase of specific antibodies more than 30 times, and save them in the body).

For a specified period of time (15 months) recurrence of the disease was not observed.

The data documented in the patient records.

Example 26

The patient is 30 years old, 8 years, the abuse of drugs barbituric acid. Initial laboratory data: the IFA has determined that 1 ml contains 1900 pmol antibodies.

The patient and what was monitorovali synthetic immunogen: the complex conjugate gamma globulin:barbanel:poly(4-nitrophenyl)acrylate, obtained in example 16.

Laboratory data: ELISA 1 ml - 85000 pmol (after 6 weeks from the start of the immunization). Increased production of antibodies; resistance humoral immunity; the absence of allergic reactions; life cell-mediated immunity.

Control laboratory data: (within 18 months of starting treatment with immunogen) ELISA 1 ml to 50,000 pmol (increase of specific antibodies in more than 25 times and save them in the body).

For a specified period of time (18 months) recurrence of the disease was not observed.

The data documented in the patient records.

Example 27

6 adult rats of both sexes were immunized with a synthetic immunogen complex conjugate diphtheria toxin:amphetamine and poly(4-nitrophenyl)acrylate obtained in example 15, at a rate of 40 mg/kg

Laboratory data: ELISA 1 ml - 75000 pmol (5 weeks after the beginning of immunization).

Was administered the lethal dose of psychoactive substances meth.

Control laboratory data: ELISA 1 ml - 54000 pmol. Antibody synthesis; absence of allergic reactions.

Example 28

6 adult rats of both sexes were immunized with a synthetic immunogen complex conjugate gamma globulin:barbanel:poly(4-nitrophenyl)acrylate obtained in example 16, at the rate of 50 mg/kg

Laboratory data: ELISA 1 ml - 76000 pmol (after 5 h the del after the beginning of immunization).

Was administered a lethal dose of sleeping pills - barbiturate.

Control laboratory data: ELISA 1 ml - 57000 pmol. Antibody synthesis; absence of allergic reactions.

Example 29

6 adult rats of both sexes were immunized with a synthetic immunogen complex conjugate of ovalbumin:morphine:poly(4-nitrophenyl)acrylate obtained in example 12, at the rate of 30 mg/kg

Laboratory data: ELISA 1 ml - 85000 pmol of specific antibodies to heroin (4 weeks after the beginning of immunization). Was administered a lethal dose of drugs heroin 100 mg/kg

Control laboratory data: ELISA 1 ml 60000 pmol antibody Synthesis; absence of allergic reactions.

As seen from the above examples and data of table 4, the use of the claimed synthetic immunogen allows any method of administration to synthesize in the body of the antibodies in the absence of allergic reactions; this ensures lifelong cellular immunity; strengthen the detoxifying functions of the body, sorption of metabolites and xenobiotics. Persistence of humoral immunity in comparison with the prototype increases from 12 to 18 months.

10
Table 1
SYNTHETIC IMMUNOGEN FOR the TREATMENT AND PREVENTION of ABUSE THE RESPONSE to DRUG AND SUBSTANCE
The connection used as an inhibitor in the competitive ELISASpecificity, %
The composition of the synthetic immunogen
ovalbumin morphine poly(4-nitrophenyl) acrylategamma globulin cannabinoid poly(4-nitrophenyl) acrylatediphtheria toxin amphetamine poly(4-nitrophenyl) acrylategamma globulin barbanel poly(4-nitrophenyl acrylatepolylysin morphine poly(4-nitrophenyl) kilat
1Amphetamineless than 0.0010,011000,70,01
2Methamphetamineless than 0.0010,07560,0020,1
3Ephedrine0,81,00,70,0040,8
4Pseudoephedrine0,0040,03less than 0.0010,050,004
5Norephedrine0,0030,050,0020,050,003
6Centerin0,007less than 0.001less than 0.001less than 0.0010,009
7Pyritinol0,005less than 0.001less than 0.001less than 0.0010,004
8Morphine1000,10,040,6100
9Δ9tetrahydrogen nabina0,81000,010,70,8
Cocaine0,0040,020,1ml0,004
11Phenobarbitalless than 0.001less than 0.0010,8740,003
12Barbanel0,2less than 0.0010,0041000,05
13Codeine780,10,0030,0159
14Heroin1000,10,0090,009100
15Methadone0,007less than 0.0010,0040,10,8
16Be Telekhany 0,005less than 0.0010,0010,030,004

/tr>
Table 2
SYNTHETIC IMMUNOGEN FOR the TREATMENT AND PREVENTION of the ABUSE of NARCOTIC AND PSYCHOACTIVE SUBSTANCES
No. wheyThe isotype IgThe specificity.
morphineheroincodeinemethadone, pseudoephedrine, norephedrine, barbanel, cannabinol
1IgG100100-*-
IgM100---
2IgG100100--
IgM100---
3IgG1210017-
IgM1000,934-
4IgG100100.1-
IgM1000,21,4-
5IgG10010.1-
IgM100ml56-
6IgG10061 0.1-
IgM-10100-
7IgG1000,140,11-
IgM100251-
8IgG100100100-
IgM1008510-
9IgG100100100-
IgM1000,1--
10IgG---
IgM100---

Table 3
The investigated antigenThe Ka band, M-1
The group of patientsThe donor group
IgGIgMIgGIgM
Amphetamine106-107107-1010103-104103-104

Table 4
SYNTHETIC IMMUNOGEN FOR the TREATMENT AND PREVENTION of the ABUSE of NARCOTIC AND PSYCHOACTIVE SUBSTANCES
No.-measure The immunogen composition: 1. macromolecular carrier 2. the hapten 3. poly (4-nitrophenyl)acrylateThe ratio of conjugate poly (4-nitrophen l)acrylatePharmacological action
21ovalbumin morphine poly (4-nitrophenyl) acrylate7:1The synthesis of antibodies; resistance humoral immunity -14 months, any route of administration; the absence of allergic reactions; life cell-mediated immunity
22ovalbumin morphine poly (4 - nitrophenyl)acrylate5:1The synthesis of antibodies; resistance humoral immunity -13 months, any route of administration; the absence of allergic reactions; life cell-mediated immunity
23polylysin morphine poly (4-nitrophenyl) acrylate3:1The synthesis of antibodies; resistance humoral immunity -16 months; any route of administration; the absence of allergic reactions; life cell-mediated immunity, increased detoxification function of the body
24gamma globulin Δ9-tetrahydro-cannabinol poly (4-n is trienyl) acrylate 2:1The synthesis of antibodies; resistance humoral immunity -18 months; any route of administration; the absence of allergic reactions; life cell-mediated immunity, increased detoxification function of the body, sorption of metabolites and xenobiotics
25diphtheria toxin amphetamine poly (4-nitrophenyl) acrylate4:1The synthesis of antibodies; resistance humoral immunity -15 months; any route of administration; the absence of allergic reactions; life cell-mediated immunity, increased detoxification function of the body, sorption of metabolites and xenobiotics
26gamma globulin barbanel poly(4 - nitrophenyl)acrylate6:1The synthesis of antibodies; resistance humoral immunity -18 months; any route of administration; the absence of allergic reactions; life cell-mediated immunity, increased detoxification function of the body, sorption of metabolites and xenobiotics.
The placeholder1. human gamma-globulin 2. naltrexone 3 polioksidony1: 1,5The synthesis of antibodies; resistance humor is a high immunity to 12 months; any route of administration; the absence of allergic reactions; life cell-mediated immunity, increased detoxification function of the body, sorption of metabolites and xenobiotics

1. Synthetic immunogen to protect against the toxic effects of narcotic and psychoactive substances constituting the conjugated macromolecular carrier selected from the range: natural or synthetic protein, oligo - or polypeptide, carbohydrate, lipid or nucleotide, and hapten - narcotic or psychotropic compounds, characterized in that it further comprises poly(4-nitrophenyl)acrylate, which is covalently linked to conjugate in the range of ratios of from 2 to 7 moles of conjugate per mole of poly(4-nitrophenyl)acrylate, the ratio of hapten and macromolecular carrier in the conjugate is 2-17 of moles of hapten per 1 mol of the media.

2. The immunogen according to claim 1, characterized in that as a macromolecular carrier selected from the group of natural proteins, it contains a compound selected from the range: ovalbumin, human gamma globulin, albumin, lysozyme, microbial toxins, proteins of the blood serum.

3. The immunogen according to claim 1, characterized in that as a hapten it contain narcotic or psychotropic compound selected from a number of opiates, cannabinoids, amphetamines, cocaine, barbiturates, be the of zodiazepine, methadone, phencyclidine, tricyclic antidepressants, cotinine and their derivatives and metabolites.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (1), having affinity to the µ-opioid receptor and the to the ORL1 receptor, a medicinal agent containing said compounds and use thereof to obtain a medicinal agent for treating pain and other diseases. In general formula (1), Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' denote -H; R1 and R2 independently denote -CH3; R3 denotes R0, where R0 denotes C1-8-alkyl; aryl, selected from phenyl which is unsubstituted or mono-substituted with -F, -Cl, -Br, -I, -CN or -OR0, where R0 denotes -C1-3-alkyl; unsubstituted heteroaryl, selected from a 5-member heteroaryl with one S atom as a heteroatom; R4 denotes R0, where R0 denotes aryl, selected from phenyl which is unsubstituted or mono-substituted with -F, -Cl, -Br, -I, -CN or -OR0, where R0 denotes -C1-3-alkyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolyl, mono-substituted with -S(O)2-phenyl; unsubstituted -dihydroisoindolyl or unsubstituted -indolyl; or R4 denotes -OR0 or -SR0, where R0 denotes a cycloaliphatic group selected from -C5-6-cycloalkyl; aryl, selected from unsubstituted phenyl; C1-2-alkylaryl, where aryl denotes phenyl, which is unsubstituted or mono-substituted with -OR0, where R0 denotes -C1-3-alkyl; and R5 denotes -H or -CH3.

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7 cl, 3 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented versions of pharmaceutical compositions able to resist the recovery of a pharmaceutical substance containing alkaloids if used for non-medical purposes and to prevent the recreational misuse. They contain at least one pharmaceutical substance (PS) of alkaloid with the properties of an anxiolytic, an anti-depressant, a hypnotic, or a psychotropic, or an anti-cold in the acid form; polyphenol able to bind to the acid form of the PS to form a complex resistant to the common recovery, and an ingredient able to bind selectively to polyphenol, and thereby release the PS from the complex. What is presented is an additive for preventing the commercial and recreational misuse of the pharmaceutical substance containing: polyphenol - the first ingredient able to bind to the acid form of the PS to form the complex resistant to the common recovery, and the second ingredient able to bind selectively to polyphenol thereby releasing the PS from the complex. There are presented the methods for preparing the above pharmaceutical compositions and the additive, and also the method for administering the PS.

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28 cl, 12 dwg

FIELD: medicine, pharmaceutics.

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3 ex

FIELD: medicine, pharmaceutics.

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33 cl, 23 dwg, 27 ex

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15 cl, 11 dwg, 33 ex

FIELD: medicine, pharmaceutics.

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20 cl, 2 dwg, 2 tbl, 51 ex

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15 cl, 4 dwg, 5 tbl, 78 ex

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24 cl, 8 ex, 1 tbl

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2 cl, 3 ex, 2 tbl

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10 cl, 4 tbl, 58 ex

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4 cl, 3 dwg, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to conjugates for the delivery of medications, which bind receptors on the cell surface, containing hydrophilic linker spacers.

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38 cl, 19 dwg, 49 ex

FIELD: medicine, pharmaceutics.

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36 cl, 12 ex, 32 dwg, 7 tbl

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24 cl, 5 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and may be used for improving rheological properties of sputum and inhibiting the bacterial biofilm formation in bronchi in treating cystic fibrosis. That is ensured by using recombinant human deoxyribonuclease-1 covalently bond to homopolymeric polysaccharide containing 80 links of alpha-2,8 sialic acid as an inhalation agent. There are also presented a method and administration of a drug preparation for improving the rheological properties of sputum.

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3 cl, 3 dwg, 4 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: group of inventions relates to a chelate amphiphilic polymer as a carrier, a particle as a carrier containing a self-assembling structure of a chelating amphiphilic polymer (polymersome), contrast agents for CEST MRT, SPECT, PET or Spectral CT, containing said particle, and a method of producing the particle. The chelate amphiphilic polymer is capable of aggregation and contains a hydrophilic block (MA), having a chelating moiety (X) as a terminal group and a hydrophobic block (MB), wherein the polymer has the formula X-[MA]n - [MB]m, (i), where n and m are integers ranging from 3 to 1000000, which represent the number of monomer links forming the corresponding blocks. The hydrophilic block is selected from polyethylene oxide, polymethacrylic acid, polyacrylamide derivatives, polyvinyl alcohol or polyhydroxyethylmethacrylate, hydrophilic polypeptides and sugar derivatives. The hydrophobic block is selected from polybutadiene, polyisoprene and polyethylethylene. The chelating moiety is selected from a group comprising polyphosphates, amino carboxylic acids, 1,3-diketones, hydroxy carboxylic acids, polyamines, amino alcohols, aromatic heterocyclic bases, phenols, amino phenols, oximes, peptides containing proximal chelate functional groups, Schiff bases, tetrapyrroles, sulphur compounds, synthetic macrocyclic compounds, phosphonic acid or a combination of two or more of said compounds.

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14 cl, 7 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: presented group of inventions refers to medicine and veterinary science. What is presented is a biocomposite for performing reparative processes following an injury in a mammal, containing a carrier, at least one nucleic acid containing genes coding VEGF and/or SDF-1, and cells ensuring reparative regeneration. There are presented methods for preparing the above biocomposite and a kit for preparing the same. There are also presented a method for providing injury healing in a mammal and a method for delivering nucleic acid.

EFFECT: presented group of inventions provides effective tissue regeneration following the injury in the mammal by using the three-component biocomposite consisting of the carrier, at least one nucleic acid and the cells ensuring reparative regeneration.

16 cl, 4 dwg, 4 ex

FIELD: medicine, pharmaceutics.

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EFFECT: producing new pharmaceutical preparations.

22 cl, 9 ex, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to conjugates for the delivery of medications, which bind receptors on the cell surface, containing hydrophilic linker spacers.

EFFECT: claimed conjugates are intended for visualisation, diagnostics and treatment of painful conditions, caused by populations of pathogenic cells.

38 cl, 19 dwg, 49 ex

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