Immunomodulatory drug


(57) Abstract:

The invention relates to medicine and veterinary medicine, namely to the new immune modulating drug on the basis of N-metrocable-9-acridone and physiologically active monosaccharides different structures. Proposed immunomodulatory drug, containing in its composition derived acridone and organic matter. As derived acridone use N-metrocable-9-acridone and/or its salts as well as organic matter - monosaccharides variety of structures included in the pharmaceutically acceptable base.

The invention relates to medicine and veterinary medicine, namely to immune modulating drug on the basis of N-metrocable-9-acridone or its salts and simple sugars.

The compound N-metrocable-9-acridone or salts thereof are inducers of interferon [1] a Number of monosaccharides has various pharmacologically chain properties [2, 3] the Role of some monosaccharides in the body revealed in the last time [4] Proved that some of them are important for the manifestation of the various functions of the immune system.

Known Lekarstvo the OU to offer, drug (prototype) includes various salts of the N-th metrocable-9-acridone and various polyribonucleotide acid in the form of potassium salts. As polyribonucleotides used salt juaneloboy, Danilovo, Yasinovka, cititravel and pridelava acids [6] Proposed drug has synergene effect compared with the entered components.

Closer in structure and composition of immunomodulatory drugs in the patent and scientific literature we have not identified.

The disadvantages of the known medicines (prototype) should include:

weak synergenic effect in a slight strengthening of the interferon-inducing activity (maximum increase twice);

the absence of antibacterial and antimycotic activities;

the unwanted side effects associated with the use in medicine of high molecular compounds (poliolefinovykh acids which the body induces the production of antibodies;

small stability obtained drugs when stored as aqueous solutions even in the slightly alkaline conditions of the IDA is injection related, apparently, with the structure proposed medication and in some cases with a high content of metal ions and the use of Tris buffer.

The objective of the invention receiving a new immunomodulatory drug that is highly effective in treating a number of serious infectious diseases, in particular slow viral infection that does not cause side effects and stable during storage. This drug should work on several components of the immune system.

To achieve a positive effect, you must use the new immunomodulating drugs, and includes N-metrocable-9-acridone and/or its salts and various monosaccharides (both natural and some synthetic abnormal). The medicines, first of all, there is a powerful synergenic effect that is much greater than the activity of both of the components used separately, and, secondly, you receive a number of new features, not found in the original substances.

Studies have shown that such effects seems to be connected with the fact that N-metrocable-9-acridone or its various salts easy way is obanno its salts have a number of groups, capable of forming hydrogen bonds (with excess electron density). This is especially true for CARBONYLS at C10 rings and carboxyl groups (carboxylate anions), as well as the nitrogen atom. Monosaccharides are composed of one molecule several groups of proton donors. Received, therefore, the complexes are much stronger than those formed during the interaction with the solvent [7] the PMR spectra recorded in D2O N-metrocable-9-acrilan, and the number of monosaccharides, taken separately, and then mixed in the same solution in approximately equivalent quantities, showed proton signals different from the sum of the signals of the individual components. The number of signals in the total spectra sharply ushirika, others changed chemical shifts (0.15 to 0.3 m D. ). This is especially true for signals of monosaccharides (region 2,5 5 M. D.). These changes with certainty indicate the interaction of the initial components even in aqueous solutions.

Presents complexes are modified chemical compounds that are associated with the emergence of a set of new pharmacological properties.

Differences offer medicines medicines (Protic both taken components;

a wide range of pharmacological activity (viruses, bacteria, fungi, tumors);

the lack of any side effects;

high storage stability even in the form of aqueous solutions (observation within 1.5 years showed no changes in the quality of medicines);

solutions of drugs have a pH close to the physiological (7,1-7,5);

getting medicines easily feasible in an industrial environment and can be implemented on existing facilities.

In immunomodulating drug use N-metrocable-9-acridone, in the form of neutral molecules, and the form of its salts with various cations: ions of alkali and alkaline earth metals and amino compounds Foundation.

As monosaccharides use, both natural and synthetic biologically active compounds: for example, D-ribose, D-deoxyribose, D-glucose, some amino-, thio - and epoxydodecane sugar, as with the free functional groups, and is shielded.

Typically, the two components are used in a ratio close to equivalent. In some cases, to enhance one or the other farmacol threeway salt of N-metrocable-9-acridone dissolved in 850 ml of pyrogen-free water. Add 60 g D-allose. The resulting solution was stirred for 15 min at room temperature. Then filtered. Add pyrogen-free water to a volume of 1 liter Bottled in ampoules of 2 ml and sterilized under normal conditions. Receive a 12.5% solution of sodium salt of N-metrocable-9-acridone containing 6% solution allose. The output of the final product is more than 95%

In doses of 0.1-0.5 ml/kg of the drug is highly active with respect to DNA-and RNA-genome viruses: plague animals, parvovirus enteritis ("Olimpico"), Eastern and Western encephalitis horses, Japanese encephalitis, Coxsackie B1, Columbia, herpes simplex type I and II, hepatitis B, Semliki forest viruses Menga and Sindbis, panleukopenia in cats, as well as with urogenital chlamydomonad animals.

Activity and pharmacological latitude of action proposed dosage form is much superior dosage form containing only the sodium salt of N-metrocable-9-acridone and solution allose used separately.

When determining the titer of interferon on the introduction of this drug was identified almost 20 fold increase in its content in the lymph. IE/ml initial 90 through 4 h after injection of the drug at a dose of 0.5 ml/kg maintained the suspension is heated to 75-85oC. Add 4.5 g of 2'-deoxy-2'-methylamino--D-glucopyranose. After 10 minutes the solution becomes transparent. To it add 10 ml of propylene glycol and 30 ml of melted vaseline. The resulting mixture was stirred for 20 min, then cooled to room temperature. Get 8% ointment light yellow color with a quantitative yield.

Used to treat wounds and burns of the skin. Side effects are completely absent.

Example 3. 50 g of N-metrocable-9-acridone mixed with 700 ml of pyrogen-free water, with stirring for 15 min, to the resulting suspension was added 57 g of 3-O(N',N'-dimethylamino-n-propyl)-1,2:0-isopropylidene-a-D-glucofuranose. Received almost clear solution is filtered, diluted with pyrogen-free water to volume 1070 ml Poured into ampoules or vials, which are sterilized in normal mode. Get 10% light yellow clear solution with a pH of 7.3, stable when stored in the dark at room temperature for 1.5 years (time of observation). The release of the drug over 95%

Used for intravenous and intramuscular injection in severe viral bacterial and fungal infections in doses of 0.05 to 1.00 ml per kg of body weight of the animal. Irritant effect of the drug is missing the initial number of components of the immune system: causes a sharp increase in the induction of interferons, stimulation of phagocytic activity of peritoneal macrophages, activate the production of cytokines, stabilize the tumor necrosis factor.

In experimental alisasis mice increased the lifespan of animals with 18-24 h (control) to 96-120 hours In 35% of the animals were observed recovery.

In experimental candidiasis (caused by C. Albicans) completely stopped the growth of the parasite at a dose of 0.5 to 1.0 ml per kg of body weight of the animal.

Turned out to be especially effective for nervous forms of distemper, and source components that are used separately in the same concentrations, not shown in this disease significant positive effect. In the experiment on the animals (white mice) received immunomodulatory agent completely inhibits the growth of tumors induced by rous Sarcoma virus as therapeutic (one hour after virus infection at a dose of IOLD50) and preventive (one hour before infection) regimen.

Example 4. 10 g dimethylamino salt N-metrocable-9-acridone mixed with 25 ml of ethyl alcohol. To the resulting, almost transparent solution, add 4.7 g of 6'-deoxy-6'-dipropyl-D-galactose. The solution is boiled for 0.5 hours Kladno 14,5% dimethylamino salt N-metrocable-9-acridone and 6%, 6'-deoxy-6'-dipropyl-D-galactose. The yield of the final product is almost quantitative.

Used to treat a number of viral and fungal infections of the external genitalia.

Example 5. 25 g of 1,2-O-Isopropylidene-5,6-epoxy-a-D-glucofuranose mixed with 25 g of 1,3-propylene glycol. To the resulting thick transparent solution was added 18 g of N-metrocable-9-acridone. The mixture is heated to 45-50oC for 15 min, cooled to room temperature. Obtain 68 g of a thick cream.

The resulting ointment is highly effective when the disease shingles (Varicella zoster) and the number of allergic diseases of the outer integument. Source components such properties do not possess.

As you can see from the above examples, the proposed immunomodulatory drug has diverse and important pharmaceutical properties. In some cases, showing new, not typical amounts are derived components, therapeutic effects.

The novelty of immune-modulating means includes the combination of N-metrocable-9-acridone and its salts with various monosaccharides structure.

Thus, the set of features of the invention allows to obtain a powerful synergenic EFV new pharmacological properties not found in the original substances.

Sources of information:

1. Chizhov N. N. Structure and biological activity of low molecular weight inducers of interferon. Antibiotics and medical biotechnology, 32, 9, 1987, S. 706-715.

2. The US patent N 2715121, W. L. Glen. Alkyl sugar derivatives and their preparation, 1955.

3. The US patent N 4047608, P. Gordon. Therareutic composition and method of therapeutically treating warm dlooded animals therewith. 1977.

4. Cetlinski S. A. Simbirtsev A. S. A. Vorobyov, A. Endogenous immunomodulators, St. Petersburg, Hippocrates, 1992, S. 256.

5. Lazarev A. N. Alekhin E. K. immune Stimulants, M. Medicine, 1982, S. 256.

6. Patent Dd N 264925 Hoffman S, Cytokin(interferon)induktoren. 1989.

7. Intedi Ya the Use of complexes in analytical chemistry, M. Mir, 1979, S. 376.

Immunomoduliruuchee drug containing derived acridone and organic compound, characterized in that the quality of the derived acridone contains N-metrocable-9-acridone and/or its salts as well as organic compounds monosaccharides, such as D-ribose, D-deoxyribose, D-glucose, amino-, thio - and epoxydodecane sugar, as with the free functional groups, and is shielded when the ratio of the components respectively 50 1 1 50.


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FIELD: medicine, phthisiology.

SUBSTANCE: one should lymphotropically introduce the mixture of 5.0 ml 0.25%-novocaine solution and 2.0 ml 1%-dioxidine solution or the mixture of 5.0 ml 0.25%-novocaine solution and 0.5 g cefazoline subcutaneously into jugular cavity and deeply behind xiphoid process, successively 1 point once daily, 5-7 injections/course. After injection the site of injection should be treated either with heparin ointment or ultrasound (1-3 MHz, PPM 0.2 W/sq. cm, for 2 min, through Vaseline oil) followed by evaluating roentgenological dynamics of the process 10-14 d later.

EFFECT: higher efficiency of differential diagnostics.

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