Immunomodulatory tool


(57) Abstract:

The invention relates to medicine and pharmacology. A new tool with immunomodulatory effects in the treatment of disorders of the immune system of a living organism, for the prevention and treatment of diseases caused by immunodeficiency, and hyperimmune state of man. As an immunomodulating funds proposed polyprenols derived from wood green conifers, the General formula

< / BR>
where n = 10-20.

The invention expands the Arsenal of drugs with immunomodulatory properties.

The invention relates to medicine, pharmacology, and can be used as a vehicle, which has an immunomodulatory effect in the treatment of disorders of the immune system of a living organism.

A number of herbal drugs with immunomodulatory effects, such as drugs Eleutherococcus and ginseng.

Known use as a tool, which has an immunomodulatory effect of an aqueous extract of the aerial parts of the bird cherry gray (EN N 2038089, 1995, A 61 K 35/78).

However, this tool has insufficient immunodeficiency, the studies, pathologically associated with the failure of the immune system.

At the present time to normalize immune function use polyisoprenoid, which represent a large group of common natural compounds, extracted, usually from plants, and by synthesis. Among these compounds are widely known polyprenols and their derivatives (N. I. Grigorieva and other Physiological activity polyisoprenoid". Chemical and pharmaceutical journal, No. 2, 1989, pp. 151-153).

It is known for the treatment and prevention of diseases caused by immune deficiency, based on the compounds of General formula

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where n = 5-7 (Japan, application N 3-49891, 1991, A 61 K 31/045).

It is used as an agent against infectious diseases in animals.

Known compounds of General formula

< / BR>
where n = 5-7, R is hydrogen, lower alkyl groups, aliphatic or aromatic acyl group, i.e. such derivatives polyprenols, have no double bonds at the end of the molecules (German patent N 3318989, 1983, A 61 K 31/045). These compounds are synthesized by chemical means of polyprenols. At the appropriate pharmaceutical carriers are used for prophylaxis and whether other diseases in humans and animals.

Known similar to the proposed polyprenols polyprenols obtained, for example, from the leaves of the plant Cedrus Lodara extraction with an organic solvent, the General formula

< / BR>
where n = 10-18 (Japan, application N 3-14006, 1991, C 07 C 33/02), or General formula

< / BR>
where n = 10-19 (Japan, application N 3-14007, C 07 C 33/02, 1991).

Polyprenol a similar formula is obtained by extraction from the leaves Seiadopitydaceae, Podocarpaceae, Cepholotaxaceae or Arucariaceae (Japan, application N 3-14009, C 07 C 33/02, 1991), or General formula

< / BR>
where n = 11-21 (Japan, application N 3-14008, C 07 C 33/02, 1991), obtained by extraction of the leaves Cupressaceae, Taxodiaceae or Taxaceae.

The above polyprenols, obtained from the leaves of plants, are used as intermediate raw materials for the production of new chemical compounds, for example, dolichols.

A known mixture of polyprenols, obtained from the needles (RU N 2053992, C 07 C 33/02, 1996), the processed first liquefied carbonic acid, and then with an organic solvent, followed by separation of the mixture, of the formula

< / BR>
where m = 2 or 3, n = 6-20.

However, as described in the patent, a mixture of polyprenols is also used as a feedstock for the synthesis of dolichols.

The challenge kotorowski properties.

The problem is solved by the fact that as immunomoduliruushimi funds will apply polyprenols derived from wood green conifers, the General formula

< / BR>
where n = 10-20.

The present invention meets the criterion of "novelty", as from publicly available sources of information is not known immunomodulatory the tools described above set of essential features.

The present invention meets the criterion of "inventive step" as it became possible to apply the polyprenols, obtained from the wood green conifers, not as an intermediate raw material, and as a means of having immunomoduliruushimi properties.

Polyprenols are a natural mixture of oligomers (isoprenyl) of the above General formula, containing structural connections, for example, formulas

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where n =10-16.

A mixture of polyprenols behaves as a single substance, can be divided into obremenitve sorbents and is a low-viscosity oily liquid yellow-orange color, soluble in vegetable oils.

Proposed as immunomodulators polyprenols of formula (1ta, cedar) using sequential extraction with an organic solvent, separation by settling and filtering with cooling coniferous wax with a melting point 72-76oC, saponification of the resulting solution of extractives in the hydrocarbon solvent 20-40% alkali solution, the separation of the saponified solution of a solution of neutral compounds in a hydrocarbon solvent and an aqueous-alkaline solution of an organic acid, followed by acidification of an aqueous-alkaline solution of salts of organic or inorganic acid to pH 1-3 and the allocation of chlorophylline acids and fractions of fatty and resin acids, removal of the solvent from the neutral substances and mark out the planting of wax with a melting point 52-56oC and subsequent vacuum distillation them at a residual pressure of not more than 400 PA, with the release fraction sesquiterpenoids with a boiling point 90-120oC, fraction of Radanovich of diterpenoids with a boiling point 120-210oC and VAT residue. VAT residue is treated with alcoholic alkali solution, distilled alcohol, dissolved in an organic solvent, then add water and separated by settling on a solution of salts of fatty acids and solution of the controlled substances by the method of solvent extraction produce sterols, polyprenols, di - and triterpenoids.

Unsaponifiables after removal of the solvent separated for cleaning of polyprenols from liberated by the hydrolysis of di - and triterpene alcohols and sterols by the method of solvent extraction. As a solvent used ethanol or 50-90% solution of isopropanol. The choice of these solvents is due to the need of greatest separation from polyprenols of organic impurities. The ratio of extractant: a partial mixture of at least 4:1, the temperature of the mixing 50-65oC, mixing time 10-15 minutes After mixing system stratified by cooling to 0-40oC for 30-40 minutes While the raffinate loses mobility and the extract is separated by siteniravam.

The raffinate from the last stage of the extraction after removal of the traces of the extractant is separated from the impurities of the polymer nature. For this purpose it is dissolved in acetone under stirring and the temperature close to the boiling temperature of acetone. The ratio of solvent: the substance is 3-9:1. Then the resulting solution is cooled to 20oC and separated by filtration of the resulting precipitate. The mother liquor is cooled to -10oC and advocate for 10-15 hours and again separate the precipitate. According them, the solvent is distilled off. The resulting product is a concentrate of polyprenols.

Practically offer polyprenols can be obtained from any of the wood green conifers and are a waste of timber harvesting.

Trials were conducted polyprenols in accordance with the "guidelines on assessment and learning immunomoduliruushimi action of medicines, 1984 and requirements of farmkomiteta health Ministry.

As the immune response can be humoral response and cell type, methodical recommendations offered on this principle to assess the effect of the drug on the immune system.

To assess the impact of polyprenols of the claimed formula for the humoral immune response it is proposed to use the definition of the number of antibody productive cells (AFC) in the spleen and level hemagglutinins in serum with T-dependent and T-independent antigen.

To assess the impact of polyprenols in cellular response reaction of hypersensitivity of the delayed type (GST) and the graft-against-host (GVHD). The effect on the functional activity of macrophages was assessed by their ability to capture and recycle the Antiga the animals and in animals with artificially induced by means of emotional stress immunodeficiency state by single intraperitoneal injection and 5-day drinking. Of the proposed polyprenols were preparing the emulsion in a 0,025% solution of tween-80. Experimental animals were injected intraperitoneally (b) 0.1 ml doses of 10.0 and 100.0 mg/kg simultaneously with the introduction of the antigen and oral (p/o) for 5 days prior to injection of antigen. As a control the on/b introduction used a 0.025% solution of tween-80, which had no directional AFC in the spleen of mice, the reaction GST, GVHD, phagocytosis, but caused a slight stimulation of the production of antibodies (index steps 1,2), and the introduction of p/o - peach oil does not cause changes in the function of the immune system. Emotional stress caused by crowding of animals within 10 days (40 mice in a cage the size 17 25 8).

Control animals throughout the experiment received daily solution of tween-80, experimental emulsion of polyprenols in a dose of 100.0 mg/kg Number of AFC in the spleen of mice was determined on day 5 after immunization optimal (1108CL) and suboptimal (2107CL) doses of EB (Erytrocyte sheep).

The definition of credits HA and DL performed at 7 and 14 days after immunization optimal and suboptimal doses of antigen in 96-well round-bottom plates.

Conducted studies on the phagocytic activity period is stressed mice.

All studies have shown that the proposed polyprenols have the ability to change the intensity of the humoral and cellular response, depending on the genotype of the animal, the dose of antigen and route of administration of the drug. Thus polyprenols obtained from softwood can be used in intact animals as immunomodulators: at the dose of 10.0 mg/kg, more can be expected stimulation functions and, when injected at a dose of 100.0 mg/kg - decrease in the intensity of immunological reactions.

In addition, the ability to identify polyprenols obtained from softwood to stimulate important factors of nonspecific resistance - phagocytosis. So when in b/W the doses of 10.0 and 100.0 mg/kg polyprenols stimulate the completion of phagocytosis, and the introduction of p/o at a dose of 100.0 mg/kg increases the number of phagocytic cells.

In animals with immune depression caused by emotional stress, introduction of polyprenols obtained from softwood, at a dose of 100.0 mg/kg p/o within 10 days prevented impairments reactions humoral immune response and reduction of functional activity of macrophages.

The proposed pranali obtained from wood green pine on what hyperimmune the human condition.

The use of polyprenols derived from wood green conifers, the General formula

< / BR>
where n=10-20,

as an immunomodulating funds.


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