LT4187B - Remedy for immunomodulating activity and for recovering of disordered propargation regulation system of tissue cells - Google Patents

Abstract

The rehabilitation substance for an immune modulation effect and disturbed reproduction tissue cell regulation system consists of an active substance; mercury dichloride or potassium arsenite or sodium arsenate 0.05-1.5 percentage of the mass and a dissolvent up to 100 percent of the total mass. As a dissolvent, a choice between a white natural grape vine containing sugar 3-4 percent of the mass or milk whey, containing sugar 3-4 percent of the mass can be used.

Description

The invention is from the medical field, and more particularly is a novel preparation for restoring immunomodulatory activity and regulating tissue cell proliferation.

Various therapeutic agents that model immune processes are widely known. For example, nucleic acid derivatives capable of specifically activating immunocompetent cells (T- and B-lymphocytes), which are capable of stimulating immune responses in the body, include pyrogenal, prodigioan and other preparations. Known preparation of levamisole [(-) 2, 3, 5, 6-tetrahydro-6-phenylimidazo - (2,1-b) -thiazole hydrochloride]. (M.D. Mashkovsky, Lekarstvenije sredstva, Moscow, "Medicine", 1992, Vol. 2, pp. 169-170) This preparation can specifically stimulate the regulatory function of T-lymphocytes, potentiate the cellular immune response, weaken the strong one and not affect normal reactions.

Also known is a preparation of timalin (composed of a complex of polypeptide fractions isolated from the parotid gland) / M.D. Mashskovsky, Lekarstvenie sredstva, Moscow, "Medicine", 1992,

t. 2, page 171), which can regulate T- and B-lymphocyte count, stimulate cellular immune responses, as well as regeneration processes.

It is used as an immunostimulant and a biostimulant in the treatment of diseases accompanied by a decrease in cellular immunity, as well as in severe chronic abscesses and inflammations, burns, immunocompromised patients with oncology and blood production disorders after chemotherapy or radiation therapy.

However, these preparations exhibit specific activity, toxicity, side effects and contraindications.

The most important cause of oncology is known to be disorders of the regulatory system of cell division (proliferation).

Various antitumor agents are known that have various chemical structures.

Such compounds can be obtained chemically as well as biologically by isolating biologically active substances from raw materials of plant and animal origin. / M.D. Mashkovsky, Lekarstvenije sredstva, Moscow, "Medicine", 1992, vol. 2, pages 423 - 468).

Antineoplastic agents such as cyclophosphane, sarcolysin, mustargen, karyolysin, etc., are known for their primary activity in the body due to their alkylating properties. They can react with nucleophilic centers of protein molecules, damaging DNA synthesis, which affects cell viability and blocks their mitotic division.

Also known are antitumor agents containing ethylenimine groups such as thiophosphamide, dipine, benzotheide, and others which inhibit the formation of proliferating, including malignant, tissue.

Nucleic acid metabolism abnormalities and mitotic cell division blockade play a key role in the mechanism of action of these substances.

Widely used antitumor agents are some antibiotics, partly semi-synthetic, derived from the nuclei of known antitumor antibiotic molecules.

The mechanism of action of these products involves specific inhibition of DNA, which is dependent on RNA synthesis, resulting in disruption of nucleic acid synthesis. However, the indicated antitumor agents have high toxicity, side effects (inhibition of hematopoiesis).

There are well-known medicinal mercury preparations, such as mercury dichloride, as an antiseptic, arsenic preparations (sodium arsenate and potassium arsenite) for the treatment of hematologic patients, which cause alterations in bone marrow erythropoietic function and inhibition of leukopoiesis.

However, the immunomodulatory effects of these agents and the effect of restoring the regulation of tissue cell proliferation are unknown.

It is an object of the present invention to provide a novel formulation with immunomodulatory activity and a restorative action of the tissue cell proliferative control system.

The object of the present invention is achieved by providing a formulation consisting of an active ingredient and a diluent, wherein the active ingredient is mercury dichloride or potassium arsenite or sodium arsenate in the following proportion by weight:

mercury dichloride or potassium arsenite or sodium arsenate 0.01 - 1.5 diluent up to 100

The diluent is a natural white grape wine containing 3-4% by weight of sugar or whey containing 3-4% by weight of sugar.

The small amount of reversible coagulated vegetable proteins with liberated sulfhydryl groups SH in natural white grape wine as well as reversible coagulated proteins in milk whey are reversibly blocked by mercury or arsenic ions, which removes the toxicity of the claimed preparation. Containing 3-4% by weight of sugar in wine and milk whey, it maintains the acidic environment in the preparation, thus improving the taste properties of the preparation.

The claimed preparation of the invention is used in the following embodiments.

The claimed preparation for external and internal use consists of the following components, by weight:

Mercury dichloride 0.01 - 0.1 Natural white grape wine containing

3 to 4% by weight of sugar or milk whey, containing

- 4% by weight of sugar up to 100,0

Preparation for internal and external use, consisting of a mixture of pig fat, natural honey and ethyl alcohol with a diluent, containing by weight:

mercury dichloride 0.03-0.13 pig fat 0.7-37.3 natural honey 30.7 - 37.3 ethyl alcohol to 100.0

Internal preparation for the treatment of acute and chronic leukemia, consisting of the following components, by weight:

Sodium arsenate or potassium arsenate 0,05 - 0,15 natural white grape wine containing:

3 to 4% by weight of sugar or milk whey, containing

3-4 wt% sugar to 100.0

This product is preferred in the treatment of acute and chronic leukemia, since blood is the main arsenic accumulator.

Preparation for external use consists of the following components, by weight:

mercury dichloride 0,3 - 1,5 natural white grape wine containing

3-4% by weight of sugar or whey containing 3-4% by weight of sugar up to 100,0

The claimed preparation is nontoxic due to the ability of mercury and arsenic ions to reversibly block sulfhydryl groups, for which they are the most closely related of all reactive groups. The common feature of all organisms and all tumors is their multiplication (division), and the order to share is passed on by receptors for specific molecules, growth factors, through other protein molecules.

The specific structure of all growth factors and the molecular structure of immunoglobulins, cytokine, lymphocyte and erythrocyte receptors and some hormones (insulin, vasopressin, etc.) are disulfide bonds which have the ability to hydrolyze in the presence of mercury ions, irrespective of the presence of other functional groups.

The specific property of all cytoplasmic receptors and more than two dozen enzymes (including proteolytic) is the presence of free sulfhydryl groups.

Tumor growth is halted by reversible blocking of the sulfhydryl groups of growth factor receptors, stereoid harmonic receptors, and adrenoenergetic receptors by mercury or arsenic ions.

Double protection of tumor growth is achieved by terminating the disulfide bonds of growth factors, immunoglobulin lymphocytes and erythrocyte receptors in the presence of mercury or arsenic ions. Discontinuation of disulfide binding of immunoglobulin, some hormones (insulin, vasopressin), cytokines, lymphocytes and erythrocyte receptors gives the product immunomodulatory properties.

The reversible blocking of the enzymes and receptors by the sulfhydryl groups protects the body from the effects of radiation.

Assuming that the surface of tumor cells contains 20 to 100 times more growth factor receptors than other cells, and that the functional group of growth factor receptors, the sulfhydryl group with which mercury ions are most closely related, also affects the tumor cells 20 to 100 times. stronger.

Mercury dichloride, the claimed active ingredient, is electrically impermeable to dissolution (non-ionized), and non-ionized molecules readily penetrate membranes, including the brain, and penetrate into the cytoplasm at a lower pH, whereas pathogenic cells, including tumors, have abnormally low pH and due to the increased acidity, it is the pathogenic cells that absorb mercury, i. y. specific effects on cells are ensured.

The claimed preparation, by virtue of its mechanism of action, has the potential to repair impaired regulation of the tissue cell proliferation system. The claimed preparation has immunomodulatory properties.

Due to the claimed effect of the preparation, the internal regulatory mechanisms are rearranged, the immune cells z

integration into a single system and normalization of immunological parameters.

The claimed preparation according to the invention contains mercury dichloride or potassium arsenite or sodium arsenate as the main active ingredient in an amount of 0.01 to 1.5% by weight with a suitable pharmaceutical diluent. The formulation for internal and external use contains mercury dichloride 0.01 EN 4187 B

0.1% by weight, using natural grape wine containing 3-4% by weight of sugar or whey with 3 to 4% by weight of sugar as the diluent; or 0.03 to 0.13% by weight of mercuric dichloride, a mixture of lard, natural honey and ethyl alcohol, respectively, as diluent.

The amounts indicated are selected experimentally and achieve the claimed effect. Reducing or increasing the levels of mercury dichloride above these limits does not give the product the expected effect.

For the treatment of severe and chronic leukemia, it is expedient to administer the claimed preparation internally, using sodium arsenate or potassium arsenite as the main active ingredient in an amount of 0, 05 to 0.15% by weight, with diluent - natural white grape wine containing 3-4% sugar or milk whey. -4% by weight of sugar.

The indicated amounts of the active substance are also selected experimentally and ensure effective action of the claimed preparation. The claimed preparation stimulates many bodily functions, weakens oxidation processes, increases nitrogen and phosphorus uptake, restricts protein degradation, improves metabolism in tissues and cells and thus provides a general tonic effect, improves general condition, increases hemoglobin and blood red blood cells.

The claimed preparation for external use contains the main active ingredient, 0.13 to 1.5% by weight of mercuric dichloride and 3 to 4% by weight of sugar as natural diluent, respectively, or milk whey, containing 3 to 4% by weight of sugar.

White natural grape wine can be used in MUCVANI, SAVINJON and other varieties. The technology used to make such wines uses the preheating to 60 ° C required to stop fermentation of some of the sugar. At the specified temperature, the plant proteins in small batches of wine undergo reversible coagulation, which liberates the sulfhydryl groups of proteins, SH, which are reversibly blocked by mercury or arsenic ions, thereby eliminating the toxicity of the solution.

Milk whey also contains reversibly coagulated proteins with liberated sulfhydryl groups - SH, which are reversibly blocked by mercury or arsenic ions, which reduces the toxicity of the solution to zero.

The claimed remedy is recommended for the treatment of the following diseases: all types of benign tumors; malignant tumors of all kinds; immunodeficiency of various origins; rheumatism; rheumatoid arthritis; polyarthritis; bronchial asthma; systemic lupus erythematosus; stomach ulcers; trophic ulcers; psoriasis; intestinal infections; for the treatment of neurodermatitis and other diseases.

Depending on the form of the disease, the stage of the disease, the tolerance to the product and other individual body characteristics, the choice and timing of application may vary, and certain treatment principles should be followed. For example, diets, such as meat, fish, eggs, should be discontinued because treatment with the proposed formulation will block the sulfhydryl groups of the proteolytic enzymes in the system, thereby reducing the body's ability to assimilate protein foods. Treatment is usually initiated with the recommended formulation of 5 ml [or 5 g] three times a day for the first three days, followed by 10 ml [or 10 g] three times a day throughout the month. Parallel to or indoors, it is applied topically in the form of compresses, tampons, rinses, enemas. Depending on the localization of the process, the affected area is affected differently by the tailbone, the armpit, the spine, the joints, the covering tissues and elsewhere. For example, in the treatment of mammary gland or female gynecological conditions, topical compresses, vaginal swabs, or enemas may be used in conjunction with internal administration.

For the treatment of stomach problems, compresses are applied in combination with the internal administration of the preparation in the armpits and on the tailbone or on the enema.

In the case of prostate disease, the product is administered inwards and compresses are applied to the groin and armpitic lymph nodes and tail.

In the case of myelogenous leukemia, in addition to internal administration, compresses are applied to the tailbone, chest and armpit lymph nodes, spine and joints.

In case of damaged soft tissues and osteogenic sarcomas, the delivered preparation is administered inwards and compresses are applied to the chest area, groin and armpit lymph nodes, spine and joints.

The claimed preparation with an elevated mercury concentration is used to treat malignant lung diseases in the form of pus or blood secretions and neglected diseases.

The claimed formulation with the main active ingredient, mercury dichloride, is well-recommended in the treatment of skin conditions such as psoriasis and neurodermatitis.

This is apparently related to the action of the immunomodulatory agent of the claimed preparation because of its anti-inflammatory and reparative properties when applied topically.

The claimed preparation contains mercury dichloride as an active ingredient for use in the treatment of trophic wounds in the lower limbs. The preparation is administered inwardly according to the general scheme and in the form of compresses. The course of treatment is one month. If necessary, treatment may be repeated after one month. The claimed preparation is prepared by blending the starting components according to known techniques. The claimed preparation was experimentally tested in animals and tested in human clinics.

The acute toxicity of the claimed substance was determined in 192 female rats weighing 180 to 220 g, which were housed under standard conditions and fed in standard manner. For 24 hours prior to testing, the animals were kept in the vivarium at constant temperature and ventilated. The animals were deprived of water and food for two hours prior to testing.

The acute toxicity parameter LD50 for all formulations was determined by the Litchfield and Wilkox method by oral administration as intended and into the abdominal cavity with significant toxicity. 10 groups of rats were selected for selection and weighing and were to receive the test preparation claimed (two variants, wine-based liquid and whey-based). Each group consisted of 6 animals. In the respective groups of rats, 5, 4, 3, 2 and 1 ml of the applied preparation were administered intraperitoneally, corresponding to 1.65, 1.32, 0.99, 0.66 and 0.33 mg / kg of active substance, respectively. Oral injections of 2, 1.5, 1 and 0.5 ml correspond to 0.66, 0.495, 0.33 and

0.165 mg / kg active substance.

For control animals, only a diluent was introduced - natural white grape wine and milk whey.

Animals were observed for 14 days following the administration of the claimed preparation. In addition, the general condition of the animals, their behavior and body weight were evaluated.

Reduced locomotor activity and somnolence were observed after administration of the product at the indicated dose level in rats. These events were more pronounced in rats given intraperitoneal administration. In addition, no mortality was observed in the first few days.

In addition, mortality was not observed at all times in rats treated with the claimed product [variants containing wine and whey]. In addition, differences in mass, behavior, and general condition compared with the control were not recorded.

Similar results were obtained by administration of the preparation (variant with wine) into the abdominal cavity. No deaths were observed and there was no increase in body weight or behavior compared to controls.

The absence of mortality despite the maximum permissible dose (liquid wine-based formulation) in both oral and intraperitoneal routes did not allow the determination of a major acute toxicity parameter LD50, indicating low toxicity of the preparation at the above dosages .

In the peritoneal cavity, rat mortality was observed at day 5, 6, 7, 8 and 9 after administration of the product (variant with milk whey). In animals, apathy, paralysis of the limbs, and a change in coat were observed before death. These lesions were not observed in the remaining living rats and their behavior and body weight did not differ from the control at day 14.

A case study of falls frequency by the Litchfield and Wilkoxon method allowed the calculation of the LD50 of the claimed preparation (variant with milk whey) after intraperitoneal administration.

The LD 50 value in rats is 5.8 (1.98 - 8.8) mg / kg body weight following intraperitoneal administration of the product (variant with milk whey).

Antitumor activity assays were performed on malignant cell cultures.

The experiments were performed on vaccinated L-41 leukocytic tumor cultures.

Culturing of the cultures was performed by a conventional method. The cell inoculum density was - 1.10 ⁵ cells per ml of medium. The medium was selected in equal proportions from 199 media and Iglo medium with 10% bovine serum and antibiotics: 100 units penicillin and 50 units sterptomycin per ml. The claimed material and the individual diluent are the wine "ERETI" and the active ingredient, mercuric dichloride, diluted in protein-free medium and injected at various concentrations into 3-4 cultures for contact with the cell monolayer. Because mercury dichloride is used as an active ingredient, the ED50 of mercury dichloride, which inhibits the growth of the tumor line L-41, was found to be 10 mg / ml as a pre-test.

On the second day of the experiment, he performed a microscopic evaluation of the performance of the preparation on a 4-point system and calculated the protein content of the cultures by Louri and modified Ojam and Iglo methods.

The criterion for cytostatic activity of the preparation is the percentage inhibition of growth of the cultures according to the decrease in protein synthesis. The test data are shown in Table 1.

According to the relevant antineoplastic screening standards, the preparation is considered active if it has an ED50 of less than or equal to 100 mg / ml.

Tests have shown that the claimed preparation has an ED50 of 10 mg / ml and 10 times the standard, which demonstrates its pronounced cytostatic effect on tumor cultures.

table

The bioavailability of the claimed preparation, the diluent (natural grape wine containing 4% by weight of sugar), mercury dichloride, was investigated in a vaccinated tumor culture line L - 41.

Preparation Mercury dichloride concentration, mg / ml Alcohol content, % Protein quantity mg / ml Cultures growth braking or stimulation Reliability, P 1 2 3 4 5 6th 1 .Control - - 294.0 ± 10.4 - 2.Claimed 1.1 0.03 318.0 ± 0 7.5 preparation stimulation 3.Claimed 3.3 0.1 238.3 ± 9.1 18.9 > 0.05 preparation braking 4.Claimed 4.8 0.15 224.0 ± 0 23.8 > 0.05 preparation braking 5.Claimed 6.6 0.2 214.0 ± 0 27.2 > 0.05 preparation braking

1 2 3 4 5 7.White Natural - 0.03 316.0 ± 25.1 6.9 grape wine stimulation 8.White Natural - 0.1 318.0 ± 0 7.5 grape wine stimulation 9. B altas natural - 0.15 318.0 ± 0 7.5 grape wine stimulation 10. White - 0.2 322.5 ± 5.6 8.8 natural stimulation grape wine 11 .White - 0.3 307.0 ± 13.8 4.2 natural stimulation grape wine 12 Mercury 1.0 - 390.3 ± 2.6 1.2 braking dichloride 13. Mercury 3.3 - 279.0 ± 27.3 5.1 braking

dichloride

1 2 3 4 5 6th 14. Mercury 5.0 - 256.0 ± 5.2 12.9 braking > 0.05 dichloride 15. Mercury 8.0 - 154.0 ± 5.0 47.6 braking > 0.05

dichloride

From the data presented, it can be seen that the claimed preparation expresses inhibitory activity against tumor cultures at 9.9 mg / ml, a concentration corresponding to its ED 50 and mercury dichloride at 8 mg / ml. Wine, at the concentrations tested, slightly stimulates the cultures at 4.2 - 8.8%.

The immunopharmacological properties of the claimed preparation were investigated.

The effect of the claimed preparation on the mass of the main organs of the immune system was investigated.

CBA and C57B1 line mice and their first generation hybrids were tested.

The claimed preparation (two variants: diluent-wine and diluent-milk whey) was administered to C57B1 mice and their first generation hybrid CBAxC57Bl line for 10 days. One day after the last administration, the animals were weighed, killed, spleen removed and weighed.

The weighing results and the mass coefficient calculations are shown in Table 2.

table

Spleen mass after treatment with the claimed preparation

Yesterday no. Preparation Number of animals in the group Spleen mass mg Deviation from control reliability (P) Masses coefficient Deviations from control reliability (P) 1 2 3 4 5 6th 7th C57B1 line 1 Checklist 23rd 86 - 0.55 2 Claimed 9th 90 > 0.05 0.56 0.05 3 preparation (diluent-milk whey) Claimed 10th 87 > 0.05 0.51 > 0.05

preparation (diluent wine)

First generation hybrid CBA C57B1 line

-

11,112> 0,05 0,48> 0,05 Preparation (whey-milk thinner)

12 114> 0.05 0.46> 0.05 Apparatus (Thinner Wine)

The data obtained show that the claimed preparation has no effect on the spleen mass and the weight factor of this organ when administered for 10 days.

In subsequent trials, the claimed preparation was administered for 30 days and then the thymus was weighed. CBA line mice were tested.

The results in Table 3 show that the preparation did not work on the weight of the thymus.

table

Thyroid mass after application of the indicated preparation (diluent-wine)

Preparation

Number of animals Thymus gland in mg (P) deviations from control

Control 8,174

Proposed Preparation 7 170> 0.05

The effect of the claimed preparation on the graft versus host response was investigated. '

These studies were performed according to the following methodology.

The first generation mouse CBA and C57B1 hybrids injected subcutaneous mouse C57B1 lymph node cells into a single hind paw cushion, with the same amount of hybrid lymph node singlenic cells injected into the parental paw. On the eighth day after the introduction of lymph node cells, the mass of lymph nodes of both paws was determined. The reaction is evaluated by the reaction index / IR / calculated by the formula:

lymph node weight upon introduction of C57B1 cells

IR = ................................................. .

lymph node weight upon introduction of hybrid cells

The claimed preparation (two variants: diluent - milk whey and diluent - wine) was administered for 10 days and 20 days for donors and recipients.

The results of these tests are shown in Tables 4-5.

table

Effect of the claimed preparation (diluent - milk whey) on the lymph node mass of the lumbar spine in the graft versus host reaction

Amount of drug applied in Animal Chema group for recipients, donors, (daily) (daily) lymph node mass Response Index (IR) control test paws, paws, mg mg

5 6

Control

2.8 9.2 3.35

7.2 7.7

1.10

1 2 3 4 5 6th Control 11th 3.3 7.1 2.4 14th - 9th 5.2 6.6 1.3 - 10th 10th 6.0 7.0 1.3 14th 10th 10th 5.2 6.6 1.4

table

Effect of the claimed preparation (diluent - wine) on the mass of the lymph nodes in the lumbar graft reaction

The claimed product administration Animal quantity Lymph node mass Reactions chema in the group index (IR) recipients, donors, control testing (days) (days) paws, paws (mg) (mg) 1 2 3 4 5 6th Control 11th 3.3 7.2 2.4 14th - 9th 6.7 8.2 1.3 - 10th 10th 4.6 6.2 1.4 14th 10th 9th 5.1 6.3 1.2

As can be seen from the data shown in Tables 4 and 5, the preparation has a major effect on cellular immunity in the "graft versus host" reaction.

The distinctiveness of the claimed action is that the effect is achieved by both the recipient and the donor administration. In all cases, lymph node mass is increased by transplanting mouse cells of the same lineage. These "control" lymph nodes become a reaction of the size of the "test" lymph nodes, that is, those in which the lymphoid lineage cells precede the hybrid genotype cells. The mass of these "test" lymph nodes is practically the same in all groups of animals, including mice that have not received the claimed preparation. Therefore, administration of the product for 10 days to both donors and recipients does not affect the lymph node mass in which the lymphocyte donor responds to the foreign body cells. With this formulation, the response index is only slightly higher than 1 in the first test group.

By extending the administration of the claimed preparation to 20 days, the mass of both lymph nodes ("test" and "control") increases and becomes larger than that of the group of animals that did not receive the claimed preparation (Table 4). In addition, there is little difference between these lymph nodes and therefore a response index of 1.24.

The effect of the claimed preparation on the amount of rosette-forming cells in the spleen of mice was investigated. The population of rosette-forming cells is mixed, but practice has shown that their detection is one of the most sensitive tests for immunotherapeutic effects of a variety of chemical compounds.

This effect was investigated in opposition line mice immunized with ram erythrocytes. The various courses of administration of the claimed preparation were commenced prior to the immunization of the animals with test-antigen and continued administration for another 5 days after immunization. At day 7 after antifungal stimulation, the mice are sacrificed and the amount of cells that bind to the erythrocytes of the ram is determined in their spleen.

The data obtained demonstrated that the therapeutic dose of the claimed preparation orally administered to mice after 10 and 20 days reduced the antigen binding cells of the mouse spleen in both the low and high response lines. In addition, a decrease in the immune response is seen in low response animal lines.

The effect of the test preparation on the amount of antibody-producing cells in the spleen of mice, as determined by testing the effect of the claimed preparation on haemolysin producing cells in this organ, immunized with ram erythrocytes. The courses of administration of the claimed preparation of various duration were commenced prior to the immunization of the animals with test antigens and continued until 3 days after the immunization. The animals were dosed orally daily with a dose equivalent to the therapeutic dose. On day 5 after immunization of the mice with ram's erythrocytes, the animals were killed and the amount of antibody-producing cells in their spleen was determined.

The data obtained showed that the claimed preparation reduces the amount of antibody-forming cells in the spleen of mice, both in the low and high response lines, by immunizing the animals with ram erythrocytes as test-anigen. In addition, the decrease in hemolysin-producing cells is dependent on the duration of administration. This decrease becomes statistically significant in both lineages over 20 days.

The effect of the claimed preparation on circulating antibody levels was investigated after 10 and 20 days, after administration of the product and after 7 days after immunization with mouse erythrocytes. The courses of administration of the claimed preparation of various duration were commenced prior to the immunization of the animals with test antigen and continued administration for 5 days after the immunization.

The results obtained showed that neither the low- or high-response line produced an effect on this humoral immune response by measuring the intensity of the immune response when administered orally after 10 and 20 days at therapeutic doses.

Thus, the amount of antibody that is the most integral indicator of the intensity of the immune response when administered the claimed preparation remains within the normal range (control).

The effect of the claimed preparation on hexenal-induced sleep duration as an indicator of the functional status of the body's monooxygenase system was also investigated.

The experiments were carried out on simple male mice weighing 20-22 g. The animals were administered orally daily for one week and three weeks; gave the control group the same volume of saline. The test metabolite (hexenal) is administered intraperitoneally at a dose of 70 mg / kg and the duration of the narcotic state of the mice is evaluated.

The results obtained showed that administration of a therapeutic dose of the claimed preparation for one or three weeks does not affect the duration of hexenal metabolism, which confirms the absence of substantial reactions from the body's enzymatic microsomal system at the time of its action.

Thus, based on studies of some of the immunopharmacological properties of the claimed preparation, a significant immunotherapeutic effect of the claimed preparation on the cellular immune response was observed. y. graft-versus-host reactions. Lymphocytes were stimulated by the claimed preparation, both before the response of foreign cells (for 3 weeks) and against cells of the same genotype but in another person (for 10 and 20 days). These results were obtained by administering the claimed preparation to both recipients and donors.

Under experimental conditions, the preparation inhibited the immune formation of rosettes and reduced the amount of antibody-forming cells in the spleens of mice. However, the integral indicators of humoral immunity circulating titers in the blood in the experimental groups remained at the same level as the control animals.

The therapeutic doses of the claimed preparation did not affect the functional activity of the monooxygenase enzyme system, together with the immune system, which is part of the unified system of the body to ensure its response to external influences. This is also indicative of the mild immunotherapeutic effect of the claimed product.

The ability of the claimed preparation to induce gene mutations was tested with standard test strains

S. typhimurium TA 100, TA 98, TA 1537 by Ames showed that the claimed preparation does not exhibit mutagenic activity.

Clinical trials of the claimed product's immunotropic properties have been performed. Volunteers (78 patients) were tested: 56 patients with various neoplasms; with rheumatoid arthritis [II

- X-ray stage III and stage II-III activity) - 22 patients.

The following parameters were examined: total lymphocyte count; B-lymphocyte and T-lymphocyte counts; Ratio of T-helper to T-suppressor; C, M, A, and E immunoglobulin levels and circulating immune complexes, functional activity of T-lymphocytes (T-helper and T-suppressors) and B-lymphocytes with various mitogens in blastoma transformation reactions; phagocytic activity and cytochemical characteristics of the enzymatic activity of immunocompetent cells.

Treatment with the claimed preparation is according to the regimen used. Immunoassays were performed prior to initiation of treatment, following the first two weeks of treatment and following one course (four weeks after starting treatment), and 2 to 3 months after stopping treatment. In some cases, studies were performed with repeated administration and up to 6 months after starting the product.

The progression of the underlying disease during the treatment with the claimed product became positive after more than two weeks of treatment.

Oncologic patients subjectively reported a marked improvement in their general condition after the course of treatment. Objectively, cases of tumor size reduction, as well as restoration of lymph nodes and intestinal transit were observed. After 2 to 3 courses of treatment, the patients positively evaluated their well-being, were able to work, and associated a certain weakness with the need to follow a diet.

In most patients with rheumatoid arthritis, physicians have found positive dynamics of joint syndrome as a result of a reduction in joint stiffness after a single course of treatment.

Under these conditions, fibroids of the external genitalia were observed per patient. Examination of patients prior to treatment with the claimed product showed mosaic characterization of immunological status changes in patients with various diseases and in one group of patients. In addition, the tested parameters of immunity parameters did not go beyond the average - physiological indices in practically healthy people. However, the proportion of Thelper: T-suppressor subpopulations was compromised in a large number of oncology patients.

The only measure of the simultaneous change in all patients is the amount of circulating immune complexes, which is also increased in oncology patients and in patients with rheumatoid arthritis.

Two weeks after the claimed start of treatment, a strong immune response was found in patients with immunoassays.

In the vast majority of patients in both groups, a general decrease in lymphocyte count was observed,

Decrease in T- and B-lymphocytes, decrease in T-helper and significant decrease in T-suppressors, decrease of various classes of immunoglobulin in different patients, characterization of monocyte and leukocyte phagocytic activity in oncology patients, and decrease of circulating immune complexes oncology patients and rheumatoid arthritis patients.

It is important to note that in the oncology patients, the T-helper: T-suppressor ratio decreased, the number of T-lymphocytes decreased, and their subpopulation decreased in various degrees. This has resulted in the restoration of the T-helper: T-suppressor ratio, albeit at a low functional level.

B-lymphocyte abnormalities, and in particular immunoglobulin abnormalities of various classes, were irregular in nature.

Proliferative lymphocyte activity assays in blastoma transformation reactions support the conclusion of a pronounced immune response following administration of the claimed product and of the major individual characteristics of this reaction occurring within the first two weeks of administration. At the end of the first course of therapy, a significant reduction in circulating immune complexes is noted among the changes in immune parameters. In the event of a general discrepancy between the remaining immunological parameters, it should be noted that they do not go beyond the physiological limits. A similar picture is maintained for immunoassays in patients 2-3 months after the first course of treatment before the second series. During the re-course, individual changes in immunological parameters in patients have the same characteristics as in the first course of treatment, but do not have a vector for general direction in all patients. During the trials, attempts were made to group patients into groups by type of change, to associate these changes with blood groups, but no clear pattern was found.

Positive dynamics of the test parameters were observed after 6 months, after 2 - 3 courses of the claimed product.

When analyzing the results of all clinical trials of the claimed product's immunotropic properties, attention is drawn to the remarkably individual response profile of the immune system in each patient. Generally, reactions occur in two stages. The former is characterized by non-directional changes in immunological parameters. Apparently, the claimed apparatus undergoes a reorientation of the internal regular mechanisms that unite immune cells into a single system. The second phase is the normalization phase of the immunological parameters. In general, there are 2 effects: reduction in the amount of circulating immune complexes and normalization of the T-helper: T-suppressor ratio of subpopulations. Both of these phenomena have a positive prognostic value as they indicate normalization of the immune system. Decrease in circulating immune complexes is observed in all patients (oncologic and rheumatoid arthritis) and the ratio of lymphocyte subpopulation »

normalization is characteristic of most patients in the given groups.

The claimed product has been tested in clinics in 250 patients. The preparation has been tested for the following diseases:

malignant and benign tumors, rheumatism, rheumatoid arthritis, bronchial asthma, neurodermatitis and other conditions.

The most common oncological diseases were: female organ diseases (mammary gland cancer, cervical and cervical cancer), haematopoietic system diseases (lymphogranulomatosis, lympholeucosis, acute lymphoblastic leukemia, myeloma), internal organ and tissue diseases, liver cancer, , leather, etc.); from benign tumors such as prostate adenoma, uterine fibromyoma, papilloma, cyst, mammary gland mastopathy, rectal polyp and others.

Patients ranged in age from 20 to 60 years; the duration of treatment with the claimed preparation ranged from 0.5 to 2 years and more.

The claimed preparation was administered according to the procedure described above: 5 ml 3 times a day for the first three days, then 10 ml 3 times a day thereafter. In parallel to the oral administration, there was a local external effect of the claimed preparation, depending on the localization of the disease. Externally, the preparation was administered in the form of dandruff, tampons, rinses, enemas. The preparation was applied to the affected areas - on the tailbone, groin lymph nodes, armpits, spine, joints, localized sites of disease, and on the covering or bone-joint tissues.

Analysis of the treatment outcome with the claimed product, including stage IV, III, II oncology patients (treatment time: greater than 0.5 years, greater than 1 year, greater than 2 years), as well as long-term maintenance therapy with the claimed medicinal product, effect on both those who have not previously been treated and those who have previously been treated.

Complete regression of the malignancy was observed in 34.3% of patients, depending on the nature, stage and time of treatment; up to 80.8% in patients with benign tumors. In a number of patients, process stabilization and tumor size reduction were observed.

Improvements in general status were noted.

Specific examples of preparation of the claimed preparation and clinical trials thereof have been carried out to explain the invention.

example

Composition of the claimed preparation:

mercury dichloride 0.01 g natural white grape wine containing by weight of sugar

100 g

The claimed material is prepared as follows.

The mercury dichloride is dissolved in the wine in the quantities indicated under normal conditions at room temperature. A clear, light yellow liquid is obtained (pH = 3, l). Store the resulting preparation in a dark glass container at a temperature not exceeding 15 ° C in a dark place. The product should be shaken before use as tartaric acid compounds may precipitate during storage.

The preparation is suitable for internal and external use.

example

Composition of the claimed material:

mercury dichloride 0,06 g natural white grape wine with a sugar content of 100% by weight

The claimed material is prepared analogously to Example 1.

A clear, light yellow liquid is obtained (pH = 3.3). The preparation is suitable for internal and external use.

example

Composition of the claimed material:

mercury dichloride 0.1 g milk whey containing 100% by weight of sugar per 100 ml

The claimed material is prepared analogously to Example 1.

A clear, creamy liquid is obtained. The preparation is suitable for internal and external use.

example

Composition of the claimed material:

mercury dichloride natural white grape wine containing by weight of sugar

0.3 g

100 g

The claimed material is prepared analogously to Example 1.

A clear, light yellow liquid is obtained (pH = 3.2). The preparation is suitable for external use.

example

Composition of the claimed material:

mercury dichloride 1.5 g of milk whey, by weight% sugar per 100 ml

The claimed material is prepared analogously to Example 1.

A clear, creamy liquid is obtained. The preparation is suitable for external use.

example

Composition of the claimed material:

mercury dichloride 0.25 g pig fat 230 g natural honey 240 g alcohol 96 ° to 750 g

The claimed material is prepared as follows.

Mercury dichloride is dissolved in ethyl alcohol. The pre-softened pig fat is mixed with natural honey in the quantities indicated. Subsequently, the mercury dichloride, once dissolved in ethyl alcohol, is carefully dissolved in small quantities and added to the pig fat with honey.

A cream-colored, light yellow formulation is obtained.

The preparation is suitable for internal and external use.

example

Composition of the claimed material:

potassium arsenite 0,05 g natural white grape wine containing 100% by weight of sugar

The material claimed is prepared by dissolving a specified quantity of potassium arsenite in wine.

A clear, light yellow liquid is obtained (pH = 3.2). The preparation is for internal use only.

example

Composition of the claimed material:

Sodium arsenate 0.15 g milk whey containing up to 100 ml of sugar

The claimed substance is prepared by dissolving a specified quantity of sodium arsenate in whey.

A clear, light yellow liquid is obtained. The preparation is for internal use only.

example

Clinical trials of the claimed substance with 99 oncology patients were performed: 67 of them had malignancies and 32 patients had benign tumors. Of the 67 patients, 32 had undergone treatment (surgery, polychemotherapy, gamma therapy), and the remaining 35 had not been treated before.

Most oncology patients: 21 patients were in stage IV, 18 patients in stage III, 6 patients in stage II. Stage 22 has not been established in 22 patients.

Patients by age ranged from 40 to 60 years with 39 patients. From 20 to 40 years - 7 patients over 60 years - 14 patients. By gender: 11 males, 56 females.

The term of treatment of the patients with the claimed preparation was as follows: 28 patients had been treated for more than 0.5 years (41.8

%), 3 patients - more than 1 year (28.3%), 19 patients (28.3%) - more than 2 years.

17 patients (25.4%) received long-term treatment with the claimed substance.

The most common malignancies are: (mammary cancer, cancer of the uterus, cervix, ovary, rectum, stomach, liver, nasopharynx, skin; hematopoietic disorders - lymphogranulomatosis, lymphoblastic leukemia, severe lymphoblastic myeloma);

Common benign neoplasms: (prostate adenoma, uterine fibrioma, papilloma, cyst, mammary gland mastopathy, rectal polyps).

(100%>) previously untreated oncology patients had the following results:

- 12 patients (34.3%) were completely cured (patients excluded).

Diseases: mammary gland cancer stage III-IV, malignant mastopathy, uterine cancer, ovarian cancer, sarcoma, melonoma, lympholeucosis.

- 12 patients (34.3%) were stabilized.

Diseases: mammary gland cancer, stage III-IV, mammary gland adenocarcinoma, prostate adenocarcinoma (lung metastases, stage IV), colorectal cancer, stage IV, nasopharyngeal cancer (metastases in the spine, brain), gastrointestinal blastoma ( Stage III).

- Tumor size reduction - 9 patients (25.8%).

Disease: Cancer of mammary glands.

- Improved general well-being in 1 patient (2.8%).

Further disease progression was seen in 1 patient (2.8%).

(100%) previously treated oncology patients had the following results:

- 6 people (18.8%) were completely healed. Full tumor regression. Removed from credit.

Diseases: mammary gland cancer stage III-IV, ovarian cancer stage IV, right-sided liver cancer (malignant form), basal cell carcinoma of the ear.

- 12 patients (37.6%) were stabilized.

Diseases: mammary gland cancer, mammary gland blastoma, stage IV (malignant form), laryngeal cancer, cervical cancer, liver cancer, gastric cancer, pancreatic cancer, chronic lymphoblastic leukemia, stage III, acute lymphoblastic leukemia.

- reduction in tumor size in 2 patients (6.2%).

Disease: Cancer of mammary glands.

No recurrence of the disease was observed in 4 patients (12, 5%).

- improvement in general well-being in 4 patients (12.5%),

- remission in 2 patients (6.2%),

-Satisfactory well-being - 1 patient (3.1%),

-Further disease progression in 1 patient (3.1%).

Positive effect of treatment with oncologic patients (79% on previously treated and untreated patients).

No effect was seen in 1 patient (2.9%).

(100%) in previously untreated oncology patients with benign tumors obtained the following results:

- 21 patients (80.8%) completely healed, complete tumor regression removed.

Diseases: mammary gland fibroadenoma, mastopathy, fibroma, uterine fibromioa, rectal polyps, uterine polyps, purulent ovarian tumors, lymphoadenitis, polycystitis and others.

- disease process stabilized in 2 patients (7.7%).

Diseases: mammary gland papilloma, mammary gland cyst.

- reduction in tumor size and improvement in general well-being in 2 patients (7.6%).

- satisfactory condition in -1 patients (3.8%).

(100%) previously treated patients had the following results:

- fully cured - 1 patient (16.7%)

Diseases: Mastopathy.

- feeling good in 3 patients (49.9%).

- 1 patient (16.7%) without relapses.

-remision -1 patient (16, 7%).

The positive effect of the claimed treatment of the non-oncological patients (non-malignant tumors) is

-81%.

example

Clinical trials of the claimed substance were performed on 157 patients, of whom 138 (87.9%) were cancer patients (malignant tumors); 19 (12.1%) had benign tumors. Of the 138 oncology groups, 94 (68.1%) had previous treatment (surgery, polychemotherapy, gamma therapy), and the remaining 44 (31.8%) had no previous treatment.

Oncological diseases (malignant tumors) include:

I - female organ diseases (mammary cancer, uterine and cervical cancer, ovarian cancer) - 72 patients.

II - cancer of the hematopoietic system (lymphogranulematoma, lymphoblastic lymphoma, leukemia, chronic lymphoblastic leukemia, acute myelogenous leukemia) -14 patients.

III - Oncological diseases of internal organs and tissues (stomach, lung, rectum, liver, bladder, prostate cancer, etc.) - 52 patients.

The treatment claimed material yielded the following results.

138 (100%) oncologic (malignant) stage II, III, IV patients had:

- complete tumor regression in 5 patients (3.6%);

- reduction in tumor size in 32 patients (23.5%);

- stabilization of malignant tumor growth in 61 patients (44.2%);

- improvement in general well-being in 28 patients (20.3%);

-Further disease progression - 12 patients (8.7%).

(100%) patients (benign tumors) received:

- tumor regression in 8 patients (42.1%);

-process stabilization - in 5 patients (26.2%);

- tumor size reduction in 4 patients (21.1%);

- Improved general well-being in 2 patients (10.5%).

The claimed material is used in medicine for the treatment of immunodeficiency of various origin, all types of malignant and benign tumors, rheumatism, rheumatoid arthritis, polyarthritis, bronchial asthma, systemic lupus erythematosus, stomach ulcer, herpes, trophic wounds, psoriasis, intestinal infection, neurodermatitis and other diseases.

Claims (6)

1. Preparation consisting of an active substance and a diluent, characterized in that the active substance is mercury dichloride or potassium arsenite or sodium arsenate by weight, in the form of an active substance and a diluent, for the repair of an immunomodulatory activity and of a tissue cell proliferative control system: mercury dichloride or potassium arsenite or sodium arsenate 0.01 -1.5 diluent to 100.0 2. Preparation according to claim 1, characterized in that the diluent is white natural grape wine containing 3-4% by weight of sugar or milk whey containing 3-4% by weight of sugar. Preparation according to claim 1, for internal or external use, characterized in that it consists of the following components, by weight: Mercury dichloride 0.01 - 0.1 Natural white grape wine containing 3-4 wt% sugar to 100.0 Preparation according to Claim 1, for use internally or externally, wherein the diluent comprises pig fat, natural honey and ethyl alcohol in the following proportion by weight: mercury dichloride 0.03-0.13 pig fat 30.7-37.3 natural honey 30.7 -37.3 ethyl alcohol to 100.0 Preparation according to claim 1, for internal or external administration, characterized in that it consists of the following components, by weight: sodium arsenate or potassium arsenite 0,05-0,15 natural white grape wine containing 3-4 wt% sugar to 100.0 6. Preparation according to claim 1, for internal or external administration, characterized in that it consists of the following components, by weight: Mercury dichloride 0,3 - 1,5 natural white grape wine containing 3 to 4% by weight of sugar or whey containing 3 to 4% by weight of sugar up to 100,0