RU2552221C2 - Method of treating obesity and accompanying metabolic disorders and medication for treating obesity and accompanying metabolic disorders - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to endocrinology, and deals with the treatment of obesity and accompanying metabolic disorders. For this purpose a medication, which contains an activated-potentiated form of antibodies to a human cannabinoid receptor type I, is introduced.

EFFECT: method makes it possible to provide effective weight reduction and correction of metabolic disorders with the absence of side effects.

6 cl, 7 tbl, 4 ex

Description

The invention relates to medicine and can be used to increase the effectiveness of the treatment of obesity, mainly exogenous-constitutional, including in combination with lipid metabolism disorders, including metabolic syndrome.

According to the International Obesity Task Force, more than 300 million people on our planet are obese, and another 800 million are overweight. While maintaining such high rates of growth in the incidence rate by 2025, a twofold increase in the number of obese patients is expected.

Overweight and obesity are one of the most common problems in developed countries and increase the risk of developing diseases of the cardiovascular system, dyslipidemia, type 2 diabetes, and cancer.

Among the modern drugs used to reduce body weight, three main groups can be distinguished - peripheral and central action drugs that enhance the “burning” of calories, drugs that reduce fat intake in the body, and central action drugs (appetite regulators) (Padwal RS, Majumdar SR, Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet 2007; 366 (9555): 71-7). Preparations of all groups have multiple side effects, and therefore their use in everyday practice is extremely limited. Thus, the development and implementation of new safe and effective drugs to reduce body weight are very relevant.

The prior art composition for the treatment of obesity and insulin resistance in the regulation of blood glucose, containing a compound isolated from a natural source and purified, selected from the group including anthocyanin, anthocyanidin and mixtures thereof (RU 2359689 C2, A61K 36/45, 09/10/2008). However, when using this composition, it is difficult to select a dose.

The use of a drug based on antibodies to lipase for the treatment of obesity in mammals is also known (WO / 1999/002187, A61K 38/00, 01/21/1999). However, this drug can cause severe side effects and, as a result, is used in a small number of cases.

A medicament is known in the art for the oral treatment of obesity, diabetes mellitus and other diseases accompanied by impaired glucose tolerance, containing antibodies to the beta subunit of the insulin receptor in activated form (WO 2007/149010 A1, A61K 39/395, 12/27/2007) . However, this drug is effective only in some patients with insulin resistance.

The invention is directed to an effective method for treating obesity and related metabolic disorders without side effects and an appropriate central and peripheral drug based on antibodies to the known human cannabinoid receptor (Ken Mackie. Cannabinoid receptors as therapeutic targets. The Annual Review of Pharmacology and Toxicology 2006. 46: 101-122).

The solution to this problem is provided by the fact that in the method of treating obesity and / or excess weight and associated metabolic disorders by introducing into the body of the drug, according to the invention, the drug contains an activated - potentiated form of antibodies to the human cannabinoid receptor in the form of an activated - potentiated water or water -alcohol solution obtained in the process of sequential multiple dilution in an aqueous or aqueous-alcoholic solvent and intermediate th external mechanical impact - vertical shaking.

It is possible to use an activated - potentiated form of antibodies to the whole molecule of the human cannabinoid receptor type I or a polypeptide fragment with a sequence selected, for example, from the following group:

QRGTQKSIII;

EKLQSVCSDIFPHIDETYL;

IQRGTQKSIIIHTSEDGKVQVTRPDQARM;

KAHSHAVRMIQRGTQKSIIIHTSEDGKVQVTRPDQARMDIRLAKT;

MSVSTDTSAEAL;

TEFYNKSLSSFKENEENIQCGENFMDIECFMVLNPS;

AQPLDNSMGDSDCLHKHAN;

GTQKSIIIHTSEDG;

MTAGDNPQLVPADQVNITEFYNKSLSSFKENEENIQCGENFMDIECFMVLN;

VVAFCLMWTIAIVI;

EFYNKSLSSFKENEENIQCGENFMDIECFMVLNPSQQLAIAVLSLTL;

NEENIQCGE;

GSPFQEKMTAGDNPQLVPADQVNITEFYNKSL;

AYKRIVTRPKAVVAFCLMWTIAIVIAVLPLLGWN.

In this case, the activated - potentiated form of antibodies to the human type I cannabinoid receptor is used in an ultra-low dose obtained by super-dilution of the initial matrix solution in 100 ¹² , 100 ³⁰ and 100 ²⁰⁰ times.

The solution to this problem is also provided by the fact that the drug for the treatment of obesity, according to the invention, contains an activated - potentiated form of antibodies to the whole molecule or polypeptide fragment of the human cannabinoid receptor in the form of an activated - potentiated aqueous or aqueous-alcoholic solution obtained in the process of serial multiple dilution in an aqueous or aqueous-alcoholic solvent and intermediate external mechanical action - vertical shaking .

In this case, an aqueous or aqueous-alcoholic solution of an activated - potentiated form of an antibody to a human type I cannabinoid receptor is obtained by repeated serial dilution and intermediate external exposure from a matrix solution of affinity-purified human type I cannabinoid receptor with a concentration of 0.5 ÷ 5.0 mg / ml

Preferably, the drug contains an activated - potentiated form of antibodies to the human type I cannabinoid receptor in an ultra-low dose prepared from a matrix solution, super-diluted in 100 ¹² , in 100 ³⁰ in 100 ²⁰⁰ , which is equivalent to a mixture of hundred-percent homeopathic dilutions of C12, C30 and C200.

In addition, the drug can be in solid dosage form and contain an effective amount of a neutral carrier saturated with an aqueous or aqueous-alcoholic solution of an activated, potentiated form of an antibody to a human type I cannabinoid receptor, and pharmaceutically acceptable additives.

Pharmaceutically acceptable additives may include lactose, microcrystalline cellulose and magnesium stearate.

The claimed technical result is due to the fact that the known type 1 cannabinoid receptors and endocannabinoids represent a single system in the hypothalamus, which, acting on specific areas of the mesolimbic region of the brain, affects the feeling of fullness and regulates appetite and, as a result, food intake. Moreover, the proposed drug based on the activated - potentiated form of antibodies to the human cannabinoid receptor (i.e., the forms of antibodies to the human cannabinoid receptor, prepared according to the homeopathic technology of potentiation by repeated serial dilution and intermediate external action - vertical shaking, which has activity in pharmacological models and / or clinical methods of treating obesity), provides an unexpected therapeutic effect project, which consists in the normalization of carbohydrate and lipid metabolism, leading to a decrease in body weight without side effects, which is confirmed experimentally on adequate (valid) models.

In addition, the technical solution obtained in accordance with the invention broadens the arsenal of centrally acting drugs intended for the effective treatment of obesity and / or overweight without side effects. Including as part of complex therapy.

The drug is prepared mainly as follows.

To prepare a homeopathically activated - potentiated form of the active substance - antibodies to the human cannabinoid receptor, monoclonal or, mainly, polyclonal antibodies are used, which can be obtained by known technologies - methods described, for example, in the book: Immunological methods, ed. G. Frimel, M., "Medicine", 1987, p. 9-33; or, for example, in an article by Laffly E., Sodoyer R. Hum. Antibodies. Monoclonal and recombinant antibodies, 30 years after. - 2005 - Vol. 14. - N 1-2. P. 33-55.

Monoclonal antibodies are obtained, for example, using hybridoma technology. Moreover, the initial stage of the process includes immunization, based on the principles already developed in the preparation of polyclonal antisera. Further stages of the work include obtaining hybrid cells producing clones of antibodies of the same specificity. Their isolation in an individual form is carried out by the same methods as in the case of polyclonal antisera.

Polyclonal antibodies can be obtained by active immunization of animals. To do this, according to a specially developed scheme, the animals are given a series of injections of the substance required by the invention, an antigen: a human type I cannabinoid receptor. As a result of such a procedure, a monospecific antiserum with a high content of antibodies is obtained, which is used to obtain an activated - potentiated form. If necessary, the antibodies present in the antiserum are purified, for example, by affinity chromatography, using fractionation by salt precipitation or ion exchange chromatography.

For immunization of rabbits, you can use as an immunogen (antigen) adjuvant and the whole molecule of the cannabinoid receptor type I person of the following sequence:

MKSILDGLAD TTFRTITTDL LYVGSNDIQY EDIKGDMASK

LGYFPQKFPL TSFRGSPFQE KMTAGDNPQL VPADQVNITE

FYNKSLSSFK ENEENIQCGE NFMDIECFMV LNPSQQLAIA

VLSLTLGTFT VLENLLVLCV ILHSRSLRCR PSYHFIGSLA

VADLLGSVIF VYSFIDFHVF HRKDSRNVFL FKLGGVTASF

TASVGSLFLT AIDRYISIHR PLAYKRIVTR PKAVVAFCLM

WTIAIVIAVL PLLGWNCEKL QSVCSDIFPH IDETYLMFWI

GVTSVLLLFI VYAYMYILWK AHSHAVRMIQ RGTQKSIIIH

TSEDGKVQVT RPDQARMDIR LAKTLVLILV VLIICWGPLL

AIMVYDVFGK MNKLIKTVFA FCSMLCLLNS TVNPIIYALR

SKDLRHAFRS MFPSCEGTAQ PLDNSMGDSD CLHKHANNAA

SVHRAAESCI KSTVKIAKVT MSVSTDTSAE AL

or, preferably, a polypeptide fragment of a human type I cannabinoid receptor with a sequence selected, for example, from the following group:

QRGTQKSIII;

EKLQSVCSDIFPHIDETYL;

IQRGTQKSIIIHTSEDGKVQVTRPDQARM;

KAHSHAVRMIQRGTQKSIIIHTSEDGKVQVTRPDQARMDIRLAKT;

MSVSTDTSAEAL;

TEFYNKSLSSFKENEENIQCGENFMDIECFMVLNPS;

AQPLDNSMGDSDCLHKHAN;

GTQKSIIIHTSEDG;

MTAGDNPQLVPADQVNITEFYNKSLSSFKENEENIQCGENFMDIECFMVLN;

VVAFCLMWTIAIVI;

EFYNKSLSSFKENEENIQCGENFMDIECFMVLNPSQQLAIAVLSLTL;

NEENIQCGE;

GSPFQEKMTAGDNPQLVPADQVNITEFYNKSL;

AYKRIVTRPKAVVAFCLMWTIAIVIAVLPLLGWN

Before blood sampling for 1-3 days, 1-3 intravenous injections are performed to increase the level of antibodies. During immunization, small blood samples are taken from rabbits to evaluate the amount of antibody. The maximum level of the immune response to the administration of most soluble antigens is achieved 40-60 days after the first injection. After the end of the first cycle of immunization of rabbits for 30 days, they restore health and re-immunization, including 1-3 intravenous injections. To obtain antisera from immunized rabbits, blood is collected in a 50 ml centrifuge tube. Using a wooden spatula, the formed clots are removed from the walls of the tube and the wand is placed in the clot formed in the center of the tube. Blood is placed in a refrigerator (temperature 4 ° C) at night. The next day, the clot attached to the spatula is removed and the remaining liquid is centrifuged at 13000 g for 10 minutes. The supernatant (supernatant) is an antiserum. The resulting antiserum, which should be yellow, is stored until use in a frozen state at a temperature of -70 ° C. To isolate antibodies to the cannabinoid receptor type I from an antiserum of a person, type 1 absorption is performed on the solid phase in the following sequence:

1. 10 ml of rabbit antiserum is diluted 2 times with 0.15 M NaCl, 6.26 g of Na ₂ SO ₄ are added, stirred and incubated for 12-16 hours at 4 ° C;

2. The precipitate formed is removed by centrifugation, dissolved in 10 ml of phosphate buffer and then dialyzed against the same buffer overnight at room temperature;

3. after removal of the precipitate by centrifugation, the solution is applied to a column with DEAE-cellulose, balanced with phosphate buffer;

4. The antibody fraction is determined by measuring the optical density of the eluate at 280 nm.

The antibodies are then purified by affinity chromatography by attaching the obtained antibodies to the human type I cannabinoid receptor, which is located on an insoluble matrix, followed by elution with concentrated salt solutions.

Thus obtained buffer solution of polyclonal rabbit antibodies to the cannabinoid receptor of human type I, purified on antigen, with a concentration of 0.5 ÷ 5.0 mg / ml, preferably 2.0 ÷ 2.5 mg / ml, is used as a matrix (primary) solution for the subsequent preparation of the activated - potentiated form.

An activated - potentiated form of the active substance - antibodies to the human type I cannabinoid receptor in an ultra-low dose is prepared by uniformly reducing the concentration as a result of successive dilution of 1 part of the matrix solution in 9 parts (for decimal dilution) or 99 parts (for hundredth dilution C) or in 999 parts (for a thousandth dilution of M) of a neutral aqueous or hydroalcoholic solvent with multiple vertical shaking - potentiation (or "dynamization") of each gender chennogo dilution and using separate containers for each subsequent dilution until the required potency - the multiplicity of homeopathic dilution method (see, e.g., V. Schwabe "Homeopathic medicines", M., 1967, p 14-29..).

For example, to prepare the 12th hundredth C12 dilution, one part of the above matrix solution of human type I cannabinoid receptor antibodies of 2.5 mg / ml is diluted in 99 parts of a neutral aqueous or aqueous-alcoholic solvent and many times (10 times or more) vertically shake - potentiate the obtained 1st hundredth C1 dilution. From the 1st hundredth C1 dilution prepare the 2nd hundredth dilution C2. This operation is repeated 11 times, obtaining the 12th hundredth dilution of C12. Thus, the 12th hundredth dilution of C12 is a solution obtained by diluting successively in different containers 12 times of the first part of the initial matrix solution of antibodies to the human cannabinoid receptor type I with a concentration of 2.5 mg / ml in 99 parts of a neutral solvent , i.e. the solution obtained by super-dilution of the initial matrix solution in 100 to ¹² times. Similar operations with the appropriate dilution ratio are carried out to obtain a dilution of C30 and C200.

When using as a biologically active liquid component a mixture of various homeopathic, mainly hundred, dilutions, active ingredients, each component of the composition (for example, C12, C30, C200) is prepared separately according to the technology described above to their last but one dilution (respectively, to obtain C11, C29, C199) and then, in accordance with the composition of the mixture, one part of each component is added to one container and mixed with the required amount of solvent (respectively, with 97 parts for hundred-percent dilution). In this case, an activated - potentiated form of antibodies to the human type I cannabinoid receptor is obtained in an ultra-low dose obtained by super-dilution of the initial matrix solution 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times, equivalent to a mixture of hundred-percent homeopathic dilutions of C12, C30, C200.

It is possible to use the active substance in the form of a mixture of other various homeopathic dilutions, for example, decimal and / or hundredths (D20, C30, C100 or C12, C30, C50, etc.), the effectiveness of which is determined experimentally.

When potentiating instead of shaking in the process of decreasing the concentration, it is also possible to exert external influence by ultrasound, electromagnetic or other physical effect.

The claimed drug can be used in solid dosage form, which contains an effective amount of granules of a neutral carrier - lactose, saturated by impregnation to saturation with an aqueous or aqueous-alcoholic solution of an activated - potentiated form of antibodies to the human cannabinoid receptor type I, and pharmaceutically acceptable additives, including mainly lactose, microcrystalline cellulose and magnesium stearate. A solid dosage form is prepared by tabletting from a tablet mass, which contains 8 ÷ 10 masses. parts of lactose granules irrigated in a fluidized bed with an aqueous or aqueous-alcoholic solution of an activated - potentiated form of antibodies to the cannabinoid receptor of human type I, 2-7 mass. parts of lactose moistened with 70% alcohol, soaked to the saturation with an aqueous or aqueous-alcoholic solution of an activated, potentiated form of antibodies to the human type I cannabinoid receptor, and pharmaceutically acceptable additives, including 75 ÷ 95 wt. parts of pure lactose, 8 ÷ 15 mass. parts of microcrystalline cellulose and 0.8 ÷ 1.2 mass. parts of magnesium stearate. The weight of the tablet may be 150 ÷ 500 mg. It is preferable to use tablets weighing 250–300 mg, which include 3.0–6.0 mg / tablet of an activated — potentiated form of water-alcohol dilutions of a substance — the active substance of polyclonal rabbit antibodies to human cannabinoid receptors of type I, purified on antigen, in an ultra-low dose obtained by super-dilution of the initial matrix solution 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times, the equivalent mixture of hundred-percent homeopathic dilutions C12, C30, C200 (ultra-low doses - SMD anti-KR).

Preferably, for the effective treatment of obesity or overweight, it is recommended to use the claimed drug in 1-2 tablets (keep in the mouth until completely dissolved) 2-4 times a day.

To conduct experimental studies, polyclonal antibodies were used, prepared by order of a specialized pharmaceutical company.

Example 1

For the treatment of obesity, attempts have been repeatedly made to use psychoactive substances (antidepressants, nootropics, various endorphins, enkephalins, endocannabinoids) that affect the system of positive emotional support and, above all, the functional activity of the “pleasure centers” in the lateral hypothalamus. However, due to the expressed side effects, the development of addiction (addiction), an effective and at the same time safe central-acting drug has not yet been created.

The claimed drug in the direction of action - type 1 cannabinoid receptor - is central, but due to the use of special potentiation technology, it affects the receptor, leading to its sensitization and, as a result, to increased sensitivity to endogenous cannabinoids.

This effect is confirmed by the following experiment: a study was made of the effect of the drug on the basis of an activated - potentiated form of polyclonal rabbit antibodies to the human type I cannabinoid receptor, purified on antigen, in an ultra-low dose obtained by super-dilution of the initial matrix solution 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times, the equivalent mixture of hundreds of homeopathic dilutions C12, C30, C200 (ultra-low doses - SMD anti-KR) on the functional state of type 1 cannabinoid receptor (in vitro) in 2 modes: in agonist mode and in p bench antagonist.

Agonist Mode:

Prior to insertion into the wells of a microplate (96-well plate, well volume 250 μl), the cells were suspended in HBSS buffer (Invitrogen) containing 20 mM HEPES (pH = 7.4). Cells were preincubated for 10 minutes at room temperature with the addition of 20 μl of anti-Raman SMD. After pre-incubation, NKH477 adenylate cyclase activator was added to the wells. Cells were incubated for 10 minutes at 37 ° C and lysed. A fluorescent acceptor (cAMP labeled with D2) and a fluorescent donor (antibodies to cAMP labeled with europium cryptate) were added to the wells.

As a basal control, instead of the SMD anti-CR preparation, the cell suspension was preincubated in the presence of HBSS buffer (20 μl). As a stimulated control, instead of SMD anti-CR, the cell suspension was preincubated in the presence of the reference agonist CP 55940 (20 μl).

Functional activity (by cAMP concentration) was evaluated by time-resolved homogeneous fluorescence (HTRF). The fluorescence intensity in the basal control is taken as the background and its value is subtracted from the fluorescence intensities in the experiment (SMD anti-Raman) and control (CP 55940):

The measured specific response of the cell to the introduction of SMD anti-Raman is calculated by the formula: the fluorescence intensity in the experiment (SMD anti-Raman) is the fluorescence intensity in the basal control.

The measured specific response of the cell to the introduction of a reference agonist (CP 55940) is calculated by the formula: fluorescence intensity in the control (CP 55940) - fluorescence intensity in the basal control.

The results are expressed as a percentage of the specific response of the cell to the introduction of a reference agonist in stimulated control:

% response of the reference agonist = ((measured specific response / specific response in the control on the introduction of the reference agonist) × 100%).

Antagonist Mode:

Prior to insertion into the wells of a microplate (96-well plate, well volume 250 μl), the cells were suspended in HBSS buffer (Invitrogen) containing 20 mM HEPES (pH = 7.4). Cells were preincubated for 5 minutes at room temperature with the addition of 20 μl of anti-Raman SMD. After adding the reference agonist of CP 55940 to the wells, the cells were incubated for 10 minutes at room temperature. Next, NKH477 adenylate cyclase activator was added to the wells. Cells were incubated for 10 minutes at 37 ° C and lysed. A fluorescent acceptor (cAMP labeled with D2) and a fluorescent donor (antibodies to cAMP labeled with europium cryptate) were added to the wells.

As a basal control, instead of SMD anti-Raman cell suspension, the cell suspension was preincubated in the presence of the reference antagonist AM 281 (20 μl). The reference agonist of CP 55940 was not added to the wells with the basal control. As a stimulated control, the cell suspension was preincubated in the presence of HBSS buffer containing 20 mM HEPES (pH = 7.4) and the reference agonist of CP 55940 (20 μl).

Functional activity (by cAMP concentration) was evaluated by time-resolved homogeneous fluorescence (HTRF). The fluorescence intensity in the basal control is taken as the background and its value is subtracted from the fluorescence intensities in the experiment (SMD anti-Raman) and control (CP 55940):

The measured specific response of the cell to the introduction of SMD anti-Raman is calculated by the formula: the fluorescence intensity in the experiment (SMD anti-Raman) is the fluorescence intensity in the basal control.

The measured specific response of the cell to the introduction of a reference agonist (CP 55940) is calculated by the formula: fluorescence intensity in the control (CP 55940) - fluorescence intensity in the basal control.

The results are expressed as percent inhibition of the specific response of the cell to the introduction of a reference agonist (CP 55940) in the control:

% inhibition of the response of the reference agonist = 100% - ((measured specific response / specific response in the control on the introduction of the reference agonist) × 100%)

As a result of studies, it was shown (see Table 1) that SMD anti-KR alters the functional activity of type 1 cannabinoid receptor, estimated by the concentration of intracellular cAMP.

The sample (ultra-low doses of antibodies to the cannabinoid receptor type I (a mixture of homeopathic dilutions C12 + C30 + C200)) shows the properties of an agonist of the cannabinoid receptor type I, the severity of the modifying effect of which is 21% of the effect of the standard agonist CP55940 (the effect of the standard agonist is taken as 100%) .

Table 1 Receptor A drug The content of SMD anti-Raman in the well (% by volume) (total volume of all compounds in the well is 200 μl) Agonist mode Agonist mode Explanation of the results % response to SMD anti-KR Standard agonist % inhibition of agonist response Standard antagonist CB1 Type 1 Cannabinoid Receptor SMD anti-KR 10% 21 SR 55940 0 AM 281 SMD anti-KR have an agonist effect, the severity of which is 21% of the effect of a standard agonist (taken as 100%)

Example 2

To study the properties of the claimed drug, we used an aqueous solution of the activated - potentiated form of polyclonal rabbit antibodies to the human type I cannabinoid receptor, purified on antigen, in an ultra-low dose obtained by super-diluting the initial matrix solution with 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times equivalent to a mixture of hundred homeopathic dilutions C12, C30, C200 (ultra-low doses - SMD anti-KR).

The study used 40 male mice of the C57B1 line (weight at the beginning of the study 13.5-15.5 g). 10 mice received the usual standard food (standard diet), 30 mice received the standard food with high-calorie supplements (high-calorie diet) and at the same time either distilled water (control, 0.4 ml / kg) or sibutramine ¹ ( ¹ Meridia 10 mg capsule, Abbott GMBH, Germany) (10 mg / kg), or SMD anti-KR (0.4 ml / kg). All drugs were administered intragastrically 1 time per day for 5 months. Before the introduction of drugs (initially), as well as every week after the start of their administration, the consumption of feed by mice was measured. Feed intake was estimated as the average amount of food (g) consumed by the mouse for 1 and 2 months of the study, and as the average amount of feed per 10 g of mouse body weight.

Mice in the low-calorie diet group consumed, on average, 15% less feed over the entire observation period than mice on a high-calorie diet (Table 2). Both sibutramine and SMD anti-KR reduced feed intake, and the effect of sibutramine was slightly higher: the drug reduced feed consumption per week by 19.3% (p <0.05), while SMD anti-KR - only by 9 , 3% relative to control (p> 0.05). Table 2 presents the results of the influence of SMD of anti-KR and sibutramine on food intake by C57B1 mice (average values over 5 months of observation), M ± m.

table 2 A drug Feed intake (g / mouse) per day Feed intake (g per 10 g body weight) per day Standard diet 2.95 ± 1.42 1.35 ± 0.05 High calorie diet + distilled water 3.41 ± 1.64 # 1.54 ± 0.05 # High calorie diet + sibutramine 2.75 ± 1.36 ** 1.28 ± 0.05 ** High calorie diet + diet 3.10 ± 2.02 1.44 ± 0.08 Note: ** - differences from the control are significant, p <0.01; # - differences from the standard diet are significant, p <0.05

However, when analyzing the dynamics of feed intake, the following features were identified. In the twentieth week of the experiment, mice on a high-fat diet treated with anti-Raman SMD consumed more food than the first week of the experiment, as shown in Table 3.

Table 3 The effect of SMD anti-Raman and sibutramine on the body weight gain of C57B1 mice and food consumption per 10 g of weight over the last 20 weeks of the experiment.

Note: ** - differences from the control are significant, p <0.01; *** - p <0.001

At the same time, in mice treated with anti-Raman SMD, a decrease in body weight gain of 51.2% was still observed relative to the control. Sibutramine in the last twentieth week of the experiment also reduced body weight gain by 51.5% compared with the control group.

Example 3

To study the properties of the claimed drug, we used an aqueous solution of an activated - potentiated form of polyclonal rabbit antibodies to the human type I cannabinoid receptor, purified on antigen, in an ultra-low dose, an ultra-low dose obtained by super-diluting the initial matrix solution 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times , the equivalent mixture of hundreds of homeopathic dilutions C12, C30, C200 (ultra-low doses - SMD anti-KR).

The study used 33 male mice of the C57B1 line (weight at the beginning of the study 13.09 ± 0.738 g). The mice received a modified diet with a high (45%) fat content and at the same time either distilled water (control, 0.2 ml / kg), or sibutramine (10 mg / kg), or antibodies to the human type I cannabinoid receptor, purified on antigen, a mixture of hundreds of homeopathic dilutions C12 + C30 + C200 (ultra-low doses - SMD anti-KR) (0.2 ml / kg). All SMD anti-KR drugs were administered intragastrically 1 time per day for 2 months. Prior to the introduction of the preparations (initially), as well as every week after the beginning of their administration, the weight of mice was measured on an Philips Cucina HR 239016 electronic balance (Hungary). The increase in body weight of mice was evaluated in% of the original.

Starting from the 6th week of administration, SMD anti-KR reduced the weight gain of mice on a high-fat diet. Table 3 presents the average weekly weight (g) of C57B16 mice fed a high-fat diet and SMD anti-KR (0.2 ml / mouse) or sibutramine 10 mg / kg) (M ± m). Table 4 shows the gain in body weight of mice.

Table 4 Group Body weight (g), weeks of study 0 one 2 3 four 5 6 7 8 Distil. water 12.18 ± 0.501 15.27 ± 0.982 15.27 ± 0.488 16.00 ± 0.972 18.18 ± 0.569 17.27 ± 0.557 20.18 ± 0.501 20.55 ± 0.608 21.45 ± 0.857 Δ to the original 25,4 25,4 31.3 49.3 41.8 65.7 68.7 76.1 Sibutramine 13.82 ± 1.094 13.45 ± 0.474 16.73 ± 0.407 * 19.82 ± 0.501 ** 20.18 ± 0.784 20.91 ± 0.563 ** 22.36 ± 0.927 23.64 ± 1.343 22.91 ± 1.091 Δ to the original -2.6 21.1 43,4 46.1 51.3 61.8 71.1 65.8 SMD anti-KR 13.27 ± 0.619 16.18 ± 0.182 17.45 ± 0.282 ** 19.64 ± 0.453 ** 20.18 + 0.423 * 20.18 + 0.423 ** 19.82 ± 0.501 21.64 ± 0.364 22.00 ± 0.467 Δ to the original 21.9 31,4 47.9 52.1 52.1 49.43 63.0 65.8 Note: * - p <0.05 with respect to the control group; ** - p <0.001 in relation to the control group

Thus, the SMD anti-KR drug reduces the body weight gain of mice on a high-fat diet, reducing their food intake and is not inferior in effectiveness to the well-known drug sibutramine widely used to reduce body weight.

Example 4

To study the properties of the claimed medicinal product, 300 mg tablets were used, impregnated with an aqueous-alcoholic solution (6 mg / tablet) of an activated, potentiated form of polyclonal rabbit antibodies to the human type I cannabinoid receptor, purified on antigen, in an ultra-low dose obtained by super-dilution of the original matrix solution in 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times, equivalent to a mixture of hundreds of homeopathic dilutions C12, C30, C200 (ultra-low doses - SMD anti-KR).

The study involved 80 volunteers (20 men and 60 women) aged 20 to 69 years (mean age 40.2 ± 1.26 years), 68.7% of whom were overweight or obese (I-III degrees), which were taken on the 1st tablet 2 times a day. Table 5 presents the demographic and anthropometric indicators of the patients included in the study. The safety analysis included data from all patients participating in the study (n = 80). During the entire period of observation of patients, good tolerability of the drug was noted. Adverse events were absent. All patients of the study groups completed the treatment within the time period established by the study protocol; there were no prematurely retired patients. When assessing the effect of SMD anti-KR on the change in body weight of the subjects, it was found that the use of the drug led to a decrease in body weight of 56 (70%) patients. In 24 (30%) patients, the weight remained unchanged, or increased slightly, however, it should be noted that among these patients, 14 (17.5%) initially had normal body weight (BMI <25 kg / m ² ).

Table 5 Indicator Value Age years M ± m 40.2 ± 1.26 Height, cm M ± m 167.1 ± 0.89 Weight, kg M ± m 80.3 ± 1.85 Floor men 20 people (25%) women 60 people (75%) BMI, kg / m ² M ± m 28.7 ± 0.6 BMI, kg / m ² less than 25 25 people (31.3%) Normal body weight 25-29.99 28 people (35%) Overweight (obesity) 30-34.99 20 people (25%) Obesity I degree 35-39,99 5 people (6.2%) Obesity II degree 40 and more 2 people (2.5%) III degree obesity

In the dynamics of observation in patients responding to therapy, there was a statistically significant decrease in body weight (p <0.001), which after 15 days of receiving SMD anti-KR was 1.1 kg (1.3%), and after 1 month reached 1 , 9 kg (2.2%) of the initial value, as shown in Table 6.

Table 6

Note: *** - P from ref <0.001

Also, in this group of patients, 1 week after the start of SMD anti-KR, there was a statistically significant (p <0.001) decrease in the waist circumference and hip circumference, which reached 2.3% and 2.7% by the end of therapy, respectively. Table 7 presents the dynamics of changes in the waist circumference and hip circumference.

Table 7 Day 1 (ref) Day 7 Day 14 Day 15 Day 16 Day 22 Day 29 Day 30 waist circumference, cm M ± m, cm 96.3 ± 1.97 95.2 ± 2.07 ** 93.7 ± 1.82 *** 94.2 ± 1.96 *** 95.1 ± 2.16 *** 94.5 ± 2.16 *** 94.3 ± 2.10 *** 94.1 ± 2.07 *** Δ from ref,% -1.1% -2.7% -2.2% -1.2% -1.9% -2.1% -2.3% thigh circumference, cm M ± m, cm 110.8 ± 1.52 110.8 ± 1.66 *** 109.3 ± 1.37 ** 109.9 ± 1.50 *** 108.7 ± 1.60 *** 108.3 ± 1.56 *** 108.1 ± 1.58 *** 107.8 ± 1.69 *** Δ from ref,% 0,0% -1.4% -0.8% -1.9% -2.3% -2.4% -2.7% Note: ** - P from ref <0.01; *** - P from ref <0.001

When assessing the severity of hunger in patients on the Visual Analogue Scale (VAS), it was initially shown that the highest intensity of hunger was observed in patients in the evening. At the end of 1 month of taking SMD anti-KR, the level of hunger in the evening hours decreased significantly (p <0.001) from 49.4 ± 3.75 to 42.0 ± 4.32 points. In the morning and afternoon, there was also a tendency to a decrease in the severity of hunger (from 20.5 ± 3.23 to 13.6 ± 1.78 points in the morning, from 44.7 ± 3.45 to 27.3 ± 3, 72 points in the daytime), which, however, did not reach statistically significant values at the end of therapy, which is possibly due to an insufficient number of patients and moderate baseline values.

Thus, in a clinical study of SMD anti-KR, the drug was highly tolerated, there were no adverse effects when taking the drug.

Claims (6)

1. A method of treating obesity and concomitant metabolic disorders by introducing a drug into the body, characterized in that the drug contains an activated-potentiated form of antibodies to the human cannabinoid receptor in the form of an activated-potentiated aqueous or aqueous-alcoholic solution obtained in the course of multiple serial dilution matrix solution in an aqueous or aqueous-alcoholic solvent and intermediate external mechanical stress - vertical The leg shaking. 2. The method according to claim 1, characterized in that they use an activated-potentiated form of antibodies to a whole molecule or polypeptide fragment of a human type I cannabinoid receptor. 3. The drug for the treatment of obesity and related metabolic disorders according to claim 1, characterized in that it contains an activated-potentiated form of antibodies to the human cannabinoid receptor type I in the form of an activated-potentiated aqueous or aqueous-alcoholic solution obtained in the process of serial multiple dilutions in an aqueous or aqueous-alcoholic solvent and intermediate external mechanical action - vertical shaking. 4. The drug according to claim 3, characterized in that the aqueous or aqueous-alcoholic solution of the activated-potentiated form of antibodies to the type I cannabinoid receptor is obtained by multiple serial dilution and intermediate external exposure from a matrix solution of affinity-purified type I cannabinoid receptor antibodies person with a concentration of 0.5-5.0 mg / ml. 5. The drug according to claim 3, characterized in that it is made in solid dosage form and contains an effective amount of granules of a neutral carrier saturated with an aqueous or aqueous-alcoholic solution of an activated-potentiated form of human type I cannabinoid receptor antibodies, and pharmaceutically acceptable additives. 6. The drug according to claim 5, characterized in that the pharmaceutically acceptable additives include lactose, microcrystalline cellulose and magnesium stearate.