WO2009005483A1 - Method for treating metabolic syndrome x - Google Patents

Abstract

The invention relates to medicine, in particular to endocrinology. The inventive method for treating metabolic syndrome X consists in administring to a patient a pharmaceutical composition which contains (+)-cis-3-(2'-benzimidazolyl)-1,2,2-trimethylcyclopentane carbonic acid or optically active isomers thereof or physiologically acceptable salts in a daily dose ranging from 25 to 750 mg. The method also consist in administring the above-mentioned composition in a quantity ranging from 200 to 750 mg in combination with at least one additional antidiabetic agent, substantially with metformin or in administring said composition together with a combined antidiabetic preparation containing metformin and another antidiabetic preparation, the antidiabetic agents being injected in quantities of 60% or less of the initial daily dose.

Description

 METHOD FOR TREATING METABOLIC SYNDROME X

Technical field

The invention relates to medicine, and specifically to a method for the treatment of metabolic syndrome X, including the use of drugs.

BACKGROUND OF THE INVENTION

Metabolic Syndrome X is a complex of interrelated disorders of carbohydrate and lipid metabolism, as well as mechanisms of regulation of blood pressure and endothelial function, due to a decrease in tissue sensitivity to insulin - insulin resistance [1].

According to leading researchers in the world, it is metabolic syndrome X that is the basis for the development of atherosclerosis, ischemic and hypertension, diabetes mellitus and obesity.

According to epidemiological studies conducted in Europe (Vetpa Stud), the disease 10% of the population with normal glucose tolerance, 40% with glucose intolerance and 70% of patients with type 2 diabetes mellitus are closely associated with metabolic syndrome X (insulin resistance syndrome) [2]. The main of the 12 components of pathogenetic factors of metabolic syndrome X are: insulin resistance (decrease in insulin-dependent utilization of glucose by tissues); hyperinsulinemia (compensatory mechanism); impaired glucose tolerance, later - impaired carbohydrate metabolism (fasting hyperglycemia> 5.5 mmol / l); hypertriglyceridemia (> 2.2 mmol / L); low cholesterol of high density lipoproteins (HDL-C) (XC <1 mmol / L); coronary heart disease; hypertension and others. For the diagnosis of metabolic syndrome X, 2-3 of its main manifestations are sufficient.

Timely correction of the links of metabolic syndrome X makes it possible to prevent these manifestations. For this reason, the search for drugs that can affect the main pathogenetic links of metabolic syndrome X is the most urgent problem of modern medicine.

Numerous studies in this area have established a close relationship between insulin resistance and deficiency of hormone secretion, according to which both defects reinforce each other, especially in the case of severe hyperglycemia [3]. In connection with the foregoing, successful therapy aimed at reducing hyperglycemia before achieving euglycemia (normoglycemia) will simultaneously affect the two above metabolic defects. In addition, the main goal of the treatment of metabolic manifestations is not only the correction of the symptoms of dysglycemia by lowering the concentration of glucose in the blood to normal (5-6 mmol / l on an empty stomach), but also the correction of the symptoms of dyslipidemia, which are the main factor in the development of micro- and macrovascular complications. The implementation of these tasks in practice turns out to be a rather complicated problem, which is currently being solved with the help of a low-calorie diet, oral antidiabetic drugs and insulin. In addition, the well-known drug therapy is not in all cases able to positively simultaneously affect all pathogenetic links of metabolic syndrome X to obtain reliable results. Conducted research on patent and medical literature revealed a number of methods for treating metabolic syndrome X and its manifestations.

A known method of treating metabolic syndrome X, in which drugs are used derivatives of thiazolidinedione (troglitazone, rosiglitazone and pioglitazone), which positively affect lipid and carbohydrate metabolism [4], and similar in pharmacological action to the present invention.

The disadvantage of this known method are such side effects of the used thiazolidinediones as hepatotoxicity, edema, upper respiratory tract infection, headache, anemia, dose-dependent weight gain, etc., which limits their clinical use [5].

Closest to the pharmacological action of the closest analogues to the present invention is a known method for the treatment of metabolic syndrome X, which comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition in the form of an acceptable dosage form containing the active substance from the biguanide group metformin in combination with one and more pharmaceutically acceptable excipients, selected as a prototype [6]. Metformin hydrochloride (Glucorhage), as the most active of the biguanide class drugs, has the greatest use in the treatment of metabolic syndrome X. During treatment, a daily dose of l, 5g to 2 g is administered to a subject. Metformin improves the sensitivity of liver tissue and peripheral tissues to insulin, while reducing body weight, but does not fully provide a decrease in insulin resistance.

At the same time, the positive effect of metformin on the manifestations of metabolic syndrome X is accompanied by an increased risk of lactic acidosis, side effects from the gastrointestinal tract, which also limits its clinical use, especially in elderly patients with renal failure and impaired liver function. These disadvantages of the known method as a whole lead to an insufficient breadth of the therapeutic index with a relatively high toxicity and a significant dose of the active substance metformin. This leads to a decrease in the effectiveness of treatment with an increase in the side effects of drug therapy, and consequently, an increase in the cost of treating patients. All this significantly limits the possibility of using metformin in patients with metabolic syndrome X.

Summary of the invention The basis of the invention is the task of improving the method of treatment of metabolic syndrome X, in which by using a pharmaceutical composition with another main active substance, a significant reduction in toxicity and dose of the active substance, which cause an increase in the breadth of the therapeutic index, is achieved, when comparable with the prototype by the severity of the pharmacological action, which will improve the effectiveness of treatment with a decrease in side s effects of drug therapy, and hence reduce the cost of treatment of patients.

As a result of using the claimed invention, a technical result is obtained, consisting in a significant reduction in toxicity and doses of the active substance, which determine an increase in the breadth of the therapeutic index, while ensuring the achievement of a pharmacological action comparable to the prototype.

This object is achieved in that in a method of treating metabolic syndrome X in mammalian subjects, comprising administering to a subject a therapeutically effective amount of at least one pharmaceutical composition in an acceptable dosage form containing an active substance in combination with one or more pharmaceutically acceptable excipients, according to the invention , in need of the subject, depending on the condition, weight and age, is administered, preferably orally, the main pharmaceutical the composition in individual dosage forms, (±) -cyc-3- (2'-benzimidazolyl) -1,2,2-trimethylcyclopentanecarboxylic acid or its optically active isomers of the formula are used as the main active substance of the main pharmaceutical composition

или её/их физиологически приемлемые соли, которую выбирают в суточной дозе от 25 мг до 750 мг, или вводят указанную основную фармацевтическую композицию в раздельных лекарственных формах в суточной дозе от 200 мг до 750 мг, в сочетании с по меньшей мере одним дополнительным антидиабетическим лекарственным средством, содержащим не менее одно активное вещество, преимущественно метформин, от одного до трех раз в сутки, при этом дополнительное анти- диабетическое лекарственное средство, содержащее метформин в комбинации с любым иным антидиабетическим активным веществом в одной общей индивидуальной лекарственной форме, используют в виде комбинированного препарата, вместе с тем дозы антидиабетических лекарственных средств вводят в количествах от 60% и ниже от их начальной суточной дозы. Кроме того:

or her / their physiologically acceptable salts, which are selected in a daily dose of from 25 mg to 750 mg, or enter the specified pharmaceutical composition in separate dosage forms in a daily dose of from 200 mg to 750 mg, in combination with at least one additional antidiabetic drug means containing at least one active substance, mainly metformin, from one to three times a day, with additional anti- a diabetic drug containing metformin in combination with any other antidiabetic active substance in one common individual dosage form is used in the form of a combined preparation, however, doses of antidiabetic drugs are administered in amounts of 60% or lower of their initial daily dose. Besides:

- as the optically active isomers of the main active substance of the main pharmaceutical composition, (+) - cis-3- is used

(2'-benzimidazolyl) -l, 2,2-trimethylcyclopentanecarboxylic acid or its physiologically acceptable salts;

- as the optically active isomers of the main active substance of the main pharmaceutical composition, (-) - cis-3- (2'-benzimidazolyl) -l, 2,2-trimethylcyclopentanecarboxylic acid or its physiologically acceptable salts are used;

- as physiologically acceptable salts of the main active substance of the main pharmaceutical composition use salts obtained by reacting acids or bases of an organic or inorganic nature with the main active substance of the formula 1;

- an additional other antidiabetic drug is selected from the group comprising metformin, sulfonylurea, methiglinide, glucosidase inhibitor, glucagon-like peptide 1 (GLP-1), insulin, insulin sensitizer, mainly glitazone, dipeptyl peptidase IV inhibitor (DPP IV), mainly sieve;

- any additional additional antidiabetic active substance contained in the combined preparation with metformin is selected from the group comprising a glucosidase inhibitor, mainly acarbose, methiglinide, mainly repaglinide, sulfonylurea, preferably glyburide, thiazolidinedione, predominantly rosiglitazone, a DPP IV inhibitor, predominantly sitagliptin;

- the mammal is a human subject; - for the introduction of the main pharmaceutical composition, a dosage form is used orally in the form of tablets with or without coating, effervescent tablets, gelatin capsules, microcapsules, suspensions and solutions, as well as other sustained release dosage forms; - for the introduction of the main pharmaceutical composition, it is rectally used in the form of suppositories;

- therapeutically effective amounts of the main active substance of the main pharmaceutical composition in the individual dosage forms for administration to humans are selected, preferably in a dose of 125 mg to 250 mg;

- the basic pharmaceutical composition in individual dosage forms is administered to a person in a daily dose, preferably from 500 mg to 750 mg, and after achieving euglycemia, in a daily dose, preferably from 200 mg to 400 mg, from one to three times a day; - the basic pharmaceutical composition is administered to a person separately in combination with an additional antidiabetic drug in the form of individual oral dosage forms or as injections;

- the basic pharmaceutical composition, when administered in combination with an additional antidiabetic drug, is administered to a person in a daily dose, preferably from 375 mg to 750 mg, from one to three times a day;

- when administering to a needy subject the pharmaceutical compositions indicated in claim 1 of the claims, both in the form of monotherapy and in combination therapy with several antidiabetic they are used to treat manifestations of metabolic syndrome X such as insulin resistance, impaired glucose tolerance, hypertriglyceridemia, low cholesterol of high density lipoproteins, high cholesterol of low density lipoproteins and cardiovascular complications.

The use in the treatment of metabolic syndrome X as the main active substance of the main pharmaceutical composition of (±) -cyc-3- (2'-benzimidazolyl) - 1,2,2-trimethylcyclopentanecarboxylic acid or its optically active isomers of formula 1, or its / their physiologically acceptable salts, allows compared with the prototype significantly (14 times) to reduce the toxicity and dose (2 times) of the active substance, which cause an increase in the breadth of the therapeutic index (30 times), which is confirmed by experimental studies.

The mechanism of the specific action of the main pharmaceutical composition is realized by inhibiting the manifestations of metabolic syndrome X, namely, reducing insulin resistance by improving glucose utilization by peripheral tissues, decreasing glucose production by the liver, improving glucose tolerance, and reducing cardiovascular risks by reducing hypertriglyceridemia, an increased level free fatty acids and atherogenic fraction of low density lipoproteins. DETAILED DESCRIPTION OF THE INVENTION

The proposed method for the treatment of metabolic syndrome X is carried out depending on the condition, weight and age of the mammal in need, including humans, monkeys, dogs, etc., using the basic pharmaceutical composition proposed in Claim 1, used both as monotherapy and and in the form of combination therapy - the main pharmaceutical composition in combination with one or more antidiabetic drugs manufactured by the industry. According to this invention, the proposed method for the treatment of metabolic syndrome X with one or more of its manifestations in mammalian subjects involves the use of the main pharmaceutical composition in individual dosage forms, the main active substance of which is (±) -cyc-Z- (2'-benzimidazole ) -l, 2,2-trimethylcyclopentane-carboxylic acid or its optically active isomers of the formula

, или её/их физиологически приемлемые соли, которую выбирают в суточной дозе от 25 мг до 750 мг. Терапевтически эффективные количества основного активного вещества для введения человеку, содержащейся в индивидуальной лекарственной форме, выбирают, предпочтительно в дозе от 125 мг до 250 мг.

, or her / their physiologically acceptable salts, which are selected in a daily dose of from 25 mg to 750 mg. Therapeutically effective amounts of a basic active substance for administration to a human individual dosage form are selected, preferably in a dose of 125 mg to 250 mg.

In the treatment of metabolic syndrome X using a basic pharmaceutical composition in an individual dosage form, a person is administered it, preferably orally, in a daily dose, preferably from 500 mg to 750 mg, and after achieving euglycemia, in a daily dose, preferably from 200 mg to 400 mg, from one to three times a day.

Depending on the condition of the subject, as well as on the number of manifestations of metabolic syndrome X, combined therapy is used in the treatment, in which the indicated main pharmaceutical the composition, preferably orally, in a daily dose of from 200 mg to 750 mg in separate dosage forms in combination with at least one additional antidiabetic drug containing at least one active substance, mainly metformin, from one to three times a day, while an additional antidiabetic drug containing metformin in combination with any other antidiabetic active substance in one common individual dosage form is used as a combined the drug. However, doses of antidiabetic drugs are administered in lower quantities depending on the condition, weight and age of the subject in need.

A compound of formula I or its optically active isomers as bases can be converted into a salt by known addition of an inorganic or organic acid by reaction of equivalent amounts of a compound of formula I or its optically active isomers in a known inert solvent. Suitable inorganic or organic acids for this reaction are those which form physiologically acceptable salts with a compound of formula I or its optically active isomers. Thus, mineral acids, for example, hydrohalic acids, or organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic acids and others, can be used.

A compound of formula I or its optically active isomers as acids can also be converted to a salt by known addition of an inorganic or organic base by reaction of equivalent amounts of a compound of formula I or its optically And active isomers in a known inert solvent. Suitable bases of an inorganic or organic nature for this reaction are those which form physiologically acceptable salts with a compound of formula I or its optically active isomers. Thus, sodium hydroxide, potassium hydroxide, biguanide derivatives, dimethylamine, triethanolamine, morpholine and others can be used.

The pharmaceutical composition of this invention is preferably administered orally, although other methods of administration, such as, for example, rectal administration, are not excluded.

For oral administration, the pharmaceutical composition of the invention in a unit dosage form can be presented in the form of gelatin capsules, effervescent tablets, coated or uncoated tablets, microcapsules, or sustained release forms. In the pharmaceutical composition for oral administration, known pharmaceutically acceptable excipients are used, such as fillers, binders, lubricants, loosening agents and other substances, in an amount of about 1 to 80 weight. % The quantitative and qualitative composition of these excipients is determined experimentally, and the production of dosage forms is carried out according to well-known specialists in this field of technology.

Treatment of metabolic syndrome X using the main pharmaceutical composition in combination with an additional other antidiabetic drug in separate dosage forms involves the choice of a drug from the group including metformin, sulfonylurea, methiglinide, glucosidase inhibitor, glucagon-like peptide 1 (GLP-I), insulin, sensitizer insulin, mainly glitazone, a dipeptyl peptidase IV inhibitor (DPP IV), mainly sitagliptin. And additional any other antidiabetic active substance contained in the combined preparation with metformin is selected from the group comprising a glucosidase inhibitor, mainly acarbose, methiglinide, mainly repaglinide, sulfonylurea, mainly glyburide, thiazolidinedione, mainly rosiglitazone, a DPP IV inhibitor, mainly sieve. In this case, the basic pharmaceutical composition is administered to a person separately in combination with an additional antidiabetic drug in the form of individual oral dosage forms or in the form of injections in a daily dose, preferably from 375 mg to 750 mg, from one to three times a day.

Dosages of the additional antidiabetic drugs of the above, which are used in combination with the main pharmaceutical composition of this invention, are preferably administered in lower doses, preferably in amounts of 60% or lower of their initial daily dose, as prescribed in standard medical practice for the treatment of metabolic X syndrome and related complications. The use of the main pharmaceutical composition in combination with the additional antidiabetic drug used in the individual dosage forms increases the effectiveness of the correction of the manifestations of metabolic syndrome X and the associated impaired carbohydrate metabolism, in comparison with the result that would result from the treatment of each of these drugs separately.

The administered dose of the main pharmaceutical composition, as well as additional antidiabetic drugs, administered in combination with it in individual dosage forms, are carefully selected in accordance with the age, weight and condition of the needy subject, as well as in accordance with the method of application (monotherapy or combination therapy), dosage form, regimen and expected result. An additional antidiabetic drug, metformin, refers to metformin or a physiologically acceptable salt thereof, such as hydrochloride, metformin fumarate (2: 1) and metformin succinate (2: 1); hydrobromide, p-chlorophenoxyacetate or embonate and other known salts of metformin mono- and dibasic carboxylic acids, all of these salts are generally called metformin. Preferably, metformin used in combination with the pharmaceutical compositions of this invention is a hydrochloride salt of metformin, namely metformin hydrochloride, marketed under the name Glucorhage T. The additional antidiabetic drug may also be a glucosidase inhibitor such as acarbose, vaglibose, miglitol, which can be taken as a separate oral dosage form or as a single dosage form common with metformin. An additional antidiabetic drug may be meglitinide, for example, repaglinide (Prodip T, Novo Nordisk) or nateglinide (Starlix T, Novartis), which can be used as a separate oral dosage form or as a single dosage form common with metformin. An additional antidiabetic drug sulfonylurea refers to such preparations, for example, glyburide, glimepiride and other sulfonylurea derivatives, which can be used as a separate oral dosage form or as a single dosage form common with metformin or rosiglitazone, pioglitazone and repaglinide. An additional antidiabetic drug thiazolidinedione refers to rosiglitazone, pioglitazone or troglitazone, which can be used in the form of a separate oral dosage form or in the form of a single dosage form common with metformin or glyburide.

An additional antidiabetic drug may also be insulin or a glucagon-like peptide 1

(GLP-I) such as GLP-I (1-36) amide, GLP-I (7-36) amide, GLP-i (7-37), which can be administered by injection using either the transdermal or buccal method.

An additional antidiabetic drug, GLP peptides, can also be administered in combination with the main pharmaceutical composition of this invention in the form of separate oral buccal preparations or nasally.

An additional antidiabetic drug may also be DPP-IV inhibitors, such as, for example, sitagliptin and others, which can be used as a separate or as a single dosage form common with metformin. Industrial applicability

The examples below show the advantages of the proposed method for the treatment of metabolic syndrome X according to this invention, evidence of its implementation and obtaining a technical result.

The effect of the pharmaceutical composition on glucose homeostasis in rats with metabolic syndrome X, (X ± S _x ) (n = 5), is presented in Table 1. The effect of the pharmaceutical composition on the activity of liver enzymes in rats with metabolic syndrome X, (X ± S _X ),

(n = 5), are presented in Table 2. The effect of the pharmaceutical composition on lipid metabolism in rats with metabolic syndrome X, (X ± S _X ), (n = 5), are presented in Table 3. Serum lipid metabolism blood of rabbits with metabolic syndrome X ₅ (X ± S _X ) ₅ (n = 5) are presented in Table 4. Lipid metabolism in serum of rabbits with metabolic syndrome X ₅ (XiS _x ), (n = 5) are presented in Table 5. The acute toxicity parameters of the main pharmaceutical composition for single oral administration to rats are presented in Table 6.

Example 1. The study of the influence of the main pharmaceutical composition on indicators of glucose homeostasis in rats with metabolic syndrome X during their treatment. The study was conducted on 20 sexually mature Wistar male rats. A model of metabolic syndrome X was induced by chronic administration of fructose (200 mg / l with drinking water for 6 weeks) [7]. It is believed that a high concentration of fructose can disrupt the early stages of transduction of the insulin signal, namely, the phosphorylation of the insulin receptor and insulin receptor substrate (IRS-I) [8]. The main pharmaceutical composition in the form of a (±) form, its hydrochloric acid salt and (-) - form of the compound of formula 1, was administered orally to animals in separate dosage forms using a probe at a dose of 25 mg per 1 kg of animal body weight in the form of an aqueous suspension with Tween -80 or an aqueous solution, the combined preparation of metformin with glyburide (Glybomet) was administered at a dose of 50 mg per 1 kg of animal body weight also orally under the indicated conditions in a separate dosage form, and the prototype preparation metformin (Glucorhage) at a dose of 50 mg per 1 kg enter the body weight of the animal and also orally at the indicated conditions for 4 weeks, starting with 3 weeks of the experiment, in an individual dosage form in combination with (±) -fopmoy compound of formula 1 in separate dosage forms. The control group of animals in accordance with a similar scheme was administered a placebo -3-5% finely dispersed aqueous emulsion of Tween-80. Subject's glucose homeostasis animals were evaluated by the following indicators: glycemia, insulinemia and intraperitoneal glucose tolerance test (VBTTG) (3g per 1 kg of animal body weight). The area under the glycemic curves (AUC - arehidescurve) during VBTTG was calculated using the Mathlab computer program. Basal insulinemia was determined by the dual-antibody radio-immunological method using the Rio-INC-PG- ¹²⁵ I kits (Belarus). The insulin sensitivity coefficient was calculated using a short insulin test [9]. Statistical analysis of the results was carried out by methods of variation statistics using standard Exel software packages (version 7), Biostat and Statistisa (Stat. Sof. Ips, USA). Comparison of the two groups with normal separation was carried out using the parametric classical Student t-test for independent samples and the modified Student t-test with separation estimates of variances. The discrepancy between the results was considered statistically significant at p <0.05. The keeping and use of laboratory animals was in accordance with the “General Ethical Principles of Animal Experiments”. As a result of the study, it was found that a 6-week administration of fructose to experimental animals at the above dose leads to the development of insulin resistance in them. This is evidenced by the established coefficient of tissue sensitivity to insulin in experimental animals that were administered fructose and placebo. This coefficient in this group of animals was reduced almost three times in comparison with the same coefficient of the group of animals of intact control (table.l). Confirmation of the achievement of the induction of metabolic syndrome X is hyperinsulinemia, as well as an increase in AUC during the carbohydrate tolerance test in the group of animals that were administered fructose and placebo (Table 1). In addition, the development of insulin resistance in animals of the experimental group, which were administered fructose and placebo, was confirmed by a three-fold increase in the activity of the key gluconeogenesis enzyme - glucose-6-phosphatase in rat liver homogenates (Table 2).

It was found that administration to animals with fructose-induced metabolic syndrome X of the main pharmaceutical composition according to this invention at a dose of 25 mg / kg body weight, including both in combination with metformin and a combined preparation containing metformin and glyburide, used in separate dosage forms , leads to an increase in the coefficient of tissue sensitivity to insulin in these groups of animals by more than 2 times, compared with the group of animals that were administered fructose and placebo (Table 1). The positive effect of the main pharmaceutical composition of this invention on reducing insulin resistance is also confirmed by a decrease in hyperinsulinemia, an improvement in glucose tolerance (decrease in AUC during VBTTG) (Table 1) and a decrease in glucose-b-phosphatase activity (decrease in liver glucose production) ( Table 2) in the group of animals to which the main pharmaceutical composition was administered at a dose of 25 mg per 1 kg of body weight, including both in combination with metformin and with a combined preparation containing metformin and glyburide, in separate dosage forms in comparison with a group of animals that were administered fructose and placebo (Table 1). Comparable in severity, the above pharmacological effect is also characteristic of the drug prototype metformin. In addition, the administration to animals with fructose-induced metabolic syndrome X of the main pharmaceutical composition of the present invention at a dose of 25 mg per 1 kg of body weight does not change the physiological index of basal glycemia. The advantage of treating metabolic syndrome X using the main pharmaceutical composition of this invention over metformin is a lower - 2-fold dose of the main pharmaceutical composition, which provides a therapeutic effect (25 mg / kg for the main pharmaceutical composition and 50 mg / kg for metformin ) Thus, the obtained results indicate the effectiveness of the treatment of metabolic syndrome X using the main pharmaceutical composition according to this invention, including in combination with metformin or a combination preparation containing metformin and any other antidiabetic active substance used in separate dosage forms for the treatment of metabolic syndrome X in mammalian subjects, namely reducing insulin resistance by improving peripheral glucose utilization and tissues, reducing hepatic glucose output and improve glucose tolerance without changing the indicator normoglycemia.

Example 2. The study of the influence of the main pharmaceutical composition on lipid metabolism in rats with metabolic syndrome X during their treatment. The study was conducted on 20 sexually mature Wistar male rats. A model of metabolic syndrome X was induced by chronic administration of fructose (200 mg / l with drinking water for 6 weeks) [7]. The main pharmaceutical composition according to this invention in the specified Example 1 form and metformin both in the individual dosage form and in the form of a combined preparation with glyburide in separate dosage forms were administered to animals under the conditions and doses described above (Example 1). The development of metabolic syndrome X in experimental animals and impaired lipid metabolism due to the administration of fructose, evaluated by non-esterified fatty acids (NEFA) and triglycerides. The concentration of NEFA in serum was determined photocolorimetrically [10], and the level of triglycerides was determined spectrophotometrically [11]. It is known that an increased level of NEFA inhibits the utilization of glucose by peripheral tissues, promotes the development of insulin resistance, stimulates gluconeogenesis in the liver, reduces the sensitivity of the liver to insulin [12] and is the main stimulus for the production of atherogenic low density lipoproteins [13], which ultimately leads to the development of cardiovascular pathologies. As a result of the studies, it was found that chronic administration of fructose leads to an increase in the level of NEFA by more than 6 times and the level of triglycerides in the experimental group of animals that were administered fructose and placebo, relative to the same indicators of the control group of animals (Table 3). This confirms the achievement of the induction of metabolic syndrome X with dyslipidemia in experimental groups of animals that were administered fructose. The administration to animals with fructose-induced metabolic syndrome X of the main pharmaceutical composition according to this invention, including in combination with metformin or a combination preparation containing metformin and glyburide, in separate dosage forms at a dose of 25 mg per 1 kg of body weight leads to a significant decrease in NEFA and triglycerides in this group of animals. A similar therapeutic effect was observed in the group of animals with metabolic syndrome X, which were administered metformin, but at a dose of 50 mg per kg of body weight (Table 3). The advantage of treating metabolic syndrome X using the main pharmaceutical composition of this invention over metformin is a lower - 2 times the dose of pharmaceutical a composition that achieves the maximum therapeutic effect (25 mg per 1 kg of body weight for the main pharmaceutical composition and 50 mg per 1 kg of body weight for metformin). The results obtained indicate the effectiveness of the treatment of metabolic syndrome X using the main pharmaceutical composition of this invention in mammalian subjects, including in combination with metformin or a combination preparation containing metformin or any other antidiabetic active substance, in separate dosage forms to reduce cardiovascular risks by attenuating metabolic syndrome X factors such as hypertriglyceridemia and elevated levels of free irnyh acids.

Example 3. The study of the influence of the main pharmaceutical composition on lipid metabolism in rabbits with metabolic syndrome X during their treatment. The study was conducted on 20 mature chinchilla male rabbits with metabolic syndrome X with dysglycemia, which was induced by intraperitoneal administration of dithizone to experimental animals at a dose of 35 mg per 1 kg of body weight [14]. The main pharmaceutical composition in the above form (Example 1) was administered orally to rabbits daily at a dose of 25 mg per 1 kg of body weight for 2 months, the combined preparation of metformin with glyburide (Glybomet) was administered at a dose of 50 mg per 1 kg of animal body weight also orally in the form of an aqueous suspension with Tween-80 in a separate dosage form, and the prototype metformin drug, both in an individual dosage form and in combination with the main pharmaceutical composition in separate dosage forms, was administered to rabbits at a dose of 50 m g per 1 kg of body weight according to a similar pattern. The state of glucose homeostasis in experimental animals was evaluated every month by the dynamics of basal glycemia, as well as by indicators of insulinemia and VVTG (intravenous glucose tolerance test, 500 mg / kg body weight) according to the methods described in Example 1. The state of lipid metabolism in experimental animals was evaluated by the concentrations of NEFA [10], triglycerides [11] and total cholesterol [15] in blood serum. The concentration of high-density lipoprotein cholesterol (Ch-JWHP) was determined by the enzymatic method using standard kits from Boeringer-Mannheim GT diagnostics (Germany). Low density lipoprotein cholesterol (XC-J and IHl 1) and the atherogenic index were calculated using the corresponding formulas Frieved W.T. [16] and Gerasimova E.N. [17]. The choice of the above model of dyslipidemia in the presence of chronic insulin deficiency is due to the fact that chronic hyperglycemia for 2 months in rabbits induced by dithizone leads to severe disturbances in the structural and functional state of the kidneys and allows the use of this model to recreate diabetic dyslipidemia against the background of dysglycemia [ eighteen]. In addition, long-term insulin deficiency caused by the administration of dithizone to mammalian subjects leads to the formation of atherogenic toxic complexes with zinc [14], which ultimately leads to the development of cardiovascular pathologies. It is also known that chronic hyperglycemia can cause quantitative and qualitative changes in the composition of lipids and lipoproteins, which are the cause of accelerated atherosclerosis. As a result of studies, it was found that chronic administration of dithizone to rabbits for 2 months leads to the development of severe insulin deficiency due to impaired carbohydrate metabolism, as well as atherogenic changes characteristic of metabolic syndrome X. This is confirmed by the assessment of the lipid profile of rabbits the experimental group who were administered dithizone and placebo, in comparison with the control group of animals (tables. 4 and 5).

It was found that the content of total cholesterol, triglycerides and the atherogenic fraction of LDL-C in the blood serum of rabbits administered with dithizone and placebo was significantly higher, and the content of HDL-HDL was significantly lower in comparison with the indicated indices of the control group of animals, which contributed to an increase in atherogenic index 3 times in the group of animals with metabolic syndrome X (Table 4). Under conditions of insulin deficiency, a weakened inhibition of the activity of hormone-sensitive lipase is also noted, which in turn leads to an increase in the hydrolysis of triglycerides in adipose tissue and the accumulation of NEFA in the liver.

An increase in the content of NEFA is the main stimulus for the production of atherogenic low-density lipoproteins [13]. As a result of the studies, it was found that in experimental rabbits that were administered dithizone and placebo, the concentration of NEFA was increased by 6 times in comparison with the control group of animals (Table 4), which also indicates the achievement of lipid metabolism in mammalian subjects with the introduction of dithizone. The positive effect of the basic pharmaceutical composition of this invention on the lipid metabolism of rabbits with metabolic syndrome X, including in combination with metformin or a combination preparation containing metformin and glyburide, administered to animals at a dose of 25 mg per 1 kg of body weight in separate dosage forms in within 2 months, confirmed by a significant decrease in the level of triglycerides, NEFA and total cholesterol in the blood serum of the experimental group of animals that were administered dithizone and the main pharmacy eskuyu composition in the above doses, in comparison with a group of animals treated with dithizone and placebo (table 4). The severity of anti-atherogenic properties of the main pharmaceutical composition according to this invention is comparable with the severity of these properties of the prototype drug - metformin. At the same time, the advantage of the main pharmaceutical composition of this invention over metformin is the dose of the main pharmaceutical composition, which helps to achieve the maximum therapeutic effect and which is 2 times lower than the dose of metformin (25 mg per 1 kg of body weight for the new pharmaceutical composition and 50 mg per 1 kg of body weight for metformin). Confirmation of the antiatherogenic properties of the main pharmaceutical composition according to this invention, which was administered to rabbits with impaired lipid metabolism at a dose of 25 mg per 1 kg of body weight, is also a significant decrease in the XC-J And Shi I index and an increase in the antiatherogenic fraction of HDL-C in the blood serum of rabbits of this groups, in comparison with similar indicators of groups of experimental animals that were administered dithizone and placebo or dithizone and metformin (Table 4). An increase in the anti-atherogenic fraction of HDL-C in the blood serum of rabbits, which were administered the basic pharmaceutical composition of this invention at a dose of 25 mg per 1 kg of body weight for 2 months, significantly reduced the atherogenic index in this group of animals compared to the atherogenic index in groups of animals that were administered dithizone and placebo or dithizone and metformin in the above doses (table 4). The results obtained indicate the effectiveness of the treatment of metabolic syndrome X using the main pharmaceutical composition of this invention in mammalian subjects, including in combination with metformin or a combination preparation containing metformin or any other antidiabetic active substance in separate dosage forms to reduce cardiovascular risks, due to metabolic X syndrome, by reducing hypertriglyceridemia, elevated levels of free fatty acids and the atherogenic fraction of low density lipoprotein cholesterol, as well as increasing high density lipoprotein cholesterol.

Example 4. The study of acute toxicity of the main pharmaceutical composition. The acute toxicity of the main pharmaceutical composition of this invention was studied on outbred white male rats according to the guidelines [19]. The basic pharmaceutical composition of this invention was administered to experimental animals on an empty stomach once orally (via a tube) in a 1% starch solution. The observation time for the experimental animals was 2 weeks. During this period, survival, mortality, signs of intoxication, and reactions to stimuli were taken into account. Mortal doses of the main pharmaceutical composition of this invention were calculated according to the Litchfield and Wilcoxon method [20] using a probit analysis of mortality curves.

The signs of acute poisoning during intragastric administration to experimental animals were characterized by the first 15 minutes of increased excitability, which was replaced by depression, adynamia, constricted pupils, refusal to eat, and piloerection. The death of animals from higher doses occurred within the first hour after administration of the pharmaceutical composition. From doses below 10,000 mg per 1 kg of body weight, the death of experimental animals occurred in the lateral position during the first day of the experiment. Already on the third day of the experiment, the surviving rats did not differ from the control group of animals. The data obtained indicate that the main pharmaceutical composition according to this invention, when administered orally, belongs to the class of low toxic substances. Mid-lethal the dose (LD _5O ) of the main pharmaceutical composition of this invention when administered orally to male rats is 14,900 mg per kg body weight (9100 ± 20700). The average lethal dose (LDso) of the metformin prototype drug in rats when administered orally is 1000 mg per 1 kg of body weight [21]. The advantages of the main pharmaceutical composition of this invention over the prototype metformin preparation are evident when comparing the breadth of their therapeutic indices (LD ₅ o / ED _5O ), which is 30 times higher than the metformin for the pharmaceutical composition (596 for the pharmaceutical composition, and for metformin 20) (Table 6).

Thus, the claimed method of treatment of metabolic syndrome X, when used, can significantly (14 times) reduce the toxicity and dose (2 times) of the active substance, which cause an increase in the breadth of the therapeutic index (30 times) in comparison with the prototype, which confirmed by the above studies.

This will improve the treatment of manifestations of metabolic syndrome X, such as insulin resistance, impaired glucose tolerance, hypertriglyceridemia, low cholesterol of high density lipoproteins, high cholesterol of low density lipoproteins and cardiovascular complications with a decrease in the number of side effects and their manifestations, which is significantly reduces the cost of treating patients.

Information sources.

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4. An aptidiabetis thiazolidiopediope is a high affinity ligapd for a parcho rpoliters reactivator (PPAR) / J.M. Lehmapp, L.B. Moore, T.A. Smith-Oliver et al. // J. Biol. Chem. - 1995. - VoI. 270. - P. 12953-12956.

5. Freid J., Evritt D., Voscia J. Rosiglitazope apd heratis failure // Applied IPalpis Medisipe. - 2000. - VoI. 132. - P. 164-165.

6. Wellt H.C., Baileu CJ. And the risk-benefit assessmept of metformip ture 2 diets mellitus // Drug Safetu. - 1999. - VoI. 20, JVsb. - P. 489-503 (prototype).

7. Levi V., Werman M. Lög therm frustos sopsumrtiop asselérétés glustiop apd several égérélétéd varálabes ip malé rats // S. Nutritiop. - 1998. - VoI. 128 .-- P. 1442 - 1449.

8. Vezerra R.M., Uepo M., Silva M.S. et al. A high fructose diet affection thе earlu sters оf ipsulip apiop ip musl apd livеr оf rats // S. Nutritiop. - 2000. -

VoL 130, JSToIO. - P. 1531 - 1535.

9. Thе shоrt іspulip tоlеrаpsе tеt fоr deterіmpіrpіtiop оf іspulіp seсpitivitu: а сomparrisop with егlусеемс сламр / A. Акипмокуп, P. Селбу, K. Рамаауа е. // Diabetes. Honey. - 1992. - VoL 9, No 5. - P. 432 - 437. 10. Dumсombе W.С. Tolorimetriс miсro-dethermipatiop оf lopg-shaip fаttu asids // Вісхем. J. - 1963. - VoL 188, Xa 1. - P. 7 - 10.

11. Fletsher MJ. Estimatiop оf thе triaculgluserols іp thе segam // CHn. Chim. Assa. - 1968. VoL 22. - P. 393.

12. Salorpta C, Koivisto V., Widep E. et al. Soptributiof оf musсlе apd Нvеrtо glucosose-fаttu asids сuspе hum humps // Am. J. Phusiol. - 1993. - VoI. 264. - P. E599 - E605.

13. Betteridge DJ. LDL heterohepitis: imprisopiop for atheropecip insulin resistance and NIDDM // Diabetes. - 1995. VoI. 40 (Srl. 2). - P. S149 - S151.

14. Okomato, H. Regulatiof of the propsulis supptsis ip rasreatis islet apd and the first test to ipulis-diets diets // Moles. Sell. Bioshem. - 1981. - VoI. 3. - P. 43 - 61.

15. Kolb B.G., Kamyshnikov V.S. Clinical biochemistry. - Minsk: Belarus, 1982.- 432 p.

16. Friedewald W.T., Levu R.I., Frederiksop D. S. Estimatiof of tse sceptr-tiopiof lou-depsitu li-rorototep-cholesterol, with usu-étépértépétpértrep-terp Chem. - 1972. - VoI. 18, Ni. 6. - P. 499 - 502. 17. Gerasimova E.N. Dyslipoproteinemia and hormones in the blood plasma of men 40-59 years old // Dyslipoproteinemia and coronary heart disease. - M .: Medicine, 1980 .-- S. 83 - 102.

18. Vitamin E Delauss Diabetes Perforate Developmental / N. Gorbecko, V. Poultask, A. Gladkish et al. // Vlas Sea Diab. Меtiпп, Isrпbul, Оct. 30 ^th - Nov. l ^st , 1997 .-- Istapbul (Turku), 1997 .-- P. D-48.

19. Pharmacological screening of new physiologically active substances // Methodological recommendations. - Kiev. - 1985. - 24 p.

20. Belenky M. L. Elements of a quantitative assessment of the pharmacological effect (2nd ed.). JI .: Medgiz (Leningrad branch). - 1963. - 152 p.

21. The Merck Index (13), 2001, Monograph Ns 5963, P. 1061. Table 1

The effect of the pharmaceutical composition on glucose homeostasis in rats with metabolic syndrome X, (X ± S _x ) (n = 5)

Продолжение табл.l

Continuation of table.l

Notes: Pi - deviation likely relative to the group

"Intact control)); P ₂ - the deviation is likely relative to the group

"Fructose + placebo"; P ₃ - the deviation is probably relative to the group “Fryctoza + metformin)).

table 2

The effect of the pharmaceutical composition on the activity of liver enzymes in rats with metabolic syndrome X, (X ± S _X ), (n = 5)

Продолжение тaбл.2

Continuation of table 2

Notes: P ₁ - deviation likely relative to the group

"Intact control)); P ₂ - the deviation is likely relative to the group

"Fructose + placebo"; P ₃ - the deviation is probably relative to the group “Fryctoza + metformin)).

Table 3

The effect of the pharmaceutical composition on lipid metabolism in rats with metabolic syndrome X, (X ± S _X ), (n = 5)

Продолжение табл.З

Continuation of table.Z

Notes: Pi - the deviation is probably relative to the group "Intact control"; P ₂ - the deviation is probably relative to the group "Fructose + placebo"; P ₃ - the deviation is probably relative to the group "Fructose + metformin". Table 4

Lipid metabolism in serum of rabbits with metabolic syndrome X ₅ (X ± S _X ), (n = 5)

Notes: P ₁ - significance of changes in comparison with the group "Intact control)); P ₂ - significance of changes in comparison with the group “Dithizone + placebo)); P ₃ - significance of changes in comparison with the group “Dithizone + metformin)). Table 5

Serum lipid metabolism in rabbits with metabolic syndrome X, (X ± S _X ), (n = 5)

Notes: P ₁ - significance of changes in comparison with the group "Intact control)); P ₂ - significance of changes in comparison with the group “Dithizone + placebo)); P ₃ - significance of changes in comparison with the group "Dithizone + metformin". Table 6

Acute toxicity parameters of the main pharmaceutical composition for single oral administration to rats

Claims

CLAIM 1. A METHOD FOR TREATING A METABOLIC SYNDROME X in mammalian subjects, comprising administering to a subject a therapeutically effective amount of at least one pharmaceutical composition in an acceptable dosage form containing an active substance in combination with one or more pharmaceutically acceptable excipients, characterized in that, to the needy subject. depending on the condition, weight and age, preferably administered orally, the basic pharmaceutical composition in individual dosage form forms, the main active substance of the main pharmaceutical composition is (±) -cyc-3- (2 ^! -benzimidazolyl) -l, 2,2-trimethylcyclopentanecarboxylic acid or its optically active isomers of the formula

or her / their physiologically acceptable salts, which are selected in a daily dose of from 25 mg to 750 mg, or enter the specified pharmaceutical composition in separate dosage forms in a daily dose of from 200 mg to 750 mg, in combination with at least one additional antidiabetic drug means containing at least one active substance, mainly metformin, from one to three times a day, with an additional antidiabetic drug containing metformin in combination with any other antidiabetic active substance in one common individual dosage form is used in the form of a combined preparation, however, doses of antidiabetic drugs are administered in amounts of 60% or lower of their initial daily dose. 2. The method according to claim 1, characterized in that (+) - cis-3- (2'-benzimidazolyl) - 1,2,2-trimethylcyclopentanecarboxylic acid or its physiologically used as optically active isomers of the main active substance of the main pharmaceutical composition acceptable salts. 3. The method according to claim 1, characterized in that (-) - cis-3- (2'-benzimidazolyl) -l, 2,2-trimethylcyclopentanecarboxylic acid or its physiologically used as optically active isomers of the main active substance of the main pharmaceutical composition acceptable salts. 4. The method according to claim 1, characterized in that salts obtained by reacting acids or bases of an organic or inorganic nature with the main active substance of formula 1 are used as physiologically acceptable salts of the main active substance of the main pharmaceutical composition. 5. The method according to claim 1, characterized in that the additional other antidiabetic drug is selected from the group consisting of metformin, sulfonylurea, methiglinide, glucosidase inhibitor, glucagon-like peptide 1 (GLP-I), insulin, insulin sensitizer, mainly glitazone, dipeptyl peptidase inhibitor IV (DPP IV), mainly sitagliptin. 6. The method according to p. 1, characterized in that the additional any other antidiabetic active substance contained in the combined preparation with metformin is selected from the group comprising a glucosidase inhibitor, mainly acarbose, methiglinide, mainly repaglinide, sulfonylurea, mainly glyburide, thiazolidinedione, mainly rosiglitazone, a DPP IV inhibitor, mainly sitagliptin. 7. The method according to claim 1, characterized in that the mammal is a human subject. 8. The method according to p. 1, characterized in that for the introduction of the main pharmaceutical composition orally use the dosage form in the form of tablets with or without coating, effervescent tablets, gelatin capsules, microcapsules, suspensions and solutions, as well as other extended release dosage forms . 9. The method according to p. 1, characterized in that for the introduction of the main pharmaceutical composition, it is rectally used in the form of suppositories. 10. The method according to p. 1, characterized in that the therapeutically effective amounts of the main active substance of the main pharmaceutical composition in individual dosage forms for administration to humans are selected, preferably in a dose of from 125 mg to 250 mg. 11. The method according to p. 1, characterized in that the basic pharmaceutical composition in individual dosage forms is administered to a person in a daily dose, preferably from 500 mg to 750 mg, and after achieving euglycemia, in a daily dose, preferably from 200 mg to 400 mg, from one to three times a day. 12. The method according to p. 1, characterized in that the basic pharmaceutical composition is administered to a person separately in combination with an additional antidiabetic drug in the form of individual oral dosage forms or in the form of injections. 13. The method according to p. L and p. 12, characterized in that the main pharmaceutical composition, when administered in combination with an additional antidiabetic drug, is administered a person in a daily dose, preferably from 375 mg to 750 mg, from one to three times a day. 14. The method according to p. 1, characterized in that when the pharmaceutical compositions indicated in p. 1 are administered as a monotherapy or in combination therapy with several antidiabetic agents when administered to a needy subject, they are used to treat such manifestations of the metabolic syndrome as insulin resistance, impaired glucose tolerance, hypertriglyceridemia, low cholesterol of high density lipoproteins, high cholesterol of low density lipoproteins and cardiovascular complications.