RU2598347C1 - Agent possessing hypolipidemic and antiatherosclerotic activity - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and it can be used for treating dislipoproteinemia and atherosclerosis. For this purpose benzene sulphonate 1-methyl-3-ethyl is applied, 4,5 (bis-N-methylcarbamoyl) of imidazolium as a hypolipidemic and antiatherosclerotic agent for treatment of atherogenic dislipoproteinemia and atherosclerosis of various localizations.

EFFECT: invention allows to reduce level of cholesterol and triglycerides in blood serum, it reduces the atherosclerotic aorta and has low toxicity.

1 cl, 6 tbl

Description

The invention relates to medicine, namely to pharmacology, and can be used in the treatment of patients with cardiovascular diseases associated with metabolic disorders.

The invention relates to a biologically active compound, namely 1-methyl-3-ethyl benzenesulfonate, 4,5 (bis-N-methylcarbamoyl) imidazolium (the claimed preparation), which expands the arsenal of lipid-lowering and anti-atherosclerotic agents.

The inventive drug lowers cholesterol and triglycerides in blood serum and reduces cholesterol in the aorta. The ability to reduce serum lipids indicates a pronounced hypolipidemic effect. The decrease in cholesterol in the aorta and the percentage of its atherosclerotic lesion reflects the antiatherosclerotic effect of the claimed drug.

The inventive drug exhibits hypolipidemic activity in various experimental models of dyslipoproteinemia, has low toxicity. Its synthesis is simple and affordable.

A pharmacological analysis showed that the claimed drug, in addition to improving lipid parameters in the blood and aorta, lowers cholesterol and triglycerides in the liver, cholesterol in the adrenal glands, and also significantly reduces the value of the atherogenic index (estimated risk of developing atherosclerosis). The severity of the lipid-lowering effect of the claimed drug is close to the well-known lipid-lowering drug Gemfibrozil and exceeds the effect of other drugs - Clofibrate and Parmidin.

Preclinical trials of the claimed drug - 1-methyl-3-ethyl benzenesulfonate, 4,5 (bis-N-methylcarbamoyl) imidazolium - allow it to be recommended as a lipid-lowering drug in the treatment of atherogenic dyslipoproteinemia (DLP) and / or anti-atherosclerotic agents for the treatment of atherosclerosis ( AS) of various localization.

The pathogenesis of AS - a chronic disease - is complex and not fully understood [Klimov A.N. Honey. Acad. Jr. 2007; 1 (7): 4-11; Nagornev V.A. The pathogenesis of atherosclerosis. M .: St. Petersburg, 2006; Martsevich S.Yu. Atherosclerosis. Clinical relevance and potential for prevention. M., 2005; Aronov D.M., Akhmedzhanov N.M., Gutkovskaya L.A. Ross cardiol. g. 2006; 3 (59): 34-40]. AS is a lesion of large and medium-sized arteries, characterized by an increase in permeability, deposition and accumulation in the inner shell of low-density oxidized (peroxide-modified) low density lipoproteins (LP) (LDL), structural and cellular changes, reactive proliferation of connective tissue with the formation of atherosclerotic plaques [ Klimov A.N., Nagornev V.A. Cardiology, 1993; 3: 5-10]. In addition to metabolic disorders of the arterial wall, the development of AS is promoted by: hypoxia, expression of adhesive, pro-inflammatory and growth factors. The synthesis of protective substances (prostacyclin, nitric oxide, heparan sulfate), as well as fibrinolytic and a number of other substances, is reduced. In the late stages of AS progression, abnormalities in the blood coagulation system are observed: platelet adhesion occurs, blood clots form, blood vessel lumen suddenly clogs; dangerous cardiovascular catastrophes occur [Pokrovskaya E.V., Graziansky N.A., Vaulin N.A., Deev A.D. Cardiology 2004; 7: 40-45]. With the progression of AS and its complications - coronary heart disease (IHD), myocardial infarction (MI), stroke, AS of the lower extremities, lipid and lipoprotein metabolism disorders are closely associated [Diagnosis and correction of lipid metabolism disorders for the prevention and treatment of atherosclerosis. GFCF, M .: 2005; Litovsky I.A., Gordienko A.V. Atherosclerosis and hypertension, 2013; Ragino Yu.I. et al. Atherosclerosis 2014; 10 (2), 15-23].

The leading cause of the development of AS is atherogenic DLP - a prolonged increase in blood lipoproteins (LP) and lipids: triglycerides (TG), total cholesterol (cholesterol), atherogenic low-density drugs (LDL) and very low-density drugs (VLDL), as well as a decrease in anti-atherogenic High Density Drugs (HDL). The lipid profile of a patient with AS is characterized by a significant increase in the levels of atherogenic LDL and VLDL and / or a decrease in the concentration of anti-atherogenic HDL. Atherogenic DLP in patients is determined in diagnostic lipid centers: the nature of the blood lipid spectrum is assessed, for which the classification from type I to V proposed by Fredrickson is used. This classification is guided by cardiologists and therapists in the appointment of lipid-lowering therapy [Fredrickson D.S., Levy R.I., Lees R.S. New Engl J. Med. 1967; 276: 34-42; Kukharchuk B.B., Bubnova M.G., Katelnitskaya L.I. et al. Cardiology, 2003; 5: 42-47].

For the prevention and treatment of AS, early, intensive pharmacotherapy with effective lipid-lowering and / or anti-atherosclerotic agents is necessary [European guidelines on Cardiovascular Disease Prevention in Clinical Practice. Eur. Heart J. 2003; 24 (17): 1601-1610; The National Cholesterol Education Program. Expert Panel of detection, evaluation and treatment of high blood cholesterol in adults. JAMA 2001; 285: 2486-2497; LEFT. Diagnosis and correction of lipid metabolism disorders in order to prevent and treat atherosclerosis. M., 2004].

Lipid-lowering therapy

Treatment of patients with DLP and patients with AS is carried out in two ways: 1) by reducing the DLP of an atherogenic nature and improving the lipid profile of the blood; 2) by improving the metabolism of the vascular wall and reducing the content of lipid components in plaques [Klimov AN, Nikulcheva NG The exchange of lipids and lipoproteins and its disorders. 1999; Yu.A. Karpov, E.V. Sorokin. Cardiology, 2005; 8: 4-7]. Two main groups of drugs are most often used as lipid-lowering agents for the correction of atherogenic DLP in the clinic: fibrates (clofibrate, probucol, gemfibrozil, befibrate, fenofibrate) and statins (lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin and [rosuvastatin]. Robins. Correction of lipid disorders. Basic principles and practical implementation of therapeutic interventions. M., 2001: 108-109; Hanninghake D.B., Stein E.A., Bays N.E. Coron. Artery Dis. 2004; 15: 115-123; Bubnova M.G. Doctor 2006; 10: 61-66]. Experimental and clinical studies of clofibrate revealed a number of negative side effects, in particular hepatomegaly [Nassrin D., Ontko J. Atherosclerosis 1983; 49: 225-266]. Clofibrate is an analogue of the claimed drug as a drug with lipid-lowering properties [Mashkovsky M.D. Medicines 13th ed., 1998; t. 1: 456]. Gemfibrozil is used to lower TG, total cholesterol, and VLDL in the blood. It causes dry mouth, nausea, vomiting, constipation, diarrhea [Vidal. Medicines in Russia. 1995: p. 371]. Gemfibrozil is a prototype of the claimed drug as a lipid-lowering agent [Mashkovsky M.D. Medicines 13th ed., 1998; t. 1: 457]. Therapy of DLP with statins is long, sometimes lifelong, expensive and not available to all patients. With a pronounced lipid-lowering effect of lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin and rosuvastatin with prolonged use, cerebral pathology, muscle pain, development of rhabdomyolysis are noted [S.J. Robins. Correction of lipid disorders. Basic principles and practical implementation of therapeutic interventions. M., 2001; Law M.R., Wald N.J., Rudnicka A.R. BMJ 2003; 326 (7404): 1423-1438; Olsson A.G. Rosuvastatin. Science Press, 2004; 1-77; Mashkovsky M.D. Medicines 15th ed., 2005; 467-471].

Antiatherosclerotic therapy. Statins - simvastatin, atorvastatin and rosuvastatin are also used for intensive care of AS, reducing the lipid component in atherosclerotic plaques. However, these drugs can have negative effects: affect the liver and kidneys, exacerbate the development of cataracts [Mashkovsky M.D. Medicines 13th ed., 1998; T. 1: 458-460]. Another antiatherosclerotic agent is parmidin. Parmidin is a specific anti-bradykinin drug for the complex treatment of AS [Ryzhenkov V.E et al. Farmakol. toxicol. 1976; 5: 558-559]. As an angioprotector, it reduces the content of cholesterol and the degree of atherosclerotic lesion of the aorta. Parmidin is a prototype of the claimed drug as an antiatherosclerotic agent [Mashkovsky M.D. Medicines 13th ed. 1998; vol. 1: 448-449].

The essence of the invention is that the claimed drug - 1-methyl-3-ethyl benzenesulfonate, 4,5 (bis-N-methylcarbamoyl) imidazolium - actively reduces the level of lipids and atherogenic LDL in blood serum when modeling DLP in animals of different species and is effective in experimental cholesterol atherosclerosis in rabbits.

Found two fundamentally new properties of the claimed drug - lipid-lowering and antiatherosclerotic.

The preclinical study of the hypolipidemic and antiatherosclerotic action of the claimed drug was carried out in accordance with the current requirements [Guidelines for preclinical studies of drugs. Ed. A.N. Mironov. Part I, M., 2012: Ch. 26, p. 445-452].

Its hypolipidemic effect has been established for oral use: it significantly reduces the level of total cholesterol and triglycerides, increases the concentration of cholesterol anti-atherogenic HDL in the blood serum, and reduces the content of cholesterol and triglycerides in the liver. The inventive drug inhibits lipidosis in the adrenal glands, reducing their cholesterol content. The effectiveness of the lipid-lowering effect of the claimed drug is close to the analogue from the group of fibrates - clofibrate, as well as to the prototype - gemfibrozil, but differs from them in more pronounced lipid-lowering activity.

It was also established that it has an anti-atherosclerotic effect: it reduces the percentage of atherosclerotic lesions of the aorta in rabbits with experimental AS, reduces lipid aortic infiltration. The claimed drug more pronounced protects the aorta of rabbits from AS damage than clofibrate, and is similar in action to a lipid-lowering agent with anti-atherosclerotic properties - parmidine (prototype of the claimed drug).

Imidazolium benzenesulfonate 1-methyl-3-ethyl, 4,5 (bis-N-methylcarbamoyl) is claimed as a treatment for atherogenic DLP and atherosclerosis (AS) of various localization.

No similar compounds were found in Russia and abroad by the authors.

The inventive preparation relates to low toxicity compounds. The authors of the application could not determine its LD ₅₀ - dosis letalis ₅₀ when administered orally to small laboratory animals. But a dose is determined that does not cause toxic effects: when administered orally to mice, it is 15,000 mg, and to rats, 20,000 mg. The introduction of large doses caused technical difficulties.

In preliminary experiments, the following doses of the studied drug were used: 50, 100, and 500 mg / kg when administered orally to adult male rats under experimental DLP: express models of triton DLP and chronic nutritional DLP. It was found that the minimum dose of the claimed drug 50 mg / kg does not have a significant effect on blood and liver lipids in the conditions of the above models. A large dose of 500 mg / kg in rats causes increased hyperemia of the liver. A dose of 100 mg / kg, which is 1/200 of the dose that does not have a toxic effect, was chosen by the authors of the application as optimally effective, since in experimental animals no visible side effects were observed.

In an experimental study of the specific effect of the compounds on lipid and lipid metabolism, it was shown that by oral administration of the claimed drug for 14 days at a dose of 100 mg / kg to control male rats, a decrease of 20% in the level of total cholesterol in the blood serum and liver was observed. This effect was close to the effect of the drug clofibrate used at a dose of 200 mg / kg also orally. It should be emphasized that the effective dose of clofibrate is approximately 1/20 part of the LD ₅₀ , while in the inventive drug, a similar dose was used as 1/200 of the dose that does not cause toxic effects.

Material and research methods

The study of the lipid-lowering and anti-atherosclerotic effect of the claimed drug on the level of lipids and LP in animals with experimental DLP of an atherogenic nature was carried out in rats, guinea pigs and rabbits, using models of the pathological state, in accordance with the methodological recommendations of the Guidelines for conducting preclinical studies of drugs. (Part I. M., 2012: 445-452). In accordance with the recommendations of the All-Russian Scientific Society of Cardiology (GFCF, 2004), unified biochemical methods were used to determine blood lipids. The level of cholesterol in the blood serum of rats and rabbits was determined by the colorimetric enzymatic method (CHOD-PAP) using a set of reagents from Vital Diagnostics using an SF-26 spectrophotometer. Determination of HDL cholesterol in the blood serum of rats and rabbits was carried out by the above method using reagents of the same company at a wavelength of 546 nm at SF-26, after preliminary precipitation of atherogenic drugs with heparin in the presence of manganese ions. To determine the TG in the blood serum of rats and rabbits, a set of reagents from Vital Diagnostics was used. The obtained quinoneimine with a maximum absorption of 500 nm was measured spectrophotometrically and evaluated proportionally to the concentration of TG in the sample [Wahlfeld A.W. In: Methods of enzymatic analysis. Acad. Press, NY; 1974: 1831]. The content of cholesterol in the liver was determined using the standard color Lieberman-Burchard reaction after extraction of a portion of the liver with a mixture of chloroform and carbinol [Bragdon G.H. In: Lipids and steroid hormons in clinical medicine. Ph. 1960: 6-10]. The content of TG in the liver was determined by the method of Neri and Frings (1973), modified by the authors, consisting in replacing the sorbent (zeolite mixture) with aluminum oxide [Okunevich IV, Sapronov NS, Indenbom M.L. Chem.-farm. g. 1999; 11: 14-16]. The content of total cholesterol in the rabbit aorta was carried out colorimetrically using the Lieberman-Burchard reaction after extraction of the sample. To prepare the chloroform extract, the aorta was ground with quartz sand [Ryzhenkov V.E., Khromov-Borisov N.V., Mosina I.V. Farmakol. toxicol. 1979; 6: 632-635]. The content of cholesterol in the adrenal glands was determined by the extraction method, as described above, after homogenizing a tissue sample, extracting it with chloroform and applying the subsequent Lieberman-Burkhard reaction [Okunevich IV, Ryzhenkov V.E. Pat. fiziol. expert. ter. 2002; 2: 14-18].

The results of studies of the lipid-lowering activity of the claimed drug in experimental models of DLP.

Experience 1. Model triton dyslipoproteinemia (DLP) in rats

The lipid-lowering activity of the claimed drug was studied in 60 male rats on an express model of DLP caused by the detergent triton WR-1339 (225 mg / kg once, intraperitoneally). This model is characterized by the development of persistent hyperlipidemia - a significant increase in the level of cholesterol and triglycerides in the blood of rats (weighing 250-300 g) compared with the content of these indicators in intact animals [Shurr R.E., Shultz Y.R. Lipids 1972; 7 (1): 68-74].

The inventive preparation was administered to rats at a dose of 100 mg / kg orally twice (prior to administration and together with the administration of WR-1339 triton). For comparison, an analogue of the claimed drug was used - clofibrate at a dose of 100 mg / kg and a prototype of the claimed drug gemfibrozil at a dose of 50 mg / kg, both orally. After 10 hours, the degree of development of hyperlipidemia was determined by the value of cholesterol and triglycerides in blood serum. There were 12 animals in each group. The results are presented in table 1.

As can be seen from table 1, in comparison with lipids significantly increased under the conditions of the triton DLP under the influence of the claimed preparation, a 2.4-fold decrease in the levels of cholesterol and triglycerides is observed, which indicates its pronounced hypolipidemic effect. Oral administration of comparison drugs causes lesser shifts: cholesterol and triglyceride levels decrease 1.4 times (clofibrate) and 2 times (gemfibrozil). By lipid-lowering effect, the claimed drug is close to gemfibrozil and superior to clofibrate.

The lipid and LP blood spectra of experimental rodent animals differ: in rabbits, cholesterol is distributed evenly in LP fractions, and in rats, it is mainly found in anti-atherogenic HDL [Wilgram G.F. J. Exp. Med. 1959; 109 (3): 293-309]. In this regard, rats are more resistant to the induction of experimental DLP than rabbits. To create a DLP model in rats, it is necessary to add to the diet containing cholesterol such additional damaging agents as the thyroid-suppressing agent 6-methyl thiouracil, sodium cholate, or vitamin D2 [Thomas W.A., Hartroft W.S. Circulation 1959; 19: 65-72].

Experience 2. Chronic alimentary dyslipoproteinemia (DLP) in rats

The lipid-lowering effect of the claimed drug was confirmed in a chronic model of alimentary DLP in rats.

The experiments were performed on 60 male rats (weighing 230-250 g) in the conditions of nutritional DLP, characterized by an increased level of cholesterol and triglyceride lipids in the blood serum and liver, while at the same time the cholesterol content of antiatherogenic HDL in the blood was reduced. These disorders were caused by a diet containing 7.5% cholesterol, 30% a mixture of animal fats, warm sunflower oil (2: 1) and 500,000 MI of vitamin D ₂ . The duration of the experiment was 24 days. The peculiarity of the applied diet is that against its background it is possible to study not only the lipid-lowering effect of the new compound, but also, by analyzing the cholesterol atherogenicity index (IA), to judge its potential anti-atherosclerotic effect.

The inventive drug was administered to 12 rats orally at a dose of 100 mg / kg for 24 days, against the background of a special hypercholesterolemic diet (GHS diet). For comparison, we used an analogue of the claimed drug - clofibrate, and a prototype - gemfibrozil, both at a dose of 100 mg / kg orally. In rat blood serum, the levels of total cholesterol, TG, and HDL cholesterol were determined. Based on these indicators, the atherogenic LDL cholesterol was calculated according to the generally accepted Friedwald formula LDL cholesterol = cholesterol - (Chlpvp + TG / 2.2). The value of cholesterol IA was determined using Klimov’s formula (HDL-C). In the liver, the content of cholesterol and TG was tested. The results are shown in tables 2 and 3.

As can be seen from table 2, feeding rats with HCV diet led to the development of persistent DLP, while the concentration of cholesterol anti-atherogenic HDL decreased by 2.3 times. Levels of cholesterol, triglycerides and calculated values of cholesterol content of atherogenic LDL and cholesterol IA are significantly exceeded, which is a poor prognosis for the development of AS (table 2, group 2). In these conditions, the use of the claimed drug causes a significant lipid-lowering effect: in the blood serum levels of cholesterol (1.7 times) and TG (1.6 times) decrease. A significant 1.5-fold increase in the concentration of cholesterol of antiatherogenic HDL was found. It was shown that the calculated values of the content of LDL cholesterol and cholesterol IA became lower. These facts reflect a positive prognosis in preventing the development of AS when using the inventive preparation (table 2, group 3).

Identified property of the claimed drug to increase the concentration of cholesterol anti-atherogenic HDL is important. Under the same conditions, the use of an analogue of the claimed drug, clofibrate, did not change the level of cholesterol and a reduced concentration of cholesterol of antiatherogenic HDL. The use of gemfibrozil (a prototype of the claimed drug) led to a significant improvement in the blood lipid spectrum and its inherent ability to significantly increase HDL cholesterol (table 2, group 5).

As can be seen from table 3, the use of the claimed drug caused a pronounced decrease in lipid infiltration of the liver, simulated by feeding the GHS diet: the content of cholesterol decreased by 1.9 times, TG - by 2.1 times. A lower liver weight index was observed compared to hyperlipidemic rats characterizing liver protection (Table 3, Groups 3). In conditions of DLP, clofibrate (an analogue of the claimed drug) showed less activity. When using clofibrate, the content of cholesterol in the liver did not decrease (table 3, group 4). In addition, the use of clofibrate contributed to an increase in the weight index - the relative mass of the liver, which may indicate a hepatomegal effect (table 3, group 4). It should be noted that in clinical practice, the use of clofibrate and other fibrates in patients with DLP causes impaired liver function, intrahepatic cholestasis, exacerbation of gallstone disease [Mashkovsky M.D. Medicines 1998; 13th ed., T. 1 .: 455-456].

Thus, on the model of chronic alimentary dyslipoproteinemia in rats, the claimed drug showed a pronounced lipid-lowering effect, superior to the effect of its analogue, clofibrate, and close to the action of its prototype gemfibrozil.

Experience 3. The hypolipidemic effect of the claimed drug in the experiment when modeling chronic alimentary DLP in guinea pigs

The lipid profile of the blood of guinea pigs in the spectrum of the distribution of cholesterol in drugs in serum is close to that in humans. In this regard, the simulation of DLP in guinea pigs is preferable than in rats [West k.l., Fernandez M.l. Cardiovasc. Drug Rev. 2004; 22 (1): 55-77].

Alimentary DLP is induced as follows: a heated mixture of 2% edible cholesterol with pork fat and sunflower oil (2: 1) is injected into the experimental animals with an oral probe for 21-24 days [Sapronov N.S., Khnychenko L.K., Okunevich I.V. Adv. Exp. Med. Biol. 2006, v. 583: 515-521].

The studies were conducted on 40 male guinea pigs weighing 350-450 g. The inventive preparation was administered at a dose of 100 mg / kg orally with the introduction of the GHS diet for 24 days. Clofibrate (analogue) and gemfibrozil (prototype) of the claimed preparation was used at a dose of 100 mg / kg, both orally under the same conditions.

The results of this series of experiments are presented in table 4.

As can be seen from the table, under the influence of the GHS diet, an increase in the content of lipids in the blood and liver is observed. In blood serum, the levels of cholesterol and triglycerides increased by 5 times and 9 times, respectively, and the concentration of cholesterol of antiatherogenic HDL decreased by 3.6 times. In this regard, calculated by the formula (HDL-C) / HDL-C, the cholesterol IA increased by 22.6 times compared with intact animals. Significant liver lipidosis occurred (increase in cholesterol and triglycerides) and an increase in cholesterol aorta was noted (table 4, group 2). In the conditions of alimentary DLP in guinea pigs, the use of the inventive preparation had a reliable lipid-lowering effect on blood lipids. So, in the blood serum, the level of cholesterol decreased by 2.2 times, TG - by 9.4 times, and the concentration of cholesterol of antiatherogenic HDL decreased in conditions of DLP increased 1.7 times. In this regard, the calculated value of cholesterol IA was reduced by 4 times, indicating a positive prognosis regarding the risk of developing AS (table 4, group 3).

Under the influence of the claimed drug due to its significant hypolipidemic effect, the cholesterol content in the aorta decreased 2.1 times, which suggests the presence of potential protective properties for this compound in relation to the aorta (table 4, group 3). As a result of treatment with the claimed drug, liver lipidosis significantly decreased (a 1.6-fold decrease in cholesterol and a 1.8-fold decrease in TG) compared with the group of hyperlipidemic animals not treated (table 4, groups 3 and 2). These data were close in effectiveness to the results of the lipid-lowering effect of gemfibrozil (prototype of the claimed drug). The table shows that with the introduction of gemfibrozil there was an improvement in the lipid spectrum of the blood, a decrease in the lipid content in the liver and the concentration of cholesterol in the aorta (table 4, group 5). Under the same modeling conditions, the use of clofibrate (an analogue of the claimed compound) did not affect TG in blood serum and liver, cholesterol content in the aorta, and also did not increase the decreased cholesterol concentration of anti-atherogenic HDL (table 4, group 4).

Thus, in the model of chronic alimentary DLP in guinea pigs, the inventive preparation showed a pronounced lipid-lowering effect, similar in effect to gemfibrozil (prototype) and superior in efficacy to clofibrate (analogue).

Antiatherosclerotic effect of the claimed drug

Experiment 4. Model of experimental alimentary (cholesterol) atherosclerosis (AS) in rabbits

In a chronic experiment, 50 male rabbits (weighing 3.0-3.5 kg) were used on a cholesterol AS model. They were divided into 5 groups: group 1 - intact rabbits, groups 2, 3, 4, and 5 — experimental rabbits who received an HCS diet (0.5 g / kg cholesterol in 5% warmed sunflower oil) for 3 months. Animals of group 3 were additionally injected with the claimed drug, and rabbits of group 5 its analogue was clofibrate, both at a dose of 100 mg / kg orally. Parmidin (prototype) was used at a dose of 50 mg / kg (rabbits of the 4th group). After 3 months at the end of the term, the animals were taken out of the experiment, received blood, secreted the liver and adrenal glands, and the aorta was extracted. In the blood, total cholesterol, HDL cholesterol, and TG were determined. By calculation, we analyzed the content of LDL cholesterol and the value of IA. The content of cholesterol and triglycerides was determined in the liver, and cholesterol in the adrenal glands. The content of cholesterol and the degree of atherosclerotic lesion of the aorta in percent were tested in the aorta. The data obtained in the experiment with a simulated alimentary AS in rabbits are presented in tables 5 and 6.

As can be seen from table 5, the simulation of alimentary AS in rabbits was accompanied by the creation of a powerful DLP in blood serum as compared with intact animals: the level of cholesterol increased by 25 times and TG by 16 times, the concentration of cholesterol anti-atherogenic HDL cholesterol decreased by 4 times (table 5 , group 2). The levels of cholesterol-containing LDL cholesterol and cholesterol IA increased, which indicates a poor prognosis of AS risk (table 4, group 2). There was pronounced lipidosis in the organs - multiple accumulation of lipids in the liver, cholesterol in the aorta and adrenal glands (table 6, group 2). An increase in cholesterol in the adrenal glands - organs of the pituitary-adrenal system - additionally characterizes the degree of lipid metabolism disturbance. A planimetric study of the aorta showed a pronounced atherosclerotic effect of the GHS diet, which was reflected in a large number of atherosclerotic lesions of both a multilayer and diffuse nature. In the aorta of hyperlipidemic rabbits, a significant increase in the content of cholesterol and atherosclerotic aortic lesions was observed (table 6, group 2).

In the conditions of developed DLP and alimentary AS, the administration of the inventive preparation improved the lipid profile of the blood and decreased lipid infiltration of the liver, decreased the content of adrenal and cholesterol cholesterol (tables 5 and 6, group 3). It was found that in the blood serum the level of cholesterol decreased by 2.3 times, TG - by 2.6 times, while the HDL cholesterol value did not change. The calculated values of the content of LDL cholesterol and cholesterol IA were significantly lower than in rabbits in group 2 who received only the GHS diet. These indicators indicate a pronounced hypolipidemic effect of the test compound and characterize a positive prognosis at risk of developing the atherosclerotic process. Under the influence of the claimed drug, lipid infiltration of the liver was also significantly reduced: the content of cholesterol and TG decreased 2.2 and 1.8 times, respectively, in addition, the content of cholesterol in the adrenal glands was 1.6 times lower compared to hyperlipidemic rabbits (table 6, group 3).

The anti-atherosclerotic effect of the claimed drug was expressed in a decrease in aortic lipidosis and the degree of damage to its AS wall: the content of aortic cholesterol decreased by 2.6 times, and the value of atherosclerotic lesion by 4 times compared with animals without treatment (table 6, groups 3 and 2).

The detected anti-atherosclerotic properties of the claimed drug were higher than that of parmidin (prototype), which had a protective effect on the aorta, but the percentage of aortic lesions was 2 times that of the claimed drug (table 6, group 4). In the absence of lipid-lowering effect, the anti-atherosclerotic effect of clofibrate (analogue) was even less pronounced - the percentage of aortic lesions was 2.9 times lower than that of the claimed drug (table 6, group 5).

Thus, in experiments on rabbits with alimentary cholesterol atherosclerosis, a pronounced lipid-lowering and anti-atherosclerotic effect of the claimed drug was found to be superior to the similar effects of the prototype - parmidin, and an analogue of the claimed compound - clofibrate.

As a result of the study, it was found:

1. In experiments on rats and guinea pigs with induced dyslipoproteinemia, a pronounced hypolipidemic effect of the claimed preparation — 1-methyl-3-ethyl benzenesulfonate, 4,5 (bis-N-methylcarbamoyl) imidazolium — on serum lipids and liver lipids was found.

2. The claimed drug in experiments on rats has the ability to restore low cholesterol of high density antiatherogenic lipoproteins in the blood.

3. In experiments on rabbits with alimentary cholesterol atherosclerosis, a pronounced lipid-lowering and anti-atherosclerotic effect of the claimed drug is shown — a decrease in cholesterol in the aorta and a percentage of atherosclerotic aortic lesions in experimental animals.

4. The low toxicity of the claimed drug and the effectiveness of oral administration in a small dose indicate the promise of using it as a lipid-lowering and anti-atherosclerotic agent for the treatment of atherogenic dyslipoproteinemia and atherosclerosis of various localization.

Claims (1)

The use of 1-methyl-3-ethyl, 4,5 (bis-N-methylcarbamoyl) imidazolium benzenesulfonate as a lipid-lowering and anti-atherosclerotic agent for the treatment of atherogenic dyslipoproteinemia and atherosclerosis of various localization.