RU2372897C1 - Agent with hypolipidemic and antiatherosclerotic action - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: use of disodium salt of 4,4'-di(sulphophenyl) sulphone as a hypolipidemic and an antiatherosclerotic agent during treatment of dislipoproteinemia of atherogenic nature and atherosclerosis of various localisation is proposed. The proposed preparation reduces level of cholesterol and triglycerides in blood plasma (hypolipidemic action), reduces cholesterol content in the aorta and degree of its atherosclerotic damage (antiatherosclerotic action).

EFFECT: preparation exhibits low toxicity and efficiency during oral administration.

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Description

The invention relates to medicine, namely to pharmacology.

The invention relates to a biologically active compound, namely, disodium salt of 4,4'-Di (sulfophenyl) sulfone, expanding the arsenal of lipid-lowering and anti-atherosclerotic drugs used in the treatment of cardiovascular diseases associated with metabolic disorders. The inventive drug reduces the level of cholesterol and triglycerides in the blood serum (lipid-lowering effect), reduces the cholesterol content in the aorta and the degree of its atherosclerotic lesion (anti-atherosclerotic effect).

Disodium salt of 4,4'-Di (sulfophenyl) sulfone in various experimental models of dyslipoproteinemia exhibits lipid-lowering and anti-atherosclerotic activity, has low toxicity. Its synthesis is simple and affordable.

A pharmacological analysis showed that the claimed drug, along with the normalization of lipid parameters in the blood and aorta, helps to reduce cholesterol and triglycerides in the liver, cholesterol in the adrenal glands, as well as lower the atherogenicity index (estimated risk of developing atherosclerosis).

Preclinical trials of disodium salt of 4,4'-Di (sulfophenyl) sulfone allow us to recommend it as a lipid-lowering and anti-atherosclerotic agent in the treatment of atherogenic dyslipoproteinemia, atherosclerosis of various localization.

Atherosclerosis (At), associated with a violation of regulatory processes in the body, is manifested by arterial damage, is characterized by deposition and accumulation of low-density plasma lipoproteins (LDL), accompanied by structural and cellular changes, reactive proliferation of connective tissue and the formation of fibrous plaques in the vascular wall [Klimov A. N., Nagornev V.A. Cardiology 1993; 3: 5-10]. At - a chronic, wave-like process with a constant change of causes and effects, due to the interaction of oxidized (peroxide-modified) LDL and the permeability of the vascular wall [Nagornev V.A. Honey. Acad. g. 2005; 5 (3) 6: 121-134]. Atherosclerosis is the basis of serious complications - coronary heart disease (CHD), myocardial infarction (MI), stroke, At lower extremities. The pathogenesis of At is complex and is not fully understood [Klimov A.N. Honey. Acad. g. 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]. The development of At is promoted by: hypoxia, metabolic disorders of the arterial wall and an increase in its permeability, expression of adhesive, pro-inflammatory and growth factors. It is known that when At occurs, the synthesis of protective substances (prostacyclin, nitric oxide, heparan sulfate), fibrinolytic substances decreases, fibrous atherosclerotic plaques (At plaques) are formed. In the early stages of At, plaques do not disturb the blood flow process, but reduce it as vascular stenosis develops, which contributes to the development of complex occlusive atherosclerotic lesions [Nasonov EA Cardiology 1999; 39 (2): 81-85; Klimov A.N., Nagornev V.A., Denisenko A.D. Honey. Acad. g. 2005; 2 (5): 18-32]. In the late stages of At progression, abnormalities in the blood coagulation system are observed leading to fatal outcomes [Pokrovskaya E.V., Graziansky N.A., Vaulin N.A., Deev A.D. Cardiology 2004; 7: 40-45]. Epidemiological, clinical and experimental studies indicate a relationship between lipid and lipid metabolism disorders with the progression of At and its complications [Hansson G.K. N. Engl. J. Med. 2005; 352: 1685-1695; Bubnova M.G., Oganov R.G. Therapist, archive 2004; 1: 73-78; Shalnova S.A., Deev A.D., Oganov R.G. Cardiovascular Therapy and Prevention 2005; 352: 1685-1695].

One of the reasons for the development of At is dyslipoproteinemia (DLP) of an atherogenic nature. In the blood of patients with DLP, there is an increase in the level of lipoproteins (LP): LDL, very low density LP (VLDL), special drugs (a), as well as in the composition of these drugs lipids - triglycerides (TG), total cholesterol (cholesterol), cholesterol cholesterol . In addition, there is a decrease in the concentration of high density cholesterol cholesterol (HDL) with antiatherogenic properties [Klimov AN, Nikulcheva NG The exchange of lipids and lipoproteins and its disorders, 1999; Kwiterowich P.O. Am J. Cardiol. 2001; 82 (12A): 3U-17U].

For diagnostic purposes, in order to detect atherogenic DLP in patients, the blood lipid spectrum is analyzed using the classification from type I to V proposed by Fredrickson. This classification is guided by therapists and pharmacologists in the appointment or study of lipid-lowering drugs [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].

According to modern concepts, lipid profile normalization in patients with At is carried out in two ways: 1 - by reducing atherogenic DLP and improving blood lipid profile; 2 - by improving the metabolism of the vascular wall and reducing the content of lipid components in At plaques [Klimov AN, Nikulcheva NG The exchange of lipids and lipoproteins and its disorders, 1999; Karpov Yu.A., Sorokin E.V. Cardiology 2005; 8: 4-7].

Early pharmacotherapy with the use of effective lipid-lowering and / or anti-atherosclerotic agents is necessary for the treatment of At [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].

In the treatment of atherogenic DLP, two main groups of drugs are used as lipid-lowering drugs: statins (lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin and rosuvastatin) and fibrates (clofibrate, probucol, gemfibrozil, bezafibrat, fenofibrat [C.]. 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].

The lipid-lowering effect of statins is accompanied by side effects - damage to the liver and kidneys, brain pathology, muscle pain, the development of cataracts and rhabdomyolysis [Mashkovsky MD Medicines, 15th ed., 2005, p. 467-471].

Clofibrate, belonging to the first generation of fibrates, is an analogue of the claimed compounds, as a drug with lipid-lowering properties [Mashkovsky M.D. Medicines, 13th ed., 1998, v. 1, p. 455-456]. In experimental studies, a side effect of clofibrate, hepatomegaly, was detected, and with clinical use, the formation of gallstones was noted [Nassrin D., Ontko J. Atherosclerosis 1983; 49: 225-266; Klimov A.H., Nikulcheva N.G. The exchange of lipids and lipoproteins and its disorders, 1999].

The authors chose probucol, which is a lipid-lowering agent, used to correct impaired lipid metabolism [Tvorogova MG, Lupanov VP, Rozhkova TA, an analogue of the claimed drug. Cardiology 1996; 11: 32-37]. Side effect of this drug is manifested in a decrease in the concentration of anti-atherogenic HDL [Kovskiy M.D. Medicines 13th ed. 1998; t. 1, p. 457].

Gemfibrozil, being an effective hypolipidemic drug from the group of fibrates, at the same time exhibits an antiatherosclerotic effect, having a protective effect. In this regard, the authors of the application gemfibrozil selected the prototype of the claimed compounds as lipid-lowering and anti-atherosclerotic drugs [Mashkovsky M.D. Medicines, 15th ed., 2005, p. 466]. The drug has a side effect on the gastrointestinal tract and liver. With prolonged use of gemfibrozil dry mouth, nausea, vomiting, constipation, diarrhea are noted [Vidal. Medicines in Russia 1995: p. 371].

For the treatment of At, simvastatin, atorvastatin and rosuvastatin are the latest generation statins that reduce the lipid component in At plaques [Law M.R., Wald N.J., Rudnicka A.R. BMJ 2003; 326 (7404): 1423-1438; Olsson A.G. Rosuvastatin. Science Press, 2004; 1-77]. These drugs have a side effect: they affect the liver and kidneys, exacerbate the development of cataracts [Mashkovsky M.D. Medicines, 15th ed., 2005, p. 467-471].

For the complex treatment of At, parmidin is used - a specific anti-bradykinin drug. Parmidin (an analogue of the claimed drug as an anti-atherosclerotic agent) reduces the degree of atherosclerotic lesion of the aorta and the content of cholesterol in At plaques. The therapeutic effect is achieved after prolonged (6 months) use, with weak hypolipidemic effect [Mashkovsky M.D. Medicines, 13th ed., 1998, v. 1, p. 448-449].

The preclinical study of the lipid-lowering and anti-atherosclerotic action of 4,4'-Di (sulfophenyl) sulfone disodium salt was carried out in comparison with the known drugs (clofibrate, probucol, parmidin, gemfibrozil) used in the clinic, and in accordance with the requirements of the Russian Pharmacological Committee [Experimental Manual , preclinical study of new pharmacological substances. M., 2000: 224-227].

The essence of the invention is that the disodium salt of 4,4'-Di (sulfophenyl) sulfone has a lipid-lowering and anti-atherosclerotic effect.

During testing, the hypolipidemic effect of disodium salt of 4,4'-Di (sulfophenyl) sulfone was established, which manifests itself in a decrease in the level of total cholesterol and triglycerides, an increase in the concentration of cholesterol anti-atherogenic HDL in the blood serum, and a decrease in the content of cholesterol and triglycerides in the liver. The inventive drug inhibits lipidosis in the adrenal glands, reducing their cholesterol content. In terms of the effectiveness of the lipid-lowering effect, the claimed drug is close to the analogous drugs from the fibrate group - clofibrate and probucol, as well as to the prototype - gemfibrozil, but differs from them in more pronounced lipid-lowering activity and the absence of side effects such as hepatomegaly, impaired liver and gastrointestinal tract.

When checking the claimed drug, its anti-atherosclerotic effect was established: a decrease in the degree of atherosclerotic lesion of the aorta and its lipid infiltration due to a significant decrease in the content of cholesterol. The claimed drug more effectively protects the aorta from At damage than the anti-atherosclerotic drug parmidin (an analogue of the claimed drug) and approaches the action of a lipid-lowering agent with anti-atherosclerotic properties - gemfibrozil (prototype of the claimed drug).

As a result of the study, two fundamentally new properties of 4,4'-Di (sulfophenyl) sulfone disodium salt were revealed - hypolipidemic and antiatherosclerotic. The inventive drug is effective when administered orally.

The disodium salt of 4,4'-Di (sulfophenyl) sulfone is claimed as a tool for the treatment of atherogenic DLP and At various localization.

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

The inventive preparation relates to low toxicity compounds. The dose that does not cause toxic effects when administered orally to mice is 4000 mg, and for rats - 3000 mg. The introduction of even larger doses was limited by technical difficulties. In this regard, the authors of the application failed to determine the LD ₅₀ - dosis letalis ₅₀ disodium salt of 4,4'-Di (sulfophenyl) sulfone when administered orally.

The inventive drug was studied at doses of 30, 100 and 300 mg / kg in preliminary experiments on adult male rats, when administered orally in the conditions of screening models of DLP: triton and ethanol DLP. It was found that the use of disodium salt of 4,4'-Di (sulfophenyl) sulfone in the minimum dose (30 mg / kg) did not change blood and liver lipids in the conditions of the above models, and at the maximum dose (300 mg / kg) caused a side effect ( increased postischemic hyperemia of the liver). Based on the results, the authors of the application selected a dose of 100 mg / kg, amounting to 1/30 of a dose of 3000 mg / kg, for further in-depth studies. A dose of 100 mg / kg is optimally effective at which no visible side effects are observed in animals.

Material and research methods.

The study of the lipid-lowering and anti-atherosclerotic effect of disodium salt of 4,4'-Di (sulfophenyl) sulfone on the level of lipids and LP in animals with experimental DLP of an atherogenic nature was carried out in rats and rabbits using models of the pathological condition.

To determine lipids, unified biochemical methods were used in accordance with the recommendations of the All-Russian Scientific Society of Cardiology (GFCF, 2004). 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. 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 after preliminary precipitation of atherogenic drugs. To determine the TG in the blood serum of rats and rabbits, a set of reagents from Vital Diagnostics was used [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 - a 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., Indenbom M.L. 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. an expert. ter. 2002; 2: 14-18].

Research results.

Hypolipidemic activity of 4,4'-Di (sulfophenyl) sulfone disodium salt in DLP models.

Experience 1. Model of triton dyslipoproteinemia (DLP) in rats.

The lipid-lowering activity of 4,4'-Di (sulfophenyl) sulfone disodium salt was studied in 60 male rats on a screening model of DLP induced 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 P.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 simultaneously with the administration of WR-1339 triton). For comparison, clofibrate (an analogue of the claimed drug) was used at a dose of 100 mg / kg and gemfibrozil (prototype of the claimed drug) at a dose of 50 mg / kg, both orally. After 10 hours, the degree of development of hyperlipidemia was determined by the level of cholesterol and TG in serum. The results are presented in table 1.

From table 1 it can be seen that during therapy with the claimed preparation (group 3), a significant decrease in the levels of cholesterol and triglycerides increased in the conditions of tritone DLP is observed: by 25% and 50%, respectively. Oral administration of clofibrate (group 4) and gemfibrozil (group 5) causes less pronounced shifts: the level of cholesterol decreases by 24.5% -22.5%, TG - by 37% -33.7%, respectively.

Thus, a pronounced hypolipidemic effect of 4,4'-Di (sulfophenyl) sulfone disodium salt was found in the model of tritone dyslipoproteinemia, which is close to the effects of the clofibrate analogue drug and the gemfibrozil prototype drug.

Experience 2. Hypolipidemic effect of disodium salt of 4,4'-Di (sulfophenyl) sulfone in a model of chronic alimentary DLP in rats.

It is known that the lipid and LP spectra of the blood of experimental animals are different: in rabbits, cholesterol is distributed evenly in LP fractions, and in rats, it is mainly found in anatiatric HDL [Wilgram GFJ 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 D ₂ [Thomas WA, Hartroft WS Circulation 1959; 19: 65-72].

The experiments were performed on 72 male rats (weighing 230-250 g) in the conditions of nutritional DLP, characterized by an increased level of lipids and LP in the blood serum and liver and at the same time a decreased content of cholesterol anti-atherogenic HDL in the blood. These disorders were caused by a diet containing 7.5% cholesterol, 30% a mixture of animal fats and warm sunflower oil (2: 1) and 500,000 MI of vitamin D ₂ . The duration of the experiment was 21 days. The peculiarity of the applied diet: against its background, not only the lipid-lowering effect of the new compound is studied, but, by analyzing the cholesterol atherogenicity index (IA), they are judged about its potential anti-atherosclerotic effect.

The disodium salt of 4,4'-Di (sulfophenyl) sulfone at a dose of 100 mg / kg was orally administered to rats for 21 days on the background of a special hypercholesterolemic diet (GHS diet). For comparison, we used analogues of the claimed drug - lipid-lowering drugs clofibrate and probucol, both at a dose of 100 mg / kg orally under the same conditions. Serum levels of total cholesterol, TG, and HDL cholesterol were determined. Based on these indicators, atherogenic LDL cholesterol was calculated according to the generally accepted Friedwald formula. The Klimov formula (cholesterol - HDL cholesterol) / HDL cholesterol determined the value of the cholesterol atherogenicity index (IA). The content of cholesterol and triglycerides was determined in the liver. The results are shown in tables 2 and 3.

As can be seen from table 2, feeding rats with HCV diet leads to the development of DLP: a 2.6-fold increase in cholesterol, a 2.9-fold increase in TG, and a 2.3-fold decrease in the concentration of anti-atherogenic HDL cholesterol. In addition, the calculated values of the cholesterol content of atherogenic LDL and cholesterol IA increase significantly, reflecting the development of At (table 2, group 2). Under these conditions, the use of the claimed drug causes a significant lipid-lowering effect: serum cholesterol and TG levels are reduced - by 27.4% and 31.7%, respectively, the concentration of cholesterol anti-atherogenic HDL increases by more than one and a half times. Estimated levels of LDL cholesterol and cholesterol IA are reduced. These facts indicate a positive prognosis in preventing the development of At in experimental animals during therapy with 4,4'-Di (sulfophenyl) sulfone disodium salt (table 2, group 3). An important feature of the claimed drug is the ability to increase antiatherogenic HDL. A similar property is characteristic only of lipid-lowering drugs from the groups of fibrates and, to a lesser extent, statins.

In the blood serum of rats with DLP during treatment with clofibrate or probucol (analogues of the claimed drug), the decreased concentration of cholesterol of antiatherogenic HDL has not changed. The calculated values of the content of LDL cholesterol and cholesterol IA remained high (table 2, groups 4 and 5). In animals treated with gemfibrozil (prototype of the claimed drug), the level of HDL cholesterol in the blood increased (table 2, group 6).

The results of the effect of disodium salt of 4,4'-Di (sulfophenyl) sulfone on liver lipids and weight index characterizing the synthetic cholester-forming function of the liver are presented in table 3.

From table 3 it is seen that in animals that were orally injected with disodium salt of 4,4'-Di (sulfophenyl) sulfone (table 3, group 3), there was a pronounced decrease in lipid infiltration of the liver, simulated by feeding an HCS diet: the content of cholesterol decreased by 1.6 times, TG - 2.1 times. When using the inventive preparation, a lower value of the weight index of the liver was noted, compared with hyperlipidemic rats (table 3, group 2).

In terms of DLP, clofibrate and probucol (analogues) and gemfibrozil (prototype) of the claimed drug showed less activity. So, in the group of rats treated with clofibrate, the content of cholesterol and triglycerides decreased by 22.1% and 41.2%, respectively.

In animals treated with probucol, the content of cholesterol was significantly reduced (table 3, group 5), and gemfibrozil - the content of TG in the liver tissue (table 3, group 6).

The use of clofibrate, in contrast to probucol and gemfibrozil, 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 intrahepatic cholestasis, exacerbation of gallstone disease [Mashkovsky MD Medicines, 1998, 13th ed., Vol. 1, p. 455-456].

Thus, in the model of chronic alimentary dyslipoproteinemia, the hypolipidemic effect of disodium salt of 4,4'-Di (sulfophenyl) sulfone was found to be superior to the effect of clofibrate and probucol (analogues) - and close to the action of gemfibrozil (prototype of the drug).

Antiatherosclerotic effect of 4,4'-Di (sulfophenyl) sulfone.

Experience 3. A model of experimental alimentary (cholesterol) atherosclerosis (At) in rabbits.

In a chronic experiment, 40 male rabbits (weight 3.0-3.5 kg) were used on a cholesterol At model. The animals were divided into 5 groups: group 1 — intact rabbits, groups 2, 3, 4, and 5 — rabbits treated with the GHS diet (0.3 g / kg cholesterol in 5% warmed sunflower oil) for 3 months. Animals of groups 3 and 4 were additionally administered orally at the same dose of 100 mg / kg disodium salt of 4,4'-Di (sulfophenyl) sulfone and its analogue clofibrate, and group 5 - gemfibrozil (prototype of the claimed preparation) at a dose of 50 mg / kg . Treatment of rabbits with At was carried out in parallel with the introduction of the GHS diet for 3 months. At the end of the term, the animals were taken out of the experiment, received blood, the liver, adrenal glands and aorta were isolated. In the blood, total cholesterol, HDL cholesterol, and TG were determined. The LDL-C content and cholesterol IA were calculated. The content of cholesterol and triglycerides was determined in the liver, and cholesterol in the adrenal glands and the aorta.

Data on the effectiveness of the lipid-lowering effect of disodium salt of 4,4'-Di (sulfophenyl) sulfone obtained in experiments with simulated alimentary At in rabbits are presented in Tables 4 and 5, and the results reflecting the antiatherosclerotic effect, as well as the effect on liver lipids, adrenal glands and aorta in table 5.

From tables 4 and 5 it is seen that in the blood serum of animals with At increased the content of cholesterol and triglycerides and decreased - cholesterol antiatherogenic HDL, which characterizes the development of DLP. Significantly increased the level of cholesterol cholesterol cholesterol and cholesterol IA, indicating the progression of At (table 4, group 2). In addition, in the liver, aorta, and adrenal glands of rabbits, lipidosis was observed - multiple accumulation of lipids (table 5, group 2). The planimetric study of the aorta confirmed the atherosclerotic effect of the GHS diet, which is expressed by a significant number of lesions of the wall of a multilayer and diffuse nature. In the aortic tissue of rabbits treated with the GHS diet, the degree of damage and the content of cholesterol in it increased significantly (Table 5, group 2).

In the blood serum of rabbits with simulated DLP and At (Tables 4 and 5, group 2), which were injected with 4,4'-Di (sulfophenyl) sulfone disodium salt, the concentration of cholesterol and triglyceride decreased by 44.5% and 45.6%, respectively and the HDL cholesterol value increased 2 times. In addition, lipidosis decreased in the tissue of the liver and adrenal glands: in the liver, the content of cholesterol and triglycerides decreased by 2.2 and 1.8 times, respectively, and in the adrenal glands of cholesterol by 1.7 times, compared with indicators in animals that did not receive treatment ( table 4, group 2).

The lipid-lowering and anti-atherosclerotic effect of the claimed drug was expressed in a decrease in aortic lipidosis and the degree of damage to its wall: the content of aortic cholesterol decreased by 2.6 times, the value of atherosclerotic lesion - by 80.3%. The calculated values of the concentration of LDL cholesterol and especially the cholesterol atherogenic index were also significantly lower than in animals of group 2 (without treatment). These indicators characterize a positive prognosis in containing the atherosclerotic process under the influence of disodium salt of 4,4'-Di (sulfophenyl) sulfone.

In the group of animals with At that was injected with parmidin, the lipid content decreased only in the liver tissue. The magnitude of atherosclerotic lesions of the aorta of these rabbits decreased to a lesser extent than during therapy with the claimed compound (table 5, group 4). The results indicate the anti-atherosclerotic property of the disodium salt of 4,4'-Di (sulfophenyl) sulfone, superior to that of parmidine. Antiatherosclerotic effect of the hypolipidemic drug gemfibrozil compared with that of the claimed drug is less pronounced. So, the magnitude of the aortic lesion is 3 times less than in animals that received the disodium salt of 4,4'-Di (sulfophenyl) sulfone. In the treatment of rabbits with At parmidin and gemfibrozil, the cholesterol content in the adrenal tissue did not change.

Thus, in experiments on rabbits with alimentary cholesterol atherosclerosis, it was found that the lipid-lowering and anti-atherosclerotic property of 4,4'-Di (sulfophenyl) sulfone disodium salt exceeds the similar effect of parmidine (analogue of the claimed drug) and is comparable in effect to gemfibrozil (prototype of the claimed compound).

As a result of the study of the claimed drug found:

1 - Disodium salt of 4,4'-Di (sulfophenyl) sulfone has a pronounced lipid-lowering effect on serum lipids and lipoproteins, liver lipids, adrenal cholesterol.

2 - Disodium salt of 4,4'-Di (sulfophenyl) sulfone has the ability to increase low cholesterol of high density antiatherogenic lipoproteins in the blood.

3 - Disodium salt of 4,4'-Di (sulfophenyl) sulfone has a pronounced lipid-lowering and anti-atherosclerotic effect - it reduces the content of lipids in the liver, cholesterol in the adrenal glands and in the aorta. The claimed compound reduces the degree of atherosclerotic lesions of the aortic wall.

Low toxicity and effectiveness when administered orally indicate the promise of using disodium salt of 4,4'-Di (sulfophenyl) sulfone as a lipid-lowering and anti-atherosclerotic agent for the treatment of atherogenic dyslipoproteinemia and atherosclerosis of various localization.

Claims (1)

The use of disodium salt of 4,4'-Di (sulfophenyl) sulfone as a lipid-lowering and anti-atherosclerotic agent for the treatment of atherogenic dyslipoproteinemia and atherosclerosis.