RU2372923C2 - Hypolipidemic and antiatherosclerotic agent - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely application of sodium thiosulphate as a hypolipidemic and antiatherosclerotic agent for oral introduction to treat dislipoproteinemia and atherosclerosis.

EFFECT: there is disclosed hypolipidemic and antiatherosclerotic agent.

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Description

The invention relates to medicine, namely to pharmacology.

The invention relates to a biologically active compound, namely sodium thiosulfate (Natrii thiosulfas), expanding the arsenal of lipid-lowering and anti-atherosclerotic drugs in the treatment of cardiovascular diseases associated with metabolic disorders. Sodium thiosulfate lowers serum cholesterol and triglycerides and lowers cholesterol in the aorta. The ability to reduce serum lipids indicates a pronounced hypolipidemic effect, and a decrease in cholesterol in the aorta reflects the antiatherosclerotic effect of sodium thiosulfate.

Previously, this drug has been described as an anti-toxic, anti-inflammatory and anti-allergic agent (Vidal Handbook, 1999, E-211). Its synthesis is simple and affordable.

Sodium thiosulfate exhibits lipid-lowering activity in various experimental models of dyslipoproteinemia (hyperlipidemia), has low toxicity.

A pharmacological analysis showed that sodium thiosulfate, in addition to normalizing lipid parameters in the blood and aorta, reduces the content of cholesterol and triglycerides in the liver and cholesterol in the adrenal glands, and also significantly reduces the value of the atherogenic index (an indicator of the risk of developing atherosclerosis).

Preclinical trials of the drug make it possible to recommend it as a lipid-lowering and anti-atherosclerotic agent in the treatment of cardiovascular diseases: hypercholesterolemia, atherogenic dyslipoproteinemia, and atherosclerosis of various localization.

Experimental, clinical, and epidemiological studies indicate a relationship between lipid and lipoprotein metabolism disorders and the development of atherosclerosis (At) and its severe 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].

The leading cause of the development of At is dyslipoproteinemia (DLP) of an atherogenic nature, which is a persistent, long-term increase in blood lipids: triglycerides (TG), total cholesterol (cholesterol) and / or cholesterol cholesterol low density lipoproteins (LP) and LDL of very low density (VLDL), as well as special drugs (a). The lipid profile of the blood of the patient At is characterized by a significant decrease in the concentration of cholesterol of antiatherogenic high-density drugs (HDL) [Klimov A.N. Honey. Acad. g. 2007; 1 (7): 4-11; Nagornev V.A. The pathogenesis of atherosclerosis. M .: SPb., 2006].

At - the main reason for temporary disability, disability and mortality of the adult population of Russia [GFCF. Russian recommendations. Diagnosis and correction of lipid metabolism disorders in order to prevent and treat atherosclerosis. M., 2004]. At leads to stenosis and obstruction of the coronary arteries, a dangerous lesion of the cerebral arteries and arteries of the lower extremities.

An important role in the progression of the atherosclerotic process is played by vascular endothelial dysfunction, which, at present, is considered as an independent risk factor for At and atherothrombosis [Sidorenko B.A. Kremlin medicine, 1999; 2: 51-54; Nagornev V.A. The pathogenesis of atherosclerosis. M .: SPb., 2006].

Dyslipoproteinemia (DLP) of an atherogenic nature in patients with At of different localization is determined instrumentally in lipid centers, and the nature of the blood lipid profile is assessed; why use the classification according to phenotypes proposed by Frederickson: from type I to type V. 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 Engi J. Med., 1967; 276: 34-42].

Atherosclerosis (At) is a complex, periodically exacerbating chronic process of vascular damage caused by a violation of the properties of the vascular endothelium, cholesterol metabolism, and proliferation of connective tissue, which leads to the formation of an atherosclerotic plaque (At plaque). At and its complications - coronary heart disease, stroke, damage to the vessels of the lower extremities At continue to be the most common cause of disability and mortality in the economically developed countries of Europe, the USA and especially Russia [European Guidelines on Cardiovascular Disease. Eur. Heart J. 2003; 24 (17): 1601-1610; NCEP. Adult Treatment Panel III Guidelines. Circulation 2004; 110: 227-239; LEFT. Russian recommendations. Diagnosis and correction of lipid metabolism disorders in order to prevent and treat atherosclerosis. M., 2004; 36 p.].

It has been established that atherosclerosis affects various organs and systems: coronary arteries of the heart, arteries of the brain, thoracic and abdominal aorta, carotid arteries, arteries of the kidneys and lower extremities. The first manifestations of At in the form of lipid spots can occur in humans at an early age. Their appearance is associated with local deposition of lipoproteins in the intima of the arteries, it is from lipid spots that atherosclerotic lesions - At plaques - subsequently develop. Excessive accumulation of drugs in the intima of the arteries is facilitated by a prolonged increased concentration of cholesterol and cholesterol-containing atherogenic drugs and / or low levels of cholesterol antiatherogenic drugs of high density (HDL). In addition, in the progression of atherosclerotic lesions, other modifiable risk factors for At are important: arterial hypertension, diabetes mellitus, smoking, obesity, a sedentary lifestyle [Martsevich S.Yu. Atherosclerosis. Clinical relevance and potential for prevention. M., 2005; Aronov D.M., Akhmedzhanov N.M., Gutkovskaya L.A. Ross cardiol. J., 2006; 3 (59): 34-40].

In the early stages of At, plaques do not interfere with the blood flow process and therefore At does not manifest itself clinically. However, the occurrence of atherosclerotic vascular stenosis leads to a gradual decrease in blood flow, the appearance and development of occlusive atherosclerotic lesions. On the surface of At plaques breaks occur. In the late stages of At progression, abnormalities in the blood coagulation system are observed: platelet adhesion occurs, blood clots form, blood vessel lumen suddenly clogs. This process leads to cardiovascular catastrophes: myocardial infarction, stroke, critical ischemia of limb arteries [Pokrovskaya EV, Graziansky NA, Vaulin NA, Deev AD Cardiology, 2004; 7: 40-45].

It is important to note that in the initiation of atherogenesis (in addition to impaired lipid metabolism) metabolic disorders of the arterial wall are of great importance, leading to its hypoxia, increased permeability, expression of adhesive, pro-inflammatory, growth factors. The synthesis of protective substances such as prostacyclin, nitric oxide, heparan sulfate, as well as fibrinolytic and some other substances is reduced [Nasonov EA Cardiology, 1999; 39 (2): 81-85; Klimov A.N., Nagornev V.A., Denisenko A.D. Honey. Acad. J., 2005; 2 (5): 18-32].

Instrumental intravital detection of atherosclerotic lesions in the walls of blood vessels is a complex procedure, which is carried out according to indications only in specialized centers under the supervision of cardiologists and cardiac surgeons. But in real life, the presence of At more often ascertain after the death of patients. Therefore, timely continuous therapy with anti-atherosclerotic drugs is so important.

For the prevention and treatment of At and its main clinical manifestations, 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].

Treatment of patients with DLP and patients with At is carried out in two ways:

1) by reducing DLP 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 At plaques.

In the clinic, several groups of drugs are used as lipid-lowering agents for the correction of atherogenic DLP: bile sequestrants (cholestyramine, colestipol); nicotinic acid preparations (niaspan, niacin); fibrates (clofibrate, probucol, gemfibrozil); statins (lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin and rosuvastatin) [S.J. Robins. Correction of lipid disorders. Basic principles and practical implementation of therapeutic interventions. M., 2001: 108-109].

Cholestyramine and colestipol reduce the level of atherogenic low-density lipoproteins and cholesterol by 25% due to the binding of cholesterol in the intestine and excretion from the body. The use of these drugs disrupts the activity of the gastrointestinal tract and liver, which forces patients to abandon their use [Vidal. Medicines in Russia, 1995; p. 963].

Niaspan and niacin reduce the synthesis rate of very low density lipoproteins containing a large amount of triglycerides by 20-35%. Side effects of nicotinic acid preparations are skin hyperemia, hyperuricemia, hyperglycemia, gastrointestinal disorders [Vidal. Medicines in Russia, 1999; B-772; C.J. Robins. Correction of lipid disorders. Basic principles and practical implementation of therapeutic interventions. M., 2001: 108-109].

Clofibrate belongs to the first generation of fibric acid derivatives. Experimental and clinical studies revealed a number of negative side effects (hepatomegaly, increased mortality in patients). Clofibrate is an analogue of the claimed drug as a drug with lipid-lowering effect [Mashkovsky M.D. Medicines 13th ed. 1998; t.1: 456].

Probucol is used to correct impaired lipid metabolism, but it reduces the concentration of high density antiatherogenic lipoproteins. Probucol is an analogue of the claimed drug as a hypolipidemic drug [Mashkovsky M.D. Medicines 13th ed. 1998; t.1: 457].

Gemfibrozil is used to reduce the level of TG, total cholesterol, VLDL; but when taken, it causes dry mouth, nausea, vomiting, constipation, diarrhea [Vidal. Medicines in Russia, 1995: p. 371; C.J. Robins. Correction of lipid disorders. Basic principles and practical implementation of therapeutic interventions. M., 2001]. Gemfibrozil is a prototype of the claimed drug as a hypolipidemic drug [Mashkovsky M.D. Medicines 13th ed. 1998; t.1: 457].

Lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin and rosuvastatin are used to treat DLP. The pronounced lipid-lowering effect of these drugs is accompanied by serious side effects: liver and kidney damage, brain pathology, muscle pain, cataracts and rhabdomyolysis [Law M.R., Wald N.J., Rudnicka A.R. BMJ 2003; 326 (7404): 1423-1438; Kukharchuk V.V., Bubnova M.G., Katelnitskaya L.I. et al. Cardiology, 2003; 5: 42-47; Olsson A.G. Rosuvastatin in dyslipidemia and coronary heart disease. Science Press, 2004; 1-77].

As antiatherosclerotic agents, fish oil preparations are used: maxepa, eikonol and Vitrum cardio omega-3 with a high content of omega-3 polyunsaturated fatty acids [Mazur N.A. Omega-3 polyunsaturated fatty acids and their role in the prevention of atherosclerosis, 2007; 16 p.]. These drugs are used to reduce the atherosclerotic process in the vessel wall. The use of drugs based on fish oil is complicated by side effects from the gastrointestinal tract [S.J. Robins. Correction of lipid disorders. Basic principles and practical implementation of therapeutic interventions. M., 2001, 108-109].

Hemfibrozil, bezafibrat, fenofibrat positively affect the progression of the At process, providing an atheroprotective effect. They have a side effect on the gastrointestinal tract and liver. Gemfibrozil is an analogue of the claimed compounds as antiatherosclerotic agents. [Vidal. Medicines in Russia, 1999; E-194, E-28, E-102, E-57, B-358].

Simvastatin, atorvastatin and rosuvastatin are used for intensive care of atherosclerosis. They reduce the lipid component in At plaques. The drugs have a side effect: they affect the liver and kidneys, exacerbate the development of cataracts [Mashkovsky M. D. Medicines 13th ed. 1998; T. 1: 458-460].

Parmidin is recognized as a specific drug for the complex treatment of At [Ryzhenkov V.E. et al., 1976; 5: 558-559]. It reduces the degree of atherosclerotic lesion of the aorta and reduces the content of cholesterol in At plaques. Parmidin is a prototype of the claimed drug as an antiatherosclerotic agent [Mashkovsky M.D. Medicines 13th ed. 1998; t.1: 448-449].

For the treatment of dyslipoproteinemia and atherosclerosis, the authors of the application propose sodium thiosulfate, a specific antidote, a sulfa-containing compound with antitoxic properties, which is used in medical practice for heavy metal poisoning. It is able to relieve pain and reactions in the treatment of arthritis, neuralgia, allergies [Mashkovsky MD Medicines 13th ed. 1998; vol.2: 213]. A preclinical study of the lipid-lowering and anti-atherosclerotic action of the claimed compound sodium thiosulfate was carried out in accordance with the requirements of the Russian Pharmacological Committee [guidelines for the study of lipid-lowering and anti-atherosclerotic effects of pharmacological substances. Guidelines for the experimental preclinical study of new pharmacological substances. M., 2000: 224-227]. An experimental study of the activity of this compound was carried out in comparison with the known drugs (clofibrate, probucol, gemfibrozil, parmidin) used in the clinic [Mashkovsky MD Medicines 13th ed. 1998; T. 1: 448; 455-456; 457].

When checking the preparation of sodium thiosulfate, it was found that it significantly reduces the level of total cholesterol in the blood serum, as well as its content in the liver and aorta in rabbits with experimental At. It more significantly reduces the content of cholesterol in the adrenal glands compared with gemfibrozil. Sodium thiosulfate effectively protects the rabbit aorta from At damage, as well as the antiatherosclerotic drug parmidin (prototype anti-atherosclerotic drug), and actively reduces cholesterol in the blood, liver and adrenal glands as a lipid-lowering drug gemfibrozil (prototype drug lipid-lowering action).

The essence of the invention is that sodium thiosulfate actively reduces the level of serum lipids - cholesterol and triglycerides, as well as atherogenic drugs in experiments on animals of different species. Found a fundamentally new property of sodium thiosulfate - hypolipidemic. In addition, sodium thiosulfate has another valuable property - antiatherosclerotic. Sodium thiosulfate in severity of hypocholesterolemic action is not inferior to the antiatherosclerotic drug parmidin and approaches the drug gemfibrozil. The drug is effective when administered orally. Sodium thiosulfate, which has a pronounced effect on the model of atherosclerosis in rabbits, is claimed as a tool for the treatment of atherosclerosis.

In terms of the severity of the hypolipidemic effect of sodium, thiosulfate approaches the analogues of the fibrate group - clofibrate and probucol, as well as the prototype hemphibrozil, but differs from them in the absence of side effects such as hepatomegaly, impaired liver and gastrointestinal tract. The drug is effective when administered orally. Sodium thiosulfate, which has a pronounced effect on DLP models in various animal species (rats, guinea pigs, rabbits), is claimed to be a treatment for dyslipoproteinemia.

The drug has no analogues in Russia and abroad.

Sodium thiosulfate is a low-toxic compound. 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 5000 mg, and to rats, 4000 mg. The introduction of large doses caused technical difficulties.

In preliminary experiments, the following doses of the test drug were used: 25, 100 and 250 mg / kg once, when administered orally to sexually mature male rats, in experimental DLP: triton DLP and ethanol hypertriglyceridemia. It was found that the minimum dose of sodium thiosulfate 25 mg / kg does not have a significant effect on blood and liver lipids in the conditions of the above models. A large dose of 250 mg / kg causes increased postischemic hyperemia of the liver in rats. A dose of 100 mg / kg, which is 1/40 of the dose that does not have a toxic effect, was optimally effective, since in experimental animals no visible side effects were observed.

Material and research methods

The study of the lipid-lowering and anti-atherosclerotic effect of the claimed drug sodium thiosulfate on the level of TG and cholesterol in animals with experimental DLP of an atherogenic nature was carried out in rats, guinea pigs and rabbits, using models of the pathological condition, in accordance with the requirements of the Pharmacological Committee of the Ministry of Health of the Russian Federation [Methodological recommendations for experimental preclinical the study of new pharmacological substances. M., 2000: 224-227].

For this, the following biochemical methods were used.

Determination of cholesterol in blood serum

The level of cholesterol in the blood serum of rats and guinea pigs was determined in accordance with the recommendations of the All-Russian Scientific Society of Cardiology (VNOK, 2004) using the colorimetric enzymatic method (CHOD-PAP) using a set of reagents from Vital Diagnostics. The principle of the method is based on the production of cholesterol from esters under the influence of cholesterol esterase followed by its oxidation to cholestenone and the release of hydrogen peroxide. Then, under the action of peroxidase, a colored product is formed, the concentration of which is analyzed on an SF-26 spectrophotometer.

Determination of HDL cholesterol in blood serum

The study of the content of HDL cholesterol in rat blood serum was carried out as described above using reagents from Vital Diagnostics, at a wavelength of 546 nm on SF-26, after preliminary precipitation of atherogenic drugs with heparin in the presence of manganese ions.

Determination of TG in serum

To determine the TG in the blood serum of rats and guinea pigs, a standard set of reagents of the same company was used. The unified method is based on a cascade of TG cleavage reactions, at the end of which a colored compound is formed from 4-aminoantipyrine and 4-phenol with the participation of hydrogen peroxide and peroxidase. The obtained quinoneimine with an absorption maximum of 500 nm is determined photometrically in proportion to the concentration of TG in the sample [Wahlfeld A.W. In: Methods of enzymatic analysis. Acad. Press, NY; 1974: 1831].

Determination of cholesterol in the liver

The content of cholesterol was carried out colorimetrically using the Lieberman-Burchard reaction [Bragdon G.H. after the extraction of a liver sample with a mixture of chloroform and carbinol] In: Lipids and steroid hormons in clinical medicine. Ph. 1960: 6-10].

Determination of TG in the liver

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 zeolite mixture as aluminum sorbent [Okunevich IV, Sapronov NS, Indenbom M.L. Chem.-farm. J., 1999; 11: 14-16].

Determination of total cholesterol content in the aorta

The content of total cholesterol was carried out colorimetrically using the Lieberman-Burchard reaction after extraction of a portion of the aorta. The aorta was isolated along the entire length before bifurcation and ground with quartz sand to prepare a chloroform extract [Ryzhenkov V.E., Khromov-Borisov N.V., Mosina I.V., Indenbom M.L. Farmakol. Toxicol., 1979; 6: 632-635].

Determination of cholesterol in the adrenal glands

The content of cholesterol in the adrenal glands was determined as described above, after homogenization of a tissue sample with a mixture of chloroform with carbinol and the subsequent Lieberman-Burkhard reaction [Okunevich IV, Ryzhenkov V.E. Pat. fiziol. an expert. ter., 2002; 2: 14-18].

The results of studies of the activity of the claimed drug - sodium thiosulfate - in experimental models of dyslipoproteinemia.

Rat Triton Hyperlipidemia Model

The hypolipidemic activity of sodium thiosulfate was studied using a model of triton hyperlipidemia caused by the detergent triton WR-1339 (225 mg / kg once intraperitoneally) (Serva, Switzerland). This model is characterized by the development of powerful, persistent hyperlipidemia in male rats weighing 250-300 g [Shurr P.E., Shultz Y.R. Lipids 1972; 7 (1): 68-74]. Triton, being a lipo-carbohydrate, forms a layer on the surface of VLDLP, which prevents the formation of an enzyme-substrate complex with PL. In this case, an increase in the level of cholesterol is 5-6 times, and TG - 10-20 times compared with the content of these indicators in normolipidemic animals.

Sodium thiosulfate was administered to rats orally at a dose of 100 mg / kg twice (prior to and with the administration of WR-1339 triton). The degree of hyperlipidemia was evaluated by the level of lipids: cholesterol and triglycerides in rat serum. Clofibrate was administered orally at a dose of 100 mg / kg as a reference preparation. After 10 hours, the degree of development of hyperlipidemia was determined by the value of cholesterol and triglycerides in blood serum. The results are presented in table 1.

As can be seen from the table, under the influence of sodium thiosulfate, a significant decrease in the levels of cholesterol and TG increased by 36% and 40%, respectively, is observed under the conditions of triton hyperlipidemia. Oral administration of clofibrate in the same dose of 100 mg / kg causes the same changes: the level of cholesterol and TG decreases by 40% and 41%, respectively.

Thus, in one of the models of experimental dyslipoproteinemia - triton hyperlipidemia in rats, the lipid-lowering effect of sodium thiosulfate was shown.

Rat Alcoholic Hypertriglyceridemia Model

In experiments on male rats weighing 220-250 g to create alcoholic hypertriglyceridemia, the Woicicki J. method [Woicicki J. Azneimittel-Forsch. 1976; 26 (11): 2047-2048]. It consists of a three-time oral administration of a 50% ethanol solution at a dose of 6 g / kg. In the blood serum and liver of rats, the content of TG significantly increases. The test substance, sodium thiosulfate, was preliminarily administered at a dose of 100 mg / kg orally for 5 days (last administration 30 minutes before the introduction of ethanol). Gemfibrozil, another drug from the fibrate group, was used as a reference. Gemfibrozil was used under the same conditions, at a dose of 50 mg / kg, orally. The results of this series of experiments are presented in table 2.

As can be seen from the table, as a result of the introduction of ethanol in the experimental group of rats, an increase in the level of TG in blood serum is observed by a factor of 5.6 and in the liver by a factor of 3.5 (group 2). Under the influence of the studied sodium thiosulfate compound, there is a significant decrease in the TG content in the blood by 53% and in the liver by 62%. Against the background of the action of the comparison drug gemfibrozil, the level of TG in blood serum decreases by 55%, the content of TG in the liver - by 66%.

Thus, in a model of alcoholic hypertriglyceridemia in rats, it was found that the use of sodium thiosulfate has a pronounced TG-lowering effect.

Alimentary dyslipoproteinemia in rats

The lipid and LP spectra of the blood of experimental rodent animals are different: in rabbits, cholesterol is distributed evenly among the LP fractions, in guinea pigs, almost all cholesterol is contained in atherogenic drugs, and in rats, it is mainly found in anti-atherogenic HDL. In this regard, rats are more resistant to the induction of experimental DLP [Wilgram GFJExp.Med. 1959; 109 (3): 293-309]. To create a model of dyslipoproteinemia (DLP) in rats, it is necessary to add 6-methylthiouracil (6-MTU), sodium cholate, vitamin D ₂ to the diet containing cholesterol, such as the thyroid-suppressing agent [Thomas WA, Hartroft WS Circulation, 1959; 19: 65-72].

The experiments were performed on male rats weighing 230-250 g in 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 reduced content of cholesterol anti-atherogenic HDL. These disorders were caused by a diet containing 3% cholesterol, 0.12% 6-MTU, and 30% a mixture of animal fats and warmed sunflower oil (2: 1). The duration of such a model was 21 days [Okunevich I.V., Sapronov N.S., Indenbom M.L. and others. Chem. - farm. J., 1999; 11: 14-16]. The peculiarity of the applied diet is that against its background it is possible to study not only the lipid-lowering effect of new compounds, but also, by analyzing the cholesterol atherogenicity index, to judge their potential anti-atherosclerotic effect.

Sodium thiosulfate at a dose of 100 mg / kg was orally administered for 21 days against a background of a special hypercholesterolemic diet (HCS diet). For comparison, we used the drug probucol at a dose of 100 mg / kg orally, administered under the same conditions. In rat blood serum, the levels of total cholesterol, TG, and HDL cholesterol were determined. Based on these indicators, the cholesterol atherogenicity index was calculated by the formula (HDL-C). In the liver, the content of cholesterol and TG was tested. The results are shown in table 3.

As can be seen from the table, feeding the GCS diet to rats leads to an increase in the level of cholesterol by 2.8 times, cholesterol and TG of the liver - by 6.4 and 10.3 times, respectively. It should be noted that the use of the thyroid-suppressing agent 6-MTU in the diet leads to a decrease in blood serum TG and a significant increase in TG content in rat liver due to suppression of thyroid function, therefore, the authors consider the increase in TG levels to be a positive change. Under the influence of the GHS diet, there is also a decrease in HDL cholesterol - the antiatherogenic fraction of LP (group 2). Under these conditions, the use of sodium thiosulfate leads to a clear hypocholesterolemic effect - the content of cholesterol in the blood serum is reduced by 25% and in the liver by 45% (table 3, group 3).

The value of the cholesterol atherogenicity index calculated by the formula (total cholesterol - HDL cholesterol) / HDL cholesterol decreases by almost 2 times compared with the group of rats that received only the GHS diet (groups 2 and 3). In this regard, the presence of anti-atherosclerotic action in sodium thiosulfate is assumed. It is important to emphasize that the detected increase in the cholesterol of anti-atherogenic HDL under the influence of sodium thiosulfate is characteristic mainly for lipid-lowering drugs from the group of statins and fibrates. In this experiment, probucol did not show an increase in HDL cholesterol, since it tends to reduce the level of anti-atherogenic HDL (group 4).

Thus, a pronounced hypocholesterolemic effect of sodium thiosulfate was revealed in the model of alimentary dyslipoproteinemia in rats.

Alimentary dyslipoproteinemia in guinea pigs

In guinea pigs, in connection with the characteristics of the blood lipid profile, alimentary HLP is induced as follows: a heated mixture of 2% edible cholesterol with pork fat and sunflower oil (2: 1) is orally administered for 15-20 days [Sapronov NS, Khnychenko LK, Okunevich iv and Gavrovskaya L.K. Adv. Exp. Med. Biol. 2006, v. 583 (Taurine Book 6): 515-521].

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, a multiple increase in the levels of cholesterol and triglycerides is observed, and the concentration of cholesterol of antiatherogenic HDL decreases by 3 times. In this regard, calculated by the formula (total. HDL-C), HDL-C, the atherogenic cholesterol index increases by 18 times compared with normolipidemic animals. Under these conditions, the use of sodium thiosulfate in experimental guinea pigs has a significant lipid-lowering effect on the content of blood and liver lipids. So, the level of cholesterol in blood serum decreases by 2.8 times, and the content of blood TG - by 22%. Under the influence of sodium thiosulfate due to its significant hypocholesterolemic effect, the cholesterol atherogenicity index decreases by a factor of 2, which confirms the presence of potential anti-atherosclerotic properties in this compound. As a result of treatment of rats with sodium thiosulfate, liver lipidosis significantly decreases: the content of total cholesterol and triglycerides decreases by 1.6 times compared with the group of hyperlipidemic animals (groups 2 and 3).

Thus, in the model of nutritional dyslipoproteinemia in guinea pigs, a pronounced lipid-lowering effect of sodium thiosulfate was revealed.

Experimental rabbit atherosclerosis model

Data on the effectiveness of sodium thiosulfate obtained in experiments with simulated alimentary At in rabbits to determine the lipid-lowering and anti-atherosclerotic effects of the claimed drug are presented in table 5.

As can be seen from the table, the modeling of nutritional antibodies in rabbits was accompanied by the creation of a powerful DLP in the blood and a significant accumulation of lipids in the organs: liver, adrenal gland and aorta. So, the level of total cholesterol increased by 40 times, TG - by 15 times, while the concentration of cholesterol of antiatherogenic HDL in the blood serum decreased by 3.6 times compared with intact animals. Pronounced liver lipidosis was observed - the lipid content in the liver increased: cholesterol - 16 times, TG - 8 times (group 2). The accumulation of cholesterol in the adrenal glands (1.8 times) - the organs of the pituitary-adrenal system - is considered as an adverse factor in lipid metabolism. A multiple increase in cholesterol and the degree of damage to the aorta At occurred in the aorta of control rabbits, which was visualized and analyzed using morphometric studies and expressed a significant amount of At lesions of both a multilayer and diffuse nature (group 2).

In the conditions of developed DLP and At, the introduction of sodium thiosulfate contributed to an improvement in the lipid profile of the blood and a decrease in lipid infiltration of the liver, adrenal glands, and aorta. So, under the influence of sodium thiosulfate, the level of cholesterol in blood serum decreased by 1.5 times, and the value of HDL cholesterol increased by 2 times. The content of cholesterol in the liver and adrenal glands was lower compared to control rabbits by 28.1% and 43%, respectively (group 3). The hypocholesterolemic and anti-atherosclerotic effect of the studied sodium thiosulfate compound was expressed in a decrease in aortic lipidosis and the degree of damage to its wall At: the content of aortic cholesterol decreased by 31%, and the value of atherosclerotic lesion by 3 times compared with hyperlipidemic animals.

The discovered properties of sodium thiosulfate turned out to be close to those of the antiatherosclerotic drug parmidin, in which, despite the moderate nature of the lipid-lowering effect, a pronounced protective effect against the aorta was observed (group 4). As for the effectiveness of the lipid-lowering drug gemfibrozil, its antiatherosclerotic effect was expressed to a slightly lesser extent than that of the studied compound (group 5). It is important to emphasize that under the influence of gemfibrozil there was no positive effect - a decrease in the content of cholesterol in the adrenal glands, which was noted in the claimed preparation - sodium thiosulfate (groups 3 and 5).

Thus, in experiments on rabbits with alimentary atherosclerosis, the lipid-lowering and anti-atherosclerotic effect of sodium thiosulfate was established.

The search for new lipid-lowering and anti-atherosclerotic agents consists in screening compounds that can eliminate disorders in the exchange of lipids and atherogenic lipoproteins, metabolic disorders in the arterial wall, normalizing its permeability, reduce the content of the lipid component in atherosclerotic plaques, and other negative changes.

Analyzing the above research results, it is seen that in experiments on rats with induced dyslipoproteinemia, a pronounced lipid-lowering effect of sodium thiosulfate on serum, liver and aortic cholesterol lipids was revealed. The compound also has the ability to increase lowered cholesterol of high density anti-atherogenic lipoproteins.

In experiments on guinea pigs with alimentary dyslipoproteinemia and liver and aortic lipidosis, the lipid-lowering effect of sodium thiosulfate on blood serum, liver, and aortic tissue lipids was shown to be equal to the similar hypolipidemic effect of the gemfibrozil comparison drug. Sodium thiosulfate significantly reduces the main factor of atherosclerosis - atherogenic dyslipoproteinemia.

Under the influence of sodium thiosulfate in experiments with experimentally induced alimentary atherosclerosis in rabbits, its pronounced hypocholesterolemic effect on cholesterol of blood serum, liver, adrenal glands and aorta was revealed. The compound is able to protect the aortic wall of experimental animals from atherosclerotic lesions.

The low toxicity of sodium thiosulfate, its effectiveness when used in a small dose orally indicates the promise of using this substance as a lipid-lowering and anti-atherosclerotic agent for the treatment of dyslipoproteinemia and atherosclerosis.

Claims (1)

The use of sodium thiosulfate as a lipid-lowering and anti-atherosclerotic agent when administered orally for the treatment of dyslipoproteinemia and atherosclerosis.