RU2228746C1 - Antihyperlipidemic agent (variants) - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: invention relates to antihyperlipidemic and antihyperproteinemic agents. Agent represents a combination of regulators of energetic metabolism, at least on of that represents succinic acid or its salt, either by the combined using the known antihyperlipidemic agent in combination of some regulators of energetic metabolism or one of that taken in pharmacologically effective doses. Invention provides preparing agent being practically without adverse effects that can be used in treatment of atherosclerosis, ischemic heart disease and obesity. EFFECT: valuable medicinal properties of agent. 15 cl, 5 tbl, 11 ex

Description

The invention relates to medicine and relates to antihyperlipidemic and antihyperlipoproteinemic agents.

The main areas of application of these drugs are the treatment of atherosclerosis, reducing the risk of coronary heart disease (coronary heart disease), as well as the treatment of nutritional lipemia.

Atherosclerosis and its complications continue to be the most common cause of disability and mortality. Numerous studies indicate that one of the risk factors is impaired lipid and lipoprotein metabolism. Significant is an increase in blood atherogenic lipoproteins, such as low density lipoproteins (LDL), very low density lipoproteins, reflected in an increase in triglycerides (TG) in the blood; decrease in high density lipoproteins. In the initiation of atherogenesis, metabolic disorders of the arterial wall are of great importance. At the same time, the synthesis of protective substances, for example, prostacyclin, nitric oxide, heparan sulfate, etc., is reduced, and vice versa, the formation of damaging molecules - thromboxane A2, endothelin, and also superoxide radicals increases. As a result, the penetration of low density lipoproteins into the arteries and their oxidation are increased. With damage, the activity of macrophage monocytes that capture oxidized LDL increases, which leads to the formation of lipid-overflowing cells with the subsequent formation of an atherosclerotic plaque.

Thus, one of the important factors when choosing lipid-lowering drugs is their effect on the level of TG. It is regarded as normal (<200 mg / dl, or 2.3 mmol / L), moderately elevated (from 200 mg / dl to 400 mg / dl, or 4.5 mmol / L), high (from 400 mg / dl up to 1000 mg / dl, or 11.3 mmol / l) and very high (> 1000 mg / dl).

Some lipid-lowering drugs do not significantly reduce the level of TG, but affect the level of cholesterol (cholesterol). Some drugs reduce both the level of TG and the level of cholesterol. The choice of certain pharmacotherapy agents depends on the type of hyperlipemia.

The main modern means with antihyperlipidemic action include:

- Anion exchange resins, or sequestrants of fatty acids (cholestyramine, colestipol). They form nonabsorbable complexes with bile acids in the intestine, which enhances the excretion of bile acids from the body and reduces the absorption of cholesterol in the intestine. Side effects - impaired absorption of fat-soluble vitamins, increased gas formation in the intestines, bloating, nausea, and sometimes - diarrhea or constipation.

- Nicotinic acid and some of its derivatives. They are prosthetic groups of enzymes that are hydrogen carriers and participate in redox reactions. Reduce total plasma cholesterol, low density lipoproteins and triglycerides; increase the content of high density lipoproteins. The hypolipidemic effect develops only after a month of taking large doses. However, large doses have a hepatotoxic effect, and prolonged use causes liver dystrophy. They reduce glucose tolerance, cause vasodilation of the face and upper body, nettle rash, paresthesia. Contraindicated in gastric ulcer and duodenal ulcer, in case of impaired liver function, gout and hyperuricemia, as well as in patients with diabetes.

- Fibrates are derivatives of fibroic acid (clofibrate, bezafibrate, fenofibrate). The mechanism of action is associated with a decrease in plasma cholesterol and triglycerides, a decrease in the content of triglycerides in very low density lipoproteins and cholesterol in low density lipoproteins (in atherogenic lipoproteins). At the same time, they increase the cholesterol content in high density lipoproteins (anti-atherogenic). The action is associated with the ability to block the reductase of hydroxymethylglutaric coenzyme A involved in cholesterol biosynthesis. Side effects - gastrointestinal disorders (nausea, vomiting), skin itching, urticaria, muscle pain, muscle weakness; weight gain due to water retention in the body. May cause intrahepatic cholestasis, exacerbation of cholelithiasis. They are contraindicated in liver disease, severe kidney disease, pregnancy, lactation; not recommended for children.

- Probukol. It inhibits the synthesis of cholesterol, reduces its absorption with food. When using, dyspeptic phenomena are possible. It is contraindicated in pregnancy and lactation.

- Statins (lovastatin, simvastatin, pravastatin, fluvastatin). They are inhibitors of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A-reductase, which catalyzes the initial and intermediate stages of cholesterol biosynthesis (formation of mevalonate). All are characterized by side effects associated with a change in liver function with an increase in serum transaminases, dyspepsia, headaches, and skin rashes. Muscle pains are possible, sometimes changes in the muscles associated with an increase in the content of creatine phosphokinase in the blood and muscle tissue, with the appearance of myopathy, general weakness. Contraindicated in pregnancy, breast-feeding, acute liver diseases. Drugs are not prescribed for children. (Grazinsky N.A. Lipid-lowering drugs. Cardiology, N3, 1994, p. 49-69; Mashkovsky M.D. Medicines. - M., 1993).

Another modern drug is betaine citrate, which is used as an antihyperlipidemic agent by activating metabolic methylation in the liver (RLS-2001, ed. 8, p. 138).

Also known is a lipid-lowering agent based on derivatives of alpha and omega-dicarboxylic acids, which is intended for the treatment of hyperlipidemia and diabetes (DE 3423166 A, Epis SA, publ. 2.1.1986). A known remedy is contraindicated in significant violations of the liver.

The present invention is the creation of a new highly effective lipid-lowering agent, practically devoid of or with fewer side effects.

This problem is solved by the proposed tool based on a combination of energy metabolism regulators, at least one of which is succinic acid or its salt, or by combined use of a known antihyperlipidemic agent and a combination of several energy metabolism regulators or one of them.

Such regulators can preferably include preparations that support the high activity of the fast metabolic cluster of mitochondria, for example, malic, glutamic, isolimonic, alpha-ketoglutaric, beta-hydroxybutyric acid, alpha-glycerophosphate. In addition, mitochondrial oxidation activators, agents that support the maintenance of succinate dehydrogenase activity, transaminases, agents that support the formation of endogenous succinic acid, agents that support the resistance of the energy production system under load, ensure that the intracellular content of adenosine triphosphoric acid and the concentration ratio are also included to adenosine diphosphoric acid, interfering with impaired functioning cycle of tricarboxylic acids and coupled with the synthesis of adenosine triphosphoric acid electron transfer in the electron transport chain of mitochondria. Among these, funds may be indicated that possess independent antiradical, antioxidant activity, as well as support the activity of natural antioxidant defense systems of the body; agents that prevent the oxidation of SH-groups of thiol enzymes; agents that promote the synthesis of new mitochondria in the cell. For example, isocitrate, malate are potent activators of inhibited succinate dehydrogenase, glutamate is a source of endogenous succinic acid. Activation of the inhibited succinate dehydrogenase supports the activity of the fast metabolic mitochondrial cluster, and when it is active, endogenous succinic acid is produced from other substrates.

The doses of the ingredients administered depend on many factors, including the nature of the regulator of energy metabolism, the age, sex of the patient, the severity of the disease, the presence of concomitant metabolic disorders, the inclusion of active additives, etc.

Preferably succinic acid or its salts are administered in a unit dose of 1-200 mg. In individual combinations, the dose may be increased.

To implement a variant of the composition, including the well-known antihyperlipidemic agent, any of the above preparations, preferably fibrates, statins, nicotinic acid in effective doses, can be used as the latter.

Preparations that support the high activity of the fast metabolic cluster of mitochondria are pharmacologically active in humans in doses ranging from a few mg; There is evidence of their use in the clinic with grams per appointment.

Glutamate is used from 10 to 300 mg. Carnitine is effective when taken at least 100 mg, but can be prescribed up to several grams, for example, in athletes. Flavonoids are effective in dosages corresponding to several mg, but they are sometimes prescribed in hundreds of mg.

When included in the composition, vitamins B ₂ , B ₆ , B ₁₂ have a potentizing effect.

Also bioflavonoids - rutin, quercetin, baicalin, etc. will have a potentiating effect. (separately and in combination with ascorbic acid).

As a rule, most of the ingredients in the composition are used in pharmacologically acceptable doses that are approved for use. So, for some ingredients, they can be:

Glutamic acid 0.05-0.5 g

Methionine 0.05-0.5 g

Lysine 0.05-0.5 g

L-carnitine 0.05-0.5 g

Vitamin B ₂ 0.5-100 mg

Vitamin B ₆ 1-100 mg

Vitamin B ₁₂ 5-500 mcg

Vitamin C 10-300 mg

Malic acid 5-300 mg

Isolimonic acid 5-300 mg

The proposed combinations can be processed into acceptable dosage forms for oral or parenteral use. To do this, they are mixed with pharmaceutically acceptable carriers, diluents and other excipients by methods traditional in pharmacy. Examples of targeted additives can be water, ethanol, sucrose, lactose, cyclodextrins, pectins, PVP, starch, cellulose derivatives, stearic acid and its salts, citric acid, surfactants, bisphosphates, and the like.

The possibility of carrying out the invention can be illustrated by the following examples:

Example 1

Capsules of lipid-lowering drugs:

Ammonium Succinate 50 mg

Glutamic acid 100 mg

Corn starch 200 mg

Lactose 150 mg

Example 2

Hypolipidemic tablets:

Succinic acid 50 mg

Malic Acid 50 mg

Edible gelatin 100 mg

Magnesium Stearate 200 mg

Calcium Diphosphate 100 mg

Example 3

Hypolipidemic tablets:

Succinic acid 20 mg

Vitamin B ₆ 1 mg

Ascorbic acid 100 mg

Cellulose 200 mg

Calcium Stearate 100 mg

Lactose 79 mg

Example 4

Solution for parenteral administration:

Succinic acid 1 mg

alpha-ketoglutaric acid 2 mg

Water for injection 1 ml

Example 5

Hypolipidemic tablets:

Succinic acid 50 mg

Isolimonic acid 50 mg

Glucose 400 mg

Example 6

Hypolipidemic tablets:

Succinic acid 50 mg

Isolimonic acid 50 mg

Lovastatin 20 mg

Glucose 400 mg

Example 7

Capsules of lipid-lowering drugs:

Ammonium Succinate 100 mg

Isolimonic acid 100 mg

Lovastatin 20 mg

Acetyl-L-Carnitine 200 mg

Example 8

Hypolipidemic tablets:

Succinic acid 50 mg

Motherwort Extract 5 mg

20 mg Badan Extract

Glucose 425 mg

Example 9

The control group of adult mature rabbits for 2 months was given an atherogenic diet containing cholesterol mixed with vegetables at the rate of 10 g per 1 kg of animal weight (Anichkov N.N., 1956). Experimental groups of animals received an antihyperlipidemic agent or energy metabolism regulator, or a combination of the following, from a probe in 3 ml of starch mucus once a day with a probe:

Antihyperlipidemic agent:

1. Lovastatin 20 mg / kg.

2. Niacin 50 mg / kg.

3. Clofibrate 250 mg / kg.

Energy metabolism regulator:

4. Ammonium succinate (CA) + malic acid (YAB) at 50 mg / kg, respectively.

5. Succinic acid (UC) + isolimonic acid (IR) at 50 and 10 mg / kg, respectively.

6. Succinic acid + extract of badan leaves (EB) + motherwort extract (EP) at 50, 20 and 5 mg / kg, respectively.

7. Potassium succinate (SC) + acetyl-L-carnitine (AK) + isolimonic acid at 100, 80 and 10 mg / kg, respectively.

Combination:

8. Lovastatin + succinic acid + isolimonic acid at 20, 50 and 10 mg / kg, respectively.

9. Niacin + CA + YAB at 50 mg / kg each.

10. Clofibrate - 250 mg / kg + UC + EB + EP at 50, 20 and 5 mg / kg, respectively.

After 2 months, the content of lecithin and cholesterol in the venous blood was evaluated in animals of all groups, their ratio was calculated (Table 1). The measured indicators are accepted for assessing the severity of the development of atherosclerosis (Rozhdestvensky Y.I., 1952; Goltskener S.L., 1954). It was established that in animals treated with an atherogenic diet, a pronounced change in the studied parameters was observed, indicating the development of pathology. In the experimental groups, the protective effect of the studied drugs was noted. Moreover, it was more pronounced when using energy metabolism regulators compared with lovastatin. It is shown that energy metabolism regulators enhance the antihyperlipidemic effect of lovastatin.

Some animals that were on an atherogenic diet, after the development of signs of atherosclerosis by the 2nd month, received another 1 month for the therapeutic purpose of the above funds. It was established that energy metabolism regulators exhibit a therapeutic antihyperlipidemic effect, more pronounced than with known antihyperlipidemic agents (Table 2).

Comparison in percent of the magnitude of the change relative to the control of lecithin, cholesterol and their relationship with pathology, as well as in groups combining the indicators of animals treated with antihyperlipidemic drugs (lovastatin, nicotinic acid and clofibrate - group No. 1), energy metabolism regulators (CA + AK, YAK + IR, SK + AK + IR - group No. 2) and antihyperlipidemic drugs together with energy metabolism regulators (group No. 3) indicate greater efficiency of groups No. 2 and No. 3 compared to group No. 1 (Table 3).

Example 10

Assessment of hepatotoxicity of antihyperlipidemic agents and energy metabolism regulators.

The study was conducted on male Wistar rats weighing 180-200 g. Preparations in doses 4 times higher than those that exerted an antihyperlipidemic effect on rabbits were injected inside with a probe in the form of a suspension in 1% starch mucus 1 time per day for 2 weeks . To assess the state of the liver in the venous blood of animals, the activity of aspartate and alanine aminotransferases (ACT and ALT) was determined according to the generally accepted method (Kolb V.G., Kamyshnikov B.C., 1982). The controls were intact animals.

The results of the study showed that all antihyperlipidemic agents to varying degrees violated the integrity of the membranes of hepatocytes, increasing the activity of aminotransferases in the blood, which indicates the manifestation of hepatotoxicity of these drugs described in the literature. Regulators of energy metabolism did not affect the activity of blood aminotransferases and reduced the hepatotoxicity of antihyperlipidemic agents (Table 4).

Example 11

Evaluation of the antihyperlipidemic effect of drugs in the clinic. The study was conducted on patients aged 55-76 years with a diagnosis of cerebral arteriosclerosis, coronary, cardiosclerosis, coronary heart disease. All patients underwent a preliminary examination to determine the level of total (cholesterol) and associated with high-density lipoprotein cholesterol (a-cholesterol) and the calculation of the atherogenesis coefficient AK = - (cholesterol-a-cholesterol) / a-cholesterol. AK is one of the most important criteria for the development of atherosclerosis (Kolb, Kamyshnikov, 1982). Its value fluctuates normally in the range of 1.98-2.51 with the level of a-cholesterol> 1.8; exceeding 3 indicates a threat, and a value of 4 indicates the presence of atherosclerosis.

All patients selected for the study to reduce the severity of atherosclerosis received within 1 month antihyperlipidemic drug or energy metabolism regulator, or a combination of the following list.

Antihyperlipidemic drugs:

1. Lovastatin - 10 mg 2 times a day.

2. Nicotinic acid - 1.0 g 3 times a day.

3. Clofibrate - 0.5 g 3 times a day.

Regulators of energy metabolism:

4. Amber-cardio (UC 50 mg + YAB 50 mg) - 1 tablet 3 times a day.

5. Amber-cardio phyto (UC 50 mg + EB 20 mg + EP 5 mg) - 1 tablet 3 times a day.

6. Amber-geronto (UC 50 mg + microcrystalline cellulose 250 mg) - 1 tablet 3 times a day.

7. Amber-geronto phyto (UC 50 mg + EB 20 mg + chaga extract 20 mg + microcrystalline cellulose 250 mg) - 1 tablet 3 times a day.

8. Amber-balancer (ammonium succinate 0.1 g) - 1 tablet 3 times a day.

Combinations:

9. Lovastatin + Amber-cardio phyto.

10. Nicotinic acid + Amber-cardio.

11. Clofibrate + Amber-geronto phyto.

The results of the examination of patients participating in the work before and after taking antihyperlipidemic therapy are given in Table 5. It can be seen that all the agents used reduced the manifestation of atherosclerosis. At the same time, judging by the value of AK, antihyperlipidemic drugs reduced the manifestation of pathology by an average of 32.2%, energy metabolism regulators by 34.0%, and their combined use - by 41.1%. It should be noted that in the groups taking lovastatin, nicotinic acid or clofibrate, side effects characteristic of these drugs were noted after the second week of administration. In the groups that took energy metabolism regulators or their combination with antihyperlipidemic agents, no side effects were observed.

As follows from the examples presented as an illustration, the proposed compositions of antihyperlipidemic agents are highly effective in virtually no side effects. They can be recommended for implementation in practical medicine, nutrition.

Literature

1. Gracinsky N.A. Hypolipidemic agents. Cardiology, N3, 1994, pp. 49-69.

2. Mashkovsky M.D. Medicines - M., 1993. Radar-2001, ed. 8, p. 138.

3. Anichkov N.N. The importance of experimental research for understanding the pathogenesis of atherosclerosis. // Atherosclerosis and coronary insufficiency. - M., 1956.

4. Christmas Y.N. On the significance of changes in the lipid content in the blood serum of patients with hypertension. // Hypertonic disease. Proceedings of the Academy of Medical Sciences of the USSR, 1952, v. 2, pp. 103-107.

5. Goltskener S. L. Therapeutic Archive. 1954, v. 26, issue 5, p. 83 and 84.

6. Kolb V.G., Kamyshnikov B.C. Clinical biochemistry. - Minsk, 1982, 366 p.

Claims (15)

1. An antihyperlipidemic agent, characterized in that it is a combination of energy metabolism regulators, at least one of which is succinic acid or its salt in pharmacologically effective doses. 2. The antihyperlipidemic agent according to claim 1, characterized in that as a regulator of energy metabolism, it contains at least one drug that supports the high activity of the fast metabolic mitochondrial cluster. 3. The antihyperlipidemic agent according to claim 2, characterized in that the preparation supporting the high activity of the fast metabolic mitochondrial cluster is selected from the group consisting of malic, glutamic, isolimonic, alpha-ketoglutaric, beta-hydroxybutyric acid, their salts, alpha-glycerophosphate or mixtures of these drugs. 4. The antihyperlipidemic agent according to claim 1, characterized in that as a regulator of energy metabolism it contains a drug selected from the group: mitochondrial oxidation activators, agents that support the maintenance of succinate dehydrogenase activity, transaminases, agents that support the formation of endogenous succinic acid, agents that promote maintaining the resistance of the energy production system under load, ensuring the normal maintenance of the intracellular content of adenosine triphosphoric acid and relative eniya concentrations of adenosine to adenosine diphosphoric acid, preventing disruption of the functioning of the tricarboxylic acid cycle and conjugated with the synthesis of adenosine triphosphate electron transport in the electron transport chain of mitochondria. 5. The antihyperlipidemic agent according to claim 1, characterized in that the unit dose of each of these energy metabolism regulators is from 1 to 200 mg. 6. An antihyperlipidemic agent according to any one of claims 1 to 5, characterized in that it further comprises a pharmaceutically acceptable carrier. 7. The antihyperlipidemic agent according to claim 6, characterized in that it is made in the form of a tablet or capsule. 8. An antihyperlipidemic agent, characterized in that it is a combination of at least one energy metabolism regulator and a lipid-lowering drug in pharmacologically effective doses. 9. The antihyperlipidemic agent of claim 8, characterized in that as a regulator of energy metabolism, it contains a drug selected from the group including: a agent that maintains high activity of a fast metabolic cluster of mitochondria, an activator of mitochondrial oxidation, an agent that helps maintain the activity of succinate dehydrogenase, transaminase , a tool that supports the formation of endogenous succinic acid, a tool that helps maintain the resistance of the energy production system under load e, ensuring the maintenance of the normal intracellular content of adenosine triphosphoric acid and the ratio of concentrations of adenosine triphosphoric to adenosine diphosphoric acid, which impedes the disruption of the functioning of the tricarboxylic acid cycle and the transfer of electrons associated with the synthesis of adenosine triphosphoric acid in the electron transport chain of mitochondria. 10. Antihyperlipidemic agent according to claim 8 or 9, characterized in that it contains succinic acid as a regulator of energy metabolism. 11. An antihyperlipidemic agent according to any one of claims 8 to 10, characterized in that, as a lipid-lowering drug, it contains a drug selected from the group: fibrates, statins, nicotinic acid, probucol, cholestyramine, colestipol. 12. The antihyperlipidemic agent according to claim 11, characterized in that the above statin is lovastatin or pravastatin. 13. An antihyperlipidemic agent according to any one of claims 8-12, characterized in that it further comprises a pharmaceutically acceptable carrier. 14. Antihyperlipidemic agent according to any one of the preceding paragraphs, characterized in that it further comprises a vitamin from group B. 15. Antihyperlipidemic agent according to any one of the preceding paragraphs, characterized in that it further comprises at least one bioflavonoid and / or ascorbic acid.